FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Huang, Y Hauck, FR Signore, C Yu, AR Raju, TNK Huang, TTK Fein, SB AF Huang, Yi Hauck, Fern R. Signore, Caroline Yu, Airong Raju, Tonse N. K. Huang, Terry T. -K. Fein, Sara B. TI Influence of Bedsharing Activity on Breastfeeding Duration Among US Mothers SO JAMA PEDIATRICS LA English DT Article ID INFANT-DEATH-SYNDROME; UNITED-STATES; SLEEPING ENVIRONMENT; RECOMMENDATIONS; EXPANSION; TRENDS; RISK; SIDS AB IMPORTANCE Some professional associations advocate bedsharing to facilitate breastfeeding, while others recommend against it to reduce the risk of sudden infant death syndrome and suffocation deaths. A better understanding of the quantitative influence of bedsharing on breastfeeding duration is needed to guide policy. OBJECTIVE To quantify the influence of bedsharing on breastfeeding duration. DESIGN, SETTING, AND PARTICIPANTS Longitudinal data were from the Infant Feeding Practices Study II, which enrolled mothers while pregnant and followed them through the first year of infant life. Questionnaires were sent at infant ages 1 to 7,9,10, and 12 months, and 1846 mothers answered at least 1 question regarding bedsharing and were breastfeeding at infant age 2 weeks. EXPOSURES Bedsharing, defined as the mother lying down and sleeping with her infant on the same bed or other sleeping surfaces for nighttime sleep or during the major sleep period. MAIN OUTCOMES AND MEASURES Survival analysis to investigate the effect of bedsharing on duration of any and exclusive breastfeeding. RESULTS Longer duration of bedsharing, indicated by a larger cumulative bedsharing score, was associated with a longer duration of any breastfeeding but not exclusive breastfeeding, after adjusting for covariates. Breastfeeding duration was longer among women who were better educated, were white, had previously breastfed, had planned to breastfeed, and had not returned to work in the first year postpartum. CONCLUSIONS AND RELEVANCE Multiple factors were associated with breastfeeding, including bedsharing. Given the risk of sudden infant death syndrome related to bedsharing, multipronged strategies to promote breastfeeding should be developed and tested. C1 [Huang, Yi] Univ Maryland Baltimore Cty, Dept Math & Stat, Baltimore, MD 21228 USA. [Hauck, Fern R.] Univ Virginia, Sch Med, Dept Family Med, Charlottesville, VA 22908 USA. [Hauck, Fern R.] Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Signore, Caroline; Raju, Tonse N. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, US Dept HHS, Bethesda, MD USA. [Yu, Airong] Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. [Huang, Terry T. -K.] Univ Nebraska Med Ctr, Coll Publ Hlth, Dept Hlth Promot Social & Behav Hlth, Omaha, NE USA. [Fein, Sara B.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Hauck, FR (reprint author), Univ Virginia, Sch Med, Dept Family Med, POB 800729, Charlottesville, VA 22908 USA. EM frh8e@virginia.edu FU US Department of Health and Human Services FX The data collection was supported by several agencies in the US Department of Health and Human Services. NR 30 TC 17 Z9 18 U1 1 U2 13 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD NOV PY 2013 VL 167 IS 11 BP 1038 EP 1044 DI 10.1001/jamapediatrics.2013.2632 PG 7 WC Pediatrics SC Pediatrics GA 291PX UT WOS:000329842300016 PM 24061708 ER PT J AU Li, Q Mei, QB Ting, HY Xie, L Che, S Yang, H Zhang, MJ Huang, QS AF Li, Qi Mei, Qibing Ting Huyan Xie, Li Che, Su Yang, Hui Zhang, Mingjie Huang, Qingsheng TI Effects of formaldehyde exposure on human NK cells in vitro SO ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Formaldehyde; Natural killer cell; Cytotoxicity; In vitro ID PROTEIN CROSS-LINKS; RISK-ASSESSMENT; DNA; LYMPHOCYTES; PROLIFERATION; INDUCTION; TOXICITY; WORKERS; BLOOD AB Natural killer (NK) cells play a pivotal role in human immunologic surveillance. Formaldehyde (FA), a ubiquitous environmental contaminant, has been classified as a carcinogen to humans. Although it is known that immune cells are sensitive to FA, so far little is known about how it's affecting the activity of human NK cells. To probe it, the primary human NK cells were treated with different concentrations of FA (3200, 1600, 800, 400, 200, 100, 50, and 0 mu M) in vitro. The morphology, viability, apoptosis, cytotoxicity (killing tumor cell activity) and cytokine and cytolytic proteins secretion of NK cells were evaluated respectively. Our results reveal that FA could induce NK cells death obviously in a concentration-dependent manner. With the decreased concentrations of FA from 3200 mu M to 800 mu M, accordingly, the viability of NK cells increased from 65. 2 +/- 12.1% to 78.48 +/- 10.3% (p <0.05), and the cytotoxicity of NK cells recovered from 29.2 +/- 8.5% to 63.9 +/- 5.9% (p <0.05). The secretion of perforin was affected significantly by FA, whereas the secretion of IFN-gamma and granzyme-B altered slightly. It is concluded that human NK cell is sensitive to FA, 800 mu M may be a critical concentration of FA inhibiting the activity of human NK cell. (C) 2013 Elsevier B.V. All rights reserved. C1 [Li, Qi; Mei, Qibing; Ting Huyan; Xie, Li; Che, Su; Yang, Hui; Zhang, Mingjie; Huang, Qingsheng] Northwestern Polytech Univ, Sch Life Sci, Key Lab Space Biosci & Biotechnol, Xian 710072, Shaanxi, Peoples R China. [Zhang, Mingjie] US FDA, Mol Virol Lab, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP Huang, QS (reprint author), Northwestern Polytech Univ, Sch Life Sci, Xian 710072, Shaanxi, Peoples R China. EM yellowqs@yahoo.com FU National Natural Science Foundation of China (NSFC) [31000067]; Northwestern Polytechnical University [JC201277] FX We gratefully acknowledge financial support from The National Natural Science Foundation of China (NSFC, Grant No. 31000067) and the Basic Research Fund of Northwestern Polytechnical University (Grant No. JC201277). NR 26 TC 2 Z9 2 U1 0 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1382-6689 EI 1872-7077 J9 ENVIRON TOXICOL PHAR JI Environ. Toxicol. Pharmacol. PD NOV PY 2013 VL 36 IS 3 BP 948 EP 955 DI 10.1016/j.etap.2013.08.005 PG 8 WC Environmental Sciences; Pharmacology & Pharmacy; Toxicology SC Environmental Sciences & Ecology; Pharmacology & Pharmacy; Toxicology GA 287GS UT WOS:000329530600026 PM 24035925 ER PT J AU Zhang, YT Carlton, E Fein, SB AF Zhang, Yuanting Carlton, Ewa Fein, Sara B. TI The Association of Prenatal Media Marketing Exposure Recall with Breastfeeding Intentions, Initiation, and Duration SO JOURNAL OF HUMAN LACTATION LA English DT Article DE breastfeeding; breastfeeding outcomes; breastfeeding promotion; breast milk substitutes; exclusive breastfeeding; infant formula; media marketing ID HOSPITALS; FORMULA; COHORT AB Background: Infant formula marketing, either directly to consumers or through health care providers, may influence women's breastfeeding intentions, initiation, and duration. However, little is known about the impact of different types of media marketing on infant feeding intentions and behavior. Objective: This study investigated whether different types of recalled prenatal media marketing exposure to formula and breastfeeding information are related to breastfeeding intentions and behavior. Methods: Data were from the Infant Feeding Practices Study II, a longitudinal study from pregnancy through the infants' first year. Sample sizes ranged from 1384 to 2530. Negative binomial, logistic regression, and survival models were used to examine associations between recalled prenatal exposure to formula or breastfeeding information and breastfeeding intentions and behavior. Results: Exposure to infant formula information from print media was associated with shorter intended duration of exclusive breastfeeding, and formula information from websites was related to lower odds of both intended and actual initiation. Exposure to breastfeeding information from websites was related to higher odds of both intended and actual initiation and longer intended duration of any breastfeeding. Breastfeeding information from print media was associated with longer duration of any breastfeeding, but information from broadcast media was associated with shorter duration of any breastfeeding. Conclusion: Mothers who recall exposure to formula information from print or websites are more likely to intend to use formula or to intend to use formula earlier and are less likely to initiate breastfeeding than mothers who do not recall seeing such information. C1 [Zhang, Yuanting; Carlton, Ewa; Fein, Sara B.] US FDA, College Pk, MD 20740 USA. RP Zhang, YT (reprint author), US FDA, Ctr Food Safety & Appl Nutr, HFS 002,5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Yuanting.zhang@fda.hhs.gov FU Food and Drug Administration, Centers for Disease Control and Prevention, Office of Women's Health, National Institutes of Health; Maternal and Child Health Bureau in the US Department of Health and Human Services; Food and Drug Administration FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The data collection was funded by the Food and Drug Administration, Centers for Disease Control and Prevention, Office of Women's Health, National Institutes of Health, and the Maternal and Child Health Bureau in the US Department of Health and Human Services. This analysis was funded by the Food and Drug Administration. NR 25 TC 7 Z9 7 U1 4 U2 9 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0890-3344 EI 1552-5732 J9 J HUM LACT JI J. Hum. Lact. PD NOV PY 2013 VL 29 IS 4 BP 500 EP 509 DI 10.1177/0890334413487256 PG 10 WC Nursing; Obstetrics & Gynecology; Pediatrics SC Nursing; Obstetrics & Gynecology; Pediatrics GA 287XN UT WOS:000329575700013 PM 23686404 ER PT J AU Wang, SJ Hung, HMJ AF Wang, Sue-Jane Hung, H. M. James TI Adaptive enrichment with subpopulation selection at interim: Methodologies, applications and design considerations SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Biomarker; Dual-composite null hypothesis; Flexible dual-independent null hypothesis; Pharmacogenomics; Rigorous dual-independent null hypothesis ID RANDOMIZED CLINICAL-TRIALS; SIGNATURE DESIGN; SAMPLE-SIZE; BIOMARKER; STRATEGIES; ONCOLOGY; THERAPY AB There is a growing interest in pursuing adaptive enrichment for drug development because of its potential to achieve the goal of personalized medicine. There are many versions of adaptive enrichment proposed across many disease indications. Some are exploratory adaptive enrichment and others aim at confirmatory adaptive enrichment. In this paper, we give a brief overview on adaptive enrichment and the methodologies that are growing in statistical literature. A case example is provided to illustrate a regulatory experience that led to drug approval. There were two design elements used for adaptation in this case example: population adaptation and statistical information adaptation. We articulate the challenges in the implementation of a confirmatory adaptive enrichment trial. The challenges include logistic aspects on the appropriate choice of study population for adaptation and the ability to follow the pre-specified rules for statistical information or sample size adaptation. We assess the consistency of treatment effect before and after adaptation using the approach laid out in Wang et al. (2013). We provide the rationales for what would be an appropriate treatment effect estimate for reporting in the drug label. We discuss and articulate design considerations for adaptive enrichment among a dual-composite null hypothesis, a flexible dual-independent null hypothesis and a rigorous dual-independent null hypothesis. Published by Elsevier Inc. C1 [Wang, Sue-Jane] US FDA, Off Biostat, OTS CDER, Silver Spring, MD 20993 USA. [Hung, H. M. James] US FDA, Div Biometr 1, OB OTS CDER, Silver Spring, MD 20993 USA. RP Wang, SJ (reprint author), US FDA, Off Biostat, OTS CDER, 10903 New Hampshire Ave,Bldg 21,HFD 710,Mail Stop, Silver Spring, MD 20993 USA. EM suejane.wang@fda.hhs.gov FU RSR funds [05-02, 05-14] FX We wish to thank Dr. Mei-Chiung Shih for her kind invitation to contribute to the special issue on Personalized Medicine. We acknowledge the regulatory statistical review of adaptive enrichment for the case example performed by Dr. Xiang Ling. The regulatory research work presented here was supported by the RSR funds, #05-02 and #05-14, provided by the Center for. Drug Evaluation and Research of the US Food and Drug Administration. NR 28 TC 7 Z9 7 U1 4 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD NOV PY 2013 VL 36 IS 2 BP 673 EP 681 DI 10.1016/j.cct.2013.09.008 PG 9 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 283RS UT WOS:000329265300037 PM 24076485 ER PT J AU Kramer, J Brown, CK Reppas, C Barker, AR Buhse, L Cecil, TL Friedel, HD Keitel, S Morris, M Shah, VP Yomota, C AF Kraemer, Johannes Brown, Cynthia K. Reppas, Christos Barker, Amy R. Buhse, Lucinda Cecil, Todd L. Friedel, Horst-Dieter Keitel, Susanne Morris, Michael Shah, Vinod P. Yomota, Chikako CA Programming Comm TI AAPS Workshop Report on Biorelevant In Vitro Performance Testing of Orally Administered Dosage Forms SO DISSOLUTION TECHNOLOGIES LA English DT Article C1 [Brown, Cynthia K.; Barker, Amy R.] Eli Lilly & Co, Indianapolis, IN USA. [Reppas, Christos] Univ Athens, Athens, Greece. [Buhse, Lucinda] US FDA, Rockville, MD 20857 USA. [Cecil, Todd L.] US Pharmacopeial Convent Inc, Rockville, MD USA. [Friedel, Horst-Dieter] Bayer Pharma Aktiengesellschaft, Berlin, Germany. [Keitel, Susanne] European Directorate Qual Med & Hlth Care, Strasbourg, France. [Kraemer, Johannes] PHAST, Hamburg, Germany. [Morris, Michael] Irish Med Board, Dublin, Ireland. [Shah, Vinod P.] Int Pharmaceut Federat FIP, The Hague, Netherlands. [Yomota, Chikako] Natl Inst Hlth Sci, Tokyo, Japan. RP Kramer, J (reprint author), PHAST, Hamburg, Germany. NR 2 TC 0 Z9 0 U1 0 U2 0 PU DISSOLUTION TECHNOLOGIES, INC PI HOCKESSIN PA 9 YORKRIDGE TRAIL, HOCKESSIN, DE 19707-9633 USA SN 1521-298X J9 DISSOLUT TECHNOL JI Dissolut. Technol. PD NOV PY 2013 VL 20 IS 4 BP 45 EP 49 PG 5 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 278XA UT WOS:000328922000008 ER PT J AU De Alwis, HG Girard, L Kijak, PJ Rummel, N AF De Alwis, Hemakanthi G. Girard, Lauren Kijak, Philip J. Rummel, Nathan TI Determination of Erythromycin in Medicated Salmonid Fish Feed by Liquid Chromatography and UV Spectroscopy SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID TANDEM MASS-SPECTROMETRY; SOLID-PHASE EXTRACTION; MACROLIDE ANTIBIOTICS; WASTE-WATER; MATRICES AB A simple, robust LC-UV method was developed to assay erythromycin in medicated salmonid feed. In this method, erythromycin was extracted from feed with acetonitrile and water, cleaned up by SPE, evaporated to dryness, reconstituted, and analyzed by LC-UV. The resulting method produced high accuracy, 82-90%, for both salmon and trout feed that represented varied pellet sizes and ingredient amounts. The intraday and interday precisions, at <= 6 and 5%, respectively, indicated the method's good repeatability. Calibration was linear over the range of drug concentrations typically used in medicated feed. An independent analyst validation further demonstrated the repeatability of the method. The developed method could support the drug approval process for erythromycin in medicated salmonid fish feed. C1 [De Alwis, Hemakanthi G.; Girard, Lauren; Kijak, Philip J.; Rummel, Nathan] US FDA, Ctr Vet Med, Res Off, Laurel, MD 20708 USA. RP De Alwis, HG (reprint author), US FDA, Ctr Vet Med, Res Off, 8401 Muirkirk Rd, Laurel, MD 20708 USA. EM hemakanthi.dealwis@fda.hhs.gov FU FDA FX We thank David Heller of the FDA Center for Veterinary Medicine (CVM) Office of Research for initial helpful discussions. This work was supported in part by an appointment to the Research Participation Program at the CVM, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the FDA. NR 11 TC 3 Z9 3 U1 1 U2 8 PU AOAC INT PI GAITHERSBURG PA 481 N FREDRICK AVE, STE 500, GAITHERSBURG, MD 20877-2504 USA SN 1060-3271 EI 1944-7922 J9 J AOAC INT JI J. AOAC Int. PD NOV-DEC PY 2013 VL 96 IS 6 BP 1233 EP 1238 DI 10.5740/jaoacint.12-368 PG 6 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA 278YR UT WOS:000328926300010 PM 24645499 ER PT J AU Gharst, G Bark, DH Newkirk, R Guillen, L Wang, Q Abeyta, C AF Gharst, Greg Bark, Don H. Newkirk, Robert Guillen, Lacey Wang, Qian Abeyta, Carlos, Jr. TI Evaluation and Single-Laboratory Verification of a Proposed Modification to the US Food and Drug Administration Method for Detection and Identification of Campylobacter jejuni or Campylobacter coli from Raw Silo Milk SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID HUMANS; CATTLE AB The current U.S. Food and Drug Administration (FDA) methodology for detection of Campylobacter, a leading source for foodborne illness, is outdated. The purpose of this study, therefore, was to improve and update the cultural and identification methods found in the FDA/Bacteriological Analytical Manual (BAM). Raw silo milk samples containing typical and atypical strains of Campylobacter jejuni and Campylobacter coil at different levels (5 CFU/25 g, 50 CFU/25 g, and 125 CFU/25 g) were analyzed. Valid results were obtained from 240 test portions. Six inoculated (at the levels described above) and two uninoculated samples were sent to a participating laboratory to mimic a "real-world" scenario. These combined data indicated that the use of sheep blood in combination with enrichment is not necessary. R& F (R) Campylobacter jejuni/Campylobacter coil Chromogenic Plating Medium is significantly (P < 0.05) more sensitive for detection of C. jejuni or C. coil at low inoculation levels than the modified Cefoperazone Charcoal Deoxycholate Agar used in the BAM. The quantitative PCR method described demonstrated rapid confirmation and identification of C. jejuni or C. coli. It reduced the time to isolate C. jejuni or C. coil, and increased the sensitivity compared to the current BAM protocol. C1 [Gharst, Greg; Newkirk, Robert] US FDA, Ctr Food Safety & Appl Nutr, Bedford Pk, IL 60501 USA. [Bark, Don H.; Abeyta, Carlos, Jr.] US FDA, Off Regulatory Affairs, Bothell, WA 98021 USA. [Guillen, Lacey] Texas Tech Univ, Dept Anim & Food Sci, Lubbock, TX 79409 USA. [Wang, Qian] IIT, Bedford Pk, IL 60501 USA. RP Gharst, G (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM gregory.gharst@fda.hhs.gov NR 16 TC 0 Z9 0 U1 0 U2 9 PU AOAC INT PI GAITHERSBURG PA 481 N FREDRICK AVE, STE 500, GAITHERSBURG, MD 20877-2504 USA SN 1060-3271 EI 1944-7922 J9 J AOAC INT JI J. AOAC Int. PD NOV-DEC PY 2013 VL 96 IS 6 BP 1336 EP 1342 DI 10.5740/jaoacint.13-093 PG 7 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA 278YR UT WOS:000328926300023 PM 24645512 ER PT J AU Wendorf, M Feldpausch, E Pinkava, L Luplow, K Hosking, E Norton, P Biswas, P Mozola, M Rice, J Chen, Y Ryser, E Odumeru, J AF Wendorf, Michael Feldpausch, Emily Pinkava, Lisa Luplow, Karen Hosking, Edan Norton, Paul Biswas, Preetha Mozola, Mark Rice, Jennifer Chen, Yi Ryser, Elliot Odumeru, Joseph CA Performance Tested MethodSM 2012 TI Validation of the ANSR (R) Listeria Method for Detection of Listeria spp. in Environmental Samples SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article AB ANSR (R) Listeria is a new diagnostic assay for detection of Listeria spp. in sponge or swab samples taken from a variety of environmental surfaces. The method is an isothermal nucleic acid amplification assay based on the nicking enzyme amplification reaction technology. Following single-step sample enrichment for 16-24 h, the assay is completed in 40 min, requiring only simple instrumentation. In inclusivity testing, 48 of 51 Listeria strains tested positive, with only the three strains of L. grayi producing negative results. Further investigation showed that L. grayi is reactive in the ANSR assay, but its ability to grow under the selective enrichment conditions used in the method is variable. In exclusivity testing, 32 species of non-Listeria, Gram-positive bacteria all produced negative ANSR assay results. Performance of the ANSR method was compared to that of the U.S. Department of Agriculture-Food Safety and Inspection Service reference culture procedure for detection of Listeria spp. in sponge or swab samples taken from inoculated stainless steel, plastic, ceramic tile, sealed concrete, and rubber surfaces. Data were analyzed using Chi-square and probability of detection models. Only one surface, stainless steel, showed a significant difference in performance between the methods, with the ANSR method producing more positive results. Results of internal trials were supported by findings from independent laboratory testing. The ANSR Listeria method can be used as an accurate, rapid, and simple alternative to standard culture methods for detection of Listeria spp. in environmental samples. C1 [Wendorf, Michael; Feldpausch, Emily; Pinkava, Lisa; Luplow, Karen; Hosking, Edan; Norton, Paul; Biswas, Preetha; Mozola, Mark; Rice, Jennifer; Performance Tested MethodSM 2012] Neogen Corp, Lansing, MI 48912 USA. [Chen, Yi] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Ryser, Elliot] Michigan State Univ, Dept Food Sci & Human Nutr, E Lansing, MI 48824 USA. [Odumeru, Joseph] Univ Guelph, Lab Serv Div, Guelph, ON H1H 8J7, Canada. RP Mozola, M (reprint author), Neogen Corp, 620 Lesher Pl, Lansing, MI 48912 USA. EM mmozola@neogen.com NR 5 TC 5 Z9 5 U1 0 U2 3 PU AOAC INT PI GAITHERSBURG PA 481 N FREDRICK AVE, STE 500, GAITHERSBURG, MD 20877-2504 USA SN 1060-3271 EI 1944-7922 J9 J AOAC INT JI J. AOAC Int. PD NOV-DEC PY 2013 VL 96 IS 6 BP 1414 EP 1424 DI 10.5740/jaoacint.12-453 PG 11 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA 278YR UT WOS:000328926300034 PM 24645523 ER PT J AU Dabrazhynetskaya, A Volokhov, DV Lin, TL Beck, B Gupta, RK Chizhikov, V AF Dabrazhynetskaya, Alena Volokhov, Dmitriy V. Lin, Tsai-Lien Beck, Brian Gupta, Rajesh K. Chizhikov, Vladimir TI Collaborative study report: Evaluation of the ATCC experimental mycoplasma reference strains panel prepared for comparison of NAT-based and conventional mycoplasma detection methods SO BIOLOGICALS LA English DT Article DE Mycoplasma detection; Alternative method; Method comparison; Reference material ID CELL-CULTURES; STORAGE; INFECTIONS; FROZEN AB The main goal of this collaborative study was to evaluate the experimental panel of cryopreserved mycoplasma reference strains recently prepared by the American Type Culture Collection (ATCC (R)) in order to assess the viability and dispersion of cells in the mycoplasma stocks by measuring the ratio between the number of genomic copies (GC) and the number of colony forming units (CFU) in the reference preparations. The employment of microbial reference cultures with low GC/CFU ratios is critical for unbiased and reliable comparison of mycoplasma testing methods based on different methodological approaches, i.e., Nucleic Acid Testing (NAT) and compendial culture-based techniques. The experimental panel included ten different mycoplasma species known to represent potential human and animal pathogens as well as common contaminants of mammalian and avian cell substrates used in research, development, and manufacture of biological products. Fifteen laboratories with expertise in field of mycoplasma titration and quantification of mycoplasmal genomic DNA participated in the study conducted from February to October of 2012. The results of this study demonstrated the feasibility of preparing highly viable and dispersed (possessing low GC/CFU ratios) frozen stocks of mycoplasma reference materials, required for reliable comparison of NAT-based and conventional mycoplasma detection methods. Published by Elsevier Ltd on behalf of The International Alliance for Biological Standardization. C1 [Dabrazhynetskaya, Alena; Volokhov, Dmitriy V.; Chizhikov, Vladimir] US FDA, CBER, Div Viral Prod, Rockville, MD 20852 USA. [Lin, Tsai-Lien] Div Biostat, Rockville, MD 20852 USA. [Beck, Brian] ATCC, Manassas, VA 20110 USA. [Gupta, Rajesh K.] Div Biol Stand & Qual Control, Rockville, MD 20852 USA. RP Chizhikov, V (reprint author), US FDA, Ctr Biol Evaluat & Res, Off Vaccine Res & Review, Div Viral Prod,Lab Methods Dev, HFM 470,1401 Rockville Pike, Rockville, MD 20852 USA. EM vladimir.chizhikov@fda.hhs.gov FU Medical Counter-measures Initiative, FDA FX This work was financially supported by the Medical Counter-measures Initiative, FDA. NR 26 TC 1 Z9 1 U1 0 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1045-1056 EI 1095-8320 J9 BIOLOGICALS JI Biologicals PD NOV PY 2013 VL 41 IS 6 BP 377 EP 383 DI 10.1016/j.biologicals.2013.07.002 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 274HG UT WOS:000328596800006 PM 23910092 ER PT J AU Burbelo, PD Ragheb, JA Kapoor, A Zhang, YJ AF Burbelo, Peter D. Ragheb, Jack A. Kapoor, Amit Zhang, Yanjin TI The serological evidence in humans supports a negligible risk of zoonotic infection from porcine circovirus type 2 SO BIOLOGICALS LA English DT Article DE Antibodies; Porcine circovirus; PCV-2; Seroepidemiology; Porcine-derived supplements ID CATTLE; SEROCONVERSION; ANTIBODIES; VACCINES; DISEASE; ABSENCE; CANADA; PCV-2; FECES; ASSAY AB There are two porcine circovirus (PCV) genotypes, PCV-1 and PCV-2. In pigs, PCV-1 infection is asymptomatic but PCV-2 infection can cause severe respiratory disease and other pathology. Although humans ingest PCV-contaminated foods and are exposed to PCV through other sources, the potential of PCV-2 as a zoonotic agent in humans and other species has not been fully explored. Here, four recombinant proteins derived from the PCV-2 capsid gene were examined as antigens using the Luciferase Immunoprecipitation System (LIPS) assay for serological analysis of PCV-2 infection. PCV-2-CAP-Delta 1 was the optimum recombinant protein in the LIPS assay with a sensitivity of 93% and specificity of 100% using porcine samples. Testing of healthy human blood donors, equine and bovine serum samples failed to demonstrate the presence of anti-PCV-2 antibodies. Additionally, analysis of two high-risk human groups, cystic fibrosis patients taking porcine derived oral supplements and type I diabetes patients who had undergone porcine islet cell transplantation, showed no evidence of anti-PCV-2 antibodies. These results extend the extensively demonstrated use of LIPS as a robust approach for identifying humoral responses and provide evidence that PCV-2 is likely not infectious in humans. Published by Elsevier Ltd on behalf of The International Alliance for Biological Standardization. C1 [Burbelo, Peter D.] Natl Inst Dent & Craniofacial Res, Clin Dent Res Core, NIH, Bethesda, MD 20892 USA. [Ragheb, Jack A.] US FDA, Div Therapeut Prot, OBP OPS, CDER, Bethesda, MD 20892 USA. [Kapoor, Amit] Columbia Univ, Ctr Infect & Immun, New York, NY 10032 USA. [Zhang, Yanjin] Univ Maryland, Dept Vet Med, College Pk, MD 20742 USA. RP Burbelo, PD (reprint author), NIH, 10 Ctr Dr,Bldg 10,Rm 1N102, Bethesda, MD 20892 USA. EM burbelop@nidcr.nih.gov FU Division of Intramural Research, National Institute of Dental and Craniofacial Research, NIH; CDER, Food and Drug Administration; NIH [AI090196, AI081132]; University of Maryland FX This work was supported by the Division of Intramural Research, National Institute of Dental and Craniofacial Research, NIH and the CDER, Food and Drug Administration and from NIH grants AI090196, AI081132 and funding from the University of Maryland. We thank Haicheng Song and Chinta Lamichhane at Synbiotics for supplying the porcine serum samples and ELISA results for the samples. We are indebted to Michael Konstan (Case Western Reserve University) for making available the cystic fibrosis serum samples and to Annika Tibell (Karolinska Univ), Bill Switzer and Walid Heneine (CDC) for the xenotransplant serum samples. We also thank Shasta McClenahan and Phil Krause (FDA) for the PCV-1 anti-serum. NR 30 TC 5 Z9 5 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1045-1056 EI 1095-8320 J9 BIOLOGICALS JI Biologicals PD NOV PY 2013 VL 41 IS 6 BP 430 EP 434 DI 10.1016/j.biologicals.2013.09.005 PG 5 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 274HG UT WOS:000328596800013 PM 24120888 ER PT J AU Mastelic, B Garcon, N Del Giudice, G Golding, H Gruber, M Neels, P Fritzell, B AF Mastelic, Beatris Garcon, Nathalie Del Giudice, Giuseppe Golding, Hana Gruber, Marion Neels, Pieter Fritzell, Bernard TI Predictive markers of safety and immunogenicity of adjuvanted vaccines SO BIOLOGICALS LA English DT Article DE Vaccine; Adjuvant; Vaccine safety ID BOVINE-NEONATAL-PANCYTOPENIA; DENDRITIC CELL SUBSETS; INFLUENZA VACCINE; MASS CYTOMETRY; INTRADERMAL VACCINATION; SYSTEMS BIOLOGY; VETERINARY VACCINES; IMMUNE-RESPONSES; GENE-EXPRESSION; HEALTHY-ADULTS AB Vaccination represents one of the greatest public health triumphs; in part due to the effect of adjuvants that have been included in vaccine preparations to boost the immune responses through different mechanisms. Although a variety of novel adjuvants have been under development, only a limited number have been approved by regulatory authorities for human vaccines. This report reflects the conclusions of a group of scientists from academia, regulatory agencies and industry who attended a conference on the current state of the art in the adjuvant field. Held at the U.S. Pharmacopeial Convention (USP) in Rockville, Maryland, USA, from 18 to 19 April 2013 and organized by the International Association for Biologicals (IABS), the conference focused particularly on the future development of effective adjuvants and adjuvanted vaccines and on overcoming major hurdles, such as safety and immunogenicity assessment, as well as regulatory scrutiny. More information on the conference output can be found on the IABS website, http://www.iabs.org/. C1 [Mastelic, Beatris] Univ Geneva, WHO Ctr Vaccinol & Neonatal Immunol, CMU, CH-1211 Geneva 4, Switzerland. [Garcon, Nathalie] GlaxoSmithKline Vaccines, Rixensart, Belgium. [Del Giudice, Giuseppe] Novartis Vaccines & Diagnost, I-53100 Siena, Italy. [Golding, Hana] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Gruber, Marion] US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Neels, Pieter] EMA CHMP, Fed Agcy Med & Hlth Prod, Brussels, Belgium. [Fritzell, Bernard] IABS Human Vaccines Comm, Paris, France. RP Mastelic, B (reprint author), Univ Geneva, WHO Ctr Vaccinol & Neonatal Immunol, CMU, 1 Rue Michel Servet, CH-1211 Geneva 4, Switzerland. EM beatris.mastelic@unige.ch FU CSL; Sanofi Pasteur; Novartis FX We would like to thank members of the IABS board, the scientific committee and the speakers for their excellent organization of the meeting. This workshop was made possible by unrestricted educational grants from CSL, Sanofi Pasteur and Novartis. We would also like to thank the U.S. Pharmacopeial Convention (USP) for the perfect venue. We would like to thank Victor Popoola for his valuable contribution for the manuscript revision. NR 78 TC 20 Z9 20 U1 1 U2 12 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1045-1056 EI 1095-8320 J9 BIOLOGICALS JI Biologicals PD NOV PY 2013 VL 41 IS 6 BP 458 EP 468 DI 10.1016/j.biologicals.2013.08.006 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 274HG UT WOS:000328596800018 PM 24071553 ER PT J AU Hammad, TA Margulis, AV Ding, YL Strazzeri, MM Epperly, H AF Hammad, Tarek A. Margulis, Andrea V. Ding, Yulan Strazzeri, Marian M. Epperly, Holly TI Determining the predictive value of Read codes to identify congenital cardiac malformations in the UK Clinical Practice Research Datalink SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE Clinical Practice Research Datalink; Read; OXMIS codes; validation of congenital cardiac malformation; heart defects; congenital abnormalities; pharmacoepidemiology ID PRACTICE RESEARCH DATABASE; HEART-DEFECTS AB PurposesThe purposes of this study were to determine (i) the positive predictive value (PPV) of multiple Read codes used to identify congenital cardiac malformation (CCM) cases in the UK Clinical Practice Research Datalink (CPRD); (ii) the accuracy of the diagnosis date; and (iii) the source of information that the general practitioners (GPs) use for validating the diagnosis suggested by the code. MethodsEight hundred eighty-eight records with Read diagnostic and procedures codes for CCM, between January 1996 and November 2010, were identified from CPRD. Questionnaires were sent to GPs to verify the diagnoses and date of the code-identified events. ResultsA total of 719 questionnaires were returned (81% response rate). The PPV of the CCM codes was 93% (670/719). Thirty-one percent of cases had a different event date than the one recorded in the electronic medical record (EMR); 10% of these differing dates were within 30days of the code-identified CCM date. GPs used a variety of data sources to confirm CCM diagnoses. Although the EMR was the most frequently used data source (70%), 66% reported using consultation letters, 9% reported using clinical notes or paper charts, and 35% of GPs reported using the hospital record to confirm the CCM diagnosis. ConclusionsClinical Practice Research Datalink Read codes for CCMs have 93% PPV and most likely point to true cases. However, the accuracy of diagnosis dates and the age at diagnosis may not be as reliable. The findings of this study indicate that GPs use information beyond what is available for researchers in the EMR to confirm clinical diagnoses when responding to validation questionnaires. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. C1 [Hammad, Tarek A.; Margulis, Andrea V.; Ding, Yulan; Strazzeri, Marian M.; Epperly, Holly] US FDA, CDER OSE DEPI I, Silver Spring, MD USA. RP Hammad, TA (reprint author), US FDA, CDER OSE DEPI I, Silver Spring, MD USA. EM tarek_hammad@hotmail.com RI CPRD, CPRD/B-9594-2017; OI Margulis, Andrea/0000-0001-7388-6082 FU US Food and Drug Administration; US Department of Energy's Oak Ridge Institute for Science and Education (ORISE) FX Funding for this study came from the US Food and Drug Administration. A. V. M. received a stipend from the US Department of Energy's Oak Ridge Institute for Science and Education (ORISE). NR 12 TC 3 Z9 3 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD NOV PY 2013 VL 22 IS 11 BP 1233 EP 1238 DI 10.1002/pds.3511 PG 6 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 274OG UT WOS:000328615200005 PM 24002995 ER PT J AU Weinstein, AA Wang, Y Liotta, LA Gerber, LH AF Weinstein, A. A. Wang, Y. Liotta, L. A. Gerber, L. H. TI CANCER-RELATED FATIGUE IS NOT ONE SIZE FITS ALL SO GERONTOLOGIST LA English DT Meeting Abstract C1 [Weinstein, A. A.; Liotta, L. A.; Gerber, L. H.] George Mason Univ, Ctr Study Chron Illness & Disabil, Fairfax, VA 22030 USA. [Wang, Y.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 EI 1758-5341 J9 GERONTOLOGIST JI Gerontologist PD NOV PY 2013 VL 53 SU 1 BP 525 EP 525 PG 1 WC Gerontology SC Geriatrics & Gerontology GA 258EN UT WOS:000327442105543 ER PT J AU Mosholder, AD Racoosin, JA Young, S Wernecke, M Shoaibi, A MaCurdy, TE Worrall, C Kelman, JA AF Mosholder, Andrew D. Racoosin, Judith A. Young, Stephanie Wernecke, Michael Shoaibi, Azadeh MaCurdy, Thomas E. Worrall, Christopher Kelman, Jeffrey A. TI Bleeding Events Following Concurrent Use of Warfarin and Oseltamivir by Medicare Beneficiaries SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE warfarin; oseltamivir; drug-drug interaction; influenza; bleeding ID POSITIVE PREDICTIVE-VALUE; INFLUENZA; DATABASE; DISEASE; CODES; RISK AB Background: During the 2009 H1N1 influenza pandemic, the UK Medicines and Healthcare Products Regulatory Agency received case reports suggesting a potentiation of warfarin anticoagulation by the antiviral drug oseltamivir. We evaluated this putative interaction using Medicare data. Objective: To determine the frequency of bleeding following addition of oseltamivir or comparator drugs among Medicare beneficiaries taking warfarin. Methods: This was a retrospective cohort evaluation using Medicare nationwide data. Cohort members were Medicare Parts A, B, and D beneficiaries from June 30, 2006 to October 31, 2010 receiving warfarin for at least 1 month prior to a concomitant drug of interest (oseltamivir, ampicillin, trimethoprim-sulfamethoxazole (TMP-SMX), and angiotensin-converting enzyme (ACE) inhibitors). Bleeding within 14 days of new prescriptions for oseltamivir or comparators was identified using inpatient or emergency department ICD-9 (International Classification of Diseases, ninth revision) discharge diagnosis codes for gastrointestinal hemorrhage, epistaxis, hematuria, and intracranial bleeding. Patients with bleeding within 30 days preceding the prescription concomitant to warfarin were excluded. Results: With concomitant ACE inhibitors as reference, adjusted odds ratios (ORs) for any bleeding events within 14 days were 1.47 (95% confidence interval [CI] = 1.08-1.88), 1.24 (95% CI = 0.97-1.57), and 2.74 (95% CI = 2.53-3.03), for warfarin plus ampicillin, oseltamivir, and TMP-SMX, respectively. In a sensitivity analysis, adjusted ORs over a 7-day period were 1.89 (95% CI = 1.29-2.59), 1.47 (95% CI = 1.06-2.02), and 3.07 (95% CI = 2.76-3.49) for warfarin plus ampicillin, oseltamivir, and TMP-SMX, respectively. Conclusions: Bleeding with oseltamivir plus warfarin was not significantly increased over a 14-day observation period; a sensitivity analysis showed a statistically significant increase over a 7-day period; in contrast, the data consistently showed the known tendency of TMP-SMX to potentiate the effects of warfarin. The results should be interpreted with the limitations of this approach in mind, including the inability to control for unmeasured confounders. C1 [Mosholder, Andrew D.; Racoosin, Judith A.; Shoaibi, Azadeh] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Young, Stephanie] Univ Calif Los Angeles, Los Angeles, CA USA. [Wernecke, Michael; MaCurdy, Thomas E.] Acumen LLC, Burlingame, CA USA. [MaCurdy, Thomas E.] Stanford Univ, Stanford, CA 94305 USA. [Worrall, Christopher; Kelman, Jeffrey A.] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. RP Mosholder, AD (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Pharmacovigilance & Epidemiol, Div Epidemiol 2, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM andrew.mosholder@fda.hhs.gov FU SafeRx Project, a joint initiative of the Centers for Medicare & Medicaid Services (CMS); US Food and Drug Administration (FDA); US Department of Health and Human Services (HHS) Office of the Assistant Secretary for Planning and Evaluation (ASPE) FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article:; This work was supported by the SafeRx Project, a joint initiative of the Centers for Medicare & Medicaid Services (CMS), US Food and Drug Administration (FDA), and the US Department of Health and Human Services (HHS) Office of the Assistant Secretary for Planning and Evaluation (ASPE). Acumen LLC is a contractor to CMS. NR 18 TC 0 Z9 0 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1060-0280 EI 1542-6270 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD NOV PY 2013 VL 47 IS 11 BP 1420 EP 1428 DI 10.1177/1060028013500940 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 268DA UT WOS:000328147400005 PM 24285759 ER PT J AU Teeguarden, JG Fisher, JW Doerge, DR AF Teeguarden, Justin G. Fisher, Jeffrey W. Doerge, Daniel R. TI Exposure Conditions and Pharmacokinetic Principles: Interpreting Bisphenol A Absorption in the Canine Oral Cavity SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter C1 [Teeguarden, Justin G.] Pacific NW Natl Lab, Richland, WA 99352 USA. [Fisher, Jeffrey W.; Doerge, Daniel R.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Teeguarden, JG (reprint author), Pacific NW Natl Lab, Richland, WA 99352 USA. EM jt@pnl.gov NR 7 TC 3 Z9 3 U1 0 U2 8 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD NOV-DEC PY 2013 VL 121 IS 11-12 BP A323 EP A323 DI 10.1289/ehp.1307424 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 266ZA UT WOS:000328061900003 PM 24284408 ER PT J AU Jones, JL Ludeke, CHM Bowers, JC DePaola, A AF Jones, Jessica L. Luedeke, Catharina H. M. Bowers, John C. DePaola, Angelo TI Comparison of plating media for recovery of total and virulent genotypes of Vibrio vulnificus in US market oysters SO INTERNATIONAL JOURNAL OF FOOD MICROBIOLOGY LA English DT Article DE Vibrio vulnificus; Virulence; Genotype; Media ID UNITED-STATES; CRASSOSTREA-VIRGINICA; PATHOGENS; SEAWATER; STRAINS AB Vibrio vulnificus is the leading cause of seafood associated mortality in the United States and is generally associated with consumption of raw oysters. Two genetic markers have emerged as indicators of strain virulence, 16S rDNA type B (rrnB) and virulence correlated gene type C (vcgC). While much is known about the distribution of V. vulnificus in oysters, a limited number of studies have addressed the more virulent subtypes. Therefore, the goals of this study were to (1) determine the suitability of media for recovery of total and virulent genotypes of V. vulnificus and (2) evaluate the geographical and seasonal distribution of these genotypes. Market oysters from across the United States and the strains isolated from them during a year-long study in 2007 were used. For media evaluation, VVA and CPC+ were compared using direct plating of oyster tissues while mCPC and CPC+ were compared for isolation following MPN enrichment. Representative isolates from each media/method were tested for rrn and vcg types to determine their seasonal and geographical distribution. No statistically significant difference was observed between VVA/CPC+ or mCPC/CPC+ for isolation of total or virulent (rrnB/vcgC) genotypes of V. vulnificus. Overall, 32% of recovered isolates possessed the virulent genotype. The prevalence of these genotypes was highest in oysters from the Gulf Coast during Oct-Dec, and demonstrated a statistically significant geographical and seasonal pattern. This is the first report on the distribution of virulent V. vulnificus genotypes across the United States, which provides novel insight into the occurrence of this pathogen. Published by Elsevier B.V. C1 [Jones, Jessica L.; Luedeke, Catharina H. M.; DePaola, Angelo] US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL USA. [Luedeke, Catharina H. M.] Univ Hamburg, Hamburg Sch Food Sci, Hamburg, Germany. [Bowers, John C.] US FDA, Ctr Food Safety & Appl Nutr, Div Publ Hlth Informat & Analyt, College Pk, MD USA. RP Jones, JL (reprint author), 1 Iberville Dr, Dauphin Isl, AL 36528 USA. EM Jessica.Jones@fda.hhs.gov NR 20 TC 3 Z9 3 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1605 EI 1879-3460 J9 INT J FOOD MICROBIOL JI Int. J. Food Microbiol. PD NOV 1 PY 2013 VL 167 IS 3 BP 322 EP 327 DI 10.1016/j.ijfoodmicro.2013.09.017 PG 6 WC Food Science & Technology; Microbiology SC Food Science & Technology; Microbiology GA 263SW UT WOS:000327829300004 PM 24184610 ER PT J AU Ragupathy, V Devadas, K Tang, SX Wood, O Lee, S Dastyer, A Wang, X Dayton, A Hewlett, I AF Ragupathy, Viswanath Devadas, Krishnakumar Tang, Shixing Wood, Owen Lee, Sherwin Dastyer, Armeta Wang, Xue Dayton, Andrew Hewlett, Indira TI Effect of sex steroid hormones on replication and transmission of major HIV subtypes SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE HIV; Subtypes; Replication kinetics; Transmission kinetics; Sex hormones ID VIRUS TYPE-1 HIV-1; PLASMACYTOID DENDRITIC CELLS; MENSTRUAL-CYCLE; T-CELLS; PROGESTERONE; INHIBITION; INFECTION; ACQUISITION; PREGNANCY; WOMEN AB Background: The HIV epidemic is expanding worldwide with an increasing number of distinct viral subtypes and circulating recombinant forms (CRFs). Out of 34 million adults living with HIV and AIDS, women account for one half of all HIV-1 infections worldwide. These gender differences in HIV pathogenesis may be attributed to sex hormones. Little is known about the role of sex hormone effects on HIV Subtypes pathogenesis. The aim of our study was to determine sex hormone effects on replication and transmissibility of HIV subtypes. Methods: Peripheral blood mononuclear cells (PBMC) and monocyte derived dendritic cells (MDDC) from male and female donors were infected with HIV subtypes A-D and CRF02_AG, CRF01_AE, MN (lab adapted), Group-O, Group-N and HIV-2 at a concentration of 5 ng/ml of p24 or p27. Virus production was evaluated by measuring p24 and p27 levels in culture supernatants. Similar experiments were carried out in the presence of physiological concentrations of sex steroid hormones. R5/X4 expressions measured by flow cytometry and transmissibility was evaluated by transfer of HIV from primary dendritic cells (DC) to autologous donor PBMC. Results: Our results from primary PBMC and MDDC from male and female donors indicate in the absence of physiological concentrations of hormone treatment virus production was observed in three clusters; high replicating virus (subtype B and C), moderate replicative virus (subtype A, D, CRF01_AE, Group_N) and least replicative virus (strain MN). However, dose of sex steroid hormone treatment influenced HIV replication and transmission kinetics in PBMC, DCs and cell lines. Such effects were inconsistent between donors and HIV subtypes. Sex hormone effects on HIV entry receptors (CCR5/CXCR4) did not correlate with virus production. Conclusions: Subtypes B and C showed higher replication in PBMC from males and females and were transmitted more efficiently through DC to male and female PBMC compared with other HIV-1 subtypes, HIV-1 Group 0 and HIV-2. These findings are consistent with increased worldwide prevalence of subtype B and C compared to other subtypes. Sex steroid hormones had variable effect on replication or transmission of different subtypes. These findings suggest that subtype, gender and sex hormones may play a crucial role in the replication and transmission of HIV. Published by Elsevier Ltd. C1 [Ragupathy, Viswanath; Devadas, Krishnakumar; Tang, Shixing; Wood, Owen; Lee, Sherwin; Dastyer, Armeta; Wang, Xue; Dayton, Andrew; Hewlett, Indira] US FDA, Mol Virol Lab, Div Emerging Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Hewlett, I (reprint author), US FDA, Mol Virol Lab, Ctr Biol Evaluat & Res, Bldg 29B,Room 4NN16,8800 Rockville Pike, Bethesda, MD 20892 USA. EM Ragupathy.Viswanath@fda.hhs.gov; Indira.hewlett@fda.hhs.gov FU FDA's Office of Women's Health FX The authors wish to acknowledge Dr. Ming Zhang and Dr. Jiangqin Zhao and Dr. Robin Biswas for review of the manuscript. This work was supported by an intramural grant from the FDA's Office of Women's Health. The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy. NR 32 TC 7 Z9 7 U1 1 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD NOV PY 2013 VL 138 BP 63 EP 71 DI 10.1016/j.jsbmb.2013.03.002 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 264UK UT WOS:000327906300007 PM 23542659 ER PT J AU Piao, YS Wiesenfeld, P Sprando, R Arnold, JT AF Piao, Yun-shang Wiesenfeld, Paddy Sprando, Robert Arnold, Julia T. TI TGF beta 1 alters androgenic metabolites and hydroxysteroid dehydrogenase enzyme expression in human prostate reactive stromal primary cells: Is steroid metabolism altered by prostate reactive stromal microenvironment? SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE TGF beta 1; Reactive prostate stroma; Androstenedione; Testosterone; DHEA; Steroid metabolism ID TRANSFORMING-GROWTH-FACTOR; 3-BETA-HYDROXYSTEROID DEHYDROGENASE; 5 17-BETA-HYDROXYSTEROID-DEHYDROGENASE; FACTOR-BETA; ESTROGEN METABOLISM; EPITHELIAL-CELLS; CANCER; TYPE-2; DHEA; GROWTH-FACTOR-BETA-1 AB The inflammatory tissue microenvironment can be an active promoter in preneoplastic cancer lesions. Altered steroid hormone metabolism as induced by the inflammatory microenvironment may contribute to epithelial cancer progression. Dehydroepiandrosterone sulfate (DHEAS) is the most abundant endogenous steroid hormone present in human serum and can be metabolized to DHEA, androgens and/or estrogens in peripheral tissues. We have previously reported that TGF beta 1-induced reactive prostate stromal cells increase DHEA metabolism to active androgens and alter prostate cancer cell gene expression. While much of the focus on mechanisms of prostate cancer and steroid metabolism is in the epithelial cancer cells, this study focuses on TGF beta 1-induced effects on DHEA metabolic pathways and enzymes in human prostate stromal cells. In DHEA-treated primary prostate stromal cells, TGF beta 1 produced time-and dose-dependent increases in metabolism of DHEA to androstenedione and testosterone. Also TGF beta 1-treated prostate stromal cells exhibited changes in the gene expression of enzymes involved in steroid metabolism including up-regulation of 3 beta hydroxysteroid dehydrogenase (HSD), and down-regulation of 17 beta HSD5, and 17 beta HSD2. These studies suggest that reactive prostate stroma and the inflammatory microenvironment may contribute to altered steroid metabolism and increased intratumoral androgens. Published by Elsevier Ltd. C1 [Piao, Yun-shang; Arnold, Julia T.] NIH, Div Intramural Res, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Wiesenfeld, Paddy; Sprando, Robert] US FDA, Div Toxicol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Arnold, JT (reprint author), NCI, NIH, 9609 Med Ctr Dr,Rm 3W206, Rockville, MD 20850 USA. EM jarnold@mail.nih.gov FU National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, MD [Z01 AT000006-09] FX The authors thank Dr. Guenter Vollmer (Technical University, Dresden, Germany) for constructive comments in reviewing this manuscript. This work was supported by the Intramural Research Program, (Z01 AT000006-09) National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, MD. NR 45 TC 6 Z9 6 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD NOV PY 2013 VL 138 BP 206 EP 213 DI 10.1016/j.jsbmb.2013.05.016 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 264UK UT WOS:000327906300022 PM 23770322 ER PT J AU Xuan, JK Yu, Y Qing, T Guo, L Shi, LM AF Xuan, Jiekun Yu, Ying Qing, Tao Guo, Lei Shi, Leming TI Next-generation sequencing in the clinic: Promises and challenges SO CANCER LETTERS LA English DT Review DE Whole-genome sequencing; Exome sequencing; RNA-Seq; Bioinformatics; FFPE; Tumor heterogeneity; Clinical applications ID RNA-SEQ DATA; LONG NONCODING RNAS; CHRONIC LYMPHOCYTIC-LEUKEMIA; WHOLE-GENOME SEQUENCE; CELL LUNG CARCINOMAS; SHORT READ ALIGNMENT; PROSTATE-CANCER; GENE FUSIONS; BREAST-CANCER; SOMATIC MUTATIONS AB The advent of next generation sequencing (NGS) technologies has revolutionized the field of genomics, enabling fast and cost-effective generation of genome-scale sequence data with exquisite resolution and accuracy. Over the past years, rapid technological advances led by academic institutions and companies have continued to broaden NGS applications from research to the clinic. A recent crop of discoveries have highlighted the medical impact of NGS technologies on Mendelian and complex diseases, particularly cancer. However, the ever-increasing pace of NGS adoption presents enormous challenges in terms of data processing, storage, management and interpretation as well as sequencing quality control, which hinder the translation from sequence data into clinical practice. In this review, we first summarize the technical characteristics and performance of current NGS platforms. We further highlight advances in the applications of NGS technologies towards the development of clinical diagnostics and therapeutics. Common issues in NGS workflows are also discussed to guide the selection of NGS platforms and pipelines for specific research purposes. Published by Elsevier Ireland Ltd. C1 [Xuan, Jiekun; Yu, Ying; Qing, Tao; Shi, Leming] Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China. [Xuan, Jiekun; Guo, Lei; Shi, Leming] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Guo, L (reprint author), Fudan Univ, Sch Pharm, 826 Zhangheng Rd, Shanghai 201203, Peoples R China. EM lei.guo@fda.hhs.gov; leming.shi@gmail.com NR 195 TC 60 Z9 64 U1 7 U2 72 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD NOV 1 PY 2013 VL 340 IS 2 SI SI BP 284 EP 295 DI 10.1016/j.canlet.2012.11.025 PG 12 WC Oncology SC Oncology GA 256EV UT WOS:000327293400019 PM 23174106 ER PT J AU Parsons, BL Manjanatha, MG Myers, MB Mckim, KL Shelton, SD Wang, YY Gollapudi, BB Moore, NP Haber, LT Moore, MM AF Parsons, Barbara L. Manjanatha, Mugimane G. Myers, Meagan B. McKim, Karen L. Shelton, Sharon D. Wang, Yiying Gollapudi, B. Bhaskar Moore, Nigel P. Haber, Lynne T. Moore, Martha M. TI Temporal Changes in K-ras Mutant Fraction in Lung Tissue of Big Blue B6C3F(1) Mice Exposed to Ethylene Oxide SO TOXICOLOGICAL SCIENCES LA English DT Article DE mode of action; risk assessment; reactive oxygen species; oxidative stress; cII mutation frequency; dose response ID DNA-ADDUCTS; OXIDATIVE STRESS; IN-VIVO; INHALATION EXPOSURE; MUTATION SPECTRUM; RISK-ASSESSMENT; CANCER-RISK; CELLS; SENESCENCE; RATS AB Ethylene oxide (EO) is a genotoxicant and a mouse lung carcinogen, but whether EO is carcinogenic through a mutagenic mode of action remains unclear. To investigate this question, 8-week-old male Big Blue B6C3F(1) mice (10 mice/group) were exposed to EO by inhalationu6h/day, 5 days/week for 4 weeks (0, 10, 50, 100, or 200 ppm EO) and 8 or 12 weeks (0, 100, or 200 ppm EO). Lung DNA samples were analyzed for levels of 3 K-ras codon 12 mutations (GGTGAT, GGTGTT, and GGTTGT) using ACB-PCR. No measureable level of K-ras codon 12 TGT mutation was detected (ie, all lung mutant fractions [MFs] 10(5)). Four weeks of inhalation of 100 ppm EO caused a significant increase in K-ras codon 12 GGTGTT MF relative to controls, whereas 50, 100, and 200 ppm EO caused significant increases in K-ras codon 12 GGTGAT MF. In addition, significant inverse correlations were observed between K-ras codon 12 GGTGTT MF and cII mutant frequency in the lungs of the same mice exposed to 50, 100, or 200 ppm EO for 4 weeks. Surprisingly, 8 weeks of exposure to 100 and 200 ppm EO caused significant decreases in K-ras MFs relative to controls. Thus, the changes in K-ras MF as a function of cumulative EO dose were nonmonotonic and were consistent with EO causing early amplification of preexisting K-ras mutations, rather than induction of K-ras mutation through genotoxicity at codon 12. The possibility that these changes reflect K-ras mutant cell selection under varying degrees of oxidative stress is discussed. C1 [Parsons, Barbara L.; Manjanatha, Mugimane G.; Myers, Meagan B.; McKim, Karen L.; Shelton, Sharon D.; Wang, Yiying; Moore, Martha M.] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Gollapudi, B. Bhaskar] Dow Chem Co USA, Toxicol & Environm Res & Consulting, Midland, MI 48674 USA. [Moore, Nigel P.] Dow Europe GmbH, Toxicol & Environm Res & Consulting, Horgen, Switzerland. [Haber, Lynne T.] Toxicol Excellence Risk Assessment, Cincinnati, OH 45211 USA. RP Parsons, BL (reprint author), US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, HFT 120,3900 NCTR Rd, Jefferson, AR 72079 USA. EM Barbara.parsons@fda.hhs.gov FU Ethylene Oxide and Derivatives Producers' Association; Lower Olefins Sector Group of Cefic; European Chemical Industry Association; Cooperative Research and Development Agreement between Toxicology Excellence for Risk Assessment and National Center for Toxicological Research FX Member companies of the Ethylene Oxide and Derivatives Producers' Association and Lower Olefins Sector Group of Cefic, the European Chemical Industry Association; Cooperative Research and Development Agreement between Toxicology Excellence for Risk Assessment and National Center for Toxicological Research. NR 53 TC 3 Z9 3 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD NOV PY 2013 VL 136 IS 1 BP 26 EP 38 DI 10.1093/toxsci/kft190 PG 13 WC Toxicology SC Toxicology GA 258KQ UT WOS:000327458600004 PM 24029818 ER PT J AU Chen, MJ Hong, HX Fang, H Kelly, R Zhou, GX Borlak, J Tong, WD AF Chen, Minjun Hong, Huixiao Fang, Hong Kelly, Reagan Zhou, Guangxu Borlak, Jurgen Tong, Weida TI Quantitative Structure-Activity Relationship Models for Predicting Drug-Induced Liver Injury Based on FDA-Approved Drug Labeling Annotation and Using a Large Collection of Drugs SO TOXICOLOGICAL SCIENCES LA English DT Article DE drug-induced liver injury; predictive model; quantitative structure-activity relationship; drug label; therapeutic categories; external validation ID COMPUTATIONAL TOXICOLOGY; DECISION FOREST; SAFETY; DESCRIPTORS; CONFIDENCE; ATTRITION; FAILURE; SCIENCE; DOMAIN AB Drug-induced liver injury (DILI) is one of the leading causes of the termination of drug development programs. Consequently, identifying the risk of DILI in humans for drug candidates during the early stages of the development process would greatly reduce the drug attrition rate in the pharmaceutical industry but would require the implementation of new research and development strategies. In this regard, several in silico models have been proposed as alternative means in prioritizing drug candidates. Because the accuracy and utility of a predictive model rests largely on how to annotate the potential of a drug to cause DILI in a reliable and consistent way, the Food and Drug Administrationapproved drug labeling was given prominence. Out of 387 drugs annotated, 197 drugs were used to develop a quantitative structure-activity relationship (QSAR) model and the model was subsequently challenged by the left of drugs serving as an external validation set with an overall prediction accuracy of 68.9%. The performance of the model was further assessed by the use of 2 additional independent validation sets, and the 3 validation data sets have a total of 483 unique drugs. We observed that the QSAR models performance varied for drugs with different therapeutic uses; however, it achieved a better estimated accuracy (73.6%) as well as negative predictive value (77.0%) when focusing only on these therapeutic categories with high prediction confidence. Thus, the models applicability domain was defined. Taken collectively, the developed QSAR model has the potential utility to prioritize compounds risk for DILI in humans, particularly for the high-confidence therapeutic subgroups like analgesics, antibacterial agents, and antihistamines. C1 [Chen, Minjun; Hong, Huixiao; Kelly, Reagan; Zhou, Guangxu; Tong, Weida] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Fang, Hong] US FDA, Off Sci Coordinat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Borlak, Jurgen] Hannover Med Sch, Ctr Pharmacol & Toxicol, Hannover, Germany. RP Tong, WD (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM weida.tong@fda.hhs.gov FU German Federal Ministry for Education and Research [031 6154] FX German Federal Ministry for Education and Research as part of the Virtual Liver Network initiative (031 6154 to J.B.). Furthermore, J.B. is recipient of an ORISE Stipend of the Food and Drug Administration, which is gratefully acknowledged. NR 37 TC 21 Z9 21 U1 1 U2 17 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD NOV PY 2013 VL 136 IS 1 BP 242 EP 249 DI 10.1093/toxsci/kft189 PG 8 WC Toxicology SC Toxicology GA 258KQ UT WOS:000327458600021 PM 23997115 ER PT J AU Feng, PCH Reddy, S AF Feng, Peter C. H. Reddy, Shanker TI Prevalences of Shiga Toxin Subtypes and Selected Other Virulence Factors among Shiga-Toxigenic Escherichia coli Strains Isolated from Fresh Produce SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID HEMOLYTIC-UREMIC SYNDROME; MULTIPLEX PCR; SUBTILASE CYTOTOXIN; ENTEROCYTE EFFACEMENT; PUTATIVE ADHESINS; GENE VARIANTS; SAA GENE; CATTLE; FOOD; PROFILES AB Shiga-toxigenic Escherichia coli (STEC) strains were isolated from a variety of fresh produce, but mostly from spinach, with an estimated prevalence rate of 0.5%. A panel of 132 produce STEC strains were characterized for the presence of virulence and putative virulence factor genes and for Shiga toxin subtypes. About 9% of the isolates were found to have the eae gene, which encodes the intimin binding protein, and most of these belonged to known pathogenic STEC serotypes, such as O157:H7 and O26:H11, or to serotypes that reportedly have caused human illness. Among the eae-negative strains, there were three O113:H21 strains and one O91:H21 strain, which historically have been implicated in illness and therefore may be of concern as well. The ehxA gene, which encodes enterohemolysin, was found in similar to 60% of the isolates, and the saa and subAB genes, which encode STEC agglutinating adhesin and subtilase cytotoxin, respectively, were found in similar to 30% of the isolates. However, the precise roles of these three putative virulence factors in STEC pathogenesis have not yet been fully established. The stx(1a) and stx(2a) subtypes were present in 22% and 56%, respectively, of the strains overall and were the most common subtypes among produce STEC strains. The stx(2d) subtype was the second most common subtype (28% overall), followed by stx(2c) (7.5%), and only 2 to 3% of the produce STEC strains had the stx(2e) and stx(2g) subtypes. Almost half of the produce STEC strains had only partial serotypes or were untyped, and most of those that were identified belonged to unremarkable serotypes. Considering the uncertainties of some of these Stx subtypes and putative virulence factors in causing human illness, it is difficult to determine the health risk of many of these produce STEC strains. C1 [Feng, Peter C. H.] US FDA, Div Microbiol, College Pk, MD USA. [Reddy, Shanker] USDA, Monitoring Programs Div, Manassas, VA USA. RP Feng, PCH (reprint author), US FDA, Div Microbiol, College Pk, MD USA. EM peter.feng@fda.hhs.gov NR 46 TC 23 Z9 23 U1 1 U2 16 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD NOV PY 2013 VL 79 IS 22 BP 6917 EP 6923 DI 10.1128/AEM.02455-13 PG 7 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 259CE UT WOS:000327504200011 PM 23995936 ER PT J AU Freise, KJ Lin, TL Fan, TM Recta, V Clark, TP AF Freise, K. J. Lin, T. -L. Fan, T. M. Recta, V. Clark, T. P. TI Evidence-Based Medicine: The Design and Interpretation of Noninferiority Clinical Trials in Veterinary Medicine SO JOURNAL OF VETERINARY INTERNAL MEDICINE LA English DT Review DE Ethics; Placebo; Positive control; Statistical methods ID ACTIVE-CONTROL TRIALS; PLACEBO-CONTROLLED TRIALS; NON-INFERIORITY TRIALS; ACUTE PAIN; MUSCULOSKELETAL DISORDERS; CANINE OSTEOARTHRITIS; ORAL ROBENACOXIB; DOGS; MELOXICAM; EFFICACY AB Noninferiority trials are clinical studies designed to demonstrate that an investigational drug is at least as effective as an established treatment within a predetermined margin. They are conducted, in part, because of ethical concerns of administering a placebo to veterinary patients when an established effective treatment exists. The use of noninferiority trial designs has become more common in veterinary medicine with the increasing number of established veterinary therapeutics and the desire to eliminate potential pain or distress in a placebo-controlled study. Selecting the appropriate active control and an a priori noninferiority margin between the investigational and active control drug are unique and critical design factors for noninferiority studies. Without reliable historical knowledge of the disease response in the absence of treatment and of the response to the selected active control drug, proper design and interpretation of a noninferiority trial is not possible. Despite the appeal of conducting noninferiority trials to eliminate ethical concerns of placebo-controlled studies, there are real limitations and possible ethical conundrums associated with noninferiority trials. The consequences of incorrect study conclusions because of poor noninferiority trial design need careful attention. Alternative trial designs to typical noninferiority studies exist, but these too have limitations and must also be carefully considered. C1 [Freise, K. J.; Lin, T. -L.; Clark, T. P.] Nexcyon Pharmaceut Inc, Madison, WI 53703 USA. [Fan, T. M.] Univ Illinois, Coll Vet Med, Urbana, IL 61801 USA. [Recta, V.] US FDA, Ctr Vet Med, Rockville, MD 20857 USA. RP Clark, TP (reprint author), Nexcyon Pharmaceut Inc, 644 West Washington Ave, Madison, WI 53703 USA. EM clarktp@nexcyon.com OI Lin, Ting-Li/0000-0002-7578-3367 NR 68 TC 4 Z9 4 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0891-6640 EI 1939-1676 J9 J VET INTERN MED JI J. Vet. Intern. Med. PD NOV PY 2013 VL 27 IS 6 BP 1305 EP 1317 DI 10.1111/jvim.12211 PG 13 WC Veterinary Sciences SC Veterinary Sciences GA 251ZA UT WOS:000326972600003 PM 24128266 ER PT J AU Popescu, LM Myers, KJ AF Popescu, Lucretiu M. Myers, Kyle J. TI CT image assessment by low contrast signal detectability evaluation with unknown signal location SO MEDICAL PHYSICS LA English DT Article DE image quality; computed tomography (CT); signal searching; EFROC; LROC; radiation dose; iterative image reconstruction ID OBSERVER PERFORMANCE; MODEL OBSERVERS; RECONSTRUCTION; SYSTEMS; LROC; METRICS; MDCT AB Purpose: To devise a new methodology for CT image quality evaluation in order to assess the dose reduction potential of new iterative reconstruction algorithms (IRA). Methods: Because of the nonlinear behavior of IRA, the authors propose a task-based methodology consisting of measuring the detectability of small, low contrast signals at random locations. The authors test, via simulations, a phantom design that facilitates human and numerical observer studies in such conditions. The setup allows for the random selection of regions of interest (ROT) around each signal, so that the relative signal location is unknown if the ROIs are shown separately. With such a setup one can perform signal detectability measurements with a variety of image reading arrangements and data analysis methods. In this work, the authors demonstrate the use of the localization relative operating characteristic method. The phantom design also allows for efficient image evaluation utilizing an automatic signal search technique and a recently developed nonparametric data analysis method using the exponential transformation of the free response characteristic curve. Results: The authors present the application of these methods by performing a comparison between the filtered back projection (FBP) algorithm and a polychromatic iterative image reconstruction algorithm. In this generic illustration of the image evaluation framework, the expected improved performance of the IRA over FBP is confirmed. Conclusions: The results demonstrate the ability of these methods to determine signal detectability indices with good accuracy with only a small number, of the order of a few tens, of image samples. (C) 2013 American Association of Physicists in Medicine. C1 [Popescu, Lucretiu M.; Myers, Kyle J.] US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Popescu, LM (reprint author), US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM lucretiu.popescu@fda.hhs.gov NR 31 TC 9 Z9 9 U1 0 U2 15 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD NOV PY 2013 VL 40 IS 11 AR 111908 DI 10.1118/1.48240551 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 252FZ UT WOS:000326991800035 PM 24320441 ER PT J AU Wunderlich, A Abbey, CK AF Wunderlich, Adam Abbey, Craig K. TI Utility as a rationale for choosing observer performance assessment paradigms for detection tasks in medical imaging SO MEDICAL PHYSICS LA English DT Article DE ROC analysis; decision theory; image quality assessment; free-response ID FREE-RESPONSE; STATISTICAL POWER; MAMMOGRAPHY; LOCALIZATION; CURVE; ROC; VALIDATION; IMAGES; AREA AB Purpose: Studies of lesion detectability are often carried out to evaluate medical imaging technology. For such studies, several approaches have been proposed to measure observer performance, such as the receiver operating characteristic (ROC), the localization ROC (LROC), the free-response ROC (FROC), the alternative free-response ROC (AFROC), and the exponentially transformed FROC (EFROC) paradigms. Therefore, an experimenter seeking to carry out such a study is confronted with an array of choices. Traditionally, arguments for different approaches have been made on the basis of practical considerations (statistical power, etc.) or the gross level of analysis (case-level or lesion-level). This article contends that a careful consideration of utility should form the rationale for matching the assessment paradigm to the clinical task of interest. Methods: In utility theory, task performance is commonly evaluated with total expected utility, which integrates the various event utilities against the probability of each event. To formalize the relationship between expected utility and the summary curve associated with each assessment paradigm, the concept of a "natural" utility structure is proposed. A natural utility structure is defined for a summary curve when the variables associated with the summary curve axes are sufficient for computing total expected utility, assuming that the disease prevalence is known. Results: Natural utility structures for ROC, LROC, FROC, AFROC, and EFROC curves are introduced, clarifying how the utilities of correct and incorrect decisions are aggregated by summary curves. Further, conditions are given under which general utility structures for localization-based methodologies reduce to case-based assessment. Conclusions: Overall, the findings reveal how summary curves correspond to natural utility structures of diagnostic tasks, suggesting utility as a motivating principle for choosing an assessment paradigm. (C) 2013 American Association of Physicists in Medicine. C1 [Wunderlich, Adam] US FDA, Div Imaging & Appl Math, OSEL, CDRH, Silver Spring, MD 20993 USA. [Abbey, Craig K.] Univ Calif Santa Barbara, Dept Psychol & Brain Sci, Santa Barbara, CA 93106 USA. RP Wunderlich, A (reprint author), US FDA, Div Imaging & Appl Math, OSEL, CDRH, Silver Spring, MD 20993 USA. EM adam.wunderlich@fda.hhs.gov; craig.abbey@psych.ucsb.edu OI Wunderlich, Adam/0000-0002-8463-9156 FU NSF [CBET-1238502] FX The authors thanks Brian S. Garra and Berkman Sahiner for helpful discussions regarding clinical examples. A.W. was supported by an appointment to the Research Participation Program at the Center for Devices and Radiological Health administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. C.K.A was supported by a NSF Fellowship (CBET-1238502). The contents of this work are solely the responsibility of the authors. NR 36 TC 5 Z9 5 U1 0 U2 9 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD NOV PY 2013 VL 40 IS 11 AR 111903 DI 10.1118/1.4823755 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 252FZ UT WOS:000326991800030 PM 24320436 ER PT J AU Anello, C AF Anello, Chuck TI Introduction to Part II of the Special Issue Honoring Dr. Robert T. O'Neill's Contribution to Regulatory Statistical Science SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Editorial Material C1 [Anello, Chuck] US FDA, Ctr Drug Evaluat & Res, Off Biostat, Silver Spring, MD 20993 USA. RP Anello, C (reprint author), Appl Stat Concepts LLC, 9886 Bluefield Dr, Boynton Beach, FL 33473 USA. EM chuckanello@aol.com NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PD NOV PY 2013 VL 5 IS 4 SI SI BP 280 EP 281 DI 10.1080/19466315.2013.852874 PG 2 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 257OP UT WOS:000327394600001 ER PT J AU Wang, SJ Brannath, W Brueckner, M Hung, HMJ Koch, A AF Wang, Sue-Jane Brannath, Werner Brueckner, Matthias Hung, H. M. James Koch, Armin TI Unblinded Adaptive Statistical Information Design Based on Clinical Endpoint or Biomarker SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Adaptive weighted (or unweighted) Z-statistic; Biomarker (or surrogate) outcome; Correlation; Heterogeneity (or inconsistency); Maximum Type I error probability ID COMBINING P-VALUES; SAMPLE-SIZE; CONDITIONAL POWER; I ERROR; TRIALS; RANDOMIZATION; TESTS AB The most frequently seen adaptation of a clinical trial design in regulatory submission is adaptation of statistical information, for example, sample size or number of events. Such adaptation can be based solely on the clinical endpoint of interest or early biomarker. In this article, we articulate the technical merits and discuss challenges when statistical information based solely on the clinical endpoint is used as the design aspect for adaptation. We present the interplay between the weighted and unweighted adaptive Z-statistics with, versus without, additional criteria. We contrast Fisher's p-value product test and the modified version to the adaptive weighted Z-test to elucidate a way to minimize the potential heterogeneity of the observed treatment effects between stages in a two-stage adaptive design setting. Another framework pertains when one is using shorter-term biomarker data for adaptation of statistical information, where the final analysis is to test the null hypothesis of no treatment effect based on the ultimate clinical outcome. It has been argued that under such a framework, no additional Type I error rate control is needed for the final analysis since the clinical endpoint is not used for adaptation. However, we show analytically that, for such an adaptation, the maximum Type I error probability can be far greater than the conventional Type I error level. We conclude by providing a few recommendations. C1 [Wang, Sue-Jane; Hung, H. M. James] US FDA, CDER, Off Translat Sci, Off Biostat, Rockville, MD 20857 USA. [Brannath, Werner; Brueckner, Matthias] Univ Bremen, Competence Ctr Clin Trials, D-28359 Bremen, Germany. [Koch, Armin] Hannover Med Sch, Inst Biometr, Hannover, Germany. RP Wang, SJ (reprint author), US FDA, CDER, Off Translat Sci, Off Biostat, Rockville, MD 20857 USA. EM suejane.wang@fda.hhs.gov; brannath@math.uni-bremen.de; mwb@math.uni-bremen.de; hsienming.hung@fda.hhs.gov; armin.koch@mh-hannover.de FU RSR funds [06-14, 05-02, 05-12]; Center for Drug Evaluation and Research of the U.S. Food and Drug Administration; FWF fund [P21763]; Austrian Research Foundation FX The authors thank Dr. Jose Pinheiro for kindly inviting this article to a special issue in honor of Dr. Robert O'Neill. The authors also thank many colleagues from Office of Biostatistics and Office of New Drugs for their work with the Office on adaptive design submissions. This research work presented in this article was supported by the RSR funds #06-14, #05-02, #05-12, awarded by the Center for Drug Evaluation and Research of the U.S. Food and Drug Administration and the FWF fund P21763 awarded by Austrian Research Foundation. NR 33 TC 5 Z9 5 U1 1 U2 5 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PD NOV PY 2013 VL 5 IS 4 SI SI BP 293 EP 310 DI 10.1080/19466315.2013.791639 PG 18 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 257OP UT WOS:000327394600003 ER PT J AU Huque, MF Dmitrienko, A D'Agostino, R AF Huque, Mohammad F. Dmitrienko, Alex D'Agostino, Ralph TI Multiplicity Issues in Clinical Trials With Multiple Objectives SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Alpha-propagation; Coprimary and composite endpoints; Gatekeeping methods; Multiple comparisons; Primary and secondary endpoints; Type I error rate control ID SAMPLE-SIZE DETERMINATION; END-POINTS; TESTING PROCEDURES; GATEKEEPING STRATEGIES; COMPONENTS; POWER AB Modern clinical trials for evaluating efficacy and safety of new treatments frequently include multiple objectives with questions of varying clinical importance. Answering them generally requires performing a number of statistical tests and analyses which raise multiplicity of tests issues. These issues can be complex and multidimensional in nature. For example, one dimension may relate to the assessment of the effects of the treatment on multiple endpoints, the other to the effects of multiple doses of the treatment, and yet another to the type of the tests (e. g., superiority or noninferiority-type tests). Also, the trial may seek claims for treatment benefits either for the total patient population or for targeted subgroups. In addition, there may be interest in finding whether or not a certain consistency of results persists across certain multiple endpoints; in some situations this may be measuring different but critical features of a disorder, or in other situations may be measuring the same underlying pathophysiology of the disorder. Addressing such problems in clinical trials for the purpose of controlling the Type I error rate requires the use of advanced statistical test strategies and methods, some of which have only recently appeared. Actually, the last decade has witnessed a number of novel methods as well as innovative extensions of old methods for addressing complex multiplicity problems in clinical trials. The main purpose of this article is to present-at the conceptual level-how multiplicity issues of confirmatory clinical trials that include multiple objectives can be addressed by using some of these new statistical methods that use a-propagation and gatekeeping concepts. One additional goal of this contribution is to address some issues that often arise in the use of coprimary and composite endpoints in clinical trials. C1 [Huque, Mohammad F.] US FDA, CDER, Off Biostat, OTS,Div Biometr 4, Silver Spring, MD 20993 USA. [Dmitrienko, Alex] Quintiles Inc, Ctr Stat Drug Dev, Overland Pk, KS 66211 USA. [D'Agostino, Ralph] Boston Univ, Dept Math, Boston, MA 02215 USA. RP Huque, MF (reprint author), US FDA, CDER, Off Biostat, OTS,Div Biometr 4, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM mohammad.huque@fda.hhs.govs; Alex.Dmitrienko@quintiles.com; ralph@bu.edu NR 42 TC 4 Z9 4 U1 0 U2 8 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PD NOV PY 2013 VL 5 IS 4 SI SI BP 321 EP 337 DI 10.1080/19466315.2013.807749 PG 17 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 257OP UT WOS:000327394600005 ER PT J AU Campbell, G AF Campbell, Gregory TI Similarities and Differences of Bayesian Designs and Adaptive Designs for Medical Devices: A Regulatory View SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Clinical trial simulation; Operational bias; Predictive modeling; Prior information; Sample size reestimation; Treatment response adaptive design ID SPONTANEOUS REPORTING SYSTEM; LARGE FREQUENCY TABLES; CLINICAL-TRIALS; SAMPLE-SIZE; CONDITIONAL POWER; ATRIAL-FIBRILLATION; DRUG DEVELOPMENT; DOSE-RESPONSE; ACUTE STROKE; FDA AB This article provides a regulatory view of the design of clinical trials using Bayesian statistics and adaptive methods. The foci are the similarities and differences between Bayesian and adaptive designs for clinical studies for medical devices and the contrast with trials of pharmaceutical drugs. The critical role of the U. S. Food and Drug Administration in such designs is highlighted. The previous device experience with Bayesian trials has provided some important insight into the planning of adaptive trials. This article discusses both frequentist and Bayesian adaptive designs and presents several real examples of designs for medical device studies. The crucial role that simulations play in assessing the operating characteristics of the designs is emphasized. The unique advantage of predictive modeling in the Bayesian adaptive design is explored. For adaptive designs there are challenging problems including operational bias and logistical issues. The reporting of both Bayesian and adaptive trials is discussed. C1 US FDA, Ctr Devices & Radiol Hlth, Div Biostat, Silver Spring, MD 20993 USA. RP Campbell, G (reprint author), US FDA, Ctr Devices & Radiol Hlth, Div Biostat, Silver Spring, MD 20993 USA. EM greg.campbell@fda.hhs.gov NR 46 TC 3 Z9 3 U1 2 U2 7 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PD NOV PY 2013 VL 5 IS 4 SI SI BP 356 EP 368 DI 10.1080/19466315.2013.846873 PG 13 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 257OP UT WOS:000327394600008 ER PT J AU Permutt, T AF Permutt, Thomas TI Multiplicity in Regulatory Statistical Review SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Review DE Analysis of covariance; Clinical trials; Missing data; Prespecification; Sensitivity analysis AB In planning trials, good practice requires prespecification of analyses to control the probability of false positives and to enable a coherent interpretation of the result. In reviewing trials, analyses are usually not preplanned. Although the goals of reviewers are neither the same as nor opposite to those of planners, reviews are also subject to concerns about multiple, post hoc analyses. The probability of false negatives is not controlled, and the multiple analyses can be difficult or impossible to interpret together coherently. We consider several types of multiplicity that arise in reviews rather than in submissions and offer advice for coping with them. C1 US FDA, Silver Spring, MD USA. RP Permutt, T (reprint author), US FDA, Silver Spring, MD USA. EM thomas.permutt@fda.hhs.gov NR 2 TC 1 Z9 1 U1 0 U2 5 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PD NOV PY 2013 VL 5 IS 4 SI SI BP 394 EP 401 DI 10.1080/19466315.2013.851032 PG 8 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 257OP UT WOS:000327394600011 ER PT J AU Stephenson, D Aviles, E Bain, LJ Brumfield, M Carrillo, M Comery, TA Compton, C Corrigan, B Gordon, MF Jack, CR Katz, R Logovinsky, V Satlin, A Marek, K Nicholas, T Polhamus, D Angersbach, BS Raghavan, N Romano, G Romero, K Shaw, L Woodcock, J Vradenburg, G Isaac, M AF Stephenson, Diane Aviles, Enrique Bain, Lisa J. Brumfield, Martha Carrillo, Maria Comery, Thomas A. Compton, Carolyn Corrigan, Brian Gordon, Mark Forrest Jack, Clifford R., Jr. Katz, Russell Logovinsky, Veronika Satlin, Andrew Marek, Ken Nicholas, Timothy Polhamus, Dan Angersbach, B. Steven Raghavan, Nandini Romano, Gary Romero, Klaus Shaw, Leslie Woodcock, Janet Vradenburg, George Isaac, Maria TI Coalition Against Major Diseases: Precompetitive Collaborations and Regulatory Paths to Accelerating Drug Development for Neurodegenerative Diseases SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article DE Alzheimer disease; Parkinson disease; disease modeling; regulatory qualification; biomarkers ID SOCIETY-SPONSORED REVISION; SCALE MDS-UPDRS; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; BIOMARKERS AB Precompetitive collaborations have been successful in several disease areas and industries. Such collaborations are critical to address the gaps and challenges in therapeutic development for chronic neurodegenerative diseases. On November 5, 2012, members of the scientific community, advocates, regulators, industry, and government officials met at the US Food and Drug Administration to develop tools to expedite drug development and maximize the potential for success in future drug trials for Alzheimer disease and Parkinson disease. The meeting established that multiple collaborative approaches are essential for accelerating drug development. Such approaches include precompetitive data sharing, regulatory qualification of biomarkers and clinical outcome assessments, implementation of data standards, and development of quantitative drug disease trial models. While challenges to collaboration among industry partners are formidable, they are not insurmountable. The Coalition Against Major Diseases (CAMD) has several positive examples to highlight. This review represents proceedings from CAMD's annual conference and discusses the key themes that are being advanced by the Critical Path Institute. C1 [Stephenson, Diane; Aviles, Enrique; Brumfield, Martha; Angersbach, B. Steven; Romero, Klaus] Crit Path Inst, Tucson, AZ 85718 USA. [Carrillo, Maria] Alzheimers Assoc, Chicago, IL USA. [Comery, Thomas A.; Corrigan, Brian; Nicholas, Timothy] Pfizer Inc, New London, CT USA. [Compton, Carolyn] Arizona State Univ, Phoenix, AZ USA. [Gordon, Mark Forrest] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA. [Jack, Clifford R., Jr.] Mayo Clin, Rochester, MN USA. [Katz, Russell] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Logovinsky, Veronika; Satlin, Andrew] Eisai Inc, Woodcliff Lake, NJ USA. [Marek, Ken] Inst Neurodegenerat Disorders, New Haven, CT USA. [Polhamus, Dan] Metrum Res Grp, Tariffville, CT USA. [Raghavan, Nandini; Romano, Gary] Johnson & Johnson, Raritan, NJ USA. [Shaw, Leslie] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Woodcock, Janet] US FDA, Silver Spring, MD USA. [Vradenburg, George] USAgainst Alzheimers, Washington, DC USA. [Isaac, Maria] EMA, London, England. RP Stephenson, D (reprint author), Crit Path Inst, 1730 East River Rd, Tucson, AZ 85718 USA. EM DStephenson@c-path.org RI Jack, Clifford/F-2508-2010 OI Jack, Clifford/0000-0001-7916-622X FU US Food and Drug Administration [U01FD003865]; Science Foundation Arizona [SRG 0335-08] FX Critical Path Institute's Coalition Against Major Diseases is supported by the US Food and Drug Administration (grant U01FD003865) and Science Foundation Arizona (grant SRG 0335-08). NR 29 TC 5 Z9 5 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD NOV PY 2013 VL 47 IS 6 BP 632 EP 638 DI 10.1177/2168479013498386 PG 7 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA 257NM UT WOS:000327391600003 ER PT J AU Woodcock, J Rowzee, AM AF Woodcock, Janet Rowzee, Anne M. TI The Multiple Sclerosis Outcome Assessments Consortium: Bringing the Community Together to Shape the Future of Multiple Sclerosis Drug Development SO THERAPEUTIC INNOVATION & REGULATORY SCIENCE LA English DT Article C1 [Woodcock, Janet; Rowzee, Anne M.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Rowzee, AM (reprint author), US FDA, Ctr Drug Evaluat & Res, 10001 New Hampshire Ave,Hillandale Bldg,Room 4116, Silver Spring, MD 20993 USA. EM Anne.Rowzee@fda.hhs.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2168-4790 EI 2168-4804 J9 THER INNOV REGUL SCI JI Ther. Innov. Regul. Sci. PD NOV PY 2013 VL 47 IS 6 BP 639 EP 640 DI 10.1177/2168479013502656 PG 2 WC Medical Informatics; Pharmacology & Pharmacy SC Medical Informatics; Pharmacology & Pharmacy GA 257NM UT WOS:000327391600004 ER PT J AU Trumbo, PR AF Trumbo, Paula R. TI Evidence Needed to Inform the Next Dietary Reference Intakes for Iodine SO ADVANCES IN NUTRITION LA English DT Article ID THYROID-FUNCTION; EUTHYROID SUBJECTS; URINARY IODINE; UNITED-STATES; PREGNANCY; SUPPLEMENTATION; POPULATION; BALANCE; ACCUMULATION; CLEARANCE AB In 2001, Dietary Reference Intakes (DRIs) for iodine were set for the different gender and life-stage groups by the Institute of Medicine. Because of the serious consequences of iodine deficiency for the developing fetus and infant, there is particular interest in further understanding optimal iodine nutrition and improving the monitoring of iodine status, particularly during infancy, pregnancy, and lactation. This review discusses the basis for the current DRIs for iodine and the evidence that may be needed for considering and conducting the reevaluation of one or more of the DRIs. C1 US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Trumbo, PR (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM paula.trumbo@fda.hhs.gov NR 40 TC 4 Z9 4 U1 1 U2 9 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 EI 2156-5376 J9 ADV NUTR JI Adv. Nutr. PD NOV PY 2013 VL 4 IS 6 BP 718 EP 722 DI 10.3945/an.113.004804 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 253TT UT WOS:000327112900015 PM 24228203 ER PT J AU Keys, AL Dailey, RC Hitchins, AD Smiley, RD AF Keys, Ashley L. Dailey, Rachel C. Hitchins, Anthony D. Smiley, R. Derike TI Postenrichment Population Differentials Using Buffered Listeria Enrichment Broth: Implications of the Presence of Listeria innocua on Listeria monocytogenes in Food Test Samples SO JOURNAL OF FOOD PROTECTION LA English DT Article ID MULTIPLEX PCR ASSAY; CULTURES AB The recovery of low levels of Listeria monocytogenes from foods is complicated by the presence of competing microorganisms. Nonpathogenic species of Listeria pose a particular problem because variation in growth rate during the enrichment step can produce more colonies of these nontarget cells on selective and/or differential media, resulting in a preferential recovery of nonpathogens, especially Listeria innocua. To gauge the extent of this statistical barrier to pathogen recovery, 10 isolates each of L. monocytogenes and L. innocua were propagated together from approximately equal initial levels using the current U. S. Food and Drug Administration's enrichment procedure. In the 100 isolate pairs, an average 1.3-log decrease was found in the 48-h enrichment L. monocytogenes population when L. innocua was present. In 98 of the 100 isolate pairs, L. innocua reached higher levels at 48 h than did L. monocytogenes, with a difference of 0.2 to 2.4 log CFU/ml. The significance of these population differences was apparent by an increase in the difficulty of isolating L. monocytogenes by the streak plating method. L. monocytogenes went completely undetected in 18 of 30 enrichment cultures even after colony isolation was attempted on Oxoid chromogenic Listeria agar. This finding suggests that although both Listeria species were present on the plate, the population differential between them restricted L. monocytogenes to areas of the plate with confluent growth and that isolated individual colonies were only L. innocua. C1 [Keys, Ashley L.; Dailey, Rachel C.; Smiley, R. Derike] US FDA, Arkansas Reg Lab, Jefferson, AR 72079 USA. [Hitchins, Anthony D.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20705 USA. RP Smiley, RD (reprint author), US FDA, Arkansas Reg Lab, 3900 NCTR Rd,Bldg 26, Jefferson, AR 72079 USA. EM ronald.smiley@fda.hhs.gov FU Intramural FDA HHS [FD999999] NR 18 TC 6 Z9 6 U1 3 U2 13 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD NOV PY 2013 VL 76 IS 11 BP 1854 EP 1862 DI 10.4315/0362-028X.JFP-13-089 PG 9 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 253NV UT WOS:000327096000005 PM 24215687 ER PT J AU Gendel, SM Zhu, JM AF Gendel, Steven M. Zhu, Jianmei TI Analysis of US Food and Drug Administration Food Allergen Recalls after Implementation of the Food Allergen Labeling and Consumer Protection Act SO JOURNAL OF FOOD PROTECTION LA English DT Article AB To avoid potentially life-threatening reactions, food allergic consumers rely on information on food labels to help them avoid exposure to a food or ingredient that could trigger a reaction. To help consumers in the United States obtain the information that they need, the Food Allergen Labeling and Consumer Protection Act of 2004 defined a major food allergen as being one of eight foods or food groups and any ingredient that contains protein from one of these foods or food groups. A food that contains an undeclared major food allergen is misbranded under the U.S. Food, Drug, and Cosmetic Act and is subject to recall. Food allergen labeling problems are the most common cause of recalls for U.S. Food and Drug Administration (FDA)-regulated food products. To help understand why food allergen recalls continue to occur at a high rate, information on each food allergen recall that occurred in fiscal years 2007 through 2012 was obtained from the FDA recall database. This information was analyzed to identify the food, allergen, root cause, and mode of discovery for each food allergen recall. Bakery products were the most frequently recalled food type, and milk was the most frequently undeclared major food allergen. Use of the wrong package or label was the most frequent problem leading to food allergen recalls. These data are the first reported that indicate the importance of label and package controls as public health measures. C1 [Gendel, Steven M.; Zhu, Jianmei] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Gendel, SM (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy,HFS 200, College Pk, MD 20740 USA. EM steven.gendel@fda.hhs.gov NR 15 TC 18 Z9 18 U1 4 U2 23 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD NOV PY 2013 VL 76 IS 11 BP 1933 EP 1938 DI 10.4315/0362-028X.JFP-13-171 PG 6 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 253NV UT WOS:000327096000016 PM 24215698 ER PT J AU Wang, JQ Wu, HY Song, M Li, FQ Zhu, JH Xi, ML Wang, X Xia, XD Meng, JH Yang, BW Cui, SH AF Wang, Jiaqi Wu, Haiyun Song, Miao Li, Fengqin Zhu, Jianghui Xi, Meili Wang, Xin Xia, Xiaodong Meng, Jianghong Yang, Baowei Cui, Shenghui TI Prevalence and Quantitative Detection of Salmonella in Retail Raw Chicken in Shaanxi, China SO JOURNAL OF FOOD PROTECTION LA English DT Article ID ANTIMICROBIAL RESISTANCE; PRODUCTS; POULTRY; MEAT; ETHIOPIA; SEROVARS AB Quantitative Salmonella concentrations and prevalence of Salmonella in raw chicken at the retail level in Shaanxi province, China, was determined in this study. Two hundred forty samples were collected in Yangling and the surrounding cities, in Shaanxi Province, China, for data collection over 12 successive months from April 2011 to March 2012. During the whole surveillance year, the overall Salmonella contamination rate of retail raw chicken was identified as 43.3%, the most-probable-number (MPN) values ranged from 0.0036 to 0.8596 MPN per g, and the average value was 0.1655 MPN per g, except in 11 of the samples, which had MPN values of more than 11 MPN per g. In April 2011, the highest prevalence rate, which was 80.0%, was observed, and the corresponding MPN value was 0.8596 MPN per g. Observed in November 2011, the lowest prevalence rate and the corresponding MPN value were 5.0% and 0.0036 MPN per g, respectively. Prevalence of Salmonella in chicken collected from the supermarket (49.2%) was higher but not significantly different from that in the wet markets (37.5%), although the MPN value of samples in the wet market (0.1912 MPN per g) was higher than that in the supermarket (0.1396 MPN per g). Prevalence of Salmonella was the highest in the frozen chicken (53.3%) compared with chilled chicken (45.0%) and freshly slaughtered chicken (37.5%); however, the MPN value of the freshly slaughtered chicken (0.1912 MPN per g) was higher than those of either frozen chicken (0.1804 MPN per g) or the chilled chicken (0.0988 MPN per g). C1 [Wang, Jiaqi; Wu, Haiyun; Song, Miao; Xi, Meili; Wang, Xin; Xia, Xiaodong; Meng, Jianghong; Yang, Baowei] Northwest A&F Univ, Coll Food Sci & Engn, Xianyang 712100, Shaanxi, Peoples R China. [Wu, Haiyun] Shanghai Jiao Tong Univ, Sch Pharm, Shanghai 200240, Peoples R China. [Li, Fengqin; Zhu, Jianghui] China Natl Ctr Food Safety Risk Assessment, Beijing 100021, Peoples R China. [Meng, Jianghong] Univ Maryland, Joint Inst Food Safety & Appl Nutr, College Pk, MD 20742 USA. [Meng, Jianghong] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Cui, Shenghui] Natl Inst Food & Drug Control, Beijing 100050, Peoples R China. RP Yang, BW (reprint author), Northwest A&F Univ, Coll Food Sci & Engn, Xianyang 712100, Shaanxi, Peoples R China. EM ybwsheng@163.com FU Centers for Disease Control and Prevention, Ministry of Health of the People's Republic of China FX This study was financially supported by the Centers for Disease Control and Prevention, Ministry of Health of the People's Republic of China. We also appreciate Dr. Shuangkui Du for his helpful discussions and advice on statistical analysis. NR 19 TC 4 Z9 4 U1 2 U2 23 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD NOV PY 2013 VL 76 IS 11 BP 1958 EP 1962 DI 10.4315/0362-028X.JFP-13-168 PG 5 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 253NV UT WOS:000327096000019 PM 24215701 ER PT J AU Lionetti, G Kimura, Y Schanberg, LE Beukelman, T Wallace, CA Ilowite, NT Winsor, J Fox, K Natter, M Sundy, JS Brodsky, E Curtis, JR Del Gaizo, V Iyasu, S Jahreis, A Meeker-O'Connell, A Mittleman, BB Murphy, BM Peterson, ED Raymond, SC Setoguchi, S Siegel, JN Sobel, RE Solomon, D Southwood, TR Vesely, R White, PH Wulffraat, NM Sandborg, CI AF Lionetti, Geraldina Kimura, Yukiko Schanberg, Laura E. Beukelman, Timothy Wallace, Carol A. Ilowite, Norman T. Winsor, Jane Fox, Kathleen Natter, Marc Sundy, John S. Brodsky, Eric Curtis, Jeffrey R. Del Gaizo, Vincent Iyasu, Solomon Jahreis, Angelika Meeker-O'Connell, Ann Mittleman, Barbara B. Murphy, Bernard M. Peterson, Eric D. Raymond, Sandra C. Setoguchi, Soko Siegel, Jeffrey N. Sobel, Rachel E. Solomon, Daniel Southwood, Taunton R. Vesely, Richard White, Patience H. Wulffraat, Nico M. Sandborg, Christy I. TI Using Registries to Identify Adverse Events in Rheumatic Diseases SO PEDIATRICS LA English DT Article DE medication safety; immunomodulatory therapy; biologic products; juvenile rheumatic disease ID JUVENILE IDIOPATHIC ARTHRITIS; CROSS-SECTIONAL ANALYSIS; LONG-TERM SAFETY; CHILDHOOD ARTHRITIS; CARRA REGISTRY; CHILDREN; ETANERCEPT; METHOTREXATE; MALIGNANCY; DRUGS AB The proven effectiveness of biologics and other immunomodulatory products in inflammatory rheumatic diseases has resulted in their widespread use as well as reports of potential short-and long-term complications such as infection and malignancy. These complications are especially worrisome in children who often have serial exposures to multiple immunomodulatory products. Post-marketing surveillance of immunomodulatory products in juvenile idiopathic arthritis (JIA) and pediatric systemic lupus erythematosus is currently based on product-specific registries and passive surveillance, which may not accurately reflect the safety risks for children owing to low numbers, poor long-term retention, and inadequate comparators. In collaboration with the US Food and Drug Administration (FDA), patient and family advocacy groups, biopharmaceutical industry representatives and other stakeholders, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the Duke Clinical Research Institute (DCRI) have developed a novel pharmacosurveillance model (CARRA Consolidated Safety Registry [CoRe]) based on a multi-center longitudinal pediatric rheumatic diseases registry with over 8000 participants. The existing CARRA infrastructure provides access to much larger numbers of subjects than is feasible in single-product registries. Enrollment regardless of medication exposure allows more accurate detection and evaluation of safety signals. Flexibility built into the model allows the addition of specific data elements and safety outcomes, and designation of appropriate disease comparator groups relevant to each product, fulfilling post-marketing requirements and commitments. The proposed model can be applied to other pediatric and adult diseases, potentially transforming the paradigm of pharmacosurveillance in response to the growing public mandate for rigorous post-marketing safety monitoring. C1 [Lionetti, Geraldina; Sandborg, Christy I.] Stanford Univ, Dept Pediat, Palo Alto, CA 94304 USA. [Kimura, Yukiko] Hackensack Univ Med Ctr, Joseph M Sanzari Childrens Hosp, Dept Pediat, Hackensack, NJ 07601 USA. [Schanberg, Laura E.] Duke Univ Med Ctr, Dept Pediat, Durham, NC USA. [Beukelman, Timothy; Curtis, Jeffrey R.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Wallace, Carol A.] Seattle Childrens Hosp, Dept Pediat, Seattle, WA USA. [Ilowite, Norman T.] Childrens Hosp Montefiore, Dept Pediat, Bronx, NY USA. [Winsor, Jane; Fox, Kathleen; Sundy, John S.; Peterson, Eric D.; Setoguchi, Soko] Duke Clin Res Inst, Durham, NC USA. [Natter, Marc] Boston Childrens Hosp, Dept Pediat, Boston, MA USA. [Brodsky, Eric; Iyasu, Solomon; Meeker-O'Connell, Ann] US FDA, Silver Spring, MD USA. [Del Gaizo, Vincent] Friends Childhood Arthrit & Rheumatol Res Allianc, Whitehouse Stn, NJ USA. [Jahreis, Angelika; Siegel, Jeffrey N.] Genentech Inc, San Francisco, CA 94080 USA. [Mittleman, Barbara B.] NIH, Bethesda, MD 20892 USA. [Murphy, Bernard M.; White, Patience H.] Arthrit Fdn, Atlanta, GA USA. [Raymond, Sandra C.] Lupus Fdn Amer, Washington, DC USA. [Sobel, Rachel E.] Pfizer Inc, New York, NY USA. [Solomon, Daniel] Brigham & Womens Hosp, Dept Rheumatol, Boston, MA 02115 USA. [Southwood, Taunton R.] Univ Birmingham, Sch Immun & Infect, Birmingham, W Midlands, England. [Vesely, Richard] European Med Agcy, London, England. [Wulffraat, Nico M.] Univ Med Ctr Utrecht, Dept Pediat, Utrecht, Netherlands. RP Kimura, Y (reprint author), Hackensack Univ Med Ctr, Joseph M Sanzari Childrens Hosp, 30 Prospect Ave, Hackensack, NJ 07601 USA. EM YKimura@HackensackUMC.org OI Sobel, Rachel/0000-0002-4492-9562 FU NIH [AR063890]; NIH ARRA [AR058934]; Arthritis Foundation; Friends of CARRA; National Institutes of Health (NIH) FX Supported in part by NIH grant AR063890 and NIH ARRA grant AR058934, Arthritis Foundation, Friends of CARRA, and contributions from Abbott Laboratories, Amgen, Inc, Bristol Myers Squibb Company, Genentech, Inc, Human Genome Sciences, Inc, Novartis Pharmaceuticals, and Pfizer, Inc. Funded by the National Institutes of Health (NIH). NR 30 TC 6 Z9 6 U1 0 U2 6 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2013 VL 132 IS 5 BP E1384 EP E1394 DI 10.1542/peds.2013-0755 PG 11 WC Pediatrics SC Pediatrics GA 245PE UT WOS:000326475000030 PM 24144710 ER PT J AU Manthripragada, AD Pinheiro, SP MaCurdy, TE Saneinejad, S Worrall, CM Kelman, JA Graham, DJ AF Manthripragada, Angelika D. Pinheiro, Simone P. MaCurdy, Thomas E. Saneinejad, Shahin Worrall, Chris M. Kelman, Jeffrey A. Graham, David J. TI Off-Label Topical Calcineurin Inhibitor Use in Children SO PEDIATRICS LA English DT Article DE topical calcineurin inhibitors; pharmacoepidemiology; off-label drug use AB OBJECTIVE: To assess off-label use of the topical calcineurin inhibitors (TCIs), tacrolimus and pimecrolimus, in children during periods before and after regulatory action by the US Food and Drug Administration (FDA) in 2005. METHODS: We identified new pediatric (age <20 years) users of topical tacrolimus or pimecrolimus in US Medicaid from 2001 to 2009, and examined the annual rate of drug use (pre-and postregulatory action) by age. We assessed medical claims for diagnoses consistent with an indication for a TCI, and assessed prescriptions for evidence of first-line atopic dermatitis therapy use before TCI initiation. RESULTS: There were 57 664 eligible pediatric tacrolimus users and 425 242 eligible pediatric pimecrolimus users at baseline. The rate of TCI use decreased substantially after FDA regulatory action. The proportion of new users younger than 2 years of age significantly decreased for both tacrolimus (36.7% to 22.5%, P,.001) and pimecrolimus (47.0% to 33.7%, P < .001) after regulatory actions. Previous use of topical corticosteroids increased by similar to 7% for both TCIs from the pre-to postregulatory period. However, after regulatory actions, there was only a small increase in the proportion of tacrolimus or pimecrolimus users with an atopic dermatitis or eczema diagnosis before drug initiation, and high strength use of tacrolimus was unchanged. CONCLUSIONS: The rate of TCI use in children younger than 2 years of age fell substantially after FDA regulatory action in 2005. Off-label use of TCI as first-line therapy changed little. C1 [Manthripragada, Angelika D.; Pinheiro, Simone P.; Graham, David J.] US FDA, Silver Spring, MD USA. [MaCurdy, Thomas E.; Saneinejad, Shahin] Acumen LLC, Burlingame, CA USA. [MaCurdy, Thomas E.] Stanford Univ, Dept Econ, Stanford, CA 94305 USA. [Worrall, Chris M.; Kelman, Jeffrey A.] Ctr Medicare, Washington, DC USA. [Worrall, Chris M.; Kelman, Jeffrey A.] Ctr Medicaid Serv, Washington, DC USA. RP Manthripragada, AD (reprint author), Amgen Inc, Ctr Observat Res, 1 Amgen Dr, Newbury Pk, CA 91320 USA. EM awahnerm@amgen.com NR 7 TC 4 Z9 4 U1 0 U2 2 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2013 VL 132 IS 5 BP E1327 EP E1332 DI 10.1542/peds.2013-0931 PG 6 WC Pediatrics SC Pediatrics GA 245PE UT WOS:000326475000025 PM 24127469 ER PT J AU Nadler, Z Wang, B Wollstein, G Nevins, JE Ishikawa, H Kagemann, L Sigal, IA Ferguson, RD Hammer, DX Grulkowski, I Liu, JJ Kraus, MF Lu, CD Hornegger, J Fujimoto, JG Schuman, JS AF Nadler, Zach Wang, Bo Wollstein, Gadi Nevins, Jessica E. Ishikawa, Hiroshi Kagemann, Larry Sigal, Ian A. Ferguson, R. Daniel Hammer, Daniel X. Grulkowski, Ireneusz Liu, Jonathan J. Kraus, Martin F. Lu, Chen D. Hornegger, Joachim Fujimoto, James G. Schuman, Joel S. TI Automated lamina cribrosa microstructural segmentation in optical coherence tomography scans of healthy and glaucomatous eyes SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID NERVE-FIBER LAYER; SCANNING LASER OPHTHALMOSCOPY; IMAGE-ANALYSIS; THICKNESS; DAMAGE; PORES; HEAD AB We demonstrate an automated segmentation method for in-vivo 3D optical coherence tomography (OCT) imaging of the lamina cribrosa (LC). Manual segmentations of coronal slices of the LC were used as a gold standard in parameter selection and evaluation of the automated technique. The method was validated using two prototype OCT devices; each had a subject cohort including both healthy and glaucomatous eyes. Automated segmentation of in-vivo 3D LC OCT microstructure performed comparably to manual segmentation and is useful for investigative research and in clinical quantification of the LC. (C) 2013 Optical Society of America C1 [Nadler, Zach; Wang, Bo; Wollstein, Gadi; Nevins, Jessica E.; Ishikawa, Hiroshi; Kagemann, Larry; Sigal, Ian A.; Schuman, Joel S.] Univ Pittsburgh, Sch Med, Inst Eye & Ear, UPMC Eye Ctr,Ophthalmol & Visual Sci Res Ctr, Pittsburgh, PA 15260 USA. [Wang, Bo; Ishikawa, Hiroshi; Kagemann, Larry; Sigal, Ian A.; Schuman, Joel S.] Univ Pittsburgh, Swanson Sch Engn, Dept Bioengn, Pittsburgh, PA USA. [Ferguson, R. Daniel] Phys Sci Inc, Andover, MA 01810 USA. [Hammer, Daniel X.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Grulkowski, Ireneusz; Liu, Jonathan J.; Kraus, Martin F.; Lu, Chen D.; Fujimoto, James G.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Kraus, Martin F.; Hornegger, Joachim] Univ Erlangen Nurnberg, Pattern Recognit Lab, Nurnberg, Germany. [Kraus, Martin F.; Hornegger, Joachim] Univ Erlangen Nurnberg, SAOT, Nurnberg, Germany. RP Nadler, Z (reprint author), Univ Pittsburgh, Sch Med, Inst Eye & Ear, UPMC Eye Ctr,Ophthalmol & Visual Sci Res Ctr, Pittsburgh, PA 15260 USA. EM wollsteing@upmc.edu RI Grulkowski, Ireneusz/N-9655-2013; Schuman, Joel/K-7304-2012; OI Grulkowski, Ireneusz/0000-0001-7688-1826; Schuman, Joel/0000-0002-8885-3766; Kagemann, Larry/0000-0001-8961-0187; Ishikawa, Hiroshi/0000-0001-6310-5748 FU NIH [R01-EY013178, R01-EY011289, R44-EY018986, P30-EY008098]; Eye and Ear Foundation (Pittsburgh, PA); Research to Prevent Blindness (New York, NY); German Research Foundation [DFG-HO-1791/11-1]; Erlangen Graduate School in Advanced Optical Technologies (SAOT) [DFG-GSC80-SAOT] FX The authors acknowledge this work would not have been possible without funding and support from: NIH R01-EY013178, R01-EY011289, R44-EY018986, P30-EY008098; Eye and Ear Foundation (Pittsburgh, PA); Research to Prevent Blindness (New York, NY); German Research Foundation DFG-HO-1791/11-1, DFG Training Group 1773 " Heterogeneous Image Systems" and Erlangen Graduate School in Advanced Optical Technologies (SAOT) DFG-GSC80-SAOT. NR 36 TC 18 Z9 20 U1 1 U2 7 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD NOV 1 PY 2013 VL 4 IS 11 BP 2596 EP 2608 DI 10.1364/BOE.4.002596 PG 13 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 246ZW UT WOS:000326582500027 PM 24298418 ER PT J AU Ghazarian, LN Diana, J Beaudoin, L Larsson, PG Puri, RK van Rooijen, N Flodstrom-Tullberg, M Lehuen, A AF Ghazarian, Liana Diana, Julien Beaudoin, Lucie Larsson, Par G. Puri, Raj K. van Rooijen, Nico Flodstrom-Tullberg, Malin Lehuen, Agnes TI Protection Against Type 1 Diabetes Upon Coxsackievirus B4 Infection and iNKT-Cell Stimulation SO DIABETES LA English DT Article ID KILLER T-CELLS; PANCREATIC-ISLET CELLS; BETA-CELLS; DENDRITIC CELLS; NKT CELLS; VIRAL-INFECTION; INDOLEAMINE 2,3-DIOXYGENASE; TRYPTOPHAN CATABOLISM; ENTEROVIRUS INFECTION; ADOPTIVE TRANSFER AB Invariant natural killer T (iNKT) cells belong to the innate immune system and exercise a dual role as potent regulators of autoimmunity and participate in responses against different pathogens. They have been shown to prevent type 1 diabetes development and to promote antiviral responses. Many studies in the implication of environmental factors on the etiology of type 1 diabetes have suggested a link between enteroviral infections and the development of this disease. This study of the pancreatropic enterovirus Coxsackievirus B4 (CVB4) shows that although infection accelerated type 1 diabetes development in a subset of proinsulin 2-deficient NOD mice, the activation of iNKT cells by a specific agonist, -galactosylceramide, at the time of infection inhibited the disease. Diabetes development was associated with the infiltration of pancreatic islets by inflammatory macrophages, producing high levels of interleukin (IL)-1, IL-6, and tumor necrosis factor- and activation of anti-islet T cells. On the contrary, macrophages infiltrating the islets after CVB4 infection and iNKT-cell stimulation expressed a number of suppressive enzymes, among which indoleamine 2,3-dioxygenase was sufficient to inhibit anti-islet T-cell response and to prevent diabetes. This study highlights the critical interaction between virus and the immune system in the acceleration or prevention of type 1 diabetes. C1 [Ghazarian, Liana; Diana, Julien; Beaudoin, Lucie; Lehuen, Agnes] Hosp Cochin St Vincent de Paul, INSERM, U1016, Paris, France. [Ghazarian, Liana; Diana, Julien; Beaudoin, Lucie; Lehuen, Agnes] Univ Paris 05, Paris, France. [Ghazarian, Liana; Diana, Julien; Beaudoin, Lucie; Lehuen, Agnes] Sorbonne Paris Cite, Lab Excellence INFLAMEX, Paris, France. [Larsson, Par G.; Flodstrom-Tullberg, Malin] Karolinska Inst, Ctr Infect Med, Dept Med, Stockholm, Sweden. [Puri, Raj K.] US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [van Rooijen, Nico] Vrije Univ Amsterdam, Med Ctr, Dept Mol Cell Biol & Immunol, Amsterdam, Netherlands. RP Lehuen, A (reprint author), Hosp Cochin St Vincent de Paul, INSERM, U1016, Paris, France. EM agnes.lehuen@inserm.fr RI DIANA, Julien/A-2873-2014; OI DIANA, Julien/0000-0001-7542-042X; Flodstrom Tullberg, Malin/0000-0003-2685-2052 FU Ministere de l'Education Nationale; INSERM; CNRS; Laboratoire d'Excellence INFLAMEX; [ANR-09-GENO-023] FX L.G. was supported by doctoral fellowships from the Ministere de l'Education Nationale. This work was supported by funds from INSERM and CNRS and grant ANR-09-GENO-023 and Laboratoire d'Excellence INFLAMEX to A. L. A. L. is the recipient of an Assistance Publique-Hopitaux de Paris-CNRS Contrat Hospitalier de Recherche Translationnelle. NR 54 TC 2 Z9 2 U1 0 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD NOV PY 2013 VL 62 IS 11 BP 3785 EP 3796 DI 10.2337/db12-0958 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 243BF UT WOS:000326290700023 PM 23894189 ER PT J AU Dibaji, SAR Banerjee, RK Soneson, JE Myers, MR AF Dibaji, Seyed Ahmad Reza Banerjee, Rupak K. Soneson, Joshua E. Myers, Matthew R. TI Nonlinear derating of high-intensity focused ultrasound beams using Gaussian modal sums SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID HEAT TRANSFER EQUATION; ATTENUATION AB A method is introduced for using measurements made in water of the nonlinear acoustic pressure field produced by a high-intensity focused ultrasound transducer to compute the acoustic pressure and temperature rise in a tissue medium. The acoustic pressure harmonics generated by nonlinear propagation are represented as a sum of modes having a Gaussian functional dependence in the radial direction. While the method is derived in the context of Gaussian beams, final results are applicable to general transducer profiles. The focal acoustic pressure is obtained by solving an evolution equation in the axial variable. The nonlinear term in the evolution equation for tissue is modeled using modal amplitudes measured in water and suitably reduced using a combination of "source derating" (experiments in water performed at a lower source acoustic pressure than in tissue) and "endpoint derating" (amplitudes reduced at the target location). Numerical experiments showed that, with proper combinations of source derating and endpoint derating, direct simulations of acoustic pressure and temperature in tissue could be reproduced by derating within 5% error. Advantages of the derating approach presented include applicability over a wide range of gains, ease of computation (a single numerical quadrature is required), and readily obtained temperature estimates from the water measurements. C1 [Dibaji, Seyed Ahmad Reza; Banerjee, Rupak K.] Univ Cincinnati, Mech Engn Program, Sch Dynam Syst, Cincinnati, OH 45221 USA. [Soneson, Joshua E.; Myers, Matthew R.] US FDA, Div Solid & Fluid Mech, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Myers, MR (reprint author), US FDA, Div Solid & Fluid Mech, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM matthew.myers@fda.hhs.gov NR 16 TC 2 Z9 2 U1 0 U2 7 PU ACOUSTICAL SOC AMER AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0001-4966 EI 1520-8524 J9 J ACOUST SOC AM JI J. Acoust. Soc. Am. PD NOV PY 2013 VL 134 IS 5 BP 3435 EP 3445 DI 10.1121/1.4824336 PN 1 PG 11 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA 247SO UT WOS:000326640800023 PM 24180754 ER PT J AU Zhi, L Chi, X Vostal, JG AF Zhi, Li Chi, Xuan Vostal, Jaroslav G. TI In Vitro and In Vivo Characterization of Ultraviolet Light C-Irradiated Human Platelets in a 2 Event Mouse Model of Transfusion SO PLOS ONE LA English DT Article ID PATHOGEN REDUCTION TECHNOLOGY; ACUTE LUNG INJURY; BLOOD COMPONENTS; AMOTOSALEN HCL; A LIGHT; SAFETY; INACTIVATION; ACTIVATION; PLASMA; RIBOFLAVIN AB UV-based pathogen reduction technologies have been developed in recent years to inactivate pathogens and contaminating leukocytes in platelet transfusion products in order to prevent transfusion-transmitted infections and alloimmunization. UVC-based technology differs from UVA or UVB-based technologies in that it uses a specific wavelength at 254 nm without the addition of any photosensitizers. Previously, it was reported that UVC irradiation induces platelet aggregation and activation. To understand if UVC-induced changes of platelet quality correlate with potential adverse events when these platelets are transfused into animals, we used a 2-event SCID mouse model in which the predisposing event was LPS treatment and the second event was infusion of UVC-irradiated platelets. We analyzed lung platelet accumulation, protein content in bronchoalveolar lavage fluid as an indication of lung injury, and macrophage inflammatory protein-2 (MIP-2) release in mice received UVC-irradiated or untreated control platelets. Our results showed UVC-irradiated platelets accumulated in lungs of the mice in a dose-dependent manner. High-doses of UVC-irradiated platelets were sequestered in the lungs to a similar level as we previously reported for UVB-irradiated platelets. Unlike UVB-platelets, UVC-platelets did not lead to lung injury or induce MIP-2 release. This could potentially be explained by our observation that although UVC treatment activated platelet surface aIIb beta 3, it failed to activate platelet cells. It also suggests lung platelet accumulation and subsequent lung damage are due to different and separate mechanisms which require further investigation. C1 [Zhi, Li; Chi, Xuan; Vostal, Jaroslav G.] US FDA, Lab Cellular Hematol, Div Hematol, OBRR,Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Vostal, JG (reprint author), US FDA, Lab Cellular Hematol, Div Hematol, OBRR,Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM jaroslav.vostal@fda.hhs.gov FU US FDA FX This work was supported by Critical Path Funding from the US FDA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 3 Z9 3 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 1 PY 2013 VL 8 IS 11 AR e79869 DI 10.1371/journal.pone.0079869 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 245XZ UT WOS:000326499300094 PM 24224014 ER PT J AU Gonzalez, JM Johnson, FR Fairchild, A Irony, T Ho, M AF Gonzalez, J. M. Johnson, F. R. Fairchild, A. Irony, T. Ho, M. TI PATIENTS AT THE CENTER OF REGULATORY DECISIONS: USING STATED-PREFERENCE DATA TO HELP REGULATORS ANSWER DIFFICULT QUESTIONS SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Gonzalez, J. M.; Johnson, F. R.; Fairchild, A.] RTI Hlth Solut, Res Triangle Pk, NC USA. [Irony, T.; Ho, M.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD NOV PY 2013 VL 16 IS 7 BP A387 EP A387 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 242MY UT WOS:000326247600356 ER PT J AU Naegeli, AN Nikai, E Burke, LB Coons, SJ Strand, V Simon, LS Piault, E Hayes, RP AF Naegeli, A. N. Nikai, E. Burke, L. B. Coons, S. J. Strand, V Simon, L. S. Piault, E. Hayes, R. P. TI EXPANDING THE MEASUREMENT OF TREATMENT BENEFIT IN RHEUMATOID ARTHRITIS: THE ROLE OF THE PATIENT-REPORTED OUTCOME CONSORTIUM'S RA WORKING GROUP SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Naegeli, A. N.; Hayes, R. P.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Nikai, E.] UCB Pharma SA, Brussels, Belgium. [Burke, L. B.] CDER FDA, Silver Spring, MD USA. [Coons, S. J.] Crit Path Inst, Tucson, AZ USA. [Strand, V] Stanford Univ, Palo Alto, CA 94304 USA. [Simon, L. S.] SDG LLC, Cambridge, MA USA. [Piault, E.] Genentech Inc, San Francisco, CA 94080 USA. NR 0 TC 0 Z9 0 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD NOV PY 2013 VL 16 IS 7 BP A569 EP A569 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 242MY UT WOS:000326247602129 ER PT J AU Hamasaki-Katagiri, N Salari, R Wu, A Ql, Y Schiller, T Filiberto, AC Schisterman, EF Komar, AA Przytycka, TM Kimchi-Sarfaty, C AF Hamasaki-Katagiri, Nobuko Salari, Raheleh Wu, Andrew Ql, Yini Schiller, Tal Filiberto, Amanda C. Schisterman, Enrique F. Komar, Anton A. Przytycka, Teresa M. Kimchi-Sarfaty, Chava TI A Gene-Specific Method for Predicting Hemophilia-Causing Point Mutations SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISM; COAGULATION-FACTOR-VIII; MISSENSE MUTATIONS; PROTEIN; DISEASE; RNA; PHOSPHORYLATION; IDENTIFICATION; VARIANTS; RESOURCE AB A fundamental goal of medical genetics is the accurate prediction of genotype phenotype correlations. As an approach to develop more accurate in silico tools for prediction of disease-causing mutations of structural proteins, we present a gene- and disease-specific prediction tool based on a large systematic analysis of missense mutations from hemophilia A (HA) patients. Our HA-specific prediction tool, HApredictor, showed disease prediction accuracy comparable to other publicly available prediction software. In contrast to those methods, its performance is not limited to non-synonymous mutations. Given the role of synonymous mutations in disease and drug codon optimization, we propose that utilizing a gene- and disease-specific method can be highly useful to make functional predictions possible even for synonymous mutations. Incorporating computational metrics at both nucleotide and amino acid levels along with multiple protein sequence/structure alignment significantly improved the predictive performance of our tool. HApredictor is freely available for download at http://www.ncbi.nlm.nih.gov/CBBresearch/Przytycka/HA_Predict/index.htm. Published by Elsevier Ltd. C1 [Hamasaki-Katagiri, Nobuko; Wu, Andrew; Ql, Yini; Kimchi-Sarfaty, Chava] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Salari, Raheleh] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Filiberto, Amanda C.; Schisterman, Enrique F.] NICHHD, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. [Komar, Anton A.] Cleveland State Univ, Dept Biol, Ctr Gene Regulat Hlth & Dis, Cleveland, OH 44115 USA. [Przytycka, Teresa M.] NCI, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Kimchi-Sarfaty, C (reprint author), 29 Lincoln Dr, Bethesda, MD 20892 USA. EM Chava.kimchi-sarfaty@fda.hhs.gov FU National Institutes of Health Intramural Research Funding (National Library of Medicine); Natural Sciences and Engineering Research Council Postdoctoral Fellowships FX We would like to thank Ms. Erin Needlman, Ms. Natasha Nelson, Mr. Max Katz, Mr. Jeong Lee, Mr. Stephen Gross, and Mr. Matt landoli for helping with construction of datasets. We are grateful to Ms. Sandra C. Tseng, Dr. Ryan Hunt, Dr. Zuben Sauna (Center for Biologics Evaluation and Research, Food and Drug Administration), Dr. Deanna Church, and Mr. John Garner (NCBI, National Institutes of Health) for insightful commentary. We thank Dr. Geoffrey Kemball-Cook (University College London) for maintaining HADB, data from which is now included in CHAMP. The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any agency determination or policy. T.M.P. is supported by National Institutes of Health Intramural Research Funding (National Library of Medicine). R.S. was funded partially by Natural Sciences and Engineering Research Council Postdoctoral Fellowships. NR 33 TC 9 Z9 9 U1 2 U2 13 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD NOV 1 PY 2013 VL 425 IS 21 BP 4023 EP 4033 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 242QM UT WOS:000326257100011 PM 23920358 ER PT J AU Nagle, SM Sundar, G Schafer, ME Harris, GR Vaezy, S Gessert, JM Howard, SM Moore, MK Eaton, RM AF Nagle, Samuel M. Sundar, Guru Schafer, Mark E. Harris, Gerald R. Vaezy, Shahram Gessert, James M. Howard, Samuel M. Moore, Mary K. Eaton, Richard M. TI Challenges and Regulatory Considerations in the Acoustic Measurement of High-Frequency (> 20 MHz) Ultrasound SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Review DE acoustic measurement uncertainty; Food and Drug Administration track 3 clearance; high-frequency ultrasound; hydrophone measurement errors; premarket notification ID PLANAR SCANNING TECHNIQUE; DIAGNOSTIC ULTRASOUND; PHASE CALIBRATION; HYDROPHONE; FIELDS; BACKSCATTER; EXPOSIMETRY; ATTENUATION; AMPLITUDE; PRESSURE AB This article examines the challenges associated with making acoustic output measurements at high ultrasound frequencies (>20 MHz) in the context of regulatory considerations contained in the US Food and Drug Administration industry guidance document for diagnostic ultrasound devices. Error sources in the acoustic measurement, including hydrophone calibration and spatial averaging, nonlinear distortion, and mechanical alignment, are evaluated, and the limitations of currently available acoustic measurement instruments are discussed. An uncertainty analysis of acoustic intensity and power measurements is presented, and an example uncertainty calculation is done on a hypothetical 30-MHz high-frequency ultrasound system. This analysis concludes that the estimated measurement uncertainty of the acoustic intensity is +73%/-86%, and the uncertainty in the mechanical index is +37%/-43%. These values exceed the respective levels in the Food and Drug Administration guidance document of 30% and 15%, respectively, which are more representative of the measurement uncertainty associated with characterizing lower-frequency ultrasound systems. Recommendations made for minimizing the measurement uncertainty include implementing a mechanical positioning system that has sufficient repeatability and precision, reconstructing the time-pressure waveform via deconvolution using the hydrophone frequency response, and correcting for hydrophone spatial averaging. C1 [Nagle, Samuel M.; Moore, Mary K.] SonoSite Inc, Bothell, WA 98021 USA. [Sundar, Guru] Visual Son Inc, Toronto, ON, Canada. [Schafer, Mark E.] Son Tech Inc, Ambler, PA USA. [Harris, Gerald R.; Vaezy, Shahram] US FDA, Silver Spring, MD USA. [Gessert, James M.] Acertara Acoust Labs, Longmont, CO USA. [Howard, Samuel M.] Onda Corp, Sunnyvale, CA USA. [Eaton, Richard M.] Med Imaging & Technol Alliance, Arlington, VA USA. RP Nagle, SM (reprint author), SonoSite Inc, 21919 30th Dr SE, Bothell, WA 98021 USA. EM sam.nagle@sonosite.com NR 47 TC 2 Z9 2 U1 0 U2 10 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 EI 1550-9613 J9 J ULTRAS MED JI J. Ultrasound Med. PD NOV PY 2013 VL 32 IS 11 BP 1897 EP 1911 DI 10.7863/ultra.32.11.1897 PG 15 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 244WU UT WOS:000326421700002 PM 24154893 ER PT J AU Cibull, SL Harris, GR Nell, DM AF Cibull, Sarah L. Harris, Gerald R. Nell, Diane M. TI Trends in Diagnostic Ultrasound Acoustic Output From Data Reported to the US Food and Drug Administration for Device Indications That Include Fetal Applications SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE acoustic output; bioeffects; fetal; output display standard; safety; thermal index ID DISPLAY STANDARD; BONE INTERFACE; PREGNANCY; MEDICINE; EXPOSURE; INDEXES; SAFETY AB Objectives-A survey was conducted of acoustic output data received by the US Food and Drug Administration for diagnostic ultrasound devices whose indications for use include fetal applications to assess trends in maximum available acoustic output over time. Methods-Data were collected from 124 regulatory submissions received between 1984 and 2010. Data collection excluded transducers not indicated for diagnostic fetal imaging. The output parameters of ultrasonic power, mean center frequency, and bone thermal index (TIB) were extracted or computed from the submissions for 3 periods: 1984-1989, 1992-1997, and 2005-2010. The data were stratified according to the following imaging modes: M-mode, B/M-mode, pulsed wave Doppler, color flow Doppler, and continuous wave Doppler. Results-Ultrasonic power and maximum TB values have increased roughly an order of magnitude from pre-1991 to post-1991 periods; the center frequency has decreased somewhat (4.2 to 3.4 MHz). The percentage of Doppler-mode transducers has increased substantially over time, with the majority of the diagnostic fetal imaging transducers currently designed to operate in Doppler modes; this increase is particularly important, since Doppler modes generate much higher TB levels than B/M-modes. Color flow Doppler ultrasound currently operates at the highest mean ultrasonic power level (with a 14-fold increase over time). Conclusions-The observed trends in increased acoustic output for both Doppler and non-Doppler modes underscore the widely recognized importance of adherence to the ALARA (as low as reasonably achievable) principle and prudent use in fetal ultrasound imaging. C1 [Cibull, Sarah L.] US Marine Corps, Quantico, VA USA. [Harris, Gerald R.; Nell, Diane M.] US FDA, Silver Spring, MD 20993 USA. RP Harris, GR (reprint author), US FDA, 10903 New Hampshire Ave,Room WO62-2104, Silver Spring, MD 20993 USA. EM gerald.harris@fda.hhs.gov NR 40 TC 1 Z9 1 U1 0 U2 5 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 EI 1550-9613 J9 J ULTRAS MED JI J. Ultrasound Med. PD NOV PY 2013 VL 32 IS 11 BP 1921 EP 1932 DI 10.7863/ultra.32.11.1921 PG 12 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 244WU UT WOS:000326421700004 PM 24154895 ER PT J AU Hansen, C Joski, P Freiman, H Andrade, S Toh, S Dublin, S Cheetham, C Cooper, W Pawloski, P Li, DK Beaton, S Kaplan, S Scott, P Hammad, T Davis, R AF Hansen, Craig Joski, Peter Freiman, Heather Andrade, Susan Toh, Sengwee Dublin, Sascha Cheetham, Craig Cooper, William Pawloski, Pamala Li, De-Kun Beaton, Sarah Kaplan, Sigal Scott, Pamela Hammad, Tarek Davis, Robert TI Medication Exposure in Pregnancy Risk Evaluation Program: The Prevalence of Asthma Medication Use During Pregnancy SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Asthma; Pregnancy; Medication; Prevalence ID MATERNAL ASTHMA; INHIBITORS; ALLERGY; WOMEN; DATE AB Asthma is one of the most common chronic diseases in women of reproductive age, occurring in up to 8 % of pregnancies. The objective of this study is to assess the prevalence of asthma medication use during pregnancy in a large diverse cohort. We identified women aged 15-45 years who delivered a live born infant between 2001 and 2007 across 11 U.S. health plans within the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP). Using health plans' administrative and claims data, and birth certificate data, we identified deliveries for which women filled asthma medications from 90 days before pregnancy through delivery. Prevalence (%) was calculated for asthma diagnosis and medication dispensing. There were 586,276 infants from 575,632 eligible deliveries in the MEPREP cohort. Asthma prevalence among mothers was 6.7 %, increasing from 5.5 % in 2001 to 7.8 % in 2007. A total of 9.7 % (n = 55,914) of women were dispensed asthma medications during pregnancy. The overall prevalence of maintenance-only medication, rescue-only medication, and combined maintenance and rescue medication was 0.6, 6.7, and 2.4 % respectively. The prevalence of maintenance-only use doubled during the study period from 0.4 to 0.8 %, while rescue-only use decreased from 7.4 to 5.8 %. In this large population-based pregnancy cohort, the prevalence of asthma diagnoses increased over time. The dispensing of maintenance-only medication increased over time, while rescue-only medication dispensing decreased over time. C1 [Hansen, Craig; Joski, Peter; Freiman, Heather; Davis, Robert] Kaiser Permanente Georgia, Ctr Hlth Res Southeast, Atlanta, GA USA. [Andrade, Susan] Univ Massachusetts, Sch Med, Meyers Primary Care Inst, Worcester, MA USA. [Toh, Sengwee] Harvard Univ, Sch Med, Dept Populat Med, Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Dublin, Sascha] Grp Hlth Res Inst, Seattle, WA USA. [Cheetham, Craig] Kaiser Permanente, Pharm Analyt Serv, Downey, CA USA. [Cooper, William] Vanderbilt Univ, Sch Med, Dept Pediat & Prevent Med, Nashville, TN 37212 USA. [Pawloski, Pamala] HealthPartners Res Fdn, Bloomington, MN USA. [Li, De-Kun] Kaiser Permanente, Div Res, Oakland, CA USA. [Beaton, Sarah] Lovelace Res, Albuquerque, NM USA. [Kaplan, Sigal; Scott, Pamela; Hammad, Tarek] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Hansen, C (reprint author), Kaiser Permanente Georgia, Ctr Hlth Res Southeast, Atlanta, GA USA. EM craig.a.hansen@kp.org RI Hansen, Craig /C-7543-2014; Toh, Sengwee/D-7567-2017 OI Hansen, Craig /0000-0002-5227-0155; Toh, Sengwee/0000-0002-5160-0810 FU NIA NIH HHS [K23 AG028954, K23AG028954]; PHS HHS [HHSF223200510008C, HHSF223200510012C, HHSF223200510009C] NR 20 TC 11 Z9 11 U1 0 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD NOV PY 2013 VL 17 IS 9 BP 1611 EP 1621 DI 10.1007/s10995-012-1173-x PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 243EJ UT WOS:000326299300011 PM 23108737 ER PT J AU desVignes-Kendrick, M Reynolds, K Lee, T Gaul, L Klein, K Irvin, K Wellman, A Hardin, A Williams, I Wiegand, R Harris, J Parise, M Abanyie, F Harvey, RR AF desVignes-Kendrick, M. Reynolds, Kaye Lee, Teresa Gaul, Linda Klein, Kate Irvin, Kari Wellman, Allison Hardin, Angela Williams, Ian Wiegand, Ryan Harris, Julie Parise, Monica Abanyie, Francisca Harvey, R. Reid TI Outbreaks of Cyclosporiasis - United States, June-August 2013 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article C1 [Irvin, Kari; Wellman, Allison; Hardin, Angela] US FDA, Coordinated Outbreak Response & Evaluat Network, Off Foods & Vet Med, Rockville, MD 20857 USA. [Abanyie, Francisca; Harvey, R. Reid] CDC, Atlanta, GA 30333 USA. RP Harvey, RR (reprint author), CDC, Atlanta, GA 30333 USA. EM rharvey@cdc.gov NR 2 TC 0 Z9 0 U1 0 U2 4 PU CENTER DISEASE CONTROL & PREVENTION PI ATLANTA PA MAILSTOP E-90, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD NOV 1 PY 2013 VL 62 IS 43 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 245GU UT WOS:000326451500004 ER PT J AU Bandarra, S Fernandes, AS Magro, I Guerreiro, PS Pingarilho, M Churchwell, MI Gil, OM Batinic-Haberle, I Goncalves, S Rueff, J Miranda, JP Marques, MM Beland, FA Castro, M Gaspar, JF Oliveira, NG AF Bandarra, Susana Fernandes, Ana S. Magro, Ines Guerreiro, Patricia S. Pingarilho, Marta Churchwell, Mona I. Gil, Octavia Monteiro Batinic-Haberle, Ines Goncalves, Sandrina Rueff, Jose Miranda, Joana P. Matilde Marques, M. Beland, Frederick A. Castro, Matilde Gaspar, Jorge F. Oliveira, Nuno G. TI Mechanistic insights into the cytotoxicity and genotoxicity induced by glycidamide in human mammary cells SO MUTAGENESIS LA English DT Article ID DIETARY ACRYLAMIDE INTAKE; DNA ADDUCT FORMATION; PROTECTIVE ROLE; BREAST-CANCER; HEMOGLOBIN ADDUCTS; MAILLARD REACTION; FISCHER-344 RATS; OXIDATIVE INJURY; EPITHELIAL-CELLS; MAMMALIAN-CELLS AB Acrylamide (AA) is a well-known industrial chemical classified as a probable human carcinogen. Benign and malignant tumours at different sites, including the mammary gland, have been reported in rodents exposed to AA. This xenobiotic is also formed in many carbohydrate-rich foods prepared at high temperatures. For this reason, AA is an issue of concern in terms of human cancer risk. The epoxide glycidamide (GA) is thought to be the ultimate genotoxic AA metabolite. Despite extensive experimental and epidemiological data focused on AA-induced breast cancer, there is still lack of information on the deleterious effects induced by GA in mammary cells. The work reported here addresses the characterisation and modulation of cytotoxicity, generation of reactive oxygen species, formation of micronuclei (MN) and quantification of specific GADNA adducts in human MCF10A epithelial cells exposed to GA. The results show that GA significantly induces MN, impairs cell proliferation kinetics and decreases cell viability at high concentrations by mechanisms not involving oxidative stress. KU55933, an inhibitor of ataxia telangiectasia mutated kinase, enhanced the cytotoxicity of GA (P < 0.05), supporting a role of this enzyme in regulating the repair of GA-induced DNA lesions. Moreover, even at low GA levels, N7-GA-Gua adducts were generated in a linear doseresponse manner in MCF10A cells. These results confirm that human mammary cells are susceptible to GA toxicity and reinforce the need for additional studies to clarify the potential correlation between dietary AA exposure and breast cancer risk in human populations. C1 [Bandarra, Susana; Fernandes, Ana S.; Magro, Ines; Guerreiro, Patricia S.; Goncalves, Sandrina; Miranda, Joana P.; Castro, Matilde; Oliveira, Nuno G.] Univ Lisbon, Fac Pharm, Res Inst Med & Pharmaceut Sci iMed UL, P-1649003 Lisbon, Portugal. [Bandarra, Susana] ISCSEM, Ctr Invest Interdisciplinar Egas Moniz CiiEM, P-2829511 Monte De Caparica, Portugal. [Fernandes, Ana S.] Univ Lusofona Res Ctr Biosci & Hlth Technol, CBIOS, P-1749024 Lisbon, Portugal. [Pingarilho, Marta; Rueff, Jose; Gaspar, Jorge F.] New Univ Lisbon CIGMH, Fac Med Sci, Dept Genet, P-1349008 Lisbon, Portugal. [Churchwell, Mona I.; Beland, Frederick A.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Gil, Octavia Monteiro] Univ Lisbon, Inst Super Tecn, IST ITN, P-2695066 Bobadela Lrs, Portugal. [Batinic-Haberle, Ines] Duke Univ, Sch Med, Dept Radiat Oncol, Durham, NC 27710 USA. [Matilde Marques, M.] Univ Lisbon, Inst Super Tecn, Ctr Quim Estrutural, P-1049001 Lisbon, Portugal. RP Oliveira, NG (reprint author), Univ Lisbon, Fac Pharm, Res Inst Med & Pharmaceut Sci iMed UL, Av Prof Gama Pinto, P-1649003 Lisbon, Portugal. EM ngoliveira@ff.ul.pt RI Gaspar, Jorge/M-9078-2013; Marques, M. Matilde/E-2535-2012; iMed.ULisboa, CBT /B-4215-2014; PTMS, RNEM/C-1589-2014; Faculdade de Ciencias Medicas, Nova Medical School/K-6209-2013; iMed.ULisboa, iMed.ULisboa/C-6292-2014; Castro, Matilde/A-9468-2014; Oliveira, Nuno/A-7407-2014; Fernandes, Ana/H-4789-2013; Monteiro Gil, Octavia/K-2518-2013; Miranda, Joana/J-3698-2013 OI Bandarra, Susana/0000-0001-9226-6997; Rueff, Jose/0000-0002-0969-610X; Rueff, Jose/0000-0002-8456-7295; Gaspar, Jorge/0000-0002-2102-4920; Marques, M. Matilde/0000-0002-7526-4962; Castro, Matilde/0000-0002-6314-8251; Oliveira, Nuno/0000-0001-6114-6829; Fernandes, Ana/0000-0001-6350-0641; Monteiro Gil, Octavia/0000-0002-0366-8124; Miranda, Joana/0000-0002-7804-4068 FU Fundacao para a Ciencia e a Tecnologia (FCT), Portugal [PTDC/SAU-OSM/105572/2008, PEst-OE/SAU/UI4013/2011, PEst-OE/QUI/UI0100/2013, SFRH/BD/70293/2010, SFRH/BD/22612/2005] FX This work was supported by Fundacao para a Ciencia e a Tecnologia (FCT), Portugal (Projects PTDC/SAU-OSM/105572/2008, PEst-OE/SAU/UI4013/2011 and PEst-OE/QUI/UI0100/2013, Programme Ciencia 2008, and PhD grants SFRH/BD/70293/2010 and SFRH/BD/22612/2005). NR 56 TC 4 Z9 4 U1 1 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0267-8357 EI 1464-3804 J9 MUTAGENESIS JI Mutagenesis PD NOV PY 2013 VL 28 IS 6 BP 721 EP 729 DI 10.1093/mutage/get052 PG 9 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 244IA UT WOS:000326380000012 PM 24150595 ER PT J AU Yu, L Takeda, K Markoff, L AF Yu, Li Takeda, Kazuyo Markoff, Lewis TI Protein-protein interactions among West Nile non-structural proteins and transmembrane complex formation in mammalian cells SO VIROLOGY LA English DT Article DE NS protein interactions; Transmembrane complex; Flavivirus replication complex ID DEPENDENT RNA-POLYMERASE; DENGUE-VIRUS TYPE-2; HEPATITIS-C VIRUS; FLAVIVIRUS KUNJIN; FLUORESCENCE COMPLEMENTATION; ENDOPLASMIC-RETICULUM; REPLICATION COMPLEX; SECONDARY STRUCTURE; LIVING CELLS; POLYCLONAL ANTISERA AB To study the membrane orientation of flavivirus non-structural proteins (NSPs) in the replication complex, the seven major West Nile (WN) NSPs were separately expressed in monkey cells, and their subcellular localization was investigated by imaging-based techniques. First, we observed by confocal microscopy that four small transmembrane proteins (TP) (NS2A, NS2B, NS4A, and NS4B) were located to the endoplasmic reticulum (ER), whereas the largest NSPs, NS1, NS3, and NS5 were not. We then analyzed the colocalization and the association of WN NSPs using the methods of confocal microscopy, fluorescence resonance energy transfer (FRET), and biologic fluorescence complementation (BiFC). Through these combined imaging techniques, protein-protein interactions (PPI) among WNNSPs were detected. Our data demonstrate that there are interactions between NS2A and NS4A, and interactions of NS2B with three other TPs (NS2A, NS4A, and NS4B) as well as the expected interaction with NS3. PPI between NS2A and NS4B or between NS4A and NS4B were not detected. By the criteria of these techniques, NS5 interacted only with NS3, and NS1 was not shown to be in close proximity with other NSPs. In addition, homo-oligomerization of some NSPs was observed and three-way interactions between NS2A, NS4A, and NA4B with NS2B-NS3 were also observed, respectively. Our results suggest that the four TPs are required for formation of transmembrane complex. NS2B protein seems to play a key role in bringing the TPs together on the ER membrane and in bridging the TPs with non-membrane-associated proteins (NS3 and NS5). Published by Elsevier Inc. C1 [Yu, Li; Markoff, Lewis] FDA, CBER, Microscopy & Imaging Core Facil, Off Vaccines Res & Review,Div Viral Prod,Lab Vect, Bethesda, MD USA. [Takeda, Kazuyo] FDA, CBER, Microscopy & Imaging Core Facil, Bethesda, MD USA. RP Yu, L (reprint author), Bg 29A,Room 1B18,NIH Campus,8800 Rockville Pike, Bethesda, MD 20892 USA. EM li.yu@fda.hhs.gov NR 78 TC 17 Z9 17 U1 3 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD NOV PY 2013 VL 446 IS 1-2 BP 365 EP 377 DI 10.1016/j.virol.2013.08.006 PG 13 WC Virology SC Virology GA 236ZX UT WOS:000325839100041 PM 24074601 ER PT J AU Gavrielides, MA Li, Q Zeng, RP Myers, KJ Sahiner, B Petrick, N AF Gavrielides, Marios A. Li, Qin Zeng, Rongping Myers, Kyle J. Sahiner, Berkman Petrick, Nicholas TI Minimum Detectable Change in Lung Nodule Volume in a Phantom CT Study SO ACADEMIC RADIOLOGY LA English DT Article DE Volumetric computed tomography; lung nodule; phantom study; treatment response; nodule; detectable change ID RECIST NO LONGER; PULMONARY NODULES; RESPONSE EVALUATION; TUMOR MEASUREMENTS; SHARPEST TOOL; SOLID TUMORS; TRIALS; CANCER; SIZE; VARIABILITY AB Rationale and Objectives: The change in volume of lung nodules is being examined as a measure of response to treatment. The aim of this study was to determine the minimum detectable change in nodule volume with the use of computed tomography. Materials and Methods: Four different layouts of synthetic nodules with different shapes but with the same size (5, 8, 9, or 10 mm) for each layout were placed within an anthropomorphic phantom and scanned with a 16-detector-row computed tomography scanner using multiple imaging parameters. Nodule volume estimates were determined using a previously developed matched-filter estimator. Analysis of volume change was then conducted as a detection problem. For each nodule size, the pooled distribution of volume estimates was shifted by a percentage c to simulate a changing nodule, while accounting for standard deviation. The value of c resulting in a prespecified area under the receiver operating characteristic curve (AUC) was deemed the minimum detectable change for that AUC value. Results: Both nodule size at baseline and choice of slice collimation protocol had an effect on the value of minimum detectable growth. For AUC = 0.95, the minimum detectable nodule growth in volume when using the thin-slice collimation protocol (16 x 0.75 mm) was 17%, 19%, and 15% for nodule sizes of 5, 8, and 9 mm, respectively. Conclusions: Our results indicate that an approximate bound for detectable nodule growth in subcentimeter nodules may be relatively small, on the order of 20% or less in volume for a thin-slice CT acquisition protocol. C1 [Gavrielides, Marios A.; Li, Qin; Zeng, Rongping; Myers, Kyle J.; Sahiner, Berkman; Petrick, Nicholas] US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Gavrielides, MA (reprint author), US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,Bldg 62,Rm 4114, Silver Spring, MD 20993 USA. EM marios.gavrielides@fda.hhs.gov FU FDA Critical Path Initiative FX This work was supported in part by funding from the FDA Critical Path Initiative. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services. NR 24 TC 7 Z9 7 U1 0 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD NOV PY 2013 VL 20 IS 11 BP 1364 EP 1370 DI 10.1016/j.acra.2013.08.019 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 241AW UT WOS:000326139800006 PM 24119348 ER PT J AU Virnik, K Hockenbury, M Ni, Y Beren, J Kulkarni, V Rosati, M Alicea, C Pavlakis, GN Felber, BK Berkower, I AF Virnik, K. Hockenbury, M. Ni, Y. Beren, J. Kulkarni, V. Rosati, M. Alicea, C. Pavlakis, G. N. Felber, B. K. Berkower, I. TI HIV and SIV Vaccine Antigens Expressed by Live Attenuated Rubella Vectors Elicit Durable Immunity in Rhesus Macaques SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Virnik, K.; Hockenbury, M.; Ni, Y.; Beren, J.; Berkower, I.] FDA, Bethesda, MD USA. [Kulkarni, V.; Rosati, M.; Alicea, C.; Pavlakis, G. N.; Felber, B. K.] NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A36 EP A36 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500082 ER PT J AU Weiss, C Vassell, R Dey, A He, Y Sun, Y Srivastava, I Barnett, S AF Weiss, C. Vassell, R. Dey, A. He, Y. Sun, Y. Srivastava, I. Barnett, S. TI Immunogenicity of Oligomeric gp41 Immunogens Exposing the MPER of HIV-1 Envelope Glycoprotein SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Weiss, C.; Vassell, R.; He, Y.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Dey, A.; Sun, Y.; Srivastava, I.; Barnett, S.] Novartis Vaccines & Diagnost, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A152 EP A152 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500398 ER PT J AU Zinszner, H Voronin, Y Allen, M Busch, M Fruth, U Golding, H Khurana, S Mulenga, J Peel, S Schito, M Fast, P AF Zinszner, H. Voronin, Y. Allen, M. Busch, M. Fruth, U. Golding, H. Khurana, S. Mulenga, J. Peel, S. Schito, M. Fast, P. TI Vaccine-Induced Antibodies: Impact for HIV Diagnosis, Clinical Trial Participants and Public Health SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Zinszner, H.; Voronin, Y.] Global HIV Vaccine Enterprise, New York, NY USA. [Allen, M.] NIAID, NIH, Bethesda, MD 20892 USA. [Busch, M.] Blood Syst Res Inst, San Francisco, CA USA. [Fruth, U.] WHO, CH-1211 Geneva, Switzerland. [Golding, H.; Khurana, S.] US FDA, Bethesda, MD 20014 USA. [Mulenga, J.] Natl Blood Transfus Serv, Lusaka, Zambia. [Peel, S.; Schito, M.] US MHRP, Bethesda, MD USA. [Fast, P.] IAVI, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A182 EP A182 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500476 ER PT J AU Hoelzer, K Pouillot, R AF Hoelzer, Karin Pouillot, Regis TI Practical Considerations for the Interpretation of Microbial Testing Results Based on Small Numbers of Samples SO FOODBORNE PATHOGENS AND DISEASE LA English DT Review ID MICROBIOLOGICAL QUALITY; LISTERIA-MONOCYTOGENES; FRESH PRODUCE; CONFIDENCE; SPP. AB While adequate, statistically designed sampling plans should be used whenever feasible, inference about the presence of pathogens in food occasionally has to be made based on smaller numbers of samples. To help the interpretation of such results, we reviewed the impact of small sample sizes on pathogen detection and prevalence estimation. In particular, we evaluated four situations commonly encountered in practice. The first two examples evaluate the combined impact of sample size and pathogen prevalence (i.e., fraction of contaminated food items in a given lot) on pathogen detection and prevalence estimation. The latter two examples extend the previous example to consider the impact of pathogen concentration and imperfect test sensitivity. The provided examples highlight the difficulties of making inference based on small numbers of samples, and emphasize the importance of using appropriate statistical sampling designs whenever possible. C1 [Hoelzer, Karin; Pouillot, Regis] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Hoelzer, K (reprint author), US FDA, Ctr Food Safety & Appl Nutr HFS 005, 5100 Paint Branch Pkwy,Room 2A-031, College Pk, MD 20740 USA. EM Karin.Hoelzer@fda.hhs.gov RI Pouillot, Regis/E-8103-2010 OI Pouillot, Regis/0000-0002-6107-5212 FU U.S. Food and Drug Administration FX The authors acknowledge Jerome Schneidman for his insights and advice. This work was supported by the U.S. Food and Drug Administration and, in part, by appointments to the Research Participation Program at the Center for Food Safety and Applied Nutrition administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 30 TC 5 Z9 5 U1 0 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1535-3141 EI 1556-7125 J9 FOODBORNE PATHOG DIS JI Foodborne Pathog. Dis. PD NOV 1 PY 2013 VL 10 IS 11 BP 907 EP 915 DI 10.1089/fpd.2013.1531 PG 9 WC Food Science & Technology SC Food Science & Technology GA 240QG UT WOS:000326111400001 PM 23869961 ER PT J AU Akhtar, A AF Akhtar, Aysha TI The need to include animal protection in public health policies SO JOURNAL OF PUBLIC HEALTH POLICY LA English DT Article DE animals; public health; animal treatment; emerging infectious diseases; medical research; domestic violence ID PATHOGENIC AVIAN INFLUENZA; INFECTIOUS-DISEASES; WILDLIFE TRADE; EBOLA-VIRUS; BACKYARD POULTRY; RISK-FACTORS; H5N1; MODELS; EMERGENCE; SWINE AB Many critical public health issues require non-traditional approaches. Although many novel strategies are used, one approach not widely applied involves improving the treatment of animals. Emerging infectious diseases are pressing public health challenges that could benefit from improving the treatment of animals. Other human health issues, that overlap with animal treatment issues, and that warrant further exploration, are medical research and domestic violence. The diverse nature of these health issues and their connection with animal treatment suggest that there may be other similar intersections. Public health would benefit by including the treatment of animals as a topic of study and policy development. C1 [Akhtar, Aysha] Oxford Ctr Anim Eth, Oxford OX4 1EG, England. [Akhtar, Aysha] FDA, Off Counterterrorism & Emerging Threats, Silver Spring, MD 20993 USA. RP Akhtar, A (reprint author), Oxford Ctr Anim Eth, 91 Iffley Rd, Oxford OX4 1EG, England. EM aysha_akhtar@hotmail.com NR 67 TC 5 Z9 5 U1 0 U2 36 PU PALGRAVE MACMILLAN LTD PI BASINGSTOKE PA BRUNEL RD BLDG, HOUNDMILLS, BASINGSTOKE RG21 6XS, HANTS, ENGLAND SN 0197-5897 EI 1745-655X J9 J PUBLIC HEALTH POL JI J. Public Health Policy PD NOV PY 2013 VL 34 IS 4 BP 549 EP 559 DI 10.1057/jphp.2013.29 PG 11 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 236QP UT WOS:000325814500007 PM 23803712 ER PT J AU Chou, AY Kennett, NJ Nix, EB Schmerk, CL Nano, FE Elkins, KL AF Chou, Alicia Y. Kennett, Nikki J. Nix, Eli B. Schmerk, Crystal L. Nano, Francis E. Elkins, Karen L. TI Generation of protection against Francisella novicida in mice depends on the pathogenicity protein PdpA, but not PdpC or PdpD SO MICROBES AND INFECTION LA English DT Article DE Francisella; Pathogenicity island; T lymphocytes; Protective immunity; Mice ID TULARENSIS SUBSP NOVICIDA; LIVE VACCINE STRAIN; VI SECRETION; T-CELLS; IN-VIVO; INTRACELLULAR GROWTH; PULMONARY CHALLENGE; TULAREMIA VACCINES; GAMMA-INTERFERON; UNIQUE PHENOTYPE AB Previous results suggest that mutations in most genes in the Francisella pathogenicity island (FPI) attenuate the bacterium. Using a mouse model, here we determined the impact of mutations in pdpA, pdpC, and pdpD in Francisella novicida on in vitro replication in macrophages, and in vivo immunogenicity. In contrast to most FPI genes, deletion of pdpC (Fn Delta pdpC) and pdpD (Fn Delta pdpD) from E novicida did not impact growth in mouse bone-marrow derived macrophages. Nonetheless, both Fn Delta pdpC and Fn Delta pdpD were highly attenuated when administered intradermally. Infected mice produced relatively normal anti-F. novicida serum antibodies. Further, splenocytes from infected mice controlled intramacrophage Francisella replication, indicating T cell priming, and mice immunized by infection with Fn Delta pdpC or Fn Delta pdpD survived secondary lethal parenteral challenge with either E novicida or Francisella tularensis LVS. In contrast, deletion of pdpA (Fn Delta pdpA) ablated growth in macrophages in vitro. Fn Delta pdpA disseminated and replicated poorly in infected mice, accompanied by development of some anti-F. novicida serum antibodies. However, primed Th1 cells were not detected, and vaccinated mice did not survive even low dose challenge with either E novicida or LVS. Taken together, these results suggest that successful priming of Th1 cells, and protection against lethal challenge, depends on expression of PdpA. Published by Elsevier Masson SAS on behalf of Institut Pasteur. C1 [Chou, Alicia Y.; Kennett, Nikki J.; Elkins, Karen L.] US FDA, Lab Mycobacterial Dis & Cellular Immunol, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Nix, Eli B.; Schmerk, Crystal L.; Nano, Francis E.] Univ Victoria, Dept Biochem & Microbiol, Victoria, BC, Canada. RP Elkins, KL (reprint author), US FDA, Lab Mycobacterial Dis & Cellular Immunol, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, 1401 Rockville Pike,HFM-431, Rockville, MD 20852 USA. EM karen.elkins@fda.hhs.gov FU National Institute of Allergy and Infectious Disease [Y1-AI-6153-01, 224-06-1322]; NIH, Bethesda, MD; Canadian Institutes of Health Research [MOP 89812] FX We are grateful to our CBER colleagues, Dr. Siobhan Cowley and Sherry Kurtz, for thoughtful and careful review of the manuscript. This work was supported in part by an Interagency Agreement with the National Institute of Allergy and Infectious Disease (#Y1-AI-6153-01/#224-06-1322), NIH, Bethesda, MD, and by a grant from the Canadian Institutes of Health Research (MOP 89812). NR 57 TC 4 Z9 4 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 EI 1769-714X J9 MICROBES INFECT JI Microbes Infect. PD NOV PY 2013 VL 15 IS 12 BP 816 EP 827 DI 10.1016/j.micinf.2013.07.005 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 237YL UT WOS:000325907500008 PM 23880085 ER PT J AU Oakley, MS Sahu, BR Lotspeich-Cole, L Solanki, NR Majam, V Pham, PT Banerjee, R Kozakai, Y Derrick, SC Kumar, S Morris, SL AF Oakley, Miranda S. Sahu, Bikash R. Lotspeich-Cole, Leda Solanki, Nehal R. Majam, Victoria Phuong Thao Pham Banerjee, Rajdeep Kozakai, Yukiko Derrick, Steven C. Kumar, Sanjai Morris, Sheldon L. TI The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis during Plasmodium berghei ANKA Murine Malaria SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EXPERIMENTAL CEREBRAL MALARIA; COLONY-STIMULATING FACTOR; TUMOR-NECROSIS-FACTOR; MONOCYTE CHEMOATTRACTANT PROTEIN-1; IFN-GAMMA; LINEAGE COMMITMENT; IMMUNE-RESPONSES; CELL FUNCTION; FACTOR-ALPHA; BRAIN AB The pathogenesis of experimental cerebral malaria (ECM) is an immunologic process, mediated in part by Th1 CD4(+) T cells. However, the role of the Th1 CD4(+) T cell differentiation program on the ability to control parasitemia and susceptibility to ECM disease during blood stage malaria has never been assessed directly. Using the Plasmodium berghei ANKA murine model of ECM and mice deficient for the transcription factor T-bet (the master regulator of Th1 cells) on the susceptible C57BL/6 background, we demonstrate that although T-bet plays a role in the regulation of parasite burden, it also promotes the pathogenesis of ECM. T-bet-deficient (Tbx21(-/-)) mice had higher parasitemia than wild type controls did during the ECM phase of disease (17.7 +/- 3.1% versus 10.9 +/- 1.5%). In addition, although 100% (10/10) of wild type mice developed ECM by day 9 after infection, only 30% (3/10) of Tbx21(-/-) mice succumbed to disease during the cerebral phase of infection. Resistance to ECM in Tbx21(-/-) mice was associated with diminished numbers of IFN-gamma-producing CD4(+) T cells in the spleen and a lower accumulation of CD4(+) and CD8(+) T cells in the brain. An augmented Th2 immune response characterized by enhanced production of activated GATA-3(+) CD4(+) T cells and elevated levels of the eotaxin, MCP-1, and G-CSF cytokines was observed in the absence of T-bet. Our results suggest that in virulent malarias, immune modulation or therapy resulting in an early shift toward a Th2 response may help to ameliorate the most severe consequences of malaria immunopathogenesis and the prospect of host survival. C1 [Oakley, Miranda S.; Lotspeich-Cole, Leda; Solanki, Nehal R.; Derrick, Steven C.; Morris, Sheldon L.] US FDA, Div Bacterial Parasit & Allergen Prod, Rockville, MD 20852 USA. [Sahu, Bikash R.; Majam, Victoria; Phuong Thao Pham; Banerjee, Rajdeep; Kozakai, Yukiko; Kumar, Sanjai] US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Kensington, MD 20895 USA. RP Kumar, S (reprint author), US FDA, Ctr Biol Evaluat & Res, 5516 Nicholson Lane, Kensington, MD 20895 USA. EM sanjai.kumar@fda.hhs.gov FU U.S. Food and Drug Administration FX This work was supported by intramural grants from the U.S. Food and Drug Administration. NR 62 TC 15 Z9 15 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 1 PY 2013 VL 191 IS 9 BP 4699 EP 4708 DI 10.4049/jimmunol.1300396 PG 10 WC Immunology SC Immunology GA 238FS UT WOS:000325929000027 PM 24078698 ER PT J AU O'Connor, AB Turk, DC Dworkin, RH Katz, NP Colucci, R Haythornthwaite, JA Klein, M O'Brien, C Posner, K Rappaport, BA Reisfield, G Adams, EH Balster, RL Bigelow, GE Burke, LB Comer, SD Cone, E Cowan, P Denisco, RA Farrar, JT Foltin, RW Haddox, JD Hertz, S Jay, GW Junor, R Kopecky, EA Leiderman, DB McDermott, MP Palmer, PP Raja, SN Rauschkolb, C Rowbotham, MC Sampaio, C Setnik, B Smith, SM Sokolowska, M Stauffer, JW Walsh, SL Zacny, JP AF O'Connor, Alec B. Turk, Dennis C. Dworkin, Robert H. Katz, Nathaniel P. Colucci, Robert Haythornthwaite, Jennifer A. Klein, Michael O'Brien, Charles Posner, Kelly Rappaport, Bob A. Reisfield, Gary Adams, Edgar H. Balster, Robert L. Bigelow, George E. Burke, Laurie B. Comer, Sandra D. Cone, Edward Cowan, Penney Denisco, Richard A. Farrar, John T. Foltin, Richard W. Haddox, J. David Hertz, Sharon Jay, Gary W. Junor, Roderick Kopecky, Ernest A. Leiderman, Deborah B. McDermott, Michael P. Palmer, Pamela P. Raja, Srinivasa N. Rauschkolb, Christine Rowbotham, Michael C. Sampaio, Cristina Setnik, Beatrice Smith, Shannon M. Sokolowska, Marta Stauffer, Joseph W. Walsh, Sharon L. Zacny, James P. TI Abuse liability measures for use in analgesic clinical trials in patients with pain: IMMPACT recommendations SO PAIN LA English DT Article DE Abuse; Abuse liability; Clinical trial; Opioids; Prescription drug abuse; Risk of abuse; Study design ID CHRONIC OPIOID THERAPY; CHRONIC NONCANCER PAIN; ABERRANT DRUG BEHAVIOR; CORE OUTCOME MEASURES; CROSS-VALIDATION; MISUSE MEASURE; UNITED-STATES; SOAPP-R; RISK; SCREENER AB Assessing and mitigating the abuse liability (AL) of analgesics is an urgent clinical and societal problem. Analgesics have traditionally been assessed in randomized clinical trials (RCTs) designed to demonstrate analgesic efficacy relative to placebo or an active comparator. In these trials, rigorous, prospectively designed assessment for AL is generally not performed. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) convened a consensus meeting to review the available evidence and discuss methods for improving the assessment of the AL of analgesics in clinical trials in patients with pain. Recommendations for improved assessment include: (1) performing trials that include individuals with diverse risks of abuse; (2) improving the assessment of AL in clinical trials (eg, training study personnel in the principles of abuse and addiction behaviors, designing the trial to assess AL outcomes as primary or secondary outcome measures depending on the trial objectives); (3) performing standardized assessment of outcomes, including targeted observations by study personnel and using structured adverse events query forms that ask all subjects specifically for certain symptoms (such as euphoria and craving); and (4) collecting detailed information about events of potential concern (eg, unexpected urine drug testing results, loss of study medication, and dropping out of the trial). The authors also propose a research agenda for improving the assessment of AL in future trials. (C) 2013 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved. C1 [O'Connor, Alec B.] Univ Rochester, Dept Med, Rochester, NY USA. [Turk, Dennis C.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Dworkin, Robert H.] Univ Rochester, Dept Anesthesiol, Rochester, NY USA. [Katz, Nathaniel P.] Analges Solut, Natick, MA USA. [Katz, Nathaniel P.] Tufts Univ, Sch Med, Dept Anesthesiol, Boston, MA 02111 USA. [Colucci, Robert] Colucci & Associates LLC, Newtown, CT USA. [Haythornthwaite, Jennifer A.; Bigelow, George E.; Cone, Edward] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Klein, Michael; Rappaport, Bob A.; Burke, Laurie B.; Hertz, Sharon] US FDA, Silver Spring, MD USA. [O'Brien, Charles] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Posner, Kelly; Comer, Sandra D.; Foltin, Richard W.] Columbia Univ, Coll Phys & Surg, New York State Psychiat Inst, Ctr Suicide Risk Assessment, New York, NY USA. [Reisfield, Gary] Univ Florida, Dept Psychiat, Coll Med, Gainesville, FL 32611 USA. [Adams, Edgar H.] Covance, Princeton, NJ USA. [Balster, Robert L.] Virginia Commonwealth Univ, Inst Drug & Alcohol Studies, Richmond, VA USA. [Cowan, Penney] Amer Chron Pain Assoc, Rocklin, CA USA. [Denisco, Richard A.] NIDA, Rockville, MD USA. [Farrar, John T.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Haddox, J. David] Purdue Pharma LP, Stamford, CT USA. [Haddox, J. David] Tufts Univ, Sch Med, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. [Jay, Gary W.] Pfizer Inc, Ann Arbor, MI USA. [Junor, Roderick] Eisai Ltd, Woodcliff Lake, NJ USA. [Kopecky, Ernest A.] Endo Pharmaceut Inc, Chadds Ford, PA USA. [Leiderman, Deborah B.] CNS Drug Consulting LLC, Mclean, VA USA. [McDermott, Michael P.] Univ Rochester, Dept Biostat & Computat Biol, Rochester, NY USA. [Palmer, Pamela P.] AcelRx Pharmaceut Inc, Redwood City, CA USA. [Raja, Srinivasa N.] Johns Hopkins Univ, Baltimore Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21218 USA. [Rauschkolb, Christine] Johnson & Johnson Pharmaceut Res & Dev LLC, Raritan, NJ USA. [Rowbotham, Michael C.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Sampaio, Cristina] Fac Med Lisbon, Clin Pharmacol & Therapeut Lab, Lisbon, Portugal. [Setnik, Beatrice; Smith, Shannon M.] King Pharmaceut Inc, Cary, NC USA. [Sokolowska, Marta] Grunenthal USA Inc, Bedminster, NJ USA. [Stauffer, Joseph W.] Durect Corp, Cupertino, CA USA. [Walsh, Sharon L.] Univ Kentucky, Ctr Drug & Alcohol Res, Dept Behav Sci, Lexington, KY 40506 USA. [Zacny, James P.] Univ Chicago, Dept Anesthesia & Crit Care, Chicago, IL 60637 USA. RP Turk, DC (reprint author), Univ Washington, Dept Anesthesiol & Pain Med, Box 356540, Seattle, WA 98195 USA. EM turkdc@uw.edu OI Yang, Shuman/0000-0002-9638-0890 FU University of Rochester Office of Continuing Professional Education FX The views expressed in this article are those of the authors, none of whom have financial conflicts of interest related to the specific issues discussed herein. At the time of the consensus meeting on which this article is based, 9 of the authors were employed by one of the companies that provided unrestricted grants to the University of Rochester Office of Continuing Professional Education to support the activities of IMMPACT, including the consensus meeting; these companies were AcelRx, Durect, Eisai, Endo, Grunenthal, Johnson & Johnson, King, Pfizer, and Purdue Pharma LP. No official endorsement by the U.S. Food and Drug Administration, U.S. National Institutes of Health, or the pharmaceutical companies that provided unrestricted grants to the University of Rochester Office of Continuing Professional Education should be inferred. NR 58 TC 14 Z9 14 U1 5 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD NOV PY 2013 VL 154 IS 11 BP 2324 EP 2334 DI 10.1016/j.pain.2013.06.035 PG 11 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 238FG UT WOS:000325927500014 PM 24148704 ER PT J AU Solomon, DH Rassen, JA Kuriya, B Chen, L Harrold, LR Graham, DJ Lewis, JD Lii, J Liu, LY Griffin, MR Curtis, JR AF Solomon, Daniel H. Rassen, Jeremy A. Kuriya, Bindee Chen, Lang Harrold, Leslie R. Graham, David J. Lewis, James D. Lii, Joyce Liu, Liyan Griffin, Marie R. Curtis, J. R. TI Heart failure risk among patients with rheumatoid arthritis starting a TNF antagonist SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article DE Rheumatoid Arthritis; Cardiovascular Disease; TNF-alpha; Treatment ID TUMOR-NECROSIS-FACTOR; FACTOR-ALPHA; PROPENSITY SCORE; FACTOR THERAPY; POPULATION; ETANERCEPT; GLUCOCORTICOIDS; DYSFUNCTION; DISEASE; SAFETY AB Background While heart failure (HF) is associated with elevations in tumor necrosis factor (TNF), several trials of TNF antagonists showed no benefit and possibly worsening of disease in those with known severe HF. We studied the risk of new or recurrent HF among a group of patients receiving these agents to treat rheumatoid arthritis (RA). Methods We used data from four different US healthcare programmes. Subjects with RA receiving methotrexate were eligible to enter the study cohort if they added or switched to a TNF antagonist or another non-biological disease modifying antirheumatic drug (nbDMARD). These groups were compared in Cox regression models stratified by propensity score decile and adjusted for oral glucocorticoid dosage, prior HF hospitalisations, and the use of loop diuretics. Results We compared 8656 new users of a nbDMARD with 11587 new users of a TNF antagonist with similar baseline covariates. The HR for the TNF antagonists compared with nbDMARD was 0.85 (95% CI 0.63 to 1.14). The HR was also not elevated in subjects with a history of HF. But, it was elevated prior to 2002 (HR 2.17, 95% CI 0.45 to 10.50, test for interaction p=0.036). Oral glucocorticoids were associated with a dose-related gradient of HF risk: compared with no use, 15mg HR 1.30 (95% CI 0.91 to 1.85), 5mg HR 1.54 (95% CI 1.09 to 2.19). Conclusions TNF antagonists were not associated with a risk of HF hospital admissions compared with nbDMARDs in this RA population. C1 [Solomon, Daniel H.; Rassen, Jeremy A.; Lii, Joyce] Brigham & Womens Hosp, Div Pharmacoepidemiol, Boston, MA 02115 USA. [Kuriya, Bindee] Univ Toronto, Dept Med, Toronto, ON, Canada. [Chen, Lang; Curtis, J. R.] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Harrold, Leslie R.] Univ Massachusetts, Dept Med, Worcester, MA 01605 USA. [Graham, David J.] US FDA, Off Drug Safety, Baltimore, MD USA. [Lewis, James D.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Liu, Liyan] Kaiser Permanente, Div Res, Oakland, CA USA. [Griffin, Marie R.] Vanderbilt Univ, Dept Prevent Med, Memphis, TN USA. [Griffin, Marie R.] Vet Affairs Tennessee Valley Hlth Care Syst, Memphis, TN USA. RP Solomon, DH (reprint author), Brigham & Womens Hosp, Div Rheumatol, Div Pharamacoepidemiol, 75 Francis St, Boston, MA 02115 USA. EM dsolomon@partners.org FU Agency for Healthcare Research and Quality (AHRQ); Food and Drug Administration (FDA) US Department of Health and Human Services (DHHS) [1U18 HSO17919-0] FX This work was supported by the Agency for Healthcare Research and Quality (AHRQ) and the Food and Drug Administration (FDA) US Department of Health and Human Services (DHHS) as part of a grant (No. 1U18 HSO17919-0) administered through the AHRQ CERTs Program. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by AHRQ, FDA or DHHS. NR 29 TC 13 Z9 13 U1 1 U2 8 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD NOV PY 2013 VL 72 IS 11 BP 1813 EP 1818 DI 10.1136/annrheumdis-2012-202136 PG 6 WC Rheumatology SC Rheumatology GA 232YZ UT WOS:000325532200015 PM 23155221 ER PT J AU Chen, YS Mukherjee, S Hoffmann, M Kotewicz, ML Young, S Abbott, J Luo, Y Davidson, MK Allard, M McDermott, P Zhao, SH AF Chen, Yuansha Mukherjee, Sampa Hoffmann, Maria Kotewicz, Michael L. Young, Shenia Abbott, Jason Luo, Yan Davidson, Maureen K. Allard, Marc McDermott, Patrick Zhao, Shaohua TI Whole-Genome Sequencing of Gentamicin-Resistant Campylobacter coli Isolated from US Retail Meats Reveals Novel Plasmid-Mediated Aminoglycoside Resistance Genes SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID JEJUNI; EVOLUTION; ALIGNMENT; PATHOGEN AB Aminoglycoside resistance in Campylobacter has been routinely monitored in the United States in clinical isolates since 1996 and in retail meats since 2002. Gentamicin resistance first appeared in a single human isolate of Campylobacter coli in 2000 and in a single chicken meat isolate in 2007, after which it increased rapidly to account for 11.3% of human isolates and 12.5% of retail isolates in 2010. Pulsed-field gel electrophoresis analysis indicated that gentamicin-resistant C. coli isolates from retail meat were clonal. We sequenced the genomes of two strains of this clone using a next-generation sequencing technique in order to investigate the genetic basis for the resistance. The gaps of one strain were closed using optical mapping and Sanger sequencing, and this is the first completed genome of C. coli. The two genomes are highly similar to each other. A self-transmissible plasmid carrying multiple antibiotic resistance genes was revealed within both genomes, carrying genes encoding resistance to gentamicin, kanamycin, streptomycin, streptothricin, and tetracycline. Bioinformatics analysis and experimental results showed that gentamicin resistance was due to a phosphotransferase gene, aph(2 '')-Ig, not described previously. The phylogenetic relationship of this newly emerged clone to other Campylobacter spp. was determined by whole-genome single nucleotide polymorphisms (SNPs), which showed that it clustered with the other poultry isolates and was separated from isolates from livestock. C1 [Chen, Yuansha; Mukherjee, Sampa; Hoffmann, Maria; Young, Shenia; Abbott, Jason; Davidson, Maureen K.; McDermott, Patrick; Zhao, Shaohua] US FDA, Res Off, Ctr Vet Med, Laurel, MD USA. [Kotewicz, Michael L.; Luo, Yan; Allard, Marc] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Chen, YS (reprint author), US FDA, Res Off, Ctr Vet Med, Laurel, MD USA. EM yuansha.chen@fda.hhs.gov RI Luan, Gan/B-3211-2015 NR 32 TC 16 Z9 16 U1 1 U2 26 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD NOV PY 2013 VL 57 IS 11 BP 5398 EP 5405 DI 10.1128/AAC.00669-13 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 235ZY UT WOS:000325764000026 PM 23959310 ER PT J AU Kolisetty, N Delker, DA Muralidhara, S Bull, RJ Cotruvo, JA Fisher, JW Cummings, BS AF Kolisetty, Narendrababu Delker, Don A. Muralidhara, Srinivasa Bull, Richard J. Cotruvo, Joseph A. Fisher, Jeff W. Cummings, Brian S. TI Changes in mRNA and protein expression in the renal cortex of male and female F344 rats treated with bromate SO ARCHIVES OF TOXICOLOGY LA English DT Article DE Bromate; Sex-dependent nephrotoxicity; Kidney; F344 rats ID OXIDATIVE DNA-DAMAGE; POTASSIUM BROMATE; CELL-PROLIFERATION; DOSE-RESPONSE; CARCINOGENICITY; STRESS; KIDNEY; CANCER; OSTEOPONTIN; BIOMARKERS AB Bromate (BrO3 (-)), a by-product of ozonation of drinking water, induces nephrotoxicity in male rats at much lower doses than in female rats. This difference appears to be related to the development of alpha-2(u)-globulin nephropathy in males. To determine sex-dependent changes in mRNA and protein expression in the renal cortex attributable to alpha-2(u)-globulin nephropathy, we performed microarray and immunohistochemical analyses in proximal renal tubules of male and female F344 rats treated with KBrO3 for 28 days. Particular attention was paid to molecular biomarkers of renal tubular injury. Microarray analysis of male and female rats treated with BrO3 (-) at low doses (125 mg/L KBrO3) displayed marked sex-dependent changes in renal gene expression. The greatest differences were seen in genes encoding for cellular differentiation, apoptosis, ion transport, and cell proliferation. Differences by sex were especially prominent for the cell cycle checkpoint gene p21, the renal injury protein Kim-1, and the kidney injury and cancer biomarker protein osteopontin. Dose-related nephrotoxicity, assessed by hematoxylin and eosin staining, was greater in males compared to female rats, as was cellular proliferation, assessed by bromodeoxyuridine staining. The fraction of proximal renal cells with elevated 8-oxodeoxyguanosine (8-OH-dG) was only increased at the high dose and did not differ by sex. Dose-dependent increases in the expression of osteopontin were detected immunohistochemically only in male rats and were localized in proximal tubule cells. Similarly, BrO3 (-) treatment increased clusterin and Kim-1 staining in the proximal tubules; however, staining for these proteins did not differ appreciably between males and females. These data demonstrate both qualitative and quantitative differences in the response of male versus female kidneys to BrO3 (-)-treatment. These sex-dependent effects likely contribute to renal carcinogenesis of BrO3 (-) in the male rat. C1 [Kolisetty, Narendrababu; Muralidhara, Srinivasa; Cummings, Brian S.] Univ Georgia, Coll Pharm, Dept Pharmaceut & Biomed Sci, Athens, GA 30602 USA. [Delker, Don A.] Univ Utah, Sch Med, Salt Lake City, UT 84132 USA. [Bull, Richard J.] MoBull Consulting, Richland, WA 99352 USA. [Cotruvo, Joseph A.] Joseph Cotruvo & Associates LLC, Washington, DC 20016 USA. [Fisher, Jeff W.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Cummings, BS (reprint author), Univ Georgia, Coll Pharm, Dept Pharmaceut & Biomed Sci, Athens, GA 30602 USA. EM bsc@rx.uga.edu FU Georgia Cancer Coalition; Joseph Cotruvo Associates LLC; Water Research Foundation [4042] FX We thank Dr. James Bruckner for use of his lab facilities to conduct many of the in vivo studies. We also thank Dr. Robert Arnold for use of his microscope for the immunohistochemistry studies. This work was supported by the Georgia Cancer Coalition and Joseph Cotruvo & Associates LLC with grants from the Water Research Foundation Project #4042-International Ozone Assoc., Environment Agency of Abu Dhabi, Veolia Water, Metropolitan Water District of Southern Calif., Los Angeles Department of Water and Power, Singapore Public Utilities Bureau, National Water Research Institute, Walkerton Clean Water Centre, Calleguas Municipal Water District, Long Beach Water Department, and in-kind contributions of the participants. We gratefully acknowledge and thank the Water Research Foundation and all of the sponsors for their financial, technical, and administrative assistance in funding the project through which this information was discovered. NR 35 TC 7 Z9 7 U1 1 U2 10 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 EI 1432-0738 J9 ARCH TOXICOL JI Arch. Toxicol. PD NOV PY 2013 VL 87 IS 11 BP 1911 EP 1925 DI 10.1007/s00204-013-1052-2 PG 15 WC Toxicology SC Toxicology GA 235EW UT WOS:000325700300003 PM 23588252 ER PT J AU Zhou, EH Kaplan, S Mosholder, A Moeny, D Ding, YL Wu, YT Iyasu, S Hammad, TA AF Zhou, Esther H. Kaplan, Sigal Mosholder, Andrew Moeny, David Ding, Yulan Wu, Yute Iyasu, Solomon Hammad, Tarek A. TI Antidepressant medication dispensing among montelukast initiators SO JOURNAL OF ASTHMA LA English DT Article DE Antidepressant; interrupted time-series analysis; montelukast ID RANDOMIZED CONTROLLED-TRIALS; CLINICAL-TRIALS; ADULTS; ASTHMA; RISK; ASSOCIATIONS; SUICIDALITY; CHILDREN; SAFETY AB Objective: This study investigates the potential association between montelukast use and psychiatric adverse events by monitoring changes in antidepressant medication dispensing rates before and after initiating montelukast. Methods: The primary study group of montelukast initiators was identified using the Wolters Kluwer's SOURCE Lx (R) pharmacy claims database (WK). This group included 232 159 patients <= 45 years old who had at least two montelukast prescriptions from 2003 to 2007. Comparison groups comprised of 264 704 fluticasone initiators and 89 635 long-acting beta-agonist corticosteroid (LABA/ICS) initiators were also identified. Antidepressant medication dispensing rates in these three groups were determined using WK, and changes in rates before and after the first asthma controller medication prescription date were evaluated using interrupted time- series analysis (ITS). ITS was performed separately for four age categories, with a focus on youth (12-17 years) and young adult (18-24 years). Results: For patients 18-24 years old, antidepressant medication dispensing rates increased significantly after initiating montelukast [1.93% (1.55-2.32%, p<0.001)] but also after initiating fluticasone and LABA/ICS [1.72% (1.30-2.15%, p<0.001) and 2.76% (2.35-3.17%, p<0.001)]. Similar patterns were observed across the three medication groups for other age categories but these differences were not all significant. Conclusions: Small increases in antidepressant medication dispensing rates occurred after initiating montelukast. However, similar increases were observed in the fluticasone and LABA/ICS comparison groups. The results of this study cannot support a specific association between initiation of montelukast treatment and an increase in psychiatric adverse effects. C1 [Zhou, Esther H.; Kaplan, Sigal; Mosholder, Andrew; Moeny, David; Ding, Yulan; Iyasu, Solomon; Hammad, Tarek A.] Ctr Drug Evaluat & Res Food & Drug Adm, Off Surveillance & Epidemiol, Div Epidemiol 1, Silver Spring, MD 20993 USA. [Wu, Yute] Ctr Drug Evaluat & Res Food & Drug Adm, Off Biostat, Silver Spring, MD 20993 USA. RP Zhou, EH (reprint author), Ctr Drug Evaluat & Res Food & Drug Adm, Off Surveillance & Epidemiol, Div Epidemiol 1, 10903 New Hampshire Ave,Bldg 22,Room 2421, Silver Spring, MD 20993 USA. EM esther.zhou@fda.hhs.gov NR 23 TC 0 Z9 1 U1 0 U2 3 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0277-0903 EI 1532-4303 J9 J ASTHMA JI J. Asthma PD NOV PY 2013 VL 50 IS 9 BP 990 EP 995 DI 10.3109/02770903.2013.823445 PG 6 WC Allergy; Respiratory System SC Allergy; Respiratory System GA 236AS UT WOS:000325766500012 PM 23841530 ER PT J AU Narang, AS Chang, RK Hussain, MA AF Narang, Ajit S. Chang, Rong-Kun Hussain, Munir A. TI Pharmaceutical Development and Regulatory Considerations for Nanoparticles and Nanoparticulate Drug Delivery Systems SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE nano milling; nanoparticles; nanotechnology; micelle; microemulsion; liposomes; polymeric drug delivery systems; polymeric drug carrier; polymeric drugs ID CEFUROXIME AXETIL NANOPARTICLES; WATER-SOLUBLE DRUGS; SOLID DOSAGE FORMS; EXCIPIENT INTERACTIONS; LIPOPHILIC DRUGS; ORAL ABSORPTION; PARTICLE-SIZE; SAS PROCESS; BIOAVAILABILITY; DISSOLUTION AB Pharmaceutical nanomaterials (NMs) encompass a wide variety of materials including drug nanoparticles (NPs), which can be amorphous or crystalline; or nanoparticulate drug delivery systems, such as micelles, microemulsions, liposomes, drug-polymer conjugates, and antibody-drug conjugates. These NMs are either transient or persistentdepending on whether the integrity of their structure and size is maintained until reaching the site of drug action. Examples of several approved drug products are included as pharmaceutical nanoparticulate systems along with a commentary on the current development issues and paradigms for various categories ofNPs. This commentary discusses the preparation of nanoparticulate systems for commercial development, and the biopharmaceutical and pharmacokinetic advantages of these systems. A criterion of criticality is defined that incorporates the structure, in addition to size requirement of pharmaceutical NPs to identify systems that may require special development and regulatory considerations. (c) 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3867-3882, 2013 C1 [Narang, Ajit S.; Hussain, Munir A.] Bristol Myers Squibb Co, New Brunswick, NJ 08901 USA. [Chang, Rong-Kun] US FDA, Ctr Drug Evaluat & Res, Off Gener Drugs, Rockville, MD 20855 USA. RP Hussain, MA (reprint author), Bristol Myers Squibb Co, New Brunswick, NJ 08901 USA. EM Munir.Hussain@bms.com NR 69 TC 15 Z9 15 U1 2 U2 54 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD NOV PY 2013 VL 102 IS 11 BP 3867 EP 3882 DI 10.1002/jps.23691 PG 16 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 233EZ UT WOS:000325550400001 PM 24037829 ER PT J AU Siddiqui, A Rahman, Z Sayeed, VA Khan, MA AF Siddiqui, Akhtar Rahman, Ziyaur Sayeed, Vilayat A. Khan, Mansoor A. TI Chemometric Evaluation of Near Infrared, Fourier Transform Infrared, and Raman Spectroscopic Models for the Prediction of Nimodipine Polymorphs SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE chemometrics; polymorphs; nimodipine; spectroscopy; chemical imaging; Crystallization; FTIR; Mathematical model; Near-infrared spectroscopy; Raman spectroscopy ID SOLID DISPERSIONS; BETA-CYCLODEXTRIN; TABLETS; INDOMETHACIN; FORMULATIONS; DESIGN AB The objective of this study was to assess the performance of the chemometric model to predict the proportion of the recrystallized polymorphs of nimodipine from the cosolvent formulations. Ranging from 100% to 0% (w/w) of polymorph I, the two polymorphs mixtures were prepared and characterized spectroscopically using Fourier transformed infrared spectroscopy (FTIR), near-infrared spectroscopy (NIR), and Raman spectroscopy. Instrumental responses were treated to construct multivariate calibration model using principal component regression (PCR) and partial least square regression approaches. Treated data showed better model fitting than without treatment, which demonstrated higher correlation coefficient (R-2) and lower root mean square of standard error (RMSE) and standard error (SE). Multiple scattering correction and standard normal variate exhibited higher R-2 and lower RMSE and SE values than second derivative. Goodness of fit for FTIR and NIR (R-2 approximate to 0.99) data was better than Raman (R-2 approximate to 0.95). Furthermore, the models were applied on the recrystallized polymorphs obtained by storing nimodipine-cosolvent formulations at selected stability conditions. The relative composition of the polymorphs differed with storage conditions. NIR-chemical imaging on recrystallized sample of nimodipine at 15 degrees C qualitatively corroborated the model-based prediction of the two polymorphs. Therefore, these studies strongly suggest the importance of the potential utility of the chemometric model in predicting nimodipine polymorphs. (c) 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:4024-4035, 2013 C1 [Siddiqui, Akhtar; Rahman, Ziyaur; Khan, Mansoor A.] US FDA, Div Prod Qual Res, Off Testing & Res, OPS,CDER, Silver Spring, MD USA. [Sayeed, Vilayat A.] US FDA, Div Chem 3, Off Gener Drug, OPS,CDER, Silver Spring, MD USA. RP Khan, MA (reprint author), US FDA, Div Prod Qual Res, Off Testing & Res, OPS,CDER, Silver Spring, MD USA. EM Mansoor.Khan@fda.hhs.gov OI Rahman, Ziyaur/0000-0002-0402-825X FU Oak Ridge Institute for Science and Education (ORISE) FX The authors would like to thank Medical Counter Measure Initiative (MCMi) for infrastructure support and Oak Ridge Institute for Science and Education (ORISE) for supporting postdoctoral research program. NR 29 TC 7 Z9 7 U1 1 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD NOV PY 2013 VL 102 IS 11 BP 4024 EP 4035 DI 10.1002/jps.23712 PG 12 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 233EZ UT WOS:000325550400018 PM 23963767 ER PT J AU Zhang, ZW Wang, CG Nie, L Soon, GX AF Zhang, Zhiwei Wang, Chenguang Nie, Lei Soon, Guoxing TI Assessing the heterogeneity of treatment effects via potential outcomes of individual patients SO JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES C-APPLIED STATISTICS LA English DT Article DE Causal inference; Conditional independence; Copula; Counterfactual; Random effect; Sensitivity analysis ID R5 HIV-1 INFECTION; MARAVIROC; INFERENCE; MODELS AB There is growing interest in understanding the heterogeneity of treatment effects (HTE), which has important implications in treatment evaluation and selection. The standard approach to assessing HTE (i.e. subgroup analyses based on known effect modifiers) is informative about the heterogeneity between subpopulations but not within. It is arguably more informative to assess HTE in terms of individual treatment effects, which can be defined by using potential outcomes. However, estimation of HTE based on potential outcomes is challenged by the lack of complete identifiability. The paper proposes methods to deal with the identifiability problem by using relevant information in baseline covariates and repeated measurements. If a set of covariates is sufficient for explaining the dependence between potential outcomes, the joint distribution of potential outcomes and hence all measures of HTE will then be identified under a conditional independence assumption. Possible violations of this assumption can be addressed by including a random effect to account for residual dependence or by specifying the conditional dependence structure directly. The methods proposed are shown to reduce effectively the uncertainty about HTE in a trial of human immunodeficiency virus. C1 [Zhang, Zhiwei; Nie, Lei; Soon, Guoxing] US FDA, Silver Spring, MD 20993 USA. [Wang, Chenguang] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Zhang, ZW (reprint author), US FDA, Ctr Devices & Radiol Hlth, Div Biostat, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM zhiwei.zhang@yahoo.com FU NCI NIH HHS [P30 CA006973] NR 23 TC 6 Z9 6 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0035-9254 EI 1467-9876 J9 J R STAT SOC C-APPL JI J. R. Stat. Soc. Ser. C-Appl. Stat. PD NOV PY 2013 VL 62 IS 5 BP 687 EP 704 DI 10.1111/rssc.12012 PG 18 WC Statistics & Probability SC Mathematics GA 231ZQ UT WOS:000325457500003 PM 25506088 ER PT J AU Bird, ST Brophy, JM Hartzema, AG Delaney, JAC Etminan, M AF Bird, Steven T. Brophy, James M. Hartzema, Abraham G. Delaney, Joseph A. C. Etminan, Mahyar TI Male Breast Cancer and 5 alpha-Reductase Inhibitors Finasteride and Dutasteride SO JOURNAL OF UROLOGY LA English DT Article DE breast neoplasms, male; 5-alpha reductase inhibitors ID BENIGN PROSTATIC HYPERPLASIA; RISK; MEN; EFFICACY; SAFETY; WOMEN AB Purpose: We examined the association between 5 alpha-reductase inhibitors and male breast cancer. Materials and Methods: Study participants were men 40 to 85 years old, with prescription and medical coverage, enrolled in the United States IMS LifeLink (TM) Health Plan claims database between 2001 and 2009. Cases required a primary breast cancer diagnosis (ICD-9-CM 175. x) on 2 different dates and a procedural code for mastectomy or lumpectomy/partial mastectomy with evidence of continuous care (radiation/chemotherapy or diagnoses in 2 or more months). Eligible controls were within 5 years in age and had duration of prior health care enrollment within 6 weeks. Risk set sampling selected 20 controls per case. We assessed the rate ratio for male breast cancer with 5 alpha-reductase inhibitor exposure using conditional logistic regression. Analyses were stratified by duration of health care enrollment before diagnosis (1 year or more, 2 years or more and 3 years or more), each incremental 180 and 365 days of cumulative 5a-reductase inhibitor exposure, and period specific time frames before diagnosis (years 1, 2 and 3). Results: We identified 339 breast cancer cases matched to 6,780 controls. No statistically significant associations were observed between 5 alpha-reductase inhibitors and breast cancer regardless of exposure assessment before the index date (1 year or moredRR 0.70, 95% CI 0.34-1.45; 2 years or moredRR 0.59, 95% CI 0.24-1.48; or 3 years or moredRR 0.75, 95% CI 0.27-2.10). Each subsequent 180 days (RR 1.02, 95% CI 0.67-1.53) and 365 days (RR 1.03, 95% CI 0.45-2.37) of cumulative 5a-reductase inhibitor therapy and period specific rate ratios also showed null associations. Conclusions: The lack of an association in our study suggests that the development of breast cancer should not influence the prescribing of 5a-reductase inhibitor therapy. C1 [Bird, Steven T.] US FDA, US Dept HHS, Ctr Drug Evaluat & Res,Dept Epidemiol, Off Pharmacovigilance & Epidemiol,Off Surveillanc, Silver Spring, MD USA. [Bird, Steven T.; Hartzema, Abraham G.] Univ Florida, Coll Pharm, Dept Pharmaceut Outcomes & Policy, Gainesville, FL USA. [Brophy, James M.] McGill Univ, Royal Victoria Hosp, Dept Med, Montreal, PQ H3A 1A1, Canada. [Etminan, Mahyar] Univ British Columbia, Child & Family Res Inst British Columbia, Vancouver, BC V5Z 1M9, Canada. [Delaney, Joseph A. C.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. RP Etminan, M (reprint author), Univ British Columbia, Fac Med, Child & Family Res Inst British Columbia, A4-198 WS 2,709-650 West 28th Ave, Vancouver, BC, Canada. EM metminan@popi.ubc.ca FU McGill University Health Center; Fonds de la Recherche en Sante du Quebec; Ministere de la Sante et des Services Sociaux FX Supported by an unrestricted operating grant funded in part by the McGill University Health Center, Fonds de la Recherche en Sante du Quebec (JMB), and the Ministere de la Sante et des Services Sociaux. NR 15 TC 11 Z9 11 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD NOV PY 2013 VL 190 IS 5 BP 1811 EP 1814 DI 10.1016/j.juro.2013.04.132 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 232DV UT WOS:000325471400058 PM 23665270 ER PT J AU Betts, KR Hinsz, VB AF Betts, Kevin R. Hinsz, Verlin B. TI Group Marginalization: Extending Research on Interpersonal Rejection to Small Groups SO PERSONALITY AND SOCIAL PSYCHOLOGY REVIEW LA English DT Article DE group marginalization; rejection; ostracism; aggression involving groups; terrorist cells ID INTERINDIVIDUAL-INTERGROUP DISCONTINUITY; SELF-ESTEEM; SOCIAL EXCLUSION; GROUP IDENTIFICATION; HUMAN-AGGRESSION; MOTIVATION; OSTRACISM; IDENTITY; DISCRIMINATION; INDIVIDUALS AB An extensive research literature has examined the reactions of individuals facing interpersonal rejection. Small groups can also be rejected, but current research tells us little about the experiences of groups and their members directly. We integrate findings from various literatures to gain insight into shared rejection experiences and their outcomes. Of most practical importance, we argue that groups can be expected to react with more hostility than individuals when rejected. Four existing models that account for how group processes might alter such reactions are examined: a need-threat model, a rejection-identification model, a multimotive model, and a dual attitudes model. Aspects of these models are then integrated into a unifying framework that is useful for understanding hostile reactions to group marginalization. Implications for natural groups such as terrorist cells, school cliques, racial and ethnic minorities, and gangs are discussed. C1 [Betts, Kevin R.] US FDA, Silver Spring, MD 20993 USA. [Hinsz, Verlin B.] N Dakota State Univ, Fargo, ND 58105 USA. RP Betts, KR (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM kevin.betts@fda.hhs.gov NR 84 TC 4 Z9 5 U1 4 U2 35 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1088-8683 J9 PERS SOC PSYCHOL REV JI Pers. Soc. Psychol. Rev. PD NOV PY 2013 VL 17 IS 4 BP 355 EP 370 DI 10.1177/1088868313497999 PG 16 WC Psychology, Social SC Psychology GA 232FB UT WOS:000325476000003 PM 23928559 ER PT J AU Rosas-Hernandez, H Cuevas, E Lantz, SM Hamilton, WR Ramirez-Lee, MA Ali, SF Gonzalez, C AF Rosas-Hernandez, Hector Cuevas, Elvis Lantz, Susan M. Hamilton, W. Ryan Ramirez-Lee, Manuel A. Ali, Syed F. Gonzalez, Carmen TI Prolactin and Blood-Brain Barrier Permeability SO CURRENT NEUROVASCULAR RESEARCH LA English DT Article DE Blood-brain barrier; Brain endothelial cells; Permeability; Prolactin; Prolactin receptor; Tight junctions ID ENDOTHELIAL-CELL PROLIFERATION; NITRIC-OXIDE SYNTHASE; MAMMARY-GLAND; MILK SECRETION; ANGIOGENESIS; EXPRESSION; PATHWAYS; DEXAMETHASONE; INFLAMMATION; DYSFUNCTION AB The blood-brain barrier (BBB) consists in part of a highly specialized set of cells which separates the brain from the vascular system. The BBB controls the entry and exit of substances from the brain tissue through tight junctions (TJs) between endothelial cells. It is known that the hormone prolactin (PRL) is able to regulate endothelial-dependent processes, like the balance between proliferation and apoptosis and the mammary epithelial permeability. However, the effects of PRL and the role it plays in the BBB permeability are still not well understood. A primary culture of bovine brain microvessel endothelial cells was used as in vitro model of BBB. Cells were treated with PRL (0.1, 1, 10 and 100 nM) for 24 hours. PRL significantly increased cellular proliferation at 10 and 100 nM, but did not modify basal apoptosis. These effects were dependent on the production of the mitogenic factor nitric oxide (NO). PRL significantly decreased the permeability and promoted an increase in trans-endothelial electrical resistance in a NO-independent way. PRL also increased the expression of the TJs proteins claudin-5 and occludin. The short form of the PRL receptor was detected in these cells but its expression was not modified by PRL. Together, these results suggest that PRL has the ability to increase cellular proliferation associated with a decrease on BBB permeability by increasing the expression of TJs proteins. C1 [Rosas-Hernandez, Hector; Ramirez-Lee, Manuel A.; Gonzalez, Carmen] Univ Autonoma San Luis Potosi, Fac Ciencias Quim, Lab Fisiol Celular, San Luis Potosi 78210, Mexico. [Rosas-Hernandez, Hector; Cuevas, Elvis; Lantz, Susan M.; Hamilton, W. Ryan; Ali, Syed F.; Gonzalez, Carmen] US FDA, Neurochem Lab, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Gonzalez, C (reprint author), Univ Autonoma San Luis Potosi, Fac Ciencias Quim, Lab Fisiol Celular, Av Manuel Nava 6, San Luis Potosi 78210, Mexico. EM cgonzalez.uaslp@gmail.com RI Hector, Rosas-Hernandez/J-5130-2015; OI Rosas-Hernandez, Hector/0000-0002-2736-8302 FU appointment (HRH) to the Research Participation Program at the National Center for Toxicological Research (NCTR); National Council of Science and Technology of Mexico [317768] FX This study was supported in part by an appointment (HRH) to the Research Participation Program at the National Center for Toxicological Research (NCTR) administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. We thank the National Council of Science and Technology of Mexico for the fellow ship provided (317768) and to the Secretariat of Research of the University of San Luis Potosi. NR 36 TC 5 Z9 6 U1 3 U2 19 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2026 J9 CURR NEUROVASC RES JI Curr. Neurovasc. Res. PD NOV PY 2013 VL 10 IS 4 BP 278 EP 286 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 224DY UT WOS:000324863500002 PM 23937200 ER PT J AU Rosas-Hernandez, H Cuevas, E Lantz-McPeak, SM Ali, SF Gonzalez, C AF Rosas-Hernandez, Hector Cuevas, Elvis Lantz-McPeak, Susan M. Ali, Syed F. Gonzalez, Carmen TI Prolactin Protects Against the Methamphetamine-Induced Cerebral Vascular Toxicity SO CURRENT NEUROVASCULAR RESEARCH LA English DT Article DE Blood-brain barrier; brain endothelial cells; methamphetamine; prolactin; tight junctions; trans-endothelial electrical resistance ID BLOOD-BRAIN-BARRIER; ACETYLCYSTEINE AMIDE PROTECTS; TIGHT JUNCTION PROTEINS; APOPTOTIC CELL-DEATH; ENDOTHELIAL-CELLS; INDUCED NEUROTOXICITY; MAMMARY EPITHELIUM; OXIDATIVE STRESS; MILK SECRETION; CULTURE MODEL AB Methamphetamine (Meth) is a highly addictive drug of abuse which alters the dopaminergic system and damages the blood-brain barrier (BBB), structure that protects the brain tissue from the circulating substances in the blood, keeping a low permeability through the presence of tight junctions (TJs) between endothelial cells. Meth increases BBB permeability by decreasing the TJs proteins claudin-5 and occludin and by decreasing the viability of endothelial cells. Individuals abused of Meth have increased blood concentrations of prolactin (PRL); hormone related with milk production, but able to increase the expression of TJs proteins and to decrease permeability on the mammary epithelium and brain endothelial cells. However, the effects of PRL on the permeability of the BBB in the presence of Meth have not been studied. Here, we report Meth-induced apoptosis and decreased cellular proliferation as well as the trans-endothelial electrical resistance (TEER), related to a decrease of claudin-5 and occludin in primary cultured bovine brain microvessel endothelial cells. The expression of the PRL receptor was not altered. Administration of PRL prevented a decrease in cellular proliferation, an increase in apoptosis and restored the TEER and TJs proteins to basal levels. This protection was absent at high Meth concentrations. These data suggest that PRL protects brain endothelial cells against the Meth-induced toxicity. Further investigation is required to study the mechanisms involved and to confirm these effects in vivo. C1 [Rosas-Hernandez, Hector; Gonzalez, Carmen] Univ Autonoma San Luis Potosi, Lab Fisiol Celular, Fac Ciencias Quim, San Luis Potosi 78210, Mexico. [Rosas-Hernandez, Hector; Cuevas, Elvis; Lantz-McPeak, Susan M.; Ali, Syed F.] US FDA, Neurochem Lab, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Gonzalez, C (reprint author), Univ Autonoma San Luis Potosi, Lab Fisiol Celular, Fac Ciencias Quim, Av Manuel Nava 6, San Luis Potosi 78210, Mexico. EM cgonzalez.uaslp@gmail.com RI Hector, Rosas-Hernandez/J-5130-2015; OI Rosas-Hernandez, Hector/0000-0002-2736-8302 FU U.S. Department of Energy; U.S. Food and Drug Administration; National Council of Science and Technology of Mexico [317768]; Secretariat of Research of the University of San Luis Potosi FX This study was supported in part by an appointment to the Research Participation Program (HRH) at the National Center for Toxicological Research (NCTR) administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. We thank the National Council of Science and Technology of Mexico for the fellowship provided (317768) and to the Secretariat of Research of the University of San Luis Potosi NR 47 TC 6 Z9 6 U1 3 U2 13 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2026 J9 CURR NEUROVASC RES JI Curr. Neurovasc. Res. PD NOV PY 2013 VL 10 IS 4 BP 346 EP 355 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 224DY UT WOS:000324863500009 PM 23988027 ER PT J AU Chekhun, VF Lukyanova, NY Burlaka, AP Bezdenezhnykh, NA Shpyleva, SI Tryndyak, VP Beland, FA Pogribny, IP AF Chekhun, Vasyl F. Lukyanova, Natalia Yu Burlaka, Anatoliy P. Bezdenezhnykh, Natalia A. Shpyleva, Svitlana I. Tryndyak, Volodymyr P. Beland, Frederick A. Pogribny, Igor P. TI Iron metabolism disturbances in the MCF-7 human breast cancer cells with acquired resistance to doxorubicin and cisplatin SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE breast cancer; iron metabolism; drug resistance ID FERRITIN; ANTHRACYCLINES; GROWTH; ASSAY; EXPRESSION; CHELATORS; TARGETS; TUMORS AB The development of resistance of cancer cells to therapeutic agents is the major obstacle in the succesful treatment of breast cancer and the main cause of breast cancer recurrence. The results of several studies have demonstrated an important role of altered cellular iron metabolism in the progression of breast cancer and suggested that iron metabolism may be involved in the acquisition of a cancer cell drug-resistant phenotype. In the present study, we show that human MCF-7 breast cancer cells with an acquired resistance to the chemotherapeutic drugs doxorubicin (MCF-7/DOX) and cisplatin (MCF-7/CDDP) exhibited substantial alterations in the intracellular iron content and levels of iron-regulatory proteins involved in the cellular uptake, storage and export of iron, especially in profoundly increased levels of ferritin light chain (FTL) protein. The increased levels of FTL in breast cancer indicate that FTL may be used as a diagnostic and prognostic marker for breast cancer. Additionally, we demonstrate that targeted downregulation of FTL protein by the microRNA miR-133a increases sensitivity of MCF-7/DOX and MCF-7/CDDP cells to doxorubicin and cisplatin. These results suggest that correction of iron metabolism abnormalities may substantially improve the efficiency of breast cancer treatment. C1 [Chekhun, Vasyl F.; Lukyanova, Natalia Yu; Burlaka, Anatoliy P.; Bezdenezhnykh, Natalia A.; Tryndyak, Volodymyr P.] RE Kavetsky Inst Expt Pathol Oncol & Radiobiol, Dept Mech Anticanc Therapy, Kiev, Ukraine. [Shpyleva, Svitlana I.; Tryndyak, Volodymyr P.; Beland, Frederick A.; Pogribny, Igor P.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Pogribny, IP (reprint author), NCTR, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM igor.pogribny@fda.hhs.gov NR 34 TC 6 Z9 8 U1 1 U2 20 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 EI 1791-2423 J9 INT J ONCOL JI Int. J. Oncol. PD NOV PY 2013 VL 43 IS 5 BP 1481 EP 1486 DI 10.3892/ijo.2013.2063 PG 6 WC Oncology SC Oncology GA 225SN UT WOS:000324982700017 PM 23969999 ER PT J AU Ramirez-Lee, MA Rosas-Hernandez, H Salazar-Garcia, S Gutierrez-Hernandez, JM Espinosa-Tanguma, R Gonzalez, FJ Ali, SF Gonzalez, C AF Alejandro Ramirez-Lee, Manuel Rosas-Hernandez, Hector Salazar-Garcia, Samuel Manuel Gutierrez-Hernandez, Jose Espinosa-Tanguma, Ricardo Gonzalez, Francisco J. Ali, Syed F. Gonzalez, Carmen TI Silver nanoparticles Induce Anti-Proliferative Effects on Airway Smooth Muscle Cells. Role of Nitric Oxide and Muscarinic Receptor Signaling Pathway SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Alejandro Ramirez-Lee, Manuel; Rosas-Hernandez, Hector; Salazar-Garcia, Samuel; Espinosa-Tanguma, Ricardo; Gonzalez, Carmen] Univ Autonoma San Luis Potosi, San Luis Potosi, Mexico. [Rosas-Hernandez, Hector; Ali, Syed F.; Gonzalez, Carmen] Natl Ctr Toxicol Res, Jefferson, AR USA. [Manuel Gutierrez-Hernandez, Jose; Gonzalez, Francisco J.] Univ Autonoma San Luis Potosi, Coordinac Innovac & Aplicac Cienc, San Luis Potosi, Mexico. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2013 VL 65 SU 2 MA 232 BP S104 EP S104 DI 10.1016/j.freeradbiomed.2013.10.653 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA V40JU UT WOS:000209475700250 ER PT J AU Irwin, D Buehler, P Eigenberger, P Lisk, C Maltzhan, J Hassel, K Nuss, R AF Irwin, David Buehler, Paul Eigenberger, Paul Lisk, Christina Maltzhan, Joanne Hassel, Kathryn Nuss, Rachelle TI Cell Free Hemoglobin Directly and Indirectly Initiates Smooth Muscle Cell Proliferation SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Irwin, David; Eigenberger, Paul; Lisk, Christina; Maltzhan, Joanne; Hassel, Kathryn] Univ Colorado Denver, Denver, CO USA. [Buehler, Paul] US FDA, Rockville, MD 20857 USA. [Nuss, Rachelle] Childrens Hosp Colorado, Aurora, CO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2013 VL 65 SU 2 MA 122 BP S63 EP S63 DI 10.1016/j.freeradbiomed.2013.10.540 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA V40JU UT WOS:000209475700141 ER PT J AU Irwin, D Buehler, P Eigenberger, P Lisk, C Maltzhan, J Hassel, K Nozik-Grayck, E Loomis, Z AF Irwin, David Buehler, Paul Eigenberger, Paul Lisk, Christina Maltzhan, Joanne Hassel, Kathryn Nozik-Grayck, Eva Loomis, Zoe TI Haptoglobin Therapy in a Rodent Model of Severe Pulmonary Vascular Disease Mediated by Hemoglobin Reduces Disease Progression SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Irwin, David; Eigenberger, Paul; Lisk, Christina; Maltzhan, Joanne; Hassel, Kathryn; Nozik-Grayck, Eva; Loomis, Zoe] Univ Colorado Denver, Denver, CO USA. [Buehler, Paul] US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2013 VL 65 SU 2 MA 117 BP S61 EP S61 DI 10.1016/j.freeradbiomed.2013.10.535 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA V40JU UT WOS:000209475700136 ER PT J AU Ye, HP Toby, TK Sommers, CD Ghasriani, H Trehy, ML Ye, W Kolinski, RE Buhse, LF Al-Hakim, A Keire, DA AF Ye, Hongping Toby, Timothy K. Sommers, Cynthia D. Ghasriani, Houman Trehy, Michael L. Ye, Wei Kolinski, Richard E. Buhse, Lucinda F. Al-Hakim, Ali Keire, David A. TI Characterization of currently marketed heparin products: Key tests for LMWH quality assurance SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Heparin; LMWH; SAX-HPLC; NMR; CE; Factor-IIa ID LOW-MOLECULAR-WEIGHT; NITROUS-ACID; SULFATE; SODIUM; DEPOLYMERIZATION; SPECTROSCOPY; CONTAMINANTS; ENOXAPARIN AB During the 2007-2008 heparin crisis it was found that the United States Pharmacopeia (USP) testing monograph for heparin sodium or low molecular weight heparins did not detect the presence of the contaminant, oversulfated chondroitin sulfate (OSCS). In response to this concern, new tests and specifications were developed by the Food and Drug Administration (FDA) and USP and put in place to detect not only the contaminant OSCS, but also to improve assurance of quality and purity of these drug products. The USP monographs for the low molecular weight heparins (LMWHs) approved for use in the United States (dalteparin, tinzaparin and enoxaparin) are also undergoing revision to include many of the same tests used for heparin sodium, including; one-dimensional (1D) 500 MHz H-1 NMR, SAX-HPLC, percent galactosamine in total hexosamine and anticoagulation time assays with purified Factor IIa or Factor X-a. These tests represent orthogonal approaches for heparin identification, measurement of bioactivity and for detection of process impurities or contaminants in these drug products. Here we describe results from a survey of multiple lots from three types of LMWHs in the US market which were collected after the 2009 heparin sodium monograph revision. In addition, innovator and generic versions of formulated enoxaparin products purchased in 2011 are compared using these tests and found to be highly similar within the discriminating power of the assays applied. Published by Elsevier B.V. C1 [Ye, Hongping; Toby, Timothy K.; Sommers, Cynthia D.; Ghasriani, Houman; Trehy, Michael L.; Ye, Wei; Kolinski, Richard E.; Buhse, Lucinda F.; Keire, David A.] US FDA, CDER, Div Pharmaceut Anal, St Louis, MO 63101 USA. [Al-Hakim, Ali] US FDA, CDER, Off New Drug Qual Assessment, Silver Spring, MD 20993 USA. RP Keire, DA (reprint author), FDA DPA, 1114 Market St, St Louis, MO 63101 USA. EM David.Keire@fda.hhs.gov FU FDA Critical Path grant program FX The agency gratefully acknowledges receipt of APIs from Eisai Pharmaceuticals via Pfizer Inc. (dalteparin sodium), Celgene Corporation (tinzaparin sodium) and sanofi-aventis U.S. LLC (enoxaparin sodium) which were used to develop the tests described in this work. The work performed in the study was supported in part by the FDA Critical Path grant program. NR 38 TC 11 Z9 11 U1 1 U2 28 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD NOV PY 2013 VL 85 BP 99 EP 107 DI 10.1016/j.jpba.2013.06.033 PG 9 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 217HS UT WOS:000324351200014 PM 23917037 ER PT J AU Sommers, CD Pang, ES Ghasriani, H Berendt, RT Vilker, VL Keire, DA Boyne, MT AF Sommers, Cynthia D. Pang, Eric S. Ghasriani, Houman Berendt, Robert T. Vilker, Vincent L. Keire, David A. Boyne, Michael T., II TI Analyses of marketplace tacrolimus drug product quality: Bioactivity, NMR and LC-MS SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Drug product quality; Ascomycin; Drug product impurities; Immunosuppression; Generic drugs ID TANDEM MASS-SPECTROMETRY; LIQUID-CHROMATOGRAPHY; CYCLOSPORINE-A; TRANSPLANT RECIPIENTS; RENAL-TRANSPLANTATION; GENERIC DRUGS; WHOLE-BLOOD; FK506; IMMUNOSUPPRESSION; FK-506 AB Tacrolimus (FK506) is a potent, narrow therapeutic index, immunosuppressive drug used to avoid organ rejection in patients that have undergone organ transplantation. Recent clinical reports suggested a significant reduction in the tacrolimus concentration/dose ratio in the plasma of liver and kidney recipients when the reference listed drug was substituted with a generic drug. In response to these concerns about switching between tacrolimus from different approved manufacturers during treatment, the FDA initiated purity, potency and quality studies of the innovator and generic tacrolimus products available in the US marketplace. A combination of analytical methods, including mass spectrometry (LC-MS), nuclear magnetic resonance (NMR) and bioactivity assay were developed and validated to assess the quality of tacrolimus. These tests measured the identity, impurities and activity of tacrolimus from active pharmaceutical ingredient (API) sources and with formulated drug product from five different approved manufactures. In addition, some testing was performed on tacrolimus capsules obtained from a non US approved Indian source. The data obtained showed no discernible difference in the impurity profiles and potency between the generic and innovator tacrolimus products. (C) 2013 Published by Elsevier B.V. C1 [Sommers, Cynthia D.; Ghasriani, Houman; Keire, David A.; Boyne, Michael T., II] US FDA, CDER, Div Pharmaceut Anal, St Louis, MO 63101 USA. [Pang, Eric S.] US FDA, CDER, Div Drug Safety Res, Silver Spring, MD 20993 USA. [Berendt, Robert T.] US FDA, CDER, Div Prod Qual Res, Silver Spring, MD 20993 USA. [Vilker, Vincent L.] US FDA, CDER, Off Testing & Res, Silver Spring, MD 20993 USA. RP Boyne, MT (reprint author), 10903 New Hampshire Ave,WO 64 Rm 2062, Silver Spring, MD 20993 USA. EM Michael.Boyne@fda.hhs.gov FU Center for Drug Evaluation and Research; US Food and Drug Administration FX This project was supported in part by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Engineering and the US Food and Drug Administration for E.P and H.G. NR 38 TC 4 Z9 4 U1 0 U2 22 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD NOV PY 2013 VL 85 BP 108 EP 117 DI 10.1016/j.jpba.2013.07.001 PG 10 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 217HS UT WOS:000324351200015 PM 23917038 ER PT J AU Zhang, BL Chen, JJ Di, X Zhang, YQ AF Zhang, Baolin Chen, Junjie Di, Xu Zhang, Yaqin TI Overcoming cancer resistance to death receptor targeted therapies SO MOLECULAR CANCER THERAPEUTICS LA English DT Meeting Abstract C1 [Zhang, Baolin; Chen, Junjie; Di, Xu; Zhang, Yaqin] US FDA, Bethesda, MD 20014 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD NOV PY 2013 VL 12 IS 11 SU S MA B246 DI 10.1158/1535-7163.TARG-13-B246 PG 1 WC Oncology SC Oncology GA V40RX UT WOS:000209496800414 ER PT J AU Desai, D Wang, J Wen, H Li, XH Timmins, P AF Desai, Divyakant Wang, Jennifer Wen, Hong Li, Xuhong Timmins, Peter TI Formulation design, challenges, and development considerations for fixed dose combination (FDC) of oral solid dosage forms SO PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY LA English DT Review DE Fixed dose combination; FDC; formulations; an active coating; HME; bi-layer tablet ID DRUG-DELIVERY SYSTEM; BILAYER TABLETS; RELEASE FORMULATIONS; IMMEDIATE-RELEASE; SUSTAINED-RELEASE; MATRIX TABLET; IN-VITRO; PELLETS; SPHERONIZATION; HYDROCHLORIDE AB Fixed dose combination (FDC) products are common in the treatment of hypertension, diabetes, human immunodeficiency virus, and tuberculosis. They make it possible to combine two or more drug molecules with different modes of pharmacological actions in a single dosing unit and optimize the treatment. From a patient perspective, they offer convenience, reduced dosing unit burden, and cost savings. From a clinical perspective, aging population in developed countries will need multiple medications to treat age related diseases and co-morbidities. FDC products simplify dosing regimen and enhance patient compliance. As outlined in the article, the number of FDC products has grown over the years and the trend is likely to continue. This review article gives an overview to pharmaceutical scientists about recent trends in the formulation development of the FDC products and provides decision trees to select most optimum formulation development strategy. While some formulation technologies such as multi-layer tablets, multiparticulate systems, active film coating, and hot-melt granulation are discussed in more detail, a few specialized technologies are also introduced briefly to the readers. C1 [Desai, Divyakant; Wang, Jennifer] Bristol Myers Squibb Co, Drug Prod Sci & Technol, New Brunswick, NJ 08903 USA. [Wen, Hong] Pentian Pharmaceut Co, Shanghai, Peoples R China. [Li, Xuhong] US FDA, CDER, Silver Spring, MD USA. [Timmins, Peter] Bristol Myers Squibb Co, Drug Prod Sci & Technol, Moreton, Merseyside, England. RP Desai, D (reprint author), Bristol Myers Squibb Co, Drug Prod Sci & Technol, POB 191, New Brunswick, NJ 08903 USA. EM divyakant.desai@bms.com NR 66 TC 11 Z9 12 U1 1 U2 113 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1083-7450 J9 PHARM DEV TECHNOL JI Pharm. Dev. Technol. PD NOV-DEC PY 2013 VL 18 IS 6 BP 1265 EP 1276 DI 10.3109/10837450.2012.660699 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 209CD UT WOS:000323730700001 PM 22339230 ER PT J AU Gordon, S Naelapaa, K Rantanen, J Selen, A Mullertz, A Ostergaard, J AF Gordon, Sarah Naelapaa, Kaisa Rantanen, Jukka Selen, Arzu Mullertz, Anette Ostergaard, Jesper TI Real-time dissolution behavior of furosemide in biorelevant media as determined by UV imaging SO PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY LA English DT Article DE Flow through Raman spectroscopy; UV/Vis spectroscopy; biorelevant dissolution testing; simulated intestinal media ID CONVECTIVE-DIFFUSION MODEL; CHANNEL FLOW CELL; INTRINSIC DISSOLUTION; PHARMACEUTICAL APPLICATIONS; PHASE-TRANSFORMATIONS; SOLUBLE DRUGS; DOSAGE FORMS; RELEASE; BIOAVAILABILITY; SPECTROSCOPY AB The potential of UV imaging as a new small scale flow-through dissolution testing platform and its ability to incorporate biorelevant media was tested. Furosemide was utilized as a model poorly soluble drug, and dissolution media simulating conditions in the small intestine (5/1.25 mM and 40/10 mM bile salt/phospholipid, pH 6.5) together with corresponding blank buffer were employed. Dissolution rates as a function of flow rate (0.2-1.0 mL/min) were determined directly from UV images, and by analysis of collected effluent using UV spectrophotometry. A good agreement in dissolution rates was observed, however repeatability of data based on measurement of collected effluent was superior to that obtained by UV imaging in the utilized prototypic flow cell. Both methods indicated that biorelevant media did not markedly increase the dissolution rate of furosemide as compared to buffer. Qualitatively, UV images indicated that uncontrolled swelling/precipitation of furosemide on the compact surface was occurring in some samples. In situ Raman spectroscopy together with X-ray diffraction analysis confirmed that the observations were not due to a solid form transformation of furosemide. The presented results highlight the complementary features of the utilized techniques and, in particular, the detailed information related to dissolution behavior which can be achieved by UV imaging. C1 [Gordon, Sarah; Naelapaa, Kaisa; Rantanen, Jukka; Mullertz, Anette; Ostergaard, Jesper] Univ Copenhagen, Dept Pharm, Fac Hlth & Med Sci, DK-2100 Copenhagen, Denmark. [Selen, Arzu] US FDA, Silver Spring, MD USA. [Mullertz, Anette] Univ Copenhagen, Bioneer FARMA, Dept Pharm, Fac Hlth & Med Sci, DK-2100 Copenhagen, Denmark. RP Ostergaard, J (reprint author), Univ Copenhagen, Dept Pharm, Fac Hlth & Med Sci, Univ Pk 2, DK-2100 Copenhagen, Denmark. EM jesper.ostergaard@sund.ku.dk RI Ostergaard, Jesper/A-9922-2011; Rantanen, Jukka/B-9413-2008; OI Rantanen, Jukka/0000-0002-8211-5607; Mullertz, Anette/0000-0003-3020-8892 FU FDA Center for Drug Evaluation and Research Critical Path Funding Program FX This research project was in part financially supported by the FDA Center for Drug Evaluation and Research Critical Path Funding Program. The views expressed in this article are those of the authors and do not necessarily reflect the opinions of their companies/institutions or the official policy of the FDA. No official endorsement by the FDA is intended or should be inferred. The authors report no conflict of interest. The authors alone are responsible for the content and writing of this paper. NR 48 TC 5 Z9 5 U1 0 U2 23 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1083-7450 J9 PHARM DEV TECHNOL JI Pharm. Dev. Technol. PD NOV-DEC PY 2013 VL 18 IS 6 BP 1407 EP 1416 DI 10.3109/10837450.2012.737808 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 209CD UT WOS:000323730700018 PM 23136844 ER PT J AU Lienau, EK Blazar, JM Wang, C Brown, EW Stones, R Musser, S Allard, MW AF Lienau, E. Kurt Blazar, Jeffrey M. Wang, Charles Brown, Eric W. Stones, Robert Musser, Steven Allard, Marc W. TI Phylogenomic Analysis Identifies Gene Gains That Define Salmonella enterica Subspecies I SO PLOS ONE LA English DT Article ID TREE; EVOLUTION; CLASSIFICATION; PATHOGENS; LIFE AB Comparative methods for analyzing whole genome sequence (WGS) data enable us to assess the genetic information available for reconstructing the evolutionary history of pathogens. We used the comparative approach to determine diagnostic genes for Salmonella enterica subspecies I. S. enterica subsp. I strains are known to infect warm-blooded organisms regularly while its close relatives tend to infect only cold-blooded organisms. We found 71 genes gained by the common ancestor of Salmonella enterica subspecies I and not subsequently lost by any member of this subspecies sequenced to date. These genes included many putative functional phenotypes. Twenty-seven of these genes are found only in Salmonella enterica subspecies I; we designed primers to test these genes for use as diagnostic sequence targets and data mined the NCBI Sequence Read Archive (SRA) database for draft genomes which carried these genes. We found that the sequence specificity and variability of these amplicons can be used to detect and discriminate among 317 different serovars and strains of Salmonella enterica subspecies I. C1 [Lienau, E. Kurt; Blazar, Jeffrey M.; Wang, Charles; Brown, Eric W.; Musser, Steven; Allard, Marc W.] US FDA, Off Ctr Director, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Lienau, E. Kurt] Evolut Ind LLC, Frederick, MD USA. [Blazar, Jeffrey M.] Univ Maryland, Dept Biol, College Pk, MD 20742 USA. [Stones, Robert] Food & Environm Res Agcy, York, N Yorkshire, England. RP Lienau, EK (reprint author), US FDA, Off Ctr Director, Ctr Food Safety & Appl Nutr, College Pk, MD USA. EM kurt.lienau@evolutionindustriesllc.com; marc.allard@fda.hhs.gov FU Center for Food Safety and Applied Nutrition (CFSAN) of the United States Internal Food and Drug Administration (FDA); Oak Ridge Institute for Science Education; Evolution Industries LLC FX All funds for this research came from The Center for Food Safety and Applied Nutrition (CFSAN) of the United States Internal Food and Drug Administration (FDA) research funds. E. Kurt Lienau was partially supported by a grant from the Oak Ridge Institute for Science Education and by Evolution Industries LLC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 3 Z9 3 U1 2 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 28 PY 2013 VL 8 IS 10 AR e76821 DI 10.1371/journal.pone.0076821 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 242KW UT WOS:000326241200014 PM 24204679 ER PT J AU Nemecek, J Nag, N Carlson, CM Schneider, JR Heisey, DM Johnson, CJ Asher, DM Gregori, L AF Nemecek, Julie Nag, Nabanita Carlson, Christina M. Schneider, Jay R. Heisey, Dennis M. Johnson, Christopher J. Asher, David M. Gregori, Luisa TI Red-Backed Vole Brain Promotes Highly Efficient In Vitro Amplification of Abnormal Prion Protein from Macaque and Human Brains Infected with Variant Creutzfeldt-Jakob Disease Agent SO PLOS ONE LA English DT Article ID MISFOLDING CYCLIC AMPLIFICATION; BLOOD-TRANSFUSION; PRPSC; ASSAY; VCJD; PROPAGATION; CONVERSION; PATIENT; BSE; CJD AB Rapid antemortem tests to detect individuals with transmissible spongiform encephalopathies (TSE) would contribute to public health. We investigated a technique known as protein misfolding cyclic amplification (PMCA) to amplify abnormal prion protein (PrPTSE) from highly diluted variant Creutzfeldt-Jakob disease (vCJD)-infected human and macaque brain homogenates, seeking to improve the rapid detection of PrPTSE in tissues and blood. Macaque vCJD PrPTSE did not amplify using normal macaque brain homogenate as substrate (intraspecies PMCA). Next, we tested interspecies PMCA with normal brain homogenate of the southern red-backed vole (RBV), a close relative of the bank vole, seeded with macaque vCJD PrPTSE. The RBV has a natural polymorphism at residue 170 of the PrP-encoding gene (N/N, S/S, and S/N). We investigated the effect of this polymorphism on amplification of human and macaque vCJD PrPTSE. Meadow vole brain (170N/N PrP genotype) was also included in the panel of substrates tested. Both humans and macaques have the same 170S/S PrP genotype. Macaque PrPTSE was best amplified with RBV 170S/S brain, although 170N/N and 170S/N were also competent substrates, while meadow vole brain was a poor substrate. In contrast, human PrPTSE demonstrated a striking narrow selectivity for PMCA substrate and was successfully amplified only with RBV 170S/S brain. These observations suggest that macaque PrPTSE was more permissive than human PrPTSE in selecting the competent RBV substrate. RBV 170S/S brain was used to assess the sensitivity of PMCA with PrPTSE from brains of humans and macaques with vCJD. PrPTSE signals were reproducibly detected by Western blot in dilutions through 10(-12) of vCJD-infected 10% brain homogenates. This is the first report showing PrPTSE from vCJD-infected human and macaque brains efficiently amplified with RBV brain as the substrate. Based on our estimates, PMCA showed a sensitivity that might be sufficient to detect PrPTSE in vCJD-infected human and macaque blood. C1 [Nemecek, Julie; Nag, Nabanita; Asher, David M.; Gregori, Luisa] US FDA, Lab Bacterial & TSE Agents, Div Emerging Transfus Transmitted Dis, Off Blood Res & Review,Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Carlson, Christina M.; Schneider, Jay R.; Heisey, Dennis M.; Johnson, Christopher J.] US Geol Survey, Natl Wildlife Hlth Ctr, Madison, WI USA. [Carlson, Christina M.] Univ Wisconsin, Program Cellular & Mol Biol, Madison, WI USA. RP Gregori, L (reprint author), US FDA, Lab Bacterial & TSE Agents, Div Emerging Transfus Transmitted Dis, Off Blood Res & Review,Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. EM luisa.gregori@fda.hhs.gov RI Johnson, Christopher/B-1436-2009; Carlson, Christina/D-8327-2013; Carlson, Christina/P-6507-2015 OI Johnson, Christopher/0000-0003-4539-2581; Carlson, Christina/0000-0002-4950-8273; Carlson, Christina/0000-0002-4950-8273 FU FDA Commissioner's fellowship program; FDA Chief Scientist Challenge Award; USGS Wildlife: Terrestrial and Endangered Resources Program FX This work was supported by the FDA Commissioner's fellowship program and by an FDA Chief Scientist Challenge Award. Support also came from the USGS Wildlife: Terrestrial and Endangered Resources Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 4 Z9 4 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 24 PY 2013 VL 8 IS 10 AR e78710 DI 10.1371/journal.pone.0078710 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 241FR UT WOS:000326152300080 PM 24205298 ER PT J AU Cheng, J Greshock, J Shi, LM Zheng, S Menius, A Lee, K AF Cheng, Jie Greshock, Joel Shi, Leming Zheng, Shu Menius, Alan Lee, Kwan TI Good practice guidelines for biomarker discovery from array data: a case study for breast cancer prognosis SO BMC SYSTEMS BIOLOGY LA English DT Article ID VALIDATION; SIGNATURE; THERAPY; WOMEN AB Background: Biomarker discovery holds the promise for advancing personalized medicine as the biomarkers can help match patients to optimal treatment to improve patient outcomes. However, serious concerns have been raised because very few molecular biomarkers or signatures discovered from high dimensional array data can be successfully validated and applied to clinical use. We propose good practice guidelines as well as a novel tool for biomarker discovery and use breast cancer prognosis as a case study to illustrate the proposed approach. Results: We applied the proposed approach to a publicly available breast cancer prognosis dataset and identified small numbers of predictive markers for patient subpopulations stratified by clinical variables. Results from an independent cross-platform validation set show that our model compares favorably to other gene signature and clinical variable based prognostic tools. About half of the discovered candidate markers can individually achieve very good performance, which further demonstrate the high quality of feature selection. These candidate markers perform extremely well for young patient with estrogen receptor-positive, lymph node-negative early stage breast cancers, suggesting a distinct subset of these patients identified by these markers is actually at high risk of recurrence and may benefit from more aggressive treatment than cur-rent practice. Conclusion: The results show that by following good practice guidelines, we can identify highly predictive genes in high dimensional breast cancer array data. These predictive genes have been successfully validated using an independent cross-platform dataset. C1 [Cheng, Jie; Menius, Alan; Lee, Kwan] GlaxoSmithKline, Quantitat Sci, Collegeville, PA 19426 USA. [Greshock, Joel] GlaxoSmithKline, Canc Res, Collegeville, PA 19426 USA. [Shi, Leming] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Zheng, Shu] Zhejiang Univ, Inst Canc, Hangzhou 310009, Zhejiang, Peoples R China. RP Cheng, J (reprint author), GlaxoSmithKline, Quantitat Sci, Collegeville, PA 19426 USA. NR 15 TC 4 Z9 4 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD OCT 23 PY 2013 VL 7 SU 4 AR S2 DI 10.1186/1752-0509-7-S4-S2 PG 7 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 249VU UT WOS:000326808900002 PM 24565120 ER PT J AU Zhao, K Zhang, LZ Wang, JJ Li, QX He, WW Yin, JJ AF Zhao, Kun Zhang, Lizhi Wang, Jiajun Li, Qunxiang He, Weiwei Yin, Jun Jie TI Surface Structure-Dependent Molecular Oxygen Activation of BiOCl Single-Crystalline Nanosheets SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PHOTOCATALYTIC ACTIVITY; ELECTRONIC-STRUCTURE; TIO2(110); O-2; OXIDATION; DIOXYGEN; SUPEROXIDE; MECHANISM; RADICALS AB We demonstrate that BiOCl single-crystalline nanosheets possess surface structure-dependent molecular oxygen activation properties under UV light. The (001) surface of BiOCl prefers to reduce O-2 to center dot O-2(-) through one-electron transfer, while the (010) surface favors the formation of O-2(2-) via two-electron transfer, which is cogoverned by the surface atom exposure and the situ generated oxygen vacancy characteristics of the (001) and (010) surfaces under UV light irradiation. C1 [Zhao, Kun; Zhang, Lizhi] Cent China Normal Univ, Coll Chem, Inst Environm Chem, Minist Educ,Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China. [Wang, Jiajun; Li, Qunxiang] Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230026, Anhui, Peoples R China. [He, Weiwei; Yin, Jun Jie] Food & Drug Adm, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Zhang, LZ (reprint author), Cent China Normal Univ, Coll Chem, Inst Environm Chem, Minist Educ,Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China. EM zhanglz@mail.ccnu.edu.cn RI Li, Qunxiang/D-3705-2009; Yin, Jun Jie /E-5619-2014; Wang, Jiajun/B-7287-2017 OI Li, Qunxiang/0000-0003-1988-1971; FU National Basic Research Program of China (973 Program) [2013CB632402, 2011CB921404]; National Science Foundation of China [21073069, 91023010, 21177048]; FDA Nanotechnology CORES Program; Office of Cosmetics and Colors, CFSAN/FDA FX This work was supported by the National Basic Research Program of China (973 Program) (grants 2013CB632402 and 2011CB921404) and the National Science Foundation of China (grants 21073069, 91023010, and 21177048) and was partially supported by a regulatory science grant under the FDA Nanotechnology CORES Program and by the Office of Cosmetics and Colors, CFSAN/FDA (W.H and J.Y). We would like to thank Barbara Berman for the English writing improvement. NR 28 TC 118 Z9 119 U1 46 U2 279 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 EI 1520-5126 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD OCT 23 PY 2013 VL 135 IS 42 BP 15750 EP 15753 DI 10.1021/ja4092903 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 242CV UT WOS:000326215900022 PM 24116848 ER PT J AU Nazarov, C Lo Surdo, J Bauer, SR Wei, CH AF Nazarov, Cristina Lo Surdo, Jessica Bauer, Steven R. Wei, Cheng-Hong TI Assessment of immunosuppressive activity of human mesenchymal stem cells using murine antigen specific CD4 and CD8 T cells in vitro SO STEM CELL RESEARCH & THERAPY LA English DT Article ID STROMAL CELLS; LYMPHOCYTE-PROLIFERATION; CEREBRAL-ISCHEMIA; INTERFERON-GAMMA; INHIBIT; EXPRESSION; RESPONSES; SUPPRESS; REPAIR; DIFFERENTIATION AB Introduction: Mesenchymal stem cells (MSCs) have immunosuppressive activity. They do not induce allospecific T cell responses, making them promising tools for reducing the severity of graft versus host disease (GVHD) as well as treating various immune diseases. Currently, there is a need in the MSC field to develop a robust in vitro bioassay which can characterize the immunosuppressive function of MSCs. Methods: Murine clonal CD4 and CD8 T cells were stimulated with cognate peptide antigen and antigen presenting cells (APCs) in the absence or presence of human MSCs, different aspects of T cell activation were monitored and analyzed using flow cytometery, real time RT-PCR and cytokine measurement. Results: Human MSCs (hMSCs) can alter multiple aspects of murine T cell activation induced by stimulation with specific antigen, including: reduced proliferation, inhibited or stimulated cell surface marker expression (CD25, CD69, CD44 and CD62L), inhibited mRNA expression of transcription factors (T-bet and GATA-3) and decreased cytokine expression (interferon-gamma, interleukin-10). Disappearance of activation-induced cluster formation and decreased apoptosis of CD8 T cells were also observed. Moreover, the effects are specific to MSCs; incubating the T cells with non-MSC control cell lines had no effect on T cell proliferation and activation. Conclusions: Clonal murine T cells can be used to measure, characterize, and quantify the in vitro immunosuppressive activity of human MSCs, representing a promising approach to improve bioassays for immunosuppression. C1 [Nazarov, Cristina; Wei, Cheng-Hong] US FDA, Gene Transfer & Immunogen Branch, Div Cellular & Gene Therapies, Off Cellular Tissue & Gene Therapies,Ctr Biol Eva, Bethesda, MD 20892 USA. [Lo Surdo, Jessica; Bauer, Steven R.] US FDA, Cellular & Tissue Therapies Branch, Div Cellular & Gene Therapies, Off Cellular Tissue & Gene Therapies,Ctr Biol Eva, Bethesda, MD 20892 USA. [Wei, Cheng-Hong] US FDA, Ctr Biol Evaluat & Res, NIH, Bethesda, MD 20892 USA. RP Wei, CH (reprint author), US FDA, Gene Transfer & Immunogen Branch, Div Cellular & Gene Therapies, Off Cellular Tissue & Gene Therapies,Ctr Biol Eva, Bethesda, MD 20892 USA. EM chenghong.wei@fda.hhs.gov FU FDA Modernizing Science grant program; FDA medical countermeasures initiative (MCMi); Division of Cellular and Gene Therapies; Oak Ridge Institute for Science and Education FX This work was supported by the FDA Modernizing Science grant program, the FDA medical countermeasures initiative (MCMi) as well as the Division of Cellular and Gene Therapies. Cristina Nazarov and Jessica Lo Surdo were supported through fellowship administered by the Oak Ridge Institute for Science and Education. The authors would like to thank Drs. Andrew Byrnes and Graeme Price for critically reviewing this manuscript and Jean Manirarora for assistance with the breeding and typing of the TCR transgenic mice. NR 48 TC 8 Z9 9 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-6512 J9 STEM CELL RES THER JI Stem Cell Res. Ther. PD OCT 22 PY 2013 VL 4 AR 128 DI 10.1186/scrt339 PG 15 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 282PD UT WOS:000329183300001 PM 24406271 ER PT J AU Lipshultz, SE Adams, J Colan, SD Constine, LS Herman, EH Hsu, DT Hudson, MM Kremer, LC Landy, DC Miller, TL Oeffinger, KC Rosenthal, DN Sable, CA Sallan, SE Singh, GK Steinberger, J Cochran, TR Wilkinson, JD AF Lipshultz, Steven E. Adams, Jacob Colan, Steven D. Constine, Louis S. Herman, Eugene H. Hsu, Daphne T. Hudson, Melissa M. Kremer, Leontien C. Landy, David C. Miller, Tracie L. Oeffinger, Kevin C. Rosenthal, David N. Sable, Craig A. Sallan, Stephen E. Singh, Gautam K. Steinberger, Julia Cochran, Thomas R. Wilkinson, James D. CA Council Cardiovasc Dis Young Council Basic Cardiovasc Sci Council Cardiovasc Stroke Nursing Council Cardiovasc Radiology Council Clinical Cardiology Council Epidemiology Prevention Council Nutr Phys Activity Metab TI Long-term Cardiovascular Toxicity in Children, Adolescents, and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research Directions A Scientific Statement From the American Heart Association SO CIRCULATION LA English DT Article DE AHA Scientific Statements; adolescent; antineoplastic agents; cancer; children; prevention and control; toxicity ID ACUTE LYMPHOBLASTIC-LEUKEMIA; BODY-MASS-INDEX; CORONARY-ARTERY-DISEASE; ANTHRACYCLINE-INDUCED CARDIOTOXICITY; GROWTH-HORMONE DEFICIENCY; DOXORUBICIN-INDUCED CARDIOMYOPATHY; HEMATOPOIETIC-CELL TRANSPLANTATION; PEDIATRIC HODGKINS-DISEASE; GH-REPLACEMENT THERAPY; CARDIAC RISK-FACTORS C1 [Lipshultz, Steven E.; Landy, David C.; Miller, Tracie L.; Cochran, Thomas R.; Wilkinson, James D.] Univ Miami, Miller Sch Med, Coral Gables, FL 33124 USA. [Adams, Jacob] Univ Rochester, Rochester, NY 14627 USA. [Colan, Steven D.] Childrens Hosp Boston, Boston, MA USA. [Constine, Louis S.] Univ Rochester, Med Ctr, Rochester, NY 14627 USA. [Herman, Eugene H.] US FDA, Rockville, MD 20857 USA. [Hsu, Daphne T.] Childrens Hosp Montefiore, New York, NY USA. [Hudson, Melissa M.] St Jude Childrens Res Hosp, Memphis, TN USA. [Kremer, Leontien C.] Acad Med Ctr Meibergdreeg Amsterdam, Amsterdam, Netherlands. [Oeffinger, Kevin C.] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Rosenthal, David N.] Stanford Univ, Stanford, CA 94305 USA. [Sable, Craig A.] Childrens Natl Med Ctr, Washington, DC USA. [Sallan, Stephen E.] Dana Farber Canc Inst, Boston, MA USA. [Singh, Gautam K.] Washington Univ, St Louis, MO 63130 USA. [Steinberger, Julia] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. RP Lipshultz, SE (reprint author), Univ Miami, Miller Sch Med, Coral Gables, FL 33124 USA. OI Steinberger, Julia/0000-0002-2892-8594 NR 699 TC 90 Z9 91 U1 2 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 22 PY 2013 VL 128 IS 17 BP 1927 EP 1995 DI 10.1161/CIR.0b013e3182a88099 PG 69 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 239LP UT WOS:000326026200019 PM 24081971 ER PT J AU Brunner, CC Kyprianou, IS AF Brunner, Claudia C. Kyprianou, Iacovos S. TI Material-specific transfer function model and SNR in CT SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID COMPUTED-TOMOGRAPHY; NOISE; MTF; PERFORMANCE; ALGORITHMS; RESOLUTION; OBSERVER AB This study presents an analytical model for the edge spread function (ESF) of a clinical CT system that allows reliable fits of noisy ESF data. The model was used for the calculation of the material-specific transfer function T-F and an estimation of the signal transfer and the signal-to-noise ratio (SNR) in 2D. Images of the Catphan phantom were acquired with a clinical Siemens Somatom Sensation Cardiac 64 CT scanner combining four different x-ray tube outputs (40, 150, 250 and 350 mAs) with four different reconstruction filters, which covered the range from very smooth (B10s) to very sharp (B70s). The images of the high-and mid-contrast cylinders of the phantom's 'Geometry and Sensitometry' module (air, Teflon, Delrin and PMP) were used to sample material-specific ESF curves. The ESF curves were fitted with the analytical model we developed based on a linear combination of Boltzmann and Gaussian functions. The analytical model of the ESF was used to obtain the Fourier-based material-specific transfer function T-F, as well as the spatial-domain point spread function (PSF). T-F was subsequently used to estimate the signal transfer, which was compared to the actual reconstructed image of a 3.0 mm diameter Teflon pin. The noise power spectrum (NPS) was calculated from images of a uniform water phantom under the same technique parameters. The task-specific SNR was calculated for all technique parameters from the model-based T-F, the measured NPS and simulated 3 mm diameter disc signals modeling the aforementioned materials. Bootstrapping was performed to estimate the standard deviation of the T-F and the SNR. The analytical model we developed accurately captured the features of the CT ESF data. The coefficient of determination R-2, a metric that describes the goodness of the fit, had a median value of 0.9995, and decreased for low tube output, low contrast and the sharp reconstruction filter. Our analysis showed that ESF, PSF and T-F depended not only on the reconstruction filter, but also on the tube output and the material of the cylinders. For B40s and B70s, the T-F of Delrin was significantly higher than the T-F of other materials in the frequency range of 0.4-0.9 mm(-1). The estimated signal transfer agreed well with the actual reconstructed image of the Teflon pin. For the technique parameters we used the SNR values ranged between [64, 320], [64, 281], [37, 137] and [33, 117] for air, Teflon, Delrin and PMP respectively. While for high-contrast materials the smoothest reconstruction filter resulted in the highest SNR, for mid-contrast materials the standard filter gave the best results. The presented approach provides an accurate, analytical description of the material-specific ESF, PSF and T-F as well as an estimate of the signal transfer. The transfer function T-F together with the NPS and simulated signals allow the calculation of a task-specific SNR. C1 [Brunner, Claudia C.; Kyprianou, Iacovos S.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Kyprianou, IS (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM iacovos.kyprianou@fda.hhs.gov NR 28 TC 4 Z9 4 U1 2 U2 3 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD OCT 21 PY 2013 VL 58 IS 20 BP 7447 EP 7461 DI 10.1088/0031-9155/58/20/7447 PG 15 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 228FY UT WOS:000325172500025 PM 24081016 ER PT J AU Martinez-Urtaza, J Baker-Austin, C Jones, JL Newton, AE Gonzalez-Aviles, GD DePaola, A AF Martinez-Urtaza, Jaime Baker-Austin, Craig Jones, Jessica L. Newton, Anna E. Gonzalez-Aviles, Gladys D. DePaola, Angelo TI Spread of Pacific Northwest Vibrio parahaemolyticus Strain SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter AB In this letter, the virulent Pacific Northwest clone of Vibrio parahaemolyticus was shown to have spread and caused considerable illness in persons on the Atlantic coasts of the United States and Spain.To the Editor: Globally, Vibrio parahaemolyticus is a leading cause of seafood-associated gastroenteritis. Historically, the V. parahaemolyticus serotypes O4:K12 and O4:KUT, which have been shown to be more virulent than other pathogenic V. parahaemolyticus strains, have been unique to the Pacific Northwest region.(1) These strains, which were first identified in the Pacific Northwest in 1988, caused large U.S. outbreaks in 1997 and 2004.(2) The outbreaks were linked to consumption of Pacific shellfish, but these strains have not been linked to illness or isolated outside the Pacific Northwest until recently. During the summer of 2012, outbreaks of V. parahaemolyticus infection caused ... C1 [Martinez-Urtaza, Jaime] European Ctr Dis Prevent & Control, Stockholm, Sweden. [Baker-Austin, Craig] Ctr Environm Fisheries & Aquaculture Sci, Weymouth, England. [Jones, Jessica L.; DePaola, Angelo] US FDA, Dauphin Isl, AL USA. [Newton, Anna E.; Gonzalez-Aviles, Gladys D.] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Martinez-Urtaza, J (reprint author), European Ctr Dis Prevent & Control, Stockholm, Sweden. EM craig.baker-austin@cefas.co.uk RI Martinez-Urtaza, Jaime/A-5528-2015 FU Intramural CDC HHS [CC999999] NR 5 TC 24 Z9 25 U1 0 U2 13 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 17 PY 2013 VL 369 IS 16 BP 1573 EP 1574 DI 10.1056/NEJMc1305535 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 267MJ UT WOS:000328101700030 PM 24131194 ER PT J AU Botros, LL Jablonski, J Chang, C Bergana, MM Wehling, P Harnly, JM Downey, G Harrington, P Potts, AR Moore, JC AF Botros, Lucy L. Jablonski, Joseph Chang, Claire Bergana, Marti Mamula Wehling, Paul Harnly, James M. Downey, Gerard Harrington, Peter Potts, Alan R. Moore, Jeffrey C. TI Exploring Authentic Skim and Nonfat Dry Milk Powder Variance for the Development of Nontargeted Adulterant Detection Methods Using Near-Infrared Spectroscopy and Chemometrics SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE skim milk powder; nonfat dry milk; melamine; NIR spectroscopy; chemometrics; PCA; varimax; compendial; diffuse reflectance; variance ID DAIRY-PRODUCTS; FOOD PROTEIN; SPECTRA AB A multinational collaborative team led by the U.S. Pharmacopeial Convention is currently investigating the potential of near-infrared (NW) spectroscopy for nontargeted detection of adulterants in skim and nonfat dry milk powder. The development of a compendial method is challenged by the range of authentic or nonadulterated milk powders available worldwide. This paper investigates the sources of variance in 41 authentic bovine skim and nonfat milk powders as detected by NIR diffuse reflectance spectroscopy and chemometrics. Exploratory analysis by principal component analysis and varimax factor rotation revealed significant variance in authentic samples and highlighted outliers from a single manufacturer. Spectral preprocessing and outlier removal methods reduced ambient and measurement sources of variance, most likely linked to changes in moisture together with sampling, preparation, and presentation factors. Results indicate that significant chemical variance exists in different skim and nonfat milk powders that will likely affect the performance of adulterant detection methods by NIR spectroscopy. C1 [Botros, Lucy L.; Potts, Alan R.; Moore, Jeffrey C.] US Pharmacopeial Convent Inc, Rockville, MD 20852 USA. [Jablonski, Joseph; Chang, Claire] US FDA, Ctr Food Safety & Appl Nutr, Div Food Proc Sci & Technol, Bedford Pk, IL 60501 USA. [Bergana, Marti Mamula] Abbott Labs, Abbott Nutr Div, Columbus, OH 43219 USA. [Wehling, Paul] Gen Mills Inc, Minneapolis, MN 55414 USA. [Harnly, James M.] ARS, Food Composit & Methods Dev Lab, Beltsville Human Nutr Res Ctr, USDA,BARC East, Beltsville, MD 20817 USA. [Downey, Gerard] Teagasc Food Res Ctr Ashtown, Dublin 15, Ireland. [Harrington, Peter] Ohio Univ, Ctr Intelligent Chem Instrumentat, Dept Chem & Biochem, Clippinger Labs, Athens, OH 45701 USA. RP Botros, LL (reprint author), US Pharmacopeial Convent Inc, 12601 Twinbrook Pkwy, Rockville, MD 20852 USA. EM lyb@usp.org RI Downey, Gerard/G-5840-2011; OI Downey, Gerard/0000-0002-6633-1270; Harrington, Peter/0000-0003-0268-8630 NR 21 TC 12 Z9 12 U1 1 U2 44 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 EI 1520-5118 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD OCT 16 PY 2013 VL 61 IS 41 BP 9810 EP 9818 DI 10.1021/jf4023433 PG 9 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA 240VF UT WOS:000326125100009 PM 24040827 ER PT J AU Sarkar, S Raymick, J Paule, MG Schmued, L AF Sarkar, Sumit Raymick, James Paule, Merle G. Schmued, Larry TI In situ demonstration of Fluoro-Turquoise conjugated gelatin for visualizing brain vasculature and endothelial cells and their characterization in normal and kainic acid exposed animals SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Endothelial cell; Blood-brain barrier; Blood vessel; Fluorescent dextran; FT-gel; Fluoro-Turquoise.; Kainic acid ID SCANNING-ELECTRON-MICROSCOPY; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; GRIFFONIA-SIMPLICIFOLIA; SUBSTANTIA-NIGRA; CORROSION CASTS; BLOOD-VESSELS; RAT-BRAIN; BARRIER; MOUSE AB The present study describes a new method for the visualization of the vasculature lumen and endothelial cells and characterizes their morphology in the brains of normal and kainic acid (KA) treated rats. Herein, labeling was accomplished using Fluoro-Turquoise (FT), a novel reactive blue fluorochrome conjugated to gelatin. Strong blue fluorescence was observed throughout the brain vasculature following intra-cardiac perfusion with FT-gel in normal animals. However, in the brains of KA treated rats (hippocampus, midline and ventral thalamus, piriform cortex), the vascular lumen was typically constricted, sclerotic and only faintly stained. The advantages of FT-gel over other markers can be attributed to its unique chemical and spectral properties. Specifically, Fluoro-Turquoise is a very bright blue UV excitable dye that does not bleed through when visualized using other filters, making it ideal for multiple immunofluorescent labeling studies. Its brightness at low magnification also makes it ideal for low magnification whole brain imaging. Compared to alternative techniques for visualizing blood vessels, such as India ink, fluorescent dye-conjugated dextran, the corrosion technique, endothelial cell markers and lectins, the present method results in excellent visualization of blood vessels. Published by Elsevier B.V. C1 [Sarkar, Sumit; Paule, Merle G.; Schmued, Larry] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Raymick, James] Toxicol Pathol Associates, Jefferson, AR 72079 USA. RP Schmued, L (reprint author), US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Bldg 53D,HFT-132, Jefferson, AR 72079 USA. EM Larry.Schmued@FDA.hhs.gov FU FDA [E-7312] FX This work was supported by FDA protocol E-7312. NR 47 TC 4 Z9 4 U1 2 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD OCT 15 PY 2013 VL 219 IS 2 BP 276 EP 284 DI 10.1016/j.jneumeth.2013.07.020 PG 9 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 246SW UT WOS:000326560400010 PM 23954779 ER PT J AU Kolisetty, N Bull, RJ Muralidhara, S Costyn, LJ Delker, DA Guo, ZX Cotruvo, JA Fisher, JW Cummings, BS AF Kolisetty, Narendrababu Bull, Richard J. Muralidhara, Srinivasa Costyn, Leah J. Delker, Don A. Guo, Zhongxian Cotruvo, Joseph A. Fisher, Jeffrey W. Cummings, Brian S. TI Association of brominated proteins and changes in protein expression in the rat kidney with subcarcinogenic to carcinogenic doses of bromate SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Kidney; Nephrotoxicity; Bromate; Water disinfection byproduct; Apoptosis; 3-Bromotyrosine ID POTASSIUM BROMATE; HYPOBROMOUS ACID; OXIDATIVE STRESS; F344 RATS; IN-VIVO; RESPONSE RELATIONSHIP; INDUCED ASTHMA; BIOMARKERS; CLUSTERIN; CELLS AB The water disinfection byproduct bromate (BrO3-) produces cytotoxic and carcinogenic effects in rat kidneys. Our previous studies demonstrated that BrO caused sex-dependent differences in renal gene and protein expression in rats and the elimination of brominated organic carbon in their urine. The present study examined changes in renal cell apoptosis and protein expression in male and female F344 rats treated with BrO3- and associated these changes with accumulation of 3-bromotyrosine (3-BT)-modified proteins. Rats were treated with 0, 11.5, 46 and 308 mg/L BrOi in drinking water for 28 days and renal sections were prepared and examined for apoptosis (TUNEL-staining), 8-oxo-deoxyguanosine (8-oxoG), 3-BT, osteopontin, Kim-1, clusterin, and p-21 expression. TUNEL-staining in renal proximal tubules increased in a dose-related manner beginning at 11.5 mg BrOVL in female rats and 46 mg/L in males. Increased 8-oxoG staining was observed at doses as low as 46 mg/L. Osteopontin expression also increased in a dose-related manner after treatment with 46 mg/L, in males only. In contrast, Kim-1 expression increased in a dose-related manner in both sexes, although to a greater extent in females at the highest dose. Clusterin and p21 expression also increased in a dose-related manner in both sexes. The expression of 3-BT-modified proteins only increased in male rats, following a pattern previously reported for accumulation of alpha-2(u)-globulin. Increases in apoptosis in renal proximal tubules of male and female rats at the lowest doses suggest a common mode of action for renal carcinogenesis for the two sexes that is independent of alpha-2(u)-globulin nephropathy. (C) 2013 Elsevier Inc. All rights reserved. C1 [Kolisetty, Narendrababu; Muralidhara, Srinivasa; Costyn, Leah J.; Cummings, Brian S.] Univ Georgia, Coll Pharm, Dept Pharmaceut & Biomed Sci, Athens, GA 30602 USA. [Bull, Richard J.] MoBull Consulting, Richland, WA 99352 USA. [Delker, Don A.] Univ Utah, Sch Med, Salt Lake City, UT 84132 USA. [Guo, Zhongxian] Publ Util Board, Water Qual Off, Singapore 608576, Singapore. [Cotruvo, Joseph A.] LLC, Joseph Cotruvo & Associates, Washington, DC 20016 USA. [Fisher, Jeffrey W.] FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Cummings, BS (reprint author), Univ Georgia, Coll Pharm, Dept Pharmaceut & Biomed Sci, Athens, GA 30602 USA. EM bsc@rx.uga.edu FU Georgia Cancer Coalition; Joseph Cotruvo Associates LLC; Water Research Foundation [4042]; Water Research Foundation FX We thank Dr. James Bruckner for use of his lab facilities to conduct many of the in vivo studies. We also thank Dr. Robert Arnold for use of his microscope for the immunohistochemistry studies. This work was supported by the Georgia Cancer Coalition and Joseph Cotruvo Associates LLC with grants from the Water Research Foundation Project #4042 International Ozone Assoc., Environment Agency of Abu Dhabi, Veolia Water, Metropolitan Water District of Southern Calif., Los Angeles Department of Water and Power, Singapore Public Utilities Bureau, National Water Research Institute, Walkerton Clean Water Centre, Calleguas Municipal Water District, Long Beach Water Department, and in-kind contributions of the participants. We gratefully acknowledge and thank the Water Research Foundation and all of the sponsors for their financial, technical and administrative assistance in funding the project through which this information was discovered. NR 47 TC 4 Z9 4 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD OCT 15 PY 2013 VL 272 IS 2 BP 391 EP 398 DI 10.1016/j.taap.2013.06.018 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 237XS UT WOS:000325905500015 PM 23811332 ER PT J AU Rahman, Z Siddiqui, A Khan, MA AF Rahman, Ziyaur Siddiqui, Akhtar Khan, Mansoor A. TI Assessing the impact of nimodipine devitrification in the ternary cosolvent system through quality by design approach SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Nimodipine; Polymorph; Crystallization; Cosolvents; Dissolution; NI-chemical imaging ID SOLID DISPERSIONS; FORMULATION; POLYMORPHISM; NANOPARTICLES; OPTIMIZATION; NIFEDIPINE; RAMAN AB Nimodipine (NM) commercial formulation has been recalled due to drug crystallization in the product. Aim of present investigation was to systematically evaluate NM ternary cosolvents systems, characterize the crystallized drug and develop discriminating dissolution method that could detect the drug crystallization in the product. Mixture design was constructed using independent components namely water (X-1), glycerin (X-2) and polyethylene glycol 400 (X-3, PEG-400). Nineteen formulations were developed using various level of cosolvents mixture while drug concentration was kept constant. The response selected was the drug crystallized in the formulations kept at four storage conditions 5 degrees C, 15 degrees C, 25 degrees C and 25 degrees C/60% RH for four weeks. The crystallized drug was characterized by Fourier transformed infrared (FTIR), near infrared (NIR), NIR-chemical imaging and Raman spectroscopies, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and scanning electron microscopy. Dissolution of formulation and modification was tested by USP method 2 in 0.25 and 0.5% sodium lauryl sulphate (SLS) aqueous media and run at 50 and 75 rpm. X1 promoted drug crystallization at all conditions of storage and reverse was true for X-3. Characterization data indicated that the crystallized drug in most of the formulations were modification II, but a few formulations contained significant proportion of the modification I. Dissolution in 0.25% (w/v) SLS at 75 rpm was more discriminating in detecting the crystallization in the product compared to dissolution in 0.5% (w/v) SLS media. In summary, cosolvents system of NM was prone to crystallization depending upon the cosolvents composition and storage conditions. A more rational approach to develop NM formulation would entail a then through understanding of the causes of crystallization and their characterization in a variety of storage conditions. Published by Elsevier B.V. C1 [Rahman, Ziyaur; Siddiqui, Akhtar; Khan, Mansoor A.] US FDA, Div Prod Qual & Res, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Khan, MA (reprint author), US FDA, Div Prod Qual & Res, Ctr Drug Evaluat & Res, LS Bldg 64,Room 1070,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Mansoor.Khan@fda.hhs.gov OI Rahman, Ziyaur/0000-0002-0402-825X FU Oak Ridge Institute for Science and Education (ORISE) FX The authors would like to thank the Oak Ridge Institute for Science and Education (ORISE) for supporting the post-doctoral research of Dr. Akhtar Siddiqui. NR 31 TC 9 Z9 9 U1 1 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 J9 INT J PHARMACEUT JI Int. J. Pharm. PD OCT 15 PY 2013 VL 455 IS 1-2 BP 113 EP 123 DI 10.1016/j.ijpharm.2013.07.049 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 219QC UT WOS:000324522100014 PM 23911342 ER PT J AU Jain, HV Takeda, K Tami, C Verthelyi, D Beaucage, SL AF Jain, Harsh V. Takeda, Kazuyo Tami, Cecilia Verthelyi, Daniela Beaucage, Serge L. TI Assessment of the cellular internalization of thermolytic phosphorothioate DNA oligonucleotide prodrugs SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Thermolytic DNA prodrugs; fma-Thiophosphate protecting group; Positively charged DNA prodrug; Cellular internalization; Nuclear localization; Nucleic acid-based drug delivery ID LIPOPHILIC PRO-OLIGONUCLEOTIDES; ANTISENSE OLIGONUCLEOTIDES; BIOLOGICAL BARRIERS; PROTECTING GROUP; BACTERIAL-DNA; HELA-CELLS; DELIVERY; TRANSPORTERS; TRAFFICKING; MECHANISMS AB The bioactivity of a CpG-containing phosphorothioate DNA oligonucleotide with thermolytic 2-(N-formyl-N-methylamino) ethyl (fma) thiophosphate groups in mice led us to investigate the parameters affecting the internalization of these thermosensitive DNA prodrugs in various cell lines. Flow cytometry and confocal microscopy analyses indicate that 5'-fluoresceinated fma-phosphorothioate DNA sequences are poorly internalized in Vero, HeLa and GC-2 cells. However, when four fma-thiophosphate groups of a 15-nucleotide long oligothymidylate prodrug are replaced with 3-(N, N-dimethylamino) prop-1-yl thiophosphate functions, internalization of the positively charged prodrug, under physiological conditions, increased fourfold in HeLa and 40-fold in Vero or GC-2 cells. No cytotoxic effects are observed in Vero cells even at an extracellular prodrug concentration of 50 mu M over a period of 72 h. Confocal microscopy studies show that internalization of the positively charged oligothymidylate prodrug in Vero cells is time-dependent with early trafficking of the DNA sequence through endosomal vesicles and, eventually, to the nucleus of the cells. Thus, the incorporation of four 3-(N, N-dimethylamino) prop-1-yl thiophosphate groups into thermosentive fma-phosphorothioate DNA prodrugs is an attractive strategy for efficient cellular internalization of these nucleic acid-based drugs for potential therapeutic indications. Published by Elsevier Ltd. C1 [Jain, Harsh V.; Beaucage, Serge L.] FDA CDER, Chem Lab, Bethesda, MD 20892 USA. [Takeda, Kazuyo] FDA CBER, Confocal Microscopy Core Facil, Bethesda, MD 20892 USA. [Tami, Cecilia; Verthelyi, Daniela] FDA CDER, Immunol Lab, Bethesda, MD 20892 USA. RP Beaucage, SL (reprint author), FDA CDER, Chem Lab, 8800 Rockville Pike, Bethesda, MD 20892 USA. EM serge.beaucage@fda.hhs.gov OI Jain, Harsh/0000-0001-8163-6219 FU Postgraduate Research Participation Program at the Center for Drug Evaluation and Research FX We thank our colleague, Dr. Cristina Ausin, for her thoughtful comments on this manuscript. This research is supported in part by an appointment to the Postgraduate Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 38 TC 6 Z9 6 U1 1 U2 30 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD OCT 15 PY 2013 VL 21 IS 20 BP 6224 EP 6232 DI 10.1016/j.bmc.2013.04.071 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 228CF UT WOS:000325162000019 PM 23755885 ER PT J AU Lo, SC Hung, GC Li, BJ Lei, HY Li, TW Nagamine, K Zhang, J Tsai, S Bryant, R AF Lo, Shyh-Ching Hung, Guo-Chiuan Li, Bingjie Lei, Haiyan Li, Tianwei Nagamine, Kenjiro Zhang, Jing Tsai, Shien Bryant, Richard TI Isolation of Novel Afipia septicemium and Identification of Previously Unknown Bacteria Bradyrhizobium sp OHSU_III from Blood of Patients with Poorly Defined Illnesses SO PLOS ONE LA English DT Article ID NEWLY DISCOVERED MYCOPLASMA; GENOME SEQUENCE; UROGENITAL TRACT; SP-NOV; STRAIN; SPIROPLASMA; INFECTION; PENETRANS; DISEASE; PROJECT AB Cultures previously set up for isolation of mycoplasmal agents from blood of patients with poorly-defined illnesses, although not yielding positive results, were cryopreserved because of suspicion of having low numbers of unknown microbes living in an inactive state in the broth. We re-initiated a set of 3 cultures for analysis of the "uncultivable" or poorly-grown microbes using NGS technology. Broth of cultures from 3 blood samples, submitted from OHSU between 2000 and 2004, were inoculated into culture flasks containing fresh modified SP4 medium and kept at room temperature (RT), 30 degrees C and 35 degrees C. The cultures showing evidence of microbial growth were expanded and subjected to DNA analysis by genomic sequencing using Illumina MiSeq. Two of the 3 re-initiated blood cultures kept at RT after 7-8 weeks showed evidence of microbial growth that gradually reached into a cell density with detectable turbidity. The microbes in the broth when streaked on SP4 agar plates produced microscopic colonies in similar to 2 weeks. Genomic studies revealed that the microbes isolated from the 2 blood cultures were a novel Afipia species, tentatively named Afipia septicemium. Microbes in the 3 rd culture (OHSU_III) kept at RT had a limited level of growth and could not reach a plateau with high cell density. Genomic sequencing identified the microbe in the culture as a previously unknown species of Bradyrhizobium bacteria. This study reports on the isolation of novel Afipia and Bradyrhizobium species. Isolation of Bradyrhizobium species bacteria has never been reported in humans. The study also reveals a previously unrecognized nature of hematogenous infections by the 2 unique groups of Bradyrhizobiaceae. Our studies show that improvement of culture system plus effective use of NGS technology can facilitate findings of infections by unusual microbes in patients having poorly-defined, sometimes mysterious illnesses. C1 [Lo, Shyh-Ching; Hung, Guo-Chiuan; Li, Bingjie; Lei, Haiyan; Li, Tianwei; Nagamine, Kenjiro; Zhang, Jing; Tsai, Shien] US FDA, Tissue Microbiol Lab, Div Cellular & Gene Therapies, Off Cellular Tissue & Gene Therapies,Ctr Biol Eva, Bethesda, MD 20014 USA. [Bryant, Richard] Oregon Hlth & Sci Univ, Dept Infect Dis, Portland, OR 97201 USA. RP Lo, SC (reprint author), US FDA, Tissue Microbiol Lab, Div Cellular & Gene Therapies, Off Cellular Tissue & Gene Therapies,Ctr Biol Eva, Bethesda, MD 20014 USA. EM shyhching.lo@fda.hhs.gov FU FDA Modernizing Science research grant FX The study was supported in part by FDA Modernizing Science research grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. NR 28 TC 4 Z9 4 U1 0 U2 18 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 14 PY 2013 VL 8 IS 10 AR e76142 DI 10.1371/journal.pone.0076142 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 237RD UT WOS:000325887300022 PM 24155888 ER PT J AU Tesfaye, A Stift, J Maric, D Cui, QW Dienes, HP Feinstone, SM AF Tesfaye, Abeba Stift, Judith Maric, Dragan Cui, Qingwen Dienes, Hans-Peter Feinstone, Stephen M. TI Chimeric Mouse Model for the Infection of Hepatitis B and C Viruses SO PLOS ONE LA English DT Article ID LIVER-CANCER; GAMMA-CHAIN; GENOTYPE 1; MICE; HEPATOCYTES; REPLICATION; CHIMPANZEES; TRANSPLANTATION; REPOPULATION; DYSFUNCTION AB While the chimpanzee remains the only animal that closely models human hepatitis C virus (HCV) infection, transgenic and immunodeficient mice in which human liver can be engrafted serve as a partial solution to the need for a small animal model for HCV infection. The established system that was based on mice carrying a transgene for urokinase-type plasminogen activator (uPA) gene under the control of the human albumin promoter has proved to be useful for studies of virus infectivity and for testing antiviral drug agents. However, the current Alb-uPA transgenic model with a humanized liver has practical limitations due to the inability to maintain non-engrafted mice as dizygotes for the transgene, poor engraftment of hemizygotes, high neonatal and experimental death rates of dizygous mice and a very short time window for hepatocyte engraftment. To improve the model, we crossed transgenic mice carrying the uPA gene driven by the major urinary protein promoter onto a SCID/Beige background (MUP-uPA SCID/Bg). These transgenic mice are healthy relative to Alb-uPA mice and provide a long window from about age 4 to 12 months for engraftment with human hepatocytes and infection with hepatitis C or hepatitis B (HBV) viruses. We have demonstrated engraftment of human hepatocytes by immunohistochemistry staining for human albumin (30-80% engraftment) and observed a correlation between the number of human hepatocytes inoculated and the level of the concentration of human albumin in the serum. We have shown that these mice support the replication of both HBV and all six major HCV genotypes. Using HBV and HCV inocula that had been previously tittered in chimpanzees, we showed that the mice had approximately the same sensitivity for infection as chimpanzees. These mice should be useful for isolating non-cell culture adapted viruses as well as testing of antiviral drugs, antibody neutralization studies and examination of phenotypic changes in viral mutants. C1 [Tesfaye, Abeba; Cui, Qingwen; Feinstone, Stephen M.] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Stift, Judith; Dienes, Hans-Peter] Med Univ Vienna, Inst Pathol, Vienna, Austria. [Maric, Dragan] NINDS, Div Intramural Res, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. RP Tesfaye, A (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. EM abeba.tesfaye@fda.hhs.gov FU Food and Drug Administration FX This work was supported by internal funding from the Food and Drug Administration. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 19 Z9 21 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 14 PY 2013 VL 8 IS 10 AR UNSP e77298 DI 10.1371/journal.pone.0077298 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 237RD UT WOS:000325887300073 PM 24155939 ER PT J AU Park, E Willard, J Bi, DQ Fiszman, M Kozeli, D Koerner, J AF Park, Eunjung Willard, James Bi, Daoqin Fiszman, Monica Kozeli, Devi Koerner, John TI The impact of drug-related QT prolongation on FDA regulatory decisions SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Letter DE QT prolongation; Safety warning; Drug approval C1 [Park, Eunjung; Willard, James; Bi, Daoqin; Fiszman, Monica; Kozeli, Devi; Koerner, John] US FDA, Div Cardiovasc & Renal Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Koerner, J (reprint author), US FDA, Div Cardiovasc & Renal Prod, Off New Drugs, Ctr Drug Evaluat & Res, Bldg 22,Room 4178,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM john.koerner@fda.hhs.gov NR 3 TC 13 Z9 14 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD OCT 12 PY 2013 VL 168 IS 5 BP 4975 EP 4976 DI 10.1016/j.ijcard.2013.07.136 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 242EI UT WOS:000326219800121 PM 23920061 ER PT J AU Bisgin, H Chen, MJ Wang, YP Kelly, R Fang, H Xu, XW Tong, WD AF Bisgin, Halil Chen, Minjun Wang, Yuping Kelly, Reagan Fang, Hong Xu, Xiaowei Tong, Weida TI A systems approach for analysis of high content screening assay data with topic modeling SO BMC BIOINFORMATICS LA English DT Article; Proceedings Paper CT 10th Annual Conference of the MidSouth-Computational-Biology-and-Bioinformatics-Society (MCBIOS) on Discovery in a Sea of Data CY APR 05-06, 2013 CL Columbia, MO SP MidSouth Computat Biol & Bioinformat Soc ID LATENT DIRICHLET ALLOCATION; ACTIVATED PROTEIN-KINASE; INDUCED LIVER-INJURY; FDA DRUG LABELS; CELL BIOLOGY; APOPTOSIS; NECROSIS; DEATH; REGENERATION; HEPATOCYTES AB Background: High Content Screening (HCS) has become an important tool for toxicity assessment, partly due to its advantage of handling multiple measurements simultaneously. This approach has provided insight and contributed to the understanding of systems biology at cellular level. To fully realize this potential, the simultaneously measured multiple endpoints from a live cell should be considered in a probabilistic relationship to assess the cell's condition to response stress from a treatment, which poses a great challenge to extract hidden knowledge and relationships from these measurements. Method: In this work, we applied a text mining method of Latent Dirichlet Allocation (LDA) to analyze cellular endpoints from in vitro HCS assays and related to the findings to in vivo histopathological observations. We measured multiple HCS assay endpoints for 122 drugs. Since LDA requires the data to be represented in document-term format, we first converted the continuous value of the measurements to the word frequency that can processed by the text mining tool. For each of the drugs, we generated a document for each of the 4 time points. Thus, we ended with 488 documents (drug-hour) each having different values for the 10 endpoints which are treated as words. We extracted three topics using LDA and examined these to identify diagnostic topics for 45 common drugs located in vivo experiments from the Japanese Toxicogenomics Project (TGP) observing their necrosis findings at 6 and 24 hours after treatment. Results: We found that assay endpoints assigned to particular topics were in concordance with the histopathology observed. Drugs showing necrosis at 6 hour were linked to severe damage events such as Steatosis, DNA Fragmentation, Mitochondrial Potential, and Lysosome Mass. DNA Damage and Apoptosis were associated with drugs causing necrosis at 24 hours, suggesting an interplay of the two pathways in these drugs. Drugs with no sign of necrosis we related to the Cell Loss and Nuclear Size assays, which is suggestive of hepatocyte regeneration. Conclusions: The evidence from this study suggests that topic modeling with LDA can enable us to interpret relationships of endpoints of in vitro assays along with an in vivo histological finding, necrosis. Effectiveness of this approach may add substantially to our understanding of systems biology. C1 [Bisgin, Halil; Chen, Minjun; Wang, Yuping; Kelly, Reagan; Xu, Xiaowei; Tong, Weida] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Fang, Hong] US FDA, Off Sci Coordinat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Xu, Xiaowei] Univ Arkansas, Dept Informat Sci, Little Rock, AR 72204 USA. RP Tong, WD (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM weida.tong@fda.hhs.gov NR 40 TC 2 Z9 2 U1 1 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD OCT 9 PY 2013 VL 14 SU 14 AR S11 DI 10.1186/1471-2105-14-S14-S11 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 249AA UT WOS:000326747100011 PM 24267543 ER PT J AU Shen, J Zhang, WQ Fang, H Perkins, R Tong, WD Hong, HX AF Shen, Jie Zhang, Wenqian Fang, Hong Perkins, Roger Tong, Weida Hong, Huixiao TI Homology modeling, molecular docking, and molecular dynamics simulations elucidated alpha-fetoprotein binding modes SO BMC BIOINFORMATICS LA English DT Article; Proceedings Paper CT 10th Annual Conference of the MidSouth-Computational-Biology-and-Bioinformatics-Society (MCBIOS) on Discovery in a Sea of Data CY APR 05-06, 2013 CL Columbia, MO SP MidSouth Computat Biol & Bioinformat Soc ID SERUM-ALBUMIN; PROTEIN; RAT; RECEPTOR; SEQUENCE; ALPHA-1-FETOPROTEIN; IDENTIFICATION; ALIGNMENTS; ACTIVATION; MECHANICS AB Background: An important mechanism of endocrine activity is chemicals entering target cells via transport proteins and then interacting with hormone receptors such as the estrogen receptor (ER). alpha-Fetoprotein (AFP) is a major transport protein in rodent serum that can bind and sequester estrogens, thus preventing entry to the target cell and where they could otherwise induce ER-mediated endocrine activity. Recently, we reported rat AFP binding affinities for a large set of structurally diverse chemicals, including 53 binders and 72 non-binders. However, the lack of three-dimensional (3D) structures of rat AFP hinders further understanding of the structural dependence for binding. Therefore, a 3D structure of rat AFP was built using homology modeling in order to elucidate rat AFP-ligand binding modes through docking analyses and molecular dynamics (MD) simulations. Methods: Homology modeling was first applied to build a 3D structure of rat AFP. Molecular docking and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) scoring were then used to examine potential rat AFP ligand binding modes. MD simulations and free energy calculations were performed to refine models of binding modes. Results: A rat AFP tertiary structure was first obtained using homology modeling and MD simulations. The rat AFP-ligand binding modes of 13 structurally diverse, representative binders were calculated using molecular docking, (MM-GBSA) ranking and MD simulations. The key residues for rat AFP-ligand binding were postulated through analyzing the binding modes. Conclusion: The optimized 3D rat AFP structure and associated ligand binding modes shed light on rat AFP-ligand binding interactions that, in turn, provide a means to estimate binding affinity of unknown chemicals. Our results will assist in the evaluation of the endocrine disruption potential of chemicals. C1 [Shen, Jie; Zhang, Wenqian; Perkins, Roger; Tong, Weida; Hong, Huixiao] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Fang, Hong] US FDA, Off Sci Coordinat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Hong, HX (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM huixiao.hong@fda.hhs.gov NR 45 TC 22 Z9 22 U1 2 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD OCT 9 PY 2013 VL 14 SU 14 AR S6 DI 10.1186/1471-2105-14-S14-S6 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 249AA UT WOS:000326747100006 PM 24266910 ER PT J AU Zou, W Tang, HL Zhao, WZ Meehan, J Foley, SL Lin, WJ Chen, HC Fang, H Nayak, R Chen, JJ AF Zou, Wen Tang, Hailin Zhao, Weizhong Meehan, Joe Foley, Steven L. Lin, Wei-Jiun Chen, Hung-Chia Fang, Hong Nayak, Rajesh Chen, James J. TI Data mining tools for Salmonella characterization: application to gel-based fingerprinting analysis SO BMC BIOINFORMATICS LA English DT Article; Proceedings Paper CT 10th Annual Conference of the MidSouth-Computational-Biology-and-Bioinformatics-Society (MCBIOS) on Discovery in a Sea of Data CY APR 05-06, 2013 CL Columbia, MO SP MidSouth Computat Biol & Bioinformat Soc ID ENTERICA SEROVAR ENTERITIDIS; DRAFT GENOME SEQUENCES; TANDEM REPEAT ANALYSIS; UNITED-STATES; MICROARRAY ANALYSIS; ELECTROPHORESIS; PULSENET; STRAINS; IDENTIFICATION; SURVEILLANCE AB Background: Pulsed field gel electrophoresis (PFGE) is currently the most widely and routinely used method by the Centers for Disease Control and Prevention (CDC) and state health labs in the United States for Salmonella surveillance and outbreak tracking. Major drawbacks of commercially available PFGE analysis programs have been their difficulty in dealing with large datasets and the limited availability of analysis tools. There exists a need to develop new analytical tools for PFGE data mining in order to make full use of valuable data in large surveillance databases. Results: In this study, a software package was developed consisting of five types of bioinformatics approaches exploring and implementing for the analysis and visualization of PFGE fingerprinting. The approaches include PFGE band standardization, Salmonella serotype prediction, hierarchical cluster analysis, distance matrix analysis and two-way hierarchical cluster analysis. PFGE band standardization makes it possible for cross-group large dataset analysis. The Salmonella serotype prediction approach allows users to predict serotypes of Salmonella isolates based on their PFGE patterns. The hierarchical cluster analysis approach could be used to clarify subtypes and phylogenetic relationships among groups of PFGE patterns. The distance matrix and two-way hierarchical cluster analysis tools allow users to directly visualize the similarities/dissimilarities of any two individual patterns and the inter-and intra-serotype relationships of two or more serotypes, and provide a summary of the overall relationships between user-selected serotypes as well as the distinguishable band markers of these serotypes. The functionalities of these tools were illustrated on PFGE fingerprinting data from PulseNet of CDC. Conclusions: The bioinformatics approaches included in the software package developed in this study were integrated with the PFGE database to enhance the data mining of PFGE fingerprints. Fast and accurate prediction makes it possible to elucidate Salmonella serotype information before conventional serological methods are pursued. The development of bioinformatics tools to distinguish the PFGE markers and serotype specific patterns will enhance PFGE data retrieval, interpretation and serotype identification and will likely accelerate source tracking to identify the Salmonella isolates implicated in foodborne diseases. C1 [Zou, Wen; Tang, Hailin; Zhao, Weizhong; Meehan, Joe; Chen, Hung-Chia; Chen, James J.] US FDA, Div Bioinformat & Biostat, Jefferson, AR USA. [Foley, Steven L.; Nayak, Rajesh] US FDA, Div Microbiol, Jefferson, AR USA. [Lin, Wei-Jiun] Feng Chia Univ, Dept Appl Math, Taichung 40724, Taiwan. [Chen, Hung-Chia] China Med Univ, Grad Inst Biostat, Taichung, Taiwan. [Chen, Hung-Chia] China Med Univ, Biostat Ctr, Taichung, Taiwan. [Fang, Hong] US FDA, Off Sci Coordinat, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Zou, W (reprint author), US FDA, Div Bioinformat & Biostat, Jefferson, AR USA. EM wen.zou@fda.hhs.gov NR 33 TC 3 Z9 3 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD OCT 9 PY 2013 VL 14 SU 14 AR S15 DI 10.1186/1471-2105-14-S14-S15 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 249AA UT WOS:000326747100015 PM 24267777 ER PT J AU Moro, PL Harrington, T Shimabukuro, T Cano, M Museru, OI Menschik, D Broder, K AF Moro, Pedro L. Harrington, Theresa Shimabukuro, Tom Cano, Maria Museru, Oidda I. Menschik, David Broder, Karen TI Adverse events after Fluzone (R) Intradermal vaccine reported to the Vaccine Adverse Event Reporting System (VAERS), 2011-2013 SO VACCINE LA English DT Article DE Adverse event; Intradermal; Surveillance; Trivalent inactivated influenza vaccine; Vaccine safety ID IMMUNIZATION PRACTICES ACIP; SEASONAL INFLUENZA; ADVISORY-COMMITTEE; UNITED-STATES; SAFETY; RECOMMENDATIONS; IMMUNOGENICITY; PREVENTION; ADULTS AB Background: In May 2011, the first trivalent inactivated influenza vaccine exclusively for intradermal administration (TIV-ID) was licensed in the US for adults aged 18-64 years. Objective: To characterize adverse events (AEs) after TIV-ID reported to the US Vaccine Adverse Event Reporting System (VAERS), a spontaneous reporting surveillance system. Methods: We searched VAERS for US reports after TIV-ID among persons vaccinated from July 1, 2011-February 28, 2013. Medical records were requested for reports coded as serious (death, hospitalization, prolonged hospitalization, disability, life-threatening-illness), and those suggesting anaphylaxis. Clinicians reviewed available information and assigned a primary clinical category to each report. Empirical Bayesian data mining was used to identify disproportional AE reporting following TIV-ID. Causality was not assessed. Results: VAERS received 466 reports after TIV-ID; 9(1.9%) were serious, including one reported fatality in an 88-year-old vaccinee. Median age was 43 years (range 4-88 years). The most common AE categories were: 218(46.8%) injection site reactions; 89(19.1%) other non-infectious (comprised mainly of constitutional signs and symptoms); and 74 (15.9%) allergy. Eight reports (1.7%) of anaphylaxis were verified by the Brighton criteria or a documented physician diagnosis. Disproportional reporting was identified for three AEs: 'injection site nodule', 'injection site pruritus', and 'drug administered to patient of inappropriate age'. The findings for the first two AEs were expected. Twenty-four reports of vaccinees <18 years or >= 65 years were reported, and 14 of 24 were coded with the AE 'drug administered to patient of inappropriate age'. Conclusions: Review of VAERS reports did not identify any new or unexpected safety concerns after TIV-ID. Injection site reactions were the most commonly reported AEs, similar to the pre-licensure clinical trials. Use of TIV-ID in younger and older individuals outside the approved age range highlights the need for education of healthcare providers regarding approved TIV-ID use. Published by Elsevier Ltd. C1 [Moro, Pedro L.; Harrington, Theresa; Shimabukuro, Tom; Cano, Maria; Museru, Oidda I.; Broder, Karen] Ctr Dis Control & Prevent, Immunizat Safety Off, Atlanta, GA 30329 USA. [Menschik, David] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP Moro, PL (reprint author), Ctr Dis Control & Prevent, Immunizat Safety Off, Atlanta, GA 30329 USA. EM psm9@cdc.gov FU CDC budget; FDA budget FX The study was implemented by the Centers for Disease Control and Prevention (CDC) and Food and Drug Administration (FDA). The only funds used were from CDC and FDA budgets. This study had no external sponsors. NR 21 TC 8 Z9 8 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD OCT 9 PY 2013 VL 31 IS 43 BP 4984 EP 4987 DI 10.1016/j.vaccine.2013.08.001 PG 4 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 242PV UT WOS:000326255400009 PM 23994022 ER PT J AU Kwekel, JC Desai, VG Moland, CL Vijay, V Fuscoe, JC AF Kwekel, Joshua C. Desai, Varsha G. Moland, Carrie L. Vijay, Vikrant Fuscoe, James C. TI Life Cycle Analysis of Kidney Gene Expression in Male F344 Rats SO PLOS ONE LA English DT Article ID AGE-RELATED DIFFERENCES; INCREASED SUSCEPTIBILITY; NEPHROTOXICITY; INJURY; ASSOCIATION; BIOMARKERS; INFANTS; FDA AB Age is a predisposing condition for susceptibility to chronic kidney disease and progression as well as acute kidney injury that may arise due to the adverse effects of some drugs. Age-related differences in kidney biology, therefore, are a key concern in understanding drug safety and disease progression. We hypothesize that the underlying suite of genes expressed in the kidney at various life cycle stages will impact susceptibility to adverse drug reactions. Therefore, establishing changes in baseline expression data between these life stages is the first and necessary step in evaluating this hypothesis. Untreated male F344 rats were sacrificed at 2, 5, 6, 8, 15, 21, 78, and 104 weeks of age. Kidneys were collected for histology and gene expression analysis. Agilent whole-genome rat microarrays were used to query global expression profiles. An ANOVA (p<0.01) coupled with a fold-change>1.5 in relative mRNA expression, was used to identify 3,724 unique differentially expressed genes (DEGs). Principal component analyses of these DEGs revealed three major divisions in life-cycle renal gene expression. K-means cluster analysis identified several groups of genes that shared age-specific patterns of expression. Pathway analysis of these gene groups revealed age-specific gene networks and functions related to renal function and aging, including extracellular matrix turnover, immune cell response, and renal tubular injury. Large age-related changes in expression were also demonstrated for the genes that code for qualified renal injury biomarkers KIM-1, Clu, and Tff3. These results suggest specific groups of genes that may underlie age-specific susceptibilities to adverse drug reactions and disease. This analysis of the basal gene expression patterns of renal genes throughout the life cycle of the rat will improve the use of current and future renal biomarkers and inform our assessments of kidney injury and disease. C1 [Kwekel, Joshua C.; Desai, Varsha G.; Moland, Carrie L.; Vijay, Vikrant; Fuscoe, James C.] US FDA, Personalized Med Branch, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Kwekel, JC (reprint author), US FDA, Personalized Med Branch, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Joshua.Kwekel@fda.hhs.gov; James.Fuscoe@fda.hhs.gov RI Vijay, Vikrant/E-7651-2010 OI Vijay, Vikrant/0000-0001-8425-1285 FU U.S. Food and Drug Administration; FDA Office of Women's Health FX This work was funded by the U.S. Food and Drug Administration. The research was supported in part by an appointment to the Research Participation Program at the National Center for Toxicological Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U. S. Food and Drug Administration. The authors thank the FDA Office of Women's Health for support of this project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 6 Z9 6 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 7 PY 2013 VL 8 IS 10 AR e75305 DI 10.1371/journal.pone.0075305 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 232NS UT WOS:000325501300024 PM 24116033 ER PT J AU Sahu, SN Anriany, Y Grim, CJ Kim, S Chang, Z Joseph, SW Cinar, HN AF Sahu, Surasri N. Anriany, Yuda Grim, Christopher J. Kim, Sungji Chang, Zenas Joseph, Sam W. Cinar, Hediye N. TI Identification of Virulence Properties in Salmonella Typhimurium DT104 Using Caenorhabditis elegans SO PLOS ONE LA English DT Article ID ENTERICA SEROVAR TYPHIMURIUM; MULTIDRUG-RESISTANCE REGION; UNFOLDED PROTEIN RESPONSE; INNATE IMMUNE-RESPONSE; C-ELEGANS; ANTIMICROBIAL PEPTIDES; MODEL HOST; INTESTINE; PATHOGEN; PATHWAY AB Salmonella enterica serover Typhimurium definitive phage type DT104, resistant to multiple antibiotics, is one of the most widespread Salmonella species in human infection worldwide. Although several cohort studies indicate that DT104 carrying the multidrug resistance (MDR) locus on salmonella genomic island 1 is a possible hyper-virulent strain compared to DT104 strains without MDR, or other Salmonella enterica serotypes, existing experimental evidence regarding virulence properties associated with the MDR region is controversial. To address this question, we constructed an isogenic MDR deletion (Delta MDR) mutant strain of DT104, SNS12, by allelic exchange and used Caenorhabditis elegans as a host model to assess differences in virulence between these two strains. SNS12 exhibited decreased virulence in C. elegans, and we observed increased colonization and proliferation of the intestine of C. elegans by DT104. The immune response against MDR-carrying DT104 appears to function through a non-canonical Unfolded Protein Response (UPR) pathway, namely prion-like-(QN-rich)-domain-bearing protein pathway (PQN), in a ced-1 dependent manner in C. elegans. Further, we also demonstrate that genes of the PQN pathway and antimicrobial peptide gene abf-2, are expressed at higher transcriptional levels in worms immediately following exposure to DT104, in comparison with worms exposed to SNS12. Altogether, our results suggest that the MDR region of Salmonella Typhimurium DT104 has a direct role in virulence against Caenorhabditis elegans. C1 [Sahu, Surasri N.; Grim, Christopher J.; Cinar, Hediye N.] US FDA, Div Virulence Assessment, Laurel, MD USA. [Sahu, Surasri N.; Grim, Christopher J.] Oak Ridge Inst Sci & Educ, Oak Ridge, TN USA. [Anriany, Yuda] Prince Georges Community Coll, Dept Biol Sci, Laurel, MD USA. [Kim, Sungji; Joseph, Sam W.] Kyungpook Natl Univ KNU, Taegu, South Korea. [Chang, Zenas] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. RP Sahu, SN (reprint author), US FDA, Div Virulence Assessment, Laurel, MD USA. EM surasri.sahu@fda.hhs.gov FU Food and Drug Administration FX This study was funded by Food and Drug Administration intramural funding. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 3 Z9 6 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 4 PY 2013 VL 8 IS 10 AR e76673 DI 10.1371/journal.pone.0076673 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 232JF UT WOS:000325489100144 PM 24124587 ER PT J AU Gokulan, K Khare, S Rooney, AW Han, J Lynne, AM Foley, SL AF Gokulan, Kuppan Khare, Sangeeta Rooney, Anthony W. Han, Jing Lynne, Aaron M. Foley, Steven L. TI Impact of Plasmids, Including Those EncodingVirB4/D4 Type IV Secretion Systems, on Salmonella enterica serovar Heidelberg Virulence in Macrophages and Epithelial Cells SO PLOS ONE LA English DT Article ID ESCHERICHIA-COLI; ANTIMICROBIAL RESISTANCE; BRUCELLA-ABORTUS; INTRACELLULAR SURVIVAL; ENDOPLASMIC-RETICULUM; IMMUNE-RESPONSE; UNITED-STATES; VIRB OPERON; INFECTION; MICE AB Salmonella enterica serovar Heidelberg (S. Heidelberg) can cause foodborne illness in humans following the consumption of contaminated meat and poultry products. Recent studies from our laboratory have demonstrated that certain S. Heidelberg isolated from food-animal sources harbor multiple transmissible plasmids with genes that encode antimicrobial resistance, virulence and a VirB4/D4 type-IV secretion system. This study examines the potential role of these transmissible plasmids in bacterial uptake and survival in intestinal epithelial cells and macrophages, and the molecular basis of host immune system modulation that may be associated with disease progression. A series of transconjugant and transformant strains were developed with different combinations of the plasmids to determine the roles of the individual and combinations of plasmids on virulence. Overall the Salmonella strains containing the VirB/D4 T4SS plasmids entered and survived in epithelial cells and macrophages to a greater degree than those without the plasmid, even though they carried other plasmid types. During entry in macrophages, the VirB/D4 T4SS encoding genes are up-regulated in a time-dependent fashion. When the potential mechanisms for increased virulence were examined using an antibacterial Response PCR Array, the strain containing the T4SS down regulated several host innate immune response genes which likely contributed to the increased uptake and survival within macrophages and epithelial cells. C1 [Gokulan, Kuppan; Khare, Sangeeta; Rooney, Anthony W.; Han, Jing; Foley, Steven L.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Rooney, Anthony W.] Univ Minnesota, Dept Chem, Morris, MN 56267 USA. [Lynne, Aaron M.] Sam Houston State Univ, Dept Biol Sci, Huntsville, TX 77340 USA. RP Foley, SL (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR USA. EM steven.foley@fda.hhs.gov FU FDA-National Center for Toxicological Research FX The research is internally funded through the FDA-National Center for Toxicological Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 8 Z9 9 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 3 PY 2013 VL 8 IS 10 AR e77866 DI 10.1371/journal.pone.0077866 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 232HM UT WOS:000325483600090 PM 24098597 ER PT J AU Chen, B Kumar, G Co, CC Ho, CC AF Chen, Bo Kumar, Girish Co, Carlos C. Ho, Chia-Chi TI Geometric Control of Cell Migration SO SCIENTIFIC REPORTS LA English DT Article ID MICROTUBULE-ORGANIZING CENTER; ENDOTHELIAL-CELLS; ADHESION MOLECULES; FOCAL ADHESIONS; NUCLEAR SHAPE; LIVING CELLS; RHO-GTPASES; POLARIZATION; FIBROBLASTS; POLARITY AB Morphological polarization involving changes in cell shape and redistribution of cellular signaling machinery, initiate the migration of mammalian cells. Golgi complex typically localizes in front of the nucleus, and this frontwards polarization has been proposed to be involved in directional migration. However, the sequence of events remains unresolved. Does Golgi polarization precede directional migration or vice-versa? We address this question by constraining cells to specific areas and shapes then tracking their motile behavior and the spatio-temporal distribution of Golgi apparatus upon release. Results show that while the position of the Golgi complex depends on the cell geometry, the subcellular localization of the Golgi complex does not define the cell's leading edge. Cells constrained within elongated geometries exhibit polarized extension of lamellipodia and upon release, migrate preferentially along the long axis of the cell. Minimally constrained cells released from larger areas however, exhibit retarded migration regardless of lamellipodia protrusion activity. C1 [Chen, Bo; Kumar, Girish; Co, Carlos C.; Ho, Chia-Chi] Univ Cincinnati, Chem & Mat Engn Program, Cincinnati, OH 45221 USA. [Kumar, Girish] US FDA, Div Biol, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Ho, CC (reprint author), Univ Cincinnati, Chem & Mat Engn Program, Cincinnati, OH 45221 USA. EM hocc@ucmail.uc.edu FU National Institutes of Health [R01EB010043, R21EB3979]; National Science Foundation [CBET0928219] FX This work was supported by the National Institutes of Health (R01EB010043 and R21EB3979) and the National Science Foundation (CBET0928219). We thank Kyu-Shik Mun for assistance with the data analysis. NR 53 TC 11 Z9 11 U1 2 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 3 PY 2013 VL 3 AR 2827 DI 10.1038/srep02827 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 227SS UT WOS:000325135300001 PM 24089214 ER PT J AU Bird, ST Delaney, JAC Cooper-DeHoff, RM Nichols, GA Winterstein, AG AF Bird, Steven T. Delaney, Joseph A. C. Cooper-DeHoff, Rhonda M. Nichols, Gregory A. Winterstein, Almut G. TI Misclassification in Assessment of Diabetogenic Risk Using Laboratory-Enhanced Claims Data SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Bird, Steven T.; Delaney, Joseph A. C.; Winterstein, Almut G.] Univ Florida, Dept Pharmaceut Outcomes & Policy, Gainesville, FL USA. [Bird, Steven T.] US FDA, Dept Epidemiol, Silver Spring, MD USA. [Delaney, Joseph A. C.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Cooper-DeHoff, Rhonda M.] Univ Florida, Dept Pharmacotherapy & Translat Res, Gainesville, FL USA. [Nichols, Gregory A.] Kaiser Permanente Ctr Hlth Res, Portland, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 6 BP 3 EP 4 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876100007 ER PT J AU Du, DY McKean, S Kelman, J Laschinger, J Johnson, C Warnock, R Worrall, C MaCurdy, TE Izurieta, H AF Du, Dongyi McKean, Stephen Kelman, Jeffrey Laschinger, John Johnson, Chris Warnock, Rob Worrall, Chris MaCurdy, Thomas E. Izurieta, Hector TI Comparison of Early Mortality after Aortic Valve Replacement with Biological vs. Mechanical Prosthetic Valve among Medicare Beneficiaries SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Du, Dongyi; Izurieta, Hector] US FDA, CBER OBE, Rockville, MD 20857 USA. [McKean, Stephen; Johnson, Chris; Warnock, Rob; MaCurdy, Thomas E.] Acumen LLC, Burlingame, CA USA. [Kelman, Jeffrey; Worrall, Chris] Ctr Medicare & Medicaid Serv, Washington, DC USA. [Laschinger, John] US FDA, CDRH ODE, White Oak, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 21 BP 11 EP 12 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876100022 ER PT J AU Menis, M Sridhar, G Selvam, N Ovanesov, MV Divan, HA Liang, YD Scott, D Golding, B Forshee, R Ball, R Anderson, SA Izurieta, HS AF Menis, Mikhail Sridhar, Gayathri Selvam, Nandini Ovanesov, Mikhail V. Divan, Hozefa A. Liang, Yideng Scott, Dorothy Golding, Basil Forshee, Richard Ball, Robert Anderson, Steven A. Izurieta, Hector S. TI Hyperimmune Globulins (HIGs) and Same-Day Thrombotic Adverse Events (TEs) in a Large Health-Care Database SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Menis, Mikhail; Ovanesov, Mikhail V.; Liang, Yideng; Scott, Dorothy; Golding, Basil; Forshee, Richard; Ball, Robert; Anderson, Steven A.; Izurieta, Hector S.] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Sridhar, Gayathri; Selvam, Nandini; Divan, Hozefa A.] HealthCore Inc, Alexandria, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 38 BP 20 EP 20 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876100039 ER PT J AU Noel, R Primatesta, P Dal Pan, G Wolf, M Smith, M Bahri, P Morrato, E Dey, D AF Noel, Rebecca Primatesta, Paola Dal Pan, Gerald Wolf, Michael Smith, Meredith Bahri, Priya Morrato, Elaine Dey, Debashish TI Benefit-Risk Assessment, Communication and Evaluation (BRACE): Embrace the Challenges and Opportunities (Submitted on Behalf of the BRACE SIG) SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Noel, Rebecca; Dey, Debashish] Eli Lilly & Co, Global Patient Safety, Indianapolis, IN 46285 USA. [Primatesta, Paola] Novartis Pharma AG, Drug Safety & Epidemiol, Basel, Switzerland. [Dal Pan, Gerald] US FDA, Off Surveillance & Epidemiol, CDER, Silver Spring, MD USA. [Wolf, Michael] Northwestern Univ, Feinberg Sch Med, Div Learning Sci, Inst Healthcare Studies, Chicago, IL 60611 USA. [Smith, Meredith] AbbVie, Risk Management, Abbott Pk, IL USA. [Bahri, Priya] European Med Agcy, Sect Pharmacovigilance & Risk Management, London, England. [Morrato, Elaine] Univ Colorado, Colorado Sch Publ Hlth Hlth Syst Management & Pol, Aurora, CO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 73 BP 39 EP 39 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876100074 ER PT J AU Critchlow, C Curtis, J Dore, D Rothman, K Pedersen, L Sprafka, M Staffa, J Sturkenboom, M Xue, F AF Critchlow, Cathy Curtis, Jeffrey Dore, David Rothman, Kenneth Pedersen, Lars Sprafka, Michael Staffa, Judy Sturkenboom, Miriam Xue, Fei TI Post-Marketing Pharmacoepidemiologic (PE) Database Studies To Assess Drug Safety SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Critchlow, Cathy; Sprafka, Michael; Xue, Fei] Amgen Inc, Ctr Observat Res CfOR, Thousand Oaks, CA 91320 USA. [Curtis, Jeffrey] Univ Alabama Birmingham, Birmingham, AL USA. [Dore, David] Brown Univ, Providence, RI 02912 USA. [Sturkenboom, Miriam] Erasmus Univ, Rotterdam, Netherlands. [Rothman, Kenneth] RTI Int, Boston, MA USA. [Pedersen, Lars] Aarhus Univ Hosp, Dept Clin Epidemiol, DK-8000 Aarhus, Denmark. [Staffa, Judy] US FDA, Div Epidemiol 2, Washington, DC 20204 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 78 BP 42 EP 42 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876100079 ER PT J AU Baer, B Nguyen, M Woo, EJ Winiecki, S Scott, J Martin, D Botsis, T Ball, R AF Baer, Bethany Nguyen, Michael Woo, Emily Jane Winiecki, Scott Scott, John Martin, David Botsis, Taxiarchis Ball, Robert TI Reducing Words without Losing Clinical Meaning Can Text Mining Accelerate Review of Spontaneous Reports? SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Baer, Bethany; Nguyen, Michael; Woo, Emily Jane; Winiecki, Scott; Scott, John; Martin, David; Botsis, Taxiarchis; Ball, Robert] US FDA, Off Biostat & Epidemiol, CBER, Rockville, MD 20857 USA. [Botsis, Taxiarchis] Univ Tromso, Dept Comp Sci, Tromso, Norway. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 171 BP 85 EP 85 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876100161 ER PT J AU Houstoun, M Reichman, ME Graham, DJ Nambiar, S Shamsuddin, H Jones, SC Cao, K Wernecke, M Lam, C Worrall, CM MaCurdy, TE Kelman, JA AF Houstoun, Monika Reichman, Marsha E. Graham, David J. Nambiar, Sumathi Shamsuddin, Hala Jones, S. Christopher Cao, Kelly Wernecke, Michael Lam, Chelsea Worrall, Chris M. MaCurdy, Thomas E. Kelman, Jeffrey A. TI Quinine Sulfate Use and Hematologic Adverse Events: Active Surveillance in Medicare SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Houstoun, Monika; Reichman, Marsha E.; Graham, David J.; Jones, S. Christopher; Cao, Kelly] US FDA, CDER, OSE, Silver Spring, MD USA. [Nambiar, Sumathi; Shamsuddin, Hala] US FDA, CDER, OND, Silver Spring, MD USA. [Wernecke, Michael; Lam, Chelsea] Acumen LLC, Burlingame, CA USA. [Worrall, Chris M.; Kelman, Jeffrey A.] CMS, CM, Washington, DC USA. [MaCurdy, Thomas E.] Stanford Univ, Stanford, CA 94305 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 185 BP 91 EP 91 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876100174 ER PT J AU Seeger, JD Rothman, AT Gerhard-Herman, MD Jalbert, JJ Nguyen, LL Chen, CY Williams, LA Setoguchi, S AF Seeger, John D. Rothman, Andrew T. Gerhard-Herman, Marie D. Jalbert, Jessica J. Nguyen, Louis L. Chen, Chi-Ying Williams, Lauren A. Setoguchi, Soko TI Feasibility of Linking Administrative Claims Data to Institution-Specific Laboratory and Electronic Health Record Data for Comparative Effectiveness Research SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Seeger, John D.; Gerhard-Herman, Marie D.; Jalbert, Jessica J.; Nguyen, Louis L.; Chen, Chi-Ying; Williams, Lauren A.; Setoguchi, Soko] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Seeger, John D.; Rothman, Andrew T.; Setoguchi, Soko] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Jalbert, Jessica J.] LaSer, New York, NY USA. [Chen, Chi-Ying] US FDA, Silver Spring, MD USA. [Setoguchi, Soko] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 266 BP 128 EP 128 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876100246 ER PT J AU Ahmad, SR Miller, MS Slaughter, SR AF Ahmad, Syed Rizwanuddin Miller, Mark S. Slaughter, Shelley R. TI Is there any Evidence for Fetal Harm with Prolonged Use of Magnesium Sulfate in Pregnant Women? SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Ahmad, Syed Rizwanuddin] CDER, FDA, Off Pharmacovigilance & Epidemiol, Div Epidemiol,OSE, Silver Spring, MD USA. [Miller, Mark S.] CDER, FDA, Off Pharmacovigilance & Epidemiol, Div Pharmacovigilance,OSE, Silver Spring, MD USA. [Slaughter, Shelley R.] CDER, FDA, Div Reprod & Urol Prod, Off New Drugs, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 292 BP 141 EP 141 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876100271 ER PT J AU Gliklich, R Dreyer, N Hernandez-Diaz, S Cragan, J Tassinari, M Covington, D Ephross, S Chambers, C Berliner, E Leavy, M Khurana, L AF Gliklich, Richard Dreyer, Nancy Hernandez-Diaz, Sonia Cragan, Janet Tassinari, Melissa Covington, Deborah Ephross, Sara Chambers, Christina Berliner, Elise Leavy, Michelle Khurana, Laura TI Best Practices for Pregnancy Registries SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Gliklich, Richard; Dreyer, Nancy; Leavy, Michelle; Khurana, Laura] Outcome, Cambridge, MA USA. [Hernandez-Diaz, Sonia] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Cragan, Janet] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev DIsabil, Atlanta, GA USA. [Tassinari, Melissa] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Covington, Deborah] PPD, Wilmington, NC USA. [Ephross, Sara] GlaxoSmithKline, Res Triangle Pk, NC USA. [Chambers, Christina] Univ Calif San Diego, La Jolla, CA 92093 USA. [Berliner, Elise] Agcy Healthcare Res & Qual, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 310 BP 150 EP 150 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876100289 ER PT J AU Tabacova, S Szarfman, A AF Tabacova, Sonia Szarfman, Ana TI Adverse Developmental Events Reported to FDA in Association with Maternal Use of Topiramate in Pregnancy SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Tabacova, Sonia; Szarfman, Ana] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 346 BP 167 EP 168 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876100323 ER PT J AU McNeill, AM Andrews, E Gilsenan, A Rubino, A Dal Pan, G AF McNeill, Ann Marie Andrews, Elizabeth Gilsenan, Alicia Rubino, Annalisa Dal Pan, Gerald TI Best Practices and Areas of Future Research in the Development of Educational Material To Communicate Risk to Patients and Clinicians SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [McNeill, Ann Marie] Merck Sharp & Dohme Corp, Epidemiol, White House Stn, NJ USA. [Andrews, Elizabeth; Gilsenan, Alicia] RTI Hlth Solut, Epidemiol, Res Triangle Pk, NC USA. [Rubino, Annalisa] European Med Agcy, Pharmacovigilance & Risk Management, London, England. [Dal Pan, Gerald] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 423 BP 207 EP 208 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876100400 ER PT J AU Graham, DJ Calia, K Nelson, L Yang, J Bhattacharya, J MaCurdy, TE Worrall, C Kelman, JA AF Graham, David J. Calia, Katlyn Nelson, Lorene Yang, Jeff Bhattacharya, Jay MaCurdy, Thomas E. Worrall, Chris Kelman, Jeffrey A. TI A High-Performing, SEER-Validated Algorithm for Identifying Patients With Incident Cancer of the Esophagus or Cardia Using Medicare Claims Data SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Graham, David J.] US FDA, Off Epidemiol & Surveillance, Silver Spring, MD USA. [Calia, Katlyn; Yang, Jeff; MaCurdy, Thomas E.] Acumen LLC, Burlingame, CA USA. [Nelson, Lorene; Bhattacharya, Jay; MaCurdy, Thomas E.] Stanford Univ, Palo Alto, CA 94304 USA. [Worrall, Chris; Kelman, Jeffrey A.] Ctr Medicare & Medicaid Serv, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 477 BP 234 EP 235 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876101047 ER PT J AU Zhou, EH Gelperin, K Graham, DJ Ding, YL Levenson, M Rose, M Davillier, SF Hammad, TA AF Zhou, Esther H. Gelperin, Kate Graham, David J. Ding, Yulan Levenson, Mark Rose, Martin Davillier, Shannin F. Hammad, Tarek A. TI Validation of Stroke in the Clinical Practice Research Datalink (CPRD) SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Zhou, Esther H.; Gelperin, Kate; Graham, David J.; Ding, Yulan; Davillier, Shannin F.; Hammad, Tarek A.] US FDA, Off Surveillance & Epidemiol, Silver Spring, MD USA. [Levenson, Mark] US FDA, Off Biostat, Silver Spring, MD USA. [Rose, Martin] US FDA, Off New Drugs, Silver Spring, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 476 BP 234 EP 234 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876101046 ER PT J AU Bird, ST Brophy, JM Etminan, M Delaney, JAC Hartzema, AG AF Bird, Steven T. Brophy, James M. Etminan, Mahyar Delaney, Joseph A. C. Hartzema, Abraham G. TI Drospirenone and Risk for Venous Thromboembolism; A Comparison by Dosage of Ethinyl-Estradiol SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Bird, Steven T.; Hartzema, Abraham G.] Univ Florida, Dept Pharmaceut Outcomes & Policy, Gainesville, FL USA. [Bird, Steven T.] US FDA, Dept Epidemiol, Silver Spring, MD USA. [Brophy, James M.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Brophy, James M.] McGill Univ, Dept Epidemiol, Montreal, PQ, Canada. [Etminan, Mahyar] Univ British Columbia, Dept Med, Child & Family Res Inst, Vancouver, BC, Canada. [Delaney, Joseph A. C.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 532 BP 261 EP 262 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876101101 ER PT J AU Bird, ST Etminan, M Brophy, JM Hartzema, AG Delaney, JA AF Bird, Steven T. Etminan, Mahyar Brophy, James M. Hartzema, Abraham G. Delaney, Joseph Ac TI Fluoroquinolones and Risk for Acute Kidney Injury SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Bird, Steven T.; Hartzema, Abraham G.] Univ Florida, Dept Pharmaceut Outcomes & Policy, Gainesville, FL USA. [Bird, Steven T.] US FDA, Dept Epidemiol, Silver Spring, MD USA. [Etminan, Mahyar] Univ British Columbia, Dept Med, Child & Family Res Inst, Vancouver, BC, Canada. [Brophy, James M.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Brophy, James M.] McGill Univ, Dept Epidemiol, Montreal, PQ, Canada. [Delaney, Joseph Ac] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 533 BP 262 EP 262 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876101102 ER PT J AU Weibel, D Dodd, C Black, S Izurieta, H Sankoh, O Laserson, K Chen, R Sevene, E Oduro, A Bonhoeffer, J Sturkenboom, MCJM AF Weibel, Daniel Dodd, Caitlin Black, Steve Izurieta, Hector Sankoh, Osman Laserson, Kayla Chen, Robert Sevene, Esperanca Oduro, Abraham Bonhoeffer, Jan Sturkenboom, Miriam C. J. M. TI Need for Collaborative International Vaccine Benefit-Risk Studies in Low-Income Countries: A Pilot Project SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Weibel, Daniel; Sturkenboom, Miriam C. J. M.] Erasmus Univ, Dept Med Informat, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [Dodd, Caitlin; Black, Steve] Cincinnati Childrens Hosp Med Ctr, Global Child Hlth Ctr, Cincinnati, OH 45229 USA. [Izurieta, Hector] US FDA, Silver Spring, MD USA. [Sankoh, Osman] INDEPTH Network, Accra, Ghana. [Laserson, Kayla; Chen, Robert] KEMRI CDC Res & Publ Hlth Collaborat, Kisumu, Kenya. [Sevene, Esperanca] Eduardo Mondlane Univ, Manhica Hlth Res Ctr, Manhica, Mozambique. [Oduro, Abraham] Navrongo Hlth Ctr, Navrongo, Ghana. [Bonhoeffer, Jan] Brighton Collaborat Fdn, Basel, Switzerland. [Bonhoeffer, Jan] Univ Childrens Hosp Basel, Basel, Switzerland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 534 BP 262 EP 263 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876101103 ER PT J AU Lo Re, V Haynes, K Goldberg, D Forde, KA Carbonari, DM Leidl, KBF Hennessy, S Reddy, R Pawloski, PA Daniel, GW Cheetham, TC Iyer, A Coughlin, KO Toh, S Boudreau, DM Cooper, WO Selvam, N Selvan, MS VanWormer, JJ Avigan, MI Houstoun, M Zornberg, GL Racoosin, JA Shoaibi, A AF Lo Re, Vincent, III Haynes, Kevin Goldberg, David Forde, Kimberly A. Carbonari, Dena M. Leidl, Kimberly B. F. Hennessy, Sean Reddy, Rajender Pawloski, Pamala A. Daniel, Gregory W. Cheetham, T. Craig Iyer, Aarthi Coughlin, Kara O. Toh, Sengwee Boudreau, Denise M. Cooper, William O. Selvam, Nandini Selvan, Mano S. VanWormer, Jeffrey J. Avigan, Mark I. Houstoun, Monika Zornberg, Gwen L. Racoosin, Judith A. Shoaibi, Azadeh TI Validity of Diagnostic Codes to Identify Cases of Severe Acute Liver Injury in the US Food and Drug Administration's Mini-Sentinel Distributed Database SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Lo Re, Vincent, III; Haynes, Kevin; Goldberg, David; Forde, Kimberly A.; Carbonari, Dena M.; Hennessy, Sean; Reddy, Rajender] Univ Penn, Perelman Sch Med, Ctr Pharmacoepidemiol Res & Training, Philadelphia, PA 19104 USA. [Lo Re, Vincent, III; Haynes, Kevin; Goldberg, David; Forde, Kimberly A.; Carbonari, Dena M.; Leidl, Kimberly B. F.; Hennessy, Sean] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Lo Re, Vincent, III; Goldberg, David; Forde, Kimberly A.; Reddy, Rajender] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Pawloski, Pamala A.] HealthPartners Inst Educ & Res, Bloomington, MN USA. [Daniel, Gregory W.; Selvam, Nandini] HealthCore Inc, Wilmington, DE USA. [Daniel, Gregory W.] Brookings Inst, Engelberg Ctr Hlth Care Reform, Washington, DC 20036 USA. [Cheetham, T. Craig] Kaiser Permanente So Calif, Pharm Analyt Serv, Downey, CA USA. [Iyer, Aarthi; Coughlin, Kara O.; Toh, Sengwee] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Iyer, Aarthi; Coughlin, Kara O.; Toh, Sengwee] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Boudreau, Denise M.] Grp Hlth Res Inst, Seattle, WA USA. [Cooper, William O.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Selvan, Mano S.] Humana Inc, Competit Hlth Analyt, Louisville, KY USA. [VanWormer, Jeffrey J.] Marshfield Clin Res Fdn, Marshfield, WI USA. [Avigan, Mark I.; Houstoun, Monika; Zornberg, Gwen L.; Racoosin, Judith A.; Shoaibi, Azadeh] US FDA, Silver Spring, MD USA. RI Carbonari, Dena/H-3366-2011; Lo Re, Vincent/N-7817-2015 OI Carbonari, Dena/0000-0003-0310-270X; NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 598 BP 297 EP 298 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876101166 ER PT J AU Torosyan, Y Marinac-Dabic, D AF Torosyan, Yelizaveta Marinac-Dabic, Danica TI The Opportunities and Challenges of Generating Evidence on Medical Device Associated Biomarkers and Implementing the Biomarker-Based Regulatory Research Applications SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Torosyan, Yelizaveta; Marinac-Dabic, Danica] US FDA, Ctr Devices & Radiol Hlth, Div Epidemiol, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 653 BP 326 EP 327 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876101220 ER PT J AU McMahon, AW Weinel, P Wharton, GT Abrams, B Damilano, CP DeLeon, D Lieu, P Yen, L Taketomo, CK Thornton, PS Sood, B Doe, E Baker, RL Rodriguez, W Murphy, MD AF McMahon, Ann W. Weinel, Pamela Wharton, Gerold T. Abrams, Barbara Damilano, Cecilia P. DeLeon, Diva Phuong Lieu Yen, Lilly Taketomo, Carol K. Thornton, Paul S. Sood, Beena Doe, Edwin Baker, Robin L. Rodriguez, William Murphy, M. Dianne TI Analysis of Method To Capture Adverse Events in Neonates and Children in Tertiary Care Pediatric Hospitals SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [McMahon, Ann W.; Weinel, Pamela; Wharton, Gerold T.; Abrams, Barbara; Rodriguez, William; Murphy, M. Dianne] US FDA, Off Pediat Therapeut, Silver Spring, MD USA. [DeLeon, Diva] Childrens Hosp Philadelphia, Dept Endocrinol, Philadelphia, PA 19104 USA. [Phuong Lieu; Yen, Lilly; Taketomo, Carol K.] Childrens Hosp Los Angeles, Serv Pharm, Los Angeles, CA 90027 USA. [Phuong Lieu; Yen, Lilly; Taketomo, Carol K.] Childrens Hosp Los Angeles, Nutr Serv, Los Angeles, CA 90027 USA. [Thornton, Paul S.] Cook Childrens Med Ctr, Ft Worth, TX USA. [Sood, Beena] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Doe, Edwin; Baker, Robin L.] Fairfax Neonatal Associates, Fairfax, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 685 BP 342 EP 343 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876101252 ER PT J AU Knox, CA Hampp, C Willy, M Winterstein, A Dal Pan, G AF Knox, Caitlin A. Hampp, Christian Willy, Mary Winterstein, Almut Dal Pan, Gerald TI Patient Understanding of Drug Risk: Analysis of Medication Guide Assessments SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Knox, Caitlin A.; Winterstein, Almut] Univ Florida, Gainesville, FL USA. [Hampp, Christian; Willy, Mary; Dal Pan, Gerald] US FDA, Off Surveillance & Epidemiol, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 720 BP 361 EP 361 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876101287 ER PT J AU Lo Re, V Cheetham, C Zornberg, GL AF Lo Re, Vincent Cheetham, Craig Zornberg, Gwen L. TI Challenges in Studying Drug-Induced Liver Injury in Pharmacoepidemiology Data Sources SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Lo Re, Vincent] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Cheetham, Craig] US FDA, Off Surveillance & Epidemiol, Silver Spring, MD USA. [Zornberg, Gwen L.] Kaiser Permanente So Calif, Pharm Analyt Serv, Div Res, Downey, CA USA. RI Lo Re, Vincent/N-7817-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 736 BP 369 EP 369 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876101303 ER PT J AU Edlavitch, SA Dal Pan, GJ Raine, JM Leufkens, B Avorn, J Xue, SL AF Edlavitch, Stanley A. Dal Pan, Gerald J. Raine, June M. Leufkens, Bert Avorn, Jerry Xue, Songlin TI Improving the Science of Regulatory Decision-Making - Advances in 2012/2013 SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Edlavitch, Stanley A.] Univ Missouri, Sch Med, Kansas City, MO 64108 USA. [Dal Pan, Gerald J.] US FDA, OSE, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Raine, June M.] Med & Healthcare Prod Regulatory Agcy, London, England. [Leufkens, Bert] Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands. [Avorn, Jerry] Harvard Univ, Sch Med, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA USA. [Xue, Songlin] Takeda Pharmaceut, Global Pharmacovigilance, Deerfield, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 739 BP 371 EP 371 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876101306 ER PT J AU Reefhuis, J Bobo, W van Puijenbroek, E Sahin, L AF Reefhuis, Jennita Bobo, William van Puijenbroek, Eugene Sahin, Leyla TI Interpreting and Communicating Risk of Medications in Pregnancy, Using SSRIs as an Example SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Reefhuis, Jennita] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA USA. [Bobo, William] Mayo Clin, Rochester, MN USA. [van Puijenbroek, Eugene] Netherlands Pharmacovigilance Ctr Lareb, Shertogenbosch, Netherlands. [Sahin, Leyla] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 740 BP 371 EP 372 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876101307 ER PT J AU Kulldorff, M Nguyen, M Balsbaugh, C Dashevsky, I Davis, R Gil-Prieto, R Lee, G Martin, D Russek-Cohen, E Ball, R AF Kulldorff, Martin Michael Nguyen Balsbaugh, Carolyn Dashevsky, Inna Davis, Robert Gil-Prieto, Ruth Lee, Grace Martin, David Russek-Cohen, Estelle Ball, Robert TI Self-Control Tree Scan Data Mining for Vaccine Adverse Events SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Kulldorff, Martin; Balsbaugh, Carolyn; Dashevsky, Inna; Gil-Prieto, Ruth; Lee, Grace] Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA. [Michael Nguyen; Martin, David; Russek-Cohen, Estelle; Ball, Robert] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Davis, Robert] Kaiser Permanente Southeast, Ctr Hlth Res, Atlanta, GA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 765 BP 384 EP 385 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876101332 ER PT J AU Divan, HA Menis, M Sridhar, G Selvam, N Forshee, R Izurieta, HS AF Divan, Hozefa A. Menis, Mikhail Sridhar, Gayathri Selvam, Nandini Forshee, Richard Izurieta, Hector S. TI Occurrence of Hemolytic Reactions (HRs) on the Same Day as Immune Globulin (IG) Product Administrations during 2008-2012 SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Divan, Hozefa A.; Sridhar, Gayathri; Selvam, Nandini] HealthCore Inc, Alexandria, VA USA. [Menis, Mikhail; Forshee, Richard; Izurieta, Hector S.] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 868 BP 436 EP 436 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876101431 ER PT J AU Sridhar, G Menis, M Izurieta, HS Divan, HA Forshee, R Selvam, N AF Sridhar, Gayathri Menis, Mikhail Izurieta, Hector S. Divan, Hozefa A. Forshee, Richard Selvam, Nandini TI Immune Globulins (IGs) and Risk for Thrombotic Adverse Events (TEs) during 2008-2012 Study Period SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Sridhar, Gayathri; Divan, Hozefa A.; Selvam, Nandini] HealthCore Inc, Alexandria, VA USA. [Menis, Mikhail; Izurieta, Hector S.; Forshee, Richard] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 877 BP 440 EP 440 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876101439 ER PT J AU Hampp, C Kang, EM Borders-Hemphill, V AF Hampp, Christian Kang, Elizabeth M. Borders-Hemphill, Vicky TI Use of Prescription Weight-Loss Drugs in the United States, 1993-2011 SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Hampp, Christian; Kang, Elizabeth M.; Borders-Hemphill, Vicky] US FDA, Ctr Drug Evaluat & Res, Off Surveillance & Epidemiol, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 938 BP 470 EP 470 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876102054 ER PT J AU Zhou, EH Kang, EM Seymour, S Iyasu, S AF Zhou, Esther H. Kang, Elizabeth M. Seymour, Sally Iyasu, Solomon TI Long-Acting Beta2-Adrenergic Agonists (LABA) Use in Pediatric and Adolescent Asthma Patients, 2003-2011 SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Zhou, Esther H.; Kang, Elizabeth M.; Iyasu, Solomon] US FDA, Off Surveillance & Epidemiol, Silver Spring, MD USA. [Seymour, Sally] US FDA, Off New Drugs, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 1039 BP 517 EP 517 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876102144 ER PT J AU Zito, JM Burcu, M Lemtouni, S Safer, DJ Schmid, I Pamer, C McKean, S Lam, C Slavin, D AF Zito, Julie M. Burcu, Mehmet Lemtouni, Salma Safer, Daniel J. Schmid, Ian Pamer, Carol McKean, Stephen Lam, Chelsea Slavin, Dale TI Regional Variations in Complex Antipsychotic Medication Regimens in US Foster Care Youth SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Zito, Julie M.; Burcu, Mehmet] Univ Maryland, Dept Pharmaceut Hlth Serv Res, Baltimore, MD 21201 USA. [Lemtouni, Salma; Schmid, Ian; Pamer, Carol; Slavin, Dale] US FDA, Safe Use Initiat, Silver Spring, MD USA. [Safer, Daniel J.] Johns Hopkins Univ, Dept Psychiat, Baltimore, MD USA. [Safer, Daniel J.] Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21218 USA. [McKean, Stephen; Lam, Chelsea] Acumen LLC, Burlingame, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 1040 BP 518 EP 518 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876102145 ER PT J AU Anderson-Smits, C O'Neill, A Corrado, J Marinac-Dabic, D AF Anderson-Smits, Colin O'Neill, Allison Corrado, Julia Marinac-Dabic, Danica TI Long Acting Reversible Contraceptives and Female Sterilization in Medicaid Population, 1999-2009 SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Anderson-Smits, Colin; O'Neill, Allison; Marinac-Dabic, Danica] US FDA, Ctr Devices & Radiol Hlth, Off Surveillance & Biometr, Silver Spring, MD USA. [Corrado, Julia] US FDA, Ctr Devices & Radiol Hlth, Off Device Evaluat, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 1042 BP 519 EP 519 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876102147 ER PT J AU Anderson-Smits, C Corrado, J Sansing, V Marinac-Dabic, D AF Anderson-Smits, Colin Corrado, Julia Sansing, Veronica Marinac-Dabic, Danica TI The Development of the Pelvic Floor Disorder Registry (PFDR) SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Anderson-Smits, Colin; Sansing, Veronica; Marinac-Dabic, Danica] US FDA, Off Surveillance & Biometr, Div Epidemiol, Silver Spring, MD USA. [Corrado, Julia] US FDA, Off Device Evaluat, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 1043 BP 519 EP 520 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876102148 ER PT J AU Sansing, VV Canos, D Anderson-Smits, C Marinac-Dabic, D AF Sansing, Veronica V. Canos, Daniel Anderson-Smits, Collin Marinac-Dabic, Danica TI The Development and Opportunities of a Transcatheter Aortic Valve Replacement Therapy (TVT) Registry SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Sansing, Veronica V.; Canos, Daniel; Anderson-Smits, Collin; Marinac-Dabic, Danica] US FDA, Div Epidemiol, Off Surveillance & Biometr, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 1046 BP 520 EP 521 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876102150 ER PT J AU Epstein, JS Jaffe, HW Alter, HJ Klein, HG AF Epstein, Jay S. Jaffe, Harold W. Alter, Harvey J. Klein, Harvey G. TI Blood system changes since recognition of transfusion-associated AIDS SO TRANSFUSION LA English DT Editorial Material ID NON-B-HEPATITIS; WEST-NILE-VIRUS; CHRONIC-FATIGUE-SYNDROME; NON-A-HEPATITIS; UNITED-STATES; TRYPANOSOMA-CRUZI; VIRAL-HEPATITIS; POSTTRANSFUSION HEPATITIS; TRANSMITTED VIRUSES; AUSTRALIA-ANTIGEN C1 [Epstein, Jay S.] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Jaffe, Harold W.] CDC, Off Associate Director Sci, Atlanta, GA 30333 USA. [Alter, Harvey J.; Klein, Harvey G.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. RP Epstein, JS (reprint author), US FDA, Ctr Biol Evaluat & Res, HFM-300,1401 Rockville Pike, Rockville, MD 20852 USA. EM Jay.Epstein@FDA.HHS.gov NR 71 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD OCT PY 2013 VL 53 IS 10 SI SI BP 2365 EP 2374 DI 10.1111/trf.12373 PN 2 PG 10 WC Hematology SC Hematology GA 238UY UT WOS:000325978000003 PM 24032622 ER PT J AU Sakata, H Matsubayashi, K Ihara, H Sato, S Kato, T Wakisaka, A Tadokoro, K Yu, MYW Baylis, SA Ikeda, H Takamoto, S AF Sakata, Hidekatsu Matsubayashi, Keiji Ihara, Hiromi Sato, Shinichiro Kato, Toshiaki Wakisaka, Akemi Tadokoro, Kenji Yu, Mei-ying W. Baylis, Sally A. Ikeda, Hisami Takamoto, Shigeru TI Impact of chemiluminescent enzyme immunoassay screening for human parvovirus B19 antigen in Japanese blood donors SO TRANSFUSION LA English DT Article ID MEDIATED HEMAGGLUTINATION ASSAY; FACTOR-VIII CONCENTRATE; HUMAN ERYTHROVIRUSES; GENETIC DIVERSITY; HIGH-PURITY; DNA; INFECTION; IDENTIFICATION; TRANSMISSION; GENOTYPE-1 AB BackgroundTo reduce the risk of human parvovirus B19 (B19V) transmission through contaminated blood for transfusion and plasma-derived products, the Japanese Red Cross (JRC) Blood Centers introduced B19V antigen screening by chemiluminescent enzyme immunoassay (CLEIA-B19V) in 2008. Study Design and MethodsDonor samples that were positive by CLEIA-B19V screening were tested for B19V DNA. The sensitivity of CLEIA-B19V was tested using samples of all three genotypes and B19V DNA-positive donations. B19V DNA-positive donations and pooled plasma were quantitatively assayed for B19V DNA. B19V DNA-positive donations were phylogenetically analyzed by polymerase chain reaction direct sequencing. ResultsThe sensitivity of CLEIA-B19V was inferred to be approximately 6.3 log IU/mL with the genotype samples and 6.4 log IU/mL with B19V DNA-positive donor samples. Of 417 CLEIA-B19V-positive samples from 1,035,560 donations in Hokkaido, Japan, 101 were positive for B19V DNA. The 198 strains of B19V DNA-positive donations in Hokkaido over the past 15 years clustered exclusively with Genotype 1. After introduction of CLEIA-B19V, the viral load for B19V DNA in all 772 pooled plasma for fractionation from donors in nationwide Japan did not exceed 4 log IU/mL. ConclusionCLEIA-B19V can detect all three genotypes of B19V (viral load >6.3 log IU/mL) and limit the viral load (<4 log IU/mL) in pooled plasma, and thus such screening has further reduced the risk of transfusion-transmitted B19V infection. These results show that CLEIA-B19V screening at the JRC Blood Centers can be an alternative approach to comply with recommendations regarding B19V in the United States and Europe. C1 Japanese Red Cross Hokkaido Block Blood Ctr, Sapporo, Hokkaido 0630002, Japan. Japanese Red Cross Plasma Fractionat Ctr, Chitose, Japan. Japanese Red Cross Blood Serv Headquarters, Tokyo, Japan. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. Paul Ehrlich Inst, Langen, Germany. RP Sakata, H (reprint author), Japanese Red Cross Hokkaido Block Blood Ctr, Nishi Ku, 2-2 Yamanote, Sapporo, Hokkaido 0630002, Japan. EM sakata@hokkaido.bc.jrc.or.jp NR 36 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD OCT PY 2013 VL 53 IS 10 SI SI BP 2556 EP 2566 DI 10.1111/j.1537-2995.2012.03949.x PN 2 PG 11 WC Hematology SC Hematology GA 238UY UT WOS:000325978000022 PM 23145866 ER PT J AU Navarro, VJ Barnhart, HX Bonkovsky, HL Davern, TJ Fontana, RJ Grant, L Hoofnagle, JH Reddy, KR Seeff, LB Serrano, J Sherker, AH Stolz, A Talwalkar, JA Vega, M Vuppalanchi, R AF Navarro, Victor J. Barnhart, Huiman X. Bonkovsky, Herbert L. Davern, Timothy J. Fontana, Robert J. Grant, Lafaine Hoofnagle, Jay H. Reddy, K. Rajender Seeff, Leonard B. Serrano, Jose Sherker, Averell H. Stolz, Andrew Talwalkar, Jayant A. Vega, Maricruz Vuppalanchi, Raj TI The Rising Burden of Herbal and Dietary Supplement Induced Hepatotoxicity in the U. S. A SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Navarro, Victor J.; Vega, Maricruz] Albert Einstein Med Ctr, Div Hepatol, Philadelphia, PA 19141 USA. [Stolz, Andrew] Univ So Calif, Los Angeles, CA USA. [Hoofnagle, Jay H.; Serrano, Jose; Sherker, Averell H.] NIDDK, Bethesda, MD 20892 USA. [Reddy, K. Rajender] Univ Penn, Div Gastroenterol & Hepatol, Philadelphia, PA 19104 USA. [Davern, Timothy J.] Calif Pacific Med Ctr, San Francisco, CA USA. [Bonkovsky, Herbert L.] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Barnhart, Huiman X.] Duke Clin Res Inst, Durham, NC USA. [Grant, Lafaine] Univ Texas Southwestern, Austin, TX USA. [Fontana, Robert J.] Univ Michigan, Ann Arbor, MI 48109 USA. [Talwalkar, Jayant A.] Mayo Clin, Rochester, MN USA. [Vuppalanchi, Raj] Indiana Univ, Indianapolis, IN 46204 USA. [Seeff, Leonard B.] CDER, Silver Spring, MD USA. NR 0 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 113 BP 264A EP 264A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252201113 ER PT J AU Halegoua-De Marzio, D Vega, M Weber, JS Aithal, GP Andrade, RJ Bessone, F Bjornsson, E Bjornsson, HK Larrey, DG Lizarzabal, M Lucena, MI Caliz, IM Mengual, E Olafsson, S Ripault, MP Seeff, LB Serrano, J Shouval, D Stephens, C Stickel, F Navarro, VJ AF Halegoua-De Marzio, Dina Vega, Maricruz Weber, Joel Schifter Aithal, Guruprasad P. Andrade, Raul J. Bessone, Fernando Bjornsson, Einar Bjornsson, Helgi K. Larrey, Dominique G. Lizarzabal, Maribel Lucena, M. I. Medina Caliz, Inmaculada Mengual, Edgardo Olafsson, Sigurdur Ripault, Marie-Pierre Seeff, Leonard B. Serrano, Jose Shouval, Daniel Stephens, C. Stickel, Felix Navarro, Victor J. TI An International Effort to Assess Hepatotoxicity Associated with Some Herbalife (R) Products SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Vega, Maricruz; Weber, Joel Schifter; Navarro, Victor J.] Albert Einstein Med Ctr, Philadelphia, PA 19141 USA. [Halegoua-De Marzio, Dina] Thomas Jefferson Unviers Hosp, Philadelphia, PA USA. [Aithal, Guruprasad P.] Univ Nottingham, Nottingham NG7 2RD, England. [Andrade, Raul J.; Lucena, M. I.; Medina Caliz, Inmaculada; Stephens, C.] Univ Malaga, E-29071 Malaga, Spain. [Bessone, Fernando] Univ Nacl Rosario, Sch Med, RA-2000 Rosario, Santa Fe, Argentina. [Bjornsson, Einar; Bjornsson, Helgi K.; Olafsson, Sigurdur] Landspitali Univ Hosp, Reykjavik, Iceland. [Larrey, Dominique G.; Ripault, Marie-Pierre] St Eloi Hosp, Montpellier, France. [Lizarzabal, Maribel; Mengual, Edgardo] Univ Hosp Maracaibo, Maracaibo, Venezuela. [Seeff, Leonard B.] Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Serrano, Jose] NIDDK, Bethesda, MD 20892 USA. [Shouval, Daniel] Hadassah Univ Hosp, IL-91120 Jerusalem, Israel. [Stickel, Felix] Univ Bern, Bern, Switzerland. NR 0 TC 4 Z9 4 U1 2 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 360 BP 383A EP 384A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252201360 ER PT J AU Duan, HY Zubkova, I Choi, Y Wells, F Chang, E Pirollo, KF Krawczynski, K Lanford, R Feinstone, S Major, ME AF Duan, Hongying Zubkova, Iryna Choi, Youkyung Wells, Frances Chang, Esther Pirollo, Kathleen F. Krawczynski, Kris Lanford, Robert Feinstone, Stephen Major, Marian E. TI Gene-Expression Profiling to Predict Outcome of Infection in Chimpanzees Vaccinated Against Hepatitis C Virus (HCV) SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Duan, Hongying; Zubkova, Iryna; Wells, Frances; Feinstone, Stephen; Major, Marian E.] US FDA, CBER, Bethesda, MD 20014 USA. [Choi, Youkyung; Krawczynski, Kris] CDC, Div Viral Hepatitis, Atlanta, GA 30333 USA. [Chang, Esther; Pirollo, Kathleen F.] Georgetown Univ, Dept Oncol, Washington, DC USA. [Lanford, Robert] Texas Biomed Res Inst, Dept Virol & Immunol, San Antonio, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1263 BP 822A EP 823A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252204047 ER PT J AU Carpentier, A Tesfaye, A Chu, V Major, ME Feinstone, S Liang, TJ AF Carpentier, Arnaud Tesfaye, Abeba Chu, Virginia Major, Marian E. Feinstone, Stephen Liang, T. Jake TI Engraftment and in vivo HCV infection of human hepatocytes differentiated from embryonic and induced pluripotent stem cells SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Carpentier, Arnaud; Chu, Virginia; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Tesfaye, Abeba; Major, Marian E.; Feinstone, Stephen] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1650 BP 1003A EP 1003A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252204433 ER PT J AU Leymarie, N Griffin, PJ Jonscher, K Kolarich, D Orlando, R McComb, M Zaia, J Aguilan, J Alley, WR Altmann, F Ball, LE Basumallick, L Bazemore-Walker, CR Behnken, H Blank, MA Brown, KJ Bunz, SC Cairo, CW Cipollo, JF Daneshfar, R Desaire, H Drake, RR Go, EP Goldman, R Gruber, C Halim, A Hathout, Y Hensbergen, PJ Horn, DM Hurum, D Jabs, W Larson, G Ly, M Mann, BF Marx, K Mechref, Y Meyer, B Moginger, U Neususs, C Nilsson, J Novotny, MV Nyalwidhe, JO Packer, NH Pompach, P Reiz, B Resemann, A Rohrer, JS Ruthenbeck, A Sanda, M Schulz, JM Schweiger-Hufnagel, U Sihlbom, C Song, E Staples, GO Suckau, D Tang, HX Thaysen-Andersen, M Viner, RI An, YM Valmuv, L Wada, Y Watson, M Windwarder, M Whittal, R Wuhrer, M Zhu, YY Zou, CX AF Leymarie, Nancy Griffin, Paula J. Jonscher, Karen Kolarich, Daniel Orlando, Ron McComb, Mark Zaia, Joseph Aguilan, Jennifer Alley, William R. Altmann, Friederich Ball, Lauren E. Basumallick, Lipika Bazemore-Walker, Carthene R. Behnken, Henning Blank, Michael A. Brown, Kristy J. Bunz, Svenja-Catharina Cairo, Christopher W. Cipollo, John F. Daneshfar, Rambod Desaire, Heather Drake, Richard R. Go, Eden P. Goldman, Radoslav Gruber, Clemens Halim, Adnan Hathout, Yetrib Hensbergen, Paul J. Horn, David M. Hurum, Deanna Jabs, Wolfgang Larson, Goran Ly, Mellisa Mann, Benjamin F. Marx, Kristina Mechref, Yehia Meyer, Bernd Moeginger, Uwe Neusuess, Christian Nilsson, Jonas Novotny, Milos V. Nyalwidhe, Julius O. Packer, Nicolle H. Pompach, Petr Reiz, Bela Resemann, Anja Rohrer, Jeffrey S. Ruthenbeck, Alexandra Sanda, Miloslav Schulz, Jan Mirco Schweiger-Hufnagel, Ulrike Sihlbom, Carina Song, Ehwang Staples, Gregory O. Suckau, Detlev Tang, Haixu Thaysen-Andersen, Morten Viner, Rosa I. An, Yanming Valmuv, Leena Wada, Yoshinao Watson, Megan Windwarder, Markus Whittal, Randy Wuhrer, Manfred Zhu, Yiying Zou, Chunxia TI Interlaboratory Study on Differential Analysis of Protein Glycosylation by Mass Spectrometry: The ABRF Glycoprotein Research Multi-Institutional Study 2012 SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID PROSTATE-SPECIFIC ANTIGEN; N-GLYCOLYLNEURAMINIC ACID; SEMINAL PLASMA; LINKED OLIGOSACCHARIDES; GLYCAN CHARACTERIZATION; CANCER; PSA; IDENTIFICATION; METASTASIS; BIOMARKERS AB One of the principal goals of glycoprotein research is to correlate glycan structure and function. Such correlation is necessary in order for one to understand the mechanisms whereby glycoprotein structure elaborates the functions of myriad proteins. The accurate comparison of glycoforms and quantification of glycosites are essential steps in this direction. Mass spectrometry has emerged as a powerful analytical technique in the field of glycoprotein characterization. Its sensitivity, high dynamic range, and mass accuracy provide both quantitative and sequence/structural information. As part of the 2012 ABRF Glycoprotein Research Group study, we explored the use of mass spectrometry and ancillary methodologies to characterize the glycoforms of two sources of human prostate specific antigen (PSA). PSA is used as a tumor marker for prostate cancer, with increasing blood levels used to distinguish between normal and cancer states. The glycans on PSA are believed to be biantennary N-linked, and it has been observed that prostate cancer tissues and cell lines contain more antennae than their benign counterparts. Thus, the ability to quantify differences in glycosylation associated with cancer has the potential to positively impact the use of PSA as a biomarker. We studied standard peptide-based proteomics/glycomics methodologies, including LC-MS/MS for peptide/glycopeptide sequencing and label-free approaches for differential quantification. We performed an interlaboratory study to determine the ability of different laboratories to correctly characterize the differences between glycoforms from two different sources using mass spectrometry methods. We used clustering analysis and ancillary statistical data treatment on the data sets submitted by participating laboratories to obtain a consensus of the glycoforms and abundances. The results demonstrate the relative strengths and weaknesses of top-down glycoproteomics, bottom-up glycoproteomics, and glycomics methods. C1 [Leymarie, Nancy; McComb, Mark; Zaia, Joseph] Boston Univ, Sch Med, Ctr Biomed Mass Spectrometry, Boston, MA 02118 USA. [Griffin, Paula J.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Jonscher, Karen] Univ Colorado, Dept Anesthesiol, Aurora, CO 80045 USA. [Kolarich, Daniel; Moeginger, Uwe] Max Planck Inst Colloids & Interfaces, D-14476 Potsdam, Germany. [Orlando, Ron] Univ Georgia, Complex Carbohydrates Res Ctr, Athens, GA 30602 USA. [Aguilan, Jennifer] Albert Einstein Coll Med, Lab Macromol Anal, Bronx, NY 10461 USA. [Aguilan, Jennifer] Albert Einstein Coll Med, Prote Facil, Bronx, NY 10461 USA. [Alley, William R.; Mann, Benjamin F.; Novotny, Milos V.] Indiana Univ, Dept Chem, Bloomington, IN 47405 USA. [Altmann, Friederich; Gruber, Clemens; Windwarder, Markus] Univ Nat Resources & Life Sci, Dept Chem, A-1180 Vienna, Austria. [Ball, Lauren E.; Drake, Richard R.] Med Univ S Carolina, MUSC Prote Ctr, Charleston, SC 29425 USA. [Basumallick, Lipika; Hurum, Deanna; Rohrer, Jeffrey S.] Thermo Fisher Sci, Dionex Prod, Applicat Dev, Sunnyvale, CA 94085 USA. [Bazemore-Walker, Carthene R.; Zhu, Yiying] Brown Univ, Dept Chem, Providence, RI 02912 USA. [Behnken, Henning; Meyer, Bernd; Ruthenbeck, Alexandra; Schulz, Jan Mirco] Univ Hamburg, D-20146 Hamburg, Germany. [Blank, Michael A.; Horn, David M.; Viner, Rosa I.] Thermo Fisher Sci, San Jose, CA 95134 USA. [Brown, Kristy J.; Hathout, Yetrib] Childrens Natl Med Ctr, Ctr Genet Med, Washington, DC 20310 USA. [Bunz, Svenja-Catharina; Neusuess, Christian] Aalen Univ, Fac Chem, D-73430 Aalen, Germany. [Cairo, Christopher W.; Daneshfar, Rambod; Reiz, Bela; Whittal, Randy; Zou, Chunxia] Univ Alberta, Dept Chem, Edmonton, AB T6G 2G2, Canada. [Cairo, Christopher W.; Daneshfar, Rambod; Zou, Chunxia] Univ Alberta, Alberta Glyc Ctr, Edmonton, AB T6G 2G2, Canada. [Cipollo, John F.; An, Yanming] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20993 USA. [Desaire, Heather; Go, Eden P.] Univ Kansas, Lawrence, KS 66045 USA. [Goldman, Radoslav; Pompach, Petr; Sanda, Miloslav] Georgetown Univ, Dept Oncol, Washington, DC 20007 USA. [Halim, Adnan; Larson, Goran; Nilsson, Jonas] Univ Gothenburg, Sahlgrenska Acad, Dept Clin Chem & Transfus Med, S-41345 Gothenburg, Sweden. [Hensbergen, Paul J.; Wuhrer, Manfred] Leiden Univ, Med Ctr, Biomol Mass Spectrometry Unit, NL-233ZA Leiden, Netherlands. [Jabs, Wolfgang; Marx, Kristina; Resemann, Anja; Schweiger-Hufnagel, Ulrike; Suckau, Detlev] Bruker Daltonik GmbH, D-28359 Bremen, Germany. [Ly, Mellisa; Staples, Gregory O.] Agilent Technol, Agilent Labs, Santa Clara, CA 95051 USA. [Mechref, Yehia; Song, Ehwang] Texas Tech Univ, Dept Chem & Biochem, Lubbock, TX 79409 USA. [Nyalwidhe, Julius O.; Watson, Megan] Eastern Virginia Med Sch, Leroy T Canoles Jr Canc Res Ctr, Dept Microbiol & Mol Cell Biol, Norfolk, VA 23507 USA. [Packer, Nicolle H.; Thaysen-Andersen, Morten] Macquarie Univ, Dept Chem & Biomol Sci, Biomol Frontiers Res Ctr, Sydney, NSW 2109, Australia. [Sihlbom, Carina] Gothenburg Univ, Prote Core Facil, Gothenburg, Sweden. [Tang, Haixu] Indiana Univ, Sch Informat, Bloomington, IN 47405 USA. [Valmuv, Leena] Finnish Red Cross Blood Serv, Helsinki 00310, Finland. [Wada, Yoshinao] Osaka Med Ctr Maternal & Child Hlth, Res Inst, Izumi Ku, Osaka 5941101, Japan. RP Zaia, J (reprint author), Boston Univ, Sch Med, Ctr Biomed Mass Spectrometry, 670 Albany St,Ste 507, Boston, MA 02118 USA. EM mccomb@bu.edu; jzaia@bu.edu RI Cairo, Christopher/B-5355-2009; Bazemore-Walker, Carthene/I-1879-2013; Pompach, Petr/J-6209-2014; Meyer, Bernd/A-8828-2008; Viner, Russell/A-1441-2009; OI Mechref, Yehia/0000-0002-6661-6073; Wuhrer, Manfred/0000-0002-0814-4995; Cairo, Christopher/0000-0003-3363-8708; Ball, Lauren/0000-0001-6780-1679; Altmann, Friedrich/0000-0002-0112-7877; Kolarich, Daniel/0000-0002-8452-1350; Viner, Russell/0000-0003-3047-2247; McComb, Mark/0000-0002-4249-485X; Nilsson, Jonas/0000-0001-5263-2454; Bazemore-Walker, Carthene/0000-0001-5157-4440; Zaia, Joseph/0000-0001-9497-8701 FU NIH [R01 098050, P41 P41GM104603, N01 HV 00239, S10 RR 015942, S10 RR 020946, S10 RR 025082] FX The ABRF Glycoprotein Research Group 2012 Quantitative Glycoprotein Study was supported by NIH grants R01 098050, P41 P41GM104603, N01 HV 00239, S10 RR 015942, S10 RR 020946, and S10 RR 025082. NR 54 TC 56 Z9 56 U1 3 U2 32 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD OCT PY 2013 VL 12 IS 10 BP 2935 EP 2951 DI 10.1074/mcp.M113.030643 PG 17 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 301MS UT WOS:000330537000021 PM 23764502 ER PT J AU Nguyen, RT Sayeed, VA AF Nguyen, Ryan T. Sayeed, Vilayat A. TI Repackaged oral dosage forms: Beyond-use dating and product safety concerns SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Editorial Material ID DOSE ADMINISTRATION AIDS; STABILITY; CONTAINERS C1 [Nguyen, Ryan T.; Sayeed, Vilayat A.] US FDA, Div Chem 3, Off Gener Drugs, Off Pharmaceut Sci, Rockville, MD 20855 USA. RP Sayeed, VA (reprint author), US FDA, Div Chem 3, Ctr Drug Evaluat & Res, 7500 Standish Pl,MPN 2,HFD 630,Room E-133, Rockville, MD 20855 USA. EM vilayat.sayeed@fda.hhs.gov NR 12 TC 0 Z9 0 U1 0 U2 3 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 EI 1535-2900 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD OCT 1 PY 2013 VL 70 IS 19 BP 1724 EP 1727 DI 10.2146/ajhp130100 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 298MC UT WOS:000330327000019 PM 24048609 ER PT J AU Pennello, GA AF Pennello, Gene A. TI Analytical and clinical evaluation of biomarkers assays: When are biomarkers ready for prime time? SO CLINICAL TRIALS LA English DT Article; Proceedings Paper CT University-of-Pennsylvania 5th Annual Conference on Statistical Issues in Clinical Trials - Emerging Statistical Issues in Biomarker Validation for Clinical Trials CY 2012 CL Univ Penn, Philadelphia, PA HO Univ Penn ID DIAGNOSTICS; MODELS; TRIALS; RECOMMENDATIONS; PERFORMANCE; FRAMEWORK; ACCURACY; MEDICINE; MARKERS; LIMIT AB Background Biomarker assays can be evaluated for analytical performance (ability of assay to measure the biomarker quantity) and clinical performance (ability of assay result to inform of the clinical condition of interest). Additionally, a biomarker assay is said to have clinical utility if it ultimately improves patient outcomes when used as intended. Purpose This article reviews analytical and clinical performance studies of biomarker assay tests and also some designs of clinical utility studies. Results Appropriate design and statistical analysis of analytical and clinical evaluation studies depend on the intended clinical use of the test. Some key aspects to valid performance studies include using subjects who are independent of those used to develop the test, masking users of the test to any other available test or reference results, and including in the primary statistical analysis subjects with unavailable results in an intention-to-diagnose analysis. Ingenuity in study design and analysis may be required for efficient and unbiased estimation of performance. Limitations Performance studies need to be carefully planned as they can be prone to many sources of bias. Analytical inaccuracy can hamper the clinical performance of biomarkers. Conclusions As biomedical research and technology advance, challenges in study design and statistical analysis will continue to emerge for analytical and clinical performance studies of biomarker assays. Although not emphasized in some circles, the analytical performance of a biomarker assay is important to characterize. Analytical performance studies have many study design and statistical analysis challenges that deserve further attention. C1 US FDA, Diagnost Devices Branch, Div Biostat, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Pennello, GA (reprint author), US FDA, Diagnost Devices Branch, Div Biostat, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,White Oak Bldg 66, Silver Spring, MD 20993 USA. EM gene.pennello@fda.hhs.gov NR 63 TC 10 Z9 10 U1 1 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD OCT PY 2013 VL 10 IS 5 BP 666 EP 676 DI 10.1177/1740774513497541 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 301IP UT WOS:000330526300004 PM 23983159 ER PT J AU DeMets, D Wittes, J Siegel, J Mietlowski, W Sargent, D Rubin, E McShane, L Ellenberg, S Pennello, G Wang, SB Liao, J Tandon, PK Gilbert, H Chappell, R AF DeMets, David Wittes, Janet Siegel, Jay Mietlowski, William Sargent, Dan Rubin, Eric McShane, Lisa Ellenberg, Susan Pennello, Gene Wang, Songbai Liao, Jason Tandon, P. K. Gilbert, Houston Chappell, Richard TI University of Pennsylvania 5th annual conference on statistical issues in clinical trials: Emerging statistical issues in biomarker validation (Morning Session) SO CLINICAL TRIALS LA English DT Editorial Material C1 [DeMets, David; Chappell, Richard] Univ Wisconsin, Madison, WI 53706 USA. [Siegel, Jay] Johnson & Johnson, New Brunswick, NJ USA. [Sargent, Dan] Mayo Clin, Rochester, MN USA. [McShane, Lisa] NCI, Bethesda, MD 20892 USA. [Ellenberg, Susan] Univ Penn, Philadelphia, PA 19104 USA. [Pennello, Gene] US FDA, Rockville, MD 20857 USA. [Wang, Songbai] Ortho Clin Diagnost, Rochester, NY USA. [Liao, Jason] Penn State Hershey Canc Inst, Hershey, PA USA. [Tandon, P. K.] Genzyme Corp, Cambridge, MA USA. [Gilbert, Houston] Genentech Inc, South San Francisco, CA USA. RP DeMets, D (reprint author), Univ Wisconsin, Madison, WI 53706 USA. FU NCI NIH HHS [5R13CA132565-05] NR 2 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD OCT PY 2013 VL 10 IS 5 BP 680 EP 689 DI 10.1177/1740774513500388 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 301IP UT WOS:000330526300006 PM 24130200 ER PT J AU Rubin, E LaVange, L DeGruttola, V Ellenberg, S Tan, C Betensky, R Maislin, G Beckman, B Wang, SJ Mietlowski, B Shen, L Pennello, G Begg, C Ji, RR AF Rubin, Eric LaVange, Lisa DeGruttola, Victor Ellenberg, Susan Tan, Charles Betensky, Rebecca Maislin, Greg Beckman, Bob Wang, Sue-Jane Mietlowski, Bill Shen, Lei Pennello, Gene Begg, Colin Ji, Rui-Ru TI University of Pennsylvania 5th annual conference on statistical issues in Clinical Trials: Emerging statistical issues in biomarker validation (afternoon session) SO CLINICAL TRIALS LA English DT Editorial Material ID CANCER; DESIGN C1 [LaVange, Lisa; Wang, Sue-Jane; Pennello, Gene] US FDA, Rockville, MD 20857 USA. [DeGruttola, Victor; Betensky, Rebecca] Harvard, Boston, MA USA. [Ellenberg, Susan; Maislin, Greg] Univ Penn, Philadelphia, PA 19104 USA. [Tan, Charles] Pfizer, New York, NY USA. [Shen, Lei] Eli Lilly, Indianapolis, IN USA. [Begg, Colin] Mem Sloan Kettering, New York, NY USA. [Ji, Rui-Ru] Bristol Myers Squibb, Princeton, NJ USA. FU NCI NIH HHS [5R13CA132565-05] NR 8 TC 0 Z9 0 U1 1 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD OCT PY 2013 VL 10 IS 5 BP 701 EP 708 DI 10.1177/1740774513500082 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 301IP UT WOS:000330526300010 PM 23988466 ER PT J AU Dodd, LE Korn, EL Freidlin, B Gu, WJ Abrams, JS Bushnell, WD Canetta, R Doroshow, JH Gray, RJ Sridhara, R AF Dodd, Lori E. Korn, Edward L. Freidlin, Boris Gu, Wenjuan Abrams, Jeffrey S. Bushnell, William D. Canetta, Renzo Doroshow, James H. Gray, Robert J. Sridhara, Rajeshwari TI An audit strategy for time-to-event outcomes measured with error: Application to five randomized controlled trials in oncology SO CLINICAL TRIALS LA English DT Article; Proceedings Paper CT University-of-Pennsylvania 5th Annual Conference on Statistical Issues in Clinical Trials - Emerging Statistical Issues in Biomarker Validation for Clinical Trials CY 2012 CL Univ Penn, Philadelphia, PA HO Univ Penn ID METASTATIC BREAST-CANCER; CLINICAL-TRIALS; PLUS CAPECITABINE; PROGRESSION; LAPATINIB; SURVIVAL AB Background Measurement error in time-to-event end points complicates interpretation of treatment effects in clinical trials. Non-differential measurement error is unlikely to produce large bias [1]. When error depends on treatment arm, bias is of greater concern. Blinded-independent central review (BICR) of all images from a trial is commonly undertaken to mitigate differential measurement-error bias that may be present in hazard ratios (HRs) based on local evaluations. Similar BICR and local evaluation HRs may provide reassurance about the treatment effect, but BICR adds considerable time and expense to trials. Methods We describe a BICR audit strategy [2] and apply it to five randomized controlled trials to evaluate its use and to provide practical guidelines. The strategy requires BICR on a subset of study subjects, rather than a complete-case BICR, and makes use of an auxiliary-variable estimator. Results When the effect size is relatively large, the method provides a substantial reduction in the size of the BICRs. In a trial with 722 participants and a HR of 0.48, an average audit of 28% of the data was needed and always confirmed the treatment effect as assessed by local evaluations. More moderate effect sizes and/or smaller trial sizes required larger proportions of audited images, ranging from 57% to 100% for HRs ranging from 0.55 to 0.77 and sample sizes between 209 and 737. Limitations The method is developed for a simple random sample of study subjects. In studies with low event rates, more efficient estimation may result from sampling individuals with events at a higher rate. Conclusion The proposed strategy can greatly decrease the costs and time associated with BICR, by reducing the number of images undergoing review. The savings will depend on the underlying treatment effect and trial size, with larger treatment effects and larger trials requiring smaller proportions of audited data. C1 [Dodd, Lori E.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Korn, Edward L.; Freidlin, Boris] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. [Gu, Wenjuan] NCI, Biostat Res Branch, SAIC Frederick Inc, Frederick, MD 21701 USA. [Abrams, Jeffrey S.] NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. [Canetta, Renzo] Bristol Myers Squibb Co, Wallingford, CT 06492 USA. [Doroshow, James H.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Gray, Robert J.] Harvard Univ, Dept Biostat, Boston, MA 02115 USA. [Sridhara, Rajeshwari] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Dodd, LE (reprint author), NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM doddl@mail.nih.gov FU PHS HHS [HHSN261200800001E] NR 13 TC 1 Z9 1 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD OCT PY 2013 VL 10 IS 5 BP 754 EP 760 DI 10.1177/1740774513493973 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 301IP UT WOS:000330526300015 PM 23935162 ER PT J AU Hwang, MY Buckley, PF AF Hwang, Michael Y. Buckley, Peter F. TI Comorbidities in Schizophrenia: Clinical Management and Conceptual Issues SO PSYCHIATRIC ANNALS LA English DT Editorial Material C1 [Hwang, Michael Y.] New York Med Coll, Valhalla, NY 10595 USA. [Hwang, Michael Y.] Albert Einstein Coll Med, Bronx, NY USA. [Hwang, Michael Y.] US FDA, Psychopharmacol Advisory Board, Rockville, MD 20857 USA. [Buckley, Peter F.] Amer Psychiat Assoc, Washington, DC 20005 USA. [Buckley, Peter F.] Assoc Amer Med Coll, Washington, DC 20037 USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 EI 1938-2456 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD OCT PY 2013 VL 43 IS 10 BP 435 EP 436 DI 10.3928/00485713-20131003-02 PG 2 WC Psychiatry SC Psychiatry GA 282SG UT WOS:000329192600002 ER PT J AU Lu, QJ Hofferbert, BV Koo, G Malinauskas, RA AF Lu, Qijin Hofferbert, Bryan V. Koo, Grace Malinauskas, Richard A. TI In Vitro Shear Stress-Induced Platelet Activation: Sensitivity of Human and Bovine Blood SO ARTIFICIAL ORGANS LA English DT Article DE Platelet activation; Shear stress; P-selectin; Serotonin; Human blood; Bovine blood; Platelet count ID VENTRICULAR ASSIST DEVICE; FLOW-CYTOMETRY; WHOLE-BLOOD; HEART-VALVE; HEPARIN; AGGREGATION; THROMBOSIS; THROMBOGENICITY; AGONISTS; PUMPS AB As platelet activation plays a critical role in physiological hemostasis and pathological thrombosis, it is important in the overall hemocompatibility evaluation of new medical devices and biomaterials to assess their effects on platelet function. However, there are currently no widely accepted in vitro test methods to perform this assessment. In an effort to develop effective platelet tests for potential use in medical device evaluation, this study compared the sensitivity of platelet responses to shear stress stimulation of human and bovine blood using multiple platelet activation markers. Fresh whole blood samples anticoagulated with heparin or anticoagulant citrate dextrose, solution A (ACDA) were exposed to shear stresses up to 40Pa for 2min using a cone-and-plate rheometer model. Platelet activation was characterized by platelet counts, platelet surface P-selectin expression, and serotonin release into blood plasma. The results indicated that exposure to shear stresses above 20Pa caused significant changes in all three of the platelet markers for human blood and that the changes were usually greater with ACDA anticoagulation than with heparin. In contrast, for bovine blood, the markers did not change with shear stress stimulation except for plasma serotonin in heparin anticoagulated blood. The differences observed between human and bovine platelet responses suggest that the value of using bovine blood for in vitro platelet testing to evaluate devices may be limited. C1 [Lu, Qijin; Hofferbert, Bryan V.; Koo, Grace; Malinauskas, Richard A.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Lu, QJ (reprint author), US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,WO62 Rm 2106, Silver Spring, MD 20993 USA. EM qijin.lu@fda.hhs.gov NR 47 TC 12 Z9 13 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0160-564X EI 1525-1594 J9 ARTIF ORGANS JI Artif. Organs PD OCT PY 2013 VL 37 IS 10 BP 894 EP 903 DI 10.1111/aor.12099 PG 10 WC Engineering, Biomedical; Transplantation SC Engineering; Transplantation GA 270NM UT WOS:000328325300009 PM 23738621 ER PT J AU Jahouh, F Xu, P Vann, WF Kovac, P Banoub, JH AF Jahouh, Farid Xu, Peng Vann, Willie F. Kovac, Pavol Banoub, Joseph H. TI Mapping the glycation sites in the neoglycoconjugate from hexasaccharide antigen of Vibrio cholerae, serotype Ogawa and the recombinant tetanus toxin C-fragment carrier SO JOURNAL OF MASS SPECTROMETRY LA English DT Article DE nano-LC-ESI-QqTOF-MS; MS; neoglycoconjugate vaccine; recombinant tetanus toxin C-fragment (rTT-Hc); Trypsin digestion; GluC V8 digestion; MALDI-TOF-MS ID TANDEM MASS-SPECTROMETRY; SWISS-MODEL; O-PS; TRANSCUTANEOUS IMMUNIZATION; PROTECTIVE IMMUNITY; PROTEIN CARRIER; H-C; CONJUGATION; VACCINES; OLIGOSACCHARIDES AB We report herein the glycation sites in a vaccine candidate for cholera formed by conjugation of the synthetic hexasaccharide fragment of the O-specific polysaccharide of Vibrio cholerae, serotype Ogawa, to the recombinant tetanus toxin C-fragment (rTT-Hc) carrier. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis of the vaccine revealed that it is composed of a mixture of neoglycoconjugates with carbohydrate:protein ratios of 1.9:1, 3.0:1, 4.0:1, 4.9:1, 5.9:1, 6.9:1, 7.9:1 and 9.1:1. Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis of the tryptic and GluC V8 digests allowed identification of 12 glycation sites in the carbohydrate-protein neoglycoconjugate vaccine. The glycation sites are located exclusively on lysine (Lys) residues and are listed as follows: Lys 22, Lys 61, Lys 145, Lys 239, Lys 278, Lys 318, Lys 331, Lys 353, Lys 378, Lys 389, Lys 396 and Lys 437. Based on the 3-D representation of the rTT-Hc protein, all the glycation sites correspond to lysines located at the outer surface of the protein. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Jahouh, Farid; Banoub, Joseph H.] Mem Univ Newfoundland, Dept Biochem, St John, NF A1B 3X7, Canada. [Xu, Peng; Kovac, Pavol] NIDDK, NIH, Lbc Bethesda, MD 20892 USA. [Vann, Willie F.] US FDA, Lab Bacterial Toxins OVRR, CBER, Bethesda, MD 20892 USA. [Banoub, Joseph H.] Fisheries & Oceans Canada, Sci Branch, Special Projects, St John, NF A1C 5X1, Canada. RP Banoub, JH (reprint author), Fisheries & Oceans Canada, Sci Branch, Special Projects, POB 5667, St John, NF A1C 5X1, Canada. EM Joe.Banoub@dfo-mpo.gc.ca RI Xu, Peng/K-7036-2012 FU Intramural NIH HHS [ZIA DK059701-39, Z99 DK999999] NR 29 TC 4 Z9 4 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1076-5174 EI 1096-9888 J9 J MASS SPECTROM JI J. Mass Spectrom. PD OCT PY 2013 VL 48 IS 10 BP 1083 EP 1090 DI 10.1002/jms.3258 PG 8 WC Biochemical Research Methods; Chemistry, Analytical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA 272PU UT WOS:000328473500003 PM 24130011 ER PT J AU Woo, EJ AF Woo, Emily Jane TI End-plate measurements as early markers of disc degeneration and herniation SO SPINE JOURNAL LA English DT Letter C1 US FDA, Rockville, MD 20857 USA. RP Woo, EJ (reprint author), US FDA, Rockville, MD 20857 USA. NR 4 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1529-9430 EI 1878-1632 J9 SPINE J JI Spine Journal PD OCT PY 2013 VL 13 IS 10 BP 1418 EP 1418 DI 10.1016/j.spinee.2013.06.062 PG 1 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 258AP UT WOS:000327430300045 PM 24237712 ER PT J AU Durmowicz, AG Witzmann, KA Rosebraugh, CJ Chowdhury, BA AF Durmowicz, Anthony G. Witzmann, Kimberly A. Rosebraugh, Curtis J. Chowdhury, Badrul A. TI Understanding the Relationship Between Sweat Chloride and Lung Function in Cystic Fibrosis Response SO CHEST LA English DT Letter C1 [Durmowicz, Anthony G.; Witzmann, Kimberly A.; Chowdhury, Badrul A.] US FDA, Div Pulm Allergy & Rheumatol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Rosebraugh, Curtis J.] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Rosebraugh, Curtis J.] US FDA, Off Drug Evaluat 2, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Durmowicz, AG (reprint author), US FDA, Div Pulm Allergy & Rheumatol Prod, White Oak Bldg 22,Room 3318,10903 New Hampshire A, Silver Spring, MD 20993 USA. EM anthony.durmowicz@fda.hhs.gov NR 3 TC 1 Z9 1 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 EI 1931-3543 J9 CHEST JI Chest PD OCT PY 2013 VL 144 IS 4 BP 1418 EP 1419 DI 10.1378/chest.13-1517 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 241JJ UT WOS:000326162600053 PM 24081359 ER PT J AU Karesh, A Tomaino, J Mulberg, AE AF Karesh, Alyson Tomaino, Juli Mulberg, Andrew E. TI Off-label use of medicine in pediatrics: focus on gastrointestinal diseases SO CURRENT OPINION IN PEDIATRICS LA English DT Review DE drug development; gastrointestinal; off-label; pediatric ID PROTON PUMP INHIBITORS; ADVERSE DRUG-REACTIONS; PRESCRIBING PATTERNS; BOWEL PREPARATION; UNITED-STATES; CHILDREN; INFANTS; GASTROENTEROLOGY; PHARMACOTHERAPY; PERSPECTIVES AB Purpose of reviewTo provide current information on off-label medication use in pediatric gastroenterology, including a discussion on US legislative efforts to address the issue. Recent findingsMedications used to treat pediatric gastrointestinal illnesses are frequently prescribed off-label. Acid suppressors, antiemetics, laxatives, and antitumor necrosis factor therapies are types of medications frequently used off-label in the pediatric gastroenterology arena. Pediatric studies conducted under US Federal laws are generating much-needed data on the safety and effectiveness of medications used to treat pediatric patients. Moreover, a new US law, the Food and Drug Administration Safety and Innovation Act, may further the development of pediatric medications in part by requiring pediatric-specific study plans earlier in the overall drug development process. As of today, there still are gaps in our knowledge about these medications, including for the treatment of pediatric gastroenterology diseases. SummaryMedications are widely used off-label in pediatrics, including medications intended to treat gastrointestinal diseases, such as antitumor necrosis factor and laxatives. Although legislation is helping to generate and make available important information about pediatric medications, most still do not contain pediatric data. Therefore, providers need to understand the potential risks and benefits of prescribing off-label products to pediatric patients. C1 [Karesh, Alyson] US FDA, Silver Spring, MD USA. [Tomaino, Juli; Mulberg, Andrew E.] US FDA, Div Gastroenterol & Inborn Errors Prod, Silver Spring, MD USA. RP Mulberg, AE (reprint author), Div Gastroenterol & Inborn Errors Prod, 10903 New Hampshire Ave,Bldg 22,Room 5120, Silver Spring, MD 20993 USA. EM Andrew.Mulberg@fda.hhs.gov NR 47 TC 4 Z9 4 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8703 EI 1531-698X J9 CURR OPIN PEDIATR JI CURR. OPIN. PEDIATR. PD OCT PY 2013 VL 25 IS 5 BP 612 EP 617 DI 10.1097/MOP.0b013e328363ed4e PG 6 WC Pediatrics SC Pediatrics GA 248XI UT WOS:000326738700009 PM 23995427 ER PT J AU Hoffmann, M Monday, SR Fischer, M Brown, EW AF Hoffmann, Maria Monday, Steven R. Fischer, Markus Brown, Eric W. TI Threat from the Sea SO DEUTSCHE LEBENSMITTEL-RUNDSCHAU LA German DT Article C1 [Hoffmann, Maria; Monday, Steven R.; Brown, Eric W.] US FDA, Div Microbiol, Off Regulatory Sci, Ctr Food Safety & Nutr, College Pk, MD 20740 USA. [Fischer, Markus] Univ Hamburg, Hamburg Sch Food Sci, Inst Lebensmittelchem, D-20146 Hamburg, Germany. RP Hoffmann, M (reprint author), US FDA, Div Microbiol, Off Regulatory Sci, Ctr Food Safety & Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM maria.hoffman@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU B BEHES VERLAG GMBH & CO KG PI HAMBURG PA AVERHOFFSTRASSE 10, HAMBURG, 22085, GERMANY SN 0012-0413 J9 DEUT LEBENSM-RUNDSCH JI Dtsch. Lebensm.-Rundsch. PD OCT PY 2013 VL 109 IS 10 BP 533 EP 538 PG 6 WC Food Science & Technology SC Food Science & Technology GA 248BQ UT WOS:000326669100009 ER PT J AU Fan, Y Ma, L Pippins, J Limb, S Xu, Y Sahajwalla, CG AF Fan, Ying Ma, Lian Pippins, Jennifer Limb, Susan Xu, Yun Sahajwalla, Chandrahas G. TI Impact of Study Design on the Evaluation of Inhaled and Intranasal Corticosteroids' Effect on Hypothalamic-Pituitary-Adrenal Axis Function, Part I: General Overview of HPA Axis Study Design SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Review DE pulmonary; regulatory science; pharmacodynamics; study design; inhaled corticosteroids; intranasal corticosteroids; hypothalamic-pituitary-adrenal axis ID AQUEOUS NASAL SPRAY; DRY-POWDER INHALER; PERENNIAL ALLERGIC RHINITIS; METERED-DOSE INHALER; FLUTICASONE PROPIONATE; BECLOMETHASONE DIPROPIONATE; MOMETASONE FUROATE; TRIAMCINOLONE ACETONIDE; HEALTHY-VOLUNTEERS; SYSTEMIC BIOACTIVITY AB Inhaled and intranasal corticosteroids (ICS and INS) are among the mainstays of the treatment for asthma and allergic rhinitis, respectively, and also carry the potential to suppress the hypothalamic-pituitary-adrenal (HPA) axis. Several important factors affect the interpretability of trials investigating the impact of ICS and INS on the HPA axis. This paper reviews 106 published clinical trials, peer-reviewed articles, and New Drug Application reviews of approved ICS and INS, using MEDLINE and Drugs@FDA database. The trials included in this review evaluated the potential impact on HPA axis function of eight approved single-ingredient ICS and INS (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone furoate, flucticasone propionate, mometasone furoate, and triamcinolone acetonide) and combination products containing these ingredients. The most commonly utilized design was blinded, placebo controlled, and short term (<6 weeks) for adult trials and blinded, placebo controlled, and long term (6 weeks) for pediatric trials. Factors potentially affecting trial results include the choice of dose, dosing duration, assay sensitivity, statistical methodology, and the study population evaluated (patients or healthy volunteers). All of these factors have the potential to affect the level of adrenal suppression detected. In conclusion, to be informative, a HPA axis study should be well designed and carefully implemented to minimize variability in results and improve the overall interpretability of data obtained. (c) 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3513-3527, 2013 C1 [Fan, Ying; Xu, Yun; Sahajwalla, Chandrahas G.] US FDA, Div Clin Pharmacol 2, Off Clin Pharmacol, Silver Spring, MD USA. [Ma, Lian] Oregon State Univ, Coll Pharm, Corvallis, OR 97331 USA. [Pippins, Jennifer; Limb, Susan] US FDA, Div Pulm Allergy & Rheumatol Prod, Off Drug Evaluat 2, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Sahajwalla, CG (reprint author), US FDA, Div Clin Pharmacol 2, Off Clin Pharmacol, Silver Spring, MD USA. EM chandrahas.sahajwalla@fda.hhs.gov NR 105 TC 6 Z9 6 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD OCT PY 2013 VL 102 IS 10 BP 3513 EP 3527 DI 10.1002/jps.23689 PG 15 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 216VS UT WOS:000324314200003 PM 23918409 ER PT J AU Yerlikaya, F Ozgen, A Vural, I Guven, O Karaagaoglu, E Khan, MA Capan, Y AF Yerlikaya, Firat Ozgen, Aysegul Vural, Imran Guven, Olgun Karaagaoglu, Ergun Khan, Mansoor A. Capan, Yilmaz TI Development and Evaluation of Paclitaxel Nanoparticles Using a Quality-by-Design Approach SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE paclitaxel; quality by design; design of experiments; Plackett-Burman; Box-Behnken; formulation; multivariate analysis; mathematical model; nanoparticles; polymeric drug delivery systems ID PLACKETT-BURMAN DESIGN; DRUG-DELIVERY SYSTEMS; FORMULATION VARIABLES; CYCLOSPORINE-A; PLGA NANOPARTICLES; CANCER-CELLS; IN-VITRO; QBD; MICROSPHERES; LIPOSOMES AB The aims of this study were to develop and characterize paclitaxel nanoparticles, to identify and control critical sources of variability in the process, and to understand the impact of formulation and process parameters on the critical quality attributes (CQAs) using a quality-by-design (QbD) approach. For this, a risk assessment study was performed with various formulation and process parameters to determine their impact on CQAs of nanoparticles, which were determined to be average particle size, zeta potential, and encapsulation efficiency. Potential risk factors were identified using an Ishikawa diagram and screened by Plackett-Burman design and finally nanoparticles were optimized using Box-Behnken design. The optimized formulation was further characterized by Fourier transform infrared spectroscopy, X-ray diffractometry, differential scanning calorimetry, scanning electron microscopy, atomic force microscopy, and gas chromatography. It was observed that paclitaxel transformed from crystalline state to amorphous state while totally encapsulating into the nanoparticles. The nanoparticles were spherical, smooth, and homogenous with no dichloromethane residue. In vitro cytotoxicity test showed that the developed nanoparticles are more efficient than free paclitaxel in terms of antitumor activity (more than 25%). In conclusion, this study demonstrated that understanding formulation and process parameters with the philosophy of QbD is useful for the optimization of complex drug delivery systems. (c) 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3748-3761, 2013 C1 [Yerlikaya, Firat; Vural, Imran; Capan, Yilmaz] Hacettepe Univ, Fac Pharm, Dept Pharmaceut Technol, TR-06100 Ankara, Turkey. [Ozgen, Aysegul] Hacettepe Univ, Dept Chem, Fac Sci, Div Phys Chem, TR-06532 Ankara, Turkey. [Guven, Olgun] Hacettepe Univ, Dept Chem, Fac Sci, Div Polymer Chem, TR-06532 Ankara, Turkey. [Karaagaoglu, Ergun] Hacettepe Univ, Fac Med, Dept Biostat, TR-06100 Ankara, Turkey. [Khan, Mansoor A.] US FDA, Div Prod Qual Res, Off Testing & Res, OPS,CDER, Silver Spring, MD USA. RP Capan, Y (reprint author), Hacettepe Univ, Fac Pharm, Dept Pharmaceut Technol, TR-06100 Ankara, Turkey. EM ycapan@hacettepe.edu.tr RI Bayram, Cem/D-7403-2013 OI Bayram, Cem/0000-0001-8717-4668 NR 40 TC 10 Z9 10 U1 3 U2 35 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD OCT PY 2013 VL 102 IS 10 BP 3748 EP 3761 DI 10.1002/jps.23686 PG 14 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 216VS UT WOS:000324314200026 PM 23918313 ER PT J AU He, Z Ferguson, SA Cui, L Greenfield, LJ Paule, MG AF He, Zhen Ferguson, Sherry Ann Cui, Li Greenfield, Lazar John Paule, Merle Gale TI Development of the sexually dimorphic nucleus of the preoptic area and the influence of estrogen-like compounds SO NEURAL REGENERATION RESEARCH LA English DT Review DE neural regeneration; review; sexual orientation; sexual behavior; calbindin D28K; estrogen-like compound; bisphenol A; neural stem cells; grants-supported paper; neuroregeneration ID GONADOTROPIN-RELEASING-HORMONE; MESSENGER-RNA EXPRESSION; ADULT-RAT BRAIN; SEX-DIFFERENCES; BISPHENOL-A; FEMALE RATS; AREA/ANTERIOR HYPOTHALAMUS; STRIA TERMINALIS; POSTNATAL RATS; BED NUCLEUS AB One of the well-defined sexually dimorphic structures in the brain is the sexually dimorphic nucleus, a cluster of cells located in the preoptic area of the hypothalamus. The rodent sexually dimorphic nucleus of the preoptic area can be delineated histologically using conventional Nissl staining or immunohistochemically using calbindin D28K immunoreactivity. There is increasing use of the calbindin D28K-delineated neural cluster to define the sexually dimorphic nucleus of the preoptic area in rodents. Several mechanisms are proposed to underlie the processes that contribute to the sexual dimorphism (size difference) of the sexually dimorphic nucleus of the preoptic area. Recent evidence indicates that stem cell activity, including proliferation and migration presumably from the 3rd ventricle stem cell niche, may play a critical role in the postnatal development of the sexually dimorphic nucleus of the preoptic area and its distinguishing sexually dimorphic feature: a significantly larger volume in males. Sex hormones and estrogen-like compounds can affect the size of the sexually dimorphic nucleus of the preoptic area. Despite considerable research, it remains unclear whether estrogen-like compounds and/or sex hormones increase size of the sexually dimorphic nucleus of the preoptic area via an increase in stem cell activity originating from the 3rd ventricle stem cell niche. C1 [He, Zhen; Ferguson, Sherry Ann; Paule, Merle Gale] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [He, Zhen; Cui, Li; Greenfield, Lazar John] Univ Arkansas Med Sci, Dept Neurol, Little Rock, AR 72005 USA. RP He, Z (reprint author), US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Off Room 53D-203N,HFT-132,3900 NCTR Rd, Jefferson, AR 72079 USA. EM zhen.he@fda.hhs.gov FU National Center for Toxicological Research/FDA; UAMS; NIH [R01-NS049389]; UAMS institutional funds FX This study was supported by the National Center for Toxicological Research/FDA (Protocol P00710 to He Z and Protocol P00706 to Ferguson SA) Cui L was supported by UAMS Hornick Award to her and NIH Grant R01-NS049389 and UAMS institutional funds to Greenfield LJ. NR 72 TC 1 Z9 1 U1 1 U2 9 PU SHENYANG EDITORIAL DEPT NEURAL REGENERATION RES PI SHENYANG PA PO BOX 1234, SHENYANG, LIAONING 110004, PEOPLES R CHINA SN 1673-5374 J9 NEURAL REGEN RES JI Neural Regen. Res. PD OCT PY 2013 VL 8 IS 29 BP 2763 EP 2774 DI 10.3969/j.issn.1673-5374.2013.29.008 PG 12 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 244VW UT WOS:000326419300008 PM 25206587 ER PT J AU Shen, J Xu, L Fang, H Richard, AM Bray, JD Judson, RS Zhou, GX Colatsky, TJ Aungst, JL Teng, C Harris, SC Ge, WG Dai, SY Su, ZQ Jacobs, AC Harrouk, W Perkins, R Tong, WD Hong, HX AF Shen, Jie Xu, Lei Fang, Hong Richard, Ann M. Bray, Jeffrey D. Judson, Richard S. Zhou, Guangxu Colatsky, Thomas J. Aungst, Jason L. Teng, Christina Harris, Steve C. Ge, Weigong Dai, Susie Y. Su, Zhenqiang Jacobs, Abigail C. Harrouk, Wafa Perkins, Roger Tong, Weida Hong, Huixiao TI EADB: An Estrogenic Activity Database for Assessing Potential Endocrine Activity SO TOXICOLOGICAL SCIENCES LA English DT Article DE endocrine disruptor; estrogen receptor; estrogenic activity; database ID DISRUPTING CHEMICALS; RECEPTOR MODULATORS; BINDING AFFINITIES; SIGNALING PATHWAYS; UPDATE; INFORMATION; MECHANISMS; DISCOVERY; TOXICITY; LIGANDS AB Endocrine-active chemicals can potentially have adverse effects on both humans and wildlife. They can interfere with the bodys endocrine system through direct or indirect interactions with many protein targets. Estrogen receptors (ERs) are one of the major targets, and many endocrine disruptors are estrogenic and affect the normal estrogen signaling pathways. However, ERs can also serve as therapeutic targets for various medical conditions, such as menopausal symptoms, osteoporosis, and ER-positive breast cancer. Because of the decades-long interest in the safety and therapeutic utility of estrogenic chemicals, a large number of chemicals have been assayed for estrogenic activity, but these data exist in various sources and different formats that restrict the ability of regulatory and industry scientists to utilize them fully for assessing risk-benefit. To address this issue, we have developed an Estrogenic Activity Database (EADB; ) and made it freely available to the public. EADB contains 18,114 estrogenic activity data points collected for 8212 chemicals tested in 1284 binding, reporter gene, cell proliferation, and in vivo assays in 11 different species. The chemicals cover a broad chemical structure space and the data span a wide range of activities. A set of tools allow users to access EADB and evaluate potential endocrine activity of chemicals. As a case study, a classification model was developed using EADB for predicting ER binding of chemicals. C1 [Shen, Jie; Zhou, Guangxu; Harris, Steve C.; Ge, Weigong; Su, Zhenqiang; Perkins, Roger; Tong, Weida; Hong, Huixiao] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Xu, Lei] Changan Univ, Sch Mat Sci & Engn, Xian 710064, Peoples R China. [Fang, Hong] US FDA, Off Sci Coordinat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Richard, Ann M.; Judson, Richard S.] US EPA, Natl Ctr Computat Toxicol, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Bray, Jeffrey D.] US FDA, Div Reprod & Urol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Colatsky, Thomas J.] US FDA, Div Drug Safety Res, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Aungst, Jason L.] US FDA, Div Food Contact Notificat, Off Food Addit Safety, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Teng, Christina] NIEHS, Div Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. [Dai, Susie Y.] Texas A&M Univ, Off Texas State Chem & Vet Pathobiol, College Stn, TX 77843 USA. [Jacobs, Abigail C.] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Harrouk, Wafa] US FDA, Div Nonprescript Clin Evaluat, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Hong, HX (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM huixiao.hong@fda.hhs.gov OI Judson, Richard/0000-0002-2348-9633 FU Research Participation Program at the National Center for Toxicological Research FX Research Participation Program at the National Center for Toxicological Research (J.S.) administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 39 TC 25 Z9 25 U1 2 U2 24 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD OCT PY 2013 VL 135 IS 2 BP 277 EP 291 DI 10.1093/toxsci/kft164 PG 15 WC Toxicology SC Toxicology GA 244JM UT WOS:000326384200004 PM 23897986 ER PT J AU Lin, Y Liu, T Yang, X Wang, Y Khan, MK AF Lin, Y. Liu, T. Yang, X. Wang, Y. Khan, M. K. TI Respiratory-Induced Prostate Motion Using Wavelet Decomposition of the Real-Time Electromagnetic Tracking Signal SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY SEP 22-25, 2013 CL Atlanta, GA SP Amer Soc Radiat Oncol C1 [Lin, Y.] Univ Calif Irvine, Dept Radiol Sci, Tu & Yuen Ctr Funct Oncoimaging, Irvine, CA 92717 USA. [Liu, T.; Yang, X.; Khan, M. K.] Emory Univ Hosp, Winship Canc Inst, Dept Radiat Oncol, Atlanta, GA 30322 USA. [Wang, Y.] US FDA, CDRH, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2013 VL 87 IS 2 SU S BP S362 EP S362 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 219JY UT WOS:000324503601331 ER PT J AU Verrill, L Zhang, Y Kane, R AF Verrill, L. Zhang, Y. Kane, R. TI Food label usage and reported difficulty with following a gluten-free diet among individuals in the USA with coeliac disease and those with noncoeliac gluten sensitivity SO JOURNAL OF HUMAN NUTRITION AND DIETETICS LA English DT Article DE coeliac disease; food allergy; food labelling; intolerance ID QUALITY-OF-LIFE; ADHERENCE; MORTALITY; ADULTS; HEALTH; IMPACT AB Background: Individuals with coeliac disease (CD) and those with noncoeliac gluten sensitivity (GS) have reported difficulty following a gluten-free diet (GFD); however, few studies have explored the link between the food label, gluten-free (GF) claims and the difficulty associated with following a GFD. Methods: The present study surveyed adults with CD (n = 1,583) and adults with GS (n = 797) about their reported difficulty following a GFD, including assessing the role of food labels and GF claims, as well as other factors known to contribute to this difficulty. A two-sample t-test and chi-squared tests for equality of means or proportions were used for the descriptive data and ordinal logistic regression (OLR) was used to model associations. Results: On average, individuals with GS reported slightly more difficulty following the GFD than did participants with CD. According to the OLR results, reading the food label often was significantly associated with less reported difficulty following a GFD, whereas consuming packaged processed foods and looking for GF claims more often were significantly associated with more reported difficulty for both respondent groups. Conclusions: Individuals with GS may rely more heavily on the GF claim for information about a product's gluten content. Individuals with CD, on the other hand, may be more experienced food label readers and may rely more on the ingredient list for finding GF foods. More studies are needed aiming to understand the role of the food label in facilitating consumers' ability to follow a GFD. C1 [Verrill, L.; Zhang, Y.; Kane, R.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Verrill, L (reprint author), 5100 Paint Branch Pkwy,HFS 005,Rm 1B-052, College Pk, MD 20740 USA. EM linda.verrill@fda.hhs.gov NR 29 TC 6 Z9 6 U1 1 U2 30 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3871 EI 1365-277X J9 J HUM NUTR DIET JI J. Hum. Nutr. Diet. PD OCT PY 2013 VL 26 IS 5 BP 479 EP 487 DI 10.1111/jhn.12032 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 216YZ UT WOS:000324324400009 PM 23347179 ER PT J AU Goodman, JL AF Goodman, Jesse L. TI Marseillevirus, Blood Safety, and the Human Virome SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material DE Marseillevirus; blood safety; organ safety; virome; microbiome; giant viruses ID CHALLENGES C1 US FDA, Silver Spring, MD 20993 USA. RP Goodman, JL (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM jesse.goodman@fda.hhs.gov NR 7 TC 5 Z9 5 U1 2 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 1 PY 2013 VL 208 IS 7 BP 1039 EP 1041 DI 10.1093/infdis/jit291 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 239ST UT WOS:000326046400001 PM 23821722 ER PT J AU Balsam, J Bruck, HA Rasooly, A AF Balsam, Joshua Bruck, Hugh Alan Rasooly, Avraham TI Orthographic projection capillary array fluorescent sensor for mHealth SO METHODS LA English DT Article DE mHealth; Capillary; Telecentric lens; Orthographic projection; Fluorescence; Mobile and smart phone; Camera ID CELL-PHONE; PLATFORM; HEALTH; POINT AB TO overcome the limited sensitivity of phone cameras for mobile health (mHealth) fluorescent detection, we have previously developed a capillary array which enables a similar to 100x increase in detection sensitivity. However, for an effective detection platform, the optical configuration must allow for uniform measurement sensitivity between channels when using such a capillary array sensor. This is a challenge due to the parallax inherent in imaging long parallel capillary tubes with typical lens configurations. To enable effective detection, we have developed an orthographic projection system in this work which forms parallel light projection images from the capillaries using an object-space telecentric lens configuration. This optical configuration results in a significantly higher degree of uniformity in measurement between channels, as well as a significantly reduced focal distance, which enables a more compact sensor. A plano-convex lens (f = 150 mm) was shown to produce a uniform orthographic projection when properly combined with the phone camera's built in lens (f = 4 mm), enabling measurements of long capillaries (125 mm) to be made from a distance of 160 mm. The number of parallel measurements which can be made is determined by the size of the secondary lens. Based on these results, a more compact configuration with shorter 32 mm capillaries and a plano-convex lens with a shorter focal length (f = 10 mm) was constructed. This optical system was used to measure serial dilutions of fluorescein with a limit of detection (LOD) of 10 nM, similar to the LOD of a commercial plate reader. However, many plate readers based on standard 96 well plate requires sample volumes of 100 Ill for measurement, while the capillary array requires a sample volume of less than 10 mu l. This optical configuration allows for a device to make use of the similar to 100x increase in fluorescent detection sensitivity produced by capillary amplification while maintaining a compact size and capability to analyze extremely small sample volumes. Such a device based on a phone or other optical mHealth technology will have the sensitivity of a conventional plate reader but have greater mHealth clinical utility, especially for telemedicine and for resource-poor settings and global health applications. Published by Elsevier Inc. C1 [Balsam, Joshua; Rasooly, Avraham] FDA, Div Biol, Off Sci & Engn, Silver Spring, MD 20993 USA. [Balsam, Joshua; Bruck, Hugh Alan] Univ Maryland, College Pk, MD 20742 USA. [Rasooly, Avraham] NCI, Div Canc Biol, Bethesda, MD 20892 USA. RP Balsam, J (reprint author), NCI, Div Canc Biol, Bethesda, MD 20892 USA. EM rasoolya@mail.nih.gov FU FDA's Center for Devices and Radiological Health, Division of Biology; National Cancer Institute FX This work was supported by the FDA's Center for Devices and Radiological Health, Division of Biology and the National Cancer Institute. The views expressed are those of the authors and do not represent those of the U.S. Government. NR 22 TC 2 Z9 2 U1 0 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD OCT PY 2013 VL 63 IS 3 BP 276 EP 281 DI 10.1016/j.ymeth.2013.07.044 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 240ZI UT WOS:000326135800010 PM 24018203 ER PT J AU Bruck, HA Yang, MH Kostov, Y Rasooly, A AF Bruck, Hugh Alan Yang, Minghui Kostov, Yordan Rasooly, Avraham TI Electrical percolation based biosensors SO METHODS LA English DT Article DE Biosensor; Semiconductor; Carbon nanotubes; Electrical percolation; Antibody ID STAPHYLOCOCCAL-ENTEROTOXIN-B; CARBON NANOTUBES; FOOD; FUNCTIONALIZATION; IMMUNODETECTION; IMMUNOASSAY; COMPOSITES; SENSORS; CONDUCTIVITY; WIRES AB A new approach to label free biosensing has been developed based on the principle of "electrical percolation". In electrical percolation, long-range electrical connectivity is formed in randomly oriented and distributed systems of discrete elements. By applying this principle to biological interactions, it is possible to measure biological components both directly and electronically. The main element for electrical percolation biosensor is the biological semiconductor (BSC) which is a multi-layer 3-D carbon nano-tube-antibody network. In the BSC, molecular interactions, such as binding of antigens to the antibodies, disrupt the network continuity causing increased resistance of the network. BSCs can be fabricated by immobilizing conducting elements, such as pre-functionalized single-walled carbon nanotubes (SWNTs)-antibody complex, directly onto a substrate, such as a Poly(methyl methacrylate) (PMMA) surface (also known as plexi-glass or Acrylic). BSCs have been demonstrated for direct (label-free) electronic measurements of antibody-antigen binding using SWNTs. If the concentration of the SWNT network is slightly above the electrical percolation threshold, then binding of a specific antigen to the pre-functionalized SWNT dramatically increases the electrical resistance due to changes in the tunneling between the SWNTs. Using anti-staphylococcal enterotoxin B (SEB) IgG as a "gate" and SEB as an "actuator", it was demonstrated that the BSC was able to detect SEB at concentrations of 1 ng/ml. Based on this concept, an automated configuration for BSCs is described here that enables real time continuous detection. The new BSC configuration may permit assembly of multiple sensors on the same chip to create "biological central processing units (CPUs)" with multiple biological elements, capable of processing and sorting out information on multiple analytes simultaneously. Published by Elsevier Inc. C1 [Bruck, Hugh Alan] Univ Maryland, College Pk, MD 20742 USA. [Yang, Minghui] Cent S Univ, Coll Chem & Chem Engn, Changsha 410083, Hunan, Peoples R China. [Kostov, Yordan] Univ Maryland Baltimore Cty, Baltimore, MD 21250 USA. [Rasooly, Avraham] US FDA, Div Biol, Off Sci & Engn, Silver Spring, MD 20993 USA. [Rasooly, Avraham] NCI, Rockville, MD 20850 USA. RP Rasooly, A (reprint author), NCI, NIH, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM rasoolya@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 43 TC 2 Z9 2 U1 1 U2 20 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD OCT PY 2013 VL 63 IS 3 BP 282 EP 289 DI 10.1016/j.ymeth.2013.08.031 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 240ZI UT WOS:000326135800011 PM 24041756 ER PT J AU Kimchi-Sarfaty, C Schiller, T Hamasaki-Katagiri, N Khan, MA Yanover, C Sauna, ZE AF Kimchi-Sarfaty, Chava Schiller, Tal Hamasaki-Katagiri, Nobuko Khan, Mansoor A. Yanover, Chen Sauna, Zuben E. TI Building better drugs: developing and regulating engineered therapeutic proteins SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review DE drug development; immunogenicity; drug safety; risk mitigation; quality by design ID RECOMBINANT FACTOR-VIII; CHRONIC KIDNEY-DISEASE; ESCHERICHIA-COLI; SYNONYMOUS MUTATIONS; POSITIONAL ISOMERS; GENE-EXPRESSION; CODON BIAS; TRANSLATION; RECEPTOR; DESIGN AB Most native proteins. do not make Optimal drugs and thus a second- and third-generation of therapeutic proteins, which have been engineered to improve product attributes or to enhance process characteristics, are rapidly becoming the norm. There has been unprecedented progress, during the past decade, in the development of platform technologies that further these ends. Although the advantages of engineered therapeutic proteins are considerable, the alterations can affect the safety and efficacy of the drugs. We discuss both the key technological innovations with respect to engineered therapeutic proteins and advancements in the underlying basic science. The latter would permit the design of science-based criteria for the prediction and assessment of potential risks and the development of appropriate risk management plans. This in turn holds promise for more predictable criteria for the licensure of a class of products that are extremely challenging to develop but represent an increasingly important component of modern medical practice. C1 [Kimchi-Sarfaty, Chava; Schiller, Tal; Hamasaki-Katagiri, Nobuko; Sauna, Zuben E.] US FDA, Lab Hemostasis, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Khan, Mansoor A.] US FDA, Div Prod Qual Res, Ctr Drugs Evaluat & Res, Silver Spring, MD 20993 USA. [Yanover, Chen] Fred Hutchinson Canc Res Ctr, Program Computat Biol, Seattle, WA 98104 USA. RP Kimchi-Sarfaty, C (reprint author), US FDA, Lab Hemostasis, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM chava.kimchi-sarfaty@fda.hhs.gov; zuben.sauna@fda.hbs.gov RI Yanover, Chen/A-3754-2012 OI Yanover, Chen/0000-0003-3663-4286 FU Laboratory of Hemostasis, Center for Biologics Evaluation and Research; Food and Drug Administration's Modernization of Science program FX We thank Dr Jay Epstein and Dr Basil Golding for helpful discussions. We thank Mr Ofer Kimchi, Mr Andrew Wu, and Ms Yini Qi for editorial assistance. This work was supported by funds from the Laboratory of Hemostasis, Center for Biologics Evaluation and Research (C.K-S. and Z.E.S.) and the Food and Drug Administration's Modernization of Science program (Z.E.S.). NR 67 TC 24 Z9 24 U1 0 U2 19 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD OCT PY 2013 VL 34 IS 10 BP 534 EP 548 DI 10.1016/j.tips.2013.08.005 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 243LB UT WOS:000326316800003 PM 24060103 ER PT J AU Wysocki, AB Bhalla-Regev, SK Tierno, PM Stevens-Riley, M Wiygul, RC AF Wysocki, Annette B. Bhalla-Regev, Sandhya K. Tierno, Philip M., Jr. Stevens-Riley, Marla Wiygul, Ryan-Claire TI Proteolytic Activity by Multiple Bacterial Species Isolated From Chronic Venous Leg Ulcers Degrades Matrix Substrates SO BIOLOGICAL RESEARCH FOR NURSING LA English DT Article DE wound; bacteria; extracellular matrix; leg ulcer; protease ID PLASMINOGEN-ACTIVATOR; STAPHYLOCOCCUS-AUREUS; MICROBIAL-FLORA; SWAB CULTURE; WOUND FLUID; INFECTION; VIRULENCE; METALLOPROTEINASES; EXPRESSION; PROTEASES AB Background: A major feature of chronic wounds is the loss of tissue, with the exposure of dermal components preventing primary closure and leading to bacterial colonization. Bacterial colonization has been proposed as one of the common underlying pathologies present in chronic wounds. The objective of this exploratory study was to identify bacteria cultured from chronic venous leg ulcers and test for proteolytic activity that degrades matrix substrates. Method: Bacteria were isolated, cultured, and identified from six subjects (average age = 62.8 years) over 2-10 months under an approved protocol using swabs and microbiological culture media. Proteolytic activity against (a) gelatin, (b) an elastin substrate, and (c) a serine/trypsin-sensitive substrate was determined using a colorimetric plate assay with an ELISA plate reader and zymography. Results: We identified 13 bacteria that expressed proteolytic activity against one or more of the tested substrates. Of these, six were Gram-positive (Staphylococcus aureus, Enterococcus faecalis, Staphylococcus epidermidis, Streptococcus agalactiae, Corynebacterium, and Streptococcus bovis) and seven were Gram-negative (Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Morganella morganii, Klebsiella pneumoniae, Bacteroides fragilis, and Serratia marcescens) organisms. Two of these, S. aureus and P. aeruginosa, are recognized wound pathogens. Conclusions: Multiple bacteria species isolated from colonized venous leg ulcers have the capacity to secrete proteases capable of degrading components of the extracellular matrix important for wound healing. Matrix degradation by bacteria may contribute to delays in tissue deposition and repair, suggesting that treatment of chronic wounds should include appropriate management of colonizing bacteria. C1 [Wysocki, Annette B.] Univ Massachusetts, Sch Nursing, Amherst, MA 01003 USA. [Bhalla-Regev, Sandhya K.; Tierno, Philip M., Jr.] NYU, Med Ctr, Clin Microbiol Lab, New York, NY 10003 USA. [Bhalla-Regev, Sandhya K.; Tierno, Philip M., Jr.] NYU, Med Ctr, Dept Pathol & Microbiol, New York, NY 10003 USA. [Stevens-Riley, Marla] US FDA, Rockville, MD 20857 USA. [Wiygul, Ryan-Claire] Univ Mississippi, Med Ctr, Dept Surg, Sch Nursing, Jackson, MS 39216 USA. [Wiygul, Ryan-Claire] Univ Mississippi, Med Ctr, Sch Med, Jackson, MS 39216 USA. RP Wysocki, AB (reprint author), Univ Massachusetts, Sch Nursing, 138 Skinner Hall,651 North Pleasant St, Amherst, MA 01003 USA. EM annettew@nursing.umass.edu FU NIH [NR03212]; NIH/NINR Intramural Research Program FX The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This research was supported by NIH grant # NR03212 and the NIH/NINR Intramural Research Program. NR 40 TC 4 Z9 4 U1 1 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1099-8004 EI 1552-4175 J9 BIOL RES NURS JI Biol. Res. Nurs. PD OCT PY 2013 VL 15 IS 4 BP 407 EP 415 DI 10.1177/1099800412464683 PG 9 WC Nursing SC Nursing GA 217XI UT WOS:000324395900005 PM 23118301 ER PT J AU Younis, IR Rogers, H Zhang, HX Zhu, H Uppoor, RS Mehta, MU AF Younis, Islam R. Rogers, Hobart Zhang, Huixia Zhu, Hao Uppoor, Ramana S. Mehta, Mehul U. TI An Integrated Clinical Pharmacology Approach for Deriving Dosing Recommendations in a Regulatory Setting: Review of Recent Cases in Psychiatry Drugs SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Review DE clinical pharmacology (CPH); psychiatry (PSY); pharmacogenetics (PGN); pharmacokinectics & drug metabolism (PDM); regulatory; scientific affairs (REG) ID DOUBLE-BLIND; PIMOZIDE; SCHIZOPHRENIA; PHARMACOKINETICS; METHYLPHENIDATE; PROLONGATION; VOLUNTEERS; DISORDER; SAFETY AB Clinical pharmacology as an interdisciplinary science is unique in its capacity and the diversity of the methods and approaches it can provide to derive dosing recommendations in various subpopulations. This article illustrates cases where an integrated clinical pharmacology approach was used to derive dosing recommendations for psychiatry drugs within regulatory settings. The integrated approach is based on the view that once a drug is shown to be effective in the general population, it is reasonable to take into consideration other relevant findings and the use of alternative scientific tools and analysis to derive dosing recommendations in specific populations. The method provides useful means to solve the challenges of the paucity of available data and lead to clear dosing instructions. This in turn expands the benefits of any given drug to all individuals in which the drug is likely to be effective. C1 [Younis, Islam R.; Rogers, Hobart; Zhang, Huixia; Zhu, Hao; Uppoor, Ramana S.; Mehta, Mehul U.] Food & Drug Adm, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Younis, IR (reprint author), Food & Drug Adm, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, 10993 New Hampshire Ave,Bldg 51,Room 2175, Silver Spring, MD 20993 USA. EM islam.younis@fda.hhs.gov NR 14 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD OCT PY 2013 VL 53 IS 10 BP 1005 EP 1009 DI 10.1002/jcph.118 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 237JL UT WOS:000325865600001 PM 23842865 ER PT J AU Yang, QR Chen, SY Ge, BL AF Yang, Qianru Chen, Siyi Ge, Beilei TI Detecting Salmonella Serovars in Shell Eggs by Loop-Mediated Isothermal Amplification SO JOURNAL OF FOOD PROTECTION LA English DT Article ID IN-GROUND BEEF; RAPID DETECTION; ENTERICA; PRODUCE; TYPHIMURIUM; MONOAZIDE; PATHOGENS; CHICKENS; ASSAYS; FOODS AB Shell eggs contaminated with Salmonella Enteritidis pose serious food safety and public health concerns. More vigilant product testing calls for rapid, accurate, and reliable detection methods for Salmonella. Two loop-mediated isothermal amplification (LAMP) assays targeting different regions of the Salmonella invasion protein (encoded by invA) have been reported. In this study, performance of the two LAMP assays was compared with that of PCR in detecting Salmonella Enteritidis and Salmonella Typhimurium strains in experimentally contaminated egg homogenates. Both LAMP assays were highly specific. The detection limits were approximately 1 CFU per reaction for both Salmonella serovars in pure culture, 100-fold more sensitive than that of PCR. Standard curves generated suggested a good linear relationship between Salmonella cell numbers and LAMP turbidity signals. In spiked egg homogenate, the LAMP assays could detect both Salmonella serovars down to 10(4) CFU/25 ml without enrichment and 10(0) CFU/25 ml with 8-h enrichment. In contrast, PCR was unable to detect either Salmonella serovar in egg homogenates spiked with less than 10(6) CFU/25 ml by direct testing and required at least 12 h of enrichment for samples spiked with 10(1) CFU/25 ml and 24 h for those with 10(0) CFU/25 ml. The complete LAMP assay took about 10 h (including 8 h of enrichment) to complete. In conclusion, the two LAMP assays were rapid, accurate, and reliable methods for detecting Salmonella serovars in shell eggs and may be adopted in routine egg testing for Salmonella to improve egg safety and protect public health. C1 [Yang, Qianru; Chen, Siyi; Ge, Beilei] Louisiana State Univ, Ctr Agr, Dept Food Sci, Baton Rouge, LA 70803 USA. RP Ge, BL (reprint author), US FDA, Div Anim & Food Microbiol, Res Off, Ctr Vet Med, 8401 Muirkirk Rd, Laurel, MD 20708 USA. EM beilei.ge@fda.hhs.gov NR 39 TC 6 Z9 6 U1 0 U2 8 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD OCT PY 2013 VL 76 IS 10 BP 1790 EP 1796 DI 10.4315/0362-028X.JFP-13-140 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 240HQ UT WOS:000326086400019 PM 24112582 ER PT J AU John, SD Moore, QT Herrmann, T Don, S Powers, K Smith, SN Morrison, G Charkot, E Mills, TT Rutz, L Goske, MJ AF John, Susan D. Moore, Quentin T. Herrmann, Tracy Don, Steven Powers, Kevin Smith, Susan N. Morrison, Greg Charkot, Ellen Mills, Thalia T. Rutz, Lois Goske, Marilyn J. TI The Image Gently Pediatric Digital Radiography Safety Checklist: Tools for Improving Pediatric Radiography SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Digital radiography; radiation dose; quality; safety; children; checklist ID DOSE REDUCTION; CR; POPULATION; SYSTEM; STATE AB Transition from film-screen to digital radiography requires changes in radiographic technique and workflow processes to ensure that the minimum radiation exposure is used while maintaining diagnostic image quality. Checklists have been demonstrated to be useful tools for decreasing errors and improving safety in several areas, including commercial aviation and surgical procedures. The Image Gently campaign, through a competitive grant from the FDA, developed a checklist for technologists to use during the performance of digital radiography in pediatric patients. The checklist outlines the critical steps in digital radiography workflow, with an emphasis on steps that affect radiation exposure and image quality. The checklist and its accompanying implementation manual and practice quality improvement project are open source and downloadable at www.imagegently.org. The authors describe the process of developing and testing the checklist and offer suggestions for using the checklist to minimize radiation exposure to children during radiography. C1 [John, Susan D.] Univ Texas Med Sch, Dept Diagnost & Intervent Imaging, Houston, TX 77030 USA. [John, Susan D.] Univ Texas Med Sch, Dept Pediat, Houston, TX 77030 USA. [Moore, Quentin T.] Mercy Coll Ohio, Toledo, OH USA. [Herrmann, Tracy] Univ Cincinnati, Blue Ash Coll, Cincinnati, OH USA. [Don, Steven] Washington Univ, Med Ctr, Mallinckrodt Inst Radiol, Elect Radiol Lab, St Louis, MO 63110 USA. [Don, Steven] St Louis Childrens Hosp, St Louis, MO 63178 USA. [Don, Steven] Washington Univ, Sch Med, St Louis, MO USA. [Powers, Kevin; Morrison, Greg] Amer Soc Radiol Technologists, Albuquerque, NM USA. [Smith, Susan N.; Goske, Marilyn J.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Charkot, Ellen] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Mills, Thalia T.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Rutz, Lois] GAMMEX Inc, Middleton, WI USA. RP John, SD (reprint author), Univ Texas Med Sch, Dept Radiol, 6431 Fannin, Houston, TX 77030 USA. EM susan.d.john@uth.tmc.edu NR 27 TC 7 Z9 7 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD OCT PY 2013 VL 10 IS 10 BP 781 EP 788 DI 10.1016/j.jacr.2013.02.026 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 237ZF UT WOS:000325909500016 PM 24091048 ER PT J AU Trumbo, PR Barr, SI Murphy, SP Yates, AA AF Trumbo, Paula R. Barr, Susan I. Murphy, Suzanne P. Yates, Allison A. TI Dietary reference intakes: cases of appropriate and inappropriate uses SO NUTRITION REVIEWS LA English DT Review DE dietary planning; dietary reference intakes; intake assessment; nutrient requirements AB The dietary reference intakes (DRIs) are a set of reference intake levels for nutrients that can be used for planning diets and assessing nutrient inadequacies of individuals and groups. Since the publication of the DRI reports 1997-2004, the reference intake levels have been used for various purposes. While DRIs have been used appropriately for planning and assessing diets for many different situations, there have been instances in which specific DRI categories have not been applied as intended. In this review, cases are described in which DRIs were applied correctly, as well as cases from the growing number of examples in which the wrong DRI was used or DRIs were used incorrectly. (C) 2013 International Life Sciences Institute C1 [Trumbo, Paula R.] US FDA, College Pk, MD 20740 USA. [Barr, Susan I.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Murphy, Suzanne P.] Univ Hawaii Manoa, Honolulu, HI 96822 USA. [Yates, Allison A.] USDA, Beltsville, MD 20705 USA. RP Trumbo, PR (reprint author), US FDA, 5100 Paint Branch Pkwy,HFS 830, College Pk, MD 20740 USA. EM paula.trumbo@fda.hhs.gov NR 29 TC 5 Z9 5 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0029-6643 EI 1753-4887 J9 NUTR REV JI Nutr. Rev. PD OCT PY 2013 VL 71 IS 10 BP 657 EP 664 DI 10.1111/nure.12067 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 234BU UT WOS:000325615400002 PM 24117790 ER PT J AU Lorenz, SC Son, I Maounounen-Laasri, A Lin, A Fischer, M Kase, JA AF Lorenz, Sandra C. Son, Insook Maounounen-Laasri, Anna Lin, Andrew Fischer, Markus Kase, Julie A. TI Prevalence of Hemolysin Genes and Comparison of ehxA Subtype Patterns in Shiga Toxin-Producing Escherichia coli (STEC) and Non-STEC Strains from Clinical, Food, and Animal Sources SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID URINARY-TRACT INFECTION; NEIGHBOR-JOINING METHOD; UREMIC SYNDROME; ENTEROCYTE EFFACEMENT; MOLECULAR ANALYSIS; UNITED-STATES; ENTEROHEMOLYSIN PRODUCTION; VIRULENCE FACTORS; EMERGING ISSUES; BLOOD AGAR AB Shiga toxin-producing Escherichia coli (STEC) belonging to certain serogroups (e. g., O157 and O26) can cause serious conditions like hemolytic-uremic syndrome (HUS), but other strains might be equally pathogenic. While virulence factors, like stx and eae, have been well studied, little is known about the prevalence of the E. coli hemolysin genes (hlyA, ehxA, e-hlyA, and sheA) in association with these factors. Hemolysins are potential virulence factors, and ehxA and hlyA have been associated with human illness, but the significance of sheA is unknown. Hence, 435 E. coli strains belonging to 62 different O serogroups were characterized to investigate gene presence and phenotypic expression of hemolysis. We further investigated ehxA subtype patterns in E. coli isolates from clinical, animal, and food sources. While sheA and ehxA were widely distributed, e-hlyA and hlyA were rarely found. Most strains (86.7%) were hemolytic, and significantly more hemolytic (95%) than nonhemolytic strains (49%) carried stx and/or eae (P < 0.0001). ehxA subtyping, as performed by using PCR in combination with restriction fragment length polymorphism analysis, resulted in six closely related subtypes (>94.2%), with subtypes A/D being eae-negative STECs and subtypes B, C, E, and F eae positive. Unexpectedly, ehxA subtype patterns differed significantly between isolates collected from different sources (P < 0.0001), suggesting that simple linear models of exposure and transmission need modification; animal isolates carried mostly subtypes A/C (39.3%/42.9%), food isolates carried mainly subtype A (81.9%), and clinical isolates carried mainly subtype C (66.4%). Certain O serogroups correlated with particular ehxA subtypes: subtype A with O104, O113, and O8; B exclusively with O157; C with O26, O111, and O121. C1 [Lorenz, Sandra C.; Son, Insook; Maounounen-Laasri, Anna; Kase, Julie A.] US FDA, Ctr Food Safety & Appl Nutr, Div Microbiol, College Pk, MD USA. [Lorenz, Sandra C.; Fischer, Markus] Univ Hamburg, Hamburg Sch Food Sci, Inst Food Chem, Hamburg, Germany. [Lin, Andrew] US FDA, San Francisco Dist Lab, Alameda, CA USA. RP Lorenz, SC (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Div Microbiol, College Pk, MD USA. EM sandra.lorenz@fda.hhs.gov FU Center for Food Safety and Applied Nutrition; FDA FX This project was supported by an appointment (S.C.L.) to the Research Fellowship Program for the Center for Food Safety and Applied Nutrition administered by the Oak Ridge Associated Universities through a contract with the FDA. This project is further part of the PhD program (S.C.L.) at the University of Hamburg, Germany, under the supervision of Markus Fischer. NR 78 TC 15 Z9 15 U1 1 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD OCT PY 2013 VL 79 IS 20 BP 6301 EP 6311 DI 10.1128/AEM.02200-13 PG 11 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 236OH UT WOS:000325807200013 PM 23934487 ER PT J AU Momper, JD Mulugeta, Y Green, DJ Karesh, A Krudys, KM Sachs, HC Yao, LP Burckart, GJ AF Momper, Jeremiah D. Mulugeta, Yeruk Green, Dionna J. Karesh, Alyson Krudys, Kevin M. Sachs, Hari C. Yao, Lynn P. Burckart, Gilbert J. TI Adolescent Dosing and Labeling Since the Food and Drug Administration Amendments Act of 2007 SO JAMA PEDIATRICS LA English DT Article ID PHARMACOKINETICS; CHILDREN; CLEARANCE; AGE; PREDICTION AB IMPORTANCE During pediatric drug development, dedicated pharmacokinetic studies are generally performed in all relevant age groups to support dose selection for subsequent efficacy trials. To our knowledge, no previous assessments regarding the need for an intensive pharmacokinetic study in adolescents have been performed. OBJECTIVES To compare US Food and Drug Administration (FDA)-approved adult and adolescent drug dosing and to assess the utility of allometric scaling for the prediction of drug clearance in the adolescent population. DESIGN Adult and adolescent dosing and drug clearance data were obtained from FDA-approved drug labels and publicly available databases containing reviews of pediatric trials submitted to the FDA. Dosing information was compared for products with concordant indications for adolescent and adult patients. Adolescent drug clearance was predicted from adult pharmacokinetic data by using allometric scaling and compared with observed values. MAIN OUTCOMES AND MEASURES Adolescent and adult dosing information and drug clearance. RESULTS There were 126 unique products with pediatric studies submitted to the FDA since the FDA Amendments Act of 2007, of which 92 had at least 1 adolescent indication concordant with an adult indication. Of these 92 products, 87 (94.5%) have equivalent dosing for adults and adolescent patients. For 18 of these 92 products, a minimum weight or body surface area threshold is recommended for adolescents to receive adult dosing. Allometric scaling predicted adolescent drug clearance with an overall mean absolute percentage error of 17.0%. CONCLUSIONS AND RELEVANCE Approved adult and adolescent drug dosing is equivalent for 94.5% of products with an adolescent indication studied since the FDA Amendments Act of 2007. Allometric scaling may be a useful tool to avoid unnecessary dedicated pharmacokinetic studies in the adolescent population during pediatric drug development, although each development program in adolescents requires a full discussion of drug dosing with the FDA. C1 [Momper, Jeremiah D.; Mulugeta, Yeruk; Green, Dionna J.; Krudys, Kevin M.; Burckart, Gilbert J.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. [Karesh, Alyson; Sachs, Hari C.; Yao, Lynn P.] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. RP Burckart, GJ (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, White Oak Bldg 51,Room 3184,10903 New Hampshire A, Silver Spring, MD 20903 USA. EM gilbert.burckart@fda.hhs.gov NR 25 TC 11 Z9 11 U1 2 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD OCT PY 2013 VL 167 IS 10 BP 926 EP 932 DI 10.1001/jamapediatrics.2013.465 PG 7 WC Pediatrics SC Pediatrics GA 232GQ UT WOS:000325480900014 PM 23921678 ER PT J AU Murphy, L Kisielewski, D Brown, D Piccardo, P Hogan, K Fragkoudis, R Fazakerley, J Freeman, T Perry, H Manson, J AF Murphy, Lita Kisielewski, Dorothy Brown, Debbie Piccardo, Pedro Hogan, Kris Fragkoudis, Rennos Fazakerley, John Freeman, Tom Perry, Hugh Manson, Jean TI The impact of viral infection on the innate immune response within the brain during chronic neurodegeneration SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 12th International Symposium on NeuroVirology CY OCT 29-NOV 02, 2013 CL Washington, DC C1 [Murphy, Lita; Kisielewski, Dorothy; Brown, Debbie; Piccardo, Pedro; Hogan, Kris; Freeman, Tom; Manson, Jean] Univ Edinburgh, Roslin Inst, Neurobiol Div, Edinburgh EH8 9YL, Midlothian, Scotland. [Piccardo, Pedro] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Fragkoudis, Rennos; Fazakerley, John] Pirbright Inst, Woking, Surrey, England. [Perry, Hugh] Univ Southampton, Ctr Biol Sci, Southampton Gen Hosp, Southampton SO9 5NH, Hants, England. EM Lita.Murphy@roslin.ed.ac.uk NR 0 TC 0 Z9 0 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2013 VL 19 SU 1 MA P125 BP S60 EP S60 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 236EM UT WOS:000325777200126 ER PT J AU Fang, JL Beland, FA AF Fang, Jia-Long Beland, Frederick A. TI Differential responses of human hepatocytes to the non-nucleoside HIV-1 reverse transcriptase inhibitor nevirapine SO JOURNAL OF TOXICOLOGICAL SCIENCES LA English DT Article DE Nevirapine; Cell cycle; Apoptosis; Reverse transcriptase; Cell senescence ID CELL-CYCLE PROGRESSION; IN-VITRO; ANTIRETROVIRAL THERAPY; RISK-FACTORS; SENESCENCE; CARCINOMA; P53; HEPATOTOXICITY; PROLIFERATION; ZIDOVUDINE AB Nevirapine is a non-nucleoside reverse transcriptase (RT) inhibitor used for the treatment of AIDS and the prevention of mother-to-child transmission of HIV-1. Despite its therapeutic benefits, treatment with nevirapine has been associated with significant incidences of liver and dermal toxicity. The present study examined the effects of nevirapine on cell growth and death in human hepatocyte HepG2 cells and THLE2 cells and the possible pathways involved in these effects. The concentrations of nevirapine inhibiting 50% cell growth were similar for both cell lines. Nevirapine (0-250 mu M) treatment caused a slight increase in the amount of lactate dehydrogenase released into the medium. Apoptotic cell death did not contribute to the decrease in viable cells. Exposing of HepG2 cells to nevirapine caused G2/M phase arrest, and the activity of senescence-associated beta-galactosidase was not altered. In THLE2 cells, the percentage of cells in G1/G0 phase was increased and cellular senescence was induced in a concentration-dependent manner. Endogenous non-telomeric RT activity was not detected in either cell line. Western blot analysis indicated lower levels of p53 and phospho-p53 (ser15) in HepG2 cells as compared to THLE2 cells; no significant changes in p53 or phospho-p53 (ser15) were noted with nevirapine treatment. These data demonstrate that nevirapine inhibits cell growth, induces cell cycle arrest at different phases, and has different effects on cellular senescence in HepG2 cells and THLE2 cells. The differential responses appear to be related to differences in the basal levels of p53 in the HepG2 cells and THLE2 cells. C1 [Fang, Jia-Long; Beland, Frederick A.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Fang, JL (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. EM jia-long.fang@fda.hhs.gov FU National Center for Toxicological Research, U.S. Food and Drug Administration [NCTR/FDA IAG: 224-12-0003, NIH AES12013]; National Toxicology Program, National Institute of Environmental Health Sciences [NCTR/FDA IAG: 224-12-0003, NIH AES12013] FX This research was supported through an interagency agreement between the National Center for Toxicological Research, U.S. Food and Drug Administration and the National Toxicology Program, National Institute of Environmental Health Sciences. (NCTR/FDA IAG: 224-12-0003; NIH AES12013). NR 33 TC 2 Z9 2 U1 0 U2 10 PU JAPANESE SOC TOXICOLOGICAL SCIENCES PI TOKYO PA INTERNATIONAL MEDICAL INFORMATION CENTER, SHINANOMACHI RENGAKAN, 35 SHINANO-MACHI, SHINJUKU-KU, TOKYO, 160-0016, JAPAN SN 0388-1350 EI 1880-3989 J9 J TOXICOL SCI JI J. Toxicol. Sci. PD OCT PY 2013 VL 38 IS 5 BP 741 EP 752 PG 12 WC Toxicology SC Toxicology GA 233VQ UT WOS:000325598000011 PM 24067722 ER PT J AU Kenny, JR Liu, MM Chow, AT Earp, JC Evers, R Slatter, JG Wang, DD Zhang, L Zhou, HH AF Kenny, Jane R. Liu, Maggie M. Chow, Andrew T. Earp, Justin C. Evers, Raymond Slatter, J. Greg Wang, Diane D. Zhang, Lei Zhou, Honghui TI Therapeutic Protein Drug-Drug Interactions: Navigating the Knowledge Gaps-Highlights from the 2012 AAPS NBC Roundtable and IQ Consortium/FDA Workshop SO AAPS JOURNAL LA English DT Article DE cytochrome P450s; drug-drug interactions; pro-inflammatory cytokines; small molecule; therapeutic protein ID CRYOPRESERVED HUMAN HEPATOCYTES; ACUTE-PHASE RESPONSE; HEPATIC CYTOCHROME-P450; RHEUMATOID-ARTHRITIS; METABOLIZING-ENZYMES; PHARMACEUTICAL RESEARCH; MONOCLONAL-ANTIBODY; IN-VITRO; PHARMACOKINETICS; INTERLEUKIN-6 AB The investigation of therapeutic protein drug-drug interactions has proven to be challenging. In May 2012, a roundtable was held at the American Association of Pharmaceutical Scientists National Biotechnology Conference to discuss the challenges of preclinical assessment and in vitro to in vivo extrapolation of these interactions. Several weeks later, a 2-day workshop co-sponsored by the U.S. Food and Drug Administration and the International Consortium for Innovation and Quality in Pharmaceutical Development was held to facilitate better understanding of the current science, investigative approaches and knowledge gaps in this field. Both meetings focused primarily on drug interactions involving therapeutic proteins that are pro-inflammatory cytokines or cytokine modulators. In this meeting synopsis, we provide highlights from both meetings and summarize observations and recommendations that were developed to reflect the current state of the art thinking, including a four-step risk assessment that could be used to determine the need (or not) for a dedicated clinical pharmacokinetic interaction study. C1 [Kenny, Jane R.] Genentech Inc, Dept Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA. [Liu, Maggie M.] Drinker Biddle & Reath LLP, Pharmaceut Consortia Management Practice Grp, Washington, DC USA. [Chow, Andrew T.] Amgen Inc, Dept Pharmacokinet & Drug Metab, Quantitat Pharmacol, Thousand Oaks, CA 91320 USA. [Earp, Justin C.; Zhang, Lei] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Evers, Raymond] Merck & Co Inc, PK PD & Drug Metab, Rahway, NJ USA. [Slatter, J. Greg] Amgen Inc, Med Sci Early Dev, Seattle, WA USA. [Wang, Diane D.] Pfizer, Oncol Business Unit, Clin Pharmacol, La Jolla, CA USA. [Zhou, Honghui] Janssen Res & Dev LLC, Biol Clin Pharmacol, Spring House, PA USA. RP Kenny, JR (reprint author), Genentech Inc, Dept Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA. EM kenny.jane@gene.com FU AAPS; U.S. FDA; International Consortium for Innovation and Quality in Pharmaceutical Development FX We thank all members of the TP-DDI Steering Committee (Fig. 1) and the in vitro TP-DDI and POP-PK TP-DDI Working Groups for their scientific contributions and valuable discussions. We also thank Dan Lu and Amita Joshi for concept discussions around Fig. 4 and Shannon Dallas, Manish Gupta, Amita Joshi, Eugenia Kraynov, and Min Zhu for critical review of this manuscript. Additionally, we acknowledge the contribution of the presenters and moderators of both the AAPS NBC meeting (Raymond Evers, Amita Joshi, Jane Kenny, Greg Slatter, Lei Zhang, and Honghui Zhou) and the workshop (Andrew Chow, Leslie Dickmann, Justin Earp, Raymond Evers, Eva Gill Berglund, Manish Gupta, Chuanpu Hu, Graham Jang, Jane Kenny, Eugenia Kraynov, Bernd Meibohm, Edward T. Morgan, Christophe Schmitt, Greg Slatter, Diane Wang, Lei Zhang, and Honghui Zhou). The roundtable was sponsored by the AAPS. The workshop was co-sponsored by the U.S. FDA and the International Consortium for Innovation and Quality in Pharmaceutical Development (www.iqconsortium.org), a not-for-profit organization of pharmaceutical and biotechnology companies with a mission of advancing science-based and scientifically driven standards and regulations for pharmaceutical and biotechnology products worldwide. NR 44 TC 8 Z9 8 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD OCT PY 2013 VL 15 IS 4 BP 933 EP 940 DI 10.1208/s12248-013-9495-1 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 227PR UT WOS:000325126300004 PM 23794076 ER PT J AU Gao, HY Jacobs, A White, RE Booth, BP Obach, RS AF Gao, Hongying Jacobs, Abigail White, Ronald E. Booth, Brian P. Obach, R. Scott TI Meeting Report: Metabolites in Safety Testing (MIST) Symposium-Safety Assessment of Human Metabolites: What's REALLY Necessary to Ascertain Exposure Coverage in Safety Tests? SO AAPS JOURNAL LA English DT Article DE MIST; safety assessment of human metabolites; metabolite exposure coverage in safety test; ICH M3(R2); LC/MS/MS ID RELATIVE PLASMA EXPOSURES; MASS-SPECTROMETRY METHOD; DRUG METABOLITES; ADDRESS AB In the 2012 AAPS metabolites in safety testing (MIST) symposium held in Chicago, IL, USA, on October 15, 2012, regulatory experts and industrial scientists joined together to discuss their perspectives and strategies in addressing contemporary MIST recommendations (FDA 2008, International Conference on Harmonization (ICH) M3(R2), ICH M(R2) Q&A). Overall, these regulatory guidances indicate that metabolites identified in human plasma should circulate at similar or greater concentrations in at least one of the animal species used in nonclinical safety assessment of the parent drug. However, synthetic standards for the metabolites often do not exist or they are intractable to synthesize, thus introducing multiple challenges in drug development for the quantitative comparison of metabolites between human and animals. A tiered bioanalytical strategy for metabolite analysis is a prevalent approach to demonstrate coverage in animals. Recent developments in bioanalytical methodology have yielded several time- and resource-sparing strategies to provide fit-for-purpose approaches that can enable critical decisions related to metabolite quantification and monitoring in plasma. This report summarizes the presentations and panel discussions at the symposium. C1 [Gao, Hongying; Obach, R. Scott] Pfizer Inc, Pharmacokinet Dynam & Metab, Groton, CT 06340 USA. [Jacobs, Abigail] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [White, Ronald E.] XenoBiot Labs Inc, DMPK Sci & Technol, Plainsboro, NJ USA. [Booth, Brian P.] US FDA, OTS OCP DCP V, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Gao, HY (reprint author), Pfizer Inc, Pharmacokinet Dynam & Metab, Groton, CT 06340 USA. EM Hongying.Gao@pfizer.com FU PPDM section; CPTR section FX The authors gratefully acknowledge the efforts of Dr. Debra R. Luffer-Atlas in helping moderate the discussion at the symposium and editing this summary. The authors would like to thank PPDM and CPTR sections for sponsoring our symposium at 2012 AAPS annual meeting. NR 16 TC 15 Z9 15 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD OCT PY 2013 VL 15 IS 4 BP 970 EP 973 DI 10.1208/s12248-013-9502-6 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 227PR UT WOS:000325126300008 PM 23821354 ER PT J AU Davit, B Braddy, AC Conner, DP Yu, LX AF Davit, Barbara Braddy, April C. Conner, Dale P. Yu, Lawrence X. TI International Guidelines for Bioequivalence of Systemically Available Orally Administered Generic Drug Products: A Survey of Similarities and Differences SO AAPS JOURNAL LA English DT Review DE bioequivalence; biopharmaceutics classification system; biowaivers; generic drugs; regulatory authority ID CLINICAL-TRIALS; BIOAVAILABILITY; DESIGNS AB The objective of this article is to discuss the similarities and differences among bioequivalence approaches used by international regulatory authorities when reviewing applications for marketing new generic drug products which are systemically active and intended for oral administration. We focused on the 13 jurisdictions and organizations participating in the International Generic Drug Regulators Pilot. These are Australia, Brazil, Canada, China, Chinese Taipei, the European Medicines Association, Japan, Mexico, Singapore, South Korea, Switzerland, the USA, and the World Health Organization. We began with a comparison of how the various jurisdictions and organizations define a generic product and its corresponding reference product. We then compared the following bioequivalence approaches: recommended bioequivalence study designs, method of pharmacokinetic calculations and bioequivalence acceptance limits, recommendations for modifying bioequivalence study designs and limits for highly variable drugs and narrow therapeutic index drugs, provisions for waiving bioequivalence study requirements (granting biowaivers), and implementation of the Biopharmaceutics Classification System. We observed that, overall, there are more similarities than differences in bioequivalence approaches among the regulatory authorities surveyed. C1 [Davit, Barbara] Merck Pharmaceut, Rahway, NJ USA. [Braddy, April C.; Conner, Dale P.; Yu, Lawrence X.] US FDA, Off Gener Drugs, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. RP Davit, B (reprint author), Merck Pharmaceut, Rahway, NJ USA. EM barbara.davit@merck.com NR 52 TC 18 Z9 23 U1 0 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD OCT PY 2013 VL 15 IS 4 BP 974 EP 990 DI 10.1208/s12248-013-9499-x PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 227PR UT WOS:000325126300009 PM 23821352 ER PT J AU Chen, ML Sadrieh, N Yu, L AF Chen, Mei-Ling Sadrieh, Nakissa Yu, Lawrence TI Impact of Osmotically Active Excipients on Bioavailability and Bioequivalence of BCS Class III Drugs SO AAPS JOURNAL LA English DT Article DE BCS; bioavailability/bioequivalence; drug absorption; excipient; osmotic potential ID BIOPHARMACEUTICS CLASSIFICATION-SYSTEM; PROTEIN-SURFACTANT INTERACTIONS; SMALL-INTESTINAL TRANSIT; IN-VIVO BIOAVAILABILITY; LOW-PERMEABILITY DRUGS; POLYETHYLENE-GLYCOL; HEALTHY-VOLUNTEERS; GASTROINTESTINAL ABSORPTION; RANITIDINE; INHIBITION C1 [Chen, Mei-Ling; Sadrieh, Nakissa; Yu, Lawrence] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Chen, ML (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM meiling.chen@fda.hhs.gov RI Yu, Lawrence/L-6280-2016 NR 44 TC 8 Z9 8 U1 1 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD OCT PY 2013 VL 15 IS 4 BP 1043 EP 1050 DI 10.1208/s12248-013-9509-z PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 227PR UT WOS:000325126300015 PM 23868749 ER PT J AU Zajicek, A Fossler, MJ Barrett, JS Worthington, JH Ternik, R Charkoftaki, G Lum, S Breitkreutz, J Baltezor, M Macheras, P Khan, M Agharkar, S MacLaren, DD AF Zajicek, Anne Fossler, Michael J. Barrett, Jeffrey S. Worthington, Jeffrey H. Ternik, Robert Charkoftaki, Georgia Lum, Susan Breitkreutz, Joerg Baltezor, Mike Macheras, Panos Khan, Mansoor Agharkar, Shreeram MacLaren, David Douglas TI A Report from the Pediatric Formulations Task Force: Perspectives on the State of Child-Friendly Oral Dosage Forms SO AAPS JOURNAL LA English DT Editorial Material DE children; drugs; formulations; manufacturing; palatability; pediatrics; regulatory ID BIOPHARMACEUTICS CLASSIFICATION-SYSTEM; ELECTRONIC TONGUE; DOSING ACCURACY; YOUNG-CHILDREN; DRUGS; SUSPENSIONS; ADHERENCE; SELECTION; DELIVERY; DEVICES AB Despite the fact that a significant percentage of the population is unable to swallow tablets and capsules, these dosage forms continue to be the default standard. These oral formulations fail many patients, especially children, because of large tablet or capsule size, poor palatability, and lack of correct dosage strength. The clinical result is often lack of adherence and therapeutic failure. The American Association of Pharmaceutical Scientists formed a Pediatric Formulations Task Force, consisting of members with various areas of expertise including pediatrics, formulation development, clinical pharmacology, and regulatory science, in order to identify pediatric, manufacturing, and regulatory issues and areas of needed research and regulatory guidance. Dosage form and palatability standards for all pediatric ages, relative bioavailability requirements, and small batch manufacturing capabilities and creation of a viable economic model were identified as particular needs. This assessment is considered an important first step for a task force seeking creative approaches to providing more appropriate oral formulations for children. C1 [Zajicek, Anne] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Fossler, Michael J.] GlaxoSmithKline, Clin Pharmacol Modeling & Simulat, King Of Prussia, PA USA. [Barrett, Jeffrey S.] Childrens Hosp Philadelphia, Clin Pharmacol & Therapeut Div, Philadelphia, PA 19104 USA. [Worthington, Jeffrey H.] Senopsys LLC, Woburn, MA USA. [Ternik, Robert] Eli Lilly & Co, Small Mol Design & Dev, Indianapolis, IN 46285 USA. [Charkoftaki, Georgia; Macheras, Panos] Univ Athens, Fac Pharm, Lab Biopharmaceut & Pharmacokinet, Athens 11528, Greece. [Lum, Susan] Hlth Canada, Bur Pharmaceut Sci, Therapeut Prod Directorate, Ottawa, ON K1A 0L2, Canada. [Breitkreutz, Joerg] Univ Dusseldorf, Inst Pharmaceut & Biopharmaceut, D-40225 Dusseldorf, Germany. [Baltezor, Mike] Univ Kansas, Inst Adv Med Innovat, Biotechnol Innovat & Optimizat Ctr, Lawrence, KS 66045 USA. [Khan, Mansoor] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Agharkar, Shreeram] Sanofi R&D, Global CMC Strategy & Sci Affairs, Lead Generat & Candidate Realizat, Bridgewater, NJ USA. [MacLaren, David Douglas] Eli Lilly & Co, Drug Product Dev & CT Mfg, Indianapolis, IN 46285 USA. RP Zajicek, A (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. EM zajiceka@mail.nih.gov RI Breitkreutz, Joerg/B-9581-2017 OI Breitkreutz, Joerg/0000-0002-3982-9823 NR 49 TC 17 Z9 17 U1 1 U2 27 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD OCT PY 2013 VL 15 IS 4 BP 1072 EP 1081 DI 10.1208/s12248-013-9511-5 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 227PR UT WOS:000325126300018 PM 23907486 ER PT J AU Gold, KM Hitchins, VM AF Gold, Kathryn M. Hitchins, Victoria M. TI Cleaning assessment of disinfectant cleaning wipes on an external surface of a medical device contaminated with artificial blood or Streptococcus pneumoniae SO AMERICAN JOURNAL OF INFECTION CONTROL LA English DT Article DE Infection control; Reprocessing; Disinfection; Medical equipment ID CARE-ASSOCIATED INFECTIONS; TRANSMISSION; PREVENTION; MORTALITY; ASSAYS AB Background: Improperly cleaned, disinfected, or sterilized reusable medical devices are a critical cause of health care-associated infections. More effective studies are required to address the improvement of cleaning and disinfection instructions, as well as selection of cleaning and disinfecting agents, for surfaces of reusable devices and equipment. Methods: Six commercially available disinfectant cleaning wipes were evaluated for their effectiveness to remove a coagulated blood test soil or Streptococcus pneumoniae bacteria from the surface of a reusable medical device. Liquid aliquots of the coagulated blood or bacteria were dried onto the surface of the device and removed with the wipes. Effectiveness of the wipes was assessed by 3 methods: residual protein debris by o-phthaldialdehyde analysis, bacterial survival by adenosine triphosphate measurement, and force required to remove the dried debris by force measurement. Results: A sodium hypochlorite wipe was most effective in removing protein debris from the device surface. All tested wipes were equivalent in disinfecting bacterial contamination from the device surface. Conclusion: The active ingredient, wipe design, and wipe wetness are important factors to consider when selecting a disinfectant cleaning wipe. Additionally, achieving conditions that effectively clean, disinfect, and/or inactivate surface bacterial contamination is critical to preventing the spread of health care-associated infections. Published by Elsevier Inc. on behalf of the Association for Professionals in Infection Control and Epidemiology, Inc. C1 [Gold, Kathryn M.; Hitchins, Victoria M.] US FDA, Div Biol, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Hitchins, VM (reprint author), US FDA, Div Biol, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM victoria.hitchins@fda.hhs.gov FU Center for Devices and Radiological Health FX Supported in part by an appointment to the Research Participation Program at the Center for Devices and Radiological Health administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Food and Drug Administration and from the US Food and Drug Administration's Medical Countermeasures Initiative. NR 35 TC 6 Z9 7 U1 1 U2 16 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-6553 J9 AM J INFECT CONTROL JI Am. J. Infect. Control PD OCT PY 2013 VL 41 IS 10 BP 901 EP 907 DI 10.1016/j.ajic.2013.01.029 PG 7 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 229HY UT WOS:000325254600014 PM 23643450 ER PT J AU Gray, RA Mashburn, DN Sidorov, VY Roth, BJ Pathmanathan, P Wikswo, JP AF Gray, Richard A. Mashburn, David N. Sidorov, Veniamin Y. Roth, Bradley J. Pathmanathan, Pras Wikswo, John P. TI Transmembrane Current Imaging in the Heart during Pacing and Fibrillation SO BIOPHYSICAL JOURNAL LA English DT Article ID REGIONAL MYOCARDIAL ISCHEMIA; SPATIAL FILTER APPROACH; VOLTAGE-SENSITIVE DYES; ACTION-POTENTIALS; VENTRICULAR-FIBRILLATION; CARDIAC FIBRILLATION; ACTIVATION PATTERNS; CONDUCTION; STIMULATION; PROPAGATION AB Recently, we described a method to quantify the time course of total transmembrane current (I-m) and the relative role of its two components, a capacitive current (I-c) and a resistive current (I-ion), corresponding to the cardiac action potential during stable propagation. That approach involved recording high-fidelity (200 kHz) transmembrane potential (V-m) signals with glass microelectrodes at one site using a spatiotemporal coordinate transformation via measured conduction velocity. Here we extend our method to compute these transmembrane currents during stable and unstable propagation from fluorescence signals of V-m at thousands of sites (3 kHz), thereby introducing transmembrane current imaging. In contrast to commonly used linear Laplacians of extracellular potential (V-e) to compute I-m, we utilized nonlinear image processing to compute the required second spatial derivatives of V-m. We quantified the dynamic spatial patterns of current density of I-m and I-ion for both depolarization and repolarization during pacing (including nonplanar patterns) by calibrating data with the nnicroelectrode signals. Compared to planar propagation, we found that the magnitude of I-ion was significantly reduced at sites of wave collision during depolarization but not repolarization. Finally, we present uncalibrated dynamic patterns of I-m during ventricular fibrillation and show that I-m at singularity sites was monophasic and positive with a significant nonzero charge (I-m integrated over 10 ms) in contrast with nonsingularity sites. Our approach should greatly enhance the understanding of the relative roles of functional (e.g., rate-dependent membrane dynamics and propagation patterns) and static spatial heterogeneities (e.g., spatial differences in tissue resistance) via recordings during normal and compromised propagation, including arrhythmias. C1 [Gray, Richard A.; Pathmanathan, Pras] US FDA, Div Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Gray, Richard A.] Univ Alabama Birmingham, Dept Biomed Engn, Birmingham, AL 35294 USA. [Gray, Richard A.; Sidorov, Veniamin Y.; Roth, Bradley J.; Wikswo, John P.] Vanderbilt Univ, Vanderbilt Inst Integrat Biosyst Res & Educ, Nashville, TN 37235 USA. [Sidorov, Veniamin Y.; Wikswo, John P.] Vanderbilt Univ, Dept Biomed Engn, Nashville, TN 37235 USA. [Mashburn, David N.; Wikswo, John P.] Vanderbilt Univ, Dept Phys & Astron, Nashville, TN 37235 USA. [Wikswo, John P.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Roth, Bradley J.] Oakland Univ, Dept Phys, Rochester, MI USA. RP Gray, RA (reprint author), US FDA, Div Phys, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. EM richard.gray@fda.hhs.gov RI Roth, Bradley/A-4920-2008; Gray, Richard/F-3916-2015 OI Gray, Richard/0000-0003-2798-6378 FU National Institutes of Health [R01-HL58241]; American Heart Association [0635037N]; Vanderbilt Institute for Integrative Biosystems Research and Education FX Supported in part by the National Institutes of Health (grant No. R01-HL58241), the American Heart Association (grant No. 0635037N), and the Vanderbilt Institute for Integrative Biosystems Research and Education. NR 30 TC 0 Z9 0 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD OCT 1 PY 2013 VL 105 IS 7 BP 1710 EP 1719 DI 10.1016/j.bpj.2013.08.019 PG 10 WC Biophysics SC Biophysics GA 230ZO UT WOS:000325383000020 PM 24094412 ER PT J AU Xu, ZH Hertzberg, VS AF Xu, Zhiheng Hertzberg, Vicki S. TI Bayesian area-age-period-cohort model with carcinogenesis age effects in estimating cancer mortality SO CANCER EPIDEMIOLOGY LA English DT Article DE AAPC; Bayesian; Prior; Spatial; Temporal; Nonidentifiability ID SPACE-TIME VARIATION; MULTISTAGE CARCINOGENESIS; TEMPORAL VARIATION; DISEASE RISK; RATES; TRENDS AB Objective: Area-age-period-cohort (AAPC) model has been widely used in studying the spatial and temporal pattern of disease incidence and mortality rates. However, lack of biological plausibility and ease of interpretability on temporal components especially for age effects are generally the weakness of AAPC models. We develop a Bayesian AAPC model where carcinogenesis age effect is incorporated to explain age effects from the underlying disease process. An autoregressive prior structure and an arbitrary linear constraint are used to solve the nonidentifiability issues. Methods: Two multistage carcinogenesis models are employed to derive the hazard functions to substitute the age effects in the AAPC models. The Iowa county-wide lung cancer mortality data are used for the model fitting and Deviance Information Criteria (DIC) is used for model comparison. Results: Our study shows that conventional AAPC model (DIC = 19,231.30), AAPC model with Armitage-Doll age effect (DIC = 19,233.00) and with two-stage clonal expansion (TSCE) age effect (DIC = 19,234.70) achieved the similar DIC values which indicated consistent model fitting among three models. The spatial pattern shows that the high spatial effects are clustered in the south of Iowa and also in largely populated areas. The lung cancer mortality rate is continuously declining by birth cohorts while increasing by the calendar period until 2000-2004. The age effects show an increasing pattern over time which can be easily explained by Armitage-Doll carcinogenesis model since we assume a log-linear relationship between age and hazard function. Conclusions: Our finding suggests that the proposed Bayesian AAPC model can be used to replace the conventional AAPC model without affecting model performance while providing a more biological sound approach from the underlining disease process. Published by Elsevier Ltd. C1 [Xu, Zhiheng] US FDA, Silver Spring, MD 20993 USA. [Hertzberg, Vicki S.] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. RP Xu, ZH (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM zhiheng.xu@fda.hhs.gov NR 29 TC 1 Z9 1 U1 1 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD OCT PY 2013 VL 37 IS 5 BP 593 EP 600 DI 10.1016/j.canep.2013.07.002 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 230UY UT WOS:000325369800012 PM 23891684 ER PT J AU Abdul-Sater, AA Tattoli, I Jin, L Grajkowski, A Levi, A Koller, BH Allen, IC Beaucage, SL Fitzgerald, KA Ting, JPY Cambier, JC Girardin, SE Schindler, C AF Abdul-Sater, Ali A. Tattoli, Ivan Jin, Lei Grajkowski, Andrzej Levi, Assaf Koller, Beverly H. Allen, Irving C. Beaucage, Serge L. Fitzgerald, Katherine A. Ting, Jenny P. -Y. Cambier, John C. Girardin, Stephen E. Schindler, Christian TI Cyclic-di-GMP and cyclic-di-AMP activate the NLRP3 inflammasome SO EMBO REPORTS LA English DT Article DE inflammasome; cyclic-di-GMP; cyclic-di-AMP; PAMP; cytokines ID I INTERFERON RESPONSE; NALP3 INFLAMMASOME; AIM2 INFLAMMASOME; IMMUNE-RESPONSE; HOST-DEFENSE; LETHAL TOXIN; DNA; RECOGNIZES; CRYSTALS; SUSCEPTIBILITY AB The cyclic dinucleotides 3'-5'diadenylate (c-diAMP) and 3'-5' diguanylate (c-diGMP) are important bacterial second messengers that have recently been shown to stimulate the secretion of type I Interferons (IFN-Is) through the c-diGMP-binding protein MPYS/STING. Here, we show that physiologically relevant levels of cyclic dinucleotides also stimulate a robust secretion of IL-1 beta through the NLRP3 inflammasome. Intriguingly, this response is independent of MPYS/STING. Consistent with most NLRP3 inflammasome activators, the response to c-diGMP is dependent on the mobilization of potassium and calcium ions. However, in contrast to other NLRP3 inflammasome activators, this response is not associated with significant changes in mitochondrial potential or the generation of mitochondrial reactive oxygen species. Thus, cyclic dinucleotides activate the NLRP3 inflammasome through a unique pathway that could have evolved to detect pervasive bacterial pathogen-associated molecular patterns associated with intracellular infections. C1 [Abdul-Sater, Ali A.; Schindler, Christian] Columbia Univ, Dept Microbiol & Immunol, New York, NY 10032 USA. [Tattoli, Ivan; Girardin, Stephen E.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A8, Canada. [Jin, Lei; Cambier, John C.] Univ Colorado, Integrated Dept Immunol, Denver Sch Med, Denver, CO 80206 USA. [Jin, Lei; Cambier, John C.] Natl Jewish Hlth, Denver, CO 80206 USA. [Grajkowski, Andrzej; Beaucage, Serge L.] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. [Levi, Assaf] Univ Chicago, Dept Microbiol, Cummings Life Sci Ctr, Chicago, IL 60637 USA. [Koller, Beverly H.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Koller, Beverly H.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Allen, Irving C.; Ting, Jenny P. -Y.] Univ N Carolina, Dept Microbiol Immunol, Chapel Hill, NC 27599 USA. [Allen, Irving C.; Ting, Jenny P. -Y.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Inst Inflammatory Dis, Chapel Hill, NC 27599 USA. [Fitzgerald, Katherine A.] Univ Massachusetts, Sch Med, Div Infect Dis & Immunol, Worcester, MA 01605 USA. [Schindler, Christian] Columbia Univ, Dept Med, New York, NY 10032 USA. RP Schindler, C (reprint author), Columbia Univ, Dept Microbiol & Immunol, New York, NY 10032 USA. EM cws4@columbia.edu OI Cambier, John/0000-0002-7803-242X; jin, lei/0000-0001-6836-1142 FU NIH [AI096088, AI058211, AI062739, T32AI074491, AR061491, AI057157, R37-AI029564] FX Anthrax lethal toxin was a kind gift from Jeremy Mogridge (Department of Laboratory Medicine & Pathobiology, University of Toronto, ON, Canada). These studies were supported by the NIH grants AI096088 (C. S.), AI058211 (C. S.), AI062739 (J.C.C.), T32AI074491 (L.J.), AR061491 (B. H. K.), AI057157 (J.P.-Y.T.) and R37-AI029564 (J.P.-Y.T.). NR 51 TC 16 Z9 18 U1 2 U2 21 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1469-221X J9 EMBO REP JI EMBO Rep. PD OCT PY 2013 VL 14 IS 10 BP 900 EP 906 DI 10.1038/embor.2013.132 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 229HL UT WOS:000325253100014 PM 24008845 ER PT J AU Banda, M Recio, L Parsons, BL AF Banda, Malathi Recio, Leslie Parsons, Barbara L. TI ACB-PCR Measurement of Spontaneous and Furan-Induced H-ras Codon 61 CAA to CTA and CAA to AAA Mutation in B6C3F1 Mouse Liver SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE furan; H-ras codon 61 mutations; hepatocarcinogenesis; B6C3F1 mouse; mode of action ID CELL-PROLIFERATION; OXIDATIVE STRESS; GENE-MUTATIONS; TUMORS; GENOTOXICITY; PROTOONCOGENE; ACTIVATION; RATS; MICE; DNA AB Furan is a rodent liver carcinogen, but the mode of action for furan hepatocarcinogenicity is unclear. H-ras codon 61 mutations have been detected in spontaneous liver tumors of B6C3F1 mice, and the fraction of liver tumors carrying H-ras codon 61 CAA to AAA mutation increased in furan-treated mice. Allele-specific competitive blocker PCR (ACB-PCR) has been used previously to quantify early, carcinogen-induced increases in tumor-associated mutations. The present pilot study investigated whether furan drives clonal expansion of pre-existing H-ras mutant cells in B6C3F1 mouse liver. H-ras codon 61 CAA to CTA and CAA to AAA mutations were measured in DNA isolated from liver tissue of female mice treated with 0, 1, 2, 4, or 8 mg furan/kg body weight, five days per week for three weeks, using five mice per treatment group. Spontaneous levels of mutation were low, with two of five control mice having an H-ras codon 61 CTA or AAA mutant fraction (MF) greater than 10(-5). Several furan-treated mice had H-ras codon 61 AAA or CTA MFs greater than those measured in control mice and lower bound estimates of induced MF were calculated. However, no statistically-significant differences were observed between treatment groups. Therefore, while sustained exposure to furan is carcinogenic, at the early stage of carcinogenesis examined in this study (three weeks), there was not a significant expansion of H-ras mutant cells. Environ. Mol. Mutagen. 54:659-667, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Banda, Malathi; Parsons, Barbara L.] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Recio, Leslie] Integrated Syst Lab, Res Triangle Pk, NC USA. RP Banda, M (reprint author), US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, HFT 130,3900 NCTR Rd, Jefferson, AR 72079 USA. EM malathi.banda@fda.hhs.gov FU Postgraduate Research Program at the NCTR FX Grant sponsor: Postgraduate Research Program at the NCTR administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration (FDA). NR 37 TC 4 Z9 4 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD OCT PY 2013 VL 54 IS 8 SI SI BP 659 EP 667 DI 10.1002/em.21808 PG 9 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 232DD UT WOS:000325469000006 PM 24038307 ER PT J AU Song, YS Koontz, JL Juskelis, RO Zhao, Y AF Song, Yoon S. Koontz, John L. Juskelis, Rima O. Zhao, Yang TI Static liquid permeation cell method for determining the migration parameters of low molecular weight organic compounds in polyethylene terephthalate SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE chromatography - GC-MS; migration - diffusion; PET; packaging - migration modelling; packaging - food simulants ID DIFFUSION-COEFFICIENTS; FUNCTIONAL BARRIERS; ADDITIVE DIFFUSION; POLY(ETHYLENE-TEREPHTHALATE); FOOD; POLYOLEFINS; PRODUCTS; POLYMERS; SORPTION; FILMS AB The migration of low molecular weight organic compounds through polyethylene terephthalate (PET) films was determined by using a custom permeation cell assembly. Fatty food simulant (Miglyol 812) was added to the receptor chamber, while the donor chamber was filled with 1% and 10% (v/v) migrant compounds spiked in simulant. The permeation cell was maintained at 40 degrees C, 66 degrees C, 100 degrees C or 121 degrees C for up to 25 days of polymer film exposure time. Migrants in Miglyol were directly quantified without a liquid-liquid extraction step by headspace-GC-MS analysis. Experimental diffusion coefficients (D-P) of toluene, benzyl alcohol, ethyl butyrate and methyl salicylate through PET film were determined. Results from Limm's diffusion model showed that the predicted D-P values for PET were all greater than the experimental values. D-P values predicted by Piringer's diffusion model were also greater than those determined experimentally at 66 degrees C, 100 degrees C and 121 degrees C. However, Piringer's model led to the underestimation of benzyl alcohol (A'(P) = 3.7) and methyl salicylate (A'(P) = 4.0) diffusion at 40 degrees C with its revised "upper-bound" A'(P) value of 3.1 at temperatures below the glass transition temperature (T-g) of PET (<70 degrees C). This implies that input parameters of Piringer's model may need to be revised to ensure a margin of safety for consumers. On the other hand, at temperatures greater than the T-g, both models appear too conservative and unrealistic. The highest estimated A'(P) value from Piringer's model was 2.6 for methyl salicylate, which was much lower than the "upper-bound" A'(P) value of 6.4 for PET. Therefore, it may be necessary further to refine "upper-bound" A'(P) values for PET such that Piringer's model does not significantly underestimate or overestimate the migration of organic compounds dependent upon the temperature condition of the food contact material. C1 [Song, Yoon S.; Koontz, John L.] US FDA, OFS, Proc Engn Branch, Bedford Pk, IL 60501 USA. [Juskelis, Rima O.; Zhao, Yang] IIT, Inst Food Safety & Hlth, Bedford Pk, IL 60501 USA. RP Song, YS (reprint author), US FDA, OFS, Proc Engn Branch, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM yoon.song@fda.hhs.gov NR 23 TC 4 Z9 4 U1 2 U2 22 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1944-0049 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PD OCT 1 PY 2013 VL 30 IS 10 BP 1837 EP 1848 DI 10.1080/19440049.2013.816878 PG 12 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA 224QR UT WOS:000324903700020 PM 23883310 ER PT J AU Kwegyir-Afful, EE DeJager, LS Handy, SM Wong, J Begley, TH Luccioli, S AF Kwegyir-Afful, Ernest E. DeJager, Lowri S. Handy, Sara M. Wong, Jon Begley, Timothy H. Luccioli, Stefano TI An investigational report into the causes of pine mouth events in US consumers SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Dysgeusia; Pine nuts; Taste disturbance; Metallogeusia; Pinus armandii ID TASTE; NUTS; DISORDERS; SMELL; DYSGEUSIA; STORAGE; CELLS AB Between July 2008 and June 2012, the US Food and Drug Administration received 501 consumer reports of prolonged taste disturbances consistent with pine mouth syndrome. Consumers consistently reported a delayed bitter or metallic taste beginning hours to days following consumption of pine nuts that recurred with intake of any food or meal. This dysgeusia lasted in some cases up to a few weeks, but would eventually resolve without serious health consequences. To evaluate these reports, a questionnaire was developed to address various characteristics of the pine nuts consumed, pertinent medical history of complainants and other dysgeusia-related factors. Pine nut samples associated with 15 complaints were collected for analysis. The investigation of reports found no clear evidence of an underlying medical cause or common trigger that could adequately explain the occurrence of dysgeusia in complainants. Rather, the results of our investigation suggest that the occurrence of "pine mouth syndrome" in US consumers is correlated with the consumption of the pine nut species Pinus armandii. Published by Elsevier Ltd. C1 [Kwegyir-Afful, Ernest E.; Luccioli, Stefano] CFSAN, Off Food Addit Safety, College Pk, MD 20740 USA. [DeJager, Lowri S.; Handy, Sara M.; Wong, Jon; Begley, Timothy H.] CFSAN, Div Analyt Chem, Off Regulatory Sci, College Pk, MD 20740 USA. RP Kwegyir-Afful, EE (reprint author), CFSAN, Off Food Addit Safety, 5100 Paint Branch Pkwy,HFS 200,Rm 3061, College Pk, MD 20740 USA. EM Ernest.Kwegyir-Afful@fda.hhs.gov RI Handy, Sara/C-6195-2008 NR 35 TC 5 Z9 5 U1 1 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD OCT PY 2013 VL 60 BP 181 EP 187 DI 10.1016/j.fct.2013.07.038 PG 7 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA 228ZN UT WOS:000325231700022 PM 23891758 ER PT J AU Bobo, WV Cooper, WO Stein, CM Olfson, M Graham, D Daugherty, J Fuchs, DC Ray, WA AF Bobo, William V. Cooper, William O. Stein, C. Michael Olfson, Mark Graham, David Daugherty, James Fuchs, D. Catherine Ray, Wayne A. TI Antipsychotics and the Risk of Type 2 Diabetes Mellitus in Children and Youth SO JAMA PSYCHIATRY LA English DT Article ID ATYPICAL ANTIPSYCHOTICS; PROPENSITY SCORES; BIPOLAR DISORDER; US CHILDREN; MEDICATIONS; ADOLESCENTS; SCHIZOPHRENIA; MEDICAID; PHARMACOEPIDEMIOLOGY; OVERWEIGHT AB IMPORTANCE The increased prescribing of antipsychotics for children and youth has heightened concerns that this practice increases the risk of type 2 diabetes mellitus. OBJECTIVE To compare the risk of type 2 diabetes in children and youth 6 to 24 years of age for recent initiators of antipsychotic drugs vs propensity score-matched controls who had recently initiated another psychotropic medication. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of the Tennessee Medicaid program with 28 858 recent initiators of antipsychotic drugs and 14 429 matched controls. The cohort excluded patients who previously received a diagnosis of diabetes, schizophrenia, or some other condition for which antipsychotics are the only generally recognized therapy. MAIN OUTCOMES AND MEASURES Newly diagnosed diabetes during follow-up, as identified from diagnoses and diabetes medication prescriptions. RESULTS Users of antipsychotics had a 3-fold increased risk for type 2 diabetes (HR = 3.03 [95% CI = 1.73-5.32]), which was apparent within the first year of follow-up (HR = 2.49 [95% CI = 1.27-4.88]). The risk increased with cumulative dose during follow-up, with HRs of 2.13 (95% CI = 1.06-4.27), 3.42 (95% CI = 1.88-6.24), and 5.43 (95% CI = 2.34-12.61) for respective cumulative doses (gram equivalents of chlorpromazine) of more than 5 g, 5 to 99 g, and 100 g or more (P < .04). The risk remained elevated for up to 1 year following discontinuation of antipsychotic use (HR = 2.57 [95% CI = 1.34-4.91]). When the cohort was restricted to children 6 to 17 years of age, antipsychotic users had more than a 3-fold increased risk of type 2 diabetes (HR = 3.14 [95% CI = 1.50-6.56]), and the risk increased significantly with increasing cumulative dose (P < .03). The risk was increased for use restricted to atypical antipsychotics (HR = 2.89 [95% CI = 1.64-5.10]) or to risperidone (HR = 2.20 [95% CI = 1.14-4.26]). CONCLUSIONS AND RELEVANCE Children and youth prescribed antipsychotics had an increased risk of type 2 diabetes that increased with cumulative dose. C1 [Bobo, William V.; Fuchs, D. Catherine] Vanderbilt Univ, Sch Med, Dept Psychiat, Nashville, TN 37212 USA. [Cooper, William O.] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37212 USA. [Stein, C. Michael] Vanderbilt Univ, Sch Med, Div Clin Pharmacol, Dept Internal Med, Nashville, TN 37212 USA. [Olfson, Mark] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Graham, David] US FDA, Silver Spring, MD USA. [Daugherty, James; Ray, Wayne A.] Vanderbilt Univ, Sch Med, Div Pharmacoepidemiol, Dept Prevent Med, Nashville, TN 37212 USA. RP Ray, WA (reprint author), Vanderbilt Univ, Sch Med, Div Pharmacoepidemiol, Dept Prevent Med, 1500 21st Ave S,Ste 2600, Nashville, TN 37212 USA. EM wayne.ray@vanderbilt.edu FU Agency for Healthcare Research and Quality, Centers for Education and Research on Therapeutics [HS1-16974] FX This study was supported by the Agency for Healthcare Research and Quality, Centers for Education and Research on Therapeutics cooperative agreement (grant HS1-16974). NR 43 TC 64 Z9 64 U1 3 U2 20 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-622X J9 JAMA PSYCHIAT JI JAMA Psychiatry PD OCT PY 2013 VL 70 IS 10 BP 1067 EP 1075 DI 10.1001/jamapsychiatry.2013.2053 PG 9 WC Psychiatry SC Psychiatry GA 228KE UT WOS:000325184100011 PM 23965896 ER PT J AU Tegenge, MA Mitkus, RJ AF Tegenge, Million A. Mitkus, Robert J. TI A physiologically-based pharmacokinetic (PBPK) model of squalene-containing adjuvant in human vaccines SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Article DE Squalene; Adjuvants; Vaccine; MF59; ASO3; Pharmacokinetics ID INTRAVENOUSLY ADMINISTERED SQUALENE; INTRAMUSCULAR INJECTION; INFLUENZA VACCINE; METABOLIC-FATE; ADIPOSE-TISSUE; HUMAN SKIN; MF59; SAFETY; MICE; EMULSIONS AB Squalene is used in the oil phase of certain emulsion vaccine adjuvants, but its fate as a vaccine component following intramuscular (IM) injection in humans is unknown. In this study, we constructed a physiologically-based pharmacokinetic (PBPK) model for intramuscularly injected squalene-in-water (SQ/W) emulsion, in order to make a quantitative estimation of the tissue distribution of squalene following a single IM injection in humans. The PBPK model incorporates relevant physicochemical properties of squalene; estimates of the time course of cracking of a SQ/W emulsion; anatomical and physiological parameters at the injection site and beyond; and local, preferential lymphatic transport. The model predicts that a single dose of SQ/W emulsion will be removed from human deltoid muscle within six days following IM injection. The major proportion of the injected squalene will be distributed to draining lymph nodes and adipose tissues. The model indicates slow decay from the latter compartment most likely due to partitioning into neutral lipids and a low rate of squalene biotransformation there. Parallel pharmacokinetic modeling for mouse muscle suggests that the kinetics of SQ/W emulsion correspond to the immunodynamic time course of a commercial squalene-containing adjuvant reported in that species. In conclusion, this study makes important pharmacokinetic predictions of the fate of a squalene-containing emulsion in humans. The results of this study may be relevant for understanding the immunodynamics of this new class of vaccine adjuvants and may be useful in future quantitative risk analyses that incorporate mode-of-action data. C1 [Tegenge, Million A.; Mitkus, Robert J.] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Tegenge, MA (reprint author), US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, 1401 Rockville Pike, Rockville, MD 20852 USA. EM million.tegenge@fda.hhs.gov FU U.S. Department of Energy; U.S. Food and Drug Administration FX We thank Dr. Sorell Schwartz for his careful review of the manuscript and for his recommendation of modeling software. This project was supported in part by an appointment (M.A.T.) to the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 60 TC 5 Z9 6 U1 2 U2 10 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2013 VL 40 IS 5 BP 545 EP 556 DI 10.1007/s10928-013-9328-y PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 229KT UT WOS:000325263800001 PM 23912214 ER PT J AU Pandey, GS Yanover, C Miller-Jenkins, LM Garfield, S Cole, SA Curran, JE Moses, EK Rydz, N Simhadri, V Kimchi-Sarfaty, C Lillicrap, D Viel, KR Przytycka, TM Pierce, GF Howard, TE Sauna, ZE AF Pandey, Gouri Shankar Yanover, Chen Miller-Jenkins, Lisa M. Garfield, Susan Cole, Shelley A. Curran, Joanne E. Moses, Eric K. Rydz, Natalia Simhadri, Vijaya Kimchi-Sarfaty, Chava Lillicrap, David Viel, Kevin R. Przytycka, Teresa M. Pierce, Glenn F. Howard, Tom E. Sauna, Zuben E. CA PATH Personalized Alternative TI Endogenous factor VIII synthesis from the intron 22-inverted F8 locus may modulate the immunogenicity of replacement therapy for hemophilia A SO NATURE MEDICINE LA English DT Article ID COAGULATION-FACTOR VIII; MONOCLONAL-ANTIBODIES; HUMAN-LIVER; INHIBITOR; ANTIGEN; HISTORY; GENE AB Neutralizing antibodies (inhibitors) to replacement factor VIII (FVIII, either plasma derived or recombinant) impair the effective management of hemophilia A1. Individuals with hemophilia A due to major deletions of the FVIII gene (F8) lack antigenically cross-reactive material in their plasma ("CRM-negative"), and the prevalence of inhibitors in these individuals may be as high as 90%. Conversely, individuals with hemophilia A caused by F8 missense mutations are CRM-positive, and their overall prevalence of inhibitors is < 10% (ref. 2). Individuals with the F8 intron 22 inversion (found in similar to 50% of individuals with severe hemophilia A) have been grouped with the former on the basis of their genetic defect and CRM-negative status. However, only similar to 20% of these individuals develop inhibitors3. Here we demonstrate that the levels of F8 mRNA and intracellular FVIII protein in B lymphoblastoid cells and liver biopsies from individuals with the intron 22 inversion are comparable to those in healthy controls. These results support the hypothesis that most individuals with the intron 22 inversion are tolerized to FVIII and thus do not develop inhibitors. Furthermore, we developed a new pharmacogenetic algorithm that permits the stratification of inhibitor risk for individuals and subpopulations by predicting the immunogenicity of replacement FVIII using, as input, the number of putative T cell epitopes in the infused protein and the competence of major histocompatibility complex class II molecules to present such epitopes. This algorithm showed statistically significant accuracy in predicting the presence of inhibitors in 25 unrelated individuals with the intron 22 inversion. C1 [Pandey, Gouri Shankar; Simhadri, Vijaya; Kimchi-Sarfaty, Chava; Sauna, Zuben E.] US FDA, Ctr Biol Evaluat & Res, Div Hematol, Lab Hemostasis, Bethesda, MD 20892 USA. [Yanover, Chen] Fred Hutchinson Canc Res Ctr, Program Computat Biol, Seattle, WA 98104 USA. [Miller-Jenkins, Lisa M.] NCI, Lab Cell Biol, Expt Carcinogenesis Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Garfield, Susan] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Cole, Shelley A.; Curran, Joanne E.; Moses, Eric K.] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA. [Rydz, Natalia; Lillicrap, David] Queens Univ, Dept Pathol & Mol Med, Kingston, ON, Canada. [Viel, Kevin R.] Histonis, Atlanta, GA USA. [Przytycka, Teresa M.] Natl Ctr Biotechnol Informat, Natl Lib Med, NIH, Bethesda, MD USA. [Pierce, Glenn F.] Biogen Idec Hemophilia, Waltham, MA USA. [Howard, Tom E.] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Pathol & Lab Med, Los Angeles, CA USA. [Howard, Tom E.] Univ So Calif, Keck Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90033 USA. [Howard, Tom E.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. RP Sauna, ZE (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Hematol, Lab Hemostasis, Bethesda, MD 20892 USA. EM tom.howard@va.gov; zuben.sauna@fda.hhs.gov RI Yanover, Chen/A-3754-2012 OI Yanover, Chen/0000-0003-3663-4286 FU US National Institute of Allergy and Infectious Diseases Committee on Human Research [10-01178]; modernization of science program of the Center for Biologics Evaluation and Research, US Food and Drug Administration; National Heart, Lung and Blood Institute, National Institutes of Health [1RC2-HL101851, HL-71130, HL-72533)]; Bayer Healthcare Corporation; Bayer Hemophilia Awards Program; Baxter Healthcare Corporation; Clinical Translational Science Institute at the University of Southern California; Intramural Program of the US National Library of Medicine, NIH FX We would like to thank P. Matzinger, B. Golding, J. Lozier, D. Levin, M. Carcao, V. Blanchette, G. Rivard and V. La Terza for helpful comments and J. Sauna for help with the graphics. We thank S. V. Ambudkar (US National Cancer Institute) for the use of facilities, M. J. Lenardo and K. Shafer-Weaver (US National Institute of Allergy and Infectious Diseases) for the gift of the purified C2 domain of FVIII and P. Stock (University of California, San Francisco) for liver tissue samples. These samples were obtained under the University of California University-Wide AIDS Research Program (TP-99-SF-001) Committee on Human Research (H802423454) and the Solid Organ Transplantation in HIV: Multi-Site Study (AI052748) funded by the US National Institute of Allergy and Infectious Diseases Committee on Human Research (10-01178). Research conducted in the laboratory of Z. E. S. is funded by the modernization of science program of the Center for Biologics Evaluation and Research, US Food and Drug Administration. Research conducted in the laboratory of T. E. H. is funded by grants from the National Heart, Lung and Blood Institute, National Institutes of Health (1RC2-HL101851, HL-71130 and HL-72533), the Bayer Healthcare Corporation, Bayer Hemophilia Awards Program, Baxter Healthcare Corporation and the Clinical Translational Science Institute at the University of Southern California. The work of T. M. P. is fully supported by the Intramural Program of the US National Library of Medicine, NIH. NR 22 TC 27 Z9 27 U1 2 U2 19 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD OCT PY 2013 VL 19 IS 10 BP 1318 EP + DI 10.1038/nm.3270 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 232YW UT WOS:000325531700032 PM 24037092 ER PT J AU Deming, DJ Patel, N McCarthy, MP Mishra, L Shapiro, AM Suzich, JA AF Deming, Damon J. Patel, Nita McCarthy, Michael P. Mishra, Lalji Shapiro, Alan M. Suzich, JoAnn A. TI POTENTIAL FOR PALIVIZUMAB INTERFERENCE WITH COMMERCIALLY AVAILABLE ANTIBODY-ANTIGEN BASED RESPIRATORY SYNCYTIAL VIRUS DIAGNOSTIC ASSAYS SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE assay interference; palivizumab; respiratory syncytial virus ID MONOCLONAL-ANTIBODY; INFECTIONS; INFANTS AB Palivizumab is a monoclonal antibody indicated for the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus infection in infants. The potential for palivizumab to interfere with commercially available respiratory syncytial virus diagnostic tests was demonstrated. Negative test results in palivizumab-treated subjects should be interpreted with caution and confirmed by a nucleic acid amplification-based assay. C1 [Deming, Damon J.; Mishra, Lalji; Shapiro, Alan M.] US FDA, Ctr Drug Evaluat & Res, Off New Drugs, Off Antimicrobial Prod,Div Antiviral Prod, Silver Spring, MD 20993 USA. [Patel, Nita; McCarthy, Michael P.; Suzich, JoAnn A.] MedImmune LLC, Gaithersburg, MD USA. RP Deming, DJ (reprint author), US FDA, Ctr Drug Evaluat & Res, Div Antiviral Prod, 10903 New Hampshire Ave,White Oak Bldg 22,Rm 6375, Silver Spring, MD 20993 USA. EM damon.deming@fda.hhs.gov FU MedImmune FX This work was funded by MedImmune. N.P., M. P. M. and J.A.S. are employed by MedImmune. The authors have no other funding or conflicts of interest to disclose. NR 10 TC 3 Z9 3 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD OCT PY 2013 VL 32 IS 10 BP 1144 EP 1146 DI 10.1097/INF.0b013e31829561dd PG 3 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 224ML UT WOS:000324890500027 PM 23584584 ER PT J AU Rubin, S Beeler, J AF Rubin, Steven Beeler, Judy TI Mumps Vaccines Do We Need a New One? SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Letter ID US MILITARY RECRUITS; RUBELLA VACCINE; MEASLES; OUTBREAK; POPULATION; ANTIBODIES C1 [Rubin, Steven; Beeler, Judy] Ctr Biol Evaluat & Res, Food & Drug Adm, Bethesda, MD USA. RP Rubin, S (reprint author), Ctr Biol Evaluat & Res, Food & Drug Adm, Bethesda, MD USA. NR 12 TC 2 Z9 2 U1 0 U2 32 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD OCT PY 2013 VL 32 IS 10 BP 1156 EP 1157 DI 10.1097/INF.0b013e31829aa51b PG 2 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 224ML UT WOS:000324890500034 PM 24067559 ER PT J AU Jones, SC Budnitz, DS Sorbello, A Mehta, H AF Jones, S. Christopher Budnitz, Daniel S. Sorbello, Alfred Mehta, Hina TI US-based emergency department visits for fluoroquinolone-associated hypersensitivity reactions SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE fluoroquinolone; hypersensitivity; allergy; moxifloxacin; ciprofloxacin; levofloxacin; pharmacoepidemiology ID MEDIATED HYPERSENSITIVITY; ALLERGIC REACTIONS; CROSS-REACTIVITY; QUINOLONES AB PurposeTo estimate the rate of hypersensitivity reactions per 100,000 prescription dispensings of fluoroquinolones based on care rendered in a nationally representative sample of US hospital emergency departments (ED). MethodsWe analyzed the frequency of fluoroquinolone-associated hypersensitivity reactions using the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance system (2004-2010) in conjunction with US retail outpatient prescription data from IMS Health (2004-2010). We further categorized reaction severity into three subgroups (mild, moderate, and severe). ResultsBased on 1422 cases of fluoroquinolone-associated hypersensitivity reactions and national drug utilization projections, we estimated risk of hypersensitivity reactions for moxifloxacin, ciprofloxacin, and levofloxacin. The absolute risk of a fluoroquinolone-related hypersensitivity reaction of any severity was low (44.0 (95% CI 34.8-53.3) ED visits/100,000 prescriptions); however, we identified a statistically significant difference in the relative risk (rate ratios) of seeking care in an ED attributed to moxifloxacin hypersensitivity compared to either levofloxacin or ciprofloxacin. For all reaction severities, the estimated ED visits/100,000 prescriptions were 141.3 (95% CI 99.9-182.7) for moxifloxacin, 40.8 (95% CI 31.5-50.0) for levofloxacin, and 26.3 (95% CI 20.8-31.9) for ciprofloxacin. When the rates were stratified by reaction severity category (mild or moderate-severe), moxifloxacin continued to be implicated in more ED visits per 100,000 prescriptions dispensed than either levofloxacin or ciprofloxacin. ConclusionFluoroquinolones may cause hypersensitivity reactions requiring care in an ED, and relative to use, the rate of moxifloxacin-related hypersensitivity reactions is higher compared to levofloxacin or ciprofloxacin. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. C1 [Jones, S. Christopher; Sorbello, Alfred; Mehta, Hina] US FDA, Off Surveillance & Epidemiol, Silver Spring, MD 20993 USA. [Budnitz, Daniel S.] US Ctr Dis & Control & Prevent, Div Healthcare Qual Promot, Atlanta, GA USA. RP Jones, SC (reprint author), US FDA, Ctr Drug Evaluat & Res, Off Surveillance & Epidemiol, Div Pharmacovigilance, 10903 New Hampshire Ave Bldg 22 Room 3464, Silver Spring, MD 20993 USA. EM Steven.Jones@fda.hhs.gov FU Intramural CDC HHS [CC999999] NR 15 TC 7 Z9 7 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 IS 10 BP 1099 EP 1106 DI 10.1002/pds.3499 PG 8 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 227WJ UT WOS:000325146100010 PM 23963962 ER PT J AU Cunningham, WC AF Cunningham, W. C. TI Use of water activity characteristics enables a simplified approach for defining the reference moisture condition for FDA cocoa powder in-house reference material SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Reference material; Water activity; Relative humidity; Isotherm ID CHOCOLATE AB The Food and Drug Administration uses water activity behavior characteristics when adjusting test portion mass to correct for the moisture condition of its cocoa powder in-house reference material. The cocoa powder's moisture condition, and therefore weight, equilibrates according to the relative humidity (RH) of its surroundings. This process is predictable and defined by an isotherm. The reference values in the certificate of analysis are relative to the material's condition at 30 % RH, which is assumed to be mid-range for typical laboratory settings. Since mass variations are relatively small within a 15-50 % RH range, the mass may be measured immediately after removing a test portion from a storage bottle and used without correction if a standard uncertainty of 0.7 % is acceptable for the mass. If greater accuracy is needed and the laboratory RH is known, a very simple and quick procedure can be used whereby the test portion is left open and exposed to the laboratory air overnight before weighing. After applying a correction, the standard uncertainty for mass measurement drops to 0.3 %. C1 US FDA, Div Bioanalyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Cunningham, WC (reprint author), US FDA, Div Bioanalyt Chem, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM william.cunningham@fda.hhs.gov NR 17 TC 0 Z9 0 U1 0 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD OCT PY 2013 VL 405 IS 26 BP 8615 EP 8620 DI 10.1007/s00216-013-7175-8 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 227LQ UT WOS:000325114900022 PM 23942587 ER PT J AU Kummar, S Gutierrez, ME Anderson, LW Klecker, RW Chen, A Murgo, AJ Doroshow, JH Collins, JM AF Kummar, Shivaani Gutierrez, Martin E. Anderson, Lawrence W. Klecker, Raymond W., Jr. Chen, Alice Murgo, Anthony J. Doroshow, James H. Collins, Jerry M. TI Pharmacogenetically driven patient selection for a first-in-human phase I trial of batracylin in patients with advanced solid tumors and lymphomas SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Pharmacogenetics; N-acetyl-batracylin; NAT2 ID POLYMORPHISM; NSC-320846; PHENOTYPE AB Batracylin (daniquidone), an ATP-insensitive topoisomerase I/II inhibitor, demonstrated wide interspecies variation in preclinical models consistent with formation of a toxic metabolite, N-acetyl-batracylin, following metabolism by N-acetyl-transferase 2 (NAT2). To minimize exposure to this toxic metabolite, this first-in-human study was conducted in patients with advanced refractory solid tumors or lymphomas demonstrated to have a slow NAT2 acetylator genotype. The objectives were to determine the safety, maximum tolerated dose (MTD), and pharmacokinetics of batracylin and its metabolites. Based on the MTD for rats, the most sensitive species, the starting dose was 5 mg/day for 7 days in 28-day cycles. Dose escalation followed accelerated titration design 4B, with restaging performed every 2 cycles. Thirty-one patients were enrolled. Treatment was well tolerated; one patient experienced grade 3 toxicity (lymphopenia). Dose escalation was stopped at 400 mg/day due to grade 1 and 2 hemorrhagic cystitis. No objective responses were observed, but prolonged disease stabilization was observed in 2 patients, one with peritoneal mesothelioma (8 cycles) and another with adrenocortical cancer (18 cycles). Across an 80-fold range of doses, the ratios of systemic exposures for batracylin and N-acetyl batracylin were near 1. Pharmacogenetically selected patients reached a dose that was 20-fold higher than the MTD in rats and 70 % of the MTD in mice. This genotype-guided strategy was successful in safely delivering batracylin to patients. However, due to unexpected cystitis, not preventable by hydration, and in the absence of a stronger signal for antitumor activity, further development of batracylin has been stopped. C1 [Kummar, Shivaani; Gutierrez, Martin E.; Doroshow, James H.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Kummar, Shivaani; Anderson, Lawrence W.; Chen, Alice; Murgo, Anthony J.; Doroshow, James H.; Collins, Jerry M.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Klecker, Raymond W., Jr.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Collins, JM (reprint author), NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. EM collinsje@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported [in part] by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 15 TC 4 Z9 4 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD OCT PY 2013 VL 72 IS 4 BP 917 EP 923 DI 10.1007/s00280-013-2244-4 PG 7 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 224JB UT WOS:000324879100022 PM 23912694 ER PT J AU Lionberger, R Jiang, W Huang, SM Geba, G AF Lionberger, R. Jiang, W. Huang, S-M Geba, G. TI Confidence in Generic Drug Substitution SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material AB Patients should have confidence that the generic drugs they are prescribed in the United States can be effectively substituted for the brand product or another generic product. Through new bioequivalence study designs for narrow therapeutic index (NTI) drugs and postapproval studies of generic substitution, the US Food and Drug Administration's (FDA's) ongoing generic drug regulatory science activities are designed to ensure successful generic substitution for all drug products. C1 [Lionberger, R.; Jiang, W.; Geba, G.] US FDA, Off Gener Drugs, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. [Huang, S-M] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Lionberger, R (reprint author), US FDA, Off Gener Drugs, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. EM robert.lionberger@fda.hhs.gov NR 9 TC 4 Z9 4 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD OCT PY 2013 VL 94 IS 4 BP 438 EP 440 DI 10.1038/clpt.2013.104 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 220IL UT WOS:000324576100017 PM 24048239 ER PT J AU Zannad, F Garcia, AA Anker, SD Armstrong, PW Calvo, G Cleland, JGF Cohn, JN Dickstein, K Domanski, MJ Ekman, I Filippatos, GS Gheorghiade, M Hernandez, AF Jaarsma, T Koglin, J Konstam, M Kupfer, S Maggioni, AP Mebazaa, A Metra, M Nowack, C Pieske, B Pina, IL Pocock, SJ Ponikowski, P Rosano, G Ruilope, LM Ruschitzka, F Severin, T Solomon, S Stein, K Stockbridge, NL Stough, WG Swedberg, K Tavazzi, L Voors, AA Wasserman, S Woehrle, H Zalewski, A McMurray, JJV AF Zannad, Faiez Garcia, Angeles Alonso Anker, Stefan D. Armstrong, Paul W. Calvo, Gonzalo Cleland, John G. F. Cohn, Jay N. Dickstein, Kenneth Domanski, Michael J. Ekman, Inger Filippatos, Gerasimos S. Gheorghiade, Mihai Hernandez, Adrian F. Jaarsma, Tiny Koglin, Joerg Konstam, Marvin Kupfer, Stuart Maggioni, Aldo P. Mebazaa, Alexandre Metra, Marco Nowack, Christina Pieske, Burkert Pina, Ileana L. Pocock, Stuart J. Ponikowski, Piotr Rosano, Giuseppe Ruilope, Luis M. Ruschitzka, Frank Severin, Thomas Solomon, Scott Stein, Kenneth Stockbridge, Norman L. Stough, Wendy Gattis Swedberg, Karl Tavazzi, Luigi Voors, Adriaan A. Wasserman, ScottM. Woehrle, Holger Zalewski, Andrew McMurray, John J. V. TI Clinical outcome endpoints in heart failure trials: a European Society of Cardiology Heart Failure Association consensus document SO EUROPEAN JOURNAL OF HEART FAILURE LA English DT Review DE Heart failure; Morbidity; Mortality; Clinical trials ID WORSENING RENAL-FUNCTION; IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS; VENTRICULAR SYSTOLIC DYSFUNCTION; INITIATE LIFESAVING TREATMENT; PRESERVED EJECTION FRACTION; VISUAL ANALOG SCALES; QUALITY-OF-CARE; MYOCARDIAL-INFARCTION; EVENTS COMMITTEE; VASOPRESSIN ANTAGONISM AB Endpoint selection is a critically important step in clinical trial design. It poses major challenges for investigators, regulators, and study sponsors, and it also has important clinical and practical implications for physicians and patients. Clinical outcomes of interest in heart failure trials include all-cause mortality, cause-specific mortality, relevant non-fatal morbidity (e.g. all-cause and cause-specific hospitalization), composites capturing both morbidity and mortality, safety, symptoms, functional capacity, and patient-reported outcomes. Each of these endpoints has strengths and weaknesses that create controversies regarding which is most appropriate in terms of clinical importance, sensitivity, reliability, and consistency. Not surprisingly, a lack of consensus exists within the scientific community regarding the optimal endpoint(s) for both acute and chronic heart failure trials. In an effort to address these issues, the Heart Failure Association of the European Society of Cardiology (HFA-ESC) convened a group of expert heart failure clinical investigators, biostatisticians, regulators, and pharmaceutical industry scientists (Nice, France, 1213 February 2012) to evaluate the challenges of defining heart failure endpoints in clinical trials and to develop a consensus framework. This report summarizes the groups recommendations for achieving common views on heart failure endpoints in clinical trials. C1 [Zannad, Faiez] INSERM, Ctr Invest Clin 9501, Nancy, France. [Zannad, Faiez] Ctr Hosp Univ, Unite 961, Nancy, France. [Zannad, Faiez] Univ Lorraine, Nancy Univ, Dept Cardiol, Nancy, France. [Garcia, Angeles Alonso] Sci AdviceWorking Party European Med Agcy, Madrid, Spain. [Anker, Stefan D.] Campus Virchow Klinikum, Charite Med Sch, Dept Cardiol, Berlin, Germany. [Armstrong, Paul W.] Univ Alberta, Edmonton, AB, Canada. [Calvo, Gonzalo] Hosp Clin Barcelona, Barcelona, Spain. [Cleland, John G. F.] Castle Hill Hosp, Dept Cardiol, Kingston Upon Hull, Yorks, England. [Cohn, Jay N.] Univ Minnesota, Div Cardiovasc, Minneapolis, MN 55455 USA. [Dickstein, Kenneth] Univ Bergen, Stavanger Univ Hosp, Bergen, Norway. [Domanski, Michael J.] Mt Sinai Sch Med, Cardiovasc Inst, New York, NY USA. [Ekman, Inger] Gothenburg Univ, Sahlgrenska Acad, Ctr Person Ctr Care Res GPCC, Gothenburg, Sweden. [Filippatos, Gerasimos S.] Univ Athens, Hosp Attikon, Athens, Greece. [Gheorghiade, Mihai] Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, Chicago, IL 60611 USA. [Hernandez, Adrian F.] Duke Univ, Med Ctr, Durham, NC USA. [Hernandez, Adrian F.] Duke Clin Res Inst, Durham, NC USA. [Jaarsma, Tiny] Linkoping Univ, Dept Social & Welf Studies, S-58183 Linkoping, Sweden. [Koglin, Joerg] Merck Sharpe & Dohme Corp, Whitehouse Stn, NJ USA. [Konstam, Marvin] Tufts Univ, New England Med Ctr, Dept Cardiol, Boston, MA 02111 USA. [Kupfer, Stuart] Takeda Pharmaceut, Deerfield, IL USA. [Maggioni, Aldo P.] ANMCO Res Ctr, Florence, Italy. [Mebazaa, Alexandre] Hop Lariboisiere, Dept Anesthesia, F-75475 Paris, France. [Metra, Marco] Univ Brescia, Brescia, Italy. [Nowack, Christina] Bayer Pharma AG, Wuppertal, Germany. [Pieske, Burkert] Med Univ Graz, Dept Cardiol, Graz, Austria. [Pina, Ileana L.] Montefiore Med Ctr, Dept Med, Div Cardiol, Bronx, NY 10467 USA. [Pocock, Stuart J.] London Sch Hyg & Trop Med, Dept Med Stat, London WC1, England. [Ponikowski, Piotr] Med Univ, Mil Hosp, Wroclaw, Poland. [Rosano, Giuseppe] IRCCS San Raffaele Hosp, Dept Med Sci, Rome, Italy. [Ruilope, Luis M.] Hosp 12 Octubre, Hypertens Unit, E-28041 Madrid, Spain. [Ruschitzka, Frank] Univ Zurich Hosp, CH-8091 Zurich, Switzerland. [Severin, Thomas] Novartis Pharma AG, Basel, Switzerland. [Solomon, Scott] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Stein, Kenneth] Boston Sci Corp, St Paul, MN USA. [Stockbridge, Norman L.] US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. [Stough, Wendy Gattis] Campbell Univ, Coll Pharm & Hlth Sci, Buies Creek, NC 27506 USA. [Swedberg, Karl] Sahlgrenska Univ, Ostra Hosp, Gothenburg, Sweden. [Tavazzi, Luigi] Villa Maria Cecilia Hosp, GVM Hosp Care & Res, Cotignola, Italy. [Voors, Adriaan A.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Thoraxctr, Groningen, Netherlands. [Wasserman, ScottM.] Amgen Inc, Thousand Oaks, CA 91320 USA. [Woehrle, Holger] ResMed, Ulm, Germany. [Zalewski, Andrew] Novartis Pharmaceut, E Hanover, NJ USA. [McMurray, John J. V.] Univ Glasgow, Western Infirm, Glasgow G11 6NT, Lanark, Scotland. [McMurray, John J. V.] Univ Glasgow, British Heart Fdn, Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. RP Zannad, F (reprint author), CHU, Hop Jeanne Arc, INSERM, CIC, F-54200 Toul, France. EM f.zannad@chu-nancy.fr RI Lainscak, Mitja/F-3237-2015; Ponikowski, Piotr/O-6454-2015; Stough, Wendy/R-4287-2016; Hernandez, Adrian F./A-7818-2016; OI Ponikowski, Piotr/0000-0002-3391-7064; Stough, Wendy/0000-0001-8290-1205; Metra, Marco/0000-0001-6691-8568; Hernandez, Adrian F./0000-0003-3387-9616; Cleland, John/0000-0002-1471-7016; Maggioni, Aldo Pietro/0000-0003-2764-6779; mcmurray, john/0000-0002-6317-3975 FU Heart Failure Association of the European Society of Cardiology (HFA-ESC) FX The Heart Failure Association of the European Society of Cardiology (HFA-ESC) NR 112 TC 48 Z9 48 U1 1 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1388-9842 EI 1879-0844 J9 EUR J HEART FAIL JI Eur. J. Heart Fail. PD OCT PY 2013 VL 15 IS 10 BP 1082 EP 1094 DI 10.1093/eurjhf/hft095 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 228HD UT WOS:000325175700003 PM 23787718 ER PT J AU McDermott, MK Kim, CS Saylor, DM Patwardhan, DV AF McDermott, Martin K. Kim, Chang-Soo Saylor, David M. Patwardhan, Dinesh V. TI Impact of copolymer ratio on drug distribution in styrene-isobutylene-styrene block copolymers SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS LA English DT Article DE controlled release; stents; block copolymer; atomic force microscopy; molecular modeling ID TRIBLOCK COPOLYMER; CONTROLLED-RELEASE; STENT COATINGS; ELUTING STENT; IN-VITRO; TETRACYCLINE; PACLITAXEL; MORPHOLOGY; DELIVERY; FILMS AB Drug-polymer composite coatings, composed of styrene-isobutylene-styrene (SIBS) tri-block copolymers, are frequently used in controlled drug release biomedical device applications. In this work, we used atomic force microscopy to characterize the effects of different drug loadings and polymer chemistries (i.e., block copolymer ratio) on the variation of surface structures and compositions of SIBS-tetracycline (SIBS-TC) cast composites including tetracycline (TC) drug amount, drug phase size distribution, and drug and polymer phase morphologies. We tested the structural variations by fabricating and characterizing two types of composite specimens, that is, SIBS15 and SIBS30, composed of 15 and 30 Wt % of polystyrene (PS), respectively. The differences in the distribution of TC drug, PS, and polyisobutylene (PIB) polymer phase structures observed in SIBS15 and SIBS30 resulted in more drug at the surface of SIBS30 compared to SIBS15. To support the experimental findings, we have determined the Hildebrand solubility parameter of TC using molecular dynamics (MD) computation and compared it to the polymer components, PS and PIB. The MD results show that the solubility parameter of TC is much closer to that of PS than PIB, which demonstrates a higher thermodynamic stability of TC-PS mixtures. (c) 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 101B: 1191-1199, 2013. C1 [McDermott, Martin K.; Saylor, David M.; Patwardhan, Dinesh V.] US FDA, Div Chem & Mat Sci, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Kim, Chang-Soo] Univ Wisconsin, Dept Mat Sci & Engn, Milwaukee, WI 53211 USA. RP McDermott, MK (reprint author), US FDA, Div Chem & Mat Sci, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM Martin.McDermott@fda.hhs.gov; kimcs@uwm.edu FU Catalyst grant through the UWM research foundation FX The work at UWM was supported by the Catalyst grant through the UWM research foundation. NR 27 TC 2 Z9 2 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4973 J9 J BIOMED MATER RES B JI J. Biomed. Mater. Res. Part B PD OCT PY 2013 VL 101 IS 7 BP 1191 EP 1199 DI 10.1002/jbm.b.32930 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 216RQ UT WOS:000324302100009 PM 23564439 ER PT J AU Ge, BL Wang, F Sjolund-Karlsson, M McDermott, PF AF Ge, Beilei Wang, Fei Sjoelund-Karlsson, Maria McDermott, Patrick F. TI Antimicrobial resistance in Campylobacter: Susceptibility testing methods and resistance trends SO JOURNAL OF MICROBIOLOGICAL METHODS LA English DT Review DE Campylobacter; Susceptibility testing; Molecular; Antimicrobial resistance; Trend ID AGAR DILUTION METHODS; JEJUNI SUBSP JEJUNI; DISK DIFFUSION METHOD; REAL-TIME PCR; LEVEL ERYTHROMYCIN RESISTANCE; QUALITY-CONTROL RANGES; DNA-SEQUENCE ANALYSIS; CMEABC EFFLUX PUMP; LINE PROBE ASSAY; MACROLIDE RESISTANCE AB Most Campylobacter infections are self-limiting but antimicrobial treatment (e.g., macrolides, fluoroquinolones) is necessary in severe or prolonged cases. Susceptibility testing continues to play a critical role in guiding therapy and epidemiological monitoring of resistance. The methods of choice for Campylobacter recommended by the Clinical and Laboratory Standards Institute (CLSI) are agar dilution and broth microdilution, while a disk diffusion method was recently standardized by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Macrolides, quinolones, and tetracyclines are among the common antimicrobials recommended for testing. Molecular determination of Campylobacter resistance via DNA sequencing or PCR-based methods has been performed. High levels of resistance to tetracycline and ciprofloxacin are frequently reported by many national surveillance programs, but resistance to erythromycin and gentamicin in Campylobacter jejuni remains low. Nonetheless, variations in susceptibility observed over time underscore the need for continued public health monitoring of Campylobacter resistance from humans, animals, and food. Published by Elsevier B.V. C1 [Ge, Beilei; Wang, Fei; McDermott, Patrick F.] US FDA, Div Anim & Food Microbiol, Res Off, Ctr Vet Med, Laurel, MD 20708 USA. [Wang, Fei] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Sjoelund-Karlsson, Maria] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Atlanta, GA 30329 USA. RP Ge, BL (reprint author), 8401 Muirkirk Rd, Laurel, MD 20708 USA. EM beilei.ge@fda.hhs.gov RI Wang, Fei/J-4353-2014 NR 104 TC 30 Z9 33 U1 3 U2 37 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7012 EI 1872-8359 J9 J MICROBIOL METH JI J. Microbiol. Methods PD OCT PY 2013 VL 95 IS 1 SI SI BP 57 EP 67 DI 10.1016/j.mimet.2013.06.021 PG 11 WC Biochemical Research Methods; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 222GG UT WOS:000324718600008 PM 23827324 ER PT J AU Gharst, G Oyarzabal, OA Hussain, SK AF Gharst, Gregory Oyarzabal, Omar A. Hussain, Syeda K. TI Review of current methodologies to isolate and identify Campylobacter spp. from foods SO JOURNAL OF MICROBIOLOGICAL METHODS LA English DT Article DE Aerobic enrichment; Broiler; Campylobacter jejuni; Campylobacter coli; Chicken; Isolation ID RETAIL BROILER MEAT; POLYMERASE-CHAIN-REACTION; FETUS SUBSPECIES JEJUNI; GUILLAIN-BARRE-SYNDROME; VIBRIO-FETUS; CYTOPLASMIC MEMBRANE; ESCHERICHIA-COLI; ENRICHMENT MEDIA; SELECTIVE MEDIUM; UNITED-STATES AB This article summarizes the most effective protocols to isolate Campylobacter spp. (mainly Campylobacter jejuni and Campylobacter coil) from food, primarily poultry products, and includes a summary of the current methods recommended by the Food and Drug Administration and the U.S. Department of Agriculture in the USA, and ISO in Europe. The recommended temperature for incubation of the samples throughout the isolation procedure is 42 degrees C. The enrichment of the samples for 48 h, which can be performed under aerobic conditions, is recommended to achieve a detectable number of Campylobacter cells. Bolton broth or buffered peptone water supplemented with cefoperazone and amphotericin B is commonly used enrichment broths. The transfer of the enriched samples to plate media using membrane filters helps to obtain pure Campylobacter colonies. Charcoal cefoperazone deoxycholate (CCDA) is the best choice among all plate media. There is no need to add oxygen quenching substances or blood to enrichment broth for the isolation of Campylobacter spp. However, the addition of blood to plate media aids in differential identification of presumptive colonies. Phase contrast microscopy and latex agglutination tests are confirmatory tests for presumptive Campylobacter isolates. The use of multiplex polymerase chain reaction (mPCR) assays is the simplest and most rapid method to identify isolates to the species level. mPCR assays, or other methods assessing DNA sequence variations, will probably become the confirmation procedure of choice in the future. Recent work with retail broiler meat has revealed that the rinsing of meat is more sensitive for the recovery of naturally contaminated retail broiler meat than current reference methods and requires less time for preparation and processing of the samples. This protocol could be coupled with DNA-based methods for a fast screening of positive samples. (C) 2013 Elsevier B.V. All rights reserved. C1 [Gharst, Gregory] US FDA, Bedford Pk, IL USA. [Oyarzabal, Omar A.] IEH Labs & Consulting Grp, Lake Forest Pk, WA USA. [Hussain, Syeda K.] Alabama State Univ, Dept Biol Sci, Montgomery, AL 36101 USA. RP Oyarzabal, OA (reprint author), 15300 Bothell Way NE, Lake Forest Pk, WA 98155 USA. EM oaoyarzabal@gmail.com OI Oyarzabal, Omar/0000-0002-7863-2767 NR 77 TC 12 Z9 13 U1 1 U2 45 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7012 J9 J MICROBIOL METH JI J. Microbiol. Methods PD OCT PY 2013 VL 95 IS 1 SI SI BP 84 EP 92 DI 10.1016/j.mimet.2013.07.014 PG 9 WC Biochemical Research Methods; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 222GG UT WOS:000324718600011 PM 23899774 ER PT J AU Aguel, F Kurtzman, SB Patel-Raman, S Hillebrenner, M Zuckerman, BD AF Aguel, Fernando Kurtzman, Steven B. Patel-Raman, Sonna Hillebrenner, Matthew Zuckerman, Bram D. TI Food and Drug Administration commentary on "A new paradigm for obtaining marketing approval for pediatric-sized prosthetic heart valves" SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Editorial Material C1 [Aguel, Fernando; Kurtzman, Steven B.; Patel-Raman, Sonna; Hillebrenner, Matthew; Zuckerman, Bram D.] US FDA, Div Cardiovasc Devices, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Aguel, F (reprint author), 10903 New Hampshire Ave,WO66 Room 1234, Silver Spring, MD 20993 USA. EM fernando.aguel@fda.hhs.gov NR 2 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD OCT PY 2013 VL 146 IS 4 BP 887 EP 887 DI 10.1016/j.jtcvs.2013.06.003 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 219CE UT WOS:000324481400036 PM 23870153 ER PT J AU Patterson, TA Wood, WG Andrews, RJ Slikker, W AF Patterson, Tucker A. Wood, W. Gibson Andrews, Russell J. Slikker, William, Jr. TI Preface SO MOLECULAR NEUROBIOLOGY LA English DT Editorial Material C1 [Patterson, Tucker A.; Slikker, William, Jr.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Wood, W. Gibson] Univ Minnesota, Sch Med, Dept Pharmacol, Geriatr Res Educ & Clin Ctr,VA Med Ctr, Minneapolis, MN 55455 USA. [Andrews, Russell J.] NASA, Ames Res Ctr, Moffett Field, CA 94035 USA. RP Slikker, W (reprint author), US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM William.Slikker@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD OCT PY 2013 VL 48 IS 2 BP 271 EP 273 DI 10.1007/s12035-013-8513-8 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 221EN UT WOS:000324640600001 PM 23884619 ER PT J AU Wang, C Liu, F Patterson, TA Paule, MG Slikker, W AF Wang, Cheng Liu, Fang Patterson, Tucker A. Paule, Merle G. Slikker, William, Jr. TI Utilization of Neural Stem Cell-Derived Models to Study Anesthesia-Related Toxicity and Preventative Approaches SO MOLECULAR NEUROBIOLOGY LA English DT Article DE Neural stem cells; Development; Anesthesia; Toxicology; Neuroprotection ID POSITRON-EMISSION-TOMOGRAPHY; RAT FOREBRAIN CULTURE; D-ASPARTATE RECEPTORS; IN-VIVO; PROGENITOR-CELL; POLYSIALIC ACID; LIVING SUBJECTS; GENE-THERAPY; KETAMINE; NEURONS AB Early-life stress has been shown in both preclinical and clinical studies to cause neuroanatomical and biological alterations and disruptions in homeostasis. These alterations can lead to dysfunction in critical regulatory systems and concomitant increases in risk for the development of pathology. The existing data from research using in vivo animal models have implicated some general anesthetics as being toxic to the developing brain and causing cognitive deficits later in life. Because of obvious limitations, it is not possible to thoroughly explore the effects of early-life stress-e.g., prolonged exposure to anesthetic agents-on neurons in vivo in human infants or children. However, the availability of stem cell-derived models, especially human embryonic neural stem cells, along with their capacity for proliferation and ability to differentiate, has provided a potentially invaluable tool for examining the developmental effects of anesthetic agents in vitro. This review focuses on how embryonic neural stem cells, when combined with biochemical, pathological, and pharmacokinetic assessments, might serve as a bridging platform to provide the most expeditious approaches toward decreasing the uncertainty in extrapolating preclinical data to the human condition. This review presents key concepts in stem cell biology with respect to the nervous system, presents an overview of neural development, and summarizes the involvement of neural cell types in developmental neurotoxicity associated with anesthetic exposure. C1 [Wang, Cheng; Liu, Fang; Patterson, Tucker A.; Paule, Merle G.] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Slikker, William, Jr.] US FDA, Off Director, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Wang, Cheng] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Wang, C (reprint author), US FDA, Natl Ctr Toxicol Res, HFT 132, Jefferson, AR 72079 USA. EM Cheng.Wang@fda.hhs.gov NR 50 TC 3 Z9 3 U1 0 U2 7 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD OCT PY 2013 VL 48 IS 2 BP 302 EP 307 DI 10.1007/s12035-013-8501-z PG 6 WC Neurosciences SC Neurosciences & Neurology GA 221EN UT WOS:000324640600006 PM 23846129 ER PT J AU Virmani, A Pinto, L Binienda, Z Ali, S AF Virmani, Ashraf Pinto, Luigi Binienda, Zbigniew Ali, Syed TI Food, Nutrigenomics, and Neurodegeneration-Neuroprotection by What You Eat! SO MOLECULAR NEUROBIOLOGY LA English DT Review DE Nutrition; Nutrigenomics; Neuroprotection; Nutraceuticals; L-Carnitine; Polyphenols; Vitamins; Coenzyme Q(10) ID ASPARTATE-INDUCED APOPTOSIS; MULTIPLE-SCLEROSIS LESIONS; INDUCED NEURONAL DEATH; ACETYL-L-CARNITINE; OXIDATIVE STRESS; SYSTEMS BIOLOGY; MITOCHONDRIAL DYSFUNCTION; CEREBROCORTICAL NEURONS; HUMAN GENOME; DRUG-ABUSE AB Diet in human health is no longer simple nutrition, but in light of recent research, especially nutrigenomics, it is linked via evolution and genetics to cell health status capable of modulating apoptosis, detoxification, and appropriate gene response. Nutritional deficiency and disease especially lack of vitamins and minerals is well known, but more recently, epidemiological studies suggest a role of fruits and vegetables, as well as essential fatty acids and even red wine (French paradox), in protection against disease. In the early 1990s, various research groups started considering the use of antioxidants (e.g., melatonin, resveratrol, green tea, lipoic acid) and metabolic compounds (e.g., nicotinamide, acetyl-l-carnitine, creatine, coenzyme Q(10)) as possible candidates in neuroprotection. They were of course considered on par with snake oil salesman (women) at the time. The positive actions of nutritional supplements, minerals, and plant extracts in disease prevention are now mainstream and commercial health claims being made are subject to regulation in most countries. Apart from efficacy and finding, the right dosages, the safety, and especially the level of purification and lack of contamination are all issues that are important as their use becomes widespread. From the mechanistic point of view, most of the time these substances replenish the body's deficiency and restore normal function. However, they also exert actions that are not sensu stricto nutritive and could be considered pharmacological especially that, at times, higher intake than recommended (RDA) is needed to see these effects. Free radicals and neuroinflammation processes underlie many neurodegenerative conditions, even Parkinson's disease and Alzheimer's disease. Curcumin, carotenoids, acetyl-l-carnitine, coenzyme Q(10), vitamin D, and polyphenols and other nutraceuticals have the potential to target multiple pathways in these conditions. In summary, augmenting neuroprotective pathways using diet and finding new natural substances that can be more efficacious, i.e., induction of health-promoting genes and reduction of the expression of disease-promoting genes, could be incorporated into neuroprotective strategies of the future. C1 [Virmani, Ashraf; Pinto, Luigi] Sigma Tau Pharmaceut Co, Res Innovat & Dev, I-00040 Rome, Italy. [Binienda, Zbigniew] US FDA, Neurophysiol Lab, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Ali, Syed] US FDA, Neurochem Lab, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Virmani, A (reprint author), Sigma Tau Pharmaceut Co, Res Innovat & Dev, Via Pontina Km 30,400, I-00040 Rome, Italy. EM ashraf.virmani@sigma-tau.it NR 82 TC 34 Z9 35 U1 9 U2 152 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 EI 1559-1182 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD OCT PY 2013 VL 48 IS 2 BP 353 EP 362 DI 10.1007/s12035-013-8498-3 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 221EN UT WOS:000324640600011 PM 23813102 ER PT J AU Clayton, JA Eydelman, M Vitale, S Manukyan, Z Kramm, R Datiles, M Temple, A Murphy, E Kim, J Hilmantel, G Rorer, E Hammel, K Ferris, F AF Clayton, Janine Austin Eydelman, Malvina Vitale, Susan Manukyan, Zorayr Kramm, Robert Datiles, Manuel, III Temple, Alana Murphy, Elizabeth Kim, Jonghyeon Hilmantel, Gene Rorer, Eva Hammel, Keri Ferris, Frederick, III TI Web-based versus Paper Administration of Common Ophthalmic Questionnaires Comparison of Subscale Scores SO OPHTHALMOLOGY LA English DT Article ID DRY EYE DISEASE; VISUAL FUNCTION QUESTIONNAIRE; PSYCHOMETRIC PROPERTIES; OUTCOME MEASURES; LIFE; EQUIVALENCE; RELIABILITY; AGREEMENT; IMPACT; TRIAL AB Objective: To compare participants' responses to Web-based and paper-and-pencil versions of an ophthalmic, patient-reported outcome (PRO) questionnaire. Design: Questionnaire development. Participants: Matched subjects with ocular surface disease (OSD) (n = 68) and without OSD (controls, n = 50). Methods: Subjects completed a standard, paper-and-pencil and a Web-based version of the same questionnaire in randomized order. The administered questionnaire included several ophthalmic PRO subscales: the National Eye Institute's (NEI's) Refractive Error Quality of Life Instrument's Clarity of Vision, Near Vision, Far Vision, Glare, Symptoms, Worry, and Satisfaction with Correction subscales; the Ocular Surface Disease Index's (OSDI's) Symptoms subscale; and the NEI's Visual Function Questionnaire's Driving subscale. Possible scores for each subscale ranged from 0 (no difficulty) to 100 (most difficulty). Agreement of subscale scores between modes of administration was assessed using the Bland-Altman approach and multivariable logistic regression. Main Outcome Measures: Subscale scores and an unweighted average total score for each mode of administration. Results: Mean differences in scores between modes of administration ranged from -2.1 to +2.3 units. Although no differences were found to be statistically significant, the Worry and Satisfaction with Correction subscales approached statistical significance (P = 0.07 and 0.08, respectively). Although most subscale mean differences in score did not differ significantly by gender, age (>= 40 vs. <40 years), disease status (OSD vs. control), order of administration, or time between completion of the questionnaires, women had slightly greater score differences than men for the Driving (P = 0.04) and Clarity of Vision (P = 0.03) subscales; those with OSD had greater score differences for Clarity of Vision than did controls (P = 0.0006); and those aged >= 40 years had slightly greater differences in OSDI Symptoms subscale than those aged <40 years (P = 0.04). Conclusions: To our knowledge, this Food and Drug Administration and NEI collaboration is the first study to evaluate the equivalence of Web-based and paper versions of ophthalmic PRO questionnaires. We found no evidence of clinically significant differences between scores obtained by the 2 modes for any of the examined subscales. A Web-based instrument should yield scores equivalent to those obtained by standard methods, providing a useful tool that may facilitate ophthalmic innovation. (C) 2013 by the American Academy of Ophthalmology. C1 [Clayton, Janine Austin] NIH, Off Res Womens Hlth, Off Director, Bethesda, MD 20892 USA. [Clayton, Janine Austin; Vitale, Susan; Datiles, Manuel, III; Temple, Alana; Murphy, Elizabeth; Ferris, Frederick, III] NEI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Eydelman, Malvina; Kramm, Robert; Hilmantel, Gene; Rorer, Eva] US FDA, Div Ophthalm & Ear Nose & Throat Devices, Off Device Evaluat, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Manukyan, Zorayr; Kim, Jonghyeon; Hammel, Keri] Emmes Corp, Rockville, MD USA. RP Eydelman, M (reprint author), 10903 New Hampshire Ave,Bldg 66,2410, Silver Spring, MD 20993 USA. EM Malvina.eydelman@fda.hhs.gov OI Datiles, Manuel III B./0000-0003-4660-1664 FU National Eye Institute Intramural Research Program/National Institutes of Health/Department of Health and Human Services; FDA Office of Women's Health FX National Eye Institute Intramural Research Program/National Institutes of Health/Department of Health and Human Services, and FDA Office of Women's Health. The mention of commercial products, their sources, or their use in connection with material reported is not to be construed as an actual or implied endorsement of such products by the Department of Health and Human Services. NR 20 TC 6 Z9 6 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD OCT PY 2013 VL 120 IS 10 BP 2151 EP 2159 DI 10.1016/j.ophtha.2013.03.019 PG 9 WC Ophthalmology SC Ophthalmology GA 227CQ UT WOS:000325086400035 PM 23714321 ER PT J AU Lin, YT Liu, T Yang, XF Wang, YN Khan, MK AF Lin, Yuting Liu, Tian Yang, Xiaofeng Wang, Yuenan Khan, Mohammad K. TI Respiratory-Induced Prostate Motion Using Wavelet Decomposition of the Real-Time Electromagnetic Tracking Signal SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID CANCER; RADIOTHERAPY; LOCALIZATION; SYSTEM; GLAND AB Purpose: The objective of this work is to characterize and quantify the impact of respiratory-induced prostate motion. Methods and Materials: Real-time intrafraction motion is observed with the Calypso 4-dimensional nonradioactive electromagnetic tracking system (Calypso Medical Technologies, Inc. Seattle, Washington). We report the results from a total of 1024 fractions from 31 prostate cancer patients. Wavelet transform was used to decompose the signal to extract and isolate the respiratory-induced prostate motion from the total prostate displacement. Results: Our results show that the average respiratory motion larger than 0.5 mm can be observed in 68% of the fractions. Fewer than 1% of the patients showed average respiratory motion of less than 0.2 mm, whereas 99% of the patients showed average respiratory-induced motion ranging between 0.2 and 2 mm. The maximum respiratory range of motion of 3 mm or greater was seen in only 25% of the fractions. In addition, about 2% patients showed anxiety, indicated by a breathing frequency above 24 times per minute. Conclusions: Prostate motion is influenced by respiration in most fractions. Real-time intrafraction data are sensitive enough to measure the impact of respiration by use of wavelet decomposition methods. Although the average respiratory amplitude observed in this study is small, this technique provides a tool that can be useful if one moves to smaller treatment margins (<= 5 mm). This also opens ups the possibility of being able to develop patient specific margins, knowing that prostate motion is not unpredictable. (c) 2013 Elsevier Inc. C1 [Lin, Yuting] Univ Calif Irvine, Dept Radiol Sci, Tu & Yuen Ctr Funct Oncoimaging, Irvine, CA 92717 USA. [Liu, Tian; Yang, Xiaofeng; Khan, Mohammad K.] Emory Univ Hosp, Dept Radiat Oncol, Winship Canc Inst, Atlanta, GA 30345 USA. [Wang, Yuenan] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Khan, MK (reprint author), Emory Univ Hosp, Dept Radiat Oncol, Winship Canc Inst, 1365 Clifton Rd NE, Atlanta, GA 30345 USA. EM drkhurram2000@gmail.com OI Khan, Mohammad/0000-0001-7344-8592 FU NCI NIH HHS [K01 CA114313] NR 18 TC 3 Z9 3 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2013 VL 87 IS 2 BP 370 EP 374 DI 10.1016/j.ijrobp.2013.05.018 PG 5 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 216UN UT WOS:000324310500026 PM 23871196 ER PT J AU Chiesa, OA Idowu, OR Heller, D Smith, M Nochetto, C Chamberlain, PL Gehring, R von Bredow, J AF Chiesa, O. A. Idowu, O. R. Heller, D. Smith, M. Nochetto, C. Chamberlain, P. L. Gehring, R. von Bredow, J. TI A holstein cow-calf model for the transfer of ciprofloxacin through milk after a long-term intravenous infusion SO JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS LA English DT Article ID RESISTANCE PROTEIN BCRP/ABCG2; HUMAN-BREAST-MILK; DISPOSITION KINETICS; LACTATING GOATS; ENERGY-EXPENDITURE; URINARY-EXCRETION; CATTLE WALKING; PHARMACOKINETICS; PENETRATION; ENROFLOXACIN AB This study is part of an ongoing effort to develop animal models that provide milk and sufficient infant (offspring) plasma samples to fully describe a drug's pharmacokinetics to quantitate the risk to the nursing infant. Ciprofloxacin was administered to six healthy Holstein cows as a constant rate intravenous infusion (flow rate was weight adjusted) to achieve a steady-state concentration of approximately 300ng/mL for 7days. Plasma and milk samples were collected from the cow at regular intervals over the course of the 7days. The plasma and milk samples were analyzed for ciprofloxacin by high-performance liquid chromatography. The milk was fed to calves, and calf plasma samples were analyzed to study the lactational transfer of ciprofloxacin from dam to nursing neonate. Remarkably, concentrations of ciprofloxacin in milk were 45 times higher than plasma drug concentrations in the dam. Approximately 6% of the administered dose was transferred to the milk, resulting in an average oral dose of 0.5mg/kg to the calves with every feeding. The drug did not accumulate in the calves, and plasma concentrations were between one-tenth and one-fifth the plasma concentrations of the dam. C1 [Chiesa, O. A.; Idowu, O. R.; Heller, D.; Smith, M.; Nochetto, C.; Chamberlain, P. L.; von Bredow, J.] US FDA, Ctr Vet Med, Res Off, Div Appl Vet Res, Laurel, MD 20708 USA. [Chiesa, O. A.; Idowu, O. R.; Heller, D.; Smith, M.; Nochetto, C.; Chamberlain, P. L.; von Bredow, J.] US FDA, Div Residue Chem, Ctr Vet Med, Res Off, Laurel, MD 20708 USA. [Gehring, R.] Kansas State Univ, Dept Clin Sci, Manhattan, KS 66506 USA. RP Chiesa, OA (reprint author), US FDA, Ctr Vet Med, Res Off, Div Appl Vet Res, 8401 Muirkirk Rd, Laurel, MD 20708 USA. EM ochiesa@cvm.fda.gov FU FDA Office of Women's Health FX We thank Drs. Keesla Moulton and Jim Peggins for their assistance in sample collection (Moulton) and pilot study (Peggins). We thank Neil Schibblehut for his assistance on harness design. This research project is funded by the FDA Office of Women's Health. NR 50 TC 0 Z9 0 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0140-7783 J9 J VET PHARMACOL THER JI J. Vet. Pharmacol. Ther. PD OCT PY 2013 VL 36 IS 5 BP 425 EP 433 DI 10.1111/jvp.12014 PG 9 WC Pharmacology & Pharmacy; Veterinary Sciences SC Pharmacology & Pharmacy; Veterinary Sciences GA 212YP UT WOS:000324019300003 PM 23030707 ER PT J AU Hausner, EA Hicks, KA Leighton, JK Szarfman, A Thompson, AM Harlow, P AF Hausner, E. A. Hicks, K. A. Leighton, J. K. Szarfman, A. Thompson, A. M. Harlow, P. TI Qualification of cardiac troponins for nonclinical use: A regulatory perspective SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Cardiac troponins; Biomarkers; Qualification; Analytical; Drug Development Tools; Safety assessment; Histopathology ID ACUTE MYOCARDIAL-INFARCTION; CRITICALLY-ILL PATIENTS; DIFFERENTIAL REACTIVITY; HISTOLOGICAL-FINDINGS; LABORATORY-ANIMALS; DRUG DEVELOPMENT; SKELETAL-MUSCLE; T IMMUNOASSAYS; SERUM-LEVELS; INJURY AB The US Food and Drug Administration (FDA) Biomarker Qualification Review Team presents its perspective on the recent qualification of cardiac troponins for use in nonclinical safety assessment studies. The goal of this manuscript is to provide greater transparency into the qualification process and factors that were considered in reaching a regulatory decision. This manuscript includes an overview of the data that were submitted and a discussion of the strengths and shortcomings of these data supporting the qualification decision. The cardiac troponin submission is the first literature-based biomarker application to be reviewed by the FDA and insights gained from this experience may aid future submissions and help streamline the characterization and qualification of future biomarkers. Published by Elsevier Inc. C1 [Hausner, E. A.; Hicks, K. A.; Thompson, A. M.; Harlow, P.] US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Off New Drugs, Rockville, MD 20857 USA. [Leighton, J. K.] US FDA, Off Hematol & Oncol Prod, Ctr Drug Evaluat & Res, Off New Drugs, Rockville, MD 20857 USA. [Szarfman, A.] US FDA, Div Biometr 6, Ctr Drug Evaluat & Res, Off Biostat,Off Translat Sci, Rockville, MD 20857 USA. RP Hausner, EA (reprint author), 10903 New Hampshire Ave,Bldg 22,Room4145, Silver Spring, MD 20993 USA. EM Elizabeth.hausner@fda.hhs.gov NR 53 TC 4 Z9 4 U1 0 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD OCT PY 2013 VL 67 IS 1 BP 108 EP 114 DI 10.1016/j.yrtph.2013.07.006 PG 7 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA 218PA UT WOS:000324443400011 PM 23876748 ER PT J AU Chalbot, MC Nikolich, G Etyemezian, V Dubois, DW King, J Shafer, D da Costa, GG Hinton, JF Kavouras, IG AF Chalbot, M. -C. Nikolich, G. Etyemezian, V. Dubois, D. W. King, J. Shafer, D. da Costa, G. Gamboa Hinton, J. F. Kavouras, I. G. TI Soil humic-like organic compounds in prescribed fire emissions using nuclear magnetic resonance spectroscopy SO ENVIRONMENTAL POLLUTION LA English DT Article DE Biomass burning; Mineral dust; Wildfires; Organic carbon; Nuclear magnetic resonance; Aerosol ID PARTICULATE MATTER; DUST AEROSOLS; UNITED-STATES; PO VALLEY; SUBSTANCES; DISTRIBUTIONS; PARTICLES; GROWTH; FOREST; MODEL AB Here we present the chemical characterization of the water-soluble organic carbon fraction of atmospheric aerosol collected during a prescribed fire burn in relation to soil organic matter and biomass combustion. Using nuclear magnetic resonance spectroscopy, we observed that humic-like substances in fire emissions have been associated with soil organic matter rather than biomass. Using a chemical mass balance model, we estimated that soil organic matter may contribute up to 41% of organic hydrogen and up to 27% of water-soluble organic carbon in fire emissions. Dust particles, when mixed with fresh combustion emissions, substantially enhances the atmospheric oxidative capacity, particle formation and microphysical properties of clouds influencing the climatic responses of atmospheric aeroso. Owing to the large emissions of combustion aerosol during fires, the release of dust particles from soil surfaces that are subjected to intense heating and shear stress has, so far, been lacking. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Chalbot, M. -C.; Kavouras, I. G.] Univ Arkansas Med Sci, Dept Environm & Occupat Hlth, Little Rock, AR 72205 USA. [Nikolich, G.; Etyemezian, V.; King, J.; Kavouras, I. G.] Desert Res Inst, Div Atmospher Sci, Las Vegas, NV 89119 USA. [Dubois, D. W.] New Mexico State Univ, Div Plant & Environm Sci, Las Cruces, NM 88003 USA. [Shafer, D.] US DOE, Off Legacy Management, Westminster, CO 80021 USA. [da Costa, G. Gamboa] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Hinton, J. F.] Univ Arkansas, Dept Chem & Biochem, Fayetteville, AR 72701 USA. RP Chalbot, MC (reprint author), Univ Arkansas Med Sci, Dept Environm & Occupat Hlth, 4301 W Markham St, Little Rock, AR 72205 USA. EM ikavouras@uams.edu RI DuBois, David/F-6380-2015; King, James/O-3047-2015; Kavouras, Ilias/H-7056-2012 OI DuBois, David/0000-0003-2560-505X; King, James/0000-0003-0494-153X; Kavouras, Ilias/0000-0003-0342-5306; Kavouras, Ilias/0000-0003-0436-3784 FU National Science Foundation [EAR-0952272]; U.S. Department of Energy, National Nuclear Security Administration [DE-AC52-06NA26383] FX We thank the Bureau of Land Management, Ely District Office in Nevada for their helpful logistical support. The study was partially supported by the National Science Foundation (Grant No. EAR-0952272) and the U.S. Department of Energy, National Nuclear Security Administration (Contract No. DE-AC52-06NA26383). The opinions expressed here do not necessarily represent those of the US Food and Drug Administration. NR 35 TC 9 Z9 10 U1 2 U2 36 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0269-7491 J9 ENVIRON POLLUT JI Environ. Pollut. PD OCT PY 2013 VL 181 BP 167 EP 171 DI 10.1016/j.envpol.2013.06.008 PG 5 WC Environmental Sciences SC Environmental Sciences & Ecology GA 210CW UT WOS:000323807900023 PM 23867697 ER PT J AU Hunt, PR Marquis, BJ Tyner, KM Conklin, S Olejnik, N Nelson, BC Sprando, RL AF Hunt, Piper Reid Marquis, Bryce J. Tyner, Katherine M. Conklin, Sean Olejnik, Nicholas Nelson, Bryant C. Sprando, Robert L. TI Nanosilver suppresses growth and induces oxidative damage to DNA in Caenorhabditis elegans SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE nanosilver; silver ions; growth suppression; DNA damage; endotoxin; toxicity screen ID CHROMATOGRAPHY MASS-SPECTROMETRY; SILVER NANOPARTICLES; ANTIBACTERIAL ACTIVITY; ESCHERICHIA-COLI; NANO-SILVER; BASE DAMAGE; TOXICITY; CELLS; GENOTOXICITY; MECHANISMS AB Studies on the effects of nanomaterial exposure in mammals are limited, and new methods for rapid risk assessment of nanomaterials are urgently required. The utility of Caenorhabditis elegans cultured in axenic liquid media was evaluated as an alternative in vivo model for the purpose of screening nanomaterials for toxic effects. Spherical silver nanoparticles of 10 nm diameter (10nmAg) were used as a test material, and ionic silver from silver acetate as a positive control. Silver uptake and localization, larval growth, morphology and DNA damage were utilized as endpoints for toxicity evaluation. Confocal reflection analysis indicated that 10nmAg localized to the lumen and tissues of the digestive tract of C. elegans. 10nmAg at 10 mu g ml(-1) reduced the growth of C. elegans larvae, and induced oxidative damage to DNA as measured by 8-OH guanine levels. Consistent with previously published studies using mammalian models, ionic silver suppressed growth in C. elegans larvae to a greater extent than 10nmAg. Our data suggest that medium-throughput growth screening and DNA damage analysis along with morphology assessments in C. elegans could together provide powerful tools for rapid toxicity screening of nanomaterials. Published 2013. This article is a US Government work and is in the public domain in the USA. C1 [Hunt, Piper Reid; Olejnik, Nicholas; Sprando, Robert L.] US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Div Toxicol, Laurel, MD 20708 USA. [Marquis, Bryce J.; Nelson, Bryant C.] NIST, Mat Measurement Lab, Gaithersburg, MD 20899 USA. [Tyner, Katherine M.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Conklin, Sean] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA. RP Hunt, PR (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Appl Res & Safety Assessment, Div Toxicol, Laurel, MD 20708 USA. EM Piper.Hunt@fda.hhs.gov RI Hunt, Piper/G-1555-2012 OI Hunt, Piper/0000-0003-0538-7606 FU United States Food and Drug Administration/Center for Food Safety and Applied Nutrition/Office of Applied Research and Safety Assessment/Division of Toxicology; National Research Council FX The authors would like to thank Li Ni Komatsu (L.N.K.) for beginning this study, Dr Jeffrey Yourick for careful reading of this manuscript, Dr Dave Sebba of NanoComposix, Inc. for technical assistance in handling silver nanoparticles, and Thomas N. Black and Michael Scott for assistance in preparing media. Author contributions: experimental concept design, R. L. S.; nanoparticle characterization, K. T., B.J.M.; COPAS analysis, P. R. H., NO; confocal reflection, L. N. K., P. R. H.; morphology assessments, P. R. H, L. N. K.; DNA damage, B.J.M., B. C. N.; ICP-MS, S. C., P. R. H.; manuscript preparation, P. R. H., R. L. S., K. T., B.J.M., BCN. Funding Source: United States Food and Drug Administration/Center for Food Safety and Applied Nutrition/Office of Applied Research and Safety Assessment/Division of Toxicology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare there are no conflicts of interest. B.J.M. was supported by a National Research Council associateship provided by the National Academy of Sciences. The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services. Certain commercial equipment, instruments and materials are identified in this paper to specify an experimental procedure as completely as possible. In no case does the identification of particular equipment or materials imply a recommendation or endorsement by the National Institute of Standards and Technology nor does it imply that the materials, instruments, or equipment are necessarily the best available for the purpose. NR 75 TC 15 Z9 16 U1 0 U2 78 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0260-437X J9 J APPL TOXICOL JI J. Appl. Toxicol. PD OCT PY 2013 VL 33 IS 10 BP 1131 EP 1142 DI 10.1002/jat.2872 PG 12 WC Toxicology SC Toxicology GA 190IF UT WOS:000322331900011 PM 23636779 ER PT J AU Derrick, SC Yabe, IM Yang, A Kolibab, K Hollingsworth, B Kurtz, SL Morris, S AF Derrick, Steven C. Yabe, Idalia M. Yang, Amy Kolibab, Kristopher Hollingsworth, Brynn Kurtz, Sherry L. Morris, Sheldon TI Immunogenicity and protective efficacy of novel Mycobacterium tuberculosis antigens SO VACCINE LA English DT Article DE Tuberculosis; BCG ID PUBLISHED LITERATURE; T-CELLS; VACCINE; PROTEINS; IMMUNITY; IDENTIFICATION; PREVENTION; CANDIDATE; RESPONSES; ADJUVANT AB With tuberculosis continuing to be a major cause of global morbidity and mortality, a new vaccine is urgently needed. Tuberculosis subunit vaccines have been shown to induce robust immune responses in humans and are a potentially safer alternative to BCG for use in HIV-endemic areas. In this study, we investigated the protective efficacy of 16 different novel Mycobacterium tuberculosis antigens using an aerogenic mouse model of pulmonary tuberculosis. These antigens were tested as subunit vaccines formulated in dimethyl dioctadecyl ammonium bromide (DDA) - D(+) with trehalose 6,6 dibenenate (TDB) (DDA/TDB) adjuvant administered alone as monovalent vaccines or in combination. Six of these antigens (Rv1626, Rv1735, Rv1789, Rv2032, Rv2220, and Rv3478) were shown to consistently and significantly reduce bacterial burdens in the lungs of mice relative to nonvaccinated controls. Three of these six (Rv1789, Rv2220, and Rv3478) induced levels of protective immunity that were essentially equivalent to protection induced by the highly immunogenic antigen 85B (>0.5 log(10) CFU reduction in the lungs relative to naive mice). Importantly, when these three antigens were combined, protection essentially equivalent to that mediated by BCG was observed. When either Rv1626 or Rv2032 were combined with the highly protective E6-85 fusion protein (antigen 85B fused to ESAT-6), the protection observed was equivalent to BCG-induced protection at one and three months post-aerosol infection and was significantly greater than the protection observed when E6-85 was administered alone at 3 months post-infection. Using multiparameter flow cytometry, monofunctional IFN gamma CD4T cells and different multifunctional CD4T cell subsets capable of secreting multiple cytokines (IFN gamma, TNF alpha and/or IL-2) were shown to be induced by the three most protective antigens with splenocyte CD4T cell frequencies significantly greater than observed in naive controls. The identification of these highly immunogenic TB antigens and antigen combinations should allow for improved immunization strategies against tuberculosis. Published by Elsevier Ltd. C1 [Derrick, Steven C.; Yabe, Idalia M.; Yang, Amy; Kolibab, Kristopher; Hollingsworth, Brynn; Kurtz, Sherry L.; Morris, Sheldon] US FDA, Lab Mycobacterial Dis & Cellular Immunol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Derrick, SC (reprint author), CBER FDA, Bldg 29 Room 505,29 Lincoln Dr, Bethesda, MD 20892 USA. EM steven.derrick@fda.hhs.gov NR 35 TC 9 Z9 11 U1 1 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD SEP 23 PY 2013 VL 31 IS 41 BP 4641 EP 4646 DI 10.1016/j.vaccine.2013.07.032 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 239FP UT WOS:000326008300026 PM 23906890 ER PT J AU Hariharan, P Freed, M Myers, MR AF Hariharan, Prasanna Freed, Melanie Myers, Matthew R. TI Use of computational fluid dynamics in the design of dynamic contrast enhanced imaging phantoms SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID MRI; JETS; CT AB Phantoms for dynamic contrast enhanced (DCE) imaging modalities such as DCE computed tomography (DCE-CT) and DCE magnetic resonance imaging (DCE-MRI) are valuable tools for evaluating and comparing imaging systems. It is important for the contrast-agent distribution within the phantom to possess a time dependence that replicates a curve observed clinically, known as the 'tumor-enhancement curve'. It is also important for the concentration field within the lesion to be as uniform as possible. This study demonstrates how computational fluid dynamics (CFD) can be applied to achieve these goals within design constraints. The distribution of the contrast agent within the simulated phantoms was investigated in relation to the influence of three factors of the phantom design. First, the interaction between the inlets and the uniformity of the contrast agent within the phantom was modeled. Second, pumps were programmed using a variety of schemes and the resultant dynamic uptake curves were compared to tumor-enhancement curves obtained from clinical data. Third, the effectiveness of pulsing the inlet flow rate to produce faster equilibration of the contrast-agent distribution was quantified. The models employed a spherical lesion and design constraints (lesion diameter, inlet-tube size and orientation, contrast-agent flow rates and fluid properties) taken from a recently published DCE-MRI phantom study. For DCE-MRI in breast cancer detection, where the target tumor-enhancement curve varies on the scale of hundreds of seconds, optimizing the number of inlet tubes and their orientation was found to be adequate for attaining concentration uniformity and reproducing the target tumor-enhancement curve. For DCE-CT in liver tumor detection, where the tumor-enhancement curve varies on a scale of tens of seconds, the use of an iterated inlet condition (programmed into the pump) enabled the phantom to reproduce the target tumor-enhancement curve within a few per cent beyond about 6 s of wash-in. This time was cut in half by the final CFD-derived strategy of flow pulsing. Driving the pump with a 25% duty cycle pulsatile waveform produced a nearly uniform concentration in the phantom in just a few seconds under typical conditions. Comparisons with published x-ray measurements using tumor-enhancement curves for both benign and malignant breast lesions showed a difference of approximately 4% between the CFD predictions and measurements of the contrast-agent concentration averaged over the lesion volume. The techniques derived using CFD optimization can be used in future phantom designs, including as starting points for future CFD phantom studies employing new lesion geometries and tumor-enhancement curves. C1 [Hariharan, Prasanna; Freed, Melanie; Myers, Matthew R.] US FDA, Silver Spring, MD USA. [Freed, Melanie] NYU, Sch Med, Dept Radiol, Bernard & Irene Schwartz Ctr Biomed Imaging, New York, NY USA. RP Hariharan, P (reprint author), US FDA, Silver Spring, MD USA. EM Prasanna.hariharan@fda.hhs.gov FU FDA's Office of Women's Health FX We wish to thank Mike Mikailov and Bryan Fitzgerald from FDA/CDRH/DESE's High Performance Computing Center for helping with troubleshooting our parallel computing efforts using the FDA's Betsy and Blue Meadow clusters. This project was partially funded by the FDA's Office of Women's Health. NR 20 TC 1 Z9 1 U1 3 U2 13 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD SEP 21 PY 2013 VL 58 IS 18 BP 6369 EP 6391 DI 10.1088/0031-9155/58/18/6369 PG 23 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 220HL UT WOS:000324573400010 PM 23999605 ER PT J AU Kryndushkin, D Pripuzova, N Burnett, BG Shewmaker, F AF Kryndushkin, Dmitry Pripuzova, Natalia Burnett, Barrington G. Shewmaker, Frank TI Non-targeted Identification of Prions and Amyloid-forming Proteins from Yeast and Mammalian Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PAIRED HELICAL FILAMENT; SACCHAROMYCES-CEREVISIAE; ENVIRONMENTAL-STRESS; HUNTINGTONS-DISEASE; CELLULAR TOXICITY; ALZHEIMER-DISEASE; GLOBAL ANALYSIS; SUP35 POLYMERS; PSI+; FIBRILS AB The formation of amyloid aggregates is implicated both as a primary cause of cellular degeneration in multiple human diseases and as a functional mechanism for providing extraordinary strength to large protein assemblies. The recent identification and characterization of several amyloid proteins from diverse organisms argues that the amyloid phenomenon is widespread in nature. Yet identifying new amyloid-forming proteins usually requires a priori knowledge of specific candidates. Amyloid fibers can resist heat, pressure, proteolysis, and denaturation by reagents such as urea or sodium dodecyl sulfate. Here we show that these properties can be exploited to identify naturally occurring amyloid-forming proteins directly from cell lysates. This proteomic-based approach utilizes a novel purification of amyloid aggregates followed by identification by mass spectrometry without the requirement for special genetic tools. We have validated this technique by blind identification of three amyloid-based yeast prions from laboratory and wild strains and disease-related polyglutamine proteins expressed in both yeast and mammalian cells. Furthermore, we found that polyglutamine aggregates specifically recruit some stress granule components, revealing a possible mechanism of toxicity. Therefore, core amyloid-forming proteins as well as strongly associated proteins can be identified directly from cells of diverse origin. C1 [Kryndushkin, Dmitry; Shewmaker, Frank] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. [Burnett, Barrington G.] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. [Pripuzova, Natalia] US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Kryndushkin, D (reprint author), Uniformed Serv Univ Hlth Sci, Dept Pharmacol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM dkrynd@yahoo.com; frank.shewmaker@usuhs.edu FU National Institutes of Health [1R03DA035194]; Uniformed Services University of the Health Sciences [RO75QF, CS75QF] FX This work was supported, in whole or in part, by National Institutes of Health Grant 1R03DA035194. This work was also supported by Uniformed Services University of the Health Sciences Grants RO75QF and CS75QF. NR 70 TC 17 Z9 19 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 20 PY 2013 VL 288 IS 38 BP 27100 EP 27111 DI 10.1074/jbc.M113.485359 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302IG UT WOS:000330597300010 PM 23926098 ER PT J AU Lalmansingh, AS Arora, K DeMarco, RA Hager, GL Nagaich, AK AF Lalmansingh, Avin S. Arora, Kamalpreet DeMarco, Richard A. Hager, Gordon L. Nagaich, Akhilesh K. TI High-Throughput RNA FISH Analysis by Imaging Flow Cytometry Reveals That Pioneer Factor Foxa1 Reduces Transcriptional Stochasticity SO PLOS ONE LA English DT Article ID TUMOR VIRUS PROMOTER; GENE-EXPRESSION; GLUCOCORTICOID-RECEPTOR; LIVING CELLS; NATURAL PROMOTER; CHROMATIN; BINDING; MODES AB Genes are regulated at the single-cell level. Here, we performed RNA FISH of thousands of cells by flow cytometry (flow-RNA FISH) to gain insight into transcriptional variability between individual cells. These experiments utilized the murine adenocarcinoma 3134 cell line with 200 copies of the MMTV-Ras reporter integrated at a single genomic locus. The MMTV array contains approximately 800-1200 binding sites for the glucocorticoid receptor (GR) and 600 binding sites for the pioneer factor Foxa1. Hormone activation of endogenous GR by dexamethasone treatment resulted in highly variable changes in the RNA FISH intensity (25-300 pixel intensity units) and size (1.25-15 mu m), indicative of probabilistic or stochastic mechanisms governing GR and cofactor activation of the MMTV promoter. Exogenous expression of the pioneer factor Foxa1 increased the FISH signal intensity and size as expected for a chromatin remodeler that enhances transcriptional competence through increased chromatin accessibility. In addition, specific analysis of Foxa1-enriched cell sub-populations showed that low and high Foxa1 levels substantially lowered the cell-to-cell variability in the FISH intensity as determined by a noise calculation termed the % coefficient of variation. These results suggest that an additional function of the pioneer factor Foxa1 may be to decrease transcriptional noise. C1 [Lalmansingh, Avin S.; Arora, Kamalpreet; Nagaich, Akhilesh K.] US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. [DeMarco, Richard A.] EMD Millipore Corp, Amnis, Seattle, WA USA. [Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Nagaich, AK (reprint author), US FDA, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. EM akhilesh.nagaich@fda.hhs.gov FU United States Food and Drug Administration (FDA) within the Center for Drug Evaluation and Research (CDER); United States Department of Energy; FDA FX This work was supported by the United States Food and Drug Administration (FDA) within the Center for Drug Evaluation and Research (CDER). This project was supported in part by an appointment to the Research Participation Program at CDER administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the United States Department of Energy and FDA [to A.S.L.]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 2 Z9 2 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 20 PY 2013 VL 8 IS 9 AR e76043 DI 10.1371/journal.pone.0076043 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 222YC UT WOS:000324768000097 PM 24073287 ER PT J AU Liu, W Zhang, B Zhang, ZW Zhou, XH AF Liu, Wei Zhang, Bo Zhang, Zhiwei Zhou, Xiao-Hua TI Joint Modeling of Transitional Patterns of Alzheimer's Disease SO PLOS ONE LA English DT Article ID LONGITUDINAL BINARY DATA; UNIFORM DATA SET; LIKELIHOOD; DEMENTIA; EDUCATION; SELECTION; OUTCOMES; CENTERS; ONSET; UDS AB While the experimental Alzheimer's drugs recently developed by pharmaceutical companies failed to stop the progression of Alzheimer's disease, clinicians strive to seek clues on how the patients would be when they visit back next year, based upon the patients' current clinical and neuropathologic diagnosis results. This is related to how to precisely identify the transitional patterns of Alzheimer's disease. Due to the complexities of the diagnosis of Alzheimer's disease, the condition of the disease is usually characterized by multiple clinical and neuropathologic measurements, including Clinical Dementia Rating (CDRGLOB), Mini-Mental State Examination (MMSE), a score derived from the clinician judgement on neuropsychological tests (COGSTAT), and Functional Activities Questionnaire (FAQ). In this research article, we investigate a class of novel joint random-effects transition models that are used to simultaneously analyze the transitional patterns of multiple primary measurements of Alzheimer's disease and, at the same time, account for the association between the measurements. The proposed methodology can avoid the bias introduced by ignoring the correlation between primary measurements and can predict subject-specific transitional patterns. C1 [Liu, Wei] Harbin Inst Technol, Dept Math, Harbin 150006, Peoples R China. [Zhang, Bo] Oregon State Univ, Coll Publ Hlth & Human Sci, Sch Biol & Populat Hlth Sci, Biostat Core, Corvallis, OR 97331 USA. [Zhang, Zhiwei] US FDA, Div Biostat, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Zhou, Xiao-Hua] Univ Washington, Sch Publ Hlth & Community Med, Dept Biostat, HSR&D Ctr Excellence,US Dept Vet Affairs Puget So, Seattle, WA 98195 USA. RP Zhang, B (reprint author), Oregon State Univ, Coll Publ Hlth & Human Sci, Sch Biol & Populat Hlth Sci, Biostat Core, Corvallis, OR 97331 USA. EM Bo.Zhang@oregonstate.edu FU Fundamental Research Funds for the Central Universities [HIT.NSRIF.2012063]; National Institute on Aging [U01 AG016976] FX Dr. Wei Liu's research was partially supported by "the Fundamental Research Funds for the Central Universities" through Grant HIT.NSRIF.2012063. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The National Alzheimer's Coordinating Center database is funded by National Institute on Aging Grant U01 AG016976. NR 35 TC 0 Z9 0 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 20 PY 2013 VL 8 IS 9 AR e75487 DI 10.1371/journal.pone.0075487 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 222YC UT WOS:000324768000078 ER PT J AU Virnik, K Hockenbury, M Ni, YS Beren, J Pavlakis, GN Felber, BK Berkower, I AF Virnik, Konstantin Hockenbury, Max Ni, Yisheng Beren, Joel Pavlakis, George N. Felber, Barbara K. Berkower, Ira TI Live attenuated rubella vectors expressing SIV and HIV vaccine antigens replicate and elicit durable immune responses in rhesus macaques SO RETROVIROLOGY LA English DT Article DE Live viral vector; Rubella vaccine strain RA27/3; Rhesus macaque; HIV MPER; SIV Gag; Highly immunogenic; Long lasting; Memory B cells ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; VIRAL VECTORS; CELL RESPONSES; CAPSID PROTEIN; CHALLENGE; ENVELOPE; NEUTRALIZATION; DESIGN; MEMORY AB Background: Live attenuated viruses are among our most potent and effective vaccines. For human immunodeficiency virus, however, a live attenuated strain could present substantial safety concerns. We have used the live attenuated rubella vaccine strain RA27/3 as a vector to express SIV and HIV vaccine antigens because its safety and immunogenicity have been demonstrated in millions of children. One dose protects for life against rubella infection. In previous studies, rubella vectors replicated to high titers in cell culture while stably expressing SIV and HIV antigens. Their viability in vivo, however, as well as immunogenicity and antibody persistence, were unknown. Results: This paper reports the first successful trial of rubella vectors in rhesus macaques, in combination with DNA vaccines in a prime and boost strategy. The vectors grew robustly in vivo, and the protein inserts were highly immunogenic. Antibody titers elicited by the SIV Gag vector were greater than or equal to those elicited by natural SIV infection. The antibodies were long lasting, and they were boosted by a second dose of replication- competent rubella vectors given six months later, indicating the induction of memory B cells. Conclusions: Rubella vectors can serve as a vaccine platform for safe delivery and expression of SIV and HIV antigens. By presenting these antigens in the context of an acute infection, at a high level and for a prolonged duration, these vectors can stimulate a strong and persistent immune response, including maturation of memory B cells. Rhesus macaques will provide an ideal animal model for demonstrating immunogenicity of novel vectors and protection against SIV or SHIV challenge. C1 [Virnik, Konstantin; Hockenbury, Max; Ni, Yisheng; Berkower, Ira] FDA, Ctr Biol, Div Viral Prod, Lab Immunoregulat,Off Vaccines, Bethesda, MD 20892 USA. [Beren, Joel] Ctr Biol, Div Vet Serv, Bethesda, MD 20892 USA. [Pavlakis, George N.] NCI, Human Retrovirus Sect, Frederick, MD 21702 USA. [Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Frederick, MD 21702 USA. [Beren, Joel] FDA, CDER, OCTEC, Silver Spring, MD 20993 USA. RP Berkower, I (reprint author), FDA, Ctr Biol, Div Viral Prod, Lab Immunoregulat,Off Vaccines, NIH Campus, Bethesda, MD 20892 USA. EM ira.berkower@fda.hhs.gov FU NIH Intramural AIDS Targeted Research Program FX The authors wish to thank Lewis Shankle of CBER and Dr. Deborah Weiss of Advanced BioScience Laboratories, Inc. for their essential contributions to this work; K. Broderick and N. Sardesai of Inovio Pharmaceuticals, Inc. for the DNA delivery method; Dr. Margherita Rosati of NCI Frederick and Dr. Carol Weiss of CBER for helpful discussions; and Dr. John Moore for providing SOSIP gp140 trimers. This research was supported in part by the NIH Intramural AIDS Targeted Research Program. NR 47 TC 3 Z9 3 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 16 PY 2013 VL 10 AR 99 DI 10.1186/1742-4690-10-99 PG 15 WC Virology SC Virology GA 228CZ UT WOS:000325164100002 PM 24041113 ER PT J AU Salazar, JK Wu, ZC Yang, WX Freitag, NE Tortorello, ML Wang, H Zhang, W AF Salazar, Joelle K. Wu, Zhuchun Yang, Weixu Freitag, Nancy E. Tortorello, Mary Lou Wang, Hui Zhang, Wei TI Roles of a Novel Crp/Fnr Family Transcription Factor Lmo0753 in Soil Survival, Biofilm Production and Surface Attachment to Fresh Produce of Listeria monocytogenes SO PLOS ONE LA English DT Article ID ESCHERICHIA-COLI O157/H7; VIRULENCE REGULATOR PRFA; UNITED-STATES; PROCESSING PLANTS; STAINLESS-STEEL; FOOD-INDUSTRY; ILLNESS; MICROORGANISMS; PERSPECTIVE; SANITATION AB Listeria monocytogenes is a foodborne bacterial pathogen and the causative agent of an infectious disease, listeriosis. L. monocytogenes is ubiquitous in nature and has the ability to persist in food processing environments for extended periods of time by forming biofilms and resisting industrial sanitization. Human listeriosis outbreaks are commonly linked to contaminated dairy products, ready-to-eat meats, and in recent years, fresh produce such as lettuce and cantaloupes. We identified a putative Crp/Fnr family transcription factor Lmo0753 that is highly specific to human-associated genetic lineages of L. monocytogenes. Lmo0753 possesses two conserved functional domains similar to the major virulence regulator PrfA in L. monocytogenes. To determine if Lmo0753 is involved in environmental persistence-related mechanisms, we compared lmo0753 deletion mutants with respective wild type and complementation mutants of two fully sequenced L. monocytogenes genetic lineage II strains 10403S and EGDe for the relative ability of growth under different nutrient availability and temperatures, soil survival, biofilm productivity and attachment to select fresh produce surfaces including romaine lettuce leaves and cantaloupe rinds. Our results collectively suggested that Lmo0753 plays an important role in L. monocytogenes biofilm production and attachment to fresh produce, which may contribute to the environmental persistence and recent emergence of this pathogen in human listeriosis outbreaks linked to fresh produce. C1 [Salazar, Joelle K.; Wu, Zhuchun; Yang, Weixu; Zhang, Wei] Illinois Inst Technol, Inst Food Safety & Hlth, Bedford Pk, IL USA. [Freitag, Nancy E.] Univ Illinois, Coll Med, Dept Microbiol & Immunol, Chicago, IL 60612 USA. [Tortorello, Mary Lou] US FDA, Bedford Pk, IL USA. [Wang, Hui] Chinese Acad Sci, Shanghai Inst Biol Sci, Food Safety Res Ctr, Shanghai, Peoples R China. [Zhang, Wei] Wuhan Polytech Univ, Sch Biol & Pharmaceut Engn, Wuhan, Peoples R China. RP Zhang, W (reprint author), Illinois Inst Technol, Inst Food Safety & Hlth, Bedford Pk, IL USA. EM zhangw@iit.edu FU U.S. Food and Drug Administration; Department of Education of Hubei Province FX This work was partly supported by the U.S. Food and Drug Administration research funds to the Institute for Food Safety and Health of the Illinois Institute of Technology. This work was also partly supported by the Chu Tian Lecturing Professorship from the Department of Education of Hubei Province to Wuhan Polytechnic University. The sponsors had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 5 Z9 5 U1 2 U2 38 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 16 PY 2013 VL 8 IS 9 AR e75736 DI 10.1371/journal.pone.0075736 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219GJ UT WOS:000324494000167 PM 24066185 ER PT J AU Polakowski, LL Sandhu, SK Martin, DB Ball, R MaCurdy, TE Franks, RL Gibbs, JM Kropp, GF Avagyan, A Kelman, JA Worrall, CM Sun, GY Kliman, RE Burwen, DR AF Polakowski, Laura L. Sandhu, Sukhminder K. Martin, David B. Ball, Robert MaCurdy, Thomas E. Franks, Riley L. Gibbs, Jonathan M. Kropp, Garner F. Avagyan, Armen Kelman, Jeffrey A. Worrall, Christopher M. Sun, Guoying Kliman, Rebecca E. Burwen, Dale R. TI Chart-Confirmed Guillain-Barre Syndrome After 2009 H1N1 Influenza Vaccination Among the Medicare Population, 2009-2010 SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Fisher Syndrome; Guillain-Barre Syndrome; human influenza; vaccination ID SAFETY DATALINK PROJECT; UNITED-STATES; A H1N1; VACCINES; ASSOCIATION; RISK; SURVEILLANCE; CAMPAIGN; RECEIPT; PROGRAM AB Given the increased risk of Guillain Barre Syndrome (GBS) found with the 1976 swine influenza vaccine, both active surveillance and end of season analyses on chart-confirmed cases were performed across multiple US vaccine safety monitoring systems, including the Medicare system, to evaluate the association of GBS after 2009 monovalent H1N1 influenza vaccination. Medically reviewed cases consisted of H1N1-vaccinated Medicare beneficiaries who were hospitalized for GBS. These cases were then classified by using Brighton Collaboration diagnostic criteria. Thirty one persons had Brighton level 1, 2, or 3 GBS or Fisher Syndrome, with symptom onset 1-119 days after vaccination. Self controlled risk interval analyses estimated GBS risk within the 6 week period immediately following H1N1 vaccination compared with a later control period, with additional adjustment for seasonality. Our results showed an elevated risk of GBS with 2009 monovalent H1N1 vaccination (incidence rate ratio = 2.41, 95% confidence interval: 1.14, 5.11; attributable risk = 2.84 per million doses administered, 95% confidence interval: 0.21, 5.48).This observed risk was slightly higher than that seen with previous seasonal influenza vaccines; however, additional results that used a stricter case definition (Brighton level 1 or 2) were not statistically significant, and our ability to account for preceding respiratory gastrointestinal illness was limited. Furthermore, the observed risk was substantially lower than that seen with the 1976 swine influenza vaccine. C1 [Polakowski, Laura L.; Sandhu, Sukhminder K.; Martin, David B.; Ball, Robert; Sun, Guoying; Burwen, Dale R.] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [MaCurdy, Thomas E.; Franks, Riley L.; Gibbs, Jonathan M.; Kropp, Garner F.; Avagyan, Armen] Acumen LLC, Burlingame, CA USA. [Kelman, Jeffrey A.; Worrall, Christopher M.] Ctr Medicare & Medicaid Serv, Ctr Medicare, Baltimore, MD USA. [Kliman, Rebecca E.] Ctr Medicare & Medicaid Serv, Off Clin Stand & Qual, Baltimore, MD USA. RP Polakowski, LL (reprint author), US PHS, US FDA, Room 327N,HFM-225,1401 Rockville Pike, Rockville, MD 20852 USA. EM laura.polakowski@fda.hhs.gov NR 43 TC 12 Z9 12 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 15 PY 2013 VL 178 IS 6 BP 962 EP 973 DI 10.1093/aje/kwt051 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 227YC UT WOS:000325150600019 PM 23652165 ER PT J AU Blumenthal, GM Scher, NS Cortazar, P Chattopadhyay, S Tang, SH Song, PF Liu, Q Ringgold, K Pilaro, AM Tilley, A King, KE Graham, L Rellahan, BL Weinberg, WC Chi, B Thomas, C Hughes, P Ibrahim, A Justice, R Pazdur, R AF Blumenthal, Gideon M. Scher, Nancy S. Cortazar, Patricia Chattopadhyay, Somesh Tang, Shenghui Song, Pengfei Liu, Qi Ringgold, Kimberly Pilaro, Anne M. Tilley, Amy King, Kathryn E. Graham, Laurie Rellahan, Barbara L. Weinberg, Wendy C. Chi, Bo Thomas, Colleen Hughes, Patricia Ibrahim, Amna Justice, Robert Pazdur, Richard TI First FDA Approval of Dual Anti-HER2 Regimen: Pertuzumab in Combination with Trastuzumab and Docetaxel for HER2-Positive Metastatic Breast Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID PLUS; CHEMOTHERAPY; EFFICACY; HER2 AB On June 8, 2012, the U. S. Food and Drug Administration (FDA) approved pertuzumab (Perjeta, Genentech) for use in combination with trastuzumab (Herceptin, Genentech) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 808 patients with HER2-positive MBC. Patients were randomized (1: 1) to receive pertuzumab (n = 402) or placebo (n = 406) in combination with trastuzumab and docetaxel. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). A statistically significant improvement in PFS (difference in medians of 6.1 months) was observed in patients receiving pertuzumab [HR, 0.62; 95% confidence interval (CI), 0.51-0.75; P < 0.0001]. A planned interim analysis suggested an improvement in OS (HR, 0.64; 95% CI, 0.47-0.88; P = 0.0053) but the HR and P value did not cross the stopping boundary. Common adverse reactions (>30%) observed in patients on the pertuzumab arm included diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. No additive cardiac toxicity was observed. Significant manufacturing issues were identified during the review. On the basis of substantial evidence of efficacy for pertuzumab in MBC and the compelling public health need, FDA did not delay availability to patients pending final resolution of all manufacturing concerns. Therefore, FDA approved pertuzumab but limited its approval to lots not affected by manufacturing problems. The applicant agreed to multiple manufacturing and testing postmarketing commitments under third-party oversight to resolve manufacturing issues. (C) 2013 AACR. C1 [Blumenthal, Gideon M.; Scher, Nancy S.; Cortazar, Patricia; Chattopadhyay, Somesh; Tang, Shenghui; Song, Pengfei; Liu, Qi; Ringgold, Kimberly; Pilaro, Anne M.; Tilley, Amy; King, Kathryn E.; Graham, Laurie; Rellahan, Barbara L.; Weinberg, Wendy C.; Chi, Bo; Thomas, Colleen; Hughes, Patricia; Ibrahim, Amna; Justice, Robert; Pazdur, Richard] US FDA, Ctr Drug Evaluat & Res, White Oak, MD USA. RP Blumenthal, GM (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM gideon.blumenthal@fda.hhs.gov NR 13 TC 28 Z9 30 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2013 VL 19 IS 18 BP 4911 EP 4916 DI 10.1158/1078-0432.CCR-13-1212 PG 6 WC Oncology SC Oncology GA 219NF UT WOS:000324513000003 PM 23801166 ER PT J AU Weng, ZQ Suda, M Ohtani, K Mei, N Kawamoto, T Nakajima, T Wang, RS AF Weng, Zuquan Suda, Megumi Ohtani, Katsumi Mei, Nan Kawamoto, Toshihiro Nakajima, Tamie Wang, Rui-Sheng TI Subchronic exposure to ethyl tertiary butyl ether resulting in genetic damage in Aldh2 knockout mice SO TOXICOLOGY LA English DT Article DE Ethyl tertiary butyl ether; Genetic damage; Aldh2; Knockout mice; Kinetics ID M ALDEHYDE DEHYDROGENASE; DNA-DAMAGE; PERIPHERAL LYMPHOCYTES; CELL-PROLIFERATION; KINETIC-PROPERTIES; ALCOHOL-DRINKING; FISCHER-344 RATS; TARGETING MOUSE; IN-VITRO; METHYL AB Ethyl tertiary butyl ether (ETBE) is biofuel additive recently used in Japan and some other countries. Limited evidence shows that ETBE has low toxicity. Acetaldehyde (AA), however, as one primary metabolite of ETBE, is clearly genotoxic and has been considered to be a potential carcinogen. The aim of this study was to evaluate the effects of ALDH2 gene on ETBE-induced genotoxicity and metabolism of its metabolites after inhalation exposure to ETBE. A group of wild-type (WT) and Aldh2 knockout (KO) C57BL/6 mice were exposed to 500 ppm ETBE for 1-6 h, and the blood concentrations of ETBE metabolites, including AA, tert-butyl alcohol and 2-methyl-1,2-propanediol, were measured. Another group of mice of WT and KO were exposed to 0, 500, 1750, or 5000 ppm ETBE for 6 h/day with 5 days per weeks for 13 weeks. Genotoxic effects of ETBE in these mice were measured by the alkaline comet assay, 8-hydroxyguanine DNA-glycosylase modified comet assay and micronucleus test. With short-term exposure to ETBE, the blood concentrations of all the three metabolites in KO mice were significantly higher than the corresponding concentrations of those in WT mice of both sexes. After subchronic exposure to ETBE, there was significant increase in DNA damage in a dose-dependent manner in MO male mice, while only 5000 ppm exposure significantly increased DNA damage in male WT mice. Overall, there was a significant sex difference in genetic damage in both genetic types of mice. These results showed that ALDH2 is involved in the detoxification of ETBE and lack of enzyme activity may greatly increase the sensitivity to the genotoxic effects of ETBE, and male mice were more sensitive than females. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Weng, Zuquan; Suda, Megumi; Ohtani, Katsumi; Wang, Rui-Sheng] Japan Natl Inst Occupat Safety & Hlth, Kawasaki, Kanagawa 2148585, Japan. [Mei, Nan] Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Kawamoto, Toshihiro] Univ Occupat & Environm Hlth, Dept Environm Hlth, Kitakyushu, Fukuoka 807, Japan. [Nakajima, Tamie] Chubu Univ, Coll Life & Hlth Sci, Nagoya, Aichi, Japan. RP Wang, RS (reprint author), Natl Inst Occupat Safety & Hlth, Div Hlth Effects Res, 6-21-1 Nagao, Kawasaki, Kanagawa 2148585, Japan. EM wang@h.jniosh.go.jp RI mei, nan/E-8915-2011 OI mei, nan/0000-0002-3501-9014 FU Japan National Institute of Occupational Safety and Health, Japan [P21-03] FX We are grateful to Ms. S. Watanabe for her assistance in the manipulation of the animals. This work was supported by grant-in-aid for project research from the Japan National Institute of Occupational Safety and Health, Japan (P21-03). The views presented in this paper do not necessarily reflect those of the U.S. Food and Drug Administration. NR 46 TC 4 Z9 4 U1 0 U2 16 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD SEP 15 PY 2013 VL 311 IS 3 BP 107 EP 114 DI 10.1016/j.tox.2013.06.005 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 220TG UT WOS:000324609200003 PM 23810710 ER PT J AU Euling, SY White, LD Kim, AS Sen, B Wilson, VS Keshava, C Keshava, N Hester, S Ovacik, MA Ierapetritou, MG Androulakis, IP Gaido, KW AF Euling, Susan Y. White, Lori D. Kim, Andrea S. Sen, Banalata Wilson, Vickie S. Keshava, Channa Keshava, Nagalakshmi Hester, Susan Ovacik, Meric A. Ierapetritou, Marianthi G. Androulakis, Ioannis P. Gaido, Kevin W. TI Use of genomic data in risk assessment case study: II. Evaluation of the dibutyl phthalate toxicogenomic data set SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Phthalates; Toxicogenomic; Risk assessment; Male reproduction; Development; Testosterone; Testicular dysgenesis syndrome; Phthalate syndrome ID IN-UTERO EXPOSURE; FETAL-RAT TESTIS; TESTICULAR DYSGENESIS SYNDROME; DOSE-DEPENDENT ALTERATIONS; GENE-EXPRESSION; DI(N-BUTYL) PHTHALATE; MICROARRAY EXPERIMENTS; INSL3; STEROIDOGENESIS; CRYPTORCHIDISM AB An evaluation of the toxicogenomic data set for dibutyl phthalate (DBP) and male reproductive developmental effects was performed as part of a larger case study to test an approach for incorporating genomic data in risk assessment. The DBP toxicogenomic data set is composed of nine in vivo studies from the published literature that exposed rats to DBP during gestation and evaluated gene expression changes in testes or Wolffian ducts of male fetuses. The exercise focused on qualitative evaluation, based on a lack of available dose-response data, of the DBP toxicogenomic data set to postulate modes and mechanisms of action for the male reproductive developmental outcomes, which occur in the lower dose range. A weight-of-evidence evaluation was performed on the eight DBP toxicogenomic studies of the rat testis at the gene and pathway levels. The results showed relatively strong evidence of DBP-induced downregulation of genes in the steroidogenesis pathway and lipid/sterol/cholesterol transport pathway as well as effects on immediate early gene/growth/differentiation, transcription, peroxisome proliferator-activated receptor signaling and apoptosis pathways in the testis. Since two established modes of action (MOAs), reduced fetal testicular testosterone production and Insl3 gene expression, explain some but not all of the testis effects observed in rats after in utero DBP exposure, other MOAs are likely to be operative. A reanalysis of one DBP microarray study identified additional pathways within cell signaling, metabolism, hormone, disease, and cell adhesion biological processes. These putative new pathways may be associated with DBP effects on the testes that are currently unexplained. This case study on DBP identified data gaps and research needs for the use of toxicogenomic data in risk assessment. Furthermore, this study demonstrated an approach for evaluating toxicogenomic data in human health risk assessment that could be applied to future chemicals. Published by Elsevier Inc. C1 [Euling, Susan Y.; Kim, Andrea S.; Keshava, Channa; Keshava, Nagalakshmi] US EPA, Natl Ctr Environm Assessment, Washington, DC 20460 USA. [White, Lori D.; Sen, Banalata] US EPA, Natl Ctr Environm Assessment, Res Triangle Pk, NC 27711 USA. [Wilson, Vickie S.; Hester, Susan] US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Ovacik, Meric A.; Ierapetritou, Marianthi G.; Androulakis, Ioannis P.] Rutgers State Univ, Environm Bioinformat & Computat Toxicol Ctr EbCTC, Natl Ctr Environm Res Sci Achieve Results STAR, Bioinformat Ctr, Piscataway, NJ USA. [Ovacik, Meric A.; Ierapetritou, Marianthi G.; Androulakis, Ioannis P.] Univ Med & Dent New Jersey, Piscataway, NJ 08854 USA. [Gaido, Kevin W.] US FDA, Ctr Vet Med, Rockville, MD 20855 USA. RP Euling, SY (reprint author), US EPA, Natl Ctr Environm Assessment, Off Res & Dev, 1200 Penn Ave NW,Mail Code 8623P, Washington, DC 20460 USA. EM euling.susan@epa.gov OI Wilson, Vickie/0000-0003-1661-8481 NR 39 TC 15 Z9 16 U1 3 U2 32 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD SEP 15 PY 2013 VL 271 IS 3 BP 349 EP 362 DI 10.1016/j.taap.2011.06.014 PG 14 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 221OZ UT WOS:000324669500006 PM 21745491 ER PT J AU Ovacik, MA Sen, B Euling, SY Gaido, KW Ierapetritou, MG Androulakis, IP AF Ovacik, Meric A. Sen, Banalata Euling, Susan Y. Gaido, Kevin W. Ierapetritou, Marianthi G. Androulakis, Ioannis P. TI Pathway modeling of microarray data: A case study of pathway activity changes in the testis following in utero exposure to dibutyl phthalate (DBP) SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Dibutyl Phthalate (DBP); Microarray data; Pathway analysis; Singular value decomposition (SVD); Time course ID GENE-EXPRESSION DATA; SINGULAR-VALUE DECOMPOSITION; REPRODUCTIVE-TRACT LESIONS; FETAL-RAT TESTIS; DI(N-BUTYL) PHTHALATE; METABOLIC PATHWAYS; MOUSE; CLASSIFICATION; PROLIFERATION; PREDICTION AB Pathway activity level analysis, the approach pursued in this study, focuses on all genes that are known to be members of metabolic and signaling pathways as defined by the KEGG database. The pathway activity level analysis entails singular value decomposition (SVD) of the expression data of the genes constituting a given pathway. We explore an extension of the pathway activity methodology for application to time-course microarray data. We show that pathway analysis enhances our ability to detect biologically relevant changes in pathway activity using synthetic data. As a case study, we apply the pathway activity level formulation coupled with significance analysis to microarray data from two different rat testes exposed in utero to Dibutyl Phthalate (DBP). In utero DBP exposure in the rat results in developmental toxicity of a number of male reproductive organs, including the testes. One well-characterized mode of action for DBP and the male reproductive developmental effects is the repression of expression of genes involved in cholesterol transport, steroid biosynthesis and testosterone synthesis that lead to a decreased fetal testicular testosterone. Previous analyses of DBP testes microarray data focused on either individual gene expression changes or changes in the expression of specific genes that are hypothesized, or known, to be important in testicular development and testosterone synthesis. However, a pathway analysis may inform whether there are additional affected pathways that could inform additional modes of action linked to DBP developmental toxicity. We show that Pathway activity analysis may be considered for a more comprehensive analysis of microarray data. (C) 2010 Published by Elsevier Inc. C1 [Ovacik, Meric A.; Ierapetritou, Marianthi G.; Androulakis, Ioannis P.] Rutgers State Univ, Chem & Biochem Engn Dept, Piscataway, NJ 08854 USA. [Sen, Banalata] US EPA, Natl Ctr Environm Assessment, Res Triangle Pk, NC 27709 USA. [Euling, Susan Y.] US EPA, Natl Ctr Environm Assessment, Off Res & Dev, Washington, DC 20460 USA. [Gaido, Kevin W.] US FDA, Ctr Vet Med, Off New Anim Drug Evaluat, Div Human Food Safety, Rockville, MD 20855 USA. [Androulakis, Ioannis P.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. RP Androulakis, IP (reprint author), Rutgers State Univ, Dept Biomed Engn, 599 Taylor Rd, Piscataway, NJ 08854 USA. EM yannis@rci.rutgers.edu FU USEPA; Environmental Bioinformatics and Computational Toxicology Center (ebCTC), under STAR Grant [GAD R 832721-010] FX Support for this work has been partially provided by the USEPA-funded Environmental Bioinformatics and Computational Toxicology Center (ebCTC), under STAR Grant number GAD R 832721-010. This work has not been reviewed by and does not represent the opinions of the funding agency. The authors acknowledge fruitful discussions with Prof. P. Georgopoulos and Prof. W. Welsh. We acknowledge helpful suggestions from the DBP Case Study team, especially Weihsueh Chiu and Susan Hester. NR 59 TC 2 Z9 2 U1 2 U2 23 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD SEP 15 PY 2013 VL 271 IS 3 BP 386 EP 394 DI 10.1016/j.taap.2010.09.008 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 221OZ UT WOS:000324669500009 PM 20850466 ER PT J AU Fine, AJ Sorbello, A Kortepeter, C Scarazzini, L AF Fine, Andrew J. Sorbello, Alfred Kortepeter, Cindy Scarazzini, Linda TI Central Nervous System Herpes Simplex and Varicella Zoster Virus Infections in Natalizumab-Treated Patients SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material DE HSV; VZV; encephalitis; meningitis; natalizumab ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; MULTIPLE-SCLEROSIS; ENCEPHALITIS; REACTIVATION; DISEASE; TRIAL; RASH AB We report on 20 natalizumab-treated patients with multiple sclerosis who developed laboratory-confirmed central nervous system (CNS) herpesvirus infections. In addition to progressive multifocal leukoencephalopathy, other CNS opportunistic infections have been rarely reported during natalizumab treatment. We encourage heightened awareness due to the risk for serious outcomes. C1 [Fine, Andrew J.; Sorbello, Alfred; Kortepeter, Cindy] US FDA, Ctr Drug Evaluat & Res, Off Surveillance & Epidemiol, Silver Spring, MD 20993 USA. [Scarazzini, Linda] AbbVie Inc, Global Pharmacovigilance, N Chicago, IL USA. RP Fine, AJ (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM andrew.fine@fda.hhs.gov NR 23 TC 25 Z9 25 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 15 PY 2013 VL 57 IS 6 BP 849 EP 852 DI 10.1093/cid/cit376 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 212YF UT WOS:000324018100016 PM 23728144 ER PT J AU Tran, K Mactal, LP Cromer, MR Vocque, RH Smith, RE AF Tran, Kevin Mactal, Lucie P. Cromer, Michele R. Vocque, Ralph H. Smith, Robert E. TI Development and validation of ethylenethiourea determination in foods using methanol-based extraction, solid-phase extraction cleanup and LC-MS/MS SO FOOD CHEMISTRY LA English DT Article DE Ethylenethiourea; Ethylene-bis-dithiocarbamate; Imidazolidine-2-thione; ETU; EBDCs; LC-MS/MS ID CHROMATOGRAPHY; ETU AB To response to the need for a rapid, cost-effective, eco-friendly and efficient extraction process, a sensitive method for the determination of ethylenethiourea (ETU) in food matrices by high-performance liquid chromatography-mass spectrometry (HPLC-LC/MS) was developed and validated. ETU was extracted from food commodities with methanol, cleaned up by alumina-SPE column, and then determined by HPLC-MS/MS. The MS detection was operated in positive ionization mode. For confirmation of target compound, two precursor ion > product ion transitions were selected by multi-reaction monitoring mode (MRM). The method showed good linearity with correlation coefficient higher than 0.9950. Recoveries at three spiked levels (10, 50, 100 ng/g) in random selected food matrices were in range of 71-121% with RSDs not larger than 25%. The limit of quantitation for the analyte was estimated at 5 ng/g. Published by Elsevier Ltd. C1 [Tran, Kevin; Mactal, Lucie P.; Cromer, Michele R.; Vocque, Ralph H.; Smith, Robert E.] US FDA, Total Diet & Pesticide Res Ctr, Off Regulatory Affairs, Lenexa, KS 66214 USA. RP Tran, K (reprint author), US FDA, Total Diet & Pesticide Res Ctr, Off Regulatory Affairs, 11510 W 80th St, Lenexa, KS 66214 USA. EM kevin.tran@fda.hhs.gov NR 11 TC 1 Z9 3 U1 1 U2 92 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0308-8146 EI 1873-7072 J9 FOOD CHEM JI Food Chem. PD SEP 15 PY 2013 VL 140 IS 1-2 BP 340 EP 342 DI 10.1016/j.foodchem.2013.02.029 PG 3 WC Chemistry, Applied; Food Science & Technology; Nutrition & Dietetics SC Chemistry; Food Science & Technology; Nutrition & Dietetics GA 134ER UT WOS:000318193500045 PM 23578651 ER PT J AU Lugovtsev, VY Melnyk, D Weir, JP AF Lugovtsev, Vladimir Y. Melnyk, Darya Weir, Jerry P. TI Heterogeneity of the MDCK Cell Line and Its Applicability for Influenza Virus Research SO PLOS ONE LA English DT Article ID CANINE KIDNEY-CELLS; DOME FORMATION; EPITHELIAL-CELLS; CYCLIC-AMP; 2 STRAINS; DIFFERENTIATED PROPERTIES; CULTURED MONOLAYERS; OCCLUDING JUNCTIONS; ESTABLISHED LINE; EMBRYONATED EGGS AB Single-cell clones have been established from the MDCK cell line, characterized for their morphology and evaluated for their suitability for influenza virus research. Three discrete cell morphotypes were identified using light microscopy. Besides morphological features, the cell types can be distinguished by the level of expression of surface glycans recognized by peanut agglutinin (PNA). All clones were susceptible to infection by influenza viruses of different subtypes of influenza A virus (H1N1, H1N1pdm09, H3N2, H5N1) and influenza B virus, and all possessed on their surface terminally sialylated glycans with both types of glycosidic linkage (alpha 2-3 and alpha 2-6). The Type-1 cell lines were able to support a multicycle replication of influenza A and B viruses without help of an exogenous trypsin. In contrast, cell lines exhibiting Type-2 morphology were unable to support multicycle replication of influenza A viruses without trypsin supplementation. Western blot analysis of the hemagglutinin of H1N1 strains demonstrated that Type-2 cells were deficient in production of proteolytically activated hemagglutinin (no cleavage between HA1/HA2 was observed). HA1/HA2 cleavage of influenza B viruses in the Type-2 cells was also significantly impaired, but not completely abrogated, producing sufficient amount of activated HA to support efficient virus replication without trypsin. In contrast, all clones of Type-1 cells were able to produce proteolytically activated hemagglutinin of influenza A and B viruses. However, the growth kinetics and plaque size of influenza A viruses varied significantly in different clones. Influenza B virus also showed different plaque size, with the biggest plaque formation in the Type-2 cells, although the growth kinetics and peak infectivity titers were similar in all clones. Taken together, the study demonstrates that the population of original MDCK cells is represented by various types of cells that differ in their capacities to support replication of influenza A and B viruses. C1 [Lugovtsev, Vladimir Y.; Melnyk, Darya; Weir, Jerry P.] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Lugovtsev, VY (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. EM vladimir.lugovtsev@fda.hhs.gov FU Center for Biologics Evaluation and Research, Food and Drug Administration FX This work was supported by the Center for Biologics Evaluation and Research, Food and Drug Administration. NR 96 TC 8 Z9 8 U1 1 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 13 PY 2013 VL 8 IS 9 AR e75014 DI 10.1371/journal.pone.0075014 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218BU UT WOS:000324408400105 PM 24058646 ER PT J AU Beigi, RH Goldkind, SF Jevaji, I AF Beigi, Richard H. Goldkind, Sara F. Jevaji, Indira TI Research on vaccines and antimicrobials during pregnancy: Challenges and opportunities SO VACCINE LA English DT Editorial Material ID IMMUNIZATION; INFLUENZA; WOMEN C1 [Beigi, Richard H.] Univ Pittsburgh Med Ctr, Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci, Div Reprod Infect Dis, Pittsburgh, PA 15213 USA. [Beigi, Richard H.] Univ Pittsburgh Med Ctr, Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci, Div Obstet Specialties, Pittsburgh, PA 15213 USA. [Goldkind, Sara F.] US FDA, Off Good Clin Practice, Off Commissioner, Silver Spring, MD USA. [Jevaji, Indira] NIH, Off Res Womens Hlth, Div Program Coordinat Planning & Strateg Initiat, Off Director, Bethesda, MD 20892 USA. RP Beigi, RH (reprint author), Univ Pittsburgh Med Ctr, Magee Womens Hosp, 300 Halket St, Pittsburgh, PA 15213 USA. EM rbeigi@mail.magee.edu NR 8 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 13 PY 2013 VL 31 IS 40 BP 4261 EP 4263 DI 10.1016/j.vaccine.2013.05.060 PG 3 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 219MG UT WOS:000324510500001 PM 23978280 ER PT J AU Dodd, CN Romio, SA Black, S Vellozzi, C Andrews, N Sturkenboom, M Zuber, P Hua, W Bonhoeffer, J Buttery, J Crawford, N Deceuninck, G de Vries, C De Wals, P Gutierrez-Gimeno, MV Heijbel, H Hughes, H Hur, K Hviid, A Kelman, J Kilpi, T Chuang, SK Macartney, K Rett, M Lopez-Callada, VR Salmon, D Sanchez, FG Sanz, N Silverman, B Storsaeter, J Thirugnanam, U van der Maas, N Yih, K Zhang, T Izurieta, H AF Dodd, Caitlin N. Romio, Silvana A. Black, Steven Vellozzi, Claudia Andrews, Nick Sturkenboom, Miriam Zuber, Patrick Hua, Wei Bonhoeffer, Jan Buttery, Jim Crawford, Nigel Deceuninck, Genevieve de Vries, Corinne De Wals, Philippe Gutierrez-Gimeno, M. Victoria Heijbel, Harald Hughes, Hayley Hur, Kwan Hviid, Anders Kelman, Jeffrey Kilpi, Tehri Chuang, S. K. Macartney, Kristine Rett, Melisa Lopez-Callada, Vesta Richardson Salmon, Daniel Sanchez, Francisco Gimenez Sanz, Nuria Silverman, Barbara Storsaeter, Jann Thirugnanam, Umapathi van der Maas, Nicoline Yih, Katherine Zhang, Tao Izurieta, Hector CA Global H1N1 GBS Consortium TI International collaboration to assess the risk of Guillain Barre Syndrome following Influenza A (H1N1) 2009 monovalent vaccines SO VACCINE LA English DT Article DE Guillain Barre Syndrome (GBS); Monovalent H1N1 Vaccine (H1N1); Self-controlled case-series method (SCCS); International; Adjuvant; Adverse events following immunization (AEFI) ID CONTROLLED CASE SERIES; UNITED-KINGDOM; ADJUVANTED VACCINE; ADVERSE EVENTS; SAFETY; IMMUNIZATION; LICENSURE; SURVEILLANCE; ASSOCIATION; PROGRAM AB Background: The global spread of the 2009 novel pandemic influenza A (H1N1) virus led to the accelerated production and distribution of monovalent 2009 Influenza A (H1N1) vaccines (pH1N1). This pandemic provided the opportunity to evaluate the risk of Guillain-Barre syndrome (GBS), which has been an influenza vaccine safety concern since the swine flu pandemic of 1976, using a common protocol among high and middle-income countries. The primary objective of this project was to demonstrate the feasibility and utility of global collaboration in the assessment of vaccine safety, including countries both with and without an established infrastructure for vaccine active safety surveillance. A second objective, included a priori, was to assess the risk of GBS following pH1N1 vaccination. Methods: The primary analysis used the self-controlled case series (SCCS) design to estimate the relative incidence (RI) of GBS in the 42 days following vaccination with pH1N1 vaccine in a pooled analysis across databases and in analysis using a meta-analytic approach. Results: We found a relative incidence of GBS of 2.42(95% CI 1.58-3.72) in the 42 days following exposure to pH1N1 vaccine in analysis of pooled data and 2.09(95% CI 1.28-3.42) using the meta-analytic approach. Conclusions: This study demonstrates that international collaboration to evaluate serious outcomes using a common protocol is feasible. The significance and consistency of our findings support a conclusion of an association between 2009 H1N1 vaccination and GBS. Given the rarity of the event the relative incidence found does not provide evidence in contradiction to international recommendations for the continued use of influenza vaccines. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Dodd, Caitlin N.] Cincinnati Childrens Hosp Med Ctr, Dept Biostat & Epidemiol, Cincinnati, OH 45229 USA. [Romio, Silvana A.; Sturkenboom, Miriam] Erasmus Univ, Med Ctr, Dept Med Informat, Rotterdam, Netherlands. [Black, Steven] Cincinnati Childrens Hosp Med Ctr, Dept Global Child Hlth, Cincinnati, OH 45229 USA. [Vellozzi, Claudia] Ctr Dis Control & Prevent, Atlanta, GA USA. [Andrews, Nick] Hlth Protect Agcy, London, England. [Zuber, Patrick] WHO, Dept Immunizat Vaccines & Biol IVB, CH-1211 Geneva, Switzerland. [Hua, Wei; Izurieta, Hector] US FDA, Ctr Biol Evaluat & Res, Off Biost & Epidemiol, Rockville, MD 20857 USA. [Bonhoeffer, Jan] Brighton Collaborat Fdn, Basel, Switzerland. [Bonhoeffer, Jan] Univ Childrens Hosp, Basel, Switzerland. [Buttery, Jim] Monash Univ, Dept Paediat, Murdoch Childrens Res Inst, Clayton, Vic 3800, Australia. [Crawford, Nigel] Univ Melbourne, Dept Paediat, Melbourne, Vic, Australia. [Deceuninck, Genevieve; De Wals, Philippe] Quebec Univ Hosp, Res Ctr, Publ Hlth Res Unit, Quebec City, PQ, Canada. [de Vries, Corinne] Univ Bath, Dept Pharm & Pharmacol, Bath, Avon, England. [Gutierrez-Gimeno, M. Victoria] Ctr Publ Hlth Res CSISP FISABIO, Vaccine Dept, Valencia, Spain. [Heijbel, Harald] Swedish Inst Infect Dis, Lund, Sweden. [Hughes, Hayley] US Dept Def, Washington, DC 20305 USA. [Hur, Kwan] Hines Vet Affairs Hosp, Pharm Benefit Management Serv, Ctr Med Safety, Hines, IL USA. [Hviid, Anders] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [Kelman, Jeffrey] Ctr Medicare Serv, Ctr Drug & Hlth Plan Choice, Baltimore, MD USA. [Kelman, Jeffrey] Ctr Medicaid Serv, Baltimore, MD USA. [Kilpi, Tehri] Natl Inst Hlth & Welf, Helsinki, Finland. [Chuang, S. K.] Ctr Hlth Protect, Dept Hlth, Hong Kong, Hong Kong, Peoples R China. [Macartney, Kristine] Childrens Hosp Westmead, Westmead, NSW, Australia. [Rett, Melisa; Yih, Katherine] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Rett, Melisa; Yih, Katherine] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Lopez-Callada, Vesta Richardson] Natl Ctr Child & Adolescent Hlth, Mexico City, DF, Mexico. [Salmon, Daniel] US Dept Hlth & Human Serv, Off Assistant Secretary Hlth, Natl Vaccine Program Off, Washington, DC USA. [Salmon, Daniel] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Salmon, Daniel] Johns Hopkins Bloomberg Sch Publ Hlth, Inst Vaccine Safety, Baltimore, MD USA. [Sanchez, Francisco Gimenez] Torrecardenas Hosp, Dept Pediat, Almeria, Spain. [Sanz, Nuria] Hosp Clin & Prov Barcelona SCReN, Barcelona, Spain. [Silverman, Barbara] Maccabi Healthcare Serv, Tel Aviv, Israel. [Storsaeter, Jann] Norwegian Inst Publ Hlth, Oslo, Norway. [Thirugnanam, Umapathi] Natl Neurosci Inst, Singapore, Singapore. [van der Maas, Nicoline] RIVM, Bilthoven, Netherlands. Fudan Univ, Dept Epidemiology, Sch Publ Hlth, Key Lab Publ Hlth Safety,Minist Educ, Shanghai 200433, Peoples R China. RP Dodd, CN (reprint author), Cincinnati Childrens Hosp Med Ctr, Dept Biostat & Epidemiol, Cincinnati, OH 45229 USA. EM c.dodd@erasmusmc.nl RI Bonhoeffer, Jan/E-5903-2014; Sammon, Cormac/B-7340-2015; Addis, Antonio/J-7894-2016; CPRD, CPRD/B-9594-2017; OI Sammon, Cormac/0000-0002-7921-4858; Addis, Antonio/0000-0003-0962-9959; Kulldorff, Martin/0000-0002-5284-2993; Clothier, Hazel Joanne/0000-0001-7594-0361; Silverman, Barbara/0000-0002-0337-4919; Cheng, Allen/0000-0003-3152-116X FU World Health Organization; US Food and Drug Administration FX Minimal funding was provided by the World Health Organization and by the US Food and Drug Administration for creation and maintenance of an online workspace as well as travel for group statisticians to conduct data analysis. No funding was provided to investigators for their participation. NR 46 TC 29 Z9 29 U1 8 U2 194 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 13 PY 2013 VL 31 IS 40 BP 4448 EP 4458 DI 10.1016/j.vaccine.2013.06.032 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 219MG UT WOS:000324510500027 PM 23770307 ER PT J AU Strauss, DG Loring, Z Selvester, RH Gerstenblith, G Tomaselli, G Weiss, RG Wagner, GS Wu, KC AF Strauss, David G. Loring, Zak Selvester, Ronald H. Gerstenblith, Gary Tomaselli, Gordon Weiss, Robert G. Wagner, Galen S. Wu, Katherine C. TI Right, But Not Left, Bundle Branch Block Is Associated With Large Anteroseptal Scar SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE ischemic heart disease; left bundle branch block; myocardial infarction; nonischemic cardiomyopathy; right bundle branch block ID CARDIAC-RESYNCHRONIZATION THERAPY; CARDIOVASCULAR MAGNETIC-RESONANCE; CHRONIC HEART-FAILURE; ACUTE MYOCARDIAL-INFARCTION; HYPERTROPHIC CARDIOMYOPATHY; CONDUCTION SYSTEM; QUANTIFICATION; DEFIBRILLATOR; METAANALYSIS; ENHANCEMENT AB Objectives This study sought to test the hypothesis that right bundle branch block (RBBB) patients have larger scar size than left bundle branch block (LBBB) patients do. Background A proximal septal perforating branch of the left anterior descending (LAD) coronary artery most commonly perfuses the right bundle branch and left anterior fascicle, but not the left posterior fascicle. Thus, proximal LAD occlusions should cause RBBB, not LBBB. Methods We performed electrocardiograms and magnetic resonance imaging for scar quantification in 233 patients with left ventricular (LV) ejection fraction <= 35% who were receiving primary prevention implantable cardioverter-defibrillators (ICD cohort). Scar size and location were compared among patients with RBBB, LBBB, nonspecific LV conduction delay, and QRS <120 ms. A second cohort of 20 hypertrophic cardiomyopathy patients undergoing alcohol septal ablation was studied to determine whether controlled infarction in a proximal LAD septal perforator caused RBBB or LBBB. Results In the ICD cohort, LV ejection fraction was similar between RBBB and LBBB patients (24.9% vs. 25.0%; p = 0.98); however, RBBB patients had significantly larger scar size (24.0% vs. 6.5%; p < 0.0001). Patients with nonspecific LV conduction delay or QRS <120 ms had intermediate scar size (12.9% and 14.4%, respectively). Those with RBBB (compared with LBBB) were more likely to have ischemic heart disease (79% vs. 29%; p < 0.0001). In the alcohol septal ablation cohort, 15 of 20 patients (75%) developed RBBB, but no patients developed LBBB. Conclusions In patients with LV ejection fraction <= 35%, RBBB is associated with significantly larger scar size than LBBB is, and occlusion of a proximal LAD septal perforator causes RBBB. In contrast, LBBB is most commonly caused by nonischemic pathologies. (C) 2013 by the American College of Cardiology Foundation C1 [Strauss, David G.; Loring, Zak] US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn, Silver Spring, MD USA. [Loring, Zak] Duke Univ, Sch Med, Durham, NC USA. [Selvester, Ronald H.] Mem Hosp, Res Ctr, Long Beach, CA USA. [Gerstenblith, Gary; Tomaselli, Gordon; Weiss, Robert G.; Wu, Katherine C.] Johns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Wagner, Galen S.] Duke Clin Res Inst, Durham, NC USA. RP Strauss, DG (reprint author), Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,WO62-1126, Silver Spring, MD 20993 USA. EM david.strauss@fda.hhs.gov FU U.S. Food and Drug Administration's Critical Path Initiative; Donald W. Reynolds Cardiovascular Research Center at Johns Hopkins University; National Heart, Lung, and Blood Institute, National Institutes of Health [HL103812, HL91062, HL61912] FX This project was supported in part by the U.S. Food and Drug Administration's Critical Path Initiative; Donald W. Reynolds Cardiovascular Research Center at Johns Hopkins University; and the National Heart, Lung, and Blood Institute, National Institutes of Health (#HL103812 to Dr. Wu, #HL91062 to Dr. Tomaselli, and #HL61912 to Dr. Selvester). Use of the custom research software tool, Cinetool, was obtained through a research agreement between Dr. Wu and GE Healthcare. Dr. Wu has received modest royalties for the licensing rights to use the gray zone methodology described in this paper. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 32 TC 18 Z9 18 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 10 PY 2013 VL 62 IS 11 BP 959 EP 967 DI 10.1016/j.jacc.2013.04.060 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 213HP UT WOS:000324046900003 PM 23707313 ER PT J AU Carroll, JD Edwards, FH Marinac-Dabic, D Brindis, RG Grover, FL Peterson, ED Tuzcu, EM Shahian, DM Rumsfeld, JS Shewan, CM Hewitt, K Holmes, DR Mack, MJ AF Carroll, John D. Edwards, Fred H. Marinac-Dabic, Danica Brindis, Ralph G. Grover, Frederick L. Peterson, Eric D. Tuzcu, E. Murat Shahian, David M. Rumsfeld, John S. Shewan, Cynthia M. Hewitt, Kathleen Holmes, David R., Jr. Mack, Michael J. TI The STS-ACC Transcatheter Valve Therapy National Registry A New Partnership and Infrastructure for the Introduction and Surveillance of Medical Devices and Therapies SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE aortic stenosis; mitral regurgitation; registry; valves ID END-POINT DEFINITIONS; CONSENSUS DOCUMENT; THORACIC SURGEONS; AORTIC-STENOSIS; IMPLANTATION; OUTCOMES; SOCIETY; LINKING AB The Society of Thoracic Surgeons (STS) and American College of Cardiology (ACC) transcatheter valve therapy (TVT) registry is a novel, national registry for all new TVT devices created through a partnership of the STS and the ACC in close collaboration with the Food and Drug Administration, the Center for Medicare and Medicaid Services, and the Duke Clinical Research Institute. The registry will serve as an objective, comprehensive, and scientifically based resource to improve the quality of patient care, to monitor the safety and effectiveness of TVT devices, to serve as an analytic resource for TVT research, and to enhance communication among key stakeholders. (C) 2013 by the American College of Cardiology Foundation C1 [Carroll, John D.; Grover, Frederick L.] Univ Colorado, Sch Med, Aurora, CO USA. [Edwards, Fred H.] Univ Florida, Hlth Sci Ctr, Jacksonville, FL 32209 USA. [Marinac-Dabic, Danica] US FDA, Div Epidemiol, Ctr Devices & Radiol Hlth, Washington, DC 20204 USA. [Brindis, Ralph G.] Univ Calif San Francisco, Philip R Lee Inst Hlth Policy Studies, San Francisco, CA 94143 USA. [Peterson, Eric D.] Duke Clin Res Inst, Durham, NC USA. [Tuzcu, E. Murat] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Shahian, David M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rumsfeld, John S.] Univ Colorado, Denver VA Med Ctr, Denver, CO 80202 USA. [Shewan, Cynthia M.] Soc Thorac Surg, Chicago, IL USA. [Hewitt, Kathleen] Amer Coll Cardiol Fdn, Natl Cardiovasc Data Registry, Washington, DC USA. [Holmes, David R., Jr.] Mayo Clin, Rochester, MN USA. [Mack, Michael J.] Med City Hosp, Dallas, TX USA. RP Carroll, JD (reprint author), Univ Colorado Denver, Anschutz Med Campus,Leprino Bldg,12401 East 17th, Aurora, CO 80045 USA. EM john.carroll@ucdenver.edu FU Edwards Lifesciences; Eli Lilly; Janssen Pharmaceuticals; Pfizer; Boehringer Ingleheim FX Dr. Carroll is an investigator for the PARTNER II clinical trial sponsored by Edwards Lifesciences; and a consultant to the Steering Committee of the RESPECT trial of St. Jude Medical. Dr. Marinac-Dabic is director of the Division of Epidemiology, Food and Drug Administration. Dr. Peterson receives research support from Eli Lilly, Janssen Pharmaceuticals, Pfizer, and Boehringer Ingleheim. Dr. Rumsfeld is chief science officer for the National Cardiovascular Data Registry. Dr. Shewan is a co-investigator for the ASCERT study. Dr. Mack is an uncompensated member of the executive committee of the PARTNER trial with travel expenses paid for by Edwards Lifesciences. All other authors have reported they have no relationships relevant to the contents of this paper to disclose. NR 30 TC 50 Z9 50 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 10 PY 2013 VL 62 IS 11 BP 1026 EP 1034 DI 10.1016/j.jacc.2013.03.060 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 213HP UT WOS:000324046900015 PM 23644082 ER PT J AU Ottesen, AR Gonzalez, A Bell, R Arce, C Rideout, S Allard, M Evans, P Strain, E Musser, S Knight, R Brown, E Pettengill, JB AF Ottesen, Andrea R. Gonzalez, Antonio Bell, Rebecca Arce, Caroline Rideout, Steven Allard, Marc Evans, Peter Strain, Errol Musser, Steven Knight, Rob Brown, Eric Pettengill, James B. TI Co-Enriching Microflora Associated with Culture Based Methods to Detect Salmonella from Tomato Phyllosphere SO PLOS ONE LA English DT Article ID ESCHERICHIA-COLI; ENRICHMENT BIAS; METAGENOMICS; MEDIA; DIVERSITY; OUTBREAK AB The ability to detect a specific organism from a complex environment is vitally important to many fields of public health, including food safety. For example, tomatoes have been implicated numerous times as vehicles of foodborne outbreaks due to strains of Salmonella but few studies have ever recovered Salmonella from a tomato phyllosphere environment. Precision of culturing techniques that target agents associated with outbreaks depend on numerous factors. One important factor to better understand is which species co-enrich during enrichment procedures and how microbial dynamics may impede or enhance detection of target pathogens. We used a shotgun sequence approach to describe taxa associated with samples pre-enrichment and throughout the enrichment steps of the Bacteriological Analytical Manual's (BAM) protocol for detection of Salmonella from environmental tomato samples. Recent work has shown that during efforts to enrich Salmonella (Proteobacteria) from tomato field samples, Firmicute genera are also co-enriched and at least one co-enriching Firmicute genus (Paenibacillus sp.) can inhibit and even kills strains of Salmonella. Here we provide a baseline description of microflora that co-culture during detection efforts and the utility of a bioinformatic approach to detect specific taxa from metagenomic sequence data. We observed that uncultured samples clustered together with distinct taxonomic profiles relative to the three cultured treatments (Universal Pre-enrichment broth (UPB), Tetrathionate (TT), and Rappaport-Vassiliadis (RV)). There was little consistency among samples exposed to the same culturing medias, suggesting significant microbial differences in starting matrices or stochasticity associated with enrichment processes. Interestingly, Paenibacillus sp. (Salmonella inhibitor) was significantly enriched from uncultured to cultured (UPB) samples. Also of interest was the sequence based identification of a number of sequences as Salmonella despite indication by all media, that samples were culture negative for Salmonella. Our results substantiate the nascent utility of metagenomic methods to improve both biological and bioinformatic pathogen detection methods. C1 [Ottesen, Andrea R.; Bell, Rebecca; Arce, Caroline; Allard, Marc; Evans, Peter; Strain, Errol; Musser, Steven; Brown, Eric; Pettengill, James B.] US FDA, Mol Methods & Subtyping Branch, Div Microbiol, Off Regulatory Sci,Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Gonzalez, Antonio] Univ Colorado, Biofrontiers Inst, Boulder, CO 80309 USA. [Rideout, Steven] Virginia Tech, Virginia Agr Expt Stn, Painter, VA USA. [Knight, Rob] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. [Knight, Rob] Univ Colorado, Howard Hughes Med Inst, Boulder, CO 80309 USA. RP Ottesen, AR (reprint author), US FDA, Mol Methods & Subtyping Branch, Div Microbiol, Off Regulatory Sci,Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM Andrea.Ottesen@fda.hhs.gov FU federal tax dollars designated for food borne pathogen prevention FX This research was supported by federal tax dollars designated for food borne pathogen prevention. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 13 Z9 13 U1 4 U2 28 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 9 PY 2013 VL 8 IS 9 AR e73079 DI 10.1371/journal.pone.0073079 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 244QV UT WOS:000326405300047 PM 24039862 ER PT J AU Aldridge, A AF Aldridge, Allison TI Building a strong community through collaborations SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Aldridge, Allison] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM Allison.Aldridge@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 16-CMA PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618402036 ER PT J AU Chatterjee, S AF Chatterjee, Sharmista TI Regulatory perspective on continuous manufacturing SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Chatterjee, Sharmista] US FDA, Silver Spring, MD 20993 USA. EM sharmista.chatterjee@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 280-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618405432 ER PT J AU Chu, PS Johnson, T Song, W Evans, E AF Chu, Pak-Sin Johnson, Tricia Song, Wei Evans, Eric TI Determination of hormone residues in rainbow trout muscle using liquid chromatography-tandem mass spectrometry SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Chu, Pak-Sin; Johnson, Tricia; Song, Wei; Evans, Eric] US FDA, Ctr Vet Med, Laurel, MD 20708 USA. EM pak.chu@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 49-AGRO PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618400282 ER PT J AU Doell, D Honigfort, M Folmer, D Lee, H Carberry, S AF Doell, Diana Honigfort, Mical Folmer, Daniel Lee, Hyoung Carberry, Susan TI Updated exposure estimate to industrially-produced trans fatty acids (IP-TFA) from the use of partially hydrogenated oils (PHOs) SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Doell, Diana; Honigfort, Mical; Folmer, Daniel; Lee, Hyoung; Carberry, Susan] US FDA, College Pk, MD 20740 USA. EM Diana.Doell@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 140-AGFD PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618400209 ER PT J AU Gao, Y Yang, X Salminen, W Mendrick, DL Yu, LR AF Gao, Yuan Yang, Xi Salminen, William Mendrick, Donna L. Yu, Li-Rong TI Proteomic analysis of acetaminophen-induced hepatotoxicity in rats SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Gao, Yuan; Yang, Xi; Salminen, William; Mendrick, Donna L.; Yu, Li-Rong] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM lirong.yu@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 100-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618407275 ER PT J AU Hur, J Guo, A Feldman, EL Bai, JPF AF Hur, Junguk Guo, Abra Feldman, Eva L. Bai, Jane P. F. TI Informatics tools for interacting with literature and chemical databases to build pharmacological network of drug-induced neuropathy SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Hur, Junguk; Feldman, Eva L.] Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USA. [Guo, Abra] Univ Michigan, Coll Literature Sci & Arts, Ann Arbor, MI 48109 USA. [Hur, Junguk; Bai, Jane P. F.] US FDA, Off Clin Pharmacol, Silver Spring, MD 20993 USA. EM juhur@umich.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 25-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618401826 ER PT J AU Koenig, M AF Koenig, Michael TI The Tobacco Control Act and the FDA Center for Tobacco Products SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Koenig, Michael] Ctr Tobacco Prod, Rockville, MD USA. EM Michael.Koenig@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 23-CHAL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618401366 ER PT J AU Li, J Meyer, TY AF Li, Jian Meyer, Tara Y. TI Engineering hydrolysis behavior of poly(lactic-co-glycolic acid) through precise control of monomer sequence SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Li, Jian] US FDA, Div Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth,Off Med Prod & Tobacco, Silver Spring, MD 20993 USA. [Meyer, Tara Y.] Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA. [Meyer, Tara Y.] Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA 15260 USA. EM jian.li@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 123-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618406778 ER PT J AU Norcross, MA AF Norcross, Michael A. TI Autoimmune model for HLA-associated immunological drug reactions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Norcross, Michael A.] US FDA, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. EM michael.norcross@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 4-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618407183 ER PT J AU Pillai, K Ntim, SA Jin, Z Noonan, G Duncan, T AF Pillai, Karthik Ntim, Susana Addo Jin, Zhen Noonan, Gregory Duncan, Timothy TI Polymer nanocomposites in food contact materials: Preparation of nanocomposites for testing migration of nanoparticles to food simulants SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Pillai, Karthik; Duncan, Timothy] US FDA CFSAN OFS, Div Food Proc Sci & Technol, Bedford Pk, IL 60501 USA. [Ntim, Susana Addo; Noonan, Gregory] US FDA CFSAN ORS, Div Analyt Chem Method Dev, College Pk, MD 20740 USA. [Jin, Zhen] IIT, Inst Food Safety & Hlth, Bedford Pk, IL 60501 USA. EM Karthik.pillai@fda.hhs.gov NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 18-AGFD PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618400098 ER PT J AU Silverstein, JS Forrey, C Limm, W Begley, TH Saylor, DM AF Silverstein, Joshua S. Forrey, Christopher Limm, William Begley, Timothy H. Saylor, David M. TI Measuring transport properties in controlled release coatings SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 246th National Meeting of the American-Chemical-Society (ACS) CY SEP 08-12, 2013 CL Indianapolis, IN SP Amer Chem Soc C1 [Silverstein, Joshua S.; Forrey, Christopher; Saylor, David M.] US FDA, Off Med Prod & Tobacco, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs,Div Chem & Mat Sci, Silver Spring, MD 20993 USA. [Limm, William; Begley, Timothy H.] US FDA, Off Foods & Vet Med, Ctr Food Safety & Nutr, Off Regulatory Sci,Div Analyt Chem,Methods Dev Br, College Pk, MD 20740 USA. EM Joshua.Silverstein@fda.hhs.gov NR 0 TC 0 Z9 0 U1 2 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD SEP 8 PY 2013 VL 246 MA 299-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 288NJ UT WOS:000329618407056 ER PT J AU Corey, C Wang, BG Johnson, SE Apelberg, B Husten, C King, BA McAfee, TA Bunnell, R Arrazola, RA Dube, SR AF Corey, Catherine Wang, Baoguang Johnson, Sarah E. Apelberg, Benjamin Husten, Corinne King, Brian A. McAfee, Tim A. Bunnell, Rebecca Arrazola, Rene A. Dube, Shanta R. TI Electronic Cigarette Use Among Middle and High School Students - United States, 2011-2012 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article C1 [Corey, Catherine; Wang, Baoguang; Johnson, Sarah E.; Apelberg, Benjamin; Husten, Corinne] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. [King, Brian A.; McAfee, Tim A.; Bunnell, Rebecca; Arrazola, Rene A.; Dube, Shanta R.] CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. RP King, BA (reprint author), CDC, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. EM baking@cdc.gov NR 4 TC 205 Z9 205 U1 3 U2 33 PU CENTER DISEASE CONTROL & PREVENTION PI ATLANTA PA MAILSTOP E-90, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD SEP 6 PY 2013 VL 62 IS 35 BP 729 EP 730 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 239WQ UT WOS:000326057100006 ER PT J AU Archdeacon, P Shaffer, RN Winkelmayer, WC Falk, RJ Roy-Chaudhury, P AF Archdeacon, Patrick Shaffer, Rachel N. Winkelmayer, Wolfgang C. Falk, Ronald J. Roy-Chaudhury, Prabir TI Fostering Innovation, Advancing Patient Safety: The Kidney Health Initiative SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIALS; NEPHROLOGY; QUALITY AB To respond to the serious and underrecognized epidemic of kidney disease in the United States, the US Food and Drug Administration and the American Society of Nephrology have founded the Kidney Health Initiativea public-private partnership designed to create a collaborative environment in which the US Food and Drug Administration and the greater kidney community can interact to optimize the evaluation of drugs, devices, biologics, and food products. The Kidney Health Initiative will bring together all the necessary stakeholders, including patients, regulators, industry, health care providers, academics, and other governmental agencies, to improve patient safety and foster innovation. This initiative is intended to enable the kidney community as a whole to provide the right drug, device, or biologic for administration to the right patient at the right time by fostering partnerships that will facilitate development and delivery of those products and addressing challenges that currently impede these goals. C1 [Archdeacon, Patrick] US FDA, Ctr Drug Evaluat & Res, Off Med Policy, Rockville, MD 20857 USA. [Shaffer, Rachel N.] Amer Soc Nephrol, Washington, DC 20006 USA. [Winkelmayer, Wolfgang C.] Stanford Univ, Sch Med, Div Nephrol, Palo Alto, CA 94304 USA. [Falk, Ronald J.] Univ N Carolina, Div Nephrol & Hypertens, Dept Med, Chapel Hill, NC USA. [Roy-Chaudhury, Prabir] Univ Cincinnati, Sch Med, Div Nephrol & Hypertens, Cincinnati, OH USA. RP Shaffer, RN (reprint author), Amer Soc Nephrol, 1510 H St NW,Suite 800, Washington, DC 20006 USA. EM rshaffer@asn-online.org FU WL Gore FX P.A. has no conflicts to report. R.N.S. is an employee of the American Society of Nephrology. W.C.W. reports having served as a scientific advisor to Affymax, Amgen, Bayer, Fibrogen, and Glaxo-SmithKline. R.J.F. is an employee of the University of North Carolina Chapel Hill School of Medicine. P.R.-C. is an advisory board member and research grant recipient for WL Gore, a consultant for Medtronic, a consultant (current) and research grant recipient (in the last year but not currently) for Proteon Therapeutics, a consultant and research grant recipient (in the last year but not currently) for Shire, a consultant for Bioconnect Systems, and an alternate scientific board member for Schulman Associates Institutional Review Board. NR 15 TC 9 Z9 9 U1 0 U2 1 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD SEP 6 PY 2013 VL 8 IS 9 BP 1609 EP 1617 DI 10.2215/CJN.01140113 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 235GR UT WOS:000325705500023 PM 23744001 ER PT J AU Mihalik, KB Feigelstock, DA AF Mihalik, Kathleen B. Feigelstock, Dino A. TI Sensitivity of a Ribavirin Resistant Mutant of Hepatitis C Virus to Other Antiviral Drugs SO PLOS ONE LA English DT Article ID DEPENDENT RNA-POLYMERASE; HCV AGENT 2'-C-METHYLCYTIDINE; ERROR-PRONE REPLICATION; MOUTH-DISEASE VIRUS; IN-VITRO; HEPATOCELLULAR-CARCINOMA; SUBGENOMIC REPLICONS; PROTEASE INHIBITOR; EFFICIENT PRODRUG; PLUS RIBAVIRIN AB Background: While ribavirin mono-therapy regimens have minimal effect on patients with chronic hepatitis C virus (HCV) infections, they can be efficacious when combined with interferon. Clinical studies show that interferon-free combination therapies containing ribavirin are also efficacious, suggesting that an interferon-free therapy could be adopted in the near future. However, generation of drug resistant mutants and cross resistance to other drugs could impair the efficacy of the treatment. Therefore, understanding the mechanism of HCV resistance to ribavirin and cross resistance to other antiviral drugs could be of major importance. Methods: We tested the ability of a J6/JFH1 derived HCV ribavirin resistant mutant to grow in tissue cultured Huh7D cells in the presence of the mutagen 5-Fluorouracil and the nucleoside analog 2'-C-Methylcytidine. Virus replication was assessed by detecting HCV antigens by immunofluorescence and by titrating virus present in the supernatants. Recovered viruses were amplified by RT-PCR and sequenced. Results: The sensitivity of HCV-RR relative to parental J6/JFH1 to the tested drugs varied. HCV-RR was more resistant than J6/JFH1 to 5-Fluorouracil but was not more resistant than J6/JFH1 to 2'-C-Methylcytidine. Growth of HCV-RR in 5-Fluorouracil allowed the selection of an HCV-RR derived mutant resistant to 5-Fluorouracil (HCV-5FU). HCV-5FU grows to moderate levels in the presence of high concentrations of 5-Fluorouracil and to parental levels in the absence of the drug. Sequence of its genome shows that HCV-5FU accumulated multiple synonymous and non-synonymous mutations. Conclusions: These results indicate that determinants of resistance to ribavirin could also confer resistance to other anti-HCV drugs, shedding light toward understanding the mechanism of action of ribavirin and highlighting the importance of combination drug selection for HCV treatment. The results also show that it is possible to select a 5-Fluorouracil HCV resistant mutant that replicates to levels similar to parental virus when grown in the absence of 5-Fluorouracil. C1 [Mihalik, Kathleen B.; Feigelstock, Dino A.] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD USA. RP Feigelstock, DA (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD USA. EM dino.feigelstock@fda.hhs.gov FU Food and Drug Administration FX This work was supported by internal funding from the Food and Drug Administration. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 1 Z9 1 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 5 PY 2013 VL 8 IS 9 AR e74027 DI 10.1371/journal.pone.0074027 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219CG UT WOS:000324481600113 PM 24040153 ER PT J AU McCollum, JT Cronquist, AB Silk, BJ Jackson, KA O'Connor, KA Cosgrove, S Gossack, JP Parachini, SS Jain, NS Ettestad, P Ibraheem, M Cantu, V Joshi, M DuVernoy, T Fogg, NW Gorny, JR Mogen, KM Spires, C Teitell, P Joseph, LA Tarr, CL Imanishi, M Neil, KP Tauxe, RV Mahon, BE AF McCollum, Jeffrey T. Cronquist, Alicia B. Silk, Benjamin J. Jackson, Kelly A. O'Connor, Katherine A. Cosgrove, Shaun Gossack, Joe P. Parachini, Susan S. Jain, Neena S. Ettestad, Paul Ibraheem, Mam Cantu, Venessa Joshi, Manjiri DuVernoy, Tracy Fogg, Norman W., Jr. Gorny, James R. Mogen, Kathryn M. Spires, Charlotte Teitell, Paul Joseph, Lavin A. Tarr, Cheryl L. Imanishi, Maho Neil, Karen P. Tauxe, Robert V. Mahon, Barbara E. TI Multistate Outbreak of Listeriosis Associated with Cantaloupe SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SURVEILLANCE NETWORK FOODNET; UNITED-STATES; FRESH PRODUCE; MONOCYTOGENES VIRULENCE; FOODBORNE ILLNESS; PULSENET; DISEASES; ESTABLISHMENT; EVOLUTION; PATHOGENS AB BACKGROUND Although new pathogen-vehicle combinations are increasingly being identified in produce-related disease outbreaks, fresh produce is a rarely recognized vehicle for listeriosis. We investigated a nationwide listeriosis outbreak that occurred in the United States during 2011. METHODS We defined an outbreak-related case as a laboratory-confirmed infection with any of five outbreak-related subtypes of Listeria monocytogenes isolated during the period from August 1 through October 31, 2011. Multistate epidemiologic, trace-back, and environmental investigations were conducted, and outbreak-related cases were compared with sporadic cases reported previously to the Listeria Initiative, an enhanced surveillance system that routinely collects detailed information about U.S. cases of listeriosis. RESULTS We identified 147 outbreak-related cases in 28 states. The majority of patients (127 of 147, 86%) were 60 years of age or older. Seven infections among pregnant women and newborns and one related miscarriage were reported. Of 145 patients for whom information about hospitalization was available, 143 (99%) were hospitalized. Thirty-three of the 147 patients (22%) died. Patients with outbreak-related illness were significantly more likely to have eaten cantaloupe than were patients 60 years of age or older with sporadic illness (odds ratio, 8.5; 95% confidence interval, 1.3 to infinity). Cantaloupe and environmental samples collected during the investigation yielded isolates matching all five outbreak-related subtypes, confirming that whole cantaloupe produced by a single Colorado farm was the outbreak source. Unsanitary conditions identified in the processing facility operated by the farm probably resulted in contamination of cantaloupes with L. monocytogenes. CONCLUSIONS Raw produce, including cantaloupe, can serve as a vehicle for listeriosis. This outbreak highlights the importance of preventing produce contamination within farm and processing environments. C1 [McCollum, Jeffrey T.; O'Connor, Katherine A.; Jain, Neena S.; Ibraheem, Mam; Imanishi, Maho] Ctr Dis Control & Prevent, Epidem Intelligence Serv, Atlanta, GA 30329 USA. [Silk, Benjamin J.; Jackson, Kelly A.; O'Connor, Katherine A.; Joseph, Lavin A.; Tarr, Cheryl L.; Imanishi, Maho; Neil, Karen P.; Tauxe, Robert V.; Mahon, Barbara E.] Ctr Dis Control & Prevent, Natl Ctr Emerging & Zoonot Infect Dis, Div Foodborne Waterborne & Environm Dis, Atlanta, GA USA. Ctr Dis Control & Prevent, Sci Educ & Profess Dev Program Off, Atlanta, GA USA. [McCollum, Jeffrey T.; Cronquist, Alicia B.; Cosgrove, Shaun; Gossack, Joe P.; Parachini, Susan S.] Colorado Dept Publ Hlth & Environm, Denver, CO USA. [Ettestad, Paul; Ibraheem, Mam] New Mexico Dept Hlth, Santa Fe, NM USA. [Cantu, Venessa] Dept State Hlth Serv, Austin, TX USA. [Joshi, Manjiri] Nebraska Dept Hlth & Human Serv, Lincoln, NE USA. [DuVernoy, Tracy; Fogg, Norman W., Jr.; Gorny, James R.; Mogen, Kathryn M.; Spires, Charlotte; Teitell, Paul] US FDA, Silver Spring, MD USA. RP McCollum, JT (reprint author), Ctr Dis Control & Prevent, Epidem Intelligence Serv, Atlanta, GA 30329 USA. EM jeffrey.mccollum@us.army.mil NR 35 TC 70 Z9 73 U1 6 U2 84 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 5 PY 2013 VL 369 IS 10 BP 944 EP 953 DI 10.1056/NEJMoa1215837 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 211KV UT WOS:000323906900011 PM 24004121 ER PT J AU Hoekenga, OA Srinivasan, J Barry, G Bartholomaeus, A AF Hoekenga, Owen A. Srinivasan, Jannavi Barry, Gerard Bartholomaeus, Andrew TI Compositional Analysis of Genetically Modified (GM) Crops: Key Issues and Future Needs SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE genetically modified; transgenic; breeding; safety assessment; appropriate comparator; unintended effects; inherent variability ID GENOME AB Effective symposia need two strong legs to stand upon: informative presentations of recent research paired with lively discussion of these topics. Although it is easy for the organizers of a symposium to predict the usefulness of the former, as they select the speakers and their topic areas, guaranteeing productive discussion is a far more difficult task. For the Crop Composition Workshop sponsored by the International Life Sciences Institutes Committee on Food and Biotechnology (ILSI IFBIC), the organizers scheduled four roundtable discussions with preselected questions and with rapporteurs drawn from governmental organizations and public-sector research institutes (the authors). It was also the organizers intent to let these discussions flow on the basis of the experiences of the participants and pressing issues within the overall debate on the role of crop compositional analysis within safety assessment of biotechnology as it exists now and in the future. The goal of this perspective is to summarize the issues raised, providing references when possible, and to describe the consensus statements reached through the course of these discussions. C1 [Hoekenga, Owen A.] ARS, USDA, Ithaca, NY USA. [Srinivasan, Jannavi] US FDA, College Pk, MD USA. [Barry, Gerard] Int Rice Res Inst, Manila 1099, Philippines. [Bartholomaeus, Andrew] Univ Canberra, Canberra, ACT 2601, Australia. [Bartholomaeus, Andrew] Univ Queensland, Canberra, ACT, Australia. RP Hoekenga, OA (reprint author), ARS, USDA, Ithaca, NY USA. EM ifbic@ilsi.org RI Bartholomaeus, Andrew/F-4417-2014 OI Bartholomaeus, Andrew/0000-0002-9095-8460 NR 16 TC 4 Z9 4 U1 3 U2 39 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 EI 1520-5118 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD SEP 4 PY 2013 VL 61 IS 35 BP 8248 EP 8253 DI 10.1021/jf401141r PG 6 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA 240WU UT WOS:000326129200002 PM 23746303 ER PT J AU Nie, L Soon, GX Qi, KR Chen, Y Chu, HT AF Nie, Lei Soon, Guoxing (Greg) Qi, Karen Chen, Yong Chu, Haitao TI A Note on Partial Covariate-Adjustment and Design Considerations in Noninferiority Trials When Patient-Level Data are not Available SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Constancy assumption; Covariate-adjustment approach; Fixed margin approach; Generalized linear model; Noninferiority margin ID RESISTANT HIV-1 INFECTION; GENOTYPE 1 INFECTION; ISSUES; RALTEGRAVIR; BOCEPREVIR; CHOICE; DELTA AB The traditional fixed margin approach to evaluating an experimental treatment through an active-controlled noninferiority trial is simple and straightforward. However, its utility relies heavily on the constancy assumption of the experimental data. The recently developed covariate-adjustment method permits more flexibility and improved discriminatory capacity compared to the fixed margin approach. However, one major limitation of this covariate-adjustment methodology is its adherence on the patient-level data, which may not be accessible to investigators in practice. In this article, under some assumptions, we examine the feasibility of a partial covariate-adjustment approach based on data typically available from journal publications or other public data when the patient-level data are unavailable. We illustrate the usefulness of this approach through two real examples. We also provide design considerations on the efficiency of the partial covariate-adjustment approach. C1 [Nie, Lei; Soon, Guoxing (Greg); Qi, Karen] US FDA, Div Biometr 4, Off Biometr CDER OTS FDA, Silver Spring, MD 20993 USA. [Chen, Yong] Univ Texas Hlth Sci Ctr Houston, Div Biostat, Houston, TX 77030 USA. [Chu, Haitao] Univ Minnesota, Sch Publ Hlth, Dept Biostat, Minneapolis, MN USA. [Nie, Lei] Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. RP Nie, L (reprint author), US FDA, Div Biometr 4, Off Biometr CDER OTS FDA, WO21 Room 3511,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM lei.nie@fda.hhs.gov OI Chu, Haitao/0000-0003-0932-598X FU Center for Drug Evaluation and Research of the U.S. Food and Drug Administration; [RSR-10-19] FX We thank the referee, an associate editor, and the editor for their comments and suggestions on an earlier version of the article, which were incorporated in the article and substantially improved it. This research was supported by the Review Science Research Funds number RSR-10-19, granted by the Center for Drug Evaluation and Research of the U.S. Food and Drug Administration. This article reflects the views of the authors and should not be construed to represent the U.S. FDA's views or policies. NR 19 TC 0 Z9 0 U1 0 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1054-3406 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PD SEP 3 PY 2013 VL 23 IS 5 BP 1042 EP 1053 DI 10.1080/10543406.2013.813523 PG 12 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA 204ZJ UT WOS:000323409500007 PM 23957514 ER PT J AU Rothmann, M Koti, K Lee, KY Lu, HL Shen, YL Zhang, JJ Jin, M Zhou, HJ AF Rothmann, Mark Koti, Kallappa Lee, Kyung Yul Lu, Hong Laura Shen, Yuan Li Zhang, Jenny J. Jin, Mei Zhou, Haojin TI Evaluating and Adjusting for Premature Censoring of Progression-Free Survival SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Loss to follow-up; Overall survival; Progression-free survival AB The intent-to-treat principle, grouping subjects as they were randomized and following all subjects to the endpoint or the end of study, allows valid statistical comparisons. Progression-free survival (PFS) has been used as a decision-making endpoint in oncology. It can be difficult to have a meaningful intent-to-treat analysis of PFS as some studies have extensive loss to follow-up for PFS. In the analysis, subjects lost to follow-up for PFS have their PFS times censored, with the censoring treated as noninformative. We use remaining overall survival to investigate whether premature censoring for PFS is informative and the potential bias in treating such censoring as noninformative. C1 [Rothmann, Mark; Koti, Kallappa; Lee, Kyung Yul; Lu, Hong Laura; Shen, Yuan Li; Zhang, Jenny J.; Jin, Mei; Zhou, Haojin] US FDA, Ctr Drug Evaluat & Res, Div Biometr 5, Silver Spring, MD 20993 USA. RP Rothmann, M (reprint author), US FDA, Ctr Drug Evaluat & Res, Div Biometr 5, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Mark.Rothmann@fda.hhs.gov FU RSR [09-05, 10-31] FX This research is supported by an internal grant, RSR #09-05 and #10-31. The views expressed in this article are those of the authors and do not necessarily represent those of the U.S. Food and Drug Administration. The work by Mei Jin and Haojin Zhou on this article was while they were interns at the FDA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1054-3406 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PD SEP 3 PY 2013 VL 23 IS 5 BP 1091 EP 1105 DI 10.1080/10543406.2013.813526 PG 15 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA 204ZJ UT WOS:000323409500011 PM 23957518 ER PT J AU Yan, QQ Power, KA Cooney, S Fox, E Gopinath, GR Grim, CJ Tall, BD McCusker, MP Fanning, S AF Yan, Qiongqiong Power, Karen A. Cooney, Shane Fox, Edward Gopinath, Gopal R. Grim, Christopher J. Tall, Ben D. McCusker, Matthew P. Fanning, Seamus TI Complete genome sequence and phenotype microarray analysis of Cronobacter sakazakii SP291: a persistent isolate cultured from a powdered infant formula production facility SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE complete genome; plasmid; Cronobacter sakazakii; stress response; antibiotic resistance; toxic compounds ID SPP. ENTEROBACTER-SAKAZAKII; ESCHERICHIA-COLI; SALMONELLA-ENTERICA; PROTEOMICS APPROACH; TRANSPORT-SYSTEM; MILK FORMULA; IDENTIFICATION; PATHOGEN; GENES; INFECTIONS AB Outbreaks of human infection linked to the powdered infant formula (PIF) food chain and associated with the bacterium Cronobacter, are of concern to public health. These bacteria are regarded as opportunistic pathogens linked to life-threatening infections predominantly in neonates, with an under developed immune system. Monitoring the microbiological ecology of PIF production sites is an important step in attempting to limit the risk of contamination in the finished food product. Cronobacter species, like other microorganisms can adapt to the production environment. These organisms are known for their desiccation tolerance, a phenotype that can aid their survival in the production site and PIF itself. In evaluating the genome data currently available for Cronobacter species, no sequence information has been published describing a Cronobacter sakazakii isolate found to persist in a PIF production facility. Here we report on the complete genome sequence of one such isolate, Cronobacter sakazakii SP291 along with its phenotypic characteristics. The genome of C. sakazakii SP291 consists of a 4.3-Mb chromosome (56.9% GC) and three plasmids, denoted as pSP291-1, [118.1-kb (57.2% GC)], pSP291-2, [52.1-kb (49.2% GC)], and pSP291-3, [4.4-kb (54.0% GC)]. When C. sakazakii SP291 was compared to the reference C. sakazakii ATCC BAA-894, which is also of PIF origin, the annotated genome data identified two interesting functional categories, comprising of genes related to the bacterial stress response and resistance to antimicrobial and toxic compounds. Using a phenotypic microarray (PM), we provided a full metabolic profile comparing C. sakazakii SP291 and the previously sequenced C. sakazakii ATCC BAA-894. These data extend our understanding of the genome of this important neonatal pathogen and provides further insights into the genotypes associated with features that can contribute to its persistence in the PIF environment. C1 [Yan, Qiongqiong; Power, Karen A.; Cooney, Shane; Fox, Edward; McCusker, Matthew P.; Fanning, Seamus] Natl Univ Ireland Univ Coll Dublin, UCD Ctr Food Safety, Sch Publ Hlth Physiotherapy & Populat Sci, WHO Collaborating Ctr Res Reference & Training Cr, Dublin 4, Ireland. [Gopinath, Gopal R.; Grim, Christopher J.; Tall, Ben D.] US FDA, Virulence Mechanisms Branch HFS 025, MOD Facil 1, OARSA,Ctr Food Safety & Appl Nutr,Div Virulence A, Laurel, MD USA. RP Fanning, S (reprint author), Natl Univ Ireland Univ Coll Dublin, UCD Ctr Food Safety, UCD Ctr Mol Innovat Drug Discovery, Sci Ctr South, Room S104, Dublin 4, Ireland. EM sfanning@ucd.ie OI Fanning, Seamus/0000-0002-1922-8836; Tall, Ben/0000-0003-0399-3629 NR 79 TC 7 Z9 8 U1 2 U2 20 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD SEP 2 PY 2013 VL 4 AR 256 DI 10.3389/fmicb.2013.00256 PG 20 WC Microbiology SC Microbiology GA AA9SV UT WOS:000331434100001 PM 24032028 ER PT J AU Merkel, TJ Perera, PY Lee, GM Verma, A Hiroi, T Yokote, H Waldmann, TA Perera, LP AF Merkel, Tod J. Perera, Pin-Yu Lee, Gloria M. Verma, Anita Hiroi, Toyoko Yokote, Hiroyuki Waldmann, Thomas A. Perera, Liyanage P. TI Protective-antigen (PA) based anthrax vaccines confer protection against inhalation anthrax by precluding the establishment of a systemic infection SO HUMAN VACCINES & IMMUNOTHERAPEUTICS LA English DT Article DE anthrax; vaccines; protective antigen; vaccinia; IL-15; bioluminescence ID BACILLUS-ANTHRACIS; DNA VACCINE; MODEL; DISSEMINATION; CHALLENGE; RABBITS; TOXIN; ELECTROPORATION; DISEASE; SPORES AB An intense effort has been launched to develop improved anthrax vaccines that confer rapid, long lasting protection preferably with an extended stability profile amenable for stockpiling. Protective antigen (PA)-based vaccines are most favored as immune responses directed against PA are singularly protective, although the actual protective mechanism remains to be unraveled. Herein we show that contrary to the prevailing view, an efficacious PA-based vaccine confers protection against inhalation anthrax by preventing the establishment of a toxin-releasing systemic infection. Equally importantly, antibodies measured by the in vitro lethal toxin neutralization activity assay (TNA) that is considered as a reliable correlate of protection, especially for PA protein-based vaccines adjuvanted with aluminum salts appear to be not absolutely essential for this protective immune response. C1 [Merkel, Tod J.; Lee, Gloria M.; Verma, Anita] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Perera, Pin-Yu] Vet Affairs Med Ctr, Washington, DC 20422 USA. [Hiroi, Toyoko] NIA, Lymphocyte Differentiat Sect, Baltimore, MD 21224 USA. [Yokote, Hiroyuki] Chemoserotherapeut Res Inst, Kumamoto, Japan. [Waldmann, Thomas A.; Perera, Liyanage P.] NCI, Metab Branch, Bethesda, MD 20892 USA. RP Perera, LP (reprint author), NCI, Metab Branch, Bethesda, MD 20892 USA. EM pereral@mail.nih.gov FU Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH; Trans-NIH/FDA Intramural Biodefense Program; Biodefense and Emerging Infections Research Resources Repository (BEI Resources, NIAID) FX This work was in part supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH and by a 3-y competitive research funding award to L.P.P from the Trans-NIH/FDA Intramural Biodefense Program. We gratefully acknowledge the receipt of reagents from the Biodefense and Emerging Infections Research Resources Repository (BEI Resources, NIAID) for this study. We also express our gratitude to Drs Anne Boyer and John Barr at the CDC for assistance with LF measurements in the rabbit sera. NR 26 TC 2 Z9 2 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2164-5515 EI 2164-554X J9 HUM VACC IMMUNOTHER JI Human Vaccines Immunother. PD SEP PY 2013 VL 9 IS 9 BP 1841 EP 1848 DI 10.4161/hv.25337 PG 8 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA 298AJ UT WOS:000330295900011 PM 23787486 ER PT J AU Matthews, JD Siefert, CJ Blais, MA Park, LT Siefert, CJ Welch, CA DuBois, CM van Nieuwenhuizen, AO Rooney, KO Seabrook, RC Durham, LE Adams, HC Fava, M AF Matthews, John D. Siefert, Caleb J. Blais, Mark A. Park, Lawrence T. Siefert, Caleb J. Welch, Charles A. DuBois, Christina M. van Nieuwenhuizen, Adrienne O. Rooney, Kathryn O. Seabrook, Rita C. Durham, Lauren E. Adams, Heather C. Fava, Maurizio TI A Double-blind, Placebo-Controlled Study of the Impact of Galantamine on Anterograde Memory Impairment During Electroconvulsive Therapy SO JOURNAL OF ECT LA English DT Article DE galantamine; electroconvulsive therapy; anterograde memory impairment ID DIFFERENT STIMULUS INTENSITIES; RANDOMIZED CONTROLLED-TRIAL; RESISTANT MAJOR DEPRESSION; ACETYLCHOLINESTERASE INHIBITION; NEUROPSYCHOLOGICAL STATUS; REPEATABLE BATTERY; BRAIN LEVELS; ECT; EFFICACY; RECEPTORS AB Background: Electroconvulsive therapy (ECT) continues to be an effective treatment option for patients who fail to respond to pharmacological interventions, are unable to tolerate medications, and show a suboptimal response to behavioral and psychotherapeutic treatments. However, risks for cognitive impairment may contribute to some patients' refusal of ECT. Methods: The present study examined galantamine as a pharmacological intervention to reduce cognitive adverse effects from ECT. Thirty-nine inpatients diagnosed with major depressive disorder; bipolar disorder, depressed type; or schizoaffective disorder, depressed type and admitted for ECT were randomized to galantamine or placebo. Study drugs were initiated 24 to 48 hours before starting ECT and continued throughout the course of ECT. A neuropsychological test battery was administered at baseline and 24 to 48 hours after completing a course of ECT treatments. Depression severity was monitored using the 17-item Hamilton Rating Scale for Depression and Clinical Global Impression Scale at baseline, weekly, and end point. Self-rated adverse effects were monitored weekly. Results: Thirty participants (12 patients in the galantamine group, 18 patients in the placebo group) had both pretreatment and post-treatment neuropsychological ratings. Those in the galantamine group scored significantly higher at discharge for delayed memory (t(28) = 2.44, P < 0.05). Hierarchical regressions examined if treatment condition predicted changes in delayed memory scores from baseline to discharge. Inclusion of the treatment condition in the final model made a significant incremental improvement in prediction (Delta R-2 = 0.12, F-1,F-27 change = 4.65, P < 0.05; beta = 0.37, t = 2.16, P < 0.05). Galantamine was well tolerated with no clinically significant bradycardia or prolonged paralysis when administered with ECT. Conclusions: Galantamine may be protective against impairment in retention of new learning. Galantamine exhibited minimal adverse effects and was safe when administered during ECT. The present findings require replication by future researchers using larger samples before broad conclusions can be drawn. C1 [Matthews, John D.; Blais, Mark A.; Welch, Charles A.; DuBois, Christina M.; van Nieuwenhuizen, Adrienne O.; Rooney, Kathryn O.; Seabrook, Rita C.; Durham, Lauren E.; Adams, Heather C.; Fava, Maurizio] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Matthews, John D.; Park, Lawrence T.; Welch, Charles A.; Fava, Maurizio] Harvard Univ, Sch Med, Boston, MA USA. [Siefert, Caleb J.] Univ Michigan, Dearborn, MI 48128 USA. [Park, Lawrence T.; Siefert, Caleb J.] US FDA, Silver Spring, MD USA. RP Matthews, JD (reprint author), 55 Fruit St,Blake 11, Boston, MA 02114 USA. EM jmatthews@partners.org FU Janssen Pharmaceutica FX This study was funded by Janssen Pharmaceutica. NR 70 TC 8 Z9 8 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1095-0680 EI 1533-4112 J9 J ECT JI J. ECT PD SEP PY 2013 VL 29 IS 3 BP 170 EP 178 DI 10.1097/YCT.0b013e31828b3523 PG 9 WC Behavioral Sciences; Psychiatry SC Behavioral Sciences; Psychiatry GA 298YX UT WOS:000330362100015 PM 23519225 ER PT J AU Huang, SM Abernethy, DR Wang, YN Zhao, P Zineh, I AF Huang, Shiew-Mei Abernethy, Darrell R. Wang, Yaning Zhao, Ping Zineh, Issam TI The Utility of Modeling and Simulation in Drug Development and Regulatory Review SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Review DE regulatory science; PBPK; Modeling and simulation; systems pharmacology; pharmacodynamics; drug interactions; dose-response; pharamcokinetics ID PHYSIOLOGICALLY-BASED PHARMACOKINETICS; IN-VIVO EXTRAPOLATION; CRITICAL PATH; CLINICAL-PHARMACOLOGY; SAFETY ASSESSMENT; SCIENCE; PREDICTION; TRANSPORTERS; FESOTERODINE; INFORMATICS AB US Food and Drug Administration (FDA) has identified innovation in clinical evaluations as a major scientific priority area. This paper provides case studies and updates to describe the efforts by the FDA's Office of Clinical Pharmacology in its development and application of regulatory science, focusing on modeling and simulation. Key issues and challenges are identified that need to be addressed to promote the uptake of modeling and simulation approaches in drug regulation. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. C1 [Huang, Shiew-Mei; Abernethy, Darrell R.; Wang, Yaning; Zhao, Ping; Zineh, Issam] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Huang, SM (reprint author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM ShiewMei.Huang@FDA.HHS.GOV NR 43 TC 50 Z9 53 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD SEP PY 2013 VL 102 IS 9 SI SI BP 2912 EP 2923 DI 10.1002/jps.23570 PG 12 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 297FK UT WOS:000330240900006 PM 23712632 ER PT J AU Wagner, C Thelen, K Willmann, S Selen, A Dressman, JB AF Wagner, Christian Thelen, Kirstin Willmann, Stefan Selen, Arzu Dressman, Jennifer B. TI Utilizing In Vitro and PBPK Tools to Link ADME Characteristics to Plasma Profiles: Case Example Nifedipine Immediate Release Formulation SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE absorption; bioavailability; computational ADME; cytochrome P450; dissolution; drug metabolizing enzymes; first-pass metabolism; pharmacokinetics; quality by design (QbD) ID DETAILED PHYSIOLOGICAL MODEL; GRAPEFRUIT-JUICE; CLINICAL PHARMACOKINETICS; BIORELEVANT DISSOLUTION; GASTROINTESTINAL TRANSIT; PARACETAMOL ABSORPTION; CALCIUM-ANTAGONISTS; 1ST-PASS METABOLISM; ORAL AVAILABILITY; DRUG-INTERACTIONS AB One of the most prominent food-drug interactions is the inhibition of intestinal cytochrome P450 (CYP) 3A enzymes by grapefruit juice ingredients, and, as many drugs are metabolized via CYP 3A, this interaction can be of clinical importance. Calcium channel-blocking agents of the dihydropyridine type, such as felodipine and nifedipine, are subject to extensive intestinal first pass metabolism via CYP 3A, thus resulting in significantly enhanced in vivo exposure of the drug when administered together with grapefruit juice. Physiologically based pharmacokinetic (PBPK) modeling was used to simulate pharmacokinetics of a nifedipine immediate release formulation following concomitant grapefruit juice ingestion, that is, after inhibition of small intestinal CYP 3A enzymes. For this purpose, detailed data about CYP 3A levels were collected from the literature and implemented into commercial PBPK software. As literature reports show that grapefruit juice (i) leads to a marked delay in gastric emptying, and (ii) rapidly lowers the levels of intestinal CYP 3A enzymes, inhibition of intestinal first pass metabolism following ingestion of grapefruit juice was simulated by altering the intestinal CYP 3A enzyme levels and simultaneously decelerating the gastric emptying rate. To estimate the in vivo dispersion and dissolution behavior of the formulation, dissolution tests in several media simulating both the fasted and fed state stomach and small intestine were conducted, and the results from the in vitro dissolution tests were used as input function to describe the in vivo dissolution of the drug. Plasma concentration-time profiles of the nifedipine immediate release formulation both with and without simultaneous CYP 3A inhibition were simulated, and the results were compared with data gathered from the literature. Using this approach, nifedipine plasma profiles could be simulated well both with and without enzyme inhibition. A reduction in small intestinal CYP 3A levels by 60% was found to yield the best results, with simulated nifedipine concentration-time profiles within 20% of the in vivo observed results. By additionally varying the dissolution input of the PBPK model, a link between the dissolution characteristics of the formulation and its in vivo performance could be established. (C) 2013 Wiley Periodicals, Inc. C1 [Wagner, Christian; Dressman, Jennifer B.] Goethe Univ, Inst Pharmaceut Technol, D-60438 Frankfurt, Germany. [Thelen, Kirstin; Willmann, Stefan] Bayer Technol Serv GmbH, Technol Package Computat Syst Biol, D-51368 Leverkusen, Germany. [Selen, Arzu] US FDA, Off New Drug Qual Assessment OPS CDER, Silver Spring, MD 20993 USA. RP Dressman, JB (reprint author), Goethe Univ, Inst Pharmaceut Technol, D-60438 Frankfurt, Germany. EM dressman@em.uni-frankfurt.de RI Fachbereich14, Dekanat/C-8553-2015 FU FDA FX Christian Wagner received partial financial support for this project through a grant from the FDA. An academic license of PK-Sim (R) and MoBi (R) was provided by Bayer Technology Services, Leverkusen, Germany. NR 79 TC 11 Z9 11 U1 2 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD SEP PY 2013 VL 102 IS 9 SI SI BP 3205 EP 3219 DI 10.1002/jps.23611 PG 15 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 297FK UT WOS:000330240900028 PM 23696038 ER PT J AU Xia, QS Zhao, YW Von Tungeln, LS Doerge, DR Lin, G Cai, LN Fu, PP AF Xia, Qingsu Zhao, Yuewei Von Tungeln, Linda S. Doerge, Daniel R. Lin, Ge Cai, Lining Fu, Peter P. TI Pyrrolizidine Alkaloid-Derived DNA Adducts as a Common Biological Biomarker of Pyrrolizidine Alkaloid-Induced Tumorigenicity SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID TANDEM MASS-SPECTROMETRY; BIG BLUE RATS; METABOLIC-ACTIVATION; CROSS-LINKING; IN-VIVO; DIETARY-SUPPLEMENTS; MEDICINAL-PLANTS; ISLET-CELL; N-OXIDES; RIDDELLIINE AB Pyrrolizidine alkaloid-containing plants are the most common poisonous plants affecting livestock, wildlife, and humans. The U.S. National Toxicology Program (NTP) classified riddelliine, a tumorigenic pyrrolizidine alkaloid, as "reasonably anticipated to be a human carcinogen" in the NTP 12th Report on Carcinogens in 2011. We previously determined that four DNA adducts were formed in rats dosed with riddelliine. The structures of the four DNA adducts were elucidated as (i) a pair of epimers of 7-hydroxy-9-(deoxyguanosin-N-2-yl)dehydrosupinidine adducts.(termed as DHP-dG-3 and DHP-dG-4) as the predominant adducts; and (ii) a pair of epimers of 7-hydroxy-9-(deoxyadenosin-N-6-yl)dehydrosupinidine adducts (termed as DHP-dA-3 and DHP-dA-4 adducts). In this study, we selected a nontumorigenic pyrrolizidine alkaloid, platyphylliine, a pyrrolizidine alkaloid N-oxide, riddelliine N-oxide, and nine tumorigenic pyrrolizidine alkaloids (riddelliine, retrorsine, monocrotaline, lycopsamine, retronecine, lasiocarpine, heliotrine, clivorine, and senkirkine) for study in animals. Seven of the nine tumorigenic pyrrolizidine alkaloids, with the exception of lycopsamine and retronecine, are liver carcinogens. At 8-10 weeks of age, female F344 rats were orally gavaged for 3 consecutive days with 4.5 and 24 mu mol/kg body weight test article in 0.5 mL of 10% DMSO in water. Twenty-four hours after the last dose, the rats were sacrificed, livers were removed, and liver DNA was isolated for DNA adduct analysis. DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4 adducts were formed in the liver of rats treated with the individual seven hepatocarcinogenic pyrrolizidine alkaloids and riddelliine N-oxide. These DNA adducts were not formed in the liver of rats administered retronecine, the nontumorigenic pyrrolizidine alkaloid, platyphylliine, or vehicle control. These results indicate that this set of DNA adducts, DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4, is a common biological biomarker of pyrrolizidine alkaloid-induced liver tumor formation. To date, this is the first finding that a set of exogenous DNA adducts are commonly formed from a series of tumorigenic xenobiotics. C1 [Xia, Qingsu; Zhao, Yuewei; Von Tungeln, Linda S.; Doerge, Daniel R.; Fu, Peter P.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Lin, Ge] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. [Cai, Lining] Biotranex LLC, Monmouth Jct, NJ 08852 USA. RP Fu, PP (reprint author), Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM peter.fu@fda.hhs.gov FU U.S. Department of Energy; FDA FX This research was supported in part by appointment (Y.Z.) to the Postgraduate Research Program at the NCTR administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the FDA. NR 55 TC 27 Z9 27 U1 6 U2 22 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X EI 1520-5010 J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD SEP PY 2013 VL 26 IS 9 BP 1384 EP 1396 DI 10.1021/tx400241c PG 13 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 295DA UT WOS:000330095600011 PM 23937665 ER PT J AU Lewis, JP Stephens, SH Horenstein, RB O'Connell, JR Ryan, K Peer, CJ Figg, WD Spencer, SD Pacanowski, MA Mitchell, BD Shuldiner, AR AF Lewis, J. P. Stephens, S. H. Horenstein, R. B. O'Connell, J. R. Ryan, K. Peer, C. J. Figg, W. D. Spencer, S. D. Pacanowski, M. A. Mitchell, B. D. Shuldiner, A. R. TI The CYP2C19*17 variant is not independently associated with clopidogrel response SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Clopidogrel; drug metabolism; poor; CYP2C19-related; linkage disequilibrium; pharmacogenetics; platelets ID 2C19-ASTERISK-17 ALLELIC VARIANT; CORONARY STENT PLACEMENT; TREATED PATIENTS; ANTIPLATELET TREATMENT; CARDIOVASCULAR EVENTS; PLATELET-AGGREGATION; CLINICAL-EFFICACY; BLEEDING EVENTS; POLYMORPHISMS; THROMBOSIS AB SummaryBackground Cytochrome P450 2C19 (CYP2C19) is the principal enzyme responsible for converting clopidogrel into its active metabolite, and common genetic variants have been identified, most notably CYP2C19*2 and CYP2C19*17, that are believed to alter its activity and expression, respectively. Objective We evaluated whether the consequences of the CYP2C19*2 and CYP2C19*17 variants on clopidogrel response were independent of each other or genetically linked through linkage disequilibrium (LD). Patients/Methods We genotyped the CYP2C19*2 and CYP2C19*17 variants in 621 members of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and evaluated the effects of these polymorphisms singly and then jointly, taking into account LD, on clopidogrel prodrug level, clopidogrel active metabolite level, and adenosine 5 '-diphosphate (ADP)-stimulated platelet aggregation before and after clopidogrel exposure. Results The CYP2C19*2 and CYP2C19*17 variants were in LD (|D '| = 1.0; r(2) = 0.07). In association analyses that did and did not account for the effects of CYP2C19*17, CYP2C19*2 was strongly associated with levels of clopidogrel active metabolite (beta = -5.24, P = 3.0 x 10(-9) and beta = -5.36, P = 3.3 x 10(-14), respectively) and posttreatment ADP-stimulated platelet aggregation (beta = 7.55, P = 2.9 x 10(-16) and beta = 7.51, P = 7.0 x 10(-15), respectively). In contrast, CYP2C19*17 was marginally associated with clopidogrel active metabolite levels and ADP-stimulated platelet aggregation before (beta = 1.57, P = 0.04 and beta = -1.98, P = 0.01, respectively) but not after (beta = 0.40, P = 0.59 and beta = -0.13, P = 0.69, respectively) adjustment for the CYP2C19*2 variant. Stratified analyses of CYP2C19*2/CYP2C19*17 genotype combinations revealed that CYP2C19*2, and not CYP2C19*17, was the primary determinant in altering clopidogrel response. Conclusions Our results suggest that CYP2C19*17 has a small (if any) effect on clopidogrel-related traits and that the observed effect of this variant is due to LD with the CYP2C19*2 loss-of-function variant. C1 [Lewis, J. P.; Stephens, S. H.; Horenstein, R. B.; O'Connell, J. R.; Ryan, K.; Mitchell, B. D.; Shuldiner, A. R.] Univ Maryland, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Lewis, J. P.; Stephens, S. H.; Horenstein, R. B.; O'Connell, J. R.; Ryan, K.; Mitchell, B. D.; Shuldiner, A. R.] Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA. [Peer, C. J.; Figg, W. D.] NCI, Clin Pharmacol Program, Bethesda, MD 20892 USA. [Spencer, S. D.] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. [Pacanowski, M. A.] US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol, Silver Spring, MD USA. [Shuldiner, A. R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA. RP Shuldiner, AR (reprint author), Univ Maryland, Sch Med, 685 West Baltimore St,Rm 379, Baltimore, MD 21201 USA. EM ashuldin@medicine.umaryland.edu RI Figg Sr, William/M-2411-2016; OI Mitchell, Braxton/0000-0003-4920-4744 FU National Institutes of Health [NIH U01 GM074518, U01 HL105198, U01 HL084756, U01 GM074492, R01074730, K23 GM102678, GM074518-05S1]; Mid-Atlantic Nutrition and Obesity Center [P30 DK072488]; University of Maryland General Clinical Research Center [M01 RR16500]; Baltimore Veterans Administration Geriatric Research and Education Clinical Center FX This study was supported by National Institutes of Health grants NIH U01 GM074518, U01 HL105198, U01 HL084756, U01 GM074492, R01074730, and K23 GM102678, GM074518-05S1, the Mid-Atlantic Nutrition and Obesity Center (P30 DK072488), the University of Maryland General Clinical Research Center (M01 RR16500), and the Baltimore Veterans Administration Geriatric Research and Education Clinical Center. NR 23 TC 20 Z9 22 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD SEP PY 2013 VL 11 IS 9 BP 1640 EP 1646 DI 10.1111/jth.12342 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 216UU UT WOS:000324311400002 PM 23809542 ER PT J AU McEvoy, BW Nandy, RR Tiwari, RC AF McEvoy, Bradley W. Nandy, Rajesh R. Tiwari, Ram C. TI Bayesian Approach for Clinical Trial Safety Data Using an Ising Prior SO BIOMETRICS LA English DT Article DE Bayes Factor; Drug safety; High-dimensional data analysis; Ising prior; Markov random field; MedDRA ID VARIABLE SELECTION; DRUG AB In drug safety, development of statistical methods for multiplicity adjustments has exploited potential relationships among adverse events (AEs) according to underlying medical features. Due to the coarseness of the biological features used to group AEs together, which serves as the basis for the adjustment, it is possible that a single adverse event can be simultaneously described by multiple biological features. However, existing methods are limited in that they are not structurally flexible enough to accurately exploit this multi-dimensional characteristic of an adverse event. In order to preserve the complex dependencies present in clinical safety data, a Bayesian approach for modeling the risk differentials of the AEs between the treatment and comparator arms is proposed which provides a more appropriate clinical description of the drug's safety profile. The proposed procedure uses an Ising prior to unite medically related AEs. The proposed method and an existing Bayesian method are applied to a clinical dataset, and the signals from the two methods are presented. Results from a small simulation study are also presented. C1 [McEvoy, Bradley W.; Tiwari, Ram C.] US FDA, Off Biostat, CDER, Silver Spring, MD 20993 USA. [Nandy, Rajesh R.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Nandy, Rajesh R.] Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA 90095 USA. RP McEvoy, BW (reprint author), US FDA, Off Biostat, CDER, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM bradley.mcevoy@fda.hhs.gov NR 20 TC 1 Z9 1 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD SEP PY 2013 VL 69 IS 3 BP 661 EP 672 DI 10.1111/biom.12051 PG 12 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 283ZO UT WOS:000329285700014 PM 23845253 ER PT J AU Ampofo, WK Baylor, N Cobey, S Cox, NJ Daves, S Edwards, S Ferguson, N Grohmann, G Hay, A Katz, J Kullabutr, K Lambert, L Levandowski, R Mishra, AC Monto, A Siqueira, M Tashiro, M Waddell, AL Wairagkar, N Wood, J Zambon, M Zhang, WQ AF Ampofo, William K. Baylor, Norman Cobey, Sarah Cox, Nancy J. Daves, Sharon Edwards, Steven Ferguson, Neil Grohmann, Gary Hay, Alan Katz, Jacqueline Kullabutr, Kornnika Lambert, Linda Levandowski, Roland Mishra, A. C. Monto, Arnold Siqueira, Marilda Tashiro, Masato Waddell, Anthony L. Wairagkar, Niteen Wood, John Zambon, Maria Zhang, Wenqing CA WHO Writing Grp TI Improving influenza vaccine virus selection: report of a WHO informal consultation held at WHO headquarters, Geneva, Switzerland, 14-16 June 2010 SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Article DE influenza vaccine viruses; vaccine virus selection; WHO recommendations C1 [Ampofo, William K.] Natl Influenza Ctr, Accra, Ghana. [Baylor, Norman] Food & Drug Adm, Rockville, MA USA. [Cobey, Sarah] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Cox, Nancy J.; Katz, Jacqueline] Ctr Dis Control & Prevent CDC, Atlanta, GA USA. [Daves, Sharon] NAMRU 3, Cairo, Egypt. [Edwards, Steven] Network Expertise Anim Influenzas OFFLU Steering, Hereford, England. [Ferguson, Neil] Imperial Coll Sch Med St Marys, London, England. [Grohmann, Gary] Therapeut Goods Adm Labs, Symonston, Australia. [Hay, Alan] Natl Inst Med Res, London NW7 1AA, England. [Kullabutr, Kornnika] Minist Publ Hlth, Nonthaburi, Thailand. [Lambert, Linda] NIH, Bethesda, MD 20892 USA. [Mishra, A. C.] Natl Influenza Ctr, Pune, Maharashtra, India. [Monto, Arnold] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Siqueira, Marilda] Inst Oswaldo Cruz, BR-20001 Rio De Janeiro, Brazil. [Tashiro, Masato] WHO Collaborating Ctr Reference & Res Influenza, Tokyo, Japan. [Wairagkar, Niteen; Zhang, Wenqing] WHO, CH-1211 Geneva, Switzerland. [Wood, John] NIBSC, Potters Bar, Herts, England. [Zambon, Maria] Hlth Protect Agcy, London, England. RP Zhang, WQ (reprint author), WHO, CH-1211 Geneva, Switzerland. EM zhangw@who.int RI Ferguson, Neil/B-8578-2008 OI Ferguson, Neil/0000-0002-1154-8093 NR 2 TC 3 Z9 3 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1750-2640 EI 1750-2659 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD SEP PY 2013 VL 7 SU 2 SI SI BP 52 EP 53 DI 10.1111/irv.12081 PG 2 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA 265KE UT WOS:000327949400008 PM 24034484 ER PT J AU Grinev, A Chancey, C Anez, G Ball, C Winkelman, V Williamson, P Foster, GA Stramer, SL Rios, M AF Grinev, Andriyan Chancey, Caren Anez, German Ball, Christopher Winkelman, Valerie Williamson, Phillip Foster, Gregory A. Stramer, Susan L. Rios, Maria TI Genetic Analysis of West Nile Virus Isolates from an Outbreak in Idaho, United States, 2006-2007 SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE Flavivirus; West Nile virus; genetic variation; WNV evolution; indel motifs; next generation sequencing ID DNA-SEQUENCE COMPLEXITY; DENGUE TYPE-1 VIRUS; 3 NONCODING REGION; PHYLOGENETIC ANALYSIS; VARIABLE REGION; NORTH-AMERICA; MUTANT SPECTRUM; COMPLETE GENOME; FLAVIVIRUS RNA; BLOOD-DONORS AB West Nile virus (WNV) appeared in the U.S. in 1999 and has since become endemic, with yearly summer epidemics causing tens of thousands of cases of serious disease over the past 14 years. Analysis of WNV strains isolated during the 2006-2007 epidemic seasons demonstrates that a new genetic variant had emerged coincidentally with an intense outbreak in Idaho during 2006. The isolates belonging to the new variant carry a 13 nt deletion, termed ID-13, located at the variable region of the 3UTR, and are genetically related. The analysis of deletions and insertions in the 3UTR of two major lineages of WNV revealed the presence of conserved repeats and two indel motifs in the variable region of the 3UTR. One human and two bird isolates from the Idaho 2006-2007 outbreaks were sequenced using Illumina technology and within-host variability was analyzed. Continued monitoring of new genetic variants is important for public health as WNV continues to evolve. C1 [Grinev, Andriyan; Chancey, Caren; Anez, German; Rios, Maria] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Ball, Christopher] Idaho Bur Labs, Boise, ID 83712 USA. [Winkelman, Valerie; Williamson, Phillip] Creat Testing Solut, Tempe, AZ 85282 USA. [Foster, Gregory A.; Stramer, Susan L.] Amer Red Cross, Gaithersburg, MD 20877 USA. RP Grinev, A (reprint author), US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM andriyan.grinev@fda.hhs.gov; caren.chancey@fda.hhs.gov; german.anez@fda.hhs.gov; ballc1@dhw.idaho.gov; VWinkelman@mycts.org; PWilliamson@mycts.org; Gregory.Foster@redcross.org; Susan.Stramer@redcross.org; maria.rios@fda.hhs.gov OI Anez, German/0000-0001-5361-3001 FU FDA Intramural Program FX The findings and conclusions in this article have not been formally disseminated by the U.S. Food and Drug Administration and should not be construed to represent any Agency determination or policy. We would like to thank Vahan Simonyan for help with using HIVE for NGS data analysis. This study was partially supported by the FDA Intramural Program. NR 71 TC 2 Z9 2 U1 0 U2 6 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD SEP PY 2013 VL 10 IS 9 BP 4486 EP 4506 DI 10.3390/ijerph10094486 PG 21 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 274QD UT WOS:000328620200040 PM 24065039 ER PT J AU Mbondji-Wonje, C Ragupathy, V Lee, S Wood, O Awazi, B Hewlett, IK AF Mbondji-Wonje, Christelle Ragupathy, Viswanath Lee, Sherwin Wood, Owen Awazi, Bih Hewlett, Indira K. TI Seroprevalence of Human Herpesvirus-8 in HIV-1 Infected and Uninfected Individuals in Cameroon SO VIRUSES-BASEL LA English DT Article DE HHV-8; HIV-1; serology; prevalence; Cameroon ID KAPOSIS-SARCOMA; PRIMARY INFECTION; SEROLOGIC ASSAYS; AFRICA; EPIDEMIOLOGY; TRANSMISSION; MULTICENTER; ANTIBODIES; HHV-8; RISK AB We evaluated the prevalence of HHV-8 antibodies in 516 plasma samples collected from HIV positive and negative patients from blood banks and urban areas of Cameroon. Among HIV-1 positive samples, HHV-8 seropositivity rate was 61% based on combined reactivity using both ELISA and IFA techniques. HIV negative samples showed 62% seropositivity rate for HHV-8 antibodies. Our results indicate a high HHV-8 prevalence rate in both HIV infected and uninfected individuals in Cameroon. C1 [Mbondji-Wonje, Christelle; Ragupathy, Viswanath; Lee, Sherwin; Wood, Owen; Hewlett, Indira K.] US FDA, Mol Virol Lab, Div Emerging & Transmiss Transmitted Dis, Off Blood Review & Res,Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Mbondji-Wonje, Christelle] Chantal Biya Int Reference Ctr, Yaounde 3077, Cameroon. [Awazi, Bih] Lab Anal Med Nkoldongo, Yaounde 20025, Cameroon. RP Mbondji-Wonje, C (reprint author), US FDA, Mol Virol Lab, Div Emerging & Transmiss Transmitted Dis, Off Blood Review & Res,Ctr Biol Evaluat & Res, 1401 Rockville Pike, Rockville, MD 20852 USA. EM Christelle.Mbondji@fda.hhs.gov; Indira.Hewlett@fda.hhs.gov FU National Heart, Lung and Blood Institute of the National Institutes of Health, USA through the Inter-Agency [BY1-HB-5026-01] FX The authors would like to thank Shixing Tang, Andrew Dayton and Hira Nakhasi for review of this manuscript. The findings and conclusions in this article have not been formally disseminated by the FDA and should not be construed to represent any Agency determination or policy. The authors wish to acknowledge the National Heart, Lung and Blood Institute of the National Institutes of Health, USA, for funding part of this work through the Inter-Agency Agreement BY1-HB-5026-01. NR 26 TC 2 Z9 2 U1 0 U2 2 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD SEP PY 2013 VL 5 IS 9 BP 2253 EP 2259 DI 10.3390/v5092253 PG 7 WC Virology SC Virology GA 274NZ UT WOS:000328614500010 PM 24056671 ER PT J AU Nie, L Zhang, ZW Rubin, D Chu, JX AF Nie, Lei Zhang, Zhiwei Rubin, Daniel Chu, Jianxiong TI LIKELIHOOD REWEIGHTING METHODS TO REDUCE POTENTIAL BIAS IN NONINFERIORITY TRIALS WHICH RELY ON HISTORICAL DATA TO MAKE INFERENCE SO ANNALS OF APPLIED STATISTICS LA English DT Article DE Bias; generalized linear model; inverse probability weighting; noninferiority; propensity score ID RESPIRATORY SYNCYTIAL VIRUS; MARGINAL STRUCTURAL MODELS; PROPENSITY SCORE; CLINICAL-TRIALS; TARGET POPULATIONS; RISK; RALTEGRAVIR; SUICIDALITY; REGRESSION; INFECTION AB It is generally believed that bias is minimized in well-controlled randomized clinical trials. However, bias can arise in active controlled noninferiority trials because the inference relies on a previously estimated effect size obtained from a historical trial that may have been conducted for a different population. By implementing a likelihood reweighting method through propensity scoring, a study designed to estimate a treatment effect in one trial population can be used to estimate the treatment effect size in a different target population. We illustrate this method in active controlled noninferiority trials, although it can also be used in other types of studies, such as historically controlled trials, meta-analyses, and comparative effectiveness analyses. C1 [Nie, Lei; Rubin, Daniel] US FDA, Div Biometr 4, Off Biostat, CDER, Silver Spring, MD 20993 USA. [Zhang, Zhiwei; Chu, Jianxiong] US FDA, Div Biostat, Off Surveillance & Biometr, CDER, Silver Spring, MD 20993 USA. RP Nie, L (reprint author), US FDA, Div Biometr 4, Off Biostat, CDER, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM zhiwei.zhang@fda.hhs.gov NR 30 TC 1 Z9 1 U1 2 U2 8 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 1932-6157 J9 ANN APPL STAT JI Ann. Appl. Stat. PD SEP PY 2013 VL 7 IS 3 BP 1796 EP 1813 DI 10.1214/13-AOAS655 PG 18 WC Statistics & Probability SC Mathematics GA 268VM UT WOS:000328198700023 ER PT J AU Chen, YY Meng, FY Fang, H Yu, YN Liu, J Jing, ZW Lv, AP Wang, Z Wang, YY AF Chen, Yinying Meng, Fanyun Fang, Hong Yu, Yanan Liu, Jun Jing, Zhiwei Lv, Aiping Wang, Zhong Wang, Yongyan TI Hierarchical Profiles of Signaling Pathways and Networks Reveal Two Complementary Pharmacological Mechanisms SO CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS LA English DT Article DE Cerebral ischemia; Ca2+ signaling; Ingenuity Pathway Analysis; networks function; signaling pathway; pharmacological mechanism ID FOCAL CEREBRAL-ISCHEMIA; NF-KAPPA-B; OXIDATIVE STRESS; ARACHIDONIC-ACID; GENE-EXPRESSION; DRUG DISCOVERY; BREAST-CANCER; IN-VIVO; PROTEIN; BRAIN AB Until now the overlapping and diverse pharmacological protective mechanisms of different compounds in the treatment of cerebral ischemia, both on the signaling pathway and network levels have not been revealed. In order to find differential pathway networks from gene expression profiles of hippocampus of ischemic mice treated with baicalin (BA), ursodeoxycholic acid (UA) and jasminoidin (JA), a microarray comprising 16,463 genes, FDA Arraytrack software and Ingenuity Pathway Analysis, was employed. A total of 5, 8, 11, 9 networks and 6, 7, 40, 16 pathways were found in vehicle (vs sham), BA, UA and JA (vs vehicle), respectively. Only 4 and 7 overlapping pathways were shared between BA and UA, UA and JA, accounting for 9.3% and 14.3% of the total number of all pathways, respectively. BA, UA and JA all acted on Ca2+-dependent signaling cascades in diverse links. BA intervened in arachidonic acid metabolism. UA affected eicosanoid, cyclin-dependent kinase 5, nuclear factor-kappa B, and T-helper 1 cell cytokine production. It was found that JA might decrease oxidative damage via nuclear factor erythroid 2-related factor 2-mediated antioxidant response. Compared to vehicle, no overlapping pathways were found among three groups. However, the total of 60 (71.4%) overlapping functions could be approximately divided into diseases and disorders, molecular and cellular functions, physiological system development and function as categories with ratio of 1:1:1. Analysis of network functions and known pathways may be two complementary paradigms for revealing potential pharmacological mechanisms based on the same phenotype variation. C1 [Chen, Yinying; Yu, Yanan; Liu, Jun; Jing, Zhiwei; Lv, Aiping; Wang, Zhong; Wang, Yongyan] China Acad Chinese Med Sci, Inst Basic Res Clin Med, Beijing 100700, Peoples R China. [Meng, Fanyun] Beijing Normal Univ, Inst Nat Med & Chinese Med Resources, Beijing 100875, Peoples R China. [Fang, Hong] US FDA, Z Tech Corp, Jefferson, AR 72007 USA. RP Wang, Z (reprint author), China Acad Chinese Med Sci, Inst Basic Res Clin Med, Beijing 100700, Peoples R China. EM zhonw@vip.sina.com FU National 11th Five-years-plan Supporting RD Project [2006BAI08B04-06] FX This work was supported by National 11th Five-years-plan Supporting R&D Project (2006BAI08B04-06). NR 55 TC 4 Z9 5 U1 3 U2 7 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5273 EI 1996-3181 J9 CNS NEUROL DISORD-DR JI CNS Neurol. Disord.-Drug Targets PD SEP PY 2013 VL 12 IS 6 BP 882 EP 893 PG 12 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 263HD UT WOS:000327797200020 PM 23469837 ER PT J AU Huang, L Midthune, D Krapcho, M Zou, ZH Horner, MJ Feuer, EJ AF Huang, Lan Midthune, Douglas Krapcho, Martin Zou, Zhaohui Horner, Marie-Joseph Feuer, Eric J. TI Adjusting for reporting delay in cancer incidence when combining different sets of cancer registries SO BIOMETRICAL JOURNAL LA English DT Article DE Adjusted cancer incidence; Delay models; Delay adjustment factor; Reporting delay; SEER ID AIDS INCIDENCE; REGRESSION; RATES; SURVEILLANCE; TRENDS AB Cancer registries collect cancer incidence data that can be used to calculate incidence rates in a population and track changes over time. For incidence rates to be accurate, it is critical that diagnosed cases be reported in a timely manner. Registries typically allow a fixed amount of time (e.g. two years) for diagnosed cases to be reported before releasing the initial case counts for a particular diagnosis year. Inevitably, however, additional cases are reported after the initial counts are released; these extra cases are included in subsequent releases that become more complete over time, while incidence rates based on earlier releases will underestimate the true rates. Statistical methods have been developed to estimate the distribution of reporting delay (the amount of time until a diagnosed case is reported) and to correct incidence rates for underestimation due to reporting delay. Since the observed reporting delays must be less than the length of time the registry has been collecting data, most methods estimate a truncated delay distribution. These methods can be applied to a group of registries that began collecting data in the same diagnosis year. In this paper, we extend the methods to two groups of registries that began collecting data in two different diagnosis years (so that the delay distributions are truncated at different times). We apply the proposed method to data from the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) program, a consortium of U.S. cancer registries that includes nine registries with data collection beginning in 1981 and four registries with data collection beginning in 1992. We use the method to obtain delay-adjusted incidence rates for melanoma, liver cancer, and Hodgkin lymphoma. C1 [Huang, Lan] FDA CDER, Silver Spring, MD 20993 USA. [Midthune, Douglas; Feuer, Eric J.] NCI, NIH, Rockville, MD 20850 USA. [Krapcho, Martin; Zou, Zhaohui] Informat Management Serv Inc, Calverton, MD 20705 USA. [Horner, Marie-Joseph] Univ N Carolina, Dept Epidemiol, UNC Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. RP Feuer, EJ (reprint author), NCI, NIH, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM feuerr@mail.nih.gov NR 13 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0323-3847 EI 1521-4036 J9 BIOMETRICAL J JI Biom. J. PD SEP PY 2013 VL 55 IS 5 BP 755 EP 770 DI 10.1002/bimj.201100191 PG 16 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 263OC UT WOS:000327816900008 PM 23873707 ER PT J AU Di, X Zhang, GF Zhang, YQ Takeda, K Rosado, LAR Zhang, BL AF Di, Xu Zhang, Guofeng Zhang, Yaqin Takeda, Kazuyo Rosado, Leslie A. Rivera Zhang, Baolin TI Accumulation of autophagosomes in breast cancer cells induces TRAIL resistance through downregulation of surface expression of death receptors 4 and 5 SO ONCOTARGET LA English DT Article DE TRAIL resistance; basal autophagosomes; death receptors; cell surface expression ID TUMOR-NECROSIS-FACTOR; PANCREATIC DUCTAL ADENOCARCINOMA; INDUCED APOPTOSIS; CROSS-PRESENTATION; OVARIAN-CANCER; LIGAND TRAIL; LUNG-CANCER; PHASE-I; INHIBITION; SURVIVAL AB TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis through death receptors (DRs) 4 and/or 5 expressed on the surface of target cells. We have previously shown that deficiency of DR4 and DR5 on the surface membrane is a critical mechanism of cancer cell resistance to the recombinant human TRAIL and its receptor agonistic antibodies, which are being evaluated clinically for treating cancers. In certain cancer cells, DR4 and DR5 were found to be mislocalized in intracellular compartments yet to be characterized. Here, we report a novel role of autophagy in the regulation of dynamics of TRAIL death receptors. We first assessed basal levels of autophagosomes in a panel of 11 breast cancer cell lines using complementary approaches (LC3 immunoblotting, RFP-LC3 fluorescence microscopy, and electron microscopy). We found high levels of basal autophagosomes in TRAIL resistant breast cancer cell lines (e.g. BT474 and AU565) and relevant mouse xenograft models under nutrition-rich conditions. Notably, DR4 and DR5 co-localized with LC3-II in the autophagosomes of TRAIL-resistant cells. Disruption of basal autophagosomes successfully restored the surface expression of the death receptors which was accompanied by sensitization of TRAIL-resistant cells to TRAIL induced apoptosis. By contrast, TRAIL-sensitive cell lines (MDA-MB-231) are characterized by high levels of surface DR4/DR5 and an absence of basal autophagosomes. Inhibition of lysosomal activity induced an accumulation of autophagosomes and a decrease in surface DR4 and DR5, and the cells became less sensitive to TRAIL-induced apoptosis. These findings demonstrate a novel role for the basal autophagosomes in the regulation of TRAIL death receptors. Further studies are warranted to explore the possibility of using autophagosome markers such as LC3-II/LC3-I ratios for prediction of tumor resistance to TRAIL related therapies. The results also provide a rationale for future non-clinical and clinical studies testing TRAIL agonists in combination with agents that directly inhibit autophagosome assembly. C1 [Di, Xu; Zhang, Yaqin; Rosado, Leslie A. Rivera; Zhang, Baolin] US FDA, Div Therapeut Prot, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. [Zhang, Guofeng] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Takeda, Kazuyo] US FDA, Confocal Microscopy Core Facil, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Zhang, BL (reprint author), US FDA, Div Therapeut Prot, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. EM Baolin.Zhang@fda.hhs.gov FU FDA Critical Path Initiative FX This work was supported by the FDA Critical Path Initiative funding. NR 62 TC 25 Z9 27 U1 0 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP PY 2013 VL 4 IS 9 BP 1349 EP 1364 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 257QJ UT WOS:000327400300007 PM 23988408 ER PT J AU Cuevas, E Trickler, WJ Guo, XQ Ali, SF Paule, MG Kanungo, J AF Cuevas, Elvis Trickler, William J. Guo, Xiaoqing Ali, Syed F. Paule, Merle G. Kanungo, Jyotshna TI Acetyl L-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Ketamine; Motor neuron; Rohon-Beard neuron; Acetyl L-camitine; Transgenic zebrafish ID D-ASPARTATE RECEPTOR; RAT FOREBRAIN CULTURE; PROGRAMMED CELL-DEATH; ALPHA-LIPOIC ACID; APOPTOTIC NEURODEGENERATION; DEVELOPMENTAL NEUROTOXICITY; PARKINSONS-DISEASE; DEVELOPING BRAIN; GENE-EXPRESSION; IN-VIVO AB Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) type glutamate receptors is commonly used as a pediatric anesthetic. Multiple studies have shown ketamine to be neurotoxic, particularly when administered during the brain growth spurt. Previously, we have shown that ketamine is detrimental to motor neuron development in the zebrafish embryos. Here, using both wild type (WT) and transgenic (hb9:GFP) zebrafish embryos, we demonstrate that ketamine is neurotoxic to both motor and sensory neurons. Drug absorption studies showed that in the WT embryos, ketamine accumulation was approximately 0.4% of the original dose added to the exposure medium. The transgenic embryos express green fluorescent protein (GFP) localized in the motor neurons making them ideal for evaluating motor neuron development and toxicities in vivo. The hb9:GFP zebrafish embryos (28 h post fertilization) treated with 2 mM ketamine for 20 h demonstrated significant reductions in spinal motor neuron numbers, while co-treatment with acetyl L-carnitine proved to be neuroprotective. In whole mount immunohistochemical studies using WT embryos, a similar effect was observed for the primary sensory neurons. In the ketamine-treated WT embryos, the number of primary sensory Rohon-Beard (RB) neurons was significantly reduced compared to that in controls. However, acetyl L-carnitine co-treatment prevented ketamine-induced adverse effects on the RB neurons. These results suggest that acetyl L-camitine protects both motor and sensory neurons from ketamine-induced neurotoxicity. Published by Elsevier Inc. C1 [Cuevas, Elvis; Trickler, William J.; Guo, Xiaoqing; Ali, Syed F.; Paule, Merle G.; Kanungo, Jyotshna] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Trickler, William J.] Toxicol Pathol Associates, Jefferson, AR 72079 USA. RP Kanungo, J (reprint author), US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM jyotshnabala.kanungo@fda.hhs.gov FU National Center for Toxicological Research (NCIR)/U.S. Food and Drug Administration (FDA) FX This work was supported by the National Center for Toxicological Research (NCIR)/U.S. Food and Drug Administration (FDA). We thank Melanie Dumas for zebrafish breeding. NR 74 TC 11 Z9 12 U1 1 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 EI 1872-9738 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD SEP-OCT PY 2013 VL 39 BP 69 EP 76 DI 10.1016/j.ntt.2013.07.005 PG 8 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 246SE UT WOS:000326558600009 PM 23896048 ER PT J AU Grinev, A Chancey, C Anez, G Heisey, DA Volkova, E Winkelman, V Williamson, PC Stramer, SL Rios, M AF Grinev, A. Chancey, C. Anez, G. Heisey, D. A. Volkova, E. Winkelman, V. Williamson, P. C. Stramer, S. L. Rios, M. TI New Genotype of West Nile Virus was Found in the 2012 US Epidemic Season SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 12-15, 2013 CL Denver, CO SP AABB C1 [Grinev, A.; Chancey, C.; Anez, G.; Heisey, D. A.; Volkova, E.; Rios, M.] CBER FDA, Bethesda, MD USA. [Winkelman, V.; Williamson, P. C.] Creat Testing Solut, Tempe, AZ USA. [Stramer, S. L.] Amer Red Cross, Gaithersburg, MD USA. EM andriyan.grinev@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2013 VL 53 SU 2 SI SI BP 26A EP 26A PG 1 WC Hematology SC Hematology GA 218CA UT WOS:000324409000033 ER PT J AU Anez, G Heisey, DA Espina, LM Stramer, SL Rios, M AF Anez, G. Heisey, D. A. Espina, L. M. Stramer, S. L. Rios, M. TI Molecular, Virological, and Phylogenetic Characterization of Dengue Virus Types 1 and 4 in Blood Donors from Puerto Rico, 2012-2013 SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 12-15, 2013 CL Denver, CO SP AABB C1 [Anez, G.; Heisey, D. A.; Espina, L. M.; Rios, M.] US FDA, CBER, Bethesda, MD 20014 USA. [Stramer, S. L.] Amer Red Cross, Gaithersburg, MD USA. EM German.Anez@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2013 VL 53 SU 2 SI SI BP 27A EP 27A PG 1 WC Hematology SC Hematology GA 218CA UT WOS:000324409000035 ER PT J AU Haddad, S Barash, F Espinola, R Illoh, O Cannon, S AF Haddad, S. Barash, F. Espinola, R. Illoh, O. Cannon, S. TI Bacterial Contamination of Transfused Platelet Products: A Six-Year Review of Fatalities Reported to the US Food and Drug Administration(FDA) SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 12-15, 2013 CL Denver, CO SP AABB C1 [Haddad, S.; Barash, F.; Espinola, R.; Illoh, O.; Cannon, S.] US FDA, Rockville, MD 20857 USA. EM salim.haddad@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2013 VL 53 SU 2 SI SI BP 43A EP 44A PG 2 WC Hematology SC Hematology GA 218CA UT WOS:000324409000072 ER PT J AU Skripchenko, A Vostal, JG Gelderman, MP Thompson-Montgomery, D Awatefe, H Turgeon, AM Wagner, SJ AF Skripchenko, A. Vostal, J. G. Gelderman, M. P. Thompson-Montgomery, D. Awatefe, H. Turgeon, A. M. Wagner, S. J. TI Human Platelets, Stored in an Automated Temperature Cycler Between 4.5 C and 37 C for 7 Days, Exhibited Improved In Vitro Properties and In Vivo Recovery in SCID Mice Compared to Continuous Cold Storage SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 12-15, 2013 CL Denver, CO SP AABB C1 [Skripchenko, A.; Thompson-Montgomery, D.; Awatefe, H.; Turgeon, A. M.; Wagner, S. J.] Amer Red Cross, Holland Lab, Blood Components, Rockville, MD USA. [Vostal, J. G.; Gelderman, M. P.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. EM Andrey.Skripchenko@redcross.org NR 0 TC 1 Z9 1 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2013 VL 53 SU 2 SI SI BP 72A EP 72A PG 1 WC Hematology SC Hematology GA 218CA UT WOS:000324409000143 ER PT J AU Menis, M Anderson, SA Forshee, R McKean, S Gondalia, R Warnock, R Golding, B Kelman, JA Ball, R Izurieta, HS AF Menis, M. Anderson, S. A. Forshee, R. McKean, S. Gondalia, R. Warnock, R. Golding, B. Kelman, J. A. Ball, R. Izurieta, H. S. TI Post-Transfusion Purpura (PTP) Occurrence among the Inpatient Elderly Medicare Beneficiaries as Recorded in Large Administrative Databases During 2011 SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 12-15, 2013 CL Denver, CO SP AABB C1 [Menis, M.; Anderson, S. A.; Forshee, R.; Golding, B.; Ball, R.; Izurieta, H. S.] FDA CBER, Rockville, MD USA. [McKean, S.; Gondalia, R.; Warnock, R.] Acumen LLC, Burlingame, CA USA. [Kelman, J. A.] CMS, Baltimore, MD USA. EM Mikhail.Menis@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2013 VL 53 SU 2 SI SI BP 138A EP 138A PG 1 WC Hematology SC Hematology GA 218CA UT WOS:000324409000308 ER PT J AU Menis, M Anderson, SA Forshee, R McKean, S Gondalia, R Warnock, R Golding, B Kelman, JA Ball, R Izurieta, HS AF Menis, M. Anderson, S. A. Forshee, R. McKean, S. Gondalia, R. Warnock, R. Golding, B. Kelman, J. A. Ball, R. Izurieta, H. S. TI Febrile Non-Hemolytic Transfusion Reaction (FNHTR) Occurrence among Inpatient Elderly Medicare Beneficiaries as Recorded in Large Administrative Databases in 2011 SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 12-15, 2013 CL Denver, CO SP AABB C1 [Menis, M.; Anderson, S. A.; Forshee, R.; Golding, B.; Ball, R.; Izurieta, H. S.] FDA CBER, Rockville, MD USA. [McKean, S.; Gondalia, R.; Warnock, R.] Acumen LLC, Burlingame, CA USA. [Kelman, J. A.] CMS, Baltimore, MD USA. EM Mikhail.Menis@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2013 VL 53 SU 2 SI SI BP 140A EP 140A PG 1 WC Hematology SC Hematology GA 218CA UT WOS:000324409000312 ER PT J AU Liu, M Mercado, TC Liu, Z AF Liu, M. Mercado, T. C. Liu, Z. TI Development of Genomic DNA Reference Panels for Blood Group Genotyping Tests SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 12-15, 2013 CL Denver, CO SP AABB C1 [Liu, M.; Liu, Z.] FDA, CBER, OBRR, DBA,DRB,Lab Immunohematol & Mol Testing, Kensington, MD USA. [Mercado, T. C.] FDA, CBER, OBRR, DBA,DRB, Kensington, MD USA. EM meihong.liu@fda.hhs.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2013 VL 53 SU 2 SI SI BP 162A EP 162A PG 1 WC Hematology SC Hematology GA 218CA UT WOS:000324409000368 ER PT J AU Stramer, SL Foster, GA Brodsky, J Munoz-Jordan, JL Hunsperger, E Lanteri, MC Anez, G Rios, M Cory, R Linnen, JM AF Stramer, S. L. Foster, G. A. Brodsky, J. Munoz-Jordan, J. L. Hunsperger, E. Lanteri, M. C. Anez, G. Rios, M. Cory, R. Linnen, J. M. TI Investigational Dengue Testing Yields High Rates of Ribonucleic acid (RNA)-Positive Donors in Puerto Rico SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 12-15, 2013 CL Denver, CO SP AABB C1 [Stramer, S. L.; Foster, G. A.] Amer Red Cross, Biomed Serv, Sci Support Off, Gaithersburg, MD USA. [Brodsky, J.] Qual Analyt Inc, Riverwoods, IL USA. [Munoz-Jordan, J. L.; Hunsperger, E.] Ctr Dis Control & Prevent CDC, San Juan, PR USA. [Lanteri, M. C.] Blood Syst Res Inst, San Francisco, CA USA. [Anez, G.; Rios, M.] US FDA, DETTD, OBRR, CBER, Bethesda, MD 20014 USA. [Cory, R.; Linnen, J. M.] Hol Gen Probe, San Diego, CA USA. EM susan.stramer@redcross.org NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD SEP PY 2013 VL 53 SU 2 SI SI BP 216A EP 216A PG 1 WC Hematology SC Hematology GA 218CA UT WOS:000324409000507 ER PT J AU Bao, L Liang, CZ Trucksess, MW Xu, YL Lv, N Wu, ZX Jing, P Fry, FS AF Bao, Lei Liang, Chengzhu Trucksess, Mary W. Xu, Yanli Lv, Ning Wu, Zhenxing Jing, Ping Fry, Fred S. TI Determination of Aflatoxins B-1, B-2, G(1), and G(2) in Olive Oil, Peanut Oil, and Sesame Oil Using Immunoaffinity Column Cleanup, Postcolumn Derivatization, and Liquid Chromatography with Fluorescence Detection: First Action 2013.05 SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article AB A collaborative study of a method for determination of aflatoxins (AFs) B-1, B-2, G(1), and G(2) in olive oil, peanut oil, and sesame oil using immunoaffinity column cleanup, postcolumn derivatization, and LC with fluorescence detection, previously published in J. AOAC int. 95, 1689-1700 (2012), was approved as First Action 2013.05 on March 29, 2013 by the Method-Centric Committee for Aflatoxins in Edible Oils. The method uses methanol for extraction followed by filtration. The extract is applied to an immunoaffinity column with antibodies specific for AFs, which are then eluted from the column with a methanol solution. Determination and quantification occur using RP-LC with fluorescence detection after postcolumn derivatization. The average recovery of AFs in olive, peanut, and sesame oils in spiked samples (levels between 2.0 and 20.0 mu g/kg) ranged from 84 to 92%. The recoveries for AFs B-1, B-2, G(1), and G(2) were 86-93, 89-95, 85-97, and 76-85%, respectively. Within-laboratory RSD (RSDr) values for AFs ranged from 3.4 to 10.2%. RSDr values for AF B-1, B-2, G(1), and G(2) were 3.5-10.9, 3.2-9.5, 6.5-14.9, and 4.8-14.2%, respectively. Between-laboratory RSD (RSDR) values for AFs were 6.1-14.5%. RSDR values for AFs B-1, B-2, G(1), and G(2) were 7.5-15.4, 7.1-14.6, 10.8-18.1, and 7.6-23.7%, respectively. Horwitz ratio values were <= 2 for the analytes in the three matrixes. C1 [Bao, Lei; Liang, Chengzhu; Xu, Yanli; Lv, Ning; Wu, Zhenxing; Jing, Ping] Shandong Exit Entry Inspect & Quarantine Bur Chin, Qing Dao 266002, Peoples R China. [Trucksess, Mary W.; Fry, Fred S.] US FDA, College Pk, MD 20740 USA. RP Bao, L (reprint author), Shandong Exit Entry Inspect & Quarantine Bur Chin, Qing Dao 266002, Peoples R China. EM leibaoqd@yahoo.com NR 2 TC 4 Z9 5 U1 5 U2 26 PU AOAC INT PI GAITHERSBURG PA 481 N FREDRICK AVE, STE 500, GAITHERSBURG, MD 20877-2504 USA SN 1060-3271 EI 1944-7922 J9 J AOAC INT JI J. AOAC Int. PD SEP-OCT PY 2013 VL 96 IS 5 BP 1017 EP 1018 DI 10.5740/jaoacint.13-129 PG 2 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA 241WE UT WOS:000326198600014 PM 24282940 ER PT J AU Liao, BS Sram, JC Files, DJ AF Liao, Benjamin S. Sram, Jacqueline C. Files, Darin J. TI Determination of Free Sulfites (SO3-2) in Dried Fruits Processed with Sulfur Dioxide by Ion Chromatography through Anion Exchange Column and Conductivity Detection SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID MONIER-WILLIAMS METHOD; ELECTROCHEMICAL DETECTION; LIQUID-CHROMATOGRAPHY; FOODS; OXIDATION; RIPPER; GRAPES; WINES AB A simple and effective anion ion chromatography (IC) method with anion exchange column and conductivity detector has been developed to determine free sulfites (SO3-2) in dried fruits processed with sulfur dioxide. No oxidation agent, such as hydrogen peroxide, is used to convert sulfites to sulfates for IC analysis. In addition, no stabilizing agent, such as formaldehyde, fructose or EDTA, is required during the sample extraction. This method uses aqueous 0.2 N NaOH as the solvent for standard preparation and sample extraction. The sulfites, either prepared from standard sodium sulfite powder or extracted from food samples, are presumed to be unbound SO3-2 in aqueous 0.2 N NaOH (pH > 13), because the bound sulfites in the sample matrix are released at pH > 10. In this study, sulfites in the standard solutions were stable at room temperature (i.e., 15-25 degrees C) for up to 12 days. The lowest standard of the linear calibration curve is set at 1.59 mu g/mL SO3-2 (equivalent to 6.36 mu g/g sample with no dilution) for analysis of processed dried fruits that would contain high levels (>1000 mu g/g) of sulfites. As a consequence, this method typically requires significant dilution of the sample extract. Samples are prepared with a simple procedure of sample compositing, extraction with aqueous 0.2 N NaOH, centrifugation, dilution as needed, and filtration prior to IC. The sulfites in these sample extracts are stable at room temperature for up to 20 h. Using anion IC, the sulfites are eluted under isocratic conditions with 10 mM aqueous sodium carbonate solution as the mobile phase passing through an anion exchange column. The sulfites are easily separated, with an analysis run time of 18 min, regardless of the dried fruit matrix. Recoveries from samples spiked with sodium sulfites were demonstrated to be between 81 and 105% for five different fruit matrixes (apricot, golden grape, white peach, fig, and mango). Overall, this method is simple to perform and effective for the determination of high levels of sulfites in dried fruits. C1 [Liao, Benjamin S.; Sram, Jacqueline C.; Files, Darin J.] US FDA, Pacific Reg Lab Southwest, Irvine, CA 92612 USA. RP Liao, BS (reprint author), US FDA, Pacific Reg Lab Southwest, Irvine, CA 92612 USA. EM Benjamin.liao@fda.hhs.gov NR 24 TC 5 Z9 5 U1 7 U2 33 PU AOAC INT PI GAITHERSBURG PA 481 N FREDRICK AVE, STE 500, GAITHERSBURG, MD 20877-2504 USA SN 1060-3271 EI 1944-7922 J9 J AOAC INT JI J. AOAC Int. PD SEP-OCT PY 2013 VL 96 IS 5 BP 1103 EP 1108 DI 10.5740/jaoacint.11-053 PG 6 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA 241WE UT WOS:000326198600027 PM 24282955 ER PT J AU Chang, Y Burckart, GJ Lesko, LJ Dowling, TC AF Chang, Yang Burckart, Gilbert J. Lesko, Lawrence J. Dowling, Thomas C. TI Evaluation of Hepatic Impairment Dosing Recommendations in FDA-Approved Product Labels SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE new molecular entity; NME; drug dosing; hepatic impairment; FDA; guidance; clinical pharmacology ID ADJUSTMENT AB Pharmacokinetic (PK) studies in patients with liver disease are an important clinical pharmacology component of drug development. In 2003, FDA released the guidance for industry on "Pharmacokinetics in Patients with Impaired Hepatic Function," which provides recommendations to sponsors on study design, data analysis, and impact on dosing and labeling. We evaluated the quality and consistency of hepatic dosing recommendations, and compared contemporary clinical practice of dosing in patients with impaired hepatic function with product labels. All new molecular entities (NME) and labels approved by the FDA during the period of January 2004 to December 2011 were reviewed. The fraction of the dose hepatically eliminated, quality of hepatic impairment PK studies reported, and any dose recommendations provided in the label and in a tertiary clinical reference (Micromedex) were reviewed. Out of 157 NMEs, 67 met the criteria for evaluation of dosing in hepatic disease. Problem areas were identified related to the lack of specific hepatic metabolism information in 90% of FDA-approved labels, inconsistent terminology, and "use with caution in liver disease" in 27% of NME. Updating the FDA guidance on PK studies in patients with impaired hepatic function could provide a standardized approach to improve the clinical usefulness of this dosing information for practitioners. C1 [Chang, Yang; Dowling, Thomas C.] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. [Burckart, Gilbert J.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Lesko, Lawrence J.] Univ Florida, Coll Pharm, Ctr Pharmacometr & Syst Pharmacol, Orlando, FL USA. RP Dowling, TC (reprint author), Univ Maryland, 20 North Pine St,Room PH N413, Baltimore, MD 21201 USA. EM tdowling@rx.umaryland.edu RI Dowling, Thomas/D-2147-2013 OI Dowling, Thomas/0000-0003-3214-9283 NR 24 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD SEP PY 2013 VL 53 IS 9 BP 962 EP 966 DI 10.1002/jcph.128 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 237JA UT WOS:000325864400011 PM 23832278 ER PT J AU Enache, E Kataoka, A Black, DG Weddig, L Hayman, M Bjornsdottir-Butler, K AF Enache, Elena Kataoka, Ai Black, D. Glenn Weddig, Lisa Hayman, Melinda Bjornsdottir-Butler, Kristin TI Heat Resistance of Histamine-Producing Bacteria in Irradiated Tuna Loins SO JOURNAL OF FOOD PROTECTION LA English DT Article ID MORGANELLA-MORGANII; SKIPJACK TUNA; KATSUWONUS-PELAMIS; FORMING BACTERIA; FISH; TEMPERATURE; OUTBREAK; MACKEREL; STORAGE; TIME AB Consumption of foods high in biogenic amines leads to an illness known as histamine, or scombrotoxin, poisoning. The illness is commonly associated with consumption of fish with high levels of histamine (>= 500 ppm). The objective of this study was to determine and compare the heat resistance of five histamine-producing bacteria in irradiated albacore tuna loins. Heat-resistance parameters (D-and z-values) were determined for Morganella morganii, Raoultella planticola, Hafnia alvei, and Enterobacter aerogenes. D-or z-values were not determined for Photobacterium damselae, which was the most heat-sensitive organism in this study. P. damselae declined >5.9 log CFU/g after a heat treatment of 50 degrees C for 10 min, 54 degrees C for 3 min, and 56 degrees C for 0.5 min. M. morganii was the most heat-resistant histamine-producing bacteria in albacore tuna loins, followed by E. aerogenes, H. alvei, and R. planticola. M. morganii and E. aerogenes had the highest D-50 degrees C, 49.7 +/- 17.57 and 51.8 +/- 17.38 min, respectively. In addition, M. morganii had the highest D-values for all other temperatures (54, 56, and 58 degrees C) tested. D-and z-values were also determined for M. morganii in skipjack tuna. While no significant (P. 0.05) difference was observed between D-54 degrees C and D-56 degrees C of M. morganii in either albacore or skipjack tuna, the D-58 degrees C (0.4 +/- 0.17 min) was significantly lower (P, 0.05) in skipjack than in albacore (0.9 +/- 0.24 min). The z-values for all organisms tested were in the range of 3.2 to 3.8 degrees C. This study suggests that heat treatment designed to control M. morganii in tuna loins is sufficient for controlling histamine-producing bacteria in canned-tuna processing environments. C1 [Enache, Elena; Kataoka, Ai; Black, D. Glenn; Hayman, Melinda] Grocery Mfg Assoc, Washington, DC 20005 USA. [Weddig, Lisa] Natl Fisheries Inst, Mclean, VA 22102 USA. [Bjornsdottir-Butler, Kristin] US FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. RP Enache, E (reprint author), Grocery Mfg Assoc, 1350 I St NW,Suite 300, Washington, DC 20005 USA. EM eenache@gmaonline.org FU National Fisheries Institute Tuna Council FX This study was supported by funds from the National Fisheries Institute Tuna Council. The authors thank Carla Napier for the technical assistance and the National Fisheries Institute and Tuna Council for commenting on the manuscript. NR 51 TC 0 Z9 0 U1 3 U2 19 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD SEP PY 2013 VL 76 IS 9 BP 1608 EP 1614 DI 10.4315/0362-028X.JFP-12-467 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 240HH UT WOS:000326085500014 PM 23992506 ER PT J AU Liu, YH Ceruso, M Jiang, YJ Datta, AR Carter, L Strain, E Pepe, T Anastasi, A Fratamico, P AF Liu, Yanhong Ceruso, Marina Jiang, Yuji Datta, Atin R. Carter, Laurenda Strain, Errol Pepe, Tiziana Anastasi, Aniello Fratamico, Pina TI Construction of Listeria monocytogenes Mutants with In-Frame Deletions in the Phosphotransferase Transport System (PTS) and Analysis of Their Growth under Stress Conditions SO JOURNAL OF FOOD SCIENCE LA English DT Article DE Listeria monocytogenes; phosphotransferase transport system (PTS); stress response ID CLASS IIA BACTERIOCINS; GENE-EXPRESSION; FOOD; PATHOGEN; PROTEIN; COMPONENTS; RESISTANCE; PRODUCTS; INSIGHTS; STRAINS AB Listeria monocytogenes is a foodborne pathogen that is difficult to eliminate due to its ability to survive under different stress conditions such as low pH and high salt. To better control this pathogen in food, it is important to understand its survival mechanisms under these stress conditions. LMOf2365_0442, 0443, and 0444 encode for phosphotransferase transport system (PTS) permease (fructose-specific IIABC components) that is responsible for sugar transport. LMOf2365_0445 encodes for glycosyl hydrolase. These genes were induced by high pressure and inhibited under salt treatments; therefore, we hypothesized that genes encoding these PTS proteins may be involved in general stress responses. To study the function of these genes, deletion mutants of the PTS genes (LMOf2365_0442, LMOf2365_0443, and LMOf2365_0444) and the downstream gene LMOf2365_0445 were created in L. monocytogenes strain F2365. These deletion mutants were tested under different stress conditions. The growth of Delta LMOf2365_0445 was increased under nisin (125 mu g/mL) treatments compared to the wild-type (P < 0.01). The growth of Delta LMOf2365_0442 in salt (brain-heart infusion medium with 5% NaCl) was significantly increased (P < 0.01), and Delta LMOf2365_0442 showed increased growth under acidic conditions (pH 5.0) compared to the wild-type (P < 0.01). The results from phenotypic arrays demonstrated that some of these mutants showed slightly slower growth under different carbon sources and basic conditions. The results indicate that deletion mutants Delta LMOf2365_0442 and Delta LMOf2365_0445 were more resistant to multiple stress conditions compared to the wild-type, suggesting that they may contribute to the general stress response in L. monocytogenes. An understanding of the growth of these mutants under multiple stress conditions may assist in the development of intervention strategies to control L. monocytogenes in food. C1 [Liu, Yanhong; Fratamico, Pina] ARS, Mol Characterizat Foodborne Pathogens Res Unit, Eastern Reg Res Ctr, USDA, Wyndmoor, PA 19038 USA. [Ceruso, Marina; Pepe, Tiziana; Anastasi, Aniello] Univ Naples Federico II, Fac Med Vet, Sez Ispez, Dipto Sci Zootecn & Ispez Alimenti, Naples 80137, Italy. [Jiang, Yuji] Fujian Agr & Forestry Univ, Coll Food Sci, Fuzhou 50002 3, Fujian, Peoples R China. [Datta, Atin R.; Carter, Laurenda; Strain, Errol] US FDA, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Liu, YH (reprint author), ARS, Mol Characterizat Foodborne Pathogens Res Unit, Eastern Reg Res Ctr, USDA, 600 East Mermaid Lane, Wyndmoor, PA 19038 USA. EM yanhong.liu@ars.usda.gov OI CERUSO, Marina/0000-0002-0574-9542 NR 39 TC 0 Z9 0 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-1147 EI 1750-3841 J9 J FOOD SCI JI J. Food Sci. PD SEP PY 2013 VL 78 IS 9 BP M1392 EP M1398 DI 10.1111/1750-3841.12181 PG 7 WC Food Science & Technology SC Food Science & Technology GA 217BN UT WOS:000324331600010 PM 23909479 ER PT J AU Balsam, J Bruck, HA Rasooly, A AF Balsam, Joshua Bruck, Hugh Alan Rasooly, Avraham TI Capillary array waveguide amplified fluorescence detector for mHealth SO SENSORS AND ACTUATORS B-CHEMICAL LA English DT Article DE Microfabrication; Microfluidics; CMOS; Fluorescence; Mobile phone; Smartphone ID STAPHYLOCOCCAL-ENTEROTOXIN-B; GLOBAL HEALTH; FOOD SAMPLES; CELL-PHONE; BIOSENSOR; IMMUNOSENSOR; CARE; PLATFORM; IMMUNOASSAY; ANALYTES AB Mobile health (mHealth) analytical technologies are potentially useful for carrying out modern medical diagnostics in resource-poor settings. Effective mHealth devices for underserved populations need to be simple, low cost, and portable. Although cell phone cameras have been used for biodetection, their sensitivity is a limiting factor because currently it is too low to be effective for many mHealth applications, which depend on detection of weak fluorescent signals. To improve the sensitivity of portable phones, a capillary tube array was developed to amplify fluorescence signals using their waveguide properties. An array configured with 36 capillary tubes was demonstrated to have a similar to 100x increase in sensitivity, lowering the limit of detection (LOD) of mobile phones from 1000 nM to 10 nM for fluorescein. To confirm that the amplification was due to waveguide behavior, we coated the external surfaces of the capillaries with silver. The silver coating interfered with the waveguide behavior and diminished the fluorescence signal, thereby proving that the waveguide behavior was the main mechanism for enhancing optical sensitivity. The optical configuration described here is novel in several ways. First, the use of capillaries waveguide properties to improve detection of weak florescence signal is new. Second we describe here a three dimensional illumination system, while conventional angular laser waveguide illumination is spot (or line), which is functionally one-dimensional illumination, can illuminate only a single capillary or a single column (when a line generator is used) of capillaries and thus inherently limits the multiplexing capability of detection. The planar illumination demonstrated in this work enables illumination of a two dimensional capillary array (e.g., x columns and y rows of capillaries). In addition, the waveguide light propagation via the capillary wall provides a third dimension for illumination along the axis of the capillaries. Such an array can potentially be used for sensitive analysis of multiple fluorescent detection assays simultaneously. The simple phone based capillary array approach presented in this paper is capable of amplifying weak fluorescent signals thereby improving the sensitivity of optical detectors based on mobile phones. This may allow sensitive biological assays to be measured with low sensitivity detectors and may make mHealth practical for many diagnostics applications, especially in resource-poor and global health settings. Published by Elsevier B.V. C1 [Balsam, Joshua; Rasooly, Avraham] US FDA, Off Sci & Engn, Div Biol, Silver Spring, MD 20993 USA. [Balsam, Joshua; Bruck, Hugh Alan] Univ Maryland, College Pk, MD 20742 USA. [Rasooly, Avraham] NCI, Div Canc Biol, Bethesda, MD 20892 USA. RP Rasooly, A (reprint author), US FDA, Off Sci & Engn, Div Biol, Silver Spring, MD 20993 USA. EM rasoolya@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 53 TC 7 Z9 7 U1 5 U2 42 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0925-4005 J9 SENSOR ACTUAT B-CHEM JI Sens. Actuator B-Chem. PD SEP PY 2013 VL 186 BP 711 EP 717 DI 10.1016/j.snb.2013.06.030 PG 7 WC Chemistry, Analytical; Electrochemistry; Instruments & Instrumentation SC Chemistry; Electrochemistry; Instruments & Instrumentation GA 215PU UT WOS:000324223600095 PM 24039345 ER PT J AU Lawal, A Kirtley, ML van Lier, CJ Erova, TE Kozlova, EV Sha, J Chopra, AK Rosenzweig, JA AF Lawal, Abidat Kirtley, Michelle L. van Lier, Christina J. Erova, Tatiana E. Kozlova, Elena V. Sha, Jian Chopra, Ashok K. Rosenzweig, Jason A. TI The Effects of Modeled Microgravity on Growth Kinetics, Antibiotic Susceptibility, Cold Growth, and the Virulence Potential of a Yersinia pestis ymoA-Deficient Mutant and Its Isogenic Parental Strain SO ASTROBIOLOGY LA English DT Article DE Type three secretion system (T3SS); Low-shear modeled microgravity; High-aspect ratio vessel; Cell culture infection models; Mouse infection model ID BACTERIAL GENE-EXPRESSION; BIOFILM FORMATION; ESCHERICHIA-COLI; POLYNUCLEOTIDE PHOSPHORYLASE; SIMULATED MICROGRAVITY; SECRETION SYSTEM; III SECRETION; SHEAR-STRESS; SPACE-FLIGHT; PLAGUE AB Previously, we reported that there was no enhancement in the virulence potential (as measured by cell culture infections) of the bacterial pathogen Yersinia pestis (YP) following modeled microgravity/clinorotation growth. We have now further characterized the effects of clinorotation (CR) on YP growth kinetics, antibiotic sensitivity, cold growth, and YP's virulence potential in a murine model of infection. Surprisingly, none of the aforementioned phenotypes were altered. To better understand why CR did not enhance YP's virulence potential as it did for other bacterial pathogens, a YP ymoA isogenic mutant in the KIM/D27 background strain that is unable to produce the histone-like YmoA protein and influences DNA topography was used in both cell culture and murine models of infection. YmoA represses type three secretion system (T3SS) virulence gene expression in the yersiniae. Similar to our CR-grown parental YP strain data, the CR-grown ymoA mutant induced reduced HeLa cell cytotoxicity with concomitantly decreased Yersinia outer protein E (YopE) and low calcium response V (LcrV) antigen production and secretion. Important, however, were our findings that, although no significant differences were observed in survival of mice infected intraperitoneally with either normal gravity (NG)- or CR-grown parental YP, the ymoA mutant induced significantly more mortality in infected mice than did the parental strain following CR growth. Taken together, our data demonstrate that CR did enhance the virulence potential of the YP ymoA mutant in a murine infection model (relative to the CR-grown parental strain), despite inducing less HeLa cell rounding in our cell culture infection assay due to reduced T3SS activity. Therefore, CR, which induces a unique type of bacterial stress, might be enhancing YP's virulence potential in vivo through a T3SS-independent mechanism when the histone-like YmoA protein is absent. C1 [Lawal, Abidat; Rosenzweig, Jason A.] Texas So Univ, Dept Biol, Dept Environm & Interdisciplinary Sci, CBER, Houston, TX 77004 USA. [Kirtley, Michelle L.; van Lier, Christina J.; Erova, Tatiana E.; Kozlova, Elena V.; Sha, Jian; Chopra, Ashok K.] Univ Texas Med Branch, Dept Microbiol & Immunol, Sealy Ctr Vaccine Dev, Inst Human Infect & Immun, Galveston, TX 77555 USA. [Kirtley, Michelle L.; van Lier, Christina J.; Erova, Tatiana E.; Kozlova, Elena V.; Sha, Jian; Chopra, Ashok K.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA. RP Rosenzweig, JA (reprint author), 3100 Cleburne St, Houston, TX 77004 USA. EM rosenzweigja@tsu.edu FU NASA [NNX08B4A47A]; NIH/NIAID [AI064389] FX We would like to thank Greg Plano for his generosity in sharing YP KIM parental and Delta ymoA, Delta cspA, Delta rnr, and Delta rnb mutant strains as well as polyclonal anti-YopM, YopE, and LcrV antibodies with us. Also, we would like to thank Duane L. Pierson and C. Mark Ott for discussion and guidance in our pursuit of space microbiology knowledge. Additionally, we would like to thank Kurt Schesser for guidance and insight as well as Adebayo Oyekan and Shishir Shishodia for valuable discussion and feedback. Work on this manuscript was supported by the NASA cooperative agreement NNX08B4A47A (J.A.R.) and NIH/NIAID AI064389 awarded to A.K.C. NR 45 TC 5 Z9 6 U1 1 U2 12 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1531-1074 EI 1557-8070 J9 ASTROBIOLOGY JI Astrobiology PD SEP 1 PY 2013 VL 13 IS 9 BP 821 EP 832 DI 10.1089/ast.2013.0968 PG 12 WC Astronomy & Astrophysics; Biology; Geosciences, Multidisciplinary SC Astronomy & Astrophysics; Life Sciences & Biomedicine - Other Topics; Geology GA 219TU UT WOS:000324534100003 PM 23988036 ER PT J AU Zhang, X Paule, MG Wang, C Slikker, W AF Zhang, Xuan Paule, Merle G. Wang, Cheng Slikker, William, Jr. TI Application of microPET imaging approaches in the study of pediatric anesthetic-induced neuronal toxicity SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Review DE molecular imaging; anesthetic agent; neuronal cell death ID PERIPHERAL BENZODIAZEPINE-RECEPTORS; POSITRON-EMISSION-TOMOGRAPHY; DEVELOPING RAT-BRAIN; SMALL ANIMAL PET; BIRTH-WEIGHT INFANTS; IN-VIVO; ANNEXIN-V; CELL-DEATH; APOPTOTIC NEURODEGENERATION; EARLY EXPOSURE AB Advances in pediatric and obstetric surgery have resulted in an increase in the complexity, duration and number of anesthetic procedures. Currently, the general anesthetics that are used most often have either NMDA receptor blocking or GABA receptor activating properties. It has been reported that prolonged exposure of the developing brain to a clinically relevant concentration of anesthetics that have NMDA antagonist or GABA-mimetic properties, and/or their combinations, resulted in an extensive abnormal pattern of neuroapoptosis, and subsequent cognitive deficits in animals. Molecular imaging using positron emission tomography (PET) is a leading modality for obtaining non- or minimally invasive in vivo measurements of multiple biological processes in various organs. The development of microPET imaging applications has provided the ability to collect sensitive and quantitative three-dimensional molecular information from the living brains of a variety of animals. The main aim of this review was to describe molecular imaging approaches that have been used in the study of pediatric anesthetic-induced neuronal toxicity. Published 2013. This article is a US Government work and is in the public domain in the USA. C1 [Zhang, Xuan; Paule, Merle G.; Wang, Cheng] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Slikker, William, Jr.] US FDA, Off Director, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Zhang, X (reprint author), US FDA, Natl Ctr Toxicol Res, HFT 132, Jefferson, AR 72079 USA. EM Xuan.zhang@fda.hhs.gov NR 87 TC 5 Z9 5 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0260-437X EI 1099-1263 J9 J APPL TOXICOL JI J. Appl. Toxicol. PD SEP PY 2013 VL 33 IS 9 BP 861 EP 868 DI 10.1002/jat.2857 PG 8 WC Toxicology SC Toxicology GA 238DZ UT WOS:000325923300001 PM 23400798 ER PT J AU Hoelzer, K Chen, Y Dennis, S Evans, P Pouillot, R Silk, BJ Walls, I AF Hoelzer, K. Chen, Y. Dennis, S. Evans, P. Pouillot, R. Silk, B. J. Walls, I. TI New Data, Strategies, and Insights for Listeria monocytogenes Dose-Response Models: Summary of an Interagency Workshop, 2011 SO RISK ANALYSIS LA English DT Article DE risk assessment; Dose-response; Listeria monocytogenes ID TO-EAT FOODS; QUANTITATIVE RISK-ASSESSMENT; NONHUMAN PRIMATE MODEL; PREGNANT GUINEA-PIGS; KNOCK-OUT MICE; INDUCED STILLBIRTHS; GENETIC-CONTROL; ANIMAL-MODELS; UNITED-STATES; A/J MICE AB Listeria monocytogenes is a leading cause of hospitalization, fetal loss, and death due to foodborne illnesses in the United States. A quantitative assessment of the relative risk of listeriosis associated with the consumption of 23 selected categories of ready-to-eat foods, published by the U.S. Department of Health and Human Services and the U.S. Department of Agriculture in 2003, has been instrumental in identifying the food products and practices that pose the greatest listeriosis risk and has guided the evaluation of potential intervention strategies. Dose-response models, which quantify the relationship between an exposure dose and the probability of adverse health outcomes, were essential components of the risk assessment. However, because of data gaps and limitations in the available data and modeling approaches, considerable uncertainty existed. Since publication of the risk assessment, new data have become available for modeling L. monocytogenes dose-response. At the same time, recent advances in the understanding of L. monocytogenes pathophysiology and strain diversity have warranted a critical reevaluation of the published dose-response models. To discuss strategies for modeling L. monocytogenes dose-response, the Interagency Risk Assessment Consortium (IRAC) and the Joint Institute for Food Safety and Applied Nutrition (JIFSAN) held a scientific workshop in 2011 (details available at http://foodrisk.org/irac/events/). The main findings of the workshop and the most current and relevant data identified during the workshop are summarized and presented in the context of L. monocytogenes dose-response. This article also discusses new insights on dose-response modeling for L. monocytogenes and research opportunities to meet future needs. C1 [Hoelzer, K.; Chen, Y.; Dennis, S.; Evans, P.; Pouillot, R.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Evans, P.] US Food Safety & Inspect Serv, Microbiol Issues Branch, Off Publ Hlth Sci, USDA, Washington, DC 20250 USA. [Silk, B. J.] Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Atlanta, GA USA. [Walls, I.] Natl Inst Food & Agr, USDA, Washington, DC USA. RP Hoelzer, K (reprint author), US FDA, Ctr Food Safety & Appl Nutr HFS 005, College Pk, MD USA. EM Karin.Hoelzer@fda.hhs.gov RI Pouillot, Regis/E-8103-2010; OI Pouillot, Regis/0000-0002-6107-5212; Walls, Isabel/0000-0002-9643-8845 FU Research Participation Program at the Center for Food Safety and Applied Nutrition; U.S. Department of Energy; U.S. Food and Drug Administration FX This work was supported, in part, by appointments to the Research Participation Program at the Center for Food Safety and Applied Nutrition administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 86 TC 5 Z9 5 U1 0 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0272-4332 EI 1539-6924 J9 RISK ANAL JI Risk Anal. PD SEP PY 2013 VL 33 IS 9 BP 1568 EP 1581 DI 10.1111/risa.12005 PG 14 WC Public, Environmental & Occupational Health; Mathematics, Interdisciplinary Applications; Social Sciences, Mathematical Methods SC Public, Environmental & Occupational Health; Mathematics; Mathematical Methods In Social Sciences GA 217VV UT WOS:000324391400002 PM 23311571 ER PT J AU Loring, Z Zareba, W McNitt, S Strauss, DG Wagner, GS Daubert, JP AF Loring, Zak Zareba, Wojciech McNitt, Scott Strauss, David G. Wagner, Galen S. Daubert, James P. TI ECG Quantification of Myocardial Scar and Risk Stratification in MADIT-II SO ANNALS OF NONINVASIVE ELECTROCARDIOLOGY LA English DT Article DE sudden death; heart failure; implantable cardioverter-defibrillator; electrocardiography; electrophysiology; tachyarrhythmias ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; CONGESTIVE-HEART-FAILURE; LEFT-VENTRICULAR DYSFUNCTION; CARDIAC MAGNETIC-RESONANCE; CORONARY-ARTERY-DISEASE; PRIMARY PREVENTION; PROGNOSTIC VALUE; INFARCTION; TRIAL; MORTALITY AB BackgroundLow left ventricular ejection fraction (LVEF) increases risk for both sudden cardiac death (SCD) and for heart failure (HF) death; however, implantable cardioverter-defibrillators (ICDs) reduce the incidence of SCD, not HF death. Distinguishing individuals at risk for HF death (non-SCD) versus SCD could improve ICD patient selection. ObjectiveThis study evaluated whether electrocardiogram (ECG) quantification of myocardial infarction (MI) could discriminate risk for SCD versus non-SCD. MethodsSelvester QRS scoring was performed on 995 MADIT-II trial subjects' ECGs to quantify MI size. MIs were categorized as small (0-3 QRS points), medium (4-7) or large (8). Mortality, SCD and non-SCD rates in the conventional medical therapy (CMT) arm and mortality and ventricular tachycardia/fibrillation (VT/VF) rates in the ICD arm were analyzed by QRS score group. Both arms were analyzed to determine ICD efficacy by QRS score group. ResultsIn the CMT arm, mortality, SCD and non-SCD rates were similar across QRS score groups (P = 0.73, P = 0.92, and P = 0.77). The ICD arm showed similar rates of mortality (P = 0.17) and VT/VF (P = 0.24) across QRS score groups. ICD arm mortality was lower than CMT arm mortality across QRS score groups with greatest benefit in the large scar group. ConclusionRecently, QRS score was shown to be predictive of VT/VF in the SCD-HeFT population consisting of both ischemic and nonischemic HF and having a maximum LVEF of 35% versus 30% for MADIT-II. Our study found that QRS score did not add prognostic value in the MADIT-II population exhibiting relatively more severe cardiac dysfunction. C1 [Loring, Zak] Duke Univ, Sch Med, Durham, NC USA. [Zareba, Wojciech] Univ Rochester, Med Ctr, Dept Med, Cardiol Unit, Rochester, NY 14642 USA. [McNitt, Scott] Univ Rochester, Med Ctr, Heart Res Follow Up Program, Rochester, NY 14642 USA. [Strauss, David G.] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Wagner, Galen S.; Daubert, James P.] Duke Clin Res Inst, Durham, NC USA. [Daubert, James P.] Duke Univ, Med Ctr, Div Cardiol, Electrophysiol Sect, Durham, NC 27710 USA. [Daubert, James P.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. RP Daubert, JP (reprint author), DUMC Box 3174, Durham, NC 27710 USA. EM james.daubert@duke.edu FU Duke University's CTSA grant from NCRR/NIH [TL1RR024126] FX Zak Loring thanks Dr. James P. Daubert and Dr. Galen Wagner for their ongoing mentorship and support. This ongoing research is supported in part by Duke University's CTSA grant TL1RR024126 from NCRR/NIH. The authors thank the MADIT-II Investigators for collecting the original data for this study. NR 27 TC 4 Z9 4 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1082-720X EI 1542-474X J9 ANN NONINVAS ELECTRO JI Ann. Noninvasive Electrocardiol. PD SEP PY 2013 VL 18 IS 5 BP 427 EP 435 DI 10.1111/anec.12065 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 219QD UT WOS:000324522300003 PM 24047486 ER PT J AU Stokes, W Srinivas, G McFarland, R Kulpa-Eddy, J Casey, W Walker, A Draayer, H Sebring, R Brown, K Balks, E Stirling, C Klaasen, E Hill, R Rippke, B Ruby, K Alt, D Mukhopadhyay, S Kojima, H Johnson, N Rinckel, L Doelling, V Jones, B AF Stokes, William Srinivas, Geetha McFarland, Richard Kulpa-Eddy, Jodie Casey, Warren Walker, Angela Draayer, Hans Sebring, Randy Brown, Karen Balks, Elisabeth Stirling, Catrina Klaasen, Eric Hill, Richard Rippke, Byron Ruby, Kevin Alt, David Mukhopadhyay, Suman Kojima, Hajime Johnson, Nelson Rinckel, Lori Doelling, Vivian Jones, Brett TI Report on the international workshop on alternative methods for Leptospira vaccine potency testing: State of the science and the way forward SO BIOLOGICALS LA English DT Article DE Leptospira vaccines; Alternative methods; Potency; Replacement; Refinement; Reduction ID RELATIVE POTENCY; LETHAL INFECTION; DISEASE; ASSAY; BUPRENORPHINE; INTERROGANS; BACTERINS; PATHOGEN; POMONA AB Routine potency testing of Leptospira vaccines is mostly conducted using a vaccination challenge test that involves large numbers of hamsters and unrelieved pain and distress. NICEATM, ICCVAM, and their international partners organized a workshop to review the state of the science of alternative methods that might replace, reduce, and refine the use of animals for veterinary Leptospira vaccine potency testing and to identify ways to advance improved alternative methods. Vaccine manufacturers were encouraged to initiate or continue product-specific validation using in vitro enzyme-linked immunosorbent assays as replacements for potency testing of four common Leptospira serogroups. Participants discussed the potential for eliminating the back-titration procedure in the hamster challenge assay, which could reduce animal use by 50% for each individual potency test. Further animal reduction may also be possible by using cryopreserved Leptospira stock to replace continual passaging through hamsters. Serology assays were identified as a way to further reduce and refine animal use but should be considered only after attempting in vitro assays. Workshop participants encouraged consideration of analgesics and use of earlier humane endpoints when the hamster vaccination challenge potency assay is used. International harmonization of alternative potency methods was recommended to avoid duplicative potency testing to meet regionally different requirements. C1 [Stokes, William; Casey, Warren] NIEHS, Natl Toxicol Program Interagcy Ctr Evaluat Altern, Div Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. [Srinivas, Geetha; Walker, Angela; Hill, Richard; Rippke, Byron; Ruby, Kevin] USDA, Ctr Vet Biol, Ames, IA 50010 USA. [McFarland, Richard] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Kulpa-Eddy, Jodie] USDA, Anim & Plant Hlth Inspect Serv, Riverdale, MD 20737 USA. [Draayer, Hans] Gourdneck View Consulting LLC, Portage, MI 49002 USA. [Sebring, Randy] Colorado Serum Co, Denver, CO 80216 USA. [Brown, Karen] Pair ODocs Consultants, Parkville, MO 64152 USA. [Balks, Elisabeth] Paul Ehrlich Inst, D-63225 Langen, Germany. [Stirling, Catrina] Pfizer Ltd, Sandwich CT13 9NJ, Kent, England. [Klaasen, Eric] MSD Anim Hlth, NL-5830 AA Boxmeer, Netherlands. [Alt, David] USDA ARS, Ames, IA 50010 USA. [Mukhopadhyay, Suman] NIAID, Bethesda, MD 20892 USA. [Kojima, Hajime] Natl Inst Hlth Sci, Japanese Ctr Validat Alternat Methods, Setagaya Ku, Tokyo 1585801, Japan. [Johnson, Nelson; Rinckel, Lori; Doelling, Vivian; Jones, Brett] Integrated Lab Syst Inc, Morrisville, NC 27560 USA. RP Casey, W (reprint author), NIEHS, Natl Toxicol Program Interagcy Ctr Evaluat Altern, Div Natl Toxicol Program, NIH, POB 12233,MD K2-16, Res Triangle Pk, NC 27709 USA. EM warren.casey@nih.gov FU NICEATM; ICCVAM; EURL ECVAM; JaCVAM FX The authors extend their sincere appreciation to all participants in the international workshop for their contributions leading to the workshop conclusions and recommendations. The members of the Leptospira Workshop Organizing Committee, ICCVAM Interagency Biologics Working Group, and NICEATM staff are acknowledged for their contributions to the planning of the workshop, and all the invited experts are acknowledged for their presentations and contributions to breakout group discussions and workshop proceedings. Participating national/international validation organizations from the International Cooperation on Alternative Test Methods, including NICEATM, ICCVAM, EURL ECVAM, and JaCVAM, are also gratefully acknowledged for their scientific contributions and financial support. Finally, the authors gratefully acknowledge Dr. Raymond Tice and Dr. John Bucher from the National Institute of Environmental Health Sciences, National Institutes of Health, USA for their review of the manuscript. NR 62 TC 0 Z9 0 U1 0 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1045-1056 J9 BIOLOGICALS JI Biologicals PD SEP PY 2013 VL 41 IS 5 SI SI BP 279 EP 294 DI 10.1016/j.biologicals.2013.06.013 PG 16 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 231VU UT WOS:000325447300001 PM 23890729 ER PT J AU Yang, J Shord, S Zhao, H Men, YX Rahman, A AF Yang, Jun Shord, Stacy Zhao, Hong Men, Yuxin Rahman, Atiqur TI Are Hepatic Impairment Studies Necessary for Therapeutic Proteins? SO CLINICAL THERAPEUTICS LA English DT Article DE hepatic impairment; pharmacokinetics; therapeutic proteins ID COLONY-STIMULATING FACTOR; MONOCLONAL-ANTIBODY; POPULATION PHARMACOKINETICS; CANCER-PATIENTS; RENAL-FUNCTION; BREAST-CANCER; LIVER; MICE AB Objective: This study assessed whether trials to investigate the effect of hepatic impairment on the pharmacokinetics of therapeutic proteins (TPs), which are conducted for small molecule drugs, are necessary. Methods: The product labeling for 91 TPs that have been approved by the US Food and Drug Administration were reviewed. A PubMed search was also conducted to identify completed studies that assessed the effect of hepatic impairment on the pharmacokinetics of TPs. Biologic License Applications were subsequently reviewed to gather further descriptions of the trials conducted in patients with hepatic impairment and data analyses. Results: No dedicated pharmacokinetics trials were conducted in patients with hepatic impairment for these approved TPs, but subgroup (n = 2 [2.2%]) or population (n = 5 [5.5%]) pharmacokinetic analyses were performed for 7 TPs. The pharmacokinetics of these proteins were not affected by the hepatic dysfunction, with the exception that the clearance of drotrecogin alfa seemed 25% higher in patients with hepatic impairment than in patients without hepatic impairment; however, no dose reduction was recommended. Thus, the effect of hepatic impairment on the pharmacokinetics of TPs is unclear based on the limited analyses completed to date. Conclusions: A dedicated pharmacokinetics trial for TPs in patients with hepatic impairment is not necessary. Recognizing that the data are very limited, it would be important to continue collecting pharmacokinetic data of TP in patients with hepatic impairment and using population pharmacokinetic analyses to evaluate the effect of hepatic impairment on the pharmacokinetics of TP. Published by Elsevier HS Journals, Inc. C1 [Yang, Jun; Shord, Stacy; Zhao, Hong; Men, Yuxin; Rahman, Atiqur] US FDA, Off Clin Pharmacol, Off Translat Sci, Silver Spring, MD USA. RP Yang, J (reprint author), 10903 New Hampshire Ave,Bldg 51,Room 2197, Silver Spring, MD 20993 USA. EM jun.yang@fda.hhs.gov NR 27 TC 1 Z9 1 U1 2 U2 3 PU ELSEVIER PI BRIDGEWATER PA 685 ROUTE 202-206, BRIDGEWATER, NJ 08807 USA SN 0149-2918 J9 CLIN THER JI Clin. Ther. PD SEP PY 2013 VL 35 IS 9 BP 1444 EP 1451 DI 10.1016/j.clinthera.2013.06.010 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 231BS UT WOS:000325388600018 PM 23891362 ER PT J AU Xu, XM Gupta, A Faustino, P Sathe, PM Sayeed, VA Khan, MA AF Xu, Xiaoming Gupta, Abhay Faustino, Patrick Sathe, Pradeep M. Sayeed, Vilayat A. Khan, Mansoor A. TI Development and Validation of a HPLC Method for Dissolution and Stability Assay of Liquid-Filled Cyclosporine Capsule Drug Products SO AAPS PHARMSCITECH LA English DT Article DE cyclosporine; degradation; dissolution; HPLC; liquid-filled capsules ID RENAL-TRANSPLANTATION; ABSORPTION; EMULSION; DISEASE AB To assay the dissolution samples of a drug product from several sources, a simple but broadly applicable analytical method is always desired. For the liquid-filled cyclosporine capsules, while analyzing the dissolution samples, the current compendial and literature HPLC methods have been found to be inadequate to provide satisfactory separation of the drug and the excipient peaks. Accordingly, a suitable isocratic reverse-phase HPLC method was developed for the analysis of dissolution samples of liquid-filled cyclosporine capsules. The method successfully separated the cyclosporine peak from the interfering chromatographic peaks of the excipients. The method was validated according to the ICH and FDA guidelines. Specificity, selectivity, linearity, accuracy, precision, and robustness were established over 3 days as part of method validation. Additionally, the degradation kinetics of cyclosporine in dissolution media was determined. Cyclosporine degradation followed a zero-order kinetics in the dissolution media with the respective rate constants of -3.5, -1.5, and -0.3%/ h at 37 degrees C, 25 degrees C, and 10 degrees C. C1 [Xu, Xiaoming; Gupta, Abhay; Faustino, Patrick; Khan, Mansoor A.] US FDA, Div Prod Qual Res, OTR OPS, Silver Spring, MD 20993 USA. [Sathe, Pradeep M.; Sayeed, Vilayat A.] OPS, Off Gener Drugs, Rockville, MD 20855 USA. RP Khan, MA (reprint author), US FDA, Div Prod Qual Res, OTR OPS, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Mansoor.Khan@fda.hhs.gov OI Xu, Xiaoming/0000-0003-1672-0830 FU FDA; ORISE FX This project was funded by regulatory science and review enhancement (RSR) funding from FDA, and was supported in part by an appointment to the ORISE Research Participation Program at the CDER administered by the Oak Ridge Institute for Science and Education through an agreement between the U.S. Department of Energy and CDER. NR 18 TC 3 Z9 3 U1 2 U2 19 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-9932 J9 AAPS PHARMSCITECH JI AAPS PharmSciTech PD SEP PY 2013 VL 14 IS 3 BP 959 EP 967 DI 10.1208/s12249-013-9983-8 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 219DZ UT WOS:000324487200007 PM 23761263 ER PT J AU Guo, CN Ngo, D Ahadi, S Doub, WH AF Guo, Changning Ngo, Diem Ahadi, Shafiq Doub, William H. TI Evaluation of an Abbreviated Impactor for Fine Particle Fraction (FPF) Determination of Metered Dose Inhalers (MDI) SO AAPS PHARMSCITECH LA English DT Article DE abbreviated impactor; cascade impactor; fine particle fraction; MDI; particle size distribution ID DISTRIBUTION APSD METRICS; CASCADE IMPACTORS; (PMDI)-BASED FORMULATION; RELATIVE PRECISION; FULL RESOLUTION AB Abbreviated impactors have been developed recently to allow more rapid evaluation of inhalation products as alternates to the eight-stage Andersen Cascade Impactor (ACI) which has been widely used in the pharmaceutical industry for assessing aerodynamic particle size distribution. In this paper, a two-stage abbreviated impactor, Westech Fine Particle Dose Impactor (WFPD), was used to characterize the aerodynamic particle size of metered dose inhaler (MDI) products, and the results were compared with those obtained using the standard eight-stage ACI. Seven commercial MDI products, with different propellants (chlorofluorocarbon/hydrofluoroalkane) and formulation types (suspension/solution, dry/normal/wet), were tested in this study by both WFPD and ACI. Substantially equivalent measures of fine particle fraction were obtained for most of the tested MDI products, but larger coarse particle fraction and extra-fine particle fraction values were measured from WFPD relative to those measured using the ACI. Use of the WFPD also produced more wall loss than the ACI. Therefore, it is recommended that the system suitability be evaluated on a product-by-product basis to establish substantial equivalency before implementing an abbreviated impactor measurement methodology for routine use in inhaler product characterization. C1 [Guo, Changning; Ngo, Diem; Ahadi, Shafiq; Doub, William H.] US FDA, Div Pharmaceut Anal, St Louis, MO 63101 USA. [Ahadi, Shafiq] US FDA, Off Regulatory Affairs, St Louis, MO 63143 USA. RP Guo, CN (reprint author), US FDA, Div Pharmaceut Anal, 1114 Market St,Room 1002, St Louis, MO 63101 USA. EM changning.guo@fda.hhs.gov NR 12 TC 1 Z9 1 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-9932 J9 AAPS PHARMSCITECH JI AAPS PharmSciTech PD SEP PY 2013 VL 14 IS 3 BP 1004 EP 1011 DI 10.1208/s12249-013-9984-7 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 219DZ UT WOS:000324487200011 PM 23780781 ER PT J AU Uribarri, J Calvo, MS AF Uribarri, Jaime Calvo, Mona S. TI Dietary Phosphorus Excess: A Risk Factor in Chronic Bone, Kidney, and Cardiovascular Disease? SO ADVANCES IN NUTRITION LA English DT Editorial Material AB There is growing evidence in the nephrology literature supporting the deleterious health effect of excess dietary phosphorus intake. This issue has largely escaped the attention of nutrition experts until this symposium, which raised the question of whether the same health concerns should be extended to the general population. The potential hazard of a high phosphorus intake in the healthy population is illustrated by findings from acute and epidemiologic studies. Acute studies in healthy young adults demonstrate that phosphorus intakes in excess of nutrient needs may significantly disrupt the hormonal regulation of phosphorus contributing to disordered mineral metabolism, vascular calcification, bone loss, and impaired kidney function. One of the hormonal factors acutely affected by dietary phosphorus loading is fibroblast growth factor-23, which may be a key factor responsible for many of the cardiovascular disease (CVD) complications of high phosphorus intake. Increasingly, large epidemiological studies suggest that mild elevations of serum phosphorus within the normal range are associated with CVD risk in healthy populations. Few population studies link high dietary phosphorus intake to mild changes in serum phosphorus due to study design issues specific to phosphorus and inaccurate nutrient composition databases. The increasing phosphorus intake due to the use of phosphorus-containing ingredients in processed food and the growing consumption of processed convenience and fast foods is an important factor that needs to be emphasized. C1 [Uribarri, Jaime] Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA. [Calvo, Mona S.] US FDA, US Ctr Food Safety & Appl Nutr, Laurel, MD USA. RP Uribarri, J (reprint author), Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA. EM jaime.uribarri@mssm.edu FU American Society for Nutrition; American Society of Nephrology FX This article is a summary of the symposium "Dietary Phosphorus Excess: A Risk Factor in Chronic Bone, Kidney, and Cardiovascular Disease" held April 24, 2013 at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2013 in Boston, MA. The symposium was sponsored by the American Society for Nutrition and supported in part by the American Society of Nephrology. The organizer has indicated that related reviews of this symposium will be submitted for publication in an upcoming issue of Advances of Nutrition. NR 0 TC 2 Z9 2 U1 0 U2 7 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 EI 2156-5376 J9 ADV NUTR JI Adv. Nutr. PD SEP PY 2013 VL 4 IS 5 BP 542 EP 544 DI 10.3945/an.113.004234 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 217KH UT WOS:000324357900011 PM 24038251 ER PT J AU Geda, YE Schneider, LS Gitlin, LN Miller, DS Smith, GS Bell, J Evans, J Lee, M Porsteinsson, A Lanctot, KL Rosenberg, PB Sultzer, DL Francis, PT Brodaty, H Padala, PP Onyike, CU Ortiz, LA Ancoli-Israel, S Bliwise, DL Martin, JL Vitiello, MV Yaffe, K Zee, PC Herrmann, N Sweet, RA Ballard, C Khin, NA Alfaro, C Murray, PS Schultz, S Lyketsos, CG AF Geda, Yonas E. Schneider, Lon S. Gitlin, Laura N. Miller, David S. Smith, Gwenn S. Bell, Joanne Evans, Jovier Lee, Michael Porsteinsson, Anton Lanctot, Krista L. Rosenberg, Paul B. Sultzer, David L. Francis, Paul T. Brodaty, Henry Padala, Prasad P. Onyike, Chiadikaobi U. Ortiz, Luis Agueera Ancoli-Israel, Sonia Bliwise, Donald L. Martin, Jennifer L. Vitiello, Michael V. Yaffe, Kristine Zee, Phyllis C. Herrmann, Nathan Sweet, Robert A. Ballard, Clive Khin, Ni A. Alfaro, Cara Murray, Patrick S. Schultz, Susan Lyketsos, Constantine G. CA Neuropsychiat Syndromes TI Neuropsychiatric symptoms in Alzheimer's disease: Past progress and anticipation of the future SO ALZHEIMERS & DEMENTIA LA English DT Article DE Neuropsychiatric symptoms; Behavioral and psychological symptoms of dementia; Agitation/aggression; Sleep disorders; Depression; Apathy; Psychosis; Delusions; Hallucinations; Dementia; Alzheimer's disease; Mild cognitive impairment; Mild behavioral impairment ID MILD COGNITIVE IMPAIRMENT; VASCULAR DEPRESSION HYPOTHESIS; PITTSBURGH COMPOUND-B; ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; BEHAVIORAL SYMPTOMS; NATIONAL INSTITUTE; RANDOMIZED-TRIAL; RATING-SCALE; DOUBLE-BLIND AB Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimer's first case, Frau Auguste D., presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimer's Association convened a research roundtable on the topic of NPS in AD. A major outcome of the roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimer's Research and Treatment (ISTAART). The NPS-PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome-specific synthetic reviews and recommendations prepared by NPS-PIA workgroups on depression, apathy, sleep, agitation, and psychosis. (C) 2013 The Alzheimer's Association. All rights reserved. C1 [Geda, Yonas E.] Mayo Clin, Coll Med, Dept Psychiat, Scottsdale, AZ USA. [Geda, Yonas E.] Mayo Clin, Coll Med, Dept Neurol, Scottsdale, AZ USA. [Schneider, Lon S.] Univ So Calif, Los Angeles, CA USA. [Gitlin, Laura N.] Johns Hopkins Univ, Sch Nursing, Baltimore, MD USA. [Miller, David S.] Bracket, Wayne, PA USA. [Smith, Gwenn S.; Rosenberg, Paul B.; Onyike, Chiadikaobi U.; Lyketsos, Constantine G.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Div Geriatr Psychiat & Neuropsychiat, Baltimore, MD 21218 USA. [Evans, Jovier] NIMH, Geriatr Res Branch, Geriatr Translat Neurosci & MultiModal Interv Pro, Geriatr Pharmacol Intervent, Bethesda, MD 20892 USA. [Lee, Michael] Univ Minnesota, Inst Translat Neurosci, Dept Neurosci, Minneapolis, MN USA. [Lee, Michael] Univ Minnesota, Inst Translat Neurosci, Ctr Neurodegenerat Dis, Minneapolis, MN USA. [Porsteinsson, Anton] Univ Rochester, Sch Med & Dent Rochester, Dept Psychiat, Rochester, NY USA. [Lanctot, Krista L.] Sunnybrook Res Inst, Brain Sci Program, Toronto, ON, Canada. [Lanctot, Krista L.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Lanctot, Krista L.] Univ Toronto, Dept Pharmacol, Toronto, ON, Canada. [Lanctot, Krista L.] Univ Toronto, Dept Toxicol, Toronto, ON, Canada. [Sultzer, David L.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Sultzer, David L.] VA Greater Angeles Healthcare Syst, Psychiat Serv, Los Angeles, CA USA. [Francis, Paul T.] Kings Coll London, Wolfson Ctr Age Related Dis, London, England. [Brodaty, Henry] Univ New S Wales, Dementia Collaborat Res Ctr, Sydney, NSW, Australia. [Padala, Prasad P.] Cent Arkansas Vet Healthcare Syst, Geriatr Res Educ & Clin Ctr, Little Rock, AR USA. [Padala, Prasad P.] Univ Arkansas Med Sci, Dept Psychiat, Little Rock, AR 72205 USA. [Ortiz, Luis Agueera] C1BERSAM, Madrid, Spain. [Ortiz, Luis Agueera] Univ Hosp Doce Octubre, Madrid, Spain. [Ancoli-Israel, Sonia] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Ancoli-Israel, Sonia] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Bliwise, Donald L.] Emory Univ, Sch Med, Wesley Woods Hlth Ctr, Dept Neurol, Atlanta, GA USA. [Martin, Jennifer L.] Univ Calif Los Angeles, Educ & Clin Ctr, VA Greater Angeles Healthcare Geriatr Res, Los Angeles, CA USA. [Martin, Jennifer L.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Vitiello, Michael V.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Zee, Phyllis C.] Northwestern Univ, Feinberg Sch Med, Dept Neurol, Chicago, IL 60611 USA. [Sweet, Robert A.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Sweet, Robert A.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Sweet, Robert A.; Murray, Patrick S.] VA Pittsburgh Healthcare Syst, VISN 4 Mental Illness Res Educ & Clin Ctr MIRECC, Pittsburgh, PA USA. [Ballard, Clive] Kings Coll London, Wolfson Ctr Age Related Dis, Biomed Res Unit, Inst Psychiat & Alzheimers Soc, London WC2R 2LS, England. [Khin, Ni A.; Alfaro, Cara] US FDA, Ctr Drug Evaluat & Res, Off Drug Evaluat 1 OND, Div Psychiat Prod, Silver Spring, MD USA. [Schultz, Susan] Univ Iowa, Carver Coll Med, Dept Psychiat, Iowa City, IA USA. RP Lyketsos, CG (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Div Geriatr Psychiat & Neuropsychiat, Baltimore, MD 21218 USA. RI Lee, Michael/D-9491-2013; Francis, Paul/A-9199-2008; OI Lee, Michael/0000-0001-5865-9682; Murray, Patrick/0000-0002-6525-2888; Vitiello, Michael/0000-0002-9776-0473; Lanctot, Krista L./0000-0001-7024-6637 FU NIMH [K01-MH68351, R24-MH074779, R01-MH079814, RC1-MH090770-01]; NIA [U01-AG006786]; National Center for Research Resources [RR024150]; Robert Wood Johnson Foundation; European Union Regional Development Fund [FNUSA-ICRC: CZ.1.05/1.1.00/02.0123]; Baxter; Elan Pharmaceuticals; Johnson Johnson; Eli Lilly; Myriad; Novartis; Pfizer; Abbott Laboratories; AC Immune; Allergan; Allon; Alzheimer Drug Discovery Foundation; AstraZeneca; Bristol-Myers Squibb; Elan; Exonhit; Forest; GlaxoSmithKline; Ipsen Pharmaceuticals; Lundbeck; Medavante; Medivation; Merck; Merz; Roche; Sanofi-Aventis; Schering-Plough; Schwabe; Toyama; Transition Therapeutics; Alzheimer's Association [IIRG-07-28686]; Johns Hopkins Alzheimer's Disease Research Center [P50-AG005146]; NIMH, MA; Associated Jewish Federation of Baltimore; Weinberg Foundation; Eisai; Lilly; Ortho-McNeil; Bristol-Myers; National Football League; Functional Neuromodulation Inc. FX The authors thank Dr. Michelle M. Mielke for her helpful comments and feedback on early drafts of this manuscript. Dr. Geda was supported by NIMH grant K01-MH68351, NIA grant U01-AG006786 (the Mayo Clinic Study of Aging), National Center for Research Resources grant RR024150 (Mayo Clinic CTSA [Career Transition Award]), the Robert Wood Johnson Foundation (Harold Amos Scholar), and the European Union Regional Development Fund (Project FNUSA-ICRC: CZ.1.05/1.1.00/02.0123). Dr. Schneider reports being an editor on the Cochrane Collaboration Dementia and Cognitive Improvement Group, which oversees systematic reviews of drugs for cognitive impairment and dementia. He received a grant from the Alzheimer's Association for a registry for dementia and cognitive impairment trials; he is also in receipt of grant or research support from Baxter, Elan Pharmaceuticals, Johnson & Johnson, Eli Lilly, Myriad, Novartis, and Pfizer. He has served as a consultant for or received consulting fees from Abbott Laboratories, AC Immune, Allergan, Allon, the Alzheimer Drug Discovery Foundation, AstraZeneca, Bristol-Myers Squibb, Elan, Eli Lilly, Exonhit, Forest, GlaxoSmithKline, Ipsen Pharmaceuticals, Johnson & Johnson, Lundbeck, Myriad, Medavante, Medivation, Merck, Merz, Novartis, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, Schwabe, Toyama, and Transition Therapeutics. Dr. Gitlin was supported by NIMH grants R24-MH074779, R01-MH079814, and RC1-MH090770-01 and Alzheimer's Association grant IIRG-07-28686 and served on the Phillips Life Line Falls Advisory Board. Dr. Miller is a full-time employee of Bracket. Dr. Lyketsos was supported by the Johns Hopkins Alzheimer's Disease Research Center (P50-AG005146). He has received grant support (research or CME) from NIMH, MA, the Associated Jewish Federation of Baltimore, the Weinberg Foundation, Forest, GlaxoSmithKline, Eisai, Pfizer, AstraZeneca, Lilly, Ortho-McNeil, Bristol-Myers, Novartis, the National Football League, Elan, and Functional Neuromodulation Inc. He has served as consultant/advisor for AstraZeneca, GlaxoSmithKline, Eisai, Novartis, Forest, Supernus, Adlyfe, Takeda, Wyeth, Lundbeck, Merz, Lilly, Pfizer, Genentech, Elan, the NFL Players Association, the NFL Benefits Office, Avanir, and Zinfandel. He has also received honorarium or travel support from Pfizer, Forest, GlaxoSmithKline, and Health Monitor. NR 68 TC 75 Z9 76 U1 7 U2 42 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD SEP PY 2013 VL 9 IS 5 BP 602 EP 608 DI 10.1016/j.jalz.2012.12.001 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 222IN UT WOS:000324724500015 PM 23562430 ER PT J AU Cheng, TF Patton, GW Muldoon-Jacobs, K AF Cheng, Tsu-Fan Patton, Geoffrey W. Muldoon-Jacobs, Kristi TI Can the L5178Y Tk(+/-) mouse lymphoma assay detect epigenetic silencing? SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Epigenetics; DNA methylation; Mouse Lymphoma Assay; TK L5178Y; Genetic toxicology ID THYMIDINE KINASE LOCUS; CELL MUTAGENESIS ASSAY; INDUCED DNA HYPERMETHYLATION; TK-/-MUTANTS; CYTOGENETIC CHARACTERIZATION; PROMOTER HYPERMETHYLATION; 5-AZACYTIDINE TREATMENT; ETHYL METHANESULFONATE; DRUG-RESISTANCE; POINT MUTATIONS AB The mouse lymphoma L5178Y Tk(+/-) assay is broadly used in toxicology to assess genotoxicity because of its known sensitivity to genotoxicants that act through a variety of mechanisms, which may include epigenetic DNA methylation. This brief article highlights the studies that have contributed to this conjecture and suggests an addition to the experimental design that could identify if the test substance is a potential epimutagen acting via hypermethylation. (c) 2013 Published by Elsevier Ltd. C1 [Cheng, Tsu-Fan; Patton, Geoffrey W.; Muldoon-Jacobs, Kristi] US FDA, Ctr Food Safety & Appl Nutr, OFAS, DFCN, College Pk, MD 20740 USA. RP Muldoon-Jacobs, K (reprint author), US FDA, Ctr Food Safety & Appl Nutr, OFAS, DFCN, HFS 275,5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM Kristi.Jacobs@fda.hhs.gov NR 51 TC 2 Z9 2 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD SEP PY 2013 VL 59 BP 187 EP 190 DI 10.1016/j.fct.2013.06.007 PG 4 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA 216JR UT WOS:000324280000024 PM 23778052 ER PT J AU Korsnes, MS Espenes, A Hermansen, LC Loader, JI Miles, CO AF Korsnes, Monica Suarez Espenes, Arild Hermansen, Lene C. Loader, Jared I. Miles, Christopher O. TI Cytotoxic responses in BC3H1 myoblast cell lines exposed to 1-desulfoyessotoxin SO TOXICOLOGY IN VITRO LA English DT Article DE 1-Desulfoyessotoxin; Yessotoxin; Paraptosis; Cytoplasmic vacuolation; Mitochondria; Endoplasmic reticulum; DNA fragmentation; p38; Hsp70; Intracellular signalling ID HEAT-SHOCK PROTEINS; PROTOCERATIUM-RETICULATUM; HUMAN-LYMPHOCYTES; OKADAIC ACID; INDUCED APOPTOSIS; DEATH PATHWAYS; ACTIVATED RAS; ONCOGENIC RAS; CANCER-CELLS; IN-VITRO AB 1-Desulfoyessotoxin (1-dsYTX) is a desulfated polyether compound belonging to the yessotoxin group of marine toxins. This analogue has been detected in mussels. There are so far no reports on the mechanisms of action of 1-dsYTX in in vitro cell systems. This work evaluates cytotoxic responses in BC3H1 cells exposed to 100 nM 1-dsYTX. The toxicity of 1-dsYTX seems to be similar to that of yessotoxin (YTX). 1-Desulfoyessotoxin induced morphological and biochemical traits typical of a non-apoptotic form of cell death resembling paraptosis. Treated BC3H1 cells showed extensive cytoplasmic vacuolation, enlargement of mitochondria and endoplasmic reticulum and lack of DNA fragmentation. Western blotting analysis revealed phosphorylation of the protein kinase p38 and involvement of the heat shock protein Hsp70. This activation suggests involvement of different signalling pathways for programmed cell death. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Korsnes, Monica Suarez; Espenes, Arild; Hermansen, Lene C.] Norwegian Sch Vet Sci, N-0033 Oslo, Norway. [Miles, Christopher O.] Norwegian Vet Inst, N-0106 Oslo, Norway. [Loader, Jared I.; Miles, Christopher O.] AgResearch, Ruakura Res Ctr, Hamilton 3240, New Zealand. [Loader, Jared I.] FDA, Div Seafood Sci & Technol, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. RP Korsnes, MS (reprint author), Norwegian Sch Vet Sci, POB 8146 Dep, N-0033 Oslo, Norway. EM monica.suarez.korsnes@nvh.no FU Norwegian School of Veterinary Science, Department of Basic Sciences and Aquatic Medicine and Olav Raagholt og Gerd Meidel Raagholts legacy; New Zealand Foundation for Research, Science and Technology [AGRX0402]; Marie Curie International Incoming Fellowship; European Community [221117] FX The authors thank the Norwegian School of Veterinary Science, Department of Basic Sciences and Aquatic Medicine and Olav Raagholt og Gerd Meidel Raagholts legacy for supporting this work. This study was partly supported by a Postdoctoral Fellowship to J.I.L. (Contract AGRX0402) funded by the New Zealand Foundation for Research, Science and Technology, and a Marie Curie International Incoming Fellowship to C.O.M. within the seventh European Community Framework Programme (FP7/2007-2013) under grant agreement No. 221117. NR 71 TC 5 Z9 5 U1 1 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-2333 J9 TOXICOL IN VITRO JI Toxicol. Vitro PD SEP PY 2013 VL 27 IS 6 BP 1962 EP 1969 DI 10.1016/j.tiv.2013.06.012 PG 8 WC Toxicology SC Toxicology GA 223YG UT WOS:000324847800042 PM 23851005 ER PT J AU Hansen, DK George, NI White, GE Abdel-Rahman, A Pellicore, LS Fabricant, D AF Hansen, Deborah K. George, Nysia I. White, Gene E. Abdel-Rahman, Ali Pellicore, Linda S. Fabricant, Daniel TI Cardiovascular Toxicity of Citrus aurantium in Exercised Rats SO CARDIOVASCULAR TOXICOLOGY LA English DT Article DE Bitter orange; Citrus aurantium; Cardiotoxicology; Blood pressure; Heart rate; Weight loss ID EPHEDRA-FREE XENADRINE; BITTER ORANGE; DIETARY-SUPPLEMENT; P-SYNEPHRINE; WEIGHT-LOSS; MUSCARINIC RECEPTORS; OCTOPAMINE; ALKALOIDS; CAFFEINE; EXTRACT AB When safety concerns forced the removal of ephedra from the market, other botanicals, including Citrus aurantium or bitter orange (BO) were used as replacements. A major component of the BO extract is synephrine, a chemical that is structurally similar to ephedrine. Because ephedrine has cardiovascular effects that may be exacerbated during physical exercise, the purpose of this study was to determine whether extracts containing synephrine produced adverse effects on the cardiovascular system in exercising rats. Sprague-Dawley rats were dosed daily by gavage for 28 days with 10 or 50 mg of synephrine/kg body weight from one of two different extracts; caffeine was added to some doses. The rats ran on a treadmill for 30 min/day, 3 days/week. Heart rate, blood pressure, body temperature, and QT interval were monitored. Both doses of both extracts significantly increased systolic and diastolic blood pressure for up to 8 h after dosing. Effects on heart rate and body temperature appeared to be due primarily to the effects of caffeine. These data suggest that the combination of synephrine, caffeine, and exercise can have significant effects on blood pressure and do not appear to be effective in decreasing food consumption or body weight. C1 [Hansen, Deborah K.] US FDA, NCTR, Div Syst Biol, Jefferson, AR 72079 USA. [George, Nysia I.] US FDA, NCTR, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [White, Gene E.] Toxicol Pathol Associates, Jefferson, AR 72079 USA. [Abdel-Rahman, Ali; Fabricant, Daniel] US FDA, Ctr Food Safety & Nutr, Off Nutr Labeling & Dietary Supplements, College Pk, MD 20740 USA. [Pellicore, Linda S.] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. RP Hansen, DK (reprint author), US FDA, NCTR, Div Syst Biol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM deborah.hansen@fda.hhs.gov; nysia.george@fda.hhs.gov; gene.white@fda.hhs.gov; ali.abdel-rahman@fda.hhs.gov; linda.pellicore@fda.hhs.gov; daniel.fabricant@fda.hhs.gov FU FDA:NCTR [FDA 224-07-0007, NIH Y1ES1027]; NIEHS:NTP [FDA 224-07-0007, NIH Y1ES1027] FX The authors would also like to thank Mr. Andy Matson and the rest of the Bionetics Diet Prep Staff for dosage preparation; Mr. Paul Siitonen and Mr. Ron Evans in the Department of Biochemical Toxicology for analysis and quantitation of dosage solutions; Ms. Beth Juliar for statistical analysis of body weight and food consumption; Ms. Michelle Vanlandingham, Carol Cain, and the animal care technicians from the Bionetics staff for excellent animal care. This work was supported by Interagency Agreement between FDA:NCTR and the NIEHS:NTP (FDA 224-07-0007) (NIH Y1ES1027). NR 39 TC 4 Z9 5 U1 1 U2 16 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1530-7905 J9 CARDIOVASC TOXICOL JI Cardiovasc. Toxicol. PD SEP PY 2013 VL 13 IS 3 BP 208 EP 219 DI 10.1007/s12012-013-9199-x PG 12 WC Cardiac & Cardiovascular Systems; Toxicology SC Cardiovascular System & Cardiology; Toxicology GA 214DC UT WOS:000324110000003 PM 23397375 ER PT J AU Herndon, TM Deisseroth, A Kaminskas, E Kane, RC Koti, KM Rothmann, MD Habtemariam, B Bullock, J Bray, JD Hawes, J Palmby, TR Jee, J Adams, W Mahayni, H Brown, J Dorantes, A Sridhara, R Farrell, AT Pazdur, R AF Herndon, Thomas M. Deisseroth, Albert Kaminskas, Edvardas Kane, Robert C. Koti, Kallappa M. Rothmann, Mark D. Habtemariam, Bahru Bullock, Julie Bray, Jeffrey D. Hawes, Jessica Palmby, Todd R. Jee, Josephine Adams, William Mahayni, Houda Brown, Janice Dorantes, Angelica Sridhara, Rajeshwari Farrell, Ann T. Pazdur, Richard TI U.S. Food and Drug Administration Approval: Carfilzomib for the Treatment of Multiple Myeloma SO CLINICAL CANCER RESEARCH LA English DT Article ID PROTEIN-DEGRADATION; BORTEZOMIB; UBIQUITIN; PROTEASOMES AB The U.S. Food and Drug Administration (FDA) review leading to accelerated approval of carfilzomib is described. A single-arm trial enrolled 266 patients with multiple myeloma refractory to the most recent therapy who had received prior treatment with bortezomib and an immunomodulatory agent (IMID). Patients received carfilzomib by intravenous infusion over 2 to 10 minutes at a dose of 20 mg/m(2) on days 1, 2, 8, 9, 15, and 16 of the 28 days of cycle 1, and at a dose of 27 mg/m(2) on the same schedule in cycle 2 and subsequent cycles. The primary efficacy endpoint was overall response rate (ORR) as determined by an independent review committee using International Myeloma Working Group Uniform Response Criteria. The safety of carfilzomib was evaluated in 526 patients with multiple myeloma treated with various dosing regimens. The ORR was 23%. The median duration of response was 7.8 months. The most common adverse reactions associated with carfilzomib infusion were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and fever. The most common serious adverse events were pneumonia, acute renal failure, fever, and congestive heart failure. Infusion reactions to carfilzomib could be reduced by pretreatment with dexamethasone and intravenous fluids. On July 20, 2012, the FDA granted accelerated approval of carfilzomib for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an IMID and who have shown disease progression while on therapy or within 60 days of completion of the last therapy. (C)2013 AACR. C1 [Herndon, Thomas M.; Deisseroth, Albert; Kaminskas, Edvardas; Kane, Robert C.; Bray, Jeffrey D.; Hawes, Jessica; Palmby, Todd R.; Farrell, Ann T.; Pazdur, Richard] US FDA, Off Hematol & Oncol Drug Prod, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Koti, Kallappa M.; Rothmann, Mark D.; Sridhara, Rajeshwari] US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Habtemariam, Bahru; Bullock, Julie] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Habtemariam, Bahru; Bullock, Julie] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Jee, Josephine; Adams, William; Mahayni, Houda; Brown, Janice; Dorantes, Angelica] US FDA, Off New Drug Qual Assessment, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Herndon, TM (reprint author), US FDA, Div Hematol Prod, 10903 New Hampshire Ave,Bldg 22,Room 5222, Silver Spring, MD 20993 USA. EM Thomas.Herndon@fda.hhs.gov NR 17 TC 67 Z9 70 U1 0 U2 12 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 1 PY 2013 VL 19 IS 17 BP 4559 EP 4563 DI 10.1158/1078-0432.CCR-13-0755 PG 5 WC Oncology SC Oncology GA 213ZE UT WOS:000324098400004 PM 23775332 ER PT J AU Dickensheets, H Sheikh, F Shepard, R Hillyer, P Rabin, RL Donnelly, RP AF Dickensheets, Harold Sheikh, Faruk Shepard, Rachel Hillyer, Philippa Rabin, Ronald L. Donnelly, Raymond P. TI Interferon-lambda is produced by and induces autocrine expression of interferon-stimulated genes in human bronchial epithelial cells SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Dickensheets, Harold; Sheikh, Faruk; Donnelly, Raymond P.] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. [Shepard, Rachel; Hillyer, Philippa; Rabin, Ronald L.] US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. NR 0 TC 0 Z9 0 U1 0 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 259 EP 259 DI 10.1016/j.cyto.2013.06.072 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700081 ER PT J AU El Fiky, A Perreault, R McGinnis, GJ Rabin, RL AF El Fiky, Ashraf Perreault, Roger McGinnis, Gwendolyn J. Rabin, Ronald L. TI Interferon Regulatory Factor 4 (IRF4) mediates IFN-beta and lambda 1 expression upon TLR4 and MR challenge in human alternatively activated macrophages SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [El Fiky, Ashraf; Perreault, Roger; McGinnis, Gwendolyn J.; Rabin, Ronald L.] US FDA, Lab Immunobiochem, Div Bacterial Parasit & Allergen Prod, Off Vaccines Res & Review,Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 261 EP 261 DI 10.1016/j.cyto.2013.06.078 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700087 ER PT J AU Muchmore, B Tang, W Porter-Gill, P Kohaar, I Liu, LY Brand, N Park, H Dickensheets, H Sheikh, F Rehermann, B Donnelly, RP O'Brien, TR Prokunina-Olsson, L AF Muchmore, Brian Tang, Wei Porter-Gill, Patricia Kohaar, Indu Liu, Luyang Brand, Nathan Park, Heiyoung Dickensheets, Harold Sheikh, Faruk Rehermann, Barbara Donnelly, Raymond P. O'Brien, Thomas R. Prokunina-Olsson, Ludmila TI Identification and characterization of interferon-lambda 4 (IFN-lambda 4), a novel class-2 cytokine which impairs clearance of hepatitis C virus SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Muchmore, Brian; Tang, Wei; Porter-Gill, Patricia; Kohaar, Indu; Liu, Luyang; Brand, Nathan; Prokunina-Olsson, Ludmila] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Park, Heiyoung; Rehermann, Barbara] NIDDK, Immunol Sect, Liver Dis Branch, Bethesda, MD USA. [Dickensheets, Harold; Sheikh, Faruk; Donnelly, Raymond P.] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. [O'Brien, Thomas R.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 286 EP 286 DI 10.1016/j.cyto.2013.06.185 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700194 ER PT J AU Renn, LA Theisen, TC Hillyer, P Rabin, RL AF Renn, Lynnsey A. Theisen, Terence C. Hillyer, Philippa Rabin, Ronald L. TI Characterization of human interferon subtype and interferon-stimulated gene signatures SO CYTOKINE LA English DT Meeting Abstract CT Annual Joint Conference of the International-Cytokine-Society and the International-Society-for-Interferon-and-Cytokine-Research CY SEP 29-OCT 03, 2013 CL San Francisco, CA SP Int Cytokine Soc, Int Soc Interferon & Cytokine Res C1 [Renn, Lynnsey A.; Theisen, Terence C.; Hillyer, Philippa; Rabin, Ronald L.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD SEP PY 2013 VL 63 IS 3 SI SI BP 292 EP 293 DI 10.1016/j.cyto.2013.06.213 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 212WO UT WOS:000324013700222 ER PT J AU Agrawal, A Shindell, E Jordan, F Baeva, L Pfefer, J Godar, DE AF Agrawal, Anant Shindell, Eli Jordan, Fredrick Baeva, Larissa Pfefer, Joshua Godar, Dianne E. TI UV Radiation Increases Carcinogenic Risks for Oral Tissues Compared to Skin SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID PYRIMIDINE DIMER FORMATION; ALLERGIC RHINITIS; LIGHTING SOURCES; LICHEN-PLANUS; CANCER; PHOTOTHERAPY; EXPRESSION; PREVENTION; MUCOSA; CELLS AB People can expose their oral cavities to UV (290-400 nm) by simply opening their mouths while outdoors. They can also have their oral cavities exposed to UV indoors to different UV-emitting devices used for diagnoses, treatments and procedures like teeth whitening. Because the World Health Organization declared UV radiation as a complete human carcinogen in 2009, we asked if oral tissues are at a similar or higher carcinogenic risk compared to skin tissue. To understand the UVB (290-320 nm)-related carcinogenic risks to these tissues, we measured initial DNA damage in the form of cyclobutane pyrimidine dimers (CPD), the repair rate of CPD (24 h) and the number of apoptotic dead cells over time resulting from increasing doses of erythemally weighted UV radiation. We used commercially available 3D-engineered models of human skin (EpiDerm (TM)), gingival (EpiGingival (TM)) and oral (EpiOral (TM)) tissues and developed an analytical approach for our tri-labeling fluorescent procedure to identify total DNA, CPD and apoptotic cells so we can simultaneously quantify DNA repair rates and dead cells. Both DNA repair and apoptotic cell numbers are significantly lower in oral cells compared with skin cells. The combined results suggest UVB-exposed oral tissues are at a significantly higher carcinogenic risk than skin tissues. C1 [Agrawal, Anant; Jordan, Fredrick; Baeva, Larissa; Pfefer, Joshua; Godar, Dianne E.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Shindell, Eli] Univ Maryland, College Pk, MD 20742 USA. RP Godar, DE (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. EM Dianne.Godar@FDA.HHS.GOV OI GODAR, DIANNE/0000-0002-7690-5223 NR 37 TC 7 Z9 7 U1 0 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD SEP PY 2013 VL 89 IS 5 BP 1193 EP 1198 DI 10.1111/php.12140 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 213DI UT WOS:000324033900023 PM 23855371 ER PT J AU Lin, CTJ Gao, ZF Lee, JY AF Lin, Chung-Tung Jordan Gao, Zhifeng Lee, Jonq-Ying TI Associations between self-reported weight management methods with diet quality as measured by the Healthy Eating Index-2005 SO PREVENTIVE MEDICINE LA English DT Article DE Diet quality; Obesity; Weight management ID REGRESSION-ANALYSIS; PHYSICAL-ACTIVITY; RISK-FACTORS; LIFE-STYLE; US ADULTS; FOOD; BEHAVIORS; SECURITY AB Objective. We examine the relationship between weight management practices and diet quality. Method. Regressions were used to analyze the associations between self-reported weight management methods and diet quality, as measured by the Healthy Eating Index-2005 (HEI-2005), of 1,933 respondents who tried to lose or not gain weight in the 2003-2004 National Health and Nutrition Examination Survey (NHANES). The regressions controlled for sociodemographics, lifestyle behaviors, and other health-related behaviors and perceptions. Results. Including both switching to foods with lower calories and exercise in weight management was associated with better diet quality, i.e., a higher total HEI-2005 score and higher scores in eight of the twelve HEI-2005 components than including neither method. The eight components included six components on fruit, vegetables and grains, milk, and calories from solid fat, alcohol beverages, and added sugars. Similar but smaller associations were also found among those who reported including either switching to foods with lower calories or exercise. Conclusions. Based on self-reported data, the findings suggest that including switching to lower calorie foods and exercise in weight management, as recommended by the Dietary Guidelines for Americans (DGA), is associated with diet quality that is more consistent with the key diet-related advice of the DGA. Published by Elsevier Inc. C1 [Lin, Chung-Tung Jordan] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Gao, Zhifeng; Lee, Jonq-Ying] Univ Florida, Food & Resource Econ Dept, Gainesville, FL 32611 USA. RP Lin, CTJ (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy,HFS 005, College Pk, MD 20740 USA. EM Chung-Tung.Lin@fda.hhs.gov NR 40 TC 2 Z9 2 U1 1 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD SEP PY 2013 VL 57 IS 3 BP 238 EP 243 DI 10.1016/j.ypmed.2013.05.026 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 212VS UT WOS:000324011500017 PM 23747357 ER PT J AU Woodle, SA Shibeko, AM Lee, TK Ovanesov, MV AF Woodle, S. A. Shibeko, A. M. Lee, T. K. Ovanesov, M. V. TI Determining the impact of instrument variation and automated software algorithms on the TGT in hemophilia and normalized plasma SO THROMBOSIS RESEARCH LA English DT Article DE Thrombin; Blood Coagulation assay; Deficiency; Factor VIII; Hemophilia ID THROMBIN GENERATION ASSAY; FACTOR-VIII; THROMBOGRAM; CALIBRATION; MANAGEMENT; INHIBITOR; CAT AB Background: Despite increasing recognition as a more precise test of in vivo hemostatic conditions, standardization of the thrombin generation test (TGT) continues to hinder its development as routine clinical practice. Prior efforts largely focused on comparing the effects of experimental conditions and different reagents. Commercialized kits, instruments and software have been introduced to calculate the TG curve and its parameters. However, modified versions of the TGT continue to be used worldwide on a variety of microplate reader instruments and processed using individualized algorithms. No prior study has compared the effect of instrument choice and its inherent noise profile on the processing of the TG curve and its common endpoint parameters. Materials and Methods: Hemophilia A plasma supplemented with buffer or Factor VIII, mimicking hemophilic or normalized samples respectively, was monitored for thrombin generation after activation with TF on six different fluorescent microplate readers. Each instrument was optimized for TGT signal recording prior to testing. An automated software package containing various mathematical algorithms was utilized to compute the TG curves and parameters, and compare different TG processing approaches. Results: Instruments produced unique noise profiles and end-point parameters that were incomparable in absolute signal terms. Similar relative hemophilic responses were obtained across various instruments when the normalized plasma sample was used as an internal standard. Smoothing algorithms corrected destructive instrument noise. Conclusions: Instrument-induced errors from numerical differentiation during TG curve processing cannot be eliminated by external calibrators, and require careful qualification of the instrument and implementation of noise-reducing software algorithms. Published by Elsevier Ltd. C1 [Woodle, S. A.; Shibeko, A. M.; Lee, T. K.; Ovanesov, M. V.] US FDA, Off Blood Res & Review, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Ovanesov, MV (reprint author), US FDA, 29 Lincoln Dr,N29-306, Bethesda, MD 20892 USA. EM mikhail.ovanesov@fda.hhs.gov OI Shibeko, Alexey/0000-0003-1494-3125 FU Oak Ridge Institute for Science and Education (ORISE) FX The authors thank Dr. DominiqueMonteil for evaluation of AMC and Z-GGR-AMC spectra. This study was supported in part by a Postgraduate and Postbaccalaureate Research Fellowship Award to S.A.W. from the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 26 TC 7 Z9 7 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0049-3848 J9 THROMB RES JI Thromb. Res. PD SEP PY 2013 VL 132 IS 3 BP 374 EP 380 DI 10.1016/j.thromres.2013.07.018 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 213MD UT WOS:000324060400013 PM 23953593 ER PT J AU Farrokhi, S Voycheck, CA Tashman, S Fitzgerald, GK AF Farrokhi, Shawn Voycheck, Carrie A. Tashman, Scott Fitzgerald, G. Kelley TI A Biomechanical Perspective on Physical Therapy Management of Knee Osteoarthritis SO JOURNAL OF ORTHOPAEDIC & SPORTS PHYSICAL THERAPY LA English DT Article DE arthritis; biomechanics; excessive loading; joint mechanics; patellofemoral joint; tibiofemoral joint ID PATELLOFEMORAL PAIN SYNDROME; RANDOMIZED CONTROLLED-TRIAL; MEDIAL COMPARTMENT OSTEOARTHRITIS; LATERALLY-WEDGED INSOLES; VARIABLE-STIFFNESS SHOE; GROUND-REACTION FORCE; ADDUCTION MOMENT; QUADRICEPS STRENGTH; TIBIOFEMORAL OSTEOARTHRITIS; FOOT ORTHOSES AB Altered knee joint biomechanics and excessive joint loading have long been considered as important contributors to the development and progression of knee osteoarthritis. Therefore, a better understanding of how various treatment options influence the loading environment of the knee joint could have practical implications for devising more effective physical therapy management strategies. The aim of this clinical commentary was to review the pertinent biomechanical evidence supporting the use of treatment options intended to provide protection against excessive joint loading while offering symptomatic relief and functional improvements for better long-term management of patients with knee osteoarthritis. The biomechanical and clinical evidence regarding the effectiveness of knee joint offloading strategies, including contralateral cane use, laterally wedged shoe insoles, variable-stiffness shoes, valgus knee bracing, and gait-modification strategies, within the context of effective disease management is discussed. In addition, the potential role of therapeutic exercise and neuromuscular training to improve the mechanical environment of the knee joint is considered. Management strategies for treatment of joint instability and patellofemoral compartment disease are also mentioned. Based on the evidence presented as part of this clinical commentary, it is argued that special considerations for the role of knee joint biomechanics and excessive joint loading are necessary in designing effective short- and long-term management strategies for treatment of patients with knee osteoarthritis. C1 [Farrokhi, Shawn; Fitzgerald, G. Kelley] Univ Pittsburgh, Dept Phys Therapy, Pittsburgh, PA 15260 USA. [Farrokhi, Shawn; Tashman, Scott] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15260 USA. [Voycheck, Carrie A.] Fed Drug Adm, Silver Spring, MD USA. [Tashman, Scott] Univ Pittsburgh, Dept Orthopaed Surg, Pittsburgh, PA 15260 USA. [Fitzgerald, G. Kelley] Univ Pittsburgh, Phys Therapy Clin & Translat Res Ctr, Pittsburgh, PA 15260 USA. RP Farrokhi, S (reprint author), Univ Pittsburgh, Dept Phys Therapy, 6035 Forbes Tower, Pittsburgh, PA 15260 USA. EM Farrokhi@pitt.edu NR 206 TC 9 Z9 9 U1 7 U2 57 PU J O S P T PI ALEXANDRIA PA 1111 NORTH FAIRFAX ST, STE 100, ALEXANDRIA, VA 22314-1436 USA SN 0190-6011 EI 1938-1344 J9 J ORTHOP SPORT PHYS JI J. Orthop. Sports Phys. Ther. PD SEP PY 2013 VL 43 IS 9 BP 600 EP 619 DI 10.2519/jospt.2013.4121 PG 20 WC Orthopedics; Rehabilitation; Sport Sciences SC Orthopedics; Rehabilitation; Sport Sciences GA 210ZM UT WOS:000323873900001 PM 23756435 ER PT J AU Woodcock, J AF Woodcock, J. TI The PCAST Report on Pharmaceutical Innovation: Implications for the FDA SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material AB In September 2012, the President's Council of Advisors on Science and Technology (PCAST) released the report"Propelling Innovation in Drug Discovery, Development and Evaluation:" A product of discussions with many stakeholders, the report reiterates current problems in drug development, including diminished return on basic biomedical research. The report calls for doubling the current annual output of innovative new medicines- an ambitious goal. Recommendations and resulting initiatives will probably affect the FDA's drug regulatory programs. C1 US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Woodcock, J (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM Janet.Woodcock@fda.hhs.gov NR 7 TC 5 Z9 5 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD SEP PY 2013 VL 94 IS 3 BP 297 EP 300 DI 10.1038/clpt.2013.88 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 208NR UT WOS:000323686900008 PM 23963215 ER PT J AU Hammad, TA Neyarapally, GA Iyasu, S Staffa, JA Dal Pan, G AF Hammad, T. A. Neyarapally, G. A. Iyasu, S. Staffa, J. A. Dal Pan, G. TI The Future of Population-Based Postmarket Drug Risk Assessment: A Regulator's Perspective SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID RANDOMIZED CONTROLLED-TRIALS; HEALTH-CARE; CARDIOVASCULAR EVENTS; UNITED-STATES; SAFETY; FDA; SURVEILLANCE; PERFORMANCE; MANAGEMENT; INNOVATION AB The US Food and Drug Administration emphasizes the role of regulatory science in the fulfillment of its mission to promote and protect public health and foster innovation. With respect to the evaluation of drug effects in the real world, regulatory science plays an important role in drug risk assessment and management. This article discusses opportunities and challenges with population-based drug risk assessment as well as related regulatory science knowledge gaps in the following areas: (i) population-based data sources and methods to evaluate drug safety issues; (ii) evidence-based thresholds to account for uncertainty in postmarket data; (iii) approaches to optimize the integration and interpretation of evidence from different sources; and (iv) approaches to evaluate the real-world impact of regulatory decisions. Regulators should continue the ongoing dialogue with multiple stakeholders to strengthen regulatory safety science and address these and other critical knowledge gaps. C1 [Hammad, T. A.] US FDA, Div Epidemiol, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol,Ctr Drug Evaluat & R, Silver Spring, MD USA. [Neyarapally, G. A.; Dal Pan, G.] US FDA, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Iyasu, S.] US FDA, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Staffa, J. A.] US FDA, Div Epidemiol, Off Pharmacovigilance & Epidemiol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Hammad, TA (reprint author), US FDA, Div Epidemiol, Off Pharmacovigilance & Epidemiol, Off Surveillance & Epidemiol,Ctr Drug Evaluat & R, Silver Spring, MD USA. EM tarek_hammad@hotmail.com NR 74 TC 10 Z9 10 U1 0 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD SEP PY 2013 VL 94 IS 3 BP 349 EP 358 DI 10.1038/clpt.2013.118 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 208NR UT WOS:000323686900020 PM 23739537 ER PT J AU Ouriel, K Fowl, RJ Davies, MG Forbes, TL Gambhir, RPS Morales, JP Ricci, MA AF Ouriel, Kenneth Fowl, Richard J. Davies, Mark G. Forbes, Thomas L. Gambhir, Raghvinder P. S. Morales, Jose Pablo Ricci, Michael A. TI Reporting standards for adverse events after medical device use in the peripheral vascular system SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID AORTIC-ANEURYSM REPAIR C1 [Ouriel, Kenneth] Syntactx, New York, NY 10007 USA. [Fowl, Richard J.] Mayo Clin Arizona, Div Vasc Surg, Phoenix, AZ USA. [Davies, Mark G.] Methodist Hosp, Methodist DeBakey Heart & Vasc Ctr, Houston, TX 77030 USA. [Forbes, Thomas L.] London Hlth Sci Ctr, Div Vasc Surg, London, ON, Canada. [Forbes, Thomas L.] Univ Western Ontario, London, ON, Canada. [Gambhir, Raghvinder P. S.] Army Hosp, Delhi, India. [Morales, Jose Pablo] US FDA, Div Cardiovasc Devices, Silver Spring, MD USA. [Ricci, Michael A.] Cent Maine Heart & Vasc Inst, Lewiston, ME USA. RP Ouriel, K (reprint author), Syntactx, World Trade Ctr 7, 250 Greenwich St,46th Floor, New York, NY 10007 USA. EM kouriel@syntactx.com NR 19 TC 10 Z9 10 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD SEP PY 2013 VL 58 IS 3 BP 776 EP 786 DI 10.1016/j.jvs.2013.06.059 PG 11 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 207QG UT WOS:000323616800029 PM 23972246 ER PT J AU Ansari, F Pack, LK Brooks, SS Morrison, TM AF Ansari, Farzana Pack, Lindsay K. Brooks, Steven S. Morrison, Tina M. TI Design considerations for studies of the biomechanical environment of the femoropopliteal arteries SO JOURNAL OF VASCULAR SURGERY LA English DT Review ID SUPERFICIAL FEMORAL-ARTERY; IN-VIVO; NITINOL STENTS; TRIAL; QUANTIFICATION; ANGIOGRAPHY; TORTUOSITY; DISEASE; VITRO AB Objective: The purpose of this study was to review the available literature regarding the biomechanics of the superficial femoral artery (SFA) and popliteal artery (PA) in patients with peripheral arterial disease (PAD). Stents are one of many available therapies used to treat patients with PAD. Because stents are permanent implants, they undergo a variety of deformations as patients go about their daily activities such as walking, sitting in a chair, or climbing stairs. As a part of the marketing application for United States Food and Drug Administration approval, stents need to be evaluated for long-term durability under a variety of loading modes. The information available in the literature provides direction for such evaluation. Methods: We performed a literature search of the PubMed database looking for "key vessel" and "mechanics" (all fields) or "deformation" (all fields) or "flexion" (all fields) or "mechanical environment" (all fields) or "tortuosity" (all fields) or "dynamics" (all fields) or "forces" (all fields), where the "key vessel" was "Femoral Artery," "Superficial Femoral Artery," "Popliteal Artery," and "Femoropopliteal." Results: Using a decision tree, we found 12 relevant articles that focused solely on the nonradial cyclic deformations associated with musculoskeletal motion. Despite the many limitations associated with combining these studies, we learned that under walking conditions, the proximal and mid-SFA deforms, on average, by shortening in the axial direction 4.0%, by twisting 2.1 degrees/cm, and by bending 72.1 mm; the distal SFA and proximal PA deform by shortening in the axial direction 13.9%, by twisting 3.5 degrees/cm, and by being pinched such that the aspect ratio of the lumen changes 4.6%. The distal PA deforms by shortening in the axial direction 12.3%, by twisting 3.5 degrees/cm, by bending 22.1 mm, and by being pinched such that the aspect ratio of the lumen changes 12.5%. Conclusions: A review of the current literature reveals heterogeneous study designs that confound interpretation. Studies included different physiologic settings from young to mature participants, participants with and without disease, and cadavers. Investigators used a range of imaging modalities and definitions of arterial segments, which affected our ability to compile the data as we learned that deformations vary according to the specific anatomic location within the SFA/PA. As a result of this analysis, we identified design considerations for future studies, because although this work has been valuable and significant, there are many limitations with the currently available data such that all we know about the SFA/PA environment is that we don't know. C1 [Ansari, Farzana] Univ Calif Berkeley, Dept Mech Engn, Berkeley, CA 94720 USA. [Pack, Lindsay K.; Brooks, Steven S.; Morrison, Tina M.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Morrison, TM (reprint author), 10903 New Hampshire Ave,WO66-1272, Silver Spring, MD 20993 USA. EM tina.morrison@fda.hhs.gov FU Medical Device Fellowship Program at the Center for Devices and Radiological Health FX F.A. received support from the Medical Device Fellowship Program at the Center for Devices and Radiological Health while an intern in the Peripheral Vascular Devices Branch. NR 29 TC 10 Z9 11 U1 0 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD SEP PY 2013 VL 58 IS 3 BP 804 EP 813 DI 10.1016/j.jvs.2013.03.052 PG 10 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 207QG UT WOS:000323616800036 PM 23870198 ER PT J AU Mindaye, ST Ra, M Lo Surdo, JL Bauer, SR Alterman, MA AF Mindaye, Samuel T. Ra, Moonjin Lo Surdo, Jessica L. Bauer, Steven R. Alterman, Michail A. TI Global proteomic signature of undifferentiated human bone marrow stromal cells: Evidence for donor-to-donor proteome heterogeneity SO STEM CELL RESEARCH LA English DT Article ID MESENCHYMAL STEM-CELLS; THERAPY POSITION STATEMENT; INTERNATIONAL-SOCIETY; SELF-RENEWAL; DIFFERENTIATION; DATABASE; GROWTH; POPULATIONS; PROTEINS; CULTURE AB The clinical application of human bone marrow stromal cells (hBMSCs) largely depends on their capacity to expand in vitro. We have conducted a comprehensive comparative proteomic analysis of culture-expanded hBMSCs obtained from different human donors. The data reveal extensive donor-to-donor proteomic heterogeneity. Processing and database-searching of the tandem MS data resulted in a most comprehensive to date proteomic dataset for hBMSC. A total of 7753 proteins including 712 transcription and translation regulators, 384 kinases, 248 receptor proteins, and 29 cytokines were confidently identified. The proteins identified are mainly nuclear (43.2%) and the share of proteins assigned to more than one subcellular location constitutes 10% of the identified proteome. Bioinformatics tools (IPA, DAVID, and PANTHER) were used to annotate proteins with respect to cellular locations, functions, and other physicochemical characteristics. We also compared the proteomic profile of hBMSCs to recently compiled datasets for human and mouse pluripotent stem cells. The result shows the extent of similarity between the three cell populations and also identified 253 proteins expressed uniformly by all lines of hBMSCs but not reported in the proteomic datasets of the two pluripotent stem cells. Overall, the proteomic database reported in this paper can serve as a reference map for extensive evaluation of hBMSC to explain their biology as well as identify possible marker candidates for further evaluation. Published by Elsevier B.V. C1 [Mindaye, Samuel T.; Ra, Moonjin; Alterman, Michail A.] US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Lo Surdo, Jessica L.; Bauer, Steven R.] US FDA, Cellular & Tissue Therapies Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Alterman, MA (reprint author), US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. EM Michail.Alterman@fda.hhs.gov OI Bauer, Steven/0000-0003-2831-846X FU Modernizing Science Initiative funds, Center for Biologics Evaluation and Research, US Food and Drug Administration FX This project was supported by the Modernizing Science Initiative funds provided by the Center for Biologics Evaluation and Research, US Food and Drug Administration. We appreciate critical reading of the manuscript by Syed Husain, Malcolm Moos, and Raj Puri. NR 75 TC 17 Z9 17 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1873-5061 J9 STEM CELL RES JI Stem Cell Res. PD SEP PY 2013 VL 11 IS 2 BP 793 EP 805 DI 10.1016/j.scr.2013.05.006 PG 13 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 207GJ UT WOS:000323586600011 PM 23792435 ER PT J AU Salazar, JK Wu, ZC McMullen, PD Luo, Q Freitag, NE Tortorello, ML Hu, SC Zhang, W AF Salazar, Joelle K. Wu, Zhuchun McMullen, P. David Luo, Qin Freitag, Nancy E. Tortorello, Mary Lou Hu, Shencai Zhang, Wei TI prfA-Like Transcription Factor Gene lmo0753 Contributes to L-Rhamnose Utilization in Listeria monocytogenes Strains Associated with Human Food-Borne Infections SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID CENTRAL VIRULENCE REGULATOR; BACILLUS-SUBTILIS; ESCHERICHIA-COLI; RNA-SEQ; QUINOLINATE SYNTHETASE; MUTATIONAL ACTIVATION; EXPRESSION; BIOTIN; IDENTIFICATION; BIOSYNTHESIS AB Listeria monocytogenes is a food-borne bacterial pathogen and the causative agent of human and animal listeriosis. Among the three major genetic lineages of L. monocytogenes (i.e., LI, LII, and LIII), LI and LII are predominantly associated with food-borne listeriosis outbreaks, whereas LIII is rarely implicated in human infections. In a previous study, we identified a Crp/Fnr family transcription factor gene, lmo0753, that was highly specific to outbreak-associated LI and LII but absent from LIII. Lmo0753 shares two conserved functional domains, including a DNA binding domain, with the well-characterized master virulence regulator PrfA in L. monocytogenes. In this study, we constructed lmo0753 deletion and complementation mutants in two fully sequenced L. monocytogenes LII strains, 10403S and EGDe, and compared the flagellar motility, phospholipase C production, hemolysis, and intracellular growth of the mutants and their respective wild types. Our results suggested that lmo0753 plays a role in hemolytic activity in both EGDe and 10403S. More interestingly, we found that deletion of lmo0753 led to the loss of L-rhamnose utilization in EGDe, but not in 10403S. RNA-seq analysis of EGDe Delta 0753 incubated in phenol red medium containing L-rhamnose as the sole carbon source revealed that 126 (4.5%) and 546 (19.5%) out of 2,798 genes in the EGDe genome were up-and downregulated more than 2-fold, respectively, compared to the wild-type strain. Genes related to biotin biosynthesis, general stress response, and rhamnose metabolism were shown to be differentially regulated. Findings from this study collectively suggested varied functional roles of lmo0753 in different LII L. monocytogenes strain backgrounds associated with human listeriosis outbreaks. C1 [Salazar, Joelle K.; Wu, Zhuchun; Zhang, Wei] IIT, Inst Food Safety & Hlth, Bedford Pk, IL USA. [McMullen, P. David; Freitag, Nancy E.] Univ Illinois, Coll Med, Dept Microbiol & Immunol, Chicago, IL 60612 USA. [Luo, Qin] Huazhong Normal Univ, Coll Life Sci, Wuhan, Peoples R China. [Tortorello, Mary Lou] US FDA, Bedford Pk, IL USA. [Hu, Shencai; Zhang, Wei] Wuhan Polytech Univ, Sch Biol & Pharmaceut Engn, Wuhan, Peoples R China. RP Zhang, W (reprint author), IIT, Inst Food Safety & Hlth, Bedford Pk, IL USA. EM zhangw@iit.edu FU U.S. Food and Drug Administration research funds; Chu Tian Lecturing Professorship from the Department of Education of Hubei Province FX This work was supported by U.S. Food and Drug Administration research funds to the Illinois Institute of Technology. The work was also partly supported by a Chu Tian Lecturing Professorship from the Department of Education of Hubei Province to the Wuhan Polytechnic University. NR 62 TC 3 Z9 3 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD SEP PY 2013 VL 79 IS 18 BP 5584 EP 5592 DI 10.1128/AEM.01812-13 PG 9 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 205DO UT WOS:000323421900019 PM 23835178 ER PT J AU Keefe, D AF Keefe, D. TI Safety Assessment of Food Additives, Food Contact Substances, and Supplements by the US Food and Drug Administration. SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 44th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 21-25, 2013 CL Monterey, CA SP Environm Mutagenesis & Genom Soc (EMGS) C1 [Keefe, D.] US FDA, College Pk, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2013 VL 54 SU 1 BP S20 EP S20 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 205FV UT WOS:000323429400032 ER PT J AU Mei, N Chen, S Lin, H Dobrovolsky, V Guo, L AF Mei, N. Chen, S. Lin, H. Dobrovolsky, V Guo, L. TI Berberine, a Goldenseal Constituent, Induces DNA Damage by Inhibiting Topoisomerase II Activity in Hepatic Cells SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 44th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 21-25, 2013 CL Monterey, CA SP Environm Mutagenesis & Genom Soc (EMGS) C1 [Mei, N.; Chen, S.; Lin, H.; Dobrovolsky, V; Guo, L.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2013 VL 54 SU 1 BP S26 EP S26 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 205FV UT WOS:000323429400058 ER PT J AU Powley, MW AF Powley, M. W. TI Demonstrating When Positive and Negative (Q)SAR Mutagenicity Predictions Are Wrong SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 44th Annual Meeting of the Environmental-Mutagenesis-and-Genomics-Society (EMGS) CY SEP 21-25, 2013 CL Monterey, CA SP Environm Mutagenesis & Genom Soc (EMGS) C1 [Powley, M. W.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2013 VL 54 SU 1 BP S18 EP S18 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 205FV UT WOS:000323429400025 ER PT J AU Kaml, C Fogarty, KJ Wojtala, G Dardick, W Bateson, A Bradsher, JE Weiss, CC AF Kaml, Craig Fogarty, Kieran J. Wojtala, Gerald Dardick, William Bateson, Allan Bradsher, Julia E. Weiss, Christopher C. TI The Development of a Standards-Based National Curriculum Framework for Regulatory Food Safety Training in the United States SO JOURNAL OF ENVIRONMENTAL HEALTH LA English DT Article AB In response to the recognized need for a training system to support an integrated food safety system in the U.S., the International Food Protection Training Institute (IFPTI) in Battle Creek, Michigan, designed a career-spanning curriculum framework. IFPTI collaborated with a national curriculum team consisting of regulatory officials and university academics. The curriculum framework encompasses and organizes existing professional development for the estimated 45,000 federal, state, and local food regulators in the U.S. into efficient, standards-driven learning paths. This article describes the development process leading to an integrated national food protection training curriculum framework. C1 [Kaml, Craig; Wojtala, Gerald] Int Food Protect Training Inst, Battle Creek, MI 49017 USA. [Fogarty, Kieran J.] Western Michigan Univ, Coll Hlth & Human Serv, Kalamazoo, MI 49008 USA. [Dardick, William] George Washington Univ, Grad Sch Educ & Human Dev, Washington, DC 20052 USA. [Bateson, Allan] US FDA, Off Regulatory Affairs, Rockville, MD 20857 USA. RP Kaml, C (reprint author), Int Food Protect Training Inst, 49 W Michigan Ave,Suite 300, Battle Creek, MI 49017 USA. EM craig.kaml@ifpti.org NR 5 TC 1 Z9 1 U1 1 U2 4 PU NATL ENVIRON HEALTH ASSOC PI DENVER PA 720 S COLORADO BLVD SUITE 970, SOUTH TOWER, DENVER, CO 80246 USA SN 0022-0892 J9 J ENVIRON HEALTH JI J. Environ. Health PD SEP PY 2013 VL 76 IS 2 BP 38 EP 42 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 205QW UT WOS:000323460700006 PM 24073488 ER PT J AU Magadan, JG Khurana, S Das, SR Frank, GM Stevens, J Golding, H Bennink, JR Yewdell, JW AF Magadan, Javier G. Khurana, Surender Das, Suman R. Frank, Gregory M. Stevens, James Golding, Hana Bennink, Jack R. Yewdell, Jonathan W. TI Influenza A Virus Hemagglutinin Trimerization Completes Monomer Folding and Antigenicity SO JOURNAL OF VIROLOGY LA English DT Article ID VIRAL MEMBRANE-PROTEINS; INTRACELLULAR-TRANSPORT; RECEPTOR-BINDING; MONOCLONAL-ANTIBODIES; NEUTRALIZING ANTIBODY; ENDOPLASMIC-RETICULUM; GOLGI-COMPLEX; FUSION; CELLS; SITE AB Influenza A virus (IAV) remains an important human pathogen largely because of antigenic drift, the rapid emergence of anti-body escape mutants that precludes durable vaccination. The most potent neutralizing antibodies interact with cognate epitopes in the globular "head" domain of hemagglutinin (HA), a homotrimeric glycoprotein. The H1 HA possesses five distinct regions defined by a large number of mouse monoclonal antibodies (MAbs), i.e., Ca1, Ca2, Cb, Sa, and Sb. Ca1-Ca2 sites require HA trimerization to attain full antigenicity, consistent with their locations on opposite sides of the trimer interface. Here, we show that full antigenicity of Cb and Sa sites also requires HA trimerization, as revealed by immunofluorescence microscopy of IAV-infected cells and biochemically by pulse-chase radiolabeling experiments. Surprisingly, epitope antigenicity acquired by HA trimerization persists following acid triggering of the globular domains dissociation and even after proteolytic release of monomeric heads from acid-treated HA. Thus, the requirement for HA trimerization by trimer-specific MAbs mapping to the Ca, Cb, and Sa sites is not dependent upon the bridging of adjacent monomers in the native HA trimer. Rather, complete antigenicity of HA (and, by inference, immunogenicity) requires a final folding step that accompanies its trimerization. Once this conformational change occurs, HA trimers themselves would not necessarily be required to induce a highly diverse neutralizing response to epitopes in the globular domain. C1 [Magadan, Javier G.; Das, Suman R.; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Khurana, Surender; Frank, Gregory M.; Golding, Hana] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Stevens, James] Ctr Dis Control & Prevent, Influenza Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM jyewdell@niaid.nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases FX This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases. NR 47 TC 11 Z9 11 U1 1 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2013 VL 87 IS 17 BP 9742 EP 9753 DI 10.1128/JVI.00471-13 PG 12 WC Virology SC Virology GA 201NO UT WOS:000323148500032 PM 23824811 ER PT J AU Margulis, AV Abou-Ali, A Strazzeri, MM Ding, YL Kuyateh, F Frimpong, EY Levenson, MS Hammad, TA AF Margulis, Andrea V. Abou-Ali, Adel Strazzeri, Marian M. Ding, Yulan Kuyateh, Fatmatta Frimpong, Eric Y. Levenson, Mark S. Hammad, Tarek A. TI Use of selective serotonin reuptake inhibitors in pregnancy and cardiac malformations: a propensity-score matched cohort in CPRD SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE congenital abnormalities; heart defects; propensity score; SSRIS; weighted logistic regression; mother-baby link; pharmacoepidemiology ID PRACTICE RESEARCH DATABASE; MAJOR CONGENITAL-MALFORMATIONS; ANTIDEPRESSANT CONCENTRATIONS; 1ST-TRIMESTER EXPOSURE; BIRTH-DEFECTS; HEART-DEFECTS; PAROXETINE; WOMEN; RISK; FLUOXETINE AB Purpose Research on the association of maternal selective serotonin reuptake inhibitor (SSRI) use and cardiac malformations in the offspring has yielded conflicting findings. We therefore sought to further investigate the association using data from a large population-based cohort in the UK. Methods The study population consisted of 149464 pregnancies ending in a live birth between January/1996 and November/2010 from the Clinical Practice Research Datalink's Mother Baby Link. We created propensity-score matched cohorts of first-trimester SSRI users who did not use other antidepressants in the same gestational period (SSRI users', n=3046) and non-antidepressant users (no use from the 3 months before pregnancy through the second trimester of pregnancy, non-users'; n=8991). Weighted logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of cardiac malformations overall and septal defects diagnosed in the first year of life, or in the first 6 years of life. Results Sixteen infants with cardiac malformations were identified among SSRI users; 10 of them were septal defects. Among non-users, there were 48 infants with cardiac malformations, 26 of whom had septal defects. The OR (95% CI) for cardiac malformations was 1.00 (0.50; 2.00), and for septal defects was 1.15 (0.46; 2.87). Results were similar for cardiac malformations diagnosed in the first 6 years of life, and in several sensitivity analyses that were also implemented. Conclusions The results of this study are most compatible with no association between maternal use of SSRIs in early pregnancy and cardiac malformations or septal defects in the offspring. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. C1 [Margulis, Andrea V.; Abou-Ali, Adel; Strazzeri, Marian M.; Ding, Yulan; Kuyateh, Fatmatta; Frimpong, Eric Y.; Levenson, Mark S.; Hammad, Tarek A.] US FDA, Silver Spring, MD 20993 USA. RP Hammad, TA (reprint author), US FDA, CDER OSE DEPI I, 10903 New Hampshire Ave,Bldg 22,Room 2412, Silver Spring, MD 20993 USA. EM tarek.hammad@hhs.fda.gov RI Margulis, Andrea/G-2833-2013; CPRD, CPRD/B-9594-2017 OI Margulis, Andrea/0000-0001-7388-6082; FU US Food and Drug Administration (FDA); US Department of Energy's Oak Ridge Institute for Science and Education (ORISE) FX Funding for this study came from the US Food and Drug Administration (FDA). AVM received a stipend from the US Department of Energy's Oak Ridge Institute for Science and Education (ORISE). NR 48 TC 21 Z9 21 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2013 VL 22 IS 9 BP 942 EP 951 DI 10.1002/pds.3462 PG 10 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 202WF UT WOS:000323250600004 PM 23733623 ER PT J AU Briesacher, BA Soumerai, SB Zhang, F Toh, S Andrade, SE Wagner, JL Shoaibi, A Gurwitz, JH AF Briesacher, Becky A. Soumerai, Stephen B. Zhang, Fang Toh, Sengwee Andrade, Susan E. Wagner, Joann L. Shoaibi, Azadeh Gurwitz, Jerry H. TI A critical review of methods to evaluate the impact of FDA regulatory actions SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Review DE FDA; regulatory actions; evaluation methodology; pharmacoepidemiology ID INTERRUPTED TIME-SERIES; PEDIATRIC SUICIDALITY; MINI-SENTINEL; ANTIPSYCHOTIC-DRUGS; TREATMENT PATTERNS; RISK; DEPRESSION; WARNINGS; MEDICAID; FOOD AB Purpose To conduct a synthesis of the literature on methods to evaluate the impacts of FDA regulatory actions and identify best practices for future evaluations. Methods We searched MEDLINE for manuscripts published between January 1948 and August 2011 that included terms related to FDA, regulatory actions, and empirical evaluation; the review additionally included FDA-identified literature. We used a modified Delphi method to identify preferred methodologies. We included studies with explicit methods to address threats to validity and identified designs and analytic methods with strong internal validity that have been applied to other policy evaluations. Results We included 18 studies out of 243 abstracts and papers screened. Overall, analytic rigor in prior evaluations of FDA regulatory actions varied considerably; less than a quarter of studies (22%) included control groups. Only 56% assessed changes in the use of substitute products/services, and 11% examined patient health outcomes. Among studies meeting minimal criteria of rigor, 50% found no impact or weak/modest impacts of FDA actions and 33% detected unintended consequences. Among those studies finding significant intended effects of FDA actions, all cited the importance of intensive communication efforts. There are preferred methods with strong internal validity that have yet to be applied to evaluations of FDA regulatory actions. Conclusions Rigorous evaluations of the impact of FDA regulatory actions have been limited and infrequent. Several methods with strong internal validity are available to improve trustworthiness of future evaluations of FDA policies. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Briesacher, Becky A.; Andrade, Susan E.; Gurwitz, Jerry H.] Univ Massachusetts, Sch Med, Div Geriatr Med, Worcester, MA 01605 USA. [Briesacher, Becky A.; Andrade, Susan E.; Wagner, Joann L.; Gurwitz, Jerry H.] Meyers Primary Care Inst, Reliant Med Grp, Worcester, MA USA. [Briesacher, Becky A.; Andrade, Susan E.; Wagner, Joann L.; Gurwitz, Jerry H.] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. [Soumerai, Stephen B.; Zhang, Fang; Toh, Sengwee] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Soumerai, Stephen B.; Zhang, Fang; Toh, Sengwee] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Shoaibi, Azadeh] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Briesacher, BA (reprint author), Univ Massachusetts, Sch Med, Div Geriatr Med, Biotech 4,Suite 315,377 Plantat St, Worcester, MA 01605 USA. EM Becky.Briesacher@umassmed.edu RI Toh, Sengwee/D-7567-2017 OI Toh, Sengwee/0000-0002-5160-0810 FU FDA through the Department of Health and Human Services (HHS) [HHSF223200910006I] FX This work was conducted as part of the Mini-Sentinel program. The Mini-Sentinel program is funded by the FDA through the Department of Health and Human Services (HHS) Contract number HHSF223200910006I. NR 46 TC 9 Z9 9 U1 5 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2013 VL 22 IS 9 BP 986 EP 994 DI 10.1002/pds.3480 PG 9 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 202WF UT WOS:000323250600009 PM 23847020 ER PT J AU Thorpe, PG Gilboa, SM Hernandez-Diaz, S Lind, J Cragan, JD Briggs, G Kweder, S Friedman, JM Mitchell, AA Honein, MA AF Thorpe, Phoebe G. Gilboa, Suzanne M. Hernandez-Diaz, Sonia Lind, Jennifer Cragan, Janet D. Briggs, Gerald Kweder, Sandra Friedman, Jan M. Mitchell, Allen A. Honein, Margaret A. CA Natl Birth Defects Prevention TI Medications in the first trimester of pregnancy: most common exposures and critical gaps in understanding fetal risk SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE medication; pregnancy; fetal risk; teratogen; pharmacoepidemiology ID TERATOGENICITY; WOMEN AB Purpose To determine which medications are most commonly used by women in the first trimester of pregnancy and identify the critical gaps in information about fetal risk for those medications. Methods Self-reported first-trimester medication use was assessed among women delivering liveborn infants without birth defects and serving as control mothers in two large case-control studies of major birth defects. The Teratology Information System (TERIS) expert Advisory Board ratings of quality and quantity of data available to assess fetal risk were reviewed to identify information gaps. Results Responses from 5381 mothers identified 54 different medication components used in the first trimester by at least 0.5% of pregnant women, including 31 prescription and 23 over-the-counter medications. The most commonly used prescription medication components reported were progestins from oral contraceptives, amoxicillin, progesterone, albuterol, promethazine, and estrogenic compounds. The most commonly used over-the-counter medication components reported were acetaminophen, ibuprofen, docusate, pseudoephedrine, aspirin, and naproxen. Among the 54 most commonly used medications, only two had Good to Excellent data available to assess teratogenic risk in humans, based on the TERIS review. Conclusions For most medications commonly used in pregnancy, there are insufficient data available to characterize the fetal risk fully, limiting the opportunity for informed clinical decisions about the best management of acute and chronic disorders during pregnancy. Future research efforts should be directed at these critical knowledge gaps. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Thorpe, Phoebe G.; Gilboa, Suzanne M.; Lind, Jennifer; Cragan, Janet D.; Honein, Margaret A.] Ctr Dis Control & Prevent, Div Birth Defects & Dev Disabil, Atlanta, GA 30333 USA. [Hernandez-Diaz, Sonia] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Briggs, Gerald] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Briggs, Gerald] Univ So Calif, Los Angeles, CA USA. [Briggs, Gerald] Washington State Univ, Spokane, WA USA. [Kweder, Sandra] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Friedman, Jan M.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Mitchell, Allen A.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. RP Thorpe, PG (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd,MS-E86, Atlanta, GA 30333 USA. EM pht1@cdc.gov OI Friedman, Jan/0000-0002-7482-9570 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [R01 HD046595]; Centers for Disease Control and Prevention [U50/CCU113247, PA 96043, PA 02081, FOA DD09-001] FX Drs. Hernandez-Diaz and Mitchell were supported by grant R01 HD046595 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Dr. Mitchell also receives support through Cooperative Agreement no. U50/CCU113247 with the Centers for Disease Control and Prevention to the Slone Epidemiology Center through the Massachusetts Department of Public Health. This work was also supported through cooperative agreements under PA 96043, PA 02081, and FOA DD09-001 from the Centers for Disease Control and Prevention to the Centers for Birth Defects Research and Prevention participating in the National Birth Defects Prevention Study. NR 13 TC 37 Z9 37 U1 1 U2 36 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2013 VL 22 IS 9 BP 1013 EP 1018 DI 10.1002/pds.3495 PG 6 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 202WF UT WOS:000323250600012 PM 23893932 ER PT J AU Yan, YP Li, ZC Zhang, GX Williams, MS Carey, GB Zhang, JK Rostami, A Xu, H AF Yan, Yaping Li, Zichen Zhang, Guang-Xian Williams, Mark S. Carey, Gregory B. Zhang, Jianke Rostami, Abdolmohamad Xu, Hui TI Anti-MS4a4B treatment abrogates MS4a4B-mediated protection in T cells and ameliorates experimental autoimmune encephalomyelitis SO APOPTOSIS LA English DT Article DE MS4A; T cell; Apoptosis; EAE; Antibody therapy ID MULTIPLE-SCLEROSIS; MONOCLONAL-ANTIBODIES; CYCLE PROGRESSION; INDUCED APOPTOSIS; CALCIUM INFLUX; HELPER TYPE-1; LIPID RAFTS; CD20; RECEPTOR; FAMILY AB Recent data show that anti-CD20 therapy is effective for some autoimmune diseases, including multiple sclerosis (MS). However, the efficacy of anti-CD20 therapy for MS is largely limited because anti-CD20 antibodies target only B cells. In previous studies, we have investigated the function of MS4a4B, a novel CD20 homologue, in T cell proliferation. Here, we found that MS4a4B regulates not only T cell proliferation but also T cell apoptosis. Knockdown of MS4a4B by MS4a4B-siRNA or MS4a4B-shRNA-expressing vector promoted apoptosis in primary T cells and T32 cell line. In contrast, vector-driven over-expression of MS4a4B reduced apoptosis in EL-4 cells. Machinery analysis showed that MS4a4B-mediated T cell survival was associated with decreased activity of caspases 3, 8 and 9. Interestingly, binding of anti-MS4a4B antibodies to T cells induced activated T cells to undergo apoptosis. To test whether anti-MS4a4B antibody interferes with MS4a4B-mediated protection of T cells, we injected anti-MS4a4B antibodies into mice with experimental autoimmune encephalomyelitis (EAE). The results show that anti-MS4a4B treatment ameliorated the severity of EAE, accompanied by decreased Th1 and Th17 cell responses and reduced levels of pro-inflammatory cytokines in the central nervous system, suggesting that MS4a4B may serve as a target of antibody-based therapy for T cell-mediated diseases. C1 [Yan, Yaping; Li, Zichen; Zhang, Guang-Xian; Rostami, Abdolmohamad; Xu, Hui] Thomas Jefferson Univ, Dept Neurol, Philadelphia, PA 19107 USA. [Williams, Mark S.; Carey, Gregory B.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Zhang, Jianke] Thomas Jefferson Univ, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA. [Xu, Hui] US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prot, Bethesda, MD 20892 USA. RP Rostami, A (reprint author), Thomas Jefferson Univ, Dept Neurol, 900 Walnut St,JHN 300, Philadelphia, PA 19107 USA. EM a.m.rostami@jefferson.edu; hui.xu@fda.hhs.gov OI Zhang, Jianke/0000-0002-5822-2226 FU American Heart Association; National Institutes of Health FX We are grateful to Katherine Regan for editorial assistance. We thank Hong Dai and Ke Li for helpful technical assistance. This work was supported by Grants from the American Heart Association (H. X.) and from the National Institutes of Health (A.M.R.). NR 36 TC 5 Z9 5 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1360-8185 J9 APOPTOSIS JI Apoptosis PD SEP PY 2013 VL 18 IS 9 BP 1106 EP 1119 DI 10.1007/s10495-013-0870-2 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 194WZ UT WOS:000322664700008 PM 23801080 ER PT J AU Keelara, S Scott, HM Morrow, WM Gebreyes, WA Correa, M Nayak, R Stefanova, R Thakur, S AF Keelara, Shivaramu Scott, H. Morgan Morrow, William M. Gebreyes, Wondwossen A. Correa, Maria Nayak, Rajesh Stefanova, Rossina Thakur, Siddhartha TI Longitudinal Study of Distributions of Similar Antimicrobial-Resistant Salmonella Serovars in Pigs and Their Environment in Two Distinct Swine Production Systems SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID TYPHIMURIUM DT104 INFECTIONS; UNITED-STATES; ESCHERICHIA-COLI; SLAUGHTER-LINE; SEROTYPES; ENTERICA; IDENTIFICATION; PREVALENCE; SAMPLES; CONTAMINATION AB The aim of this longitudinal study was to determine and compare the prevalences and genotypic profiles of antimicrobial-resistant (AR) Salmonella isolates from pigs reared in antimicrobial-free (ABF) and conventional production systems at farm, at slaughter, and in their environment. We collected 2,889 pig fecal and 2,122 environmental (feed, water, soil, lagoon, truck, and floor swabs) samples from 10 conventional and eight ABF longitudinal cohorts at different stages of production (farrowing, nursery, finishing) and slaughter (postevisceration, postchill, and mesenteric lymph nodes [MLN]). In addition, we collected 1,363 carcass swabs and 205 lairage and truck samples at slaughter. A total of 1,090 Salmonella isolates were recovered from the samples; these were isolated with a significantly higher prevalence in conventionally reared pigs (4.0%; n = 66) and their environment (11.7%; n = 156) than in ABF pigs (0.2%; n = 2) and their environment (0.6%; n = 5) (P < 0.001). Salmonella was isolated from all stages at slaughter, including the postchill step, in the two production systems. Salmonella prevalence was significantly higher in MLN extracted from conventional carcasses than those extracted from ABF carcasses (P < 0.001). We identified a total of 24 different serotypes, with Salmonella enterica serovar Typhimurium, Salmonella enterica serovar Anatum, Salmonella enterica serovar Infantis, and Salmonella enterica serovar Derby being predominant. The highest frequencies of antimicrobial resistance (AR) were exhibited to tetracycline (71%), sulfisoxazole (42%), and streptomycin (17%). Multidrug resistance (resistance to >= 3 antimicrobials; MDR) was detected in 27% (n = 254) of the Salmonella isolates from the conventional system. Our study reports a low prevalence of Salmonella in both production systems in pigs on farms, while a higher prevalence was detected among the carcasses at slaughter. The dynamics of Salmonella prevalence in pigs and carcasses were reciprocated in the farm and slaughter environment, clearly indicating an exchange of this pathogen between the pigs and their surroundings. Furthermore, the phenotypic and genotypic fingerprint profile results underscore the potential role played by environmental factors in dissemination of AR Salmonella to pigs. C1 [Keelara, Shivaramu; Correa, Maria; Thakur, Siddhartha] N Carolina State Univ, Coll Vet Med, Dept Populat Hlth & Pathobiol, Raleigh, NC USA. [Scott, H. Morgan] Kansas State Univ, Coll Vet Med, Dept Diagnost Med Pathobiol, Manhattan, KS 66506 USA. [Morrow, William M.] N Carolina State Univ, Coll Agr & Life Sci, Dept Anim Sci, Raleigh, NC 27695 USA. [Gebreyes, Wondwossen A.] Ohio State Univ, Coll Vet Med, Dept Vet Prevent Med, Columbus, OH 43210 USA. [Nayak, Rajesh] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Stefanova, Rossina] Arkansas Dept Hlth, Arkansas Publ Hlth Labs, Little Rock, AR 72205 USA. RP Thakur, S (reprint author), N Carolina State Univ, Coll Vet Med, Dept Populat Hlth & Pathobiol, Raleigh, NC USA. EM sthakur@ncsu.edu FU U.S. Department of Agriculture National Research Initiative [2008-529245]; U.S. Department of Agriculture National Integrated Food Safety Initiative [2008-529461]; National Pork Board (NPB) [12-001]; North Carolina State University FX This work was funded by a U.S. Department of Agriculture National Research Initiative grant (2008-529245), a U.S. Department of Agriculture National Integrated Food Safety Initiative grant (2008-529461), the National Pork Board grant (NPB project number 12-001), and a North Carolina State University Individual Faculty Research and Professional Development Award to Siddhartha Thakur. NR 52 TC 19 Z9 19 U1 2 U2 23 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD SEP PY 2013 VL 79 IS 17 BP 5167 EP 5178 DI 10.1128/AEM.01419-13 PG 12 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 197CZ UT WOS:000322828100010 PM 23793629 ER PT J AU Evers, R Dallas, S Dickmann, LJ Fahmi, OA Kenny, JR Kraynov, E Nguyen, T Patel, AH Slatter, JG Zhang, L AF Evers, Raymond Dallas, Shannon Dickmann, Leslie J. Fahmi, Odette A. Kenny, Jane R. Kraynov, Eugenia Theresa Nguyen Patel, Aarti H. Slatter, J. Greg Zhang, Lei TI Critical Review of Preclinical Approaches to Investigate Cytochrome P450-Mediated Therapeutic Protein Drug-Drug Interactions and Recommendations for Best Practices: A White Paper SO DRUG METABOLISM AND DISPOSITION LA English DT Review ID CRYOPRESERVED HUMAN HEPATOCYTES; NF-KAPPA-B; METABOLIZING-ENZYMES; MONOCLONAL-ANTIBODIES; INFLAMMATORY CYTOKINES; TRANSPLANT RECIPIENTS; RHEUMATOID-ARTHRITIS; ADJUVANT ARTHRITIS; RAT HEPATOCYTES; PRIMARY CULTURE AB Drug-drug interactions (DDIs) between therapeutic proteins (TPs) and small-molecule drugs have recently drawn the attention of regulatory agencies, the pharmaceutical industry, and academia. TP-DDIs are mainly caused by proinflammatory cytokine or cytokine modulator-mediated effects on the expression of cytochrome P450 enzymes. To build consensus among industry and regulatory agencies on expectations and challenges in this area, a working group was initiated to review the preclinical state of the art. This white paper represents the observations and recommendations of the working group on the value of in vitro human hepatocyte studies for the prediction of clinical TP-DDI. The white paper was developed following a "Workshop on Recent Advances in the Investigation of Therapeutic Protein Drug-Drug Interactions: Preclinical and Clinical Approaches" held at the Food and Drug Administration White Oak Conference Center on June 4 and 5, 2012. Results of a workshop poll, cross-laboratory data comparisons, and the overall recommendations of the in vitro working group are presented herein. The working group observed that evaluation of TP-DDI for anticytokine monoclonal antibodies is currently best accomplished with a clinical study in patients with inflammatory disease. Treatment-induced changes in appropriate biomarkers in phase 2 and 3 studies may indicate the potential for a clinically measurable treatment effect on cytochrome P450 enzymes. Cytokine-mediated DDIs observed with anti-inflammatory TPs cannot currently be predicted using in vitro data. Future success in predicting clinical TP-DDIs will require an understanding of disease biology, physiologically relevant in vitro systems, and more examples of well conducted clinical TP-DDI trials. C1 [Evers, Raymond; Theresa Nguyen] Merck & Co Inc, Pharmacokinet Pharmacodynam & Drug Metab, Rahway, NJ 07065 USA. [Dallas, Shannon] Janssen Res & Dev LLC, Drug Metab & Pharmacokinet, Spring House, PA USA. [Dickmann, Leslie J.] Amgen Inc, Pharmacokinet & Drug Metab, Seattle, WA USA. [Slatter, J. Greg] Amgen Inc, Clin Pharmacol Early Dev, Seattle, WA USA. [Fahmi, Odette A.] Pfizer, Pharmacokinet Dynam Drug Metab, Groton, CT USA. [Kenny, Jane R.] Genentech Inc, Dept Drug Metab & Pharmacokinet, San Francisco, CA USA. [Kraynov, Eugenia] Pfizer, Worldwide Res & Dev, La Jolla, CA USA. [Zhang, Lei] Food & Drug Adm, Ctr Drug Evaluat & Res, Off Translat Sci, Off Clin Pharmacol, Silver Spring, MD USA. RP Evers, R (reprint author), Merck & Co Inc, Pharmacokinet Pharmacodynam & Drug Metab, RY80-141,126 E Lincoln Ave, Rahway, NJ 07065 USA. EM Raymond_Evers@merck.com NR 65 TC 17 Z9 17 U1 2 U2 22 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD SEP PY 2013 VL 41 IS 9 BP 1598 EP 1609 DI 10.1124/dmd.113.052225 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 201HQ UT WOS:000323131700001 PM 23792813 ER PT J AU Kuhar, DT Henderson, DK Struble, KA Heneine, W Thomas, V Cheever, LW Gomaa, A Panlilio, AL AF Kuhar, David T. Henderson, David K. Struble, Kimberly A. Heneine, Walid Thomas, Vasavi Cheever, Laura W. Gomaa, Ahmed Panlilio, Adelisa L. CA US Public Hlth Serv Working Grp TI Updated US Public Health Service Guidelines for the Management of Occupational Exposures to Human Immunodeficiency Virus and Recommendations for Postexposure Prophylaxis SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID TO-CHILD TRANSMISSION; PRIOR ANTIRETROVIRAL THERAPY; CARE WORKERS; HIV-INFECTION; NEEDLESTICK INJURY; HUMAN BITE; TYPE-1 INFECTION; LACTIC-ACIDOSIS; PREGNANCY; RISK AB This report updates US Public Health Service recommendations for the management of healthcare personnel (HCP) who experience occupational exposure to blood and/or other body fluids that might contain human immunodeficiency virus (HIV). Although the principles of exposure management remain unchanged, recommended HIV postexposure prophylaxis (PEP) regimens and the duration of HIV follow-up testing for exposed personnel have been updated. This report emphasizes the importance of primary prevention strategies, the prompt reporting and management of occupational exposures, adherence to recommended HIV PEP regimens when indicated for an exposure, expert consultation in management of exposures, follow-up of exposed HCP to improve adherence to PEP, and careful monitoring for adverse events related to treatment, as well as for virologic, immunologic, and serologic signs of infection. To ensure timely postexposure management and administration of HIV PEP, clinicians should consider occupational exposures as urgent medical concerns, and institutions should take steps to ensure that staff are aware of both the importance of and the institutional mechanisms available for reporting and seeking care for such exposures. The following is a summary of recommendations: (1) PEP is recommended when occupational exposures to HIV occur; (2) the HIV status of the exposure source patient should be determined, if possible, to guide need for HIV PEP; (3) PEP medication regimens should be started as soon as possible after occupational exposure to HIV, and they should be continued for a 4-week duration; (4) new recommendationPEP medication regimens should contain 3 (or more) antiretroviral drugs (listed in Appendix A) for all occupational exposures to HIV; (5) expert consultation is recommended for any occupational exposures to HIV and at a minimum for situations described in Box 1; (6) close follow-up for exposed personnel (Box 2) should be provided that includes counseling, baseline and follow-up HIV testing, and monitoring for drug toxicity; follow-up appointments should begin within 72 hours of an HIV exposure; and (7) new recommendationif a newer fourth-generation combination HIV p24 antigen--HIV antibody test is utilized for follow-up HIV testing of exposed HCP, HIV testing may be concluded 4 months after exposure (Box 2); if a newer testing platform is not available, follow-up HIV testing is typically concluded 6 months after an HIV exposure. C1 [Kuhar, David T.; Panlilio, Adelisa L.] Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Henderson, David K.] NIH, Off Deputy Director Clin Care, Ctr Clin, Bethesda, MD 20892 USA. [Struble, Kimberly A.] US FDA, Div Antiviral Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Heneine, Walid; Thomas, Vasavi] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Atlanta, GA USA. [Cheever, Laura W.] US Hlth Resources & Serv Adm, HIV AIDS Bur, Rockville, MD 20857 USA. [Gomaa, Ahmed] NIOSH, Div Surveillance Hazard Evaluat & Hlth Studies, Ctr Dis Control & Prevent, Cincinnati, OH 45226 USA. RP Kuhar, DT (reprint author), Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. FU Bristol-Myers Squibb; Janssen; Merck; ViiV; GlaxoSmithKline; Gilead FX The expert panel consultants report the following competing interests: J.A. has a board membership with and has received funding from Bristol-Myers Squibb, Janssen, Merck, and ViiV; J.E. has consulted for Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Merck, and ViiV and has received grant funding from Bristol-Myers Squibb, GlaxoSmithKline, Merck, and ViiV; M. S. S. has consulted for Bristol-Myers Squibb, Gilead, Janssen, Merck, and ViiV and has received grant funding from Bristol-Myers Squibb, Gilead, Merck, and ViiV; M. L. T. owns Merck stock. All other authors report no conflicts of interest relevant to this article. NR 76 TC 98 Z9 102 U1 2 U2 19 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD SEP 1 PY 2013 VL 34 IS 9 BP 875 EP 892 DI 10.1086/672271 PG 18 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 195LD UT WOS:000322702900001 PM 23917901 ER PT J AU Brophy, GM Mazzeo, AT Brar, S Alves, OL Bunnell, K Gilman, C Karnes, T Hayes, RL Bullock, R AF Brophy, Gretchen M. Mazzeo, Anna Teresa Brar, Satjit Alves, Oscar Luis Bunnell, Kristen Gilman, Charlotte Karnes, Tom Hayes, Ron L. Bullock, Ross TI Exposure of Cyclosporin A in Whole Blood, Cerebral Spinal Fluid, and Brain Extracellular Fluid Dialysate in Adults with Traumatic Brain Injury SO JOURNAL OF NEUROTRAUMA LA English DT Article DE cyclosporin; neuroprotection; TBI ID MITOCHONDRIAL PERMEABILITY TRANSITION; REPERFUSION INJURY; HEALTHY-SUBJECTS; DOSE-RESPONSE; PHARMACOKINETICS; MICRODIALYSIS; DAMAGE; RAT; QUANTIFICATION; CORRELATE AB Cyclosporin A (CsA), an immunosuppressive medication traditionally used in the prevention of post-transplant rejection, is a promising neuroprotective agent for traumatic brain injury (TBI). Preliminary studies in animals and humans describe the efficacy and safety of CsA when administered following neurotrauma. The objective of this study is to describe CsA exposure in adults with severe TBI by assessing concentrations in whole blood, cerebrospinal fluid (CSF), and brain extracellular fluid (ECF) dialysate as measured by brain microdialysis. Severe TBI patients were enrolled in a randomized controlled trial following the written informed consent of their legal guardians. Patients received either CsA 5 mg/kg as a continuous infusion over 24 h, or matching placebo. Noncompartmental exposure analyses were performed using CsA concentrations in whole blood, CSF, and ECF dialysate. There were 37 patients randomized to the CsA arm of the trial and included in this exposure analysis. CsA was detected in the ECF dialysate and CSF at a fraction of the whole blood concentration. Mean CsA maximum concentrations were achieved at 24 and 30 h from the start of the 24 h infusion, in the CSF and ECF dialysate, respectively. A correlation was found between ECF dialysate and CSF concentrations. CsA was detected in the blood, CSF, and brain ECF dialysate. CsA exposure characteristic differences exist for whole blood, CSF, and ECF dialysate in severe TBI patients when administered as a continuous intravenous infusion. These exposure characteristics should be used for safer CsA dose optimization to achieve target CsA concentrations for neuroprotection in future TBI studies. C1 [Brophy, Gretchen M.; Karnes, Tom] Virginia Commonwealth Univ, Dept Pharmacotherapy & Outcomes Sci, Richmond, VA 23298 USA. [Bunnell, Kristen] Virginia Commonwealth Univ, Dept Pharm, Richmond, VA 23298 USA. [Brophy, Gretchen M.; Gilman, Charlotte] Virginia Commonwealth Univ, Dept Neurosurg, Richmond, VA 23298 USA. [Mazzeo, Anna Teresa] Univ Turin, Osped San Gioranni Betista, Dept Anaesthesia & Intens Care, Turin, Italy. [Brar, Satjit] US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol, Silver Spring, MD USA. [Alves, Oscar Luis] Univ Porto, Serv Neurocirugia, Ctr Hosp Vila Nova Gaia, Fac Med, P-4100 Oporto, Portugal. [Hayes, Ron L.] Banyan Biomarkers Inc, Alachua, FL USA. [Bullock, Ross] Univ Miami, Miller Sch Med, Dept Neurosurg, Lois Pope LIFE Ctr, Miami, FL 33136 USA. RP Brophy, GM (reprint author), Virginia Commonwealth Univ, Med Coll Virginia Campus,410 N 12th St,POB 980533, Richmond, VA 23298 USA. EM gbrophy@vcu.edu OI Mazzeo, Anna Teresa/0000-0002-8454-7243 FU NIH NINDS [P50 NS 12587-27]; Reynolds Foundation; Lind-Lawrence Foundation; Fundacao para a Ciencia e Tecnologia [SFRH/BD/3421/2000]; Fulbright Fellowship FX Funding for this study was provided by NIH NINDS grant N. P50 NS 12587-27, and Ross Bullock was supported by the Reynolds and Lind-Lawrence Foundations. Oscar L Alves was supported by grant number SFRH/BD/3421/2000 from Fundacao para a Ciencia e Tecnologia, and by a Fulbright Fellowship. NR 39 TC 4 Z9 4 U1 1 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD SEP PY 2013 VL 30 IS 17 BP 1484 EP 1489 DI 10.1089/neu.2012.2524 PG 6 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 202HX UT WOS:000323205800003 PM 23540442 ER PT J AU Weisz, A AF Weisz, Adrian TI Honoring Professor Asher Mandelbaum SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Biographical-Item C1 US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Weisz, A (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. EM adrian.weisz@fda.hhs.gov NR 1 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1044-0305 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD SEP PY 2013 VL 24 IS 9 BP 1324 EP 1325 DI 10.1007/s13361-013-0685-y PG 2 WC Biochemical Research Methods; Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA 200HX UT WOS:000323060000002 PM 23836379 ER PT J AU Schug, TT Heindel, JJ Camacho, L Delclos, KB Howard, P Johnson, AF Aungst, J Keefe, D Newbold, R Walker, NJ Zoeller, RT Bucher, JR AF Schug, Thaddeus T. Heindel, Jerrold J. Camacho, Luisa Delclos, K. Barry Howard, Paul Johnson, Anne F. Aungst, Jason Keefe, Dennis Newbold, Retha Walker, Nigel J. Zoeller, R. Thomas Bucher, John R. TI A new approach to synergize academic and guideline-compliant research: The CLARITY-BPA research program SO REPRODUCTIVE TOXICOLOGY LA English DT Review DE Bisphenol A; NIEHS; FDA; NTP; Consortium-based research; Low dose ID BISPHENOL-A AB Recently, medical research has seen a strong push toward translational research, or "bench to bedside" collaborations, that strive to enhance the utility of laboratory science for improving medical treatment. The success of that paradigm supports the potential application of the process to other fields, such as risk assessment. Close collaboration among academic, government, and industry scientists may enhance the translation of scientific findings to regulatory decision making. The National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), and U.S. Food and Drug Administration (FDA) developed a consortium-based research program to link more effectively academic and guideline-compliant research. An initial proof-of-concept collaboration, the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA), uses bisphenol A (BPA) as a test chemical. The CLARITY-BPA program combines a core perinatal guideline-compliant 2-year chronic toxicity study with mechanistic studies/endpoints conducted by academic investigators. Twelve extramural grantees were selected by NIEHS through an RFA-based initiative to participate in the overall study design and conduct disease-relevant investigations using tissues and animals from the core study. While the study is expected to contribute to our understanding of potential effects of BPA, it also has ramifications beyond this specific focus. Through CLARITY-BPA, NIEHS has established an unprecedented level of collaboration among extramural grantees and regulatory researchers. By drawing upon the strengths of academic and regulatory expertise and research approaches, CLARITY-BPA represents a potential new model for filling knowledge gaps, enhancing quality control, informing chemical risk assessment, and identifying new methods or endpoints for regulatory hazard assessments. Published by Elsevier Inc. C1 [Schug, Thaddeus T.; Heindel, Jerrold J.] NIEHS, NIH, Div Extramural Res, Res Triangle Pk, NC 27709 USA. [Camacho, Luisa; Delclos, K. Barry] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Howard, Paul] US FDA, Off Sci Coordinat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Johnson, Anne F.] MDB Inc, Durham, NC 27713 USA. [Aungst, Jason; Keefe, Dennis] US FDA, Off Food Addit Safety, College Pk, MD 20740 USA. [Newbold, Retha; Walker, Nigel J.; Bucher, John R.] NIEHS, NIH, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Zoeller, R. Thomas] Univ Massachusetts, Dept Biol, Amherst, MA 01003 USA. RP Schug, TT (reprint author), Div Extramural Res, 530 Davis Dr,Room 3041 Mail Drop K3-15, Morrisville, NC 27560 USA. EM Schugt@niehs.nih.gov RI Walker, Nigel/D-6583-2012 OI Walker, Nigel/0000-0002-9111-6855 FU NIEHS [HHSN273201100086U] FX This article is the work product of a group that includes employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) and the U.S. Food and Drug Administration (FDA); however, the statements, opinions, or conclusions contained herein do not necessarily represent the statements, opinions, or conclusions of FDA, NIEHS, NIH or the United States government. Anne Johnson is employed by MDB, Inc. under a contract to NIEHS (HHSN273201100086U). The authors declare they have no actual or potential competing financial interests. NR 18 TC 18 Z9 18 U1 1 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD SEP PY 2013 VL 40 BP 35 EP 40 DI 10.1016/j.reprotox.2013.05.010 PG 6 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 197KE UT WOS:000322849300005 PM 23747832 ER PT J AU Fox, PD Rosenberg, CB AF Fox, Peter D. Rosenberg, Charles B. TI The Hidden Tool in a Foreign Investor's Toolbox: The Trade Preference Program as a "Carrot and Stick" to Secure Compliance with International Law Obligations SO NORTHWESTERN JOURNAL OF INTERNATIONAL LAW & BUSINESS LA English DT Article AB This Article considers the use of the trade preference program as a tool to pressure a State to comply with its international law obligations. Recent international investment disputes involving Argentina, Ecuador, and the Russian Federation bring to light the increasing utility of U.S. and EU trade preference programs as retaliatory mechanisms for such noncompliance. Particularly where a host State either has not consented to arbitration or has allegedly failed to comply with an adverse award, this Article affirms that the trade preference program can have a meaningful impact on a host State and be a valuable tool for a foreign investor. C1 [Fox, Peter D.] US FDA, Washington, DC 20204 USA. [Rosenberg, Charles B.] White & Case LLP, Washington, DC USA. RP Fox, PD (reprint author), US FDA, Washington, DC 20204 USA. EM peter.fox@gmail.com; charles.rosenberg@whitecase.com NR 52 TC 1 Z9 1 U1 0 U2 0 PU NORTHWESTERN UNIV SCHOOL LAW PI CHICAGO 11 PA 357 EAST CHICAGO AVE, CHICAGO 11, IL 00000 USA SN 0196-3228 J9 NW J INT LAW BUS JI Northwest. J. Int. Bus. PD FAL PY 2013 VL 34 IS 1 BP 53 EP 80 PG 28 WC Law SC Government & Law GA V39LF UT WOS:000209411800002 ER PT J AU Mahmood, I AF Mahmood, Iftekhar TI Allometric scaling and prediction of concentration-time profiles of coagulation factors in humans from animals SO XENOBIOTICA LA English DT Article DE Allometry; coagulation factors; concentrations-time profiles; multi-compartment system; pharmacokinetics ID FACTOR-IX; PHARMACOKINETICS; BIOEQUIVALENCE; SAFETY; TRIAL AB 1. Allometric scaling is a useful tool in early drug development and can be used for the prediction of human pharmacokinetic (PK) parameters from animal PK parameters. The main objective of this work was to predict concentration-time profiles of coagulation factors in humans in a multi-compartment system using animal PK parameters. 2. The prediction of concentration-time profiles in humans in a multi-compartment system was based on the predicted values of clearance and volumes of distribution (V-c, V-ss and V-beta) from animals. Five coagulation factors from the literature were chosen that were described by two-compartment model in both humans and animals. Clearance and volumes of distribution from animals were allometrically scaled to humans and then were used to predict concentration-time profiles in humans. 3. The predicted concentration-time profile for a given coagulation factor was accurate for most of the time points. Percent prediction error range varied across coagulation factors. The prediction error >50% was observed either at 1 or a maximum of two time points for a given drug. 4. The study indicated that the allometric scaling can be useful in the prediction of concentration-time profiles of coagulation factors in humans from animals and may be helpful in designing a first-in-human study. C1 US FDA, OBRR, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP Mahmood, I (reprint author), US FDA, OBRR, Ctr Biol Evaluat & Res, 1401 Rockville Pike, Rockville, MD 20857 USA. EM iftekhar.mahmood@fda.hhs.gov NR 21 TC 2 Z9 2 U1 0 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0049-8254 J9 XENOBIOTICA JI Xenobiotica PD SEP PY 2013 VL 43 IS 9 BP 774 EP 779 DI 10.3109/00498254.2013.766778 PG 6 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 195XE UT WOS:000322736100004 PM 23391211 ER PT J AU Mans, DJ Gucinski, AC Dunn, JD Gryniewicz-Ruzicka, CM Mecker-Pogue, LC Kao, JLF Ge, X AF Mans, Daniel J. Gucinski, Ashley C. Dunn, Jamie D. Gryniewicz-Ruzicka, Connie M. Mecker-Pogue, Laura C. Kao, Jeff L. -F. Ge, Xia TI Rapid screening and structural elucidation of a novel sibutramine analogue in a weight loss supplement: 11-Desisobutyl-11-benzylsibutramine SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Dietary supplement; Sibutramine; Ion mobility spectrometry; Mass spectrometry; Nuclear magnetic resonance ID ION MOBILITY SPECTROMETRY; DIETARY-SUPPLEMENTS; METABOLITES AB A novel analogue of sibutramine, 11-desisobutyl-11-benzylsibutramine, has been discovered. During routine ion mobility spectrometry (IMS) screening of a weight loss supplement collected at an US FDA import operation facility an unknown peak was observed. Further analysis of the supplement by liquid chromatography-mass spectrometry (LC-MS) and high resolution mass spectrometry revealed an unknown peak with a relative retention time of 1.04 with respect to sibutramine and a predicted formula of C20H24NCl. In order to elucidate the analogue's structure, it was isolated from the supplement and characterized by tandem mass spectrometry and nuclear magnetic resonance (NMR), which revealed the analogue possessed a benzyl moiety at the 11 position in place of the isobutyl group associated with sibutramine. (C) 2013 Published by Elsevier B.V. C1 [Mans, Daniel J.; Gucinski, Ashley C.; Dunn, Jamie D.; Gryniewicz-Ruzicka, Connie M.; Mecker-Pogue, Laura C.] US FDA, CDER Div Pharmaceut Anal, St Louis, MO 63101 USA. [Kao, Jeff L. -F.; Ge, Xia] Washington Univ, Dept Chem, St Louis, MO 63130 USA. RP Mans, DJ (reprint author), US FDA, CDER Div Pharmaceut Anal, 1114 Market St, St Louis, MO 63101 USA. EM Daniel.Mans@fda.hhs.gov NR 16 TC 8 Z9 8 U1 0 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD SEP PY 2013 VL 83 BP 122 EP 128 DI 10.1016/j.jpba.2013.02.031 PG 7 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 173NI UT WOS:000321085800016 PM 23739298 ER PT J AU Al Sharif, M Alov, P Cronin, M Fioravanzo, E Tsakovska, I Vitcheva, V Worth, A Yang, CH Pajeva, I AF Al Sharif, Merilin Alov, Petko Cronin, Mark Fioravanzo, Elena Tsakovska, Ivanka Vitcheva, Vessela Worth, Andrew Yang, Chihae Pajeva, Ilza TI Toward better understanding of liver steatosis MoA: Molecular modelling study of PPAR gamma receptor SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 49th Congress of the European-Societies-of-Toxicology (EUROTOX) CY SEP 01-04, 2013 CL Interlaken, SWITZERLAND SP European Soc Toxicol (EUROTOX), ECETOC, Roche, Syngenta, AstraZeneca, Sanofi, Basilea Pharmaceutica, ACEA Biosciences Inc, European Crop Protect, Bioservice Sci Labs GmbH, Oekotoxzentrum Ctr Ecotox, Swiss Confederat, Fed Dept Home Affairs, Fed Off Publ Hlth (FOPH), BASF, SCAHT, Johnson & Johnson, Janssen Pharmaceut Co, Natl Ctr Replacement, Refinement & Reduct Anim Res, ILSI, SERVIER, RCC, Nestle, Suva Pro, Interpharma, Covance, Novartis, Merck, BioReliance C1 [Al Sharif, Merilin; Alov, Petko; Tsakovska, Ivanka] Inst Biophys & Biomed Engn, Sofia, Bulgaria. [Cronin, Mark] Liverpool John Moores Univ, Liverpool L3 5UX, Merseyside, England. [Fioravanzo, Elena] S IN Soluzioni Informat SRL, Vicenza, Italy. [Vitcheva, Vessela] US FDA, CFSAN, College Pk, MD USA. [Worth, Andrew] European Commiss, Joint Res Ctr, Inst Hlth & Consumer Protect, Ispra, Italy. [Yang, Chihae] Altamira LLC, Columbus, OH USA. [Pajeva, Ilza] Bulgarian Acad Sci, Inst Biophys & Biomed Engn, BU-1113 Sofia, Bulgaria. NR 0 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD AUG 28 PY 2013 VL 221 SU S BP S85 EP S85 DI 10.1016/j.toxlet.2013.05.099 PG 1 WC Toxicology SC Toxicology GA 210WO UT WOS:000323865800258 ER PT J AU da Costa, GG AF da Costa, Goncalo Gamboa TI Nephrotoxicity of melamine, cyanuric acid, and their combination SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 49th Congress of the European-Societies-of-Toxicology (EUROTOX) CY SEP 01-04, 2013 CL Interlaken, SWITZERLAND SP European Soc Toxicol (EUROTOX), ECETOC, Roche, Syngenta, AstraZeneca, Sanofi, Basilea Pharmaceutica, ACEA Biosciences Inc, European Crop Protect, Bioservice Sci Labs GmbH, Oekotoxzentrum Ctr Ecotox, Swiss Confederat, Fed Dept Home Affairs, Fed Off Publ Hlth (FOPH), BASF, SCAHT, Johnson & Johnson, Janssen Pharmaceut Co, Natl Ctr Replacement, Refinement & Reduct Anim Res, ILSI, SERVIER, RCC, Nestle, Suva Pro, Interpharma, Covance, Novartis, Merck, BioReliance C1 [da Costa, Goncalo Gamboa] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD AUG 28 PY 2013 VL 221 SU S BP S10 EP S11 DI 10.1016/j.toxlet.2013.06.038 PG 2 WC Toxicology SC Toxicology GA 210WO UT WOS:000323865800030 ER PT J AU Tami, C AF Tami, Cecilia TI Challenges with immunogenicity of biologics SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 49th Congress of the European-Societies-of-Toxicology (EUROTOX) CY SEP 01-04, 2013 CL Interlaken, SWITZERLAND SP European Soc Toxicol (EUROTOX), ECETOC, Roche, Syngenta, AstraZeneca, Sanofi, Basilea Pharmaceutica, ACEA Biosciences Inc, European Crop Protect, Bioservice Sci Labs GmbH, Oekotoxzentrum Ctr Ecotox, Swiss Confederat, Fed Dept Home Affairs, Fed Off Publ Hlth (FOPH), BASF, SCAHT, Johnson & Johnson, Janssen Pharmaceut Co, Natl Ctr Replacement, Refinement & Reduct Anim Res, ILSI, SERVIER, RCC, Nestle, Suva Pro, Interpharma, Covance, Novartis, Merck, BioReliance C1 [Tami, Cecilia] US FDA, Immunol Lab, Div Therapeut Prot, CDER, Bethesda, MD 20014 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD AUG 28 PY 2013 VL 221 SU S BP S12 EP S12 DI 10.1016/j.toxlet.2013.06.043 PG 1 WC Toxicology SC Toxicology GA 210WO UT WOS:000323865800034 ER PT J AU Thompson, KL Chen, T Couttet, P Ellinger-Ziegelbauer, H Kanki, M Kelsall, J Boitier, E Nassirpour, R Searfoss, G Sharapova, T de la Moureyre-Spire, C Yuen, P O'Lone, R AF Thompson, K. L. Chen, T. Couttet, P. Ellinger-Ziegelbauer, H. Kanki, M. Kelsall, J. Boitier, E. Nassirpour, R. Searfoss, G. Sharapova, T. de la Moureyre-Spire, C. Yuen, P. O'Lone, R. TI Multi-laboratory assessment of best practices for quantification of microRNAs associated with isoproterenol-induced myocardial injury in the urine and plasma of rats SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 49th Congress of the European-Societies-of-Toxicology (EUROTOX) CY SEP 01-04, 2013 CL Interlaken, SWITZERLAND SP European Soc Toxicol (EUROTOX), ECETOC, Roche, Syngenta, AstraZeneca, Sanofi, Basilea Pharmaceutica, ACEA Biosciences Inc, European Crop Protect, Bioservice Sci Labs GmbH, Oekotoxzentrum Ctr Ecotox, Swiss Confederat, Fed Dept Home Affairs, Fed Off Publ Hlth (FOPH), BASF, SCAHT, Johnson & Johnson, Janssen Pharmaceut Co, Natl Ctr Replacement, Refinement & Reduct Anim Res, ILSI, SERVIER, RCC, Nestle, Suva Pro, Interpharma, Covance, Novartis, Merck, BioReliance C1 [Thompson, K. L.] CDER, Silver Spring, MD USA. [Chen, T.] NCTR, Jefferson, AR USA. [Couttet, P.] Novartis Pharma AG, Basel, Switzerland. [Ellinger-Ziegelbauer, H.] Bayer Pharma AG, Wuppertal, Germany. [Kanki, M.] Astellas Pharrna Inc, Osaka, Japan. [Kelsall, J.] AstraZeneca, Macclesfield, Cheshire, England. [Boitier, E.] Sanofi, Vitry Sur Seine, France. [Nassirpour, R.] Pfizer, Andover, MA USA. [Searfoss, G.] Lilly, Indianapolis, IN USA. [Sharapova, T.] Abbott Labs, Abbott Pk, IL 60064 USA. [de la Moureyre-Spire, C.] Servier, Gidy, France. [Yuen, P.] NIDDK, NIH, Bethesda, MD USA. [O'Lone, R.] ILSI Hlth & Environm Sci Inst, Washington, DC USA. RI Yuen, Peter/B-1954-2008 OI Yuen, Peter/0000-0001-9557-3909 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD AUG 28 PY 2013 VL 221 SU S BP S66 EP S66 DI 10.1016/j.toxlet.2013.05.037 PG 1 WC Toxicology SC Toxicology GA 210WO UT WOS:000323865800199 ER PT J AU Thompson, KL Chen, T Couttet, P Ellinger-Ziegelbauer, H Kanki, M Kelsall, J Boitier, E Nassirpour, R Searfoss, G Sharapova, T de la Moureyre-Spire, C Yuen, P O'Lone, R AF Thompson, K. L. Chen, T. Couttet, P. Ellinger-Ziegelbauer, H. Kanki, M. Kelsall, J. Boitier, E. Nassirpour, R. Searfoss, G. Sharapova, T. de la Moureyre-Spire, Catherine Yuen, P. O'Lone, R. TI The HESI inter-laboratory miRNA project SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 49th Congress of the European-Societies-of-Toxicology (EUROTOX) CY SEP 01-04, 2013 CL Interlaken, SWITZERLAND SP European Soc Toxicol (EUROTOX), ECETOC, Roche, Syngenta, AstraZeneca, Sanofi, Basilea Pharmaceutica, ACEA Biosciences Inc, European Crop Protect, Bioservice Sci Labs GmbH, Oekotoxzentrum Ctr Ecotox, Swiss Confederat, Fed Dept Home Affairs, Fed Off Publ Hlth (FOPH), BASF, SCAHT, Johnson & Johnson, Janssen Pharmaceut Co, Natl Ctr Replacement, Refinement & Reduct Anim Res, ILSI, SERVIER, RCC, Nestle, Suva Pro, Interpharma, Covance, Novartis, Merck, BioReliance C1 [Thompson, K. L.] CDER, Silver Spring, MD USA. [Chen, T.] NCTR, Jefferson, AR USA. [Couttet, P.] Novartis Pharma AG, Basel, Switzerland. [Ellinger-Ziegelbauer, H.] Bayer Pharma AG, Wuppertal, Germany. [Kanki, M.] Astellas Pharma Inc, Osaka, Japan. [Kelsall, J.] AstraZeneca, Macclesfield, Cheshire, England. [Boitier, E.] Sanofi, Vitry Sur Seine, France. [Nassirpour, R.] Pfizer, Andover, MA USA. [Searfoss, G.] Lilly, Indianapolis, IN USA. [Sharapova, T.] Abbott Labs, Abbott Pk, IL 60064 USA. [de la Moureyre-Spire, Catherine] Servier, Gidy, France. [Yuen, P.] NIDDK, NIH, Bethesda, MD USA. [O'Lone, R.] ILSI Hlth & Environm Sci Inst, Washington, DC USA. RI Yuen, Peter/B-1954-2008 OI Yuen, Peter/0000-0001-9557-3909 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD AUG 28 PY 2013 VL 221 SU S BP S48 EP S48 DI 10.1016/j.toxlet.2013.06.176 PG 1 WC Toxicology SC Toxicology GA 210WO UT WOS:000323865800149 ER PT J AU Valentin, JP Koerner, J Willard, J Park, EJ Bi, DQ Link, W Fiszman, M Kozeli, D Skinner, M Cantilena, L Gintant, G Wisialowski, T Pettit, S Vargas, H AF Valentin, Jean-Pierre Koerner, John Willard, James Park, Eun Jung Bi, Daoqin Link, William Fiszman, Monica Kozeli, Devi Skinner, Matt Cantilena, Louis Gintant, Gary Wisialowski, Todd Pettit, Syril Vargas, Hugo TI Predictivity of non-clinical repolarization assay data for clinical TQT data in FDA database SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 49th Congress of the European-Societies-of-Toxicology (EUROTOX) CY SEP 01-04, 2013 CL Interlaken, SWITZERLAND SP European Soc Toxicol (EUROTOX), ECETOC, Roche, Syngenta, AstraZeneca, Sanofi, Basilea Pharmaceutica, ACEA Biosciences Inc, European Crop Protect, Bioservice Sci Labs GmbH, Oekotoxzentrum Ctr Ecotox, Swiss Confederat, Fed Dept Home Affairs, Fed Off Publ Hlth (FOPH), BASF, SCAHT, Johnson & Johnson, Janssen Pharmaceut Co, Natl Ctr Replacement, Refinement & Reduct Anim Res, ILSI, SERVIER, RCC, Nestle, Suva Pro, Interpharma, Covance, Novartis, Merck, BioReliance C1 [Valentin, Jean-Pierre; Skinner, Matt] AstraZeneca, Chesire, England. [Koerner, John; Willard, James; Park, Eun Jung; Bi, Daoqin; Link, William; Fiszman, Monica; Kozeli, Devi] US FDA, Silver Spring, MD USA. [Cantilena, Louis] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Gintant, Gary] Abbott, Abbott Pk, IL USA. [Wisialowski, Todd] Pfizer, New York, NY USA. [Pettit, Syril] ILSI HESI, Washington, DC USA. [Vargas, Hugo] Amgen Inc, Thousand Oaks, CA USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD AUG 28 PY 2013 VL 221 SU S BP S232 EP S233 DI 10.1016/j.toxlet.2013.05.566 PG 2 WC Toxicology SC Toxicology GA 210WO UT WOS:000323865800715 ER PT J AU Vitcheva, V Mostrag-Szychtying, A Nelms, M Alov, P Enoch, S Tsakovka, I Rathman, J Cronin, M AF Vitcheva, Vessela Mostrag-Szychtying, Aleksandra Nelms, Mark Alov, Petko Enoch, Steve Tsakovka, Ivanka Rathman, James Cronin, Mark TI Data mining toxicity effects through an ontology approach to investigate toxicity mode of action SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 49th Congress of the European-Societies-of-Toxicology (EUROTOX) CY SEP 01-04, 2013 CL Interlaken, SWITZERLAND SP European Soc Toxicol (EUROTOX), ECETOC, Roche, Syngenta, AstraZeneca, Sanofi, Basilea Pharmaceutica, ACEA Biosciences Inc, European Crop Protect, Bioservice Sci Labs GmbH, Oekotoxzentrum Ctr Ecotox, Swiss Confederat, Fed Dept Home Affairs, Fed Off Publ Hlth (FOPH), BASF, SCAHT, Johnson & Johnson, Janssen Pharmaceut Co, Natl Ctr Replacement, Refinement & Reduct Anim Res, ILSI, SERVIER, RCC, Nestle, Suva Pro, Interpharma, Covance, Novartis, Merck, BioReliance C1 [Vitcheva, Vessela] US FDA, CFSAN, College Pk, MD USA. [Mostrag-Szychtying, Aleksandra; Rathman, James] Altamira LLC, Columbus, MS USA. [Nelms, Mark; Enoch, Steve; Cronin, Mark] Liverpool John Moores Univ, Liverpool L3 5UX, Merseyside, England. [Alov, Petko; Tsakovka, Ivanka] Bulgarian Acad Sci, Sofia, Bulgaria. OI Nelms, Mark/0000-0003-2350-2743 NR 0 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD AUG 28 PY 2013 VL 221 SU S BP S80 EP S80 DI 10.1016/j.toxlet.2013.05.081 PG 1 WC Toxicology SC Toxicology GA 210WO UT WOS:000323865800241 ER PT J AU Williams, FM Ambrosio, M Barrett, G Cronin, M Guy, RH Plautz, J Roper, C Rothe, H Rua, D Verwei, M Yang, CH AF Williams, Faith M. Ambrosio, Massimo Barrett, G. Cronin, Mark Guy, R. H. Plautz, J. Roper, C. Rothe, Helga Rua, D. Verwei, M. Yang, Chihae TI Threshold of toxicological concern (TIC) task force: a strategy to support application of TTC to dermally applied cosmetic ingredients SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 49th Congress of the European-Societies-of-Toxicology (EUROTOX) CY SEP 01-04, 2013 CL Interlaken, SWITZERLAND SP European Soc Toxicol (EUROTOX), ECETOC, Roche, Syngenta, AstraZeneca, Sanofi, Basilea Pharmaceutica, ACEA Biosciences Inc, European Crop Protect, Bioservice Sci Labs GmbH, Oekotoxzentrum Ctr Ecotox, Swiss Confederat, Fed Dept Home Affairs, Fed Off Publ Hlth (FOPH), BASF, SCAHT, Johnson & Johnson, Janssen Pharmaceut Co, Natl Ctr Replacement, Refinement & Reduct Anim Res, ILSI, SERVIER, RCC, Nestle, Suva Pro, Interpharma, Covance, Novartis, Merck, BioReliance C1 [Williams, Faith M.] Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Ambrosio, Massimo] ILSI Europe, Brussels, Belgium. [Barrett, G.] Hlth Canada, Ottawa, ON K1A 0L2, Canada. [Cronin, Mark] Liverpool John Moores Univ, Liverpool L3 5UX, Merseyside, England. [Guy, R. H.] Univ Bath, Bath BA2 7AY, Avon, England. [Plautz, J.] DSM Nutr Prod, Basel, Switzerland. [Roper, C.] Charles River Labs, Edinburgh, Midlothian, Scotland. [Rothe, Helga] Procter & Gamble Co, Darmstadt, Germany. [Rua, D.] US FDA, Rockville, MD 20857 USA. [Verwei, M.] TNO, NL-3700 AJ Zeist, Netherlands. [Yang, Chihae] Altamira LLC, Columbus, OH USA. NR 0 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD AUG 28 PY 2013 VL 221 SU S BP S35 EP S35 DI 10.1016/j.toxlet.2013.06.125 PG 1 WC Toxicology SC Toxicology GA 210WO UT WOS:000323865800107 ER PT J AU Yang, CH Ambrosio, M Arvidson, K Barlow, S Boobis, A Checheva, M Cronin, M Felter, S Fioravanzo, E Hollnagel, H Hristozov, D Jacobs, K Keller, D Mostrag-Szylchtying, A Nelms, M Rathman, J Richarz, A Tsakovska, I Vidry, S Vitcheva, V Worth, A AF Yang, Chihae Ambrosio, Massimo Arvidson, Kirk Barlow, Sue Boobis, Alan Checheva, Maria Cronin, Mark Felter, Susan Fioravanzo, Elena Hollnagel, Heli Hristozov, Dimitar Jacobs, Kristi Keller, Detlef Mostrag-Szylchtying, Aleksandra Nelms, Mark Rathman, James Richarz, Andrea Tsakovska, Ivanka Vidry, Stephane Vitcheva, Vessela Worth, Andrew TI Development of new COSMOS oRepeatDose and non-cancer Threshold of Toxicological Concern (TTC) databases to support alternative testing methods for cosmetics related chemicals SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 49th Congress of the European-Societies-of-Toxicology (EUROTOX) CY SEP 01-04, 2013 CL Interlaken, SWITZERLAND SP European Soc Toxicol (EUROTOX), ECETOC, Roche, Syngenta, AstraZeneca, Sanofi, Basilea Pharmaceutica, ACEA Biosciences Inc, European Crop Protect, Bioservice Sci Labs GmbH, Oekotoxzentrum Ctr Ecotox, Swiss Confederat, Fed Dept Home Affairs, Fed Off Publ Hlth (FOPH), BASF, SCAHT, Johnson & Johnson, Janssen Pharmaceut Co, Natl Ctr Replacement, Refinement & Reduct Anim Res, ILSI, SERVIER, RCC, Nestle, Suva Pro, Interpharma, Covance, Novartis, Merck, BioReliance C1 [Yang, Chihae; Checheva, Maria; Mostrag-Szylchtying, Aleksandra; Rathman, James] Altamira LLC, Columbus, OH 43235 USA. [Ambrosio, Massimo; Vidry, Stephane] ILSI Europe, B-1200 Brussels, Belgium. [Arvidson, Kirk; Hristozov, Dimitar; Jacobs, Kristi; Vitcheva, Vessela] US FDA, CFSAN, College Pk, MD 20740 USA. [Barlow, Sue] Consultant Toxicol & Risk Assessment, Brighton BN1 6RE, E Sussex, England. [Boobis, Alan] Univ London Imperial Coll Sci Technol & Med, London W12 0NN, England. [Cronin, Mark; Nelms, Mark; Richarz, Andrea] Liverpool John Moores Univ, Liverpool L3 5UZ, Merseyside, England. [Felter, Susan] P&G, Cincinnati, OH 54201 USA. [Fioravanzo, Elena] S IN, Vicenza, Italy. [Hollnagel, Heli] Dow Chem, CH-8810 Horgen, Switzerland. [Keller, Detlef] Henkel KGaA, D-40191 Dusseldorf, North RhineWest, Germany. [Tsakovska, Ivanka] Bulgarian Acad Sci, BU-1113 Sofia, Bulgaria. [Worth, Andrew] EC Joint Res Ctr, I-21027 Ispra, Italy. NR 0 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD AUG 28 PY 2013 VL 221 SU S BP S80 EP S80 DI 10.1016/j.toxlet.2013.05.082 PG 1 WC Toxicology SC Toxicology GA 210WO UT WOS:000323865800242 ER PT J AU Jing, XH Soto, J Gao, YM Phy, K Ye, ZP AF Jing, Xianghong Soto, Jackeline Gao, Yamei Phy, Kathryn Ye, Zhiping TI Assessment of viral replication in eggs and HA protein yield of pre-pandemic H5N1 candidate vaccine viruses SO VACCINE LA English DT Article DE Influenza pandemic preparedness; Influenza H5N1 virus protein yield; HA bromelain cleavage; HA purification ID H1N1 INFLUENZA-VIRUS; BROMELAIN CLEAVAGE; HEMAGGLUTININ; NOMENCLATURE AB H5N1 infection and the potential for spread from human to human continue to pose a severe public health concern. Since vaccination remains the most effective way to prevent a potential H5N1 pandemic, the World Health Organization (WHO) Collaborating Centers (CCs) and Essential Regulatory Laboratories (ERLs) engineered and developed a panel of H5N1 pre-pandemic vaccine viruses for pandemic vaccine preparedness as well as production of antigen potency testing reagents (reference antigen and reference anti-serum) for vaccine standardization. To develop a strategy utilizing a number of biochemical methods for the characterization of the viral growth properties and protein yield in eggs, we have selected eight H5N1 pre-pandemic viruses and determined the viral Egg Infectious Dose 50 (EID50), total protein yield, hemagglutinin (HA) to nucleoprotein (NP) ratios (HA:NP), and HA1 content of each virus. Our results showed that all the tested H5N1 vaccine viruses grew to high titers in eggs. The total viral protein yield varies within a narrow range, whereas there were greater differences in the HA:NP protein ratios among the eight viruses. The RP-HPLC based HA1 content analysis demonstrated that the viruses A/Anhui/1/2010, A/Hubei/1/2005, and A/goose/Guiyang/337/2006 contained higher HA contents than other five viruses including A/Vietnam/1203/2003. Our approach for analyzing virus growth and protein yield will allow us identify optimal vaccine virus in a timely manner. In addition, we successfully purified the HA proteins of H5N1 vaccine viruses by optimizing bromelain cleavage conditions. Our studies on the HA protein purification may improve the quality control of the production of influenza vaccine test reagent. Published by Elsevier Ltd. C1 [Jing, Xianghong; Soto, Jackeline; Gao, Yamei; Phy, Kathryn; Ye, Zhiping] US FDA, Lab Resp Viral Dis, Div Viral Prod, Off Vaccine Res & Review, Bethesda, MD 20892 USA. RP Ye, ZP (reprint author), US FDA, Lab Resp Viral Dis, Div Viral Prod, Off Vaccine Res & Review, 8800 Rockville Pike, Bethesda, MD 20892 USA. EM Zhiping.ye@fda.hhs.gov FU Biomedical Advanced Research and Development Authority, Health and Human Services, USA FX We thank CDC, ST JUDE, and NIBSC for providing H5N1 vaccine viruses. We also thank the CBER core facility, especially to Dr. Rongfong Shen and Sang-eun Lee, for RP-HPLC service and technical support. We thank Drs. Falko Schmeisser, Vladimir Lugovtsev, and Ewan Plant for reviewing the manuscript. This work was partially supported by Biomedical Advanced Research and Development Authority, Health and Human Services, USA. NR 18 TC 3 Z9 3 U1 0 U2 16 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD AUG 28 PY 2013 VL 31 IS 38 BP 4091 EP 4097 DI 10.1016/j.vaccine.2013.07.011 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 207IF UT WOS:000323591400008 PM 23867014 ER PT J AU Khurana, S Loving, CL Manischewitz, J King, LR Gauger, PC Henningson, J Vincent, AL Golding, H AF Khurana, Surender Loving, Crystal L. Manischewitz, Jody King, Lisa R. Gauger, Phillip C. Henningson, Jamie Vincent, Amy L. Golding, Hana TI Vaccine-Induced Anti-HA2 Antibodies Promote Virus Fusion and Enhance Influenza Virus Respiratory Disease SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID A VIRUSES; AFFINITY MATURATION; YOUNG-ADULTS; HEMAGGLUTININ; SWINE; PIGS; CHILDREN; CELLS; GLYCOPROTEIN; REPLICATION AB Vaccine-induced disease enhancement has been described in connection with several viral vaccines in animal models and in humans. We investigated a swine model to evaluate mismatched influenza vaccine-associated enhanced respiratory disease (VAERD) after pH1N1 infection. Vaccinating pigs with whole inactivated H1N2 (human-like) virus vaccine (WIV-H1N2) resulted in enhanced pneumonia and disease after pH1N1 infection. WIV-H1N2 immune sera contained high titers of cross-reactive anti-pH1N1 hemagglutinin (HA) antibodies that bound exclusively to the HA2 domain but not to the HA1 globular head. No hemagglutination inhibition titers against pH1N1 (challenge virus) were measured. Epitope mapping using phage display library identified the immunodominant epitope recognized by WIV-H1N2 immune sera as amino acids 32 to 77 of pH1N1-HA2 domain, close to the fusion peptide. These cross-reactive anti-HA2 antibodies enhanced pH1N1 infection of Madin-Darby canine kidney cells by promoting virus membrane fusion activity. The enhanced fusion activity correlated with lung pathology in pigs. This study suggests a role for fusion-enhancing anti-HA2 antibodies in VAERD, in the absence of receptor-blocking virus-neutralizing antibodies. These findings should be considered during the evaluation of universal influenza vaccines designed to elicit HA2 stem-targeting antibodies. C1 [Khurana, Surender; Manischewitz, Jody; King, Lisa R.; Golding, Hana] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Loving, Crystal L.; Vincent, Amy L.] ARS, Virus & Prion Res Unit, Natl Anim Dis Ctr, USDA, Ames, IA 50010 USA. [Gauger, Phillip C.] Dept Vet Diagnost & Prod Anim Med, Ames, IA 50010 USA. [Henningson, Jamie] Kansas State Vet Diagnost Lab, Manhattan, KS 66506 USA. RP Golding, H (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM Amy.Vincent@ars.usda.gov; hana.golding@fda.hhs.gov FU Agricultural Research Service, U.S. Department of Agriculture (USDA) FX Funding was provided by Agricultural Research Service, U.S. Department of Agriculture (USDA). Mention of trade names or commercial products in this article is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the USDA. USDA is an equal opportunity provider and employer. NR 46 TC 65 Z9 65 U1 1 U2 8 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD AUG 28 PY 2013 VL 5 IS 200 AR 200ra114 DI 10.1126/scitranslmed.3006366 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 208UF UT WOS:000323705100003 PM 23986398 ER PT J AU Farkas, RH Unger, EF Temple, R AF Farkas, Ronald H. Unger, Ellis F. Temple, Robert TI Zolpidem and Driving Impairment - Identifying Persons at Risk SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Farkas, Ronald H.; Unger, Ellis F.; Temple, Robert] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Farkas, RH (reprint author), US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. NR 2 TC 29 Z9 29 U1 0 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 22 PY 2013 VL 369 IS 8 BP 689 EP 691 DI 10.1056/NEJMp1307972 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 204FA UT WOS:000323349300002 PM 23923991 ER PT J AU Fuentes, S Crim, RL Beeler, J Teng, MN Golding, H Khurana, S AF Fuentes, Sandra Crim, Roberta L. Beeler, Judy Teng, Michael N. Golding, Hana Khurana, Surender TI Development of a simple, rapid, sensitive, high-throughput luciferase reporter based microneutralization test for measurement of virus neutralizing antibodies following Respiratory Syncytial Virus vaccination and infection SO VACCINE LA English DT Article DE Respiratory Syncytial Virus; RSV; Neutralization; Antibody; Luciferase; Assay; Rapid; F protein; G protein; PRNT; RSV-Luc-NeuT; Vaccine; Infection ID CURRENT PROGRESS; F-GLYCOPROTEIN; RISK; INFANTS; ASSAY; REINFECTION; EXPRESSION; RESPONSES; CHILDREN; PROTEIN AB We have established a new reporter gene-based RSV neutralization test using Renilla luciferase. The RSV-Luciferase Neutralization Test (RSV-Luc-NeuT) is a simple, rapid, high throughput, and less labor intensive functional serological assay than the traditional RSV-PRNT, capable of measuring a broad range of anti-RSV neutralizing antibodies targeting both RSV-F and RSV-G proteins. Specificity and sensitivity of the RSV-Luc-NeuT are comparable to the RSV-PRNT. Panels of pre-vaccination and post-vaccination animal sera, monoclonal antibodies and animal polyclonal anti-RSV sera confirmed assay specificity. A panel of 60 human sera demonstrated high assay sensitivity for measurement of RSV neutralizing antibodies that strongly correlated with the RSV-PRNT titers (R-2=0.864). Neutralization in the presence of guinea pig complement (GPC) increased PRNT titers more than the RSV-Luc-NeuT neutralizing antibody titers for these human sera. This newly developed simple, high throughput, RSV-Luc-NeuT could be easily automated and applied in measurement of RSV neutralization titers in large vaccine trials. Published by Elsevier Ltd. C1 [Fuentes, Sandra; Crim, Roberta L.; Beeler, Judy; Golding, Hana; Khurana, Surender] US FDA, Div Viral Prod, CBER, Bethesda, MD 20892 USA. [Teng, Michael N.] Univ S Florida, Dept Internal Med, Div Allergy & Immunol, Tampa, FL 33612 USA. RP Khurana, S (reprint author), US FDA, Div Viral Prod, CBER, Bldg 29B,Room 4NNO2,8800 Rockville Pike, Bethesda, MD 20892 USA. EM surender.khurana@fda.hhs.gov RI Teng, Michael/I-5006-2012 OI Teng, Michael/0000-0002-0722-3659 FU NIAID NIH HHS [R01 AI081977] NR 27 TC 11 Z9 12 U1 1 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD AUG 20 PY 2013 VL 31 IS 37 BP 3987 EP 3994 DI 10.1016/j.vaccine.2013.05.088 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 218PI UT WOS:000324444200034 PM 23742994 ER PT J AU Qu, HO Tong, S Song, KJ Ma, H Bao, G Pincus, S Zhou, WL O'Connor, C AF Qu, Haiou Tong, Sheng Song, Kejing Ma, Hui Bao, Gang Pincus, Seth Zhou, Weilie O'Connor, Charles TI Controllable in Situ Synthesis of Magnetite Coated Silica-Core Water-Dispersible Hybrid Nanomaterials SO LANGMUIR LA English DT Article ID ONE-POT REACTION; NANOPARTICLE PROBES; DRUG-DELIVERY; QUANTUM DOTS; SHELL; LUMINESCENT; MICROSPHERES; NANOCRYSTALS; SPHERES; NANOSPHERES AB Magnetite nanoparticle coated silica (Fe3O4@SiO2) hybrid nanomaterials hold an important position in the fields of cell imaging and drug delivery. Here we report a large scale synthetic procedure that allows attachment of magnetite nanoparticles onto a silica surface in situ. Many different silica nanomaterials such as Stober silica nanospheres, mesoporous silica nanoparticles, and hollow silica nanotubes have been coated with a high density layer of water-dispersible magnetite nanoparticles. The size and attachment efficiency of the magnetite nanopartide can be well tuned by adjusting the precursor concentration and reflux time. The functionalization of Fe3O4@SiO2 nanoparticles with dye molecules and biocompatible polymers impart optical imaging modality and good colloidal stability in either buffer solution or serum. The functionalized materials also exhibited strong potential as negative contrast agents in T-2 weighted magnetic resonance imaging. C1 [Qu, Haiou; Ma, Hui; Zhou, Weilie; O'Connor, Charles] Univ New Orleans, Adv Mat Res Inst, New Orleans, LA 70148 USA. [Tong, Sheng; Bao, Gang] Georgia Inst Technol, Dept Biomed Engn, Atlanta, GA 30332 USA. [Tong, Sheng; Bao, Gang] Emory Univ, Atlanta, GA 30332 USA. [Song, Kejing; Pincus, Seth] Childrens Hosp, Res Inst Children, New Orleans, LA 70118 USA. RP Qu, HO (reprint author), US FDA, Off Regulatory Affairs, Arkansas Reg Lab, 3900 NCTR Rd,Bldg 26, Jefferson, AR 72079 USA. EM haiou.qu@fda.hhs.gov; coconnor@uno.edu RI Qu, Haiou/H-1332-2013 FU Louisiana Board of Regents [LEQSF(2007-12)-ENH-PKSFI-PRS-04]; National Heart Lung and Blood Institute of the NIH [HHSN268201000043C] FX This work was financially supported by a research grant from Louisiana Board of Regents Contract LEQSF(2007-12)-ENH-PKSFI-PRS-04 and by the National Heart Lung and Blood Institute of the NIH as a Program of Excellence in Nanotechnology Award (HHSN268201000043C to G.B.). NR 39 TC 12 Z9 12 U1 7 U2 158 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD AUG 20 PY 2013 VL 29 IS 33 BP 10573 EP 10578 DI 10.1021/la4022867 PG 6 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 205VD UT WOS:000323472000033 PM 23889037 ER PT J AU Li, XF Xu, YX Chen, YN Chen, S Jia, XP Sun, TC Liu, YH Li, XR Xiang, R Li, N AF Li, Xuefei Xu, Yingxi Chen, Yanan Chen, Si Jia, Xianpei Sun, Tongchao Liu, Yanhua Li, Xiru Xiang, Rong Li, Na TI SOX2 promotes tumor metastasis by stimulating epithelial-to-mesenchymal transition via regulation of WNT/beta-catenin signal network SO CANCER LETTERS LA English DT Article DE SOX2; Tumor metastasis; EMT; beta-catenin; TGF-beta 1 ID BREAST-CANCER CELLS; STEM-CELLS; E-CADHERIN; TIGHT JUNCTIONS; EXPRESSION; PLURIPOTENCY; MECHANISMS; INVASION; PATHWAY; TRAITS AB SOX2 was reported to promote metastasis in various tumor tissues; however the underlying mechanisms remain elusive. Here, we disclosed that SOX2 improves metastasis of breast and prostate cancer cells by promoting epithelial-to-mesenchymal transition (EMT) through WNT/beta-catenin, but not TGF-beta or Snaill signaling. Dual luciferase assay and chromatin immunoprecipitation revealed activation and binding of SOX2 on promoter region of beta-catenin. In addition, SOX2 affects the protein expression levels of DKK3, DVL1 and DVL3, which are regulators or downstream molecules of WNT signaling. Taken together, our findings demonstrated beta-catenin as one of vital downstream molecules that mediate the EMT induced by SOX2. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Li, Xuefei; Xu, Yingxi; Chen, Yanan; Chen, Si; Jia, Xianpei; Sun, Tongchao; Liu, Yanhua; Xiang, Rong; Li, Na] Nankai Univ, Sch Med, Tianjin 300071, Peoples R China. [Chen, Si] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Li, Xiru] Chinese Peoples Liberat Army Gen Hosp, Dept Gen Surg, Beijing 100853, Peoples R China. [Xiang, Rong; Li, Na] Tianjin Key Lab Tumor Microenvironm & Neurovasc R, Tianjin 300071, Peoples R China. RP Xiang, R (reprint author), Nankai Univ, Sch Med, 94 Weijin Rd, Tianjin 300071, Peoples R China. EM rxiang@nankai.edu.cn; lina08@nankai.edu.cn FU China 973 Program [2013CB967201]; NSFC [31000616, 81273331]; China International Cooperation Research Program [2012DFA10650]; China Junior Faculty Funds [20090031120044] FX This work was funded by: China 973 Program 2013CB967201 (to R. Xiang), NSFC (31000616 to N. Li, 81273331 to R. Xiang,), China International Cooperation Research Program 2012DFA10650 (to R. Xiang), China Junior Faculty Funds 20090031120044 (to N. Li). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 67 Z9 71 U1 2 U2 32 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD AUG 19 PY 2013 VL 336 IS 2 BP 379 EP 389 DI 10.1016/j.canlet.2013.03.027 PG 11 WC Oncology SC Oncology GA 187BB UT WOS:000322089400015 PM 23545177 ER PT J AU Karmakar, S Jin, YT Nagaich, AK AF Karmakar, Sudipan Jin, Yetao Nagaich, Akhilesh K. TI Interaction of Glucocorticoid Receptor (GR) with Estrogen Receptor (ER) alpha and Activator Protein 1 (AP1) in Dexamethasone-mediated Interference of ER alpha Activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BREAST-CANCER-CELLS; STEROID-HORMONE RECEPTORS; FACTOR-KAPPA-B; GENE-EXPRESSION; DNA-BINDING; COACTIVATOR AIB1; MONOAMINE-OXIDASE; ZINC-FINGER; TUMOR-CELLS; CROSS-TALK AB The role of glucocorticoids in the inhibition of estrogen (17-beta-estradiol (E2))-regulated estrogen receptor (ER)-positive breast cancer cell proliferation is well established. We and others have seen that synthetic glucocorticoid dexamethasone (Dex) antagonizes E2-stimulated endogenous ER alpha target gene expression. However, how glucocorticoids negatively regulate the ER alpha signaling pathway is still poorly understood. ChIP studies using ER alpha- and glucocorticoid receptor (GR)-positive MCF-7 cells revealed that GR occupies several ER alpha-binding regions (EBRs) in cells treated with E2 and Dex simultaneously. Interestingly, there was little or no GR loading to these regions when cells were treated with E2 or Dex alone. The E2+Dex-dependent GR recruitment is associated with the displacement of ER alpha and steroid receptor coactivator-3 from the target EBRs leading to the repression of ER alpha-mediated transcriptional activation. The recruitment of GR to EBRs requires assistance from ER alpha and FOXA1 and is facilitated by AP1 binding within the EBRs. The GR binding to EBRs is mediated via direct protein-protein interaction between the GR DNA-binding domain and ER alpha. Limited mutational analyses indicate that arginine 488 located within the C-terminal zinc finger domain of the GR DNA-binding domain plays a critical role in stabilizing this interaction. Together, the results of this study unravel a novel mechanism involved in glucocorticoid inhibition of ER alpha transcriptional activity and E2-mediated cell proliferation and thus establish a foundation for future exploitation of the GR signaling pathway in the treatment of ER-positive breast cancer. C1 [Karmakar, Sudipan; Jin, Yetao; Nagaich, Akhilesh K.] US FDA, CDER, OPS, Div Therapeut Prot,OBP, Bethesda, MD 20892 USA. RP Nagaich, AK (reprint author), US FDA, CDER, OPS, Div Therapeut Prot,OBP, 29 Lincoln Dr, Bethesda, MD 20892 USA. EM akhilesh.nagaich@fda.hhs.gov FU Food and Drug Administration Commissioner's Fellowship FX This project was supported in part by a Food and Drug Administration Commissioner's Fellowship (to S. K.). NR 72 TC 26 Z9 26 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 16 PY 2013 VL 288 IS 33 BP 24020 EP 24034 DI 10.1074/jbc.M113.473819 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302NO UT WOS:000330611400040 PM 23814048 ER PT J AU Kona, R Qu, HB Mattes, R Jancsik, B Fahmy, RM Hoag, SW AF Kona, Ravikanth Qu, Haibin Mattes, Robert Jancsik, Bela Fahmy, Raafat M. Hoag, Stephen W. TI Application of in-line near infrared spectroscopy and multivariate batch modeling for process monitoring in fluid bed granulation SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Fluid-bed; Near-infrared spectroscopy; Process control chart; PyroButton (R); Scores; Hotelling's T-2 ID MOISTURE-CONTENT; PRODUCT; CHARTS AB Fluid bed is an important unit operation in pharmaceutical industry for granulation and drying. To improve our understanding of fluid bed granulation, in-line near infrared spectroscopy (NIRS) and novel environmental temperature and RH data logger called a PyroButton (R) were used in conjunction with partial least square (PLS) and principal component analysis (PCA) to develop multivariate statistical process control charts (MSPC). These control charts were constructed using real-time moisture, temperature and humidity data obtained from batch experiments. To demonstrate their application, statistical control charts such as Scores, Distance to model (DModX), and Hotelling's T-2 were used to monitor the batch evolution process during the granulation and subsequent drying phase; moisture levels were predicted using a validated PLS model. Two data loggers were placed one near the bottom of the granulator bowl plenum where air enters the granulator and another inside the granulator in contact with the product in the fluid bed helped to monitor the humidity and temperature levels during the granulation and drying phase. The control charts were used for real time fault analysis, and were tested on normal batches and on three batches which deviated from normal processing conditions. This study demonstrated the use of NIRS and the use of humidity and temperature data loggers in conjunction with multivariate batch modeling as an effective tool in process understanding and fault determining method to effective process control in fluid bed granulation. Copyright (C) 2013. Published by Elsevier B.V. C1 [Kona, Ravikanth; Hoag, Stephen W.] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. [Qu, Haibin] Zhejiang Univ, Coll Pharmaceut Sci, Pharmaceut Informat Inst, Hangzhou 310058, Zhejiang, Peoples R China. [Mattes, Robert] FOSS NIRSyst Inc, Laurel, MD 20723 USA. [Jancsik, Bela] Opulus Ltd, Philadelphia, PA 19102 USA. [Fahmy, Raafat M.] US FDA, Off New Anim Drug Evaluat, Ctr Vet Med, Rockville, MD 20855 USA. RP Hoag, SW (reprint author), Univ Maryland, Sch Pharm, 20 N Pine St, Baltimore, MD 21201 USA. EM shoag@rx.umaryland.edu FU US Food and Drug Administration; CIPET FX Financial support for this project was provided by the US Food and Drug Administration and CIPET. The authors would like to acknowledge Dr. Ahmed Ashour for their technical assistance with multivariate batch modeling; Dr. Seon Hepburn and Bhavesh Kothari for their assistance with fluid bed granulation. NR 26 TC 11 Z9 17 U1 2 U2 35 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 J9 INT J PHARMACEUT JI Int. J. Pharm. PD AUG 16 PY 2013 VL 452 IS 1-2 BP 63 EP 72 DI 10.1016/j.ijpharm.2013.04.039 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 179CQ UT WOS:000321496200008 PM 23618967 ER PT J AU Madigan, D Ryan, PB Schuemie, M Stang, PE Overhage, JM Hartzema, AG Suchard, MA DuMouchel, W Berlin, JA AF Madigan, David Ryan, Patrick B. Schuemie, Martijn Stang, Paul E. Overhage, J. Marc Hartzema, Abraham G. Suchard, Marc A. DuMouchel, William Berlin, Jesse A. TI Evaluating the Impact of Database Heterogeneity on Observational Study Results SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE database; heterogeneity; methods; population characteristics; reproducibility of results; surveillance ID MEDICAL OUTCOMES PARTNERSHIP; MYOCARDIAL-INFARCTION; ORAL BISPHOSPHONATES; RISK; METAANALYSIS; CANCER AB Clinical studies that use observational databases to evaluate the effects of medical products have become commonplace. Such studies begin by selecting a particular database, a decision that published papers invariably report but do not discuss. Studies of the same issue in different databases, however, can and do generate different results, sometimes with strikingly different clinical implications. In this paper, we systematically study heterogeneity among databases, holding other study methods constant, by exploring relative risk estimates for 53 drug-outcome pairs and 2 widely used study designs (cohort studies and self-controlled case series) across 10 observational databases. When holding the study design constant, our analysis shows that estimated relative risks range from a statistically significant decreased risk to a statistically significant increased risk in 11 of 53 (21%) of drug-outcome pairs that use a cohort design and 19 of 53 (36%) of drug-outcome pairs that use a self-controlled case series design. This exceeds the proportion of pairs that were consistent across databases in both direction and statistical significance, which was 9 of 53 (17%) for cohort studies and 5 of 53 (9%) for self-controlled case series. Our findings show that clinical studies that use observational databases can be sensitive to the choice of database. More attention is needed to consider how the choice of data source may be affecting results. C1 [Madigan, David] Columbia Univ, Dept Stat, New York, NY 10027 USA. [Ryan, Patrick B.; Stang, Paul E.; Berlin, Jesse A.] Janssen Res & Dev LLC, Titusville, NJ USA. [Schuemie, Martijn] Erasmus Univ, Dept Med Informat, Med Ctr Rotterdam, NL-3000 DR Rotterdam, Netherlands. [Overhage, J. Marc] Ctr Biomed Informat, Regenstrief Inst, Indianapolis, IN USA. [Overhage, J. Marc] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Hartzema, Abraham G.] Univ Florida, Coll Pharm, Gainesville, FL USA. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biomath, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Biostat, Fielding Sch Publ Hlth, Los Angeles, CA USA. [DuMouchel, William] Oracle Hlth Sci, Burlington, MA USA. [Madigan, David; Ryan, Patrick B.; Schuemie, Martijn; Stang, Paul E.; Overhage, J. Marc; Hartzema, Abraham G.; Suchard, Marc A.; DuMouchel, William; Berlin, Jesse A.] Fdn Natl Inst Hlth, Observat Med Outcomes Partnership, Bethesda, MD USA. [Hartzema, Abraham G.] US FDA, Rockville, MD 20857 USA. RP Madigan, D (reprint author), Columbia Univ, Dept Stat, 1255 Amsterdam Ave, New York, NY 10027 USA. EM david.madigan@columbia.edu OI Overhage, Joseph/0000-0003-0223-0195 FU Foundation for the National Institutes of Health through Abbott Laboratories, Ltd.; Foundation for the National Institutes of Health through Amgen, Inc.; Foundation for the National Institutes of Health through AstraZeneca, PLC; Foundation for the National Institutes of Health through Bayer Healthcare Pharmaceuticals, Inc.; Foundation for the National Institutes of Health through Bristol-Myers Squibb Company; Foundation for the National Institutes of Health through Eli Lilly Co.; Foundation for the National Institutes of Health through GlaxoSmithKline, PLC; Foundation for the National Institutes of Health through Janssen Research and Development, LLC; Foundation for the National Institutes of Health through Lundbeck, Inc.; Foundation for the National Institutes of Health through Merck Co., Inc.; Foundation for the National Institutes of Health through Novartis Pharmaceuticals Corp.; Foundation for the National Institutes of Health through Pfizer, Inc.; Foundation for the National Institutes of Health through Pharmaceutical Research Manufacturers of America; Foundation for the National Institutes of Health through F. Hoffmann-La Roche, Ltd.; Foundation for the National Institutes of Health through Sanofi, SA; Foundation for the National Institutes of Health through Schering-Plough Corp.; Foundation for the National Institutes of Health through Takeda Pharmaceutical Co., Ltd. FX The Observational Medical Outcomes Partnership is funded by the Foundation for the National Institutes of Health through generous contributions from the following: Abbott Laboratories, Ltd.; Amgen, Inc.; AstraZeneca, PLC; Bayer Healthcare Pharmaceuticals, Inc.; Bristol-Myers Squibb Company; Eli Lilly & Co.; GlaxoSmithKline, PLC; Janssen Research and Development, LLC, Lundbeck, Inc.; Merck & Co., Inc.; Novartis Pharmaceuticals Corp.; Pfizer, Inc.; Pharmaceutical Research Manufacturers of America; F. Hoffmann-La Roche, Ltd.; Sanofi, SA; Schering-Plough Corp.; and Takeda Pharmaceutical Co., Ltd. NR 25 TC 44 Z9 44 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2013 VL 178 IS 4 BP 645 EP 651 DI 10.1093/aje/kwt010 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 200CR UT WOS:000323045400015 PM 23648805 ER PT J AU Wang, Y Wang, Z Joshi, BH Puri, RK Stultz, B Yuan, Q Bai, Y Zhou, P Yuan, Z Hursh, DA Bi, X AF Wang, Y. Wang, Z. Joshi, B. H. Puri, R. K. Stultz, B. Yuan, Q. Bai, Y. Zhou, P. Yuan, Z. Hursh, D. A. Bi, X. TI The tumor suppressor Caliban regulates DNA damage-induced apoptosis through p53-dependent and -independent activity SO ONCOGENE LA English DT Article DE Apoptosis; Caliban; p53; tumor suppressor ID S-PHASE CHECKPOINTS; CELL-DEATH; DROSOPHILA-MELANOGASTER; IN-VIVO; TELOMERE MAINTENANCE; GENOMIC INSTABILITY; IONIZING-RADIATION; P53 FUNCTION; ATM; PROTEIN AB We previously identified Caliban (Clbn) as the Drosophila homolog of human Serologically defined colon cancer antigen 1 gene and demonstrated that it could function as a tumor suppressor in human non-small-cell lung cancer (NSCLC) cells, although its mode of action was unknown. Herein, we identify roles for Clbn in DNA damage response. We generate clbn knockout flies using homologous recombination and demonstrate that they have a heightened sensitivity to irradiation. We show that normal Clbn function facilitates both p53-dependent and -independent DNA damage-induced apoptosis. Clbn coordinates different apoptosis pathways, showing a two-stage upregulation following DNA damage. Clbn has proapoptotic functions, working with both caspase and the proapoptotic gene Hid. Finally, ecotopic expression of clbn(+) in NSCLC cells suppresses tumor formation in athymic nude mice. We conclude that Caliban is a regulator of DNA damage-induced apoptosis, functioning as a tumor suppressor in both p53-dependent and -independent pathways. C1 [Wang, Y.; Wang, Z.; Yuan, Q.; Bi, X.] Chinese Acad Sci, Inst High Energy Phys, CAS Key Lab Biol Effects Nanomat & Nanosafety, Beijing 100049, Peoples R China. [Wang, Z.; Bi, X.] Dalian Med Univ, Inst Canc Stem Cell, Ctr Canc, Dalian, Peoples R China. [Joshi, B. H.; Puri, R. K.; Stultz, B.; Hursh, D. A.] US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Bethesda, MD USA. [Bai, Y.; Yuan, Z.] Chinese Acad Sci, Inst Biophys, State Key Lab Brain & Cognit Sci, Beijing 100049, Peoples R China. [Zhou, P.] Beijing Inst Radiat Med, Dept Radiat Toxicol & Oncol, Beijing, Peoples R China. RP Bi, X (reprint author), Chinese Acad Sci, Inst High Energy Phys, CAS Key Lab Biol Effects Nanomat & Nanosafety, Beijing 100049, Peoples R China. EM bixl@ihep.ac.cn RI Bi, Xiaolin/C-7038-2014; Bi, Xiaolin/E-7469-2010 OI Bi, Xiaolin/0000-0003-2837-9457; Bi, Xiaolin/0000-0002-7172-7851 FU National Basic Research Program of China (973 Program) [2010CB934004]; National Natural Science Foundation of China [30871388]; CAS; Food and Drug Administration, Center for Biologics Evaluation and Research FX We thank Drs Hermann Steller, Laura Johnston and Tin Tin Su; the Bloomington Stock Center for fly stocks; Dr Dong Han at National Center for Nanoscience and Technology for help with the scanning electron microscope; and the members of the Bi laboratory for advice and discussions. We also thank Dr Mark Mortin for generating the knockout clbn flies and for critically reading this manuscript. We are grateful for comments on this manuscript from Tehyen Chu and Brent McCright. This work was supported by grants from National Basic Research Program of China (973 Program grant no. 2010CB934004), National Natural Science Foundation of China (grant no. 30871388) and CAS Knowledge Innovation Program to XB and by the Food and Drug Administration, Center for Biologics Evaluation and Research. NR 46 TC 1 Z9 1 U1 0 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 15 PY 2013 VL 32 IS 33 BP 3857 EP 3866 DI 10.1038/onc.2012.395 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 202JH UT WOS:000323210200008 PM 22964637 ER PT J AU Troy, SB Musingwini, G Halpern, MS Huang, CH Stranix-Chibanda, L Kouiavskaia, D Shetty, AK Chumakov, K Nathoo, K Maldonado, YA AF Troy, Stephanie B. Musingwini, Georgina Halpern, Meira S. Huang, ChunHong Stranix-Chibanda, Lynda Kouiavskaia, Diana Shetty, Avinash K. Chumakov, Konstantin Nathoo, Kusum Maldonado, Yvonne A. TI Vaccine Poliovirus Shedding and Immune Response to Oral Polio Vaccine in HIV-Infected and -Uninfected Zimbabwean Infants SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE polio; OPV; shedding; immunity; HIV; infants; vaccine; VDPV ID IMMUNODEFICIENT CHILDREN; ENTEROVIRUS EXCRETION; SOUTH-AFRICA; ERADICATION; WORLDWIDE; STOOL AB Background. With prolonged replication, attenuated polioviruses used in oral polio vaccine (OPV) can mutate into vaccine-derived poliovirus (VDPV) and cause poliomyelitis outbreaks. Individuals with primary humoral immunodeficiencies can become chronically infected with vaccine poliovirus, allowing it to mutate into immunodeficiency-associated VDPV (iVDPV). It is unclear if children perinatally infected with the human immunodeficiency virus (HIV), who have humoral as well as cellular immunodeficiencies, might be sources of iVDPV. Methods. We conducted a prospective study collecting stool and blood samples at multiple time points from Zimbabwean infants receiving OPV according to the national schedule. Nucleic acid extracted from stool was analyzed by real-time polymerase chain reaction for OPV serotypes. Results. We analyzed 825 stool samples: 285 samples from 92 HIV-infected children and 540 from 251 HIV-uninfected children. Poliovirus shedding was similar after 0-2 OPV doses but significantly higher in the HIV-infected versus uninfected children after >= 3 OPV doses, particularly within 42 days of an OPV dose, independent of seroconversion status. HIV infection was not associated with prolonged or persistent poliovirus shedding. HIV infection was associated with significantly lower polio seroconversion rates. Conclusions. HIV infection is associated with decreased mucosal and humoral immune responses to OPV but not the prolonged viral shedding required to form iVDPV. C1 [Troy, Stephanie B.] Eastern Virginia Med Sch, Div Infect Dis, Dept Internal Med, Norfolk, VA 23507 USA. [Musingwini, Georgina; Stranix-Chibanda, Lynda; Shetty, Avinash K.; Maldonado, Yvonne A.] Univ Zimbabwe, Dept Community Med, Zimbabwe AIDS Prevent Project, Harare, Zimbabwe. [Stranix-Chibanda, Lynda; Nathoo, Kusum] Univ Zimbabwe, Dept Paediat & Child Hlth, Coll Hlth Sci, Harare, Zimbabwe. [Halpern, Meira S.; Huang, ChunHong; Maldonado, Yvonne A.] Stanford Univ, Sch Med, Div Pediat Infect Dis, Stanford, CA 94305 USA. [Kouiavskaia, Diana; Chumakov, Konstantin] US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. [Shetty, Avinash K.] Wake Forest Univ, Bowman Gray Sch Med, Div Pediat Infect Dis, Winston Salem, NC USA. RP Troy, SB (reprint author), Eastern Virginia Med Sch, 825 Fairfax Ave,Ste 572, Norfolk, VA 23507 USA. EM troysb@evms.edu FU United States National Institutes of Health [NIH R01 AI068577] FX This study was funded by the United States National Institutes of Health (NIH R01 AI068577 to Y. A. M.). NR 27 TC 7 Z9 7 U1 0 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2013 VL 208 IS 4 BP 672 EP 678 DI 10.1093/infdis/jit208 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 191KO UT WOS:000322412100017 PM 23661792 ER PT J AU Zhou, YT He, WW Lo, YM Hu, XN Wu, XC Yin, JJ AF Zhou, Yu-Ting He, Weiwei Lo, Y. Martin Hu, Xiaona Wu, Xiaochun Yin, Jun-Jie TI Effect of Silver Nanomaterials on the Activity of Thiol-Containing Antioxidants SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE silver nanomaterials; thiol antioxidant; free radical; ESR; nanosafety ID ELECTRON-SPIN-RESONANCE; GLUTATHIONE METABOLISM; SUPEROXIDE RADICALS; L-CYSTEINE; RAT-LIVER; NANOPARTICLES; CELLS; GOLD; NANOSILVER; TOXICITY AB The use of nanomaterials in consumer products is rapidly expanding. In most studies, nanomaterials are examined as isolated ingredients. However, consumer products such as foods, cosmetics, and dietary supplements are complex chemical matrixes. Therefore, interactions between nanomaterials and other components of the product must be investigated to ensure the product's performance and safety. Silver nanomaterials are increasingly being used in food packaging as antimicrobial agents. Thiol-containing compounds, such as reduced glutathione (GSH), cysteine, and dihydrolipoic acid, are used as antioxidants in many consumer products. In the current study, we have investigated the interaction between silver nanomaterials and thiol-containing antioxidants. The selected Ag nanomaterials were Ag coated with citrate, Ag coated with poly(vinylpyrrolidone), and Au nanorods coated with Ag in a core/shell structure. We observed direct quenching of the 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) by all three Ag nanomaterials to varying degrees. The Ag nanomaterials also reduced the quenching of DPPH by GSH to varying degrees. In addition, we determined that the mixture of GSH and Au@Ag nanorods held at 37 degrees C was less effective at quenching azo radical than at ambient temperature. Furthermore, we determined that Au@Ag nanorods significantly reduced the ability of GSH and cysteine to quench hydroxyl and superoxide radicals. The work presented here demonstrates the importance of examining the chemical interactions between nanomaterials used in products and physiologically important antioxidants. C1 [Zhou, Yu-Ting; He, Weiwei; Yin, Jun-Jie] USDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Zhou, Yu-Ting; Lo, Y. Martin] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [He, Weiwei] Xuchang Univ, Inst Surface Micro & Nanomat, Key Lab Micronano Energy Storage & Convers Mat He, Xuchang 461000, Peoples R China. [Hu, Xiaona; Wu, Xiaochun] Natl Ctr Nanosci & Technol, CAS Key Lab Standardizat & Measurement Nanotechno, Beijing 100190, Peoples R China. RP Lo, YM (reprint author), Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. EM ymlo@umd.edu; junjie.yin@fda.hhs.gov RI Yin, Jun Jie /E-5619-2014; Zhou, Yuting/I-9125-2012 FU U.S. Food and Drug Administration (FDA) Nanotechnology CORES Program; Office of Cosmetics and Colors, Center for Food Safety and Applied Nutrition (CFSAN)/FDA; Maryland NanoCenter; NispLab; National Science Foundation (NSF) as a Materials Research Science and Engineering Center (MRSEC) FX This work was partially supported by a regulatory science grant under the U.S. Food and Drug Administration (FDA) Nanotechnology CORES Program and by the Office of Cosmetics and Colors, Center for Food Safety and Applied Nutrition (CFSAN)/FDA (Y.-T.Z., W.H., and J.-J.Y.). We acknowledge the support of the Maryland NanoCenter and its NispLab. The NispLab is supported in part by the National Science Foundation (NSF) as a Materials Research Science and Engineering Center (MRSEC) shared experimental facility. NR 46 TC 4 Z9 4 U1 3 U2 68 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 EI 1520-5118 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD AUG 14 PY 2013 VL 61 IS 32 BP 7855 EP 7862 DI 10.1021/jf402146s PG 8 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA 202SV UT WOS:000323240800025 PM 23889173 ER PT J AU Gartner, JJ Parker, SCJ Prickett, TD Dutton-Regester, K Stitzel, ML Lin, JC Davis, S Simhadri, VL Jha, S Katagiri, N Gotea, V Teer, JK Wei, XM Morken, MA Bhanot, UK Chen, G Elnitski, LL Davies, MA Gershenwald, JE Carter, H Karchin, R Robinson, W Robinson, S Rosenberg, SA Collins, FS Parmigiani, G Komar, AA Kimchi-Sarfaty, C Hayward, NK Margulies, EH Samuels, Y AF Gartner, Jared J. Parker, Stephen C. J. Prickett, Todd D. Dutton-Regester, Ken Stitzel, Michael L. Lin, Jimmy C. Davis, Sean Simhadri, Vijaya L. Jha, Sujata Katagiri, Nobuko Gotea, Valer Teer, Jamie K. Wei, Xiaomu Morken, Mario A. Bhanot, Umesh K. Chen, Guo Elnitski, Laura L. Davies, Michael A. Gershenwald, Jeffrey E. Carter, Hannah Karchin, Rachel Robinson, William Robinson, Steven Rosenberg, Steven A. Collins, Francis S. Parmigiani, Giovanni Komar, Anton A. Kimchi-Sarfaty, Chava Hayward, Nicholas K. Margulies, Elliott H. Samuels, Yardena CA NISC Comparative Sequencing Progra TI Whole-genome sequencing identifies a recurrent functional synonymous mutation in melanoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TERT PROMOTER MUTATIONS; HUMAN CANCER; POSITIVE SELECTION; EVOLUTION; REVEALS; DISEASE; CONSTRAINT; SUBSTRATE; GENE; SITE AB Synonymous mutations, which do not alter the protein sequence, have been shown to affect protein function [Sauna ZE, Kimchi-Sarfaty C (2011) Nat Rev Genet 12(10):683-691]. However, synonymous mutations are rarely investigated in the cancer genomics field. We used whole-genome and -exome sequencing to identify somatic mutations in 29 melanoma samples. Validation of one synonymous somatic mutation in BCL2L12 in 285 samples identified 12 cases that harbored the recurrent F17F mutation. This mutation led to increased BCL2L12 mRNA and protein levels because of differential targeting of WT and mutant BCL2L12 by hsa-miR-671-5p. Protein made from mutant BCL2L12 transcript bound p53, inhibited UV-induced apoptosis more efficiently than WT BCL2L12, and reduced endogenous p53 target gene transcription. This report shows selection of a recurrent somatic synonymous mutation in cancer. Our data indicate that silent alterations have a role to play in human cancer, emphasizing the importance of their investigation in future cancer genome studies. C1 [Gartner, Jared J.; Parker, Stephen C. J.; Prickett, Todd D.; Stitzel, Michael L.; Gotea, Valer; Teer, Jamie K.; Wei, Xiaomu; Morken, Mario A.; Elnitski, Laura L.; Collins, Francis S.; Margulies, Elliott H.; Samuels, Yardena; NISC Comparative Sequencing Progra] NHGRI, Bethesda, MD 20892 USA. [Davis, Sean; Rosenberg, Steven A.] NCI, NIH, Bethesda, MD 20892 USA. [Dutton-Regester, Ken; Hayward, Nicholas K.] Queensland Inst Med Res, Div Genet & Computat Biol, Brisbane, Qld 4006, Australia. [Lin, Jimmy C.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Simhadri, Vijaya L.; Katagiri, Nobuko; Kimchi-Sarfaty, Chava] US FDA, Lab Hemostasis, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Jha, Sujata; Komar, Anton A.] Cleveland State Univ, Ctr Gene Regulat Hlth & Dis, Cleveland, OH 44115 USA. [Jha, Sujata; Komar, Anton A.] Cleveland State Univ, Dept Biol Geol & Environm Sci, Cleveland, OH 44115 USA. [Bhanot, Umesh K.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Chen, Guo; Davies, Michael A.; Gershenwald, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA. [Carter, Hannah; Karchin, Rachel] Johns Hopkins Univ, Inst Computat Med, Dept Biomed Engn, Baltimore, MD 21218 USA. [Robinson, William; Robinson, Steven] Univ Colorado, Sch Med, Div Med Oncol, Aurora, CO 80045 USA. [Parmigiani, Giovanni] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Parmigiani, Giovanni] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Margulies, Elliott H.] Illumina United Kingdom, Saffron Walden CB10 1XL, Essex, England. [Samuels, Yardena] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. RP Samuels, Y (reprint author), NHGRI, Bethesda, MD 20892 USA. EM yardena.samuels@weizmann.ac.il RI Karchin, Rachel/A-3385-2010; hayward, nicholas/C-1367-2015; OI hayward, nicholas/0000-0003-4760-1033; Bhanot, Umeshkumar/0000-0001-6656-1239; Gotea, Valer/0000-0001-7857-3309; Davis, Sean/0000-0002-8991-6458 FU NIGMS Postdoctoral Research Associate (PRAT) Fellowship; Intramural Research Programs of the National Human Genome Research Institute; Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; estate of Alice Schwarz-Gardos; estate of John Hunter; Knell Family; Peter and Patricia Gruber Award; National Cancer Institute [R21CA152432]; National Institutes of Health; University of Texas MD Anderson Cancer Center Melanoma Specialized Programs of Research Excellence [P50 CA093459]; Cancer Center Support Grant (CCSG) Core Grant [NCI 5P30 CA006516-46]; Human Frontier Science Program [RGP0024]; National Health and Medical Research Council of Australia [1026112, 613686]; National Cancer Institute; Eli Lilly and Company FX We thank Drs. Chris Schmidt and Peter Parsons for establishment of the majority of melanoma cell lines and V. Maduro, H. Ozel Abaan, and P. Cruz for generating the sequence data analyzed here. We thank Dr. V. G. Prieto for pathologic review of the biospecimens from the Melanoma Informatics, Tissue Resource, and Pathology Core (MelCore) at MD Anderson. We thank Dr. T. Wolfsberg for bioinformatics help, J. Jiang for sequencing help, and J. Fekecs and D. Leja for graphical assistance. We thank Drs. T. Barber and M. Willard for critical comments on the manuscript. S.C.J.P. is supported by an NIGMS Postdoctoral Research Associate (PRAT) Fellowship. This work was supported by the Intramural Research Programs of the National Human Genome Research Institute, by the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics, the estate of Alice Schwarz-Gardos, the estate of John Hunter, the Knell Family, the Peter and Patricia Gruber Award, National Cancer Institute Grant R21CA152432 (to R.K.), the National Institutes of Health, University of Texas MD Anderson Cancer Center Melanoma Specialized Programs of Research Excellence Grant P50 CA093459, Cancer Center Support Grant (CCSG) Core Grant NCI 5P30 CA006516-46 (to G.P.), the Human Frontier Science Program RGP0024 Grant (to A.A.K.), National Health and Medical Research Council of Australia Grants 1026112 and 613686, and a public-private partnership between the Intramural Research Programs of the National Human Genome Research Institute, the National Cancer Institute, and Eli Lilly and Company coordinated by the Foundation for the National Institutes of Health. NR 35 TC 63 Z9 64 U1 0 U2 18 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 13 PY 2013 VL 110 IS 33 BP 13481 EP 13486 DI 10.1073/pnas.1304227110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200LA UT WOS:000323069200063 PM 23901115 ER PT J AU Meierovics, A Yankelevich, WJC Cowley, SC AF Meierovics, Anda Yankelevich, Wei-Jen Chua Cowley, Siobhan C. TI MAIT cells are critical for optimal mucosal immune responses during in vivo pulmonary bacterial infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE tularemia; respiratory infection ID INVARIANT T-CELLS; MR1 ANTIGEN PRESENTATION; FRANCISELLA-TULARENSIS; MICROBIAL INFECTION; ALPHA-CHAIN; NKT CELLS; LVS; CD4(+); INNATE; REQUIREMENTS AB Mucosa-associated invariant T (MAIT) cells are "innate" T cells that express an invariant T-cell receptor alpha-chain restricted by the nonclassical MHC class I molecule MHC-related protein 1 (MR1). A recent discovery that MR1 presents vitamin B metabolites, presumably from pathogenic and/or commensal bacteria, distinguishes MAIT cells from peptide- or lipid-recognizing alpha beta T cells in the immune system. MAIT cells are activated by a wide variety of bacterial strains in vitro, but their role in defense against infectious assaults in vivo remains largely unknown. To investigate how MAIT cells contribute to mucosal immunity in vivo, we used a murine model of pulmonary infection by using the live vaccine strain (LVS) of Francisella tularensis. In the early acute phase of infection, MAIT cells expanded robustly in the lungs, where they preferentially accumulated after reaching their peak expansion in the late phase of infection. Throughout the course of infection, MAIT cells produced the critical cytokines IFN-gamma, TNF-alpha, and IL-17A. Mechanistic studies showed that MAIT cells required both MR1 and IL-12 40 kDa subunit (IL-12p40) signals from infected antigen presenting cells to control F. tularensis LVS intracellular growth. Importantly, pulmonary F. tularensis LVS infection of MR1-deficient (MR1(-/-)) mice, which lack MAIT cells, revealed defects in early mucosal cytokine production, timely recruitment of IFN-gamma-producing CD4(+) and CD8(+) T cells to the infected lungs, and control of pulmonary F. tularensis LVS growth. This study provides in vivo evidence demonstrating that MAIT cells are an important T-cell subset with activities that influence the innate and adaptive phases of mucosal immunity. C1 [Meierovics, Anda; Yankelevich, Wei-Jen Chua; Cowley, Siobhan C.] US FDA, Div Bacterial Parasit & Allergen Prod, Lab Mycobacterial Dis & Cellular Immunol, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Cowley, SC (reprint author), US FDA, Div Bacterial Parasit & Allergen Prod, Lab Mycobacterial Dis & Cellular Immunol, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. EM siobhan.cowley@fda.hhs.gov NR 53 TC 68 Z9 69 U1 4 U2 19 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 13 PY 2013 VL 110 IS 33 BP E3119 EP E3128 DI 10.1073/pnas.1302799110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200LA UT WOS:000323069200014 PM 23898209 ER PT J AU McClenahan, SD Scherba, G Borst, L Fredrickson, RL Krause, PR Uhlenhaut, C AF McClenahan, Shasta D. Scherba, Gail Borst, Luke Fredrickson, Richard L. Krause, Philip R. Uhlenhaut, Christine TI Discovery of a Bovine Enterovirus in Alpaca SO PLOS ONE LA English DT Article ID VIRAL-DIARRHEA-VIRUS; NEW-WORLD CAMELIDS; REVERSE TRANSCRIPTION-PCR; POLYMERASE-CHAIN-REACTION; MOUTH-DISEASE; UNITED-STATES; INFECTION; LIONS; CORONAVIRUS; SERENGETI AB A cytopathic virus was isolated using Madin-Darby bovine kidney (MDBK) cells from lung tissue of alpaca that died of a severe respiratory infection. To identify the virus, the infected cell culture supernatant was enriched for virus particles and a generic, PCR-based method was used to amplify potential viral sequences. Genomic sequence data of the alpaca isolate was obtained and compared with sequences of known viruses. The new alpaca virus sequence was most similar to recently designated Enterovirus species F, previously bovine enterovirus (BEVs), viruses that are globally prevalent in cattle, although they appear not to cause significant disease. Because bovine enteroviruses have not been previously reported in U. S. alpaca, we suspect that this type of infection is fairly rare, and in this case appeared not to spread beyond the original outbreak. The capsid sequence of the detected virus had greatest homology to Enterovirus F type 1 (indicating that the virus should be considered a member of serotype 1), but the virus had greater homology in 2A protease sequence to type 3, suggesting that it may have been a recombinant. Identifying pathogens that infect a new host species for the first time can be challenging. As the disease in a new host species may be quite different from that in the original or natural host, the pathogen may not be suspected based on the clinical presentation, delaying diagnosis. Although this virus replicated in MDBK cells, existing standard culture and molecular methods could not identify it. In this case, a highly sensitive generic PCR-based pathogen-detection method was used to identify this pathogen. C1 [McClenahan, Shasta D.; Krause, Philip R.; Uhlenhaut, Christine] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Scherba, Gail] Univ Illinois, Dept Pathobiol, Urbana, IL 61801 USA. [Scherba, Gail; Borst, Luke; Fredrickson, Richard L.] Univ Illinois, Vet Diagnost Lab, Urbana, IL 61801 USA. RP Uhlenhaut, C (reprint author), Robert Koch Inst, Ctr Biol Threats & Special Pathogens, Berlin, Germany. EM uhlenhautc@rki.de OI Krause, Philip/0000-0002-1045-7536 FU NIAID; FDA FX This work was supported by NIAID and FDA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 8 Z9 9 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 12 PY 2013 VL 8 IS 8 AR e68777 DI 10.1371/journal.pone.0068777 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200UV UT WOS:000323097300006 PM 23950875 ER PT J AU Mosholder, AD Nambiar, S AF Mosholder, Andrew D. Nambiar, Sumathi TI Cardiovascular Risks with Azithromycin REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Mosholder, Andrew D.; Nambiar, Sumathi] US FDA, Silver Spring, MD USA. RP Mosholder, AD (reprint author), US FDA, Silver Spring, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 8 PY 2013 VL 369 IS 6 BP 581 EP 581 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 197HX UT WOS:000322842000026 PM 23930274 ER PT J AU Nemes, P Hoover, WJ Keire, DA AF Nemes, Peter Hoover, William J. Keire, David A. TI High-Throughput Differentiation of Heparin from Other Glycosaminoglycans by Pyrolysis Mass Spectrometry SO ANALYTICAL CHEMISTRY LA English DT Article ID OVERSULFATED CHONDROITIN SULFATE; POTENTIOMETRIC POLYANION SENSORS; ADVERSE CLINICAL EVENTS; MICROPLATE BASED ASSAY; QUALITY-ASSURANCE; OPEN-AIR; CONTAMINANTS; ELECTROPHORESIS; SODIUM; SAMPLING/IONIZATION AB Sensors with high chemical specificity and enhanced sample throughput are vital to screening food products and medical devices for chemical or biochemical contaminants that may pose a threat to public health. For example, the rapid detection of oversulfated chondroitin sulfate (OSCS) in heparin could prevent reoccurrence of heparin adulteration that caused hundreds of severe adverse events including deaths worldwide in 2007-2008. Here, rapid pyrolysis is integrated with direct analysis in real time (DART) mass spectrometry to rapidly screen major glycosaminoglycans, including heparin, chondroitin sulfate A, dermatan sulfate, and OSCS. The results demonstrate that, compared to traditional liquid chromatography-based analyses, pyrolysis mass spectrometry achieved at least 250-fold higher sample throughput and was compatible with samples volume-limited to about 300 riL. Pyrolysis yielded an abundance of fragment ions (e.g., 150 different m/z species), many of which were specific to the parent compound. Using multivariate and statistical data analysis models, these data enabled facile differentiation of the glycosaminoglycans with high throughput. After method development was completed, authentically contaminated samples obtained during the heparin crisis by the FDA were analyzed in a blinded manner for OSCS contamination. The lower limit of differentiation and detection were 0.1% (w/w) OSCS in heparin and 100 ng/mu L (20 ng) OSCS in water, respectively. For quantitative purposes the linear dynamic range spanned approximately 3 orders of magnitude. Moreover, this chemical readout was successfully employed to find dues in the manufacturing history of the heparin samples that can be used for surveillance purposes. The presented technology and data analysis protocols are anticipated to be readily adaptable to other chemical and biochemical agents and volume-limited samples. C1 [Nemes, Peter; Hoover, William J.] US FDA, Div Chem & Mat Sci, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. [Keire, David A.] US FDA, Div Pharmaceut Anal, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. RP Nemes, P (reprint author), 10903 New Hampshire Ave,Bldg 64,Room 3068, Silver Spring, MD 20993 USA. EM peter.nemes@fda.hhs.gov RI Nemes, Peter/C-3145-2008 FU Medical Countermeasure Initiative [MCM2J260T4]; Critical Path funding program of the FDA FX This work was supported by award no. MCM2J260T4 from the Medical Countermeasure Initiative (P.N.) and by the Critical Path funding program (DAK) of the FDA. From FDA, P.N. thanks Jason A. Brookbank and Dinesh V. Patwardhan for advising on regulatory matters, Benita J. Dair for assistance during the editing of this manuscript, and Michael T. Boyne II for generously providing access and support to a high-resolution mass spectrometer (Q Exactive). The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either actual or implied endorsement of such products by the Department of Health and Human Services. In addition, the findings and conclusions in this article have not been formally disseminated by the FDA and should not be construed to represent any Agency determination or policy. NR 55 TC 8 Z9 8 U1 2 U2 30 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD AUG 6 PY 2013 VL 85 IS 15 BP 7405 EP 7412 DI 10.1021/ac401318q PG 8 WC Chemistry, Analytical SC Chemistry GA 199RW UT WOS:000323014000060 PM 23841449 ER PT J AU Chen, HC Zou, W Tien, YJ Chen, JJ AF Chen, Hung-Chia Zou, Wen Tien, Yin-Jing Chen, James J. TI Identification of Bicluster Regions in a Binary Matrix and Its Applications SO PLOS ONE LA English DT Article ID GENE-EXPRESSION DATA; SINGULAR-VALUE DECOMPOSITION; MICROARRAY DATA; ENVIRONMENTAL-CHANGES; PATTERNS; FACTORIZATION; ALGORITHMS AB Biclustering has emerged as an important approach to the analysis of large-scale datasets. A biclustering technique identifies a subset of rows that exhibit similar patterns on a subset of columns in a data matrix. Many biclustering methods have been proposed, and most, if not all, algorithms are developed to detect regions of "coherence'' patterns. These methods perform unsatisfactorily if the purpose is to identify biclusters of a constant level. This paper presents a two-step biclustering method to identify constant level biclusters for binary or quantitative data. This algorithm identifies the maximal dimensional submatrix such that the proportion of non-signals is less than a pre-specified tolerance delta. The proposed method has much higher sensitivity and slightly lower specificity than several prominent biclustering methods from the analysis of two synthetic datasets. It was further compared with the Bimax method for two real datasets. The proposed method was shown to perform the most robust in terms of sensitivity, number of biclusters and number of serotype-specific biclusters identified. However, dichotomization using different signal level thresholds usually leads to different sets of biclusters; this also occurs in the present analysis. C1 [Chen, Hung-Chia; Zou, Wen; Chen, James J.] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Chen, Hung-Chia; Chen, James J.] China Med Univ, Grad Inst Biostat, Taichung, Taiwan. [Chen, Hung-Chia; Chen, James J.] China Med Univ, Biostat Ctr, Taichung, Taiwan. [Tien, Yin-Jing] Acad Sinica, Inst Stat Sci, Taipei 11529, Taiwan. RP Chen, JJ (reprint author), US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. EM jamesj.chen@fda.hhs.gov NR 43 TC 4 Z9 4 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 5 PY 2013 VL 8 IS 8 AR e71680 DI 10.1371/journal.pone.0071680 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218XC UT WOS:000324465000222 PM 23940779 ER PT J AU Dickey, JS Gonzalez, Y Aryal, B Mog, S Nakamura, AJ Redon, CE Baxa, U Rosen, E Cheng, G Zielonka, J Parekh, P Mason, KP Joseph, J Kalyanaraman, B Bonner, W Herman, E Shacter, E Rao, VA AF Dickey, Jennifer S. Gonzalez, Yanira Aryal, Baikuntha Mog, Steven Nakamura, Asako J. Redon, Christophe E. Baxa, Ulrich Rosen, Elliot Cheng, Gang Zielonka, Jacek Parekh, Palak Mason, Karen P. Joseph, Joy Kalyanaraman, Balaraman Bonner, William Herman, Eugene Shacter, Emily Rao, V. Ashutosh TI Mito-Tempol and Dexrazoxane Exhibit Cardioprotective and Chemotherapeutic Effects through Specific Protein Oxidation and Autophagy in a Syngeneic Breast Tumor Preclinical Model SO PLOS ONE LA English DT Article ID RAT MAMMARY-CARCINOMA; ANTHRACYCLINE-INDUCED CARDIOTOXICITY; CARDIAC TROPONIN-T; CELL CLONES; INTERCELLULAR COMMUNICATION; ANTIOXIDANT PROPERTIES; METASTATIC CAPACITY; GROWTH-INHIBITION; SERUM-ALBUMIN; DNA-DAMAGE AB Several front-line chemotherapeutics cause mitochondria-derived, oxidative stress-mediated cardiotoxicity. Iron chelators and other antioxidants have not completely succeeded in mitigating this effect. One hindrance to the development of cardioprotectants is the lack of physiologically-relevant animal models to simultaneously study antitumor activity and cardioprotection. Therefore, we optimized a syngeneic rat model and examined the mechanisms by which oxidative stress affects outcome. Immune-competent spontaneously hypertensive rats (SHRs) were implanted with passaged, SHR-derived, breast tumor cell line, SST-2. Tumor growth and cytokine responses (IL-1A, MCP-1, TNF-alpha) were observed for two weeks post-implantation. To demonstrate the utility of the SHR/SST-2 model for monitoring both anticancer efficacy and cardiotoxicity, we tested cardiotoxic doxorubicin alone and in combination with an established cardioprotectant, dexrazoxane, or a nitroxide conjugated to a triphenylphosphonium cation, Mito-Tempol (4) [Mito-T (4)]. As predicted, tumor reduction and cardiomyopathy were demonstrated by doxorubicin. We confirmed mitochondrial accumulation of Mito-T (4) in tumor and cardiac tissue. Dexrazoxane and Mito-T (4) ameliorated doxorubicin-induced cardiomyopathy without altering the antitumor activity. Both agents increased the pro-survival autophagy marker LC3-II and decreased the apoptosis marker caspase-3 in the heart, independently and in combination with doxorubicin. Histopathology and transmission electron microscopy demonstrated apoptosis, autophagy, and necrosis corresponding to cytotoxicity in the tumor and cardioprotection in the heart. Changes in serum levels of 8-oxo-dG-modified DNA and total protein carbonylation corresponded to cardioprotective activity. Finally, 2D-electrophoresis/mass spectrometry identified specific serum proteins oxidized under cardiotoxic conditions. Our results demonstrate the utility of the SHR/SST-2 model and the potential of mitochondrially-directed agents to mitigate oxidative stress-induced cardiotoxicity. Our findings also emphasize the novel role of specific protein oxidation markers and autophagic mechanisms for cardioprotection. C1 [Dickey, Jennifer S.; Gonzalez, Yanira; Aryal, Baikuntha; Rosen, Elliot; Mason, Karen P.; Shacter, Emily; Rao, V. Ashutosh] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. [Mog, Steven] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Nakamura, Asako J.; Redon, Christophe E.; Parekh, Palak; Bonner, William] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Baxa, Ulrich] Frederick Natl Lab Canc Res, Electron Microscopy Lab, Adv Technol Program, Frederick, MD USA. [Cheng, Gang; Zielonka, Jacek; Joseph, Joy; Kalyanaraman, Balaraman] Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA. [Cheng, Gang; Zielonka, Jacek; Joseph, Joy; Kalyanaraman, Balaraman] Med Coll Wisconsin, Free Rad Res Ctr, Milwaukee, WI 53226 USA. [Herman, Eugene] US FDA, Div Drug Safety Res, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Rao, VA (reprint author), US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. EM ashutosh.rao@fda.hhs.gov RI Zielonka, Jacek/N-9546-2014; Parekh, Palak/B-7042-2015 OI Zielonka, Jacek/0000-0002-2524-0145; Parekh, Palak/0000-0001-9201-5194 FU Food and Drug Administration (FDA) Critical Path Initiative; National Cancer Institute-FDA Interagency Oncology Task Force Fellowship Program; National Cancer Institute [HHSN261200800001E, R01 CA152810] FX The authors would like to acknowledge support from the Food and Drug Administration (FDA) Critical Path Initiative and the National Cancer Institute-FDA Interagency Oncology Task Force Fellowship Program. The electron microscopy work was funded in part from the National Cancer Institute, Contract # HHSN261200800001E. The Mito-Tempol (4) synthesis was supported by a grant from the National Cancer Institute, R01 CA152810. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 21 Z9 22 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 5 PY 2013 VL 8 IS 8 AR e70575 DI 10.1371/journal.pone.0070575 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218XC UT WOS:000324465000090 PM 23940596 ER PT J AU Izurieta, HS Zuber, P Bonhoeffer, J Chen, RT Sankohg, O Laserson, KF Sturkenboom, M Loucq, C Weibel, D Dodd, C Black, S AF Izurieta, Hector S. Zuber, Patrick Bonhoeffer, Jan Chen, Robert T. Sankohg, Osman Laserson, Kayla F. Sturkenboom, Miriam Loucq, Christian Weibel, Daniel Dodd, Caitlin Black, Steve TI Roadmap for the international collaborative epidemiologic monitoring of safety and effectiveness of new high priority vaccines SO VACCINE LA English DT Article DE Vaccine; Safety; Effectiveness; Adverse events; Benefit-risk ID GUILLAIN-BARRE-SYNDROME; EVENT REPORTING SYSTEM; ROTAVIRUS VACCINATION; CASE SERIES; IMMUNIZATION; RISK; INTUSSUSCEPTION; CHILDREN; BENEFITS; PROGRAM AB With the advent of new vaccines targeted to highly endemic diseases in low- and middle-income countries (LMIC) and with the expansion of vaccine manufacturing globally, there is an urgent need to establish an infrastructure to evaluate the benefit-risk profiles of vaccines in LMIC. Fortunately the usual decade(s)-long time gap between introduction of new vaccines in high and low income countries is being significantly reduced or eliminated due to initiatives such as the Global Alliance for Vaccines and Immunizations (GAVI) and the Decade of Vaccines for the implementation of the Global Vaccine Action Plan. While hoping for more rapid disease control, this time shift may potentially add risk, unless appropriate capacity for reliable and timely evaluation of vaccine benefit-risk profiles in some LMIC's are developed with external assistance from regional or global level. An ideal vaccine safety and effectiveness monitoring system should be flexible and sustainable, able to quickly detect possible vaccine-associated events, distinguish them from programmatic errors, reliably and quickly evaluate the suspected event and its association with vaccination and, if associated, determine the benefit-risk of vaccines to inform appropriate action. Based upon the demonstrated feasibility of active surveillance in LMIC as shown by the Burkina Faso assessment of meningococcal A conjugate vaccine or that of rotavirus vaccine in Mexico and Brazil, and upon the proof of concept international GBS study, we suggest a sustainable, flexible, affordable and timely international collaborative vaccine safety monitoring approach for vaccines being newly introduced. While this paper discusses only the vaccine component, the same system could also be eventually used for monitoring drug effectiveness (including the use of substandard drugs) and drug safety. Published by Elsevier Ltd. C1 [Izurieta, Hector S.] US FDA, Rockville, MD 20852 USA. [Zuber, Patrick] WHO, CH-1211 Geneva, Switzerland. [Bonhoeffer, Jan] Brighton Collaborat Fdn, Basel, Switzerland. [Bonhoeffer, Jan] Univ Basel, Univ Childrens Hosp Basel, Basel, Switzerland. [Chen, Robert T.] Ctr Dis Control & Prevent CDC, Atlanta, GA USA. [Sankohg, Osman] INDEPTH Network, Accra, Ghana. [Sankohg, Osman] Univ Witwatersrand, Sch Publ Hlth, Johannesburg, South Africa. [Sankohg, Osman] Hanoi Med Sch, Hanoi, Vietnam. [Laserson, Kayla F.] KEMRI CDC Res & Publ Hlth Collaborat, Kisumu, Kenya. [Sturkenboom, Miriam; Weibel, Daniel] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [Loucq, Christian] Int Vaccine Inst, Seoul, South Korea. [Dodd, Caitlin; Black, Steve] Univ Cincinnati, Univ Childrens Hosp, Cincinnati, OH 45221 USA. RP Izurieta, HS (reprint author), US FDA, Immediate Off Director, OBE CBER, 1401 Rockville Pike,2nd Floor,Suite 200S,HFM-225, Rockville, MD 20852 USA. EM hector.izurieta@fda.hhs.gov RI Bonhoeffer, Jan/E-5903-2014 FU SIDA; Hewlett Foundation; Wellcome Trust; Gates Foundation FX Osman Sankoh is the Executive Director of the INDEPTH Network, funded by core support grants from SIDA, Hewlett Foundation, Wellcome Trust and the Gates Foundation. NR 33 TC 7 Z9 7 U1 0 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD AUG 2 PY 2013 VL 31 IS 35 BP 3623 EP 3627 DI 10.1016/j.vaccine.2013.05.027 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 205PX UT WOS:000323457900022 PM 23707171 ER PT J AU Smith, P Alday-Sanz, V Matysczak, J Moulin, G Lavilla-Pitogo, CR Prater, D AF Smith, P. Alday-Sanz, V. Matysczak, J. Moulin, G. Lavilla-Pitogo, C. R. Prater, D. TI Monitoring and surveillance of antimicrobial resistance in microorganisms asssociated with aquatic animalsle SO REVUE SCIENTIFIQUE ET TECHNIQUE-OFFICE INTERNATIONAL DES EPIZOOTIES LA English DT Article DE Antimicrobial agents; Antimicrobial susceptibility test methods; Aquatic animals; Epidemiological cut-off values; Monitoring and surveillance; Reporting data; Resistance; Sampling protocols; Standardisation and harmonisation ID SUSCEPTIBILITY TEST DATA; ANTIBIOTIC-RESISTANCE; FISH DISEASES; BACTERIA; BREAKPOINTS; AEROMONAS; CRITERIA; WATER; SET AB The World Organisation for Animal Health (OIE) Aquatic Animal Health Code recommends that programmes for the monitoring and surveillance of antimicrobial resistance in microorganisms associated with aquatic animals be initiated by the appropriate authorities. This paper discusses the classes of bacteria to be studied in such programmes and the methods of sample collection to be employed. It also discusses the susceptibility test protocols appropriate for use in such programmes, the interpretive criteria that should be applied to the data they generate and the form in which the output of such programmes should be reported. The authors argue that it is essential that all monitoring and surveillance programmes should employ standardised and internationally harmonised susceptibility test methods to the greatest extent possible. With respect to bacteria capable of infecting aquatic animals, it is recommended that the set of consensus-based standards and guidelines published by the Clinical and Laboratory Standards Institute be adopted as the basis for international harmonisation of test protocols, as they are significantly more developed than any alternatives. It is further recommended that, for the purpose of evaluating antimicrobial resistance trends, such as emerging resistance, the data generated by these protocols should be interpreted by the application of epidemiological cut-off values. However, as yet, internationally agreed cut-off values have been produced for only one species. Thus, for many species, authorities will be obliged to set their own local and laboratory-specific cut-off values. It is recommended that laboratories use a statistical and standardised method of establishing such local cut-off values. Internationally harmonised standard test protocols and interpretive criteria have, to a large extent, been developed to monitor antimicrobial resistance in bacterial species capable of infecting humans. These methods can also be applied to microorganisms capable of infecting humans that are isolated from aquatic animals reared for human consumption or for sale as companion animals. C1 [Smith, P.] Natl Univ Ireland Galway, Sch Nat Sci, Galway, Ireland. [Alday-Sanz, V.] Pescanova SA, Barcelona 08002, Spain. [Matysczak, J.] US FDA, Ctr Vet Med, Rockville, MD 20855 USA. [Moulin, G.] Natl Agcy Vet Med Prod, French Agcy Food Environm & Occupat Hlth & Safety, F-35302 Fougeres, France. [Lavilla-Pitogo, C. R.] Integrated Aquaculture Int LLC, Bandar Seri Begawan 1120, BF, Brunei. [Prater, D.] US FDA, US Miss European Union, FDA Europe Off, B-1000 Brussels, Belgium. RP Smith, P (reprint author), Natl Univ Ireland Galway, Sch Nat Sci, Galway, Ireland. EM peter.smith@nuigalway.ie NR 29 TC 5 Z9 5 U1 0 U2 3 PU OFFICE INT EPIZOOTIES PI PARIS PA 12 RUE DE PRONY, 75017 PARIS, FRANCE SN 0253-1933 J9 REV SCI TECH OIE JI Rev. Sci. Tech. Off. Int. Epizoot. PD AUG PY 2013 VL 32 IS 2 BP 583 EP 593 PG 11 WC Veterinary Sciences SC Veterinary Sciences GA AF6HR UT WOS:000334815900024 PM 24547661 ER PT J AU Lloyd, JK Duchin, JS Borchert, J Quintana, HF Robertson, A AF Lloyd, Jennifer K. Duchin, Jeffrey S. Borchert, Jerry Quintana, Harold Flores Robertson, Alison TI Diarrhetic Shellfish Poisoning, Washington, USA, 2011 SO EMERGING INFECTIOUS DISEASES LA English DT Article ID CANCER; TOXINS AB Diarrhetic shellfish poisoning is a gastrointestinal illness caused by consumption of bivalves contaminated with dinophysistoxins. We report an illness cluster in the United States in which toxins were confirmed in shellfish from a commercial harvest area, leading to product recall. Ongoing surveillance is needed to prevent similar illness outbreaks. C1 [Lloyd, Jennifer K.; Duchin, Jeffrey S.] Publ Hlth Seattle & King Cty, Seattle, WA 98118 USA. [Duchin, Jeffrey S.] Univ Washington, Seattle, WA 98195 USA. [Borchert, Jerry] Washington State Dept Hlth, Tumwater, WA USA. [Quintana, Harold Flores; Robertson, Alison] US FDA, Dauphin Isl, AL USA. RP Lloyd, JK (reprint author), Publ Hlth Seattle & King Cty, 401 5th Ave,Suite 900, Seattle, WA 98118 USA. EM jenny.lloyd@kingcounty.gov NR 15 TC 5 Z9 5 U1 3 U2 10 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD AUG PY 2013 VL 19 IS 8 BP 1314 EP 1316 DI 10.3201/eid1908.121824 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 268MA UT WOS:000328173700023 PM 23876232 ER PT J AU Mewton, N Strauss, DG Winslow, R Soliman, EZ Mcclelland, R Lima, JAC AF Mewton, N. Strauss, D. G. Winslow, R. Soliman, E. Z. Mcclelland, R. Lima, J. A. C. TI Prognostic value of electrocardiogram QRS score in asymptomatic individuals without clinical cardiovascular disease: insights from the multi-ethnic study of atherosclerosis SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 31-SEP 04, 2013 CL Amsterdam, NETHERLANDS SP European Soc Cardiol C1 [Mewton, N.] Hosp Civils Lyon, Hop Cardiovasc Louis Pradel, Ctr Invest Clin, Bron, France. [Strauss, D. G.] US FDA, Off Sci & Engn Labs, Silver Spring, MD USA. [Winslow, R.] Johns Hopkins Univ, Baltimore, MD USA. [Soliman, E. Z.] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [Mcclelland, R.] Washington Univ, Washington, DC USA. [Lima, J. A. C.] Johns Hopkins Univ, Johns Hopkins Hosp, Sch Med, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2013 VL 34 SU 1 BP 910 EP 910 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262OH UT WOS:000327744605392 ER PT J AU Reddy, NR Marshall, KM Morrissey, TR Loeza, V Patazca, E Skinner, GE Krishnamurthy, K Larkin, JW AF Reddy, N. Rukma Marshall, Kristin M. Morrissey, Travis R. Loeza, Viviana Patazca, Eduardo Skinner, Guy E. Krishnamurthy, Kathiravan Larkin, John W. TI Combined High Pressure and Thermal Processing on Inactivation of Type A and Proteolytic Type B Spores of Clostridium botulinum SO JOURNAL OF FOOD PROTECTION LA English DT Article ID FIELD GEL-ELECTROPHORESIS; BACILLUS-AMYLOLIQUEFACIENS SPORES; SPOROGENES SPORES; ENDOSPORES; STRAINS; HEAT; TEMPERATURES; PROTOCOLS; PULSENET; KINETICS AB The aim of this study was to determine the resistance of multiple strains of Clostridium botulinum type A and proteolytic type B spores exposed to combined high pressure and thermal processing and compare their resistance with Clostridium sporogenes PA3679 and Bacillus amyloliquefaciens TMW-2.479-Fad-82 spores. The resistance of spores suspended in N-(2-acetamido)-2-aminoethanesulfonic acid (ACES) buffer (0.05 M, pH 7.0) was determined at a process temperature of 105 degrees C, with high pressures of 600, 700, and 750 MPa by using a laboratory-scale pressure test system. No surviving spores of the proteolytic B strains were detected after processing at 105 degrees C and 700 MPa for 6 min. A >7-log reduction of B. amyloliquefaciens spores was observed when processed for 4 min at 105 degrees C and 700 MPa. D-values at 105 degrees C and 700 MPa for type A strains ranged from 0.57 to 2.28 min. C. sporogenes PA3679 had a D-value of 1.48 min at 105 degrees C and 700 MPa. Spores of the six type A strains with high D-values along with C. sporogenes PA3679 and B. amyloliquefaciens were further evaluated for their pressure resistance at pressures 600 and 750 MPa at 105 degrees C. As the process pressure increased from 600 to 750 MPa at 105 degrees C, D-values of some C. botulinum strains and C. sporogenes PA3679 spores decreased (i.e., 69-A, 1.91 to 1.33 min and PA3679, 2.35 to 1.29 min). Some C. botulinum type A strains were more resistant than C. sporogenes PA3679 and B. amyloliquefaciens to combined high pressure and heat, based on D-values determined at 105 degrees C. Pulsed-field gel electrophoresis (PFGE) was also performed to establish whether strains with a similar restriction banding pattern also exhibited similar D-values. However, no correlation between the genomic background of a strain and its resistance to high pressure processing was observed, based on PFGE analysis. Spores of proteolytic type B strains of C. botulinum were less resistant to combined high pressure and heat (700 MPa and 105 degrees C) treatment when compared with spores of type A strains. C1 [Reddy, N. Rukma; Marshall, Kristin M.; Morrissey, Travis R.; Skinner, Guy E.; Larkin, John W.] US FDA, Inst Food Safety & Hlth, Bedford Pk, IL 60501 USA. [Loeza, Viviana; Patazca, Eduardo; Krishnamurthy, Kathiravan] IIT, Inst Food Safety & Hlth, Bedford Pk, IL 60501 USA. RP Reddy, NR (reprint author), US FDA, Inst Food Safety & Hlth, 6502 South Archer Rd, Bedford Pk, IL 60501 USA. EM rukma.reddy@fda.hhs.gov FU U.S. Food and Drug Administration FX We acknowledge the assistance of Louis Nowaczyk for preparing samples and performing PFGE. The work was supported by a grant from the U.S. Food and Drug Administration to the Institute for Food Safety and Health at Illinois Institute of Technology. NR 34 TC 9 Z9 9 U1 0 U2 32 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD AUG PY 2013 VL 76 IS 8 BP 1384 EP 1392 DI 10.4315/0362-028X.JFP-12-538 PG 9 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 240GW UT WOS:000326084300010 PM 23905794 ER PT J AU Risum, N Strauss, D Sogaard, P Loring, Z Hansen, TF Bruun, NE Wagner, G Kisslo, J AF Risum, Niels Strauss, David Sogaard, Peter Loring, Zak Hansen, Thomas Fritz Bruun, Niels Eske Wagner, Galen Kisslo, Joseph TI Left bundle-branch block: The relationship between electrocardiogram electrical activation and echocardiography mechanical contraction SO AMERICAN HEART JOURNAL LA English DT Article ID CARDIAC-RESYNCHRONIZATION THERAPY; CHRONIC HEART-FAILURE; LEFT-VENTRICULAR DYSFUNCTION; QRS DURATION; CONDUCTION DISTURBANCES; MYOCARDIAL STRAIN; PREDICT RESPONSE; TASK-FORCE; DYSSYNCHRONY; PERFORMANCE AB Background The relationship between myocardial electrical activation by electrocardiogram (ECG) and mechanical contraction by echocardiography in left bundle-branch block (LBBB) has never been clearly demonstrated. New strict criteria for LBBB based on a fundamental understanding of physiology have recently been independently published for both ECG and echocardiography. The relationship between the 2 modalities and the relation to cardiac resynchronization therapy (CRT) response was investigated. Methods Sixty-six patients with LBBB by conventional criteria had a standard 12-lead ECG and 2-dimensional strain echocardiography performed before CRT implantation. Criteria for LBBB by echocardiography included early termination of contraction in one wall and prestretch and late contraction in opposing wall(s). New strict criteria by ECG included QRS duration >= 140 ms (men) or 130 ms (women), QS or rS in leads V-1 and V-2, and mid-QRS notching or slurring in >= 2 of leads V-1, V-2, V-5, V-6, I, and aVL. Response was defined as >15% decrease in left ventricular end-systolic volume after 6 months. Results In 64 of 66 patients, ECG analysis was possible. Echo and ECG readings for LBBB presence were concordant in 54 (84%) of 64. Thirty-seven (82%) of 45 patients with LBBB by strict ECG criteria responded to CRT, whereas only 4 (21%) of the 19 patients without LBBB responded (sensitivity 90% and specificity 65%). Thirty-six (95%) of 38 patients with concordance for the presence of LBBB responded to CRT. In patients with concordance for the absence of LBBB, 15 (94%) of 16 did not respond. Conclusion For the first time, a close relation has been demonstrated between electrical activation by ECG and mechanical contraction by echocardiography. These findings may help identify CRT candidates. C1 [Risum, Niels; Hansen, Thomas Fritz; Bruun, Niels Eske] Gentofte Univ Hosp, Dept Cardiol, DK-2900 Hellerup, Denmark. [Strauss, David; Loring, Zak] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Sogaard, Peter] Aalborg Univ, Fac Hlth Sci & Technol, Aalborg, Denmark. [Loring, Zak; Wagner, Galen; Kisslo, Joseph] Duke Univ, Med Ctr, Durham, NC USA. RP Bruun, NE (reprint author), Gentofte Univ Hosp, Dept Cardiol P, DK-2900 Hellerup, Denmark. EM nielsrisum@gmail.com NR 35 TC 30 Z9 31 U1 1 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD AUG PY 2013 VL 166 IS 2 BP 340 EP 348 DI 10.1016/j.ahj.2013.04.005 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 194JR UT WOS:000322629000020 PM 23895818 ER PT J AU Anello, C AF Anello, Chuck TI Introduction to the Special Issue Honoring Dr. Robert T. O'Neill's Contribution to Regulatory Statistical Science SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Editorial Material C1 [Anello, Chuck] US FDA, Off Biostat, CDER, Silver Spring, MD 20993 USA. RP Anello, C (reprint author), Appl Stat Concepts LLC, 9886 Bluefield Dr, Boynton Beach, FL 33473 USA. EM chuckanello@aol.com NR 0 TC 1 Z9 1 U1 0 U2 2 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PD AUG PY 2013 VL 5 IS 3 BP 156 EP 157 DI 10.1080/19466315.2013.818815 PG 2 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 219FH UT WOS:000324491000001 ER PT J AU Hung, HMJ Wang, SJ AF Hung, H. M. James Wang, Sue-Jane TI Statistical Considerations for Noninferiority Trial Designs Without Placebo SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Across-trial; As-treated; Bayesian; Intention-to-treat; Likelihood; Noninferiority margin; On-treatment; Perprotocol; Synthesis method ID NON-INFERIORITY TRIALS; INTENT-TO-TREAT; ACTIVE-CONTROLLED TRIAL; TEAM WHITE PAPER; CLINICAL-TRIALS; CONSISTENT STANDARD; EQUIVALENCE TRIALS; ISSUES; CHOICE; EFFICACY AB In a noninferiority trial without a placebo arm, a basic and vital design specification is the noninferiority margin, which is required to be smaller than or no greater than the effect of the selected active control under the noninferiority trial setting. The FDA noninferiority draft guidance document stipulates that the noninferiority margin is determined from a two-step process: (1) derive a statistical margin, relying on the guidance obtained from the selected relevant historical trials that provide the estimates of the effect of the active control and the variances associated with the estimates and taking into account unverifiable assumptions such as the constancy assumption, and (2) use clinical judgment to determine whether the statistical margin needs to be further shrunk to generate a clinical margin reflecting "noninferiority." All the methods for margin determination rest upon subjective judgment and unverifiable assumptions. Additional issues such as multiplicity and covariate adjustments need to be carefully considered in the process of deriving the margin. Synthesis methods might help at Step 2 to generate a clinical margin. When there are multiple endpoints and interim analyses involved in such noninferiority trials, additional complexity resulting from multiple testing needs further attention in handling the statistical significance level-alpha. The long-standing controversy between intent-to-treat analysis and per-protocol analysis remains, though, in some cases, on-treatment analyses may be considered as an alternative to the intention-to-treat analysis to mitigate the impact of unfavorable bias on statistical inference for noninferiority. C1 [Hung, H. M. James] US FDA, Div Biometr 1, OB OTS CDER, Silver Spring, MD 20993 USA. [Wang, Sue-Jane] US FDA, Off Biostat, OTS CDER, Silver Spring, MD 20993 USA. RP Hung, HMJ (reprint author), US FDA, Div Biometr 1, OB OTS CDER, Silver Spring, MD 20993 USA. EM HsienMing.Hung@fda.hhs.gov; suejane.wang@fda.hhs.gov NR 45 TC 2 Z9 2 U1 3 U2 15 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PD AUG PY 2013 VL 5 IS 3 BP 239 EP 247 DI 10.1080/19466315.2013.782821 PG 9 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 219FH UT WOS:000324491000010 ER PT J AU Anello, C Junod, S AF Anello, Charles Junod, Suzanne TI Contributions of Robert T. O'Neill to the Evolution of Regulatory Statistical Science SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Adequate and well controlled studies; BEMAC; Clinical trials; DESI; ICH; Safety evaluation ID CLINICAL-TRIALS; DRUG DEVELOPMENT; SAMPLE SIZES; END-POINTS; HYPOTHESIS; APPROVAL; ISSUES AB Dr. Robert T. O'Neill has been on the forefront of regulatory statistical science since he came to the Food and Drug Administration in 1970. He worked to shape the statistical framework for the drug approval process for all new drugs marketed in the United States following passage of the 1962 Kefauver-Harris Amendments. This article will focus on Dr. O'Neill's responses to challenges in the field of drug development and evaluation and Dr. O'Neill's broad and influential role in the conceptualization and evolution of a systematic, statistically based approach to answering the question "Does this drug really work?" Statisticians working in pharmaceutical science have learned from his pioneering work and sound instincts in a regulatory environment but have also profited from his willingness to communicate through talks, travel, and publications over the years. We will describe some of the statistical principles he articulated so well and consider the role of clinical trial related statistical methodology overall as it has been applied in the biomedical sciences both nationally and internationally. We will conclude with a look at the future of regulatory statistical science. C1 [Anello, Charles] US FDA, Off Biostat, CDER, Silver Spring, MD 20993 USA. [Junod, Suzanne] US FDA, Off Commun, Hist Off, Silver Spring, MD 20993 USA. RP Anello, C (reprint author), Appl Stat Concepts LLC, 9886 Bluefield Dr, Boynton Beach, FL 33473 USA. EM chuckanello@aol.com; suzanne.junod@fda.hhs.gov NR 69 TC 0 Z9 1 U1 0 U2 4 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PD AUG PY 2013 VL 5 IS 3 BP 262 EP 279 DI 10.1080/19466315.2013.818817 PG 18 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 219FH UT WOS:000324491000013 ER PT J AU Brady, RA Mocca, CP Burns, DL AF Brady, Rebecca A. Mocca, Christopher P. Burns, Drusilla L. TI Immunogenicity Analysis of Staphylococcus aureus Clumping Factor A Genetic Variants SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID FACTOR-A; VACCINE; PROTEIN; MICE; ANTIBODIES; VIRULENCE; MASTITIS; MSCRAMM AB The staphylococcal adhesin clumping factor A (ClfA) has a variant amino acid sequence, generating the potential for alterations in epitope structure and immunogenicity of this vaccine candidate. We demonstrated for two recombinant ClfA(40-531) (a slightly truncated version of the fibrinogen-binding domain of ClfA containing amino acids 40 to 531) genetic variants that strain-specific epitopes are immunodominant. This work indicates that immune responses elicited by ClfA may, at least in part, be dependent on the strain of origin of the ClfA. C1 [Brady, Rebecca A.; Mocca, Christopher P.; Burns, Drusilla L.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Burns, DL (reprint author), US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. EM drusilla.burns@fda.hhs.gov FU Intramural Research Program of the Center for Biologics Evaluation and Research, Food and Drug Administration FX This work was supported by the Intramural Research Program of the Center for Biologics Evaluation and Research, Food and Drug Administration. NR 18 TC 4 Z9 4 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD AUG PY 2013 VL 20 IS 8 BP 1338 EP 1340 DI 10.1128/CVI.00275-13 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 190CY UT WOS:000322316800032 PM 23803901 ER PT J AU Dong, ML Goyal, KG Worth, BW Makkar, SS Calhoun, WR Bali, LM Bali, S AF Dong, Miao L. Goyal, Kashika G. Worth, Bradley W. Makkar, Sorab S. Calhoun, William R. Bali, Lalit M. Bali, Samir TI Accurate in situ measurement of complex refractive index and particle size in intralipid emulsions SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE turbid media; refractive index; scattering media; optical tissue; intralipid ID HIGHLY TURBID MEDIA; OPTICAL-PROPERTIES; SCATTERING; LIGHT; WAVELENGTHS; REFLECTION; ABSORPTION; PHANTOMS; NM AB A first accurate measurement of the complex refractive index in an intralipid emulsion is demonstrated, and thereby the average scatterer particle size using standard Mie scattering calculations is extracted. Our method is based on measurement and modeling of the reflectance of a divergent laser beam from the sample surface. In the absence of any definitive reference data for the complex refractive index or particle size in highly turbid intralipid emulsions, we base our claim of accuracy on the fact that our work offers several critically important advantages over previously reported attempts. First, our measurements are in situ in the sense that they do not require any sample dilution, thus eliminating dilution errors. Second, our theoretical model does not employ any fitting parameters other than the two quantities we seek to determine, i.e., the real and imaginary parts of the refractive index, thus eliminating ambiguities arising from multiple extraneous fitting parameters. Third, we fit the entire reflectance-versus-incident-angle data curve instead of focusing on only the critical angle region, which is just a small subset of the data. Finally, despite our use of highly scattering opaque samples, our experiment uniquely satisfies a key assumption behind the Mie scattering formalism, namely, no multiple scattering occurs. Further proof of our method's validity is given by the fact that our measured particle size finds good agreement with the value obtained by dynamic light scattering. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI. C1 [Dong, Miao L.; Goyal, Kashika G.; Worth, Bradley W.; Makkar, Sorab S.; Bali, Lalit M.; Bali, Samir] Miami Univ, Dept Phys, Oxford, OH 45056 USA. [Calhoun, William R.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Bali, S (reprint author), Miami Univ, Dept Phys, Oxford, OH 45056 USA. EM balis@miamioh.edu FU Petroleum Research Fund; Dillon-Kane, LLC FX We thank Mr. Lynn Johnson, formerly in the Miami University Instrumentation Lab, for Labview help. We are grateful to Mr. Michael Eldridge, former instrument maker in the Department of Physics at Miami University, for machining support. We acknowledge Ms. Sangeeta Singh for useful discussions on goodness-of-fit. We are indebted to the Petroleum Research Fund and Dillon-Kane, LLC, for financial support. NR 37 TC 11 Z9 11 U1 5 U2 21 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD AUG PY 2013 VL 18 IS 8 AR 087003 DI 10.1117/1.JBO.18.8.087003 PG 6 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 216MN UT WOS:000324287700020 PM 23922125 ER PT J AU Calhoun, W Weiblinger, R Beylin, A Ilev, IK AF Calhoun, William Weiblinger, Richard Beylin, Alexander Ilev, Ilko K. TI Assessing the phase retardation in corneal tissues using a femtosecond laser SO REVIEW OF SCIENTIFIC INSTRUMENTS LA English DT Article ID BIREFRINGENCE; MECHANISMS; ABLATION; PULSES; CELLS; MODEL AB We developed and validated a versatile test method for precise quantification of phase retardation in corneal tissues using a femtosecond laser. It is based on an experimental system for direct measurement of corneal phase rotation due to corneal birefringence effects using a dual-polarizer, computer-controlled, femtosecond laser design. It also includes a comprehensive analytical model using Jones matrices. The test method presented is used for quantification of phase retardation in corneal tissues by employing the experimental data obtained from corneal phase rotation measurements and using analytical model assessments. The experimental and theoretical results obtained, and thus, the system's high accuracy and repeatability potential for assessing the corneal phase retardation are validated using control phase retardation evaluation. C1 [Calhoun, William; Ilev, Ilko K.] US FDA, Opt Therapeut & Med Nanophoton Lab, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. [Weiblinger, Richard; Beylin, Alexander] US FDA, Ctr Devices & Radiol Hlth, Off Device Evaluat, Silver Spring, MD 20993 USA. RP Calhoun, W (reprint author), US FDA, Opt Therapeut & Med Nanophoton Lab, Off Sci & Engn Labs, Silver Spring, MD 20993 USA. EM William.Calhoun@fda.hhs.gov NR 22 TC 1 Z9 1 U1 0 U2 7 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0034-6748 J9 REV SCI INSTRUM JI Rev. Sci. Instrum. PD AUG PY 2013 VL 84 IS 8 AR 084301 DI 10.1063/1.4816838 PG 7 WC Instruments & Instrumentation; Physics, Applied SC Instruments & Instrumentation; Physics GA 211YC UT WOS:000323947400037 PM 24007081 ER PT J AU Miloslavsky, EM Specks, U Merkel, PA Seo, P Spiera, R Langford, CA Hoffman, GS Kallenberg, CGM St Clair, EW Tchao, NK Viviano, L Ding, L Sejismundo, LP Mieras, K Ikle, D Jepson, B Mueller, M Brunetta, P Allen, NB Fervenza, FC Geetha, D Keogh, K Kissin, EY Monach, PA Peikert, T Stegeman, C Ytterberg, SR Stone, JH AF Miloslavsky, E. M. Specks, U. Merkel, P. A. Seo, P. Spiera, R. Langford, C. A. Hoffman, G. S. Kallenberg, C. G. M. St Clair, E. W. Tchao, N. K. Viviano, L. Ding, L. Sejismundo, L. P. Mieras, K. Ikle, D. Jepson, B. Mueller, M. Brunetta, P. Allen, N. B. Fervenza, F. C. Geetha, D. Keogh, K. Kissin, E. Y. Monach, P. A. Peikert, T. Stegeman, C. Ytterberg, S. R. Stone, J. H. CA Rituximab ANCA-Associated TI Clinical Outcomes of Remission Induction Therapy for Severe Antineutrophil Cytoplasmic Antibody-Associated Vasculitis SO ARTHRITIS AND RHEUMATISM LA English DT Article ID ANCA-ASSOCIATED VASCULITIS; DAILY ORAL CYCLOPHOSPHAMIDE; RANDOMIZED-TRIAL; FOLLOW-UP; RITUXIMAB; MAINTENANCE; AUTOANTIBODIES; GRANULOMATOSIS; AZATHIOPRINE; METHOTREXATE AB Objective. To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). Methods. The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). Results. Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. Conclusion. Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3- ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months. C1 [Miloslavsky, E. M.; Stone, J. H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Specks, U.; Mieras, K.; Fervenza, F. C.; Keogh, K.; Peikert, T.; Ytterberg, S. R.] Mayo Clin, Rochester, MN USA. [Merkel, P. A.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Seo, P.; Sejismundo, L. P.; Geetha, D.] Johns Hopkins Univ, Baltimore, MD USA. [Spiera, R.] Hosp Special Surg, New York, NY 10021 USA. [Langford, C. A.; Hoffman, G. S.] Cleveland Clin, Cleveland, OH 44106 USA. [Kallenberg, C. G. M.; Stegeman, C.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Kallenberg, C. G. M.; Stegeman, C.] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [St Clair, E. W.; Allen, N. B.] Duke Univ, Med Ctr, Durham, NC USA. [Tchao, N. K.] Immune Tolerance Network, San Francisco, CA USA. [Viviano, L.; Ding, L.] NIAID, NIH, Bethesda, MD 20892 USA. [Ikle, D.; Jepson, B.] Rho, Chapel Hill, NC USA. [Mueller, M.] US FDA, Silver Spring, MD USA. [Brunetta, P.] Genentech Inc, San Francisco, CA 94080 USA. [Kissin, E. Y.; Monach, P. A.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Stone, JH (reprint author), Massachusetts Gen Hosp, Rheumatol Unit, Yawkey 2C,55 Fruit St, Boston, MA 02114 USA. EM jhstone@partners.org FU Immune Tolerance Network (NIH), an international clinical research consortium headquartered at the University of California San Francisco [N01-AI-15416, ITN021AI]; NIH (National Institute of Allergy and Infectious Diseases) [N01-AI-15416, ITN021AI]; Juvenile Diabetes Research Foundation; Genentech; Biogen Idec; NIH (Mayo Clinic: National Center for Research Resources Clinical and Translational Science) [RR-024150-01]; NIH (Johns Hopkins University: National Center for Research Resources Clinical and Translational Science) [RR-025005, K23-AR-052820, K24-AR-049185, RR-025771, M01-RR-00533, K24-AR-02224]; Arthritis Foundation FX The Rituximab in ANCA-Associated Vasculitis (RAVE) trial was performed with the support of the Immune Tolerance Network (NIH contract N01-AI-15416, protocol number ITN021AI), an international clinical research consortium headquartered at the University of California San Francisco and supported by the NIH (National Institute of Allergy and Infectious Diseases contract N01-AI-15416, protocol number ITN021AI) and the Juvenile Diabetes Research Foundation. Genentech and Biogen Idec provided the study medications and partial funding for the RAVE trial. At the Mayo Clinic, Johns Hopkins University, and Boston University School of Medicine, the RAVE trial was supported by the NIH (Mayo Clinic: National Center for Research Resources Clinical and Translational Science award RR-024150-01; Johns Hopkins University: National Center for Research Resources Clinical and Translational Science grant RR-025005 and career development awards K23-AR-052820 to Dr. Seo and K24-AR-049185 to Dr. Stone; Boston University: National Center for Research Resources Clinical and Translational Science award RR-025771, grant M01-RR-00533, and career development award K24-AR-02224 to Dr. Merkel). Dr. Miloslavsky's work was supported by Genentech (Clinical Immunology Fellowship). Dr. Monach's work was supported by the Arthritis Foundation (Arthritis Investigator Award). NR 21 TC 37 Z9 39 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD AUG PY 2013 VL 65 IS 9 BP 2441 EP 2449 DI 10.1002/art.38044 PG 9 WC Rheumatology SC Rheumatology GA 205YR UT WOS:000323481400027 PM 23754238 ER PT J AU Dake, MD Thompson, M van Sambeek, M Vermassen, F Morales, JP AF Dake, M. D. Thompson, M. van Sambeek, M. Vermassen, F. Morales, J. P. CA DEFINE Investigators TI DISSECT: A New Mnemonic-based Approach to the Categorization of Aortic Dissection SO EUROPEAN JOURNAL OF VASCULAR AND ENDOVASCULAR SURGERY LA English DT Article DE Aortic dissection; Aortic endograft; Dissection type; Classification system ID STENT-GRAFT PLACEMENT; INTERNATIONAL REGISTRY; FALSE LUMEN; SURGICAL MANAGEMENT; ENDOVASCULAR REPAIR; DESCENDING AORTA; ANEURYSMS; INSIGHTS; OUTCOMES; IRAD AB Objective/Background: Classification systems for aortic dissection provide important guides to clinical decision-making, but the relevance of traditional categorization schemes is being questioned in an era when endovascular techniques are assuming a growing role in the management of this frequently complex and catastrophic entity. In recognition of the expanding range of interventional therapies now used as alternatives to conventional treatment approaches, the Working Group on Aortic Diseases of the DEFINE Project developed a categorization system that features the specific anatomic and clinical manifestations of the disease process that are most relevant to contemporary decision-making. Methods and results: The DISSECT classification system is a mnemonic-based approach to the evaluation of aortic dissection. It guides clinicians through an assessment of six critical characteristics that facilitate optimal communication of the most salient details that currently influence the selection of a therapeutic option, including those findings that are key when considering an endovascular procedure, but are not taken into account by the DeBakey or Stanford categorization schemes. The six features of aortic dissection include: duration of disease; intimal tear location; size of the dissected aorta; segmental extent of aortic involvement; clinical complications of the dissection, and thrombus within the aortic false lumen. Conclusion: In current clinical practice, endovascular therapy is increasingly considered as an alternative to medical management or open surgical repair in select cases of type B aortic dissection. Currently, endovascular aortic repair is not used for patients with type A aortic dissection, but catheter-based techniques directed at peripheral branch vessel ischemia that may complicate type A dissection are considered valuable adjunctive interventions, when indicated. The use of a new system for categorization of aortic dissection, DISSECT, addresses the shortcomings of well-known established schemes devised more than 40 years ago, before the introduction of endovascular techniques. It will serve as a guide to support a critical analysis of contemporary therapeutic options and inform management decisions based on specific features of the disease process. (C) 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved C1 [Dake, M. D.] Stanford Univ, Sch Med, Dept Cardiothorac Surg, Stanford, CA 94305 USA. [Thompson, M.] St Georges Healthcare NHS Trust, St Georges Vasc Inst, London, England. [van Sambeek, M.] Catharina Hosp, Dept Surg, Eindhoven, Netherlands. [Vermassen, F.] Univ Hosp, Dept Vasc Surg, Ghent, Belgium. [Morales, J. P.] US FDA, Div Cardiovasc Devices, Silver Spring, MD USA. RP Dake, MD (reprint author), Stanford Univ, Sch Med, Dept Cardiothorac Surg, Falk Cardiovasc Res Ctr, 300 Pasteur Dr, Stanford, CA 94305 USA. EM mddake@stanford.edu NR 32 TC 25 Z9 26 U1 0 U2 11 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1078-5884 J9 EUR J VASC ENDOVASC JI Eur. J. Vasc. Endovasc. Surg. PD AUG PY 2013 VL 46 IS 2 BP 175 EP 190 DI 10.1016/j.ejvs.2013.04.029 PG 16 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 208PF UT WOS:000323690900005 PM 23721817 ER PT J AU Zhang, Z Triplett, OA Nguyen, KT Melchior, WB Taylor, K Jackson, LS Tolleson, WH AF Zhang, Zhe Triplett, Odbert A. Nguyen, Kiet T. Melchior, William B., Jr. Taylor, Kelly Jackson, Lauren S. Tolleson, William H. TI Thermal inactivation reaction rates for ricin are influenced by pH and carbohydrates SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Ricin; Castor beans; Infant food; Thermal stability; Cytotoxicity; Bioterrorism ID CASTOR BEAN MEAL; STABILITY; PROTEIN; BINDING; CAKE; THERMODYNAMICS; DETOXIFICATION; CONFORMATION; YOGURT; ACID AB Ricin is a lethal protein toxin produced by the castor bean plant. Ricin is known to possess significant heat resistance. Therefore, we placed it in a variety of foods to study the influence of the food matrix on behavior of a thermally stable protein toxin. First order rate constants for the thermal inactivation of ricin in foods and simple buffers were measured using cytotoxicity assays. We observed greater thermal stability at 75 C for the cytotoxic activity of ricin when it was placed in a yogurt-containing fruit drink compared to its stability when placed in the other foods tested. We found that galactose and high molecular weight exopolysaccharides present in various dairy products contributed to the thermal stability of ricin. Differential scanning calorimetry also showed enhanced thermal stability for ricin at pH 4.5. Our results demonstrate the importance of considering pH and the presence of stabilizing ligands in the thermal inactivation of protein toxins in foods. Published by Elsevier Ltd. C1 [Zhang, Zhe] IIT, Inst Food Safety & Hlth, Bedford Pk, IL 60501 USA. [Triplett, Odbert A.; Nguyen, Kiet T.; Melchior, William B., Jr.; Taylor, Kelly; Tolleson, William H.] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Jackson, Lauren S.] US FDA, Ctr Food Safety & Appl Nutr, Bedford Pk, IL 60501 USA. RP Tolleson, WH (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM zhangzhe@cfsa.net.cn; odbert.triplett@fda.hhs.gov; kiet.nguyen@fda.hhs.gov; william.melchior@fda.hhs.-gov; kellytaylor007@yahoo.com; Lauren.jackson@f-da.hhs.gov; william.tolleson@fda.hhs.gov FU Illinois Institute of Technology; Arkansas STRIVE program FX The contents of this manuscript do not necessarily reflect the views and policies of the U.S. Food and Drug Administration, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. The authors wish to thank the food manufacturers that shared product information. Financial support for Z. Zhang was provided by the Illinois Institute of Technology. Financial support for K. Taylor was provided by the Arkansas STRIVE program. NR 40 TC 4 Z9 4 U1 0 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD AUG PY 2013 VL 58 BP 116 EP 123 DI 10.1016/j.fct.2013.04.012 PG 8 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA 187EG UT WOS:000322099100016 PM 23603103 ER PT J AU Davey, RJ AF Davey, Richard J. TI Iron and ice SO TRANSFUSION LA English DT Editorial Material ID RESTLESS LEGS SYNDROME; STATUS EVALUATION RISE; BLOOD-DONORS; DEFICIENCY; MANAGEMENT C1 US FDA, Div Blood Applicat, CBER, Rockville, MD 20857 USA. RP Davey, RJ (reprint author), US FDA, Div Blood Applicat, CBER, Rockville, MD 20857 USA. EM Richard.Davey@fda.hhs.gov NR 17 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD AUG PY 2013 VL 53 IS 8 BP 1623 EP 1625 DI 10.1111/trf.12319 PG 3 WC Hematology SC Hematology GA 197SB UT WOS:000322869800032 PM 23927636 ER PT J AU Li, Q Mei, QB Ting, HY Xie, L Che, S Yang, H Zhang, MJ Huang, QS AF Li, Qi Mei, Qibing Ting Huyan Xie, Li Che, Su Yang, Hui Zhang, Mingjie Huang, Qingsheng TI Effects of Simulated Microgravity on Primary Human NK Cells SO ASTROBIOLOGY LA English DT Article DE Simulated microgravity (SMG); Natural killer (NK) cells; Cytotoxicity ID NATURAL-KILLER-CELLS; EXPERIMENT PROGRAM INTERFERON; LONG-DURATION SPACEFLIGHT; MODELED MICROGRAVITY; GENE-EXPRESSION; T-LYMPHOCYTES; SPACE-FLIGHT; SIGNALING PATHWAYS; IMMUNE-RESPONSES; POTENTIAL ROLE AB The deleterious effects of microgravity on lymphocytes have been demonstrated in previous studies. However, research on the effects of microgravity on human natural killer (NK) cells remains exceedingly limited. In this study, we demonstrated that NK cell cytotoxicity was significantly decreased under simulated microgravity (SMG) conditions (p < 0.05). Several processes, including apoptosis, receptor expression, and cytokine secretion, were investigated in human NK cells under SMG. We observed decreased cytotoxicity, concurrent with increased apoptosis and necrosis, in NK cells after exposure to SMG (p < 0.05). Additionally, interferon (IFN)-gamma and perforin expression decreased significantly, and the expression of granzyme-B was only slightly reduced. Meanwhile, SMG selectively inhibited the expression of certain surface receptors on NK cells. Specifically, the expression of NKG2A and NKG2D were significantly downregulated under SMG, but the expression of NKp30 and NKp44 was not affected. We also found that interleukin (IL)-15 alone or in combination with IL-12 could counteract the inhibition of NK cell cytotoxicity under SMG. Our findings indicate that human NK cells were sensitive to SMG, as reflected by their decreased cytotoxicity. Factors such as increased early apoptosis and late apoptosis/necrosis and the decreased expression of INF-gamma, cytolytic proteins, and cell surface receptors may be responsible for the loss of cytotoxicity in human NK cells under SMG. A combination of IL-12 and IL-15 may be useful as a therapeutic strategy for overcoming the effects of microgravity on human NK cells during long space missions. C1 [Li, Qi; Mei, Qibing; Ting Huyan; Xie, Li; Che, Su; Yang, Hui; Zhang, Mingjie; Huang, Qingsheng] Northwestern Polytech Univ, Sch Life Sci, Key Lab Space Biosci & Biotechnol, Xian 710072, Shaanxi, Peoples R China. [Zhang, Mingjie] US FDA, Mol Virol Lab, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP Huang, QS (reprint author), Northwestern Polytech Univ, Sch Life Sci, Xian 710072, Shaanxi, Peoples R China. EM qingshengh@yahoo.com.cn FU National Natural Science Foundation of China (NSFC) [30971425]; Doctorate Foundation of Northwestern Polytechnical University [CX201023] FX We gratefully acknowledge financial support from the National Natural Science Foundation of China (NSFC, Grant No. 30971425) and the Doctorate Foundation of Northwestern Polytechnical University (CX201023). NR 65 TC 6 Z9 7 U1 1 U2 15 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1531-1074 J9 ASTROBIOLOGY JI Astrobiology PD AUG PY 2013 VL 13 IS 8 BP 703 EP 714 DI 10.1089/ast.2013.0981 PG 12 WC Astronomy & Astrophysics; Biology; Geosciences, Multidisciplinary SC Astronomy & Astrophysics; Life Sciences & Biomedicine - Other Topics; Geology GA 202IG UT WOS:000323206900003 PM 23919749 ER PT J AU Lanthier, M Miller, KL Nardinelli, C Woodcock, J AF Lanthier, Michael Miller, Kathleen L. Nardinelli, Clark Woodcock, Janet TI An Improved Approach To Measuring Drug Innovation Finds Steady Rates Of First-In-Class Pharmaceuticals, 1987-2011 SO HEALTH AFFAIRS LA English DT Article ID RESEARCH-AND-DEVELOPMENT; INDUSTRY; TRENDS AB For more than a decade, industry analysts and policy makers have raised concerns about declining pharmaceutical innovation, citing declining numbers of new molecular entities (NMEs) approved in the United States each year. Yet there is little consensus on whether this is the best measure of "innovation." We examined NME approvals during 1987-2011 and propose the three distinct subcategories of NMEs-first-in-class, advance-in-class, and addition-to-class-to provide more nuanced and informative insights into underlying trends. We found that trends in NME approvals were largely driven by addition-to-class, or "me too," drug approvals, while first-in-class approvals remained fairly steady over the study period. Moreover, the higher proportion of first-in-class drug approvals over the most recent decade is an encouraging sign of the health of the industry as a whole. C1 [Lanthier, Michael; Miller, Kathleen L.; Nardinelli, Clark] US FDA, Off Planning, Silver Spring, MD USA. [Miller, Kathleen L.] Univ N Carolina, Dept Hlth Policy & Management, Chapel Hill, NC USA. [Woodcock, Janet] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Lanthier, M (reprint author), US FDA, Off Planning, Silver Spring, MD USA. EM michael.lanthier@fda.hhs.gov NR 21 TC 22 Z9 23 U1 1 U2 12 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD AUG PY 2013 VL 32 IS 8 BP 1433 EP 1439 DI 10.1377/hlthaff.2012.0541 PG 7 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 201PO UT WOS:000323154800014 PM 23918488 ER PT J AU Camp, KM Lloyd-Puryear, MA Yao, L Groft, SC Parisi, MA Mulberg, A Gopal-Srivastava, R Cederbaum, S Enns, GM Ershow, AG Frazier, DM Gohagan, J Harding, C Howell, RR Regan, K Stacpoole, PW Venditti, C Vockley, J Watson, M Coates, PM AF Camp, Kathryn M. Lloyd-Puryear, Michele A. Yao, Lynne Groft, Stephen C. Parisi, Melissa A. Mulberg, Andrew Gopal-Srivastava, Rashmi Cederbaum, Stephen Enns, Gregory M. Ershow, Abby G. Frazier, Dianne M. Gohagan, John Harding, Cary Howell, R. Rodney Regan, Karen Stacpoole, Peter W. Venditti, Charles Vockley, Jerry Watson, Michael Coates, Paul M. TI Expanding research to provide an evidence base for nutritional interventions for the management of inborn errors of metabolism SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Inborn errors of metabolism; Newborn screening; Genetic; Rare diseases; Dietary supplements; Medical foods AB A trans-National Institutes of Health initiative, Nutrition and Dietary Supplement Interventions for Inborn Errors of Metabolism (NDSI-IEM), was launched in 2010 to identify gaps in knowledge regarding the safety and utility of nutritional interventions for the management of inborn errors of metabolism (IEM) that need to be filled with evidence-based research. IEM include inherited biochemical disorders in which specific enzyme defects interfere with the normal metabolism of exogenous (dietary) or endogenous protein, carbohydrate, or fat. For some of these IEM, effective management depends primarily on nutritional interventions. Further research is needed to demonstrate the impact of nutritional interventions on individual health outcomes and on the psychosocial issues identified by patients and their families. A series of meetings and discussions were convened to explore the current United States' funding and regulatory infrastructure and the challenges to the conduct of research for nutritional interventions for the management of IEM. Although the research and regulatory infrastructure are well-established, a collaborative pathway that includes the professional and advocacy rare disease community and federal regulatory and research agencies will be needed to overcome current barriers. C1 [Camp, Kathryn M.; Lloyd-Puryear, Michele A.; Regan, Karen; Coates, Paul M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Yao, Lynne; Mulberg, Andrew] US FDA, Silver Spring, MD 20993 USA. [Groft, Stephen C.; Gopal-Srivastava, Rashmi] NIH, Off Rare Dis Res, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Parisi, Melissa A.] NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Cederbaum, Stephen] Univ Calif Los Angeles, Los Angeles, CA 90095 USA. [Enns, Gregory M.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Ershow, Abby G.] NHLBI, NIH, Bethesda, MD 20892 USA. [Frazier, Dianne M.] Univ N Carolina, Chapel Hill, NC 27599 USA. [Gohagan, John] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. [Harding, Cary] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Howell, R. Rodney] Univ Miami, Miami, FL 33136 USA. [Regan, Karen] NIH, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. [Stacpoole, Peter W.] Univ Florida, Gainesville, FL 32610 USA. [Venditti, Charles] NHGRI, NIH, Bethesda, MD 20892 USA. [Vockley, Jerry] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15224 USA. [Watson, Michael] Amer Coll Med Genet & Genom, Bethesda, MD 20814 USA. RP Camp, KM (reprint author), NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. EM campkm@od.nih.gov; lloydpuryearma@od.nih.gov; Lynne.Yao@fda.hhs.gov; Stephen.Groft@nih.gov; parisima@mail.nih.gov; Andrew.Mulberg@fda.hhs.gov; gopalr@mail.nih.gov; scederbaum@mednet.ucla.edu; genns@stanford.edu; ershowa@nhlbi.nih.gov; dianne_frazier@med.unc.edu; gohaganj@mail.nih.gov; hardingc@ohsu.edu; RHowell@med.miami.edu; regank@mail.nih.gov; pws@ufl.edu; venditti@mail.nih.gov; vockleyg@upmc.edu; mwatson@acmg.net; CoatesP@od.nih.gov OI Vockley, Jerry/0000-0002-8180-6457 FU Intramural NIH HHS [Z99 OD999999] NR 42 TC 6 Z9 7 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD AUG PY 2013 VL 109 IS 4 BP 319 EP 328 DI 10.1016/j.ymgme.2013.05.008 PG 10 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 200QU UT WOS:000323084800001 PM 23806236 ER PT J AU Solomon, DH Curtis, JR Saag, KG Lii, J Chen, L Harrold, LR Herrinton, LJ Graham, DJ Kowal, MK Kuriya, B Liu, L Griffin, MR Lewis, JD Rassen, JA AF Solomon, Daniel H. Curtis, Jeffrey R. Saag, Kenneth G. Lii, Joyce Chen, Lang Harrold, Leslie R. Herrinton, Lisa J. Graham, David J. Kowal, Mary K. Kuriya, Bindee Liu, Liyan Griffin, Marie R. Lewis, James D. Rassen, Jeremy A. TI Cardiovascular Risk in Rheumatoid Arthritis: Comparing TNF-alpha Blockade with Nonbiologic DMARDs SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Cardiovascular disease; Rheumatoid arthritis; TNF-alpha blocking agents ID ACUTE MYOCARDIAL-INFARCTION; NECROSIS-FACTOR-ALPHA; PROPENSITY-SCORE; EVENTS; DISEASE; ATHEROSCLEROSIS; MORTALITY; INFLAMMATION; BIOLOGICS; ACCURACY AB BACKGROUND: Elevated tumor necrosis factor (TNF)-alpha likely contributes to the excess cardiovascular risk observed in rheumatoid arthritis. We compared the cardiovascular risk in rheumatoid arthritis patients starting a TNF-alpha blocking agent versus a nonbiologic disease-modifying antirheumatic drug (nbDMARD). METHODS: Subjects with rheumatoid arthritis participating in several different US insurance programs between 1998 and 2007 who received methotrexate were eligible. Those who added a TNF-alpha blocking agent were compared with subjects who added a nbDMARD in Cox regression models stratified by propensity score decile and adjusted for oral glucocorticoid dosage. We examined the composite cardiovascular end point of myocardial infarction, stroke, or coronary re-vascularization after 6 months. RESULTS: We compared 8656 new users of a nbDMARD with 11,587 new users of a TNF-alpha blocking agent with similar baseline covariates. Incidence rates per 100 person-years for the composite cardiovascular end point were 3.05 (95% confidence interval [CI], 2.54-3.65) for nbDMARDs and 2.52 (95% CI, 2.12-2.98) for TNF-alpha blocking agents. The hazard ratio (HR) for the TNF-alpha blocking agent compared with nbDMARD carrying the first exposure forward was 0.80 (95%, CI 0.62-1.04), while the HR for the as-treated analysis was 0.71 (95% CI, 0.52-0.97). The potential cardiovascular benefit of TNF-alpha blocking agents was strongest among individuals >= 65 years of age (HR 0.52; 95% CI, 0.34 -0.77; P for interaction 0.075). CONCLUSION: Among subjects with rheumatoid arthritis, TNF-alpha blocking agents may be associated with a reduced risk of cardiovascular events compared with an nbDMARD. Randomized controlled clinical trials should be considered to test this hypothesis. (C) 2013 Elsevier Inc. All rights reserved. C1 [Solomon, Daniel H.; Lii, Joyce; Kowal, Mary K.; Rassen, Jeremy A.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Curtis, Jeffrey R.; Saag, Kenneth G.; Chen, Lang] Univ Alabama Birmingham, Birmingham, AL USA. [Harrold, Leslie R.] Univ Massachusetts, Worcester, MA 01605 USA. [Herrinton, Lisa J.; Liu, Liyan] Kaiser Permanente, Oakland, CA USA. [Graham, David J.] US FDA, Silver Spring, MD USA. [Kuriya, Bindee] Univ Toronto, Toronto, ON M5S 1A1, Canada. [Griffin, Marie R.] Vanderbilt Univ, Nashville, TN 37235 USA. [Griffin, Marie R.] Vet Affairs Tennessee Valley Hlth Care Syst, Nashville, TN USA. [Lewis, James D.] Univ Penn, Philadelphia, PA USA. RP Solomon, DH (reprint author), Brigham & Womens Hosp, Div Pharmacoepidemiol, Div Rheumatol, 75 Francis St, Boston, MA 02115 USA. EM dhsolomon@partners.org FU Agency for Healthcare Research and Quality (AHRQ); Food and Drug Administration (FDA) US Department of Health and Human Services (DHHS) [1U18 HSO17919-0] FX This work was supported by the Agency for Healthcare Research and Quality (AHRQ) and the Food and Drug Administration (FDA) US Department of Health and Human Services (DHHS) as part of a grant (No. 1U18 HSO17919-0) administered through the AHRQ CERTs Program. NR 40 TC 9 Z9 9 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD AUG PY 2013 VL 126 IS 8 AR 730.e9 DI 10.1016/j.amjmed.2013.02.016 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 197CS UT WOS:000322827200030 PM 23885678 ER PT J AU Jevtovic-Todorovic, V Absalom, AR Blomgren, K Brambrink, A Crosby, G Culley, DJ Fiskum, G Giffard, RG Herold, KF Loepke, AW Ma, D Orser, BA Planel, E Slikker, W Soriano, SG Stratmann, G Vutskits, L Xie, Z Hemmings, HC AF Jevtovic-Todorovic, V. Absalom, A. R. Blomgren, K. Brambrink, A. Crosby, G. Culley, D. J. Fiskum, G. Giffard, R. G. Herold, K. F. Loepke, A. W. Ma, D. Orser, B. A. Planel, E. Slikker, W., Jr. Soriano, S. G. Stratmann, G. Vutskits, L. Xie, Z. Hemmings, H. C., Jr. TI Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar SO BRITISH JOURNAL OF ANAESTHESIA LA English DT Article DE anaesthesia; general; anaesthetics; cognitive disorder; neurotoxicity syndromes; postoperative complications ID POSTOPERATIVE COGNITIVE DYSFUNCTION; DEVELOPING RAT-BRAIN; KETAMINE-INDUCED NEUROAPOPTOSIS; MEDIAL PREFRONTAL CORTEX; NITROUS-OXIDE ANESTHESIA; ARTERY-BYPASS-SURGERY; D-ASPARTATE RECEPTOR; NEURONAL CELL-DEATH; NEURAL STEM-CELLS; ALZHEIMERS-DISEASE AB Although previously considered entirely reversible, general anaesthesia is now being viewed as a potentially significant risk to cognitive performance at both extremes of age. A large body of preclinical as well as some retrospective clinical evidence suggest that exposure to general anaesthesia could be detrimental to cognitive development in young subjects, and might also contribute to accelerated cognitive decline in the elderly. A group of experts in anaesthetic neuropharmacology and neurotoxicity convened in Salzburg, Austria for the BJA Salzburg Seminar on Anaesthetic Neurotoxicity and Neuroplasticity. This focused workshop was sponsored by the British Journal of Anaesthesia to review and critically assess currently available evidence from animal and human studies, and to consider the direction of future research. It was concluded that mounting evidence from preclinical studies reveals general anaesthetics to be powerful modulators of neuronal development and function, which could contribute to detrimental behavioural outcomes. However, definitive clinical data remain elusive. Since general anaesthesia often cannot be avoided regardless of patient age, it is important to understand the complex mechanisms and effects involved in anaesthesia-induced neurotoxicity, and to develop strategies for avoiding or limiting potential brain injury through evidence-based approaches. C1 [Jevtovic-Todorovic, V.] Univ Virginia, Dept Anesthesiol, Charlottesville, VA 22903 USA. [Absalom, A. R.] Univ Groningen, Univ Med Ctr Groningen, Dept Anesthesiol, Groningen, Netherlands. [Blomgren, K.] Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden. [Brambrink, A.] Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97201 USA. [Crosby, G.; Culley, D. J.] Brigham & Womens Hosp, Dept Anesthesia, Boston, MA 02115 USA. [Crosby, G.; Culley, D. J.; Soriano, S. G.] Harvard Univ, Sch Med, Boston, MA USA. [Fiskum, G.] Univ Maryland, Sch Med, Dept Anesthesiol, Baltimore, MD 21201 USA. [Giffard, R. G.] Stanford Univ, Sch Med, Dept Anesthesia, Stanford, CA 94305 USA. [Herold, K. F.; Hemmings, H. C., Jr.] Weill Cornell Med Coll, Dept Anesthesiol, New York, NY USA. [Loepke, A. W.] Cincinnati Childrens Hosp Med Ctr, Dept Anesthesia, Cincinnati, OH USA. [Loepke, A. W.] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA. [Loepke, A. W.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Ma, D.] Univ London Imperial Coll Sci Technol & Med, Sect Anaesthet Pain Med & Intens Care, Dept Surg & Canc, London, England. [Orser, B. A.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Anesthesia, Toronto, ON, Canada. [Planel, E.] Univ Laval, Dept Psychiat & Neurosci, Quebec City, PQ, Canada. [Slikker, W., Jr.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Soriano, S. G.] Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA USA. [Stratmann, G.] UCSF, Dept Anesthesia & Crit Care, San Francisco, CA USA. [Stratmann, G.] Grp Anesthesia Serv, Los Gatos, CA USA. [Vutskits, L.] Univ Hosp Geneva, Dept Anesthesiol Pharmacol & Intens Care, Geneva, Switzerland. [Xie, Z.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA USA. [Xie, Z.] Harvard Univ, Sch Med, Charlestown, MA USA. [Hemmings, H. C., Jr.] Weill Cornell Med Coll, Dept Pharmacol, New York, NY USA. RP Jevtovic-Todorovic, V (reprint author), Univ Virginia, Dept Anesthesiol, Charlottesville, VA 22903 USA. EM vj3w@hscmail.mcc.virginia.edu; hchemmi@med.cornell.edu OI Absalom, Anthony/0000-0001-7563-9157; Blomgren, Klas/0000-0002-0476-7271 FU National Institute of Academic Anaesthesia; Dutch Association of Anesthesiologists; Swedish Research Council; Swedish Childhood Cancer Foundation; Swedish Cancer Foundation; StratNeuro Network at the Karolinska Institute; Stockholm and Gothenburg Freemasons' Pediatric Research; National Institutes of Health (Bethesda, MD, USA) [K08 GM077057, R01 GM088817, 2P01 1HD16596-26, GM49831, NS053898, GM58055, NS56315]; US Air Force [FA8650-11-2-6D04]; US Army [W81XWH-13-1-0016, W81XWH-09-2-0187] FX A.R.A., National Institute of Academic Anaesthesia and Dutch Association of Anesthesiologists; K.B., Swedish Research Council, the Swedish Childhood Cancer Foundation, the Swedish Cancer Foundation, governmental grants from Agreement Concerning Research and Education of Doctors (ALF), the StratNeuro Network at the Karolinska Institute, the Stockholm and Gothenburg Freemasons' Pediatric Research grants; D.C., William F. Milton Fund, National Institutes of Health (Bethesda, MD, USA) K08 GM077057; G.C., National Institutes of Health R01 GM088817; G. F., National Institutes of Health 2P01 1HD16596-26, US Air Force FA8650-11-2-6D04, US Army W81XWH-13-1-0016 and W81XWH-09-2-0187; R.G.G., National Institutes of Health GM49831 and NS053898; H.C.H., National Institutes of Health GM58055 and NS56315; KFH HE4554/5-1 DFG (German Research Foundation); V.J.-T., NIH/NICHD HD 44517 and American Recovery and Reinvestment Act supplement HD 44517S, John E. Fogarty Award TW007423-128322, March of Dimes National Award and Harold Carron endowment. V.J.-T. was an Established Investigator of the American Heart Association; D.M., Medical Research Council, Alzheimer's Society-Bupa Foundation, BJA/RCoA, AAGBI, Westminster Medical School Research Trust, Action Medical Research and SPARKS, UK and European Society of Anesthesiology, Brussels; B.A.O., Canada Research Chair in Anesthesia, and Canadian Institutes of Health Research; E. P., Canadian Institutes for Health Research (MOP-106423, PCN-102993), Natural Sciences and Engineering Research Council (354722), Canada Foundation for Innovation (23905), and Research Scholar Career Awards (16205, 20048) from the Fonds de la Recherche en Sante du Quebec; S.G.S., Boston Children's Hospital Endowed Chair in Pediatric Neuroanesthesia; G.S., John Severinghaus Research Award Department of Anesthesia and Perioperative Care, UCSF; L.V., Swiss National Science Foundation; Z.X., National Institutes of Health R21AG038994, R01 GM088801, and R01 AG041274, Investigator-initiated research grant from Alzheimer's Association, Chicago, IL, USA, and Cure Alzheimer's Fund, Wellesley, MA, USA. NR 83 TC 74 Z9 80 U1 5 U2 26 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0007-0912 J9 BRIT J ANAESTH JI Br. J. Anaesth. PD AUG PY 2013 VL 111 IS 2 BP 143 EP 151 DI 10.1093/bja/aet177 PG 9 WC Anesthesiology SC Anesthesiology GA 190KF UT WOS:000322337900005 PM 23722106 ER PT J AU Khin, NA Yang, P Hung, HMJ Maung-U, K Chen, YF Meeker-O'Connell, A Okwesili, P Yasuda, SU Ball, LK Huang, SM O'Neill, RT Temple, R AF Khin, N. A. Yang, P. Hung, H. M. J. Maung-U, K. Chen, Y-F Meeker-O'Connell, A. Okwesili, P. Yasuda, S. U. Ball, L. K. Huang, S-M O'Neill, R. T. Temple, R. TI Regulatory and Scientific Issues Regarding Use of Foreign Data in Support of New Drug Applications in the United States: An FDA Perspective SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID ACUTE CORONARY SYNDROMES; CLINICAL-TRIALS; HEART-FAILURE; GEOGRAPHIC VARIABILITY; GLYCOPROTEIN IIB/IIIA; SCHIZOPHRENIA TRIALS; EXPLORATORY ANALYSES; INTERNATIONAL TRIAL; INTERVENTION TRIAL; EFFICACY DATA AB Globalization of clinical research has led to an increase in clinical trials conducted outside of the United States that are submitted to the US Food and Drug Administration (FDA) in new drug applications. This article discusses the FDA's experience with these submissions in specific therapeutic areas, including the extent of this practice, differences between the effectiveness and safety outcomes of studies conducted inside and outside the United States, and the FDA's approach to acceptance of these trials. C1 [Khin, N. A.; Maung-U, K.; Yasuda, S. U.; Temple, R.] US FDA, Off Drug Evaluat 1, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Yang, P.; Hung, H. M. J.; Chen, Y-F] US FDA, Off Biostat, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Meeker-O'Connell, A.; Okwesili, P.] US FDA, Off Sci Invest, Off Compliance, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Ball, L. K.] US FDA, Off Int Programs, Off Global Regulatory Operat & Policy, Silver Spring, MD USA. [Huang, S-M] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [O'Neill, R. T.] US FDA, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Temple, R.] US FDA, Off Ctr Director, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Khin, NA (reprint author), US FDA, Off Drug Evaluat 1, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA. EM ni.khin@fda.hhs.gov NR 60 TC 9 Z9 10 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD AUG PY 2013 VL 94 IS 2 BP 230 EP 242 DI 10.1038/clpt.2013.70 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 186SG UT WOS:000322064400023 PM 23588316 ER PT J AU Gorovets, A Marzella, L Rieves, D Yang, L AF Gorovets, Alexander Marzella, Louis Rieves, Dwaine Yang, Lucie TI Efficacy Considerations for US Food and Drug Administration Approval of Diagnostic Radiopharmaceuticals SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE FDA; medical imaging drugs; molecular imaging; radiopharmaceuticals AB The safety and efficacy expectations for U.S. Food and Drug Administration (FDA) approval of diagnostic radiopharmaceuticals (DRs) are described in laws that broadly apply to all prescription drugs and biologic products. These laws also outline efficacy expectations that are unique for DRs. The FDA regulations and guidance documents elaborate on DR efficacy expectations for clinical uses of the drugs, such as the delineation of anatomy, the characterization of a physiologic process, or the diagnosis of disease. As described in the FDA regulations, the approval of a DR necessitates that the imaging drug has the ability to provide clinically useful information. Here we cite approved DRs to illustrate how the imaging performance of the drugs was characterized in clinical studies and the clinical usefulness of the imaging information described in drug labels. C1 [Gorovets, Alexander; Marzella, Louis; Rieves, Dwaine; Yang, Lucie] US FDA, Div Med Imaging Prod, Off Drug Evaluat 4, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Marzella, L (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Libero.Marzella@fda.hhs.gov NR 9 TC 6 Z9 6 U1 1 U2 5 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD AUG PY 2013 VL 54 IS 8 BP 1479 EP 1484 DI 10.2967/jnumed.112.117804 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 195HH UT WOS:000322692400064 PM 23749997 ER PT J AU An, YM Rininger, JA Jarvis, DL Jing, XH Ye, ZP Aumiller, JJ Eichelberger, M Cipollo, JF AF An, Yanming Rininger, Joseph A. Jarvis, Donald L. Jing, Xianghong Ye, Zhiping Aumiller, Jared J. Eichelberger, Maryna Cipollo, John F. TI Comparative Glycomics Analysis of Influenza Hemagglutinin (H5N1) Produced in Vaccine Relevant Cell Platforms SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE hemagglutinin; influenza; glycosylation; mass spectrometry; MSE; permethylation; cell substrate; NetNGlyc ID GLYCOPROTEIN GLYCAN STRUCTURES; CURATED RELATIONAL DATABASE; LEPIDOPTERAN INSECT CELLS; TANDEM MASS-SPECTROMETRY; VIRUS HEMAGGLUTININ; N-GLYCOSYLATION; PROTEIN GLYCOSYLATION; LIQUID-CHROMATOGRAPHY; LINKED GLYCOSYLATION; BIOLOGICAL SOURCES AB Hemagglutinin (HA) is the major antigen in influenza vaccines, and glycosylation is known to influence its antigenicity. Embryonated hen eggs are traditionally used for influenza vaccine production, but vaccines produced in mammalian and insect cells were recently licensed. This raises the concern that vaccines produced with different cell systems might not be equivalent due to differences in their glycosylation patterns. Thus, we developed an analytical method to monitor vaccine glycosylation through a combination of nanoLC/MSE and quantitative MALDI-TOF MS permethylation profiling. We then used this method to examine glycosylation of HAs from two different influenza H5N1 strains produced in five different platforms, including hen eggs, three different insect cell lines (High Five, expresSF+ and glycoengineered expresSF+), and a human cell (HEK293). Our results demonstrated that (1) sequon utilization is not necessarily equivalent in different cell types, (2) there are quantitative and qualitative differences in the overall N-glycosylation patterns and structures produced by different cell types, (3) similar to 20% of the N-glycans on the HAs produced by High Five cells are core alpha 1,3-fucosylated structures, which may be allergenic in humans, and (4) our method can be used to monitor differences in glycosylation during the cellular glycoengineering stages of vaccine development. C1 [An, Yanming; Jing, Xianghong; Ye, Zhiping; Eichelberger, Maryna; Cipollo, John F.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Rininger, Joseph A.] CaroGen Corp, Hamden, CT 06518 USA. [Jarvis, Donald L.; Aumiller, Jared J.] Univ Wyoming, Dept Mol Biol, Laramie, WY 82071 USA. [Jarvis, Donald L.; Aumiller, Jared J.] Rocky Mt Reg Ctr Excellence Bioterrorism & Emergi, Ft Collins, CO 80523 USA. RP Cipollo, JF (reprint author), US FDA, Ctr Biol Evaluat & Res, Bldg 29,Rm 127,8800 Rockville Pike, Bethesda, MD 20892 USA. EM john.cipollo@fda.hhs.gov FU NIH Rocky Mountain Regional Center for Excellence in Bioterrorism and Emerging Infectious Diseases [U54 AI-065357]; CBER Pandemic Flu and Medical Counter Measures targeted internal funds FX We would like to thank Weinbin Chen and Kieron Faherty of Waters Corporation, Milford, MA, for useful and insightful discussions related to this work. We also thank Protein Sciences Corporation for the supply of expressSF+ and SfSWT-7 derived A/Vietnam/1203/2004 HAs. This study was funded by subawards to DLJ and Protein Sciences Corporation from the NIH Rocky Mountain Regional Center for Excellence in Bioterrorism and Emerging Infectious Diseases (U54 AI-065357) and the CBER Pandemic Flu and Medical Counter Measures targeted internal funds. NR 80 TC 11 Z9 11 U1 0 U2 23 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD AUG PY 2013 VL 12 IS 8 BP 3707 EP 3720 DI 10.1021/pr400329k PG 14 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 197LN UT WOS:000322852800015 PM 23848607 ER PT J AU Brunner, CC Stern, SH Minniti, R Parry, MI Skopec, M Chakrabarti, K AF Brunner, Claudia C. Stern, Stanley H. Minniti, Ronaldo Parry, Marie I. Skopec, Marlene Chakrabarti, Kish TI CT head-scan dosimetry in an anthropomorphic phantom and associated measurement of ACR accreditation-phantom imaging metrics under clinically representative scan conditions SO MEDICAL PHYSICS LA English DT Article DE CT; dose; image quality; OSLDs ID COMPUTED-TOMOGRAPHY; RADIATION-EXPOSURE; DOSE REDUCTION; ITERATIVE RECONSTRUCTION; PERSPECTIVE; STRATEGIES; QUALITY; SYSTEM AB Purpose: To measure radiation absorbed dose and its distribution in an anthropomorphic head phantom under clinically representative scan conditions in three widely used computed tomography (CT) scanners, and to relate those dose values to metrics such as high-contrast resolution, noise, and contrast-to-noise ratio (CNR) in the American College of Radiology CT accreditation phantom. Methods: By inserting optically stimulated luminescence dosimeters (OSLDs) in the head of an anthropomorphic phantom specially developed for CT dosimetry (University of Florida, Gainesville), we measured dose with three commonly used scanners (GE Discovery CT750 HD, Siemens Definition, Philips Brilliance 64) at two different clinical sites (Walter Reed National Military Medical Center, National Institutes of Health). The scanners were set to operate with the same data-acquisition and image-reconstruction protocols as used clinically for typical head scans, respective of the practices of each facility for each scanner. We also analyzed images of the ACR CT accreditation phantom with the corresponding protocols. While the Siemens Definition and the Philips Brilliance protocols utilized only conventional, filtered back-projection (FBP) image-reconstruction methods, the GE Discovery also employed its particular version of an adaptive statistical iterative reconstruction (ASIR) algorithm that can be blended in desired proportions with the FBP algorithm. We did an objective image-metrics analysis evaluating the modulation transfer function (MTF), noise power spectrum (NPS), and CNR for images reconstructed with FBP. For images reconstructed with ASIR, we only analyzed the CNR, since MTF and NPS results are expected to depend on the object for iterative reconstruction algorithms. Results: The OSLD measurements showed that the Siemens Definition and the Philips Brilliance scanners (located at two different clinical facilities) yield average absorbed doses in tissue of 42.6 and 43.1 mGy, respectively. The GE Discovery delivers about the same amount of dose (43.7 mGy) when run under similar operating and image-reconstruction conditions, i.e., without tube current modulation and ASIR. The image-metrics analysis likewise showed that the MTF, NPS, and CNR associated with the reconstructed images are mutually comparable when the three scanners are run with similar settings, and differences can be attributed to different edge-enhancement properties of the applied reconstruction filters. Moreover, when the GE scanner was operated with the facility's scanner settings for routine head exams, which apply 50% ASIR and use only approximately half of the 100%-FBP dose, the CNR of the images showed no significant change. Even though the CNR alone is not sufficient to characterize the image quality and justify any dose reduction claims, it can be useful as a constancy test metric. Conclusions: This work presents a straightforward method to connect direct measurements of CT dose with objective image metrics such as high-contrast resolution, noise, and CNR. It demonstrates that OSLD measurements in an anthropomorphic head phantom allow a realistic and locally precise estimation of magnitude and spatial distribution of dose in tissue delivered during a typical CT head scan. Additional objective analysis of the images of the ACR accreditation phantom can be used to relate the measured doses to high contrast resolution, noise, and CNR. (C) 2013 American Association of Physicists in Medicine. C1 [Brunner, Claudia C.; Stern, Stanley H.; Chakrabarti, Kish] US FDA, Silver Spring, MD 20993 USA. [Minniti, Ronaldo] NIST, Gaithersburg, MD 20899 USA. [Parry, Marie I.] Walter Reed Natl Mil Med Ctr, Bethesda, MD 20889 USA. [Skopec, Marlene] NIH, Bethesda, MD 20892 USA. RP Chakrabarti, K (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM kish.chakrabarti@fda.hhs.gov FU FDA Critical Path Initiative FX Claudia C. Brunner was funded by the FDA Critical Path Initiative. The authors wish to acknowledge the invaluable help provided by Arvel J. New (WRNMMC) and Fred Dowdell (NIH) in collecting data in clinical settings. The authors further thank John Jaeckle and Paavana Sainath of GE for lending us the GEPP and answering our questions as well as Dominic Siewko of Philips for his help. Finally, the authors want to thank Michelle O'Brien at NIST for her support in providing the x-ray reference beams at NIST. NR 39 TC 2 Z9 2 U1 1 U2 8 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD AUG PY 2013 VL 40 IS 8 AR 081917 DI 10.1118/1.4815964 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 195XC UT WOS:000322735900039 PM 23927331 ER PT J AU Petrick, N Sahiner, B Armato, SG Bert, A Correale, L Delsanto, S Freedman, MT Fryd, D Gur, D Hadjiiski, L Huo, ZM Jiang, YL Morra, L Paquerault, S Raykar, V Samuelson, F Summers, RM Tourassi, G Yoshida, H Zheng, B Zhou, C Chan, HP AF Petrick, Nicholas Sahiner, Berkman Armato, Samuel G., III Bert, Alberto Correale, Loredana Delsanto, Silvia Freedman, Matthew T. Fryd, David Gur, David Hadjiiski, Lubomir Huo, Zhimin Jiang, Yulei Morra, Lia Paquerault, Sophie Raykar, Vikas Samuelson, Frank Summers, Ronald M. Tourassi, Georgia Yoshida, Hiroyuki Zheng, Bin Zhou, Chuan Chan, Heang-Ping TI Evaluation of computer-aided detection and diagnosis systems SO MEDICAL PHYSICS LA English DT Article DE computer-aided detection and diagnosis (CAD); computer-aided detection (CADe); computer-aided diagnosis (CADx); performance assessment; standalone performance; reader performance; clinical performance ID OPERATING CHARACTERISTIC ANALYSIS; BREAST-CANCER DETECTION; MAXIMUM-LIKELIHOOD-ESTIMATION; IMAGE DATABASE CONSORTIUM; SMALL PULMONARY NODULES; MEMORIAL FUND LECTURE; CT COLONOGRAPHY; LUNG NODULES; SCREENING MAMMOGRAPHY; OBSERVER-PERFORMANCE AB Computer-aided detection and diagnosis (CAD) systems are increasingly being used as an aid by clinicians for detection and interpretation of diseases. Computer-aided detection systems mark regions of an image that may reveal specific abnormalities and are used to alert clinicians to these regions during image interpretation. Computer-aided diagnosis systems provide an assessment of a disease using image-based information alone or in combination with other relevant diagnostic data and are used by clinicians as a decision support in developing their diagnoses. While CAD systems are commercially available, standardized approaches for evaluating and reporting their performance have not yet been fully formalized in the literature or in a standardization effort. This deficiency has led to difficulty in the comparison of CAD devices and in understanding how the reported performance might translate into clinical practice. To address these important issues, the American Association of Physicists in Medicine (AAPM) formed the Computer Aided Detection in Diagnostic Imaging Subcommittee (CADSC), in part, to develop recommendations on approaches for assessing CAD system performance. The purpose of this paper is to convey the opinions of the AAPM CADSC members and to stimulate the development of consensus approaches and "best practices" for evaluating CAD systems. Both the assessment of a standalone CAD system and the evaluation of the impact of CAD on end-users are discussed. It is hoped that awareness of these important evaluation elements and the CADSC recommendations will lead to further development of structured guidelines for CAD performance assessment. Proper assessment of CAD system performance is expected to increase the understanding of a CAD system's effectiveness and limitations, which is expected to stimulate further research and development efforts on CAD technologies, reduce problems due to improper use, and eventually improve the utility and efficacy of CAD in clinical practice. (C) 2013 American Association of Physicists in Medicine. C1 [Petrick, Nicholas; Sahiner, Berkman; Samuelson, Frank] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Armato, Samuel G., III; Jiang, Yulei] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. [Bert, Alberto; Correale, Loredana; Delsanto, Silvia; Morra, Lia] im3D SpA, I-10153 Turin, Italy. [Freedman, Matthew T.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Fryd, David] Riverain Med, Miamisburg, OH 45342 USA. [Gur, David] Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15213 USA. [Hadjiiski, Lubomir; Zhou, Chuan; Chan, Heang-Ping] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. [Huo, Zhimin] Carestream Hlth Inc, Rochester, NY 14615 USA. [Raykar, Vikas] IBM Res, Nagawara Bangalore 560045, India. [Summers, Ronald M.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Tourassi, Georgia] Oak Ridge Natl Lab, Computat Sci & Engn Div, Oak Ridge, TN 37831 USA. [Yoshida, Hiroyuki] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Yoshida, Hiroyuki] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Zheng, Bin] Univ Oklahoma, Sch Elect & Comp Engn, Norman, OK 73019 USA. RP Chan, HP (reprint author), Univ Michigan, Dept Radiol, 1500 East Med Ctr Dr,MIB C479, Ann Arbor, MI 48109 USA. EM chanhp@umich.edu OI Bert, Alberto/0000-0001-8391-7508; Tourassi, Georgia/0000-0002-9418-9638; Zheng, Bin/0000-0002-7682-6648 FU Intramural Research Program of the National Institutes of Health, Clinical Center; University of Chicago; iCAD; Riverain Technologies through Georgetown University Medical Center FX The authors are grateful to the members and participants of the CADSC who have contributed to the stimulating discussions during many meetings and teleconferences. R. M. S. is supported in part by the Intramural Research Program of the National Institutes of Health, Clinical Center; the views expressed in this paper are the opinions of the authors and do not necessarily represent the views of the National Institutes of Health or the Department of Health and Human Services. S. G. A. and H.Y. receive royalties and licensing fees through the University of Chicago related to CAD. R. M. S. receives patent royalties and research support related to CAD from iCAD. M. T. F. receives funding from Riverain Technologies through Georgetown University Medical Center. NR 139 TC 9 Z9 10 U1 4 U2 34 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD AUG PY 2013 VL 40 IS 8 AR 087001 DI 10.1118/1.4816310 PG 17 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 195XC UT WOS:000322735900073 PM 23927365 ER PT J AU Rupcich, F Badal, A Popescu, LM Kyprianou, I Schmidt, TG AF Rupcich, Franco Badal, Andreu Popescu, Lucretiu M. Kyprianou, Iacovos Schmidt, Taly Gilat TI Reducing radiation dose to the female breast during CT coronary angiography: A simulation study comparing breast shielding, angular tube current modulation, reduced kV, and partial angle protocols using an unknown-location signal-detectability metric SO MEDICAL PHYSICS LA English DT Article DE CT dose; breast dose; CT image quality; signal detectability ID COMPUTED-TOMOGRAPHY; THORACIC CT; IMAGE QUALITY; MULTIDETECTOR CT; REDUCTION; PERFORMANCE; SPECTRA; SCATTER; TISSUES; PHANTOM AB Purpose: The authors compared the performance of five protocols intended to reduce dose to the breast during computed tomography (CT) coronary angiography scans using a model observer unknown-location signal-detectability metric. Methods: The authors simulated CT images of an anthropomorphic female thorax phantom for a 120 kV reference protocol and five "dose reduction" protocols intended to reduce dose to the breast: 120 kV partial angle (posteriorly centered), 120 kV tube-current modulated (TCM), 120 kV with shielded breasts, 80 kV, and 80 kV partial angle (posteriorly centered). Two image quality tasks were investigated: the detection and localization of 4-mm, 3.25 mg/ml and 1-mm, 6.0 mg/ml iodine contrast signals randomly located in the heart region. For each protocol, the authors plotted the signal detectability, as quantified by the area under the exponentially transformed free response characteristic curve estimator ((A) over cap (FE)), as well as noise and contrast-to-noise ratio (CNR) versus breast and lung dose. In addition, the authors quantified each protocol's dose performance as the percent difference in dose relative to the reference protocol achieved while maintaining equivalent (A) over cap (FE). Results: For the 4-mm signal-size task, the 80 kV full scan and 80 kV partial angle protocols decreased dose to the breast (80.5% and 85.3%, respectively) and lung (80.5% and 76.7%, respectively) with (A) over cap (FE) = 0.96, but also resulted in an approximate three-fold increase in image noise. The 120 kV partial protocol reduced dose to the breast (17.6%) at the expense of increased lung dose (25.3%). The TCM algorithm decreased dose to the breast (6.0%) and lung (10.4%). Breast shielding increased breast dose (67.8%) and lung dose (103.4%). The 80 kV and 80 kV partial protocols demonstrated greater dose reductions for the 4-mm task than for the 1-mm task, and the shielded protocol showed a larger increase in dose for the 4-mm task than for the 1-mm task. In general, the CNR curves indicate a similar relative ranking of protocol performance as the corresponding (A) over cap (FE) curves, however, the CNR metric overestimated the performance of the shielded protocol for both tasks, leading to corresponding underestimates in the relative dose increases compared to those obtained when using the (A) over cap (FE) metric. Conclusions: The 80 kV and 80 kV partial angle protocols demonstrated the greatest reduction to breast and lung dose, however, the subsequent increase in image noise may be deemed clinically unacceptable. Tube output for these protocols can be adjusted to achieve a more desirable noise level with lesser breast dose savings. Breast shielding increased breast and lung dose when maintaining equivalent (A) over cap (FE). The results demonstrated that comparisons of dose performance depend on both the image quality metric and the specific task, and that CNR may not be a reliable metric of signal detectability. (C) 2013 American Association of Physicists in Medicine. C1 [Rupcich, Franco; Schmidt, Taly Gilat] Marquette Univ, Dept Biomed Engn, Milwaukee, WI 53233 USA. [Badal, Andreu; Popescu, Lucretiu M.; Kyprianou, Iacovos] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20905 USA. RP Rupcich, F (reprint author), Marquette Univ, Dept Biomed Engn, Milwaukee, WI 53233 USA. EM franco.rupcich@mu.edu; Andreu.Badal-Soler@fda.hhs.gov; Lucretiu.Popescu@fda.hhs.gov; Iacovos.Kyprianou@fda.hhs.gov; taly.gilat-schmidt@mu.edu OI Schmidt, Taly/0000-0002-9840-0963 FU National Science Foundation [OCI-0923037, CBET-0521602] FX This study was supported in part by an appointment to the Research Participation Program at the FDA Center for Devices and Radiological Health administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the United States Department of Energy and the Food and Drug Administration, Office of Women's Health. Computer simulations were performed on the Marquette University Pere High Performance Computing Cluster, which was funded in part by National Science Foundation Award Nos. OCI-0923037 and CBET-0521602. The authors would like to thank Lars E. Olson, Ph.D. and David Herzfeld for their support with the high performance cluster. NR 51 TC 4 Z9 4 U1 0 U2 8 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD AUG PY 2013 VL 40 IS 8 AR 081921 DI 10.1118/1.4816302 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 195XC UT WOS:000322735900043 PM 23927335 ER PT J AU de Conti, A Tryndyak, V Koturbash, I Heidor, R Kuroiwa-Trzmielina, J Ong, TP Beland, FA Moreno, FS Pogribny, IP AF de Conti, Aline Tryndyak, Volodymyr Koturbash, Igor Heidor, Renato Kuroiwa-Trzmielina, Joice Ong, Thomas P. Beland, Frederick A. Moreno, Fernando S. Pogribny, Igor P. TI The chemopreventive activity of the butyric acid prodrug tributyrin in experimental rat hepatocarcinogenesis is associated with p53 acetylation and activation of the p53 apoptotic signaling pathway SO CARCINOGENESIS LA English DT Article ID TUMOR-TRANSFORMING GENE-1; HEPATOCELLULAR-CARCINOMA; GROWTH ARREST; IN-VIVO; CANCER CHEMOPREVENTION; HEPATIC PRENEOPLASIA; AUTOPHAGY; OVEREXPRESSION; TARGET; LIVER AB The reversibility of non-genotoxic phenotypic alterations has been explored in order to develop novel preventive and therapeutic approaches for cancer control. Previously, it has been demonstrated that histone deacetylase (HDAC) inhibitor tributyrin, a butyric acid prodrug, to have chemopreventive effects on rat hepatocarcinogenesis. The goal of this study was to determine molecular mechanisms associated with the chemopreventive activity of tributyrin. Male Wistar rats were allocated randomly to untreated control group and two experimental groups. Rats in the experimental group 1 were treated with maltodextrin (3g/kg body wt), and rats in experimental group 2 were treated with tributyrin (2g/kg body wt) daily for 8 weeks. Two weeks after treatment initiation, rats from experimental groups were subjected to a resistant hepatocyte model of hepatocarcinogenesis. Treatment with tributyrin resulted in lower HDAC activity and Hdac3 and Hdac4 gene expression, and an increase of histone H3 lysine 9 and 18 and histone H4 lysine 16 acetylation as compared with the experimental group 1. In addition to the increase in histone acetylation, tributyrin caused an increase in the acetylation of the nuclear p53 protein. These changes were accompanied by a normalization of the p53-signaling network, particularly by the upregulation of pro-apoptotic genes, and a consequent increase of apoptosis and autophagy in the livers of tributyrin-treated rats. These results indicate that the chemopreventive activity of tributyrin may be related to an increase of histone and p53 acetylation, which could lead to the induction of the p53 apoptotic pathway. C1 [de Conti, Aline; Heidor, Renato; Kuroiwa-Trzmielina, Joice; Ong, Thomas P.; Moreno, Fernando S.] Univ Sao Paulo, Dept Food & Expt Nutr, Lab Diet Nutr & Canc, Fac Pharmaceut Sci, BR-05508900 Sao Paulo, Brazil. [de Conti, Aline; Tryndyak, Volodymyr; Koturbash, Igor; Beland, Frederick A.; Pogribny, Igor P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Koturbash, Igor] Univ Arkansas Med Sci, Dept Environm & Occupat Hlth, Little Rock, AR 72205 USA. RP Pogribny, IP (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM rmoreno@usp.br; igor.pogribny@fda.hhs.gov RI Ong, Thomas/C-4494-2012; Heidor, Renato/P-6444-2015; Moreno, Fernando/I-1943-2013; Heidor, Renato/O-1125-2013 OI Heidor, Renato/0000-0001-7427-6518 NR 51 TC 14 Z9 14 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 2013 VL 34 IS 8 BP 1900 EP 1906 DI 10.1093/carcin/bgt124 PG 7 WC Oncology SC Oncology GA 194XU UT WOS:000322666800024 PM 23568954 ER PT J AU Elkins, CA Kotewicz, ML Jackson, SA Lacher, DW Abu-Ali, GS Patel, IR AF Elkins, C. A. Kotewicz, M. L. Jackson, S. A. Lacher, D. W. Abu-Ali, G. S. Patel, I. R. TI Genomic paradigms for food-borne enteric pathogen analysis at the USFDA: case studies highlighting method utility, integration and resolution SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE food-borne bacterial pathogens; regulatory science; genomic methods; strain discrimination ID ESCHERICHIA-COLI O157-H7; FIELD GEL-ELECTROPHORESIS; HEMOLYTIC-UREMIC SYNDROME; UNITED-STATES; SALMONELLA; OUTBREAK; STRAINS; INFECTIONS; SURVEILLANCE; SEQUENCE AB Modern risk control and food safety practices involving food-borne bacterial pathogens are benefiting from new genomic technologies for rapid, yet highly specific, strain characterisations. Within the United States Food and Drug Administration (USFDA) Center for Food Safety and Applied Nutrition (CFSAN), optical genome mapping and DNA microarray genotyping have been used for several years to quickly assess genomic architecture and gene content, respectively, for outbreak strain subtyping and to enhance retrospective trace-back analyses. The application and relative utility of each method varies with outbreak scenario and the suspect pathogen, with comparative analytical power enhanced by database scale and depth. Integration of these two technologies allows high-resolution scrutiny of the genomic landscapes of enteric food-borne pathogens with notable examples including Shiga toxin-producing Escherichia coli (STEC) and Salmonella enterica serovars from a variety of food commodities. Moreover, the recent application of whole genome sequencing technologies to food-borne pathogen outbreaks and surveillance has enhanced resolution to the single nucleotide scale. This new wealth of sequence data will support more refined next-generation custom microarray designs, targeted re-sequencing and genomic signature recognition approaches involving a combination of genes and single nucleotide polymorphism detection to distil strain-specific fingerprinting to a minimised scale. This paper examines the utility of microarrays and optical mapping in analysing outbreaks, reviews best practices and the limits of these technologies for pathogen differentiation, and it considers future integration with whole genome sequencing efforts. C1 [Elkins, C. A.; Kotewicz, M. L.; Jackson, S. A.; Lacher, D. W.; Abu-Ali, G. S.; Patel, I. R.] US FDA, Div Mol Biol, CFSAN, Laurel, MD 20708 USA. RP Elkins, CA (reprint author), US FDA, Div Mol Biol, CFSAN, Laurel, MD 20708 USA. EM chris.elkins@fda.hhs.gov FU Center for Food Safety and Applied Nutrition (CFSAN) FX The authors would like to acknowledge the visionary efforts of J. Eugene LeClerc and Thomas A. Cebula for instituting and sustaining the genomics programme for food-borne pathogen analysis within the United States Food and Drug Administration (USFDA). This initiative also received extramural support from the National Bioforensics Analysis Center (NBFAC) and the Department of Homeland Security (DHS) for development of the microarray and optical mapping programmes. This study was funded by the Center for Food Safety and Applied Nutrition (CFSAN). The views presented in this paper do not necessarily reflect those of the USFDA. NR 42 TC 7 Z9 7 U1 0 U2 17 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1944-0049 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PD AUG 1 PY 2013 VL 30 IS 8 SI SI BP 1422 EP 1436 DI 10.1080/19440049.2012.743192 PG 15 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA 195IV UT WOS:000322696500011 PM 23199033 ER PT J AU Datta, AR Laksanalamai, P Solomotis, M AF Datta, Atin R. Laksanalamai, Pongpan Solomotis, Marianne TI Recent developments in molecular sub-typing of Listeria monocytogenes SO FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT LA English DT Article DE Listeria monocytogenes; molecular sub-typing; epidemiology ID FIELD GEL-ELECTROPHORESIS; LOCUS VARIABLE-NUMBER; SINGLE-NUCLEOTIDE POLYMORPHISMS; REPEAT ANALYSIS MLVA; FEBRILE GASTROENTERITIS; OUTBREAK STRAINS; UNITED-STATES; FOODBORNE LISTERIOSIS; EPIDEMIC LISTERIOSIS; MULTIPLEX PCR AB As a vast majority of the human listeriosis cases are caused by serotypes 1/2a, 1/2b and 4b strains, it is imperative that strains from clinical as well as from food and environment are further characterised so that accurate and timely epidemiological determination of sources of the contamination can be established to minimise the disease burden. Recent developments in the field of genomics provide a great opportunity to use these tools towards the development of molecular sub-typing techniques with a greater degree of discrimination spanning the entire length of the genome. This brief review summarises a few of these DNA-based techniques with an emphasis on DNA microarray and other whole genome sequencing-based approaches and their usefulness in Listeria monocytogenes sub-typing and outbreak investigations. C1 [Datta, Atin R.; Laksanalamai, Pongpan; Solomotis, Marianne] US FDA, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD USA. RP Datta, AR (reprint author), US FDA, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD USA. EM atin.datta@fda.hhs.gov NR 67 TC 6 Z9 6 U1 2 U2 17 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1944-0049 J9 FOOD ADDIT CONTAM A JI Food Addit. Contam. Part A-Chem. PD AUG 1 PY 2013 VL 30 IS 8 SI SI BP 1437 EP 1445 DI 10.1080/19440049.2012.728722 PG 9 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA 195IV UT WOS:000322696500012 PM 23061558 ER PT J AU Broadway, MM Rogers, EA Chang, CY Huang, IH Dwivedi, P Yildirim, S Schmitt, MP Das, A Ton-That, H AF Broadway, Melissa M. Rogers, Elizabeth A. Chang, Chungyu Huang, I-Hsiu Dwivedi, Prabhat Yildirim, Suleyman Schmitt, Michael P. Das, Asis Ton-That, Hung TI Pilus Gene Pool Variation and the Virulence of Corynebacterium diphtheriae Clinical Isolates during Infection of a Nematode SO JOURNAL OF BACTERIOLOGY LA English DT Article ID GRAM-POSITIVE BACTERIA; CAENORHABDITIS-ELEGANS; MOLECULAR EPIDEMIOLOGY; GENOME SEQUENCE; TOXIN GENE; PCR ASSAY; SURFACE; PATHOGEN; DIVERSITY; STRAINS AB Toxigenic Corynebacterium diphtheriae strains cause diphtheria in humans. The toxigenic C. diphtheriae isolate NCTC13129 produces three distinct heterotrimeric pili that contain SpaA, SpaD, and SpaH, making up the shaft structure. The SpaA pili are known to mediate bacterial adherence to pharyngeal epithelial cells. However, to date little is known about the expression of different pili in various clinical isolates and their importance in bacterial pathogenesis. Here, we characterized a large collection of C. diphtheriae clinical isolates for their pilin gene pool by PCR and for the expression of the respective pilins by immunoblotting with antibodies against Spa pilins. Consistent with the role of a virulence factor, the SpaA-type pili were found to be prevalent among the isolates, and most significantly, corynebacterial adherence to pharyngeal epithelial cells was strictly correlated with isolates that were positive for the SpaA pili. By comparison, the isolates were heterogeneous for the presence of SpaD- and SpaH-type pili. Importantly, using Caenorhabditis elegans as a model host for infection, we show here that strain NCTC13129 rapidly killed the nematodes, the phenotype similar to isolates that were positive for toxin and all pilus types. In contrast, isogenic mutants of NCTC13129 lacking SpaA-type pili or devoid of toxin and SpaA pili exhibited delayed killing of nematodes with similar kinetics. Consistently, nontoxigenic or toxigenic isolates that lack one, two, or all three pilus types were also attenuated in virulence. This work signifies the important role of pili in corynebacterial pathogenesis and provides a simple host model to identify additional virulence factors. C1 [Broadway, Melissa M.; Rogers, Elizabeth A.; Chang, Chungyu; Huang, I-Hsiu; Dwivedi, Prabhat; Ton-That, Hung] Univ Texas Hlth Sci Ctr Houston, Dept Microbiol & Mol Genet, Houston, TX 77030 USA. [Yildirim, Suleyman; Das, Asis] Univ Connecticut, Ctr Hlth, Dept Mol Microbial & Struct Biol, Farmington, CT USA. [Schmitt, Michael P.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Ton-That, H (reprint author), Univ Texas Hlth Sci Ctr Houston, Dept Microbiol & Mol Genet, Houston, TX 77030 USA. EM ton-that.hung@uth.tmc.edu OI Ton-That, Hung/0000-0003-1611-0469 FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R56AI061381] FX Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award no. R56AI061381 to H. T.-T. NR 35 TC 6 Z9 6 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD AUG PY 2013 VL 195 IS 16 BP 3774 EP 3783 DI 10.1128/JB.00500-13 PG 10 WC Microbiology SC Microbiology GA 188VX UT WOS:000322226100029 PM 23772071 ER PT J AU De, A Meier, K Tang, R Li, MJ Gwise, T Gomatam, S Pennello, G AF De, Arkendra Meier, Kristen Tang, Rong Li, Meijuan Gwise, Thomas Gomatam, Shanti Pennello, Gene TI Evaluation of Heart Failure Biomarker Tests: A Survey of Statistical Considerations SO JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH LA English DT Article DE Biomarker; Reproducibility; Statistics; Prognosis; CLSI; Treatment selection ID CLINICAL-TRIALS; MISSING DATA; ROC CURVE; MARKER; PERFORMANCE; PREDICTION; REJECTION; MODELS AB Biomarkers assessing cardiovascular function can encompass a wide range of biochemical or physiological measurements. Medical tests that measure biomarkers are typically evaluated for measurement validation and clinical performance in the context of their intended use. General statistical principles for the evaluation of medical tests are discussed in this paper in the context of heart failure. Statistical aspects of study design and analysis to be considered while assessing the quality of measurements and the clinical performance of tests are highlighted. A discussion of statistical considerations for specific clinical uses is also provided. The remarks in this paper mainly focus on methods and considerations for statistical evaluation of medical tests from the perspective of bias and precision. With such an evaluation of performance, healthcare professionals could have information that leads to a better understanding on the strengths and limitations of tests related to heart failure. C1 [De, Arkendra; Meier, Kristen; Tang, Rong; Li, Meijuan; Gomatam, Shanti; Pennello, Gene] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Gwise, Thomas] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP De, A (reprint author), US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave,White Oak Bldg 66, Silver Spring, MD 20993 USA. EM arkendra.de@fda.hhs.gov NR 50 TC 5 Z9 6 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1937-5387 J9 J CARDIOVASC TRANSL JI J. Cardiovasc. Transl. Res. PD AUG PY 2013 VL 6 IS 4 SI SI BP 449 EP 457 DI 10.1007/s12265-013-9470-3 PG 9 WC Cardiac & Cardiovascular Systems; Medicine, Research & Experimental SC Cardiovascular System & Cardiology; Research & Experimental Medicine GA 184DV UT WOS:000321868500002 PM 23670231 ER PT J AU Siefert, AW Jimenez, JH Koomalsingh, KJ Aguel, F West, DS Shuto, T Snow, TK Gorman, RC Gorman, JH Yoganathan, AP AF Siefert, Andrew W. Jimenez, Jorge H. Koomalsingh, Kevin J. Aguel, Fernando West, Dustin S. Shuto, Takashi Snow, Teresa K. Gorman, Robert C. Gorman, Joseph H., III Yoganathan, Ajit P. TI Contractile mitral annular forces are reduced with ischemic mitral regurgitation SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID BIOPROSTHETIC HEART-VALVES; ANNULOPLASTY RING; IN-VIVO; MODEL AB Objective: Forces acting on mitral annular devices in the setting of ischemic mitral regurgitation are currently unknown. The aim of this study was to quantify the cyclic forces that result from mitral annular contraction in a chronic ischemic mitral regurgitation ovine model and compare them with forces measured previously in healthy animals. Methods: A novel force transducer was implanted in the mitral annulus of 6 ovine subjects 8 weeks after an inferior left ventricle infarction that produced progressive, severe chronic ischemic mitral regurgitation. Septal-lateral and transverse forces were measured continuously for cardiac cycles reaching a peak left ventricular pressure of 90, 125, 150, 175, and 200 mm Hg. Cyclic forces and their rate of change during isovolumetric contraction were quantified and compared with those measured in healthy animals. Results: Animals with chronic ischemic mitral regurgitation exhibited a mean mitral regurgitation grade of 2.3 +/- 0.5. Ischemic mitral regurgitation was observed to decrease significantly septal-lateral forces at each level of left ventricular pressure (P < .01). Transverse forces were consistently lower in the ischemic mitral regurgitation group despite not reaching statistical significance. The rate of change of these forces during isovolumetric contraction was found to increase significantly with peak left ventricular pressure (P < .005), but did not differ significantly between animal groups. Conclusions: Mitral annular forces were measured for the first time in a chronic ischemic mitral regurgitation animal model. Our findings demonstrated an inferior left ventricular infarct to decrease significantly cyclic septal-lateral forces while modestly lowering those in the transverse. The measurement of these forces and their variation with left ventricular pressure contributes significantly to the development of mitral annular ischemic mitral regurgitation devices. C1 [Siefert, Andrew W.; Jimenez, Jorge H.; West, Dustin S.; Yoganathan, Ajit P.] Georgia Inst Technol, Wallace H Coulter Dept Biomed Engn, Atlanta, GA 30332 USA. [Siefert, Andrew W.; Jimenez, Jorge H.; West, Dustin S.; Yoganathan, Ajit P.] Emory Univ, Atlanta, GA 30322 USA. [Koomalsingh, Kevin J.; Shuto, Takashi; Gorman, Robert C.; Gorman, Joseph H., III] Univ Penn, Gorman Cardiovasc Res Grp, Glenolden, PA USA. [Snow, Teresa K.] Georgia Inst Technol, Sch Appl Physiol, Atlanta, GA 30332 USA. [Aguel, Fernando] US FDA, Div Cardiovasc Devices, Silver Spring, MD USA. RP Yoganathan, AP (reprint author), 313 Ferst Dr, Atlanta, GA 30332 USA. EM ajit.yoganathan@bme.gatech.edu FU Food and Drug Administration [FDA1061718]; National Heart, Lung and Blood Institute of the National Institutes of Health, Bethesda, Md [HL63954, HL73021]; American Heart Association, Dallas, Tex FX This study was supported by a research grant awarded from the Food and Drug Administration (FDA1061718) and by grants from the National Heart, Lung and Blood Institute of the National Institutes of Health, Bethesda, Md. (HL63954 and HL73021). Dr Gorman and Dr Gorman were supported by individual Established Investigator Awards from the American Heart Association, Dallas, Tex. NR 26 TC 7 Z9 7 U1 1 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD AUG PY 2013 VL 146 IS 2 BP 422 EP 428 DI 10.1016/j.jtcvs.2012.10.006 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 194LS UT WOS:000322635400027 PM 23111017 ER PT J AU Galvin, TA Ahmed, IA Shahabuddin, M Bryan, T Khan, AS AF Galvin, Teresa A. Ahmed, Imran A. Shahabuddin, Muhammad Bryan, Theodore Khan, Arifa S. TI Identification of Recombination in the Envelope Gene of Simian Foamy Virus Serotype 2 Isolated from Macaca cyclopis SO JOURNAL OF VIROLOGY LA English DT Article ID INFECTION; EXPRESSION; GENOMES; RHESUS AB The full-length sequence of simian foamy virus serotype 2 (SFVmcy-2), isolated from a Taiwanese macaque, was determined. SFVmcy-2 was highly related to SFV serotype 1 (SFVmcy-1), an isolate from the same species, except in the putative receptor binding domain (RBD) in env, which contained novel sequences related to SFV serotype 3 (SFVagm-3), isolated from an African green monkey. The results identify a potential region of neutralization in SFVs and demonstrate recombination between genetically divergent foamy viruses. C1 [Galvin, Teresa A.; Ahmed, Imran A.; Shahabuddin, Muhammad; Bryan, Theodore; Khan, Arifa S.] US FDA, Lab Retroviruses, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Khan, AS (reprint author), US FDA, Lab Retroviruses, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. EM arifa.khan@fda.hhs.gov NR 22 TC 8 Z9 8 U1 2 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2013 VL 87 IS 15 BP 8792 EP 8797 DI 10.1128/JVI.03555-12 PG 6 WC Virology SC Virology GA 180JO UT WOS:000321590200046 PM 23698303 ER PT J AU Wan, HQ Gao, J Xu, KM Chen, HJ Couzens, LK Rivers, KH Easterbrook, JD Yang, KV Zhong, L Rajabi, M Ye, JQ Sultana, I Wan, XF Liu, XF Perez, DR Taubenberger, JK Eichelberger, MC AF Wan, Hongquan Gao, Jin Xu, Kemin Chen, Hongjun Couzens, Laura K. Rivers, Katie H. Easterbrook, Judy D. Yang, Kevin Zhong, Lei Rajabi, Mohsen Ye, Jianqiang Sultana, Ishrat Wan, Xiu-Feng Liu, Xiufan Perez, Daniel R. Taubenberger, Jeffery K. Eichelberger, Maryna C. TI Molecular Basis for Broad Neuraminidase Immunity: Conserved Epitopes in Seasonal and Pandemic H1N1 as Well as H5N1 Influenza Viruses SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN AIRWAY EPITHELIUM; A-VIRUS; MONOCLONAL-ANTIBODIES; CROSS-PROTECTION; ANTIGENIC DRIFT; VACCINE; INFECTION; NA; HEMAGGLUTININ; IMMUNIZATION AB Influenza A viruses, including H1N1 and H5N1 subtypes, pose a serious threat to public health. Neuraminidase (NA)-related immunity contributes to protection against influenza virus infection. Antibodies to the N1 subtype provide protection against homologous and heterologous H1N1 as well as H5N1 virus challenge. Since neither the strain-specific nor conserved epitopes of N1 have been identified, we generated a panel of mouse monoclonal antibodies (MAbs) that exhibit different reactivity spectra with H1N1 and H5N1 viruses and used these MAbs to map N1 antigenic domains. We identified 12 amino acids essential for MAb binding to the NA of a recent seasonal H1N1 virus, A/Brisbane/59/2007. Of these, residues 248, 249, 250, 341, and 343 are recognized by strain-specific group A MAbs, while residues 273, 338, and 339 are within conserved epitope(s), which allows cross-reactive group B MAbs to bind the NAs of seasonal H1N1 and the 1918 and 2009 pandemic (09pdm) H1N1 as well as H5N1 viruses. A single dose of group B MAbs administered prophylactically fully protected mice against lethal challenge with seasonal and 09pdm H1N1 viruses and resulted in significant protection against the highly pathogenic wild-type H5N1 virus. Another three N1 residues (at positions 396, 397, and 456) are essential for binding of cross-reactive group E MAbs, which differ from group B MAbs in that they do not bind 09pdm H1N1 viruses. The identification of conserved N1 epitopes reveals the molecular basis for NA-mediated immunity between H1N1 and H5N1 viruses and demonstrates the potential for developing broadly protective NA-specific antibody treatments for influenza. C1 [Wan, Hongquan; Gao, Jin; Couzens, Laura K.; Rivers, Katie H.; Yang, Kevin; Rajabi, Mohsen; Sultana, Ishrat; Eichelberger, Maryna C.] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Xu, Kemin; Chen, Hongjun; Perez, Daniel R.] Univ Maryland, Dept Vet Med, College Pk, MD 20742 USA. [Xu, Kemin; Chen, Hongjun; Perez, Daniel R.] Virginia Maryland Reg Coll Vet Med, College Pk, MD USA. [Easterbrook, Judy D.; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Zhong, Lei; Liu, Xiufan] Yangzhou Univ, Coll Vet Med, Anim Infect Dis Lab, Yangzhou, Jiangsu, Peoples R China. [Ye, Jianqiang; Wan, Xiu-Feng] Mississippi State Univ, Coll Vet Med, Dept Basic Sci, Mississippi State, MS 39762 USA. RP Eichelberger, MC (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. EM maryna.eichelberger@fda.hhs.gov OI Perez, Daniel/0000-0002-6569-5689 FU Intramural Research Program of the NIH; NIAID; intramural FDA funds; Major State Basic Research Development Program of China (973 Program) [2011CB505003]; NIAID, NIH [HHSN266200700010C]; Oak Ridge Institute for Science and Education FX This work was supported in part by the Intramural Research Program of the NIH and the NIAID (J.K.T.) and by intramural FDA funds. L.Z. and X. L. were funded by the Major State Basic Research Development Program of China (973 Program grant number 2011CB505003). K. X., H. C., and D. R. P. were funded by contract HHSN266200700010C from the NIAID, NIH. L. K. C., K.Y., M. R., and I. S. were supported by training funds administered by the Oak Ridge Institute for Science and Education. NR 46 TC 28 Z9 28 U1 1 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2013 VL 87 IS 16 BP 9290 EP 9300 DI 10.1128/JVI.01203-13 PG 11 WC Virology SC Virology GA 193CS UT WOS:000322535600043 PM 23785204 ER PT J AU Wilson, MR Allard, MW Brown, EW AF Wilson, Mark R. Allard, Marc W. Brown, Eric W. TI The forensic analysis of foodborne bacterial pathogens in the age of whole-genome sequencing SO CLADISTICS LA English DT Article ID CONTROL REGION SEQUENCES; SALMONELLA-ENTERICA SEROTYPES; MTDNA DATA SET; PHYLOGENETIC ANALYSIS; QUALITY ASSESSMENT; MITOCHONDRIAL-DNA; UNITED-STATES; GENERATION; TRANSMISSION; EVOLUTION AB The forensic evaluation of bacterial pathogens presents new challenges to the forensic science community. This review examines bacterial pathogens as objects of forensic comparison, focusing on their nucleic acid sequences as an important aspect of the comparison process. Because of the clonal propagation of most bacterial pathogens, a phylogenetic approach to understanding the diversity and using this understanding to address common forensic questions is explored. As a general phylogenetic framework is now employed in human mitochondrial DNA analysis, we will use the relevant concepts and approaches common in this area to develop this approach further. We also address the impact of the current ease and prevalence of whole-genome DNA sequence analysis in the forensic comparison process. (C) The Willi Hennig Society 2013. C1 [Wilson, Mark R.] Western Carolina Univ, Forens Sci Program, Cullowhee, NC 28723 USA. [Allard, Marc W.; Brown, Eric W.] US FDA, Div Microbiol HFS 710, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Wilson, MR (reprint author), Western Carolina Univ, Forens Sci Program, 325 Nat Sci Bldg, Cullowhee, NC 28723 USA. EM mwilson20@mac.com NR 51 TC 3 Z9 3 U1 2 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0748-3007 J9 CLADISTICS JI Cladistics PD AUG PY 2013 VL 29 IS 4 BP 449 EP 461 DI 10.1111/cla.12012 PG 13 WC Evolutionary Biology SC Evolutionary Biology GA 184EM UT WOS:000321870700006 ER PT J AU Edginton, AN Shah, B Sevestre, M Momper, JD AF Edginton, Andrea N. Shah, Bhavank Sevestre, Michael Momper, Jeremiah D. TI The Integration of Allometry and Virtual Populations to Predict Clearance and Clearance Variability in Pediatric Populations over the Age of 6 Years SO CLINICAL PHARMACOKINETICS LA English DT Article ID HEALTHY-VOLUNTEERS; SURFACE-AREA; PHARMACOKINETICS; CHILDREN; WEIGHT; IMPAIRMENT; ZIDOVUDINE; QUETIAPINE; INFANTS; FORMULA AB Pharmacokinetics play an integral role in the pediatric drug development process. The determination of pharmacokinetic parameters, particularly clearance, in different age groups directly informs dosing strategies for subsequent efficacy trials. Allometric scaling for prediction of pediatric clearance from the observed clearance in adults has been used in this effort. Clinical trial simulation, a powerful tool used to inform clinical trial design, requires both an estimate of clearance along with an estimate of the expected pharmacokinetic variability. The standard deviations (SD) of individual clearance values for adults are typically used and may lead to inaccurate predictions by not taking into account the more widespread distribution of factors such as body weight in the pediatric population. The objective of this study was to assess the accuracy of allometric prediction of drug clearance as well as methods for predicting clearance variability in children 6 years of age and older. US Food and Drug Administration (FDA) clinical pharmacology reviews of pediatric studies conducted from 2002 onwards were reviewed to collate adult and pediatric clearance and clearance variability for studies including children 6 years of age and older. A set of 1,000 virtual adults {A} and a set of 5,000 virtual children (aged 2-17) {P} were generated on the basis of the White American NHANES database. Pediatric clearances were predicted in method 1 by using the geometric mean adult clearance from the in vivo study and calculating pediatric clearance for each virtual child within a subset {P'} of {P} that contained only those children that were within the age range of the in vivo pediatric study. In method 2, adult clearance values were randomly generated from the geometric mean adult clearance and standard deviation and assigned to each virtual adult in {A}. For each adult, allometric clearance scaling was completed with each virtual child within {P'}. The prediction error for the predicted and observed clearance and the clearance variability metric, coefficient of variation (CV), was calculated. The prediction accuracy as a function of the lowest age range (2 years and older) included in the study was also assessed. Thirty-nine unique drugs were included in the study. For both method 1 and method 2, 100 % of predicted pediatric mean clearances were within 2-fold of the observed values and approximately 82 % were within a 30 % prediction error. There was a significant increase in the prediction accuracy of CV using method 2 vs. method 1. There was a major bias towards underprediction of pediatric CV in method 1 whereas method 2 was precise and not biased. Clearance and CV prediction accuracy were not a function of the age range included in the in vivo studies. The observed CV between the adult and pediatric study groups was not significantly different although, on average, the observed pediatric CV was 32 % greater than that from adult studies. Allometric scaling may be a useful tool during pediatric drug development to predict drug clearance and dosing requirements in children 6 years of age and older. A novel methodology is reported that employs virtual adult and pediatric populations and adult pharmacokinetic data to accurately predict clearance variability in specific pediatric subpopulations. This approach has important implications for both clinical trial simulations and sample size determination for pediatric pharmacokinetic studies. C1 [Edginton, Andrea N.; Shah, Bhavank] Univ Waterloo, Sch Pharm, Waterloo, ON N2L 3G1, Canada. [Sevestre, Michael] Design2Code Inc, Waterloo, ON, Canada. [Momper, Jeremiah D.] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Edginton, AN (reprint author), Univ Waterloo, Sch Pharm, 200 Univ St W, Waterloo, ON N2L 3G1, Canada. EM aedginto@uwaterloo.ca NR 26 TC 13 Z9 15 U1 0 U2 8 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0312-5963 EI 1179-1926 J9 CLIN PHARMACOKINET JI Clin. Pharmacokinet. PD AUG PY 2013 VL 52 IS 8 BP 693 EP 703 DI 10.1007/s40262-013-0065-6 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 185ZP UT WOS:000322010900007 PM 23588537 ER PT J AU Moore, PW Donovan, JW Burkhart, KK Haggerty, D AF Moore, P. W. Donovan, J. W. Burkhart, K. K. Haggerty, D. TI A case series of patients with lamotrigine toxicity at one center from 2003 to 2012 SO CLINICAL TOXICOLOGY LA English DT Article DE Neurotoxicity; Cardiotoxicity; Pharmacokinetics; Serotonin syndrome; Sodium channel blockade ID SEROTONIN REUPTAKE INHIBITORS; OBSESSIVE-COMPULSIVE DISORDER; FORCED SWIMMING TEST; LONG QT SYNDROME; AUGMENTATION; OVERDOSE AB Introduction. Lamotrigine is a phenyltriazine compound that inhibits voltage-gated sodium channels, decreasing release of glutamate and aspartate, and inhibits serotonin, norepinephrine and dopamine reuptake. Reports of toxicity in the literature are limited to case reports and primarily involve coingestants. This case series is intended to report the clinical manifestations of lamotrigine toxicity. Methods. This retrospective case series from 2003 to 2012 studies the effects of lamotrigine toxicity when not confounded by coingestants. Admission records at an inpatient toxicology center were reviewed for lamotrigine-only exposure based on history with supporting laboratory data when available. After identification, these charts were reviewed again to characterize vital signs, neurological examination findings, specific laboratory and electrocardiography parameters, and complications. Results. Fifty-seven patients were identified with possible lamotrigine toxicity. Nine patients, including three toddlers, had lamotrigine-only ingestions. Three of these patients had seizures, four were hypertensive, five were tachycardic, and four experienced tachypnea. Mental status was altered in all nine (depressed (n = 4), agitated (n = 5) or both (n = 3)). Five patients were hyperreflexic and experienced intermittent myoclonus, and two had inducible clonus. On electrocardiogram, two patients experienced QRS prolongation (114-116 ms), and four had QTc prolongation (463-586 ms). No patient had life-threatening symptoms or signs. Serum levels of lamotrigine were available in seven patients, and averaged 35.4 mg/L (17-90 mg/L). The therapeutic range for sLTG is 3-14 mg/L. Conclusions. Lamotrigine toxicity manifested with minor-moderate neurologic and/or electrocardiographic effects. Toxicity reflects the known pharmacologic actions of lamotrigine: serotonin, norepinephrine and dopamine reuptake inhibition, and sodium channel blockade. C1 [Moore, P. W.; Donovan, J. W.; Burkhart, K. K.; Haggerty, D.] PinnacleHlth Toxicol Ctr, Dept Internal Med, Harrisburg, PA USA. [Burkhart, K. K.] US FDA, Silver Spring, MD USA. [Moore, P. W.; Donovan, J. W.; Burkhart, K. K.] Penn State Univ, Coll Med, Dept Emergency Med, Hershey, PA USA. RP Moore, PW (reprint author), Harrisburg Hosp, Dept Med, PinnacleHlth Toxicol Ctr, 111 S Front St, Harrisburg, PA 17101 USA. EM pwmoore@pinnaclehealth.org NR 19 TC 8 Z9 8 U1 0 U2 13 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1556-3650 EI 1556-9519 J9 CLIN TOXICOL JI Clin. Toxicol. PD AUG PY 2013 VL 51 IS 7 BP 545 EP 549 DI 10.3109/15563650.2013.818685 PG 5 WC Toxicology SC Toxicology GA 188PH UT WOS:000322204400006 PM 23869656 ER PT J AU Moore, PW Donovan, JW Burkhart, KK Daniello, TC Smith, EM Andharia, N Dorai, S Eygnor, J Wirt, Y AF Moore, Philip W. Donovan, J. Ward Burkhart, Keith K. Daniello, Todd C. Smith, Erin Mancuso Andharia, Neel Dorai, Suprina Eygnor, Jessica Wirt, Yijin TI High-dose, variable-length, intravenous N-acetylcysteine (HINAC) therapy for acetaminophen poisoning SO CLINICAL TOXICOLOGY LA English DT Meeting Abstract DE Acetaminophen (paracetamol); N-acetylcysteine; Hepatotoxicity C1 [Burkhart, Keith K.] US FDA, Rockville, MD 20857 USA. [Daniello, Todd C.] Penn State Univ, Milton S Hershey Med Ctr, Hershey, PA 17033 USA. [Moore, Philip W.; Donovan, J. Ward; Andharia, Neel; Wirt, Yijin] PinnacleHlth Syst, Harrisburg, PA USA. [Smith, Erin Mancuso] Novant Hlth Presbyterian Med Ctr, Charlotte, NC USA. [Dorai, Suprina; Eygnor, Jessica] Lehigh Valley Hlth Network, Lehigh Valley, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1556-3650 J9 CLIN TOXICOL JI Clin. Toxicol. PD AUG PY 2013 VL 51 IS 7 MA 14 BP 581 EP 581 PG 1 WC Toxicology SC Toxicology GA 188PH UT WOS:000322204400024 ER PT J AU Katz, AJ Ryan, PB Racoosin, JA Stang, PE AF Katz, Aaron J. Ryan, Patrick B. Racoosin, Judith A. Stang, Paul E. TI Assessment of Case Definitions for Identifying Acute Liver Injury in Large Observational Databases SO DRUG SAFETY LA English DT Article ID 000 STATIN USERS; ADVERSE EVENTS; INCREASED RISK; UNITED-STATES; ROSUVASTATIN; SAFETY; COHORT; DRUGS; POPULATION; HEPATITIS AB Determining the aetiology of acute liver injury (ALI) may be challenging to both clinicians and researchers. Observational research is particularly useful in studying rare medical outcomes such as ALI; however, case definitions for ALI in previous observational studies lack consistency and sensitivity. ALI is a clinically important condition with various aetiologies, including drug exposure. The aim of this study was to evaluate four distinct case definitions for ALI across a diverse set of large observational databases, providing a better understanding of ALI prevalence and natural history. Seven healthcare databases: GE Healthcare, MarketScan(A (R)) Lab Database, Humana Inc., Partners HealthCare System, Regenstrief Institute, SDI Health (now IMS Health, Inc.), and the National Patient Care Database of the Veterans Health Administration. We evaluated prevalence of ALI through the application of four distinct case definitions across seven observational healthcare databases. We described how laboratory and clinical characteristics of identified case populations varied across definitions and examined the prevalence of other hepatobiliary disorders among identified ALI cases that may decrease suspicion of drug-induced liver injury (DILI) in particular. This study demonstrated that increasing the restrictiveness of the case definition resulted in fewer cases, but greater prevalence of ALI clinical features. Considerable heterogeneity in the frequency of laboratory testing and results observed among cases meeting the most restrictive definition suggests that the clinical features, monitoring patterns and suspicion of ALI are highly variable among patients. Creation of four distinct case definitions and application across a disparate set of observational databases resulted in significant variation in the prevalence of ALI. A greater understanding of the natural history of ALI through examination of electronic healthcare data can facilitate development of reliable and valid ALI case definitions that may enhance the ability to accurately identify associations between ALI and drug exposures. Considerable heterogeneity in laboratory values and frequency of laboratory testing among individuals meeting the criteria for ALI suggests that the evaluation of ALI is highly variable. C1 [Katz, Aaron J.] Univ N Carolina, UNC Eshelman Sch Pharm, Div Pharmaceut Policy & Outcomes, Chapel Hill, NC 27599 USA. [Ryan, Patrick B.; Stang, Paul E.] Janssen Res & Dev, Titusville, NJ USA. [Ryan, Patrick B.; Racoosin, Judith A.; Stang, Paul E.] Fdn Natl Inst Hlth, Observat Med Outcomes Partnership, Bethesda, MD USA. [Racoosin, Judith A.] USFDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Katz, AJ (reprint author), Univ N Carolina, UNC Eshelman Sch Pharm, Div Pharmaceut Policy & Outcomes, CB 7573, Chapel Hill, NC 27599 USA. EM aj_katz@unc.edu FU Foundation for the National Institutes of Health FX The OMOP is funded by the Foundation for the National Institutes of Health through generous contributions from the following: Abbott, Amgen Inc., AstraZeneca, Bayer Healthcare Pharmaceuticals, Inc., Bristol-Myers Squibb, Eli Lilly & Company, GlaxoSmithKline, Johnson & Johnson, Lundbeck, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Pharmaceutical Research Manufacturers of America (PhRMA), Roche, Sanofi, Schering-Plough Corporation, and Takeda. NR 29 TC 6 Z9 6 U1 0 U2 2 PU ADIS INT LTD PI AUCKLAND PA 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 1311, NEW ZEALAND SN 0114-5916 J9 DRUG SAFETY JI Drug Saf. PD AUG PY 2013 VL 36 IS 8 BP 651 EP 661 DI 10.1007/s40264-013-0060-8 PG 11 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA 188DR UT WOS:000322172800007 PM 23670723 ER PT J AU Trumbo, PR AF Trumbo, Paula R. TI Comment on "Nutrient reference values for bioactives: new approaches needed? A conference report" (European Journal of Nutrition, April 2013, Volume 52, Issue 1 Supplement, pp 1-9) SO EUROPEAN JOURNAL OF NUTRITION LA English DT Letter C1 US FDA, Nutr Programs, Off Nutr Labeling & Dietary Supplements, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Trumbo, PR (reprint author), US FDA, Nutr Programs, Off Nutr Labeling & Dietary Supplements, Ctr Food Safety & Appl Nutr, College Pk, MD USA. EM Paula.Trumbo@fda.hhs.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1436-6207 J9 EUR J NUTR JI Eur. J. Nutr. PD AUG PY 2013 VL 52 IS 5 BP 1541 EP 1541 DI 10.1007/s00394-013-0537-3 PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 185YQ UT WOS:000322008000012 PM 23728710 ER PT J AU Wang, F Yang, QR Kase, JA Meng, JH Clotilde, LM Lin, A Ge, BL AF Wang, Fei Yang, Qianru Kase, Julie A. Meng, Jianghong Clotilde, Laurie M. Lin, Andrew Ge, Beilei TI Current Trends in Detecting Non-O157 Shiga Toxin-Producing Escherichia coli in Food SO FOODBORNE PATHOGENS AND DISEASE LA English DT Review ID MEDIATED ISOTHERMAL AMPLIFICATION; REAL-TIME PCR; POLYMERASE-CHAIN-REACTION; ANTIGEN GENE-CLUSTER; IN-GROUND BEEF; ACTIVE SURVEILLANCE NETWORK; WASHED BLOOD AGAR; 10 US SITES; RAPID DETECTION; IMMUNOMAGNETIC SEPARATION AB Non-O157 Shiga toxin-producing Escherichia coli (non-O157 STEC) strains are increasingly recognized as important foodborne pathogens worldwide. Together with E. coli O157:H7, six additional STEC serogroups (O26, O45, O103, O111, O121, and O145) are now regulated as adulterants in certain raw beef products in the United States. However, effective detection and isolation of non-O157 STEC strains from food matrices remain challenging. In the past decade, great attention has been paid to developing rapid and reliable detection methods for STEC in general (targeting common virulence factors) and specific STEC serogroups in particular (targeting serogroup-specific traits). This review summarizes current trends in detecting non-O157 STEC in food, including culture, immunological, and molecular methods, as well as several novel technologies. C1 [Wang, Fei; Yang, Qianru; Ge, Beilei] Louisiana State Univ, Ctr Agr, Dept Food Sci, Baton Rouge, LA 70803 USA. [Wang, Fei; Meng, Jianghong] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Kase, Julie A.] US FDA, Div Microbiol, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Clotilde, Laurie M.; Lin, Andrew] US FDA, San Francisco Dist Lab, Off Regulatory Affairs, Alameda, CA USA. [Ge, Beilei] US FDA, Div Anim & Food Microbiol, Res Off, Ctr Vet Med, Laurel, MD 20708 USA. RP Ge, BL (reprint author), US FDA, Div Anim & Food Microbiol, Res Off, Ctr Vet Med, 8401 Muirkirk Rd, Laurel, MD 20708 USA. EM beilei.ge@fda.hhs.gov RI Wang, Fei/J-4353-2014 NR 132 TC 34 Z9 35 U1 3 U2 55 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1535-3141 J9 FOODBORNE PATHOG DIS JI Foodborne Pathog. Dis. PD AUG PY 2013 VL 10 IS 8 BP 665 EP 677 DI 10.1089/fpd.2012.1448 PG 13 WC Food Science & Technology SC Food Science & Technology GA 188TI UT WOS:000322216200001 PM 23755895 ER PT J AU Ge, BL LaFon, PC Carter, PJ McDermott, SD Abbott, J Glenn, A Ayers, SL Friedman, SL Paige, JC Wagner, DD Zhao, SH McDermott, PF Rasmussen, MA AF Ge, Beilei LaFon, Patricia C. Carter, Peggy J. McDermott, Shawn D. Abbott, Jason Glenn, Althea Ayers, Sherry L. Friedman, Sharon L. Paige, Joseph C. Wagner, David D. Zhao, Shaohua McDermott, Patrick F. Rasmussen, Mark A. TI Retrospective Analysis of Salmonella, Campylobacter, Escherichia coli, and Enterococcus in Animal Feed Ingredients SO FOODBORNE PATHOGENS AND DISEASE LA English DT Article ID ANTIMICROBIAL RESISTANCE; RETAIL MEATS; POULTRY FEEDS; CATTLE FEEDS; HUMAN HEALTH; PREVALENCE; CONTAMINATION; ENTERICA; ENTEROBACTERIACEAE; PRODUCTS AB The presence and antimicrobial susceptibility of foodborne pathogens and indicator organisms in animal feed are not well understood. In this study, a total of 201 feed ingredient samples (animal byproducts, n = 122; plant byproducts, n = 79) were collected in 2002 and 2003 from representative rendering plants and the oilseed (or cereal grain) industry across the United States. The occurrence and antimicrobial susceptibility of four bacterial genera (Salmonella, Campylobacter, Escherichia coli, and Enterococcus) were determined. Salmonella isolates were further characterized by serotyping and pulsed-field gel electrophoresis (PFGE). None of the samples yielded Campylobacter or E. coli O157:H7, whereas Salmonella, generic E. coli, and Enterococcus were present in 22.9%, 39.3%, and 86.6% of samples, respectively. A large percentage (47.8%) of Salmonella-positive samples harbored two serovars, and the vast majority (88.4%) of Enterococcus isolates were E. faecium. Animal byproducts had a significantly higher Salmonella contamination rate (34.4%) than plant byproducts (5.1%) (p < 0.05). Among 74 Salmonella isolates recovered, 27 serovars and 55 PFGE patterns were identified; all were pan-susceptible to 17 antimicrobials tested. E. coli isolates (n = 131) demonstrated similar susceptibility to these antimicrobials except for tetracycline (15.3% resistance), sulfamethoxazole (7.6%), streptomycin (4.6%), ampicillin (3.8%), and nalidixic acid (1.5%). Enterococcus isolates (n = 362) were also resistant to five of 17 antimicrobials tested, ranging from 1.1% to penicillin to 14.6% to tetracycline. Resistance rates were generally higher among isolates recovered from animal byproducts. Taken together, our findings suggest that diverse populations of Salmonella, E. coli, and Enterococcus are commonly present in animal feed ingredients, but antimicrobial resistance is not common. Future large-scale studies to monitor these pathogenic and indicator organisms in feed commodities is warranted. C1 [Ge, Beilei; LaFon, Patricia C.; Carter, Peggy J.; McDermott, Shawn D.; Abbott, Jason; Glenn, Althea; Ayers, Sherry L.; Friedman, Sharon L.; Wagner, David D.; Zhao, Shaohua; McDermott, Patrick F.; Rasmussen, Mark A.] US FDA, Div Anim & Food Microbiol, Res Off, Ctr Vet Med, Laurel, MD 20708 USA. [Paige, Joseph C.] US FDA, Off Surveillance & Compliance, Ctr Vet Med, Rockville, MD 20857 USA. RP Ge, BL (reprint author), US FDA, Div Anim & Food Microbiol, Res Off, Ctr Vet Med, 8401 Muirkirk Rd, Laurel, MD 20708 USA. EM beilei.ge@fda.hhs.gov RI Rasmussen, Mark/N-9509-2014 NR 48 TC 10 Z9 10 U1 1 U2 24 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1535-3141 J9 FOODBORNE PATHOG DIS JI Foodborne Pathog. Dis. PD AUG PY 2013 VL 10 IS 8 BP 684 EP 691 DI 10.1089/fpd.2012.1470 PG 8 WC Food Science & Technology SC Food Science & Technology GA 188TI UT WOS:000322216200003 PM 23692074 ER PT J AU Shen, JL Wang, F Li, F Housley, R Carolan, H Yasuda, I Burrows, E Binet, R Sampath, R Zhang, JM Allard, MW Meng, JH AF Shen, Jinling Wang, Fei Li, Feng Housley, Roberta Carolan, Heather Yasuda, Irene Burrows, Erik Binet, Rachel Sampath, Rangarajan Zhang, Jianmin Allard, Marc W. Meng, Jianghong TI Rapid Identification and Differentiation of Non-O157 Shiga Toxin-Producing Escherichia coli Using Polymerase Chain Reaction Coupled to Electrospray Ionization Mass Spectrometry SO FOODBORNE PATHOGENS AND DISEASE LA English DT Article ID HEMOLYTIC-UREMIC SYNDROME; STRAINS; ASSOCIATION; VARIANTS; GENES; FOOD; EVOLUTION; PATHOGENS; GENOTYPE; BACTERIA AB A polymerase chain reaction (PCR)-mass spectroscopy assay was developed to identify non-O157 Shiga toxin-producing Escherichia coli (STEC) with Plex-ID biosensor system, a platform identifying short PCR amplicons by specific base compositions. This assay simultaneously amplifies five fragments of two housekeeping genes, two subunits of stx2 gene, and four other virulence genes of STEC. A total of 164 well-characterized STEC isolates were examined with the assay to build a DNA base composition database. Another panel of 108 diverse STEC isolates was tested with the established database to evaluate the assay's identification capability. Among the 108 isolates, the assay specificity was 100% for three (stx1, eae, and aggA) out of five tested virulence genes, but 99% for stx2 and 96% for hlyA, respectively. Main stx1/stx2 subtypes and multiple alleles of stx1/stx2 could be differentiated. The assay successfully identified several clinically significant serotypes, including O91:H14, O103:H25, O145:H28/NM, O113:H21, and O104:H4. Meanwhile, it was able to group isolates with different levels of pathogenic potential. The results suggest that this high-throughput method may be useful in clinical and regulatory laboratories for STEC identification, particularly strains with increased pathogenic potential. C1 [Shen, Jinling; Meng, Jianghong] Northwest A&F Univ, Coll Food Sci & Engn, Yangling, Shaanxi Provinc, Peoples R China. [Shen, Jinling; Wang, Fei; Meng, Jianghong] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Shen, Jinling] Zhangjiagang Entry Exit Inspect & Quarantine Bur, Zhangjiagang, Jiangsu, Peoples R China. [Li, Feng; Housley, Roberta; Carolan, Heather; Yasuda, Irene; Sampath, Rangarajan] Abbott, Ibis Biosci, Carlsbad, CA USA. [Burrows, Erik; Binet, Rachel; Allard, Marc W.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Zhang, Jianmin] Shanghai Jiao Tong Univ, Shanghai 200030, Peoples R China. RP Meng, JH (reprint author), Univ Maryland, Dept Nutr & Food Sci, 0112 Skinner Bldg, College Pk, MD 20742 USA. EM jmeng@umd.edu RI Wang, Fei/J-4353-2014 FU U.S. Food and Drug Administration (FDA)/Center for Food Safety and Applied Nutrition (CFSAN); FDA Commissioner's Fellowship Program; Joint Institute for Food Safety & Applied Nutrition (JIFSAN) at the University of Maryland FX This work was supported in part by the U.S. Food and Drug Administration (FDA)/Center for Food Safety and Applied Nutrition (CFSAN) and the FDA Commissioner's Fellowship Program, and by funding from the Joint Institute for Food Safety & Applied Nutrition (JIFSAN) at the University of Maryland. NR 26 TC 3 Z9 3 U1 0 U2 15 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1535-3141 J9 FOODBORNE PATHOG DIS JI Foodborne Pathog. Dis. PD AUG PY 2013 VL 10 IS 8 BP 737 EP 743 DI 10.1089/fpd.2012.1469 PG 7 WC Food Science & Technology SC Food Science & Technology GA 188TI UT WOS:000322216200011 PM 23767822 ER PT J AU Sun, JC Schnackenberg, LK Khare, S Yang, X Greenhaw, J Salminen, W Mendrick, DL Beger, RD AF Sun, Jinchun Schnackenberg, Laura K. Khare, Sangeeta Yang, Xi Greenhaw, James Salminen, William Mendrick, Donna L. Beger, Richard D. TI Evaluating effects of penicillin treatment on the metabolome of rats SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE Penicillin; Metabolome; Gut microbiota; Host-microbial interaction; LC/MS; NMR ID GUT MICROBIOTA; MASS-SPECTROMETRY; BILE-ACIDS; HOST; IDENTIFICATION; MICROFLORA; GERMFREE; DISEASE; OBESITY; COLONIZATION AB Penicillin (PEN) V. a well-known antibiotic widely used in the treatment of Gram-positive bacterial infections, was evaluated in this study. LC/MS- and NMR-based metabolic profiling were employed to examine the effects of PEN on the host's metabolic phenotype. Male Sprague Dawley rats were randomly divided into groups that were orally administered either 0.5% methylcellulose vehicle, 100 or 2400 mg PEN/kg body weight once daily for up to 14 consecutive days. Urine, plasma and tissue were collected from groups sacrificed at 6 h, 24 h or 14 d. The body fluids were subjected to clinical chemistry and metabolomics analysis; the tissue samples were processed for histopathology. The only notable clinical chemistry observation was that gamma glutamyltransferase (GGT) significantly decreased at 24 h for both dose groups, and significantly decreased at 14d for the high-dose groups. Partial least squares discriminant analysis scores plots of the metabolomics data from urine and plasma samples showed dose- and time-dependent grouping patterns. Time- and dose-dependent decreases in urinary metabolites including indole-containing metabolites (such as 3-methyldioxyindole sulfate generated from bacterial metabolism of tryptophan), organic acids containing phenyl groups (such as hippuric acid, phenyllactic acid and 3-hydroxyanthranilic acid), and metabolites conjugated with sulfate or glucuronide (such as cresol sulfate and aminophenol sulfate) indicated that the gut microflora population was suppressed. Decreases in many host-gut microbiota urinary co-metabolites (indole- and phenyl-containing metabolites, amino acids, vitamins, nucleotides and bile acids) suggested gut microbiota play important roles in the regulation of host metabolism, including dietary nutrient absorption and reprocessing the absorbed nutrients. Decreases in urinary conjugated metabolites (sulfate, glucuronide and glycine conjugates) implied that gut microbiota might have an impact on chemical detoxification mechanisms. In all, these results clearly show that metabolic profiling is a useful tool to better understand the effects of the antibiotic penicillin has on the gut microbiota and the host. (C) 2013 Published by Elsevier B.V. C1 [Sun, Jinchun; Schnackenberg, Laura K.; Yang, Xi; Greenhaw, James; Salminen, William; Mendrick, Donna L.; Beger, Richard D.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Khare, Sangeeta] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Sun, JC (reprint author), US FDA, Div Syst Biol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Jinchun.Sun@fda.hhs.gov NR 41 TC 10 Z9 10 U1 2 U2 32 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD AUG 1 PY 2013 VL 932 BP 134 EP 143 DI 10.1016/j.jchromb.2013.05.030 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 187DY UT WOS:000322098300019 PM 23831706 ER PT J AU Hua, W Sun, GY Dodd, CN Romio, SA Whitaker, HJ Izurieta, HS Black, S Sturkenboom, MCJM Davis, RL Deceuninck, G Andrews, NJ AF Hua, Wei Sun, Guoying Dodd, Caitlin N. Romio, Silvana A. Whitaker, Heather J. Izurieta, Hector S. Black, Steven Sturkenboom, Miriam C. J. M. Davis, Robert L. Deceuninck, Genevieve Andrews, N. J. TI A simulation study to compare three self-controlled case series approaches: correction for violation of assumption and evaluation of bias SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE assumption; bias; Guillain-Barre syndrome; influenza vaccine; self-controlled case series; simulation; pharmacoepidemiology ID GUILLAIN-BARRE-SYNDROME; VACCINE SAFETY; INFLUENZA VACCINES; RECOMMENDATIONS; ASSOCIATION AB Purpose The assumption that the occurrence of outcome event must not alter subsequent exposure probability is critical for preserving the validity of the self-controlled case series (SCCS) method. This assumption is violated in scenarios in which the event constitutes a contraindication for exposure. In this simulation study, we compared the performance of the standard SCCS approach and two alternative approaches when the event-independent exposure assumption was violated. Methods Using the 2009 H1N1 and seasonal influenza vaccines and Guillain-Barre syndrome as a model, we simulated a scenario in which an individual may encounter multiple unordered exposures and each exposure may be contraindicated by the occurrence of outcome event. The degree of contraindication was varied at 0%, 50%, and 100%. The first alternative approach used only cases occurring after exposure with follow-up time starting from exposure. The second used a pseudo-likelihood method. Results When the event-independent exposure assumption was satisfied, the standard SCCS approach produced nearly unbiased relative incidence estimates. When this assumption was partially or completely violated, two alternative SCCS approaches could be used. While the post-exposure cases only approach could handle only one exposure, the pseudo-likelihood approach was able to correct bias for both exposures. Conclusions Violation of the event-independent exposure assumption leads to an overestimation of relative incidence which could be corrected by alternative SCCS approaches. In multiple exposure situations, the pseudo-likelihood approach is optimal; the post-exposure cases only approach is limited in handling a second exposure and may introduce additional bias, thus should be used with caution. Copyright (C) 2013 John Wiley & Sons, Ltd. C1 [Hua, Wei; Sun, Guoying; Izurieta, Hector S.] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Dodd, Caitlin N.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Romio, Silvana A.; Sturkenboom, Miriam C. J. M.] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [Whitaker, Heather J.] Open Univ, Dept Math & Stat, Milton Keynes MK7 6AA, Bucks, England. [Black, Steven] Cincinnati Childrens Hosp, Ctr Global Child Hlth, Cincinnati, OH USA. [Davis, Robert L.] Kaiser Permanente Georgia, Ctr Hlth Res Southeast, Atlanta, GA USA. [Deceuninck, Genevieve] Quebec Univ Hosp Res Ctr, Publ Hlth Res Unit, Quebec City, PQ, Canada. [Andrews, N. J.] Hlth Protect Agcy, Hlth Protect Serv, Stat Unit, London, England. RP Hua, W (reprint author), US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, 1401 Rockville Pike,Suite 323N,HFM 222, Rockville, MD 20852 USA. EM wei.hua@fda.hhs.gov OI Whitaker, Heather/0000-0001-5833-1863 FU US Department of Health and Human Services FX Support for this work comes entirely from the US Department of Health and Human Services. NR 16 TC 2 Z9 2 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2013 VL 22 IS 8 BP 819 EP 825 DI 10.1002/pds.3451 PG 7 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 186BL UT WOS:000322016300003 PM 23625875 ER PT J AU Lo Re, V Haynes, K Goldberg, D Forde, KA Carbonari, DM Leidl, KBF Hennessy, S Reddy, KR Pawloski, PA Daniel, GW Cheetham, TC Iyer, A Coughlin, KO Toh, S Boudreau, DM Selvam, N Cooper, WO Selvan, MS VanWormer, JJ Avigan, MI Houstoun, M Zornberg, GL Racoosin, JA Shoaibi, A AF Lo Re, Vincent, III Haynes, Kevin Goldberg, David Forde, Kimberly A. Carbonari, Dena M. Leidl, Kimberly B. F. Hennessy, Sean Reddy, K. Rajender Pawloski, Pamala A. Daniel, Gregory W. Cheetham, T. Craig Iyer, Aarthi Coughlin, Kara O. Toh, Sengwee Boudreau, Denise M. Selvam, Nandini Cooper, William O. Selvan, Mano S. VanWormer, Jeffrey J. Avigan, Mark I. Houstoun, Monika Zornberg, Gwen L. Racoosin, Judith A. Shoaibi, Azadeh TI Validity of diagnostic codes to identify cases of severe acute liver injury in the US Food and Drug Administration's Mini-Sentinel Distributed Database SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE hepatotoxicity; liver injury; validity; ICD-9 codes; pharmacoepidemiology ID HEPATOTOXICITY; FAILURE; VALIDATION; PROGRAM; SAFETY AB Purpose The validity of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes to identify diagnoses of severe acute liver injury (SALI) is not well known. We examined the positive predictive values (PPVs) of hospital ICD-9-CM diagnoses in identifying SALI among health plan members in the Mini-Sentinel Distributed Database (MSDD) for patients without liver/biliary disease and for those with chronic liver disease (CLD). Methods We selected random samples of members (149 without liver/biliary disease; 75 with CLD) with a principal hospital diagnosis suggestive of SALI (ICD-9-CM 570, 572.2, 572.4, 572.8, 573.3, 573.8, or V42.7) in the MSDD (2009-2010). Medical records were reviewed by hepatologists to confirm SALI events. PPVs of codes and code combinations for confirmed SALI were determined by CLD status. Results Among 105 members with available records and no liver/biliary disease, SALI was confirmed in 26 (PPV, 24.7%; 95% CI, 16.9-34.1%). Combined hospital diagnoses of acute hepatic necrosis (570) and liver disease sequelae (572.8) had high PPV (100%; 95% CI, 59.0-100%) and identified 7/26 (26.9%) events. Among 46 CLD members with available records, SALI was confirmed in 19 (PPV, 41.3%; 95% CI, 27.0-56.8%). Acute hepatic necrosis (570) or hepatorenal syndrome (572.4) plus any other SALI code had a PPV of 83.3% (95% CI, 51.6-97.9%) and identified 10/19 (52.6%) events. Conclusions Most individual hospital ICD-9-CM diagnoses had low PPV for confirmed SALI events. Select code combinations had high PPV but did not capture all events. Copyright (C) 2013 John Wiley & Sons, Ltd. C1 [Lo Re, Vincent, III] Univ Penn, Perelman Sch Med, Dept Med, Div Infect Dis, Philadelphia, PA 19104 USA. [Lo Re, Vincent, III; Haynes, Kevin; Goldberg, David; Forde, Kimberly A.; Carbonari, Dena M.; Leidl, Kimberly B. F.; Hennessy, Sean] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Goldberg, David; Forde, Kimberly A.; Reddy, K. Rajender] Univ Penn, Perelman Sch Med, Dept Med, Div Gastroenterol, Philadelphia, PA 19104 USA. [Pawloski, Pamala A.] HealthPartners Inst Educ & Res, Bloomington, MN USA. [Daniel, Gregory W.; Selvam, Nandini] HealthCore Inc, Wilmington, DE USA. [Daniel, Gregory W.] Brookings Inst, Engelberg Ctr Hlth Care Reform, Washington, DC 20036 USA. [Cheetham, T. Craig] Kaiser Permanente So Calif, Pharm Analyt Serv, Downey, CA USA. [Iyer, Aarthi; Coughlin, Kara O.; Toh, Sengwee] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Iyer, Aarthi; Coughlin, Kara O.; Toh, Sengwee] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Boudreau, Denise M.] Grp Hlth Res Inst, Seattle, WA USA. [Cooper, William O.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Selvan, Mano S.] Humana Inc, Competit Hlth Analyt, Louisville, KY USA. [VanWormer, Jeffrey J.] Marshfield Clin Fdn Med Res & Educ, Marshfield, WI 54449 USA. [Avigan, Mark I.; Houstoun, Monika; Zornberg, Gwen L.; Racoosin, Judith A.; Shoaibi, Azadeh] US FDA, Silver Spring, MD USA. RP Lo Re, V (reprint author), Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, 836 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM vincentl@mail.med.upenn.edu RI Carbonari, Dena/H-3366-2011; Lo Re, Vincent/N-7817-2015; Toh, Sengwee/D-7567-2017 OI Carbonari, Dena/0000-0003-0310-270X; Toh, Sengwee/0000-0002-5160-0810 FU U.S. Food and Drug Administration [HHSF223200910006I]; National Center for Research Resources; National Center for Advancing Translational Sciences FX This work was supported through funding from contract HHSF223200910006I from the U.S. Food and Drug Administration.; REDCap was initially developed by Vanderbilt University and receives collaborative support from a wide consortium of partners through the Clinical and Translational Science Awards, supported by the National Center for Research Resources and now the National Center for Advancing Translational Sciences. NR 26 TC 19 Z9 19 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2013 VL 22 IS 8 BP 861 EP 872 DI 10.1002/pds.3470 PG 12 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 186BL UT WOS:000322016300008 PM 23801638 ER PT J AU Chen, G Wang, C Shi, LM Tong, WD Qu, XF Chen, JW Yang, JM Shi, CP Chen, L Zhou, PY Lu, BX Shi, TL AF Chen, Geng Wang, Charles Shi, Leming Tong, Weida Qu, Xiongfei Chen, Jiwei Yang, Jianmin Shi, Caiping Chen, Long Zhou, Peiying Lu, Bingxin Shi, Tieliu TI Comprehensively identifying and characterizing the missing gene sequences in human reference genome with integrated analytic approaches SO HUMAN GENETICS LA English DT Article ID RNA-SEQ DATA; STRUCTURAL VARIATION; TRANSLOCATION CARRIERS; TRANSPOSABLE ELEMENTS; COPY-NUMBER; SEARCH; TOOL; QUANTIFICATION; ANNOTATION; GENERATION AB The human reference genome is still incomplete and a number of gene sequences are missing from it. The approaches to uncover them, the reasons causing their absence and their functions are less explored. Here, we comprehensively identified and characterized the missing genes of human reference genome with RNA-Seq data from 16 different human tissues. By using a combined approach of genome-guided transcriptome reconstruction coupled with genome-wide comparison, we uncovered 3.78 and 2.37 Mb transcribed regions in the human genome assemblies of Celera and HuRef either missed from their homologous chromosomes of NCBI human reference genome build 37.2 or partially or entirely absent from the reference. We further identified a significant number of novel transcript contigs in each tissue from de novo transcriptome assembly that are unalignable to NCBI build 37.2 but can be aligned to at least one of the genomes from Celera, HuRef, chimpanzee, macaca or mouse. Our analyses indicate that the missing genes could result from genome misassembly, transposition, copy number variation, translocation and other structural variations. Moreover, our results further suggest that a large portion of these missing genes are conserved between human and other mammals, implying their important biological functions. Totally, 1,233 functional protein domains were detected in these missing genes. Collectively, our study not only provides approaches for uncovering the missing genes of a genome, but also proposes the potential reasons causing genes missed from the genome and highlights the importance of uncovering the missing genes of incomplete genomes. C1 [Chen, Geng; Qu, Xiongfei; Chen, Jiwei; Yang, Jianmin; Shi, Caiping; Chen, Long; Zhou, Peiying; Lu, Bingxin; Shi, Tieliu] E China Normal Univ, Ctr Bioinformat & Computat Biol, Shanghai Key Lab Regulatory Biol, Inst Biomed Sci, Shanghai 200241, Peoples R China. [Chen, Geng; Qu, Xiongfei; Chen, Jiwei; Yang, Jianmin; Shi, Caiping; Chen, Long; Zhou, Peiying; Lu, Bingxin; Shi, Tieliu] E China Normal Univ, Sch Life Sci, Shanghai 200241, Peoples R China. [Wang, Charles] City Hope Comprehens Canc Ctr, Beckman Res Inst, Funct Genom Core, Duarte, CA 91010 USA. [Shi, Leming; Tong, Weida] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Shi, TL (reprint author), E China Normal Univ, Ctr Bioinformat & Computat Biol, Shanghai Key Lab Regulatory Biol, Inst Biomed Sci, Shanghai 200241, Peoples R China. EM tieliushi01@gmail.com FU National 973 Key Basic Research Program [2010CB945401, 2012CB910400]; National Natural Science Foundation of China [31171264, 31071162, 31240038]; Science and Technology Commission of Shanghai Municipality [11DZ2260300]; Graduate School of East China Normal University FX We thank Danielle and Jean Thierry-Mieg from NCBI, Kangping Yin, Hui Liu and Jiang Li for helpful discussions. This work was supported by the National 973 Key Basic Research Program (Grant Nos. 2010CB945401 and 2012CB910400), the National Natural Science Foundation of China (Grant No. 31171264, 31071162 and 31240038), the Science and Technology Commission of Shanghai Municipality (11DZ2260300) and the Graduate School of East China Normal University. NR 49 TC 7 Z9 8 U1 0 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD AUG PY 2013 VL 132 IS 8 BP 899 EP 911 DI 10.1007/s00439-013-1300-9 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 184QU UT WOS:000321909000004 PM 23572138 ER PT J AU Do Luu, HM Chen, A Isayeva, IS AF Do Luu, Hoan-My Chen, Angela Isayeva, Irada S. TI Comparative stability of the bioresorbable ferric crosslinked hyaluronic acid adhesion prevention solutions SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS LA English DT Article DE hyaluronic acid (HA); gel; adhesion; ferric crosslinking hyaluronic acid (FeHA); Intergel (R); FeHA adhesion prevention solution (Intergel (R); FeHA APS); abdominal tissue adhesions (ATA); adhesion barriers (AB); enzymatic degradation; hyaluronidase (Hyase); high pressure liquid chromatography (HPLC); HA digests; tetrasaccharides (4S); hexasaccharides (6S); half life (t1; 2; HA clearance ID PERFORMANCE LIQUID-CHROMATOGRAPHY; ANTIADHESION PRODUCTS; REGISTRIES; REDUCTION; EFFICACY; SURGERY; DIGESTS AB The Intergel (R) ferric crosslinked hyaluronate (FeHA) adhesion prevention solution (APS) (FDA) is associated with serious post-operative complications (Henley, http://www.lawyersandsettlements.com/features/gynecare-intergel/intergel-timeline.html, 2007; FDA, 2003; Roman et al., Fertil Steril 2005, 83 Suppl 1:1113-1118; Tang et al., Ann Surg 2006;243(4):449-455; Wiseman, Fertil Steril 2006;86(3):771; Wiseman, Fertil Steril 2006;85(4):e7). This prompted us to examine the in situ stability of crosslinked HA materials to hyaluronidase lyase degradation. Variables such as ferric ionic crosslink density, HA concentration, gel geometry, and molecular weight (MW) of HA polymer were studied. Various formulations of the crosslinked in house [Isayeva et al., J Biomed Mater Res: Part B - Appl Biomater 2010, 95B (1):9-18] FeHA (0.5%, w/v; 30, 50, 90% crosslinked), the Intergel (R) FeHA (0.5%, w/v; 90%), and the non-crosslinked HA (0.05-0.5%, w/v) were degraded at a fixed activity of hyaluronidase lyase from Streptomyces hyalurolyticus (Hyase) at 37 degrees C over time according to the method [Payan et al., J Chrom B: Biomed Sci Appl 1991;566(1):9-18]. Under our conditions, the data show that the crosslink density affects degradation the most, followed by HA concentration and then gel geometry. We found that MW has no effect. Our results are one possible explanation of the observations that the Intergel (R) FeHA APS (0.5%, w/v; 90%) material persisted an order of magnitude longer than expected [t(1/2) = 500 hrs vs. t(1/2) = 50 hrs (FDA; Johns et al., Fertil Steril 1997;68(1):37-42)]. These data also demonstrate the sensitivity of the in vitro hyaluronidase assay to predict the in situ stability of crosslinked HA medical products as previously reported [Sall et al., Polym Degrad Stabil 2007;92(5):915-919]. (c) 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2013. C1 [Do Luu, Hoan-My; Isayeva, Irada S.] US FDA, Div Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Chen, Angela] Vanderbilt Univ, Dept Hlth & Human Serv, Nashville, TN 37235 USA. RP Do Luu, HM (reprint author), US FDA, Div Chem & Mat Sci, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. EM Hoan-My.Luu@fda.hhs.gov NR 36 TC 0 Z9 0 U1 2 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4973 J9 J BIOMED MATER RES B JI J. Biomed. Mater. Res. Part B PD AUG PY 2013 VL 101B IS 6 BP 1006 EP 1013 DI 10.1002/jbm.b.32909 PG 8 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 181KA UT WOS:000321665300013 ER PT J AU Laslo, M Sun, XP Hsiao, CT Wu, WW Shen, RF Zou, SG AF Laslo, Mara Sun, Xiaoping Hsiao, Cheng-Te Wu, Wells W. Shen, Rong-Fong Zou, Sige TI A botanical containing freeze dried acai pulp promotes healthy aging and reduces oxidative damage in sod1 knockdown flies SO AGE LA English DT Article DE Aging intervention; Acai; Superoxide dismutase 1; Lifespan; Oxidative stress; Reproductive aging; Drosophila melanogaster ID EXTENDS LIFE-SPAN; AMYOTROPHIC-LATERAL-SCLEROSIS; ZINC SUPEROXIDE-DISMUTASE; AMAZONIAN PALM BERRY; OLERACEAE MART. ACAI; DROSOPHILA-MELANOGASTER; ALZHEIMERS-DISEASE; MASS-SPECTROMETRY; IMPROVES HEALTH; LABEL-FREE AB Superoxide dismutase 1 (SOD1), a critical enzyme against oxidative stress, is implicated in aging and degenerative diseases. We previously showed that a nutraceutical containing freeze-dried a double dagger ai pulp promotes survival of flies fed a high-fat diet or sod1 knockdown flies fed a standard diet. Here, we investigated the effect of a double dagger ai supplementation initiated at the early or late young adulthood on lifespan, physiological function, and oxidative damage in sod1 knockdown flies. We found that A double dagger ai supplementation extended lifespan even when started at the age of 10 days, which is the time shortly before the mortality rate of flies accelerated. Life-long a double dagger ai supplementation increased lifetime reproductive output in sod1 knockdown flies. Our molecular studies indicate that a double dagger ai supplementation reduced the protein levels of genes involved in oxidative stress response, cellular growth, and nutrient metabolism. A double dagger ai supplementation also affected the protein levels of ribosomal proteins. In addition, a double dagger ai supplementation decreased the transcript levels of genes involved in oxidative stress response and gluconeogenesis, while increasing the transcript levels of mitochondrial biogenesis genes. Moreover, a double dagger ai supplementation reduced the level of 4-hydroxynonenal-protein adducts, a lipid peroxidation marker. Our findings suggest that a double dagger ai supplementation promotes healthy aging in sod1-deficient flies partly through reducing oxidative damage, and modulating nutrient metabolism and oxidative stress response pathways. Our findings provide a foundation to further evaluate the viability of using a double dagger ai as an effective dietary intervention to promote healthy aging and alleviate symptoms of diseases with a high level of oxidative stress. C1 [Laslo, Mara; Sun, Xiaoping; Hsiao, Cheng-Te; Zou, Sige] NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. [Wu, Wells W.] NIA, Lab Clin Invest, Baltimore, MD 21224 USA. [Shen, Rong-Fong] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Zou, SG (reprint author), NIA, Lab Expt Gerontol, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM zous@grc.nia.nih.gov FU National Institute on Aging, NIH; NIH Office of Dietary Supplements FX We thank Alex Schauss to provide us the acai pulp extract and thank Ed Spangler, Alex Schauss, Don Ingram, Jim Carey, and Pablo Liedo for critical reading of the manuscript. This work was supported by funding from the Intramural Research Program of the National Institute on Aging, NIH to S.Z. and a research grant from the NIH Office of Dietary Supplements to X.P. and S.Z. NR 64 TC 3 Z9 3 U1 2 U2 19 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 J9 AGE JI Age PD AUG PY 2013 VL 35 IS 4 BP 1117 EP 1132 DI 10.1007/s11357-012-9437-3 PG 16 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 179UQ UT WOS:000321547300008 PM 22639178 ER PT J AU He, YS Li, Y Salazar, JK Yang, JY Tortorello, ML Zhang, W AF He, Yingshu Li, Ye Salazar, Joelle K. Yang, Jingyun Tortorello, Mary Lou Zhang, Wei TI Increased Water Activity Reduces the Thermal Resistance of Salmonella enterica in Peanut Butter SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID ESCHERICHIA-COLI; HEAT-RESISTANCE; SURVIVAL; INACTIVATION; ENTERITIDIS; MODEL; TYPHIMURIUM; OUTBREAK AB Increased water activity in peanut butter significantly (P < 0.05) reduced the heat resistance of desiccation-stressed Salmonella enterica serotypes treated at 90 degrees C. The difference in thermal resistance was less notable when strains were treated at 126 degrees C. Using scanning electron microscopy, we observed minor morphological changes of S. enterica cells resulting from desiccation and rehydration processes in peanut oil. C1 [He, Yingshu; Li, Ye; Salazar, Joelle K.; Zhang, Wei] Illinois Inst Technol, Inst Food Safety & Hlth, Bedford Pk, IL USA. [Yang, Jingyun] Penn State Univ, Methodol Ctr, University Pk, PA 16802 USA. [Tortorello, Mary Lou] US FDA, Bedford Pk, IL USA. RP Zhang, W (reprint author), Illinois Inst Technol, Inst Food Safety & Hlth, Bedford Pk, IL USA. EM zhangw@iit.edu FU Food Research Initiative from the USDA National Institute of Food Agriculture, Food Safety and Epidemiology: Biological Approaches for Food Safety program [93231] FX This work was supported by the Food Research Initiative, grant 2010-65201-20593 from the USDA National Institute of Food Agriculture, Food Safety and Epidemiology: Biological Approaches for Food Safety program (program code 93231). NR 29 TC 5 Z9 6 U1 5 U2 39 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD AUG PY 2013 VL 79 IS 15 BP 4763 EP 4767 DI 10.1128/AEM.01028-13 PG 5 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 175TG UT WOS:000321255600030 PM 23728806 ER PT J AU Akiyama, T Presedo, J Khan, AA AF Akiyama, Tatsuya Presedo, Jacqueline Khan, Ashraf A. TI The tetA gene decreases tigecycline sensitivity of Salmonella enterica isolates SO INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS LA English DT Article DE tetA; Tigecycline sensitivity; ramA; ramR ID MUTANT PREVENTION CONCENTRATIONS; MEDIATED MULTIDRUG-RESISTANCE; TETRACYCLINE RESISTANCE; ANTIBIOTIC-RESISTANCE; SEROVAR TYPHIMURIUM; QUINOLONE RESISTANCE; EFFLUX; COLI; FLUOROQUINOLONES; GLYCYLCYCLINES AB To determine the association of tetracycline resistance determinants with tigecycline sensitivity, tetracycline-resistant Salmonella spp. isolated from clinical and food samples were tested for the presence of tetracycline resistance determinants, tigecycline sensitivity, and the impact of tetA on tigecycline resistance. In addition, the impacts of multiple resistance mechanisms on tigecycline resistance were determined using an isolate with ramR mutation. Of the 49 tetracycline-resistant Salmonella isolates screened, 32 were positive for tetA, 13 were positive for tetB, 2 were positive for tetC and 1 isolate was positive for both tetA and tetB. The minimum inhibitory concentration (MIC) of tigecycline for tetA-carrying isolates ranged from 0.19 mg/L to 3 mg/L (mode 0.75 mg/L), whereas the MIC of tigecycline for tetB-carrying isolates ranged from 0.064 mg/L to 0.5 mg/L (modes 0.25 mg/L and 0.38 mg/L, excluding the isolate with both tetA and tetB). Double frameshift mutations in codons 201, 202 and 203 were observed in partial sequences of the tetA genes in these strains and the majority of published tetA gene sequences. Curing of the tetA genes from three isolates reduced the tigecycline MICs, whilst deletion of ramR increased tigecycline MICs. This study indicates that the tetA gene decreases sensitivity to tigecycline in Salmonella spp. at a low level. With additional resistance mechanisms, tetA-carrying strains can reach the breakpoint for tigecycline resistance. Published by Elsevier B.V. on behalf of International Society of Chemotherapy. C1 [Akiyama, Tatsuya; Presedo, Jacqueline; Khan, Ashraf A.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Presedo, Jacqueline] Boston Coll, Dept Biol, Chestnut Hill, MA 02467 USA. RP Khan, AA (reprint author), US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Ashraf.khan@fda.hhs.gov FU Postgraduate Research Program at the National Center for Toxicological Research (NCTR); Summer Student Research Program at NCTR FX Support for TA was provided by the Postgraduate Research Program at the National Center for Toxicological Research (NCTR) and administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the US Department of Energy and the US Food and Drug Administration (FDA). Support for JP was provided by the Summer Student Research Program at NCTR and administered by ORISE through an interagency agreement between the US Department of Energy and the FDA. NR 31 TC 8 Z9 10 U1 3 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-8579 J9 INT J ANTIMICROB AG JI Int. J. Antimicrob. Agents PD AUG PY 2013 VL 42 IS 2 BP 133 EP 140 DI 10.1016/j.ijantimicag.2013.04.017 PG 8 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 182LG UT WOS:000321743400004 PM 23746717 ER PT J AU Khurana, S Wu, J Dimitrova, M King, LR Manischewitz, J Graham, BS Ledgerwood, JE Golding, H AF Khurana, Surender Wu, Jian Dimitrova, Milena King, Lisa R. Manischewitz, Jody Graham, Barney S. Ledgerwood, Julie E. Golding, Hana TI DNA Priming Prior to Inactivated Influenza A(H5N1) Vaccination Expands the Antibody Epitope Repertoire and Increases Affinity Maturation in a Boost-Interval-Dependent Manner in Adults SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE H5N1; influenza; vaccine; antibody; affinity; Phage display; epitope; hemagglutinin; SPR; immune response; virus ID VIRUS; PROTECTION; VACCINES; AVIDITY AB DNA priming improves the response to inactivated influenza A(H5N1) vaccination. We compared the immunogenicity of an H5 DNA prime (using strain A/Indonesia/5/2005) followed by an H5N1 monovalent inactivated vaccine boost at 4, 8, 12, 16, or 24 weeks to that of 2 doses of H5N1 monovalent inactivated vaccine in adults. Antibody epitope repertoires were elucidated by genome-fragment phage-display library analysis, and antibody avidities for HA1 and HA2 domains were measured by surface plasmon resonance. H5 DNA priming expanded the H5-specific antibody epitope repertoire and enhanced antibody avidity to the HA1 (but not the HA2) domain in an interval-dependent manner. Enhanced HA1 binding and avidity after an interval of >= 12 weeks between prime and boost correlated with improved neutralization of homologous and heterologous H5N1 strains. C1 [Khurana, Surender; Wu, Jian; Dimitrova, Milena; King, Lisa R.; Manischewitz, Jody; Golding, Hana] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Graham, Barney S.; Ledgerwood, Julie E.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Khurana, S (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. EM surender.khurana@fda.hhs.gov RI Wu, Jian/K-2038-2015 OI Wu, Jian/0000-0001-8011-9551 FU Food and Drug Administration; National Institutes of Health FX This work was supported by the Food and Drug Administration and the National Institutes of Health. NR 15 TC 31 Z9 31 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 1 PY 2013 VL 208 IS 3 BP 413 EP 417 DI 10.1093/infdis/jit178 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 178PB UT WOS:000321458800007 PM 23633404 ER PT J AU Brinster, LR Omeir, RL Foseh, GS Macauley, JN Snoy, PJ Beren, JJ Teferedegne, B Peden, K Lewis, AM AF Brinster, Lauren R. Omeir, Romelda L. Foseh, Gideon S. Macauley, Juliete N. Snoy, Philip J. Beren, Joel J. Teferedegne, Belete Peden, Keith Lewis, Andrew M., Jr. TI Failure-to-Thrive Syndrome Associated with Tumor Formation by Madin-Darby Canine Kidney Cells in Newborn Nude Mice SO COMPARATIVE MEDICINE LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITIONS; HUMAN-MELANOMA CELLS; TUMORIGENIC PHENOTYPE; RECEPTOR ANTAGONIST; LINE MDCK; EXPRESSION; CACHEXIA; SYSTEM; GROWTH; VIRUS AB Tumors that formed in newborn nude mice that were inoculated with 10(7) Madin-Darby canine kidney (MDCK) cells were associated with a failure-to-thrive (FTT) syndrome consisting of growth retardation, lethargy, weakness, and dehydration. Scoliosis developed in 41% of affected pups. Pups were symptomatic by week 2; severely affected pups became moribund and required euthanasia within 3 to 4 wk. Mice with FTT were classified into categories of mild, moderate, and severe disease by comparing their weight with that of age-matched normal nude mice. The MDCK-induced tumors were adenocarcinomas that invaded adjacent muscle, connective tissue, and bone; 6 of the 26 pups examined had lung metastases. The induction of FTT did not correlate with cell-line aggressiveness as estimated by histopathology or the efficiency of tumor formation (tumor-forming dose 50% endpoint range = 10(2.8) to 10(7.5)); however, tumor invasion of the paravertebral muscles likely contributed to the scoliosis noted. In contrast to the effect of MDCK cells, tumor formation observed in newborn mice inoculated with highly tumorigenic, human-tumor derived cell lines was not associated with FTT development. We suggest that tumor formation and FTT are characteristics of these MDCK cell inocula and that FTT represents a new syndrome that may be similar to the cachexia that develops in humans with cancer or other diseases. C1 [Brinster, Lauren R.] NIH, Div Vet Resources, Bethesda, MD 20892 USA. [Omeir, Romelda L.; Foseh, Gideon S.; Macauley, Juliete N.; Teferedegne, Belete; Peden, Keith; Lewis, Andrew M., Jr.] CBER, Off Vaccines, Div Viral Prod, Bethesda, MD USA. [Snoy, Philip J.; Beren, Joel J.] CBER, Food & Drug Adm, Div Vet Serv, Bethesda, MD USA. RP Lewis, AM (reprint author), CBER, Off Vaccines, Div Viral Prod, Bethesda, MD USA. EM andrew.lewis@fda.hhs.gov FU Division of Microbiology and Infectious Diseases of NIAID; CBER-FDA [YI-AI-4893-02NIAID] FX This research was supported in part by a contract from the Division of Microbiology and Infectious Diseases of NIAID through an interagency agreement with CBER-FDA under contract number YI-AI-4893-02NIAID. NR 40 TC 2 Z9 2 U1 0 U2 2 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD AUG PY 2013 VL 63 IS 4 BP 323 EP 330 PG 8 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA AN7VT UT WOS:000340809800004 PM 24209967 ER PT J AU Aljaloud, SO Ibrahim, SA Fraser, AM Song, T Shahbazi, A AF Aljaloud, Sulaiman O. Ibrahim, Salam A. Fraser, Angela M. Song, Tammy Shahbazi, Abolghasem TI Microbiological quality and safety of dietary supplements sold in Saudi Arabia SO EMIRATES JOURNAL OF FOOD AND AGRICULTURE LA English DT Article DE Dietary supplements; Microbiological; Supplement quality; Supplement safety; Bacterial contamination ID FOODS AB The global market for dietary supplements has advanced in recent years capitalizing on the growing awareness of healthy living worldwide. Supplements provide enhanced nutritional levels for daily competitive performance. However, there is a need to explore the quality of dietary supplements as there are few studies related to this area. Therefore, the objective of this study was to determine the microbiological quality of dietary supplements in the local markets of Saudi Arabia. The total bacterial count, coliform, Escherichia coli, Salmonella, and Staphylococcus aureus were included in this analysis. The 80 most popular supplements were tested in this study. Our results showed that microbial contamination was present in only nine products. The microbial level ranged from 1.69-8.43 Log CFU/mL. The higher level of total count (8.43 Log CFU/mL) and S. aureus (8.39 Log CFU/mL) were found in supplement glutamine. Amino acids, dynamisan, glucosamine sulfate, glucosaiene, creatine monohydrate, whey protein, and folate acid also showed the presence of bacterial contamination. Our fmdings suggested that improvements are needed in these supplements which were tested for microbiological contamination. These findings highlight the fact that a review of product safety and quality is becoming increasingly important for consumer health. This will help to ensure safe products available for today's savvy, health-conscious consumer. C1 [Aljaloud, Sulaiman O.; Ibrahim, Salam A.] North Carolina Agr & Tech Univ, Food Microbiol Lab, Greensboro, NC USA. [Fraser, Angela M.] Clemson Univ, Dept Food Nutr & Packaging Sci, Clemson, SC 29634 USA. [Song, Tammy] US FDA, Washington, DC 20204 USA. [Shahbazi, Abolghasem] N Carolina Agr & Tech State Univ, Dept Nat Resources & Environm Design, Greensboro, NC 27411 USA. RP Ibrahim, SA (reprint author), N Carolina Agr & Tech State Univ, Food Microbiol & Biotechnol Lab, 171 Carver Hall, Greensboro, NC 27411 USA. EM ibrah001@ncat.edu FU cooperative State Research, Education and Extension Service of United State Department of Agriculture; Agricultural Research Program, North Carolina Agricultural and Technical State University FX The research work was funded, in part, through the cooperative State Research, Education and Extension Service of United State Department of Agriculture, in the Agricultural Research Program, North Carolina Agricultural and Technical State University. We would like to express our gratitude to Dr. Keith Schimmel (Energy and Environmental Interdisciplinary Studies at North Carolina A & T State University) for his support. NR 11 TC 0 Z9 0 U1 2 U2 5 PU UNITED ARAB EMIRATES UNIV PI AL AIN PA P. O. BOX 17551, AL AIN, U ARAB EMIRATES SN 2079-052X EI 2079-0538 J9 EMIR J FOOD AGR JI Emir. J. Food Agric. PD AUG PY 2013 VL 25 IS 8 BP 593 EP 596 DI 10.9755/ejfa.v25i8.16092 PG 4 WC Agronomy; Food Science & Technology SC Agriculture; Food Science & Technology GA AS7PL UT WOS:000344447500004 ER PT J AU Dorne, JL Doerge, DR Vandenbroeck, M Fink-Gremmels, J Mennes, W Knutsen, HK Vernazza, F Castle, L Edler, L Benford, D AF Dorne, Jean Lou Doerge, Daniel R. Vandenbroeck, Marc Fink-Gremmels, Johanna Mennes, Wim Knutsen, Helle K. Vernazza, Francesco Castle, Laurence Edler, Lutz Benford, Diane TI Recent advances in the risk assessment of melamine and cyanuric acid in animal feed SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Melamine; Cyanuric acid; Co-exposure; Toxicokinetics; Renal toxicity; Animal feed; Animal health; Human health ID SPRAGUE-DAWLEY RATS; F344 RATS; TOXICITY; CATS; PIGS; CARCINOGENICITY; NEPHROTOXICITY; CONTAMINANTS; DISPOSITION; DERIVATIVES AB Melamine can be present at low levels in food and feed mostly from its legal use as a food contact material in laminates and plastics, as a trace contaminant in nitrogen supplements used in animal feeds, and as a metabolite of the pesticide cyromazine. The mechanism of toxicity of melamine involves dose-dependent formation of crystals with either endogenous uric acid or a structural analogue of melamine, cyanuric acid, in renal tubules resulting in potential acute kidney failure. Co-exposure to melamine and cyanuric acid in livestock, fish, pets and laboratory animals shows higher toxicity compared with melamine or cyanuric acid alone. Evidence for crystal formation between melamine and other structural analogs i.e. ammelide and ammeline is limited. Illegal pet food adulterations with melamine and cyanuric acid and adulteration of milk with melamine resulted in melamine-cyanuric acid crystals, kidney damage and deaths of cats and dogs and melamine-uric acid stones, hospitalisation and deaths of children in China respectively. Following these incidents, the tolerable daily intake for melamine was re-evaluated by the U.S. Food and Drug Administration, the World Health Organisation, and the Scientific Panel on Contaminants in the Food Chain of the European Food Safety Authority (EFSA). This review provides an overview of toxicology, the adulteration incidents and risk assessments for melamine and its structural analogues. Particular focus is given to the recent EFSA risk assessment addressing impacts on animal and human health of background levels of melamine and structural analogues in animal feed. Recent research and future directions are discussed. (C) 2012 Elsevier Inc. All rights reserved. C1 [Dorne, Jean Lou; Vandenbroeck, Marc] European Food Safety Author, Unit Contaminants, I-43121 Parma, Italy. [Doerge, Daniel R.] US FDA, NCTR, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Fink-Gremmels, Johanna] Univ Utrecht, NL-3508 TC Utrecht, Netherlands. [Mennes, Wim] RIVM, Bilthoven, Netherlands. [Knutsen, Helle K.] Norwegian Inst Publ Hlth, Oslo, Norway. [Vernazza, Francesco] European Food Safety Author, I-43121 Parma, Italy. [Castle, Laurence] FERA, York, N Yorkshire, England. [Edler, Lutz] German Canc Res Ctr, Heidelberg, Germany. [Benford, Diane] Food Stand Agcy, London, England. RP Dorne, JL (reprint author), European Food Safety Author, Unit Emerging Risks, Largo N Palli 5-A, I-43100 Parma, Italy. EM jean-lou.dorne@efsa.europa.eu NR 62 TC 31 Z9 33 U1 23 U2 134 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD AUG 1 PY 2013 VL 270 IS 3 SI SI BP 218 EP 229 DI 10.1016/j.taap.2012.01.012 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 173OZ UT WOS:000321090100005 PM 22306862 ER PT J AU Guo, XQ Mittelstaedt, RA Guo, L Shaddock, JG Heflich, RH Bigger, AH Moore, MM Mei, N AF Guo, Xiaoqing Mittelstaedt, Roberta A. Guo, Lei Shaddock, Joseph G. Heflich, Robert H. Bigger, Anita H. Moore, Martha M. Mei, Nan TI Nitroxide TEMPO: A genotoxic and oxidative stress inducer in cultured cells SO TOXICOLOGY IN VITRO LA English DT Article DE Nitroxide; Mouse lymphoma assay; Micronucleus assay; Loss of heterozygosity; Glutathione; Oxidative stress ID MOUSE LYMPHOMA-CELLS; FREE-RADICALS; OXOAMMONIUM CATION; CYCLIC NITROXIDES; AEROBIC OXIDATION; DAMAGE; ASSAY; MUTAGENICITY; GLUTATHIONE; SYSTEM AB 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO) is a low molecular weight nitroxide and stable free radical. In this study, we investigated the cytotoxicity and genotoxicity of TEMPO in mammalian cells using the mouse lymphoma assay (MLA) and in vitro micronucleus assay. In the absence of metabolic activation (S9), 3 mM TEMPO produced significant cytotoxicity and marginal mutagenicity in the MLA; in the presence of 59, treatment of mouse lymphoma cells with 1-2 mM TEMPO resulted in dose-dependent decreases of the relative total growth and increases in mutant frequency. Treatment of TK6 human lymphoblastoid cells with 0.9-23 mM TEMPO increased the frequency of both micronuclei (a marker for clastogenicity) and hypodiploid nuclei (a marker of aneugenicity) in a dose-dependent manner; greater responses were produced in the presence of S9. Within the dose range tested, TEMPO induced reactive oxygen species and decreased glutathione levels in mouse lymphoma cells. In addition, the majority of TEMPO-induced mutants had loss of heterozygosity at the Tk locus, with allele loss of <= 34 Mbp. These results indicate that TEMPO is mutagenic in the MLA and induces micronuclei and hypodiploid nuclei in TK6 cells. Oxidative stress may account for part of the genotoxicity induced by TEMPO in both cell lines. Published by Elsevier Ltd. C1 [Guo, Xiaoqing; Mittelstaedt, Roberta A.; Shaddock, Joseph G.; Heflich, Robert H.; Moore, Martha M.; Mei, Nan] Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. [Guo, Lei] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Bigger, Anita H.] Bigger Consulting, St Augustine, FL 32092 USA. RP Mei, N (reprint author), Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. EM nan.mei@fda.hhs.gov OI MEI, NAN/0000-0002-3501-9014 NR 42 TC 7 Z9 7 U1 0 U2 22 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-2333 J9 TOXICOL IN VITRO JI Toxicol. Vitro PD AUG PY 2013 VL 27 IS 5 SI SI BP 1496 EP 1502 DI 10.1016/j.tiv.2013.02.019 PG 7 WC Toxicology SC Toxicology GA 168DP UT WOS:000320686200010 PM 23517621 ER PT J AU Shen, JL Rump, L Zhang, YF Chen, Y Wang, X Meng, JH AF Shen, Jinling Rump, Lydia Zhang, Yifan Chen, Yi Wang, Xin Meng, Jianghong TI Molecular subtyping and virulence gene analysis of Listeria monocytogenes isolates from food SO FOOD MICROBIOLOGY LA English DT Article DE Listeria monocytogenes; inlA; Epidemic clone; Listeriolysin S ID TO-EAT FOODS; MULTIPLEX PCR; EPIDEMIC CLONES; UNITED-STATES; STRAINS; PREVALENCE; INTERNALIN; INLA; EXPRESSION; RESISTANCE AB A total of 67 Listeria monogtogenes isolates from 698 raw meat samples were characterized for molecular serogroup identification and antimicrobial susceptibility. Approximately one third (32.8%) of the isolates belonged to molecular serogroup I/2a, 3a, followed by 1/2c, 3c (26.9%), 1/2b, 3b, 7 (22.4%), 4b, 4d, 4e (16.4%) and 4a, 4c (1.5%). Most of the L. monocytogenes isolates were susceptible to 14 antimicrobials tested but several were resistant to tetracycline, ciprofloxacin and nitrofurantoin. An additional 30 L. monocytogenes isolates from chicken and produce in our collection were also included to determine the presence of significant virulence markers. All 97 isolates carried inlC and inlJ except for a lineage III isolate 110-1. Most Listeriolysin S (LLS)-carrying isolates (11/12) belonged to lineage I, whereas the remaining one isolate belonged to lineage III. Five 4b, 4d, 4e isolates including two from turkey and three from produce belonged to Epidemic Clone I (ECI). Four molecular serogroup associated mutation types that lead to premature stop codons (PMSCs) in inlA were identified. PFGE and inlA sequence analysis results were concordant, and different virulence potential within 1/2a, 3a and 4b, 4d, 4e isolates were observed. The study revealed that a subset of isolates from meat and produce belonged to ECl, harbored inlC, inlJ and LLS, and produced full length InlA, suggesting that they be capable of causing human illness. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Shen, Jinling; Wang, Xin; Meng, Jianghong] Northwest A&F Univ, Coll Food Sci & Engn, Yangling 712100, Shaanxi Provinc, Peoples R China. [Shen, Jinling; Rump, Lydia; Meng, Jianghong] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Zhang, Yifan] Wayne State Univ, Dept Nutr & Food Sci, Detroit, MI 48202 USA. [Chen, Yi] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. RP Meng, JH (reprint author), Univ Maryland, Dept Nutr & Food Sci, 0112 Skinner Bldg, College Pk, MD 20742 USA. EM jmeng@umd.edu NR 41 TC 24 Z9 24 U1 3 U2 56 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0740-0020 J9 FOOD MICROBIOL JI Food Microbiol. PD AUG PY 2013 VL 35 IS 1 BP 58 EP 64 DI 10.1016/j.fm.2013.02.014 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology SC Biotechnology & Applied Microbiology; Food Science & Technology; Microbiology GA 148LD UT WOS:000319245200009 PM 23628615 ER PT J AU Kwekel, JC Desai, VG Moland, CL Vijay, V Fuscoe, JC AF Kwekel, Joshua C. Desai, Varsha G. Moland, Carrie L. Vijay, Vikrant Fuscoe, James C. TI Sex differences in kidney gene expression during the life cycle of F344 rats SO BIOLOGY OF SEX DIFFERENCES LA English DT Article AB Background: The kidney functions in key physiological processes to filter blood and regulate blood pressure via key molecular transporters and ion channels. Sex-specific differences have been observed in renal disease incidence and progression, as well as acute kidney injury in response to certain drugs. Although advances have been made in characterizing the molecular components involved in various kidney functions, the molecular mechanisms responsible for sex differences are not well understood. We hypothesized that the basal expression levels of genes involved in various kidney functions throughout the life cycle will influence sex-specific susceptibilities to adverse renal events. Methods: Whole genome microarray gene expression analysis was performed on kidney samples collected from untreated male and female Fischer 344 (F344) rats at eight age groups between 2 and 104 weeks of age. Results: A combined filtering approach using statistical (ANOVA or pairwise t test, FDR 0.05) and fold-change criteria (>1.5 relative fold change) was used to identify 7,447 unique differentially expressed genes (DEGs). Principal component analysis (PCA) of the 7,447 DEGs revealed sex-related differences in mRNA expression at early (2 weeks), middle (8, 15, and 21 weeks), and late (104 weeks) ages in the rat life cycle. Functional analysis (Ingenuity Pathway Analysis) of these sex-different genes indicated over-representation of specific pathways and networks including renal tubule injury, drug metabolism, and immune cell and inflammatory responses. The mRNAs that code for the qualified urinary protein kidney biomarkers KIM-1, Clu, Tff3, and Lcn2 were also observed to show sex differences. Conclusions: These data represent one of the most comprehensive in-life time course studies to be published, assessing sex differences in global gene expression in the F344 rat kidney. PCA and Venn analyses reveal specific periods of sexually dimorphic gene expression which are associated with functional categories (xenobiotic metabolism and immune cell and inflammatory responses) of key relevance to acute kidney injury and chronic kidney disease, which may underlie sex-specific susceptibility. Analysis of the basal gene expression patterns of renal genes throughout the life cycle of the rat will improve the use of current and future renal biomarkers and inform our assessments of kidney injury and disease. C1 [Kwekel, Joshua C.; Desai, Varsha G.; Moland, Carrie L.; Vijay, Vikrant; Fuscoe, James C.] US FDA, Personalized Med Branch, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Kwekel, JC (reprint author), US FDA, Personalized Med Branch, Div Syst Biol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Joshua.Kwekel@fda.hhs.gov; James.Fuscoe@fda.hhs.gov RI Vijay, Vikrant/E-7651-2010 OI Vijay, Vikrant/0000-0001-8425-1285 NR 0 TC 19 Z9 19 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2042-6410 J9 BIOL SEX DIFFER JI Biol. Sex Differ. PD JUL 31 PY 2013 VL 4 AR 14 DI 10.1186/2042-6410-4-14 PG 13 WC Endocrinology & Metabolism; Genetics & Heredity SC Endocrinology & Metabolism; Genetics & Heredity GA 253OH UT WOS:000327097800001 PM 23902594 ER PT J AU Sanchez-Pomales, G Mudalige, TK Lim, JH Linder, SW AF Sanchez-Pomales, Germane Mudalige, Thilak K. Lim, Jin-Hee Linder, Sean W. TI Rapid Determination of Silver in Nanobased Liquid Dietary Supplements Using a Portable X-ray Fluorescence Analyzer SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE nanoscale silver; dietary supplements; X-ray fluorescence analyzer; nanomaterials; inductively coupled plasma mass spectrometry; quantitation ID SPECTROMETRY; BEVERAGES AB This paper reports a rapid and straightforward method for the quantitation of total Ag content in nanobased commercially available liquid dietary supplements using a portable X-ray fluorescence (pXRF) analyzer. Figures of merits were evaluated by analyzing a series of AgNO3 standards. This method was shown to have a detection limit of 3 ppm, a quantitation limit of 10 ppm, and a broad linear range from the detection limit to 10000 ppm (1%). Accurate detection and quantitation of Ag content in well-characterized Ag nanoparticle samples and in nanobased liquid dietary supplements were achieved with good correlation (i.e., percentage difference average values under 15%) between the total Ag concentration obtained by the pXRF analyzer and by inductively coupled plasma mass spectrometry (ICP-MS). Furthermore, accurate quantitation of Ag in the presence of high concentrations of potential spectral interferences was also demonstrated. C1 [Sanchez-Pomales, Germane; Mudalige, Thilak K.; Lim, Jin-Hee; Linder, Sean W.] US FDA, Off Regulatory Affairs, Arkansas Reg Lab, Jefferson, AR 72079 USA. RP Linder, SW (reprint author), US FDA, Off Regulatory Affairs, Arkansas Reg Lab, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM sean.linder@fda.hhs.gov NR 18 TC 9 Z9 9 U1 3 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD JUL 31 PY 2013 VL 61 IS 30 BP 7250 EP 7257 DI 10.1021/jf402018t PG 8 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA 196DD UT WOS:000322752700011 PM 23805852 ER PT J AU Chen, S Wan, LQ Couch, L Lin, HX Li, Y Dobrovolsky, VN Mei, N Guo, L AF Chen, Si Wan, Liqing Couch, Letha Lin, Haixia Li, Yan Dobrovolsky, Vasily N. Mei, Nan Guo, Lei TI Mechanism study of goldenseal-associated DNA damage SO TOXICOLOGY LETTERS LA English DT Article DE Berberine; Comet assay; DNA damage; Goldenseal; gamma-H2A.X; Topoisomerase ID TOPOISOMERASE-II INHIBITORS; HEPG2 CELLS; MITOCHONDRIAL DYSFUNCTION; ALKALOID BERBERINE; CLEAVAGE COMPLEXES; ACUTE-LEUKEMIA; KAVA EXTRACT; SECONDARY; CANCER; CHECKPOINT AB Goldenseal has been used for the treatment of a wide variety of ailments including gastrointestinal disturbances, urinary tract disorders, and inflammation. The five major alkaloid constituents in goldenseal are berberine, palmatine, hydrastine, hydrastinine, and canadine. When goldenseal was evaluated by the National Toxicology Program (NTP) in the standard 2-year bioassay, goldenseal induced an increase in liver tumors in rats and mice; however, the mechanism of goldenseal-associated liver carcinogenicity remains unknown. In this study, the toxicity of the five goldenseal alkaloid constituents was characterized, and their toxic potencies were compared. As measured by the Comet assay and the expression of gamma-H2A. X, berberine, followed by palmatine, appeared to be the most potent DNA damage inducer in human hepatoma HepG2 cells. Berberine and palmatine suppressed the activities of both topoisomerase (Topo) I and II. In berberine-treated cells, DNA damage was shown to be directly associated with the inhibitory effect of Topo II, but not Topo I by silencing gene of Topo I or Topo II. In addition, DNA damage was also observed when cells were treated with commercially available goldenseal extracts and the extent of DNA damage was positively correlated to the berberine content. Our findings suggest that the Topo II inhibitory effect may contribute to berberine-and goldenseal-induced genotoxicity and tumorigenicity. (C) 2013 The Authors. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Chen, Si; Wan, Liqing; Couch, Letha; Guo, Lei] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Wan, Liqing] Shanghai Inst Food & Drug Control, Shanghai 201203, Peoples R China. [Lin, Haixia; Li, Yan; Dobrovolsky, Vasily N.; Mei, Nan] US FDA, Natl Ctr Toxicol Res, Div Genet & Mol Toxicol, Jefferson, AR 72079 USA. RP Guo, L (reprint author), 3900 NCTR Rd,HFT-110, Jefferson, AR 72079 USA. EM Lei.Guo@fda.hhs.gov RI Lin, Haixia /J-4772-2015; OI MEI, NAN/0000-0002-3501-9014 FU Postgraduate Research Program at the National Center for Toxicological Research; U.S. FDA's International Scientist Exchange Program FX SC, HL, and YL were supported by appointments to the Postgraduate Research Program at the National Center for Toxicological Research administered by the Oak Ridge Institute for Science Education through an interagency agreement between the U.S. Department of Energy and the U.S. FDA. LW was supported by the U.S. FDA's International Scientist Exchange Program. We thank Dr. William Melchior for his critical review of this manuscript. NR 61 TC 8 Z9 8 U1 1 U2 14 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD JUL 31 PY 2013 VL 221 IS 1 BP 64 EP 72 DI 10.1016/j.toxlet.2013.05.641 PG 9 WC Toxicology SC Toxicology GA 179DM UT WOS:000321499100010 PM 23747414 ER PT J AU Chen, WJ Samuelson, FW Gallas, BD Kang, L Sahiner, B Petrick, N AF Chen, Weijie Samuelson, Frank W. Gallas, Brandon D. Kang, Le Sahiner, Berkman Petrick, Nicholas TI On the assessment of the added value of new predictive biomarkers SO BMC MEDICAL RESEARCH METHODOLOGY LA English DT Article DE Biomarkers; Classification; Area under the ROC curve ID PERFORMANCE; IMPROVEMENT; MARKERS; CANCER AB Background: The surge in biomarker development calls for research on statistical evaluation methodology to rigorously assess emerging biomarkers and classification models. Recently, several authors reported the puzzling observation that, in assessing the added value of new biomarkers to existing ones in a logistic regression model, statistical significance of new predictor variables does not necessarily translate into a statistically significant increase in the area under the ROC curve (AUC). Vickers et al. concluded that this inconsistency is because AUC "has vastly inferior statistical properties," i.e., it is extremely conservative. This statement is based on simulations that misuse the DeLong et al. method. Our purpose is to provide a fair comparison of the likelihood ratio (LR) test and the Wald test versus diagnostic accuracy (AUC) tests. Discussion: We present a test to compare ideal AUCs of nested linear discriminant functions via an F test. We compare it with the LR test and the Wald test for the logistic regression model. The null hypotheses of these three tests are equivalent; however, the F test is an exact test whereas the LR test and the Wald test are asymptotic tests. Our simulation shows that the F test has the nominal type I error even with a small sample size. Our results also indicate that the LR test and the Wald test have inflated type I errors when the sample size is small, while the type I error converges to the nominal value asymptotically with increasing sample size as expected. We further show that the DeLong et al. method tests a different hypothesis and has the nominal type I error when it is used within its designed scope. Finally, we summarize the pros and cons of all four methods we consider in this paper. Summary: We show that there is nothing inherently less powerful or disagreeable about ROC analysis for showing the usefulness of new biomarkers or characterizing the performance of classification models. Each statistical method for assessing biomarkers and classification models has its own strengths and weaknesses. Investigators need to choose methods based on the assessment purpose, the biomarker development phase at which the assessment is being performed, the available patient data, and the validity of assumptions behind the methodologies. C1 [Chen, Weijie; Samuelson, Frank W.; Gallas, Brandon D.; Kang, Le; Sahiner, Berkman; Petrick, Nicholas] US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Chen, WJ (reprint author), US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM weijie.chen@fda.hhs.gov OI Gallas, Brandon/0000-0001-7332-1620 NR 19 TC 8 Z9 8 U1 0 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2288 J9 BMC MED RES METHODOL JI BMC Med. Res. Methodol. PD JUL 29 PY 2013 VL 13 AR 98 DI 10.1186/1471-2288-13-98 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 193CF UT WOS:000322534000001 PM 23895587 ER PT J AU Kurasawa, JH Shestopal, SA Karnaukhova, E Struble, EB Lee, TK Sarafanov, AG AF Kurasawa, James H. Shestopal, Svetlana A. Karnaukhova, Elena Struble, Evi B. Lee, Timothy K. Sarafanov, Andrey G. TI Mapping the Binding Region on the Low Density Lipoprotein Receptor for Blood Coagulation Factor VIII SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Blood Coagulation Factors; Factor VIII; Lipoprotein Receptor; Receptor Structure-Function; Recombinant Protein Expression; Hemophilia A ID CONSERVED ACIDIC RESIDUE; CORONARY-ARTERY-DISEASE; NMR SOLUTION STRUCTURE; CYSTEINE-RICH REPEATS; VON-WILLEBRAND-FACTOR; LIGAND-BINDING; LDL RECEPTOR; ALPHA-2-MACROGLOBULIN RECEPTOR; FACTOR IXA; STRUCTURAL REQUIREMENTS AB Low density lipoprotein receptor (LDLR) was shown to mediate clearance of blood coagulation factor VIII (FVIII) from the circulation. To elucidate the mechanism of interaction of LDLR and FVIII, our objective was to identify the region of the receptor necessary for binding FVIII. Using surface plasmon resonance, we found that LDLR exodomain and its cluster of complement-type repeats (CRs) bind FVIII in the same mode. This indicated that the LDLR site for FVIII is located within the LDLR cluster. Similar results were obtained for another ligand of LDLR, -2-macroglobulin receptor-associated protein (RAP), a common ligand of receptors from the LDLR family. We further generated a set of recombinant fragments of the LDLR cluster and assessed their structural integrity by binding to RAP and by circular dichroism. A number of fragments overlapping CR.2-5 of the cluster were positive for binding RAP and FVIII. The specificity of these interactions was tested by site-directed mutagenesis of conserved tryptophans within the LDLR fragments. For FVIII, the specificity was also tested using a single-chain variable antibody fragment directed against the FVIII light chain as a competitor. Both cases resulted in decreased binding, thus confirming its specificity. The mutagenic study also showed an importance of the conserved tryptophans in LDLR for both ligands, and the competitive binding results showed an involvement of the light chain of FVIII in its interaction with LDLR. In conclusion, the region of CR.2-5 of LDLR was defined as the binding site for FVIII and RAP. C1 [Kurasawa, James H.; Shestopal, Svetlana A.; Karnaukhova, Elena; Struble, Evi B.; Lee, Timothy K.; Sarafanov, Andrey G.] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Sarafanov, AG (reprint author), US FDA, Div Hematol, Off Blood Res & Review, Ctr Biol Evaluat & Res, 1401 Rockville Pike HFM-340, Rockville, MD 20852 USA. EM andrey.sarafanov@fda.hhs.gov FU Center for Biologics Evaluation and Research (CBER) of the United States Food and Drug Administration (FDA); Research Participation Program at the CBER FX This work was supported by funds from the Center for Biologics Evaluation and Research (CBER) of the United States Food and Drug Administration (FDA) and also by the Research Participation Program at the CBER administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the United States Department of Energy and the United States Food and Drug Administration. This work was initially presented at the 54th American Society of Hematology Annual Meeting, December 8-11,2012, in Atlanta, GA. NR 69 TC 2 Z9 2 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 26 PY 2013 VL 288 IS 30 AR 22033 DI 10.1074/jbc.M113.468108 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 277TJ UT WOS:000328841900049 PM 23754288 ER PT J AU Raman, FS Kawel-Boehm, N Gai, N Freed, M Han, J Liu, CY Lima, JAC Bluemke, DA Liu, ST AF Raman, Fabio S. Kawel-Boehm, Nadine Gai, Neville Freed, Melanie Han, Jing Liu, Chia-Ying Lima, Joao A. C. Bluemke, David A. Liu, Songtao TI Modified look-locker inversion recovery T1 mapping indices: assessment of accuracy and reproducibility between magnetic resonance scanners SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE T1 mapping; Partition coefficient (lambda); Extracellular volume fraction (ECV); Diffuse myocardial fibrosis; Modified look-locker with inversion recovery (MOLLI) ID DIFFUSE MYOCARDIAL FIBROSIS; EXTRACELLULAR VOLUME FRACTION; INTRAINDIVIDUAL ASSESSMENT; GD-DTPA; VALIDATION; HEART; CMR; QUANTIFICATION; ASSOCIATION; RELAXATION AB Background: Cardiovascular magnetic resonance (CMR) T1 mapping indices, such as T1 time and partition coefficient (lambda), have shown potential to assess diffuse myocardial fibrosis. The purpose of this study was to investigate how scanner and field strength variation affect the accuracy and precision/reproducibility of T1 mapping indices. Methods: CMR studies were performed on two 1.5T and three 3T scanners. Eight phantoms were made to mimic the T1/T2 of pre- and post-contrast myocardium and blood at 1.5T and 3T. T1 mapping using MOLLI was performed with simulated heart rate of 40-100 bpm. Inversion recovery spin echo (IR-SE) was the reference standard for T1 determination. Accuracy was defined as the percent error between MOLLI and IR-SE, and scan/re-scan reproducibility was defined as the relative percent mean difference between repeat MOLLI scans. Partition coefficient was estimated by Delta R1myocardium phantom/Delta R1blood phantom. Generalized linear mixed model was used to compare the accuracy and precision/reproducibility of T1 and lambda across field strength, scanners, and protocols. Results: Field strength significantly affected MOLLI T1 accuracy (6.3% error for 1.5T vs. 10.8% error for 3T, p<0.001) but not lambda accuracy (8.8% error for 1.5T vs. 8.0% error for 3T, p=0.11). Partition coefficients of MOLLI were not different between two 1.5T scanners (47.2% vs. 47.9%, p=0.13), and showed only slight variation across three 3T scanners (49.2% vs. 49.8% vs. 49.9%, p=0.016). Partition coefficient also had significantly lower percent error for precision (better scan/re-scan reproducibility) than measurement of individual T1 values (3.6% for lambda vs. 4.3%-4.8% for T1 values, approximately, for pre/post blood and myocardium values). Conclusion: Based on phantom studies, T1 errors using MOLLI ranged from 6-14% across various MR scanners while errors for partition coefficient were less (6-10%). Compared with absolute T1 times, partition coefficient showed less variability across platforms and field strengths as well as higher precision. C1 [Raman, Fabio S.; Kawel-Boehm, Nadine; Gai, Neville; Liu, Chia-Ying; Bluemke, David A.; Liu, Songtao] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Kawel-Boehm, Nadine] Univ Basel Hosp, Clin Radiol & Nucl Med, CH-4031 Basel, Switzerland. [Freed, Melanie] NYU, Sch Med, New York, NY USA. [Han, Jing] US FDA, Rockville, MD 20857 USA. [Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD USA. [Bluemke, David A.; Liu, Songtao] Natl Inst Biomed Imaging & Bioengn, Mol Biomed Imaging Lab, Bethesda, MD USA. RP Liu, ST (reprint author), NIH, Ctr Clin, 10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. EM songtao.liu@nih.gov OI Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health (NIH) Intramural program FX Funded by the National Institutes of Health (NIH) Intramural program. NR 38 TC 25 Z9 25 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD JUL 26 PY 2013 VL 15 AR 64 DI 10.1186/1532-429X-15-64 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 193QA UT WOS:000322574500001 PM 23890156 ER PT J AU Sahu, SN Lewis, J Patel, I Bozdag, S Lee, JH Sprando, R Cinar, HN AF Sahu, Surasri N. Lewis, Jada Patel, Isha Bozdag, Serdar Lee, Jeong H. Sprando, Robert Cinar, Hediye Nese TI Genomic Analysis of Stress Response against Arsenic in Caenorhabditis elegans SO PLOS ONE LA English DT Article ID FATE DETERMINATION FACTOR; DETERMINATION FACTOR DACH1; INDUCED OXIDATIVE STRESS; TRANSCRIPTION FACTOR; ENDOTHELIAL-CELLS; MYELOID-LEUKEMIA; GENE-EXPRESSION; REACTIVE OXYGEN; DNA-DAMAGE; END-POINTS AB Arsenic, a known human carcinogen, is widely distributed around the world and found in particularly high concentrations in certain regions including Southwestern US, Eastern Europe, India, China, Taiwan and Mexico. Chronic arsenic poisoning affects millions of people worldwide and is associated with increased risk of many diseases including arthrosclerosis, diabetes and cancer. In this study, we explored genome level global responses to high and low levels of arsenic exposure in Caenorhabditis elegans using Affymetrix expression microarrays. This experimental design allows us to do microarray analysis of dose-response relationships of global gene expression patterns. High dose (0.03%) exposure caused stronger global gene expression changes in comparison with low dose (0.003%) exposure, suggesting a positive dose-response correlation. Biological processes such as oxidative stress, and iron metabolism, which were previously reported to be involved in arsenic toxicity studies using cultured cells, experimental animals, and humans, were found to be affected in C. elegans. We performed genome-wide gene expression comparisons between our microarray data and publicly available C. elegans microarray datasets of cadmium, and sediment exposure samples of German rivers Rhine and Elbe. Bioinformatics analysis of arsenic-responsive regulatory networks were done using FastMEDUSA program. FastMEDUSA analysis identified cancer-related genes, particularly genes associated with leukemia, such as dnj-11, which encodes a protein orthologous to the mammalian ZRF1/MIDA1/MPP11/DNAJC2 family of ribosome-associated molecular chaperones. We analyzed the protective functions of several of the identified genes using RNAi. Our study indicates that C. elegans could be a substitute model to study the mechanism of metal toxicity using high-throughput expression data and bioinformatics tools such as FastMEDUSA. C1 [Sahu, Surasri N.; Lee, Jeong H.; Cinar, Hediye Nese] US FDA, Div Virulence Assessment, Laurel, MD USA. [Lewis, Jada; Patel, Isha] US FDA, Div Mol Biol, Laurel, MD USA. [Bozdag, Serdar] Marquette Univ, Dept Math Stat & Comp Sci, Milwaukee, WI 53233 USA. [Sahu, Surasri N.] Oak Ridge Inst Sci & Educ, Oak Ridge, TN USA. [Lee, Jeong H.] KNU, Taegu, South Korea. [Sprando, Robert] US FDA, Div Toxicol, Laurel, MD USA. RP Sprando, R (reprint author), US FDA, Div Toxicol, Laurel, MD USA. EM robert.sprando@fda.hhs.gov; hediye.cinar@fda.hhs.gov NR 90 TC 8 Z9 10 U1 0 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 24 PY 2013 VL 8 IS 7 AR e66431 DI 10.1371/journal.pone.0066431 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 188BY UT WOS:000322167900004 PM 23894281 ER PT J AU Zhou, ZH Wild, T Xiong, Y Sylvers, P Zhang, YH Zhang, LX Wahl, L Wahl, SM Kozlowski, S Notkins, AL AF Zhou, Zhao-hua Wild, Teresa Xiong, Ying Sylvers, Peter Zhang, Yahong Zhang, Luxia Wahl, Larry Wahl, Sharon M. Kozlowski, Steven Notkins, Abner L. TI Polyreactive Antibodies Plus Complement Enhance the Phagocytosis of Cells Made Apoptotic by UV-Light or HIV SO SCIENTIFIC REPORTS LA English DT Article ID NATURAL IGM ANTIBODY; BINDING B-CELLS; MONOCLONAL AUTOANTIBODIES; INTRAVENOUS IMMUNOGLOBULIN; PROMOTES PHAGOCYTOSIS; CLEARANCE; REPERTOIRE; IDENTIFICATION; AUTOIMMUNITY; LYMPHOCYTES AB Polyreactive antibodies are a major component of the natural antibody repertoire and are capable of binding a variety of structurally unrelated antigens. Many of the properties attributed to natural antibodies, in fact, are turning out to be due to polyreactive antibodies. In humans, each day, billions of cells undergo apoptosis. In the present experiments, we show by ImageStream technology that although polyreactive antibodies do not bind to live T cells they bind to both the plasma membrane and cytoplasm of late apoptotic cells, fix complement, generate the anaphylatoxin C5a and increase by as much as 5 fold complement-mediated phagocytosis by macrophages. Of particular importance, T cells undergoing apoptosis following infection with HIV also bind polyreactive antibodies and are phagocytosed. We conclude that the polyreactive antibodies in the natural antibody repertoire contribute in a major way to the clearance of cells made apoptotic by a variety of natural and infectious processes. C1 [Zhou, Zhao-hua; Sylvers, Peter; Kozlowski, Steven] US FDA, CDER, OPS, OBP,Div Monoclonal Antibodies, Rockville, MD 20857 USA. [Wild, Teresa; Xiong, Ying; Wahl, Sharon M.; Notkins, Abner L.] NIDCR, NIH, Oral Infect & Immun Branch, Bethesda, MD USA. [Zhang, Yahong; Wahl, Larry] NIDCR, Immunopathol Sect, Bethesda, MD USA. RP Kozlowski, S (reprint author), US FDA, CDER, OPS, OBP,Div Monoclonal Antibodies, Rockville, MD 20857 USA. EM Kozlowski@fda.hhs.gov; anotkins@mail.nih.gov FU Intramural Research Programs of the US National Institutes of Health; Food and Drug Administration FX The authors thank Richard A. DeMarco of Amnis Corp for comments on ImageStream analysis. This research was supported by the Intramural Research Programs of the US National Institutes of Health and Food and Drug Administration. The views expressed in this manuscript represent the opinions of the authors, and do not necessarily represent the official views of the NIH or FDA. NR 44 TC 9 Z9 9 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 24 PY 2013 VL 3 AR 2271 DI 10.1038/srep02271 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 187XB UT WOS:000322153700006 PM 23881356 ER PT J AU Jimenez-Alberto, A Alvarado-Facundo, E Ribas-Aparicio, RM Castelan-Vega, JA AF Jimenez-Alberto, Alicia Alvarado-Facundo, Esmeralda Maria Ribas-Aparicio, Rosa Castelan-Vega, Juan A. TI Analysis of Adaptation Mutants in the Hemagglutinin of the Influenza A(H1N1)pdm09 Virus SO PLOS ONE LA English DT Article ID SOLVATED INTERACTION ENERGY; MOLECULAR-DYNAMICS; RECEPTOR-BINDING; MEMBRANE-FUSION; FORCE-FIELD; SIMULATIONS; SPECIFICITY; MUTATIONS; PROTEINS; BALANCE AB Hemagglutinin is the major surface glycoprotein of influenza viruses. It participates in the initial steps of viral infection through receptor binding and membrane fusion events. The influenza pandemic of 2009 provided a unique scenario to study virus evolution. We performed molecular dynamics simulations with four hemagglutinin variants that appeared throughout the 2009 influenza A (H1N1) pandemic. We found that variant 1 (S143G, S185T) likely arose to avoid immune recognition. Variant 2 (A134T), and variant 3 (D222E, P297S) had an increased binding affinity for the receptor. Finally, variant 4 (E374K) altered hemagglutinin stability in the vicinity of the fusion peptide. Variants 1 and 4 have become increasingly predominant, while variants 2 and 3 declined as the pandemic progressed. Our results show some of the different strategies that the influenza virus uses to adapt to the human host and provide an example of how selective pressure drives antigenic drift in viral proteins. C1 [Jimenez-Alberto, Alicia; Alvarado-Facundo, Esmeralda; Maria Ribas-Aparicio, Rosa; Castelan-Vega, Juan A.] Inst Politecn Nacl, Dept Microbiol, Escuela Nacl Ciencias Biol, Mexico City, DF, Mexico. [Alvarado-Facundo, Esmeralda] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Castelan-Vega, JA (reprint author), Inst Politecn Nacl, Dept Microbiol, Escuela Nacl Ciencias Biol, Mexico City, DF, Mexico. EM jcastelv@encb.ipn.mx FU Instituto Politecnico Nacional (IPN), through SIP [20130044, 20131346, 20131349]; COFAA fellowship by the Instituto Politecnico Nacional (IPN)-Mexico; EDI fellowship by the Instituto Politecnico Nacional (IPN)-Mexico; RMR-A of COFAA fellowship by the Instituto Politecnico Nacional (IPN)-Mexico; EDD fellowship by the Instituto Politecnico Nacional (IPN)-Mexico; CONACyT-Mexico; IPN FX This work was funded by the Instituto Politecnico Nacional (IPN), through SIP grants 20130044, 20131346, and 20131349. AJ-A and JC-V are recipients of COFAA and EDI fellowships, and RMR-A of COFAA and EDD fellowships, all of them granted by the Instituto Politecnico Nacional (IPN)-Mexico. EA-F gives thanks CONACyT-Mexico and IPN for graduate studies fellowships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 5 Z9 5 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 23 PY 2013 VL 8 IS 7 AR e70005 DI 10.1371/journal.pone.0070005 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 228SX UT WOS:000325211000174 PM 23894575 ER PT J AU Kotloff, KL Nataro, JP Blackwelder, WC Nasrin, D Farag, TH Panchalingam, S Wu, Y Sow, SO Sur, D Breiman, RF Faruque, ASG Zaidi, AKM Saha, D Alonso, PL Tamboura, B Sanogo, D Onwuchekwa, U Manna, B Ramamurthy, T Kanungo, S Ochieng, JB Omore, R Oundo, JO Hossain, A Das, SK Ahmed, S Qureshi, S Quadri, F Adegbola, RA Antonio, M Hossain, MJ Akinsola, A Mandomando, I Nhampossa, T Acacio, S Biswas, K O'Reilly, CE Mintz, ED Berkeley, LY Muhsen, K Sommerfelt, H Robins-Browne, RM Levine, MM AF Kotloff, Karen L. Nataro, James P. Blackwelder, William C. Nasrin, Dilruba Farag, Tamer H. Panchalingam, Sandra Wu, Yukun Sow, Samba O. Sur, Dipika Breiman, Robert F. Faruque, Abu S. G. Zaidi, Anita K. M. Saha, Debasish Alonso, Pedro L. Tamboura, Boubou Sanogo, Doh Onwuchekwa, Uma Manna, Byomkesh Ramamurthy, Thandavarayan Kanungo, Suman Ochieng, John B. Omore, Richard Oundo, Joseph O. Hossain, Anowar Das, Sumon K. Ahmed, Shahnawaz Qureshi, Shahida Quadri, Farheen Adegbola, Richard A. Antonio, Martin Hossain, M. Jahangir Akinsola, Adebayo Mandomando, Inacio Nhampossa, Tacilta Acacio, Sozinho Biswas, Kousick O'Reilly, Ciara E. Mintz, Eric D. Berkeley, Lynette Y. Muhsen, Khitam Sommerfelt, Halvor Robins-Browne, Roy M. Levine, Myron M. TI Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study SO LANCET LA English DT Article ID ENTEROPATHOGENIC ESCHERICHIA-COLI; SUB-SAHARAN AFRICA; ROTAVIRUS VACCINATION; CHILDHOOD MORTALITY; ATTRIBUTABLE RISK; EPIDEMIOLOGY; CASE/CONTROL; CRYPTOSPORIDIOSIS; PERFORMANCE; POPULATION AB Background Diarrhoeal diseases cause illness and death among children younger than 5 years in low-income countries. We designed the Global Enteric Multicenter Study (GEMS) to identify the aetiology and population-based burden of paediatric diarrhoeal disease in sub-Saharan Africa and south Asia. Methods The GEMS is a 3-year, prospective, age-stratified, matched case-control study of moderate-to-severe diarrhoea in children aged 0-59 months residing in censused populations at four sites in Africa and three in Asia. We recruited children with moderate-to-severe diarrhoea seeking care at health centres along with one to three randomly selected matched community control children without diarrhoea. From patients with moderate-to-severe diarrhoea and controls, we obtained clinical and epidemiological data, anthropometric measure ments, and a faecal sample to identify enteropathogens at enrolment; one follow-up home visit was made about 60 days later to ascertain vital status, clinical outcome, and interval growth. Findings We enrolled 9439 children with moderate-to-severe diarrhoea and 13 129 control children without diarrhoea. By analysing adjusted population attributable fractions, most attributable cases of moderate-to-severe diarrhoea were due to four pathogens: rotavirus, Cryptosporidium, enterotoxigenic Escherichia coli producing heat-stable toxin (ST-ETEC; with or without co-expression of heat-labile enterotoxin), and Shigella. Other pathogens were important in selected sites (eg, Aeromonas, Vibrio cholerae O1, Campylobacter jejuni). Odds of dying during follow-up were 8.5-fold higher in patients with moderate-to-severe diarrhoea than in controls (odd ratio 8.5, 95% CI 5.8-12.5, p<0.0001); most deaths (167 [87.9%]) occurred during the first 2 years of life. Pathogens associated with increased risk of case death were ST-ETEC (hazard ratio [HR] 1.9; 0.99-3.5) and typical enteropathogenic E coli (HR 2.6; 1.6-4.1) in infants aged 0-11 months, and Cryptosporidium (HR 2.3; 1.3-4.3) in toddlers aged 12-23 months. Interpretation Interventions targeting five pathogens (rotavirus, Shigella, ST-ETEC, Cryptosporidium, typical enteropathogenic E coli) can substantially reduce the burden of moderate-to-severe diarrhoea. New methods and accelerated implementation of existing interventions (rotavirus vaccine and zinc) are needed to prevent disease and improve outcomes. C1 [Kotloff, Karen L.; Nataro, James P.; Blackwelder, William C.; Nasrin, Dilruba; Farag, Tamer H.; Panchalingam, Sandra; Wu, Yukun; Berkeley, Lynette Y.; Muhsen, Khitam; Levine, Myron M.] Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. [Kotloff, Karen L.; Nataro, James P.; Levine, Myron M.] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. [Kotloff, Karen L.; Nataro, James P.; Blackwelder, William C.; Nasrin, Dilruba; Farag, Tamer H.; Panchalingam, Sandra; Wu, Yukun; Muhsen, Khitam; Levine, Myron M.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Nataro, James P.] Univ Virginia, Sch Med, Dept Pediat, Charlottesville, VA 22908 USA. [Sow, Samba O.; Tamboura, Boubou; Sanogo, Doh; Onwuchekwa, Uma] Ctr Dev Vaccins, Bamako, Mali. [Sur, Dipika; Manna, Byomkesh; Ramamurthy, Thandavarayan; Kanungo, Suman] Natl Inst Cholera & Enter Dis, Kolkata, India. [Breiman, Robert F.] US Ctr Dis Control & Prevent, Kenya Off, Global Dis Detect Div, Nairobi, Kenya. [Faruque, Abu S. G.; Hossain, Anowar; Das, Sumon K.; Ahmed, Shahnawaz] Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh. [Zaidi, Anita K. M.; Qureshi, Shahida; Quadri, Farheen] Aga Khan Univ, Dept Paediat & Child Hlth, Karachi, Pakistan. [Saha, Debasish; Adegbola, Richard A.; Antonio, Martin; Hossain, M. Jahangir; Akinsola, Adebayo] Med Res Council UK Unit, Fajara, Gambia. [Alonso, Pedro L.; Mandomando, Inacio; Nhampossa, Tacilta; Acacio, Sozinho] Ctr Invest Saude Manhica, Maputo, Mozambique. [Alonso, Pedro L.] Hosp Clin Univ Barcelona, Barcelona Ctr Int Hlth Res CRESIB, Barcelona, Spain. [Ochieng, John B.; Omore, Richard; Oundo, Joseph O.] Ctr Dis Control & Prevent KEMRI CDC, Kenya Med Res Inst, Kisumu, Kenya. [Adegbola, Richard A.] GlaxoSmithKline Biol, Global Med Affairs, Wavre, Belgium. [Akinsola, Adebayo] Daffodils Pediat & Family Med, Tucker, GA USA. [Mandomando, Inacio; Nhampossa, Tacilta; Acacio, Sozinho] Minist Saude, Inst Nacl Saude, Maputo, Mozambique. [Biswas, Kousick] US Dept Vet Affairs, Cooperat Studies Program Coordinating Ctr, Perry Point, MD USA. [O'Reilly, Ciara E.; Mintz, Eric D.] US Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Atlanta, GA USA. [Berkeley, Lynette Y.] Ctr Drug Evaluat & Res, Off Antimicrobial Prod, Div Antiinfect Prod, Silver Spring, MD USA. [Sommerfelt, Halvor] Univ Bergen, Ctr Int Hlth, Bergen, Norway. [Sommerfelt, Halvor] Norwegian Inst Publ Hlth, Div Infect Dis Control, Oslo, Norway. [Robins-Browne, Roy M.] Univ Melbourne, Royal Childrens Hosp, Murdoch Childrens Res Inst, Dept Microbiol & Immunol, Parkville, Vic 3052, Australia. RP Kotloff, KL (reprint author), Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. EM kkotloff@medicine.umaryland.edu OI Robins-Browne, Roy/0000-0001-9179-7884 FU Bill & Melinda Gates Foundation FX The Bill & Melinda Gates Foundation. NR 36 TC 604 Z9 616 U1 16 U2 135 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JUL 20 PY 2013 VL 382 IS 9888 BP 209 EP 222 DI 10.1016/S0140-6736(13)60844-2 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 193FL UT WOS:000322543700031 PM 23680352 ER PT J AU Kozauer, N Katz, R AF Kozauer, Nicholas Katz, Russell TI Regulation of Drugs for Early Alzheimer's Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Kozauer, Nicholas; Katz, Russell] US FDA, Silver Spring, MD USA. RP Kozauer, N (reprint author), US FDA, Silver Spring, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 18 PY 2013 VL 369 IS 3 BP 288 EP 288 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 185DQ UT WOS:000321945800030 PM 23863069 ER PT J AU Sedrakyan, A Marinac-Dabic, D Holmes, DR AF Sedrakyan, Art Marinac-Dabic, Danica Holmes, David R., Jr. TI The International Registry Infrastructure for Cardiovascular Device Evaluation and Surveillance SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Sedrakyan, Art] Cornell Univ, Weill Cornell Med Coll, Dept Publ Hlth & Cardiac Surg, New York, NY 10021 USA. [Marinac-Dabic, Danica] US FDA, Div Epidemiol, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Holmes, David R., Jr.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA. RP Marinac-Dabic, D (reprint author), US FDA, Div Epidemiol, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM danica.marinac-dabic@fda.hhs.gov FU PHS HHS [HHSF22321110172C] NR 8 TC 8 Z9 8 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 17 PY 2013 VL 310 IS 3 BP 257 EP 258 DI 10.1001/jama.2013.7133 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 183RU UT WOS:000321835700007 PM 23860981 ER PT J AU Meng, FX Yan, J Li, Y Fu, PP Fossom, LH Sood, RK Mans, DJ Chu, PI Moore, MM Chen, T AF Meng, Fanxue Yan, Jian Li, Yan Fu, Peter P. Fossom, Linda H. Sood, Ramesh K. Mans, Daniel J. Chu, Pei-I Moore, Martha M. Chen, Tao TI Genotoxicity of 2-bromo-3 '-chloropropiophenone SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE 2-Bromo-3 '-chloropropiophenone; Bupropion; Ames test; In vitro micronucleus assay; Genotoxicity; N-Acetyl-L-cysteine ID MUTAGENICITY; GLUTATHIONE; ACETYLCYSTEINE; SPECIFICITY; BUPROPION; BROMATE; CELLS; ASSAY; DNA AB Impurities are present in any drug substance or drug product. They can be process-related impurities that are not completely removed during purification or are formed due to the degradation of the drug substance over the product shelf-life. Unlike the drug substance, impurities generally do not have beneficial effects and may present a risk without associated benefit. Therefore, their amount should be minimized. 2-Bromo-3'-chloropropiophenone (BCP) is an impurity of bupropion, a second-generation antidepressant and a smoking cessation aid. The United States Pharmacopeia recommends an acceptable level for BCP that is not more than 0.1% of the bupropion. Because exposure to genotoxic impurities even at low levels is of significant concern, it is important to determine whether or not BCP is genotoxic. Therefore, in this study the Ames test and the in vitro micronucleus assay were conducted to evaluate the genotoxicity of BCP. BCP was mutagenic with S9 metabolic activation, increasing the mutant frequencies in a concentration-dependent manner, up to 22 and 145-fold induction over the controls in Salmonella strains TA100 and TA1535, respectively. BCP was also positive in the in vitro micronucleus assay, resulting in up to 3.3- and 5.1-fold increase of micronucleus frequency for treatments in the absence and presence of S9, respectively; and 9.9- and 7.4-fold increase of aneuploidies without and with S9, respectively. The addition of N-acetyl-L-cysteine, an antioxidant, reduced the genotoxicity of BCP in both assays. Further studies showed that BCP treatment resulted in induction of reactive oxygen species (ROS) in the TK6 cells. The results suggest that BCP is mutagenic, clastogenic, and aneugenic, and that these activities are mediated via generation of reactive metabolites. Published by Elsevier Inc. C1 [Meng, Fanxue; Yan, Jian; Li, Yan; Moore, Martha M.; Chen, Tao] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Fu, Peter P.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Fossom, Linda H.; Sood, Ramesh K.; Mans, Daniel J.; Chu, Pei-I] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Chen, T (reprint author), 3900 NCTR Rd, Jefferson, AR 72079 USA. EM tao.chen@fda.hhs.gov FU National Center for Toxicological Research FX Yan Li was supported by the appointment to the Postgraduate Research Program and Research Participation Program at the National Center for Toxicological Research administered by Oak Ridge Institute for Science Education through an interagency agreement between the U.S. Department of Energy and the U.S. FDA. NR 24 TC 2 Z9 2 U1 1 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUL 15 PY 2013 VL 270 IS 2 BP 158 EP 163 DI 10.1016/j.taap.2013.04.012 PG 6 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 159YH UT WOS:000320082700010 PM 23628427 ER PT J AU Berger, M AF Berger, Mitchell TI The Value of Incentives in Blood Donation SO SCIENCE LA English DT Letter C1 [Berger, Mitchell] US FDA, Ctr Biol Evaluat & Res, Off Blood Res & Review, Rockville, MD 20852 USA. EM maz-ruia@hotmail.com NR 3 TC 0 Z9 0 U1 2 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 12 PY 2013 VL 341 IS 6142 BP 128 EP 129 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 185KA UT WOS:000321965300018 PM 23846890 ER PT J AU Al Busaidy, S Al-Gohary, A Ampofo, WK Bekshin, Z Cerkaoui, I Claes, F Cox, NJ Cracknell, W Cui, L Paiva, TM de Wit, M Diep, LDT Donabedian, A Donis, R Dormitzer, PR Eichelberger, M El Kholy, N Engelhardt, O Engelmann, HB Eropkin, MY Fasce, R Fontaine, L Ghadakchi, HF Ghedin, E Giovanni, MY Golding, H da Silva, HC Gysin, R Hamilton, K Hauge, SH Hay, A Huang, S Hungnes, O Ibrahim, SSS Immamura, T Inglis, SC Kadjo, H Katz, J Kawaoka, Y Kelso, A Khan, MI Kilander, A Klimov, A Kreij, K Kusmiaty, D Linde, A Liu, MT Lupulescu, E Mai, LQ Martinez, VR McCauley, J Meyer, Q Modi, R Mohammadi, AA Mokhtari-Azad, T Mol, E Music, T Nelson, K Neuhaus, E Neumeier, ER Niang, MN Odagiri, T Peiris, M Pohlmann, A Popow-Kraupp, T Trilar, KP Rabadan, R Rambaut, A Robertson, JS Rolls, C Sampurno, OD Savy, V Sawanpanyaltert, P Schmid, G Schweiger, B Shapira, S Shinde, V Shu, Y Siqueira, M Smith, D Spiro, D Stevens, J Takizawa, K Tashiro, M Taylor, B Thomas, Y Tsai, T Van der Werf, S Venter, M Waddell, AL Wan, XF Wang, D Webby, R Weir, JP Wentworth, D Wickramasinghe, G Ye, ZP Zambon, M Ziegler, T AF Al Busaidy, Suleiman Al-Gohary, Amany Ampofo, William K. Bekshin, Zhandarbek Cerkaoui, Imad Claes, Filip Cox, Nancy J. Cracknell, William Cui, Lin de Paiva, Terezinha Maria de Wit, Marel Lan Do Thi Diep Donabedian, Armen Donis, Ruben Dormitzer, Philip R. Eichelberger, Maryna El Kholy, Nagwa Engelhardt, Othmar Engelmann, Hans B. Eropkin, Mikhail Yurievich Fasce, Rodrigo Fontaine, Laurent Ghadakchi, Hadi Famil Ghedin, Elodie Giovanni, Maria Y. Golding, Hana da Silva, Hugo Comes Gysin, Rene Hamilton, Keith Hauge, Siri Helene Hay, Alan Huang, Sue Hungnes, Olav Ibrahim, Sally Saber Said Immamura, Tomohiko Inglis, Stephen C. Kadjo, Herve Katz, Jacqueline Kawaoka, Yoshihiro Kelso, Anne Khan, Mohammed Ilyas Kilander, Anette Klimov, Alexander Kreij, Karl Kusmiaty, Dede Linde, Annika Liu, Ming-Tsan Lupulescu, Emilia Mai, Le Quynh Martinez, Virginia Ramirez McCauley, John Meyer, Quinton Modi, Rajiv Mohammadi, Ali A. Mokhtari-Azad, Talat Mol, Els Music, Tamara Nelson, Karen Neuhaus, Elizabeth Neumeier, Elisabeth R. Niang, Mbayame Ndiaye Odagiri, Takato Peiris, Malik Pohlmann, Anne Popow-Kraupp, Therese Trilar, Katharina Prosenc Rabadan, Raul Rambaut, Andrew Robertson, James S. Rolls, Chris Sampurno, Ondri Dwi Savy, Vilma Sawanpanyaltert, Pathom Schmid, George Schweiger, Brunhilde Shapira, Sagi Shinde, Vivek Shu, Yuelong Siqueira, Marilda Smith, Derek Spiro, David Stevens, James Takizawa, Kazuyuki Tashiro, Masato Taylor, Beverly Thomas, Yves Tsai, Theodore Van der Werf, Sylvie Venter, Marietjie Waddell, Anthony L. Wan, Xiufeng Wang, Dayan Webby, Richard Weir, Jerry P. Wentworth, David Wickramasinghe, Geethani Ye, Zhiping Zambon, Maria Ziegler, Thedi TI Strengthening the influenza vaccine virus selection and development process Outcome of the 2nd WHO Informal Consultation for Improving Influenza Vaccine Virus Selection held at the Centre International de Conferences (CICG) Geneva, Switzerland, 7 to 9 December 2011 SO VACCINE LA English DT Article ID MIXED INFECTION; NEURAMINIDASE; H1N1; TRANSMISSION; EVOLUTION; ANTIBODY; A(H3N2); FERRETS C1 [Al Busaidy, Suleiman] Natl Influenza Ctr, Muscat, Oman. [Al-Gohary, Amany] Natl Influenza Ctr, Cairo, Egypt. [Ampofo, William K.] Natl Influenza Ctr, Accra, Ghana. [Bekshin, Zhandarbek] Minist Hlth, Alma Ata, Kazakhstan. [Cerkaoui, Imad] Natl Influenza Ctr, Rabat, Morocco. [Claes, Filip] OFFLU, Rome, Italy. [Cox, Nancy J.] Ctr Dis Control & Prevent CDC, Atlanta, GA USA. [Cracknell, William] CSL Biotherapies, Melbourne, Vic, Australia. [Cui, Lin] Natl Influenza Ctr, Singapore, Singapore. [de Paiva, Terezinha Maria] Natl Influenza Ctr, Sao Paulo, Brazil. [de Wit, Marel] Abbott Biol, Weesp, Netherlands. [Lan Do Thi Diep] Natl Inst Control Vaccines & Biol, Hanoi, Vietnam. [Donabedian, Armen] BARDA, Washington, DC USA. [Donis, Ruben] Ctr Dis Control & Prevent CDC, Atlanta, GA USA. [Dormitzer, Philip R.] Novartis Vaccines & Diagnost, Cambridge, MA USA. [Eichelberger, Maryna] US FDA, Bethesda, MD 20014 USA. [El Kholy, Nagwa] Natl Influenza Ctr, Cairo, Egypt. [Engelmann, Hans B.] GlaxoSmithKline Biol, Dresden, Germany. [Eropkin, Mikhail Yurievich] Natl Influenza Ctr, St Petersburg, Russia. [Fasce, Rodrigo] Natl Influenza Ctr, Santiago, Chile. [Fontaine, Laurent] Sanofi Pasteur, Val De Reuil, France. [Ghadakchi, Hadi Famil] Razi Vaccine & Serum Res Inst, Karaj, Iran. [Ghedin, Elodie] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Giovanni, Maria Y.] NIH, Bethesda, MD 20892 USA. [Golding, Hana] US FDA, Rockville, MD 20857 USA. [da Silva, Hugo Comes] GlaxoSmithKline Biol, Wavre, Belgium. [Gysin, Rene] Swissmedic, Bern, Switzerland. [Hamilton, Keith] OFFLU, Paris, France. [Hauge, Siri Helene] Norwegian Inst Publ Hlth, Oslo, Norway. [Hay, Alan] Natl Inst Med Res, London NW7 1AA, England. [Huang, Sue] Natl Influenza Ctr, Upper Hutt, New Zealand. [Hungnes, Olav] Natl Influenza Ctr, Oslo, Norway. [Ibrahim, Sally Saber Said] CAPA, Cairo, Egypt. [Immamura, Tomohiko] Denka Seiken Co Ltd, Tokyo, Japan. [Kadjo, Herve] Natl Influenza Ctr, Abidjan, Cote Ivoire. [Katz, Jacqueline] Ctr Dis Control & Prevent CDC, Atlanta, GA USA. [Kawaoka, Yoshihiro] Univ Wisconsin, Madison, WI USA. [Kelso, Anne] VIDRL, Melbourne, Vic, Australia. [Khan, Mohammed Ilyas] Hamad Med Coorporat, Doha, Qatar. [Kilander, Anette] Natl Influenza Ctr, Oslo, Norway. [Klimov, Alexander] Ctr Dis Control & Prevent CDC, Atlanta, GA USA. [Kreij, Karl] Crucell Switzerland AG, Bern, Switzerland. [Kusmiaty, Dede] NADFC, Jakarta, Pusat, Indonesia. [Linde, Annika] Swedish Inst Infect Dis Control, Solna, Sweden. [Lupulescu, Emilia] Natl Influenza Ctr, Bucharest, Romania. [Mai, Le Quynh] Natl Influenza Ctr, Hanoi, Vietnam. [Martinez, Virginia Ramirez] Fed Commiss Protect Sanit Risks, Mexico City, DF, Mexico. [McCauley, John] NIMR, London, England. [Meyer, Quinton] SA Natl Control Lab Biol Prod, Bloemfontein, South Africa. [Modi, Rajiv] Cadila Pharmaceut Ltd, Ahmadabad, Gujarat, India. [Mohammadi, Ali A.] Global Hlth & Secur Consultants, Geneva, Switzerland. [Mokhtari-Azad, Talat] Natl Influenza Ctr, Tehran, Iran. [Mol, Els] Abbott Biol, Weesp, Netherlands. [Music, Tamara] IFPMA, Geneva, Switzerland. [Nelson, Karen] Craig Venter Inst, Rockville, MD USA. [Neuhaus, Elizabeth] Ctr Dis Control & Prevent CDC, Atlanta, GA USA. [Neumeier, Elisabeth R.] GlaxoSmithKline Biol, Dresden, Germany. [Niang, Mbayame Ndiaye] Natl Influenza Ctr, Dakar, Senegal. [Odagiri, Takato] NIID, Tokyo, Japan. [Peiris, Malik] Univ Hong Kong, Hong Kong Special Adm, Hong Kong, Hong Kong, Peoples R China. [Pohlmann, Anne] Fed Res Inst Anim Hlth Greifswald, Insel Riems, Germany. [Popow-Kraupp, Therese] Natl Influenza Ctr, Vienna, Austria. [Trilar, Katharina Prosenc] Natl Influenza Ctr, Ljubljana, Slovenia. [Rabadan, Raul] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Rambaut, Andrew] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Rolls, Chris] TGA, Symonston, Australia. [Sampurno, Ondri Dwi] Natl Influenza Ctr, Jakarta, Indonesia. [Savy, Vilma] Natl Influenza Ctr, Buenos Aires, DF, Argentina. [Sawanpanyaltert, Pathom] Natl Influenza Ctr, Bangkok, Thailand. [Schmid, George] Ctr Dis Control & Prevent CDC, Alma Ata, Kazakhstan. [Schweiger, Brunhilde] Natl Influenza Ctr, Berlin, Germany. [Shapira, Sagi] Joint Ctr Syst Biol, New York, NY USA. [Shapira, Sagi] Dept Microbiol & Immunol, New York, NY USA. [Shinde, Vivek] GlaxoSmithKline Biol, Wavre, Belgium. [Shu, Yuelong] Natl Inst Viral Dis Control & Prevent, Beijing, Peoples R China. [Siqueira, Marilda] Natl Influenza Ctr, Rio De Janeiro, Brazil. [Smith, Derek] Univ Cambridge, Cambridge, England. [Spiro, David] NIH, Bethesda, MD 20892 USA. [Stevens, James] Ctr Dis Control & Prevent CDC, Atlanta, GA USA. [Takizawa, Kazuyuki] Denka Seiken Co Ltd, Niigata, Japan. [Tashiro, Masato] NIID, Tokyo, Japan. [Taylor, Beverly] Novartis Pharma SA, Liverpool, Merseyside, England. [Thomas, Yves] Natl Influenza Ctr, Geneva, Switzerland. [Tsai, Theodore] Novartis Vaccines Cambridge, Cambridge, MA USA. [Van der Werf, Sylvie] Natl Influenza Ctr, Paris, France. [Venter, Marietjie] Natl Influenza Ctr, Johannesburg, South Africa. [Wan, Xiufeng] Mississippi State Univ, Mississippi State, MS 39762 USA. [Wang, Dayan] Natl Inst Viral Dis Control & Prevent, Beijing, Peoples R China. [Webby, Richard] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Weir, Jerry P.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Wentworth, David] J Craig Venter Inst, Rockville, MD USA. [Wickramasinghe, Geethani] Natl Influenza Ctr, Colombo, Sri Lanka. [Ye, Zhiping] CBER, Bethesda, MD USA. [Zambon, Maria] Natl Influenza Ctr, London, England. [Ziegler, Thedi] Natl Influenza Ctr, Helsinki, Finland. RP Al Busaidy, S (reprint author), Natl Influenza Ctr, Muscat, Oman. RI Venter, Marietjie/P-9604-2016; Vaccine & Serum Research Institute, Razi /A-3892-2017 OI Venter, Marietjie/0000-0003-2696-824X; NR 31 TC 10 Z9 10 U1 0 U2 18 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JUL 11 PY 2013 VL 31 IS 32 BP 3209 EP 3221 DI 10.1016/j.vaccine.2013.05.049 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 179RE UT WOS:000321538200002 ER PT J AU Li, X Li, Y Hu, JD Wang, B Zhao, LJ Ji, K Guo, BF Yin, D Du, YW Kopecko, DJ Kalvakolanu, DV Zhao, XJ Xu, DQ Zhang, L AF Li, Xin Li, Yang Hu, Jiadi Wang, Bo Zhao, Lijing Ji, Kun Guo, Baofeng Yin, Di Du, Yanwei Kopecko, Dennis J. Kalvakolanu, Dhananjaya V. Zhao, Xuejian Xu, Deqi Zhang, Ling TI Plasmid-based E6-specific siRNA and co-expression of wild-type p53 suppresses the growth of cervical cancer in vitro and in vivo SO CANCER LETTERS LA English DT Article DE Cervical cancer; E6; p53; Gene therapy; Attenuated Salmonella typhimurium ID TARGETING SALMONELLA-TYPHIMURIUM; HUMAN-PAPILLOMAVIRUS E6; CARCINOMA CELLS; HPV E6; UP-REGULATION; APOPTOSIS; E7; PROTEINS; GENE; METAANALYSIS AB The E6 protein of the oncogenic HPV-16 functions by interfering with the normal cell cycle control mechanisms, particularly those controlled by p53. In this study, we developed a dual expression plasmid that coexpressed-E6-specific siRNA and wild type p53, and to evaluate its effects on cervical cancer growth. We found that simultaneous expression of pSi-E6-P53 caused a robust suppression of tumor growth when compared to the controls either E6-specific siRNA or p53 alone. In conclusion, our findings demonstrate that a combined strategy of co-expressed E6-specific siRNA and p53 synergistically and more effectively suppressed cervical tumor growth when compared with single treatment. (c) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Li, Xin; Li, Yang; Wang, Bo; Zhao, Lijing; Ji, Kun; Guo, Baofeng; Yin, Di; Du, Yanwei; Zhao, Xuejian; Zhang, Ling] Jilin Univ, Prostate Dis Prevent & Treatment Res Ctr, Changchun 130021, Peoples R China. [Li, Xin; Li, Yang; Wang, Bo; Zhao, Lijing; Ji, Kun; Guo, Baofeng; Yin, Di; Du, Yanwei; Zhao, Xuejian; Zhang, Ling] Jilin Univ, Norman Bethune Med Sch, Dept Pathophysiol, Changchun 130021, Peoples R China. [Hu, Jiadi] Univ Maryland, Sch Dent, Dept Oncol & Diagnost Sci, Baltimore, MD 21201 USA. [Kopecko, Dennis J.] US FDA, Ctr Biol Evaluat & Res, Lab Enter & Sexually Transmitted Dis, Bethesda, MD 20014 USA. [Kalvakolanu, Dhananjaya V.] Univ Maryland, Sch Med, Greenebaum Canc Ctr, Dept Microbiol & Immunol,Mol Biol Program, Baltimore, MD 21201 USA. [Xu, Deqi] Natl New Vaccine Engn Res Ctr, Beijing 100024, Peoples R China. RP Zhang, L (reprint author), Jilin Univ, Prostate Dis Prevent & Treatment Res Ctr, Changchun 130021, Peoples R China. EM dqxujl@gmail.com; zhangling3@jlu.edu.cn FU National Natural Science Foundation of China [30801354, 30970791, 81201188]; US National Institutes of Health [CA 105005] FX This work was funded by the National Natural Science Foundation of China (Nos. 30801354, 30970791 and 81201188). D.V.K. is supported by US National Institutes of Health Grant CA 105005. NR 44 TC 10 Z9 13 U1 0 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD JUL 10 PY 2013 VL 335 IS 1 BP 242 EP 250 DI 10.1016/j.canlet.2013.02.034 PG 9 WC Oncology SC Oncology GA 210RW UT WOS:000323853200031 PM 23435374 ER PT J AU Bird, ST Etminan, M Brophy, JM Hartzema, AG Delaney, JAC AF Bird, Steven T. Etminan, Mahyar Brophy, James M. Hartzema, Abraham G. Delaney, Joseph A. C. TI Risk of acute kidney injury associated with the use of fluoroquinolones SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Article ID ACUTE INTERSTITIAL NEPHRITIS; ACUTE-RENAL-FAILURE; CLINICAL-MODIFICATION CODES; INTERNATIONAL-CLASSIFICATION; CONTROL DESIGNS; CASE-CROSSOVER; CIPROFLOXACIN; AZITHROMYCIN; DISEASES; CRYSTALLURIA AB Background: Case reports indicate that the use of fluoroquinolones may lead to acute kidney injury. We studied the association between the use of oral fluoroquinolones and acute kidney injury, and we examined interaction with renin-angiotensin-system blockers. Methods: We formed a nested cohort of men aged 40-85 enrolled in the United States IMS LifeLink Health Plan Claims Database between 2001 and 2011. We defined cases as men admitted to hospital for acute kidney injury, and controls were admitted to hospital with a different presenting diagnosis. Using risk-set sampling, we matched 10 controls to each case based on hospital admission, calendar time (within 6 wk), cohort entrance (within 6 wk) and age (within 5 yr). We used conditional logistic regression to assess the rate ratio (RR) for acute kidney injury with current, recent and past use of fluoroquinolones, adjusted by potential confounding variables. We repeated this analysis with amoxicillin and azithromycin as controls. We used a case-time-control design for our secondary analysis. Results: We identified 1292 cases and 12 651 matched controls. Current fluoroquinolone use had a 2.18-fold (95% confidence interval [CI] 1.74-2.73) higher adjusted RR of acute kidney injury compared with no use. There was no association between acute kidney injury and recent (adjusted RR 0.87, 95% CI 0.66-1.16) or past (RR 0.86, 95% CI 0.66-1.12) use. The absolute in crease in acute kidney injury was 6.5 events per 10 000 person-years. We observed 1 additional case per 1529 patients given fluoroquinolones or per 3287 prescriptions dispensed. The dual use of fluoroquinolones and renin-angiotensin-system blockers had an RR of 4.46 (95% CI 2.84-6.99) for acute kidney injury. Our case-time-control analysis confirmed an increased risk of acute kidney injury with fluoroquinolone use (RR 2.16, 95% CI 1.52-3.18). The use of amoxicillin or azithro mycin was not associated with acute kidney injury. Interpretation: We found a small, but significant, increased risk of acute kidney injury among men with the use of oral fluoroquinolones, as well as a significant interaction between the concomitant use of fluoroquinolones and renin-angiotensin-system blockers. C1 [Bird, Steven T.] Off Surveillance & Epidemiol, Off Pharmacovigilance & Epidemiol, Ctr Drug Evaluat & Res, Dept Hlth & Human Serv Food & Drug Adm,Dept Epide, Silver Spring, MD USA. [Bird, Steven T.; Hartzema, Abraham G.; Delaney, Joseph A. C.] Univ Florida, Coll Pharm & Epidemiol Pharmaceut Out Comes & Pol, Gainesville, FL USA. [Etminan, Mahyar] Univ British Columbia, Fac Med, Therapeut Evaluat Unit, Prov Hlth Serv Author, Vancouver, BC, Canada. [Etminan, Mahyar] Univ British Columbia, Fac Med, Dept Pediat, Vancouver, BC, Canada. [Brophy, James M.] McGill Univ, Royal Victoria Hosp, Ctr Hlth, Montreal, PQ H3A 1A1, Canada. [Delaney, Joseph A. C.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. RP Etminan, M (reprint author), Univ British Columbia, Fac Med, Therapeut Evaluat Unit, Prov Hlth Serv Author, Vancouver, BC, Canada. EM metminan@popi.ubc.ca FU McGill University Health Centre; Fonds de la Recherche en Sante du Quebec; Ministere de la Sante et des Services Sociaux; le Fonds de la Recherche en Sante du Quebec; Agency for Healthcare Research and Quality [R21 HS019516-01] FX This work was supported by an unrestricted operating grant funded in part by the McGill University Health Centre, Fonds de la Recherche en Sante du Quebec, and the Ministere de la Sante et des Services Sociaux. James Brophy receives peer-review financial support from le Fonds de la Recherche en Sante du Quebec. Joseph Delaney receives peer-review financial support from the Agency for Healthcare Research and Quality (grant no. R21 HS019516-01). Abraham Hartzema is the principal investigator for the Observational Medical Outcomes Partnership, a private-public partnership designed to help improve drug-safety monitoring. The study sponsors had no role in the design of the study, the collection, analysis or interpretation of data, the writing of the report or the decision to submit the article for publication. NR 39 TC 21 Z9 23 U1 0 U2 4 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 5W8, CANADA SN 0820-3946 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD JUL 9 PY 2013 VL 185 IS 10 BP E475 EP E482 DI 10.1503/cmaj.121730 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 181AY UT WOS:000321641600024 PM 23734036 ER PT J AU Parra, M Liu, X Derrick, SC Yang, A Tian, JH Kolibab, K Kumar, S Morris, SL AF Parra, Marcela Liu, Xia Derrick, Steven C. Yang, Amy Tian, Jinhua Kolibab, Kristopher Kumar, Sanjai Morris, Sheldon L. TI Molecular Analysis of Non-Specific Protection against Murine Malaria Induced by BCG Vaccination SO PLOS ONE LA English DT Article ID BACILLUS-CALMETTE-GUERIN; MYCOBACTERIUM-BOVIS BCG; PLASMODIUM-FALCIPARUM; ANTIMICROBIAL PEPTIDE; CELL-FUNCTION; INFECTION; MICE; TUBERCULOSIS; CATHELICIDIN; EOSINOPHIL AB Although the effectiveness of BCG vaccination in preventing adult pulmonary tuberculosis (TB) has been highly variable, epidemiologic studies have suggested that BCG provides other general health benefits to vaccinees including reducing the impact of asthma, leprosy, and possibly malaria. To further evaluate whether BCG immunization protects against malarial parasitemia and to define molecular correlates of this non-specific immunity, mice were vaccinated with BCG and then challenged 2 months later with asexual blood stage Plasmodium yoelii 17XNL (PyNL) parasites. Following challenge with PyNL, significant decreases in parasitemia were observed in BCG vaccinated mice relative to naive controls. To identify immune molecules that may be associated with the BCG-induced protection, gene expression was evaluated by RT-PCR in i) naive controls, ii) BCG-vaccinated mice, iii) PyNL infected mice and iv) BCG vaccinated/PyNL infected mice at 0, 1, 5, and 9 days after the P. yoelii infection. The expression results showed that i) BCG immunization induces the expression of at least 18 genes including the anti-microbial molecules lactoferrin, eosinophil peroxidase, eosinophil major basic protein and the cathelicidin-related antimicrobial peptide (CRAMP); ii) an active PyNL infection suppresses the expression of important immune response molecules; and iii) the extent of PyNL-induced suppression of specific genes is reduced in BCG-vaccinated/PyNL infected mice. To validate the gene expression data, we demonstrated that pre-treatment of malaria parasites with lactoferrin or the cathelicidin LL-37 peptide decreases the level of PyNL parasitemias in mice. Overall, our study suggests that BCG vaccination induces the expression of non-specific immune molecules including antimicrobial peptides which may provide an overall benefit to vaccinees by limiting infections of unrelated pathogens such as Plasmodium parasites. C1 [Parra, Marcela; Liu, Xia; Derrick, Steven C.; Yang, Amy; Tian, Jinhua; Kolibab, Kristopher; Kumar, Sanjai; Morris, Sheldon L.] USFDA, Ctr Biol Evaluat & Review, Bethesda, MD USA. RP Morris, SL (reprint author), USFDA, Ctr Biol Evaluat & Review, Bethesda, MD USA. EM sheldon.morris@fda.hhs.gov FU FDA FX FDA internal funding supported this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 11 Z9 11 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 4 PY 2013 VL 8 IS 7 AR e66115 DI 10.1371/journal.pone.0066115 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 204FO UT WOS:000323350700005 PM 23861742 ER PT J AU Zhao, YD Rahardja, D AF Zhao, Yan D. Rahardja, Dewi TI Estimation of the Common Risk Difference in Stratified Paired Binary Data with Homogeneous Stratum Effect SO JOURNAL OF BIOPHARMACEUTICAL STATISTICS LA English DT Article DE Cochran-Manten-Hanszel test; Common risk difference; McNemar's test; Paired binary data; Stratified data AB McNemar's test is commonly used to test for the risk difference between two binary variables on matched pairs. For stratified paired binary data, recently a test for the homogeneous stratum effect (HSE) has been developed. If HSE is rejected, then McNemar's test should be applied by stratum; otherwise, in this article we propose a concept of common risk difference (CRD) across the strata and derive point estimators and confidence intervals for CRD. We use a cancer study for illustration and conduct simulations to recommend point estimators and associated confidence intervals with good statistical properties. C1 [Zhao, Yan D.] Univ Oklahoma, Hlth Sci Ctr, Dept Biostat & Epidemiol, Oklahoma City, OK USA. [Rahardja, Dewi] US FDA, Silver Spring, MD USA. RP Zhao, YD (reprint author), 801 NE 13th St,Room 325, Oklahoma City, OK 73104 USA. EM Daniel-Zhao@ouhsc.edu NR 6 TC 0 Z9 0 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1054-3406 J9 J BIOPHARM STAT JI J. Biopharm. Stat. PD JUL 4 PY 2013 VL 23 IS 4 BP 848 EP 855 DI 10.1080/10543406.2013.789888 PG 8 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA 205YA UT WOS:000323479600010 PM 23786205 ER PT J AU Zhang, K Wong, JW Hayward, DG Vaclavikova, M Liao, CD Trucksess, MW AF Zhang, Kai Wong, Jon W. Hayward, Douglas G. Vaclavikova, Marta Liao, Chia-Ding Trucksess, Mary W. TI Determination of Mycotoxins in Milk-Based Products and Infant Formula Using Stable Isotope Dilution Assay and Liquid Chromatography Tandem Mass Spectrometry SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE mycotoxins; stable isotope dilution assay; LC-MS/MS; milk-based infant formula; milk ID IMMUNOAFFINITY COLUMN CLEANUP; LC-ESI-MS; ELECTROSPRAY-IONIZATION; AFLATOXIN M-1; BOVINE-MILK; HUMAN-BLOOD; EXTRACTION; FOOD; OCHRATOXIN; LIVER AB A stable isotope dilution assay and liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of 12 rnycotoxins, aflatoxins B-1, B-2, G(1), G(2), and M-1, deoxynivalenol, fumonisins B-1, B-2, and B-3, ochratoxin A, T-2 toxin, and zearalenone, in milk-based infant formula and foods. Samples were fortified with 12 C-13 uniformly labeled mycotoxins ([C-13]-mycotoxins) that correspond to the 12 target mycotoxins and prepared by dilution and filtration, followed by LC-MS/MS analysis. Quantitation was achieved using the relative response factors of [C-13]-mycotoxins and target mycotoxins. The average recoveries in fortified milk, milk-based infant formula, milk powder, and baby yogurt of aflatoxins B-1, B-2, G(1), and G(2) (2, 10, and 50 mu g/kg), aflatoxin M-1 (0.5, 2.5, and 12.5 mu g/kg), deoxynivalenol, fumonisins B-1, B-2, and B-3 (40, 200, and 1000 mu g/kg), oduatoxin A, T-2 toxin, and zearalenone (20, 100, and 500 mu g/kg), range from 89 to 126% with RSDs of <20%. The individual recoveries in the four fortified matrices range from 72% (fumonisin B-3, 20 mu g/kg, milk-based infant formula) to 136% (T-2 toxin, 20 mu g/kg, milk powder), with RSDs ranging from 2 to 25%. The limits of quantitation (LOQs) were from 0.01 mu g/kg (aflatoxin M-1) to 2 (fumonisin B-1) mu g/kg. Aflatoxin M-1 was detected in two European Reference materials at 0.127 +/- 0.013 mu g/kg (certified value = 0.111 +/- 0.018 mu g/kg) and 0.46 +/- 0.04 mu g/kg (certified value = 0.44 +/- 0.06 mu g/kg), respectively. In 60 local market samples, aflatoxins B-1 (1.14 +/- 0.10 mu g/kg) and B-2 (0.20 +/- 0.03 mu g/kg) were detected in one milk powder sample. Aflatoxin M-1 was detected in three imported samples (condensed milk, milk-based infant formula, and table cream), ranging from 0.10 to 0.40 mu g/kg. The validated method provides sufficient selectivity, sensitivity, accuracy, and reproducibility to screen for aflatoxin M-1 at nanograms per kilogram concentrations and other mycotoxins, without using standard addition or matrix-matched calibration to compensate for matrix effects. C1 [Zhang, Kai; Wong, Jon W.; Hayward, Douglas G.; Vaclavikova, Marta; Trucksess, Mary W.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA. [Liao, Chia-Ding] Taiwan Food & Drug Adm, Dept Hlth, Taipei 115, Taiwan. RP Zhang, K (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, HFS 706,5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM kai.zhang@fda.hhs.gov NR 46 TC 20 Z9 20 U1 10 U2 67 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD JUL 3 PY 2013 VL 61 IS 26 BP 6265 EP 6273 DI 10.1021/jf4018838 PG 9 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA 179SY UT WOS:000321542800016 PM 23746324 ER PT J AU Dworkin, RH Turk, DC Peirce-Sandner, S He, H McDermott, MP Farrar, JT Katz, NP Lin, AH Rappaport, BA Rowbotham, MC AF Dworkin, Robert H. Turk, Dennis C. Peirce-Sandner, Sarah He, Hua McDermott, Michael P. Farrar, John T. Katz, Nathaniel P. Lin, Allison H. Rappaport, Bob A. Rowbotham, Michael C. TI Assay sensitivity and study features in neuropathic pain trials An ACTTION meta-analysis SO NEUROLOGY LA English DT Article ID CLINICAL-TRIALS; DIABETIC-NEUROPATHY; PLACEBO-RESPONSE; PHARMACOLOGICAL-TREATMENT; POSTHERPETIC NEURALGIA; CONTINUOUS OUTCOMES; REPORT DATABASE; OSTEOARTHRITIS; GUIDELINES; DRUG AB Objective: Our objective was to identify patient, study, and site factors associated with assay sensitivity in placebo-controlled neuropathic pain trials. Methods: We examined the associations between study characteristics and standardized effect size (SES) in a database of 200 publicly available randomized clinical trials of pharmacologic treatments for neuropathic pain. Results: There was considerable heterogeneity in the SESs among the examined trials. Univariate meta-regression analyses indicated that larger SESs were significantly associated with trials that had 1) greater minimum baseline pain inclusion criteria, 2) greater mean subject age, 3) a larger percentage of Caucasian subjects, and 4) a smaller total number of subjects. In a multiple meta-regression analysis, the associations between SES and minimum baseline pain inclusion criterion and age remained significant. Conclusions: Our analyses have examined potentially modifiable correlates of study SES and shown that a minimum pain inclusion criterion of 40 or above on a 0 to 100 scale is associated with a larger SES. These data provide a foundation for investigating strategies to improve assay sensitivity and thereby decrease the likelihood of falsely negative outcomes in clinical trials of efficacious treatments for neuropathic pain. C1 [Dworkin, Robert H.; Peirce-Sandner, Sarah] Univ Rochester, Sch Med & Dent, Dept Anesthesiol, Rochester, NY 14627 USA. [He, Hua; McDermott, Michael P.] Univ Rochester, Sch Med & Dent, Dept Biostat & Computat Biol, Rochester, NY USA. [Dworkin, Robert H.; McDermott, Michael P.] Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY 14642 USA. [Turk, Dennis C.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Farrar, John T.] Univ Penn, Dept Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Katz, Nathaniel P.] Analges Solut, Natick, MA USA. [Katz, Nathaniel P.] Tufts Univ, Boston, MA 02111 USA. [Lin, Allison H.; Rappaport, Bob A.] US FDA, Div Anesthesia Analgesia & Addict Prod, Silver Spring, MD USA. [Rowbotham, Michael C.] Calif Pacific Med Ctr, Ctr Res Inst, San Francisco, CA USA. RP Dworkin, RH (reprint author), Univ Rochester, Sch Med & Dent, Dept Anesthesiol, Rochester, NY 14627 USA. EM robert_dworkin@urmc.rochester.edu FU FDA [HHSF 223201000078C]; ACTTION; FDA FX Financial support for this project was provided by a research contract (HHSF 223201000078C) from the FDA to the University of Rochester, and by the ACTTION public-private partnership with the FDA, which has received research grants or other revenue from the FDA, various pharmaceutical companies, and other sources. NR 40 TC 15 Z9 15 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUL 2 PY 2013 VL 81 IS 1 BP 67 EP 75 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 304JC UT WOS:000330741900015 PM 23700332 ER PT J AU Ferguson, SA Maier, KL AF Ferguson, Sherry A. Maier, Kaitlyn L. TI A review of seasonal/circannual effects of laboratory rodent behavior SO PHYSIOLOGY & BEHAVIOR LA English DT Review DE Seasonal effects; Circannual effects; Endogenous oscillator; Rodent behavior ID BASAL LOCOMOTOR-ACTIVITY; WILD MONGOLIAN GERBILS; OPEN-FIELD BEHAVIOR; SEASONAL-VARIATION; INFRARED IRRADIATION; CIRCANNUAL RHYTHMS; PHOTIC ENTRAINMENT; GROUND-SQUIRRELS; SPRAGUE-DAWLEY; PINEAL-GLAND AB The existence of seasonal or circannual effects on laboratory rodent behavior has been the subject of much debate in recent conversations with colleagues. If such effects are real, they could explain poor replicability or hinder the detection of treatment effects. Here, we review the literature in which seasonal or circannual rhythms were examined under typical 12:12 h photoperiods and present our historical data of locomotor activity of male and female Sprague-Dawley rats across several seasons and years. In general, there was little evidence to indicate significant effects on the locomotor activity of rats or mice, while studies of depression behaviors were somewhat inconsistent in their findings. Results of the few anxiety behavior assessments were fairly consistent, at least in rat studies. Two studies of pain-related behaviors indicated decreased responses during spring or summer testing. If such seasonal effects are real, this would imply that laboratory rodents have a type of internal Type 2 circannual clock or endogenous oscillator. However, photoperiod, temperature, or humidity cannot be the zeitgeber. Further, the need for a circannual clock in a short-lived rodent is debatable. Published by Elsevier Inc. C1 [Ferguson, Sherry A.; Maier, Kaitlyn L.] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Ferguson, SA (reprint author), US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, HFT-132,3900 NCTR Rd, Jefferson, AR 72079 USA. EM Sheny.Ferguson@fda.hhs.gov NR 66 TC 2 Z9 2 U1 1 U2 24 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD JUL 2 PY 2013 VL 119 BP 130 EP 136 DI 10.1016/j.physbeh.2013.06.007 PG 7 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 204XX UT WOS:000323405700018 PM 23770329 ER PT J AU Kurasawa, JH Shestopal, SA Lee, TK Sarafanov, AG AF Kurasawa, J. H. Shestopal, S. A. Lee, T. K. Sarafanov, A. G. TI Activated blood coagulation factor VIII interacts with cluster III complement-type repeats of the low-density lipoprotein receptor-related protein SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Kurasawa, J. H.; Shestopal, S. A.; Lee, T. K.; Sarafanov, A. G.] US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 145 EP 146 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833601328 ER PT J AU Kurasawa, JH Shestopal, SA Karnaukhova, E Struble, E Lee, TK Sarafanov, AG AF Kurasawa, J. H. Shestopal, S. A. Karnaukhova, E. Struble, E. Lee, T. K. Sarafanov, A. G. TI Light chain of coagulation factor VIII contains a site for low-density lipoprotein receptor SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Kurasawa, J. H.; Shestopal, S. A.; Karnaukhova, E.; Struble, E.; Lee, T. K.; Sarafanov, A. G.] US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 322 EP 323 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833602056 ER PT J AU Woodle, A Gourley, M Lee, TK Ovanesov, MV AF Woodle, A. Gourley, M. Lee, T. K. Ovanesov, M., V TI Robustness of the thrombin generation assay in factor VIII-supplemented hemophilic plasma SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Woodle, A.; Gourley, M.; Lee, T. K.; Ovanesov, M., V] US FDA, Bethesda, MD 20014 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 574 EP 575 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833603036 ER PT J AU Parunov, LA Jha, K Andersen, JF Tucker, I Ataullakhanov, F Lee, TK Ovanesov, MV AF Parunov, L. A. Jha, K. Andersen, J. F. Tucker, I Ataullakhanov, F. Lee, T. K. Ovanesov, M., V TI Factors IXa and XIa promote uncontrolled clot growth under static conditions SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Parunov, L. A.; Jha, K.; Lee, T. K.; Ovanesov, M., V] US FDA, Bethesda, MD 20014 USA. [Andersen, J. F.] NIH, Bethesda, MD 20892 USA. [Tucker, I] Oregon Hlth & Sci Univ, Sch Med, Portland, OR 97201 USA. [Ataullakhanov, F.] Ctr Theoret Problems Physicochem Pharmacol, Moscow, Russia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 983 EP 983 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833604304 ER PT J AU Kaufman-Rivi, D Hazlett, AC Hardy, MA Smith, JM Seid, HB AF Kaufman-Rivi, Diana Hazlett, Antoinette C. Hardy, Mary Anne Smith, Jacquelyn M. Seid, Heather B. TI Provider Experiences with Negative-Pressure Wound Therapy Systems SO ADVANCES IN SKIN & WOUND CARE LA English DT Article DE negative-pressure wound therapy; wound care; medical device reports; wound management AB OBJECTIVE: MedWatch, the Food and Drug Administration's (FDA's) nationwide adverse event reporting system, serves to monitor device performance after a medical device is approved or cleared for market. Through the MedWatch adverse event reporting system, the FDA receives Medical Device Reports of deaths and serious injuries with negative-pressure wound therapy (NPWT) systems, many of which are used in homes and in extended-care facilities. In response to reported events, this study was conducted to obtain additional information about device issues that healthcare professionals face in these settings, as well as challenges that caregivers might encounter using this technology at home. The study was exploratory and descriptive in nature. PARTICIPANTS: The FDA surveyed wound care specialists and professional home healthcare providers to learn about users' experiences with NPWT. DESIGN: In the first phase of the study, a semistructured questionnaire was developed for telephone interviews and self-administration. In the second phase, a web-based survey was adapted from the semistructured instrument. RESULTS: Respondent concerns primarily centered on issues not directly related to the NPWT devices: NPWT prescription, provider education in addition to patient training and appropriate wound management practices, notably ongoing wound assessment, and patient monitoring. CONCLUSION: Overall, respondents thought that there was a definite benefit to NPWT, regardless of the care setting, and that it was a safe therapy when prescribed and administered appropriately. C1 [Kaufman-Rivi, Diana; Hazlett, Antoinette C.] US FDA, Ctr Devices & Radiol Hlth, Off Surveillance & Biometr, Div Patient Safety Partnerships, Silver Spring, MD 20993 USA. [Hardy, Mary Anne] Montgomery Hlth Advocates LLC, Derwood, MD USA. [Smith, Jacquelyn M.; Seid, Heather B.] Social & Sci Syst Inc, Silver Spring, MD USA. RP Kaufman-Rivi, D (reprint author), US FDA, Ctr Devices & Radiol Hlth, Off Surveillance & Biometr, Div Patient Safety Partnerships, Silver Spring, MD 20993 USA. FU Food and Drug Administration; Social & Scientific Systems, Inc for Medical Product Safety Network Activities FX The authors acknowledge the members of the Food and Drug Administration Center for Devices and Radiological Health Workgroup, who throughout the project provided excellent analytic, scientific, and clinical expertise. Special thanks to study participants and to the professional organizations who worked with the Food and Drug Administration and Social & Scientific Systems, Inc on this effort, as well as all other stakeholders that the authors have collaborated with and will continue to work with in the future to ensure the safe use of negative-pressure wound therapy. This survey was funded under the Food and Drug Administration contract with Social & Scientific Systems, Inc for Medical Product Safety Network Activities. Submitted June 27, 2012; accepted in revised form October 23, 2012. NR 24 TC 3 Z9 3 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1527-7941 EI 1538-8654 J9 ADV SKIN WOUND CARE JI Adv. Skin Wound Care PD JUL PY 2013 VL 26 IS 7 BP 311 EP 318 PG 8 WC Dermatology; Nursing; Surgery SC Dermatology; Nursing; Surgery GA 299YL UT WOS:000330431500004 PM 23777881 ER PT J AU Boyd, SD Hadigan, C Mcmanus, M Chairez, C Nieman, LK Pau, AK Alfaro, RM Kovacs, JA Calderon, MM Penzak, SR AF Boyd, Sarita D. Hadigan, Colleen Mcmanus, Maryellen Chairez, Cheryl Nieman, Lynnette K. Pau, Alice K. Alfaro, Raul M. Kovacs, Joseph A. Calderon, Monica M. Penzak, Scott R. TI Influence of Low-Dose Ritonavir With and Without Darunavir on the Pharmacokinetics and Pharmacodynamics of Inhaled Beclomethasone SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE beclomethasone; darunavir; ritonavir; drug interactions; adrenal function ID IATROGENIC CUSHINGS-SYNDROME; BOOSTED PROTEASE INHIBITORS; 1 MU-G; FLUTICASONE PROPIONATE; INFECTED PATIENTS; STIMULATION TEST; DIPROPIONATE; PATIENT; CORTICOSTEROIDS; METABOLISM AB Objective: To identify an alternative inhaled corticosteroid to fluticasone propionate that can be safely coadministered with HIV protease inhibitors, the safety and pharmacokinetics of beclomethasone dipropionate (BDP) and its active metabolite, beclomethasone 17-monopropionate (17-BMP), in combination with ritonavir (RTV) and darunavir/ritonavir (DRV/r) were assessed. Design: Open-label, prospective, randomized pharmacokinetic and pharmacodynamic study in healthy volunteers. Methods: Thirty healthy volunteers received inhaled 160 mu g bid BDP for 14 days and were then randomized (1: 1: 1) into 3 groups: group 1 (control) remained on BDP alone for 28 days, group 2 received 100 mg bid BDP + RTV for 28 days, and group 3 received 600/100 mg bid BDP + DRV/r for 28 days. Pharmacokinetic sampling for 17-BMP was performed on days 14 and 28, and pharmacokinetic parameter values were compared within patients and between groups. Cortisol stimulation testing was also performed on days 1, 14, 28, and 42 and compared within and between groups. Results: Geometric mean ratios (day 28: day 14) (90% confidence interval) for 17-BMP area under the concentration-time curve in groups 1, 2, and 3, respectively, were 0.93 (0.81 to 1.06, P = 0.27), 2.08 (1.52 to 2.65, P = 0.006), and 0.89 (0.68 to 1.09, P = 0.61). There were no significant reductions in serum cortisol levels within or between groups (P > 0.05). Conclusions: DRV/r did not increase 17-BMP exposure, whereas RTV alone produced a statistically significant but clinically inconsequential 2-fold increase in 17-BMP exposure. Adrenal suppression was not observed in any of the study groups. These data suggest that BDP can be safely coadministered with DRV/r and likely other RTV-boosted protease inhibitors. C1 [Boyd, Sarita D.] US FDA, Off Safety & Epidemiol, Silver Spring, MD 20993 USA. [Boyd, Sarita D.; Hadigan, Colleen; Chairez, Cheryl; Pau, Alice K.] NIAID, NIH, Bethesda, MD 20892 USA. [Mcmanus, Maryellen; Calderon, Monica M.] SAIC Sci Applicat Int Corp Inc, Clin Res Directorate, Clin Monitoring Res Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Nieman, Lynnette K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Kovacs, Joseph A.] NIH, Dept Crit Care Med, Clin Res Ctr, Bethesda, MD 20892 USA. RP Boyd, SD (reprint author), US FDA, Off Safety & Epidemiol, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM sarita.boyd@fda.hhs.gov FU National Institutes of Health Clinical Center; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E] FX Supported by the Intramural research programs of the National Institutes of Health Clinical Center, the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract no. HHSN261200800001E. NR 28 TC 11 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUL 1 PY 2013 VL 63 IS 3 BP 355 EP 361 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 300FB UT WOS:000330448700023 PM 23535292 ER PT J AU Chen, MJ Borlak, J Tong, WD AF Chen, Minjun Borlak, Juergen Tong, Weida TI High Lipophilicity and High Daily Dose of Oral Medications Are Associated With Significant Risk for Drug-Induced Liver Injury SO HEPATOLOGY LA English DT Article ID VIVO TOXICOLOGICAL OUTCOMES; TOXICITY; HEPATOTOXICITY; TROVAFLOXACIN; METABOLISM; MECHANISMS; DISCOVERY; BIOMARKER; HUMANS AB Drug-induced liver injury (DILI) is a leading cause of drug failure in clinical trials and a major reason for drug withdrawals from the market. Although there is evidence that dosages of >= 100 mg/day are associated with increased risk for hepatotoxicity, many drugs are safe at such dosages. There is an unmet need to predict risk for DILI more reliably, and lipophilicity might be a contributing factor. We analyzed the combined factors of daily dose and lipophilicity for 164 US Food and Drug Administration-approved oral medications and observed high risk for hepatotoxicity (odds ratio [OR], 14.05; P < 0.001) for drugs given at dosages >= 100 mg/day and octanol-water partition coefficient (logP) >= 3. This defined the "rule-of-two.'' Similar results were obtained for an independent set of 179 oral medications with 85% of the rule-of-two positives being associated with hepatotoxicity (OR, 3.89; P < 0.01). Using the World Health Organization's Anatomical Therapeutic Chemical classification system, the rule-of-two performed best in predicting DILI in seven therapeutic categories. Among 15 rule-of-two positives, 14 were withdrawn from hepatotoxic drugs, and one was over-the-counter medication labeled for liver injury. We additionally examined drug pairs that have similar chemical structures and act on the same molecular target but differ in their potential for DILI. Again, the rule-of-two predicted hepatotoxicity reliably. Finally, the rule-of-two was applied to clinical case studies to identify hepatotoxic drugs in complex comedication regimes to further demonstrate its use. Conclusion: Apart from dose, lipophilicity contributes significantly to risk for hepatotoxicity. Applying the rule-of-two is an appropriate means of estimating risk for DILI compared with dose alone. C1 [Chen, Minjun; Tong, Weida] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Borlak, Juergen] Hannover Med Sch, Ctr Pharmacol & Toxicol, Hannover, Germany. RP Tong, WD (reprint author), US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, 3900 NCTR, Jefferson, AR 72079 USA. EM weida.tong@fda.hhs.gov FU German Federal Ministry for Education and Research [031 6154]; ORISE Stipend of the US Food and Drug Administration FX Supported by the German Federal Ministry for Education and Research as part of the Virtual Liver Network initiative (grant 031 6154 to J.B.). J.B. is a recipient of an ORISE Stipend of the US Food and Drug Administration. NR 33 TC 59 Z9 61 U1 3 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD JUL PY 2013 VL 58 IS 1 BP 388 EP 396 DI 10.1002/hep.26208 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 296IU UT WOS:000330179300041 PM 23258593 ER PT J AU Kakhi, M Marroum, P Chittenden, J AF Kakhi, Maziar Marroum, Patrick Chittenden, Jason TI Analysis of level A in vitro-in vivo correlations for an extended-release formulation with limited bioavailability SO BIOPHARMACEUTICS & DRUG DISPOSITION LA English DT Article DE level A IVIVC; extended-release dosage form; numerical deconvolution; internal; external validation; model robustness ID INVITRO INVIVO CORRELATION; CORRELATION IVIVC; DISSOLUTION; VALIDATION; MODEL AB A two-stage, numerical deconvolution approach was employed to develop level A in vitro-in vivo correlations using data for three formulations of an extended-release oral dosage form. The in vitro dissolution data for all formulations exhibited near-complete dissolution within the time frame of the test. The pharmacokinetic concentration-time profiles for 16 subjects in a cross-over study demonstrated notably limited bioavailability for the slowest formulation. These data were used as the basis for the IVIVC model development. Two models were identified that satisfied the nominal requirements for a conclusive internal predictability of the IVIVC, provided that all three formulations were used as internal datasets. These were a simple linear model with absorption cut-off and a piecewise-linear variable absorption scale model. A subsequent cross-validation of the models' robustness indicated that neither model predicted satisfactorily the pharmacokinetic characteristics of all formulations in a conclusive manner. The piecewise-linear variable absorption scale model provided the most accurate results, particularly with respect to the prediction of the slowest formulation's pharmacokinetic metrics. But this latter model also involved additional free parameters compared with the simple linear model with absorption cut-off. It is argued that more complex IVIVC models with extra parameterization require comprehensive validation to ascertain the accuracy and robustness of the model. In order to achieve this, it is necessary to ensure a complete suite of supporting datasets for internal and external validation, irrespective of the mathematical approach used subsequently to develop the IVIVC. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Kakhi, Maziar] US FDA, Silver Spring, MD 20993 USA. [Marroum, Patrick] Marroum Pharmaceut Consulting, Springfield, VA 22152 USA. [Chittenden, Jason] Pharsight, Cary, NC 27518 USA. RP Kakhi, M (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM maziar.kakhi@fda.hhs.gov NR 27 TC 6 Z9 6 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0142-2782 EI 1099-081X J9 BIOPHARM DRUG DISPOS JI Biopharm. Drug Dispos. PD JUL PY 2013 VL 34 IS 5 BP 262 EP 277 DI 10.1002/bdd.1820 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 291XW UT WOS:000329867200003 PM 23097186 ER PT J AU Brady, PW Varadarajan, K Peterson, LE Lannon, C Gross, T AF Brady, Patrick W. Varadarajan, Kartik Peterson, Laura E. Lannon, Carole Gross, Thomas TI Prevalence and Nature of Adverse Medical Device Events in Hospitalized Children SO JOURNAL OF HOSPITAL MEDICINE LA English DT Article ID COMPLEX CHRONIC CONDITIONS; UNITED-STATES; POPULATION AB Our objective was to describe the prevalence and nature of adverse medical device events (AMDEs) in tertiary care children's hospitals. In our retrospective cohort study of patients at 44 children's hospitals in the Pediatric Health Information System (PHIS), we included all inpatient stays with an AMDE-related diagnosis from January 1, 2004 to December 31, 2011. We identified AMDEs by diagnoses that specified a device in their definition. We included events present on admission as well as those complicating hospital stays. We described the characteristics of these admissions and patients, and stratified analysis by device category and presence of a complex chronic condition. Of 4,115,755 admissions in the PHIS database during the study period, 136,465 (3.3%) had at least 1 AMDE. Vascular access and nervous system devices together represented 44.4% of pediatric AMDE admissions. The majority (75.5%) of AMDE admissions were of children with complex chronic conditions. The most common age group was patients aged 2 years or less at the time of their first AMDE-related admission. AMDEs occur commonly in a population cared for in tertiary children's hospitals. Research to more specifically delineate AMDEs and their predictors are next steps to understand and improve device safety in children. Journal of Hospital Medicine 2013;8:390-393. (c) 2013 Society of Hospital Medicine C1 [Brady, Patrick W.; Varadarajan, Kartik; Lannon, Carole] Cincinnati Childrens Hosp Med Ctr, Pediat Ctr Educ & Res Therapeut, Cincinnati, OH 45229 USA. [Brady, Patrick W.; Varadarajan, Kartik; Lannon, Carole] Cincinnati Childrens Hosp Med Ctr, James M Anderson Ctr Hlth Syst Excellence, Cincinnati, OH 45229 USA. [Brady, Patrick W.] Cincinnati Childrens Hosp Med Ctr, Div Hosp Med, Cincinnati, OH 45229 USA. [Gross, Thomas] US FDA, Off Surveillance & Biometr, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Brady, PW (reprint author), Cincinnati Childrens Hosp, ML 9016,3333 Burnet Ave, Cincinnati, OH 45229 USA. EM patrick.brady@cchmc.org FU Bureau of Health Professions (BHPr); Health Resources and Services Administration (HRSA); Department of Health and Human Services (DHHS) [T32 HP10027]; Agency for Healthcare Research and Quality [U18 HS016957-03] FX Dr. Brady was supported by funds from the Bureau of Health Professions (BHPr), Health Resources and Services Administration (HRSA), and Department of Health and Human Services (DHHS) under grant T32 HP10027. This project was supported by cooperative agreement number U18 HS016957-03 from the Agency for Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality. The study sponsors had no role in the study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the article for publication. The opinions and assertions presented herein are the private views of the authors and are not to be construed as conveying either an official endorsement or criticism by the US Department of Health and Human Services, The Public Health Service, or the US Food and Drug Administration. NR 13 TC 1 Z9 1 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1553-5592 EI 1553-5606 J9 J HOSP MED JI J. Hosp. Med. PD JUL PY 2013 VL 8 IS 7 BP 390 EP 393 DI 10.1002/jhm.2058 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 279JE UT WOS:000328955400006 PM 23744814 ER PT J AU Tack, DM Karem, KL Montgomery, JR Collins, L Bryant-Genevier, MG Tiernan, R Cano, M Lewis, P Engler, RJM Damon, IK Reynolds, MG AF Tack, Danielle M. Karem, Kevin L. Montgomery, Jay R. Collins, Limone Bryant-Genevier, Marthe G. Tiernan, Rosemary Cano, Maria Lewis, Paige Engler, Renata J. M. Damon, Inger K. Reynolds, Mary G. TI Unintentional transfer of vaccinia virus associated with smallpox vaccines ACAM2000 (R) compared with Dryvax (R) SO HUMAN VACCINES & IMMUNOTHERAPEUTICS LA English DT Article; Proceedings Paper CT 23rd National Immunisation Conference for Health Care Workers (NIC) CY DEC 07, 2012 CL Manchester, ENGLAND DE smallpox vaccine; adverse events; autoinoculation; contact vaccinia; vaccinia virus; Orthopoxvirus ID UNITED-STATES 1963; CONTACT TRANSMISSION; OCULAR VACCINIA; NAIVE ADULTS; VACCINATION; COMPLICATIONS; SAFETY; INOCULATION; INFECTION; MONKEYPOX AB Background: Routine vaccination against smallpox (variola) ceased in the US in 1976. However, in 2002 limited coverage for military personnel and some healthcare workers was reinstituted. In March 2008, ACAM2000 (R) replaced Dryvax (R) as the vaccine used in the United States against smallpox. Unintentional transfer of vaccinia virus from a vaccination site by autoinoculation or contact transmission, can have significant public health implications. We summarize unintentional virus transfer AEs associated with ACAM2000 (R) since March 2008 and compare with Dryvax (R). Results: We identified 309 reports for ACAM2000 (R) with skin or ocular involvement, of which 93 were autoinoculation cases and 20 were contact transmission cases. The rate for reported cases of autoinoculation was 20.6 per 100,000 vaccinations and for contact transmission was 4.4 per 100,000 vaccinations. Eighteen contact transmission cases could be attributed to contact during a sporting activity (45%) or intimate contact (45%). Of the 113 unintentional transfer cases, 6 met the case definition for ocular vaccinia. The most common locations for all autoinoculation and contact cases were arm/elbow/shoulder (35/113; 31%) and face (24/113; 21%). Methods: We reviewed 753 reports associated with smallpox in the Vaccine Adverse Event Reporting System and CDC Poxvirus consultation log, reported from March 2008 to August 2010. Reports were classified into categories based upon standard case definitions. Conclusion: Overall, unintentional transfer events for ACAM2000 (R) and Dryvax (R) are similar. We recommend continued efforts to prevent transfer events and continuing education for healthcare providers focused on recognition of vaccinia lesions, proper sample collection, and laboratory testing to confirm diagnosis. C1 [Tack, Danielle M.; Karem, Kevin L.; Damon, Inger K.; Reynolds, Mary G.] Ctr Dis Control & Prevent, Poxvirus & Rabies Branch, Atlanta, GA 30333 USA. [Tack, Danielle M.] Ctr Dis Control & Prevent, Epidem Intelligence Serv, Atlanta, GA USA. [Montgomery, Jay R.; Collins, Limone; Engler, Renata J. M.] Walter Reed Natl Mil Med Ctr, Vaccine Healthcare Ctr Network, Bethesda, MD USA. [Bryant-Genevier, Marthe G.; Tiernan, Rosemary] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Cano, Maria; Lewis, Paige] Ctr Dis Control & Prevent, Immunizat Safety Off, Atlanta, GA USA. RP Reynolds, MG (reprint author), Ctr Dis Control & Prevent, Poxvirus & Rabies Branch, Atlanta, GA 30333 USA. EM nzr6@cdc.gov NR 33 TC 2 Z9 2 U1 0 U2 5 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 2164-5515 EI 2164-554X J9 HUM VACC IMMUNOTHER JI Human Vaccines Immunother. PD JUL 1 PY 2013 VL 9 IS 7 BP 1489 EP 1496 DI 10.4161/hv.24319 PG 8 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA 273YR UT WOS:000328572700024 PM 23571177 ER PT J AU Bjornsdottir-Butler, K McCarthy, S Burkhardt, W Benner, RA AF Bjornsdottir-Butler, Kristin McCarthy, Susan Burkhardt, William, III Benner, Ronald A., Jr. TI Importance of Histamine-Producing Clostridium perfringens in Scombrotoxin-Forming Fish SO JOURNAL OF FOOD PROTECTION LA English DT Article ID LACTIC-ACID BACTERIA; DEPENDENT HISTIDINE DECARBOXYLASES; POLYMERASE-CHAIN-REACTION; REAL-TIME PCR; LACTOBACILLUS-BUCHNERI; QUANTITATIVE DETECTION; UNITED-STATES; DNA PROBES; SYSTEM; TUNA AB It has been suggested that anaerobic histamine-producing bacteria (HPB) are important contributors to scombrotoxin fish poisoning (SFP). In order to assess the role of Clostridium perfringens in SFP, we developed a real-time PCR method for rapid detection of histamine-producing (HP) C. perfringens. The real-time PCR assay was 100% inclusive for detecting 23 HP C. perfringens and did not detect any of the other 116 HP or non-HP isolates examined. The efficiency of the assay with or without internal amplification control DNA was 102%; in the presence of background flora and inhibitory matrices, it was 90 to 99%. To investigate the importance of HP C. perfringens in SFP, we examined histamine production by C. perfringens in inoculated fish samples incubated under anaerobic conditions. C. perfringens produced low histamine levels in tuna (19 ppm) and Spanish mackerel (3 ppm), whereas gram-negative HPB produced high histamine levels (6,345 ppm in tuna; 1,223 ppm in Spanish mackerel) under the same conditions. When one bonito, two bigeye tuna, nine mahi-mahi, and five yellowfin tuna were examined for the presence of HPB, none (0 of 17) of the samples contained HP C. perfringens or other gram-positive HPB, whereas 86% of the samples contained grain-negative HPB. Our study indicates that histamine production by C. perfringens in scombrotoxin-forming fish was minimal compared with that by gram-negative HPB and that C. perfringens may not be an important bacterial species associated with SFP. C1 [Bjornsdottir-Butler, Kristin; McCarthy, Susan; Burkhardt, William, III; Benner, Ronald A., Jr.] US FDA, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. RP Bjornsdottir-Butler, K (reprint author), US FDA, Gulf Coast Seafood Lab, Dauphin Isl, AL 36528 USA. EM Kristin.Butler@fda.hhs.gov NR 35 TC 0 Z9 0 U1 0 U2 4 PU INT ASSOC FOOD PROTECTION PI DES MOINES PA 6200 AURORA AVE SUITE 200W, DES MOINES, IA 50322-2863 USA SN 0362-028X EI 1944-9097 J9 J FOOD PROTECT JI J. Food Prot. PD JUL PY 2013 VL 76 IS 7 BP 1283 EP 1287 DI 10.4315/0362-028X.JFP-12-540 PG 5 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 240FX UT WOS:000326081500024 PM 23834808 ER PT J AU Dal Pan, GJ AF Dal Pan, Gerald J. TI Commentary on "The Effectiveness of Varenicline Medication Guide for Conveying Safety Information to Patients: a REMS Assessment Survey" by Enger et al. SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article ID PHARMACIES C1 US FDA, Silver Spring, MD USA. RP Dal Pan, GJ (reprint author), US FDA, Silver Spring, MD USA. EM gerald.dalpan@fda.hhs.gov NR 11 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JUL PY 2013 VL 22 IS 7 BP 716 EP 718 DI 10.1002/pds.3450 PG 3 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 237KF UT WOS:000325867800004 PM 23661561 ER PT J AU Johnson, KE Beaton, SJ Andrade, SE Cheetham, TC Scott, PE Hammad, TA Dashevsky, I Cooper, WO Davis, RL Pawloski, PA Raebel, MA Smith, DH Toh, S Li, DK Haffenreffer, K Dublin, S AF Johnson, Karin E. Beaton, Sarah J. Andrade, Susan E. Cheetham, T. Craig Scott, Pamela E. Hammad, Tarek A. Dashevsky, Inna Cooper, William O. Davis, Robert L. Pawloski, Pamala A. Raebel, Marsha A. Smith, David H. Toh, Sengwee Li, De-Kun Haffenreffer, Katherine Dublin, Sascha TI Methods of linking mothers and infants using health plan data for studies of pregnancy outcomes SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE birth certificates; Medicaid; pregnancy outcome; epidemiology; medical record linkage; pharmacoepidemiology ID HOSPITAL DISCHARGE DATA; LINKED BIRTH RECORDS; WOMEN; CERTIFICATES; MEDICATIONS; ISSUES; RISK AB Purpose Research on medication safety in pregnancy often utilizes health plan and birth certificate records. This study discusses methods used to link mothers with infants, a crucial step in such research. Methods We describe how eight sites participating in the Medication Exposure in Pregnancy Risk Evaluation Program created linkages between deliveries, infants and birth certificates for the 2001-2007 birth cohorts. We describe linkage rates across sites, and for two sites, we compare the characteristics of populations linked using different methods. Results Of 299260 deliveries, 256563 (86%; range by site, 74-99%) could be linked to infants using a deterministic algorithm. At two sites, using birth certificate data to augment mother-infant linkage increased the representation of mothers who were Hispanic or non-White, younger, Medicaid recipients, or had low educational level. A total of 236460 (92%; range by site, 82-100%) deliveries could be linked to a birth certificate. Conclusions Tailored approaches enabled linking most deliveries to infants and to birth certificates, even when data systems differed. The methods used may affect the composition of the population identified. Linkages established with such methods can support sound pharmacoepidemiology studies of maternal drug exposure outside the context of a formal registry. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Johnson, Karin E.; Dublin, Sascha] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98101 USA. [Beaton, Sarah J.] LCF Res, Hlth Serv Res Dept, Albuquerque, NM USA. [Andrade, Susan E.] Meyers Primary Care Inst, Worcester, MA USA. [Cheetham, T. Craig] Kaiser Permanente, Pharm Analyt Serv, Downey, CA USA. [Scott, Pamela E.; Hammad, Tarek A.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Dashevsky, Inna; Toh, Sengwee; Haffenreffer, Katherine] Harvard Univ, Sch Med, Boston, MA USA. [Dashevsky, Inna; Toh, Sengwee; Haffenreffer, Katherine] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Cooper, William O.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Davis, Robert L.] Kaiser Permanente, Ctr Hlth Res, Atlanta, GA USA. [Pawloski, Pamala A.] HealthPartners, Inst Educ & Res, Bloomington, MN USA. [Raebel, Marsha A.] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA. [Smith, David H.] Kaiser Permanente, Ctr Hlth Res, Portland, OR USA. [Li, De-Kun] Kaiser Permanente, Div Res, Oakland, CA USA. RP Johnson, KE (reprint author), Grp Hlth Res Inst, 1730 Minor Ave,Suite 1600, Seattle, WA 98101 USA. EM johnson.ke@ghc.org RI Toh, Sengwee/D-7567-2017 OI Toh, Sengwee/0000-0002-5160-0810 FU US FDA, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research [HHSF223200510012C, HHSF223200510009C, HHSF223200510008C]; National Institute on Aging [K23AG028954] FX We gratefully acknowledge the participating state departments of health and each site's programmers, project managers, and other project staff. Rod Walker helped calculate statistics for the within-site comparison. We would also like to thank the peer reviewers whose helpful comments improved this manuscript. This study was supported through contracts HHSF223200510012C, HHSF223200510009C, and HHSF223200510008C (US FDA, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research). Dr. Dublin was supported by National Institute on Aging grant K23AG028954. The views expressed in this paper are those of the authors and are not intended to convey official US FDA policy or guidance. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health. NR 19 TC 6 Z9 6 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JUL PY 2013 VL 22 IS 7 BP 776 EP 782 DI 10.1002/pds.3443 PG 7 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 237KF UT WOS:000325867800012 PM 23596095 ER PT J AU Berger, M AF Berger, Mitchell TI Blood product safety SO NATURE CLIMATE CHANGE LA English DT Letter ID HEALTH C1 [Berger, Mitchell] US Food & Drug Agcy, Ctr Biol Evaluat & Res, Off Blood Res, Washington, DC USA. RP Berger, M (reprint author), 203 Ravenwood Rd, Exton, PA 19341 USA. EM mazruia@hotmail.com NR 10 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1758-678X J9 NAT CLIM CHANGE JI Nat. Clim. Chang. PD JUL PY 2013 VL 3 IS 7 BP 606 EP 607 PG 3 WC Environmental Sciences; Environmental Studies; Meteorology & Atmospheric Sciences SC Environmental Sciences & Ecology; Meteorology & Atmospheric Sciences GA 219DR UT WOS:000324486300006 ER PT J AU Prestin, A AF Prestin, Abby TI The Pursuit of Hopefulness: Operationalizing Hope in Entertainment Media Narratives SO MEDIA PSYCHOLOGY LA English DT Article ID POSITIVE EMOTIONS; MASS-MEDIA; UNDERDOG; PEOPLE; CANCER; MODEL; DISADVANTAGE; CONSUMPTION; APPRAISALS; RECURRENCE AB Hope is associated with benefits for psychological and physical wellbeing; consequently, efforts to increase or sustain hopeful feelings are increasingly incorporated into wellness interventions. Although entertainment media provide a wealth of emotionally evocative content, little systematic attention has been given to discrete positive emotions and no investigations to date have identified narratives that generate hope. To address this gap, this research explores underdog narratives, or those depicting characters struggling to meet a goal despite unfavorable odds, as a means to evoke hope, as well as the effect of this emotional experience on subsequent goal-directed motivation. Participants (N = 248) were randomly assigned to one of three media conditionsunderdog narrative, comedy, nature scenesor a no-media control group. Those in the media groups viewed one 5-minute video clip a day for five consecutive days. Consistent with hypotheses, those in the underdog condition felt more hopeful and reported greater motivation to pursue their own goals than those in other conditions. Further, the emotional experience of hope was durable, with hopefulness remaining elevated above baseline levels up to three days after the final media exposure. Implications of these findings for media effects theory and health promotion are discussed. C1 [Prestin, Abby] Univ Calif Santa Barbara, Dept Commun, Santa Barbara, CA 93106 USA. RP Prestin, A (reprint author), US FDA, Off Sci, Ctr Tobacco Prod, 9200 Corp Blvd,300J, Rockville, MD 20850 USA. EM abby.prestin@fda.hhs.gov NR 82 TC 5 Z9 5 U1 1 U2 16 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1521-3269 J9 MEDIA PSYCHOL JI Media Psychol. PD JUL 1 PY 2013 VL 16 IS 3 BP 318 EP 346 DI 10.1080/15213269.2013.773494 PG 29 WC Communication; Film, Radio, Television; Psychology, Applied SC Communication; Film, Radio & Television; Psychology GA 210EL UT WOS:000323812000004 ER PT J AU Birnbaum, LS Aungst, J Schug, TT Goodman, JL AF Birnbaum, Linda S. Aungst, Jason Schug, Thaddeus T. Goodman, Jesse L. TI Working Together: Research- and Science-Based Regulation of BPA SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material ID BISPHENOL-A; MONKEYS C1 [Birnbaum, Linda S.] NIEHS, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] NIH, NTP, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. [Aungst, Jason] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Schug, Thaddeus T.] NIEHS, Cellular Organ & Syst Pathobiol Branch, Div Extramural Res & Training, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Goodman, Jesse L.] US FDA, Off Chief Scientist, Silver Spring, MD USA. RP Birnbaum, LS (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM birnbaumls@niehs.nih.gov NR 8 TC 1 Z9 1 U1 0 U2 4 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2013 VL 121 IS 7 BP A206 EP A207 DI 10.1289/ehp.1306963 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 208VY UT WOS:000323711000001 PM 23817036 ER PT J AU Marks, PW AF Marks, Peter W. TI Hematologic Manifestations of Liver Disease SO SEMINARS IN HEMATOLOGY LA English DT Article ID FRESH-FROZEN PLASMA; INVASIVE PROCEDURES; COAGULATION-FACTOR; HEPATITIS-C; CIRRHOSIS; TRANSPLANTATION; COAGULOPATHY; ANEMIA; ACID; THROMBOCYTOPENIA AB The liver plays a key role in both protein biosynthesis and lipid metabolism. As a result, hepatic synthetic dysfunction can have adverse effects on both cellular and soluble components of blood. Anemia may occur due to the hemolysis of acanthocytes (spur cells), which is ultimately due to abnormal lipid composition of the red blood cell membrane. Thrombocytopenia may result from several different mechanisms. Cytopenias also may be a consequence of hypersplenism. The liver is the primary site for synthesis of most procoagulant and anticoagulant proteins. The coagulbpathy of liver disease is therefore complex. Early in the course of liver disease, thrombocytopenia and a coagulopathy associated with a prothrombotic state are not uncommon, whereas with more advanced disease pancytopenia and coagulopathy associated with hemorrhage become manifest. Fresh frozen plasma and adjuncts to hemostasis may be used as temporizing measures in bleeding patients. However, definitive management of many of the defects due to fulminant hepatic failure requires liver transplantation. Semin Hematol 50:216-221. Published by Elsevier Inc. C1 US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Marks, PW (reprint author), US FDA, Ctr Biol Evaluat & Res, 1401 Rockville Pike,HFM-2, Rockville, MD 20852 USA. EM peter.marks@fda.hhs.gov NR 49 TC 10 Z9 10 U1 2 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD JUL PY 2013 VL 50 IS 3 BP 216 EP 221 DI 10.1053/j.seminhematol.2013.06.003 PG 6 WC Hematology SC Hematology GA 212TO UT WOS:000324005900005 PM 23953338 ER PT J AU Warfel, JM Merkel, TJ AF Warfel, J. M. Merkel, T. J. TI Bordetella pertussis infection induces a mucosal IL-17 response and long-lived Th17 and Th1 immune memory cells in nonhuman primates SO MUCOSAL IMMUNOLOGY LA English DT Article ID ADENYLATE-CYCLASE TOXIN; T-CELLS; HOST-DEFENSE; KLEBSIELLA-PNEUMONIAE; DENDRITIC CELLS; WHOLE-CELL; VACCINATION; INTERLEUKIN-17; CHILDREN; INNATE AB Despite near universal vaccine coverage, the bacterial pathogen Bordetella pertussis has re-emerged as a major public health concern. We recently developed a baboon (Papio anubis) model of pertussis that provides an excellent model of human pertussis. Using this model, the immune response to pertussis was characterized by measuring cytokines in the nasopharyngeal mucosa of infected baboons. Notably, we observed mucosal expression of interleukin-17 (IL-17) as well as IL-6, IL-23, and several cytokines and chemokines that are orchestrated by IL-17 immune responses. We also found substantial populations of circulating B. pertussis-specific Th17 and Th1 cells in convalescent animals >2 years post-infection consistent with a role in immunological memory to pertussis. Collectively, these data shed important light on the innate and adaptive immune responses to pertussis in a primate infection model and suggest that Th17 and Th1 immune responses contribute to the immunity conferred by natural pertussis infection. C1 [Warfel, J. M.; Merkel, T. J.] US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Merkel, TJ (reprint author), US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. EM tod.merkel@fda.hhs.gov FU Food and Drug Administration [Y1-AI-1727-01]; National Institutes of Health National Center For Research Resources [P40RR012317, 5R24RR016556-10]; NIH/NIAID FX We thank Dr Joel Beren, Lewis Shankle, Perry Altland, and Ernest Madison for technical assistance. We thank Dr Gary White, Dr Roman Wolf, and Dr James Papin for many helpful discussions and for invaluable help with coordinating the immunological memory experiments. We thank Dr Drusilla Burns, Dr Manuel Osorio, and Dr Brandon Feinen for critical reading of the manuscript. This work was funded by the Food and Drug Administration and NIH/NIAID through Inter-agency agreement # Y1-AI-1727-01. Baboons were obtained from the Oklahoma Baboon Research Resource. The Oklahoma Baboon Research Resource was supported by Grant Numbers P40RR012317 and 5R24RR016556-10 from the National Institutes of Health National Center For Research Resources. NR 49 TC 44 Z9 44 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD JUL PY 2013 VL 6 IS 4 BP 787 EP 796 DI 10.1038/mi.2012.117 PG 10 WC Immunology SC Immunology GA 193CU UT WOS:000322535800012 PM 23187316 ER PT J AU Cortez, KJ Proschan, MA Barrett, L Brust, DG Formentini, E Davey, RT Masur, H Polis, MA Neumann, AU Kottilil, S AF Cortez, K. J. Proschan, M. A. Barrett, L. Brust, D. G. Formentini, E. Davey, R. T. Masur, H. Polis, M. A. Neumann, A. U. Kottilil, S. TI Baseline CD4+T-Cell Counts Predict HBV Viral Kinetics to Adefovir Treatment in Lamivudine-Resistant HBV-Infected Patients with or without HIV Infection SO HIV CLINICAL TRIALS LA English DT Article DE CD4; HBV; HIV; viral kinetics ID HEPATITIS-B-VIRUS; ANTIRETROVIRAL THERAPY; ANTIVIRAL THERAPY; AIDS; INDIVIDUALS; PROGRESSION; MORTALITY; COHORT; IMPACT AB Background: Coinfection with HIV and hepatitis B virus (HBV) substantially alters the course of HBV. Directly acting anti-HBV agents suppress HBV viral levels; however, the kinetics of HBV decline in mono- and coinfected persons have not been evaluated. We investigated the role of baseline CD4+ T-cell counts as a predictor of HBV response to adefovir (ADV) therapy in chronic HBV with and without HIV coinfection. Methods: We conducted a double-blind, randomized, placebo-controlled study of HIV-infected (n = 12) and uninfected (n = 5) chronic HBV patients treated with ADV. Five HIV uninfected patients received ADV; the HIV+ patients received ADV or placebo for a total of 48 weeks. At the end of 48 weeks, all patients received open-label ADV for an additional 48 weeks. HBV, HIV viral loads, CD4+ T-cell counts, and safety labs were performed on days 0, 1, 3, 5, 7, 10, 14, and 28 and then every 4 weeks. Results: Lower HBV slopes were observed among coinfected compared to monoinfected patients (P=.027 at 4 weeks, P=.019 at 24 weeks, and P=.045 at 48 weeks). Using a mixed model analysis, we found a significant difference between the slopes of the 2 groups at 48 weeks (P=.045). Baseline CD4+ T-cell count was the only independent predictor of HBV decline in all patients. Conclusion: HIV coinfection is associated with slower HBV response to ADV. Baseline CD4+ T-cell count and not IL28B genotype is an independent predictor of HBV decline in all patients, emphasizing the role of immune status on clearance of HBV. C1 [Cortez, K. J.] US FDA, Div Human Tissues, Off Cell Therapy & Gene Therapies, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Proschan, M. A.] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Barrett, L.; Davey, R. T.; Polis, M. A.; Kottilil, S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Brust, D. G.] Lee Mem Hlth Syst, Div Infect Dis, Ft Myers, FL USA. [Formentini, E.] NIH, Div Microbiol & Infect Dis, Bethesda, MD 20892 USA. [Masur, H.] NIH, Dept Crit Care Med, Ctr Clin, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Neumann, A. U.] Bar Ilan Univ, Ramat Dan, Israel. RP Kottilil, S (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10 Rm 11N 204, Bethesda, MD 20892 USA. EM skottilil@niaid.nih.gov OI Polis, Michael/0000-0002-9151-2268 FU NIH (National Institute of Allergy and Infectious Diseases) FX This research was supported in part by the Intramural Research Program of the NIH (National Institute of Allergy and Infectious Diseases). NR 16 TC 2 Z9 2 U1 0 U2 4 PU THOMAS LAND PUBLISHERS, INC PI ST LOUIS PA 255 JEFFERSON RD, ST LOUIS, MO 63119-3627 USA SN 1528-4336 J9 HIV CLIN TRIALS JI HIV Clin. Trials PD JUL-AUG PY 2013 VL 14 IS 4 BP 149 EP 159 DI 10.1310/hct1404-149 PG 11 WC Infectious Diseases; Pharmacology & Pharmacy SC Infectious Diseases; Pharmacology & Pharmacy GA 185UA UT WOS:000321994600003 PM 23924587 ER PT J AU Poon, R Khanijow, K Umarjee, S Fadiran, E Yu, M Zhang, L Parekh, A AF Poon, Rita Khanijow, Keshav Umarjee, Sphoorti Fadiran, Emmanuel Yu, Monica Zhang, Lei Parekh, Ameeta TI Participation of Women and Sex Analyses in Late-Phase Clinical Trials of New Molecular Entity Drugs and Biologics Approved by the FDA in 2007-2009 SO JOURNAL OF WOMENS HEALTH LA English DT Article ID QTC INTERVAL; PREVALENCE AB Background: Biological sex differences may contribute to differential treatment outcomes for therapeutic products. This study tracks women's participation in late-phase clinical trials (LPCTs), where efficacy and safety of drugs and biologics are evaluated, of new molecular entity (NME) drugs and biologics approved by the U. S. Food and Drug Administration (FDA) in 2007-2009. Furthermore, presentations of sex-based analyses were assessed from the FDA reviews. Methods: New drug applications (NDAs) and biologics license applications (BLAs) were accessed from the U. S. FDA database and evaluated for women's participation in LPCTs. Sex-based analyses for efficacy and safety contained in FDA reviews were surveyed. Ratios for women's LPCT participation (PROPORTION OF STUDY SUBJECTS) to their proportion in the disease population were calculated for each approved therapeutic product and grouped into therapeutic categories. Results: Sex-specific (n = 5) and pediatric (n = 3) drug applications were excluded. Women's participation in LPCTs was 39%, 48%, and 42% in NDAs (n = 50) and 49%, 62%, and 58% in BLAs (n = 11) for 2007, 2008, and 2009, respectively. Sixty-four percent of NDAs and 91% of BLAs had participation to proportion ratios of >= 0.80. Seventy-four percent of NDA reviews and 64% of BLA reviews included safety and efficacy sex analysis. Ninety-six percent of NDA reviews and 100% of BLA reviews included efficacy sex analysis. Conclusion: Women's participation in LPCTs averaged 43% for NDAs and 57% for BLAs in 2007-2009 and varied widely by indication. As a comparison, the 2001 U. S. Government Accountability Office (GAO) reported 52% of women's participation for drug clinical trials in 1998-2000 and an FDA study reported 45% for BLAs approved from 1995 to 1999. This study showed that sex-analysis of both safety and efficacy in NDA has increased to 74% since the GAO report of 72%, while those for BLAs increased to 64% from 37% reported for therapeutic biologics approved in 1995-1999. Knowledge of disease prevalence and participation in clinical trials provides an understanding of recruitment and retention patterns of patients in these trials. C1 [Poon, Rita; Khanijow, Keshav; Umarjee, Sphoorti; Fadiran, Emmanuel; Yu, Monica; Parekh, Ameeta] US FDA, Off Womens Hlth, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Zhang, Lei] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Fadiran, E (reprint author), US FDA, Off Womens Hlth, Bldg 32,Room 2312,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM emmanuel.fadiran@fda.hhs.gov NR 24 TC 8 Z9 9 U1 0 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD JUL PY 2013 VL 22 IS 7 BP 604 EP 616 DI 10.1089/jwh.2012.3753 PG 13 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 180UI UT WOS:000321623800005 PM 23768021 ER PT J AU Freimanis, G Sedegah, M Owusu-Ofori, S Kumar, S Allain, JP AF Freimanis, Graham Sedegah, Mary Owusu-Ofori, Shirley Kumar, Sanjai Allain, Jean-Pierre TI Investigating the prevalence of transfusion transmission of Plasmodium within a hyperendemic blood donation system SO TRANSFUSION LA English DT Article ID POLYMERASE-CHAIN-REACTION; FALCIPARUM DRUG-RESISTANCE; SUB-SAHARAN AFRICA; IN-VITRO; MICROSATELLITE MARKERS; ANTIMALARIAL-DRUGS; MALARIA PARASITES; IMMUNE-RESPONSES; ASHANTI REGION; ENDEMIC AREA AB BackgroundPrevention of transfusion-transmitted malaria in at-risk children and pregnant women in endemic areas with inexpensive chloroquine is no longer effective due to widespread drug resistance. There is an urgent need for devising new strategies for transfusion malarial safety. We investigated the frequency of transfusion transmission of malaria within the Ghanaian blood donation system using blood donations from 106 asymptomatic adult Ghanaian blood donors. Study Design and MethodsPaired samples from 106 blood donations and recipients (before and after transfusion) were tested for anti-merozoite surface protein-1/2 using the commercial Lab21 malaria enzyme immunoassay (EIA), four antigen-specific in-house EIAs, and Plasmodium lactate dehydrogenase (pLDH) EIA. Additionally, Plasmodium DNA was screened for using a species-specific nested polymerase chain reaction (PCR) and a Pan-Plasmodium quantitative PCR. Donor-recipient parasite identity was defined by two concordant genotyping strategies. ResultsPlasmodium antibody prevalence was 100% in both donors and recipients, with at least one antigen. Parasitemia prevalence was 54.7% in both donors and recipients with median levels of 20 and 5.3copies/L, respectively, the difference being correlated to age (p=0.0001). Multiple species infections were frequent (8.5%). Twenty-four units of parasitemic blood were transfused to nonparasitemic recipients, of which 10 (41.7%) became infected after transfusion. Molecular genotyping with 13 distinct markers (antigenic genes and microsatellite loci) identified three to nine parasitemic recipients after transfusion with level of allelic identity suggesting 14% to 28% definite or possible transfusion-related parasitemia. ConclusionNone of the currently available screening assays appear suitable to minimize transfusion malaria without compromising the blood supply in endemic areas. C1 Univ Cambridge, Div Transfus Med, Dept Haematol, Cambridge, England. US FDA, Div Emerging Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. Komfo Anokye Teaching Hosp, Transfus Med Unit, Kumasi, Ghana. RP Allain, JP (reprint author), Cambridge Blood Ctr, Dept Haematol, Long Rd, Cambridge CB2 2PT, England. EM jpa1000@cam.ac.uk NR 59 TC 11 Z9 11 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUL PY 2013 VL 53 IS 7 BP 1429 EP 1441 DI 10.1111/j.1537-2995.2012.03943.x PG 13 WC Hematology SC Hematology GA 180RI UT WOS:000321612400010 PM 23113534 ER PT J AU Cruz, CN Tyner, KM Velazquez, L Hyams, KC Jacobs, A Shaw, AB Jiang, WL Lionberger, R Hinderling, P Kong, Y Brown, PC Ghosh, T Strasinger, C Suarez-Sharp, S Henry, D Van Uitert, M Sadrieh, N Morefield, E AF Cruz, Celia N. Tyner, Katherine M. Velazquez, Lydia Hyams, Kenneth C. Jacobs, Abigail Shaw, Arthur B. Jiang, Wenlei Lionberger, Robert Hinderling, Peter Kong, Yoon Brown, Paul C. Ghosh, Tapash Strasinger, Caroline Suarez-Sharp, Sandra Henry, Don Van Uitert, Maat Sadrieh, Nakissa Morefield, Elaine TI CDER Risk Assessment Exercise to Evaluate Potential Risks from the Use of Nanomaterials in Drug Products SO AAPS JOURNAL LA English DT Article DE CDER; nanomaterial; nanotechnology; risk assessment; risk management AB The Nanotechnology Risk Assessment Working Group in the Center for Drug Evaluation and Research (CDER) within the United States Food and Drug Administration was established to assess the possible impact of nanotechnology on drug products. The group is in the process of performing risk assessment and management exercises. The task of the working group is to identify areas where CDER may need to optimize its review practices and to develop standards to ensure review consistency for drug applications that may involve the application of nanotechnology. The working group already performed risk management exercises evaluating the potential risks from administering nanomaterial active pharmaceutical ingredients (API) or nanomaterial excipients by various routes of administration. This publication outlines the risk assessment and management process used by the working group, using nanomaterial API by the oral route of administration as an example. C1 [Cruz, Celia N.; Tyner, Katherine M.; Velazquez, Lydia; Hyams, Kenneth C.; Jacobs, Abigail; Shaw, Arthur B.; Jiang, Wenlei; Lionberger, Robert; Hinderling, Peter; Kong, Yoon; Brown, Paul C.; Ghosh, Tapash; Strasinger, Caroline; Suarez-Sharp, Sandra; Henry, Don; Van Uitert, Maat; Sadrieh, Nakissa; Morefield, Elaine] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Morefield, E (reprint author), US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM elaine.morefield@fda.hhs.gov NR 15 TC 4 Z9 4 U1 1 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD JUL PY 2013 VL 15 IS 3 BP 623 EP 628 DI 10.1208/s12248-013-9466-6 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 172XU UT WOS:000321041000001 PM 23512727 ER PT J AU Chang, RK Raw, A Lionberger, R Yu, L AF Chang, Rong-Kun Raw, Andre Lionberger, Robert Yu, Lawrence TI Generic Development of Topical Dermatologic Products, Part II: Quality by Design for Topical Semisolid Products SO AAPS JOURNAL LA English DT Article DE dermatologic product; generic; quality by design; semisolid; topical product ID QBD AB The emergence of quality by design as a relatively new systematic science and risk-based approach has added a new dimension to pharmaceutical development and manufacturing. This review attempts to discuss the quality by design elements and concepts applied for topical semisolid products. Quality by design begins with defining a quality target product profile as well as critical quality attributes. Subsequently, this is followed by risk identification/risk analysis/risk evaluation to recognize critical material attributes and critical process parameters, in conjunction with design of experiments or other appropriate methods to establish control strategies for the drug product. Several design-of-experiment examples are included as practical strategies for the development and optimization of formulation and process for topical drug products. C1 [Chang, Rong-Kun; Raw, Andre; Lionberger, Robert; Yu, Lawrence] US FDA, Off Gener Drugs, Ctr Drug Evaluat & Res, Rockville, MD 20855 USA. RP Chang, RK (reprint author), US FDA, Off Gener Drugs, Ctr Drug Evaluat & Res, 7500 Standish Pl, Rockville, MD 20855 USA. EM richard.chang@fda.hhs.gov RI Yu, Lawrence/L-6280-2016 NR 13 TC 8 Z9 9 U1 1 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD JUL PY 2013 VL 15 IS 3 BP 674 EP 683 DI 10.1208/s12248-013-9472-8 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 172XU UT WOS:000321041000006 PM 23572241 ER PT J AU Li, BV Jin, FY Lee, SL Bai, T Chowdhury, B Caramenico, HT Conner, DP AF Li, Bing V. Jin, Feiyan Lee, Sau L. Bai, Tao Chowdhury, Badrul Caramenico, Hoainhon T. Conner, Dale P. TI Bioequivalence for Locally Acting Nasal Spray and Nasal Aerosol Products: Standard Development and Generic Approval SO AAPS JOURNAL LA English DT Article DE bioequivalence; generic; locally acting drug; nasal aerosol; nasal spray AB Demonstrating bioequivalence (BE) for nasal spray/aerosol products for local action has been very challenging because the relationship between the drug in systemic circulation and the drug reaching the nasal site of action has not been well established. Thus, the current BE standard for these drug/device combination products is based on a weight-of-evidence approach, which contains three major elements: equivalent in vitro performance, equivalent systemic exposure, and equivalent local delivery. In addition, formulation sameness and device similarity are evidences to support BE. This paper presents a comprehensive review of the scientific rationale of the current BE standard and their development history for nasal spray/aerosol products, as well as the Food and Drug Administration's review and approval status of generic nasal sprays/aerosols with the application of these BE standard. C1 [Li, Bing V.; Bai, Tao; Caramenico, Hoainhon T.; Conner, Dale P.] US FDA, Div Bioequivalence, Off Gener Drugs, Ctr Drug Evaluat & Res, Rockville, MD 20855 USA. [Jin, Feiyan; Lee, Sau L.] US FDA, Div Chem, Off Gener Drugs, Ctr Drug Evaluat & Res, Rockville, MD 20855 USA. [Chowdhury, Badrul] US FDA, Div Pulm Allergy & Rheumatol Prod, Off Drug Evaluat, Off New Drugs,Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Li, BV (reprint author), US FDA, Div Bioequivalence, Off Gener Drugs, Ctr Drug Evaluat & Res, 7520 Standish Pl, Rockville, MD 20855 USA. EM bing.li@fda.hhs.gov NR 5 TC 5 Z9 5 U1 1 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD JUL PY 2013 VL 15 IS 3 BP 875 EP 883 DI 10.1208/s12248-013-9494-2 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 172XU UT WOS:000321041000025 PM 23686396 ER PT J AU Xie, C Wang, ZJ Wang, C Xu, J Wen, ZN Wang, HT Shi, LM Chow, MSS Huang, Y Zuo, Z AF Xie, Chen Wang, Zhijun Wang, Charles Xu, Jun Wen, Zhining Wang, Haitian Shi, Leming Chow, Moses S. S. Huang, Ying Zuo, Zhong TI Utilization of Gene Expression Signature for Quality Control of Traditional Chinese Medicine Formula Si-Wu-Tang SO AAPS JOURNAL LA English DT Article DE gene expression signature; pharmacokinetics; quality control; Si-Wu-Tang; traditional Chinese medicine AB The current study utilized a combined pharmacokinetic and genomic approach to demonstrate the feasibility of a new quality control method by using a panel of special differentially expressed genes (DEGs) as unique fingerprint to serve as marker of in vivo bioactivity for a representative traditional Chinese medicine (TCM) formula, Si-Wu-Tang (SWT). The method involves firstly obtaining possible in vivo active components, i.e., the "absorbable" components from the permeate of the Caco-2 monolayer model to simulate oral administration of two specific SWT products (CU-SWT, J-SWT), their component single herbs (Angelicae, Chuanxiong, Paeoniae, and Rehmanniae), and a standard mixture of active compounds (ferulic acid, ligustilide, senkyunolide A). Then, these respective absorbable components were incubated with MCF-7 cells to determine the gene expression profile using microarray processing/analysis as well as real-time PCR. From the available DEGs identified following the incubation, the magnitude of change in DEGs by real-time PCR was found to be consistent with that by microarray. The designated DEGs from the CU-SWT permeate were found to be distinct from other 19 products. Furthermore, the changes in the DEGs resulting from MCF-7 cells treated by eight replicate extracts of CU-SWT on three separate days were consistent. These results demonstrated sufficient specificity and consistency of the DEG panel which could serve as a unique bioactive "fingerprint" for the designated SWT product. The present method for DEG determination may be applied to other TCM products and with further definitive study can potentially provide a unique method for quality control of TCM in the future. C1 [Xie, Chen; Zuo, Zhong] Chinese Univ Hong Kong, Fac Med, Sch Pharm, Shatin, Hong Kong, Peoples R China. [Wang, Zhijun; Chow, Moses S. S.; Huang, Ying] Western Univ Hlth Sci, Coll Pharm, Ctr Adv Drug Res & Evaluat, Pomona, CA 91766 USA. [Shi, Leming] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Wang, Charles] City Hope Comprehens Canc Ctr, Beckman Res Inst, Funct Genom Core, Duarte, CA USA. [Xu, Jun] Univ Calif Los Angeles, David Geffen Sch Med, Cedars Sinai Med Ctr, Clin Transcript Genom Core,Med Genet Inst, Los Angeles, CA 90095 USA. [Shi, Leming] Fudan Univ, Sch Pharm, Dept Clin Pharm, Shanghai 200433, Peoples R China. [Shi, Leming] Fudan Univ, Sch Pharm, Ctr Pharmacogen, Shanghai 200433, Peoples R China. [Wen, Zhining] Sichuan Univ, Coll Chem, Chengdu 610064, Sichuan, Peoples R China. [Wang, Haitian] Chinese Univ Hong Kong, Sch Publ Hlth & Primary Care, Div Biostat, Shatin, Hong Kong, Peoples R China. RP Huang, Y (reprint author), Western Univ Hlth Sci, Coll Pharm, Ctr Adv Drug Res & Evaluat, Pomona, CA 91766 USA. EM yhuang@westernu.edu; joanzuo@cuhk.edu.hk RI Zuo, Zhong/B-6884-2008; Wang, Maggie Haitian/F-5954-2017 OI Wang, Maggie Haitian/0000-0003-1223-4595 FU Innovation and Technology Commission of the Hong Kong Special Administrative Region of the People's Republic of China [ITS/446/09] FX This work was supported by the Innovation and Technology Fund (ITS/446/09) from the Innovation and Technology Commission of the Hong Kong Special Administrative Region of the People's Republic of China. NR 16 TC 0 Z9 0 U1 0 U2 33 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD JUL PY 2013 VL 15 IS 3 BP 884 EP 892 DI 10.1208/s12248-013-9491-5 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 172XU UT WOS:000321041000026 PM 23703112 ER PT J AU Calvo, MS Uribarri, J AF Calvo, Mona S. Uribarri, Jaime TI Public health impact of dietary phosphorus excess on bone and cardiovascular health in the general population SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Review ID GROWTH-FACTOR 23; NUTRITION EXAMINATION SURVEY; SERUM PARATHYROID-HORMONE; CHRONIC KIDNEY-DISEASE; 3RD NATIONAL-HEALTH; LOW-CALCIUM DIETS; PHOSPHATE ADDITIVES; MORTALITY RISK; BLOOD-PRESSURE; YOUNG-ADULTS AB This review explores the potential adverse impact of the increasing phosphorus content in the American diet on renal, cardiovascular, and bone health of the general population. Increasingly, studies show that phosphorus intakes in excess of the nutrient needs of a healthy population may significantly disrupt the hormonal regulation of phosphate, calcium, and vitamin D, which contributes to disordered mineral metabolism, vascular calcification, impaired kidney function, and bone loss. Moreover, large epidemiologic studies suggest that mild elevations of serum phosphate within the normal range are associated with cardiovascular disease (CVD) risk in healthy populations without evidence of kidney disease. However, few studies linked high dietary phosphorus intake to mild changes in serum phosphate because of the nature of the study design and inaccuracies in the nutrient composition databases. Although phosphorus is an essential nutrient, in excess it could be linked to tissue damage by a variety of mechanisms involved in the endocrine regulation of extracellular phosphate, specifically the secretion and action of fibroblast growth factor 23 and parathyroid hormone. Disordered regulation of these hormones by high dietary phosphorus may be key factors contributing to renal failure, CVD, and osteoporosis. Although systematically underestimated in national surveys, phosphorus intake seemingly continues to increase as a result of the growing consumption of highly processed foods, especially restaurant meals, fast foods, and convenience foods. The increased cumulative use of ingredients containing phosphorus in food processing merits further study given what is now being shown about the potential toxicity of phosphorus intake when it exceeds nutrient needs. C1 [Calvo, Mona S.] US FDA, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Dept Hlth & Human Serv, Laurel, MD USA. [Uribarri, Jaime] Mt Sinai Sch Med, New York, NY USA. RP Uribarri, J (reprint author), 1 Gustave Levy Pl, New York, NY 10029 USA. EM jaime.uribarri@mssm.edu NR 59 TC 32 Z9 32 U1 1 U2 68 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUL PY 2013 VL 98 IS 1 BP 6 EP 15 DI 10.3945/ajcn.112.053934 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 171EZ UT WOS:000320909200003 PM 23719553 ER PT J AU Walters, SP Gonzalez-Escalona, N Son, I Melka, DC Sassoubre, LM Boehm, AB AF Walters, Sarah P. Gonzalez-Escalona, Narjol Son, Insook Melka, David C. Sassoubre, Lauren M. Boehm, Alexandria B. TI Salmonella enterica Diversity in Central Californian Coastal Waterways SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID FIELD GEL-ELECTROPHORESIS; MOLECULAR EVOLUTIONARY GENETICS; SEQUENCE TYPING DATA; UNITED-STATES; BIOGEOGRAPHIC PATTERNS; ESCHERICHIA-COLI; SEROTYPES; SEROVAR; MARINE; CLONES AB Salmonella enterica is one of the most important bacterial enteric pathogens worldwide. However, little is known about its distribution and diversity in the environment. The present study explored the diversity of 104 strains of Salmonella enterica isolated over 2 years from 12 coastal waterways in central California. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing were used to probe species diversity. Seventy-four PFGE patterns and 38 sequence types (STs) were found, including 18 newly described STs. Nineteen of 25 PFGE patterns were indistinguishable from those of clinical isolates in PulseNet. The most common ST was consistent with S. enterica serovar Typhimurium, and other frequently detected STs were associated with the serovars Heidelberg and Enteritidis; all of these serovars are important etiologies of salmonellosis. An investigation into S. enterica biogeography was conducted at the level of ST and subspecies. At the ST and subspecies level, we found a taxon-time relationship but no taxon-area or taxon-environmental distance relationships. STs collected during wet versus dry conditions tended to be more similar; however, STs collected from waterways adjacent to watersheds with similar land covers did not tend to be similar. The results suggest that the lack of dispersal limitation may be an important factor affecting the diversity of S. enterica in the region. C1 [Walters, Sarah P.; Sassoubre, Lauren M.; Boehm, Alexandria B.] Stanford Univ, Dept Civil & Environm Engn, Stanford, CA 94305 USA. [Gonzalez-Escalona, Narjol; Son, Insook; Melka, David C.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. RP Boehm, AB (reprint author), Stanford Univ, Dept Civil & Environm Engn, Stanford, CA 94305 USA. EM aboehm@stanford.edu OI Gonzalez-Escalona, Narjol/0000-0003-4568-0022 FU National Research Initiative of the USDA Cooperative State Research, Education, and Extension Service [2007-35102-18139]; FDA Foods Program intramural funds FX S.P.W., A.B.B., and L.M.S. were supported by the National Research Initiative of the USDA Cooperative State Research, Education, and Extension Service (grant 2007-35102-18139). N.G.-E., I.S., and D.C.M. were supported by FDA Foods Program intramural funds. NR 55 TC 7 Z9 7 U1 1 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD JUL PY 2013 VL 79 IS 14 BP 4199 EP 4209 DI 10.1128/AEM.00930-13 PG 11 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 170LS UT WOS:000320852900002 PM 23624479 ER PT J AU Kawai, VK Grijalva, CG Arbogast, PG Curtis, JR Solomon, DH Delzell, E Chen, L Ouellet-Hellstrom, R Herrinton, L Liu, LY Mitchell, EF Stein, CM Griffin, MR AF Kawai, Vivian K. Grijalva, Carlos G. Arbogast, Patrick G. Curtis, Jeffrey R. Solomon, Daniel H. Delzell, Elizabeth Chen, Lang Ouellet-Hellstrom, Rita Herrinton, Lisa Liu, Liyan Mitchell, Edward F., Jr. Stein, C. Michael Griffin, Marie R. TI Initiation of Tumor Necrosis Factor Antagonists and Risk of Fractures in Patients With Selected Rheumatic and Autoimmune Diseases SO ARTHRITIS CARE & RESEARCH LA English DT Article ID BONE-MINERAL DENSITY; POPULATION-BASED COHORT; TNF-ALPHA THERAPY; CROHNS-DISEASE; HIP FRACTURE; VERTEBRAL FRACTURES; RANDOMIZED-TRIAL; TURNOVER MARKERS; ELDERLY-WOMEN; ARTHRITIS AB ObjectiveWe tested the hypothesis that initiation of tumor necrosis factor (TNF) antagonists reduced the risk of fractures compared to nonbiologic comparators in patients with autoimmune diseases. MethodsUsing 4 large administrative databases, we assembled retrospective cohorts of patients with autoimmune diseases who initiated either a TNF antagonist or a nonbiologic medication. We identified 3 mutually exclusive disease groups: rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and a combined group: psoriasis (PsO), psoriatic arthritis (PsA), or ankylosing spondylitis (AS). We used baseline covariate data to calculate propensity scores (PS) for each disease group and used Cox regression to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs). We compared the risk of combined hip, radius/ulna, humerus, or pelvic fractures between PS-matched cohorts of new users of TNF antagonists and nonbiologic comparators. ResultsWe identified 9,020, 2,014, and 2,663 new PS-matched episodes of TNF antagonist and nonbiologic comparator use in RA, IBD, and PsO-PsA-AS cohorts, respectively. The risk of combined fractures was similar between new users of TNF antagonists and nonbiologic comparators for each disease (HR 1.17, 95% CI 0.91-1.51; HR 1.49, 95% CI 0.72-3.11; and HR 0.92, 95% CI 0.47-1.82 for RA, IBD, and PsO-PsA-AS, respectively). In RA, the risk of combined fractures was associated with an average daily dosage of prednisone equivalents >10 mg/day at baseline compared with no glucocorticoid (HR 1.54, 95% CI 1.03-2.30). ConclusionThe risk of fractures did not differ between initiators of a biologic agent and a nonbiologic comparator for any disease studied. Among RA patients, use of >10 mg/day of prednisone equivalents at baseline increased the fracture risk. C1 [Kawai, Vivian K.; Grijalva, Carlos G.; Mitchell, Edward F., Jr.; Stein, C. Michael; Griffin, Marie R.] Vanderbilt Univ, Sch Med, Nashville, TN 37232 USA. [Curtis, Jeffrey R.; Delzell, Elizabeth] Univ Alabama Birmingham, Birmingham, AL USA. [Solomon, Daniel H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Ouellet-Hellstrom, Rita] US FDA, Silver Spring, MD USA. [Herrinton, Lisa; Liu, Liyan] Kaiser Permanente No Calif, Oakland, CA USA. [Griffin, Marie R.] VA Tennessee Valley Hlth Care Syst, Midsouth Geriatr Res Educ & Clin Ctr, Nashville, TN USA. RP Griffin, MR (reprint author), Vanderbilt Univ, Sch Med, Dept Prevent Med, Suite 2600,1500 21st Ave South, Nashville, TN 37232 USA. EM marie.griffin@vanderbilt.edu FU Food and Drug Administration; NIH [T32-GM-007569, AR-053351, P60-AR-56116]; Vanderbilt Physician Scientist Development Award; Agency for Healthcare Research and Quality [U18-HS017919, R01-HS018517]; Abbott; Crescendo; Pfizer; BMS; Amgen; Centocor; Consortium of Rheumatology Researchers of North America; Roche/Genentech; UCB; Lilly; Proctor Gamble; Genentech; Scimetrika; Rocky Mountain Poison and Drug Center; McNeil FX Supported by the Food and Drug Administration. Dr. Kawai's work was supported by the NIH (grant T32-GM-007569) and a Vanderbilt Physician Scientist Development Award. Dr. Curtis' work was supported by the Agency for Healthcare Research and Quality (grants U18-HS017919 and R01-HS018517) and the NIH (grant AR-053351). Drs. Grijalva, Stein, and Griffin's work was supported by the NIH (grant P60-AR-56116).; Dr. Curtis has received consultant fees, speaking fees, and/or honoraria (less than $10,000 each) from Abbott, Crescendo, Pfizer, and BMS, and (more than $10,000 each) from Amgen, Centocor, the Consortium of Rheumatology Researchers of North America, Roche/Genentech, and UCB. Dr. Solomon has received research support from Lilly, Amgen, Abbott, and the Consortium of Rheumatology Researchers of North America. Dr. Herrinton has received research support from Centocor, Proctor & Gamble, Genentech, and Scimetrika. Dr. Griffin has received consultant fees (less than $10,000) from Rocky Mountain Poison and Drug Center, which is funded by McNeil. NR 50 TC 10 Z9 10 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X J9 ARTHRIT CARE RES JI Arthritis Care Res. PD JUL PY 2013 VL 65 IS 7 BP 1085 EP 1094 DI 10.1002/acr.21937 PG 10 WC Rheumatology SC Rheumatology GA 174VF UT WOS:000321184000010 PM 23281339 ER PT J AU Agrawal, A Chen, CW Baxi, J Chen, Y Pfefer, TJ AF Agrawal, Anant Chen, Chao-Wei Baxi, Jigesh Chen, Yu Pfefer, T. Joshua TI Multilayer thin-film phantoms for axial contrast transfer function measurement in optical coherence tomography SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID OCULAR FUNDUS TISSUES; MONTE-CARLO; SCATTERING AB In optical coherence tomography (OCT), axial resolution is one of the most critical parameters impacting image quality. It is commonly measured by determining the point spread function (PSF) based on a specular surface reflection. The contrast transfer function (CTF) provides more insights into an imaging system's resolving characteristics and can be readily generated in a system-independent manner, without consideration for image pixel size. In this study, we developed a test method for determination of CTF based on multi-layer, thin-film phantoms, evaluated using spectral-and time-domain OCT platforms with different axial resolution values. Phantoms representing six spatial frequencies were fabricated and imaged. The fabrication process involved spin coating silicone films with precise thicknesses in the 8-40 mu m range. Alternating layers were doped with a specified concentration of scattering particles. Validation of layer optical properties and thicknesses were achieved with spectrophotometry and stylus profilometry, respectively. OCT B-scans were used to calculate CTFs and results were compared with convetional PSF measurements based on specular reflections. Testing of these phantoms indicated that our approach can provide direct access to axial resolution characteristics highly relevant to image quality. Furthermore, tissue phantoms based on our thin-film fabrication approach may have a wide range of additional applications in optical imaging and spectroscopy. (C) 2013 Optical Society of America C1 [Agrawal, Anant; Baxi, Jigesh; Pfefer, T. Joshua] Ctr Devices & Radiol Hlth Food & Drug Adm, Silver Spring, MD USA. [Chen, Chao-Wei; Chen, Yu] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. RP Agrawal, A (reprint author), Ctr Devices & Radiol Hlth Food & Drug Adm, Silver Spring, MD USA. EM anant.agrawal@fda.hhs.gov FU National Science Foundation [CBET-1135514] FX Chao-Wei Chen and Yu Chen gratefully acknowledge funding from the National Science Foundation grant CBET-1135514. The authors also gratefully acknowledge Daniel X. Hammer for helpful discussions. NR 24 TC 6 Z9 6 U1 1 U2 15 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD JUL 1 PY 2013 VL 4 IS 7 BP 1166 EP 1175 DI 10.1364/BOE.4.001166 PG 10 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 176WH UT WOS:000321336500016 PM 23847740 ER PT J AU Giacomini, KM Huang, SM AF Giacomini, K. M. Huang, S-M TI Transporters in Drug Development and Clinical Pharmacology SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material ID CRITICAL PATH; CONSORTIUM; FDA AB More than 400 membrane transporters in two major superfamilies-ATP-binding cassette (ABC) and solute carrier (SLC)-are annotated in the human genome. Preclinical and clinical studies indicate that transport is an important determinant of drug disposition, as well as therapeutic and adverse drug effects. Importantly, transporters may represent the rate-determining step of drug absorption, distribution, and elimination in the intestine, liver, kidney, and blood-brain barrier (BBB), and they are often the sites of drug-drug interactions. C1 [Giacomini, K. M.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Huang, S-M] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Giacomini, KM (reprint author), Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. EM Kathy.Giacomini@ucsf.edu; ShiewMei.Huang@fda.hhs.gov NR 22 TC 50 Z9 50 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD JUL PY 2013 VL 94 IS 1 BP 3 EP 9 DI 10.1038/clpt.2013.86 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 172TT UT WOS:000321028500001 PM 23778703 ER PT J AU Giacomini, KM Balimane, PV Cho, SK Eadon, M Edeki, T Hillgren, KM Huang, SM Sugiyama, Y Weitz, D Wen, Y Xia, CQ Yee, SW Zimdahl, H Niemi, M AF Giacomini, K. M. Balimane, P. V. Cho, S. K. Eadon, M. Edeki, T. Hillgren, K. M. Huang, S-M Sugiyama, Y. Weitz, D. Wen, Y. Xia, C. Q. Yee, S. W. Zimdahl, H. Niemi, M. CA Int Transporter Consortium TI International Transporter Consortium Commentary on Clinically Important Transporter Polymorphisms SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material ID MARKEDLY AFFECTS; PHARMACOKINETICS; ROSUVASTATIN; VARIANTS AB This Commentary focuses on genetic polymorphisms in membrane transporters. We present two polymorphisms for which there is a compelling body of literature supporting their clinical relevance: OATP1B1 (c.521T>C, p.V174A, rs4149056) and BCRP (c.421C>A, p.Q141K, rs2231142). The clinical evidence demonstrating their role in variation in pharmacokinetics and pharmacodynamics is described along with their allele frequencies in ethnic populations. Recommendations for incorporating studies of transporter polymorphisms in drug development are provided, along with the regulatory implications. C1 [Giacomini, K. M.; Yee, S. W.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Balimane, P. V.] Bristol Myers Squibb Co, Princeton, NJ USA. [Cho, S. K.] Yonsei Univ, Coll Med, Dept Pharmacol, Seoul, South Korea. [Eadon, M.] Univ Chicago, Dept Med, Nephrol Sect, Chicago, IL 60637 USA. [Edeki, T.] AstraZeneca, Wilmington, DC USA. [Hillgren, K. M.] Lilly Res Labs, Indianapolis, IN USA. [Huang, S-M] US FDA, Ctr Drug Evaluat & Res, Off Clin Pharmacol, Off Translat Sci, Silver Spring, MD USA. [Sugiyama, Y.] RIKEN Inst Phys & Chem Res, Res Cluster Innovat, RIKEN Innovat Ctr, Yokohama, Kanagawa, Japan. [Weitz, D.] Sanofi Aventis Deutschland, Res & Dev Drug Disposit, Frankfurt, Germany. [Wen, Y.] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA. [Xia, C. Q.] Millennium Pharmaceut Inc, Cambridge, MA USA. [Zimdahl, H.] Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. [Niemi, M.] Univ Helsinki, Dept Clin Pharmacol, SF-00250 Helsinki, Finland. RP Giacomini, KM (reprint author), Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. EM kathy.giacomini@ucsf.edu; mikko.niemi@helsinki.fi RI Niemi, Mikko/A-1088-2008; OI Niemi, Mikko/0000-0003-4550-2189 FU NIGMS NIH HHS [U01 GM061390, U19 GM061390] NR 14 TC 49 Z9 49 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD JUL PY 2013 VL 94 IS 1 BP 23 EP 26 DI 10.1038/clpt.2013.12 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 172TT UT WOS:000321028500008 PM 23778707 ER PT J AU Hillgren, KM Keppler, D Zur, AA Giacomini, KM Stieger, B Cass, CE Zhang, L AF Hillgren, K. M. Keppler, D. Zur, A. A. Giacomini, K. M. Stieger, B. Cass, C. E. Zhang, L. CA Int Transporter Consortium TI Emerging Transporters of Clinical Importance: An Update From the International Transporter Consortium SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID SALT EXPORT PUMP; RESISTANCE-ASSOCIATED PROTEIN-3; HUMAN NUCLEOSIDE TRANSPORTERS; INDUCED LIVER-INJURY; INTRAHEPATIC CHOLESTASIS; GENETIC POLYMORPHISMS; SUBSTRATE-SPECIFICITY; TUBULAR SECRETION; DRUG-INTERACTIONS; MULTIDRUG AB The International Transporter Consortium (ITC) has recently described seven transporters of particular relevance to drug development. Based on the second ITC transporter workshop in 2012, we have identified additional transporters of emerging importance in pharmacokinetics, interference of drugs with transport of endogenous compounds, and drug-drug interactions (DDIs) in humans. The multidrug and toxin extrusion proteins (MATEs, gene symbol SLC47A) mediate excretion of organic cations into bile and urine. MATEs are important in renal DDIs. Multidrug resistance proteins (MRPs or ABCCs) are drug and conjugate efflux pumps, and impaired activity of MRP2 results in conjugated hyperbilirubinemia. The bile salt export pump (BSEP or ABCB11) prevents accumulation of toxic bile salt concentrations in hepatocytes, and BSEP inhibition or deficiency may cause cholestasis and liver injury. In addition, examples are presented on the roles of nucleoside and peptide transporters in drug targeting and disposition. C1 [Hillgren, K. M.] Lilly Res Labs, Indianapolis, IN USA. [Keppler, D.] German Canc Res Ctr, Heidelberg, Germany. [Zur, A. A.; Giacomini, K. M.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Giacomini, K. M.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Stieger, B.] Univ Zurich Hosp, Dept Clin Pharmacol & Toxicol, CH-8091 Zurich, Switzerland. [Cass, C. E.] Univ Alberta, Cross Canc Inst, Dept Oncol, Edmonton, AB, Canada. [Zhang, L.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Hillgren, KM (reprint author), Lilly Res Labs, Indianapolis, IN USA. EM k_hillgren@lilly.com RI Keppler, Dietrich/A-5528-2013 FU NIGMS NIH HHS [U01 GM061390, U19 GM061390] NR 72 TC 100 Z9 100 U1 5 U2 29 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD JUL PY 2013 VL 94 IS 1 BP 52 EP 63 DI 10.1038/clpt.2013.74 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 172TT UT WOS:000321028500013 PM 23588305 ER PT J AU Zamek-Gliszczynski, MJ Lee, CA Poirier, A Bentz, J Chu, X Ellens, H Ishikawa, T Jamei, M Kavass, JC Nagar, S Pang, KS Korzekwa, K Swaan, PW Taub, ME Zhao, P Galetin, A AF Zamek-Gliszczynski, M. J. Lee, C. A. Poirier, A. Bentz, J. Chu, X. Ellens, H. Ishikawa, T. Jamei, M. Kavass, J. C. Nagar, S. Pang, K. S. Korzekwa, K. Swaan, P. W. Taub, M. E. Zhao, P. Galetin, A. CA Int Transporter Consortium TI ITC Recommendations for Transporter Kinetic Parameter Estimation and Translational Modeling of Transport-Mediated PK and DDIs in Humans SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Review ID DRUG-DRUG INTERACTIONS; PHYSIOLOGICALLY-BASED PHARMACOKINETICS; CANCER RESISTANCE PROTEIN; IN-VIVO EXTRAPOLATION; INTESTINAL 1ST-PASS METABOLISM; CONFLUENT CELL MONOLAYER; COA REDUCTASE INHIBITORS; CENTRAL-NERVOUS-SYSTEM; BLOOD-BRAIN-BARRIER; RAT HEPATOCYTES AB This white paper provides a critical analysis of methods for estimating transporter kinetics and recommendations on proper parameter calculation in various experimental systems. Rational interpretation of transporter-knockout animal findings and application of static and dynamic physiologically based modeling approaches for prediction of human transporter-mediated pharmacokinetics and drug drug interactions (DDIs) are presented. The objective is to provide appropriate guidance for the use of in vitro, in vivo, and modeling tools in translational transporter science. C1 [Zamek-Gliszczynski, M. J.] Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA. [Lee, C. A.] QPS DMPK Hepat Biosci, Res Triangle Pk, NC USA. [Poirier, A.] F Hoffmann La Roche & Co Ltd, Nonclin Drug Safety, Basel, Switzerland. [Bentz, J.] Drexel Univ, Dept Biol, Philadelphia, PA 19104 USA. [Chu, X.] Merck & Co Inc, Dept Pharmacokinet Pharmacodynam & Drug Metab, Rahway, NJ 07065 USA. [Ellens, H.] GlaxoSmithKline, Drug Metab & Pharmacokinet, King Of Prussia, PA USA. [Ishikawa, T.] RIKEN Yokohama Inst, Om Sci Ctr, Yokohama, Kanagawa, Japan. [Jamei, M.] Simcyp, Sheffield, S Yorkshire, England. [Kavass, J. C.] Abbott Labs, Expt Kinet & Anal, Abbott Pk, IL 60064 USA. [Nagar, S.; Korzekwa, K.] Temple Univ, Dept Pharmaceut Sci, Philadelphia, PA 19122 USA. [Pang, K. S.] Univ Toronto, Leslie Dan Fac Pharm, Toronto, ON M5S 1A1, Canada. [Swaan, P. W.] Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Taub, M. E.] Boehringer Ingelheim Pharmaceut Inc, Drug Metab & Pharmacokinet, Ridgefield, CT 06877 USA. [Zhao, P.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Galetin, A.] Univ Manchester, Sch Pharm & Pharmaceut Sci, Manchester, Lancs, England. RP Galetin, A (reprint author), Univ Manchester, Sch Pharm & Pharmaceut Sci, Manchester, Lancs, England. EM Aleksandra.Galetin@manchester.ac.uk RI Jamei, Masoud/H-6281-2013; OI Galetin, Aleksandra/0000-0002-3933-5217; Swaan, Peter/0000-0003-1767-1487 FU NIGMS NIH HHS [R01 GM104178] NR 75 TC 67 Z9 67 U1 1 U2 23 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD JUL PY 2013 VL 94 IS 1 BP 64 EP 79 DI 10.1038/clpt.2013.45 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 172TT UT WOS:000321028500014 PM 23588311 ER PT J AU Kalvass, JC Polli, JW Bourdet, DL Feng, B Huang, SM Liu, X Smith, QR Zhang, LK Zamek-Gliszczynski, MJ AF Kalvass, J. C. Polli, J. W. Bourdet, D. L. Feng, B. Huang, S-M Liu, X. Smith, Q. R. Zhang, L. K. Zamek-Gliszczynski, M. J. CA Int Transporter Consortium TI Why Clinical Modulation of Efflux Transport at the Human Blood-Brain Barrier Is Unlikely: The ITC Evidence-Based Position SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Review ID CANCER RESISTANCE PROTEIN; CENTRAL-NERVOUS-SYSTEM; CEREBROSPINAL-FLUID CONCENTRATION; P-GLYCOPROTEIN INHIBITION; MEDIATED DRUG TRANSPORT; IN-VITRO; SPECIES-DIFFERENCES; ENDOTHELIAL-CELLS; CF-1 MICE; VIVO AB Drug interactions due to efflux transport inhibition at the blood-brain barrier (BBB) have been receiving increasing scrutiny because of the theoretical possibility of adverse central nervous system (CNS) effects identified in preclinical studies. In this review, evidence from pharmacokinetic, pharmacodynamic, imaging, pharmacogenetic, and pharmacovigilance studies, along with drug safety reports, is presented supporting a low probability of modulating transporters at the human BBB by currently marketed drugs. C1 [Kalvass, J. C.] Abbott Labs, Expt Kinet & Anal, Abbott Pk, IL 60064 USA. [Polli, J. W.] GlaxoSmithKline Inc, Drug Metab & Pharmacokinet, Res Triangle Pk, NC USA. [Bourdet, D. L.] Theravance Inc, Drug Metab & Pharmacokinet, San Francisco, CA USA. [Feng, B.] Pfizer Inc, Pharmacokinet & Drug Metab, Groton, CT 06340 USA. [Huang, S-M] US FDA, Ctr Drug Evaluat & Res, Off Translat Sci, Off Clin Pharmacol, Silver Spring, MD USA. [Liu, X.] Genentech Inc, Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA. [Smith, Q. R.] Texas Tech Univ, Hlth Sci Ctr, Dept Pharmaceut Sci, Amarillo, TX USA. [Zhang, L. K.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Zamek-Gliszczynski, M. J.] Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Zamek-Gliszczynski, MJ (reprint author), Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA. EM m_zamek-gliszczynski@lilly.com NR 74 TC 72 Z9 73 U1 8 U2 30 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD JUL PY 2013 VL 94 IS 1 BP 80 EP 94 DI 10.1038/clpt.2013.34 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 172TT UT WOS:000321028500015 PM 23588303 ER PT J AU Tweedie, D Polli, JW Berglund, EG Huang, SM Zhang, L Poirier, A Chu, X Feng, B AF Tweedie, D. Polli, J. W. Berglund, E. Gil Huang, S. M. Zhang, L. Poirier, A. Chu, X. Feng, B. CA Int Transporter Consortium TI Transporter Studies in Drug Development: Experience to Date and Follow-Up on Decision Trees From the International Transporter Consortium SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Review ID P-GLYCOPROTEIN; CYCLOSPORINE-A; INHIBITION; STATINS; ACID; ATORVASTATIN; SIMVASTATIN; MYOPATHY AB The International Transporter Consortium (ITC) organized a second workshop in March 2012 to expand on the themes developed during the inaugural ITC workshop held in 2008. The final session of the workshop provided perspectives from regulatory and industry-based scientists, with input from academic scientists, and focused primarily on the decision trees published from the first workshop. These decision trees have become a central part of subsequent regulatory drug-drug interaction (DDI) guidances issued over the past few years. C1 [Tweedie, D.] Boehringer Ingelheim Pharmaceut Inc, Drug Metab & Pharmacokinet, Ridgefield, CT 06877 USA. [Polli, J. W.] GlaxoSmithKline, Drug Metab & Pharmacokinet, Res Triangle Pk, NC USA. [Berglund, E. Gil] Med Prod Agcy, Uppsala, Sweden. [Huang, S. M.; Zhang, L.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Poirier, A.] F Hoffmann La Roche & Co Ltd, Nonclin Safety, CH-4002 Basel, Switzerland. [Chu, X.] Merck & Co Inc, Dept Pharmacokinet Pharmacodynam & Drug Metab, Rahway, NJ 07065 USA. [Feng, B.] Pfizer Inc, Pharmacokinet & Drug Metab, Groton, CT 06340 USA. RP Tweedie, D (reprint author), Boehringer Ingelheim Pharmaceut Inc, Drug Metab & Pharmacokinet, 90 E Ridge POB 368, Ridgefield, CT 06877 USA. EM donald.tweedie@boehringer-ingelheim.com NR 42 TC 44 Z9 44 U1 4 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD JUL PY 2013 VL 94 IS 1 BP 113 EP 125 DI 10.1038/clpt.2013.77 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 172TT UT WOS:000321028500017 PM 23588318 ER PT J AU Chu, X Korzekwa, K Elsby, R Fenner, K Galetin, A Lai, Y Matsson, P Moss, A Nagar, S Rosania, GR Bai, JPF Polli, JW Sugiyama, Y Brouwer, KLR AF Chu, X. Korzekwa, K. Elsby, R. Fenner, K. Galetin, A. Lai, Y. Matsson, P. Moss, A. Nagar, S. Rosania, G. R. Bai, J. P. F. Polli, J. W. Sugiyama, Y. Brouwer, K. L. R. CA Int Transporter Consortium TI Intracellular Drug Concentrations and Transporters: Measurement, Modeling, and Implications for the Liver SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Review ID PHYSIOLOGICALLY-BASED PHARMACOKINETICS; LIPOPHILIC AMINE DRUGS; HEPATOBILIARY TRANSPORT; EFFLUX TRANSPORTERS; RAT HEPATOCYTES; P-GLYCOPROTEIN; HEPATIC-UPTAKE; CAPILLARY-ELECTROPHORESIS; ABCC2 MRP2; IN-VITRO AB Intracellular concentrations of drugs and metabolites are often important determinants of efficacy, toxicity, and drug interactions. Hepatic drug distribution can be affected by many factors, including physicochemical properties, uptake/efflux transporters, protein binding, organelle sequestration, and metabolism.This white paper highlights determinants of hepatocyte drug/metabolite concentrations and provides an update on model systems, methods, and modeling/simulation approaches used to quantitatively assess hepatocellular concentrations of molecules. The critical scientific gaps and future research directions in this field are discussed. C1 [Chu, X.] Merck & Co Inc, Dept Pharmacokinet Pharmacodynam & Drug Metab, Rahway, NJ 07065 USA. [Korzekwa, K.; Nagar, S.] Temple Univ, Sch Pharm, Dept Pharmaceut Sci, Philadelphia, PA 19122 USA. [Elsby, R.; Fenner, K.] AstraZeneca R&D Alderley Pk, Global DMPK, Macclesfield, Cheshire, England. [Galetin, A.] Univ Manchester, Sch Pharm & Pharmaceut Sci, Manchester, Lancs, England. [Lai, Y.] Pfizer Inc, Pharmacokinet Dynam & Metab, Groton, CT 06340 USA. [Matsson, P.] Uppsala Univ, Dept Pharm, Uppsala Univ Drug Optimizat & Pharmaceut Platform, Uppsala, Sweden. [Moss, A.] Seattle Genet Inc, Clin Pharmacol, Bothell, WA USA. [Rosania, G. R.] Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA. [Bai, J. P. F.] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Polli, J. W.] GlaxoSmithKline Inc, Drug Metab & Pharmacokinet, Res Triangle Pk, NC USA. [Sugiyama, Y.] RIKEN Res Cluster Innovat, RIKEN Innovat Ctr, Sugiyama Lab, Yokohama, Kanagawa, Japan. [Brouwer, K. L. R.] Univ N Carolina, Div Pharmacotherapy & Expt Therapeut, UNC Eshelman Sch Pharm, Chapel Hill, NC USA. RP Brouwer, KLR (reprint author), Merck & Co Inc, Dept Pharmacokinet Pharmacodynam & Drug Metab, Rahway, NJ 07065 USA. EM xiaoyan_chu@merck.com; korzekwa@temple.edu; kbrouwer@unc.edu OI Galetin, Aleksandra/0000-0002-3933-5217; Matsson, Par/0000-0002-9094-2581; Lai, Yurong /0000-0001-9505-333X FU National Institutes of Health from the National Institute of General Medical Sciences [R01GM41935, R01GM078200, R01GM104178] FX This work was supported, in part, by funding from the National Institutes of Health through award numbers R01GM41935 (K.L.R.B.), R01GM078200 (G.R.R.), and R01GM104178 (K.K. and S.N.) from the National Institute of General Medical Sciences. The content is solely the responsibility of the authors and the views expressed do not necessarily represent the position of, nor imply endorsement from, the National Institutes of Health, the US Food and Drug Administration, or the US government. NR 75 TC 81 Z9 81 U1 5 U2 55 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD JUL PY 2013 VL 94 IS 1 BP 126 EP 141 DI 10.1038/clpt.2013.78 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 172TT UT WOS:000321028500018 PM 23588320 ER PT J AU Behr, ER January, C Schulze-Bahr, E Grace, AA Kaab, S Fiszman, M Gathers, S Buckman, S Youssef, A Pirmohamed, M Roden, D AF Behr, Elijah R. January, Craig Schulze-Bahr, Eric Grace, Andrew A. Kaeaeb, Stefan Fiszman, Monica Gathers, Shaniece Buckman, ShaAvhree Youssef, Ashraf Pirmohamed, Munir Roden, Dan TI The International Serious Adverse Events Consortium (iSAEC) phenotype standardization project for drug-induced torsades de pointes SO EUROPEAN HEART JOURNAL LA English DT Article ID LONG-QT SYNDROME; CLINICAL-FEATURES; PROLONGATION; ARRHYTHMIA; QUINIDINE; INJURY; KCNE1; SCN5A; RISK; GENE C1 [Behr, Elijah R.] St Georges Univ London, Cardiovasc Res Ctr, London SW17 0RE, England. [January, Craig] Univ Wisconsin, Madison, WI USA. [Schulze-Bahr, Eric] Univ Hosp, Inst Genet Heart Dis, Dept Cardiol & Angiol, Munster, Germany. [Grace, Andrew A.] Univ Cambridge, Cambridge, England. [Kaeaeb, Stefan] Ludwig Maximilians Univ Hosp Munich, Dept Med 1, Munich, Germany. [Fiszman, Monica] US FDA, Div Cardiovasc & Renal Prod, CDER, Silver Spring, MD USA. [Gathers, Shaniece] US FDA, Off Translat Sci, CDER, Silver Spring, MD USA. [Buckman, ShaAvhree] US FDA, Silver Spring, MD USA. [Youssef, Ashraf] Takeda Global R&D Ctr, Deerfield, IL USA. [Pirmohamed, Munir] Univ Liverpool, Inst Translat Med, Liverpool L69 3BX, Merseyside, England. [Roden, Dan] Vanderbilt Univ, Med Ctr, Sch Med, Oates Inst Expt Therapeut, Nashville, TN 37232 USA. RP Behr, ER (reprint author), St Georges Univ London, Cardiovasc Res Ctr, London SW17 0RE, England. EM ebehr@sgul.ac.uk; dan.roden@vanderbilt.edu RI Pirmohamed, Munir/H-6004-2011 OI Pirmohamed, Munir/0000-0002-7534-7266 FU Abbott; Amgen; Astra-Zeneca; Daiichi-Sankyo; GSK; Merck; Novartis; Pfizer; Takeda; Wellcome Trust; International Serious Adverse Events Consortium; Biotronik; Boston Scientific FX We also thank other members of the working group who contributed to the manuscript, including Sarah Mee, Aidan Power, Peter Shaw, and Miriam Sturkenboom. Finally, we are indebted to the International Serious Adverse Events consortium (Isaec) and its member companies (Abbott, Amgen, Astra-Zeneca, Daiichi-Sankyo, GSK, Merck, Novartis, Pfizer, Takeda, and Wellcome Trust) for their funding and support of this work.; E.R.B. receives research and fellowship funds from the International Serious Adverse Events Consortium, Biotronik and Boston Scientific. C.J. is a cofounder of Cellular Dynamics International, Inc. D.R. is a consultant to Merck, Sanofi, Dai-ichi-Sankyo, and Vitae Pharmaceutical, and receives royalities for a patent to predict drug-induced arrhythmia. A.A.G. is a consultant for Xention Pharma Ltd. M.F., S.B., and S.G. are employed full time by the US Food and Drug Administration and have no financial interests to disclose. The views expressed are those of the authors and are not necessarily those of the FDA. M.P., S.K., and A.Y. have no financial conflicts to disclose. NR 23 TC 12 Z9 12 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD JUL PY 2013 VL 34 IS 26 BP 1958 EP 1963 DI 10.1093/eurheartj/ehs172 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 183QJ UT WOS:000321831900008 PM 22752616 ER PT J AU Pierson, JB Berridge, BR Brooks, MB Dreher, K Koerner, J Schultze, AE Sarazan, RD Valentin, JP Vargas, HM Pettit, SD AF Pierson, Jennifer B. Berridge, Brian R. Brooks, Marjory B. Dreher, Kevin Koerner, John Schultze, A. Eric Sarazan, R. Dustan Valentin, Jean-Pierre Vargas, Hugo M. Pettit, Syril D. TI A public-private consortium advances cardiac safety evaluation: Achievements of the HESI Cardiac Safety Technical Committee SO JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS LA English DT Article DE Animal models; Cardiac repolarization; Cardiac safety; Cardiac biomarkers; FDA; ILSI/HESI; Integrated risk assessment; Stem cells ID ENVIRONMENTAL SCIENCES INSTITUTE; TORSADES-DE-POINTES; MYOCARDIAL INJURY; RECOMMENDATIONS; TROPONINS; HEALTH; SERUM; OPPORTUNITIES; PROLONGATION; PHARMACOLOGY AB Introduction: The evaluation of cardiovascular side-effects is a critical element in the development of all new drugs and chemicals. Cardiac safety issues are a major cause of attrition and withdrawal due to adverse drug reactions (ADRs) in pharmaceutical drug development. Methods: The evolution of the HESI Technical Committee on Cardiac Safety from 2000-2013 is presented as an example of an effective international consortium of academic, government, and industry scientists working to improve cardiac safety. Results and Discussion: The HESI Technical Committee Working Groups facilitated the development of a variety of platforms for resource sharing and communication among experts that led to innovative strategies for improved drug safety. The positive impacts arising from these Working Groups are described in this article. (C) 2013 Elsevier Inc. All rights reserved. C1 [Pierson, Jennifer B.; Pettit, Syril D.] Hlth & Environm Sci Inst, Washington, DC 20005 USA. [Berridge, Brian R.] GlaxoSmithKline Res & Dev Ltd, Res Triangle Pk, NC 27709 USA. [Brooks, Marjory B.] Cornell Univ, Comparat Coagulat Sect, Dept Populat Med & Diagnost Sci, Ithaca, NY 14850 USA. [Dreher, Kevin] US EPA, Environm Publ Hlth Div, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Koerner, John] US FDA, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Schultze, A. Eric] Lilly Res Labs, Dept Pathol, Indianapolis, IN 46285 USA. [Sarazan, R. Dustan] DSI, St Paul, MN USA. [Valentin, Jean-Pierre] AstraZeneca, Global Safety Assessment, Macclesfield SK10 4TG, Cheshire, England. [Vargas, Hugo M.] Amgen Inc, Toxicol Sci, Thousand Oaks, CA 91320 USA. RP Pierson, JB (reprint author), Hlth & Environm Sci Inst, 1156 15th St Northwest,Suite 200, Washington, DC 20005 USA. NR 31 TC 9 Z9 9 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8719 EI 1873-488X J9 J PHARMACOL TOX MET JI J. Pharmacol. Toxicol. Methods PD JUL-AUG PY 2013 VL 68 IS 1 BP 7 EP 12 DI 10.1016/j.vascn.2013.03.008 PG 6 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 178IW UT WOS:000321442300176 PM 23567075 ER PT J AU Bairi, VG Bourdo, SE Moore, JA Schnackenberg, LK Berry, BC Biris, AS Viswanathan, T AF Bairi, Venu Gopal Bourdo, Shawn E. Moore, Joshua A. Schnackenberg, Laura K. Berry, Brian C. Biris, Alexandru S. Viswanathan, Tito TI Separation and spectroscopic/molecular weight analysis of crude and purified polyaniline(s) SO JOURNAL OF POLYMER RESEARCH LA English DT Article DE Polyaniline; Soxhlet extraction; Gel-Permeation chromatography; Nuclearmagnetic resonance spectroscopy; FT-IR spectroscopy; UV-Visible spectroscopy ID MOLECULAR-WEIGHT; ANILINE OLIGOMERS; OXIDATION; PERSULFATE; STATE AB Inherently conducting polymers have gained increased attention due to the many unique optoelectronic properties they exhibit. The properties of polymers vary depending on the purity, molecular weight distribution, and synthetic conditions; all of these are important for widespread use in many touted applications. These studies have been undertaken in order to separate the low molecular weight and high molecular weight fractions from the crude product. The results demonstrate an efficient separation of different molecular weights of polyaniline (PANI) by the soxhlet extraction procedure with a series of solvents (methanol, chloroform, tetrahydrofuran and benzyl alcohol). The purified products and extracts were characterized by gel permeation chromatography (GPC) to determine their molecular weight distributions. UV-visible, infrared, and nuclear magnetic resonance (NMR) spectroscopy were performed for structural analysis of the polyanilines. Low molecular weight polyanilines can promote the aggregation in polyaniline chains and increase the solubility of polyanilines. C1 [Bairi, Venu Gopal; Moore, Joshua A.; Berry, Brian C.; Viswanathan, Tito] Univ Arkansas, Dept Chem, Little Rock, AR 72204 USA. [Bourdo, Shawn E.; Biris, Alexandru S.] Univ Arkansas, Ctr Integrat Nanotechnol Sci, Little Rock, AR 72204 USA. [Schnackenberg, Laura K.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Bairi, VG (reprint author), Univ Arkansas, Dept Chem, 2801 S Univ Ave, Little Rock, AR 72204 USA. EM vxbairi@ualr.edu; txviswanatha@ualr.edu FU US Department of Energy [DE-FG36-06GO86072] FX US Department of Energy (Grant No. DE-FG36-06GO86072). NR 24 TC 2 Z9 2 U1 2 U2 32 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1022-9760 J9 J POLYM RES JI J. Polym. Res. PD JUL PY 2013 VL 20 IS 7 AR 193 DI 10.1007/s10965-013-0193-6 PG 8 WC Polymer Science SC Polymer Science GA 181KY UT WOS:000321667700021 ER PT J AU Calvo, MS Whiting, SJ AF Calvo, Mona S. Whiting, Susan J. TI Survey of current vitamin D food fortification practices in the United States and Canada SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article; Proceedings Paper CT 15th Vitamin D Workshop CY JUN 20-22, 2012 CL Houston, TX DE Vitamin D fortification; Vitamin D3; Cholecalciferol; Vitamin D2; Ergocalciferol AB Widespread poor vitamin D status in all age and gender groups in the United States (USA) and Canada increases the need for new food sources. Currently similar to 60% of the intake of vitamin D from foods is from fortified foods in these countries. Those groups in greatest need are consuming significantly lower amounts of commonly fortified foods such as milk. Both countries allow voluntary vitamin D fortification of some other foods, although in Canada this practice is only done on a case-by-case basis. Novel approaches to vitamin D fortification of food in both countries now include "bio-addition" in which food staples are fortified through the addition of another vitamin D-rich food to animal feed during production, or manipulation of food post-harvest or pre-processing. These bio-addition approaches provide a wider range of foods containing vitamin D, and thus appeal to differing preferences, cultures and possibly economic status. An example is the post-harvest exposure of edible mushrooms to ultraviolet light. However, further research into safety and efficacy of bio-addition needs to be established in different target populations. This article is part of a Special Issue entitled 'Vitamin D Workshop'. C1 [Calvo, Mona S.] US FDA, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, US Dept HHS, Laurel, MD 20708 USA. [Whiting, Susan J.] Univ Saskatchewan, Coll Pharm & Nutr, Saskatoon, SK S7N 5C9, Canada. RP Calvo, MS (reprint author), US FDA, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, US Dept HHS, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM mona.calvo@fda.hhs.gov NR 12 TC 19 Z9 20 U1 2 U2 42 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD JUL PY 2013 VL 136 SI SI BP 211 EP 213 DI 10.1016/j.jsbmb.2012.09.034 PG 3 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 177WJ UT WOS:000321405800043 PM 23104118 ER PT J AU Huo, ZM Summers, RM Paquerault, S Lo, J Hoffmeister, J Armato, SG Freedman, MT Lin, J Lo, SCB Petrick, N Sahiner, B Fryd, D Yoshida, H Chan, HP AF Huo, Zhimin Summers, Ronald M. Paquerault, Sophie Lo, Joseph Hoffmeister, Jeffrey Armato, Samuel G., III Freedman, Matthew T. Lin, Jesse Lo, Shih-Chung Ben Petrick, Nicholas Sahiner, Berkman Fryd, David Yoshida, Hiroyuki Chan, Heang-Ping TI Quality assurance and training procedures for computer-aided detection and diagnosis systems in clinical use SO MEDICAL PHYSICS LA English DT Article DE computer-aided diagnosis; computer-aided detection; quality assurance; user training ID CT COLONOGRAPHY; SCREENING MAMMOGRAPHY; CAD; METHODOLOGIES; PERFORMANCE AB Computer-aided detection/diagnosis (CAD) is increasingly used for decision support by clinicians for detection and interpretation of diseases. However, there are no quality assurance (QA) requirements for CAD in clinical use at present. QA of CAD is important so that end users can be made aware of changes in CAD performance both due to intentional or unintentional causes. In addition, end-user training is critical to prevent improper use of CAD, which could potentially result in lower overall clinical performance. Research on QA of CAD and user training are limited to date. The purpose of this paper is to bring attention to these issues, inform the readers of the opinions of the members of the American Association of Physicists in Medicine (AAPM) CAD subcommittee, and thus stimulate further discussion in the CAD community on these topics. The recommendations in this paper are intended to be work items for AAPM task groups that will be formed to address QA and user training issues on CAD in the future. The work items may serve as a framework for the discussion and eventual design of detailed QA and training procedures for physicists and users of CAD. Some of the recommendations are considered by the subcommittee to be reasonably easy and practical and can be implemented immediately by the end users; others are considered to be "best practice" approaches, which may require significant effort, additional tools, and proper training to implement. The eventual standardization of the requirements of QA procedures for CAD will have to be determined through consensus from members of the CAD community, and user training may require support of professional societies. It is expected that high-quality CAD and proper use of CAD could allow these systems to achieve their true potential, thus benefiting both the patients and the clinicians, and may bring about more widespread clinical use of CAD for many other diseases and applications. It is hoped that the awareness of the need for appropriate CAD QA and user training will stimulate new ideas and approaches for implementing such procedures efficiently and effectively as well as funding opportunities to fulfill such critical efforts. (C) 2013 American Association of Physicists in Medicine. C1 [Huo, Zhimin] Carestream Hlth Inc, Rochester, NY 14615 USA. [Summers, Ronald M.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Paquerault, Sophie; Petrick, Nicholas; Sahiner, Berkman] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Lo, Joseph] Duke Univ, Med Ctr, Durham, NC 27705 USA. [Hoffmeister, Jeffrey] ICAD Inc, Nashua, NH 03062 USA. [Armato, Samuel G., III] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. [Freedman, Matthew T.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Lin, Jesse] FUJIFILM Med Syst USA Inc, Stamford, CT 06902 USA. [Lo, Shih-Chung Ben] Georgetown Univ, Washington, DC 20057 USA. [Fryd, David] Riverain Med, Miamisburg, OH 45342 USA. [Yoshida, Hiroyuki] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Yoshida, Hiroyuki] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Chan, Heang-Ping] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. RP Chan, HP (reprint author), Univ Michigan, Dept Radiol, 1500 East Med Ctr Dr,MIB C477, Ann Arbor, MI 48109 USA. EM chanhp@umich.edu FU Intramural Research Program of the National Institutes of Health (NIH), Clinical Center; University of Chicago; Riverain Technologies through The University of Chicago; iCAD; Riverain Technologies through Georgetown University Medical Center FX The authors are grateful to the members and participants of the CADSC who have contributed to the stimulating discussions during many meetings and teleconferences. R.M.S. is supported by the Intramural Research Program of the National Institutes of Health (NIH), Clinical Center; the views expressed in this paper are the opinions of the authors and do not necessarily represent the views of the National Institutes of Health or Department of Health and Human Services. S. G. A. and H.Y. receive royalties and licensing fees through the University of Chicago related to CAD. S. G. A. receives research funding from Riverain Technologies through The University of Chicago. R.M.S. receives patent royalties and research support related to CAD from iCAD. M.T.F. and S.C.B.L. receive funding from Riverain Technologies through Georgetown University Medical Center. NR 14 TC 4 Z9 4 U1 1 U2 10 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUL PY 2013 VL 40 IS 7 AR 077001 DI 10.1118/1.4807642 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 175ZK UT WOS:000321272200059 PM 23822459 ER PT J AU Levi, MS Patton, RE Hanig, JP Tranter, KM George, NI James, LP Davis, KJ Bowyer, JF AF Levi, Mark S. Patton, Ralph E. Hanig, Joseph P. Tranter, Karen M. George, Nysia I. James, Laura P. Davis, Kelly J. Bowyer, John F. TI Serum myoglobin, but not lipopolysaccharides, is predictive of AMPH-induced striatal neurotoxicity SO NEUROTOXICOLOGY LA English DT Article DE Amphetamine; Neurotoxicity; Lipopolysaccharides; Muscle; Liver; Kidney ID METHAMPHETAMINE-INDUCED NEUROTOXICITY; MICROGLIAL ACTIVATION; INDUCED HYPERTHERMIA; HEAT-SHOCK; DOPAMINERGIC NEUROTOXICITY; SUBSTITUTED AMPHETAMINES; NEURONAL DEGENERATION; ENDOPLASMIC-RETICULUM; C57BL/6J MOUSE; MESSENGER-RNA AB Determinants of amphetamine (AMPH)-induced neurotoxicity are poorly understood. The role of lipopolysaccharides (LPS) and organ injury in AMPH-induced neurotoxicity was examined in adult male Sprague-Dawley rats that were give AMPH and became hyperthermic during the exposure. Environmentally-induced hyperthermia (EIH) in the rat was compared to AMPH to determine whether AMPH-induced increases in LPS and peripheral toxicities were solely attributable to hyperthermia. Muscle, liver, and kidney function were determined biochemically at 3 h or 1 day after AMPH or EIH exposure and histopathology at 1 day after treatment. Circulating levels of LPS were monitored (via limulus amoebocyte coagulation assay) during AMPH or EIH exposure. Blood LPS levels were detected in 40-50% of the AMPH and EIH rats, but the presence of LPS in the serum had no effect on organ damage or striatal dopamine depletions (neurotoxicity). In both CR and NCTR rats, serum bound urea nitrogen and creatinine levels increased at 3 h after EIH or AMPH (2- to 3-fold above control) but subsided by 1 day. Alanine transaminase was increased (indicating liver dysfunction) by both AMPH and EIH at 3 h (2- to 10-fold above control) in CR rats, but the levels were not significantly different between the control and AMPH groups in NCTR animals. Mild liver necrosis was detected in 1 of 7 rats examined in the AMPH group and in 1 of 5 rats examined in the EIH group (only NCTR rats were examined). Serum myoglobin increased (indicating muscle damage) in both CR and NCTR rats at 3 h and was more pronounced with AMPH (approximate to 5-fold above control) than ELM. Our results indicate that: (1) "free" blood borne LPS often increases with EIH and AMPH but may not be necessary for striatal neurotoxicity and CNS immune responses; (2) liver or kidney dysfunction may result from muscle damage; however, it is not sufficient nor necessary to produce, but may exacerbate, neurotoxicity; (3) AMPH-induced serum myoglobin release is a potential biomarker and possibly a factor in AMPH-induced toxicity processes. Published by Elsevier Inc. C1 [Levi, Mark S.; Bowyer, John F.] US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Jefferson, AR 72079 USA. [Patton, Ralph E.; Tranter, Karen M.; Davis, Kelly J.] US FDA, Natl Ctr Toxicol Res, Toxicol Pathol Associates, Jefferson, AR 72079 USA. [George, Nysia I.] US FDA, Natl Ctr Toxicol Res, Div Bioinformat & Biostat, Jefferson, AR 72079 USA. [Hanig, Joseph P.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [James, Laura P.] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72202 USA. [James, Laura P.] Arkansas Childrens Hosp Res Inst, Little Rock, AR 72202 USA. RP Bowyer, JF (reprint author), Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 132, Jefferson, AR 72079 USA. EM mark.levi@fda.hhs.gov; ralph.patton@fda.hhs.gov; joseph.hanig@fda.hhs.gov; karen.tranter@fda.hhs.gov; nysia.george@fda.hhs.gov; JamesLauraP@uams.edu; kelly.davis@fda.hhs.gov; john.bowyer@fda.hhs.gov NR 57 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD JUL PY 2013 VL 37 BP 40 EP 50 DI 10.1016/j.neuro.2013.04.003 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 177ZH UT WOS:000321413400006 PM 23608161 ER PT J AU Tyburczy, C Mossoba, MM Rader, JI AF Tyburczy, Cynthia Mossoba, Magdi M. Rader, Jeanne I. TI Determination of trans fat in edible oils: current official methods and overview of recent developments SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Review DE Trans fat; Edible oils; Attenuated total reflection; Fourier-transform infrared spectroscopy; Gas chromatography; Official methods of analysis ID ACID METHYL-ESTERS; MULTIDIMENSIONAL GAS-CHROMATOGRAPHY; VIRGIN OLIVE OIL; CP-SIL 88; INFRARED-SPECTROSCOPY; RAPID-DETERMINATION; STATIONARY PHASES; MASS-SPECTROMETRY; X GC; REGULATORY COMPLIANCE AB The adverse effects of dietary trans fat on biomarkers of chronic disease are well documented. Regulatory authorities in many countries have enacted legislation aimed at reducing trans fat content of their food supplies, either by requiring trans fat labeling on pre-packaged foods or by limiting the amount of trans fat in oils used for food production. Increased use by the food industry of oils with a low trans fat content necessitates reevaluation of official methods used by the food industry and regulatory agencies for the determination of total trans fat. Attenuated total reflection-Fourier-transform infrared (ATR-FTIR) spectroscopy and gas chromatography with flame ionization detection (GC-FID) are two techniques used in official methods approved by method-endorsing organizations, for example AOAC International and the American Oil Chemists' Society. Here, we review current official ATR-FTIR and GC-FID methods for determination of trans fat, with a focus on factors affecting quantification of low levels of trans fat. We include new data on method performance that have only recently become available, and provide an overview of notable recent developments in lipid analysis (e.g. IR spectroscopy procedures, ionic-liquid GC columns, and multidimensional chromatographic techniques) that have the potential to substantially improve the accuracy, sensitivity, and/or speed of trans fat determination. C1 [Tyburczy, Cynthia; Mossoba, Magdi M.; Rader, Jeanne I.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA. RP Tyburczy, C (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM cynthia.tyburczy@fda.hhs.gov NR 87 TC 1 Z9 2 U1 4 U2 90 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD JUL PY 2013 VL 405 IS 17 BP 5759 EP 5772 DI 10.1007/s00216-013-7005-z PG 14 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 173GD UT WOS:000321065500015 PM 23689347 ER PT J AU Martin, D Menschik, D Bryant-Genevier, M Ball, R AF Martin, David Menschik, David Bryant-Genevier, Marthe Ball, Robert TI Data Mining for Prospective Early Detection of Safety Signals in the Vaccine Adverse Event Reporting System (VAERS): A Case Study of Febrile Seizures after a 2010-2011 Seasonal Influenza Virus Vaccine SO DRUG SAFETY LA English DT Article ID LARGE FREQUENCY TABLES; STRATIFICATION; PHARMACOVIGILANCE; SURVEILLANCE; DRUGS AB Background Reports of data mining results as an initial indication of a prospectively detected safety signal in the US Vaccine Adverse Event Reporting System (VAERS) have been limited. In April 2010 a vaccine safety signal for febrile seizures after Fluvax((R)) and Fluvax((R)) Junior was identified in Australia without the aid of data mining. In order to refine Northern Hemisphere influenza vaccine safety surveillance, VAERS data mining analyses based on vaccine brand name were initiated during the 2010-2011 influenza season. Objective We describe the strategies that led to the finding of a novel safety signal using empirical Bayesian data mining. Methods The primary US VAERS analysis calculated an empirical Bayesian geometric mean (EBGM), which was adjusted for age group, sex and year received. A secondary age-stratified analysis calculated a separate EBGM for 11 pre-defined age subsets. These bi-weekly analyses were generated with database restrictions that separated live and inactivated vaccines as well as with the US VAERS database. A cutoff of 2.0 at the fifth percentile of the confidence interval (CI) for the EBGM, the EB05, was used to identify vaccine adverse event combinations for further evaluation. Examination of potential interactions among concomitantly administered vaccines is based on the Interaction Signal Score (INTSS), which is a relative measure of how much excess disproportionality is present in the three-dimensional combination of two vaccines and one adverse event term. An INTSS > 1 indicates that the CI for the three-dimensional analysis is larger than and does not overlap with the CI from the highest two-dimensional analysis. We subsequently examined the possibility of masking by removing all 2,095 Fluzone((R)) (2010-2011) reports from the 10 December 2010 version of the VAERS database. In addition, we calculated relative reporting ratios to observe the relative contribution of adjustment and the Multi-Item Gamma Poisson Shrinker (MGPS) algorithm to EBGM values. Results On 10 December 2010, US VAERS analyses we found an EB05 > 2 for Fluzone((R)) (2010-2011) and the Medical Dictionary for Regulatory Activities (MedDRA((R))) term "febrile seizure". MedDRA((R)) terminology is the medical terminology developed under the auspices of the International Conference on Harmonization of technical requirements for Registration of Pharmaceuticals for Human Use (ICH). No other vaccine products had independent vaccine-febrile seizure combinations with an EB05 > 2. Three-dimensional analyses to examine possible interactions among vaccine products concomitantly administered with Fluzone((R)) (2010-2011) yielded Interaction Signal Score values < 1. Removal of all Fluzone((R)) (2010-2011) reports from the VAERS database failed to demonstrate a previously masked vaccine adverse event pair with an EB05 > 2. The inactivated vaccine database restriction resulted in a 41 % reduction in background VAERS reports and a 24 % reduction in foreground VAERS reports. Conclusion Empirical Bayesian data mining in VAERS prospectively detected the safety signal for febrile seizures after Fluzone((R)) (2010-2011) in young children. The EB05 threshold, database restrictions, adjustment and baseline data mining were strategies adopted a priori to enhance the specificity of the 2010-2011 influenza vaccine data mining analyses. A database restriction used to separate live vaccines resulted in a reduced EB05. Adjustment of data mining analyses had a larger effect on estimates of disproportionality than the MGPS algorithm. Masking did not appear to influence our findings. This case study illustrates the value of VAERS data mining for vaccine safety monitoring. C1 [Martin, David; Menschik, David; Bryant-Genevier, Marthe; Ball, Robert] FDA Ctr Biol Evaluat & Res, Off Biostat & Epidemiol, Rockville, MD 20852 USA. RP Martin, D (reprint author), FDA Ctr Biol Evaluat & Res, Off Biostat & Epidemiol, WOC1 Bldg,Room 455S,1401 Rockville Pike, Rockville, MD 20852 USA. EM David.Martin@fda.hhs.gov NR 32 TC 16 Z9 16 U1 1 U2 11 PU ADIS INT LTD PI AUCKLAND PA 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 1311, NEW ZEALAND SN 0114-5916 J9 DRUG SAFETY JI Drug Saf. PD JUL PY 2013 VL 36 IS 7 BP 547 EP 556 DI 10.1007/s40264-013-0051-9 PG 10 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA 170VX UT WOS:000320884000006 PM 23657824 ER PT J AU Botsis, T Woo, EJ Ball, R AF Botsis, Taxiarchis Woo, Emily Jane Ball, Robert TI Application of Information Retrieval Approaches to Case Classification in the Vaccine Adverse Event Reporting System SO DRUG SAFETY LA English DT Article ID IMMUNIZATION SAFETY DATA; MEDDRA; SIMILARITY; GUIDELINES; COLLECTION; FEATURES AB Background Automating the classification of adverse event reports is an important step to improve the efficiency of vaccine safety surveillance. Previously we showed it was possible to classify reports using features extracted from the text of the reports. Objective The aim of this study was to use the information encoded in the Medical Dictionary for Regulatory Activities (MedDRA((R))) in the US Vaccine Adverse Event Reporting System (VAERS) to support and evaluate two classification approaches: a multiple information retrieval strategy and a rule-based approach. To evaluate the performance of these approaches, we selected the conditions of anaphylaxis and Guillain-Barr, syndrome (GBS). Methods We used MedDRA((R)) Preferred Terms stored in the VAERS, and two standardized medical terminologies: the Brighton Collaboration (BC) case definitions and Standardized MedDRA((R)) Queries (SMQ) to classify two sets of reports for GBS and anaphylaxis. Two approaches were used: (i) the rule-based instruments that are available by the two terminologies (the Automatic Brighton Classification [ABC] tool and the SMQ algorithms); and (ii) the vector space model. Results We found that the rule-based instruments, particularly the SMQ algorithms, achieved a high degree of specificity; however, there was a cost in terms of sensitivity in all but the narrow GBS SMQ algorithm that outperformed the remaining approaches (sensitivity in the testing set was equal to 99.06 % for this algorithm vs. 93.40 % for the vector space model). In the case of anaphylaxis, the vector space model achieved higher sensitivity compared with the best values of both the ABC tool and the SMQ algorithms in the testing set (86.44 % vs. 64.11 % and 52.54 %, respectively). Conclusions Our results showed the superiority of the vector space model over the existing rule-based approaches irrespective of the standardized medical knowledge represented by either the SMQ or the BC case definition. The vector space model might make automation of case definitions for spontaneous report review more efficient than current rule-based approaches, allowing more time for critical assessment and decision making by pharmacovigilance experts. C1 [Botsis, Taxiarchis; Woo, Emily Jane; Ball, Robert] US FDA, Off Biostat & Epidemiol, CBER, Rockville, MD 20852 USA. [Botsis, Taxiarchis] Univ Tromso, Dept Comp Sci, Tromso, Norway. RP Botsis, T (reprint author), US FDA, Off Biostat & Epidemiol, CBER, Woodmont Off Complex 1,Rm 306N,1401 Rockville Pik, Rockville, MD 20852 USA. EM Taxiarchis.Botsis@fda.hhs.gov FU Taxiarchis Botsis FX This project was supported in part by the appointment of Taxiarchis Botsis to the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US FDA. NR 20 TC 4 Z9 4 U1 0 U2 2 PU ADIS INT LTD PI AUCKLAND PA 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 1311, NEW ZEALAND SN 0114-5916 J9 DRUG SAFETY JI Drug Saf. PD JUL PY 2013 VL 36 IS 7 BP 573 EP 582 DI 10.1007/s40264-013-0064-4 PG 10 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA 170VX UT WOS:000320884000009 PM 23703591 ER PT J AU Valerio, LG Balakrishnan, S Fiszman, ML Kozeli, D Li, M Moghaddam, S Sadrieh, N AF Valerio, Luis G., Jr. Balakrishnan, Suchitra Fiszman, Monica L. Kozeli, Devi Li, Mike Moghaddam, Sarvin Sadrieh, Nakissa TI Development of cardiac safety translational tools for QT prolongation and torsade de pointes SO EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY LA English DT Review DE cardiac safety; drug safety; in silico; QT prolongation; torsade de pointes ID VALIDATION; AGREEMENT; MODEL AB Objective: A regulatory science priority at the Food and Drug Administration (FDA) is to promote the development of new innovative tools such as reliable and validated computational (in silico) models. This FDA Critical Path Initiative project involved the development of predictive clinical computational models for decision-support in CDER evaluations of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. Methods: Several classification models were built using predictive technologies of quantitative structure-activity relationship analysis using clinical in-house and public data on induction of QT prolongation and torsade de pointes (TdP) in humans. Specific models were geared toward prediction of high-risk drugs with attention to outcomes from thorough QT studies and TdP risk based on clinical in-house data. Models used were independent of non-clinical data or known molecular mechanisms. The positive predictive performance of the in silico models was validated using cross-validation and independent external validation test sets. Results: Optimal performance was observed with high sensitivity (87%) and high specificity (88%) for predicting QT interval prolongation using in-house data, and 77% sensitivity in predicting drugs withdrawn from the market. Furthermore, the article describes alerting substructural features based on drugs tested in the clinical trials. Conclusions: The in silico models provide evidence of a structure-based explanation for these cardiac safety endpoints. The models will be made publically available and are under continual prospective external validation testing and updating at CDER using TQT study outcomes. C1 [Valerio, Luis G., Jr.; Moghaddam, Sarvin; Sadrieh, Nakissa] US FDA, Off New Drugs, Div Metab & Endocrinol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. [Balakrishnan, Suchitra; Fiszman, Monica L.; Kozeli, Devi] US FDA, Off New Drugs, Div Cardiovasc & Renal Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. RP Valerio, LG (reprint author), US FDA, Off New Drugs, Div Metab & Endocrinol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. EM luis.valerio@fda.hhs.gov FU FDA Critical Path Initiative; ORISE Research Participation Program at the Center for Drug Evaluation and Research FX The authors are all employees of the FDA. The FDA has non-financial Research Collaboration Agreements with the Prous Institute for Biomedical Research (Barcelona, Spain), and Leadscope, Inc. (Columbus, OH). This study was supported by intramural funding from the FDA Critical Path Initiative. This project was supported in part by an appointment to the ORISE Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an agreement between the U.S. Department of Energy and CDER. NR 23 TC 5 Z9 5 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1742-5255 EI 1744-7607 J9 EXPERT OPIN DRUG MET JI Expert Opin. Drug Metab. Toxicol. PD JUL PY 2013 VL 9 IS 7 BP 801 EP 815 DI 10.1517/17425255.2013.783819 PG 15 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 164ZA UT WOS:000320450600001 PM 23537164 ER PT J AU Lawler, TS Stanfill, SB Zhang, LQ Ashley, DL Watson, CH AF Lawler, Tameka S. Stanfill, Stephen B. Zhang, Liqin Ashley, David L. Watson, Clifford H. TI Chemical characterization of domestic oral tobacco products: Total nicotine, pH, unprotonated nicotine and tobacco-specific N-nitrosamines SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Oral tobacco; Smokeless tobacco; Nicotine; Unprotonated Nicotine; pH; Tobacco-specific N-nitrosamines ID SMOKELESS TOBACCO; MOIST SNUFF; MASS-SPECTROMETRY; SURVEILLANCE AB In the United States, moist snuff has been studied more widely than other distinct categories of oral tobacco. In this study, we measured pH, moisture, nicotine (total and unprotonated), and tobacco-specific N-nitrosamines (TSNAs) for other established (twist, loose leaf, plug, and dry snuff without pouch) and emerging oral tobacco products (dry snuff pouch, US-made snus, and dissolvable tobacco). Among the seven product categories, product pH ranged from 4.7 to 7.9, and total nicotine concentration spanned from 3.9 to 40.1 mg/g. The most readily absorbable form of nicotine (unprotonated nicotine) varied more than 350-fold, ranging from 0.01 to 3.7 mg/g. While the highest total nicotine concentrations were observed in twist products, snus and dissolvable tobacco had the highest unprotonated nicotine levels. Among all products, total TSNA concentrations ranged from 313 to 76,500 ng/g with dry snuff having the highest total TSNA concentrations. This study demonstrates the diversity among oral tobacco products and highlights the potential of these products to deliver a wide range of nicotine and carcinogenic TSNAs. Characterizing the chemical content of these products may be helpful in further understanding the risk of marketing these products to oral tobacco users and smokers as an alternative and discrete form of tobacco. Published by Elsevier Ltd. C1 [Lawler, Tameka S.; Stanfill, Stephen B.; Zhang, Liqin; Watson, Clifford H.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Div Sci Lab, Tobacco & Volatiles Branch, Atlanta, GA 30341 USA. [Ashley, David L.] Off Sci, Ctr Tobacco Prod, Food & Drug Adm, Rockville, MD USA. RP Lawler, TS (reprint author), Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, 4770 Buford Highway NE,MS F-55, Atlanta, GA 30341 USA. EM tlawler@cdc.gov FU Centers for Disease Control and Prevention (CDC) FX The authors report no conflicts of interest. All research was supported by internal funds of the Centers for Disease Control and Prevention (CDC). Use of trade names is for identification only and does not imply endorsement by the Centers for Disease Control and Prevention or by the US Department of Health and Human Services. The findings and conclusions in this report are those of the author(s) and do not necessarily represent the views of the Centers for Disease Control and Prevention. NR 34 TC 17 Z9 17 U1 6 U2 50 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD JUL PY 2013 VL 57 BP 380 EP 386 DI 10.1016/j.fct.2013.03.011 PG 7 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA 165QL UT WOS:000320498300047 PM 23517910 ER PT J AU Lai, J Wang, Y Shen, JZ Li, RC Han, J Foley, SL Wu, CM AF Lai, Jing Wang, Yang Shen, Jianzhong Li, Ruichao Han, Jing Foley, Steven L. Wu, Congming TI Unique Class 1 Integron and Multiple Resistance Genes Co-located on IncHI2 Plasmid Is Associated with the Emerging Multidrug Resistance of Salmonella Indiana Isolated from Chicken in China SO FOODBORNE PATHOGENS AND DISEASE LA English DT Article ID FIELD GEL-ELECTROPHORESIS; SPECTRUM BETA-LACTAMASES; ANTIMICROBIAL RESISTANCE; ESCHERICHIA-COLI; PREVALENCE; SUSCEPTIBILITY; OUTBREAK; FOOD AB The objective of this study was to clarify the molecular antimicrobial resistance mechanisms of Salmonella enterica serovar Indiana isolated from chickens in China. A total of 327 chicken intestinal content and feces were collected in Shandong, China in 2009. Isolates were serotyped and antimicrobial susceptibility testing was performed. Thirty-five (10.7%) Salmonella isolates were recovered, and 16 (45.7%) were Salmonella enterica serovar Indiana, which were resistant to at least 14 of 15 antimicrobial agents. The 16 Salmonella enterica serovar Indiana detected and other 13 Salmonella enterica serovar Indiana that were selected from 133 Salmonella enterica serovar Indiana isolated in 2008 were subjected to pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Then class 1 integron and drug resistance genes were detected by polymerase chain reaction. Linkage between plasmids and resistance components was determined by conjugation, electrotransformation, S1 nuclease-PFGE, polymerase chain reaction-based replicon typing and Southern blot assays. Regions flanking integrons were sequenced by modified random primer walking strategy. PFGE and MLST suggested that all the 29 Salmonella enterica serovar Indiana isolates that shared >78% similarity in PFGE patterns were of the same MLST type, ST17. Two kinds of class 1 integrons had different integrase genes and the same variable region (dfrA7/aadA4/IS26/aac(6')-Ib/bla(OXA-1)/catB3/arr-3), and additional antimicrobial resistance genes such as bla(CTX-M-24), floR, and so on were detected on IncHI2 plasmids in 29 Salmonella enterica serovar Indiana, and seven plasmids were conjugative. Analysis of the genetic environment of the integrons suggested that these integrons might have been formed by the help of IS26. To our knowledge, the variable region in class 1 integrons is the longest reported in Salmonella to date. The unique integrons and multiple resistance genes co-located on the IncHI2 plasmid contributed to the dissemination of multidrug resistance. C1 [Lai, Jing; Wang, Yang; Shen, Jianzhong; Li, Ruichao; Wu, Congming] China Agr Univ, Coll Vet Med, Beijing Key Lab Detect Technol Anim Derived Food, Beijing 100193, Peoples R China. [Han, Jing; Foley, Steven L.] US FDA, Div Microbiol, Natl Ctr Toxicol Res, Jefferson, AR USA. RP Wu, CM (reprint author), China Agr Univ, Coll Vet Med, Beijing Key Lab Detect Technol Anim Derived Food, Beijing 100193, Peoples R China. EM wucm@cau.edu.cn RI chen, zhu/K-5923-2013; li, ruichao/E-5132-2015 OI li, ruichao/0000-0001-8333-9891 FU National Natural Science Foundation of China [30972216]; National Science and Technology Pillar Program [2012BAK01B02]; Exclusive Research Foundation for Public Welfare from Ministry of Agriculture of People's Republic of China [201203040] FX The authors are grateful to Prof. Yuqing Liu (Shandong Academy of Agricultural Sciences, Ji'nan, P. R. China) for helping with sample collection, and Prof. Minggui Wang (Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China) and Prof. G.A. Jacoby for kindly providing the reference strain E. coli J53AzR. This work was supported by National Natural Science Foundation of China (30972216), National Science and Technology Pillar Program (2012BAK01B02), and Exclusive Research Foundation for Public Welfare from Ministry of Agriculture of People's Republic of China (201203040). NR 25 TC 11 Z9 11 U1 0 U2 14 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1535-3141 J9 FOODBORNE PATHOG DIS JI Foodborne Pathog. Dis. PD JUL PY 2013 VL 10 IS 7 BP 581 EP 588 DI 10.1089/fpd.2012.1455 PG 8 WC Food Science & Technology SC Food Science & Technology GA 169GN UT WOS:000320767900001 PM 23672474 ER PT J AU Zaslavsky, BG AF Zaslavsky, Boris G. TI Bayesian design and analysis of composite endpoints in clinical trials with multiple dependent binary outcomes SO PHARMACEUTICAL STATISTICS LA English DT Article DE Bayesian analysis; composite endpoints; Dirichlet distribution; hypotheses testing; noninferiority ID RANDOMIZED-TRIALS; ISSUES; TESTS; SELECTION AB The author considers studies with multiple dependent primary endpoints. Testing hypotheses with multiple primary endpoints may require unmanageably large populations. Composite endpoints consisting of several binary events may be used to reduce a trial to a manageable size. The primary difficulties with composite endpoints are that different endpoints may have different clinical importance and that higher-frequency variables may overwhelm effects of smaller, but equally important, primary outcomes. To compensate for these inconsistencies, we weight each type of event, and the total number of weighted events is counted. To reflect the mutual dependency of primary endpoints and to make the weighting method effective in small clinical trials, we use the Bayesian approach. We assume a multinomial distribution of multiple endpoints with Dirichlet priors and apply the Bayesian test of noninferiority to the calculation of weighting parameters. We use composite endpoints to test hypotheses of superiority in single-arm and two-arm clinical trials. The composite endpoints have a beta distribution. We illustrate this technique with an example. The results provide a statistical procedure for creating composite endpoints. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. C1 US FDA, CBER, Rockville, MD 20857 USA. RP Zaslavsky, BG (reprint author), US FDA, CBER, Rockville, MD 20857 USA. EM boris.zaslavsky@fda.hhs.gov NR 20 TC 1 Z9 1 U1 3 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1539-1604 J9 PHARM STAT JI Pharm. Stat. PD JUL PY 2013 VL 12 IS 4 BP 207 EP 212 DI 10.1002/pst.1572 PG 6 WC Pharmacology & Pharmacy; Statistics & Probability SC Pharmacology & Pharmacy; Mathematics GA 178GG UT WOS:000321432800004 PM 23625660 ER PT J AU Abbey, CK Samuelson, FW Gallas, BD AF Abbey, Craig K. Samuelson, Frank W. Gallas, Brandon D. TI Statistical Power Considerations for a Utility Endpoint in Observer Performance Studies SO ACADEMIC RADIOLOGY LA English DT Article DE Utility; statistical power; observer performance endpoints ID CONTAMINATED BINORMAL MODEL; OPERATING CHARACTERISTIC CURVES; ROC ANALYSIS; DECISION-MAKING; MULTIREADER ROC; AREA; METHODOLOGY; MAMMOGRAPHY; POPULATION; SIMULATION AB Rationale and Objectives: The purpose of this investigation is to compare the statistical power of the most common measure of performance for observer performance studies, area under the ROC curve (AUC), to an expected utility (EU) endpoint. Materials and Methods: We have modified a well-known simulation procedure developed by Roe and Metz for statistical power analysis in receiver operating characteristic (ROC) studies. Starting from a set of baseline simulations, we investigate the effects of three parameters that describe properties of the observers (iso-utility slope, unequal variance, and tendency to favor more aggressive or conservative actions) and three parameters that affect experimental design (number of readers, number of cases, and fraction of positive cases). Results: The EU endpoint generally has good statistical power relative to AUC in our simulations. Of 396 total conditions simulated, EU had higher statistical power in 377 cases (95%). In 246 of these cases, EU power was 5 percentage points or more higher than AUC. In simulation runs evaluating the effect of the number of readers and cases on the baseline simulations, EU measure had equivalent power to AUC with fewer readers (9% to 28%) or fewer cases (18% to 41%). Conclusion: These simulation studies provide further motivation for considering EU in studies of screening mammography technology and they motivate investigations of utility in other diagnostic tasks. C1 [Abbey, Craig K.] Univ Calif Santa Barbara, Dept Psychol & Brain Sci, Santa Barbara, CA 93106 USA. [Abbey, Craig K.] UC Davis Med Ctr, Dept Radiol, Sacramento, CA USA. [Samuelson, Frank W.; Gallas, Brandon D.] US FDA, Div Imaging & Appl Math, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Abbey, CK (reprint author), Univ Calif Santa Barbara, Dept Psychol & Brain Sci, Santa Barbara, CA 93106 USA. EM abbey@psych.ucsb.edu OI Gallas, Brandon/0000-0001-7332-1620 NR 36 TC 3 Z9 3 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD JUL PY 2013 VL 20 IS 7 BP 798 EP 806 DI 10.1016/j.acra.2013.02.008 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 168YT UT WOS:000320744600002 PM 23611439 ER PT J AU Samuelson, FW AF Samuelson, Frank W. TI Inference Based on Diagnostic Measures from Studies of New Imaging Devices SO ACADEMIC RADIOLOGY LA English DT Article DE Diagnostic imaging; ROC analysis; clinical utility ID COMPUTER-AIDED DETECTION; SCREENING MAMMOGRAPHY; DECISION-MAKING; PERFORMANCE BENCHMARKS; LABORATORY ENVIRONMENT; OBSERVER PERFORMANCE; CANCER-DETECTION; PREVALENCE; VARIABILITY; TASKS AB Rationale and Objectives: Before using a new diagnostic imaging device regularly in a clinic, it should be studied using patients and radiologists. Often such studies report diagnostic performance in terms of sensitivity, specificity, area under the receiver operating characteristic curve (AUC), or differences thereof. In this report we look at how these studies differ from actual future clinical practice and how those differences may affect reported performance measures. Materials and Methods: We review signal detection (receiver operating characteristic) theory and decision theory. We compare diagnostic measures from several published studies in medical imaging and examine how they relate to theory and each other. Results: We see that clinical decisions can be modeled using signal detection and decision theories. Sensitivity and specificity are inextricably linked with clinical factors, such as prevalence and costs. Imaging devices are used in many different ways in clinical practice, so that sensitivities, specificities, and AUCs measured in studies of new diagnostic imaging devices will differ from those in actual future clinical use. Conclusions: Measured sensitivities, specificities, and the directions of changes thereof are not necessarily consistent or reproducible across studies of new diagnostic devices. A change in the AUC, which should be independent of clinical costs or prevalence, is a consistent measure across similar studies, and a positive change in AUC is indicative of additional diagnostic information that will be available to radiologists in a future clinical environment. C1 US FDA, Silver Spring, MD 20993 USA. RP Samuelson, FW (reprint author), US FDA, 10903 New Hampshire Ave,Bldg 62,Room 3102, Silver Spring, MD 20993 USA. EM frank.samuelson@fda.hhs.gov NR 49 TC 2 Z9 2 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD JUL PY 2013 VL 20 IS 7 BP 816 EP 824 DI 10.1016/j.acra.2013.03.002 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 168YT UT WOS:000320744600004 PM 23643364 ER PT J AU Tang, LL Kang, L Liu, CL Schisterman, EF Liu, AY AF Tang, Liansheng Larry Kang, Le Liu, Chunling Schisterman, Enrique F. Liu, Aiyi TI An Additive Selection of Markers to Improve Diagnostic Accuracy Based on a Discriminatory Measure SO ACADEMIC RADIOLOGY LA English DT Article DE Receiver operating characteristic (ROC); area under the ROC curves (AUC); discriminatory score; Box-Cox transformation ID OPERATING CHARACTERISTIC CURVES; MAXIMUM-LIKELIHOOD-ESTIMATION; CHARACTERISTIC ROC CURVES; STATISTICAL VALIDATION; MODEL; AREAS AB Rationale and Objectives: The estimation of the area under the receiver operating characteristic (ROC) curve (AUC) often relies on the assumption that the truly positive population tends to have higher marker results than the truly negative population. The authors propose a discriminatory measure to relax such an assumption and apply the measure to identify the appropriate set of markers for combination. Materials and Methods: The proposed measure is based on the maximum of the AUC and 1-AUC. The existing methods are applied to estimate the measure. The subset of markers is selected using a combination method that maximizes a function of the proposed discriminatory score with the number of markers as a penalty in the function. Results: The properties of the estimators for the proposed measure were studied through large-scale simulation studies. The application was illustrated through a real example to identify the set of markers to combine. Conclusion: Simulation results showed excellent small-sample performance of the estimators for the proposed measure. The application in the example yielded a reasonable subset of markers for combination. C1 [Tang, Liansheng Larry] George Mason Univ, Dept Stat, Fairfax, VA 22030 USA. [Kang, Le] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Liu, Chunling] Hong Kong Polytech Univ, Dept Appl Math, Hong Kong, Hong Kong, Peoples R China. [Schisterman, Enrique F.; Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. RP Liu, AY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd, Bethesda, MD USA. EM liua@mail.nih.gov RI Liu, Chunling/A-4827-2015; OI Liu, Chunling/0000-0003-3410-445X; Liu, Aiyi/0000-0002-6618-5082; Schisterman, Enrique/0000-0003-3757-641X FU Intramural NIH HHS [ZIA HD008875-01] NR 33 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD JUL PY 2013 VL 20 IS 7 BP 854 EP 862 DI 10.1016/j.acra.2013.02.009 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 168YT UT WOS:000320744600009 PM 23611438 ER PT J AU Deng, XH Wagner, HJ Popper, AN AF Deng, Xiaohong Wagner, Hans-Joachim Popper, Arthur N. TI Interspecific Variations of Inner Ear Structure in the Deep-Sea Fish Family Melamphaidae SO ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY LA English DT Article DE Melamphaes; Poromitra; Scopelogadus; saccule; utricle; otolith; hair bundle; inner ear ID HAIR-CELLS; BRAIN-AREAS; MORPHOLOGY; SACCULUS; VISION; LAGENA; DIVERSIFICATION; SENSITIVITY; PHYSIOLOGY; TELEOSTEI AB Inner ear structures are compared among three major genera of the deep-sea fish family Melamphaidae (bigscales and ridgeheads). Substantial interspecific variation is found in the saccular otoliths, including the presence of a unique otolithic spur in the genera Melamphaes and Poromitra. The variation in the saccular otolith is correlated with an increase in the number of hair bundle orientation groups on the sensory epithelia from the genera Scopelogadus to Poromitra to Melamphaes. The diverse structural variations found in the saccule may reflect the evolutionary history of these species. The sensory hair cell bundles in this family have the most variable shapes yet encountered in fish ears. In the saccule, most of the hair bundles are 15-20 m high, an exceptional height for fish otolithic end organs. These bundles have large numbers of stereovilli, including some that reach the length of the kinocilium. In the utricle, the striolar region separates into two unusually shaped areas that have not been described in any other vertebrates. The brains in all species have a relatively small olfactory bulb and optic tectum, as well as an enlarged posterior cerebellar region that is likely to be involved in inner ear and lateral line (octavolateral) functions. Data from melamphaids support the hypothesis that specialized anatomical structures are found in the ears of some (if not most) deep-sea fishes, presumably enhancing their hearing sensitivity. Anat Rec, 296:1064-1082, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Deng, Xiaohong; Popper, Arthur N.] Univ Maryland, Neurosci & Cognit Sci Program, Ctr Comparat & Evolutionary Biol Hearing, Dept Biol, College Pk, MD 20742 USA. [Wagner, Hans-Joachim] Univ Tubingen, Fak Med, Inst Anat, D-72074 Tubingen, Germany. RP Deng, XH (reprint author), US FDA, CBER, 29 Lincoln Dr,Bldg 29A,Room 3D08, Bethesda, MD 20892 USA. EM xiaohongdeng@gmail.com FU German Ministry of Education and Research (BMBF) [03G0173B]; National Institute on Deafness and Other Communication Disorders (NIDCD) of the National Institutes of Health [P-30 grant 2 P30 DC004664] FX Grant sponsor: Hans-Joachim Wagner by the German Ministry of Education and Research (BMBF); Grant number: 03G0173B. Grant sponsor: Arthur N. Popper by National Institute on Deafness and Other Communication Disorders (NIDCD) of the National Institutes of Health; Grant number: P-30 grant 2 P30 DC004664. NR 74 TC 11 Z9 11 U1 0 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-8486 J9 ANAT REC JI Anat. Rec. PD JUL PY 2013 VL 296 IS 7 BP 1064 EP 1082 DI 10.1002/ar.22703 PG 19 WC Anatomy & Morphology SC Anatomy & Morphology GA 164DM UT WOS:000320389100008 PM 23625740 ER PT J AU Gokhale, A Kanthala, S Latendresse, J Taneja, V Satyanarayanajois, S AF Gokhale, Ameya Kanthala, Shanthi Latendresse, John Taneja, Veena Satyanarayanajois, Seetharama TI Immunosuppression by Co-stimulatory Molecules: Inhibition of CD2-CD48/CD58 Interaction by Peptides from CD2 to Suppress Progression of Collagen-induced Arthritis in Mice SO CHEMICAL BIOLOGY & DRUG DESIGN LA English DT Article DE CD2; CD58; collagen-induced arthritis; cyclic peptide; docking; immune response; protein-protein interaction ID ANTIBODY-INDUCED ARTHRITIS; CELL-ADHESION MOLECULES; ALLERGIC AIRWAY DISEASE; RHEUMATOID-ARTHRITIS; T-CELLS; AUTOIMMUNE-DISEASES; PROTEIN; ACTIVATION; BLOCKADE; MODEL AB Targeting co-stimulatory molecules to modulate the immune response has been shown to have useful therapeutic effects for autoimmune diseases. Among the co-stimulatory molecules, CD2 and CD58 are very important in the early stages of generation of an immune response. Our goal was to utilize CD2-derived peptides to modulate protein-protein interactions between CD2 and CD58, thereby modulating the immune response. Several peptides were designed based on the structure of the CD58-binding domain of CD2 protein. Among the CD2-derived peptides, peptide 6 from the F and C -strand region of CD2 protein exhibited inhibition of cell-cell adhesion in the nanomolar concentration range. Peptide 6 was evaluated for its ability to bind to CD58 in Caco-2 cells and to CD48 in T cells from rodents. A molecular model was proposed for binding a peptide to CD58 and CD48 using docking studies. Furthermore, in vivo studies were carried out to evaluate the therapeutic ability of the peptide to modulate the immune response in the collagen-induced arthritis (CIA) mouse model. In vivo studies indicated that peptide 6 was able to suppress the progression of CIA. Evaluation of the antigenicity of peptides in CIA and transgenic animal models indicated that this peptide is not immunogenic. C1 [Gokhale, Ameya; Kanthala, Shanthi; Satyanarayanajois, Seetharama] Univ Louisiana Monroe, Coll Pharm, Monroe, LA 71201 USA. [Latendresse, John] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Taneja, Veena] Mayo Clin, Dept Immunol & Rheumatol, Rochester, MN 55905 USA. RP Satyanarayanajois, S (reprint author), Univ Louisiana Monroe, Coll Pharm, Monroe, LA 71201 USA. EM jois@ulm.edu FU Louisiana Board of Regents [LEQSF(2009-12)-RD-A-23(SJ)]; NIH [AI075262] FX This research was supported by Louisiana Board of Regents Grant LEQSF(2009-12)-RD-A-23(SJ). The authors thank the Mass Spectrometry Facility, Department of Chemistry, Louisiana State University, Baton Rouge, LA, for high resolution mass spectra of compounds. Docking studies were conducted using HPC resources at LSU Baton Rouge via Louisiana Optical Network Initiative (LONI). V. T. is supported by NIH Grant AI075262. NR 55 TC 7 Z9 9 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1747-0277 J9 CHEM BIOL DRUG DES JI Chem. Biol. Drug Des. PD JUL PY 2013 VL 82 IS 1 BP 106 EP 118 DI 10.1111/cbdd.12138 PG 13 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 169KW UT WOS:000320780100010 PM 23530775 ER PT J AU Anatol, R Bauer, S Epstein, S Filice, R Lauritsen, K Lee, MH Mansfield, E McMurry-Heath, M Milone, J Pena, C Pollack, S Zineh, I AF Anatol, Rachael Bauer, Steven Epstein, Suzanne Filice, Ross Lauritsen, Kristina Lee, Mark H. Mansfield, Elizabeth McMurry-Heath, Michelle Milone, Joseph Pena, Carlos Pollack, Steven Zineh, Issam TI Continuing to strengthen FDA's science approach to emerging technologies SO NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE LA English DT Article DE FDA; Science; Emerging technologies AB Emerging technologies result when advances and innovation in technology lead to discoveries. Often emerging technologies stimulate novel research in medical product development that contribute to new approaches to manufacturing and can improve the quality of products. By supporting investments in agency coordination, staff training and professional development, regulatory science research, stakeholder engagement, and enhancing opportunities for expert input, the U. S. Food and Drug Administration plays a critical role in translating innovations into novel safe and effective medical products that improve the public health. (C) 2013 Published by Elsevier Inc. C1 [Anatol, Rachael; Bauer, Steven; Epstein, Suzanne; Filice, Ross; Lauritsen, Kristina; Lee, Mark H.; Mansfield, Elizabeth; McMurry-Heath, Michelle; Milone, Joseph; Pena, Carlos; Pollack, Steven; Zineh, Issam] US FDA, Off Commissioner, Emerging Technol Programs, Silver Spring, MD 20993 USA. RP Pena, C (reprint author), US FDA, Off Commissioner, Emerging Technol Programs, Silver Spring, MD 20993 USA. EM carlos.pena@fda.hhs.gov OI Bauer, Steven/0000-0003-2831-846X NR 25 TC 4 Z9 5 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1549-9634 J9 NANOMED-NANOTECHNOL JI Nanomed.-Nanotechnol. Biol. Med. PD JUL PY 2013 VL 9 IS 5 BP 594 EP 599 DI 10.1016/j.nano.2013.04.005 PG 6 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA 166XO UT WOS:000320593600002 PM 23692697 ER PT J AU Smith, SM Wang, AT Katz, NP McDermott, MP Burke, LB Coplan, P Gilron, I Hertz, SH Lin, AH Rappaport, BA Rowbotham, MC Sampaio, C Sweeney, M Turk, DC Dworkin, RH AF Smith, Shannon M. Wang, Anthony T. Katz, Nathaniel P. McDermott, Michael P. Burke, Laurie B. Coplan, Paul Gilron, Ian Hertz, Sharon H. Lin, Allison H. Rappaport, Bob A. Rowbotham, Michael C. Sampaio, Cristina Sweeney, Michael Turk, Dennis C. Dworkin, Robert H. TI Adverse event assessment, analysis, and reporting in recent published analgesic clinical trials: ACTTION systematic review and recommendations SO PAIN LA English DT Review DE Adverse events; Clinical trials; Analgesic medications; Systematic review; CONSORT ID RANDOMIZED CONTROLLED-TRIALS; QUALITY-OF-LIFE; PLACEBO GROUPS; CHRONIC PAIN; IMMPACT RECOMMENDATIONS; DRUG-SAFETY; HARMS; SYMPTOMS; COMPLETENESS; MEDICINE AB The development of valid and informative treatment risk-benefit profiles requires consistent and thorough information about adverse event (AE) assessment and participants' AEs during randomized controlled trials (RCTs). Despite a 2004 extension of the Consolidated Standards of Reporting Trials (CONSORT) statement recommending the specific AE information that investigators should report, there is little evidence that analgesic RCTs adequately adhere to these recommendations. This systematic review builds on prior recommendations by describing a comprehensive checklist for AE reporting developed to capture clinically important AE information. Using this checklist, we coded AE assessment methods and reporting in all 80 double-blind RCTs of noninvasive pharmacologic treatments published in the European Journal of Pain, Journal of Pain, and PAIN (R) from 2006 to 2011. Across all trials, reports of AEs were frequently incomplete, inconsistent across trials, and, in some cases, missing. For example, >40% of trials failed to report any information on serious adverse events. Trials of participants with acute or chronic pain conditions and industry-sponsored trials typically provided more and better-quality AE data than trials involving pain-free volunteers or trials that were not industry sponsored. The results of this review suggest that improved AE reporting is needed in analgesic RCTs. We developed an ACTTION (Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks) AE reporting checklist that is intended to assist investigators in thoroughly and consistently capturing and reporting these critically important data in publications. (C) 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. C1 [Smith, Shannon M.] Univ Rochester, Sch Med & Dent, Dept Anesthesiol, Rochester, NY 14627 USA. [Wang, Anthony T.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Katz, Nathaniel P.] Analges Solut, Natick, MA USA. [Katz, Nathaniel P.] Tufts Univ, Boston, MA 02111 USA. [McDermott, Michael P.] Univ Rochester, Sch Med & Dent, Dept Biostat, Rochester, NY USA. [McDermott, Michael P.] Univ Rochester, Sch Med & Dent, Dept Computat Biol & Neurol, Rochester, NY USA. [Burke, Laurie B.; Hertz, Sharon H.; Lin, Allison H.; Rappaport, Bob A.] US FDA, Silver Spring, MD USA. [Coplan, Paul] Purdue Pharma LP, Stamford, CT USA. [Coplan, Paul] Univ Penn, Philadelphia, PA 19104 USA. [Gilron, Ian] Queens Univ, Kingston, ON, Canada. [Rowbotham, Michael C.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Sampaio, Cristina] CHDI, New York, NY USA. [Sweeney, Michael] Depomed, Menlo Pk, CA USA. [Turk, Dennis C.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Dworkin, Robert H.] Univ Rochester, Sch Med & Dent, Dept Anesthesiol, Rochester, NY USA. [Dworkin, Robert H.] Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY USA. [Dworkin, Robert H.] Univ Rochester, Sch Med & Dent, Ctr Human Expt Therapeut, Rochester, NY USA. RP Smith, SM (reprint author), Univ Rochester, Sch Med & Dent, Dept Anesthesiol, Rochester, NY 14627 USA. EM shannon1_smith@urmc.rochester.edu OI Coplan, Paul/0000-0002-7078-7780 FU ACTTION public-private partnership; FDA; Astellas; Bristol-Myers Squibb; Collegium; Depomed; Eli Lilly; Horizon; Jazz; Johnson Johnson; Mallinckrodt; Pfizer; Purdue; Zalicus FX The views expressed in this article are those of the authors and no official endorsement by the Food and Drug Administration (FDA) or the pharmaceutical companies that provided unrestricted grants to support the activities of the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership should be inferred. Financial support for this project was provided by the ACTTION public-private partnership, which has received research contracts, grants, or other revenue from the FDA, Astellas, Bristol-Myers Squibb, Collegium, Depomed, Eli Lilly, Horizon, Jazz, Johnson & Johnson, Mallinckrodt, Pfizer, Purdue, Zalicus, and other sources. NR 45 TC 19 Z9 19 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD JUL PY 2013 VL 154 IS 7 BP 997 EP 1008 DI 10.1016/j.pain.2013.03.003 PG 12 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 166XD UT WOS:000320592200008 PM 23602344 ER PT J AU Meek, MEB Bolger, M Bus, JS Christopher, J Conolly, RB Lewis, RJ Paolini, GM Schoeny, R Haber, LT Rosenstein, AB Dourson, ML AF Meek, M. E. Bette Bolger, Michael Bus, James S. Christopher, John Conolly, Rory B. Lewis, R. Jeffrey Paolini, Gregory M. Schoeny, Rita Haber, Lynne T. Rosenstein, Amy B. Dourson, Michael L. TI A framework for fit-for-purpose dose response assessment SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Mode of action; Fit-for-purpose; Problem formulation; Framework; Tier; Endogenous; Methods compendium ID TO-OUTCOME MODEL; RISK-ASSESSMENT; INSECTICIDE RESIDUES; DIETARY EXPOSURES; INFORMATION; CHEMICALS AB The NRC report Science and Decisions: Advancing Risk Assessment made several recommendations to improve chemical risk assessment, with a focus on in-depth chronic dose-response assessments conducted by the U.S. Environmental Protection Agency. The recommendations addressed two broad elements: improving technical analysis and utility for decision making. To advance the discussions in the NRC report, in three multi-stakeholder workshops organized by the Alliance for Risk Assessment, available and evolving risk assessment methodologies were considered through the development and application of case studies. A key product was a framework (http://www.allianceforrisk.org/Workshop/Framework/ProblemFormulation.html) to guide risk assessors and managers to various dose-response assessment methods relevant to a range of decision contexts ranging from priority setting to full assessment, as illustrated by case studies. It is designed to facilitate selection of appropriate methodology for a variety of problem formulations and includes a variety of methods with supporting case studies, for areas flagged specifically by the NRC committee for consideration - e.g., susceptible sub-populations, population variability and background. The framewok contributes to organization and communication about methodologies for incorporating increasingly biologically informed and chemical specific knowledge into dose-response analysis, which is considered critical in evolving fit-for-purpose assessment to address relevant problem formulations. (C) 2013 Elsevier Inc. All rights reserved. C1 [Meek, M. E. Bette] Univ Ottawa, McLaughlin Ctr Populat Hlth Risk Assessment, Ottawa, ON K1N 6N5, Canada. [Bolger, Michael] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Bus, James S.] Dow Chem Co USA, Toxicol & Environm Res & Consulting, Midland, MI 48674 USA. [Christopher, John] Independent Consultant, Elk Grove, CA 95757 USA. [Conolly, Rory B.] US EPA, Res Triangle Pk, NC 27711 USA. [Lewis, R. Jeffrey] ExxonMobil Biomed Sci, Annandale, NJ 08801 USA. [Paolini, Gregory M.] Risk Sci Int, Ottawa, ON K1N 7G2, Canada. [Schoeny, Rita] US EPA, Washington, DC 20460 USA. [Haber, Lynne T.; Dourson, Michael L.] Toxicol Excellence Risk Assessment, Cincinnati, OH 45211 USA. [Rosenstein, Amy B.] Independent Consultant, Lexington, MA 02421 USA. RP Meek, MEB (reprint author), Univ Ottawa, McLaughlin Ctr Populat Hlth Risk Assessment, 1 Stewart St,Suite 309, Ottawa, ON K1N 6N5, Canada. EM bmeek@uottawa.ca; mbolger33@gmail.com; jbus@exponent.com; dr.tox@comcast.net; conolly.rory@epa.gov; r.jeffrey.lewis@exxonmobil.com; gpaoli@rislcsciences.com; Schoeny.Rita@epamail.gov; haber@tera.org; EnvRiskExpABR@aol.com; dourson@-tera.org FU U.S. Environmental Protection Agency FX The information in this document has been funded in part by the U.S. Environmental Protection Agency. It has been subjected to review by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. This paper reflects the views of the authors and does not necessarily represent views or policies of the employers of the non-Agency authors. These views should also not be construed to represent those of science panel members who are not listed as contributing authors. Nor should these views be construed to represent those of the project's 55 sponsors. NR 22 TC 5 Z9 5 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD JUL PY 2013 VL 66 IS 2 BP 234 EP 240 DI 10.1016/j.yrtph.2013.03.012 PG 7 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA 167LB UT WOS:000320632400007 ER PT J AU Zhou, Q Gil-Krzewska, A Peruzzi, G Borrego, F AF Zhou, Q. Gil-Krzewska, A. Peruzzi, G. Borrego, F. TI Matrix metalloproteinases inhibition promotes the polyfunctionality of human natural killer cells in therapeutic antibody-based anti-tumour immunotherapy SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE monoclonal antibody; NK cell; polyfunctionality; tumour immunotherapy ID VIRUS TYPE-1 INFECTION; IFN-GAMMA; TUMOR-DEVELOPMENT; FC-RECEPTORS; NK CELLS; T-CELLS; IN-VIVO; IGG FC; CD16; CANCER AB Activation of human natural killer (NK) cells is associated with the cleavage of CD16 from the cell surface, a process mediated by matrix metalloproteinases (MMPs). In this report, we examined whether inhibition of MMPs would lead to improved NK cell antibody-dependent cell-mediated cytotoxicity (ADCC) function. Using an in-vitroADCC assay, we tested the anti-tumour function of NK cells with three different therapeutic monoclonal antibodies (mAbs) in the presence of MMPs inhibitor GM6001 or its control. Loss of CD16 was observed when NK cells were co-cultured with tumour targets in the presence of specific anti-tumour antibodies, and was found particularly on the majority of degranulating NK responding cells. Treatment with MMPs inhibitors not only prevented CD16 down-regulation, but improved the quality of the responding cells significantly, as shown by an increase in the percentage of polyfunctional NK cells that are capable of both producing cytokines and degranulation. Furthermore, MMPs inhibition resulted in augmented and sustained CD16-mediated signalling, as shown by increased tyrosine phosphorylation of CD3 and other downstream signalling intermediates, which may account for the improved NK cell function. Collectively, our results provide a foundation for combining MMPs inhibitors and therapeutic mAbs in new clinical trials for cancer treatment. C1 [Zhou, Q.; Gil-Krzewska, A.; Borrego, F.] US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, OBP,CDER, Bethesda, MD 20892 USA. [Peruzzi, G.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, Rockville, MD USA. RP Borrego, F (reprint author), US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, OBP,CDER, Bldg 29B,Room 3NN18,29 Lincoln Dr,HFD 123, Bethesda, MD 20892 USA. EM Francisco.BorregoRabasco@osakidetza.net OI Peruzzi, Giovanna/0000-0002-6517-9107 FU US Food and Drug Administration; NCI-FDA Interagency Oncology Task Force fellowship programme FX This work was supported by the intramural programme of the US Food and Drug Administration and by the NCI-FDA Interagency Oncology Task Force fellowship programme. The authors would like to thank Dr Wen Jin Wu and Dr Milos Dokmanovic for their generous gift of trastuzumab. NR 42 TC 20 Z9 20 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD JUL PY 2013 VL 173 IS 1 BP 131 EP 139 DI 10.1111/cei.12095 PG 9 WC Immunology SC Immunology GA 159GA UT WOS:000320032400015 PM 23607800 ER PT J AU Degheidy, HA Gadalla, SM Farooqui, MZH Abbasi, F Arthur, DC Bauer, SR Wilson, WH Wiestner, A Stetler-Stevenson, MA Marti, GE AF Degheidy, Heba A. Gadalla, Shahinaz M. Farooqui, Mohammed Z. H. Abbasi, Fatima Arthur, Diane C. Bauer, Steven R. Wilson, Wyndham H. Wiestner, Adrian Stetler-Stevenson, M. A. Marti, Gerald E. TI Bcl-2 level as a biomarker for 13q14 deletion in CLL SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Article DE chronic lymphocytic leukemia; Bcl-2; flow cytometry; del 13q14; hemizygous; homozygous deletion ID CHRONIC-LYMPHOCYTIC-LEUKEMIA; B-CELLS; EXPRESSION; APOPTOSIS; MICRORNAS; SURVIVAL; ASSOCIATION; GENES; RNA; ACCUMULATION AB Background Deletion 13q14.3 is the most common cytogenetic abnormality in chronic lymphocytic leukemia (CLL). Previously it was reported that miR-15/16 is the target of 13q14 deletions and plays a tumor suppressor role by suppressing Bcl-2. Therefore, Bcl-2 expression was examined more closely to determine whether it would predict 13q14 deletion status. Methods A multi-color flow panel consisting of anti-Bcl-2/anti-lambda/anti-kappa/CD19/CD5/CD3/CD20 was performed. The ability of Bcl-2 to predict 13q14 deletion was tested using the conventional Bcl-2 index (c-index): mean fluorescence intensity (MFI) of CLL clone/MFI of residual T cells. Fifty-four untreated CLL/MBL patients were studied. Bimodal Bcl-2 expression was evaluated to test the ability of Bcl-2 to detect intraclonal heterogeneity. Other CLL prognostic markers including CD38, CD49d, CD26, and CD69 were evaluated. FISH was performed on selected sorted populations. Results The Bcl-2 c-index strongly predicts del13q14 P < 0.0001. A statistically significant association was observed between the percentage of cells carrying the deletion and the level of Bcl-2 expression P < 0.05. Cells sorted based on Bcl-2 expression showed enrichment of both hemizygous and homozygous del 13q14 cells. Also, we observed that an alteration in Bcl-2 level over time predicts changes in 13q14 deletion status. And a statistically significant correlation between the bimodal pattern of CD69 expression and the presence of 13q14 deletion was found P < 0.0001. Conclusion Bcl-2 expression using the c-index strongly predicts 13q14 deletion and can be used to distinguish homozygous, heterozygous, and diploid CLL clonal cells. Further systematic studies of this biomarker are needed for confirmation and expansion of these findings. Published 2013 Wiley-Periodicals, Inc. C1 [Degheidy, Heba A.; Abbasi, Fatima; Bauer, Steven R.; Marti, Gerald E.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Degheidy, Heba A.; Marti, Gerald E.] Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Gadalla, Shahinaz M.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Farooqui, Mohammed Z. H.; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Arthur, Diane C.; Stetler-Stevenson, M. A.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Wilson, Wyndham H.] NCI, Metab Branch, Bethesda, MD 20892 USA. RP Marti, GE (reprint author), 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM gemarti@mac.com OI Bauer, Steven/0000-0003-2831-846X FU Oak Ridge Institute for Science and Education through US DOE; Oak Ridge Institute for Science and Education through US FDA; National, Heart, Lung and Blood Institute, National Institutes of Health and the National Cancer Institute FX Grant sponsor: Oak Ridge Institute for Science and Education through US DOE and US FDA (Heba Degheidy's appointment to the Research Participation Program at CBER); Intramural Research Program of the National, Heart, Lung and Blood Institute, National Institutes of Health and the National Cancer Institute. NR 39 TC 6 Z9 7 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD JUL-AUG PY 2013 VL 84B IS 4 BP 237 EP 247 DI 10.1002/cyto.b.21090 PG 11 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 168VC UT WOS:000320732900006 PM 23674504 ER PT J AU Bentz, J O'Connor, MP Bednarczyk, D Coleman, J Lee, C Palm, J Pak, YA Perloff, ES Reyner, E Balimane, P Brannstrom, M Chu, XY Funk, C Guo, AL Hanna, I Heredi-Szabo, K Hillgren, K Li, LB Hollnack-Pusch, E Jamei, M Lin, XN Mason, AK Neuhoff, S Patel, A Podila, L Plise, E Rajaraman, G Salphati, L Sands, E Taub, ME Taur, JS Weitz, D Wortelboer, HM Xia, CQ Xiao, GQ Yabut, J Yamagata, T Zhang, L Ellens, H AF Bentz, Joe O'Connor, Michael P. Bednarczyk, Dallas Coleman, JoAnn Lee, Caroline Palm, Johan Pak, Y. Anne Perloff, Elke S. Reyner, Eric Balimane, Praveen Brannstrom, Marie Chu, Xiaoyan Funk, Christoph Guo, Ailan Hanna, Imad Heredi-Szabo, Krisztina Hillgren, Kate Li, Libin Hollnack-Pusch, Evelyn Jamei, Masoud Lin, Xuena Mason, Andrew K. Neuhoff, Sibylle Patel, Aarti Podila, Lalitha Plise, Emile Rajaraman, Ganesh Salphati, Laurent Sands, Eric Taub, Mitchell E. Taur, Jan-Shiang Weitz, Dietmar Wortelboer, Heleen M. Xia, Cindy Q. Xiao, Guangqing Yabut, Jocelyn Yamagata, Tetsuo Zhang, Lei Ellens, Harma TI Variability in P-Glycoprotein Inhibitory Potency (IC50) Using Various in Vitro Experimental Systems: Implications for Universal Digoxin Drug-Drug Interaction Risk Assessment Decision Criteria SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID CELL-LINE CACO-2; CANCER RESISTANCE PROTEIN; FUNCTIONAL-CHARACTERISTICS; TRANSEPITHELIAL TRANSPORT; MEMBRANE TRANSPORTERS; MEDIATED TRANSPORT; PERMEABILITY; EXPRESSION; MONOLAYER; KIDNEY AB A P-glycoprotein (P-gp) IC50 working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC50 determinations. Each laboratory followed its in-house protocol to determine in vitro IC50 values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells-Porcine Kidney Nr. 1 cells transfected with MDR1 cDNA (LLC-PK1-MDR1; four laboratories), and membrane vesicles containing human P-glycoprotein (P-gp; five laboratories). For cell models, various equations to calculate remaining transport activity (e. g., efflux ratio, unidirectional flux, net-secretory-flux) were also evaluated. The difference in IC50 values for each of the inhibitors across all test systems and equations ranged from a minimum of 20- and 24-fold between lowest and highest IC50 values for sertraline and isradipine, to a maximum of 407- and 796-fold for telmisartan and verapamil, respectively. For telmisartan and verapamil, variability was greatly influenced by data from one laboratory in each case. Excluding these two data sets brings the range in IC50 values for telmisartan and verapamil down to 69- and 159-fold. The efflux ratio-based equation generally resulted in several fold lower IC50 values compared with unidirectional or net-secretory-flux equations. Statistical analysis indicated that variability in IC50 values was mainly due to interlaboratory variability, rather than an implicit systematic difference between test systems. Potential reasons for variability are discussed and the simplest, most robust experimental design for P-gp IC50 determination proposed. The impact of these findings on drug-drug interaction risk assessment is discussed in the companion article (Ellens et al., 2013) and recommendations are provided. C1 [Bentz, Joe; O'Connor, Michael P.] Drexel Univ, Dept Biol, Philadelphia, PA 19104 USA. [Bednarczyk, Dallas] Optivia, Biotechnol, Menlo Pk, CA USA. [Ellens, Harma] Drug Metab & Pharmacokinet, King Of Prussia, PA USA. [Lee, Caroline; Reyner, Eric] Pfizer Inc, Dept Pharmacokinet Dynam & Metab, San Diego, CA USA. [Palm, Johan] CVGI iMed DMPK, AstraZeneca R&D Molndal, Innovat Med, Molndal, Sweden. [Pak, Y. Anne; Hillgren, Kate] Eli Lilly & Co, Lilly Res Labs, Investigat Drug Disposit, Indianapolis, IN 46285 USA. [Perloff, Elke S.; Mason, Andrew K.] BD GentestSM Contract Res Serv, BD Biosci Discovery Labware, Woburn, MA USA. [Balimane, Praveen] Bristol Myers Squibb, Pharmaceut Candidate Optimizat, Bristol Myers Squibb, Princeton, NJ USA. [Chu, Xiaoyan; Yabut, Jocelyn] Merck & Co Inc, Dept Pharmacokinet Pharmacodynam & Drug Metab, Rahway, NJ USA. [Funk, Christoph; Hollnack-Pusch, Evelyn] F Hoffmann La Roche, Nonclin Drug Safety, Basel, Switzerland. [Guo, Ailan] Hoffmann La Roche, Nonclin Drug Safety, Nutley, NJ USA. [Hanna, Imad] Novartis Inst BioMed Res, E Hanover, NJ USA. [Heredi-Szabo, Krisztina] SOLVO Biotechnol, Budapest, Hungary. [Li, Libin] Absorpt Syst LP, Exton, PA USA. [Jamei, Masoud; Neuhoff, Sibylle] Simcyp, Sheffield, S Yorkshire, England. [Lin, Xuena] Novartis Inst BioMed Res, Cambridge, MA USA. [Podila, Lalitha; Taub, Mitchell E.] Boehringer Ingelheim Pharmaceut Inc, Drug Metab & Pharmacokinet, Ridgefield, CT USA. [Plise, Emile; Salphati, Laurent] Genentech Inc, Dept Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA. [Rajaraman, Ganesh] CellzDirect Life Technol Ltd, Austin, TX USA. [Sands, Eric; Xiao, Guangqing] Biogen Idec Inc, Drug Metab & Pharmacokinet, Cambridge, MA USA. [Taur, Jan-Shiang] Eisai Inc, Andover, MA USA. [Weitz, Dietmar] R&D DSAR Drug Disposit FF, Sanofi Aventis, Frankfurt, Germany. [Wortelboer, Heleen M.] TNO, NL-3700 AJ Zeist, Netherlands. [Xia, Cindy Q.] Millennium Pharmaceut Inc, Cambridge, MA USA. [Yamagata, Tetsuo] Merck Serono, Inst Drug Metab & Pharmacokinet, Grafing, Germany. [Zhang, Lei] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Bentz, J (reprint author), Drexel Univ, Dept Biol, Philadelphia, PA 19104 USA. RI Jamei, Masoud/H-6281-2013 FU Small Business Innovation Research Grants from the National Institutes of Health National Institute of General Medical Sciences [R43GM086970-01, R43RR031474-01] FX Work at Optivia was supported by Small Business Innovation Research Grants from the National Institutes of Health National Institute of General Medical Sciences [Grants R43GM086970-01, R43RR031474-01]. NR 34 TC 37 Z9 37 U1 5 U2 31 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD JUL PY 2013 VL 41 IS 7 BP 1347 EP 1366 DI 10.1124/dmd.112.050500 PG 20 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 163AG UT WOS:000320307100007 PM 23620485 ER PT J AU Ellens, H Deng, SB Coleman, J Bentz, J Taub, ME Ragueneau-Majlessi, I Chung, SP Heredi-Szabo, K Neuhoff, S Palm, J Balimane, P Zhang, L Jamei, M Hanna, I O'Connor, M Bednarczyk, D Forsgard, M Chu, XY Funk, C Guo, AL Hillgren, KM Li, LB Pak, AY Perloff, ES Rajaraman, G Salphati, L Taur, JS Weitz, D Wortelboer, HM Xia, CQ Xiao, GQ Yamagata, T Lee, CA AF Ellens, Harma Deng, Shibing Coleman, JoAnn Bentz, Joe Taub, Mitchell E. Ragueneau-Majlessi, Isabelle Chung, Sophie P. Heredi-Szabo, Krisztina Neuhoff, Sibylle Palm, Johan Balimane, Praveen Zhang, Lei Jamei, Masoud Hanna, Imad O'Connor, Michael Bednarczyk, Dallas Forsgard, Malin Chu, Xiaoyan Funk, Christoph Guo, Ailan Hillgren, Kathleen M. Li, LiBin Pak, Anne Y. Perloff, Elke S. Rajaraman, Ganesh Salphati, Laurent Taur, Jan-Shiang Weitz, Dietmar Wortelboer, Heleen M. Xia, Cindy Q. Xiao, Guangqing Yamagata, Tetsuo Lee, Caroline A. TI Application of Receiver Operating Characteristic Analysis to Refine the Prediction of Potential Digoxin Drug Interactions SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID GLYCOPROTEIN-MEDIATED TRANSPORT; STEADY-STATE PHARMACOKINETICS; P-GLYCOPROTEIN; HEART-FAILURE; MEMBRANE TRANSPORTERS; CALCIUM-ANTAGONISTS; CACO-2 CELLS; QUINIDINE; DILTIAZEM; EFFLUX AB In the 2012 Food and Drug Administration (FDA) draft guidance on drug-drug interactions (DDIs), a new molecular entity that inhibits P-glycoprotein (P-gp) may need a clinical DDI study with a P-gp substrate such as digoxin when the maximum concentration of inhibitor at steady state divided by IC50 ([I-1]/IC50) is >= 0.1 or concentration of inhibitor based on highest approved dose dissolved in 250 ml divide by IC50 ([I-2]/IC50) is >= 10. In this article, refined criteria are presented, determined by receiver operating characteristic analysis, using IC50 values generated by 23 laboratories. P-gp probe substrates were digoxin for polarized cell-lines and N-methyl quinidine or vinblastine for P-gp overexpressed vesicles. Inhibition of probe substrate transport was evaluated using 15 known P-gp inhibitors. Importantly, the criteria derived in this article take into account variability in IC50 values. Moreover, they are statistically derived based on the highest degree of accuracy in predicting true positive and true negative digoxin DDI results. The refined criteria of [I-1]/IC50 >= 0.03 and [I-2]/IC50 >= 45 and FDA criteria were applied to a test set of 101 in vitro-in vivo digoxin DDI pairs collated from the literature. The number of false negatives (none predicted but DDI observed) were similar, 10 and 12%, whereas the number of false positives (DDI predicted but not observed) substantially decreased from 51 to 40%, relative to the FDA criteria. On the basis of estimated overall variability in IC50 values, a theoretical 95% confidence interval calculation was developed for single laboratory IC50 values, translating into a range of [I-1]/IC50 and [I-2]/IC50 values. The extent by which this range falls above the criteria is a measure of risk associated with the decision, attributable to variability in IC50 values. C1 [Ellens, Harma; Coleman, JoAnn] GlaxoSmithKline, Stat Sci, King Of Prussia, PA USA. [Ellens, Harma] GlaxoSmithKline, Drug Metab & Pharmacokinet, King Of Prussia, PA USA. [Deng, Shibing] Pfizer Worldwide Res & Dev La Jolla Labs, Clin Res, San Diego, CA USA. [Lee, Caroline A.] Pfizer Worldwide Res & Dev La Jolla Labs, Pharmacokinet Dynam & Metab, San Diego, CA USA. [Bentz, Joe; O'Connor, Michael] Drexel Univ, Dept Biol, Philadelphia, PA 19104 USA. [Taub, Mitchell E.] Boehringer Ingelheim Pharmaceut Inc, Drug Metab & Pharmacokinet, Ridgefield, CT USA. [Ragueneau-Majlessi, Isabelle; Chung, Sophie P.] Univ Washington, Dept Pharmaceut, Drug Interact Database Program, Seattle, WA 98195 USA. [Heredi-Szabo, Krisztina] SOLVO Biotechnol, Budapest, Hungary. [Neuhoff, Sibylle; Jamei, Masoud] SimCyp, Sheffield, S Yorkshire, England. [Palm, Johan] AstraZeneca Res & Dev, CVGI iMed DMPK, Innovat Med, Molndal, Sweden. [Forsgard, Malin] AstraZeneca Res & Dev, Global Drug Metab & Pharmacokinet, Molndal, Sweden. [Balimane, Praveen] Bristol Myers Squibb, Pharmaceut Candidate Optimizat, Princeton, NJ USA. [Zhang, Lei] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Hanna, Imad] Novartis Inst BioMed Res, Drug Metab & Pharmacokinet, E Hanover, NJ USA. [Bednarczyk, Dallas] Optivia, Biotechnol, Menlo Pk, CA USA. [Chu, Xiaoyan] Merck Co, Dept Pharmacokinet Pharmacodynam & Drug Metab, Rahway, NJ USA. [Funk, Christoph] Hoffmann La Roche AG, Nonclin Drug Safety, Basel, Switzerland. [Hillgren, Kathleen M.; Pak, Anne Y.] Lilly Res Labs, Investigat Drug Disposit, Indianapolis, IN USA. [Li, LiBin] Absorpt Syst LP, Exton, PA USA. [Perloff, Elke S.] BD Gentest Contract Res Serv, BD Bioscie Discovery Labware, Woburn, MA USA. [Rajaraman, Ganesh] CellzDirect Life Technol Ltd, Austin, TX USA. [Salphati, Laurent] Genentech Inc, Dept Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA. [Taur, Jan-Shiang] Eisai Inc, Andover, MA USA. [Weitz, Dietmar] Sanofi Aventis, DSAR Drug Disposit FF, Res & Dev, Frankfurt, Germany. [Wortelboer, Heleen M.] TNO, NL-3700 AJ Zeist, Netherlands. [Xia, Cindy Q.] Millennium Pharmaceut Inc, Cambridge, MA USA. [Xiao, Guangqing] Biogen Idec Inc, Drug Metab & Pharmacokinet, Cambridge, MA USA. [Yamagata, Tetsuo] Merck Serono, Inst Drug Metab & Pharmacokinet, Grafing, Germany. RP Ellens, H (reprint author), GlaxoSmithKline, Drug Metab & Pharmacokinet, King Of Prussia, PA USA. RI Jamei, Masoud/H-6281-2013; OI Bednarczyk, Dallas/0000-0003-0735-2861 FU Small Business Innovation Research Grants from the National Institutes of Health National Institute of General Medical Sciences [R43GM086970-01, R43RR031474-01] FX Work at Optivia was supported by Small Business Innovation Research Grants from the National Institutes of Health National Institute of General Medical Sciences [Grants R43GM086970-01 and R43RR031474-01]. NR 45 TC 11 Z9 11 U1 0 U2 12 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD JUL PY 2013 VL 41 IS 7 BP 1367 EP 1374 DI 10.1124/dmd.112.050542 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 163AG UT WOS:000320307100008 PM 23620486 ER PT J AU Getie-Kebtie, M Sultana, I Eichelberger, M Alterman, M AF Getie-Kebtie, Melkamu Sultana, Ishrat Eichelberger, Maryna Alterman, Michail TI Label-free mass spectrometry-based quantification of hemagglutinin and neuraminidase in influenza virus preparations and vaccines SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Article DE Hemagglutinin; influenza; mass spectrometry; neuraminidase; proteomics ID PROTEIN QUANTIFICATION AB Please cite this paper as: Getie-Kebtie etal. (2012) Label-free mass spectrometry-based quantification of hemagglutinin and neuraminidase in influenza virus preparations and vaccines. Influenza and Other Respiratory Viruses 7(4), 521-530. Background Influenza vaccination is the primary method for preventing influenza and its severe complications. An accurate rapid method to determine hemagglutinin (HA) concentration would facilitate reference antigen preparation and consequently expedite availability of seasonal as well as pandemic vaccines. Objective The goal of this study was to develop a label-free mass spectrometry (MS) based method that enables simultaneous identification and quantification of HA, neuraminidase (NA), and other viral proteins and protein contaminations in influenza vaccine or virus preparations. Methods The method presented is based on LC/MSE analysis of vaccine or virus preparations tryptic digests spiked with a known amount of protein standard from which a universal response factor is generated and applied to calculate the concentration of proteins identified in the mixture. Results We show that, with the use of an appropriate internal standard, the label-free MS-based protein quantification method is applicable for simultaneous identification and absolute quantification of HA and identification and relative quantification of other influenza proteins as well as protein impurities in influenza vaccines and virus preparations. We show that different subtype recombinant HA is preferred internal standard that provides the most accurate results in absolute quantification of HAs and other influenza proteins. We applied this method to measure the absolute quantity of HA as well as relative quantities of other viral proteins and impurities in preparations of whole virus and monovalent vaccine, providing data to demonstrate strain-dependent differences in the amount of NA. Conclusion The label-free MS method presented here is ideally suited for timely preparation of reference material needed for potency testing of seasonal and pandemic vaccines. C1 [Getie-Kebtie, Melkamu; Alterman, Michail] US FDA, Div Cellular & Gene Therapies, OCTGT, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Sultana, Ishrat; Eichelberger, Maryna] US FDA, Div Viral Prod, OVRR, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Alterman, M (reprint author), US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bldg 29A,Room 2D12,8800 Rockville Pike, Bethesda, MD 20892 USA. EM Michail.Alterman@fda.hhs.gov FU CBER; Biomedical Advanced Research and Development Authority FX This project was supported by funding provided by the CBER (Panflu funds) and by the Biomedical Advanced Research and Development Authority. We appreciate technical help from Kevin Yang and Schafer Eichelberger and critical reading of the manuscript by Jerry Weir and John Cipollo. NR 15 TC 14 Z9 14 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1750-2640 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD JUL PY 2013 VL 7 IS 4 BP 521 EP 530 DI 10.1111/irv.12001 PG 10 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA 162PP UT WOS:000320277800005 PM 22943763 ER PT J AU Aguero, JM Beleche, T AF Agueero, Jorge M. Beleche, Trinidad TI Test-Mex: Estimating the effects of school year length on student performance in Mexico SO JOURNAL OF DEVELOPMENT ECONOMICS LA English DT Article DE Mexico; Standardized tests; School year length; Student achievement ID NATURAL EXPERIMENT; ACHIEVEMENT; EARNINGS; IMPACT AB Estimating the impact of changing school inputs on student performance is often difficult because these inputs are endogenously determined. We investigate a quasi-experiment that altered the number of instructional days prior to a nationwide test in Mexico. Our exogenous source of variation comes from across states and over time changes in the date when the school year started and. the date when the test was administered. We find that having more days of instruction prior to examination slightly improves student performance but exhibits diminishing marginal returns. The effects vary along the distribution of resources as determined by a poverty index, with lower improvements in poorer schools. These findings imply a weaker net benefit of policies expanding the length of the school year as they could widen the achievement gap by socioeconomic status. Published by Elsevier B.V. C1 [Agueero, Jorge M.] Univ Calif Riverside, Dept Econ, Riverside, CA 92521 USA. [Beleche, Trinidad] US FDA, Silver Spring, MD 20993 USA. RP Aguero, JM (reprint author), Univ Calif Riverside, Dept Econ, Riverside, CA 92521 USA. EM jorge.aguero@ucr.edu; tbeleche@gmail.com NR 26 TC 2 Z9 2 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3878 J9 J DEV ECON JI J. Dev. Econ. PD JUL PY 2013 VL 103 BP 353 EP 361 DI 10.1016/j.jdeveco.2013.03.008 PG 9 WC Economics SC Business & Economics GA 168DV UT WOS:000320686800027 ER PT J AU Bhalli, JA Shaddock, JG Pearce, MG Dobrovolsky, VN AF Bhalli, Javed A. Shaddock, Joseph G. Pearce, Mason G. Dobrovolsky, Vasily N. TI Sensitivity of the Pig-a assay for detecting gene mutation in rats exposed acutely to strong clastogens SO MUTAGENESIS LA English DT Article ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; RED-BLOOD-CELLS; ETHYL-N-NITROSOUREA; FLOW-CYTOMETRIC DETECTION; IN-VIVO GENOTOXICITY; TRANSGENIC MICE; BONE-MARROW; END-POINTS; CYCLOPHOSPHAMIDE; ERYTHROCYTES AB Clastogens are potential human carcinogens whose detection by genotoxicity assays is important for safety assessment. Although some endogenous genes are sensitive to the mutagenicity of clastogens, many genes that are used as reporters for in vivo mutation (e.g. transgenes) are not. In this study, we have compared responses in the erythrocyte Pig-a gene mutation assay with responses in a gene mutation assay that is relatively sensitive to clastogens, the lymphocyte Hprt assay, and in the reticulocyte micronucleus (MN) assay, which provides a direct measurement of clastogenicity. Male F344 rats were treated acutely with X-rays, cyclophosphamide (CP) and Cis-platin (Cis-Pt), and the frequency of micronucleated reticulocytes (MN RETs) in peripheral blood was measured 1 or 2 days later. The frequencies of CD59-deficient Pig-a mutant erythrocytes and 6-thioguanine-resistant Hprt mutant T-lymphocytes were measured at several times up to 16 weeks after the exposure. All three clastogens induced strong increases in the frequency of MN RETs, with X-rays and Cis-Pt producing near linear dose responses. The three agents also were positive in the two gene mutation assays although the assays detected them with different efficiencies. The Pig-a assay was more efficient in detecting the effect of Cis-Pt treatment, whereas the Hprt assay was more efficient for X-rays and CP. The results indicate that the erythrocyte Pig-a assay can detect the in vivo mutagenicity of clastogens although its sensitivity is variable in comparison with the lymphocyte Hprt assay. C1 [Bhalli, Javed A.; Shaddock, Joseph G.; Pearce, Mason G.; Dobrovolsky, Vasily N.] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Dobrovolsky, VN (reprint author), US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd,HFT 120, Jefferson, AR 72079 USA. EM vasily.dobrovolsky@fda.hhs.gov FU National Institutes of Health-National Institute of Environmental Health Sciences [R44ES018017]; Oak Ridge Institute for Science and Education FX Litron's contribution was supported by National Institutes of Health-National Institute of Environmental Health Sciences (R44ES018017). JAB was supported by a Research Fellowship sponsored by the Oak Ridge Institute for Science and Education. NR 42 TC 5 Z9 6 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0267-8357 J9 MUTAGENESIS JI Mutagenesis PD JUL PY 2013 VL 28 IS 4 BP 447 EP 455 DI 10.1093/mutage/get022 PG 9 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 165EE UT WOS:000320465100010 PM 23677247 ER PT J AU Hearn, BA Renner, CC Ding, YS Vaughan-Watson, C Stanfill, SB Zhang, LQ Polzin, GM Ashley, DL Watson, CH AF Hearn, Bryan A. Renner, Caroline C. Ding, Yan S. Vaughan-Watson, Christina Stanfill, Stephen B. Zhang, Liqin Polzin, Gregory M. Ashley, David L. Watson, Clifford H. TI Chemical Analysis of Alaskan Iqmik Smokeless Tobacco SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID POLYCYCLIC AROMATIC-HYDROCARBONS; MAINSTREAM CIGARETTE-SMOKE; MOIST SNUFF; NATIVES; NITROSAMINES; NICOTINE; FORM AB Iqmik, a form of smokeless tobacco (ST), is traditionally used by Cupik and Yupik Eskimo people of western Alaska. Iqmik is sometimes incorrectly considered to be a healthier alternative to smoking because its ingredients are perceived as natural. Our chemical characterization of iqmik shows that iqmik is not a safe alternative to smoking or other ST use. We measured nicotine and pH levels of tobacco and ash used to prepare iqmik. We also characterized levels of toxins which are known to be present in ST including tobacco-specific nitrosamines (TSNAs) and polycyclic aromatic hydrocarbons (PAHs) using chromatographic separations coupled with isotope dilution mass spectrometry. Nicotine content in the iqmik tobacco was very high, ranging from 35 to 43mg/g, with a mean of 39mg/g. The pH of the iqmik tobaccoash mixture was 11, an extremely high level compared with most ST products. High levels of PAHs were seen in the fire-cured tobacco samples with a benzo[a]pyrene level of 87ng/g. Average TSNA levels in the tobacco were 34, 2,700, and 340ng/g for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), N-nitrosonornicotine (NNN), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), respectively. Iqmik contains high levels of the more easily absorbed unionized nicotine as well as known carcinogenic TSNAs and PAHs. The perception that iqmik is less hazardous than other tobacco products due to the use of natural ingredients is not warranted. This chemical characterization of iqmik gives a better understanding of the risk of possible adverse health effects of its use. C1 [Hearn, Bryan A.; Ding, Yan S.; Vaughan-Watson, Christina; Stanfill, Stephen B.; Zhang, Liqin; Polzin, Gregory M.; Watson, Clifford H.] Ctr Dis Control & Prevent, Off Noncommunicable Dis Injury & Environm Hlth, Atlanta, GA 30341 USA. [Renner, Caroline C.] Alaska Native Tribal Hlth Consortium, Anchorage, AK USA. [Ashley, David L.] US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. RP Hearn, BA (reprint author), Ctr Dis Control & Prevent, Off Noncommunicable Dis Injury & Environm Hlth, 4770 Buford Highway, Atlanta, GA 30341 USA. EM bhearn@cdc.gov FU Centers for Disease Control and Prevention FX This work was supported by the Centers for Disease Control and Prevention. NR 33 TC 4 Z9 4 U1 0 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD JUL PY 2013 VL 15 IS 7 BP 1283 EP 1288 DI 10.1093/ntr/nts270 PG 6 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 165EG UT WOS:000320465300013 PM 23288872 ER PT J AU Yang, XX Doerge, DR Fisher, JW AF Yang, Xiaoxia Doerge, Daniel R. Fisher, Jeffrey W. TI Prediction and evaluation of route dependent dosimetry of BPA in rats at different life stages using a physiologically based pharmacokinetic model SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Bisphenol A; PBPK modeling; Rats; Kinetics; Rat pups; BPA ID SPRAGUE-DAWLEY RATS; BISPHENOL-A GLUCURONIDATION; SMALL-INTESTINE; ENZYME-ACTIVITIES; RHESUS-MONKEYS; MICE; METABOLISM; ADULT; EXPOSURE; HUMANS AB Bisphenol A (BPA) has received considerable attention throughout the last decade due to its widespread use in consumer products. For the first time a physiologically based pharmacokinetic (PBPK) model was developed in neonatal and adult rats to quantitatively evaluate age-dependent pharmacokinetics of BPA and its phase II metabolites. The PBPK model was calibrated in adult rats using studies on BPA metabolism and excretion in the liver and gastrointestinal tract, and pharmacokinetic data with EPA in adult rats. For immature rats the hepatic and gastrointestinal metabolism of BPA was inferred from studies on the maturation of phase II enzymes coupled with serum time course data in pups. The calibrated model predicted the measured serum concentrations of BPA and BPA conjugates after administration of 100 mu g/kg of d6-BPA in adult rats (oral gavage and intravenous administration) and postnatal days 3, 10, and 21 pups (oral gavage). The observed age-dependent BPA serum concentrations were partially attributed to the immature metabolic capacity of pups. A comparison of the dosimetry of BPA across immature rats and monkeys suggests that dose adjustments would be necessary to extrapolate toxicity studies from neonatal rats to infant humans. Published by Elsevier Inc. C1 [Yang, Xiaoxia; Doerge, Daniel R.; Fisher, Jeffrey W.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Yang, XX (reprint author), US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM Xiaoxia.Yang@fda.hhs.gov NR 60 TC 20 Z9 20 U1 0 U2 31 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUL 1 PY 2013 VL 270 IS 1 BP 45 EP 59 DI 10.1016/j.taap.2013.03.022 PG 15 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 152PW UT WOS:000319544600007 PM 23566954 ER PT J AU Zhou, WL AF Zhou, Wanlong TI Special Focus Issue: Increasing productivity: Part II SO BIOANALYSIS LA English DT Editorial Material C1 US FDA, College Pk, MD 20740 USA. RP Zhou, WL (reprint author), US FDA, 5100 Paint Branch Pkwy,HFS 717, College Pk, MD 20740 USA. EM wanlong.zhou@fda.hhs.gov NR 0 TC 0 Z9 0 U1 1 U2 2 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1757-6180 EI 1757-6199 J9 BIOANALYSIS JI Bioanalysis PD JUL PY 2013 VL 5 IS 14 BP 1725 EP 1725 PG 1 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AK8QV UT WOS:000338694000009 ER PT J AU Pariser, AR Robb, M Sherman, RE AF Pariser, Anne R. Robb, Melissa Sherman, Rachel E. TI Expedited programs for drug development and approval SO EXPERT OPINION ON ORPHAN DRUGS LA English DT Editorial Material DE drug approval; Food and Drug Administration; orphan drugs; rare diseases AB The United States Food and Drug Administration (FDA) has long recognized the key role it plays in ensuring patients have timely access to safe and effective drugs. Over the past 25 years, FDA has developed multiple programs, including Fast Track, Accelerated Approval, and Priority Review, to expedite the development and review of new drugs for the patients who need them. With the passage of the Food and Drug Administration Safety and Innovation Act (FDASIA) in 2012, FDA has an additional tool to foster efficient drug development, Breakthrough Therapy designation. Building on past successes, like Fast Track, Breakthrough focuses on early collaboration and communication between drug developers and FDA. These programs reflect the growing recognition that robust scientific drug development must also be efficient and as timely as possible. FDA continues to look for opportunities to streamline drug development, especially in areas with unmet need, while focusing on those products that show real promise to positively impact patients' health. C1 [Pariser, Anne R.] FDA, Off New Drugs, CDER, Silver Spring, MD 20993 USA. [Robb, Melissa] FDA, CDER, OMP, Off Med Policy Initiat, Silver Spring, MD 20993 USA. [Sherman, Rachel E.] FDA, CDER, OMP, Silver Spring, MD 20993 USA. RP Pariser, AR (reprint author), FDA, Off New Drugs, CDER, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Anne.Pariser@fda.hhs.gov NR 8 TC 2 Z9 2 U1 2 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 2167-8707 J9 EXPERT OPIN ORPHAN D JI Exp. Opin. Orphan Drugs PD JUL PY 2013 VL 1 IS 7 BP 507 EP 510 DI 10.1517/21678707.2013.805124 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AK1WI UT WOS:000338208600001 ER EF