FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Hageman, JC Uyeki, TM Francis, JS Jernigan, DB Wheeler, JG Bridges, CB Barenkamp, SJ Sievert, DM Srinivasan, A Doherty, MC McDougal, LK Killgore, GE Lopatin, UA Coffman, R MacDonald, JK McAllister, SK Fosheim, GE Patel, JB McDonald, LC AF Hageman, JC Uyeki, TM Francis, JS Jernigan, DB Wheeler, JG Bridges, CB Barenkamp, SJ Sievert, DM Srinivasan, A Doherty, MC McDougal, LK Killgore, GE Lopatin, UA Coffman, R MacDonald, JK McAllister, SK Fosheim, GE Patel, JB McDonald, LC TI Severe community-acquired pneumonia due to Staphylococcus aureus, 2003-04 influenza season SO EMERGING INFECTIOUS DISEASES LA English DT Article ID VALENTINE LEUKOCIDIN GENES; RESPIRATORY-TRACT; VIRUS INFECTION; WORKING ADULTS; A VIRUS; COMPLICATIONS; VACCINATION; HEALTHY; METAANALYSIS; ADHERENCE AB During the 2003-04 influenza season, 17 cases of Staphylococcus aureus community-acquired pneumonia (CAP) were reported from 9 states; 15 (88%) were associated with methicillin-resistant S. aureus (MRSA). The median age of patients was 21 years; 5 (29%) had underlying diseases, and 4 (24%) had risk factors for MRSA. Twelve (71%) had laboratory evidence of influenza virus infection. All but 1 patient, who died on arrival, were hospitalized. Death occurred in 5 (4 with MRSA). S. aureus isolates were available from 13 (76%) patients (11 MRSA). Toxin genes were detected in all isolates; 11 (85%) had only genes for Panton-Valentine leukocidin. All isolates had community-associated pulsed-field gel electrophoresis patterns; all MRSA isolates had the staphylococcal cassette chromosome mec type IVa. In communities with a high prevalence of MRSA, empiric therapy of severe CAP during periods of high influenza activity should include consideration for MRSA. C1 Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Univ Arkansas Med Sci, Coll Med, Little Rock, AR 72205 USA. St Louis Univ, Sch Med, St Louis, MO 63103 USA. Michigan Dept Community Hlth, Lansing, MI USA. NIH, Bethesda, MD USA. Oklahoma Dept Hlth, Oklahoma City, OK 73117 USA. Washington State Dept Hlth, Shoreline, WA USA. RP Hageman, JC (reprint author), Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. EM JHageman@cdc.gov OI Barenkamp, Stephen/0000-0002-3054-8910 NR 29 TC 200 Z9 209 U1 0 U2 3 PU CENTER DISEASE CONTROL PI ATLANTA PA ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD JUN PY 2006 VL 12 IS 6 BP 894 EP 899 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 046RY UT WOS:000237829900003 PM 16707043 ER PT J AU Perry, AS Foley, R Woodson, K Lawler, M AF Perry, AS Foley, R Woodson, K Lawler, M TI The emerging roles of DNA methylation in the clinical management of prostate cancer SO ENDOCRINE-RELATED CANCER LA English DT Review ID CPG ISLAND HYPERMETHYLATION; METHYLENETETRAHYDROFOLATE REDUCTASE GENE; PROLIFERATIVE INFLAMMATORY ATROPHY; ABERRANT PROMOTER METHYLATION; POLYMERASE-CHAIN-REACTION; QUANTITATIVE GSTP1 METHYLATION; METASTASIS SUPPRESSOR GENE; E-CADHERIN EXPRESSION; CARCINOMA CELL-LINES; RECEPTOR-BETA GENE AB Aberrant DNA methylation is one of the hallmarks of carcinogenesis and has been recognized in cancer cells for more than 20 years. The role of DNA methylation in malignant transformation of the prostate has been intensely studied, from its contribution to the early stages of tumour development to the advanced stages of androgen independence. The most significant advances have involved the discovery of numerous targets such as GSTP1, Ras-association domain family 1A (RASSF1A) and retinoic acid receptor beta 2 (RAR beta 2) that become inactivated through promoter hypermethylation during the course of disease initiation and progression. This has provided the basis for translational research into methylation biomarkers for early detection and prognosis of prostate cancer. Investigations into the causes of these methylation events have yielded little definitive data. Aberrant hypomethylation and how it impacts upon prostate cancer has been less well studied. Herein we discuss the major developments in the fields of prostate cancer and DNA methylation, and how this epigenetic modification can be harnessed to address some of the key issues impeding the successful clinical management of prostate cancer. C1 Univ Dublin Trinity Coll, Inst Mol Med, Dublin 2, Ireland. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Perry, AS (reprint author), Univ Dublin Trinity Coll, Inst Mol Med, Dublin 2, Ireland. EM perryan@tcd.ie OI Perry, Antoinette/0000-0002-6108-512X NR 174 TC 53 Z9 56 U1 0 U2 1 PU SOC ENDOCRINOLOGY PI BRISTOL PA 22 APEX COURT, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD JUN PY 2006 VL 13 IS 2 BP 357 EP 377 DI 10.1677/erc.1.01184 PG 21 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 053OY UT WOS:000238315700006 PM 16728568 ER PT J AU Pennisi, P Gavrilova, O Setser-Portas, J Jou, W Santopietro, S Clemmons, D Yakar, S LeRoith, D AF Pennisi, Patricia Gavrilova, Oksana Setser-Portas, Jennifer Jou, William Santopietro, Stefania Clemmons, David Yakar, Shoshana LeRoith, Derek TI Recombinant human insulin-like growth factor-I treatment inhibits gluconeogenesis in a transgenic mouse model of type 2 diabetes mellitus SO ENDOCRINOLOGY LA English DT Article ID IMPROVES GLYCEMIC CONTROL; SKELETAL-MUSCLE; IGF-I; GLUCOSE-HOMEOSTASIS; BINDING PROTEIN-3; HYBRID RECEPTORS; ADIPOSE-TISSUE; HORMONE; METABOLISM; LIVER AB IGF-I and insulin are structurally related polypeptides that mediate a similar pattern of biological effects via receptors that display considerably homology. Administration of recombinant human IGF-I (rhIGF-I) has been proven to improve glucose control and liver and muscle insulin sensitivity in patients with type 2 diabetes mellitus (DM). The effect of rhIGF-I treatment was evaluated in a mouse model of type 2 DM (MKR mouse), which expresses a dominant-negative form of the human IGF-I receptor under the control of the muscle creatine kinase promoter specifically in skeletal muscle. MKR mice have impaired IGF-I and insulin signaling in skeletal muscle, leading to severe insulin resistance in muscle, liver, and fat, developing type 2 DM at 5 wk of age. Six-week-old MKR mice were treated with either saline or rhIGF-I for 3 wk. Blood glucose levels were decreased in response to rhIGF-I treatment in MKR mice. rhIGF-I treatment also increased body weight in MKR with concomitant changes in body composition such as a decrease in fat mass and an increase in lean body mass. Insulin, fatty acid, and triglyceride levels were not affected by rhIGF-I, nor were insulin or glucose tolerance in MKR mice. Hyperinsulinemic-euglycemic clamp analysis demonstrated no improvement in overall insulin sensitivity. Pyruvate and glutamine tolerance tests proved that there was a decrease in the rate of glucose appearance in MKR mice treated with rhIGF-I, suggesting a reduction in the gluconeogenic capacity of liver, kidney, and small intestine. Taken together these results demonstrate that the improvement of the hyperglycemia was achieved by inhibition of gluconeogenesis rather than an improvement in insulin sensitivity. Also, these results suggest that a functional IGF-I receptor in skeletal muscle is required for IGF-I to improve insulin sensitivity in this mouse model of type 2 DM. C1 CUNY Mt Sinai Sch Med, Div Endocrinol & Diabet, New York, NY 10029 USA. Univ N Carolina, Div Endocrinol, Chapel Hill, NC 27599 USA. NIDDK, Diabet Branch, Bethesda, MD 20892 USA. NIDDK, Mouse Metab Core Lab, Bethesda, MD 20892 USA. RP LeRoith, D (reprint author), CUNY Mt Sinai Sch Med, Div Endocrinol & Diabet, 1 Gustave Levy Pl Box 1055, Annenberg 23-66, New York, NY 10029 USA. EM derek.leroith@mssm.edu FU Intramural NIH HHS NR 53 TC 34 Z9 39 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2006 VL 147 IS 6 SU S BP 2619 EP 2630 DI 10.1210/en.2005-1556 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 043SF UT WOS:000237621200013 PM 16513827 ER PT J AU Hiroi, T Okada, K Imaoka, S Osada, M Funae, Y AF Hiroi, Toyoko Okada, Kazushi Imaoka, Susumu Osada, Mayuko Funae, Yoshihiko TI Bisphenol A binds to protein disulfide isomerase and inhibits its enzymatic and hormone-binding activities SO ENDOCRINOLOGY LA English DT Article ID ANTI-CHAPERONE ACTIVITY; THYROID-HORMONE; ENDOPLASMIC-RETICULUM; PRENATAL EXPOSURE; GENE-EXPRESSION; RECEPTOR; CELLS; MICE; BRAIN; CHEMICALS AB Bisphenol A [2,2-bis-(4-hydroxyphenyl) propane; BPA] is a versatile industrial material for plastic products, but is increasingly being recognized as a pervasive industrial pollutant as well. Accumulating evidence indicates that the environmental contaminant BPA is one of the endocrine-disrupting chemicals that potentially can adversely affect humans as well as wildlife. To define the molecular aspects of BPA action, we first investigated the molecules with which it physically interacts. High BPA-binding activity was detected in the P2 membrane fraction prepared from rat brains. As determined by SDS-PAGE analysis, the molecular mass of a BPA-binding protein purified from the rat brain P2 fraction was 53 kDa. The N-terminal amino acid sequence of the purified BPA-binding protein was identical with that of the rat protein disulfide isomerase (PDI), which is a multifunctional protein that is critically involved in the folding, assembly, and shedding of many cellular proteins via its isomerase activity in addition to being considered to function as an intracellular hormone reservoir. The K-d value of BPA binding to recombinant rat PDI was 22.6 +/- 6.6 mu M. Importantly, the binding activity of L-T-3 and 17 beta-estradiol hormones to PDI was competitively inhibited by BPA in addition to abolishing its isomerase activities. In this paper we report that the ubiquitous and multifunctional protein PDI is a target of BPA and propose that binding to PDI and subsequent inhibition of PDI activity might be mechanistically responsible for various actions of BPA. C1 Osaka City Univ, Sch Med, Dept Biol Chem, Osaka 5458585, Japan. RP Hiroi, T (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10,Room 5N307,10 Ctr Dr, Bethesda, MD 20892 USA. EM hiroit@nhlbi.nih.gov; funae@med.osaka-cu.ac.jp NR 55 TC 55 Z9 55 U1 0 U2 7 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2006 VL 147 IS 6 SU S BP 2773 EP 2780 DI 10.1210/en.2005-1235 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 043SF UT WOS:000237621200032 PM 16543366 ER PT J AU Gore, AC Heindel, JJ Zoeller, RT AF Gore, Andrea C. Heindel, Jerrold J. Zoeller, R. Thomas TI Endocrine disruption for endocrinologists (and others) SO ENDOCRINOLOGY LA English DT Editorial Material ID EPIGENETIC TRANSGENERATIONAL ACTIONS; THYROID-HORMONE; DIETHYLSTILBESTROL; CHEMICALS; EXPOSURE; MECHANISMS; FERTILITY; DISEASE C1 Univ Texas, Div Pharmacol Toxicol, Coll Pharm, Inst Neurosci, Austin, TX 78712 USA. Univ Texas, Inst Cell & Mol Biol, Austin, TX 78712 USA. NIEHS, NIH, Dept Hlth & Human Serv, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. Univ Massachusetts, Dept Biol, Amherst, MA 01003 USA. Univ Massachusetts, Morrill Sci Ctr, Mol & Cellular Biol Program, Amherst, MA 01003 USA. RP Gore, AC (reprint author), Univ Texas, Div Pharmacol Toxicol, Coll Pharm, Inst Neurosci, Austin, TX 78712 USA. EM andrea.gore@mail.utexas.edu OI Gore, Andrea/0000-0001-5549-6793 FU NIEHS NIH HHS [R13 ES014258-01] NR 26 TC 37 Z9 39 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2006 VL 147 IS 6 SU S BP S1 EP S3 DI 10.1210/en.2005-1367 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 043SF UT WOS:000237621200001 PM 16690798 ER PT J AU Henley, DV Korach, KS AF Henley, Derek V. Korach, Kenneth S. TI Endocrine-disrupting chemicals use distinct mechanisms of action to modulate endocrine system function SO ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT 87th Annual Meeting of the Endocrine-Society CY JUN 04-07, 2005 CL San Diego, CA SP Endocrine Soc ID ESTROGEN-RECEPTOR-ALPHA; ETHYLENE-GLYCOL MONOMETHYL; NEONATAL DIETHYLSTILBESTROL EXPOSURE; N-BUTYL PHTHALATE; IN-UTERO EXPOSURE; FETAL-RAT TESTES; GENE-EXPRESSION; REPRODUCTIVE-TRACT; DI(N-BUTYL) PHTHALATE; BREAST-CANCER AB The term endocrine-disrupting chemicals is used to define a structurally diverse class of synthetic and natural compounds that possess the ability to alter various components of the endocrine system and potentially induce adverse health effects in exposed individuals and populations. Research on these compounds has revealed that they use a variety of both nuclear receptor-mediated and non-receptor-mediated mechanisms to modulate different components of the endocrine system. This review will describe in vitro and in vivo studies that highlight the spectrum of unique mechanisms of action and biological effects of four endocrine-disrupting chemicals diethylstilbestrol, genistein, di(n-butyl)phthalate, and methoxyacetic acid - to illustrate the diverse and complex nature of this class of compounds. C1 NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Korach, KS (reprint author), NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, NIH, MD B3-02POB 12233, Res Triangle Pk, NC 27709 USA. EM korach@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU Intramural NIH HHS NR 77 TC 59 Z9 61 U1 1 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2006 VL 147 IS 6 SU S BP S25 EP S32 DI 10.1210/en.2005-1117 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 043SF UT WOS:000237621200005 PM 16690802 ER PT J AU Newbold, RR Padilla-Banks, E Jefferson, WN AF Newbold, Retha R. Padilla-Banks, Elizabeth Jefferson, Wendy N. TI Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations SO ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT 87th Annual Meeting of the Endocrine-Society CY JUN 04-07, 2005 CL San Diego, CA SP Endocrine Soc ID FEMALE REPRODUCTIVE-TRACT; DEVELOPMENTAL EXPOSURE; UTERINE ADENOCARCINOMA; PRENATAL EXPOSURE; MOUSE UTERUS; DNA METHYLATION; FETAL EXPOSURE; RECEPTOR-BETA; CD-1 MICE; C-FOS AB The synthetic estrogen diethylstilbestrol (DES) is a potent perinatal endocrine disruptor. In humans and experimental animals, exposure to DES during critical periods of reproductive tract differentiation permanently alters estrogen target tissues and results in long-term abnormalities such as uterine neoplasia that are not manifested until later in life. Using the developmentally exposed DES mouse, multiple mechanisms have been identified that play a role in its carcinogenic and toxic effects. Analysis of the DES murine uterus reveals altered gene expression pathways that include an estrogen-regulated component. Thus, perinatal DES exposure, especially at low doses, offers the opportunity to study effects caused by weaker environmental estrogens and provides an example of the emerging scientific field termed the developmental origin of adult disease. As a model endocrine disruptor, it is of particular interest that even low doses of DES increase uterine tumor incidence. Additional studies have verified that DES is not unique; when other environmental estrogens are tested at equal estrogenic doses, developmental exposure results in increased incidence of uterine neoplasia similar to that caused by DES. Interestingly, our data suggest that this increased susceptibility for tumors is passed on from the maternal lineage to subsequent generations of male and female descendants; the mechanisms involved in these transgenerational events include genetic and epigenetic events. Together, our data point out the unique sensitivity of the developing organism to endocrine-disrupting chemicals, the occurrence of long-term effects after developmental exposure, and the possibility for adverse effects to be transmitted to subsequent generations. C1 NIEHS, Dev Endocrinol Sect, Res Triangle Pk, NC 27709 USA. NIEHS, Dev Endocrinol & Endocrine Disruptor Sect, Mol Toxicol Lab, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Newbold, RR (reprint author), NIEHS, Dev Endocrinol Sect, Mail Drop E4-Angle, Res Triangle Pk, NC 27709 USA. EM newbold1@niehs.nih.gov FU Intramural NIH HHS NR 53 TC 215 Z9 222 U1 4 U2 14 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2006 VL 147 IS 6 SU S BP S11 EP S17 DI 10.1210/en.2005-1164 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 043SF UT WOS:000237621200003 PM 16690809 ER PT J AU Rericha, V Kulich, M Rericha, R Shore, DL Sandler, DP AF Rericha, V Kulich, M Rericha, R Shore, DL Sandler, DP TI Incidence of leukemia, lymphoma, and multiple myeloma in Czech uranium miners: A case-cohort study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE chronic lymphocytic leukemia; ionizing radiation; leukemogenesis; occupational exposure; radon ID ATOMIC-BOMB SURVIVORS; CHRONIC LYMPHOCYTIC-LEUKEMIA; RESIDENTIAL RADON EXPOSURE; RED BONE-MARROW; RADIATION-EXPOSURE; IONIZING-RADIATION; CANCER INCIDENCE; MORTALITY; REGISTRY; RISKS AB OBJECTIVE: Uranium miners are chronically exposed to low levels of radon and its progeny. We investigated whether radon exposure is associated with increased incidence of leukemia, lymphoma, or multiple myeloma in this population. DESIGN: We conducted a retrospective case-cohort study in 23,043 uranium miners and identified a total of 177 incident cases of leukemia, lymphoma, and myeloma. Detailed information on occupational radon exposure was obtained for the cases and a randomly selected subcohort of 2,393 subjects. We used the proportional hazards model with power relative risk (RR) function to estimate and test the effects of cumulative radon exposures on incidence rates. RESULTS: Incidence of all leukemia combined and chronic lymphocytic leukemia (CLL) alone was positively associated with cumulative radon exposure. The RR comparing high radon exposure [110 working level months (WLM); 80th percentile] to low radon exposure (3 WLM; 20th percentile) was 1.75 [95% confidence interval (0), 1.10-2.78; p = 0.014] for all leukemia combined and 1.98 (95% Cl, 1.10-3.59; p = 0.016) for CLL. Myeloid leukemia and Hodgkin lymphoma were also associated with radon, but RRs were not statistically significant. There was no apparent association of radon with either non-Hodgkin lymphoma or multiple myeloma. Exposure to radon and its progeny was associated with an increased risk of developing leukemia in underground uranium miners. CLL, not previously believed to be radiogenic, was linked to radon exposure. C1 Hlth Inst Uranium Ind, Pribram, Czech Republic. Charles Univ, Dept Stat, Fac Math & Phys, CZ-18675 Prague 8, Czech Republic. Ctr Epidemiol Studies, Pribram, Czech Republic. Westat Corp, Durham, NC USA. NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Kulich, M (reprint author), Charles Univ, Dept Probabil & Stat, Fac Math & Phys, Sokolovska 83, CZ-18675 Prague 8, Czech Republic. EM kulich@karlin.mff.cuni.cz RI Kulich, Michal/B-1483-2013; OI Kulich, Michal/0000-0002-2812-8968; Sandler, Dale/0000-0002-6776-0018 FU Intramural NIH HHS NR 36 TC 57 Z9 60 U1 1 U2 9 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 JUN PY 2006 VL 114 IS 6 BP 818 EP 822 DI 10.1289/ehp.8476 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 049GS UT WOS:000238004800027 PM 16759978 ER PT J AU Ward, MH Lubin, J Giglierano, J Colt, JS Wolter, C Bekiroglu, N Camann, D Hartge, P Nuckols, JR AF Ward, MH Lubin, J Giglierano, J Colt, JS Wolter, C Bekiroglu, N Camann, D Hartge, P Nuckols, JR TI Proximity to crops and residential exposure to agricultural herbicides in Iowa SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE agriculture; exposure assessment; geographic information systems; herbicides; pesticides ID PESTICIDE EXPOSURE; CARPET DUST; SPRAY DRIFT; CHILDREN; CALIFORNIA; COMMUNITY; CHLORPYRIFOS; PATHWAYS AB Rural residents can be exposed to agricultural pesticides through the proximity of their homes to crop fields. Previously, we developed a method to create historical crop maps using a geographic information system. The aim of the present study was to determine whether crop maps are useful for Predicting levels of crop herbicides in carpet dust samples from residences. From homes of participants in a case-control study of non-Hodgkin lymphoma in Iowa (1998-2000), we collected vacuum cleaner dust and measured 14 herbicides with high use on corn and soybeans in Iowa. Of 112 homes, 58% of residences had crops within 500 m of their home, an intermediate distance for primary drift from aerial and ground applications. Detection rates for herbicides ranged from 0% for metribuzin and cyanazine to 95% for 2,4-dichlorophenoxyacetic acid. Six herbicides used almost exclusively in agriculture were detected in 28% of homes. Detections and concentrations were highest in homes with an active farmer. Increasing acreage of corn and soybean fields within 750 m of homes was associated with significantly elevated odds of detecting agricultural herbicides compared with homes with no crops within 750 m (adjusted odds ratio per 10 acres = 1.06; 95% confidence interval, 1.02-1.11). Herbicide concentrations also increased significantly with increasing acreage within 750 m. We evaluated the distance of crop fields from the home at < 100, 101-250, 251-500, and 501-750 m. Including the crop buffer distance parameters in the model did not significantly improve the fit compared with a model with total acres within 750 m. Our results indicate that crop maps may be a useful method for estimating levels of herbicides in homes from nearby crop fields. C1 NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. Iowa Geol Survey, Iowa City, IA USA. Marmara Univ, Sch Med, Dept Biostat, Istanbul, Turkey. SW Res Inst, San Antonio, TX USA. Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. RP Ward, MH (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd,EPS 8104, Bethesda, MD 20892 USA. EM wardm@mail.nih.gov FU NCI NIH HHS [R01 CA092683, R01 CA92683, N01 PC067008] NR 25 TC 61 Z9 62 U1 0 U2 20 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 JUN PY 2006 VL 114 IS 6 BP 893 EP 897 DI 10.1289/ehp.8770 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 049GS UT WOS:000238004800040 PM 16759991 ER PT J AU Arcury, TA Quandt, SA Barr, DB Hoppin, JA McCauley, L Grzywacz, JG Robson, MG AF Arcury, TA Quandt, SA Barr, DB Hoppin, JA McCauley, L Grzywacz, JG Robson, MG TI Farmworker exposure to pesticides: Methodologic issues for the collection of comparable data SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE biomonitoring; data collection; environmental assessment; farmworker; health outcomes; pesticide exposure ID DIALKYL PHOSPHATE METABOLITES; GREEN TOBACCO SICKNESS; FARM FAMILY EXPOSURE; NORTH-CAROLINA; ORGANOPHOSPHATE PESTICIDES; MIGRANT FARMWORKERS; AGRICULTURAL COMMUNITIES; LATINO FARMWORKERS; CHILDREN; HEALTH AB The exposure of migrant and seasonal farmworkers and their families to agricultural and residential pesticides is it continuing public health concern. Pesticide exposure research has been spurred on by the development of sensitive and reliable laboratory techniques that allow the detection of minute amounts of pesticides or pesticide metabolites. The power of research on farmworker pesticide exposure has been limited because of variability in the collection of exposure data, the predictors of exposure considered, the laboratory procedures used in analyzing the exposure, and the measurement of exposure. The Farmworker Pesticide Exposure Comparable Data Conference assembled 25 scientists from diverse disciplinary and organizational backgrounds to develop methodologic consensus in four areas of farmworker pesticide exposure research: environmental exposure assessment, biomarkers, personal and occupational predictors of exposure, and health outcomes of exposure. In this introduction to this mini-monograph, first, we present the rationale for the conference and its organization. Second, we discuss some of the important challenges in conducting farmworker pesticide research, including the definition and size of the farmworker population, problems in communication and access, and the organization of agricultural work. Third, we summarize major findings from each of the conference's four foci-environmental exposure assessment, biomonitoring, predictors of exposure, and health outcomes of exposure-as well as important laboratory and statistical analysis issues that cross-cut the four foci. C1 Wake Forest Univ, Sch Med, Dept Family & Community Med, Winston Salem, NC 27157 USA. Wake Forest Univ, Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA USA. NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. Univ Med & Dent New Jersey, Sch Publ Hlth, Piscataway, NJ 08854 USA. RP Arcury, TA (reprint author), Wake Forest Univ, Sch Med, Dept Family & Community Med, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM tarcury@wfubmc.edu RI Barr, Dana/E-6369-2011; Barr, Dana/E-2276-2013; OI Grzywacz, Joseph/0000-0002-2308-7781 FU NIEHS NIH HHS [R13 ES013378]; NIOSH CDC HHS [R13 OH013378] NR 41 TC 31 Z9 32 U1 3 U2 9 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 JUN PY 2006 VL 114 IS 6 BP 923 EP 928 DI 10.1289/ehp.8531 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 049GS UT WOS:000238004800045 PM 16759996 ER PT J AU Hoppin, JA Adgate, JL Eberhart, M Nishioka, M Ryan, PB AF Hoppin, JA Adgate, JL Eberhart, M Nishioka, M Ryan, PB TI Environmental exposure assessment of pesticides in farmworker homes SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE dust sampling; fiarmworkers; pesticides ID IN-HOUSE DUST; AGRICULTURAL COMMUNITY; RESIDENTIAL SURFACES; CREVICE TREATMENT; LAWN APPLICATIONS; DERMAL TRANSFER; CARPET DUST; CHILDREN; CHLORPYRIFOS; RESIDUES AB Farmworkers and their families are exposed to pesticides both at work and in their homes. Environmental exposure assessment provides a means to evaluate pesticides in the environment and human contact with these chemicals through identification of sources and routes of exposure. To date, a variety of methods have been used to assess pesticide exposure among farmworker families, mostly focusing on dust and handwipe samples. While many of the methods are similar, differences in the collection, chemical analysis, and statistical analysis, can limit the comparability of results from farmworker studies. This mini-monograph discusses the strategies used to assess pesticide exposures, presents limitations in the available data for farmworkers, and suggests research needs for future studies of pesticide exposure among farmworker Families. C1 NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. Bayer CropSci, Res Triangle Pk, NC USA. Battelle Mem Inst, Columbus, OH 43201 USA. Emory Univ, Atlanta, GA 30322 USA. RP Hoppin, JA (reprint author), NIEHS, Epidemiol Branch, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM hoppin1@niehs.nih.gov RI Ryan, P. Barry/A-7662-2009 FU NIEHS NIH HHS [R13 ES013378]; NIOSH CDC HHS [R13 OH013378] NR 57 TC 13 Z9 14 U1 1 U2 12 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 JUN PY 2006 VL 114 IS 6 BP 929 EP 935 DI 10.1289/ehp.8530 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 049GS UT WOS:000238004800046 PM 16759997 ER PT J AU Galperin, MY AF Galperin, Michael Y. TI Genomes to aid in bioremediation of dry cleaning solvents, mothballs and more SO ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID PRIMARY BILIARY-CIRRHOSIS; BURKHOLDERIA-XENOVORANS LB400; SP-NOV.; METHANOCOCCOIDES-BURTONII; NOVOSPHINGOBIUM-AROMATICIVORANS; ANAEROBIC BACTERIUM; DEEP SUBSURFACE; SEQUENCE; DESULFITOBACTERIUM; NAPHTHALENE C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Galperin, MY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM galperin@ncbi.nlm.nih.gov RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 FU Intramural NIH HHS NR 46 TC 0 Z9 0 U1 0 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1462-2912 J9 ENVIRON MICROBIOL JI Environ. Microbiol. PD JUN PY 2006 VL 8 IS 6 BP 949 EP 955 DI 10.1111/j.1462-2920.2006.01059.x PG 7 WC Microbiology SC Microbiology GA 048LV UT WOS:000237949500001 PM 16689716 ER PT J AU Chung, JS Haque, R Mazumder, DNG Moore, LE Ghosh, N Samanta, S Mitra, S Hira-Smith, MM von Ehrenstein, O Basu, A Liaw, J Smith, AH AF Chung, Joyce S. Haque, Reina Mazumder, D. N. Guha Moore, Lee E. Ghosh, Nilima Samanta, Sambit Mitra, Soma Hira-Smith, Meera M. von Ehrenstein, Ondine Basu, Arindam Liaw, Jane Smith, Allan H. TI Blood concentrations of methionine, selenium, beta-carotene, and other micronutrients in a case-control study of arsenic-induced skin lesions in West Bengal, India SO ENVIRONMENTAL RESEARCH LA English DT Article DE arsenic; drinking water; skin lesions; micronutrients; selenium; methionine; vitamin E; beta-carotene ID MULTIPLE RISK-FACTORS; DRINKING-WATER; BLACKFOOT DISEASE; DIETARY SELENIUM; 6 DISTRICTS; EXPOSURE; CANCER; SUPPLEMENTATION; METHYLATION; GROUNDWATER AB Previous studies have suggested that susceptibility to arsenic toxicity could be influenced by micronutrients, in particular selenium, methionine, and beta-carotene. A case-control study was conducted in West Bengal, India, in a region known to have groundwater arsenic contamination, to determine whether differences in micronutrient status contribute to susceptibility to arsenic-induced skin lesions. Micronutrient status was assessed by blood levels of specific micronutrients and metabolic indicators. Blood was obtained from 180 cases with skin lesions and 192 controls. Blood assays measured micronutrients and carotenoids (folate, selenium, vitamin B12, vitamin B6, retinol, alpha-tocopherol, lutein/zeaxanthin, beta-carotene, lycopene, beta-cryptoxanthin) and metabolic indicators such as glucose, cholesterol, transthyretin, amino acids, and proteins potentially associated with methylation (cysteine, homocysteine, methionine, glutathione). The distributions of nutrient concentrations were similar in cases and controls. The median selenium concentrations in cases and controls were both 1.15 pmol/L, and there was little evidence of differences in other micronutrients. Odds ratios (ORs) for arsenic-induced skin lesions were estimated for each quartile of nutrient concentrations, using the quartile with the highest nutrient level as the referent group. There were no clear trends associated with deficiencies of any micronutrient or metabolic indicator. For decreasing quartiles of selenium, the OR estimates were 1.00, 0.67, 0.99, 0.80; P = 0.81; for methionine, the OR estimates were 1.00, 0.83, 0.78, 0.72; P = 0.29. For beta-carotene, the ORs were 1.00, 0.53, 0.51, 0.96, demonstrating no increased risk at the lower quartiles. The measured micronutrients and metabolic indicators investigated do not appear to modify the risk of developing arsenic-induced skin lesions. The lack of any trend of increasing risk with lower selenium, vitamin E, and beta-carotene concentrations has important implications for proposed therapeutic interventions. The emphasis of interventions should be on reducing arsenic exposure. (c) 2005 Elsevier Inc. All rights reserved. C1 Univ Calif Berkeley, Sch Publ Hlth, Arsen Hlth Effects Res Program, Berkeley, CA 94720 USA. Kaiser Permanente So Calif, Pasadena, CA USA. Postgrad Inst Med Educ & Res, Kolkata, W Bengal, India. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Smith, AH (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Arsen Hlth Effects Res Program, Berkeley, CA 94720 USA. EM ahsmith@berkeley.edu RI Smith, Allan/F-9249-2011; Basu, Arindam/C-1224-2009 OI Basu, Arindam/0000-0003-2326-2292 FU FIC NIH HHS [D43-TW000815]; NIEHS NIH HHS [P42 ES04705]; PHS HHS [R826 137] NR 57 TC 33 Z9 34 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD JUN PY 2006 VL 101 IS 2 BP 230 EP 237 DI 10.1016/j.envres.2005.10.006 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 050SY UT WOS:000238110000010 PM 16332366 ER PT J AU Ayotte, JD Nolan, BT Nucklos, JR Cantor, KP Robinson, GR Baris, D Hayes, L Kargas, M Bress, W Silverman, DT Lubin, JH AF Ayotte, JD Nolan, BT Nucklos, JR Cantor, KP Robinson, GR Baris, D Hayes, L Kargas, M Bress, W Silverman, DT Lubin, JH TI Modeling the probability of arsenic in groundwater in New England as a tool for exposure assessment SO ENVIRONMENTAL SCIENCE & TECHNOLOGY LA English DT Article ID DRINKING-WATER; CANCER MORTALITY; UNITED-STATES; NEW-HAMPSHIRE; BLADDER; BANGLADESH; AQUIFERS; WELLS AB We developed a process-based model to predict the probability of arsenic exceeding 5 mu g/L in drinking water wells in New England bedrock aquifers. The model is being used for exposure assessment in an epidemiologic study of bladder cancer. One important study hypothesis that may explain increased bladder cancer risk is elevated concentrations of inorganic arsenic in drinking water. In eastern New England, 20-30% of private wells exceed the arsenic drinking water standard of 10 micrograms per liter. Our predictive model significantly improves the understanding of factors associated with arsenic contamination in New England. Specific rock types, high arsenic concentrations in stream sediments, geochemical factors related to areas of Pleistocene marine inundation and proximity to intrusive granitic plutons, and hydrologic and landscape variables relating to groundwater residence time increase the probability of arsenic occurrence in groundwater. Previous studies suggest that arsenic in bedrock groundwater may be partly from past arsenical pesticide use. Variables representing historic agricultural inputs do not improve the model, indicating that this source does not significantly contribute to current arsenic concentrations. Due to the complexity of the fractured bedrock aquifers in the region, well depth and related variables also are not significant predictors. C1 US Geol Survey, NH VT Water Sci Ctr, Pembroke, NH 03275 USA. US Geol Survey, Natl Ctr, Reston, VA 20192 USA. Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Dartmouth Coll Sch Med, Norris Cotton Canc Ctr, Lebanon, NH 03756 USA. Dartmouth Coll Sch Med, Epidemiol & Biostat Sect, Dept Community & Family Med, Lebanon, NH 03756 USA. Vermont Dept Hlth, Div Hlth Protect, Burlington, VT 05402 USA. RP Ayotte, JD (reprint author), US Geol Survey, NH VT Water Sci Ctr, 361 Commerce Way, Pembroke, NH 03275 USA. EM jayotte@usgs.gov FU Intramural NIH HHS NR 57 TC 54 Z9 55 U1 0 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0013-936X J9 ENVIRON SCI TECHNOL JI Environ. Sci. Technol. PD JUN 1 PY 2006 VL 40 IS 11 BP 3578 EP 3585 DI 10.1021/es051972f PG 8 WC Engineering, Environmental; Environmental Sciences SC Engineering; Environmental Sciences & Ecology GA 048AY UT WOS:000237921200028 PM 16786697 ER PT J AU Rogawski, MA AF Rogawski, Michael A. TI Diverse mechanisms of antiepileptic drugs in the development pipeline SO EPILEPSY RESEARCH LA English DT Article; Proceedings Paper CT 3rd Workshop on New Horizons in the Development of Antieplileptic Drugs CY NOV 30-DEC 01, 2005 CL Washington, DC DE antiepileptic drug; drug discovery; epilepsy models; maximal electroshock test; pentylenetetrazol test; kindling model ID METHYL-D-ASPARTATE; ENHANCED ANTICONVULSANT ACTIVITY; AMINOBUTYRIC ACID(A) RECEPTOR; KCNQ2/KCNQ3 K+ CHANNELS; GATED SODIUM-CHANNELS; VALPROIC ACID; GABA(A) RECEPTOR; NEUROACTIVE STEROIDS; POTASSIUM CHANNELS; PARTIAL SEIZURES AB There is a remarkable array of new chemical entities in the current antiepileptic drug, (AED) development pipeline. In some cases, the compounds were synthesized in an attempt improve upon the activity of marketed AEDs. In other cases. the discovery of antiepileptic potential was largely serendipitous. Entry into the pipeline begin.,; with the demonstration of activity in one or more animal screening models. Results from testing in a panel Of Such models provide a basis to differentiate agents and may offer clues as to the mechanism. Target activity may their be defined through cell-based studies, often years after the initial identification of activity. Some pipeline compounds are believed to act through conventional targets. whereas others are structurally novel and may act by novel mechanisms. Follow-on agents include the levetiracetam analogs brivaracetam and seletracetam that act as SV2A-ligands the valproate-like agents valrocemide, valnoctamide. propylisopropyl acetamide. and isovaleramide; the felbamate analog flurofelbamate. a dicarbamate. and the unrelated carbamate RWJ-333369: the oxcarbazepine analog licarbazepine, which probably acts as a use-dependent sodium channel blockers. and its prodrug acetate BIA 2-093; various selective partial benzodiazepine receptor agonists, including ELB 139, which is a positive allosteric modulator of alpha 3-containing GABA(A) receptors. A variety of AEDs that may act through novel targets are also in clinical development: lacosamide, a functionalized amino acid: talampanel, a 2.3-benzodiazepine selective noncompetitive AMPA receptor antagonists NS1209, a competitive AMPA receptor antagonist; ganaxolone, a neuroactive steroid that acts as a positive modulator of GABA(A) receptors; retigabine, a KCNQ potassium channel opener with activity as a GABA(A) receptor positive modulator: tire benzanilide KCNQ potassium channel opener ICA-27243 that is more selective than retigabine and rufinamide. a triazole of unknown mechanism. (c) 2006 Elsevier B.V. All rights reserved. C1 NINDS, Epilepsy Res Sect, NIH, Bethesda, MD 20892 USA. RP Rogawski, MA (reprint author), NINDS, Epilepsy Res Sect, NIH, 35 Convent Dr MSC 3702, Bethesda, MD 20892 USA. EM michael.rogawski@nih.gov RI Rogawski, Michael/B-6353-2009 OI Rogawski, Michael/0000-0002-3296-8193 FU NINDS NIH HHS [Z01 NS002732-19] NR 165 TC 191 Z9 197 U1 6 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-1211 J9 EPILEPSY RES JI Epilepsy Res. PD JUN PY 2006 VL 69 IS 3 BP 273 EP 294 DI 10.1016/j.eplepsyres.2006.02.004 PG 22 WC Clinical Neurology SC Neurosciences & Neurology GA 062DO UT WOS:000238925000002 PM 16621450 ER PT J AU Williams, RA Gavin, JR Phillips, RA Sumner, AE Duncan, AK Hollar, D Hennekens, CH AF Williams, Richard Allen Gavin, James R., III Phillips, Robert A. Sumner, Anne E. Duncan, Alan K. Hollar, Danielle Hennekens, Charles H. TI High-risk African Americans with multiple risk factors for cardiovascular disease: Challenges in prevention, diagnosis, and treatment SO ETHNICITY & DISEASE LA English DT Article; Proceedings Paper CT 20th Annual International Interdisciplinary Conference on Hypertension and Related Cardiovascular Risk Factors in Ethnic Populations CY JUL, 2005 CL San Juan, PR DE African Americans; cardiovascular disease; high-risk ID NUTRITION EXAMINATION SURVEY; CORONARY-HEART-DISEASE; LEFT-VENTRICULAR MASS; OPTIMAL TREATMENT HOT; 3RD NATIONAL-HEALTH; HIGH BLOOD-PRESSURE; DIABETES-MELLITUS; METABOLIC SYNDROME; RENAL-INSUFFICIENCY; RANDOMIZED-TRIAL AB Coronary heart disease (CHID) is the second leading cause of death in the United States. Despite previous downward trends, which have not persisted, CHID mortality remains higher in African Americans than in Whites. Among African American and White adolescents and adults are trends of increased physical inactivity, smoking, and obesity. Approximately 47 million Americans have metabolic syndrome, a constellation of obesity, hypertension, dyslipidemia, and insulin resistance leading to diabetes. Despite a lower prevalence of metabolic syndrome, African Americans are more insulin resistant than Whites at similar degrees of adiposity, have higher blood pressures, and among women, have more obesity. Since African Americans tend to be diagnosed later and have more risk factors, which confers greater than additive risks, we propose the term "African American multiple-risk patient (AAMRP)." The AAMRP poses clinical and public health challenges for healthcare providers. We provide clinical and public health strategies for early detection and aggressive management of AAMRP. C1 Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, Minor Hlth Inst, Los Angeles, CA USA. Morehouse Sch Med, Atlanta, GA USA. NYU, Lenox Hill Hosp, Dept Med, Sch Med, New York, NY USA. NIDDKD, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Mayo Clin & Mayo Grad Sch Med, Rochester, MN USA. Florida Atlantic Univ, Dept Biomed Sci, Ctr Excellence, Boca Raton, FL 33431 USA. Univ Miami, Sch Med, Dept Med, Miami, FL 33152 USA. Univ Miami, Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33152 USA. RP Hennekens, CH (reprint author), 2800 S Ocean Blvd,PH-A, Boca Raton, FL 33432 USA. EM PROFCHHMD@prodigy.net FU Intramural NIH HHS NR 60 TC 11 Z9 12 U1 0 U2 1 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X J9 ETHNIC DIS JI Ethn. Dis. PD SUM PY 2006 VL 16 IS 3 BP 633 EP 639 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 067FO UT WOS:000239287400003 PM 16937598 ER PT J AU Luther, EJ Bagot, KS Franken, FH Moolchan, ET AF Luther, Emily J. Bagot, Kara S. Franken, Frederick H. Moolchan, Eric T. TI Reasons for wanting to quit: Ethnic differences among cessation-seeking adolescent smokers SO ETHNICITY & DISEASE LA English DT Article ID GENDER-DIFFERENCES; SMOKING-CESSATION; YOUTH SMOKING; AMERICANS; PATTERNS; POLICIES; PRICES; BLACK AB Objective: Enhancing adolescent cessation requires an understanding of approaches that will motivate youths to quit smoking. Methods: We compared reasons for wanting to quit expressed by European Americans to those of African American youths. Adolescent cessation-seeking smokers completed telephone interviews regarding their smoking behavior and reasons for wanting to quit in an open-ended format. Responses were then classified into nine categories. Results: Participants included 1,268 Baltimore-area adolescents (mean age 15.6 +/- 1.7 years, 60% female, 58% European American, mean Fagerstrom Test for Nicotine Dependence 5.8 +/- 2.2). While both groups broadly cited health as the predominant reason for wanting to quit, chi-square analyses of further stratification of health into general, future, and current health concerns showed that European Americans were more likely to endorse current health reasons (P <.001), while African Americans were more likely to state general health reasons (P=.004). European Americans were more likely to state cost (P=.002) or to not give a reason for wanting to quit (P=.008), while African Americans more frequently reported a lack of positive (pharmacologic or social) reinforcement (P <.001). Conclusions: The development of culturally tailored messages may help enhance smoking cessation efforts among adolescents. C1 NIDA, Teen Tobacco Addict Res Clin, Clin Pharmacol & Therapeut Res Branch, Baltimore, MD USA. RP Moolchan, ET (reprint author), 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. FU Intramural NIH HHS NR 23 TC 4 Z9 4 U1 1 U2 3 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X J9 ETHNIC DIS JI Ethn. Dis. PD SUM PY 2006 VL 16 IS 3 BP 739 EP 743 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 067FO UT WOS:000239287400018 PM 16937613 ER PT J AU Wyatt, SB Crump, ME Walker, E Sarpong, D AF Wyatt, S. B. Crump, M. E. Walker, E. Sarpong, D. TI Participation in an observational study alters health behaviors in African Americans: The Jackson Heart Study baseline exam SO ETHNICITY & DISEASE LA English DT Meeting Abstract C1 Univ Mississippi, Med Ctr, Sch Nursing, Jackson Heart Study Examinat Ctr, University, MS 38677 USA. Univ Mississippi, Med Ctr, Sch Med, Jackson Heart Study Examinat Ctr, University, MS 38677 USA. NHLBI, Bethesda, MD 20892 USA. Jackson State Univ, Sch Publ Hlth, Jackson Heart Study Coordinating Ctr, Jackson, MS USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X J9 ETHNIC DIS JI Ethn. Dis. PD SUM PY 2006 VL 16 IS 3 BP S43 EP S43 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 067FO UT WOS:000239287400041 ER PT J AU Stojanov, S Hoffmann, F Kery, A Renner, ED Hartl, D Lohse, P Huss, K Fraunberger, P MalleY, JD Zellerer, S Albert, MH Belohradsky, BH AF Stojanov, Silvia Hoffmann, Florian Kery, Anja Renner, Ellen D. Hartl, Dominik Lohse, Peter Huss, Kristina Fraunberger, Peter MalleY, James D. Zellerer, Stephanie Albert, Michael H. Belohradsky, Bernd H. TI Cytokine profile in PFAPA syndrome suggests continuous inflammation and reduced anti-inflammatory response SO EUROPEAN CYTOKINE NETWORK LA English DT Article DE PFAPA syndrome; periodic fever; cytokine; inflammation; IL-1 beta; IFN-gamma ID FAMILIAL MEDITERRANEAN FEVER; PERIODIC FEVER; APHTHOUS STOMATITIS; HYPERIMMUNOGLOBULINEMIA-D; FLOW-CYTOMETRY; AUTOINFLAMMATORY DISEASES; PHARYNGITIS; ACTIVATION; ADENOPATHY; CIMETIDINE AB PFAPA syndrome is characterized by periodic episodes of high fever, aphthous stomatitis, pharyngitis, and/or cervical adenitis. It is of unknown etiology and manifests usually before 5 years of age. We determined serum and intracellular cytokine levels in six PFAPA patients (4 males, 2 females, mean age 8 years (+/- 1.2 SEM), range 4-13) during the symptom-free period as well as 6-12 hours and 18-24 hours after fever onset. Values were compared to age-matched, healthy controls. Febrile PFAPA attacks led to a significant increase in IL-6 and IFN-gamma serum concentrations compared to symptom-free periods and to controls, with IL-1 beta, TNF-alpha and IL-12p70 levels being significantly higher than in controls. Lymphocytic IFN-gamma and CD8+ IL-2 production was consistently significantly elevated compared to healthy children. During the asymptomatic period, serum concentrations of IL-1 beta, IL-6, TNF-alpha and IL-12p70 were significantly increased compared to controls. Intracellular TNF-alpha synthesis was not elevated at any time point. Soluble TNFRp55 levels were even lower in between febrile episodes, reaching values comparable to controls during attacks, whereas soluble TNFRp75 levels increased during attacks compared to healthy children. Anti-inflammatory IL-4 in serum was at all times lower in PFAPA patients compared to controls with no difference in levels of intracellular IL-4 and IL-10 or serum IL-10. The observed increase of pro-inflammatory mediators, even between febrile attacks, suggests a dysregulation of the immune response in PFAPA syndrome, with continuous pro-inflammatory cytokine activation and a reduced anti-inflammatory response. C1 NIAMSD, Genet & Genom Branch, NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. Univ Munich, Dept Clin Chem Grosshadern, D-80539 Munich, Germany. Univ Washington, Dept Pediat, Seattle, WA 98195 USA. Childrens Hosp, Seattle, WA USA. Univ Munich, Childrens Hosp, Dept Infect Dis & Immunol, D-80539 Munich, Germany. RP Stojanov, S (reprint author), NIAMSD, Genet & Genom Branch, NIH, Ctr Informat Technol, Bldg 10,Room 9N210,10 Ctr Dr, Bethesda, MD 20892 USA. EM stojanos@mail.nih.gov NR 35 TC 61 Z9 64 U1 0 U2 0 PU JOHN LIBBEY EUROTEXT LTD PI MONTROUGE PA 127 AVE DE LA REPUBLIQUE, 92120 MONTROUGE, FRANCE SN 1148-5493 J9 EUR CYTOKINE NETW JI Eur. Cytokine Netw. PD JUN PY 2006 VL 17 IS 2 BP 90 EP 97 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 068GI UT WOS:000239360300002 PM 16840027 ER PT J AU Johnson, BD Shaw, LJ Pepine, CJ Reis, SE Kelsey, SF Sopko, G Rogers, WJ Mankad, S Sharaf, BL Bittner, V Merz, CNB AF Johnson, BD Shaw, LJ Pepine, CJ Reis, SE Kelsey, SF Sopko, G Rogers, WJ Mankad, S Sharaf, BL Bittner, V Merz, CNB TI Persistent chest pain predicts cardiovascular events in women without obstructive coronary artery disease: results from the NIH-NHLBI-sponsored Women's Ischaemia Syndrome Evaluation (WISE) study SO EUROPEAN HEART JOURNAL LA English DT Article; Proceedings Paper CT 4th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke CY OCT 13-14, 2002 CL WASHINGTON, DC SP Amer Heart Assoc Council Cardiovasc Dis Young, Amer Heart Assoc Council Cardiovasc Nursing, Amer Heart Assoc Council Cardio Thorac & Vasc Surg, Amer Coll Cardiol Fdn, Dept Vet Affairs DE chest pain; prognosis; women; myocardial ischaemia ID TERM-FOLLOW-UP; CARDIAC SYNDROME-X; NATIONAL-HEART; MICROVASCULAR ANGINA; MYOCARDIAL-ISCHEMIA; PROGNOSIS; ARTERIOGRAMS; FEATURES; ABSENCE; LUNG AB Aims Women with chest pain but without obstructive coronary artery disease (CAD) are considered at low risk for cardiovascular (CV) events, but half continue to experience debilitating chest pain over many years. This study compared CV outcomes in women with persistent chest pain (PChP) vs. those without PChP Methods and results We studied 673 Women's Ischaemia Syndrome Evaluation (WISE) participants with chest pain undergoing coronary angiography for suspected myocardial ischaemia and at least 1 year of follow-up. PChP was defined as self-reported continuing chest pain after 1 year. Events occurring after that year were recorded for a median of 5.2 years. We compared CV event rates for women with and without PChP in subgroups with and without obstructive CAD. The median age was 58 years, 20% were racial minorities, 45% had PChP, 39% had obstructive CAD. Among women without CAD, those with PChP had more than twice the rate of composite CV events (P=0.03), that included non-fatal myocardial infarctions (P=0.11), strokes (P=0.03), congestive heart failure (P=0.38), and CV deaths (P=0.73), compared with those without PChP In women with CAD, there was no difference in composite CV events in those with and without PChP (P=0.72). Conclusion Among women undergoing coronary angiography for suspected myocardial ischaemia, PChP in women with no obstructive CAD predicted adverse CV outcomes. Such women might benefit from additional evaluation and aggressive risk factor modification therapy. C1 Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. Cedars Sinai Med Ctr, Cedars Sinai Res Inst, Dept Med, Div Cardiol, Los Angeles, CA 90048 USA. Univ Florida, Div Cardiovasc Med, Gainesville, FL USA. Univ Pittsburgh, Med Ctr, Cardiovasc Inst, Pittsburgh, PA USA. NHLBI, Bethesda, MD 20892 USA. Univ Alabama, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA. Allegheny Univ Hlth Sci, Dept Med, Div Cardiol, Pittsburgh, PA USA. Rhode Isl Hosp, Div Cardiol, Providence, RI 02903 USA. RP Johnson, BD (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. EM djohnson@edc.pitt.edu RI Reis, Steven/J-3957-2014; OI Bittner, Vera/0000-0001-9456-850X FU NCRR NIH HHS [M01-RR00425]; NHLBI NIH HHS [N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, U01 HL649141, U01 HL649241]; PHS HHS [U0164829] NR 52 TC 99 Z9 103 U1 0 U2 1 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 JUN PY 2006 VL 27 IS 12 BP 1408 EP 1415 DI 10.1093/eurheartj/ehl040 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 058QJ UT WOS:000238679400007 PM 16720691 ER PT J AU Domanski, MJ Jablonski, KA Rice, MM Fowler, SE Braunwald, E AF Domanski, MJ Jablonski, KA Rice, MM Fowler, SE Braunwald, E CA PEACE Investigators TI Obesity and cardiovascular events in patients with established coronary disease SO EUROPEAN HEART JOURNAL LA English DT Article DE coronary artery disease; obesity; sex ID BODY-MASS INDEX; MYOCARDIAL-INFARCTION; HEART-DISEASE; ARTERY-DISEASE; RISK; TRENDS; IMPACT; PROGNOSIS; WOMEN; MEN AB Aims To explore the association between obesity and major adverse coronary events (MACE) in patients with established coronary artery disease (CAD). Methods and results The Prevention of Events with Angiotensin Converting Enzyme-Inhibition (PEACE) Trial randomized 8290 patients with stable CAD and left ventricular (LV) ejection fraction (EF) (LVEF) >= 0.40 to trandolapril or placebo and followed them for a median of 4.8 years. In PEACE patients who were non-diabetic at baseline (5693 men and 1171 women), we used proportional hazards models to conduct a post hoc analysis to examine whether obesity, defined as a body mass index (BMI) >= 30 kg/m(2), is an independent risk factor for the composite endpoint of MACE, defined as cardiovascular death, non-fatal myocardial infarction, coronary revascularization, or stroke. The analysis was conducted separately for men and women. The baseline prevalence of obesity was 28.5% in men and 28.9% in women. After adjusting for significant confounders, obesity was associated with MACE in men [hazard ratio (HR) = 1.28, 95% CI 1.13-1.46, P < 0.01], but not in women (HR = 0.96, 95% CI 0.70-1.31, P = 0.77). Further categorization of BMI showed a J-shaped association between BMI and MACE in the men, and no association in the women. Conclusion In the presence of established CAD, obesity is associated with risk for MACE in men, but there is no support of an association in women. This finding requires further evaluation. C1 NHLBI, Clin Trials Grp, Bethesda, MD 20892 USA. George Washington Univ, Ctr Biostat, Rockville, MD USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Boston, MA 02115 USA. RP Domanski, MJ (reprint author), NHLBI, Clin Trials Grp, Bldg 10, Bethesda, MD 20892 USA. EM domanskm@nhlbi.nih.gov RI G, G/A-3459-2012 FU NHLBI NIH HHS [N01HC65149] NR 25 TC 19 Z9 21 U1 0 U2 0 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 JUN PY 2006 VL 27 IS 12 BP 1416 EP 1422 DI 10.1093/eurheartj/ehl022 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 058QJ UT WOS:000238679400008 PM 16707546 ER PT J AU Nishizuka, S AF Nishizuka, S TI Profiling cancer stem cells using protein array technology SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE protein array; cancer stem cell; 'reverse-phase' protein lysate microarray; proteomic profiling; proteomics ID CATALYZED REPORTER DEPOSITION; ACUTE MYELOID-LEUKEMIA; SIGNAL AMPLIFICATION; HIGH-THROUGHPUT; BREAST-CANCER; PROSPECTIVE IDENTIFICATION; COLORECTAL TUMORIGENESIS; PROSTATE-CANCER; SELF-RENEWAL; MICROARRAYS AB Since cancer cells and somatic stem cells share the biological characteristics of self-renewal and proliferation, it has been suggested that the principles of stem cell biology can be applied to improve our understanding of cancer biology. Recent studies have shown that the majority of cancers appear to originate from a small subset of cells that have the ability of self-renewal and to proliferate, namely 'cancer stem cells'. The isolation of cancer stem cells has been demonstrated using cell surface markers in haematopoietic and nonhaematopoietic malignancies. Advances in protein array technologies have enabled the use of minuscule amounts of biological materials to profile these cells at the molecular level. Using a combination of protein arrays and cancer stem cell isolation techniques, a higher resolution molecular profiling can be performed, which might improve therapies targeting the cancer stem cells. Published by Elsevier Ltd. C1 NCI, Mol Translat Technol Mol Therapeut Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Lab Proteom & Analyt Technol, SAIC Frederick Inc, Ft Detrick, MD 21702 USA. RP Nishizuka, S (reprint author), NCI, Mol Translat Technol Mol Therapeut Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM nishizus@mail.nih.gov FU NCI NIH HHS [N01 CO-12400] NR 90 TC 16 Z9 19 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUN PY 2006 VL 42 IS 9 BP 1273 EP 1282 DI 10.1016/j.ejca.2006.01.042 PG 10 WC Oncology SC Oncology GA 056XZ UT WOS:000238559700011 PM 16644205 ER PT J AU Yang, HP Woodson, K Taylor, PR Pietinen, P Albanes, D Virtamo, J Tangrea, JA AF Yang, HP Woodson, K Taylor, PR Pietinen, P Albanes, D Virtamo, J Tangrea, JA TI Genetic variation in interleukin 8 and its receptor genes and its influence on the risk and prognosis of prostate cancer among Finnish men in a large cancer prevention trial SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE ATBC Cancer Prevention Study; genetic polymorphism; interleukin 8 (IL-8); interleukin 8 receptors (CXCR1 and CXCR2); prostate cancer ID NEUTROPHIL-ACTIVATING PEPTIDE-2; ALPHA-TOCOPHEROL; CARCINOMA-CELLS; BETA-CAROTENE; NUDE-MICE; EXPRESSION; CHEMOKINES; TUMORIGENICITY; ANGIOGENESIS; HYPERPLASIA AB The cytokine interleukin 8 (IL-8) may play a role in the pathogenesis of prostate cancer through the modulation of tumour immune response or enhanced angiogenesis. A common polymorphism of the IL-8 (-251) gene, which may affect the production level of the cytokine, has been inversely associated with a number of diseases, including prostate cancer. We examined the most representative single nucleotide polymorphisms (SNPs) for the IL-8 and its receptors (CXCR1 and CXCR2) genes, and conducted a case-control study nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study to examine if these SNPs are associated with susceptibility to and prognosis of prostate cancer. Using incidence density sampling, 584 cases of primary prostate cancer and 584 matched controls were selected. In this population, we observed no strong association between the SNPs for IL-8 -251 (A T), CXCR1 +860 (C -> G) and CXCR2-1010 (A -> G) and either the subsequent risk of prostate cancer or individual prognostic factors among cases. Although none of the SNPs studied are likely to have major effects on prostate cancer susceptibility, a role for other polymorphisms associated within these genes cannot be excluded. European Journal of Cancer Prevention 15:249-253 (c) 2006 Lippincott Williams & Wilkins. C1 NCI, Div Canc Prevent, Prostate & Urol Canc Res Grp, NIH,Canc Prevent Studies Branch,Ctr Canc Res, Rockville, MD 20852 USA. DHHS, Emerging Leaders Program, Washington, DC USA. Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Helsinki, Finland. NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Tangrea, JA (reprint author), NCI, Div Canc Prevent, Prostate & Urol Canc Res Grp, NIH,Canc Prevent Studies Branch,Ctr Canc Res, EPN 2102,6130 Execut Blvd, Rockville, MD 20852 USA. EM tangreaj@mail.nih.gov RI Albanes, Demetrius/B-9749-2015 NR 26 TC 22 Z9 24 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-8278 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD JUN PY 2006 VL 15 IS 3 BP 249 EP 253 DI 10.1097/01.cej.0000199504.07947.e7 PG 5 WC Oncology SC Oncology GA 053ZU UT WOS:000238345800010 PM 16679868 ER PT J AU Ahmed, A Aban, IB Weaver, MT Aronow, WS Fleg, JL AF Ahmed, A Aban, IB Weaver, MT Aronow, WS Fleg, JL TI Serum digoxin concentration and outcomes in women with heart failure: A bi-directional effect and a possible effect modification by ejection fraction SO EUROPEAN JOURNAL OF HEART FAILURE LA English DT Article DE serum digoxin concentration; outcomes; women; heart failure; ejection fraction ID OLDER PATIENTS; DIG TRIAL; MORTALITY; ASSOCIATION; MORBIDITY; POPULATION; PREVALENCE; PREDICTORS; GUIDELINES; MANAGEMENT AB Background: The association between serum digoxin concentration (SDC) and outcomes in women with heart failure (HF) has not been well studied. Aims: To test the hypothesis that the effect of digoxin on outcomes in women with HF is bi-directional and dependent on SDC, as in men, and is modified by ejection fraction (EF). Methods: We studied 1366 female participants of the Digitalis Investigation Group trial in whom data on SDC (ng/ml) were available. We calculated adjusted odds ratios (AOR) and Bonferroni-adjusted 97.5% confidence intervals (CI) for various outcomes at a median follow up of 41 months, in all women and stratified by EF 35%. Results: Compared with placebo (26.9%), 40.3% with SDC > 1.2 (AOR=1.80; CI=1.14-2.86; p=0.004) and 26.6% with SDC 0.5-1.1 (AOR= 1.05; CI=0.73-1.51; p=0.762) died. Respective rates for HF-hospitalizations were: placebo (32.8%), SDC >= 1.2 (38.0%) and SDC 0.5-1.1 (25.5%). For women with EF < 35% (N=677), SDC 0.5-1.1 lowered odds for HF-hospitalizations (AOR=0.63; CI=0.39-1.00; p=0.026) without increasing odds for death (AOR=0.77; CI=0.47-1.26;p=0.233). Inwomenwith EF > 35% (N=689), SDC 0.5-1.1 had a borderline association with death (AOR=1.58; CI=0.92-2.72; p=0.058) but not with HF-hospitalization (AOR=0.95; CI=0.54-1.66; p=0.826). Conclusions: As in men, in women with HF, digoxin has a bi-directional effect based on SDC, and the beneficial effects were significant only among women with EF < 35%. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved. C1 Univ Alabama, Div Gerontol & Geriatr Med, Dept Med, Birmingham, AL 35294 USA. Vet Affairs Med Ctr, Sect Geriatr, Birmingham, AL USA. Univ Alabama, Dept Biostat, Birmingham, AL 35294 USA. Univ Alabama, Dept Epidemiol, Birmingham, AL 35294 USA. Univ Alabama, Sch Publ Hlth, Ctr Heart Failure Res, Birmingham, AL 35294 USA. Univ Alabama, Sch Nursing, Ctr Nursing Res, Birmingham, AL 35294 USA. New York Med Coll, Dept Med, Div Cardiol, Valhalla, NY 10595 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Ahmed, A (reprint author), Univ Alabama, Div Gerontol & Geriatr Med, Dept Med, 1530 3rd Ave S,CH 19,Ste 219, Birmingham, AL 35294 USA. EM aahmed@uab.edu RI Ahmed, Ali/A-2934-2008 OI Ahmed, Ali/0000-0002-6832-6424 FU NIA NIH HHS [K23 AG019211, K23 AG019211-02, K23 AG019211-03, 1-K23-AG19211-01] NR 47 TC 15 Z9 16 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-9842 J9 EUR J HEART FAIL JI Eur. J. Heart Fail. PD JUN PY 2006 VL 8 IS 4 BP 409 EP 419 DI 10.1016/j.ejheart.2005.10.002 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 059RR UT WOS:000238750400012 PM 16311070 ER PT J AU Parle-McDermott, A Kirke, PN Mills, JL Molloy, AM Cox, C O'Leary, VB Pangilinan, F Conley, M Cleary, L Brody, LC Scott, JM AF Parle-McDermott, A Kirke, PN Mills, JL Molloy, AM Cox, C O'Leary, VB Pangilinan, F Conley, M Cleary, L Brody, LC Scott, JM TI Confirmation of the R653Q polymorphism of the trifunctional C1-synthase enzyme as a maternal risk for neural tube defects in the Irish population SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE folate; NTD; spina bifida; MTHFD1; C1 synthase; Irish ID GENETIC RISK; LINKAGE DISEQUILIBRIUM; VARIANTS; SYNTHETASE; REDUCTASE; PATHWAY; DISEASE; FOLATE; MTHFD AB The risk of neural tube defects (NTDs) is known to have a significant genetic component that could act through either the NTD patient and/ or maternal genotype. The success of folic acid supplementation in NTD prevention has focused attention on polymorphisms within folate-related genes. We previously identified the 1958G > A (R653Q) polymorphism of the trifunctional enzyme MTHFD1 ( methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate- cyclohydrolase, formyltetrahydrofolate synthetase; often referred to as 'C1 synthase') as a maternal risk for NTDs, but this association remains to be verified in a separate study to rule out a chance finding. To exclude this possibility, we genotyped an independent sample of mothers with a history of an NTD-affected pregnancy derived from the same Irish population. In this sample there was a significant excess of 1958AA homozygote mothers of NTD cases (n = 245) compared to controls ( n 770). The direction and magnitude of risk ( odds ratio 1.49 (1.07 - 2.09), P = 0.019) is consistent with our earlier finding. Sequencing of the MTHFD1 gene revealed that this association is not being driven by another common variant within the coding region. We have established that the MTHFD1 1958G > A polymorphism has a significant role in influencing a mother's risk of having an NTD- affected pregnancy in the Irish population. C1 Univ Dublin Trinity Coll, Sch Biochem & Immunol, Dublin 2, Ireland. Hlth Res Board, Child Hlth Epidemiol Div, Dublin, Ireland. Natl Inst Child Hlth & Human Dev, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, NIH, Bethesda, MD USA. Univ Dublin Trinity Coll, Sch Med, Dublin 2, Ireland. NHGRI, Mol Pathogenesis Sect, Genome Technol Branch, Bethesda, MD 20892 USA. RP Scott, JM (reprint author), Univ Dublin Trinity Coll, Sch Biochem & Immunol, Dublin 2, Ireland. EM jscott@tcd.ie OI Molloy, Anne/0000-0002-1688-9049; O'Leary, Valerie/0000-0003-1171-9830 FU Intramural NIH HHS NR 15 TC 67 Z9 71 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD JUN PY 2006 VL 14 IS 6 BP 768 EP 772 DI 10.1038/sj.ejhg.5201603 PG 5 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 046IY UT WOS:000237806400016 PM 16552426 ER PT J AU Kindzelskii, AL Clark, AJ Espinoza, J Maeda, N Aratani, Y Romero, R Petty, HR AF Kindzelskii, AL Clark, AJ Espinoza, J Maeda, N Aratani, Y Romero, R Petty, HR TI Myeloperoxidase accumulates at the neutrophil surface and enhances cell metabolism and oxidant release during pregnancy SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE metabolism; myeloperoxidase; NADPH oxidase; neutrophil activation; pregnancy ID UNDERGOES RETROGRADE TRAFFICKING; POLYMORPHONUCLEAR LEUKOCYTE; SALICYLHYDROXAMIC ACID; SUPRAMOLECULAR COMPLEX; NADPH OXIDASE; HOST-DEFENSE; OSCILLATIONS; ACTIVATION; GLUCOSE-6-PHOSPHATE-DEHYDROGENASE; PREECLAMPSIA AB Pregnancy is a unique immunological state. Pregnancy neutrophils differ from those of non-pregnant women as they cannot be fully activated for oxidant production, but yet have higher levels of unstimulated oxidant production. Although reduced activation is due to decreased hexose monophosphate shunt activity, the mechanism enhancing basal oxidant levels is unknown. We hypothesize that myeloperoxidase (MPO) trafficking affects the basal oxidant release by maternal neutrophils. Immunofluorescence microscopy has demonstrated MPO at the surface of pregnancy neutrophils, whereas non-pregnancy cells do not exhibit surface MPO. Adherent pregnancy neutrophils were characterized by high-amplitude metabolic oscillations, which were blocked by MPO inactivation. Conversely, metabolic oscillatory amplitudes of control neutrophils were heightened by incubation with PMA or exogenous MPO. Importantly, MPO decoration of cell surfaces and high-amplitude metabolic oscillations were observed for neutrophils from pregnant but not from non-pregnant mice. However, cells from pregnant MPO knockout mice did not exhibit MPO expression or high-amplitude metabolic oscillations. Unstimulated neutrophils from pregnant women were found to release reactive oxygen metabolites (ROM) and reactive nitrogen intermediates (RNI), but cells from non-pregnant women did not. MPO inhibition returned ROM and RNI formation to non-pregnant levels. Hence, MPO trafficking influences metabolic activity and oxidant production in pregnancy. C1 Univ Michigan, Med Sch, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. Hutzel Hosp, Natl Inst Child Hlth & Human Dev, Perinatol Res Branch, Detroit, MI USA. Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC USA. Yokohama City Univ, Kihara Inst Biol Res, Yokohama, Kanagawa 232, Japan. Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI USA. RP Petty, HR (reprint author), Univ Michigan, Med Sch, Dept Ophthalmol & Visual Sci, 1000 Wall St, Ann Arbor, MI 48105 USA. EM hpetty@umich.edu FU Intramural NIH HHS NR 41 TC 13 Z9 13 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUN PY 2006 VL 36 IS 6 BP 1619 EP 1628 DI 10.1002/eji.200535391 PG 10 WC Immunology SC Immunology GA 054UW UT WOS:000238405100026 PM 16688678 ER PT J AU Marquez, VE AF Marquez, VE TI Regulatory domains of PKC as drug targets SO EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Meeting Abstract CT 18th Helsinki Drug Research CY JUN 01-02, 2006 CL Helsinki, FINLAND SP Univ Helsinki, Fac Pharmacy, Finnish Pharmaceut Soc, European Federat Pharmaceut Sci C1 NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0928-0987 J9 EUR J PHARM SCI JI Eur. J. Pharm. Sci. PD JUN PY 2006 VL 28 SU 1 BP S2 EP S3 DI 10.1016/j.ejps.2006.02.010 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 043XG UT WOS:000237635600005 ER PT J AU Lovblad, KO Baird, AE AF Lovblad, KO Baird, AE TI Actual diagnostic approach to the acute stroke patient SO EUROPEAN RADIOLOGY LA English DT Article DE stroke; computed tomography; magnetic resonance imaging; penumbra; diffusion imaging ID ACUTE ISCHEMIC-STROKE; DIFFUSION-WEIGHTED MR; CEREBRAL-BLOOD-FLOW; TISSUE-PLASMINOGEN ACTIVATOR; LOCAL INTRAARTERIAL THROMBOLYSIS; HIGH-RESOLUTION MEASUREMENT; ACUTE HEMISPHERIC STROKE; TRACER BOLUS PASSAGES; DENSE ARTERY SIGN; MAGNETIC-RESONANCE AB Since acute stroke is now considered a potentially treatable medical emergency, a rapid and correct diagnosis must be made. The first step is to exclude hemorrhage, then to visualize any early ischemic changes, demonstrate the presence of hypoperfusion and locate the presence of a vascular underlying pathology as well as elucidate the presence of a potential penumbra (tissue at risk). Thanks to improvements and advances in both MR and CT technology, this can now be done in a number of ways. At the moment, CT is the most widely available and fast method for obtaining imaging of the brain and neck vessels of patients presenting with acute stroke. MRI can provide more precise information, although it remains slightly more time-consuming, but is, however, the method of choice for follow-up imaging. The main point is to take the one-stop-shopping approach where imaging of the vessels and brain is done from the aortic arch to the circle of Willis in one single session in order to have all the necessary information in the acute phase. C1 HUG Geneva Univ Hosp, SRRI, Dept Radiol, Neuroradiol Unit, CH-1211 Geneva 14, Switzerland. NINDS, Stroke Neurosci Unit, Bethesda, MD 20892 USA. RP Lovblad, KO (reprint author), HUG Geneva Univ Hosp, SRRI, Dept Radiol, Neuroradiol Unit, 24 Rue Micheli Crest, CH-1211 Geneva 14, Switzerland. EM karl-olof.lovblad@hcuge.ch OI lovblad, karl-olof/0000-0003-2768-9779 NR 94 TC 25 Z9 25 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0938-7994 J9 EUR RADIOL JI Eur. Radiol. PD JUN PY 2006 VL 16 IS 6 BP 1253 EP 1269 DI 10.1007/s00330-005-0103-3 PG 17 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 049OI UT WOS:000238025500007 PM 16372164 ER PT J AU Hanakawa, T Honda, M Zito, G Dimyan, MA Hallett, M AF Hanakawa, T Honda, M Zito, G Dimyan, MA Hallett, M TI Brain activity during visuomotor behavior triggered by arbitrary and spatially constrained cues: an fMRI study in humans SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE visuomotor mapping; conditional motor behavior; prefrontal cortex; motor cortex; functional magnetic resonance imaging ID PRIMATE PREFRONTAL CORTEX; DORSAL PREMOTOR CORTEX; FRONTAL-LOBE; WORKING-MEMORY; AREAS; MONKEY; ORGANIZATION; INTEGRATION; PART; REPRESENTATIONS AB Rule-based behavior associating nonspatial visual stimuli with learned responses is called arbitrary visuomotor mapping, an ability that enriches behavioral repertoire. To better understand the underlying neural correlates, the present functional magnetic resonance imaging (fMRI) study explored brain activity during visually informed movement involving two different types of cues and two different effectors. After being trained on the tasks, six healthy subjects performed right or left finger tapping tasks according to either arbitrary cues or spatially constrained cues. An event-related fMRI experiment was conducted on a 3-T MRI. The image data were analyzed with statistical parametric mapping. With the aid of the probabilistic architectonic map in the stereotaxic space, we identified three types of task-related brain activity: cue-selective, effector-selective, and nonselective. The left ventrolateral prefrontal cortex and the rostral part of the right dorsal premotor cortex (PMd) exhibited cue-selective activity, which was greater during the arbitrary condition than the spatially constrained condition. The left ventral prefrontal activity may reflect retrieval of visuomotor association from memory in arbitrary context. The rostral part of the left PMd showed nonselective activity while the caudal part of the PMd on each side showed conspicuous effector-selective activity to the contralateral movement. These findings suggest functional demarcation of the PMd between its rostral and dorsal parts during visuomotor mapping. C1 NINCDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Natl Ctr Neurol & Psychiat, Dept Cort Funct Disorders, Kodaira, Tokyo 1878502, Japan. RP Hallett, M (reprint author), NINCDS, Human Motor Control Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov RI Dimyan, Michael/B-1715-2012; OI Dimyan, Michael/0000-0002-9715-9741 NR 40 TC 17 Z9 19 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0014-4819 J9 EXP BRAIN RES JI Exp. Brain Res. PD JUN PY 2006 VL 172 IS 2 BP 275 EP 282 DI 10.1007/s00221-005-0336-z PG 8 WC Neurosciences SC Neurosciences & Neurology GA 049NI UT WOS:000238022900011 PM 16418844 ER PT J AU Russell, P Walsh, E Chen, WP Goldwich, A Tamm, ER AF Russell, P Walsh, E Chen, WP Goldwich, A Tamm, ER TI The effect of temperature on gene silencing by siRNAs: Implications for silencing in the anterior chamber of the eye SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE temperature; gene silencing; siRNA; RNA folding; myocilin ID RNA INTERFERENCE; MYOCILIN; GLAUCOMA; EFFICIENCY; EFFICACY; CELLS AB Gene silencing by siRNAs offers the potential for reducing the expression of mutated genes that cause disease. It has been shown that the folding or secondary structure of a specific mRNA was significantly correlated to the silencing observed. Since this base pairing is dependent on free energy, the temperature of the cells may influence the effectiveness of a particular siRNA. The aqueous humor of the human eye has been measured to be around 34 degrees C with the lens acting as a thermal barrier in the eye. The trabecular meshwork, bathed by the aqueous humor, probably has a temperature lower than body temperature under normal conditions. Mutated myocilin, that is associated with primary open angle glaucoma, would appear to be a candidate for silencing by siRNAs. Silencing of the mutated myocilin might prevent additional accumulation of this protein in the rough endoplasmic reticulum. These experiments were undertaken to determine the influence of lowered temperatures on the silencing of myocilin by five siRNAs. Three different patterns of silencing emerged when the silencings were compared with cells grown at 33, 35, and 37 degrees C. For one of the siRNAs, the silencing was increased at lower temperatures. For two siRNAs, no significant changes in silencing were observed with different temperatures. Two of the siRNAs were significantly influenced by temperature with little if any silencing occurring at the lowest temperature. These data indicate that siRNAs directed to tissues in the anterior chamber of the eye should be checked at temperatures lower than 37 degrees C to determine their effectiveness. Published by Elsevier Ltd. C1 NEI, NIH, Bethesda, MD 20892 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. Univ Erlangen Nurnberg, Dept Virol, Erlangen, Germany. Univ Regensburg, Inst Human Anat & Embryol, D-8400 Regensburg, Germany. RP Russell, P (reprint author), 7 Mem Dr MSC 0703,Bldg 7,Rm 236, Bethesda, MD 20892 USA. EM russellp@nei.nih.gov OI Tamm, Ernst/0000-0002-6679-8743 FU Intramural NIH HHS; NEI NIH HHS [Z01 EY000303-11] NR 30 TC 3 Z9 3 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD JUN PY 2006 VL 82 IS 6 BP 1011 EP 1016 DI 10.1016/j.exer.2005.12.003 PG 6 WC Ophthalmology SC Ophthalmology GA 048GI UT WOS:000237935200013 PM 16466716 ER PT J AU Kroeber, M Ohlmann, A Russell, P Tamm, ER AF Kroeber, M Ohlmann, A Russell, P Tamm, ER TI Transgenic studies on the role of optineurin in the mouse eye SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE apoptosis; retinal ganglion cells; lens; TGF beta 1; aqueous humor ID OPEN-ANGLE GLAUCOMA; NECROSIS-FACTOR-ALPHA; ELEVATED INTRAOCULAR-PRESSURE; TNF-ALPHA; GENE; PROTEIN; MICE; IDENTIFICATION; APOPTOSIS; MYOCILIN AB Mutations in the OPTN gene encoding for optineurin have been associated with primary open-angle glaucoma. The functional role(s) of optineurin in the normal and glaucomatous eye are unclear. As optineurin interferes with TNF-alpha mediated cell death in vitro, an involvement of optineurin in the regulatory pathways leading to apoptosis of retinal ganglion cells has been suggested. The goal of the present study was to study the molecular properties of optineurin and its capabilities to prevent apoptosis in vivo in the eyes of transgenic mice. The chicken beta B1-crystallin promoter was used to overexpress ectopic optineurin in the lenses of transgenic mice. The expression of transgenic mRNA was monitored by northern blot analysis. The localization of transgenic optineurin was investigated by one- and two-dimensional western blot analysis and by inummohistochemistry, and compared with that of endogenous optineurin. To assess effects of transgenic optineurin on apoptosis, beta B1-crystallin-OPTN mice were crossbred with beta B1-crystallin-TGF beta 1 mice that undergo substantial TGF-beta 1-induced apoptotic cell death in the lens. Two independent beta B1-crystallin-OPTN transgenic lines were established, in which transgenic optineurin was expressed strictly lens-specific as assessed by Northern and Western blotting, and by immunohistochemistry. In contrast, endogenous optineurin was preferentially expressed in the retina, where retinal ganglion cells showed strong labeling. Immunostaining for endogenous optineurin in the anterior eye was considerably weaker than in the posterior eye and was seen in iris, ciliary epithelium, cells of corneal stroma and endothelium, and in the trabecular meshwork. Neither transgenic nor endogenous optineurin was found in the aqueous humor. Transgenic overexpression of optineurin did not have measurable effects on TGF beta 1-induced apoptosis in mixed beta B1-crystallin-OPTN/beta B1-crystallin-TGF beta 1 transgenic mice. Our results show that optineurin is a cytoplasmatic rather than a secretory protein that is preferentially expressed in retinal ganglion cells, and argue against a major role of optineurin for the modulation of apoptosis in vivo. (c) 2006 Elsevier Ltd. All rights reserved. C1 Univ Regensburg, Inst Human Anat & Embryol, D-93053 Regensburg, Germany. Univ Erlangen Nurnberg, Dept Ophthalmol, D-91054 Erlangen, Germany. NEI, NIH, Bethesda, MD 20892 USA. RP Tamm, ER (reprint author), Univ Regensburg, Inst Human Anat & Embryol, Univ Str 31, D-93053 Regensburg, Germany. EM ernst.tamm@vkl.uni-regensburg.de OI Tamm, Ernst/0000-0002-6679-8743; Ohlmann, Andreas/0000-0002-7101-9361 FU Intramural NIH HHS NR 36 TC 28 Z9 28 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD JUN PY 2006 VL 82 IS 6 BP 1075 EP 1085 DI 10.1016/j.exer.2005.11.004 PG 11 WC Ophthalmology SC Ophthalmology GA 048GI UT WOS:000237935200021 PM 16442524 ER PT J AU Solfrizzi, V Colacicco, AM D'Introno, A Capurso, C Del Parigi, A Capurso, SA Argentieri, G Capurso, A Panza, F AF Solfrizzi, Vincenzo Colacicco, Anna M. D'Introno, Alessia Capurso, Cristiano Del Parigi, Angelo Capurso, Sabrina A. Argentieri, Giovanni Capurso, Antonio Panza, Francesco TI Dietary fatty acids intakes and rate of mild cognitive impairment. The Italian Longitudinal Study on Aging SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE mild cognitive impairment; fatty acids; dementia; diet; nutrition ID INCIDENT ALZHEIMER-DISEASE; DOCOSAHEXAENOIC ACID; RISK-FACTORS; DEMENTIA; DECLINE; PREVALENCE; FISH; MEN; AGE; NETHERLANDS AB The possible impact of diet, particularly the intake of fatty acids, on cognitive decline and dementia was addressed recently by several studies. We investioated the role of dietary fatty acids on the rate of mild cognitive impairment (MCI) in a population-based, prospective study carried out on 278 and 186 nondemented elderly subjects (65-84 years) at the 1st (1992-1993) and 2nd (1995-1996) survey from the cohort of Casamassima, Bari, Italy (n = 704), one of the eight centers of the Italian Longitudinal Study on Aging. During the median follow-up of 2.6 years, 18 new events of MCI were diagnosed, and high polyunsaturated fatty acids (PUFA) intake appeared to be a protective factor against the development of MCI [hazard ratio (HR): 0.65, 95% confidence interval (CI): 0.43-0.98, trend-test, df = 1, p < 0.04]. However, when we controlled for the possible confounders (age, sex, education, Charlson comorbidity index, and total energy intake), the HR slightly changed, and the highly skewed 95% CI, while not statistically significant, may be important (HR: 0.62, 95% CI: 0.34-1.13, p = 0.12). In our population, dietary fatty acids intakes were not associated with incident MCI in older age, only high PUFA intake evidenced a borderline nonsignificant trend for a protective effect against the development of MCI. (c) 2006 Elsevier Inc. All rights reserved. C1 Univ Bari, Dept Geriatr, Ctr Aging Brain, Memory Unit,Policlin, I-70124 Bari, Italy. Univ Foggia, Dept Geriatr, Foggia, Italy. NIDDKD, NIH, Phoenix, AZ USA. RP Panza, F (reprint author), Univ Bari, Dept Geriatr, Ctr Aging Brain, Memory Unit,Policlin, Piazza G Cesare 11, I-70124 Bari, Italy. EM v.solfrizzi@geriatria.uniba.it; geriat.dot@geriatria.uniba.it OI Capurso, Cristiano/0000-0002-1152-3371; Panza, Francesco/0000-0002-7220-0656 NR 51 TC 52 Z9 53 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD JUN PY 2006 VL 41 IS 6 BP 619 EP 627 DI 10.1016/j.exger.2006.03.017 PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 061UZ UT WOS:000238899600010 PM 16697546 ER PT J AU Nilson, DG Sabatino, DE Bodine, DM Gallagher, PG AF Nilson, DG Sabatino, DE Bodine, DM Gallagher, PG TI Major erythrocyte membrane protein genes in EKLF-deficient mice SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID KRUPPEL-LIKE FACTOR; BETA-GLOBIN GENE; HUMAN GAMMA-GLOBIN; LOCUS-CONTROL REGION; CACCC PROMOTER ELEMENT; TRANSGENIC MICE; HEREDITARY SPHEROCYTOSIS; TRANSCRIPTION FACTOR; MOUSE MODEL; DEVELOPMENTAL REGULATION AB Objectives. Mice deficient in the transcription factor erythroid Kruppel-like factor, KLF1 (EKLF) die similar to 14.5 days postcoitum of anemia, attributed to decreased expression of the beta-globin gene. The objectives of this study were to rescue EKLF-deficient embryos with mice expressing gamma-globin from beta-spectrin or ankyrin promoters and to characterize expression of the major erythrocyte membrane genes in EKLF-deficient cells. Methods. Transgenic beta-spectrin/gamma-globin or ankyrin/gamma-globin mice were bred onto EKLF-deficient and wild-type backgrounds. Animals were genotyped, gamma-globin mRNA levels measured, and hemoglobin electrophoresis performed. Steady-state mRNA levels and transcriptional rates of the major erythrocyte membrane protein genes were assayed. Results. beta-spectrin/gamma-globin or ankyrin/gamma-globin mice on EKLF-deficient and wild-type backgrounds had identical levels of gamma-globin mRNA, indicating EKLF-independence of these promoters. gamma-Globin expression improved globin chain imbalance, but hemolysis was not improved and no live-born EKLF-deficient/(A)gamma-globin mice were obtained. Circulating erythroid cells from EKLF-deficient/(A)gamma-globin embryos exhibited hemolysis reminiscent of that seen in patients with severe erythrocyte membrane defects. Levels of beta-spectrin, ankyrin, and band 3 mRNA, but not alpha-spectrin, were decreased in EKLF-deficient fetal liver RNA. In a run-on assay, levels of transcription of the ankyrin and band 3 genes were decreased in EKLF-deficient fetal liver nuclei. Conclusions. These results indicate that the EKLF-responsive regions of the ankyrin and P-spectrin genes are outside their promoters and that EKLF is necessary for full transcriptional activity of the ankyrin and band 3 genes; the results also provide additional evidence that defects in addition to beta-globin deficiency, including an abnormal erythrocyte membrane, contribute to the anemia and embryonic lethality in EKLF-deficient mice. (c) 2006 International Society for Experimental Hematology. Published by Elsevier Inc. C1 Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA. NHGRI, Hematopoiesis Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Gallagher, PG (reprint author), Yale Univ, Sch Med, Dept Pediat, 333 Cedar St,POB 208064, New Haven, CT 06520 USA. EM patrick.gallagher@yale.edu FU NHLBI NIH HHS [HL65448]; NIDDK NIH HHS [DK/HL62039] NR 52 TC 35 Z9 35 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2006 VL 34 IS 6 BP 705 EP 712 DI 10.1016/j.exphem.2006.02.018 PG 8 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 051SG UT WOS:000238180500003 PM 16728274 ER PT J AU Scheinberg, P Price, DA Ambrozak, DR Barrett, AJ Douek, DC AF Scheinberg, P Price, DA Ambrozak, DR Barrett, AJ Douek, DC TI Alloreactive T cell clonotype recruitment in a mixed lymphocyte reaction: Implications for graft engineering SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID VERSUS-HOST-DISEASE; MINOR HISTOCOMPATIBILITY ANTIGENS; BONE-MARROW-TRANSPLANTATION; STEM-CELL; SELECTIVE DEPLETION; DONOR LYMPHOCYTES; GVHD PROPHYLAXIS; IMMUNOTOXIN; FREQUENCY; RESPONSES AB Objective. The selective elimination of alloreactive T cells from donor stem cell grafts prior to hematopoietic stem cell transplantation (HSCT) is an important goal in the prevention of graft-vs-host disease (GVHD). However, in HLA-identical donor-recipient pairs, it has proven difficult to identify alloreactive T cells using in vitro systems pretransplant due, in part, to their low frequency and a lack of methodological standardization. To better understand the alloresponse between HLA-identical related pairs, we characterized the alloreactive T cells generated in a mixed lymphocyte reaction (MLR) assay system. Methods. HSCT donor peripheral blood mononuclear cells (responder) were labeled with carboxyfluorescein diacetate, succinimidyl ester (CFSE) dye and cocultured with irradiated HSCT recipient cells (stimulator) in a one-way MLR. Alloreactive T cells were sorted by upregulation of activation markers (CD25 in most cases) and the responding clonotypes were defined by sequencing the complementarity region 3 (CDR3) of the T cell receptor beta-chain. Results. We show that the recruitment of alloreactive CD4(+) T cells is highly variable. Oligoclonal CD4(+) T-cell expansions in repeated MLRs performed in the same donor-recipient pair showed inconsistent recruitment of clonotypes. The recruitment of alloreactive CD8(+) T cells was more consistent in repeated assays, with the same clonotypes identified in the same donor-recipient pair performed under different conditions. Conclusion. Taken together, our data show that even in culture conditions constrained to eliminate background proliferation, stochastic events and low precursor frequencies preclude reproducible elicitation of immunodominant T cell clonotypes with the potential to cause GVHD. (c) 2006 International Society for Experimental Hematology. Published by Elsevier Inc. C1 NHLBI, Hematol Branch, Bethesda, MD 20892 USA. NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Scheinberg, P (reprint author), NHLBI, Hematol Branch, 10 Ctr Dr,Bldg 10 CRC,Rm 3-5140,MSC 1202, Bethesda, MD 20892 USA. EM scheinbp@nhlbi.nih.gov RI Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Scheinberg, Phillip/0000-0002-9047-4538 FU Intramural NIH HHS; Medical Research Council [G108/441] NR 28 TC 10 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2006 VL 34 IS 6 BP 788 EP 795 DI 10.1016/j.exphem.2006.03.001 PG 8 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 051SG UT WOS:000238180500013 PM 16728284 ER PT J AU Srinivasan, R Daniels, J Fusaro, V Lundqvist, A Killian, JK Geho, D Quezado, M Kleiner, D Rucker, S Espinac, V Whiteley, G Liotta, L Petricoin, E Pittaluga, S Hitt, B Barrett, AJ Rosenblatt, K Childs, RW AF Srinivasan, R Daniels, J Fusaro, V Lundqvist, A Killian, JK Geho, D Quezado, M Kleiner, D Rucker, S Espinac, V Whiteley, G Liotta, L Petricoin, E Pittaluga, S Hitt, B Barrett, AJ Rosenblatt, K Childs, RW TI Accurate diagnosis of acute graft-versus-host disease using serum proteomic pattern analysis SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID PROSTATE-CANCER; MASS-SPECTROMETRY AB Objective. The rapid diagnosis of acute graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (HCT) is important for optimizing the management of this life-threatening complication. Current diagnostic techniques are time-consuming and require invasive tissue sampling. We investigated serum protein pattern analysis using surface-enhanced laser desorption ionization time-of-flight (SELDI-TOF) mass spectrometry as a tool to diagnose GVHD. Patients and Methods. Eighty-eight serum samples were obtained from 34 patients undergoing HCT either pretransplant (n = 28 samples) or at various time points posttransplant (n = 60 samples), including 22 samples obtained on the day of onset of acute GVHD symptoms. Serum proteomic spectra generated from a '' training set '' of known samples were used to identify distinct proteomic patterns that best categorized a sample as either pretransplant, posttransplant non-GVHD, or GVHD; these distinct proteomic signatures were subsequently used to classify samples from a masked '' test '' sample set into the appropriate diagnostic category. Results. Proteomic pattern analysis accurately distinguished GVHD samples from both posttransplant non-GVHD samples and pretransplant samples (100% specificity and 100% sensitivity in both cases). Furthermore, distinct serum proteomic signatures were identified that distinguished pretransplant from posttransplant non-GVHD samples (100% specificity and 94% sensitivity). Conclusion. These preliminary data suggest a potential application of SELDI-TOF-based proteomic analysis as a rapid and accurate method to diagnose acute GVHD. (c) 2006 International Society for Experimental Hematology. Published by Elsevier Inc. C1 NHLBI, Hematol Branch, Bethesda, MD 20892 USA. Urol Oncol Branch, Bethesda, MD USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. SAIC Frederick Inc, Bethesda, MD USA. US FDA, Bethesda, MD 20014 USA. Correlog Syst Inc, Bethesda, MD USA. RP Childs, RW (reprint author), NIH, Hematol Branch, 10 Ctr Dr,Bldg 10-CRC,Room 35330, Bethesda, MD 20892 USA. EM childsr@nih.gov OI Kleiner, David/0000-0003-3442-4453; Espina, Virginia/0000-0001-5080-5972; Lundqvist, Andreas/0000-0002-9709-2970 NR 18 TC 45 Z9 46 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2006 VL 34 IS 6 BP 796 EP 801 DI 10.1016/j.exphem.2006.02.013 PG 6 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 051SG UT WOS:000238180500014 PM 16728285 ER PT J AU Cookson, MR AF Cookson, Mark R. TI Hero versus antihero: The multiple roles of alpha-synuclein in neurodegeneration SO EXPERIMENTAL NEUROLOGY LA English DT Editorial Material ID SPORADIC PARKINSONS-DISEASE; LEWY-BODY; LOCUS TRIPLICATION; SUBSTANTIA-NIGRA; MICE; NEURONS; MPTP; PROTEINS; BRAIN; AGGREGATION C1 NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Cookson, MR (reprint author), NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov FU Intramural NIH HHS NR 35 TC 13 Z9 13 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2006 VL 199 IS 2 BP 238 EP 242 DI 10.1016/j.expneurol.2006.03.011 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 063DB UT WOS:000238995200002 PM 16687141 ER PT J AU Gould, TD AF Gould, TD TI Targeting glycogen synthase kinase-3 as an approach to develop novel mood-stabilising medications SO EXPERT OPINION ON THERAPEUTIC TARGETS LA English DT Review DE antidepressant; bipolar disorder; depression; kinase inhibitor; mania; manic-depressive illness; mood stabiliser ID FORCED SWIM TEST; EMERGING EXPERIMENTAL THERAPEUTICS; SINGLE NUCLEOTIDE POLYMORPHISM; LITHIUM-CARBONATE TREATMENT; MANIC-DEPRESSIVE ILLNESS; INSULIN-MIMETIC ACTION; BIPOLAR DISORDER; BETA-CATENIN; IN-VIVO; ALZHEIMERS-DISEASE AB Historically, success in the pharmacological treatment of bipolar disorder has arisen either from serendipitous findings or from studies with drugs (antipsychotics and anticonvulsants) developed for other indications (schizophrenia and epilepsy, respectively). Lithium has been in widespread clinical use in the treatment of bipolar disorder for > 30 years. Development of lithium-mimetic compounds has the potential to result in a more specific medication, with fewer side effects and a less narrow dose range. However, novel medications based upon a known mechanism of action of this drug are yet to be developed. Increasing evidence suggests that a next-generation lithium compound may derive from knowledge of a direct target of lithium, glycogen synthase kinase-3 (GSK-3). GSK-3 is an intracellular enzyme implicated as a critical component in many neuronal signalling pathways. However, despite the large body of preclinical data discussed in this review, definitive validation of GSK-3 as therapeutically relevant target of lithium will require clinical trials with novel GSK-3 inhibitors. A number of recent reports suggest that it is possible to develop selective, small-molecule GSK-3 inhibitors. C1 NIMH, NIH, Lab Mol Pathophysiol, Bethesda, MD 20892 USA. RP Gould, TD (reprint author), NIMH, NIH, Lab Mol Pathophysiol, Bethesda, MD 20892 USA. EM gouldt@mail.nih.gov FU Intramural NIH HHS NR 156 TC 30 Z9 32 U1 0 U2 5 PU ASHLEY PUBLICATIONS LTD PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1472-8222 J9 EXPERT OPIN THER TAR JI Expert Opin. Ther. Targets PD JUN PY 2006 VL 10 IS 3 BP 377 EP 392 DI 10.1517/14728222.10.3.377 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 054LK UT WOS:000238378000005 PM 16706678 ER PT J AU Johnson, TR AF Johnson, Teresa R. TI Respiratory syncytial virus and innate immunity: a complex interplay of exploitation and subversion SO EXPERT REVIEW OF VACCINES LA English DT Review DE adjuvants; C-type lectins; dendritic cells; innate immunity; interferon-alpha; respiratory syncytial virus; T cells; Toll-like receptors; vaccines ID TOLL-LIKE RECEPTORS; DOUBLE-STRANDED-RNA; PLASMACYTOID DENDRITIC CELLS; AIRWAY EPITHELIAL-CELLS; HEPATITIS-C VIRUS; SURFACTANT PROTEIN; RIG-I; PULMONARY SURFACTANT; MESSENGER-RNA; MEASLES-VIRUS AB Respiratory syncytial virus causes significant disease in infants, the elderly and select groups of immunocompromised patients. Healthy individuals are also naturally infected with respiratory syncytial virus repeatedly throughout life. Therefore, safe and effective vaccines and therapies are needed. However, a number of factors have prevented development of such antiviral interventions to date. These include a failed vaccine trial, the very young age of the primary target population (neonates), the inability of natural infection to induce long-term protective immunity, and an incomplete understanding of virus-host interactions. The identification of pattern recognition receptors has led to significant increases in our understanding of induction and regulation of innate immune responses. This review will address the impact of these findings on respiratory syncytial virus research. C1 NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Johnson, TR (reprint author), NIAID, Vaccine Res Ctr, Bldg 40 Room 2614,40 Convent Dr MSC3017, Bethesda, MD 20892 USA. EM teresaj@nih.gov NR 105 TC 1 Z9 1 U1 0 U2 0 PU FUTURE DRUGS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1476-0584 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD JUN PY 2006 VL 5 IS 3 BP 371 EP 380 DI 10.1586/14760584.5.3.371 PG 10 WC Immunology SC Immunology GA 089ZZ UT WOS:000240921700015 PM 16827621 ER PT J AU Hager, GL Schiltz, RL Wiench, M Johnson, T John, S Nagaich, A Qiu, Y AF Hager, G. L. Schiltz, R. L. Wiench, M. Johnson, T. John, S. Nagaich, A. Qiu, Y. TI Transcription factor mobility and promoter progression SO FEBS JOURNAL LA English DT Meeting Abstract CT 31st Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUN 24-29, 2006 CL Istanbul, TURKEY SP Federat European Biochem Soc C1 NCI, Lab Receptor Biol & Gene Express, NCI, Bethesda, MD 20892 USA. EM hagerg@exchange.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1742-464X J9 FEBS J JI FEBS J. PD JUN PY 2006 VL 273 SU 1 BP 7 EP 8 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 061ZR UT WOS:000238914000021 ER PT J AU Bohr, A AF Bohr, A. TI DNA repair deficiencies in human premature aging SO FEBS JOURNAL LA English DT Meeting Abstract CT 31st Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUN 24-29, 2006 CL Istanbul, TURKEY SP Federat European Biochem Soc C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM vbohr@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1742-464X J9 FEBS J JI FEBS J. PD JUN PY 2006 VL 273 SU 1 BP 18 EP 19 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 061ZR UT WOS:000238914000059 ER PT J AU Klokk, TI Kurys, P Elbi, C Nagaich, AK Hendarwanto, A Slagsvold, T Chang, CY Hager, GL Saatcioglu, F AF Klokk, T. I. Kurys, P. Elbi, C. Nagaich, A. K. Hendarwanto, A. Slagsvold, T. Chang, C. Y. Hager, G. L. Saatcioglu, F. TI Ligand-specific dynamics of the androgen receptor on its target promoter in living cells SO FEBS JOURNAL LA English DT Meeting Abstract CT 31st Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUN 24-29, 2006 CL Istanbul, TURKEY SP Federat European Biochem Soc C1 Univ Oslo, Dept Mol Biosci, Oslo, Norway. Natl Canc Inst, Lab Receptor Biol & Gene Express, Bethesda, MD USA. Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1742-464X J9 FEBS J JI FEBS J. PD JUN PY 2006 VL 273 SU 1 BP 44 EP 44 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 061ZR UT WOS:000238914000145 ER PT J AU Muftuoglu, M Opresko, P Bohr, V AF Muftuoglu, M. Opresko, P. Bohr, V. TI Base excision repair pathway at telomeric DNA SO FEBS JOURNAL LA English DT Meeting Abstract CT 31st Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUN 24-29, 2006 CL Istanbul, TURKEY SP Federat European Biochem Soc C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1742-464X J9 FEBS J JI FEBS J. PD JUN PY 2006 VL 273 SU 1 BP 54 EP 54 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 061ZR UT WOS:000238914000177 ER PT J AU Uustare, A Terasmaa, A Vonk, A Rinken, A AF Uustare, A. Terasmaa, A. Vonk, A. Rinken, A. TI Isomerization of the adenosine A(2a) receptor-[(3)h] zm241385 complexes SO FEBS JOURNAL LA English DT Meeting Abstract CT 31st Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUN 24-29, 2006 CL Istanbul, TURKEY SP Federat European Biochem Soc C1 Univ Tartu, Inst Organ & Bioorgan Chem, EE-50090 Tartu, Estonia. NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. EM deffi@ut.ce RI Terasmaa, Anton/I-3312-2015 OI Terasmaa, Anton/0000-0002-5139-1764 NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1742-464X J9 FEBS J JI FEBS J. PD JUN PY 2006 VL 273 SU 1 BP 91 EP 91 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 061ZR UT WOS:000238914000309 ER PT J AU Orun, O Rasmussen, SGF Cha, JH Newman, AH Javitch, JA Gether, U AF Orun, O. Rasmussen, S. G. F. Cha, J. H. Newman, A. H. Javitch, J. A. Gether, U. TI N-terminal conformational changes of dopamine transporter determined by FRET analysis SO FEBS JOURNAL LA English DT Meeting Abstract CT 31st Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUN 24-29, 2006 CL Istanbul, TURKEY SP Federat European Biochem Soc C1 Marmara Univ, Sch Med, Dept Biophys, Istanbul, Turkey. Univ Copenhagen, Panum Inst, Dept Pharmacol, Mol Neuropharmacol Grp, DK-1168 Copenhagen, Denmark. NIDA, Med Chem Sect, IRP, Baltimore, MD 21224 USA. Columbia Univ Coll Phys & Surg, Ctr Mol Recognit, New York, NY 10032 USA. EM oyaorun@yahoo.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1742-464X J9 FEBS J JI FEBS J. PD JUN PY 2006 VL 273 SU 1 BP 96 EP 96 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 061ZR UT WOS:000238914000328 ER PT J AU Kakuk, A Friedlander, E Vereb, G Petrasch-Parwez, E Balla, T Heilmeyer, L Gergely, G Vereb, G AF Kakuk, A. Friedlander, E. Vereb, Gy. Petrasch-Parwez, E. Balla, T. Heilmeyer, L. Gergely, G. Vereb, Gy. TI Nucleolar localization of phosphatidylinositol 4-kinase pi4k230 in various mammalian cells SO FEBS JOURNAL LA English DT Meeting Abstract CT 31st Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUN 24-29, 2006 CL Istanbul, TURKEY SP Federat European Biochem Soc C1 Univ Debrecen, Fac Med, Dept Med Chem, Med & Hlth Sci Ctr, H-4012 Debrecen, Hungary. Univ Debrecen, Fac Med, Med & Hlth Sci Ctr, Dept Biophys & Cell Biol, H-4012 Debrecen, Hungary. Ruhr Univ Bochum, Inst Anat, Abt Neuroanat & Mol Hirnforsch, D-4630 Bochum, Germany. NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. Ruhr Univ Bochum, Inst Physiol Chem, Biochem Supramolek Syst Abt, D-4630 Bochum, Germany. EM elza@jaguar.dote.hu 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 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD JUN PY 2006 VL 273 SU 1 BP 112 EP 112 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 061ZR UT WOS:000238914000391 ER PT J AU Tutar, Y Song, Y Masison, D AF Tutar, Y. Song, Y. Masison, D. TI Primate chaperones Hsc70 (constitutive) and Hsp70 (induced) differ functionally in supporting growth and prion propagation in Saccharomyces cerevisiae SO FEBS JOURNAL LA English DT Meeting Abstract CT 31st Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUN 24-29, 2006 CL Istanbul, TURKEY SP Federat European Biochem Soc C1 Cumhuriyet Univ, Dept Chem, Sivas, Turkey. Liaoning Univ, Dept Life Sci, Shenyang 110036, Peoples R China. NIDDK, Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1742-464X J9 FEBS J JI FEBS J. PD JUN PY 2006 VL 273 SU 1 MA PP594 BP 237 EP 237 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 061ZR UT WOS:000238914001412 ER PT J AU Okubo, A Li, M Ashida, M Oyama, H Gustchina, A Oda, K Dunn, BM Wlodawer, A Nakayama, T AF Okubo, A Li, M Ashida, M Oyama, H Gustchina, A Oda, K Dunn, BM Wlodawer, A Nakayama, T TI Processing, catalytic activity and crystal structures of kumamolisin-As with an engineered active site SO FEBS JOURNAL LA English DT Article DE active site; autolysis; catalytic mechanism; serine proteases ID SERINE-CARBOXYL PROTEINASE; PEPTIDASE; EXPRESSION; MECHANISM; CLONING; STABILIZATION; PURIFICATION; KUMAMOLYSIN; REFINEMENT; SUBTILISIN AB Kumamolisin-As is an acid collagenase with a subtilisin-like fold. Its active site contains a unique catalytic triad, Ser278-Glu78-Asp82, and a putative transition-state stabilizing residue, Asp164. In this study, the mutants D164N and E78H/DI64N were engineered in order to replace parts of the catalytic machinery of kumamolisin-As with the residues found in the equivalent positions in subtilisin. Unlike the wild-type and D164N proenzymes, which undergo instantaneous processing to produce their 37-kDa mature, forms, the expressed E78H/DI64N proenzyme exists as an equilibrated mixture of the nicked and intact forms of the precursor. X-ray crystallographic structures of the mature forms of the two mutants showed that, in each of them, the catalytic Ser278 makes direct hydrogen bonds with the side chain of Asn164. In addition, His78 of the double mutant is distant from Ser278 and Asp82, and the catalytic triad no longer exists. Consistent with these structural alterations around the active site, these mutants showed only low catalytic activity (relative k(cat) at pH 4.0 1.3% for D164N and 0.0001% for E78H/DI64N). pH-dependent kinetic studies showed that the single D164N substitution did not significantly alter the logk(cat) vs. pH and log(k(cat)/K-m) vs. pH profiles of the enzyme. In contrast, the double mutation resulted in a dramatic switch of the logk(cat) vs. pH profile to one that was consistent with catalysis by means of the Ser278-His78 dyad and Asn164, which may also account for the observed ligation/cleavage equilibrium of the precursor of E78H/DI64N. These results corroborate the mechanistic importance of the glutamate-mediated catalytic triad and oxyanion-stabilizing aspartic acid residue for low-pH peptidase activity of the enzyme. C1 Tohoku Univ, Grad Sch Engn, Dept Biomol Engn, Sendai, Miyagi 9808579, Japan. Natl Canc Inst, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD USA. Natl Canc Inst, Basic Res Program, SAIC Frederick, Frederick, MD USA. Kyoto Inst Technol, Fac Text Sci, Dept Appl Biol, Kyoto 606, Japan. Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. RP Nakayama, T (reprint author), Tohoku Univ, Grad Sch Engn, Dept Biomol Engn, 6-6-1 Aobayama, Sendai, Miyagi 9808579, Japan. EM nakayama@seika.che.tohoku.ac.jp FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400]; NIAID NIH HHS [AI28571] NR 30 TC 11 Z9 11 U1 0 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1742-464X J9 FEBS J JI FEBS J. PD JUN PY 2006 VL 273 IS 11 BP 2563 EP 2576 DI 10.1111/j.1742-4658.2006.05266.x PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 054PA UT WOS:000238389900019 PM 16704427 ER PT J AU Saksena, R Ma, XQ Wade, TK Kovac, P Wade, WF AF Saksena, R Ma, XQ Wade, TK Kovac, P Wade, WF TI Length of the linker and the interval between immunizations influences the efficacy of Vibrio cholerae O1, Ogawa hexasaccharide neoglycoconjugates SO FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY LA English DT Article DE Vibrio cholerae; cholera vaccine; Ogawa lipopolysaccharide ID SQUARIC ACID DIESTER; SEROTYPE OGAWA; SYNTHETIC FRAGMENTS; PROTEIN CARRIER; INFANT MICE; LIPOPOLYSACCHARIDE; INABA; ANTIBODIES; TOXIN; CONJUGATION AB Ogawa hexasaccharide neoglycoconjugates induce protective antibodies in mice. Similar Ogawa conjugates but with a longer linker that connects the carrier to shorter saccharides are immunogenic, but generally ineffective at inducing vibriocidal or protective antibodies. The efficacy of Ogawa hexasaccharide neoglycoconjugates of different linker lengths were tested. The majority of mice given immunizations separated by a 14-day gap did not produce vibriocidal or protective antibodies. Mice immunized 28 days apart with immunogens containing the shortest or medium length linker, but not the longest, produced vibriocidal and protective antibodies. A nonprotective, priming dose of purified Ogawa LPS followed 5 days later with a booster of the Ogawa neoglycoconjugates (di-, tetra-, or hexasaccharide) resulted in vibriocidal antibodies at day 10. C1 Dartmouth Coll Sch Med, Dept Microbiol & Immunol, Lebanon, NH 03756 USA. NIDDK, NIH, Med Chem Lab, Bethesda, MD USA. RP Wade, WF (reprint author), Dartmouth Coll Sch Med, Dept Microbiol & Immunol, 630W Borwell Bldg, Lebanon, NH 03756 USA. EM william.wade@dartmouth.edu FU Intramural NIH HHS; NIAID NIH HHS [AI 47373] NR 30 TC 17 Z9 18 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0928-8244 J9 FEMS IMMUNOL MED MIC JI FEMS Immunol. Med. Microbiol. PD JUN PY 2006 VL 47 IS 1 BP 116 EP 128 DI 10.1111/j.1574-695X.2006.00071.x PG 13 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 043LQ UT WOS:000237603000012 PM 16706794 ER PT J AU Kwon-Chung, KJ Varma, A AF Kwon-Chung, KJ Varma, A TI Do major species concepts support one, two or more species within Cryptococcus neoformans? SO FEMS YEAST RESEARCH LA English DT Review DE Cryptococcus neoformans; Cryptococcus gattii; species concept ID SUB-SAHARAN AFRICA; FILOBASIDIELLA-NEOFORMANS; SEROTYPE-A; INTERGENIC SPACER; VAR. NEOFORMANS; VAR GATTII; VARIETIES; VIRULENCE; BACILLISPORUS; STRAINS AB Cryptococcus neoformans, the agent of cryptococcosis, had been considered a homogeneous species until 1949 when the existence of four serotypes was revealed based on the antigenic properties of its polysaccharide capsule. Such heterogeneity of the species, however, remained obscure until the two morphologically distinct teleomorphs of C. neoformans were discovered during the mid 1970s. The teleomorph Filobasidiella neoformans was found to be produced by strains of serotype A and D, and Filobasidiella bacillispora was found to be produced by strains of serotype B and C. Ensuing studies revealed numerous differences between the anamorphs of the two Filobasidiella species with regard to their ecology, epidemiology, pathobiology, biochemistry and genetics. At present, the etiologic agent of cryptococcosis is classified into two species, C. neoformans (serotypes A and D) and Cryptococcus gattii (serotypes B and C). Intraspecific genetic diversity has also been revealed as more genotyping methods have been applied for each serotype. As a result, the number of scientifically valid species within C. neoformans has become a controversial issue because of the differing opinions among taxonomists as to the appropriate definition of a species. There are three major species concepts that govern classification of organisms: phenetic (morphologic, phenotypic), biologic (interbreeding) and cladistic (evolutionary, phylogenetic). Classification of the two C. neoformans species has been based on the phenetic as well as the biologic species concept, which is also supported by the cladistic species concept. In this paper, we review and attest to the validity of the current two-species system in light of the three major species concepts. C1 NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Kwon-Chung, KJ (reprint author), NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM june_kwon-chung@nih.gov FU Intramural NIH HHS NR 64 TC 134 Z9 146 U1 4 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1567-1356 J9 FEMS YEAST RES JI FEMS Yeast Res. PD JUN PY 2006 VL 6 IS 4 BP 574 EP 587 DI 10.1111/j.1567-1364.2006.00088.x PG 14 WC Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biotechnology & Applied Microbiology; Microbiology; Mycology GA 042GX UT WOS:000237517100013 PM 16696653 ER PT J AU Flores, I Rivera, E Mousses, S Chen, YD Rozenblum, E AF Flores, I Rivera, E Mousses, S Chen, YD Rozenblum, E TI Identification of molecular markers for endometriosis in blood lymphocytes by using deoxyribonucleic acid microarrays SO FERTILITY AND STERILITY LA English DT Article; Proceedings Paper CT 9th World Congress on Endometriosis CY SEP 14-18, 2005 CL Maastricht, NETHERLANDS DE endometriosis; differential gene expression; DNA microarrays; diagnostic test; biomarker; signal recognition particle receptor; B subunit; procollagen-proline; 2-oxoglutarate 4-dioxygenase (proline 4-hydroxylase); alpha pblypeptide 1 ID GENE-EXPRESSION PROFILES; TUMOR-NECROSIS-FACTOR; OXIDASE MESSENGER-RNA; BASIC-PROTEIN GENE; PERITONEAL-FLUID; PERIPHERAL-BLOOD; MENSTRUAL-CYCLE; BREAST-CANCER; LYSYL OXIDASE; GROWTH-FACTOR AB Objective: To identify molecular biomarkers for endometriosis in peripheral blood lymphocytes by: using DNA microarrays. Design: Case-control. Setting: Multicenter academic research programs: Patient(s): Premenopausal women with or without endometriosis,, determined by obstetrics and gynecology specialists during surgery. Micro-array analysis; included-six endometriosis patients and five,controls; 15 endometriosis patients and 15 controls were analyzed by using real-time reverse-transcription, polymerase chain reaction., (RT-PCR).Patients with all disease stages. were included. Intervention(s): Peripheral blood samples were collected by venipuncture. Main Outcome Measure(S): The expression levels of mRNAs in blood lymphocytes from endometrosis patients and controls were compared with those of a standard total RNA. Gene expression data;were validated by real-time RT-PCR analysis. Result(s): A gene selection program; identified genes that were differentially expressed in samples from endometriosis patients. To validate the gene expression data, the nine most discriminatory genes were analyzed a; by real-time RT-PCR. Two of the nine genes identified, IL2RG and LOXL1, were shown: to be significantly differentially expressed. Conclusion(s): This is the first report of genes that are differentially expressed in peripheral blood lymphocytes: of patients with, endometrosis, which may provide important clues, regarding the pathogenesis of this disease:Moreover, they could be considered potential targets for noninvasive diagnostic assays for endometriosis and x need to be validated in a larger population. C1 Ponce Sch Med, Dept Microbiol, Ponce, PR 00731 USA. Translat Genom Res Inst, Gaithersburg, MD USA. NHGRI, NIH, Bethesda, MD 20892 USA. SAIC Frederick Inc, Lab Mol Technol, Frederick, MD USA. RP Flores, I (reprint author), Ponce Sch Med, Dept Microbiol, POB 7004, Ponce, PR 00731 USA. EM iflores@psm.edu FU NCRR NIH HHS [2G12RR03050, G12 RR003050] NR 71 TC 16 Z9 17 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD JUN PY 2006 VL 85 IS 6 BP 1676 EP 1683 DI 10.1016/j.fertnstert.2005.11.076 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 055CN UT WOS:000238427700012 PM 16759924 ER PT J AU Kono, H Woods, CG Maki, A Connor, HD Mason, RP Rusyn, I Fujii, H AF Kono, Hiroshi Woods, Courtney G. Maki, Akira Connor, Henry D. Mason, Ronald P. Rusyn, Ivan Fujii, Hideki TI Electron spin resonance and spin trapping technique provide direct evidence that edaravone prevents acute ischemia-reperfusion injury of the liver by limiting free radical-mediated tissue damage SO FREE RADICAL RESEARCH LA English DT Article DE ischemia/reperfusion; electron spin resonance; reactive oxygen species; liver injury ID ENDOTHELIAL-CELL; RAT-LIVER; KUPFFER CELLS; MCI-186; SCAVENGER; APOPTOSIS; PROTECTS; INVIVO; HEPATOCYTES; ENDOTOXIN AB A novel free radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone), is used for the treatment of acute ischemic stroke and is protective in several animal models of organ injury. We tested whether edaravone is protective against acute liver warm ischemia/reperfusion injury in the rat by acting as a radical scavenger. When edaravone was administered prior to ischemia and at the time of initiation of the reperfusion, liver injury was markedly reduced. Production of oxidants in the liver in this model was assessed in vivo by spin-trapping/electron spin resonance (ESR) spectroscopy. Ischemia/reperfusion caused an increase in free radical adducts rapidly, an effect markedly blocked by edaravone. Furthermore, edaravone treatment blunted ischemia/reperfusion-induced elevation in pro-inflammatory cytokines, infiltration of leukocytes and lipid peroxidation in the liver. These results demonstrate that edaravone is an effective blocker of free radicals in vivo in the liver after ischemia/reperfusion, leading to prevention of organ injury by limiting the deleterious effects of free radicals. C1 Univ N Carolina, Dept Environm Sci & Engn, Sch Publ Hlth, Chapel Hill, NC 27599 USA. Yamanashi Univ, Dept Surg 1, Yamanashi, Japan. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Rusyn, I (reprint author), Univ N Carolina, Dept Environm Sci & Engn, Sch Publ Hlth, Chapel Hill, NC 27599 USA. EM iir@unc.edu RI Rusyn, Ivan/S-2426-2016 FU NIEHS NIH HHS [ES11391, ES11660, ES13342] NR 37 TC 12 Z9 12 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1071-5762 J9 FREE RADICAL RES JI Free Radic. Res. PD JUN PY 2006 VL 40 IS 6 BP 579 EP 588 DI 10.1080/10715760600606374 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 056EM UT WOS:000238504100005 PM 16753835 ER PT J AU Sumner, AE AF Sumner, Anne E. TI The health consequences in African-Americans of each component of the metabolic syndrome SO FUTURE LIPIDOLOGY LA English DT Article DE African-Americans; hyperglycemia; hypertension; hypertriglyceridemia; insulin resistance; metabolic syndrome ID NUTRITION EXAMINATION SURVEY; TYPE-2 DIABETES-MELLITUS; IMPAIRED FASTING GLUCOSE; LIPID-LOWERING TREATMENT; 3RD NATIONAL-HEALTH; ATTACK TRIAL ALLHAT; TREATMENT PANEL-III; INSULIN-RESISTANCE; RISK-FACTORS; DIAGNOSTIC-CRITERIA AB The metabolic syndrome is founded on two principles: first, it is most likely to occur in insulinresistant individuals and second, it predicts the development of both cardiovascular disease and diabetes. Two key features of the metabolic syndrome are hypertension and diabetes. When the prevalence of the metabolic syndrome was determined in the USA, investigators were surprised to find that even though African-Americans are more insulin resistant and have a higher prevalence of obesity, diabetes, hypertension and heart disease than Caucasians, African-Americans have a lower prevalence of the metabolic syndrome. This article explores the reasons for the underdlagnosis of the metabolic syndrome in African-Americans. In addition, it is emphasized that in African-Americans the absence of the metabolic syndrome should not detract from the need to commit resources to achieve early detection and treatment of hypertension and hyperglycemia. C1 NIDDK, NIH, Clin Endocrinol Branch, Bethesda, MD 20892 USA. RP Sumner, AE (reprint author), NIDDK, NIH, Clin Endocrinol Branch, 9000 Rockville Pike Bldg 10-CRC Rm 6W-5940, Bethesda, MD 20892 USA. EM AnneS@intra.niddk.nih.gov NR 38 TC 0 Z9 0 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0875 J9 FUTURE LIPIDOL JI Future Lipidol. PD JUN PY 2006 VL 1 IS 3 BP 283 EP 289 DI 10.2217/17460875.1.3.283 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 209ZV UT WOS:000249427400011 ER PT J AU Siegel, KL Kepple, TM Stanhope, SJ AF Siegel, KL Kepple, TM Stanhope, SJ TI Using induced accelerations to understand knee stability during gait of individuals with muscle weakness SO GAIT & POSTURE LA English DT Article DE weakness; gait; quadriceps femoris; compensation; motor control ID FEMORAL NEUROPATHY; SUPPORT; PROGRESSION AB The purpose of this case series was to quantify the effectiveness of different compensatory strategies used by individuals with muscle weakness to produce knee extension during the stance phase gait. Subjects were three males with less than anti-gravity strength in the quadriceps femoris and a variable pattern of weakness elsewhere in the lower extremity. They walked independently at a self-selected speed without assistive devices. Gait analysis of the pelvis and bilateral lower extremity segments was performed with a six-camera, two force platform motion capture system. Joint angles and net internal moments were computed from the motion data. Induced acceleration analysis was performed to quantify the relative ability of each lower extremity joint moment and gravity to produce knee angular acceleration. Results showed that a variety of adaptive strategies both within and across limbs can control knee position during gait. One subject generated knee extension almost exclusively via the hip extensor moment. Another relied less oil the hip extensor moment (39%) and more on the ankle plantar flexor moment (61%) to create knee extension. The third subject used the ipsilateral hip extensor moment (24%) and the contralateral ankle plantar flexor moment (67%) to assist knee extension. The strategy selected by each subject likely was influenced by both their total pattern of impairments and the effectiveness of the available compensations. This case series demonstrates how an induced acceleration analysis can augment a traditional gait analysis to expand and enhance our understanding of compensatory movement control strategies. Published by Elsevier B.V. C1 NIH, Phys Disabil Branch, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Siegel, KL (reprint author), NIH, Phys Disabil Branch, Dept Hlth & Human Serv, Bldg 10,CRC,Room 1-1469,10 Ctr Dr,MSC 1604, Bethesda, MD 20892 USA. EM karen_siegel@nih.gov RI Siegel, Karen Lohmann/B-5898-2008; OI Siegel, Karen Lohmann/0000-0002-0788-6612 NR 12 TC 15 Z9 15 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0966-6362 J9 GAIT POSTURE JI Gait Posture PD JUN PY 2006 VL 23 IS 4 BP 435 EP 440 DI 10.1016/j.gaitpost.2005.05.007 PG 6 WC Neurosciences; Orthopedics; Sport Sciences SC Neurosciences & Neurology; Orthopedics; Sport Sciences GA 047HR UT WOS:000237870900006 PM 16098747 ER PT J AU Gallmeier, E Calhoun, ES Rago, C Brody, JR Cunningham, SC Hucl, T Gorospe, M Kohli, M Lengauer, C Kern, SE AF Gallmeier, E Calhoun, ES Rago, C Brody, JR Cunningham, SC Hucl, T Gorospe, M Kohli, M Lengauer, C Kern, SE TI Targeted disruption of FANCC and FANCG in human cancer provides a preclinical model for specific therapeutic options SO GASTROENTEROLOGY LA English DT Article ID FANCONIS ANEMIA CELLS; PANCREATIC-CANCER; GENE-MUTATIONS; CELLULAR-DNA; CROSS-LINKS; PATHWAY; REPAIR; DAMAGE; BRCA2; INSTABILITY AB Background & Aims: How specifically to treat pancreatic and other cancers harboring Fanconi anemia gene mutations has raised great interest recently, yet preclinical studies have been hampered by the lack of well-controlled human cancer models. Methods: We endogenously disrupted FANCC and FANCG in a human adenocarcinoma cell line and determined the impact of these genes on drug sensitivity, irradiation sensitivity, and genome maintenance. Results: FANCC and FANCG disruption abrogated FANCD2 monoubiquitination, confirming an impaired Fanconi anemia pathway function. On treatment with DNA interstrand-cross-linking agents, FANCC and FANCG disruption caused increased clastogenic damage, G2/M arrest, and decreased proliferation. The extent of hypersensitivity varied among agents, with ratios of inhibitory concentration 50% ranging from 2-fold for oxaliplatin to 14-fold for melphalan, a drug infrequently used in solid tumors. No hypersensitivity was observed on gemcitabine, etoposide, 3-aminobenzamide, NU:1025, or hydrogen peroxide. FANCC and FANCG disruption also resulted in increased clastogenic damage on irradiation, but only FANCG disruption caused a subsequent decrease in relative survival. Finally, FANCC and FANCG disruption increased spontaneous chromosomal breakage, supporting the role of these genes in genome maintenance and likely explaining why they are mutated in sporadic cancer. Conclusions: Our human cancer cell model provides optimal controls to elucidate fundamental biologic features of individual Fanconi anemia gene defects and facilitates preclinical studies of therapeutic options. The impact of Fanconi gene defects on drug and irradiation sensitivity renders these genes promising targets for a specific, genotype-based therapy for individual cancer patients, providing a strong rationale for clinical trials. C1 Johns Hopkins Univ, Sch Med, Dept Oncol, Sidney Kimmel Corrprehens Canc Ctr, Baltimore, MD 21231 USA. NIA, IRP, NIH, Baltimore, MD 21224 USA. Natl Inst Biomed Res, Cambridge, MA USA. RP Kern, SE (reprint author), Johns Hopkins Univ, Sch Med, Dept Oncol, Sidney Kimmel Corrprehens Canc Ctr, Canc Res Bldg 1,Rm 451,1650 Orleans St, Baltimore, MD 21231 USA. EM sk@jhmi.edu FU NCI NIH HHS [CA 62924] NR 35 TC 37 Z9 37 U1 0 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2006 VL 130 IS 7 BP 2145 EP 2154 DI 10.1053/j.gastro.2006.03.016 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 052CD UT WOS:000238207500020 PM 16762635 ER PT J AU Martin, J Magnino, F Schmidt, K Piguet, AC Lee, JS Semela, D St-Pierre, MV Ziemiecki, A Cassio, D Brenner, C Thorgeirsson, SS Dufour, JF AF Martin, Juliette Magnino, Fabrice Schmidt, Karin Piguet, Anne-Christine Lee, Ju-Seog Semela, David St-Pierre, Marie V. Ziemiecki, Andrew Cassio, Doris Brenner, Charles Thorgeirsson, Snorri S. Dufour, Jean-Francois TI Hint2, a mitochondrial apoptotic sensitizer down-regulated in hepatocellular carcinoma SO GASTROENTEROLOGY LA English DT Article ID HISTIDINE TRIAD PROTEINS; HERPES-SIMPLEX VIRUS-1; AMP-LYSINE HYDROLASE; CELL LUNG-CARCINOMA; CASEIN KINASE-II; GENE-EXPRESSION; IN-VITRO; NUCLEOTIDE; FHIT; ADENYLYLATION AB Background & Aims: Hints, histidine triad nucleotide-binding proteins, are adenosine monophosphate-lysine hydrolases of uncertain biological function. Here we report the characterization of human Hint2. Methods: Tissue distribution was determined by real-time quantitative polymerase chain reaction and immunoblotting, cellular localization by immunocytochemistry, and transfection with green fluorescent protein constructs. Enzymatic activities for protein kinase C and adenosine phosphoramidase in the presence of Hint2 were measured. HepG2 cell lines with Hint2 overexpressed or knocked down were established. Apoptosis was assessed by immunoblotting for caspases and by flow cytometry. Tumor growth was measured in SCID mice. Expression in human tumors was investigated by microarrays. Results: Hint2 was predominantly expressed in liver and pancreas. Hint2 was localized in mitochondria. Hint2 hydrolyzed adenosine monophosphate linked to an amino group (AMP-pNA; k(cat):0.0223 s(-1); K(m):128 mu mol/ L). Exposed to apoptotic stress, fewer HepG2 cells overexpressing Hint2 remained viable (32.2 +/- 0.6% vs 57.7 +/- 4.6%), and more cells displayed changes of the mitochondrial membrane potential (87.8 +/- 2.35 vs 49.7 +/- 1.6%) with more cleaved caspases than control cells. The opposite was observed in HepG2 cells with knockdown expression of Hint2. Subcutaneous injection of HepG2 cells overexpressing Hint2 in SCID mice resulted in smaller tumors (0.32 +/- 0.13 g vs 0.85 +/- 0.35 g). Microarray analyses revealed that HINT2 messenger RNA is downregulated in hepatocellular carcinomas (-0.42 +/- 0.58 log(2) vs -0.11 +/- 0.28 log(2)). Low abundance of HINT2 messenger RNA was associated with poor survival. Conclusion: Hint2 defines a novel class of mitochondrial apoptotic sensitizers down-regulated in hepatocellular carcinoma. C1 Univ Bern, Inst Clin Pharmacol, CH-3010 Bern, Switzerland. Univ Bern, Dept Clin Res, CH-3010 Bern, Switzerland. NCI, Expt Carcinogenesis Lab, Canc Res Ctr, Bethesda, MD 20892 USA. Univ Zurich, Dept Clin Pharmacol, Zurich, Switzerland. INSERM, U442, Orsay, France. Dartmouth Med Sch, Dept Genet, Lebanon, NH USA. Dartmouth Med Sch, Dept Biochem, Lebanon, NH USA. Dartmouth Med Sch, Norris Cotton Canc Ctr, Lebanon, NH USA. RP Dufour, JF (reprint author), Univ Bern, Inst Clin Pharmacol, 35 Murtenstr, CH-3010 Bern, Switzerland. EM jf.dufour@ikp.unibe.ch RI Semela, David/D-1988-2010; Brenner, Charles/D-6339-2014 OI Brenner, Charles/0000-0002-4955-3226 FU NCI NIH HHS [CA75954, R01 CA075954, R01 CA075954-09] NR 36 TC 32 Z9 33 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2006 VL 130 IS 7 BP 2179 EP 2188 DI 10.1053/j.gastro.2006.03.004 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 052CD UT WOS:000238207500023 PM 16762638 ER PT J AU Kaye, J Hayes, T AF Kaye, Jeffrey Hayes, Tamara TI Home health monitoring: A system to assess motor and cognitive funtion SO GENERATIONS-JOURNAL OF THE AMERICAN SOCIETY ON AGING LA English DT Article C1 Oregon Hlth & Sci Univ, NIA, Oregon Ctr Aging Technol Educ & Commun Hlth, Portland, OR 97201 USA. Oregon Hlth & Sci Univ, Sch Sci & Engn, Portland, OR 97201 USA. RP Kaye, J (reprint author), Oregon Hlth & Sci Univ, NIA, Oregon Ctr Aging Technol Educ & Commun Hlth, Portland, OR 97201 USA. OI Kaye, Jeffrey/0000-0002-9971-3478 NR 1 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC AGING PI SAN FRANCISCO PA 833 MARKET ST, STE 511, SAN FRANCISCO, CA 94103-1824 USA SN 0738-7806 J9 GENERATIONS JI Generations-J. Am. Soc. Aging PD SUM PY 2006 VL 30 IS 2 BP 61 EP 63 PG 3 WC Gerontology SC Geriatrics & Gerontology GA V44EG UT WOS:000202985400012 ER PT J AU Amos, CI Chen, WV Lee, A Li, W Kern, M Lundsten, R Batliwalla, F Wener, M Remmers, E Kastner, DA Criswell, LA Seldin, MF Gregersen, PK AF Amos, CI Chen, WV Lee, A Li, W Kern, M Lundsten, R Batliwalla, F Wener, M Remmers, E Kastner, DA Criswell, LA Seldin, MF Gregersen, PK TI High-density SNP analysis of 642 Caucasian families with rheumatoid arthritis identifies two new linkage regions on 11p12 and 2q33 SO GENES AND IMMUNITY LA English DT Article DE genetic linkage analysis; single-nucleotide polymorphisms; rheumatoid arthritis; stratified analysis ID JUVENILE IDIOPATHIC ARTHRITIS; LYMPHOID TYROSINE PHOSPHATASE; CYCLIC CITRULLINATED PEPTIDE; SINGLE-NUCLEOTIDE POLYMORPHISM; CHRONIC LYMPHOCYTIC-LEUKEMIA; SHARED EPITOPE HYPOTHESIS; GENOME-WIDE LINKAGE; CROHNS-DISEASE; PTPN22 GENE; SUSCEPTIBILITY LOCUS AB We have completed a genome wide linkage scan using > 5700 informative single-nucleotide polymorphism (SNP) markers (Illumina IV SNP linkage panel) in 642 Caucasian families containing affected sibling pairs with rheumatoid arthritis (RA), ascertained by the North American Rheumatoid Arthritis Consortium. The results show striking new evidence of linkage at chromosomes 2q33 and 11p12 with logarithm of odds (LOD) scores of 3.52 and 3.09, respectively. In addition to a strong and broad linkage interval surrounding the major histocompatibility complex (LOD > 16), regions with LOD > 2.5 were observed on chromosomes 5 and 10. Additional linkage evidence (LOD scores between 1.46 and 2.35) was also observed on chromosomes 4, 7, 12, 16 and 18. This new evidence for multiple regions of genetic linkage is partly explained by the significantly increased information content of the Illumina IV SNP linkage panel (75.6%) compared with a standard microsatellite linkage panel utilized previously (mean 52.6%). Stratified analyses according to whether or not the sibling pair members showed elevated anticyclic citrullinated peptide titers indicates significant variation in evidence for linkage among strata on chromosomes 4, 5, 6 and 7. Overall, these new linkage data should reinvigorate efforts to utilize positional information to identify susceptibility genes for RA. C1 Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. Feinstein Inst Med Res, Robert S Boas Ctr Genom & Human Genet, Manhasset, NY USA. Univ Washington, Sch Med, Dept Lab Med, Seattle, WA 98195 USA. NIAMS, Genet & Genom Branch, NIH, Bethesda, MD USA. Univ Calif San Francisco, Dept Med, Rosalind Russell Med Res Ctr Arthrit, San Francisco, CA 94143 USA. Univ Calif Davis, Rowe Program Genet, Davis, CA 95616 USA. RP Amos, CI (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, 1155 Pressler,Unit 1340, Houston, TX 77030 USA. EM peterg@nshs.edu OI Li, Wentian/0000-0003-1155-110X NR 65 TC 67 Z9 72 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD JUN PY 2006 VL 7 IS 4 BP 277 EP 286 DI 10.1038/sj.gene.6364295 PG 10 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 050XF UT WOS:000238122400002 PM 16691188 ER PT J AU Millstein, RA Ralpho, RJ Yang, RJ Holmes, A AF Millstein, RA Ralpho, RJ Yang, RJ Holmes, A TI Effects of repeated maternal separation on prepulse inhibition of startle across inbred mouse strains SO GENES BRAIN AND BEHAVIOR LA English DT Article DE early life stress; footshock; gene; handling; inbred; maternal separation; mouse; prepulse inhibition; postnatal; schizophrenia; startle; strain ID QUANTITATIVE TRAIT LOCI; ANXIETY-LIKE BEHAVIOR; STRESSFUL LIFE EVENT; SPRAGUE-DAWLEY RATS; ACOUSTIC STARTLE; ADULT RATS; GENE-EXPRESSION; MICE; SCHIZOPHRENIA; DEPRIVATION AB A growing body of research implicates genetic factors and childhood trauma in the etiology of neuropsychiatric diseases such as schizophrenia. However, there remains little understanding of how genetic variation influences early life stress to affect later disease susceptibility. Studies in rats have shown that postnatal maternal separation (MS) results in later deficits in prepulse inhibition of the acoustic startle response (PPI), an impairment in sensorimotor gating found in schizophrenic patients. In the present study, genetic differences in the effects of repeated MS on PPI were examined in eight inbred strains of mice (129S1/SvImJ, 129P3/J, A/J, BALB/cJ, BALB/cByJ C57BL/6J, DBA/2J and FVB/NJ). Mice were assigned to either MS (180 min/day on postnatal days P0-P13), 'handling' (15 min/day, P0-P13) or facility-reared conditions and tested for PPI at 12 weeks of age. Results demonstrated major strain differences in the production of viable offspring irrespective of MS, leading to the exclusion of 129P3/J, A/J and BALB/cJ from the study. Pups from the five remaining strains exhibited marked differences in the acoustic startle response and PPI, confirming previous strain comparisons. However, MS produced no significant effects on PPI in any of the strains tested. A second form of postnatal stress (repeated footshock) also failed to alter PPI in the one strain studied, C57BL/6J. Present results demonstrate that the form of MS studied herein does not provide a robust model of early life stress effects on PPI in the mouse strains tested. The development and validation of a reliable mouse model of early life stress remains an important research goal. C1 NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, Rockville, MD 20852 USA. Harvard Univ, McLean Hosp, Sch Med, Alcohol & Drug Abuse Res Ctr, Belmont, MA 02178 USA. RP Holmes, A (reprint author), NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, 5625 Fishers Lane,Room 2N09, Rockville, MD 20852 USA. EM holmesan@mail.nih.gov FU Intramural NIH HHS NR 56 TC 54 Z9 55 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD JUN PY 2006 VL 5 IS 4 BP 346 EP 354 DI 10.1111/j.1601-183X.2005.00172.x PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 044SP UT WOS:000237693000006 PM 16716204 ER PT J AU Hung, GC Masison, DC AF Hung, GC Masison, DC TI N-terminal domain of yeast Hsp104 chaperone is dispensable for thermotolerance and prion propagation but necessary for curing prions by Hsp104 overexpression SO GENETICS LA English DT Article ID SACCHAROMYCES-CEREVISIAE; PSI+ PRION; GUANIDINE-HYDROCHLORIDE; PROTEIN DISAGGREGATION; AGGREGATED PROTEINS; ESCHERICHIA-COLI; HSP70 CHAPERONE; ATP HYDROLYSIS; CLPB; BINDING AB Hsp104 is a hexameric protein chaperone that resolubilizes stress-damaged proteins from aggregates. Hsp104 promotes [PSI] prion propagation by breaking prion aggregates, which propagate as amyloid fibers, into more numerous prion "seeds." Inactivating Hsp104 cures cells of [PSI] and other amyloid-like yeast prions. Overexpressing Hsp104 also eliminates [PSI], presumably by completely resolubilizing prion aggregates. Inexplicably, however, excess Hsp104 does not cure the other prions. Here we identify missense mutations in Hsp104's amino-terminal domain (NTD), which is conserved among Hsp100 proteins but whose function is unknown, that improve [PSI+] propagation. Hsp104 Delta 147, engineered to lack the NTD, supported [PSI] and functioned normally in thermotolerance and protein disaggregation. Hsp104 Delta 147 failed to cure [PSI+] when overexpressed, however, implying that excess Hsp104 does not eliminate [PSI+] by direct dissolution of prion aggregates. Curing of [PSI+] by overexpressing catalytically inactive Hsp104 (Hsp104KT), which interferes with endogenous Hsp104, did not require the NTD. We further found that Hsp104 mutants defective in threading peptides through the hexamer pore had reduced ability to support [PSI] in proportion to protein resolubilization defects, suggesting that [PSI+] propagation depends on this threading and that Hsp104 "breaks" prion aggregates by extracting protein monomers from the amyloid fibers. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Masison, DC (reprint author), NIDDKD, Lab Biochem & Genet, NIH, 8 Ctr Dr, Bethesda, MD 20892 USA. EM masisond@helix.nih.gov FU Intramural NIH HHS; NIDDK NIH HHS [Z01 DK024946-08] NR 55 TC 75 Z9 76 U1 1 U2 8 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD JUN PY 2006 VL 173 IS 2 BP 611 EP 620 DI 10.1534/genetics.106.056820 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 058FM UT WOS:000238650900010 PM 16582428 ER PT J AU Morin, RD Chang, E Petrescu, A Liao, N Griffith, M Kirkpatrick, R Butterfield, YS Young, AC Stott, J Barber, S Babakaiff, R Dickson, MC Matsuo, C Wong, D Yang, GS Smailus, DE Wetherby, KD Kwong, PN Grimwood, J Brinkley, CP Brown-John, M Reddix-Dugue, ND Mayo, M Schmutz, J Beland, J Park, M Gibson, S Olson, T Bouffard, GG Tsai, M Featherstone, R Chand, S Siddiqui, AS Jang, WH Lee, E Klein, SL Blakesley, RW Zeeberg, BR Narasimhan, S Weinstein, JN Pennacchio, CP Myers, RM Green, ED Wagner, L Gerhard, DS Marra, MA Jones, SJM Holt, RA AF Morin, Ryan D. Chang, Elbert Petrescu, Anca Liao, Nancy Griffith, Malachi Kirkpatrick, Robert Butterfield, Yaron S. Young, Alice C. Stott, Jeffrey Barber, Sarah Babakaiff, Ryan Dickson, Mark C. Matsuo, Corey Wong, David Yang, George S. Smailus, Duane E. Wetherby, Keith D. Kwong, Peggy N. Grimwood, Jane Brinkley, Charles P., III Brown-John, Mabel Reddix-Dugue, Natalie D. Mayo, Michael Schmutz, Jeremy Beland, Jaclyn Park, Morgan Gibson, Susan Olson, Teika Bouffard, Gerard G. Tsai, Miranda Featherstone, Ruth Chand, Steve Siddiqui, Asim S. Jang, Wonhee Lee, Ed Klein, Steven L. Blakesley, Robert W. Zeeberg, Barry R. Narasimhan, Sudarshan Weinstein, John N. Pennacchio, Christa Prange Myers, Richard M. Green, Eric D. Wagner, Lukas Gerhard, Daniela S. Marra, Marco A. Jones, Steven J. M. Holt, Robert A. TI Sequencing and analysis of 10,967 full-length cDNA clones from Xenopus laevis and Xenopus tropicalis reveals post-tetraploidization transcriptome remodeling SO GENOME RESEARCH LA English DT Article ID DUPLICATE GENES; FROGS XENOPUS; CLAWED FROGS; EST PROJECT; EVOLUTION; DNA; TOOL; GENERATION; LIKELIHOOD; PHYLOGENY AB Sequencing of full-insert clones from full-length cDNA libraries from both Xenopus laevis and Xenopus tropicalis has been ongoing as part of the Xenopus Gene Collection Initiative. Here we present 10,967 full ORF verified cDNA clones (8049 from X. laevis and 2918 from X. tropicalis) as a community resource. Because the genome of X. laevis, but not X. tropicalis, has undergone allotetraploidization, comparison of coding sequences from these two clawed (pipid) frogs provides a unique angle for exploring the molecular evolution of duplicate genes. Within our clone set, we have identified 445 gene trios, each comprised of an allotetraploidization-derived X. laevis gene pair and their shared X. tropicalis ortholog. Pairwise d(N)/d(S), comparisons within trios show strong evidence for purifying selection acting on all three members. However, d(N)/d(S) ratios between X. laevis gene pairs are elevated relative to their X. tropicalis ortholog. This difference is highly significant and indicates an overall relaxation of selective pressures on duplicated gene pairs. We have found that the paralogs that have been lost since the tetraploidization event are enriched for several molecular functions, but have found no such enrichment in the extant paralogs. Approximately 14% of the paralogous pairs analyzed here also show differential expression indicative of subfunctionalization. C1 British Columbia Genome Sci Ctr, BCCA, Vancouver, BC V5Z 1L3, Canada. Stanford Univ, Sch Med, Stanford Human Genome Ctr, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. NIH, Genom & Bioinformat Grp, Mol Pharmacol Lab, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NICHHD, NIH, Bethesda, MD 20892 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Lawrence Livermore Natl Lab, IMAGE Consortium, Biol & Biotechnol Res Program, Livermore, CA 94550 USA. 2SRA Int, Fairfax, VA 22033 USA. RP Holt, RA (reprint author), British Columbia Genome Sci Ctr, BCCA, Vancouver, BC V5Z 1L3, Canada. EM rholt@bcgsc.ca RI Holt, Robert/C-3303-2009; Schmutz, Jeremy/N-3173-2013; Tang, Macy/B-9798-2014; Griffith, Malachi/P-1285-2014; Jones, Steven/C-3621-2009; Marra, Marco/B-5987-2008; OI Schmutz, Jeremy/0000-0001-8062-9172; Griffith, Malachi/0000-0002-6388-446X; Chow, William/0000-0002-9056-201X FU Intramural NIH HHS; NHGRI NIH HHS [U01 HG002155-06S1, U01 HG002155] NR 37 TC 45 Z9 50 U1 0 U2 10 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD JUN PY 2006 VL 16 IS 6 BP 796 EP 803 DI 10.1101/gr.4871006 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 048UY UT WOS:000237973200012 PM 16672307 ER PT J AU Chan, WY Wu, SM Ruszczyk, L Law, E Lee, TL Baxendale, V Pang, ALY Rennert, OM AF Chan, WY Wu, SM Ruszczyk, L Law, E Lee, TL Baxendale, V Pang, ALY Rennert, OM TI The complexity of antisense transcription revealed by the study of developing male germ cells SO GENOMICS LA English DT Article DE antisense transcription; intron; exon; intergenic; pseudogene; mouse; spermatogonia; spermatocytes; spermatids ID NITRIC-OXIDE SYNTHASE; MESSENGER-RNA; POSTTRANSCRIPTIONAL REGULATION; SPERMATOGENIC CELLS; HUMAN GENOME; IN-VIVO; EXPRESSION; GENES; SENSE; MOUSE AB Computational analyses have identified the widespread occurrence of antisense transcripts in the human and the mouse genome. However, the structure and the origin of the majority of the antisense transcripts are unknown. The presence of antisense transcripts for 19 of 64 differentially expressed genes during mouse spermatogenesis was demonstrated with orientation-specific RT-PCR. These antisense transcripts were derived from a wide variety of origins, including processed sense transcripts, intronic and exonic sequences of a single gene or multiple genes, intergenic sequences, and pseudogenes. They underwent normal and alternative splicing, 5' capping, and 3' polyadenylation, similar to the sense transcripts. There were also antisense transcripts that were not capped and/or polyadenylated. The testicular levels of the sense transcripts were higher than those of the antisense transcripts in all cases, while the relative expression in nontesticular tissues was variable. Thus antisense transcripts have complex origins and structures and the sense and antisense transcripts can be regulated independently. Published by Elsevier Inc. C1 NICHHD, Lab Clin Genom, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Dept Pediat, Washington, DC 20007 USA. RP Chan, WY (reprint author), NICHHD, Lab Clin Genom, NIH, Bldg 49,Room 2A08,49 Convent Dr,MSC 4429, Bethesda, MD 20892 USA. EM chanwy@mail.nih.gov RI Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 FU Intramural NIH HHS NR 49 TC 21 Z9 22 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD JUN PY 2006 VL 87 IS 6 BP 681 EP 692 DI 10.1016/j.ygeno.2005.12.006 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 051NS UT WOS:000238168400001 PM 16458478 ER PT J AU Yao, K Mandel, M Akyani, N Maynard, K Sengamalay, N Fotheringham, J Ghedin, E Kashanchi, F Jacobson, S AF Yao, K Mandel, M Akyani, N Maynard, K Sengamalay, N Fotheringham, J Ghedin, E Kashanchi, F Jacobson, S TI Differential HHV-6A gene expression in T cells and primary human astrocytes based on multi-virus array analysis SO GLIA LA English DT Article DE HHV-6; multiple sclerosis; astrocytes; multi-virus array; viral persistency ID HUMAN-HERPESVIRUS 6; OPEN READING FRAMES; SCLEROSIS LESIONS; HUMAN-HERPESVIRUS-6; DNA; ASSOCIATION; TRANSCRIPTS; GENOME; INFECTION; TROPISM AB Human herpesvirus 6 (HHV-6) is a ubiquitous virus that has been associated with a wide spectrum of diseases, such as exanthem infantum, multiple sclerosis, seizures, encephalitis/meningitis, and more recently, mesial temporal lobe sclerosis. Although HHV-6 is known to predominately infect CD4+ T lymphocytes, its ability to infect neural glial cells has been demonstrated both in vitro and in vivo. Reactivation of latent HHV-6 infection in the brain has recently been suggested to play a role in the development of neuropathogenesis. To investigate the association of viral gene expression and disease pathogenesis, we developed a multivirus array containing all open reading frames of the HHV-6 virus and other pathogenically related viruses (EBV, HBV, HHV-8, HIV-1, HTLV-1, HTLV-2) to study expression of viral gene transcripts. In this study, we infected CD4+ T lymphocytes and primary human astrocytes derived from brain biopsy material in vitro with the more neurotropic HHV-6A strain. Hierarchal cluster analysis based on gene expression over time suggested a temporally regulated herpesvirus transcription process. Furthermore, we compared viral gene expression in CD4+ T lymphocytes and primary human astrocytes at peak viral load levels (> 10(8) copies of virus/10(6) cells) at 5 days post-infection. Differential expression of HHV-6A genes was observed between CD4+ T lymphocytes and primary human astrocytes. Absence of a number of HHV-6 genes detected at 5 days post-infection in primary human astrocytes suggests an alternative replication strategy used by HHV-6 to evade immune detection and allow establishment of persistent infection in neural glial cells. (c) 2006 Wiley-Liss, Inc. C1 NINDS, Viral Immunol Sect, NIH, Bethesda, MD 20892 USA. Inst Genom Res, Rockville, MD 20850 USA. George Washington Univ, Sch Med, Washington, DC 20037 USA. Howard Hughes Med Inst, Natl Inst Hlth Res, Scholars Program, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, NIH, 9000 Rockville Pike,Bldg 10,Room 5B16, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov NR 36 TC 19 Z9 21 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0894-1491 J9 GLIA JI Glia PD JUN PY 2006 VL 53 IS 8 BP 789 EP 798 DI 10.1002/glia.20333 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 038OE UT WOS:000237231400001 PM 16541415 ER PT J AU Tiong, JDR Gosney, E Ding, J Chin, E Kopchick, JJ AF Tiong, Jean D. R. Gosney, Elahu Ding, Juan Chin, Edward Kopchick, John J. TI A liver specific gene that is expressed in growth hormone transgenic mice and in normal female mice as a function of age SO GROWTH HORMONE & IGF RESEARCH LA English DT Article DE GH; GH-regulated genes; GH transgenic mice; sexual dimorphism; liver regeneration; subtractive cDNA hybridization; alpha-1B-glycoprotein; immunoglobulin super family; aging ID DIDELPHIS-MARSUPIALIS SERUM; PARTIAL-HEPATECTOMY; HYPOPHYSECTOMIZED RATS; FACTOR-I; TRANSCRIPTIONAL CONTROL; DEOXYRIBONUCLEIC-ACID; RECEPTOR DIMERIZATION; HEPATIC REGENERATION; MICROARRAY ANALYSIS; PROTEIN AB Growth hormone (GH) acts on various organs to exert its growth and metabolic effects. GH induces transcription of a number of genes in different organs including liver. By performing subtractive hybridization analysis on liver cDNAs of GH transgenic and non-transgenic mice, differentially expressed cDNAs were obtained. This paper describes the isolation and characterization of a liver cDNA, termed cDNA #5, that contains 1897 bp and is predicted to encode a protein (P5) of 512 aa residues. P5 has five immunoglobulin related domains thus allowing it to be classified as a member of the immunoglobulin super family (IGSF). Also, P5 shows significant similarity to both rat and human alpha-1-B glycoprotein which is an acidic serum protein of unknown function. mRNA #5 was detected in the liver hepatocytes of mate and female GH transgenic mice and in the liver of female, but not of male, non-transgenic mice. mRNA #5 was not present in dwarf mice including the Ames dwarf, those that express a GH antagonist and those with the GH receptor and binding protein gene disrupted. These findings suggest that induction of mRNA #5 in the liver requires a continuous pattern of GH secretion and an intact GH-GH receptor-signaling complex. mRNA #5 levels in female non-transgenic mice were observed to vary with age implying that gender-specific age-dependent factor(s) may be involved in the induction of mRNA #5. The appearance of mRNA #5 in post-hepatectornized liver that coincides with the proliferative phase of liver regeneration suggests that it may be involved in hepatocyte proliferation. Together these data suggest that expression of cDNA #5 is liver-specific, sexually dimorphic, age-dependent, and may be involved in hepatocyte hyperplasia and liver enlargement. (c) 2006 Elsevier Ltd. All rights reserved. C1 Ohio Univ, Edison Biotechnol Inst, Konneker Res Labs, Athens, OH 45701 USA. Ohio Univ, Coll Osteopath Med, Dept Biomed Sci, Athens, OH 45701 USA. Univ Alabama Birmingham, Dept Med, Div Endocrinol, Birmingham, AL 35294 USA. NINDS, NIH, Cellular & Dev Neurobiol Sect, Bethesda, MD 20892 USA. RP Kopchick, JJ (reprint author), Ohio Univ, Edison Biotechnol Inst, Konneker Res Labs, Athens, OH 45701 USA. EM kopchick@ohio.edu RI Ding, Juan/L-5149-2013; Sustarsic, Elahu/M-5168-2013 OI Sustarsic, Elahu/0000-0002-4792-4740 FU NIA NIH HHS [AG19899-02] NR 55 TC 5 Z9 6 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1096-6374 EI 1532-2238 J9 GROWTH HORM IGF RES JI Growth Horm. IGF Res. PD JUN PY 2006 VL 16 IS 3 BP 145 EP 156 DI 10.1016/j.ghir.2006.03.011 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 077WO UT WOS:000240062600001 PM 16723264 ER PT J AU Gladwin, MT AF Gladwin, MT TI Polycythemia, HIF-1 alpha and pulmonary hypertension in Chuvash SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Editorial Material ID ARTERIAL-HYPERTENSION C1 NHLBI, Vasc Med Branch, NIH, Bethesda, MD 20892 USA. RP Gladwin, MT (reprint author), NHLBI, Vasc Med Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM mgladwin@mail.nih.gov NR 5 TC 2 Z9 2 U1 0 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA STRADA NUOVA 134, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD JUN PY 2006 VL 91 IS 6 BP 722 EP 723 PG 2 WC Hematology SC Hematology GA 053RK UT WOS:000238322400002 PM 16769565 ER PT J AU Porter, LL AF Porter, LL TI The Science of Migraine: Recent advances, future directions - Selections from the Proceedings of an NINDS-sponsored convocation of headache investigators - Boston October 13-14, 2004 - Introduction SO HEADACHE LA English DT Editorial Material C1 NINDS, NIH, Bethesda, MD 20892 USA. RP Porter, LL (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0017-8748 J9 HEADACHE JI Headache PD JUN PY 2006 VL 46 SU 1 BP S2 EP S2 DI 10.1111/j.1526-4610.2006.00482.x PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 044TQ UT WOS:000237695700002 ER PT J AU Buchanan, DR AF Buchanan, DR TI A new ethic for health promotion: Reflections on a philosophy of health education for the 21st century SO HEALTH EDUCATION & BEHAVIOR LA English DT Article DE ethics; health education; health promotion; philosophy; research ID COMMUNITY INTERVENTION TRIAL; SMOKING CESSATION COMMIT; SOCIETY AB This article describes two models for thinking about the purposes of health education-a medical model and an education model-and traces how concerns about the validity of research have driven preference for the medical model. In the medical model, the purpose of health education is to develop effective interventions that will prevent people from adopting unhealthy behaviors. Here, health educators are expected to replicate the methods identified by researchers to effect targeted changes in health behavior. The article then describes an alternative way of thinking about the purposes of health education. In pursuing a philosophy of education, the purpose of research and practice would be to clarify basic social values and to strengthen one's faculty for making value judgments. Practitioners here use research results as a stimulus for dialogue about the role of good health habits in living the kind of life that community members find most valuable. C1 NCI, Div Canc Prevent, Bethesda, MD 20872 USA. RP Buchanan, DR (reprint author), NCI, Div Canc Prevent, 6130 Execut Blvd,Room 2149, Bethesda, MD 20872 USA. EM buchanad@mail.nih.gov NR 47 TC 23 Z9 23 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD JUN PY 2006 VL 33 IS 3 BP 290 EP 304 DI 10.1177/1090198105276221 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 044EM UT WOS:000237655200001 PM 16699121 ER PT J AU Yaroch, AL Reynolds, KD Buller, DB Maloy, JA Geno, CR AF Yaroch, AL Reynolds, KD Buller, DB Maloy, JA Geno, CR TI Validity of a sun safety diary using UV monitors in middle school children SO HEALTH EDUCATION & BEHAVIOR LA English DT Article DE validity; sun safety; measurement ID SKIN-CANCER PREVENTION; ULTRAVIOLET-RADIATION EXPOSURE; SOLAR PROTECTION; MELANOMA RISK; ADOLESCENTS; SUNSCREEN; ATTITUDES; PROGRAM AB This article describes a validity study conducted among middle school students comparing self-reported sun safety behaviors from a diary with readings from ultraviolet (UV) monitors worn on different body sites. The UV monitors are stickers with panels that turn increasingly darker shades of blue in the presence of increasing amounts of UV light. Three schools participated (N = 527). Statistically significant associations were found between self-reported behaviors and the UV monitor measurements, with Kendall's tau b's ranging from 0.400 to 0.823. Multiple regression was performed and indicator variables created separately for arm (R =. 12) and leg (R = .49) coverage by protective clothing. The effect of time spent outdoors on the UV monitor measure was attenuated when the students reported having the corresponding body site covered with clothing. Self-reported shade was not a significant predictor of UV monitor change. Overall, the results provide evidence of validity of students' self-reports of time outdoors and protective clothing use. C1 NCI, Div Canc Control & Populat Sci, Hlth Promot Res Branch, Bethesda, MD 20892 USA. Univ So Calif, Keck Sch Med, Inst Hlth Promot & Dis Prevent Res, Los Angeles, CA 90089 USA. Kaiser Permanente, Denver, CO USA. Klein Buendel Inc, Golden, CO USA. RP Yaroch, AL (reprint author), NCI, Div Canc Control & Populat Sci, Hlth Promot Res Branch, 6130 Execut Blvd,Rm 4074-MSC 7335, Bethesda, MD 20892 USA. EM yarocha@mail.nih.gov FU NCI NIH HHS [R01 CA079701, R01 CA79701] NR 26 TC 17 Z9 17 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD JUN PY 2006 VL 33 IS 3 BP 340 EP 351 DI 10.1177/1090198105285329 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 044EM UT WOS:000237655200006 PM 16699124 ER PT J AU Fleischmann, KE Orav, EJ Lamas, GA Mangione, CM Schron, E Lee, KL Goldman, L AF Fleischmann, KE Orav, EJ Lamas, GA Mangione, CM Schron, E Lee, KL Goldman, L TI Pacemaker implantation and quality of life in the Mode Selection Trial (MOST) SO HEART RHYTHM LA English DT Article DE pacemakers; pacing; sinoatrial node; arrhythmia ID SINUS-NODE DYSFUNCTION; HEALTH SURVEY SF-36; CANADIAN TRIAL; LONG-TERM; VALIDITY; ATRIAL; DDD AB BACKGROUND Dual-chamber pacemakers restore AV synchrony compared with ventricular pacemakers, but the effects on health-related quality of Life (QOL) are uncertain. OBJECTIVES The purpose of this study was to assess the effect of pacemaker implantation, clinical factors, and pacing mode on QOL. METHODS The Mode Selection Trial (MOST) randomized 2,010 patients with sinus node dysfunction to rate-modulated right ventricular (VVIR) or dual-chamber (DDDR) pacing. A Longitudinal analysis of serial QOL measures (Short Form-36 [SF-36], Specific Activity Scale, and time trade-off utility) was performed. In patients who crossed over from VVIR to DDDR because of severe pacemaker syndrome, the last known QOL prior to crossover was carried forward. RESULTS Pacemaker implantation resulted in substantial improvement in almost all QOL measures. Subjects 75 years or older experienced significantly less improvement in functional status and physical component summary scores than did younger subjects. In Longitudinal analyses of the effect of pacing mode on OOL, significant improvement in three SF-36 subscales was observed with DDDR pacing compared with VVIR pacing: rote physical [62.8 points (95% confidence interval [CI] 60.2, 65.5) vs 56.4 (95% CI 53.7, 59.1)], rote emotional [85.0 (95% CI 82.9, 87.0) vs 81.9 (95% CI 79.9, 84.0)], and vitality [51.8 (95% CI 50.3, 53.3) vs 49.3 (95% CI 47.8, 50.7)], but not in other SF-36 subscales, the Specific Activity Scale, or utilities. The gains in QOL were larger than the declines associated with 1 year of aging but smaller than those associated with heart failure. CONCLUSION Pacemaker implantation improved health-related QOL. The mode selected was associated with much smaller, but significant, improvements in several domains, particularly rote physical function. C1 Univ Calif San Francisco, Med Ctr, Dept Med, San Francisco, CA 94030 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Miami Heart Inst, Mt Sinai Med Ctr, Div Cardiol, Miami Beach, FL 33140 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA USA. NHLBI, Bethesda, MD 20892 USA. Duke Clin Res Inst, Durham, NC USA. Duke Univ, Sch Med, Durham, NC USA. RP Fleischmann, KE (reprint author), Univ Calif San Francisco, Med Ctr, Dept Med, 505 Parnassus Ave,Box 0124, San Francisco, CA 94030 USA. EM fleischm@medicine.ucsf.edu FU NHLBI NIH HHS [U01-HL-49804, U01-HL-55981, U01-HL-53973]; NIA NIH HHS [P30-AG-21684] NR 18 TC 34 Z9 38 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 J9 HEART RHYTHM JI Heart Rhythm PD JUN PY 2006 VL 3 IS 6 BP 653 EP 659 DI 10.1016/j.hrthm.2006.02.1031 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 050DN UT WOS:000238067800006 PM 16731465 ER PT J AU Li, BF Sun, R Wei, HM Gao, B Tian, ZG AF Li, BF Sun, R Wei, HM Gao, B Tian, ZG TI Interleukin-15 prevents concanavalin A-induced liver injury in mice via NKT cell-dependent mechanism SO HEPATOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; INDUCED HEPATITIS; T-CELLS; MEDIATED HEPATITIS; INTERFERON-GAMMA; NATURAL-KILLER; EOSINOPHIL PEROXIDASE; MURINE MODEL; IN-VIVO; ACTIVATION AB Administration of concanavalin A (Con A) induces a rapid and severe liver injury in mice. Natural killer T (NKT) cells are recognized to be the key effector cells, and a variety of cytokines [e.g., inteleukin 4 (IL-4):, IL-5, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha)] have been shown to play vital roles in Con A-induced liver injury, whereas the role of IL-15, a critical cytokine in the development and homeostasis of NKT cells, remains obscure. In this study, pretreatment with IL-15 prevented mice from Con A-induced mortality, elevation of serum transaminase, liver necrosis, and hepatocyte apoptosis. Depletion of NKT cells abolished Con A-induced liver injury, which could be restored by adoptive transfer of purified NKT cells but not by that of in vivo or in vitro IL-15-treated hepatic NKT cells. Furthermore, transfer of wild-type NKT cells to CD1d(-/-) mice restored liver injury, whereas transfer of IL-15-treated NKT cells did not. IL-15 pretreatment decreased the NKT-derived IL-4, IL-5, and TNF-alpha production, thereby resulting in less infiltration of eosinophils, which play a critical role in Con A-induced liver injury. In conclusion, IL-15 protects against Con A-induced liver injury via an NKT cell-dependent mechanism by reducing their production of IL-4, IL-5, and infiltration of eosinophils. These findings suggest that IL-15 may be of therapeutic relevance in human autoimmune-related hepatitis. Supplementary materials for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/index.html). C1 Univ Sci & Technol China, Sch Life Sci, Hefei 230027, Anhui, Peoples R China. Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230027, Anhui, Peoples R China. Shandong Univ, Sch Pharmaceut Sci, Inst Immunopharmacol & Immunotherapy, Jinan 250002, Peoples R China. NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD USA. RP Tian, ZG (reprint author), Univ Sci & Technol China, Sch Life Sci, 443 Huangshan Rd, Hefei 230027, Anhui, Peoples R China. EM tzg@ustc.edu.cn RI Tian, Zhigang/J-3512-2013 NR 37 TC 40 Z9 45 U1 1 U2 7 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUN PY 2006 VL 43 IS 6 BP 1211 EP 1219 DI 10.1002/hep.21174 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 048ZG UT WOS:000237984500006 PM 16729307 ER PT J AU Yao, YG Salas, A Bravi, CM Bandelt, HJ AF Yao, YG Salas, A Bravi, CM Bandelt, HJ TI A reappraisal of complete mtDNA variation in East Asian families with hearing impairment SO HUMAN GENETICS LA English DT Article ID HEREDITARY OPTIC NEUROPATHY; RIBOSOMAL-RNA GENE; LARGE CHINESE FAMILY; MITOCHONDRIAL GENOME VARIATION; HYPERVARIABLE REGION-I; DNA SEQUENCE-ANALYSIS; DATA QUALITY-CONTROL; A1555G MUTATION; PHYLOGENETIC ANALYSIS; CLINICAL-EVALUATION AB In a number of recent studies, we summarized the obvious errors and shortcomings that can be spotted in many (if not most) mitochondrial DNA (mtDNA) data sets published in medical genetics. We have reanalyzed here the complete mtDNA genome data published in various recent reports of East Asian families with hearing impairment, using a phylogenetic approach, in order to demonstrate the persistence of lab-specific mistakes in mtDNA genome sequencing in cases where those caveats were (deliberately) neglected. A phylogenetic reappraisal of complete mtDNAs with mutation A1555G (or G11778A) indeed supports the suggested lack of association between haplogroup background and phenotypic presentation of these mutations in East Asians. In contrast, the claimed pathogenicity of mutation T1095C in Chinese families with hearing impairment seems unsupported, basically because this mutation is rather basal in the mtDNA phylogeny, being specific to haplogroup M11 in East Asia. The roles of other haplogroup specific or associated variants, such as A827G, T961C, T1005C, in East Asian subjects with aminoglycoside-induced and non-syndromic hearing loss are also unclear in view of the known mtDNA phylogeny. C1 Chinese Acad Sci, Kunming Inst Zool, Key Lab Cellular & Mol Evolut, Kunming, Yunnam, Peoples R China. Univ Santiago de Compostela, Fac Med, Inst Med Legal, Unidad Genet, Santiago De Compostela 15782, Spain. Inst Multidisciplinario Biol Celular, Lab Genet Mol Poblac, La Plata, Buenos Aires, Argentina. Univ Hamburg, Dept Math, D-20146 Hamburg, Germany. RP Yao, YG (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10 Rm 3-5216, Bethesda, MD 20892 USA. EM yaoy3@nhlbi.nih.gov RI Salas, Antonio/E-3977-2012 OI Salas, Antonio/0000-0002-2336-702X NR 80 TC 78 Z9 85 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD JUN PY 2006 VL 119 IS 5 BP 505 EP 515 DI 10.1007/s00439-006-0154-9 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 039FT UT WOS:000237292100004 PM 16528519 ER PT J AU Santos, JH Meyer, JN Van Houten, B AF Hertzog Santos, Janine Meyer, Joel N. Van Houten, Bennett TI Mitochondrial localization of telomerase as a determinant for hydrogen peroxide-induced mitochondrial DNA damage and apoptosis SO HUMAN MOLECULAR GENETICS LA English DT Article ID BASE EXCISION-REPAIR; OXIDATIVE STRESS; REVERSE-TRANSCRIPTASE; CATALYTIC SUBUNIT; HUMAN-CELLS; HUMAN FIBROBLASTS; GENOTOXIC STRESS; GROWTH ARREST; MTDNA DAMAGE; EXPRESSION AB We have previously shown that the protein subunit of telomerase, hTERT, has a bonafide N-terminal mitochondrial targeting sequence, and that ectopic hTERT expression in human cells correlated with increase in mtDNA damage after hydrogen peroxide treatment. In this study, we show, using a loxP hTERT construct, that this increase in mtDNA damage following hydrogen peroxide exposure is dependent on the presence of hTERT itself. Further experiments using a dominant negative hTERT mutant shows that telomerase must be catalytically active to mediate the increase in mtDNA damage. Etoposide, but not methylmethanesulfate, also promotes mtDNA lesions in cells expressing active hTERT, indicating genotoxic specificity in this response. Fibroblasts expressing hTERT not only show a similar to 2-fold increase in mtDNA damage after oxidative stress but also suffer a 10-30-fold increase in apoptotic cell death as assayed by Annexin-V staining, caspase-3 activation and PARP cleavage. Mutations to the N-terminal mitochondrial leader sequence causes a complete loss of mitochondrial targeting without affecting catalytic activity. Cells carrying this mutated hTERT not only have significantly reduced levels of mtDNA damage following hydrogen peroxide treatment, but strikingly also do not shown any loss of viability or cell growth. Thus, localization of hTERT to the mitochondria renders cells more susceptible to oxidative stress-induced mtDNA damage and subsequent cell death, whereas nuclear-targeted hTERT, in the absence of mitochondrial localization, is associated with diminished mtDNA damage, increased cell survival and protection against cellular senescence. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Physiol & Pharmacol, Newark, NJ 07103 USA. RP Santos, JH (reprint author), NIEHS, Mol Genet Lab, NIH, 111 Alexander Dr,MD D3-01, Res Triangle Pk, NC 27709 USA. EM santosja@umdnj.edu FU Intramural NIH HHS NR 45 TC 94 Z9 102 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUN 1 PY 2006 VL 15 IS 11 BP 1757 EP 1768 DI 10.1093/hmg/ddl098 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 044UA UT WOS:000237696700002 PM 16613901 ER PT J AU Kim, SJ Zhang, ZJ Hitomi, E Lee, YC Mukherjee, AB AF Kim, Sung-Jo Zhang, Zhongjian Hitomi, Emiko Lee, Yi-Ching Mukherjee, Anil B. TI Endoplasmic reticulum stress-induced caspase-4 activation mediates apoptosis and neurodegeneration in INCL SO HUMAN MOLECULAR GENETICS LA English DT Article ID UNFOLDED PROTEIN RESPONSE; NEURONAL CEROID-LIPOFUSCINOSES; THIOESTERASE; DEFICIENCY; PALMITOYLATION; TRAFFICKING; HUNTINGTIN; CHILDHOOD; MUTATIONS; ACYLATION AB Infantile neuronal ceroid lipofuscinosis (INCL), a neurodegenerative storage disorder of childhood, is caused by mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 cleaves thioester linkages in S-acylated (palmitoylated) proteins and its mutation causes abnormal intracellular accumulation of fatty-acylated proteins and peptides leading to INCL pathogenesis. Although apoptosis is the suggested cause of neurodegeneration in INCL, the molecular mechanism(s) of apoptosis remains unclear. Using the PPT1-knockout (PPT1-KO) mice that mimic INCL, we previously reported that one mechanism of apoptosis involves endoplasmic reticulum (ER) stress-induced caspase-12 activation. However, the human caspase-12 gene contains several mutations, which make it functionally inactive. Thus, it has been suggested that human caspase-4 is the counterpart of murine caspase-12. Here we report that in the human INCL brain ER stress-induced activation of unfolded protein response (UPR) mediates caspase-4 and caspase-3 activation and apoptosis. Moreover, we show that the INCL brain contains high level of growth-associated protein-43 (GAP-43), which is known to undergo palmitoylation. We also demonstrate that transfection of cultured INCL cells with a green fluorescent protein-GAP-43 cDNA construct shows abnormal localization of this protein in the ER. Further, INCL cells manifest evidence of ER stress and UPR (elevated levels of Grp-78/Bip and GADD153), caspase-4 as well as caspase-3 activation and cleavage of poly(ADP)-ribose polymerase, a compelling sign of apoptosis. Most importantly, we show that inhibition of caspase-4 activity protects INCL cells from undergoing apoptosis. Our results provide insight into at least one of the molecular mechanisms of apoptosis in INCL and may allow the identification of potential targets for therapeutic intervention. C1 NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Mukherjee, AB (reprint author), NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. EM mukherja@exchange.nih.gov FU Intramural NIH HHS NR 33 TC 98 Z9 98 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUN 1 PY 2006 VL 15 IS 11 BP 1826 EP 1834 DI 10.1093/hmg/ddl105 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 044UA UT WOS:000237696700009 PM 16644870 ER PT J AU Stredrick, DL Garcia-Closas, M Pineda, MA Bhatti, P Alexander, BH Doody, MM Lissowska, J Peplonska, B Brinton, LA Chanock, SJ Struewing, JP Sigurdson, AJ AF Stredrick, Denise L. Garcia-Closas, Montserrat Pineda, Marbin A. Bhatti, Parveen Alexander, Bruce H. Doody, Michele M. Lissowska, Jolanta Peplonska, Beata Brinton, Louise A. Chanock, Stephen J. Struewing, Jeffery P. Sigurdson, Alice J. TI The ATM missense mutation p.Ser49Cys (c.146C > G) and the risk of breast cancer SO HUMAN MUTATION LA English DT Article DE ATM; breast cancer; association; epidemiology ID ATAXIA-TELANGIECTASIA; EARLY-ONSET; RADIOLOGIC TECHNOLOGISTS; ALLELIC VARIANTS; FAMILIAL BREAST; GENE; POLYMORPHISMS; SERIES; SUSCEPTIBILITY; IDENTIFICATION AB Homozygous mutation in the ATM gene causes ataxia telangiectasia and heterozygous mutation carriers may be at increased risk of breast cancer. We studied a total of 22 ATM variants; 18 variants were analyzed in one of two large population-based studies from the U.S. and Poland, and four variants were analyzed in all 2,856 breast cancer cases and 3,344 controls from the two studies. The missense mutation Ser49Cys (c. 146C > G, p.S49C), carried by approximately 2% of subjects, was more common in cases than controls in both study populations, combined odds ratio (OR) 1.69 (95% CI, 1.19-2-40; P = 0.004). Another missense mutation at approximately 2% frequency, Phe858Leu (c.2572T > C, p.F858L), was associated with a significant increased risk in the U.S. study but not in Poland, and had a combined OR of 1.44 (95% CI, 0.98-2.11; P = 0.06). These analyses provide the most convincing evidence thus far that missense mutations in ATM, particularly p.S49C, may be breast cancer susceptibility alleles. Because of their low frequency, even larger sample sizes are required to more firmly establish these associations. C1 NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Div Environm & Occupat Hlth, Minneapolis, MN USA. Ctr Canc, Div Canc Epidemiol & Prevent, Warsaw, Poland. M Sklodowska Curie Inst Oncol, Warsaw, Poland. Nofer Inst Occupat Med, Dept Occupat & Environm Epidemiol, Lodz, Poland. NCI, Core Genotyping Facil, NIH, Bethesda, MD 20892 USA. RP Struewing, JP (reprint author), NCI, Lab Populat Genet, NIH, 41 Lib Dr,Room D702, Bethesda, MD 20892 USA. EM js140a@nih.gov RI Peplonska, Beata/F-6004-2010; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Struewing, Jeffery/I-7502-2013; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Struewing, Jeffery/0000-0002-4848-3334; Lissowska, Jolanta/0000-0003-2695-5799 FU Intramural NIH HHS; NCI NIH HHS [Z01 CP010157-05] NR 43 TC 38 Z9 40 U1 0 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD JUN PY 2006 VL 27 IS 6 BP 538 EP 544 DI 10.1002/humu.20323 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 047GU UT WOS:000237868600005 PM 16652348 ER PT J AU Kim, SS Lee, HC Lee, HH Yang, HW Kim, HS AF Kim, S. S. Lee, H. C. Lee, H. H. Yang, H. W. Kim, H. S. TI Analysis of protein expression in ovarian tissue before and after transplantation using a new proteomics technology SO HUMAN REPRODUCTION LA English DT Meeting Abstract CT 22nd Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology CY JUN 18-21, 2006 CL Prague, CZECH REPUBLIC SP European Soc Human Reproduct & Embryol C1 Hope Fertil & Gynecol Reprod Endocrinol, La Palma, CA USA. Eulji Univ, Seoul, South Korea. NIH, Immunol Lab, Bethesda, MD 20892 USA. Hanyang Univ, Coll Nat Sci, Seoul 133791, South Korea. 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 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD JUN PY 2006 VL 21 SU 1 BP I108 EP I108 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 062PO UT WOS:000238957200269 ER PT J AU Nagashima, T Maruyama, T Furuya, M Kajitani, T Masuda, H Uchida, H Arase, T Ono, M Ozato, K Yoshimura, Y AF Nagashima, T. Maruyama, T. Furuya, M. Kajitani, T. Masuda, H. Uchida, H. Arase, T. Ono, M. Ozato, K. Yoshimura, Y. TI Bromodomain protein BRD4 in mouse oocytes and early embryos: its possible involvement in zygotic gene activation and reprogramming of gene expression SO HUMAN REPRODUCTION LA English DT Meeting Abstract CT 22nd Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology CY JUN 18-21, 2006 CL Prague, CZECH REPUBLIC SP European Soc Human Reproduct & Embryol C1 Keio Univ, Sch Med Obestetr & Gynecol, Tokyo, Japan. NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, 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 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD JUN PY 2006 VL 21 SU 1 BP I15 EP I15 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 062PO UT WOS:000238957200039 ER PT J AU Hill, NJ Lal, TN Schroder, M Hinterberger, T Wilhelm, B Nijboer, F Mochty, U Widman, G Elger, C Scholkopf, B Kubler, A Birbaumer, N AF Hill, NJ Lal, TN Schroder, M Hinterberger, T Wilhelm, B Nijboer, F Mochty, U Widman, G Elger, C Scholkopf, B Kubler, A Birbaumer, N TI Classifying EEG and ECoG signals without subject training for fast BCI implementation: Comparison of nonparalyzed and completely paralyzed subjects SO IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING LA English DT Article; Proceedings Paper CT 3rd International Meeting on Brain-Computer Interface Technology CY JUN, 2005 CL Rensselaerville Inst, Rensselaerville, NY HO Rensselaerville Inst DE Amyotrophic Lateral Sclerosis (ALS); brain-brain-computer interface (BCI); computer interface human factors; electrocorticography; electroencephalography; locked-in state; paralysis; pattern classification ID INTERFACE AB We summarize results from a series of related studies that aim to develop a motor-imagery-based brain-computer interface using a single recording session of electroencephalogram (EEG) or electrocorticogram (ECoG) signals for each subject. We apply the same experimental and analytical methods to 11 nonparalysed subjects (eight EEG, three ECoG), and to five paralyzed subjects (four EEG, one ECoG) who had been unable to communicate for some time. While it was relatively easy to obtain classifiable signals quickly from most of the nonparalyzed subjects, it proved impossible to classify the signals obtained from the paralyzed patients by the same methods. This highlights the fact that though certain BCI paradigms may work well with healthy subjects, this does not necessarily indicate success with the target user group. We outline possible reasons for this failure to transfer. C1 Max Planck Inst Biol Cybernet, D-72012 Tubingen, Germany. Univ Tubingen, Dept Comp Engn, D-72076 Tubingen, Germany. Univ Tubingen, Dept Comp Engn, D-72076 Tubingen, Germany. Univ Tubingen, Inst Med Psychol & Behav Neurobiol, D-72074 Tubingen, Germany. Univ Bonn, Dept Epileptol, D-53105 Bonn, Germany. NIH, Human Cort Physiol Unit, Bethesda, MD 20892 USA. RP Hill, NJ (reprint author), Max Planck Inst Biol Cybernet, D-72012 Tubingen, Germany. RI Scholkopf, Bernhard/A-7570-2013; OI Kubler, Andrea/0000-0003-4876-0415 FU NIBIB NIH HHS [EB00856] NR 11 TC 54 Z9 54 U1 0 U2 4 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 1534-4320 J9 IEEE T NEUR SYS REH JI IEEE Trans. Neural Syst. Rehabil. Eng. PD JUN PY 2006 VL 14 IS 2 BP 183 EP 186 DI 10.1109/TNSRE.2006.875548 PG 4 WC Engineering, Biomedical; Rehabilitation SC Engineering; Rehabilitation GA 054QW UT WOS:000238394700015 PM 16792289 ER PT J AU Swain, SL Agrewala, JN Brown, DM Jelley-Gibbs, DM Golech, S Huston, G Jones, SC Kamperschroer, C Lee, WH McKinstry, KK Roman, E Strutt, T Weng, NP AF Swain, SL Agrewala, JN Brown, DM Jelley-Gibbs, DM Golech, S Huston, G Jones, SC Kamperschroer, C Lee, WH McKinstry, KK Roman, E Strutt, T Weng, NP TI CD4(+) T-cell memory: generation and multi-faceted roles for CD4(+) T cells in protective immunity to influenza SO IMMUNOLOGICAL REVIEWS LA English DT Review ID IN-VIVO; A VIRUS; HETEROSUBTYPIC IMMUNITY; INFLAMMATORY CYTOKINES; LYMPHOKINE SECRETION; TISSUE INFLAMMATION; NAIVE; ANTIGEN; EFFECTORS; RESPONSES AB We have outlined the carefully orchestrated process of CD4(+) T-cell differentiation from naive to effector and from effector to memory cells with a focus on how these processes can be studied in vivo in responses to pathogen infection. We emphasize that the regulatory factors that determine the quality and quantity of the effector and memory cells generated include (i) the antigen dose during the initial T-cell interaction with antigen-presenting cells; (ii) the dose and duration of repeated interactions; and (iii) the milieu of inflammatory and growth cytokines that responding CD4(+) T cells encounter. We suggest that heterogeneity in these regulatory factors leads to the generation of a spectrum of effectors with different functional attributes. Furthermore, we suggest that it is the presence of effectors at different stages along a pathway of progressive linear differentiation that leads to a related spectrum of memory cells. Our studies particularly highlight the multifaceted roles of CD4(+) effector and memory T cells in protective responses to influenza infection and support the concept that efficient priming of CD4(+) T cells that react to shared influenza proteins could contribute greatly to vaccine strategies for influenza. C1 Trudeau Inst Inc, Saranac Lake, NY 12983 USA. NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. RP Swain, SL (reprint author), Trudeau Inst Inc, 154 Algonquin Ave, Saranac Lake, NY 12983 USA. EM sswain@northnet.org FU Intramural NIH HHS [Z01 AG000757-10]; NHLBI NIH HHS [HL63925, P01 HL063925]; NIA NIH HHS [AG025805, R37 AG025805]; NIAID NIH HHS [P01 AI046530, AI46530, AI021600] NR 78 TC 119 Z9 128 U1 0 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD JUN PY 2006 VL 211 BP 8 EP 22 DI 10.1111/j.0105-2896.2006.00388.x PG 15 WC Immunology SC Immunology GA 052TB UT WOS:000238255700002 PM 16824113 ER PT J AU Foulds, KE Wu, CY Seder, RA AF Foulds, KE Wu, CY Seder, RA TI Th1 memory: implications for vaccine development SO IMMUNOLOGICAL REVIEWS LA English DT Review ID T-CELL RESPONSES; CYTOKINE GENE-EXPRESSION; IN-VIVO; INTERFERON-GAMMA; CUTTING EDGE; TRYPTOPHAN CATABOLISM; LINEAGE COMMITMENT; LEISHMANIA-MAJOR; TRANSCRIPTION FACTOR; CD8-T-CELL MEMORY AB T-helper 1 (Th1) cells play a critical role, via interferon-gamma (IFN-gamma) production, in mediating intracellular killing against a variety of infectious pathogens. Thus, understanding the regulation of Th1 responses could provide better insight into vaccine design for infections requiring Th1 immunity. The cellular and molecular mechanisms that control the induction of Th1 effector cells have been well characterized. More recently, there has been substantial progress in furthering our understanding of the factors that regulate the development of Th1 memory cells. It is clear that Th1 responses are functionally heterogeneous, as defined by their ability to produce IFN-gamma. Furthermore, this heterogeneity has profound implications for the capacity of distinct lineages of Th1 cells to develop into memory cells. This review emphasizes the mechanisms controlling the differentiation of naive CD4(+) T cells into effector and then memory cells in a progressive manner. It highlights the importance of IFN-gamma as a positive regulator for inducing Th1 responses but a negative regulator for sustaining Th1 effector cells. In conclusion, we discuss how this current understanding of Th1 differentiation will inform vaccine design and better define immune correlates of protection. C1 NIAID, Cellular Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Zhong Shan Med Sch, Dept Immunol, Guangzhou, Guangdong, Peoples R China. RP Seder, RA (reprint author), NIAID, Cellular Immunol Sect, Vaccine Res Ctr, NIH, 40 Convent Dr,Room 3512, Bethesda, MD 20892 USA. EM rseder@mail.nih.gov NR 81 TC 68 Z9 71 U1 0 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD JUN PY 2006 VL 211 BP 58 EP 66 DI 10.1111/j.0105-2896.2006.00400.x PG 9 WC Immunology SC Immunology GA 052TB UT WOS:000238255700006 PM 16824117 ER PT J AU Klebanoff, CA Gattinoni, L Restifo, NP AF Klebanoff, Christopher A. Gattinoni, Luca Restifo, Nicholas P. TI CD8(+) T-cell memory in tumor immunology and immunotherapy SO IMMUNOLOGICAL REVIEWS LA English DT Review ID CHRONIC VIRAL-INFECTION; MEDIATED ANTITUMOR IMMUNITY; HUMAN METASTATIC MELANOMA; IN-VIVO PERSISTENCE; TRANSFER THERAPY; CUTTING EDGE; EFFECTOR FUNCTION; HOMEOSTATIC PROLIFERATION; LINEAGE RELATIONSHIP; PROTECTIVE IMMUNITY AB The cellular and molecular mechanisms underlying the formation of distinct central, effector, and exhausted CD8(+) T-cell memory subsets were first described in the setting of acute and chronic viral diseases. The role of these T-cell memory subsets are now being illuminated as relevant to the tumor-bearing state. The generation and persistence of productive CD8(+) T-cell memory subsets is determined, in part, by antigen clearance, costimulation, responsiveness to homeostatic cytokines, and CD4(+) T-helper cells. By contrast, chronic exposure to antigen, negative costimulation, and immunomodulation by CD4(+) T regulatory cells corrupt productive CD8(+) T memory formation. It has become clear from human and mouse studies that the mere generation of CD8(+) T-cell memory is not a 'surrogate marker' for cancer vaccine efficacy. Some current cancer vaccine strategies may fail because they amplify, rather than correct or reset, the corrupted CD8(+) memory population. Thus, much of the present effort in the development of vaccines for cancer and chronic infectious diseases is aimed at creating effective memory responses. Therapeutic vaccines for cancer and chronic infectious diseases may achieve consistent efficacy by ablation of the dysfunctional immune state and the provision of newly generated, non-corrupted memory cells by adoptive cell transfer. C1 NCI, Natl Inst Hlth, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. NCI, Natl Inst Hlth, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. NCI, Natl Inst Hlth, Ctr Canc Res, Bethesda, MD 20892 USA. RP Restifo, NP (reprint author), NCI, Natl Inst Hlth, Mark O Hatfield Clin Res Ctr, Room 3-5762,10 Ctr Dr, Bethesda, MD 20892 USA. EM restifo@nih.gov RI Gattinoni, Luca/A-2281-2008; Klebanoff, Christopher/B-8088-2008; Restifo, Nicholas/A-5713-2008; Klebanoff, Christopher/D-9581-2011; OI Gattinoni, Luca/0000-0003-2239-3282; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 130 TC 246 Z9 250 U1 5 U2 28 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD JUN PY 2006 VL 211 BP 214 EP 224 DI 10.1111/j.0105-2896.2006.00391.x PG 11 WC Immunology SC Immunology GA 052TB UT WOS:000238255700019 PM 16824130 ER PT J AU Lee, SY Cisar, JO Bryant, JL Eckhaus, MA Sandberg, AL AF Lee, Si Young Cisar, John O. Bryant, Joseph L. Eckhaus, Michael A. Sandberg, Ann L. TI Resistance of Streptococcus gordonii to polymorphonuclear leukocyte killing is a potential virulence determinant of infective endocarditis SO INFECTION AND IMMUNITY LA English DT Article ID ACID-BINDING ADHESIN; TYPE-2 FIMBRIAL LECTIN; ACTINOMYCES-NAESLUNDII; VIRIDANS STREPTOCOCCI; BACTERICIDAL ACTIVITY; CONTAINING RECEPTORS; RAT MODEL; PLATELETS; SANGUIS; DL1 AB Significant differences in virulence among seven representative Streptococcus gordonii strains were observed by using the rat model of infective endocarditis. Five strains, including S. gordonii DL1, caused severe disease, while the other two strains, including S. gordonii SK12, caused minimal or no disease. The differences in virulence were evident from the visible presence of streptococci in the vegetations present on the aortic valves of catheterized rats that were challenged with individual strains and also from the much greater recovery of rifampin-resistant S. gordonii DL1 than of streptomycin-resistant S. gordonii SK12 from the hearts of animals coinfected with both organisms. Each S. gordonii strain aggregated with human platelets and bound to polymorphonuclear leukocytes (PMNs), as shown by the stimulation of PMN superoxide anion production. These interactions were reduced or abolished by pretreatment of the platelets or PMNs with sialidase, indicating that there was bacterial recognition of host sialic acid-containing receptors. Adhesin-mediated binding of each S. gordonii strain to PMNs also triggered phagocytosis. However, the subsequent PMN-dependent killing differed significantly for the seven strains. The five virulent strains included three strains that were not killed and two strains whose numbers were reduced by approximately 50%. In contrast, the level of killing of each avirulent strain under the same conditions was significantly greater and approached 90% of the bacteria added. Parallel studies performed with rat PMNs revealed comparable differences in the resistance or susceptibility of representative virulent and avirulent strains. Thus, the ability of S. gordonii to survive in PMNs following adhesin-mediated phagocytosis may be an important virulence determinant of infective endocarditis. C1 NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. NIH, Off Res Serv, Div Vet Resources, Bethesda, MD 20892 USA. RP Cisar, JO (reprint author), NIDCR, Oral Infect & Immun Branch, NIH, Bldg 30,Room 3A-301,30 Convent Dr, Bethesda, MD 20892 USA. EM john.cisar@nih.gov NR 34 TC 9 Z9 11 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD JUN PY 2006 VL 74 IS 6 BP 3148 EP 3155 DI 10.1128/IAI.00087-06 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 047EH UT WOS:000237862100008 ER PT J AU Stewart, PE Wang, XH Bueschel, DM Clifton, DR Grimm, D Tilly, K Carroll, JA Weis, JJ Rosa, PA AF Stewart, PE Wang, XH Bueschel, DM Clifton, DR Grimm, D Tilly, K Carroll, JA Weis, JJ Rosa, PA TI Delineating the requirement for the Borrelia burgdorferi virulence factor OspC in the mammalian host SO INFECTION AND IMMUNITY LA English DT Article ID LYME-DISEASE SPIROCHETE; OUTER-SURFACE PROTEIN; TOLL-LIKE RECEPTOR-2; INHIBITOR FACTOR-H; IMMUNE EVASION; ARTHRITIS DEVELOPMENT; ANTIGENIC VARIATION; CRYSTAL-STRUCTURE; GENETIC-VARIATION; ANIMAL-MODEL AB We previously demonstrated that outer surface protein C (OspC of Borrelia burgdorferi is essential for establishing mammalian infection. However, the role of OspC in mammalian infection is unknown. Here, we report experiments designed to distinguish between two models of OspC function in the mammalian host: (i) OspC fulfills an essential physiological role for growth and host adaptation or (ii) OspC provides a protective role for evasion of components of the innate immune response. We found that a B. burgdorferi ospC mutant, previously demonstrated to be noninfectious in both immunocompetent and SCH) mice, could survive in the relatively immune-privileged environment of dialysis membrane chambers implanted within the peritoneum of a rat. The ospC mutant also adapts to the mammalian environment, as determined by the protein profiles of the chamber-cultivated spirochetes. Therefore, OspC does not appear to provide a physiological function for the survival of B. burgdorferi within the mammalian host. The second model, evasion of the innate immune system, was tested by assessing the infectivity of the ospC mutant in mice deficient for myeloid differentiation protein 88 (MyD88). Recent studies have shown that B. burgdorferi is prevented from reaching high cell numbers in the mammalian host by MyD88-dependent signaling pathways. The ospC mutant was incapable of infecting MyD88-deficient mice, suggesting that the role of OspC cannot be related solely to evasion of MyD88-mediated innate immunity. These results reiterate the importance of OspC in mammalian infection and eliminate simple models of function for this enigmatic protein. C1 NIAID, Rocky Mt Labs, Lab Zoonot Pathogens, NIH, Hamilton, MT 59840 USA. Univ Utah, Dept Pathol, Salt Lake City, UT 84132 USA. Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA. RP Stewart, PE (reprint author), NIAID, Rocky Mt Labs, Lab Zoonot Pathogens, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM pestewart@niaid.nih.gov FU Intramural NIH HHS NR 50 TC 71 Z9 73 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD JUN PY 2006 VL 74 IS 6 BP 3547 EP 3553 DI 10.1128/IAI.00158-06 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 047EH UT WOS:000237862100053 PM 16714587 ER PT J AU Tilly, K Krum, JG Bestor, A Jewett, MW Grimm, D Bueschel, D Byram, R Dorward, D VanRaden, MJ Stewart, P Rosa, P AF Tilly, K Krum, JG Bestor, A Jewett, MW Grimm, D Bueschel, D Byram, R Dorward, D VanRaden, MJ Stewart, P Rosa, P TI Borrelia burgdorferi OspC protein required exclusively in a crucial early stage of mammalian infection SO INFECTION AND IMMUNITY LA English DT Article ID LYME-DISEASE SPIROCHETE; OUTER SURFACE-PROTEINS; RPOS REGULATORY PATHWAY; CIRCULAR PLASMID; GENE-EXPRESSION; TICK PROTEIN; VECTOR; GENOME; HOST; HETEROGENEITY AB This study demonstrates a strict temporal requirement for a virulence determinant of the Lyme disease spirochete Borrelia burgdorferi during a unique point in its natural infection cycle, which alternates between ticks and small mammals. OspC is a major surface protein produced by B. burgdorferi when infected ticks feed but whose synthesis decreases after transmission to a mammalian host. We have previously shown that spirochetes lacking OspC are competent to replicate in and migrate to the salivary glands of the tick vector but do not infect mice. Here we assessed the timing of the requirement for OspC by using an ospC mutant complemented with an unstable copy of the ospC gene and show that B. burgdorferi's requirement for OspC is specific to the mammal and limited to a critical early stage of mammalian infection. By using this unique system, we found that most bacterial reisolates from mice persistently infected with the initially complemented ospC mutant strain no longer carried the wild-type copy of ospC. Such spirochetes were acquired by feeding ticks and migrated to the tick salivary glands during subsequent feeding. Despite normal behavior in ticks, these ospC mutant spirochetes did not infect naive mice. ospC mutant spirochetes from persistently infected mice also failed to infect naive mice by tissue transplantation. We conclude that OspC is indispensable for establishing infection by B. burgdorferi in mammals but is not required at any other point of the mouse-tick infection cycle. C1 NIAID, Rocky Mt Lab, Lab Zoonot Pathogens, NIH, Hamilton, MT 59840 USA. NIAID, Rocky Mt Lab, Res Technol Sect, Microscopy Unit,NIH, Hamilton, MT 59840 USA. NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Tilly, K (reprint author), 903 S 4th St, Hamilton, MT 59840 USA. EM ktilly@nih.gov FU Intramural NIH HHS NR 54 TC 164 Z9 168 U1 0 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD JUN PY 2006 VL 74 IS 6 BP 3554 EP 3564 DI 10.1128/IAI.01950-05 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 047EH UT WOS:000237862100054 PM 16714588 ER PT J AU Simons-Morton, B Ouimet, MC AF Simons-Morton, B. Ouimet, M. C. TI Parent involvement in novice teen driving: a review of the literature SO INJURY PREVENTION LA English DT Article ID SCHOOL DRIVER EDUCATION; MOTOR-VEHICLE CRASHES; BRIEF INTERVENTION; LICENSING SYSTEM; LEARNER DRIVERS; RESTRICTIONS; EXPERIENCE; LIMITS; PERSISTENCE; PRIVILEGES AB Motor vehicle crashes remain elevated among novice teen drivers for at least several years after licensure. Licensing policies and driver education are the two primary countermeasures employed to decrease young driver crash risks. Graduated driver licensing policies have proved to be effective in reducing crash rates where evaluated. Driver education is an essential part of teaching teens the rules of the road and operating a vehicle, but requires few hours of professional driver training, relying mainly on parents to provide most of the supervised practice driving teens obtain before independent driving licensure. The few studies that, have been conducted to increase parent supervised practice driving have not shown positive results. Moreover, it is unclear that increases in practice would improve independent driving safety. Recent research has shown that parent management of the early independent driving experience of novice teens improves safety outcomes, and other research has shown that it is possible to increase parent management practices. This paper provides a review of the literature on parent involvement in supervised practice and independent driving, and efforts to increase parental management. C1 NICHHD, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Simons-Morton, B (reprint author), NICHHD, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,7B05, Bethesda, MD 20892 USA. EM mortonb@mail.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 NR 47 TC 43 Z9 43 U1 1 U2 6 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1353-8047 J9 INJURY PREV JI Inj. Prev. PD JUN PY 2006 VL 12 SU 1 BP 30 EP 37 DI 10.1136/ip.2006.011569 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 063JV UT WOS:000239015400007 ER PT J AU Berra, L Curto, F Bassi, GL Laquerriere, P Baccarelli, A Kolobow, T AF Berra, L Curto, F Bassi, GL Laquerriere, P Baccarelli, A Kolobow, T TI Antibacterial-coated tracheal tubes cleaned with the Mucus Shaver SO INTENSIVE CARE MEDICINE LA English DT Article DE endotracheal tube; tracheal tube suctioning; bactericidal agents; Mucus Shaver; mechanical ventilation; bacterial biofilm ID MECHANICALLY VENTILATED PATIENTS; ENDOTRACHEAL-TUBE; BACTERIAL-COLONIZATION; BIOFILM; WORK AB To assess the long-term benefit from antibacterial coatings of the tracheal tube (ETT), and to keep clean the lumen of the ETT. Experimental animal study. USA National Institutes of Health. Twelve sheep. Twelve ETTs were internally dip-coated with a silver-sulfadiazine in polyurethane. We developed a concentric inflatable silicone rubber "razor", the Mucus Shaver (MS), to shave the ETT lumen free of mucus. In a single pass, we cleaned all mucus from the internal surface of the ETT. Control group: Five intubated sheep were mechanically ventilated for 72h. The ETT was suctioned every 6h. Study group: Six sheep were intubated and mechanically ventilated for 72h. The ETT was suctioned and cleaned with the MS every 6h. An additional sheep was intubated and mechanically ventilated for 168h. Bacteriologic studies and scanning electron microscopy were performed to assess bacterial colonization and thickness of secretions on the internal surface of the ETT. In the control group, the ETT was always heavily colonized: median debris thickness was 380 mu m, range 270-550 mu m. In the study group, there was no colonization and no secretions in the ETT, except for three ETT that were colonized solely at the very tip. Silver-based coating of ETT cleaned with the MS every 6 h significantly reduces accumulation of mucus/secretion and bacterial growth within the ETT following 72h of mechanical ventilation. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. NIH, Sect Pulm & Cardiac Assist Devices, Pulm Crit Care Med Branch, Dept Hlth & Human Serv, Bethesda, MD USA. NIH, Div Bioengn & Phys Sci, Off Res Serv, Dept Hlth & Human Serv, Bethesda, MD USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Berra, L (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. EM lberra@partners.org RI Laquerriere, Patrice/P-1025-2016 OI Laquerriere, Patrice/0000-0001-7637-9094 NR 15 TC 43 Z9 43 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0342-4642 J9 INTENS CARE MED JI Intensive Care Med. PD JUN PY 2006 VL 32 IS 6 BP 888 EP 893 DI 10.1007/s00134-006-0125-6 PG 6 WC Critical Care Medicine SC General & Internal Medicine GA 044KJ UT WOS:000237670900012 PM 16601964 ER PT J AU Hou, LF Xu, JF Gao, YT Rashid, A Zheng, SL Sakoda, LC Shen, MC Wang, BS Deng, J Han, TQ Zhang, BH Meyers, DA Fraumeni, JF Hsing, AW AF Hou, LF Xu, JF Gao, YT Rashid, A Zheng, SL Sakoda, LC Shen, MC Wang, BS Deng, J Han, TQ Zhang, BH Meyers, DA Fraumeni, JF Hsing, AW TI CYP17 MspA1 polymorphism and risk of biliary tract cancers and gallstones: A population-based study in Shanghai, China SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE biliary tract cancers; gallstones; polymorphisms; epidemiology; China ID HUMAN BREAST-CANCER; BENIGN PROSTATIC HYPERPLASIA; ESTROGEN REPLACEMENT THERAPY; METABOLISM GENE CYP17; ENDOMETRIAL CANCER; GALLBLADDER-DISEASE; DIABETES-MELLITUS; IN-VITRO; CELLS; WOMEN AB Biliary tract cancers, encompassing cancers of the gallbladder, extrahepatic bile duct and ampulla of Vater, are rare but highly fatal malignancies. Other than gallstones, little is known about the risk factors for biliary tract cancers. Endogenous estrogens are thought to play a role in the etiology of gallstones and gallbladder cancer, since both conditions predominate in females and are associated with parity and obesity. In view of reports linking the CYP17 MspA1 polymorphism to high circulating levels of estrogens and a predisposition to other hormonally related cancers, we examined the relationship between CYP17 MspA1 variants and risk of biliary disease in a population-based case-control study in Shanghai. The study included 446 cancer cases (254 gallbladder, 139 extrahepatic bile duct, 53 ampullary cancers), 929 biliary stone cases (691 gallbladder, 238 bile duct) and 818 population controls. Genomic DNA from peripheral blood lymphocytes was used for genotyping. Relative to those with the A2/A2 genotype, At carriers (A1/A1 and A1/A2 genotypes) had an increased risk of gallbladder cancer (odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.1-2.1). In addition, women with the At allele and high parity (>= 3) had a 3-fold risk of gallbladder cancer (OR = 3.3, 95% CI = 1.6-6.9), compared to those with the A2/A2 genotype and lower parity, with the highest risk seen for those also having biliary stones (OR = 4.6, 95% CI = 1.8-11.7, P-interaction = 0.04). The At allele was not associated with a higher risk of gallstones except among those with body mass index (BMI) greater than 25 kg/m(2) (OR = 3.1, 95% Cl = 2.0-4.8, P-interaction = 0.02) and among those with a history of diabetes (OR = 2.5, 95% CI = 1.4-4.3, P-interaction = 0.09). No clear relation was seen between the CYP17 polymorphism and cancers of the bile duct or ampulla of Vater. The association of the CYP17 MspA1 polymorphism with an increased risk of gallbladder cancer, as well as biliary stones among overweight and diabetic individuals, suggests an interplay between genetic and hormonal risk factors in gallbladder disease. C1 NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 20852 USA. Wake Forest Univ, Sch Med, Ctr Human Genom, Winston Salem, NC 27109 USA. Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. Fudan Univ, Shanghai Tumor Hosp, Shanghai 200433, Peoples R China. Fudan Univ, Zhongsan Hosp, Dept Surg, Shanghai 200433, Peoples R China. Ruijin Hosp, Dept Surg, Shanghai, Peoples R China. Shanghai Second Mil Hosp, Inst Oriental Hepatobiliary Surg, Shanghai, Peoples R China. RP Hou, LF (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, EPS 511 MSC7236,6120 Execut Blvd, Rockville, MD 20852 USA. EM lifangh2@mail.nih.gov FU Intramural NIH HHS NR 52 TC 14 Z9 14 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JUN 1 PY 2006 VL 118 IS 11 BP 2847 EP 2853 DI 10.1002/ijc.21708 PG 7 WC Oncology SC Oncology GA 035VH UT WOS:000237029300028 PM 16381022 ER PT J AU Krucker, J Xu, S Viswanathan, A Shen, E Glossop, N Wood, B AF Kruecker, J. Xu, S. Viswanathan, A. Shen, E. Glossop, N. Wood, B. TI Clinical evaluation of electromagnetic tracking for biopsy and radiofrequency ablation guidance SO INTERNATIONAL JOURNAL OF COMPUTER ASSISTED RADIOLOGY AND SURGERY LA English DT Article DE Electromagnetic tracking; Clinical evaluation; Biopsy; Radiofrequency ablation; Abdomen AB Purpose: To demonstrate clinical feasibility and measure accuracy of electromagnetic tracking for guidance of soft-tissue biopsy and radiofrequency ablation Methods: A prototype interventional guidance system based on electromagnetic tracking was used to evaluate retrospectively the accuracy of needle tracking in 20 patients. Target organs were liver (10), kidney (6), lung (3) and spine (1). Registration between tracking space and image space was obtained by touching 5 to 7 skin fiducials with the tracked needle during expiration breath holds. Tracking accuracy was determined by comparing the tracked needle sensor position, mapped onto the pre-acquired CT scan using the registration transformation, with the needle sensor position manually identified in the confirmation CT scans. Results: A total of 65 CT-confirmed needle positions were obtained. One patient was excluded from the analysis because of his inability to consistently follow breathing commands. The mean fiducials registration error was 1.9 +/- 0.6 mm; the mean tracking accuracy was 5.8 +/- 2.6 mm. Accuracy in liver (4.7 mm) was significantly (p = 0.05) better than in lung (8.7 mm). Conclusions: Electromagnetic needle tracking is safe and provides potential benefits to interventional procedures, including more accurate needle placement and reduced procedure time The demonstrated tracking accuracy is clinically relevant and warrants clinical evaluation of tracking for procedure guidance. This research was supported in part by the Intramural Research Program of the NIH, Clinical Center. C1 [Kruecker, J.; Xu, S.; Shen, E.] Philips Res North Amer, Briarcliff Manor, NY 10510 USA. [Viswanathan, A.; Wood, B.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Glossop, N.] Traxtal Inc, Bellaire, TX USA. RP Krucker, J (reprint author), Philips Res North Amer, Briarcliff Manor, NY 10510 USA. OI Viswanathan, Anand/0000-0003-3810-6217 NR 7 TC 6 Z9 6 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1861-6410 EI 1861-6429 J9 INT J COMPUT ASS RAD JI Int. J. Comput. Assist. Radiol. Surg. PD JUN PY 2006 VL 1 SU 1 BP 169 EP 171 PG 3 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging; Surgery SC Engineering; Radiology, Nuclear Medicine & Medical Imaging; Surgery GA V32YQ UT WOS:000208986900080 ER PT J AU Weed, DL AF Weed, DL TI Commentary: Rethinking epidemiology SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID BLACK-BOX EPIDEMIOLOGY C1 NCI, Off Prevent Oncol, Div Canc Prevent, Rockville, MD 20852 USA. RP Weed, DL (reprint author), NCI, Off Prevent Oncol, Div Canc Prevent, 6130 Execut Blvd, Rockville, MD 20852 USA. EM dw102i@nih.gov NR 19 TC 6 Z9 6 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2006 VL 35 IS 3 BP 583 EP 586 DI 10.1093/ije/dyl002 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 059WO UT WOS:000238763100022 PM 16540538 ER PT J AU Merikangas, KR Low, NCP Hardy, J AF Merikangas, KR Low, NCP Hardy, J TI Commentary: Understanding sources of complexity in chronic diseases - the importance of integration of genetics and epidemiology SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID FACTOR-H POLYMORPHISM; RHEUMATOID-ARTHRITIS; MACULAR DEGENERATION; ENVIRONMENTAL-FACTORS; LINKAGE STRATEGIES; AGE; TRAITS; FAMILY; FUTURE; CANCER C1 NIMH, Sect Dev Genet Epidemiol, NIH, Bethesda, MD 20892 USA. NIMH, Neurogenet Lab, NIA, Bethesda, MD 20892 USA. RP Merikangas, KR (reprint author), NIMH, Sect Dev Genet Epidemiol, NIH, 35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. EM merikank@mail.nih.gov RI Hardy, John/C-2451-2009 FU Medical Research Council [G0701075] NR 45 TC 16 Z9 17 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2006 VL 35 IS 3 BP 590 EP 592 DI 10.1093/ije/dyl007 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 059WO UT WOS:000238763100024 PM 16540533 ER PT J AU McGlynn, KA Graubard, BI Klebanoff, MA Longnecker, MP AF McGlynn, KA Graubard, BI Klebanoff, MA Longnecker, MP TI Risk factors for cryptorchism among populations at differing risks of testicular cancer SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cryptorchism; testicular cancer; ethnicity; risk factor ID GERM-CELL TUMORS; MATERNAL AGE; UNITED-STATES; HYPOSPADIAS; ENVIRONMENT; ESTROGENS; DESCENT; TESTIS; TRENDS; BIRTHS AB Background. Cryptorchism is strongly associated with the development of testicular germ cell tumours (TGCTs), possibly owing to a common aetiology. However, while TGCT incidence varies greatly between white and black men, little variability has been reported between the two groups in cryptorchism prevalence. This may suggest that cryptorchism risk factors differ by ethnicity. Methods. To examine this hypothesis, a prospective analysis was conducted among black and white participants in the US Collaborative Perinatal Project. White participants included 238 cryptorchid sons and 12 296 non-cryptorchid sons, while black participants included 188 cryptorchid sons and 11 942 non-cryptorchid sons. Results. While cryptorchism was significantly more common among white sons (1.90% vs 1.55%; P = 0.04), the difference was incompatible with the 5-fold difference in TGCT rates. The principal maternal risk factors among white sons were age (P = 0.03), hypertension/proteinuria (P = 0.006), and length of time to become pregnant (P = 0.055), while major maternal risk factors among black sons were age (P = 0.06), height (P = 0.007), weight (P = 0.06), and radiation exposure (P = 0.02). Only maternal height, however, had a different relationship with risk among black and white sons. Neonatal associations with risk (shorter gestational age, lower birthweight, shorter length) were similar in the two groups. Conclusions. These results do not support the hypothesis that the risk factors for cryptorchism vary dramatically by ethnicity but may suggest that cryptorchism is not as closely linked to TGCT among black men as among white men. C1 NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 20852 USA. NICHHD, NIH, DHHS, Rockville, MD USA. NIEHS, NIH, DHHS, Res Triangle Pk, NC USA. RP McGlynn, KA (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,EPS 7060, Rockville, MD 20852 USA. EM mcglynnk@mail.nih.gov OI Longnecker, Matthew/0000-0001-6073-5322 FU Intramural NIH HHS [Z99 ES999999, 001-0162-000] NR 35 TC 25 Z9 25 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2006 VL 35 IS 3 BP 787 EP 795 DI 10.1093/ije/dyl024 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 059WO UT WOS:000238763100060 PM 16492711 ER PT J AU Patel, A Goudar, SS Geller, SE Kodkanyb, BS Edlavitch, SA Wagh, K Patted, SS Naik, VA Moss, N Derman, RJ AF Patel, A Goudar, SS Geller, SE Kodkanyb, BS Edlavitch, SA Wagh, K Patted, SS Naik, VA Moss, N Derman, RJ TI Drape estimation vs. visual assessment for estimating postpartum hemorrhage SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Article DE postpartum hemorrhage; maternal morbidity; maternal mortality; blood collection ID BLOOD VOLUME CHANGES; VAGINAL DELIVERY; LABOR AB Objective: To compare (1) visual estimation of postpartum blood loss with estimation using a specifically designed blood collection drape and (2) the drape estimate with a measurement of blood toss by photospectrometry. Methods: A randomized controlled study was performed with 123 women delivered at the District Hospital, Belgaum, India. The women were randomized to visual or drape estimation of blood loss. A subsample of 10 drape estimates was compared with photospectrometry results. Results: The visual estimate of blood toss was 33% less than the drape estimate. The interclass correlation of the drape estimate to photospectrometry measurement was 0.92. Conclusion: Drape estimation of blood loss is more accurate than visual estimation and may have particular utility in the developing world. Prompt detection of postpartum hemorrhage may reduce maternal morbidity and mortality in tow-resource settings. (c) 2006 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. C1 John H Stroger Jr Hosp Cook Cty, Chicago, IL USA. JN Med Coll, Belgaum, Karnataka, India. Univ Illinois, Dept Obstet & Gynecol, Chicago, IL 60680 USA. Univ Missouri, Kansas City Sch Med, Kansas City, MO 64110 USA. NICHHD, Global Network Womens & Childrens Hlth Res, Rockville, MD USA. RP Patel, A (reprint author), John H Stroger Jr Hosp Cook Cty, Chicago, IL USA. EM ashleshpatel16@yahoo.com OI GOUDAR, SHIVAPRASAD/0000-0002-8680-7053 NR 15 TC 92 Z9 98 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0020-7292 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD JUN PY 2006 VL 93 IS 3 BP 220 EP 224 DI 10.1016/j.ijgo.2006.02.014 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 057JM UT WOS:000238592100004 PM 16626718 ER PT J AU Chase, K Sargan, D Miller, K Ostrander, EA Lark, KG AF Chase, K. Sargan, D. Miller, K. Ostrander, E. A. Lark, K. G. TI Understanding the genetics of autoimmune disease: two loci that regulate late onset Addison's disease in Portuguese Water Dogs SO INTERNATIONAL JOURNAL OF IMMUNOGENETICS LA English DT Article ID CANIS-FAMILIARIS; DOMESTIC DOG; HYPOADRENOCORTICISM; POLYMORPHISM; ASSOCIATION; INHERITANCE; ALLELES; GENOME; CTLA-4; GENES AB Addison's disease, an immune-mediated disorder caused by destruction of the adrenal glands, is a rare disorder of Western European populations. Studies indicate that the disorder is polygenic in nature, involving specific alleles of the CTLA-4, DRB1*04 and DQ, Cyp27B1, VDR and MIC-A and -B loci. A similar immune form of Addison's disease occurs in several breeds of domestic dog, with frequencies ranging from 1.5 to 9.0%. The high frequency of the disease in domestic dog breeds likely reflects the small number of founders associated with many breeds, subsequent inbreeding, and the frequent use of popular sires. The Portuguese Water Dog (PWD) is a significantly affected breed. An analysis of 11 384 PWDs surveyed between 1985 and 1996 suggests a breed-specific disease incidence of 1.5%.As with humans, the disease is typically of late onset. This study involves a genetic comparison of Addison's disease in the PWD to the analogous disease in humans. The study is facilitated by the existence of complete pedigrees and a relatively high degree of inbreeding among PWDs. The breed originated from 31 founders, with 10 animals responsible for 90% of the current gene pool. We describe, specifically, the identification of two disease-associated loci, on Canis familiaris (CFA) chromosomes CFA12 and 37, which are syntenic with the human DRB1 histocompatibility locus alleles HLA-DRB1 *04 and DRB1*0301, and to a locus for immunosuppression syntenic with CTLA-4. Strong similarities exist therefore in the complex genetic background of Addison's disease in humans and in the PWD. With the completion of the canine and human genome sequence, the purebred dog is set to become an important comparative model for Addison's as well as other human immune disorders. C1 Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA. NHGRI, NIH, Comparat Genet Sect, Canc Genet Branch, Bethesda, MD 20892 USA. Georgie Project, Portland, ME USA. Univ Cambridge, Ctr Vet Sci, Dept Vet Med, Cambridge, England. RP Lark, KG (reprint author), Univ Utah, Dept Biol, 257 South 1400 East,Room 201, Salt Lake City, UT 84112 USA. EM lark@bioscience.utah.edu OI Sargan, David Richard/0000-0001-9897-2489; Ostrander, Elaine/0000-0001-6075-9738 FU Intramural NIH HHS; NIGMS NIH HHS [GM 063056, R01 GM063056, R01 GM063056-05] NR 28 TC 38 Z9 39 U1 3 U2 14 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1744-3121 J9 INT J IMMUNOGENET JI Int. J. Immunogenet. PD JUN PY 2006 VL 33 IS 3 BP 179 EP 184 DI 10.1111/j.1744-313X.2006.00593.x PG 6 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 049XU UT WOS:000238051900007 PM 16712648 ER PT J AU Zhou, RL Zarate, CA Manji, HK AF Zhou, RL Zarate, CA Manji, HK TI Identification of molecular mechanisms underlying mood stabilization through genome-wide gene expression profiling SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article ID WEEKLY SYMPTOMATIC STATUS; BIPOLAR DISORDER; NATURAL-HISTORY; POSTMORTEM; DEPRESSION; THERAPEUTICS; PLASTICITY; PATHWAYS; LITHIUM; BURDEN C1 NIMH, Lab Mol Pathophysiol, NIH, Bethesda, MD 20892 USA. RP Manji, HK (reprint author), NIMH, Lab Mol Pathophysiol, NIH, 34 Convent Dr,Bldg 35 Rm 1C-912, Bethesda, MD 20892 USA. EM manji@nih.gov FU Intramural NIH HHS NR 24 TC 2 Z9 2 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2006 VL 9 IS 3 BP 263 EP 266 DI 10.1017/S1461145705006176 PG 4 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 052PA UT WOS:000238244400001 PM 16207389 ER PT J AU Chiu, BCH Gapstur, SM Chow, WH Kirby, KA Lynch, CF Cantor, KP AF Chiu, BCH Gapstur, SM Chow, WH Kirby, KA Lynch, CF Cantor, KP TI Body mass index, physical activity, and risk of renal cell carcinoma SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE body mass index; physical activity; renal cell carcinoma ID ENDOMETRIAL CANCER RISK; BREAST-CANCER; OBESITY; WEIGHT; POPULATION; HEIGHT; COHORT; OVERWEIGHT; ETIOLOGY; HORMONES AB Objective: To investigate the association between obesity and risk of renal cell carcinoma and to examine whether the association is modified by physical activity. Subjects: A population-based case-control study of 406 patients with renal cell carcinoma and 2434 controls conducted in Iowa. Methods: Information was collected on weight at the ages 20-29, 40-49, and 60-69 years, height, nonoccupational physical activity, diet, and other lifestyle factors. Renal cell carcinoma risk was estimated by odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age, total energy intake, and other confounding factors. Results: Height and total energy intake were not associated with risk in either sex. In men, neither physical activity nor level of obesity in any period of life was significantly associated with risk. In women, lower physical activity was associated with higher risk (OR 2.5; 95% CI 1.2-5.2 comparing exercise < 1 time/month to > 1 time/day). Compared with women in the lowest quartile for BMI, the risks of renal cell carcinoma for women in the highest 10% of BMI in their 20s, 40s, and 60s were 1.4 (CI = 0.6-3.1), 1.9 (CI = 0.9-4.2), and 2.3 (CI = 0.9-6.0), respectively. When analyses were limited to self-respondent data, the corresponding ORs were 2.9 (CI = 1.2-7.4), 3.2 (CI = 1.3-7.5), and 2.1 (CI = 0.7-6.4), respectively. There was little evidence that physical activity modifies the association of BMI with renal cell carcinoma. Conclusion: Nonoccupational physical activity was inversely associated and obesity was positively associated with risk of renal cell carcinoma among women. The risk appeared to be greater for women in the highest 10% of BMI in their 40s. Our finding of little evidence of an interaction between physical activity and BMI requires confirmation. C1 Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL USA. NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD USA. Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. RP Chiu, BCH (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, 680 N Lake Shore Dr, Chicago, IL 60611 USA. EM bchiu@northwestern.edu FU NCI NIH HHS [N01-CP-51026]; PHS HHS [P30 ESO5605] NR 38 TC 23 Z9 23 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD JUN PY 2006 VL 30 IS 6 BP 940 EP 947 DI 10.1038/sj.ijo.0803231 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 047EO UT WOS:000237862800010 PM 16446746 ER PT J AU Tulla-Puche, J Getun, IV Angell, YM Alsina, J Albericio, F Woodward, C Barany, G AF Tulla-Puche, J Getun, IV Angell, YM Alsina, J Albericio, F Woodward, C Barany, G TI Synthetic approaches to disulfide-free circular bovine pancreatic trypsin inhibitor (c-BPTI) analogues SO INTERNATIONAL JOURNAL OF PEPTIDE RESEARCH AND THERAPEUTICS LA English DT Article DE backbone amide linker (BAL); bovine pancreatic trypsin inhibitor (BPTI); circular proteins; native chemical ligation; peptide thioester; side-chain anchoring; solid-phase synthesis ID SOLID-PHASE SYNTHESIS; NATIVE CHEMICAL LIGATION; NUCLEAR-MAGNETIC-RESONANCE; SIDE-CHAIN ATTACHMENT; TAIL CYCLIC-PEPTIDES; LINKER BAL STRATEGY; BACKBONE CYCLIZATION; BIOLOGICAL-ACTIVITY; GLOBULAR-PROTEINS; FOLDING PATHWAY AB Several approaches were investigated with the goal to obtain disulfide-free circularized analogues of the 58-residue small protein bovine pancreatic trypsin inhibitor (BPTI). These approaches include (1) a semisynthesis that uses as a starting point naturally occurring BPTI and takes advantage of the native proximity of the C- and N-termini; (2) a synthesis in which a peptide thioester prepared by stepwise Fmoc solid-phase chemistry is cyclized by a solution native chemical ligation step; (3) a stepwise Fmoc solid-phase synthesis of a protected circularly permuted linear sequence, followed by an attempted selective activation and head-to-tail cyclization; and (4) a stepwise Fmoc solid-phase synthesis of the same analogue, but using a different disconnection point, that features backbone amide linker (BAL) anchoring and attempted on-resin cyclization. The first two of these approaches were indeed successful in providing the desired target molecules in excellent purities and respectable yields, and could well be amenable to generalization. It is not yet clear whether or not the latter two approaches could be salvaged by modifications in the details of the chemical procedures applied. C1 Univ Minnesota, Dept Chem, Minneapolis, MN 55455 USA. Barcelona Biomed Res Inst, Barcelona 08028, Spain. NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. Affymax Inc, Palo Alto, CA 94304 USA. Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA. Univ Minnesota, Dept Biochem Mol Biol & Biophys, St Paul, MN 55108 USA. RP Barany, G (reprint author), Univ Minnesota, Dept Chem, Minneapolis, MN 55455 USA. EM barany@umn.edu OI Tulla Puche, Judit/0000-0002-2129-0700; Albericio, Fernando/0000-0002-8946-0462 NR 84 TC 1 Z9 1 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1573-3149 J9 INT J PEPT RES THER JI Int. J. Pept. Res. Ther. PD JUN PY 2006 VL 12 IS 2 BP 93 EP 104 DI 10.1007/s10989-006-9023-6 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 056UM UT WOS:000238550600001 ER PT J AU Rickman, CB Ebright, JN Zavodni, Z Yu, L Wang, T Daiger, SP Wistow, G Boon, K Hauser, MA AF Rickman, Catherine Bowes Ebright, Jessica N. Zavodni, Zachary Yu, Ling Wang, Tianyuan Daiger, Stephen P. Wistow, Graeme Boon, Kathy Hauser, Michael A. TI Defining the human macula transcriptome and 14 candidate retinal disease genes using EyeSAGE SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID OPEN-ANGLE GLAUCOMA; AGE-RELATED MACULOPATHY; SEQUENCE TAG ANALYSIS; CONE-ROD DYSTROPHY; ADULT HUMAN RETINA; GENOME-WIDE SCAN; SERIAL ANALYSIS; PIGMENT EPITHELIUM; NEIBANK PROJECT; HUMAN FOVEA AB PURPOSE. To develop large-scale, high-throughput annotation of the human macula transcriptome and to identify and prioritize candidate genes for inherited retinal dystrophies, based on ocular-expression profiles using serial analysis of gene expression (SAGE). METHODS. Two human retina and two retinal pigment epithelium (RPE)/choroid SAGE libraries made from matched macula or midperipheral retina and adjacent RPE/choroid of morphologically normal 28- to 66-year-old donors and a human central retina longSAGE library made from 41- to 66-year-old donors were generated. Their transcription profiles were entered into a relational database, EyeSAGE, including microarray expression profiles of retina and publicly available normal human tissue SAGE libraries. EyeSAGE was used to identify retina- and RPE-specific and associated genes, and candidate genes for retina and RPE disease loci. Differential and/or cell-type specific expression was validated by quantitative and single-cell RT-PCR. RESULTS. Cone photoreceptor-associated gene expression was elevated in the macula transcription profiles. Analysis of the longSAGE retina tags enhanced tag-to-gene mapping and revealed alternatively spliced genes. Analysis of candidate gene expression tables for the identified Bardet-Biedl syndrome disease gene (BBS5) in the BBS5 disease region table yielded BBS5 as the top candidate. Compelling candidates for inherited retina diseases were identified. CONCLUSIONS. The EyeSAGE database, combining three different gene-profiling platforms including the authors' multidonor-derived retina/RPE SAGE libraries and existing single-donor retina/RPE libraries, is a powerful resource for definition of the retina and RPE transcriptomes. It can be used to identify retina-specific genes, including alternatively spliced transcripts and to prioritize candidate genes within mapped retinal disease regions. C1 Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Cell Biol & Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC 27710 USA. Univ Texas, Hlth Sci Ctrhumgen, Human Genet Ctr, Houston, TX USA. NEI, Bethesda, MD 20892 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Rickman, CB (reprint author), Duke Univ, Med Ctr, Dept Ophthalmol, Box 3802 Erwin Rd, Durham, NC 27710 USA. EM bowes007@duke.edu NR 61 TC 42 Z9 42 U1 0 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUN PY 2006 VL 47 IS 6 BP 2305 EP 2316 DI 10.1167/iovs.05-1437 PG 12 WC Ophthalmology SC Ophthalmology GA 048LQ UT WOS:000237949000008 ER PT J AU Wong, TY Islam, FMA Klein, R Klein, BEK Cotch, MF Castro, C Sharrett, AR Shahar, E AF Wong, Tien Yin Islam, F. M. Amirul Klein, Ronald Klein, Barbara E. K. Cotch, Mary Frances Castro, Cecilia Sharrett, A. Richey Shahar, Eyal TI Retinal vascular caliber, cardiovascular risk factors, and inflammation: The Multi-Ethnic Study of Atherosclerosis (MESA) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID BEAVER DAM EYE; BLACK-WHITE DIFFERENCES; CORONARY HEART-DISEASE; TARGET-ORGAN DAMAGE; BLUE MOUNTAINS EYE; MICROVASCULAR ABNORMALITIES; VESSEL DIAMETERS; BLOOD-PRESSURE; DIABETES-MELLITUS; OLDER POPULATION AB PURPOSE. To describe the relationship of retinal arteriolar and venular caliber with cardiovascular risk factors, including inflammatory biomarkers, in a multiethnic population of whites, blacks, Hispanics, and Chinese. METHODS. A cross-sectional study comprising 5979 persons aged 45 to 84 years residing in six U.S. communities. Retinal vascular caliber was measured and summarized from digital retinal photographs. Standard cardiovascular risk factors, including biomarkers of inflammation (e.g., high-sensitivity C-reactive protein [hsCRP], interleukin [IL]-6, and plasma fibrinogen) and endothelial dysfunction (e.g., soluble intercellular adhesion molecule [sICAM]-1, plasminogen activator inhibitor [PAI]-1) were assessed. RESULTS. Mean retinal arteriolar caliber was 144.1 +/- 14.4 (SD) mu m, and venular caliber 214.0 +/- 22.2 mu m. In models controlling for age, gender, race-ethnicity, and center, smaller retinal arteriolar caliber was related to higher systolic and diastolic blood pressure, hypertension status, current alcohol consumption, greater body mass index, and higher levels of total homocysteine; larger retinal arteriolar caliber was related to diabetes, current cigarette smoking, and higher levels of plasma fibrinogen; and larger retinal venular caliber was related to diabetes, current cigarette smoking, greater body mass index and waist-hip ratio, higher levels of serum glucose, plasma triglyceride, plasma LDL-cholesterol, hsCRP, plasma fibrinogen, IL6, sICAM-1, and PAI-1 and lower levels of HDL-cholesterol. In multivariate analyses, blacks and Hispanics had larger retinal arteriolar and venular calibers than did whites and Chinese. CONCLUSIONS. Retinal arteriolar and venular caliber is associated with a range of cardiovascular risk factors, including hypertension, diabetes, measures of obesity, and dyslipidemia. Venular caliber is also associated with systemic inflammation. C1 Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic 3002, Australia. Natl Univ Singapore, Singapore Eye Res Inst, Singapore 117548, Singapore. Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI 53706 USA. NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY 10027 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. RP Wong, TY (reprint author), Univ Melbourne, Ctr Eye Res Australia, 32 Gisborne St, Melbourne, Vic 3002, Australia. EM twong@unimelb.edu.au OI Cotch, Mary Frances/0000-0002-2046-4350 FU Intramural NIH HHS [Z01 EY000403-06, Z01 EY000403-07, Z99 EY999999, ZIA EY000403-08, ZIA EY000403-09, ZIA EY000403-10]; NHLBI NIH HHS [HL69979-03, N01 HC095159, N01 HC095160, N01 HC095161, N01 HC095162, N01 HC095163, N01 HC095164, N01 HC095165, N01 HC095169, N01-HC-95159, N01-HC-95165, N01-HC-95169, N01HC95159, N01HC95165, N01HC95169, R01 HL069979, R01 HL069979-03] NR 58 TC 264 Z9 271 U1 4 U2 12 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUN PY 2006 VL 47 IS 6 BP 2341 EP 2350 DI 10.1167/iovs.05-1539 PG 10 WC Ophthalmology SC Ophthalmology GA 048LQ UT WOS:000237949000013 PM 16723443 ER PT J AU Gilger, BC Salmon, JH Wilkie, DA Cruysberg, LPJ Kim, J Hayat, M Kim, H Kim, S Yuan, P Lee, SS Harrington, SM Murray, PR Edelhauser, HF Csaky, KG Robinson, MR AF Gilger, BC Salmon, JH Wilkie, DA Cruysberg, LPJ Kim, J Hayat, M Kim, H Kim, S Yuan, P Lee, SS Harrington, SM Murray, PR Edelhauser, HF Csaky, KG Robinson, MR TI A novel bioerodible deep scleral lamellar cyclosporine implant for uveitis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID EQUINE RECURRENT UVEITIS; SUSTAINED-RELEASE CYCLOSPORINE; UVEOSCLERAL DRAINAGE ROUTES; DRUG-DELIVERY SYSTEM; GANCICLOVIR IMPLANT; CYTOMEGALOVIRUS RETINITIS; LEPTOSPIRA-INTERROGANS; SUPRACHOROIDAL SPACE; CALCINEURIN INHIBITION; ENDOGENOUS UVEITIS AB PURPOSE. To determine the feasibility, safety, and effectiveness of an episcleral or deep scleral lamellar sustained release cyclosporine (CsA) device in a naturally occurring animal model of uveitis. METHODS. A two-compartment perfusion chamber was used to assess in vitro human and equine scleral permeability of fluorescein, dexamethasone-fluorescein, or CsA. A biodegradable, matrix-reservoir CsA implant was designed, and release rates of CsA were determined in vitro. Tissue CsA levels were measured in eyes with the implant. Horses with equine recurrent uveitis (ERU) received episcleral or deep scleral lamellar CsA implants and were monitored for up to 3 years. RESULTS. Dexamethasone-fluorescein and CsA penetrated the in vitro equine sclera poorly; however, low but detectable levels of CsA were detected intraocularly in vivo. The implant placed episclerally failed to control inflammatory episodes in ERU. CsA implants placed in the deep sclera adjacent to the suprachoroidal space resulted in high levels of CsA in most ocular tissues. In clinical equine patients with ERU, frequency of uveitic flare-ups was significantly decreased after implantation of a deep scleral lamellar CsA implant. uCONCLUSIONS. Diffusion of CsA across the sclera from the episcleral space was not a feasible method of drug delivery to the equine eye. However, placing a deep scleral lamellar CsA implant adjacent to the suprachoroidal space was effective in achieving therapeutic ocular drug concentrations and controlling uveitis in horses with ERU. C1 N Carolina State Univ, Coll Vet Med, Dept Clin Sci, Raleigh, NC 27606 USA. Ohio State Univ, Coll Vet Med, Dept Clin Sci, Columbus, OH 43210 USA. Emory Univ, Dept Ophthalmol, Atlanta, GA 30322 USA. Emmes Corp, Rockville, MD USA. NEI, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. RP Gilger, BC (reprint author), N Carolina State Univ, Coll Vet Med, Dept Clin Sci, 4700 Hillsborough St, Raleigh, NC 27606 USA. EM brian_gilger@ncsu.edu NR 70 TC 51 Z9 52 U1 0 U2 6 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUN PY 2006 VL 47 IS 6 BP 2596 EP 2605 DI 10.1167/iovs.05-1540 PG 10 WC Ophthalmology SC Ophthalmology GA 048LQ UT WOS:000237949000046 PM 16723476 ER PT J AU Ono, S Kurotaki, T Nakasone, T Honda, M Boon-Long, J Sawanpanyalert, P Kimura, K AF Ono, Shunsuke Kurotaki, Takako Nakasone, Tadashi Honda, Mitsuo Boon-Long, Jotika Sawanpanyalert, Pathom Kimura, Kazuko TI Cost-effectiveness analysis of antiretroviral drug treatment and HIV-1 vaccination in Thailand SO JAPANESE JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID DEVELOPING-COUNTRIES; PHASE-3 TRIAL; AIDS VACCINE; HIV/AIDS; INFECTION; FUTURE AB The prevalence of adult HIV/AIDS in Thailand is declining due to intense prevention strategies, but it still continues to be a critical health problem with a prevalence of 1.5%. Several HIV vaccine candidates for the prevention of HIV infection or progress to AIDS were examined in clinical trials. We evaluated the cost-effectiveness of a vaccination regimen (rBCG prime-rDIs boost) currently in its pre-clinical phase. The cost-effectiveness of three interventions (vaccination, highly active antiretroviral treatment [HAART], and the combination of the two) through an existing vaccination program was assessed in a Markov model. The disability-adjusted life year (DALY) was the main effectiveness measure. In the base case the efficacy of the vaccine for preventing HIV infection was assumed to be 30%. The cost of the vaccine was estimated on the basis of its predicted production capacities in Thailand. The incremental cost-effectiveness ratios of vaccination, HAART, and the combination were about $US 75, $US 610, and $US 267 per DALY averted compared with the do-nothing strategy in the base case. The HAART-only strategy seemed to be less cost-effective than the other options under the current assumptions. Sensitivity analyses indicated that the new HIV infection rate and the vaccine efficacy could affect the results. C1 Kanazawa Univ, Grad Sch Nat Sci & Technol, Kanazawa, Ishikawa 9201192, Japan. NIAID, AIDS Res Ctr, Tokyo 1628640, Japan. Natl Inst Hlth, Dept Med Sci, Minist Publ Hlth, Muang Nonthaburi 11000, Thailand. RP Ono, S (reprint author), Pharmaceut & Med Devices Agcy, New Drug Review Div 1, Chiyoda Ku, Shin Kasumigaseki Bldg,3-3-2 Kasumigaseki, Tokyo 1000013, Japan. EM shunono@pep.ne.jp NR 36 TC 9 Z9 9 U1 0 U2 0 PU NATL INST INFECTIOUS DISEASES PI TOKYO PA JPN J INFECT DIS ED OFF NATL INST INFECTIOUS DISEASES TOYAMA 1-23-1, SHINJUKU-KU, TOKYO, 162-8640, JAPAN SN 1344-6304 EI 1884-2836 J9 JPN J INFECT DIS JI Jpn. J. Infect. Dis. PD JUN PY 2006 VL 59 IS 3 BP 168 EP 173 PG 6 WC Infectious Diseases SC Infectious Diseases GA 059DQ UT WOS:000238713900005 PM 16785697 ER PT J AU Paoloni, MC Adams, WM Dubielzig, RR Kurzman, I Vail, DM Hardie, RJ AF Paoloni, MC Adams, WM Dubielzig, RR Kurzman, I Vail, DM Hardie, RJ TI Comparison of results of computed tomography and radiography with histopathologic findings in trachelobronchial lymph nodes in dogs with primary lung tumors: 14 cases (1999-2002) SO JAVMA-JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION LA English DT Article; Proceedings Paper CT 13th International Meeting of the International-Veterinary-Radiology-Association CY AUG 16-22, 2003 CL Midrand, SOUTH AFRICA SP Int Vet Radiol Assoc ID PROGNOSTIC FACTORS; CANCER; CT; INVOLVEMENT; SIZE AB Objective-To compare results of computed tomography (CT) and radiography with histopathologic findings in tracheobronchial lymph nodes (TBLNs) in dogs with primary lung tumors. Design-Retrospective case series. Animals-14 client-owned dogs. Procedures-Criteria for inclusion were diagnosis of primary lung tumor, use of thoracic radiography and CT and histologic confirmation of TBLN status. Medical records were reviewed for signalment; history; and physical examination, clinicopathologic, radiographic, CT, surgical, and histopathologic findings. Results-Tracheobronchial lymphadenopathy was not identified via radiography in any dogs. Tracheobronchial lymphadenopathy was diagnosed in 5 dogs via CT Six dogs had histologic confirmation of metastasis to TBLNs. Radiographic diagnosis yielded 6 false-negative and no false-positive results for tracheobronchial lymphadenopathy. Computed tomography yielded 1 false-negative and no false-positive results. Sensitivity of CT for correctly assessing TBLN status was 83%, and specificity was 100%. Positive predictive value was 100%, and negative predictive value was 89%. Dogs with lymphadenopathy via CT histologic confirmation of TBLN metastasis, or primary tumors with a histologic grade > 1 had significantly shorter survival times than their counterparts. Conclusions and Clinical Relevance-Results of CT evaluation of TBLN status were in agreement with histopathologic findings and more accurate than use of thoracic radiography for evaluating TBLNs in dogs with primary lung tumors. Computed tomography imaging should be considered as part of the staging process to more accurately assess the TBLNs in dogs with primary lung tumors. C1 Univ Wisconsin, Dept Med Sci, Sch Vet Med, Madison, WI 53706 USA. Univ Wisconsin, Dept Pathobiol Sci, Sch Vet Med, Madison, WI 53706 USA. Univ Wisconsin, Dept Surg Sci, Sch Vet Med, Madison, WI 53706 USA. Univ Wisconsin, Ctr Comprehens Canc, Madison, WI 53706 USA. Univ Wisconsin, MacEwen Ctr Clin Trials & Translat Res, Madison, WI 53706 USA. RP Paoloni, MC (reprint author), NCI, Comparat Oncol Program, Ctr Canc Res, NIH, 9610 Med Ctr Dr, Rockville, MD 20850 USA. NR 15 TC 28 Z9 28 U1 0 U2 6 PU AMER VETERINARY MEDICAL ASSOC PI SCHAUMBURG PA 1931 N MEACHAM RD SUITE 100, SCHAUMBURG, IL 60173-4360 USA SN 0003-1488 J9 JAVMA-J AM VET MED A JI JAVMA-J. Am. Vet. Med. Assoc. PD JUN 1 PY 2006 VL 228 IS 11 BP 1718 EP 1722 DI 10.2460/javma.228.11.1718 PG 5 WC Veterinary Sciences SC Veterinary Sciences GA 048YS UT WOS:000237983100037 PM 16740073 ER PT J AU Rivera, J Gilfillan, AM AF Rivera, J Gilfillan, AM TI Molecular regulation of mast cell activation SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Review DE Fc epsilon RI; Lyn; Fyn; IgE; mast cell; degranulation ID FC-EPSILON-RI; PROTEIN-KINASE-C; AFFINITY IGE RECEPTOR; BASOPHILIC LEUKEMIA-CELLS; IMMUNOGLOBULIN-E RECEPTOR; SRC-FAMILY KINASES; LYN-DEFICIENT MICE; PHOSPHOLIPASE-D; PHOSPHOINOSITIDE 3-KINASE; TYROSINE PHOSPHORYLATION AB The mast cell is a central player in allergy and asthma. Activation of these cells induces the release of preformed inflammatory mediators localized in specialized granules and the de novo synthesis and secretion of cytokines, chemokines, and eicosanoids. The balance of engaging inhibitory and activatory cell-surface receptors on mast cells determines whether the cell becomes active on encountering a challenge. However, recent evidence suggests that, once activated, a mast cell's response is further regulated by the balance of both positive and negative intracellular molecular events that extend well beyond the traditional role of kinases and phosphatases. These functional responses are also carefully governed by other protein and lipid mediators that determine the rate and extent of the response. Molecules that have adaptor functions, modulate lipids, and provide synergistic signals add to the regulatory complexity. Considerable information has been obtained from the study of the high-affinity receptor for IgE (Fc epsilon RI), and thus it is the major focus of this review. The unifying theme is that the regulatory steps mentioned herein are required for promoting effective responses while protecting against unwanted inflammatory responses. C1 NIAMSD, Mol Inflammat Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Rivera, J (reprint author), NIAMS, NIH, 10 Room 9N228, Bethesda, MD 20892 USA. EM juan_rivera@nih.gov FU Intramural NIH HHS NR 119 TC 277 Z9 284 U1 0 U2 13 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUN PY 2006 VL 117 IS 6 BP 1214 EP 1225 DI 10.1016/j.jaci.2006.04.015 PG 12 WC Allergy; Immunology SC Allergy; Immunology GA 053UX UT WOS:000238332300002 PM 16750977 ER PT J AU Metcalfe, DD Boyce, JA AF Metcalfe, DD Boyce, JA TI Mast cell biology in evolution SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Editorial Material DE mast cell; allergy; inflammation; asthma ID W-LOCUS; SEVERITY; DISEASE C1 NIAID, NIH, Lab Allerg Dis, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. RP Metcalfe, DD (reprint author), NIAID, NIH, Lab Allerg Dis, Bldg 10,Rm 11C205,10 Ctr Dr,MSC1881, Bethesda, MD 20892 USA. EM dmetcalfe@niaid.nih.gov FU Intramural NIH HHS NR 23 TC 7 Z9 8 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUN PY 2006 VL 117 IS 6 BP 1227 EP 1229 DI 10.1016/j.jaci.2006.03.031 PG 3 WC Allergy; Immunology SC Allergy; Immunology GA 053UX UT WOS:000238332300003 PM 16750978 ER PT J AU Klion, AD Bochner, BS Gleich, GJ Nutman, TB Rothenberg, ME Simon, HU Wechsler, ME Weller, PF AF Klion, Amy D. Bochner, Bruce S. Gleich, Gerald J. Nutman, Thomas B. Rothenberg, Marc E. Simon, Hans-Uwe Wechsler, Michael E. Weller, Peter F. CA Hypereosinophilic Syndromes Workin TI Approaches to the treatment of hypereosinophilic syndromes: A workshop summary report SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Review DE eosinophil; hypereosinophilic syndromes; Churg-Strauss Syndrome; eosinophil-associated gastrointestinal disease; treatment ID CHURG-STRAUSS-SYNDROME; EOSINOPHILIC ESOPHAGITIS; INTERFERON-ALPHA; ANTI-INTERLEUKIN-5 ANTIBODY; SYSTEMIC MASTOCYTOSIS; FOLLOW-UP; IMATINIB; THERAPY; RESISTANCE; VASCULITIS AB Hypereosinophilic syndromes are a heterogeneous group of uncommon disorders characterized by the presence of marked peripheral blood eosinophilia, tissue eosinophilia, or both, resulting in a wide variety of clinical manifestations. Although corticosteroids are the first-line therapy for many of these disorders, approaches to the treatment of patients who do not tolerate or are unresponsive to corticosteroids are poorly standardized. A multidisciplinary group of 37 clinicians and scientists participated in a workshop held in May 2005 in Bern, Switzerland to discuss current and future approaches to therapy for 3 eosinophil-mediated disorders: hypereosinophilic syndrome, Churg-Strauss syndrome, and eosinophil-associated gastrointestinal disease. The goal of the workshop was to summarize available data regarding treatment of these disorders to identify the most promising therapies and approaches for further study. There was consensus among all of the participants that the identification of markers of disease progression to assess treatment responses is a research priority for all 3 disorders. Furthermore, the need for newer therapeutic strategies and novel drugs, as well as multicenter trials to assess all treatment modalities, was emphasized. C1 NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. Johns Hopkins Asthma & Allergy Ctr, Baltimore, MD 21224 USA. Univ Utah, Dept Dermatol, Salt Lake City, UT USA. Univ Utah, Dept Med, Salt Lake City, UT USA. Cincinnati Childrens Hosp, Ctr Med, Dept Pediat, Cincinnati, OH USA. Univ Bern, Dept Pharmacol, Bern, Switzerland. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pulm & Crit Care, Boston, MA 02115 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA. RP Klion, AD (reprint author), NIH, Parasit Dis Lab, Blsg 4,Rm 126,4 Ctr Dr, Bethesda, MD 20892 USA. EM aklion@niaid.nih.gov RI Wechsler, Michael /B-3979-2013; OI Wechsler, Michael /0000-0003-3505-2946; Simon, Hans-Uwe/0000-0002-9404-7736; Klion, Amy/0000-0002-4986-5326 NR 47 TC 179 Z9 194 U1 1 U2 10 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUN PY 2006 VL 117 IS 6 BP 1292 EP 1302 DI 10.1016/j.jaci.2006.02.042 PG 11 WC Allergy; Immunology SC Allergy; Immunology GA 053UX UT WOS:000238332300014 PM 16750989 ER PT J AU Heesch, KC Masse, LC Dunn, AL Frankowski, RF AF Heesch, KC Masse, LC Dunn, AL Frankowski, RF TI The association between number of homework assignments completed during a lifestyle physical activity intervention and scores on transtheoretical measures SO JOURNAL OF APPLIED SPORT PSYCHOLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; EXERCISE BEHAVIOR-CHANGE; SELF-EFFICACY; MOTIVATIONAL READINESS; DECISION-MAKING; OBESE WOMEN; MEDIATORS; MODEL; HEALTH; CARE AB An assumption of theory-based physical activity interventions is that active participation positively affects the theoretical constructs upon which the intervention is based. This assumption is rarely tested. This study assessed whether participation, defined as completion of homework, in a lifestyle physical activity intervention was associated with changes over 6 months in constructs the homework addressed: the behavioral and cognitive processes of change, self-efficacy, and decisional balance (the pros and cons). Participants were 244 sedentary adults aged 25 to 75 years. They completed an average of 12 of 20 homework assignments. Those completing at least two-thirds of the homework (n = 113) had greater changes in the theoretical constructs from pretest to posttest than those completing less (n = 90). Post-hoc analyses suggest that completing theory-based homework may impact the processes of change and self-efficacy in lifestyle physical activity interventions and, therefore, are warranted in future interventions. C1 Univ Queensland, Sch Human Movement Studies, St Lucia, Qld 4072, Australia. Univ Oklahoma, Norman, OK 73019 USA. NCI, Bethesda, MD 20892 USA. Univ Texas, Sch Publ Hlth, Houston, TX USA. RP Heesch, KC (reprint author), Univ Queensland, Sch Human Movement Studies, St Lucia, Qld 4072, Australia. EM kheesch@hms.uq.edu.au RI Heesch, Kristi/B-7863-2009; Heesch, Kristiann/J-1288-2012 OI Heesch, Kristiann/0000-0003-1931-3683 NR 42 TC 4 Z9 4 U1 2 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1041-3200 J9 J APPL SPORT PSYCHOL JI J. Appl. Sport Psychol. PD JUN PY 2006 VL 18 IS 2 BP 83 EP 96 DI 10.1080/10413200600653469 PG 14 WC Hospitality, Leisure, Sport & Tourism; Psychology, Applied; Psychology; Sport Sciences SC Social Sciences - Other Topics; Psychology; Sport Sciences GA 046YY UT WOS:000237848200001 ER PT J AU Hu, PQ Oppenheim, JJ Medsger, TA Wright, TM AF Hu, PQ Oppenheim, JJ Medsger, TA Wright, TM TI T cell lines from systemic sclerosis patients and healthy controls recognize multiple epitopes on DNA topoisomerase I SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE autoimmunity; DNA topoisomerase I; systemic sclerosis; T cell; T cell epitope ID ANTIBODY-LEVELS; SCLERODERMA; REPERTOIRE; AUTOANTIBODY; EXPANSION; RESPONSES; DISEASE AB Anti-DNA topoisomerase I (topo-I) antibodies are exclusively detected in patients with systemic sclerosis (SSc). Participation of this topo-I-specific autoimmune response in the pathogenesis of SSc has been actively investigated, but remains unproven. Here we characterized the peripheral T cell proliferative response to recombinant topo-I (rtopo-I) in 16 SSc patients with circulating anti-topo-I antibody. A low level (cpm < 2000) T cell proliferation (SI > 3) was detected in 6 (38%) of 16 patients. This low level response was similar to those previously observed in healthy controls. We established 56 topo-l-specific T cell lines recognizing 13 distinct T cell epitopes on topo-I from 4 SSc patients and 2 healthy controls. These T cell lines were established from in vitro activated PBMC (CD25(+)) by rtopo-I anti-en. However they did not have the phenotype of regulatory T cells. Notably, 40 (71%) of the 56 T cell lines recognizing a common epitope were established from one patient. DNA sequencing of the T cell receptor cDNA produced an identical sequence indicating these T cells were from a single topo-l-specific T cell precursor. These results suggest that topo-I-specific T cells can become clonally expanded in some patients and may contribute to the pathogenesis of this disease. (c) 2006 Elsevier Ltd. All rights reserved. C1 Natl Canc Inst Frederick, Lab Mol Immunoregulat, NIH, Frederick, MD USA. Univ Pittsburgh, Sch Med, Dept Med, Div Rheumatol & Clin Immunol, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Grad Program Immunol, Pittsburgh, PA USA. RP Hu, PQ (reprint author), Natl Canc Inst Frederick, Lab Mol Immunoregulat, NIH, Frederick, MD USA. EM hu1@ncifcrf.gov FU NCI NIH HHS [5T32 CA82084, P01 CA 73743]; NIAMS NIH HHS [N01 AR 92239] NR 30 TC 13 Z9 13 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD JUN PY 2006 VL 26 IS 4 BP 258 EP 267 DI 10.1016/j.jaut.2006.03.004 PG 10 WC Immunology SC Immunology GA 059DN UT WOS:000238713600005 PM 16735104 ER PT J AU Cabrera, JE Jin, DJ AF Cabrera, JE Jin, DJ TI Active transcription of rRNA operons is a driving force for the distribution of RNA polymerase in bacteria: Effect of extrachromosomal copies of rrnB on the in vivo localization of RNA polymerase SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ESCHERICHIA-COLI CHROMOSOME; SYSTEM; LEADER; REGION; ANTITERMINATION; EXPRESSION; INITIATION; MUTATIONS; PLASMIDS; UPSTREAM AB In contrast to eukaryotes, bacteria such as Escherichia coli contain only one form of RNA polymerase (RNAP), which is responsible for all cellular transcription. Using an RNAP-green fluorescent protein fusion protein, we showed previously that E. coli RNAP is partitioned exclusively in the nucleoid and that stable RNA synthesis, particularly rRNA transcription, is critical for concentrating a significant fraction of RNAP in transcription foci during exponential growth. The extent of focus formation varies under different physiological conditions, supporting the proposition that RNAP redistribution is an important element for global gene regulation. Here we show that extra, plasmid-borne copies of an rRNA operon recruit RNAP from the nucleoid into the cytoplasmic space and that this is accompanied by a reduction in the growth rate. Transcription of an intact rRNA operon is not necessary, although a minimal transcript length is required for this phenotype. Replacement of the ribosomal promoters with another strong promoter, Ptac, abolished the effect. These results demonstrate that active synthesis from rRNA promoters is a major driving force for the distribution of RNAP in bacteria. The implications of our results for the regulation of rRNA synthesis and cell growth are discussed. C1 NCI, Transcript Control Sect, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Jin, DJ (reprint author), NCI, Transcript Control Sect, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res,NIH, 1050 Boyles St,Bldg 469,Rm 127, Frederick, MD 21702 USA. EM djjin@helix.nih.gov FU Intramural NIH HHS NR 29 TC 27 Z9 27 U1 1 U2 11 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 JUN PY 2006 VL 188 IS 11 BP 4007 EP 4014 DI 10.1128/JB.01893-05 PG 8 WC Microbiology SC Microbiology GA 047PZ UT WOS:000237892500028 PM 16707692 ER PT J AU Palmer, RJ Diaz, PI Kolenbrander, PE AF Palmer, Robert J., Jr. Diaz, Patricia I. Kolenbrander, Paul E. TI Rapid succession within the Veillonella population of a developing human oral biofilm in situ SO JOURNAL OF BACTERIOLOGY LA English DT Article ID BACTERIAL ADHERENCE; GENUS VEILLONELLA; MICROBIAL-FLORA; COAGGREGATION; COLONIZATION; STREPTOCOCCUS; ACTINOMYCES; DIVERSITY; SURFACES; ENAMEL AB Streptococci are the primary component of the multispecies oral biofilm known as supragingival dental plaque; they grow by fermentation of sugars to organic acids, e.g., lactic acid. Veillonellae, a ubiquitous component of early plaque, are unable to use sugars; they ferment organic acids, such as lactate, to a mixture of shorter-chain-length acids, CO2, and hydrogen. Certain veillonellae bind to (coaggregate with) streptococci in vitro. We show that, between 4 and 8 hours into plaque development, the dominant strains of Veillonella change in their phenotypic characteristics (coaggregation and antibody reactivity) as well as in their genotypic characteristics (16S RNA gene sequences as well as strain level fingerprint patterns). This succession is coordinated with the development of mixed-species bacterial colonies. Changes in community structure can occur very rapidly in natural biofilm development, and we suggest that this process may influence evolution within this ecosystem. C1 NIDCR, Oral Biofilm Commun Unit, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Kolenbrander, PE (reprint author), NIDCR, Oral Biofilm Commun Unit, Oral Infect & Immun Branch, NIH, Bldg 30,Room 310, Bethesda, MD 20892 USA. EM pkolenbrander@dir.nidcr.nih.gov RI Diaz, Patricia/E-9465-2012 FU Intramural NIH HHS NR 36 TC 55 Z9 59 U1 0 U2 4 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 JUN PY 2006 VL 188 IS 11 BP 4117 EP 4124 DI 10.1128/JB.01958-05 PG 8 WC Microbiology SC Microbiology GA 047PZ UT WOS:000237892500039 PM 16707703 ER PT J AU Yoshida, Y Ganguly, S Bush, CA Cisar, JO AF Yoshida, Y Ganguly, S Bush, CA Cisar, JO TI Molecular basis of L-rhamnose branch formation in streptococcal coaggregation receptor polysaccharides SO JOURNAL OF BACTERIOLOGY LA English DT Article ID CELL-WALL POLYSACCHARIDES; ACTINOMYCES-VISCOSUS T14V; GENETIC-TRANSFORMATION; ORAL ACTINOMYCES; STREPTOCOCCUS-GORDONII-38; RECOGNITION; COMPETENCE; GORDONII; FIMBRIAE; MOTIFS AB The presence of L-rhamnose (Rha) branches in the coaggregation receptor polysaccharides (RPS) of Streptococcus gordonii 38 and Streptococcus oralis J22 was eliminated by replacement of wefB with ermAM in these strains. The expression of this gene in S. oralis 34 did not, however, result in the addition of Rha branches to the linear RPS of this strain, which is identical to that produced by the wefB-deficient mutant of S. gordonii 38. This paradoxical finding was explained by a subtle difference in acceptor specificity of, the galactose-1-phosphotransferases encoded by downstream wefC in S. gordonii 38 and wefH in S. oralis 34. These genes were distinguished by the unique ability of WefC to act on the branched acceptor formed by the action of WefB. C1 NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. RP Cisar, JO (reprint author), NIDCR, Oral Infect & Immun Branch, NIH, Bldg 30,Room 3A-301,30 Convent Dr, Bethesda, MD 20892 USA. EM john.cisar@nih.gov FU Intramural NIH HHS NR 21 TC 14 Z9 15 U1 0 U2 1 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 JUN PY 2006 VL 188 IS 11 BP 4125 EP 4130 DI 10.1128/JB.01843-05 PG 6 WC Microbiology SC Microbiology GA 047PZ UT WOS:000237892500040 PM 16707704 ER PT J AU Galperin, MY AF Galperin, Michael Y. TI Structural classification of bacterial response regulators: Diversity of output domains and domain combinations SO JOURNAL OF BACTERIOLOGY LA English DT Review ID 2-COMPONENT SIGNAL-TRANSDUCTION; DNA-BINDING DOMAIN; C-DI-GMP; SP STRAIN PCC-7120; BACILLUS-SUBTILIS; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; PROTEIN PHOSPHATASES; CYCLIC DIGUANYLATE; RHODOBACTER-SPHAEROIDES AB CheY-like phosphoacceptor (or receiver [REC]) domain is a common module in a variety of response regulators of the bacterial signal transduction systems. In this work, 4,610 response regulators, encoded in complete genomes of 200 bacterial and archaeal species, were identified and classified by their domain architectures. Previously uncharacterized output domains were analyzed and, in some cases, assigned to known domain families. Transcriptional regulators of the OmpR, NarL, and NtrC families were found to comprise almost 60% of all response regulators; transcriptional regulators with other DNA-binding domains (LytTR, AraC, SpoOA, Fis, YcbB, RpoE, and MerR) account for an additional 6%. The remaining one-third is represented by the stand-alone REC domain (similar to 14%) and its combinations with a variety of enzymatic (GGDEF, EAL, HD-GYP, Chell, CheC, PP2C, and HisK), RNA-binding (ANTAR and CsrA), protein- or ligand-binding (PAS, GAF, TPR, CAP-ED, and HPt) domains, or newly described domains of unknown function. The diversity of domain architectures and the abundance of alternative domain combinations suggest that fusions between the REC domain and various output domains is a widespread evolutionary mechanism that allows bacterial cells to regulate transcription, enzyme activity, and/or protein-protein interactions in response to environmental challenges. The complete list of response regulators encoded in each of the 200 analyzed genomes is available online at httP://www.ncbi.nim.nih.gov/Complete_Genomes/RRcensus.html. C1 Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Galperin, MY (reprint author), Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM galperin@ncbi.nlm.nih.gov RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 FU Intramural NIH HHS [Z99 LM999999] NR 157 TC 244 Z9 257 U1 8 U2 55 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 JUN PY 2006 VL 188 IS 12 BP 4169 EP 4182 DI 10.1128/JB.01887-05 PG 14 WC Microbiology SC Microbiology GA 051PV UT WOS:000238173900002 PM 16740923 ER PT J AU Domanski, M Tian, X Haigney, M Pitt, B AF Domanski, M Tian, X Haigney, M Pitt, B TI Diuretic use, progressive heart failure, and death in patients in the DIG study SO JOURNAL OF CARDIAC FAILURE LA English DT Article DE heart failure; diuretics; sudden cardiac death; SOLVD study ID LEFT-VENTRICULAR DYSFUNCTION; FUROSEMIDE; ENALAPRIL; RATIONALE; MORTALITY; EVALUATE; DESIGN; SOLVD AB Background: Nonpotassium-sparing diuretics (NPSDs), have been associated with increased sudden cardiac death (SCD) and progressive heart failure (HF) death in HF patients. Methods and Results: In 6797 Digitalis Investigation Group study patients, risk ratios were calculated for death, cardiovascular death (CVD), death from worsening HF, SCD, and HF hospitalization among those taking a potassium-sparing (PSD), NPSD, or no diuretic. Compared with not taking diuretic, risk of death (relative risk [RR] 1.36, 95% confidence interval [CI] 1.17-1.59, P < .0001), CVD (RR = 1.38, 95% CI 1.17-1.63, P = .0001), progressive HF death (RR = 1.41, 95% CI 1.06-1.89, P = .02), SCD (RR = 1.67, 95% CI 1.23-2.27, P = .001), and HF hospitalization (RR = 1.68, 95% CI 1.41-1.99, P < .0001) were increased with NPSD. There was no significant difference in any end point for patients taking only PSD compared to no diuretic. PSD only subjects were less likely than NPSD subjects to be hospitalized for HF (RR = 0.71, 95% CI 0.52-0.96, P = .02). Conclusion: NPSDs are associated with increased risk of death, CVD, progressive HF death, SCD, and HF hospitalization. A randomized trial is needed to assess the role of NPSDs versus PSDs in HF patients. C1 NHLBI, Clin Trials Grp, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. Uniformed Serv Med Sch, Div Cardiol, Bethesda, MD USA. Univ Michigan, Sch Med, Div Cardiol, Ann Arbor, MI 48109 USA. RP Domanski, M (reprint author), NHLBI, Clin Trials Grp, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. NR 15 TC 52 Z9 53 U1 0 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD JUN PY 2006 VL 12 IS 5 BP 327 EP 332 DI 10.1016/j.cardfail.2006.03.006 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 056JK UT WOS:000238518600001 PM 16762792 ER PT J AU Haigney, MCP Alam, S Tebo, S Marhefka, G Elkashef, A Kahn, R Chiang, CN Vocci, F Cantilena, L AF Haigney, MCP Alam, S Tebo, S Marhefka, G Elkashef, A Kahn, R Chiang, CN Vocci, F Cantilena, L TI Intravenous cocaine and QT variability SO JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY LA English DT Article ID TORSADES-DE-POINTES; POTASSIUM CHANNELS; REPOLARIZATION LABILITY; INTERVAL VARIABILITY; TRIGGERED ACTIVITY; PIG MYOCYTES; HEART-RATE; HERG; PROLONGATION; INHIBITION AB Background: Dynamic instability in cardiac repolarization may contribute to drug-induced arrhythmogenesis. We hypothesized that intravenous cocaine would significantly destabilize repolarization as measured by QT variability. Methods and Results: Twenty-nine cocaine-experienced volunteers not seeking treatment for cocaine addiction received randomized, sequential intravenous infusions of placebo or cocaine (20 and 40 mg). Five-minute epochs of digitized ECG were recorded 10 minutes before, during, and at intervals following the infusions. QT variability was measured using a semiautomated method and expressed as the log ratio of normalized QT variance to normalized heart rate variance (QTVI). Seventeen subjects received a repeat course of cocaine infusions 1 week later. Placebo infusion resulted in a small but significant increase in QTVI, while cocaine caused a highly significant, dose-dependent increase in QTVI that peaked at 10 minutes and dissipated by 45 minutes following infusion (P < 0.0001). The increase in QTVI was reproducible at 1 week (P = 0.8). Conclusions: Cocaine injection results in a significant dose-dependent increase in QT variability as indexed by QTVI. This destabilizing effect on repolarization may increase vulnerability to reentrant arrhythmias and may partially explain an increased risk of sudden cardiac death associated with cocaine use. C1 Uniformed Serv Univ Hlth Sci, Dept Med, Div Cardiol, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Dept Med, Dept Clin Pharmacol, Bethesda, MD USA. Uniformed Serv Univ Hlth Sci, Dept Med, Dept Med Toxicol, Bethesda, MD USA. NIDA, NIH, Bethesda, MD USA. RP Haigney, MCP (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med, Div Cardiol, A3060,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM mhaigney@usuhs.mil FU PHS HHS [YDA9094] NR 23 TC 16 Z9 16 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1045-3873 J9 J CARDIOVASC ELECTR JI J. Cardiovasc. Electrophysiol. PD JUN PY 2006 VL 17 IS 6 BP 610 EP 616 DI 10.1111/j.1540-8167.2006.00421.x PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 045KC UT WOS:000237740000008 PM 16836708 ER PT J AU Marom, R Shur, I Hager, GL Benayahu, D AF Marom, R Shur, I Hager, GL Benayahu, D TI Expression and regulation of CReMM, a chromodomain helicase-DNA-binding (CHD), in marrow strorna derived osteoprogenitors SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID BONE-MARROW; GENE-EXPRESSION; STROMAL CELLS; OSTEOBLAST PHENOTYPE; ESTROGEN-RECEPTOR; DEXAMETHASONE REGULATION; VITAMIN-D; IN-VITRO; DIFFERENTIATION; PROLIFERATION AB This Study follows the expression of CReMM, a new CHID family member, in osteoprogenitors. CReMM expression was analyzed in primary Cultured mesnchymal cells from rat and human. Analysis in ex vivo cultured marrow stromal cells (MSC) from rats revealed higher level of CReMM in cells from young (3 months), when compared to cells from old (15 months) rats. CReMM level was higher in human MSC then in mature trabecular bone cells (TBC). Within the MSC population, osteogenic clones showed higher levels of CReMM then non-osteogenic ones. We used bone marrow derived osteogenic cell line (MBA-15) to elaborate on the regulation of CReMM expression in correlation with cell proliferation and co-expression with alkaline phosphatase (ALK). CReMM is highly expressed in proliferating cells and is inversely related to expression of ALK. MBA-15 cells were challenged with dexamethasone (Dex) or 17 beta-estradiol and quantification of CReMM at the protein (ELISA) and mRNA (RT-PCR) levels had shown that Dex upregulated CReMM levels. Since CReMM is regulated by Dex, we analyzed the interaction of CReMM with the glucocorticoid receptor (GR), which mediates Dex action. Co-immunopercipitation (Co-IP) demonstrated an association between CReMM and GR. In summary, CReMM is a CHD protein expressed by osteoprogenitors, and we suggest it plays a role in mediating transcriptional response to hormones that coordinate osteoblast function. C1 Tel Aviv Univ, Sackler Sch Med, Dept Cell & Dev Biol, IL-69978 Tel Aviv, Israel. NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Benayahu, D (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Cell & Dev Biol, IL-69978 Tel Aviv, Israel. EM dafnab@post.tau.ac.il NR 47 TC 17 Z9 19 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD JUN PY 2006 VL 207 IS 3 BP 628 EP 635 DI 10.1002/jcp.20611 PG 8 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 040HS UT WOS:000237370200006 PM 16523501 ER PT J AU Han, JC Balagopal, P Sweeten, S Darmaun, D Mauras, N AF Han, Joan C. Balagopal, Prabharakan Sweeten, Shawn Darmaun, Dominique Mauras, Nelly TI Evidence for hypermetabolism in boys with constitutional delay of growth and maturation SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID IDIOPATHIC SHORT STATURE; RATIO MASS-SPECTROMETRY; DOUBLY LABELED WATER; ENERGY-EXPENDITURE; BODY-COMPOSITION; HORMONE TREATMENT; ORGANIC-COMPOUNDS; FINAL HEIGHT; VITAMIN-A; CHILDREN AB Context: Children with constitutional delay of growth and maturation (CDGM) tend to be thin and have a growth pattern reminiscent of nutritional insufficiency. Objective: Our objective was to compare differences in nutrition, body composition, bone mineral density, and resting and total energy expenditure (REE/TEE) in boys with CDGM and controls. We hypothesized that an imbalance between energy intake and expenditure may contribute to the pathogenesis of CDGM. D Design and Setting: We conducted an observational, cross-sectional study at an outpatient clinical research center. Patients: Patients included 36 boys (8-17 yr): 12 with CDGM (short stature, delayed bone age and puberty, and no other pathology) and 12 height-matched (pre- or early-pubertal) and 12 age-matched (pubertal) healthy controls. Main Outcome Measures: Outcome measures included doubly labeled water studies (TEE), serum nutritional/hormonal markers, dual-energy x-ray absorptiometry,dietary analysis, and indirect calorimetry Results: Nutritional markers were comparable among the groups. CDGM subjects had bone mineral density lower than age-matched controls ( P < 0.01) but comparable with height-matched controls. Even though REE did not differ between groups, CDGM subjects had 25% higher caloric intake adjusted for fat-free mass (FFM) than height-matched controls ( P < 0.05) and 78% higher caloric intake per kilogram FFM compared with age-matched controls (P < 0.00001). CDGM subjects had 46% ( P < 0.05) and 91% (P < 0.001) higher TEE per kilogram FFM than height- and age-matched controls, respectively. CDGM subjects had lower IGF-I and testosterone than age-matched controls (P < 0.001) but levels were comparable with height-matched controls. Conclusions: Boys with CDGM have higher rates of overall energy expenditure compared with age- and size-matched controls. This increased metabolism may result in impaired tempo of growth. Additional studies are needed to determine whether augmenting nutrition to match their energy needs (with or without hormonal therapy) can improve linear and ponderal growth in patients with CDGM. C1 Nemours Childrens Clin Jacksonville, Div Endocrinol, Biomed Anal Lab, Jacksonville, FL 32207 USA. Nemours Childrens Clin Jacksonville, Div Pediat Endocrinol, Jacksonville, FL 32207 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. INSERM, Human Nutr Res Ctr, F-44093 Nantes, France. RP Mauras, N (reprint author), Nemours Childrens Clin Jacksonville, Div Endocrinol, Biomed Anal Lab, 807 Childrens Way, Jacksonville, FL 32207 USA. EM nmauras@nemours.org NR 41 TC 18 Z9 19 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2006 VL 91 IS 6 BP 2081 EP 2086 DI 10.1210/jc.2005-2762 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 050NK UT WOS:000238095000015 PM 16551727 ER PT J AU Merz, CNB Johnson, BD Braunstein, GD Pepine, CJ Reis, SE Paul-Labrador, M Hale, G Sharaf, BL Bittner, V Sopko, G Kelsey, SF AF Merz, C. Noel Bairey Johnson, B. Delia Braunstein, Glenn D. Pepine, Carl J. Reis, Steven E. Paul-Labrador, Maura Hale, Georgina Sharaf, Barry L. Bittner, Vera Sopko, George Kelsey, Sheryl F. CA Womens Ischemia Syndrome Evaluatio TI Phytoestrogens and lipoproteins in women SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; SYNDROME EVALUATION WISE; SOY PROTEIN; PERIMENOPAUSAL WOMEN; POSTMENOPAUSAL WOMEN; PLASMA-LIPIDS; ISOFLAVONES; SUPPLEMENTATION; CHOLESTEROL; MENOPAUSAL AB Objectives: We undertook a study to evaluate relationships among blood phytoestrogen levels, lipoprotein levels, estrogen levels, and angiographically defined coronary artery disease in women. Background: Evidence for a beneficial role and the potential mechanism(s) of plant estrogens (phytoestrogens) on blood lipoproteins in humans is controversial. Methods: We evaluated 483 women enrolled in the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation with coronary risk factors undergoing coronary angiography for evaluation for suspected ischemia for blood phytoestrogen levels (daidzein and genistein), lipoprotein levels [total cholesterol, triglycerides, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol (HDL-C)], estrogen levels (estradiol, bioavailable estradiol, estrone), and angiographic coronary artery disease using core laboratories. Results: Higher blood levels of the phytoestrogen daidzein were associated with lower triglycerides (P=0.01), higher HDL-C (P=0.05) levels, and a beneficial total cholesterol to HDL-C ratio (P=0.02). This beneficial association was evident among the subgroup of women with low [< 184 pmol/liter (< 50 pg/ml)] blood estradiol levels, regardless of age and lipoprotein levels. The phytoestrogen associations with lipoproteins were incrementally related to the magnitude of daidzein level and independent of other lipoprotein modulators. There were no detectable relationships between the phytoestrogen levels and angiographic coronary artery disease. Conclusions: Higher blood phytoestrogen daidzein levels are associated with beneficial lipoprotein levels in women with low estrogen levels, possibly by an estrogen receptor mechanism. These results suggest a potential explanation for the variable lipoprotein results observed in prior randomized controlled trials and call for investigation regarding subgroups of subjects who may preferentially benefit from dietary intake of food products, such as soy. C1 Univ Pittsburgh, WISE Coordinating Ctr, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. Cedars Sinai Med Ctr, Div Cardiol, Dept Med, Cedar Sinai Res Inst, Los Angeles, CA 90048 USA. Univ Florida, Div Cardiovasc Med, Gainesville, FL 32611 USA. Univ Pittsburgh, Med Ctr, Cardiovasc Inst, Pittsburgh, PA 15213 USA. Rhode Isl Hosp, Providence, RI 02903 USA. Univ Alabama, Div Cardiol, Dept Med, Birmingham, AL 35294 USA. NHLBI, NIH, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. RP Merz, CNB (reprint author), Univ Pittsburgh, WISE Coordinating Ctr, Grad Sch Publ Hlth, Dept Epidemiol, 127 Parran Hall,130 DeSoto St, Pittsburgh, PA 15261 USA. RI Reis, Steven/J-3957-2014; OI Bittner, Vera/0000-0001-9456-850X FU NCRR NIH HHS [M01-RR00425]; NHLBI NIH HHS [N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164] NR 21 TC 21 Z9 21 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2006 VL 91 IS 6 BP 2209 EP 2213 DI 10.1210/jc.2005-1853 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 050NK UT WOS:000238095000036 PM 16595605 ER PT J AU Robinson-White, A Meoli, E Stergiopoulos, S Horvath, A Boikos, S Bossis, I Stratakis, CA AF Robinson-White, Audrey Meoli, Elise Stergiopoulos, Sotirios Horvath, Anelia Boikos, Sosipatros Bossis, Ioannis Stratakis, Constantine A. TI PRKAR1A mutations and protein kinase A interactions with other signaling pathways in the adrenal cortex SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ADRENOCORTICAL TUMOR-CELLS; SUBUNIT TYPE 1A; CARNEY COMPLEX; REGULATORY SUBUNIT; CYCLIC-AMP; B-RAF; MOLECULAR-MECHANISMS; MYC PROTEIN; CROSS-TALK; RI-ALPHA AB Context: Primary pigmented nodular adrenocortical disease, associated with Carney complex, is caused by mutations in PRKAR1A (mt-PRKAR1A), a gene that codes for the regulatory subunit type 1 alpha (RI alpha) of cAMP-dependent protein kinase (PKA). PRKAR1A inactivation is associated with dysregulated PKA activity that is thought to result in tumorigenesis. mt-PRKAR1A-bearing lymphocytes from Carney complex patients exhibit enhanced cell proliferation associated with increased expression of the MAPK ERK1/2 pathway. Objective: The objective of the study was to determine how PKA and its subunits and ERK1/2 and their molecular partners change in the presence of PRKAR1A mutations in adrenocortical tissue. Design: PKA activity and subunit expression, ERK1/2, other immunoassays, and immunohistochemistry on adrenocortical samples from patients with germline normal or mt-PRKAR1A were analyzed. Results: Increased cAMP-stimulated total kinase activity was associated with mt-PRKAR1A. PKA subunit expression analysis in mt-PRKAR1A tissues, by quantitative mRNA assay and immunoblotting, showed a 2.4-fold (P = 0.02) and 1.8- fold (P = 0.09) decrease in RI alpha's message and protein, respectively, and increases in other PKA subunits. Immunoassays showed 2-fold (P = 0.03) and 6-fold (P = 0.03) decreases in baseline ERK1/2, with corresponding increases in phosphorylated (p) ERK1/2 in mt-PRKAR1A samples. B-raf kinase, p-MEK1/2, and p-c-Myc, but not p-Akt/protein kinase B, were significantly increased. Immunohistochemistry studies supported these data. Conclusions: mt-PRKAR1A causes increased total cAMP-stimulated kinase activity, likely the result of up-regulation of other PKA subunits caused by down-regulation of RI alpha, as seen in human lymphocytes and mouse animal models. These changes, associated with enhanced MAPK activity, may be, in part, responsible for the proliferative signals that result in primary pigmented nodular adrenocortical disease. C1 NICHHD, Sect Endocrinol & Genet, Pediat Endocrinol Training Program, Dev Endocrinol Branch,NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHHD, Sect Endocrinol & Genet, Pediat Endocrinol Training Program, Dev Endocrinol Branch,NIH, Bldg 10,Clin Res Ctr,Room 1-3330,10 Ctr Dr,MSC110, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Intramural NIH HHS NR 39 TC 50 Z9 51 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2006 VL 91 IS 6 BP 2380 EP 2388 DI 10.1210/jc.2006-0188 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 050NK UT WOS:000238095000060 PM 16569736 ER PT J AU Wendler, DS Shah, S AF Wendler, David S. Shah, Seema TI How can medical training and informed consent be reconciled with volume-outcome data? SO JOURNAL OF CLINICAL ETHICS LA English DT Article ID HEALTH-CARE; EMERGENCY-DEPARTMENT; SURGEONS; HOSPITALS; ANGIOPLASTY; EXPERIENCE; PHYSICIANS; MORTALITY; QUALITY C1 NIH, Unit Vulnerable Populat, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Wendler, DS (reprint author), NIH, Unit Vulnerable Populat, Dept Clin Bioeth, Bldg 10, Bethesda, MD 20892 USA. EM dwendler@nih.gov; cmashah@gmail.com NR 35 TC 5 Z9 5 U1 0 U2 1 PU UNIV PUBLISHING GROUP PI HAGERSTOWN PA 138 W WASHINGTON ST, STE 403-405, HAGERSTOWN, MD 21740 USA SN 1046-7890 J9 J CLIN ETHIC JI J. Clin. Ethics PD SUM PY 2006 VL 17 IS 2 BP 149 EP 157 PG 9 WC Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Biomedical Social Sciences GA 072NF UT WOS:000239679400007 PM 16913150 ER PT J AU Alexander, DF Alving, BM Battey, JF Berg, JM Collins, FS Fauci, AS Gallin, JI Grady, PA Hodes, RJ Hrynkow, SH Insel, TR Jones, JF Katz, SI Landis, SC Li, TK Lindberg, DA Nabel, EG Niederhuber, JE Pettigrew, RI Rodgers, GP Ruffin, J Scarpa, A Schwartz, DA Sieving, PA Straus, SE Tabak, LA Volkow, ND AF Alexander, DF Alving, BM Battey, JF Berg, JM Collins, FS Fauci, AS Gallin, JI Grady, PA Hodes, RJ Hrynkow, SH Insel, TR Jones, JF Katz, SI Landis, SC Li, TK Lindberg, DA Nabel, EG Niederhuber, JE Pettigrew, RI Rodgers, GP Ruffin, J Scarpa, A Schwartz, DA Sieving, PA Straus, SE Tabak, LA Volkow, ND TI Response to: "Rescuing the NIH before it is too late" SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Letter AB We, the directors of the 27 NIH institutes and centers, wanted to respond to the points made by Andrew Marks in his recent editorial. While we appreciate that the scientific community has concerns, the current initiatives and directions of the NIH have been developed through planning processes that reflect openness and continued constituency input, all aimed at assessing scientific opportunities and addressing public health needs. C1 NICHHD, Bethesda, MD 20892 USA. NHGRI, Bethesda, MD 20892 USA. NIAID, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. NINR, Bethesda, MD 20892 USA. NIA, Bethesda, MD 20892 USA. NIMH, Bethesda, MD 20892 USA. NIAMSD, Bethesda, MD 20892 USA. NINDS, Bethesda, MD 20892 USA. NIAAA, Bethesda, MD 20892 USA. Natl Lib Med, Bethesda, MD 20894 USA. NHLBI, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NIDDK, Bethesda, MD 20892 USA. NEI, Bethesda, MD 20892 USA. NIDA, Bethesda, MD 20892 USA. RP Alexander, DF (reprint author), NICHHD, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2006 VL 116 IS 6 BP 1462 EP 1463 DI 10.1172/JC128894 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 048XL UT WOS:000237979700002 PM 16648877 ER PT J AU Bravo, NR AF Bravo, NR TI Response to: "Rescuing the NIH before it is too late" from the Deputy Director for Extramural Research SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Letter AB Andrew Marks' recent editorial eloquently reiterated a concern that many of us have voiced before, that the current policies and practices of the NIH are not serving the public well. C1 NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Bravo, NR (reprint author), NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM ruizbran@od.nih.gov NR 1 TC 3 Z9 3 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2006 VL 116 IS 6 BP 1463 EP 1464 DI 10.1172/JC128955 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 048XL UT WOS:000237979700004 ER PT J AU Picker, LJ Reed-Inderbitzin, EF Hagen, SI Edgar, JB Hansen, SG Legasse, A Planer, S Piatak, M Lifson, JD Maino, VC Axthelm, MK Villinger, F AF Picker, LJ Reed-Inderbitzin, EF Hagen, SI Edgar, JB Hansen, SG Legasse, A Planer, S Piatak, M Lifson, JD Maino, VC Axthelm, MK Villinger, F TI IL-15 induces C4+ effector memory T cell production and tissue emigration in nonhuman primates SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; HIV-INFECTED PATIENTS; IMMUNODEFICIENCY VIRUS-INFECTION; GASTROINTESTINAL-TRACT; IN-VIVO; VIRAL REPLICATION; RHESUS MACAQUES; SIV INFECTION; CD4(+); EXPRESSION AB HIV infection selectively targets CD4(+) effector memory T (T-EM) cells, resulting in dramatic depletion of CD4(+) T cells in mucosal effector sites in early infection. Regeneration of the TEM cell compartment is slow and incomplete, even when viral replication is controlled by antiretroviral therapy (ART). Here, we demonstrate that IL-15 dramatically increases in vivo proliferation of rhesus macaque (RM) CD4(+) and CD8(+) TEM cells with little effect on the naive or central memory T (T-CM) cell subsets, a response pattern that is quite distinct from that of either IL-2 or IL-7. T-EM cells produced in response to IL-15 did not accumulate in blood. Rather, 5-bromo-2'-deoxyuridine (BrdU) labeling studies suggest that many of these cells rapidly disperse to extralymphoid effector sites, where they manifest (slow) decay kinetics indistinguishable from that of untreated controls. In RMs with uncontrolled SIV infection and highly activated immune systems, IL-15 did not significantly increase CD4(+) T-EM cell proliferation, but with virologic control and concomitant reduction in immune activation by ART, IL-15 responsiveness was again observed. These data suggest that therapeutic use of IL-15 in the setting of ART might facilitate specific restoration of the CD4(+) T cell compartment that is the primary target of HIV with less risk of exhausting precursor T cell compartments or generating potentially deleterious regulatory subsets. C1 Oregon Hlth Sci Univ, Vaccine & Gene Therapy Inst, Beaverton, OR 97006 USA. Oregon Hlth Sci Univ, Dept Pathol, Beaverton, OR 97006 USA. Oregon Hlth Sci Univ, Dept Mol Microbiol & Immunol, Beaverton, OR 97006 USA. Oregon Hlth Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR 97006 USA. SAIC Frederick Inc, NCI, AIDS Vaccine Program, Frederick, MD 21701 USA. BD Biosci, San Jose, CA USA. Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. RP Picker, LJ (reprint author), Oregon Hlth Sci Univ, Vaccine & Gene Therapy Inst, W Campus,505 NW 185th Ave, Beaverton, OR 97006 USA. EM pickerl@ohsu.edu FU NCI NIH HHS [N01-CO-124000]; NCRR NIH HHS [P51 RR000163, R24 RR016988, R24 RR16988, RR00163, U24 RR018107, U42 RR016025]; NIAID NIH HHS [R0 AI054292, R01 AI054292] NR 49 TC 120 Z9 122 U1 0 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2006 VL 116 IS 6 BP 1514 EP 1524 DI 10.1172/JC127S64 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 048XL UT WOS:000237979700014 PM 16691294 ER PT J AU Kaposi-Novak, P Lee, JS Gomez-Quiroz, L Coulouarn, C Factor, VM Thorgeirsson, SS AF Kaposi-Novak, Pal Lee, Ju-Seog Gomez-Quiroz, Luis Coulouarn, Cedric Factor, Valentina M. Thorgeirsson, Snorri S. TI Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID HEPATOCYTE GROWTH-FACTOR; GENE-EXPRESSION; C-MET; INVASIVE GROWTH; OLIGONUCLEOTIDE MICROARRAY; MICROVESSEL-DENSITY; LIVER-REGENERATION; TUMOR PROGRESSION; RESPONSE ELEMENT; TYROSINE KINASE AB Identification of specific gene expression signatures characteristic of oncogenic pathways is an important step toward molecular classification of human malignancies. Aberrant activation of the Met signaling pathway is frequently associated with tumor progression and metastasis. In this study, we defined the Met-dependent gene expression signature using global gene expression profiling of WT and Met-deficient primary mouse hepatocytes. Newly identified transcriptional targets of the Met pathway included genes involved in the regulation of oxidative stress responses as well as cell motility, cytoskeletal organization, and angiogenesis. To assess the importance of a Met-regulated gene expression signature, a comparative functional genomic approach was applied to 242 human hepatocellular carcinomas (HCCs) and 7 metastatic liver lesions. Cluster analysis revealed that a subset of human HCCs and all liver metastases shared the Met-induced expression signature. Furthermore, the presence of the Met signature showed significant correlation with increased vascular invasion rate and microvessel density as well as with decreased mean survival time of HCC patients. We conclude that the genetically defined gene expression signatures in combination with comparative functional genomics constitute an attractive paradigm for defining both the function of oncogenic pathways and the clinically relevant subgroups of human cancers. C1 NCI, Lab Expt Carcinogenesis, NIH, Canc Res Ctr, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NCI, Lab Expt Carcinogenesis, NIH, Canc Res Ctr, 37 Convent Dr,Blgd 37,Room 4146, Bethesda, MD 20892 USA. EM snorri_s_thorgeirsson@nih.gov RI Gomez-Quiroz, Luis/L-8415-2013; Coulouarn, Cedric/E-5472-2011; OI Gomez-Quiroz, Luis Enrique/0000-0002-5704-5985 FU Intramural NIH HHS NR 58 TC 214 Z9 220 U1 0 U2 9 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2006 VL 116 IS 6 BP 1582 EP 1595 DI 10.1172/JCI27236 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 048XL UT WOS:000237979700020 PM 16710476 ER PT J AU Castle, PE Aftab, A Saint-Jean, G Mendez, L AF Castle, PE Aftab, A Saint-Jean, G Mendez, L TI Detection of carcinogenic human papillomavirus in specimens collected with a novel self-sampling device SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID CERVICAL-CANCER; WORLDWIDE; WOMEN AB We compared the detection of carcinogenic human papillomavirus DNA in cervicovaginal specimens self-collected using a novel device to the detection in physician-collected cervical specimens from 137 women. The kappa value was 0.66 (95% confidence interval, 0.53 to 0.78), with an 83% overall test agreement and a 68% positive test agreement. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Univ Miami, Sch Med, Dept Family & Community Hlth, Miami, FL USA. Univ Miami, Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL USA. Univ Miami, Sch Med, Dept Obstet & Gynecol, Miami, FL 33101 USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room 7074,EPS MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov NR 9 TC 8 Z9 8 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD JUN PY 2006 VL 44 IS 6 BP 2158 EP 2159 DI 10.1128/JCM.02358-05 PG 2 WC Microbiology SC Microbiology GA 053VD UT WOS:000238332900034 PM 16757614 ER PT J AU Baker, SD Sparreboom, A AF Baker, SD Sparreboom, A TI Predicting vinorelbine disposition and toxicity: Does BSA provide more than a "bad statistical association"? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID BODY-SURFACE AREA; ANTICANCER AGENTS; PHARMACOKINETICS; CANCER; DRUG; PROBES; ADULTS; MDR1 C1 Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. NCI, NIH, Bethesda, MD 20892 USA. RP Baker, SD (reprint author), Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RI Sparreboom, Alex/B-3247-2008 NR 16 TC 3 Z9 3 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 1 PY 2006 VL 24 IS 16 BP 2412 EP 2413 DI 10.1200/JCO.2005.05.4494 PG 2 WC Oncology SC Oncology GA 048IN UT WOS:000237940900004 PM 16651645 ER PT J AU Simon, MS Korczak, JF Yee, CL Malone, KE Ursin, G Bernstein, L McDonald, JA Deapen, D Strom, BL Press, MF Marchbanks, PA Burkman, RT Weiss, LK Schwartz, AG AF Simon, MS Korczak, JF Yee, CL Malone, KE Ursin, G Bernstein, L McDonald, JA Deapen, D Strom, BL Press, MF Marchbanks, PA Burkman, RT Weiss, LK Schwartz, AG TI Breast cancer risk estimates for relatives of white and African American women with breast cancer in the Women's Contraceptive and Reproductive Experiences Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 40th Annual Meeting of the American-Society-of-Clinical-Oncology CY JUN 05-08, 2004 CL New Orleans, LA SP Amer Soc Clin Oncol ID VALIDATION; REGISTRY; ONSET; AGE AB Purpose Family history is a well-recognized risk factor for breast cancer. Familial aggregation and segregation analyses have estimated breast cancer risk based on family history primarily for white women; such information is limited for African American (AA) women. The purpose of this report is to update breast cancer risk estimates associated with a family history of breast cancer for white and AA women. Methods We used family cancer history from 2,676 white and 1,525 AA women with breast cancer (probands) in the population-based National Institute of Child Health and Human Development's Women's Contraceptive and Reproductive Experiences (CARE) Study to estimate age-specific breast cancer risks in their first degree adult female relatives. Cumulative hazard curves were calculated for relatives of all probands using Cox proportional hazards models, and were stratified by the proband's race and age at diagnosis and number of relatives affected. Results Breast cancer risks for white and AA women with a family history of the disease are similar through age 49 years, but diverge afterwards, with higher risks by age 79 in white women than in AA women (17.5% [SE, 0.9%] v 12.2% [SE, 1.1%]; P < .001). These risks increase as the number of affected first degree relatives increases, reaching 25.2% (SE, 3.4%) and 16.9% (SE, 4.0%) in white and AA women with more than one affected relative, respectively (P = .3). Conclusion We found age-related racial differences in breast cancer risk in women with a family history of breast cancer and have updated risk estimates for white and AA women for clinical use. C1 Wayne State Univ, Barbara Ann Karmanos Canc Inst, Div Hematol & Oncol, Detroit, MI 48201 USA. Wayne State Univ, Barbara Ann Karmanos Canc Inst, Populat Studies & Prevent Program, Detroit, MI 48201 USA. Wayne State Univ, Barbara Ann Karmanos Canc Inst, Breast Canc Program, Detroit, MI 48201 USA. Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. Univ Washington, Sch Publ Hlth & Community Med, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA USA. Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. Baystate Med Ctr, Dept Obstet & Gynecol, Springfield, MA USA. NCI, Bethesda, MD 20892 USA. Univ Oslo, Dept Nutr, Oslo, Norway. RP Simon, MS (reprint author), Wayne State Univ, Barbara Ann Karmanos Canc Inst, Div Hematol & Oncol, Room 4221 HWCRC,4100 John R, Detroit, MI 48201 USA. EM Simonm@karmanos.org FU NCI NIH HHS [CN65064] NR 21 TC 16 Z9 16 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 1 PY 2006 VL 24 IS 16 BP 2498 EP 2504 DI 10.1200/JCO.2005.04.1087 PG 7 WC Oncology SC Oncology GA 048IN UT WOS:000237940900017 PM 16735703 ER PT J AU Duczmal, L Kulldorff, M Huang, L AF Duczmal, L Kulldorff, M Huang, L TI Evaluation of spatial scan statistics for irregularly shaped clusters SO JOURNAL OF COMPUTATIONAL AND GRAPHICAL STATISTICS LA English DT Article DE disease clusters; elliptic scan; non-compactness penalty; power evaluation; simulated annealing scan; spatial cluster detection ID AIR-POLLUTION; LUNG-CANCER; SMOKING; TESTS AB Spatial scan statistics are commonly used for geographic disease cluster detection and evaluation. We propose and implement a modified version of the simulated annealing spatial scan statistic that incorporates the concept of "non-compactness" in order to penalize clusters that are very irregular in shape. We evaluate its power for the simulated annealing scan and compare it with the circular and elliptic spatial scan statistics. We observe that, with the non-compactness penalty, the simulated annealing method is competitive with the circular and elliptic scan statistic, and both have good power performance. The elliptic scan statistic is computationally faster and is well suited for mildly irregular clusters, but the simulated annealing method deals better with highly irregular cluster shapes. The new method is applied to breast cancer mortality data from northeastern United States. C1 Univ Fed Minas Gerais, Dept Stat, BR-31270 Belo Horizonte, MG, Brazil. Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA USA. Harvard Pilgrim Hlth Care, Boston, MA USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Duczmal, L (reprint author), Univ Fed Minas Gerais, Dept Stat, Campus Pampulha, BR-31270 Belo Horizonte, MG, Brazil. EM duczmal@est.ufmg.br RI Kulldorff, Martin/H-4282-2011; OI Kulldorff, Martin/0000-0002-5284-2993 NR 24 TC 45 Z9 47 U1 0 U2 7 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 1429 DUKE ST, ALEXANDRIA, VA 22314 USA SN 1061-8600 J9 J COMPUT GRAPH STAT JI J. Comput. Graph. Stat. PD JUN PY 2006 VL 15 IS 2 BP 428 EP 442 DI 10.1198/106186006X112396 PG 15 WC Statistics & Probability SC Mathematics GA 049VB UT WOS:000238044400009 ER PT J AU Sidorov, IA Blumenthal, R Dimitrov, DS AF Sidorov, Igor A. Blumenthal, Robert Dimitrov, Dimiter S. TI A model of drug delivery to normal and cancer cells by anti body-targeted nanoliposomes SO JOURNAL OF COMPUTATIONAL AND THEORETICAL NANOSCIENCE LA English DT Article DE nanoliposome; drug delivery; cell killing; cancer ID STERICALLY STABILIZED LIPOSOMES; LONG-CIRCULATING LIPOSOMES; INTRACELLULAR DELIVERY; CYTOSOLIC DELIVERY; TUMOR-CELLS; PENETRATING PEPTIDES; TAT PEPTIDE; IN-VITRO; DOXORUBICIN; THERAPY AB A mathematical model of drug delivery to cells by antibody-conjugated liposomes is presented. The model includes variables describing concentration of free and liposome-encapsulated drug in medium, intracellular drug amount and concentration of target cells. It accounts for mechanisms of active and passive transport through cell membrane and Hill-type dependence of rate of cell death on intracellular drug amount. The model has been applied to data for cytotoxic effect of free or liposome-encapsulated doxorubicin on target melanoma cells in culture. Fitting of experimental data showed increased efficacy of 24 hours exposure with both free and liposome encapsulated doxorubicin. Simulation with parameter values after data fitting demonstrated the existence of temporary increase in intracellular amount of toxin per cell with liposome delivery, more efficient cell killing of tumor cells by liposome-encapsulated drug in culture consisting of mixture of tumor and normal cells, and non-linear dependence of therapeutic effect on drug concentration for normal and tumor cell mixture. The results may help in the design of therapeutic and diagnostic approaches. C1 NCI, CCR, Ctr Canc Res Nanobiol Program, Prot Interact Grp,NIH, Frederick, MD 21702 USA. NCI, CCR, Ctr Canc Res Nanobiol Program, Membrane Struct& Funct Sect,NIH, Frederick, MD 21702 USA. RP Sidorov, IA (reprint author), NCI, CCR, Ctr Canc Res Nanobiol Program, Prot Interact Grp,NIH, Frederick, MD 21702 USA. NR 32 TC 2 Z9 2 U1 1 U2 7 PU AMER SCIENTIFIC PUBLISHERS PI STEVENSON RANCH PA 25650 NORTH LEWIS WAY, STEVENSON RANCH, CA 91381-1439 USA SN 1546-1955 J9 J COMPUT THEOR NANOS JI J. Comput. Theor. Nanosci. PD JUN PY 2006 VL 3 IS 3 BP 405 EP 411 PG 7 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 062DD UT WOS:000238923900009 ER PT J AU Morgulis, A Gertz, EM Schaffer, AA Agarwala, R AF Morgulis, Aleksandr Gertz, E. Michael Schaffer, Alejandro A. Agarwala, Richa TI A fast and symmetric DUST implementation to mask low-complexity DNA sequences SO JOURNAL OF COMPUTATIONAL BIOLOGY LA English DT Article DE DNA database searching; sequence masking ID ALGORITHM; DATABASE; REPEATS; SEARCH AB The DUST module has been used within BLAST for many years to mask low-complexity sequences. In this paper, we present a new implementation of the DUST module that uses the same function to assign a complexity score to a sequence, but uses a different rule by which high-scoring sequences are masked. The new rule masks every nucleotide masked by the old rule and occasionally masks more. The new masking rule corrects two related deficiencies with the old rule. First, the new rule is symmetric with respect to reversing the sequence. Second, the new rule is not context sensitive; the decision to mask a subsequence does not depend on what sequences flank it. The new implementation is at least four times faster than the old on the human genome. We show that both the percentage of additional bases masked and the effect on MegaBLAST outputs are very small. C1 NCBI, NIH, DHHS, Bethesda, MD 20894 USA. RP Agarwala, R (reprint author), NCBI, NIH, DHHS, Bldg 38A,Rm 1003N,8600 Rockville Pike, Bethesda, MD 20894 USA. EM richa@helix.nih.gov RI Schaffer, Alejandro/F-2902-2012; OI Gertz, E. Michael/0000-0001-8390-4387 FU Intramural NIH HHS NR 11 TC 88 Z9 91 U1 2 U2 12 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1066-5277 J9 J COMPUT BIOL JI J. Comput. Biol. PD JUN PY 2006 VL 13 IS 5 BP 1028 EP 1040 DI 10.1089/cmb.2006.13.1028 PG 13 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 055YU UT WOS:000238488100003 PM 16796549 ER PT J AU Berger, VW AF Berger, Vance W. TI Varying the block size does not conceal the allocation SO JOURNAL OF CRITICAL CARE LA English DT Letter ID RANDOMIZATION C1 NCI, Bethesda, MD 20892 USA. Univ Maryland Baltimore Cty, Biometry Res Grp, Natl Canc Inst, Bethesda, MD 20892 USA. RP Berger, VW (reprint author), NCI, Bethesda, MD 20892 USA. EM phdvb78c@nih.gov NR 7 TC 12 Z9 12 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0883-9441 EI 1557-8615 J9 J CRIT CARE JI J. Crit. Care PD JUN PY 2006 VL 21 IS 2 BP 229 EP 229 DI 10.1016/j.jcrc.2006.01.002 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 058AN UT WOS:000238636600022 PM 16769475 ER PT J AU Magnotta, VA Friedman, L Birn, F AF Magnotta, VA Friedman, L Birn, F TI Measurement of signal-to-noise and contrast-to-noise in the fBIRN multicenter imaging study SO JOURNAL OF DIGITAL IMAGING LA English DT Article DE image quality; signal-to-noise (S/N); magnetic resonance imaging (MRI) ID HUMAN BRAIN; RELAXATION-TIMES AB The ability to analyze and merge data across sites, vendors, and field strengths depends on one's ability to acquire images with the same image quality including image smoothness, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). SNR can be used to compare different magnetic resonance scanners as a measure of comparability between the systems. This study looks at the SNR and CNR ratios in structural fast spin-echo T-2-weighted scans acquired in five individuals across ten sites that are part of Functional Imaging Research of Schizophrenia Testbed Biomedical Informatics Research Network (fBIRN). Different manufacturers, field strengths, gradient coils, and RF coils were used at these sites. The SNR of gray matter was fairly uniform (41.3-43.3) across scanners at 1.5 T. The higher field scanners produced images with significantly higher SNR values (44.5-108.7 at 3 T and 50.8 at 4 T). Similar results were obtained for CNR measurements between gray/white matter at 1.5 T (9.5-10.2), again increasing at higher fields (10.1-28.9 at 3 T and 10.9 at 4 T). C1 Univ Iowa, Dept Radiol, Iowa City, IA 52242 USA. MIND Inst, Albuquerque, NM 87106 USA. NIH, Funct Imaging Schizophrenia Testbed Biomed Inform, Natl Ctr Res Resources, Bethesda, MD 20892 USA. RP Magnotta, VA (reprint author), Univ Iowa, Dept Radiol, 0453-D JCP, Iowa City, IA 52242 USA. EM vincent-magnotta@uiowa.edu FU NCRR NIH HHS [P41RR13218, P41 RR013218] NR 22 TC 33 Z9 34 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0897-1889 J9 J DIGIT IMAGING JI J. Digit. Imaging PD JUN PY 2006 VL 19 IS 2 BP 140 EP 147 DI 10.1007/s10278-006-0264-x PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 053PQ UT WOS:000238317500008 PM 16598643 ER PT J AU Brindle, TJ Nitz, AJ Uhl, TL Kifer, E Shapiro, R AF Brindle, TJ Nitz, AJ Uhl, TL Kifer, E Shapiro, R TI Kinematic and EMG characteristics of simple shoulder movements with proprioception and visual feedback SO JOURNAL OF ELECTROMYOGRAPHY AND KINESIOLOGY LA English DT Article DE upper extremity; EMG; kinematics; kinesthesia ID SINGLE-JOINT MOVEMENTS; SPEED-INSENSITIVE STRATEGY; ORGANIZING PRINCIPLES; REACHING MOVEMENTS; MUSCLE-CONTRACTION; INERTIAL LOAD; INFORMATION; INSTABILITY; ELECTROMYOGRAPHY; COORDINATION AB The objective of this study was to determine if simple, shoulder movements use the dual control hypothesis strategy, previously demonstrated with elbow movements, and to see if this strategy also applies in the absence of visual feedback. Twenty subjects were seated with their right arm abducted to 90 degrees and externally rotated in the scapular plane. Subjects internally rotated to a target position using a custom shoulder wheel at three different speeds with and without visual feedback. Kinematics were collected with a motion analysis system and electromyographic (EMG) recordings of the pectoralis major (PECT), infraspinatus (INFRA), anterior and posterior (ADELT, PDELT) deltoid muscles were used to evaluate muscle activity patterns during movements. Kinematics changed as movement speed increased with less accuracy (p < 0.01). Greater EMG activity was observed in the PECT, PDELT, and INFRA with shorter durations for the ADELT, PDELT and INFRA. Movements with only kinesthetic feedback were less accurate (p < 0.01) and performed faster (p < 0.01) than movements with visual feedback. EMG activity suggests no major difference in CNS control strategies in movements with and without visual feedback. Greater resolution with visual feedback enables the implementation of a dual control strategy, allowing greater movement velocity while maintaining accuracy. (C) 2005 Elsevier Ltd. All rights reserved. C1 NIH, Phys Disabilities Branch, CRC, Bethesda, MD 20892 USA. Univ Kentucky, Dept Rehabil Sci, Div Phys Therapy, Lexington, KY 40536 USA. Univ Kentucky, Dept Rehabil Sci, Div Athlet Training, Lexington, KY 40536 USA. Univ Kentucky, Coll Educ, Lexington, KY 40536 USA. Univ Kentucky, Biodynam Lab, Dept Kinesiol & Hlth Promot, Lexington, KY 40536 USA. RP Brindle, TJ (reprint author), NIH, Phys Disabilities Branch, CRC, Bldg 10,Room 1-1425,MCS 1604, Bethesda, MD 20892 USA. EM tbrindle@cc.nih.gov NR 44 TC 15 Z9 15 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1050-6411 J9 J ELECTROMYOGR KINES JI J. Electromyogr. Kinesiol. PD JUN PY 2006 VL 16 IS 3 BP 236 EP 249 DI 10.1016/j.jelekin.2005.06.012 PG 14 WC Neurosciences; Physiology; Rehabilitation; Sport Sciences SC Neurosciences & Neurology; Physiology; Rehabilitation; Sport Sciences GA 049DU UT WOS:000237996800003 PM 16111896 ER PT J AU Giuliani, C Saji, M Bucci, I Fiore, G Liberatore, M Singer, DS Monaco, F Kohn, LD Napolitano, G AF Giuliani, C. Saji, M. Bucci, I. Fiore, G. Liberatore, M. Singer, D. S. Monaco, F. Kohn, L. D. Napolitano, G. TI Transcriptional regulation of major histocompatibility complex class I gene by insulin and IGF-I in FRTL-5 thyroid cells SO JOURNAL OF ENDOCRINOLOGY LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; NF-KAPPA-B; GRAVES-DISEASE; EXPRESSION; MICE; METHIMAZOLE; THYROCYTES; INTERFERON; ENHANCER; IODIDE AB Increased major histocompatibility complex (MHC) class I gene expression in nonimmune cell 'target tissues' involved in organ-specific diseases may be important in the pathogenesis of autoimmune diseases. This possibility in part evolves from studies of cultured thyrocytes where properties appear relevant to the development of thyroid autoimmune disease. In FRTL-5 rat thyroid cells in continuous culture, hormones and growth factors that regulate cell growth and function specifically decrease MHC class I gene expression. We hypothesized that this could reflect a mechanism to preserve self-tolerance and prevent autoimmune disease. The mechanisms of action of some of these hormones, namely TSH and hydrocortisone, have been already characterized. In this report, we show that IGF-I transcriptionally downregulates MHC class I gene expression and that its action is similar to that of insulin. The two hormones have a complex effect on the promoter of the MHC class I gene, PD1. In fact, they decrease the full promoter activity, but upregulate the activity of deleted mutants that have lost an upstream, tissue-specific regulatory region but still retain the enhancer A region. We show that insulin/IGF-I promotes the interactions of the p50/p65 subunits of NF-kappa B and AP-1 family members with these two regions, and that the tissue-specific region acts as a dominant silencer element on insulin/IGF-I regulation of promoter activity. These observations may be important to understand how MHC class I gene transcription is regulated in the cells. C1 Univ G dAnnunzio, Unit Endocrinol, Dept Med & Sci Aging, CeSI Gabriele annunzio Univ Fdn, I-66013 Chieti, Italy. Univ G dAnnunzio, Aging Res Ctr, CeSI Gabriele Annunzio Univ Fdn, I-66013 Chieti, Italy. Ohio State Univ, Arthur G Janes Canc Ctr, Columbus, OH 43210 USA. Ohio State Univ, Richard J Solove Res Inst, Columbus, OH 43210 USA. CeSI Gabriele Annunzio Univ Fdn, Unit Immunooncol Aging Res Ctr, Pescara, Italy. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Ohio Univ, Coll Osteopath Med, Edison Biotechnol Inst, Athens, OH 45701 USA. Ohio Univ, Coll Osteopath Med, Dept Biomed Sci, Athens, OH 45701 USA. RP Giuliani, C (reprint author), Univ G dAnnunzio, Unit Endocrinol, Dept Med & Sci Aging, CeSI Gabriele annunzio Univ Fdn, Campus Univ,Via Colle Ara, I-66013 Chieti, Italy. EM cgiulian@unich.it NR 40 TC 9 Z9 9 U1 0 U2 3 PU BIOSCIENTIFICA LTD PI BRISTOL PA 22 APEX COURT, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0022-0795 J9 J ENDOCRINOL JI J. Endocrinol. PD JUN PY 2006 VL 189 IS 3 BP 605 EP 615 DI 10.1677/joe.1.06846 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 053PE UT WOS:000238316300018 PM 16731791 ER PT J AU Walz, HA Harndahl, L Wierup, N Zmuda-Trzebiatowska, E Svennelid, F Manganiello, VC Ploug, T Sundler, F Degerman, E Ahren, B Holst, LS AF Walz, HA Harndahl, L Wierup, N Zmuda-Trzebiatowska, E Svennelid, F Manganiello, VC Ploug, T Sundler, F Degerman, E Ahren, B Holst, LS TI Early and rapid development of insulin resistance, islet dysfunction and glucose intolerance after high-fat feeding in mice overexpressing phosphodiesterase 3B SO JOURNAL OF ENDOCRINOLOGY LA English DT Article ID TYPE-2 DIABETES-MELLITUS; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; GLUCAGON-LIKE PEPTIDE-1; PROTEIN-KINASE; CELL; SECRETION; INHIBITORS; CAMP; RAT; SUPPRESSION AB Inadequate islet adaptation to insulin resistance leads to glucose intolerance and type 2 diabetes. Here we investigate whether beta-cell cAMP is crucial for islet adaptation and prevention of glucose intolerance in mice. Mice with a beta-cell-specific, 2-fold overexpression of the cAMP-degrading enzyme phosphodiesterase 3B (RIP-PDE3B/2 mice) were metabolically challenged with a high-fat diet. We found that RIP-PDE3B/2 mice early and rapidly develop glucose intolerance and insulin resistance, as compared with wild-type littermates, after 2 months of high-fat feeding. This was evident from advanced fasting hyperinsulinemia and early development of hyperglycemia, in spite of hyperinsulinemia, as well as impaired capacity of insulin to suppress plasma glucose in an insulin tolerance test. In vitro analyses of insulin-stimulated lipogenesis in adipocytes and glucose uptake in skeletal muscle did not reveal reduced insulin sensitivity in these tissues. Significant steatosis was noted in livers from high-fat-fed wild-type and RIP-PDE3B/2 mice and liver triacylglycerol content was 3-fold higher than in wild-type mice fed a control diet. Histochemical analysis revealed severe islet perturbations, such as centrally located a-cells and reduced immunostaining for insulin and GLUT2 in islets from RIP-PDE3B/2 mice. Additionally, in vitro experiments revealed that the insulin secretory response to glucagon-like peptide-1 stimulation was markedly reduced in islets from high-fat-fed RIP-PDE3B/2 mice. We conclude that accurate regulation of beta-cell cAMP is necessary for adequate islet adaptation to a perturbed metabolic environment and protective for the development of glucose intolerance and insulin resistance. C1 Lund Univ, Dept Expt Med Sci, Ctr Biomed, SE-22184 Lund, Sweden. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. Univ Copenhagen, Panum Inst, Dept Med Physiol, DK-2200 Copenhagen, Denmark. Lund Univ, Biomed Ctr, Dept Clin Sci, SE-22184 Lund, Sweden. RP Walz, HA (reprint author), Lund Univ, Dept Expt Med Sci, Ctr Biomed, C11, SE-22184 Lund, Sweden. EM helena.walz@med.lu.se RI Jones, Helena/C-8847-2013 OI Jones, Helena/0000-0002-3948-161X NR 36 TC 15 Z9 15 U1 0 U2 1 PU SOC ENDOCRINOLOGY PI BRISTOL PA 22 APEX COURT, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0022-0795 J9 J ENDOCRINOL JI J. Endocrinol. PD JUN PY 2006 VL 189 IS 3 BP 629 EP 641 DI 10.1067/joe.1.06522 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 053PE UT WOS:000238316300020 PM 16731793 ER PT J AU Matthews, G Emo, AK Funke, G Zeidner, M Roberts, RD Costa, PT Schulze, R AF Matthews, Gerald Emo, Amanda K. Funke, Gregory Zeidner, Moshe Roberts, Richard D. Costa, Paul T., Jr. Schulze, Ralf TI Emotional intelligence, personality, and task-induced stress SO JOURNAL OF EXPERIMENTAL PSYCHOLOGY-APPLIED LA English DT Article DE emotional intelligence; stress; personality; mood; performance ID TRADITIONAL STANDARDS; PERFORMANCE; VALIDITY; MODERATOR AB Emotional intelligence (EI) may predict stress responses and coping strategies in a variety of applied settings. This study compares EI and the personality factors of the Five Factor Model (FFM) as predictors of task-induced stress responses. Participants (N = 200) were randomly assigned to 1 of 4 task conditions, 3 of which were designed to be stressful. Results confirmed that low EI was related to worry states and avoidance coping, even with the FFM statistically controlled. However, EI was not specifically related to task-induced changes in stress state. Results also confirmed that Neuroticism related to distress, worry, and emotion-focused coping, and Conscientiousness predicted use of task-focused coping. The applied utility of EI and personality measures is discussed. C1 Univ Cincinnati, Dept Psychol, Cincinnati, OH 45221 USA. Univ Haifa, Dept Educ, IL-31999 Haifa, Israel. Ctr New Constructs, Educ Testing Serv, Princeton, NJ USA. NIA, Lab Personal & Cognit, NIH, Bethesda, MD 20892 USA. RP Matthews, G (reprint author), Univ Cincinnati, Dept Psychol, Cincinnati, OH 45221 USA. EM matthegd@email.uc.edu OI Costa, Paul/0000-0003-4375-1712 NR 57 TC 90 Z9 92 U1 4 U2 23 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1076-898X EI 1939-2192 J9 J EXP PSYCHOL-APPL JI J. Exp. Psychol.-Appl. PD JUN PY 2006 VL 12 IS 2 BP 96 EP 107 DI 10.1037/1076-89SX.12.2.96 PG 12 WC Psychology, Applied SC Psychology GA 059LS UT WOS:000238734900003 PM 16802891 ER PT J AU Ryder, KM Shorr, RI Tylavsky, FA Bush, AJ Bauer, DC Simonsick, EM Strotmeyer, ES Harris, TB AF Ryder, KM Shorr, RI Tylavsky, FA Bush, AJ Bauer, DC Simonsick, EM Strotmeyer, ES Harris, TB CA Hlth ABC Study TI Correlates of use of antifracture therapy in older women with low bone mineral density SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE osteoporosis; guidelines; prevention ID FRACTURE INTERVENTION TRIAL; POSTMENOPAUSAL WOMEN; HIP FRACTURE; OSTEOPOROSIS MEDICATIONS; VERTEBRAL FRACTURES; RANDOMIZED-TRIAL; RISK-FACTORS; AFRICAN-AMERICAN; ELDERLY-WOMEN; WHITE WOMEN AB BACKGROUND: Guidelines exist for treatment of low bone mineral density (BMD). Little is known about patient characteristics associated with use of treatment. OBJECTIVES: To determine patient-related correlates of medication use following screening dual x-ray absorptiometry (DXA) of older adults. DESIGN. Secondary analysis of a prospective cohort study. SETTING: Pittsburgh, PA and Memphis, TN. PARTICIPANTS: Community-dwelling women between the ages 70 and 79 years enrolled in the Health, Aging, and Body Composition (Health ABC) Study. MEASUREMENTS: Risk factors for fracture and BMD of the hip were assessed at baseline. Patients and their community physicians were supplied the results of the DXA scan. Prescription and over-the-counter medication use was collected at annual exams for 2 years. RESULTS: Of 1,584 women enrolled in Health ABC, 378 had an indication for antiffracture therapy and were not receiving such treatment at baseline. By the second annual follow-up examination, prescription antiresorptive medication was reported in 49 (13.0%), whereas 65 (17.2%) received calcium and/or vitamin D supplementation. In adjusted models, the strongest predictor for use of any antifracture medicine was presence of osteoporosis [vs osteopenia, odds ratio (OR), 2.9 (1.7 to 4.7)]. white race [OR, 2.6 (1.5 to 4.8)], and receipt of the flu shot [OR, 2.2 (1.3 to 3.8)]. Neither a history of falls nor prior fracture was associated with use of antifracture medications. CONCLUSION. Even when physicians of study participants were provided with DXA scan results, 70% of older high-functioning women with an indication for therapy did not start or remain on an antifracture therapy. Substantial room for improvement exists in fracture prevention following a diagnosis of low BMD-especially among women with a history of falls, prior fractures, and among black women. C1 Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIA, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. RP Ryder, KM (reprint author), Dept Med, Div Gen Internal Med, 66 N Pauline St,Suite 381, Memphis, TN 38163 USA. EM kryder@utmem.edu RI Strotmeyer, Elsa/F-3015-2014; OI Strotmeyer, Elsa/0000-0002-4093-6036 FU NCRR NIH HHS [K23 RR016047]; NIA NIH HHS [N01-AG-6-2106, N01-AG-6-2101, N01-AG-6-2103] NR 55 TC 10 Z9 10 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUN PY 2006 VL 21 IS 6 BP 636 EP 641 DI 10.1111/j.1525-1497.2006.00468.x PG 6 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 051FU UT WOS:000238147800016 PM 16808749 ER PT J AU Thierry-Mieg, J AF Thierry-Mieg, Jean TI Chiral-Yang-Mills theory, non commutative differential geometry, and the need for a Lie super-algebra SO JOURNAL OF HIGH ENERGY PHYSICS LA English DT Article DE differential and algebraic geometry; gauge symmetry; non-commutative geometry; BRST symmetry ID GAUGE-THEORY; HIGGS; GHOST; MODEL; SUPERCONNECTIONS; FIELDS AB In Yang-Mills theory, the charges of the left and right massless Fermions are independent of each other. We propose a new paradigm where we remove this freedom and densify the algebraic structure of Yang- Mills theory by integrating the scalar Higgs field into a new gauge-chiral 1-form which connects Fermions of opposite chiralities. Using the Bianchi identity, we prove that the corresponding covariant differential is associative if and only if we gauge a Lie-Kac super-algebra. In this model, spontaneous symmetry breakdown naturally occurs along an odd generator of the super-algebra and induces a representation of the Connes-Lott non commutative differential geometry of the 2-point finite space. C1 NCBI, Natl Lib Med, NIH, Bethesda, MD 20894 USA. CNRS, Lab Phys Theor & Astroparticules, Montpellier, France. RP Thierry-Mieg, J (reprint author), NCBI, Natl Lib Med, NIH, Bldg 38A,8600 Rockville Pl, Bethesda, MD 20894 USA. EM mieg@ncbi.nlm.nih.gov RI THIERRY-MIEG, Jean/F-1975-2017 OI THIERRY-MIEG, Jean/0000-0002-0396-6789 NR 18 TC 5 Z9 5 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1029-8479 J9 J HIGH ENERGY PHYS JI J. High Energy Phys. PD JUN PY 2006 IS 6 AR 038 PG 17 WC Physics, Particles & Fields SC Physics GA 061DB UT WOS:000238850300028 ER PT J AU Li, C Huang, TTK Cruz, M Goran, M AF Li, C Huang, TTK Cruz, M Goran, M TI Birth weight, puberty, and systolic blood pressure in children and adolescents: a longitudinal analysis SO JOURNAL OF HUMAN HYPERTENSION LA English DT Article DE systolic blood pressure; birth weight; puberty; fetal programming; paediatric; longitudinal studies ID INSULIN-RESISTANCE SYNDROME; FETAL ORIGINS HYPOTHESIS; PREPUBERTAL CHILDREN; BODY-SIZE; GROWTH; ASSOCIATION; OBESITY; DETERMINANTS; SENSITIVITY; PATTERN AB We examined the association between birth weight and systolic blood pressure (SBP) from pre-puberty to late puberty in a cohort of American children. Ninety-eight children aged 4-12 years at baseline were followed annually for 2-6 years with at least two Tanner stages. Annual measures included SBP, age, gender, race, birth weight, Tanner stage, and body composition using dual-energy X-ray absorptiometry and computed tomography. Birth weight was inversely correlated with SBP in pre-pubertal children (r = -0.23, P < 0.05), especially in white children. SBP persisted at a higher level from prepuberty through late puberty among children with low birth weight (<2500 g). However, SBP significantly increased from pre-puberty to early or late puberty among children with high birth weight (>= 4000 g). After adjusting for visceral fat, one unit change of birth weight category was associated with a 2.6 mm Hg reduction in SBP (P < 0.05), but this association was attenuated as puberty progressed. The changes in SBP across puberty followed different trajectories in children with low vs high birth weight. Attenuation in the association between birth weight and SBP from pre-puberty to late puberty may be influenced by sexual maturation. C1 Univ Kansas, Med Ctr, Dept Prevent Med & Publ Hlth, Kansas City, KS 66103 USA. NICHHD, Endocrinol Nutr & Growth Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, Coll Hlth Sci, El Paso, TX 79968 USA. Univ So Calif, Keck Sch Med, Dept Prevent Med, Inst Hlth Promot & Dis Prevent Res, Los Angeles, CA USA. RP Li, C (reprint author), Univ So Calif, Keck Sch Med, Dept Prevent Med, Inst Prevent Res, 1540 Alcazar St,Room 208-D, Los Angeles, CA 90033 USA. EM goran@hsc.usc.edu FU NCI NIH HHS [R24 CA95835-01]; NCRR NIH HHS [M01-RR-00032]; NICHD NIH HHS [R29 HD 32668, R01 HD/HL 33064] NR 39 TC 15 Z9 15 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9240 J9 J HUM HYPERTENS JI J. Hum. Hypertens. PD JUN PY 2006 VL 20 IS 6 BP 444 EP 450 DI 10.1038/sj.jhh.1002021 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 044LI UT WOS:000237673500010 PM 16617311 ER PT J AU Habib, G Basile, J Courtney, D Dart, R Einhorn, P Ellsworth, A Fendley, H Leenen, F Morrison, D Plller, L Rahman, M Simpson, L Whelton, P AF Habib, G. Basile, J. Courtney, D. Dart, R. Einhorn, P. Ellsworth, A. Fendley, H. Leenen, F. Morrison, D. Plller, L. Rahman, M. Simpson, L. Whelton, P. CA ALLHAT Collabor Res Grp TI Are ACE-inhibitors or calcium channel blockers superior to diuretics in preventing angina or peripheral arterial disease or the need for revascularization? Insights from ALLHAT SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 16th European Meeting on Hypertension CY JUN 12-15, 2006 CL Madrid, SPAIN SP European Soc Hypertens C1 Univ Texas, Sch Publ Hlth, Houston, TX USA. Michael E DeBakey VAMC, Houston, TX USA. Charleston VAMC, Charleston, SC USA. Leavenworth VAMC, Leavenworth, KS USA. Marshfield Clin Fdn Med Res & Educ, Marshfield, WI USA. NHLBI, Bethesda, MD 20892 USA. Univ Washington, Seattle, WA 98195 USA. AHEC Family Practice Ctr, Pine Bluff, AR USA. Univ Ottawa, Inst Heart, Ottawa, ON, Canada. Tucson VAMC, Tucson, AZ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 2006 VL 24 SU 4 BP S90 EP S90 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 080XE UT WOS:000240281000333 ER PT J AU Shorts, L Weiss, JM Lee, JK Welniak, LA Subleski, J Back, T Murphy, WJ Wiltrout, RH AF Shorts, L Weiss, JM Lee, JK Welniak, LA Subleski, J Back, T Murphy, WJ Wiltrout, RH TI Stimulation through CD40 on mouse and human renal cell carcinomas triggers cytokine production, leukocyte recruitment, and antitumor responses that can be independent of host CD40 expression SO JOURNAL OF IMMUNOLOGY LA English DT Article ID DENDRITIC CELLS; CD40-CD40 LIGAND; SOLID TUMORS; THERAPY; ACTIVATION; LIGATION; REQUIRES; GROWTH; CANCER; GAMMA AB CD40, a member of the TNFR superfamily, is expressed on a variety of host immune cells, as well as some tumors. In this study, we show that stimulation of CD40 expressed on both mouse and human renal carcinoma cells (RCCs) triggers biological effects in vitro and in vivo. Treatment of the CD40(+) Renca mouse RCC tumor cells in vitro with an agonistic anti-CD40 Ab induced strong expression of the genes and proteins for GM-CSF and MCP-1, and induced potent chemotactic activity. Similarly, administration of alpha CD40 to both wild-type and CD40(-/-) mice bearing Renca tumors resulted in substantial amounts of TNF-alpha and MCP-1 in the serum, increased the number of total splenocytes and MHC class II+ CD11c(+) leukocytes, and when combined with IFN-gamma, inhibited the progression of established Renca tumors in vivo in both wild-type and CD40(-/-) mice. Similarly, treatment of CD40(+) A704 and ACHN human RCC lines with mouse anti-human CD40 Ab induced strong expression of genes and proteins for MCP-1, IL-8, and GM-CSF in vitro and in vivo. Finally, in SCID mice, the numbers of ACHN pulmonary metastases were dramatically reduced by treatment with species-specific human CD40 Ab. These results show that CD40 stimulation of CD40(+) tumor cells can enhance immune responses and result in antitumor activity. C1 NCI, Expt Immunol Lab, Canc Res Ctr, Frederick, MD 21702 USA. SAIC, Intramural Res Support Program, Frederick, MD 21702 USA. Natl Inst Hlth, Natl Genome Res Inst, Seoul 122701, South Korea. Univ Nevada, Sch Med, Dept Microbiol & Immunol, Reno, NV 89557 USA. RP Wiltrout, RH (reprint author), NCI, Expt Immunol Lab, Canc Res Ctr, Bldg 560,Room 31-93, Frederick, MD 21702 USA. EM wiltroutr@ncifcrf.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, R01 CA095572, R01 CA095572-03, R01-CA-95572] NR 24 TC 14 Z9 15 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2006 VL 176 IS 11 BP 6543 EP 6552 PG 10 WC Immunology SC Immunology GA 045PN UT WOS:000237754200018 PM 16709811 ER PT J AU Mason, LH Willette-Brown, J Taylor, LS McVicar, DW AF Mason, LH Willette-Brown, J Taylor, LS McVicar, DW TI Regulation of Ly49D/DAP12 signal transduction by Src-family kinases and CD45(1,2) SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; PROTEIN-TYROSINE KINASE; AMINO-TERMINAL DOMAIN; NK CELLS; T-CELLS; FUNCTIONAL ASSOCIATION; EXTRACELLULAR DOMAINS; TARGET-CELLS; MICE LACKING; CD45 AB Activating, DAP12-coupled members of the Ly-49 family of NK cell receptors help control viral infections in mice. However, the kinases and/or phosphatases mediating tyrosine phosphorylation of Ly-49D-associated DAP12 have not been elucidated. In this study, we show for the first time that Src family tyrosine kinases are physically and functionally associated with Ly-49D/DAP12 signaling in murine NK cells. Specifically, we demonstrate the following: 1) inhibition of Src family kinases suppresses DAP12 phosphorylation and downstream DAP12 signals; 2) both Fyn and Lck are capable of phosphorylating DAP12; and 3) both kinases coimmunoprecipitate with the Ly-49D/DAP12 complex in NK cells. Although we detect enhanced phosphorylation of Fyn upon Ly-49D cross-linking in NK cells, Ly-49D-mediated events in both Fyn(-/-) and Fyn/Lck(-/-) mice appear normal, reinforcing the theme of redundancy in the ability of Src family kinases to initiate activation events. In contrast to disruption of specific Src family enzymes, Ly-49D/DAP12-mediated calcium mobilization and cytokine production by CD45 null NK cells are defective. Although others have ascribed the effects of CD45 mutation solely on the suppression of Src family activity, we demonstrate in this study that DAP12 is hyperphosphorylated in CD45 null NK cells, resulting in uncoordinated tyrosine-mediated signaling upon Ly-49D ligation. Therefore, although our data are consistent with a Src kinase activity proximally within DAP12 signaling, DAP12 also appears to be a substrate of CD45, suggesting a more complex role for this phosphatase than has been reported previously. C1 NCI, Ctr Canc Res, Expt Immunol Lab, Ft Detrick, MD 21702 USA. RP McVicar, DW (reprint author), NCI, Ctr Canc Res, Expt Immunol Lab, Bldg 560,Room 31-93, Ft Detrick, MD 21702 USA. EM mcvicar@nih.gov RI McVicar, Daniel/G-1970-2015 FU Intramural NIH HHS NR 63 TC 35 Z9 37 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2006 VL 176 IS 11 BP 6615 EP 6623 PG 9 WC Immunology SC Immunology GA 045PN UT WOS:000237754200026 PM 16709819 ER PT J AU Kan-Mitchell, J Bajcz, M Schaubert, KL Price, DA Brenchley, JM Asher, TE Douek, DC Ng, HL Yang, OO Rinaido, CR Benito, JM Bisikirska, B Hegde, R Marincola, FM Boggiano, C Wilson, D Abrams, J Blondelle, SE Wilson, DB AF Kan-Mitchell, J Bajcz, M Schaubert, KL Price, DA Brenchley, JM Asher, TE Douek, DC Ng, HL Yang, OO Rinaido, CR Benito, JM Bisikirska, B Hegde, R Marincola, FM Boggiano, C Wilson, D Abrams, J Blondelle, SE Wilson, DB TI Degeneracy and repertoire of the human HIV-1 Gag p17(77-85) CTL response SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CYTOTOXIC T-LYMPHOCYTES; CELL EFFECTOR ACTIVITY; IN-VITRO; CROSS-REACTIVITY; ESCAPE MUTATIONS; IMMUNE-RESPONSES; POPULATION-LEVEL; VIRAL LOAD; INFECTION AB CD8(+) CTL responses are important for the control of HIV-1 infection. The immunodominant HLA-A2-restricted Gag epitope, SLYNTVATL (SL9), is considered to be a poor immunogen because reactivity to it is rare in acute infection despite its paradoxical dominance in patients with chronic infection. We have previously reported SL9 to be a help-independent epitope in that it primes highly activated CTLs ex vivo from CD8(+) T cells of seronegative healthy donors. These CTLs produce sufficient cytokines for extended autocrine proliferation but are sensitive to activation-induced cell death, which may cause them to be eliminated by a proinflammatory cytokine storm. Here we identified an agonist variant of the SL9 peptide, p41 (SLYNTVAAL), by screening a large synthetic combinatorial nonapeptide library with ex vivo-primed SL9-specific T cells. p41 invariably immunized SL9-cross-reactive CTLs from other donors ex vivo and H-2Db beta(2)m double knockout mice expressing a chimeric HLA-A*0201/H2-Db MHC class I molecule. Parallel human T cell cultures showed p41-specific CTLs to be less fastidious than SL9-CTLs in the level of costimulation required from APCs and the need for exogenous IL-2 to proliferate (help dependent). TCR sequencing revealed that the same clonotype can develop into either help-independent or help-dependent CTLs depending on the peptide used to activate the precursor CD8+ T cells. Although Ag-experienced SL9-T cells from two patients were also sensitive to IL-2-mediated cell death upon restimulation in vitro, the loss of SL9 T cells was minimized with p41. This study suggests that agonist sequences can replace aberrantly immunogenic native epitopes for the rational design of vaccines targeting HIV-1. C1 Wayne State Univ, Sch Med, Karmanos Canc Inst, Detroit, MI 48201 USA. NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Dept Med & Microbiol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Immunol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Mol Genet, Los Angeles, CA 90095 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. Hosp Carlos III, Dept Mol Biol, Madrid, Spain. NIH, Immunogenet Sect, Dept Transfus Med, Bethesda, MD 20892 USA. Torrey Pines Inst Mol Studies, San Diego, CA 92121 USA. Mixture Sci Inc, San Diego, CA 92121 USA. RP Kan-Mitchell, J (reprint author), Wayne State Univ, Sch Med, Karmanos Canc Inst, HWCRC 723,110 E Warren Ave, Detroit, MI 48201 USA. EM kanmitch@karmanos.org RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 FU Medical Research Council [G108/441]; NIAID NIH HHS [R01-AI064069, R21-AI44372]; NIDA NIH HHS [R43-DA15212] NR 63 TC 22 Z9 22 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2006 VL 176 IS 11 BP 6690 EP 6701 PG 12 WC Immunology SC Immunology GA 045PN UT WOS:000237754200035 PM 16709828 ER PT J AU Mongini, PKA Inman, JK Han, H Fattah, RJ Abramson, SB Attur, M AF Mongini, PKA Inman, JK Han, H Fattah, RJ Abramson, SB Attur, M TI APRIL and BAFF promote increased viability of replicating human B2 cells via mechanism involving cyclooxygenase 2 SO JOURNAL OF IMMUNOLOGY LA English DT Review ID B-CELL DIFFERENTIATION; NECROSIS-FACTOR FAMILY; PROSTAGLANDIN E(2) RECEPTORS; DIACETATE SUCCINIMIDYL ESTER; CENTRAL-NERVOUS-SYSTEM; ACTIVATED T-CELLS; NF-KAPPA-B; TNF FAMILY; SJOGRENS-SYNDROME; DEFICIENT MICE AB Of relevance to both protective and pathogenic responses to Ag is the recent finding that soluble molecules of the innate immune system, i.e., IL-4, B cell-activation factor of the TNF family (BAFF), and C3, exhibit significant synergy in promoting the clonal expansion of human B2 cells following low-level BCR ligation. Although IL-4, BAFF, and C3dg each contribute to early cell cycle entry and progression to S phase, only BAFF promotes later sustained viability of progeny needed for continued cycling. The present study sought to further clarify the mechanisms for BAFF's multiple functions. By comparing BAFF and a proliferation-inducing ligand (APRIL) efficacy at different stages in the response (only BAFF binds BR3; both bind transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation Ag, the early role was attributed to BR3, while the later role was attributed to TACI/B cell maturation Ag. Importantly, BAFF- and APRIL-promoted viability of cycling lymphoblasts was associated with sustained expression of cyclooxygenase 2 (COX-2), the rate-limiting enzyme for PGE(2) synthesis, within replicating cells. Supernatants of cultures with BAFF and APRIL contained elevated PGE(2). Although COX-2 inhibitors diminished daughter cell viability, exogenous PGE(2) (1-1000 nM) increased the viability and recovery of lymphoblasts. Increased yield of viable progeny was associated with elevated Mcl-1, suggesting that a BAFF/APRIL -> TACI -> COX-2 -> PGE(2) -> Mcl-1 pathway reduces activation-related, mitochondrial apoptosis in replicating human B2 cell clones. C1 NYU, Hosp Joint Dis, Med Ctr, Div Rheumatol,Dept Med, New York, NY 10003 USA. NYU, Dept Pathol, Med Ctr, New York, NY 10003 USA. NIH, Immunol Lab, Bethesda, MD 20892 USA. RP Mongini, PKA (reprint author), NYU, Hosp Joint Dis, Med Ctr, Dept Rheumatol, 301 E 17th St, New York, NY 10003 USA. EM patricia.mongini@med.nyu.edu FU Intramural NIH HHS; NIAID NIH HHS [R01 AI052189] NR 115 TC 28 Z9 28 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2006 VL 176 IS 11 BP 6736 EP 6751 PG 16 WC Immunology SC Immunology GA 045PN UT WOS:000237754200040 PM 16709833 ER PT J AU Duvall, MG Jaye, A Dong, T Brenchley, JM Alabi, AS Jeffries, DJ van der Sande, M Togun, TO McConkey, SJ Douek, DC McMichael, AJ Whittle, HC Koup, RA Rowland-Jones, SL AF Duvall, Melody G. Jaye, Assan Dong, Tao Brenchley, Jason M. Alabi, Abraham S. Jeffries, David J. van der Sande, Marianne Togun, Toyin O. McConkey, Samuel J. Douek, Daniel C. McMichael, Andrew J. Whittle, Hilton C. Koup, Richard A. Rowland-Jones, Sarah L. TI Maintenance of HIV-specific CD4(+) T cell help distinguishes HIV-2 from HIV-1 infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; POLYMERASE CHAIN-REACTION; PLASMA VIRAL LOAD; WEST-AFRICA; HIV-2-INFECTED INDIVIDUALS; GASTROINTESTINAL-TRACT; CD8-T-CELL MEMORY; GAMBIAN PATIENTS; CD4-T-CELL HELP; PROVIRAL LOAD AB Unlike HIV-1-infected people, most HIV-2-infected subjects maintain a healthy CD4(+) T cell count and a strong HIV-specific CD4(+) T cell response. To define the cellular immunological correlates of good prognosis in HIV-2 infection, we conducted a crosssectional study of HIV Gag-specific T cell function in HIV-1- and HIV-2-infected Gambians. Using cytokine flow cytometry and lymphoproliferation assays, we show that HIV-specific CD4(+) T cells from HIV-2-infected individuals maintained proliferative capacity, were not terminally differentiated (CD57(-)), and more frequently produced IFN-gamma or IL-2 than CD4(+) T cells from HIV-1-infected donors. Polyfunctional (1FN-gamma(+)/1L-2(+)) HIV-specific CD4(+) T cells were found exclusively in HIV-2(+) donors. The disparity in CD4(+) T cell responses between asymptomatic HIV-1- and HIV-2-infected subjects was not associated with differences in the proliferative capacity of HIV-specific CD8(+) T cells. This study demonstrates that HIV-2-infected donors have a well-preserved and functionally heterogeneous HIV-specific memory CD4(+) T cell response that is associated with delayed disease progression in the majority of infected people. C1 MRC Labs, Banjul, Gambia. Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Human Immunol Unit,MRC, Oxford, England. NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Rowland-Jones, SL (reprint author), MRC Labs, POB 273, Banjul, Gambia. EM srowland-jones@mrc.gm RI McConkey, Samuel/E-7307-2012 FU Medical Research Council [MC_U137884180, MC_U190081958, MC_U190081962] NR 58 TC 58 Z9 60 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2006 VL 176 IS 11 BP 6973 EP 6981 PG 9 WC Immunology SC Immunology GA 045PN UT WOS:000237754200065 PM 16709858 ER PT J AU Medoff, BD Wain, JC Seung, E Jackobek, R Means, TK Ginns, LC Farber, JM Luster, AD AF Medoff, BD Wain, JC Seung, E Jackobek, R Means, TK Ginns, LC Farber, JM Luster, AD TI CXCR3 and its Ligands in a murine model of obliterative bronchiolitis: Regulation and function SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FACTOR-KAPPA-B; HEART-LUNG TRANSPLANTATION; ACUTE ALLOGRAFT-REJECTION; CHEMOKINE RECEPTOR CXCR3; GAMMA-INDUCIBLE PROTEIN; IFN-GAMMA; T-CELL; INTERFERON-GAMMA; REPERFUSION INJURY; MYD88-INDEPENDENT PATHWAY AB Lung transplantation remains the only effective therapy for patients with end-stage lung disease, but survival is limited by the development of obliterative bronchiolitis (OB). The chemokine receptor CXCR3 and two of its ligands, CXCL9 and CXCL10, have been identified as important mediators of OB. However, the relative contribution of CXCL9 and CXCL10 to the development of OB and the mechanism of regulation of these chemokines has not been well defined. In this study, we demonstrate that CXCL9 and CXCL10 are up-regulated in unique patterns following tracheal transplantation in mice. In these experiments, CXCL9 plant, while CXCL10 expression peaked at 1 day and then again 7 days posttransplant. expression peaked 7 days posttrans Expression of CXCL10 was also up-regulated in a novel murine model of lung ischemia, and in bronchoalveolar lavage fluid taken from human lungs 24 h after lung transplantation. In further analysis, we found that 3 h after transplantation CXCL10 is donor tissue derived and not dependent on IFN-gamma or STAT1, while 24 h after transplantation CXCL10 is from recipient tissue and regulated by IFN-gamma and STAT1. Expression of both CXCL9 and CXCL10 7 days posttransplant is regulated by IFN-gamma and STAT1. Finally, we demonstrate that deletion of CXCR3 in recipients reduces airway obliteration. However, deletion of either CXCL9 or obliteration. These data show that in this murine model of obliterative bronchiolitis, these che-mokines are differentially regulated following transplantation, and that deletion of either chemokine alone does not affect the development of airway obliteration. C1 Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Pulm & Crit Care Unit, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Div Thorac Surg, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Luster, AD (reprint author), Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, CNY 8301,149 13th St, Charlestown, MA 02129 USA. EM luster.andrew@mgh.harvard.edu FU NHLBI NIH HHS [K08 HL072775]; NIAID NIH HHS [R01 AI050892] NR 64 TC 35 Z9 36 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2006 VL 176 IS 11 BP 7087 EP 7095 PG 9 WC Immunology SC Immunology GA 045PN UT WOS:000237754200078 PM 16709871 ER PT J AU Bleesing, JJ Souto-Carneiro, MM Savage, WJ Brown, MR Martinez, C Yavuz, S Brenner, S Siegel, RM Horwitz, ME Lipsky, PE Malech, HL Fleisher, TA AF Bleesing, JJ Souto-Carneiro, MM Savage, WJ Brown, MR Martinez, C Yavuz, S Brenner, S Siegel, RM Horwitz, ME Lipsky, PE Malech, HL Fleisher, TA TI Patients with chronic granulomatous disease have a reduced peripheral blood memory B cell compartment SO JOURNAL OF IMMUNOLOGY LA English DT Article ID DINUCLEOTIDE PHOSPHATE OXIDASE; DISCOID LUPUS-ERYTHEMATOSUS; NADPH OXIDASE; CD27; EXPRESSION; CD40; FEATURES; MARKER; REPERTOIRE; ACTIVATION AB In this study, we have identified an altered B cell compartment in patients with chronic granulomatous disease (CGD), a disorder of phagocyte function, characterized by pyogenic infections and granuloma formation caused by defects in NADPH activity. This is characterized by an expansion of CD5-expressing B cells, and profound reduction in B cells expressing the memory B cell marker, CD27. Both findings were independent of the age, genotype, and clinical status of the patients, and were not accompanied by altered CD5 and CD27 expression on T cells. Focusing on CD27-positive B cells, considered to be memory cells based on somatically mutated Ig genes, we found that the reduction was not caused by CD27 shedding or abnormal retention of CD27 protein inside the cell. Rather, it was determined that CD27-negative B cells were, appropriately, CD27 mRNA negative, consistent with a naive phenotype, whereas CD27-positive B cells contained abundant CD27 mRNA and displayed somatic mutations, consistent with a memory B cell phenotype. Thus, it appears that CGD is associated with a significant reduction in the peripheral blood memory B cell compartment, but that the basic processes of somatic mutation and expression of CD27 are intact. X-linked carriers of CGD revealed a significant correlation between the percentage of CD27-positive B cells and the percentage of neutrophils with normal NADPH activity, reflective of the degree of X chromosome Iyonization. These results suggest a role for NADPH in the process of memory B cell formation, inviting further exploration of secondary Ab responses in CGD patients. C1 Cincinnati Childrens Hosp, Med Ctr, Div Hematol Oncol, Cincinnati, OH 45229 USA. Gulbenkian Inst Sci, P-2781 Oeiras, Portugal. NIAMSD, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NIH, Dept Lab Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Bleesing, JJ (reprint author), Cincinnati Childrens Hosp, Med Ctr, Div Hematol Oncol, MLC 7015,3333 Burnet Ave, Cincinnati, OH 45229 USA. EM jack.bleesing@cchmc.org RI Brenner, Sebastian/D-7456-2013; Souto-Carneiro, Margarida/C-4386-2016 OI Souto-Carneiro, Margarida/0000-0001-6923-0590 NR 38 TC 34 Z9 34 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2006 VL 176 IS 11 BP 7096 EP 7103 PG 8 WC Immunology SC Immunology GA 045PN UT WOS:000237754200079 PM 16709872 ER PT J AU Shipley, SM Barr, AL Graf, SJ Collins, RP McCloud, TG Newman, DJ AF Shipley, SM Barr, AL Graf, SJ Collins, RP McCloud, TG Newman, DJ TI Development of a process for the production of the anticancer lead compound pleurotin by fermentation of Hohenbuehelia atrocaerulea SO JOURNAL OF INDUSTRIAL MICROBIOLOGY & BIOTECHNOLOGY LA English DT Article; Proceedings Paper CT Symposium on Disinfectants and Microbial Control held at the Annual Meeting of the Society-for-Industrial-Microbiology CY 2004 CL Anaheim, CA SP Soc Ind Microbiol DE pleurotin; Hohenbuehelia atrocaerulea ID BASIDIOMYCETE; GROWTH AB Pleurotin is a naphthoquinone antibiotic originally isolated from Pleurotus griseus. Two pleurotin producing strains of Hohenbuehelia atrocaerulea have been identified, which, on solid substrate fermentation for 2 months yield 1-2 mg/l of the antibiotic. Described here is the lengthy developmental process which resulted in a production protocol being developed which reliably yields pleurotin from liquid fermentation at > 300 mg/l. Critical to obtaining this increase in titer was inclusion in the media of an aqueous extract of alder wood. C1 SAIC Frederick Inc, Nat Prod Support Grp, Frederick, MD 21702 USA. NCI, Dev Therapeut Program, Nat Prod Branch, Frederick, MD 21702 USA. RP McCloud, TG (reprint author), SAIC Frederick Inc, Nat Prod Support Grp, Bldg 431,Box B, Frederick, MD 21702 USA. EM mccloud@dtpax2.ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 11 TC 4 Z9 4 U1 0 U2 3 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1367-5435 J9 J IND MICROBIOL BIOT JI J. Ind. Microbiol. Biotechnol. PD JUN PY 2006 VL 33 IS 6 BP 463 EP 468 DI 10.1007/s10295-006-0089-0 PG 6 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 054LN UT WOS:000238378300009 PM 16501932 ER PT J AU Grubb, JR Dejam, A Voell, J Blackwelder, WC Sklar, PA Kovacs, JA Cannon, RO Masur, H Gladwin, MT AF Grubb, JR Dejam, A Voell, J Blackwelder, WC Sklar, PA Kovacs, JA Cannon, RO Masur, H Gladwin, MT TI Lopinavir-ritonavir: Effects on endothelial cell function in healthy subjects SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID DEPENDENT DIABETES-MELLITUS; PROTEASE INHIBITORS; NITRIC-OXIDE; DYSFUNCTION; RISK; LIPODYSTROPHY; DISEASE; HIV-1 AB To differentiate between the effects that antiretroviral drugs have on the endothelium and the secondary effects that they have on immune function, viral load, and dyslipidemia, 6 non - human immunodeficiency virus - infected human subjects were treated with lopinavir-ritonavir for 1 month and, on the basis of forearm blood flow, the treatment's effects on endothelial cell function were measured. Surprisingly, after exposure to lopinavir-ritonavir, absolute forearm blood-flow responses to the endothelium-dependent vasodilator, acetylcholine, increased significantly (P = .03), and forearm blood flow decreased to a greater extent during specific inhibition of NO synthase by NG-monomethyl-L-arginine. Thus, in this small cohort of subjects, short-term treatment with lopinavir-ritonavir does not appear to directly promote endothelial cell dysfunction. C1 NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. NIAID, Bethesda, MD 20892 USA. NIDDKD, Bethesda, MD 20892 USA. NHLBI, Vasc Med Branch, NIH, Bethesda, MD 20892 USA. RP Masur, H (reprint author), NIH, Ctr Clin, Dept Crit Care Med, Bldg 10,Rm 7043,10 Ctr Dr, Bethesda, MD 20892 USA. EM hmasur@nih.gov FU Intramural NIH HHS NR 14 TC 17 Z9 18 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 1 PY 2006 VL 193 IS 11 BP 1516 EP 1519 DI 10.1086/503807 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 038SS UT WOS:000237246700007 PM 16652279 ER PT J AU Klein, MI Coviello, S Bauer, G Benitez, A Serra, ME Schiatti, MP Delgado, MF Melendi, GA Novalli, L Pena, HG Karron, RA Kleeberger, SR Polack, FP AF Klein, MI Coviello, S Bauer, G Benitez, A Serra, ME Schiatti, MP Delgado, MF Melendi, GA Novalli, L Pena, HG Karron, RA Kleeberger, SR Polack, FP TI The impact of infection with human metapneumovirus and other respiratory viruses in young infants and children at high risk for severe pulmonary disease SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID SYNCYTIAL-VIRUS; PREMATURE-INFANTS; TRACT INFECTIONS; IMMUNE GLOBULIN; BRONCHIOLITIS; EPIDEMIOLOGY; PALIVIZUMAB; SMOKE; LIFE AB We conducted a prospective, observational study to characterize the clinical manifestations of respiratory infections caused by human metapneumovirus (hMPV) and other viruses in 194 premature infants and young children with chronic lung disease or congenital heart disease in Buenos Aires. Children had 567 episodes of respiratory illness and were monitored until they were 2 years old or until the completion of the study. hMPV elicited 12 infections (2%) year-round; 30% were of moderate or greater severity. Human parainfluenza virus type 3 caused 24 infections (4%), and 5 (25%) of 20 lung infections led to hospitalization. Respiratory syncytial virus (RSV) caused 33 episodes-17% of infections and 32% of hospitalizations during the respiratory season. None of the 10 children infected with influenza virus had severe disease. The present study of at-risk children suggests that hMPV and influenza virus are infrequent agents of severe disease and highlights the need for preventive interventions against RSV in developing countries. C1 Johns Hopkins Univ, Dept Pediat, Sch Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Int Hlth, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. Fdn INFANT, Buenos Aires, DF, Argentina. Hosp Pediat Juan P Garrahan, Buenos Aires, DF, Argentina. Maternidad Sarda, Buenos Aires, DF, Argentina. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Polack, FP (reprint author), Johns Hopkins Univ, Dept Pediat, Sch Med, 615 N Wolfe St,E5202, Baltimore, MD 21205 USA. EM fpolack@jhsph.edu FU NIAID NIH HHS [AI-054952] NR 36 TC 33 Z9 34 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 1 PY 2006 VL 193 IS 11 BP 1544 EP 1551 DI 10.1086/503806 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 038SS UT WOS:000237246700011 PM 16652283 ER PT J AU Oh, U Grant, C Griffith, C Fugo, K Takenouchi, N Jacobson, S AF Oh, U Grant, C Griffith, C Fugo, K Takenouchi, N Jacobson, S TI Reduced Foxp3 protein expression is associated with inflammatory disease during human T lymphotropic virus type 1 infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID TRANSCRIPTION FACTOR FOXP3; I PROVIRAL LOAD; HTLV-I; REGULATORY PROPERTIES; MULTIPLE-SCLEROSIS; CELL DEVELOPMENT; MYELOPATHY; ACTIVATION; FEATURES; HAM/TSP AB The Foxp3 protein is a specific marker of CD4(+)CD25(+) regulatory T (T-reg) cells, and its expression is critical to their development and function. Several studies have demonstrated the dysregulation of Foxp3 expression during human inflammatory diseases. Infection with human T lymphotropic virus type 1 (HTLV-1) is associated with the development of a number of inflammatory conditions, including myelopathy, although the majority of individuals who are infected with HTLV-1 remain asymptomatic. To examine the role played by T-reg cells in the development of inflammatory disease during HTLV-1 infection, we examined Foxp3 expression by flow cytometry. Our analysis showed that HTLV-1-associated myelopathy/tropical spastic paraparesis was associated with a lower expression ( compared with that in asymptomatic HTLV-1 carriers and healthy donors) of Foxp3 in peripheral-blood leukocytes. In individuals infected with HTLV-1, Foxp3 expression was inversely correlated with HTLV-1 tax proviral DNA load. These results suggest that impaired Foxp3 expression may contribute to the development of inflammatory disease during HTLV-1 infection. C1 NINDS, Viral Immun Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Jacobson, S (reprint author), NINDS, Viral Immun Sect, Neuroimmunol Branch, NIH, 10 Ctr Dr,Bldg 10,Rm 5B-16, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov FU Intramural NIH HHS NR 29 TC 50 Z9 52 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 1 PY 2006 VL 193 IS 11 BP 1557 EP 1566 DI 10.1086/503874 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 038SS UT WOS:000237246700013 PM 16652285 ER PT J AU Segre, JA AF Segre, Julia A. TI Epidermal differentiation complex yields a secret: Mutations in the cornification protein filaggrin underlie ichthyosis vulgaris SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID IDENTIFICATION; PROFILAGGRIN; ABSENCE; MICE AB Ichthyosis vulgaris (IV), characterized by mild scaling on limbs and lower abdomen, has an incidence of 1 in 250. Smith, McLean, and colleagues demonstrate that common mutations in filaggrin underlie IV. Filaggrin aggregates keratin intermediate filaments and is cross-linked into the cornified envelope to form the epidermal barrier. These findings reinforce the importance of the epidermal barrier in pathogenesis of skin diseases. C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Segre, JA (reprint author), NHGRI, NIH, 49 Convent Dr,Bldg 49-Room 4A26,MSC 4442, Bethesda, MD 20892 USA. EM jsegre@nhgri.nih.gov NR 11 TC 19 Z9 21 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUN PY 2006 VL 126 IS 6 BP 1202 EP 1204 DI 10.1038/sj.jid.5700367 PG 4 WC Dermatology SC Dermatology GA 062TZ UT WOS:000238968800003 PM 16702965 ER PT J AU Wang, E Voiculescu, S Le Poole, IC El-Gamil, M Li, X Sabatino, M Robbins, PF Nickoloff, BJ Marincola, FM AF Wang, Ena Voiculescu, Sonia Le Poole, Isabelle C. El-Gamil, Mona Li, Xin Sabatino, Marianna Robbins, Paul F. Nickoloff, Brian J. Marincola, Francesco M. TI Clonal persistence and evolution during a decade of recurrent melanoma SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; CELL-LINES; CYTOGENETIC CHARACTERIZATION; VACCINATION PROTOCOLS; STEM-CELLS; CANCER; INSTABILITY; EXPRESSION; ORIGIN; TUMORS AB A patient with metastatic cutaneous melanoma responsive to immunotherapy experienced several recurrences over a decade of observation. With each recurrence, biopsies were obtained and cell lines generated. A rare mutation of the beta-catenin gene and an unbalanced methylation of the androgen receptor were documented in all cell lines. Karyotyping and comparative genomic hybridization identified consistent genetic traits in spite of divergent phenotypes, suggesting that all the metastases were derived from the same primary tumor, although they were each probably not derived from the most recent previous metastasis in a sequential manner. Thus, metastatic melanoma recurs from a common progenitor cell and phenotypic changes occur around a central core of genetic stability. This observation may bear significance for the development of targeted anticancer therapies. C1 NIH, Ctr Clin, Immunogenet Sect, Dept Transfus Med, Bethesda, MD 20892 USA. Loyola Univ, Chicago Med Ctr, Skin Dis Res Program, Maywood, IL 60153 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40292 USA. RP Marincola, FM (reprint author), NIH, Ctr Clin, Immunogenet Sect, Dept Transfus Med, Bldg 10,Room 1c-711,10 Ctr Dr MSC 1502, Bethesda, MD 20892 USA. EM FMarincola@mail.cc.nih.gov FU NCI NIH HHS [P01-CA27502, P01-CA59327] NR 26 TC 41 Z9 42 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUN PY 2006 VL 126 IS 6 BP 1372 EP 1377 DI 10.1038/sj.jid.5700193 PG 6 WC Dermatology SC Dermatology GA 062TZ UT WOS:000238968800031 PM 16470173 ER PT J AU Hiebel, AC Partilla, JS Rothman, RB Jacobson, AE Rice, KC AF Hiebel, Anne-Cecile Partilla, John S. Rothman, Richard B. Jacobson, Arthur E. Rice, Kenner C. TI Synthesis of [H-3]-labelled 4-[Ethyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidi n-4-yl]amino]-2,3-[H-3]-butan-1-ol: a high affinity radioligand for the corticotropin-releasing hormone type 1 receptor SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Article DE corticotropin-releasing hormone; CRHR1 antagonist; radioligand; tritium-labelled; antalarmin ID RAT-BRAIN; NONPEPTIDE ANTAGONIST; CRF RECEPTOR; IN-VIVO; CLONING; STRESS; PITUITARY; COCAINE; INFLAMMATION; CP-154,526 AB [H-3]-Labelled 4-[ethyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-2,3-[3(H)]-butan-1-ol (3b) was prepared as a novel non-peptidic radiolabelled high affinity antagonist of the corticotropin-releasing hormone type 1 receptor (CRHR1) that could be useful as a more stable and receptor-selective alternative to the radiolabelled peptides now used to label the CRHR1 receptor for displacement studies in cell-based binding assays. The precursor (Z)-4-[ethyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]but-2-en-1-ol (2) was reduced with tritium gas using palladium as the catalyst. After HPLC purification 3b was obtained with a specific activity of 35 Ci/mmol in high radiochemical purity (> 97%). Copyright (c) 2006 John Wiley & Sons, Ltd. C1 NIDDKD, Med Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Rice, KC (reprint author), NIDDKD, Med Chem Lab, NIH, DHHS, Bldg 8,Room B1-23,8 Ctr Dr,MSC 0815, Bethesda, MD 20892 USA. EM kr21f@nih.gov NR 26 TC 1 Z9 1 U1 1 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0362-4803 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD JUN PY 2006 VL 49 IS 7 BP 635 EP 640 DI 10.1002/jlcr.1082 PG 6 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 066UG UT WOS:000239255000006 ER PT J AU Rosenberg, HF AF Rosenberg, Helene F. TI Interview with Dr. Nancy A Lee and Dr. James J Lee regarding pivotal advance: Eosinophil infiltration of solid tumors is an early and persistent inflammatory host response SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Editorial Material C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Rosenberg, HF (reprint author), NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JUN PY 2006 VL 79 IS 6 BP 1129 EP 1130 DI 10.1189/jlb.1306027 PG 2 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 119MC UT WOS:000243015400004 ER PT J AU Han, JI Huang, NN Kim, DU Kehrl, JH AF Han, Jang-Il Huang, Ning-Na Kim, Dong-Uk Kehrl, John H. TI RGS1 and RGS13 mRNA silencing in a human B lymphoma line enhances responsiveness to chemoattractants and impairs desensitization SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE B lymphocyte; calcium; chemokine ID PROTEIN-SIGNALING PROTEINS; GTPASE-ACTIVATING PROTEINS; CHEMOKINE RECEPTOR; CELL-MIGRATION; ALPHA-SUBUNITS; CHEMOTAXIS; LYMPHOCYTES; REGULATORS; RESPONSES; FAMILY AB Chemokines bind receptors that are members of the G-protein-coupled receptor family. Chemokine receptors transduce intracellular signals by activating heterotrimeric G-proteins. Acting to limit and modulate heterotrimeric G-protein signaling is a family of proteins, termed regulator of G-protein signaling (RGS). Two of these proteins, RGS1 and RGS13, are well-expressed in germinal center B cells and many Burkitt's lymphoma cell lines. Reducing RGS1 3 and to a lesser extent RGS1 expression in a Burkitt's lymphoma cell line enhances responsiveness; to two chemokines, CXC chemokine ligand 12 (CXCL12) and CXCL13, and reducing both mRNAs augments the responses more dramatically. The double knock-down (KD) cells respond better to restimulation with CXCL12 or CXCL13 after a primary stimulation with CXCL12 than do the control cells. The double-KD cells also exhibit a greater propensity to polarize and to develop multiple small lamellipodia. These results indicate that RGS1 and RGS13 act together to regulate chemokine receptor signaling in human germinal center B lymphocytes and provide evidence that they contribute significantly to the rapid desensitization of the signaling pathway. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Kehrl, JH (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 11B08,10 Ctr Dr,MSC 1876, Bethesda, MD 20892 USA. EM jkehrl@niaid.nih.gov OI Kehrl, John/0000-0002-6526-159X NR 49 TC 35 Z9 37 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JUN PY 2006 VL 79 IS 6 BP 1357 EP 1368 DI 10.1189/jlb.1105693 PG 12 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 119MC UT WOS:000243015400030 PM 16565322 ER PT J AU Khalsa, PS Eberhart, A Cotler, A Nahin, R AF Khalsa, PS Eberhart, A Cotler, A Nahin, R TI The 2005 conference on the biology of manual therapies SO JOURNAL OF MANIPULATIVE AND PHYSIOLOGICAL THERAPEUTICS LA English DT Editorial Material DE manipulation; spinal; chiropractic ID LOW-BACK-PAIN AB A historic and critically important scientific workshop for all professions involved with manual therapies was held at the National Institutes of Health (NIH) on June 9 and 10, 2005. The conference was jointly sponsored and organized by the NIH and the Canadian Institutes of Health Research and was the first ever national or international research conference to focus on the biologic mechanisms that underlie a broad range of interventions, which can be described as "manual therapies." Leading scientific experts from North America and Europe presented their latest findings and theories related to 5 different areas of science relevant to manual therapies: neuroscience, biomechanics, endocrinology, imaging, and immunology. During the conference, breakout groups composed of scientists, physicians and therapists, and patient advocates were formed in the relevant disciplines. These groups developed consensus statements on key unanswered research questions, which were then submitted back to the conference for comment and approval. The outcomes of this workshop have subsequently been incorporated into a new initiative by the NIH and Canadian Institutes of Health Research for funding research on the biology of manual therapies. This editorial includes presentation summaries and 13 key consensus recommendations relating to mechanisms of action for manual therapies. C1 NIH, Off Commun & Publ Liaison, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. NIH, Div Extramural & Res Training, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. Canadian Inst Hlth Res, Inst Neurosci Mental Hlth & Addict, Toronto, ON, Canada. RP Khalsa, PS (reprint author), NIH, Off Commun & Publ Liaison, Natl Ctr Complementary & Alternat Med, 6707 Democracy Blvd,Suite 401, Bethesda, MD 20892 USA. EM khalsap@mail.nih.gov OI Nahin, Richard/0000-0002-3682-4816 FU Intramural NIH HHS [Z99 AT999999] NR 15 TC 16 Z9 16 U1 0 U2 4 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0161-4754 J9 J MANIP PHYSIOL THER JI J. Manip. Physiol. Ther. PD JUN PY 2006 VL 29 IS 5 BP 341 EP 346 DI 10.1016/j.jmpt.2006.04.002 PG 6 WC Health Care Sciences & Services; Integrative & Complementary Medicine; Rehabilitation SC Health Care Sciences & Services; Integrative & Complementary Medicine; Rehabilitation GA 054IA UT WOS:000238368800001 PM 16762659 ER PT J AU Kim, I Huestis, MA AF Kim, Insook Huestis, Marilyn A. TI A validated method for the determination of nicotine, cotinine, trans-3'-hydroxycotinine, and norcotinine in human plasma using solid-phase extraction and liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry SO JOURNAL OF MASS SPECTROMETRY LA English DT Article DE nicotine; cotinine; trans-3'-hydroxycotinine; norcotinine; plasma ID HUMAN URINE; METABOLITES; SMOKERS; SALIVA; SERUM AB A liquid chromatographic-mass spectrometric method for the simultaneous determination of nicotine, cotinine, trans-3-hydroxycotinine, and norcotinine in human plasma was developed and validated. Analytes and deuterated internal standards were extracted from human plasma using solid-phase extraction and analyzed by liquid chromatography/atmospheric pressure chemical ionization-mass spectrometric detection with selected ion monitoring (SIM). Limits of detection and quantification were 1.0 and 2.5 ng/ml, respectively, for all analytes. Linearity ranged from 2.5 to 500 ng/ml of human plasma using a weighting factor of 1/x; correlation coefficients for the calibration curves were > 0.99. Intra- and inter-assay precision and accuracy were < 15.0%. Recoveries were 108.2-110.8% nicotine, 95.8-108.7% cotinine, 90.5-99.5% trans-3'-hydroxycotinine, and 99.5-109.5% norcotinine. The method was also partially validated in bovine serum, owing to the difficulty of obtaining nicotine-free human plasma for the preparation of calibrators and quality control (QC) samples. This method proved to be robust and accurate for the quantification of nicotine, cotinine, trans-3'-hydroxycotinine, and norcotinine in human plasma collected in clinical studies of acute nicotine effects on brain activity and on the development of neonates of maternal smokers. Copyright (c) 2006 John Wiley & Sons, Ltd. C1 NIDA, Chem & Drug Metab Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural NIH HHS NR 16 TC 30 Z9 30 U1 0 U2 4 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1076-5174 J9 J MASS SPECTROM JI J. Mass Spectrom. PD JUN PY 2006 VL 41 IS 6 BP 815 EP 821 DI 10.1002/jms.1039 PG 7 WC Biophysics; Chemistry, Organic; Spectroscopy SC Biophysics; Chemistry; Spectroscopy GA 061JF UT WOS:000238867300012 PM 16705667 ER PT J AU Biesecker, LG AF Biesecker, LG TI What you can learn from one gene: GLI3 SO JOURNAL OF MEDICAL GENETICS LA English DT Review ID PALLISTER-HALL-SYNDROME; GREIG CEPHALOPOLYSYNDACTYLY SYNDROME; CUBITUS-INTERRUPTUS PROTEIN; POLYDACTYLY TYPE-IV; ACROCALLOSAL SYNDROME; PHENOTYPE PREDICTION; MUTATIONS; DISORDERS; FAMILIES; REPRESSOR AB The study of patients with rare multiple congenital anomaly syndromes can provide illuminating insights into normal development and the pathogenesis of congenital anomalies. The GLI3 gene is a particularly good example as it illuminates the phenomena of pleiotropy, phenocopies, syndrome families, and evolutionary conservation of pathogenesis, and raises questions about how diagnoses are conceptualised. These topics are reviewed in turn, in the context of the clinical and biological data derived from patients with mutations in GLI3 and experimental work in model systems. C1 NHGRI, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, 49 Convent Dr,Room 4A80, Bethesda, MD 20892 USA. EM leslieb@helix.nih.gov FU Intramural NIH HHS NR 29 TC 40 Z9 42 U1 0 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD JUN PY 2006 VL 43 IS 6 BP 465 EP 469 DI 10.1136/jmg.2004.029181 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 048UZ UT WOS:000237973300001 PM 16740916 ER PT J AU Bendavid, C Haddad, BR Griffin, A Huizing, M Dubourg, C Gicquel, I Cavalli, LR Pasquier, L Shanske, AL Long, R Ouspenskaia, M Odent, S Lacbawan, F David, V Muenke, M AF Bendavid, C Haddad, BR Griffin, A Huizing, M Dubourg, C Gicquel, I Cavalli, LR Pasquier, L Shanske, AL Long, R Ouspenskaia, M Odent, S Lacbawan, F David, V Muenke, M TI Multicolour FISH and quantitative PCR can detect submicroscopic deletions in holoprosencephaly patients with a normal karyotype SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID SONIC-HEDGEHOG GENE; MUTATIONS; ZIC2; SHH; IDENTIFICATION; SIX3; RECOMBINATION; SPECTRUM AB Holoprosencephaly (HPE) is the most common structural malformation of the developing forebrain. At birth, nearly 50% of children with HPE have cytogenetic anomalies. Approximately 20% of infants with normal chromosomes have sequence mutations in one of the four main HPE genes (SHH, ZIC2, SIX3, and TGIF). The other non-syndromic forms of HPE may be due to environmental factors or mutations in other genes, or potentially due to submicroscopic deletions of HPE genes. We used two complementary assays to test for HPE associated submicroscopic deletions. Firstly, we developed a multicolour fluorescent in situ hybridisation (FISH) assay using probes for the four major HPE genes and for two candidate genes (DISP1 and FOXA2). We analysed lymphoblastoid cell lines (LCL) from 103 patients who had CNS findings of HPE, normal karyotypes, and no point mutations, and found seven microdeletions. We subsequently applied quantitative PCR to 424 HPE DNA samples, including the 103 samples studied by FISH: 339 with CNS findings of HPE, and 85 with normal CNS and characteristic HPE facial findings. Microdeletions for either SHH, ZIC2, SIX3, or TGIF were found in 16 of the 339 severe HPE cases (that is, with CNS findings; 4.7%). In contrast, no microdeletion was found in the 85 patients at the mildest end of the HPE spectrum. Based on our data, microdeletion testing should be considered as part of an evaluation of holoprosencephaly, especially in severe HPE cases. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Rennes 1, CNRS, UMR 6061, Grp Genet Humaine,Fac Med, Rennes, France. Georgetown Univ, Med Ctr, Inst Mol & Human Genet, Lombardi Comprehens Canc Ctr, Washington, DC USA. Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC USA. Georgetown Univ, Med Ctr, Dept Obstet & Gynecol, Washington, DC USA. Hop Sud, Unite Genet Med, Rennes, France. Childrens Hosp Montefiore, Ctr Craniofacial Disorders, Bronx, NY USA. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, 35 Convent Dr,MSC 3717,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mmuenke@nhgri.nih.gov RI Cavalli, Luciane/J-6100-2012 FU Intramural NIH HHS NR 22 TC 23 Z9 27 U1 1 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD JUN PY 2006 VL 43 IS 6 BP 496 EP 500 DI 10.1136/jmg.2005.037176 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 048UZ UT WOS:000237973300005 PM 16199538 ER PT J AU Kittles, RA Baffoe-Bonnie, AB Moses, TY Robbins, CM Ahaghotu, C Huusko, P Pettaway, C Vijayakumar, S Bennett, J Hoke, G Mason, T Weinrich, S Trent, JM Collins, FS Mousses, S Bailey-Wilson, J Furbert-Harris, P Dunston, G Powell, IJ Carpten, JD AF Kittles, RA Baffoe-Bonnie, AB Moses, TY Robbins, CM Ahaghotu, C Huusko, P Pettaway, C Vijayakumar, S Bennett, J Hoke, G Mason, T Weinrich, S Trent, JM Collins, FS Mousses, S Bailey-Wilson, J Furbert-Harris, P Dunston, G Powell, IJ Carpten, JD TI A common nonsense mutation in EphB2 is associated with prostate cancer risk in African American men with a positive family history SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID RECEPTOR GENE CAG; POPULATION STRATIFICATION; LINKAGE DISEQUILIBRIUM; ADMIXTURE DYNAMICS; GERMLINE MUTATIONS; COLORECTAL-CANCER; SRD5A2 GENE; POLYMORPHISMS; INSTABILITY; MARKERS AB Background: The EphB2 gene was recently implicated as a prostate cancer (PC) tumour suppressor gene, with somatic inactivating mutations occurring in similar to 10% of sporadic tumours. We evaluated the contribution of EphB2 to inherited PC susceptibility in African Americans (AA) by screening the gene for germline polymorphisms. Methods: Direct sequencing of the coding region of EphB2 was performed on 72 probands from the African American Hereditary Prostate Cancer Study (AAHPC). A case-control association analysis was then carried out using the AAHPC probands and an additional 183 cases of sporadic PC compared with 329 healthy AA male controls. In addition, we performed an ancestry adjusted association study where we adjusted for individual ancestry among all subjects, in order to rule out a spurious association due to population stratification. Results: Ten coding sequence variants were identified, including the K1019X (3055A -> T) nonsense mutation which was present in 15.3% of the AAHPC probands but only 1.7% of 231 European American (EA) control samples. We observed that the 3055A -> T mutation significantly increased risk for prostate cancer over twofold (Fisher's two sided test, p = 0.003). The T allele was significantly more common among AAHPC probands (15.3%) than among healthy AA male controls (5.2%) (odds ratio 3.31; 95% confidence interval 1.5 to 7.4; p = 0.008). The ancestry adjusted analyses confirmed the association. Conclusions: Our data show that the K1019X mutation in the EphB2 gene differs in frequency between AA and EA, is associated with increased risk for PC in AA men with a positive family history, and may be an important genetic risk factor for prostate cancer in AA. C1 Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Arthur G James Canc Hosp, Columbus, OH 43210 USA. Ohio State Univ, Richard J Solove Res Inst, Columbus, OH 43210 USA. Fox Chase Canc Ctr, Populat Sci Div, Human Genet Program, Philadelphia, PA 19111 USA. Translat Genom Res Inst, Genet Basis Human Dis Res Div, Phoenix, AZ USA. Howard Univ, Natl Genome Ctr, Washington, DC 20059 USA. Univ Texas, MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. Univ Calif Davis, Dept Radiat Oncol, Ctr Canc, Sacramento, CA 95817 USA. Midtown Urol Surg Ctr, Atlanta, GA USA. Columbia Univ, Med Ctr, Dept Urol, New York, NY USA. Univ Illinois, Dept Urol, Chicago, IL USA. Med Coll Georgia, Sch Nursing, Augusta, GA 30912 USA. NHGRI, Bethesda, MD 20892 USA. NIH, Ctr Inherited Dis Res, Baltimore, MD USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. RP Kittles, RA (reprint author), Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Arthur G James Canc Hosp, 494 Med Res Facil,420 W 120th Ave, Columbus, OH 43210 USA. EM pkittles.2@osu.edu OI Bailey-Wilson, Joan/0000-0002-9153-2920 FU Intramural NIH HHS; NCI NIH HHS [1U54CA91431-01, CA-06927, U54 CA091431]; NHGRI NIH HHS [1-HG-75418] NR 45 TC 36 Z9 38 U1 1 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD JUN PY 2006 VL 43 IS 6 BP 507 EP 511 DI 10.1136/jmg.2005.035790 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 048UZ UT WOS:000237973300007 PM 16155194 ER PT J AU Kang, JH Benzaria, S Sigano, DM Lewin, NE Pu, YM Peach, ML Blumberg, PM Marquez, VE AF Kang, Ji-Hye Benzaria, Samira Sigano, Dina M. Lewin, Nancy E. Pu, Yongmei Peach, Megan L. Blumberg, Peter M. Marquez, Victor E. TI Conformationally constrained analogues of diacylglycerol. 26. Exploring the chemical space surrounding the C1 domain of protein kinase C with DAG-lactones containing aryl groups at the sn-1 and sn-2 positions SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID 5-DISUBSTITUTED TETRAHYDRO-2-FURANONE TEMPLATE; HIGH BINDING-AFFINITY; CYSTEINE-RICH REGION; PHORBOL ESTER; PK-C; LIGANDS; DELTA; DESIGN; GROWTH; ALPHA AB Diacylglycerol lactones (DAG-lactones) are known to operate as effective agonists of protein kinase C (PKC), surpassing in potency the activity of natural diacylglycerol (DAG). Localization of activated PKC isozymes in the cell is determined in part by the different cellular scaffolds, the lipid composition of the specific membranes, and the targeting information intrinsic to the individual isoforms bound to DAG. This multifaceted control of diversity suggests that, to develop effective DAG-lactones capable of honing in on a specific cellular target, we need to gain a better understanding of the chemical space surrounding its binding site. Seeking to augment the chemical repertoire of DAG-lactone side chains that could steer the translocation of PKC to specific cellular domains, we report herein the effects of incorporating simple or substituted phenyl residues. A combined series of n-alkyl and phenyl substitutions were used to explore the optimal location of the phenyl group on the side chains. The substantial differences in binding affinity between DAG-lactones with identical functionalized phenyl groups at either the sn-1 or sn-2 position are consistent with the proposed binding model in which the DAG-lactone binds to the C1 domain of PKC with the acyl chain oriented toward the interior of the membrane and the alpha-alkylidene or alpha-arylalkylidene chains directed to the surface of the C1 domain adjacent to the lipid interface. We conclude that DAG-lactones containing alpha-phenylalkylidene side chains at the sn-2 position represent excellent scaffolds upon which to explore further chemical diversity. C1 NCI, Ctr Canc Res, Med Chem Lab, NIH, Frederick, MD 21702 USA. NCI, Ctr Canc Res, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. RP Marquez, VE (reprint author), NCI, Ctr Canc Res, Med Chem Lab, NIH, Frederick, MD 21702 USA. EM marquezv@mail.nih.gov RI Sigano, Dina/M-6144-2014 OI Sigano, Dina/0000-0001-7489-9555 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 42 TC 11 Z9 11 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUN 1 PY 2006 VL 49 IS 11 BP 3185 EP 3203 DI 10.1021/jm060011o PG 19 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 046SX UT WOS:000237832400019 PM 16722637 ER PT J AU Goblyos, A Gao, ZG Brussee, J Connestari, R Santiago, SN Ye, K IJzerman, AP Jacobson, KA AF Goblyos, Aniko Gao, Zhan-Guo Brussee, Johannes Connestari, Roberto Santiago, Sabrina Neves Ye, Kai IJzerman, Adriaan P. Jacobson, Kenneth A. TI Structure-activity relationships of new 1H-imidazo[4,5-c]quinolin-4-amine derivatives as allosteric enhancers of the A(3) adenosine receptor SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID AGONIST BINDING; MUSCARINIC RECEPTORS; A(1) RECEPTOR; MODULATION; 2-AMINO-3-BENZOYLTHIOPHENES; HYPERPARATHYROIDISM; ANTAGONISTS; ACTIVATION; MECHANISMS; TARGETS AB 1H-Imidazo[4,5-c] quinolin-4-amine derivatives have been synthesized as allosteric modulators of the human A(3) adenosine receptor (AR). Structural modifications were made at the 4-amino and 2 positions. The compounds were tested in both binding and functional assays, and many were found to be allosteric enhancers of the action of A(3)AR agonists by several different criteria. First, a potentiation of the maximum efficacy of the agonist Cl-IB-MECA was observed for numerous derivatives. Also, a number of these compounds decreased the rate of dissociation of the agonist [I-125]I-AB-MECA from the A(3)AR. Most prominently, compound 43 (LUF6000) was found to enhance agonist efficacy in a functional assay by 45% and decrease dissociation rate similarly without influencing agonist potency. The structural requirements for allosteric enhancement at the A(3)AR were distinct from the requirements to inhibit equilibrium binding. Thus, we have prepared allosteric enhancers of the human A(3)AR that have an improved allosteric effect in comparison to the inhibition of equilibrium binding at the orthosteric site. C1 NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Leiden Univ, Leiden Amsterdam Ctr Drug Res, Div Med Chem, NL-2300 RA Leiden, Netherlands. RP IJzerman, AP (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM ijzerman@lacdr.leidenuniv.nl; kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009; Ye, Kai/B-3640-2012; OI Jacobson, Kenneth/0000-0001-8104-1493; IJzerman, Ad/0000-0002-1182-2259 FU Intramural NIH HHS [Z01 DK031117-20] NR 36 TC 30 Z9 32 U1 2 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD JUN 1 PY 2006 VL 49 IS 11 BP 3354 EP 3361 DI 10.1021/jm060086s PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 046SX UT WOS:000237832400036 PM 16722654 ER PT J AU Sergeev, N Distler, M Vargas, M Chizhikov, V Herold, KE Rasooly, A AF Sergeev, N Distler, M Vargas, M Chizhikov, V Herold, KE Rasooly, A TI Microarray analysis of Bacillus cereus group virulence factors SO JOURNAL OF MICROBIOLOGICAL METHODS LA English DT Article DE microarray; microbial detection; microbial pathogen ID MULTIPLE SEQUENCE ALIGNMENT; HEMOLYSIN-BL; OLIGONUCLEOTIDE MICROARRAY; ANTHRAX TOXIN; PROTECTIVE ANTIGEN; ENTEROTOXIN GENES; GENOME SEQUENCE; RIBOSOMAL-RNA; STRAINS; PCR AB Bacillus cereus, B. thuringiensis and B. anthracis are closely related medically and economically important bacterial species that belong to the B. cereus group. Members of the B. cereus group carry genes encoding several important virulence factors, including enterotoxins, phospholipases and exotoxins. Since it is difficult to differentiate among B. cereus group members, and because Bacillus virulence factors are very important for pathogenesis, we explored the use of microarray-based detection of virulence factor genes as a tool for strain identification and for determining virulence. Our method requires an initial multiplex PCR amplification step, followed by identification of the PCR amplicons by hybridization to an oligonucleotide microarray containing genes for all three types of Bacillus virulence factors including B. anthracis virulence factors. The DNA chip described here contains 21 identical arrays used for analysis of seven samples in triplicates. Using the arrays, we found that virulence factors are present in several combinations in the strains analyzed. This work also demonstrates the potential of oligonucleotide microarrays for medical, food safety and biodefense analysis of microbial pathogens. Published by Elsevier B.V. C1 NCI, NIH, Rockville, MD 20852 USA. US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. Univ Maryland, College Pk, MD 20742 USA. US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP Rasooly, A (reprint author), NCI, NIH, 6130 Execut Blvd,EPN,Room 6035A, Rockville, MD 20852 USA. EM rasoolya@mail.nih.gov NR 62 TC 42 Z9 47 U1 1 U2 6 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 JUN PY 2006 VL 65 IS 3 BP 488 EP 502 DI 10.1016/j.mimet.2005.09.013 PG 15 WC Biochemical Research Methods; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 050DU UT WOS:000238068500012 PM 16242802 ER PT J AU Volpi, S Liu, Y Aguilera, G AF Volpi, S Liu, Y Aguilera, G TI Vasopressin increases GAGA binding activity to the V1b receptor promoter through transactivation of the MAP kinase pathway SO JOURNAL OF MOLECULAR ENDOCRINOLOGY LA English DT Article ID CORTICOTROPIN-RELEASING FACTOR; GROWTH-FACTOR RECEPTOR; ARGININE-VASOPRESSIN; TRANSCRIPTIONAL REGULATION; STRESS-ADAPTATION; DOWN-REGULATION; GENE; RAT; PROTEIN; SECRETION AB Previous studies show that binding of nuclear proteins to GAGA repeats (GAGA box) in the vasopressin type 1b receptor (V1bR) promoter is essential for transcriptional initiation of the gene. To determine whether increased vasopressin (VP) during stress activates V1bR expression through the GAGA box, we examined the effects of VP on GAGA binding activity and on the ability of the V1bR promoter to recruit RNA polymerase in the hypothalamic cell line, H32. In chromatin immunoprecipitation assays, VP induced RNA polymerase II recruitment by the wild type V1bR promoter but not by a construct with the major GAGA box deletion. VP (10 min) also increased binding of nuclear proteins to radiolabeled GAGA oligonucleotides in electromobility shift assays. VP-induced GAGA binding activity was potentiated by the protein kinase C inhibitor, calphostin C, and was prevented by the MEK inhibitor, UO126, and the epidermal growth factor receptor (EGFR) inhibitor, AG1478, suggesting that VP activates GAGA binding through transactivation of the EGFR. This was confirmed by western blot experiments showing rapid increases in phospho ERK after incubation with VP, an effect that was potentiated by calphostin C and inhibited by UO12 and AG1478, as well as by the ability of VP to phosphorylate the EGFR. Using receptor selective VP analogs we showed that both V1aR and V1bR subtypes can mediate GAGA binding activation in H32 cells. This study demonstrates that VP stimulates GAGA binding to the V1bR promoter through transactivation of the EGFR and MAP kinase. The data support the hypothesis that VP contributes to pituitary V1bR upregulation during stress through GAGA binding-mediated transcriptional activation. C1 NICHHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Aguilera, G (reprint author), NICHHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. EM Greti-Aguilera@nih.gov NR 36 TC 9 Z9 9 U1 0 U2 0 PU SOC ENDOCRINOLOGY PI BRISTOL PA 22 APEX COURT, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0952-5041 J9 J MOL ENDOCRINOL JI J. Mol. Endocrinol. PD JUN PY 2006 VL 36 IS 3 BP 581 EP 590 DI 10.1677/jme.1.01995 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 053PF UT WOS:000238316400015 PM 16720725 ER PT J AU Palkovits, M Kunos, G AF Palkovits, M. Kunos, G. TI Chemical analysis of individual brain nuclei microdissected in the Human Brain Tissue Bank, Budapest: concentrations of endocannabinoids in the human brain SO JOURNAL OF NEURAL TRANSMISSION LA English DT Meeting Abstract C1 Semmelweis Univ, H-1085 Budapest, Hungary. Natl Inst Hlth, Bethesda, MD USA. RI Palkovits, Miklos/F-2707-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0300-9564 J9 J NEURAL TRANSM JI J. Neural Transm. PD JUN PY 2006 VL 113 IS 6 BP V EP V PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 050PM UT WOS:000238100400028 ER PT J AU Chung, S Shin, BS Hedlund, E Pruszak, J Ferree, A Kang, UJ Isacson, O Kim, KS AF Chung, S Shin, BS Hedlund, E Pruszak, J Ferree, A Kang, UJ Isacson, O Kim, KS TI Genetic selection of sox1GFP-expressing neural precursors removes residual tumorigenic pluripotent stem cells and attenuates tumor formation after transplantation SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE embryonic stem cell; fluorescence-activated cell sorting; neural precursors; sox1; transplantation ID CENTRAL-NERVOUS-SYSTEM; DOPAMINERGIC-NEURONS; MOUSE EMBRYOS; IN-VITRO; PARKINSONS-DISEASE; RAT MODEL; DIFFERENTIATION; FETAL; MICE; PURIFICATION AB Because of their ability to proliferate and to differentiate into diverse cell types, embryonic stem (ES) cells are a potential source of cells for transplantation therapy of various diseases, including Parkinson's disease. A critical issue for this potential therapy is the elimination of undifferentiated cells that, even in low numbers, could result in teratoma formation in the host brain. We hypothesize that an efficient solution would consist of purifying the desired cell types, such as neural precursors, prior to transplantation. To test this hypothesis, we differentiated sox1-green fluorescent protein (GFP) knock-in ES cells in vitro, purified neural precursor cells by fluorescence-activated cell sorting (FACS), and characterized the purified cells in vitro as well as in vivo. Immunocytofluorescence and RT-PCR analyses showed that this genetic purification procedure efficiently removed undifferentiated pluripotent stem cells. Furthermore, when differentiated into mature neurons in vitro, the purified GFP(+) cell population generated enriched neuronal populations, whereas the GFP(-) population generated much fewer neurons. When treated with dopaminergic inducing signals such as sonic hedgehog (SHH) and fibroblast growth factor-8 (FGF8), FACS-purified neural precursor cells responded to these molecules and generated dopaminergic neurons as well as other neural subtypes. When transplanted, the GFP(+) cell population generated well contained grafts containing dopaminergic neurons, whereas the GFP(-) population generated significantly larger grafts (about 20-fold) and frequent tumor-related deaths in the transplanted animals. Taken together, our results demonstrate that genetic purification of neural precursor cells using FACS isolation can effectively remove unwanted proliferating cell types and avoid tumor formation after transplantation. C1 Harvard Univ, Sch Med, McLean Hosp, Neuroregenerat Labs, Belmont, MA 02178 USA. McLean Hosp, Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA USA. Harvard Univ, Sch Med, Mol Neurobiol Lab, Belmont, MA USA. Univ Chicago, Dept Neurol, Chicago, IL 60637 USA. RP Kim, KS (reprint author), Harvard Univ, Sch Med, McLean Hosp, Neuroregenerat Labs, MRC 216,115 Mill St, Belmont, MA 02178 USA. EM kskim@mclean.harvard.edu RI Pruszak, Jan/G-6972-2015; OI Pruszak, Jan/0000-0003-4297-4009; Hedlund, Eva/0000-0001-6347-0075 FU NIMH NIH HHS [MH48866, R01 MH048866, R29 MH048866]; NINDS NIH HHS [P50 NS039793-07, P50 NS039793, P50 NS39793] NR 50 TC 97 Z9 100 U1 1 U2 9 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2006 VL 97 IS 5 BP 1467 EP 1480 DI 10.1111/j.1471-4159.2006.03841.x PG 14 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 042GU UT WOS:000237516700023 PM 16696855 ER PT J AU Hardy, J Orr, H AF Hardy, John Orr, Harry TI The genetics of neurodegenerative diseases SO JOURNAL OF NEUROCHEMISTRY LA English DT Review DE ataxia; dementia; parkinsonism; polyglutamine; alpha-synuclein; tau ID AMYOTROPHIC-LATERAL-SCLEROSIS; PARKINSONISM-DEMENTIA COMPLEX; POLYGLUTAMINE-INDUCED DISEASE; VALOSIN-CONTAINING PROTEIN; BULBAR MUSCULAR-ATROPHY; TRANSGENIC MOUSE MODEL; AMYLOID-BETA-PROTEIN; FRONTOTEMPORAL DEMENTIA; ALZHEIMERS-DISEASE; ALPHA-SYNUCLEIN AB In the last 50 years, an enormous amount of progress has been made in dissecting the etiology of hereditary neurodegenerative diseases, including the dementias, the parkinsonisms, the ataxias and the motor-neuron diseases. In addition, these genetic findings are beginning to provide insights into the pathogeneses of the sporadic forms of the diseases. Through animal and cellular modeling studies we are beginning to gain insights into the pathogenic pathways to disease. This mechanistic understanding is now leading to therapeutic strategies based on this new understanding. As yet, however, no mechanistic therapies are in use in the clinic. C1 NIA, Neurogenet Lab, Bethesda, MD 20892 USA. UCL Natl Hosp Neurol & Neurosurg, Reta Lila Weston Inst Neurol Studies, London, England. Univ Minnesota, Dept Biochem, Dept Lab Med & Pathol, Minneapolis, MN USA. Univ Minnesota, Inst Human Genet, Minneapolis, MN 55455 USA. RP Hardy, J (reprint author), NIA, Neurogenet Lab, Porter Neurosci Bldg,35 Convent Dr, Bethesda, MD 20892 USA. EM hardyj@mail.nih.gov RI Hardy, John/C-2451-2009 FU Intramural NIH HHS; Medical Research Council [G0701075]; Parkinson's UK [G-0907] NR 74 TC 42 Z9 42 U1 1 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2006 VL 97 IS 6 BP 1690 EP 1699 DI 10.1111/j.1471-4159.2006.03979.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 051EP UT WOS:000238144200013 PM 16805777 ER PT J AU Petzold, A Keir, G Kay, A Kerr, M Thompson, EJ AF Petzold, A. Keir, G. Kay, A. Kerr, M. Thompson, E. J. TI Axonal damage and outcome in subarachnoid haemorrhage SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID COMMUNICATING ARTERY ANEURYSM; GOOD NEUROLOGICAL RECOVERY; NEURON-SPECIFIC ENOLASE; CEREBROSPINAL-FLUID; S-100 PROTEIN; PSYCHOSOCIAL OUTCOMES; APOLIPOPROTEIN-E; BRAIN-INJURY; SERUM S100B; SCALE AB Background: On the basis of preliminary evidence from patients with subarachnoid haemorrhage (SAH), axonal degeneration is thought to be an underestimated pathological feature. Methods: A longitudinal study in 17 patients with aneurysmal SAH. Ventricular CSF was collected daily for up to 14 days. The neurofilament heavy chain(SMI35) (NfH(SMI35), a biomarker for axonal damage) was quantified using a standard ELISA (upper limit of normal 0.73 ng/ml). The primary outcome measure was the Glasgow Outcome Score (GOS) at 3 months. Results: Of 148 samples from patients with SAH, pathologically high NfH levels in the CSF were found in 78 (52.7%) samples, compared with 20 (5%) of 416 samples from the reference population (p < 0.0001). A pathological increase in NfH was observed in all patients with a bad outcome (GOS 1-3) compared with 8% of those with a good outcome (GOS 4-5, p < 0.0001). This increase typically became significant 7 days after the haemorrhage (p < 0.01). The result was confirmed by analysing the individual mean NfH concentrations in the CSF (3.45 v 0.37 ng/ml, p < 0.01), and was reinforced by the inverse correlation of NfH in the CSF with the GOS (r = -0.65, p < 0.01). Severity of injury was found to be correlated to NfH(SMI35) levels in the CSF (World Federation of Neurological Surgeons, r = 0.63, p < 0.01 and Glasgow Coma Score, r = -0.61, p < 0.01). Conclusion: Patients with SAH thus have secondary axonal degeneration, which may adversely affect their outcome. C1 UCL Natl Hosp Neurol & Neurosurg, Inst Neurol, Dept Neuroimmunol, London WC1N 3BG, England. UCL Natl Hosp Neurol & Neurosurg, Tavistock Intens Care Unit, London WC1N 3BG, England. Univ Hosp Birmingham, Birmingham, W Midlands, England. NINR, NIH, Bethesda, MD 20892 USA. RP Petzold, A (reprint author), UCL Natl Hosp Neurol & Neurosurg, Inst Neurol, Dept Neuroimmunol, Queen Sq, London WC1N 3BG, England. EM a.petzold@ion.ucl.ac.uk RI Petzold, Axel/C-1090-2009 OI Petzold, Axel/0000-0002-0344-9749 NR 47 TC 29 Z9 30 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD JUN PY 2006 VL 77 IS 6 BP 753 EP 759 DI 10.1136/jnnp.2005.085175 PG 7 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 043HK UT WOS:000237591000014 PM 16705199 ER PT J AU Cassiani-Ingoni, R Cabral, ES Lunemann, JD Garza, Z Magnus, T Gelderblom, H Munson, PJ Marques, A Martin, R AF Cassiani-Ingoni, Riccardo Cabral, Erik S. Luenemann, Jan D. Garza, Zoila Magnus, Tim Gelderblom, Harald Munson, Peter J. Marques, Adriana Martin, Roland TI Borrelio burgdorferi induces TLR1 and TLR2 in human microglia and peripheral blood monocytes but differentially regulates HLA-class II expression SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE glia; HLA class II; Lyme disease; microglia; monocyte; outer surface protein A; toll-like receptor ID CENTRAL-NERVOUS-SYSTEM; ADAPTIVE IMMUNE-RESPONSES; BRAIN DENDRITIC CELLS; TUMOR-NECROSIS-FACTOR; TOLL-LIKE RECEPTORS; LYME-DISEASE; MYCOBACTERIUM-TUBERCULOSIS; MULTIPLE-SCLEROSIS; GENE-EXPRESSION; CUTTING EDGE AB The spirochete Borrelia burgdorferi is the agent of Lyme disease, which causes central nervous system manifestations in up to 20% of patients. We investigated the response of human brain microglial cells, glial progenitors, neurons, astrocytes, as well as peripheral blood monocytes to stimulation with B. burgdorferi. We used oligoarrays to detect changes in the expression of genes important for shaping adaptive and innate immune responses. We found that stimulation with B. burgdorferi lysate increased the expression of Toll-like receptors (TLRs) 1 and 2 in all cell types except neurons. However, despite similarities in global gene profiles of monocytes and microglia, only microglial cells responded to the stimulation with a robust increase in HLA-DR, HLA-DQ, and also coexpressed CD11-c, a dendritic cell marker. In contrast, a large number of HLA-related molecules were repressed at both the RNA and the protein levels in stimulated monocytes, whereas secretion of IL-10 and TNF-alpha was strongly induced. These results show that signaling through TLR1/2 in response to B. burgdorferi can elicit opposite immunoregulatory effects in blood and in brain immune cells, which could play a role in the different susceptibility of these compartments to infection. C1 Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, Cellular Immunol Sect, Bethesda, MD USA. Ctr Informat Technol, Math & Stat Comp Lab, Anal Biostat Sect, Bethesda, MD USA. NIA, Neurosci Lab, Stem Cell Biol Unit, Bethesda, MD 20892 USA. NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. Univ Roma La Sapienza, Ctr Excellence Biol & Mol Med, Dept Human Physiol & Pharmacol, Rome, Italy. RP Cassiani-Ingoni, R (reprint author), Bldg 10,Room 5B06,10 Ctr Dr, Bethesda, MD 20892 USA. EM cassianr@ninds.nih.gov RI Lunemann, Jan/G-8729-2011 OI Lunemann, Jan/0000-0002-3007-708X FU Intramural NIH HHS NR 58 TC 19 Z9 19 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2006 VL 65 IS 6 BP 540 EP 548 PG 9 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 100TP UT WOS:000241692100002 PM 16783164 ER PT J AU Lanuza, MA Gizaw, R Viloria, A Gonzalez, CM Besalduch, N Dunlap, V Tomas, J Nelson, PG AF Lanuza, MA Gizaw, R Viloria, A Gonzalez, CM Besalduch, N Dunlap, V Tomas, J Nelson, PG TI Phosphorylation of the nicotinic acetylcholine receptor in myotube-cholinergic neuron Cocultures SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE acetylcholine receptor; AChR; cyclic AMP-dependent protein kinase; neuromuscular junction; phosphorylation; PKC ID PROTEIN-KINASE-C; EMBRYONIC RAT MOTONEURONS; SRC-FAMILY KINASES; NEUROMUSCULAR-JUNCTION; MUSCLE-CELLS; IN-VITRO; TYROSINE PHOSPHORYLATION; AMPA RECEPTOR; PHORBOL ESTER; DELTA-SUBUNIT AB Acetylcholine receptor (AChR) stability in the postsynaptic membrane is affected by serine kinases. AChR are phosphorylated by protein kinase C (PKC) and PKA, and we have shown that activation of PKA and PKC have opposite effects on AChR stability and that this may play some role in the selective, activity-dependent synapse loss that occurs during development of the neuromuscular junction. Myotube cultures with and without added spinal motor neurons were probed with immunoaffinity-purified antibodies prepared against phosphorylated peptides with amino acid sequences from different AChR subunits. Different treatments activating PKC (phorbol 12-myristate 13-acetate; PMA) or PKA (dibutyryl cyclic adenosine monophosphate; cAMP) or blocking electrical activity (tetrodotoxin; TTX) of the cocultures were chosen because of their known effects, direct or indirect, on receptor stability. We asked whether the phospho-specific antibody staining in conjunction with alpha-bungarotoxin (BTX) identification of AChR aggregates could provide a direct demonstration of changes in receptor phosphorylation produced by the treatments. We found that PMA treatment did increase phosphorylation of the delta subunit and cAMP increased phosphorylation of the epsilon subunit relative to total BTX labeling in muscle-nerve cocultures, but not in muscle-only cultures. Blockade of electrical activity with TTX increased the incidence of aggregates that showed no phospho-epsilon staining. Myotube cultures grown in the absence of neurons did not show the responses of myotubes in cocultures. The results show that manipulations that alter receptor stability also produce changes in receptor phosphorylation. We suggest that phosphorylation may be a mechanism mediating the changes in receptor-stability. (c) 2006 Wiley-Liss, Inc. C1 Univ Rovira & Virgili, Fac Med & Ciencies Salut, Unitat Histol & Neurobiol, E-43201 Reus, Spain. NICHHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Lanuza, MA (reprint author), Univ Rovira & Virgili, Fac Med & Ciencies Salut, Unitat Histol & Neurobiol, C St Llorenc 21, E-43201 Reus, Spain. EM mariaangel.lanuza@urv.net NR 32 TC 10 Z9 10 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JUN PY 2006 VL 83 IS 8 BP 1407 EP 1414 DI 10.1002/jnr.20848 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 051QX UT WOS:000238176800003 PM 16555299 ER PT J AU Lee, J Kim, SJ Son, TG Chan, SL Mattson, MP AF Lee, J Kim, SJ Son, TG Chan, SL Mattson, MP TI Interferon-gamma is up-regulated in the hippocampus in response to intermittent fasting and protects hippocampal neurons against excitotoxicity SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE dietary restriction; cytokines; ribonuclease protection assay; glutamate; calcium ID DIETARY RESTRICTION; NEURODEGENERATIVE DISORDERS; CALCIUM HOMEOSTASIS; NEUROTROPHIC FACTOR; CYTOKINE RESPONSES; BRAIN-DAMAGE; ADULT MICE; CELLS; RECEPTOR; DIFFERENTIATION AB Dietary restriction (DR) increases the life span of many different organisms, and recent findings have demonstrated neuroprotective effects of DR in rodent and nonhuman primate models of neurodegenerative disorders. The neuroprotective mechanism of action of DR is unknown, but it may result from a mild cellular stress response involving increased production of neurotrophic factors. Because several different cytokines are known to be up-regulated in brain cells in response to stress, we determined whether DR affected cytokine expression in the rat brain. Levels of expression of interferon-gamma (IFN-gamma) and its receptor were significantly increased in the hippocampus of rats that had been maintained on an intermittent fasting DR regimen compared with rats on the ad libitum control diet. Pretreatment of embryonic rat hippocampal cell cultures with IFN-gamma protected neurons against glutamate-induced death. IFN-gamma-mediated neuroprotection was associated with an enhanced recovery of intracellular Ca2+ concentrations following exposure to glutamate. Our data show that intermittent fasting DR stimulates IFN-gamma-mediated neuroprotective signaling in the hippocampus, suggesting a role for this cytokine in the previously reported ability of DR to protect neurons in animal models of severe epileptic seizures, stroke, and neurodegenerative disorders. (c) 2006 Wiley-Liss, Inc. C1 Pusan Natl Univ, Coll Pharm, Dept Pharm, Pusan 609735, South Korea. Pusan Natl Univ, Longev Life Sci Inst, Res Inst Drug Dev, Pusan 609735, South Korea. Pusan Natl Univ, Inst Technol, Res Inst Drug Dev, Pusan 609735, South Korea. NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Lee, J (reprint author), Pusan Natl Univ, Coll Pharm, Dept Pharm, Pusan 609735, South Korea. EM neuron@pusan.ac.kr RI Mattson, Mark/F-6038-2012; Lee, Jaewon/N-9064-2013 FU Intramural NIH HHS NR 37 TC 23 Z9 23 U1 2 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JUN PY 2006 VL 83 IS 8 BP 1552 EP 1557 DI 10.1002/jnr.20831 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 051QX UT WOS:000238176800018 PM 16521127 ER PT J AU Yates, JR Heyes, MP Blight, AR AF Yates, Jennifer R. Heyes, Melvyn P. Blight, Andrew R. TI 4-Chloro-3-hydroxyanthranilate reduces local quinolinic acid synthesis, improves functional recovery, and preserves white matter after spinal cord injury SO JOURNAL OF NEUROTRAUMA LA English DT Article DE guinea pig; inflammation; kynurenine pathway; macrophage; neurotoxin; spinal cord trauma ID SYSTEMIC IMMUNE ACTIVATION; KYNURENINE PATHWAY METABOLISM; TRANSIENT CEREBRAL-ISCHEMIA; RECEPTOR-MEDIATED TOXICITY; TRAUMATIC BRAIN-INJURY; CONVERT L-TRYPTOPHAN; CEREBROSPINAL-FLUID; GLIAL-CELLS; 3-HYDROXYANTHRANILIC ACID; MORPHOMETRIC ANALYSIS AB Inflammatory processes within the central nervous system (CNS) contribute significantly to the pathogenesis of a broad range of neurologic diseases, including spinal cord injury (SCI). One mechanism by which immune activation causes neurologic symptoms and tissue injury is via the production of neurotoxins by activated macrophages and microglia. In the present study, the role of the endogenous tryptophan metabolite and neurotoxin quinolinic acid (QUIN) in secondary pathology following traumatic SCI was investigated. Adult Hartley guinea pigs were injured by lateral compression of the spinal cord at the 12th thoracic segment (T12). QUIN had accumulated at the site of injury on day 12 post-injury in proportion to the severity of functional neurologic deficits (as assessed by the cutaneus trunci muscle reflex and motor function score at 5 h post-injury). Systemic administration of the 3-hydroxyanthranilate-3,4-dioxygenase (3-HAD) inhibitor, 4-chloro-3-hydroxyanthranilate (4Cl-3HAA; approximately 100 mg/kg every 12 h, beginning 5 h after injury) attenuated local QUIN production and reduced QUIN accumulation at the site of injury by approximately 50% at day 12, without enhanced accumulations of the neuroprotective metabolite kynurenic acid (KYNA). The severity of secondary functional deficits was also reduced by 4Cl-3HAA. In toluidine blue-stained spinal cord sections, the area of surviving intact white matter at the injury site was increased by approximately 100% in the 4Cl-3HAA-treated group. Sparing of both axons and myelin contributed to this increase. These results support the conclusion that QUIN accumulations at the site of injury contribute to secondary functional deficits and tissue damage following SCI. C1 Univ N Carolina, Curriculum Neurobiol, Chapel Hill, NC USA. Univ N Carolina, Div Neurosurg, Chapel Hill, NC USA. NIMH, Lab Neurotoxicol, Bethesda, MD 20892 USA. RP Yates, JR (reprint author), Colby Coll, Dept Psychol, 5550 Mayflower Hill Dr, Waterville, ME 04901 USA. EM jryates@colby.edu FU NINDS NIH HHS [NS-21122] NR 60 TC 10 Z9 10 U1 0 U2 5 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 JUN PY 2006 VL 23 IS 6 BP 866 EP 881 DI 10.1089/neu.2006.23.866 PG 16 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 056TW UT WOS:000238549000004 PM 16774472 ER PT J AU Goodkin, K Vitiello, B Lyman, WD Asthana, D Atkinson, JH Heseltine, PNR Molina, R Zheng, WL Khamis, I Wilkie, FL Shapshak, P AF Goodkin, Karl Vitiello, Benedetto Lyman, William D. Asthana, Deshratn Atkinson, J. Hampton Heseltine, Peter N. R. Molina, Rebeca Zheng, Wenli Khamis, Imad Wilkie, Frances L. Shapshak, Paul TI Cerebrospinal and peripheral human immunodeficiency virus type 1 load in a multisite, randomized, double-blind, placebo-controlled trial of D-Ala(1)-peptide T-amide for HIV-1-associated cognitive-motor impairment SO JOURNAL OF NEUROVIROLOGY LA English DT Article DE CSF; clinical trial; cognition; DAPTA; HIV; peptide T; viral load ID HIV-1 MONITOR TEST; PEPTIDE-T; VIRAL LOAD; ANTIRETROVIRAL DRUGS; VERSION 1.5; INFECTION; RNA; COUNT; FLUID; OCTAPEPTIDES AB D-Ala 1 -peptide T-amide (DAPTA) has shown neuroprotection in vitro against gp120-induced loss of dendritic arborization and is promulgated as a CCR5 antagonist. A multisite, randomized, double-blind clinical trial of DAPTA versus placebo prior to combination antiretroviral therapy conducted with human immunodeficiency virus (HIV)-1 seropositive participants having cognitive impairment showed no overall cognitive effect, though subgroups with greater impairment and CD4 cell counts of 201 to 500 cells/mm 3 at baseline showed significant improvement. The objective of this study was to examine whether intranasal administration of DAPTA at a dose of 2 mg three times per day (tid) was associated with a reduction of cerebrospinal fluid (CSF) and peripheral (plasma and serum) viral load among a subgroup of participants completing 6 months of treatment. Baseline and 6-month CSF (n = 92) and peripheral (plasma n = 33; serum n = 24) viral load were measured by the Roche Ultrasensitive assay, version 1.5, with reflexive use of the AMPLICOR assay and preservation of the blind. A DAPTA treatment indicator variable was tested using generalized linear models on change in viral load. Peripheral load (combined plasma and serum) was significantly reduced in the DAPTA-treated group. No group differences in CSF viral load were found. This retrospective study on a limited subgroup of the original trial sample indicated that DAPTA treatment may reduce peripheral viral load without concomitant CSF effects. Future studies should be undertaken to confirm the existence of this result and the CSF-periphery dissociation observed with respect to HIV-1-associated cognitive-motor impairment. C1 Univ Miami, Sch Med, Dept Psychiat & Behav Sci, Miami, FL 33136 USA. Univ Miami, Sch Med, Dept Neurol, Miami, FL 33136 USA. Univ Miami, Sch Med, Dept Pathol, Miami, FL 33136 USA. NIMH, Child & Adolescent Treatment & Prevent Intervent, Bethesda, MD 20892 USA. Childrens Hosp Michigan, Childrens Res Ctr Michigan, Detroit, MI 48201 USA. Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. Univ Calif San Diego, Dept Psychiat, HIV Neurobehav Res Ctr, San Diego, CA 92103 USA. Quest Diagnost Nichols Inst, Div Infect Dis, San Juan Capistrano, CA USA. RP Goodkin, K (reprint author), Univ Miami, Sch Med, Dept Psychiat & Behav Sci, 1400 NW 10th Ave,803-A, Miami, FL 33136 USA. EM KGoodkin@med.miami.edu FU NIMH NIH HHS [N01MH00013, N01MH20007, N01MH20004] NR 44 TC 7 Z9 9 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD JUN PY 2006 VL 12 IS 3 BP 178 EP 189 DI 10.1080/13550280600827344 PG 12 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 069MN UT WOS:000239451800004 PM 16877299 ER PT J AU Shankar, LK Hoffman, JM Bacharach, S Graham, MM Karp, J Lammertsma, AA Larson, S Mankoff, DA Siegel, BA den Abbeele, A Yap, J Sullivan, D AF Shankar, LK Hoffman, JM Bacharach, S Graham, MM Karp, J Lammertsma, AA Larson, S Mankoff, DA Siegel, BA den Abbeele, A Yap, J Sullivan, D TI Consensus recommendations for the use of F-18-FDG PET as an indicator of therapeutic response in patients in national cancer institute trials SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; STANDARDIZED UPTAKE VALUE; BRAIN TRANSFER CONSTANTS; TIME UPTAKE DATA; FDG-PET; GRAPHICAL EVALUATION; FLOW-CYTOMETRY; BREAST-CANCER; SERUM GLUCOSE; LUNG-CANCER C1 NCI, Canc Imaging Program, NIH, Bethesda, MD 20892 USA. Univ Utah, Sch Med, Huntsman Canc Inst, Div Nucl Med, Salt Lake City, UT USA. Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. Univ Iowa, Dept Radiol, Div Nucl Med, Iowa City, IA 52242 USA. Univ Penn, Dept Radiol, Div Nucl Med, Philadelphia, PA 19104 USA. Vrije Univ Amsterdam, Dept Nucl Med & PET Res, NL-1081 HV Amsterdam, Netherlands. Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. Univ Washington, Div Nucl Med, Seattle, WA 98195 USA. Washington Univ, Med Ctr, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. RP Shankar, LK (reprint author), NCI, Canc Imaging Program, NIH, 6130 Execut Blvd,Room 6048, Bethesda, MD 20892 USA. EM shankarl@mail.nih.gov RI Mankoff, David/F-9576-2010 NR 32 TC 416 Z9 429 U1 2 U2 9 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 JUN PY 2006 VL 47 IS 6 BP 1059 EP 1066 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 050RE UT WOS:000238104800028 PM 16741317 ER PT J AU Fernstrom, JD Mudd, SH AF Fernstrom, JD Mudd, SH TI The 5th workshop on the assessment of adequate intake of dietary amino acids: General discussion 1 SO JOURNAL OF NUTRITION LA English DT Editorial Material C1 Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Sch Med, UPMC Weight Management Ctr, Pittsburgh, PA 15261 USA. NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Fernstrom, JD (reprint author), Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15261 USA. EM fernstromjd@upmc.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOCIETY NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUN PY 2006 VL 136 IS 6 SU S BP 1711S EP 1715S PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 049CP UT WOS:000237993400013 PM 16702344 ER PT J AU Bekris, LM Viernes, HMA Farin, FM Maier, LA Kavanagh, TJ Takaro, TK AF Bekris, LM Viernes, HMA Farin, FM Maier, LA Kavanagh, TJ Takaro, TK TI Chronic beryllium disease and glutathione biosynthesis genes SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID GAMMA-GLUTAMYLCYSTEINE SYNTHETASE; IDIOPATHIC PULMONARY-FIBROSIS; LIGASE CATALYTIC SUBUNIT; EPITHELIAL PERMEABILITY; MYOCARDIAL-INFARCTION; INDUCED APOPTOSIS; OXIDATIVE STRESS; ASSOCIATION; CELLS; POLYMORPHISM AB Objective: Because glutathione (GSH) has been reported to be increased in chronic beryllium disease (CBD) and is associated With immune modulation, associations between CBD and gene polymorphisms of the rate-limiting enzyme in GSH synthesis, glutamate cysteine ligase (GCL), were investigated. Glutamate cysteine ligase consists of a catalytic subunit (GCLC) and modifier subunit (GCLAM). Methods: Patients with CBD, beryllium-sensitized subjects (BeS), and beryllium-exposed subjects without CBD were genotyped for the GCLC GAG trinucleotide repeat polymorphism (GCLC TNR), the GCLC-129 single nucleotide polymorphism (SAP), and the GCLM-588 SAP. Results: Results indicate that GCLC TNR genotype 717 is negatively associated with CBD (odds ratio [OR] = 0.28, 95% confidence interval [CI] = 0.08-0.95) and the GCLM-588 C/C SNP genotype is associated with CBD susceptibility (OR = 3.07, 95% CI = 1.00-9.37). No differences were noted in the BeS group. Conclusions: This study suggests that GSH modulation may play a role in CBD pathogenesis, but not in sensitization to beryllium. C1 Univ Washington, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA. Univ Washington, NIEHS, Ctr Ecogenet & Environm Hlth, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Natl Jewish Med & Res Ctr, Dept Med, Denver, CO USA. RP Takaro, TK (reprint author), Univ Washington, Dept Environm & Occupat Hlth Sci, Box 354695, Seattle, WA 98195 USA. EM ttakaro@sfu.ca FU NIEHS NIH HHS [1T32ES07032, P30ES07033, 1P42ES04696] NR 44 TC 13 Z9 13 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD JUN PY 2006 VL 48 IS 6 BP 599 EP 606 DI 10.1097/01.jom.0000201845.02369.ba PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 053UV UT WOS:000238332100008 PM 16766924 ER PT J AU Kleta, R AF Kleta, Robert TI A deeper look into cysteamine absorption for the treatment of cystinosis SO JOURNAL OF PEDIATRICS LA English DT Editorial Material ID NEPHROPATHIC CYSTINOSIS; CHILDREN; THERAPY C1 Natl Human Genome Res Inst, Sect Human Biochem Genet, Med Genet Branch, Off Rare Dis,NIH, Bethesda, MD 20892 USA. RP Kleta, R (reprint author), Natl Human Genome Res Inst, Sect Human Biochem Genet, Med Genet Branch, Off Rare Dis,NIH, Bethesda, MD 20892 USA. EM kletar@mail.nih.gov NR 11 TC 4 Z9 4 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JUN PY 2006 VL 148 IS 6 BP 718 EP 719 DI 10.1016/j.jpeds.2006.03.048 PG 2 WC Pediatrics SC Pediatrics GA 053UZ UT WOS:000238332500005 PM 16769374 ER PT J AU Higgins, RD AF Higgins, Rosemary D. TI 50 years ago in The Journal of Pediatrics - Incidence of retrolental fibroplasias: Past and present SO JOURNAL OF PEDIATRICS LA English DT Editorial Material C1 NICHHD, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, NIH, Bethesda, MD 20892 USA. RP Higgins, RD (reprint author), NICHHD, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JUN PY 2006 VL 148 IS 6 BP 778 EP 778 DI 10.1016/j.jpeds.2006.04.020 PG 1 WC Pediatrics SC Pediatrics GA 053UZ UT WOS:000238332500016 ER PT J AU Li, SM Campbell, BL Katz, JL AF Li, SM Campbell, BL Katz, JL TI Interactions of cocaine with dopamine uptake inhibitors or dopamine releasers in rats discriminating cocaine SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID STIMULUS PROPERTIES; RHESUS-MONKEYS; NONHUMAN-PRIMATES; MESOLIMBIC DOPAMINE; SQUIRREL-MONKEYS; BEAGLE DOGS; FIXED-RATIO; GBR-12909; DRUGS; SCHEDULE AB Several dopamine (DA) indirect agonists have been proposed as potential medications for treating cocaine abuse. The objective of the present study was to quantify the interactions among cocaine and DA uptake inhibitors or DA releasers to better understand how these drugs may be working when administered in combination. The DA uptake inhibitors GBR 12909 [1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}- 4-(3-phenylpropyl)piperazine], WIN 35,428 [2 beta-carbomethoxy-3 beta-(4-fluorophenyl) tropane], methylphenidate, indatraline, nomifensine, and mazindol and DA releasers methamphetamine, d-amphetamine, methcathinone, cathinone, fencamfamine, and phentermine were examined alone and in combination with cocaine in rats trained to discriminate cocaine (10 mg/kg i.p.) from saline injections. All of the DA indirect agonists dose-dependently substituted for cocaine and shifted the cocaine dose-effect curve leftward. Isobolographic analysis indicated the interactions were generally additive, although both methamphetamine and d-amphetamine were quantitatively determined to be more potent than DA uptake inhibitors in shifting the cocaine dose- effect function to the left. The potential of d-amphetamine as an effective treatment for cocaine abuse and negative clinical results with dopamine uptake inhibitors suggest that differences in shifts in dose-effect curves should be further examined with emerging clinical data as a predictive index of potential treatments for cocaine abuse. C1 Natl Inst Drug Abuse, Intramural Res Program, Psychobiol Sect, Dept Hlth & Human Serv,NIH, Baltimore, MD 21224 USA. RP Katz, JL (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Psychobiol Sect, Dept Hlth & Human Serv,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM jkatz@intra.nida.nih.gov OI Katz, Jonathan/0000-0002-1068-1159 FU Intramural NIH HHS NR 41 TC 33 Z9 34 U1 1 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUN PY 2006 VL 317 IS 3 BP 1088 EP 1096 DI 10.1124/jpet.105.100594 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 044AE UT WOS:000237643600020 PM 16478825 ER PT J AU Faucette, SR Sueyoshi, T Smith, CM Negishi, M LeCluyse, EL Wang, HB AF Faucette, SR Sueyoshi, T Smith, CM Negishi, M LeCluyse, EL Wang, HB TI Differential regulation of hepatic CYP2B6 and CYP3A4 genes by constitutive androstane receptor but not pregnane X receptor SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID DISTAL ENHANCER MODULE; ADULT-RAT HEPATOCYTES; NUCLEAR RECEPTOR; TRANSCRIPTIONAL ACTIVATION; XENOBIOTIC RESPONSE; DRUG-METABOLISM; CAR; INDUCTION; EXPRESSION; LIVER AB Accumulated evidence suggests that cross-talk between the pregnane X receptor (PXR) and the constitutive androstane receptor ( AR) results in shared transcriptional activation of CYP2B and CYP3A genes. Although most data imply symmetrical cross-regulation of these genes by rodent PXR and CAR, the actual selectivities of the corresponding human receptors are unknown. The objective of this study was to evaluate the symmetry of human (h) PXR and hCAR cross-talk by comparing the selectivities of these receptors for CYP2B6 and CYP3A4. Human hepatocyte studies revealed nonselective induction of both CYP2B6 and CYP3A4 by hPXR activation but marked preferential induction of CYP2B6 by selective hCAR activation. Gel shift assays demonstrated that hPXR exhibited strong and relatively equal binding to all functional response elements in both CYP2B6 and CYP3A4 genes, whereas hCAR displayed significantly weak binding to the CYP3A4 proximal ER6 motif. In cell-based transfection assays, hCAR displayed greater activation of CYP2B6 reporter gene expression compared with CYP3A4 with constructs containing both proximal and distal regulatory elements. Furthermore, in agreement with binding observations, transfection assays using promoter constructs containing repeats of CYP2B6 DR4 and CYP3A4 ER6 motifs revealed an even greater difference in reporter activation by hCAR. In contrast, hPXR activation resulted in less discernible differences between CYP2B6 and CYP3A4 reporter gene expression. These results suggest asymmetrical cross-regulation of CYP2B6 and CYP3A4 by hCAR but not hPXR in that hCAR exhibits preferential induction of CYP2B6 relative to CYP3A4 because of its weak binding and functional activation of the CYP3A4 ER6. C1 Univ N Carolina, Sch Pharm, Div Mol Pharmaceut, Chapel Hill, NC 27599 USA. NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC USA. CellzDirect Inc, Pittsboro, NC USA. RP Wang, HB (reprint author), Univ N Carolina, Sch Pharm, Div Mol Pharmaceut, Chapel Hill, NC 27599 USA. EM wang4@email.unc.edu OI LeCluyse, Edward/0000-0002-2149-8990 FU NIDDK NIH HHS [DK061652] NR 39 TC 107 Z9 110 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUN PY 2006 VL 317 IS 3 BP 1200 EP 1209 DI 10.1124/jpet.105.098160 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 044AE UT WOS:000237643600033 PM 16513849 ER PT J AU Jutkiewicz, EM Baladi, MG Folk, JE Rice, KC Woods, JH AF Jutkiewicz, EM Baladi, MG Folk, JE Rice, KC Woods, JH TI The convulsive and electroencephalographic changes produced by nonpeptidic delta-opioid agonists in rats: Comparison with pentylenetetrazol SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID SPRAGUE-DAWLEY RATS; FREELY-MOVING RATS; ANTIDEPRESSANT TREATMENTS; RECEPTOR AGONISTS; SQUIRREL-MONKEYS; INDUCED SEIZURES; MODELS; BW373U86; OPIATE; SNC80 AB delta-Opioid agonists produce convulsions and antidepressant-like effects in rats. It has been suggested that the antidepressant-like effects are produced through a convulsant mechanism of action either through overt convulsions or nonconvulsive seizures. This study evaluated the convulsive and seizurogenic effects of nonpeptidic delta-opioid agonists at doses that previously were reported to produce antidepressant-like effects. In addition, delta-opioid agonist-induced electroencephalographic (EEG) and behavioral changes were compared with those produced by the chemical convulsant pentylenetetrazol (PTZ). For these studies, EEG changes were recorded using a telemetry system before and after injections of the delta-opioid agonists [(+)-4-[(alpha R)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl) methyl]-N,N-diethylbenz (SNC80) and [(+)-4-[alpha(R)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide [(+)-BW373U86]. Acute administration of nonpeptidic delta-opioid agonists produced bilateral ictal and paroxysmal spike and/or sharp wave discharges. delta-Opioid agonists produced brief changes in EEG recordings, and tolerance rapidly developed to these effects; however, PTZ produced longer-lasting EEG changes that were exacerbated after repeated administration. Studies with antiepileptic drugs demonstrated that compounds used to treat absence epilepsy blocked the convulsive effects of nonpeptidic delta-opioid agonists. Overall, these data suggest that delta-opioid agonist-induced EEG changes are not required for the antidepressant-like effects of these compounds and that neural circuitry involved in absence epilepsy may be related to delta-opioid agonist-induced convulsions. In terms of therapeutic development, these data suggest that it may be possible to develop delta-opioid agonists devoid of convulsive properties. C1 Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. NIDDKD, Med Chem Lab, NIH, Bethesda, MD USA. RP Jutkiewicz, EM (reprint author), Univ Michigan, Sch Med, Dept Pharmacol, 1301 Med Sci Res Bldg 3, Ann Arbor, MI 48109 USA. EM ejutkiew@umich.edu FU NIDA NIH HHS [DA00254, T32 DA07267]; NIGMS NIH HHS [T32 GM07767] NR 35 TC 29 Z9 31 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUN PY 2006 VL 317 IS 3 BP 1337 EP 1348 DI 10.1124/jpet.105.095810 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 044AE UT WOS:000237643600048 PM 16537798 ER PT J AU Zahn, R Schwarz, M Huber, W AF Zahn, Roland Schwarz, Michael Huber, Walter TI Functional activation studies of word processing in the recovery from aphasia SO JOURNAL OF PHYSIOLOGY-PARIS LA English DT Review DE aphasia; recovery; functional magnetic resonance imaging; positron emission tomography; magnetic resonance imaging; language ID TRANSCORTICAL SENSORY APHASIA; POSITRON-EMISSION-TOMOGRAPHY; CORTICAL LANGUAGE ACTIVATION; CEREBRAL-BLOOD-FLOW; POSTSTROKE APHASIA; NONFLUENT APHASIA; WERNICKES APHASIA; RIGHT-HEMISPHERE; PET ACTIVATION; BRAIN PLASTICITY AB Some reviews on theories of recovery in aphasia put an emphasis on neural network models based on empirical data from evoked-potentials in aphasia as an approach to mapping recovery of cognitive function to neural structure. We will focus here on what we call an 11 anatomical" approach to look at recovery in aphasia. "Anatomical" theories of recovery stated by classical aphasiologists have contributed to the understanding of language representations in the human brain. But many aspects of these theories can only be investigated by using modern techniques of lesion analysis, psychometric assessment and functional imaging. Whereas structure-function relations have been primarily established by looking for the association of deficit symptoms with certain lesions, functional activation methods offer a means to study more directly the functional anatomy of recovered or retained functions in neuropsychological patients. To falsify or build up anatomical theories of recovery we will propose a stepwise approach of inference. The methodological pitfalls of this approach will be discussed by focussing on anatomical hypotheses of semantic word comprehension and its impairment and recovery in aphasia. (c) 2006 Elsevier Ltd. All rights reserved. C1 Univ Techol Aachen, Rhein Westfal TH Aachen, Dept Neurol, Aachen, Germany. Univ Techol Aachen, Rhein Westfal TH Aachen, Neurolinguist Sect, Aachen, Germany. Univ Freiburg, Dept Psychiat & Psychotherapy, D-7800 Freiburg, Germany. Univ Technol Aachen, Rhein Westfal TH Aachen, Neurolinguist Sect, Aachen, Germany. RP Zahn, R (reprint author), NINDS, NIH, Cognit Neurosci Sect, Bldg 10,5C206,10 Ctr Dr,MSC 1440, Bethesda, MD 20892 USA. EM zahnr@ninds.nih.gov RI Zahn, Roland/C-4665-2008 OI Zahn, Roland/0000-0002-8447-1453 NR 102 TC 16 Z9 16 U1 2 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0928-4257 J9 J PHYSIOL-PARIS JI J. Physiol.-Paris PD JUN PY 2006 VL 99 IS 4-6 BP 370 EP 385 DI 10.1016/j.jphysparis.2006.03.013 PG 16 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 060BC UT WOS:000238775200008 PM 16730169 ER PT J AU Culp, WD Neal, R Massey, R Egevad, L Pisa, P Garland, D AF Culp, WD Neal, R Massey, R Egevad, L Pisa, P Garland, D TI Proteomic analysis of tumor establishment and growth in the B16-F10 mouse melanoma model SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE proteomics; melanoma; tumor progression; cathepsin D; albumin; VEGF ID 2-DIMENSIONAL GEL-ELECTROPHORESIS; CATHEPSIN-D; B16 MELANOMA; ALBUMIN CATABOLISM; BLOOD-VESSELS; IN-VIVO; CELLS; CANCER; ANGIOGENESIS; MECHANISMS AB The B16-F10 mouse model of melanoma is a widely used model to study many aspects of cancer biology and therapeutics in a solid tumor. Melanomas aggressively progress within a dynamic microenvironment containing in addition to tumor cells, stroma cells and components such as fibroblasts, immune cells, vascular cells, extracellular matrix (ECM) and extracellular molecules. The goal of this study was to elucidate the processes of tumor progression by identifying differentially expressed proteins in the tumor mass during specific stages of tumor growth. A comparative proteome analysis was performed on B16-F10 derived tumors in C57BL/6 mice at days 3, 5, 7, and 10. Statistical approaches were used to determine quantitative differential protein expression at each tumor time stage. Hierarchical clustering of 44 protein spots (p < 0.01) revealed a progressive change in the tumor mass when all 4 time stages were classified together, but there was a clear switch in expression of these proteins between the day 5 and the day 7 tumors. A trend analysis showed 53 protein spots (p < 0.001) following 6 predominant kinetic paths of expression as the tumor progressed. The protein spots were then identified using MALDI-TOF mass spectrometry. Proteins involved in glycolysis, inflammation, wounding, superoxide metabolism, and chemotaxis increased during tumorigenesis. From day 3 to day 7 VEGF and active cathepsin D were induced 7-fold and 4-fold, respectively. Proteins involved in electron transport, protein folding, blood coagulation, and transport decreased during tumorigenesis. This work illustrates changes in the biology of the B16-F10 tumor mass during tumor progression. C1 NEI, Prot Biochem Sect, NIH, Bethesda, MD 20892 USA. Tumor Res Inst, Washington, DC USA. Karolinska Hosp Inst, Canc Ctr Karolinska, Dept Pathol & Oncol, S-17176 Stockholm, Sweden. RP Culp, WD (reprint author), NEI, Prot Biochem Sect, NIH, 7 Mem Dr,Bldg 7 Room 237, Bethesda, MD 20892 USA. EM culpd@nei.nih.gov OI Egevad, Lars/0000-0001-8531-222X FU Intramural NIH HHS NR 49 TC 26 Z9 27 U1 2 U2 6 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 JUN PY 2006 VL 5 IS 6 BP 1332 EP 1343 DI 10.1021/pr060059q PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 048VA UT WOS:000237973400005 PM 16739985 ER PT J AU Woods, AS Ugarov, M Jackson, SN Egan, T Wang, HYJ Murray, KK Schultz, JA AF Woods, AS Ugarov, M Jackson, SN Egan, T Wang, HYJ Murray, KK Schultz, JA TI IR-MALDI-LDI combined with ion mobility orthogonal time-of-flight mass spectrometry SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE ion-mobility MALDI; UV lasers; IR lasers; adducts reduction ID ASSISTED-LASER-DESORPTION/IONIZATION; MATRIX; DESORPTION; IONIZATION AB Most MALDI instrumentation uses UV lasers. We have designed a MALDI-IM-oTOF-MS which employs both a Nd:YAG laser pumped optical parametric oscillator (OPOTEK, lambda = 2.8- 3.2 mu m at 20 Hz) to perform IR-LDI or IR-MALDI and a Nd:YLF laser (Crystalaser, lambda = 249 nm at 200 Hz) for the UV. Ion mobility (IM) gives a fast separation and analysis of biomolecules from complex mixtures in which ions of similar chemical type fall along well-defined " trend lines". Our data shows that ion mobility allows multiply charged monomers and multimers to be resolved; thus, yielding pure spectra of the singly charged protein ion which are virtually devoid of chemical noise. In addition, we have demonstrated that IR-LDI produced similar results as IR-MALDI for the direct tissue analysis of phospholipids from rat brain. C1 NIDA, IRP, NIH, Baltimore, MD 21224 USA. Ionwerks Inc, Houston, TX 77005 USA. Louisiana State Univ, Baton Rouge, LA 70803 USA. RP Woods, AS (reprint author), NIDA, IRP, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov OI Murray, Kermit/0000-0002-4976-2263 FU Intramural NIH HHS [Z99 DA999999]; NCRR NIH HHS [1R43RR020238-01, R43 RR020238]; NIDA NIH HHS [N44DA-3-7727]; PHS HHS [HHSN271200477384C] NR 14 TC 18 Z9 20 U1 2 U2 14 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 JUN PY 2006 VL 5 IS 6 BP 1484 EP 1487 DI 10.1021/pr0600551 PG 4 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 048VA UT WOS:000237973400020 PM 16740000 ER PT J AU Cardis, E Howe, G Ron, E Bebeshko, V Bogdanova, T Bouville, A Carr, Z Chumak, V Davis, S Demidchik, Y Drozdovitch, V Gentner, N Gudzenko, N Hatch, M Ivanov, V Jacob, P Kapitonova, E Kenigsberg, Y Kesminiene, A Kopecky, KJ Kryuchkov, V Loos, A Pinchera, A Reiners, C Repacholi, M Shibata, Y Shore, RE Thomas, G Tirmarche, M Yamashita, S Zvonova, I AF Cardis, E Howe, G Ron, E Bebeshko, V Bogdanova, T Bouville, A Carr, Z Chumak, V Davis, S Demidchik, Y Drozdovitch, V Gentner, N Gudzenko, N Hatch, M Ivanov, V Jacob, P Kapitonova, E Kenigsberg, Y Kesminiene, A Kopecky, KJ Kryuchkov, V Loos, A Pinchera, A Reiners, C Repacholi, M Shibata, Y Shore, RE Thomas, G Tirmarche, M Yamashita, S Zvonova, I TI Cancer consequences of the Chernobyl accident: 20 years on SO JOURNAL OF RADIOLOGICAL PROTECTION LA English DT Review ID POWER-STATION ACCIDENT; IN-UTERO EXPOSURE; THYROID-CANCER; CHILDHOOD LEUKEMIA; INFANT LEUKEMIA; CLEANUP WORKERS; EXTERNAL RADIATION; RUSSIAN-FEDERATION; BRYANSK REGION; FOLLOW-UP AB 26 April 2006 marks the 20th anniversary of the Chernobyl accident. On this occasion, the World Health Organization ( WHO), within the UN Chernobyl Forum initiative, convened an Expert Group to evaluate the health impacts of Chernobyl. This paper summarises the findings relating to cancer. A dramatic increase in the incidence of thyroid cancer has been observed among those exposed to radioactive iodines in childhood and adolescence in the most contaminated territories. Iodine deficiency may have increased the risk of developing thyroid cancer following exposure to radioactive iodines, while prolonged stable iodine supplementation in the years after exposure may reduce this risk. Although increases in rates of other cancers have been reported, much of these increases appear to be due to other factors, including improvements in registration, reporting and diagnosis. Studies are few, however, and have methodological limitations. Further, because most radiation-related solid cancers continue to occur decades after exposure and because only 20 years have passed since the accident, it is too early to evaluate the full radiological impact of the accident. Apart from the large increase in thyroid cancer incidence in young people, there are at present no clearly demonstrated radiation-related increases in cancer risk. This should not, however, be interpreted to mean that no increase has in fact occurred: based on the experience of other populations exposed to ionising radiation, a small increase in the relative risk of cancer is expected, even at the low to moderate doses received. Although it is expected that epidemiological studies will have difficulty identifying such a risk, it may nevertheless translate into a substantial number of radiation-related cancer cases in the future, given the very large number of individuals exposed. C1 Int Agcy Res Canc, F-69372 Lyon 08, France. Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. NCI, Div Epidemiol & Genet, Radiat Epidemiol Branch, Rockville, MD 20852 USA. Ukraine Acad Med Sci, Sci Ctr Radiat Med, UA-04050 Kiev, Ukraine. Ukraine Acad Med Sci, Inst Endocrinol & Metab, Morphol Endocrine Syst Lab, UA-04114 Kiev, Ukraine. WHO, Radiat & Environm Hlth Unit, CH-1211 Geneva 27, Switzerland. Univ Washington, Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98109 USA. Belarusian St Med Univ, Dept Oncol, Minsk 220013, Byelarus. Med Radiol Res Ctr, Obninsk 249020, Kaluga Region, Russia. GSF, Natl Res Ctr, Inst Radiat Protect, D-85764 Neuherberg, Germany. Republ Res Ctr Radiat Med & Human Ecol, Gomel 246042, Byelarus. Natl Commiss Radiat Protect, Minsk 220004, Byelarus. Univ Washington, Sch Publ Hlth & Community Med, Dept Biostat, Seattle, WA 98109 USA. Publ Hlth Minist Russian Federat, Inst Biophys, State Res Ctr Russian Federat, Moscow 123182, Russia. Univ Pisa, Dept Endocrinol & Metab, I-56100 Pisa, Italy. WHO, Collaborating Ctr Diag & Treatment Thyroid Canc, I-56124 Pisa, Italy. Univ Wurzburg, Dept Nucl Med, D-97080 Wurzburg, Germany. Nagasaki Univ, Grad Sch Biomed Sci, Atom Bomb Dis Inst, Nagasaki 8528523, Japan. Radiat Effects Res Fdn, Minami Ku, Hiroshima 7320815, Japan. Singleton Hosp, SW Wales Canc Inst, Swansea SA2 8QA, W Glam, Wales. Direct Radioprotect Homme, Inst Radioprotect & Surete Nucl, F-92262 Fontenay Aux Roses, France. Res Inst Radiat Hyg, Lab Internal Exposure, St Petersburg 197101, Russia. RP Cardis, E (reprint author), Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon 08, France. EM cardis@iarc.fr RI Chumak, Vadim/N-6960-2015; Ivanov, Victor/R-9385-2016; Cardis, Elisabeth/C-3904-2017; OI Chumak, Vadim/0000-0001-6045-9356; Ivanov, Victor/0000-0003-1372-0018; Yamashita, Shunichi/0000-0001-6399-6261 NR 52 TC 117 Z9 123 U1 8 U2 37 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0952-4746 J9 J RADIOL PROT JI J. Radiol. Prot. PD JUN PY 2006 VL 26 IS 2 BP 127 EP 140 DI 10.1088/0952-4746/26/2/001 PG 14 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 055AR UT WOS:000238422000002 PM 16738412 ER PT J AU Brummett, BH Babyak, MA Williams, RB Barefoot, JC Costa, PT Siegler, IC AF Brummett, BH Babyak, MA Williams, RB Barefoot, JC Costa, PT Siegler, IC TI NEO personality domains and gender predict levels and trends in body mass index over 14 years during midlife SO JOURNAL OF RESEARCH IN PERSONALITY LA English DT Article DE obesity; body mass index; personality; aging ID OBESITY; TRAITS; HEALTH; CONSCIENTIOUSNESS; NEUROTICISM; GENERATION; CHILDHOOD; BEHAVIORS; HOSTILITY; EXERCISE AB Mixed models were used to examine NEO-PI scores as predictors of body mass index (BMI) over a 14 year period during midlife. Average BMI levels during midlife were positively related to Neuroticism and negatively related to Openness, Agreeableness, and Conscientiousness. Relations for three domains were modified by gender. Neuroticism was significantly related to BMI in females only. Extraversion was positively related to BMI in males, whereas, this relation was nonsignificant in females. The relation between Conscientiousness and BMI was significant in males and females, however, the magnitude of the negative association was stronger in females. Conscientiousness also predicted change in BMI during midlife such that participants who were lower in Conscientiousness tended to show larger gains in BMI with age. (c) 2005 Elsevier Inc. All rights reserved. C1 Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. NIA, Gerontol Res Ctr, Bethesda, MD 20892 USA. RP Brummett, BH (reprint author), Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. EM brummett@duke.edu OI Costa, Paul/0000-0003-4375-1712 NR 42 TC 52 Z9 52 U1 2 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0092-6566 J9 J RES PERS JI J. Res. Pers. PD JUN PY 2006 VL 40 IS 3 BP 222 EP 236 DI 10.1016/j.jrp.2004.12.002 PG 15 WC Psychology, Social SC Psychology GA 051JB UT WOS:000238156300001 ER PT J AU Gezmu, M Flournoy, N AF Gezmu, M Flournoy, N TI Group up-and-down designs for dose-finding SO JOURNAL OF STATISTICAL PLANNING AND INFERENCE LA English DT Article; Proceedings Paper CT Fields-Institute Workshop on Adaptive Designs CY SEP 25-27, 2003 CL Toronto, CANADA SP Fields Inst DE adaptive designs; clinical trials; toxicity studies; Markov chains; random walks; applied probability; birth and death processes; phase I clinical trials ID CLINICAL-TRIALS; BIO-ASSAY AB Let toxicity to treatment be a Bernoulli random variable for which the probability of failure increases with dose. Consider the problem of identifying a dose mu having pre-specified probability of failure using data from groups of subjects who arrive sequentially for treatment. There is considerable theory available in this setting for fully sequential up-and-down procedures. This paper presents asymptotic and finite theoretical results for Markovian up-and-down procedures when subjects are treated in groups. Practical instructions are given on how to select the design parameters so as to cause the treatments to cluster around the unknown dose mu. Examples are given to illustrate how this group procedure behaves for small sample sizes. (c) 2005 Published by Elsevier B.V. C1 NIAID, NIH, Bethesda, MD 20892 USA. Univ Missouri, Columbia, MO 65211 USA. RP Gezmu, M (reprint author), NIAID, NIH, Bethesda, MD 20892 USA. EM MGEZMU@niaid.nih.gov NR 28 TC 18 Z9 21 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-3758 J9 J STAT PLAN INFER JI J. Stat. Plan. Infer. PD JUN 1 PY 2006 VL 136 IS 6 BP 1749 EP 1764 DI 10.1016/j.jspi.2005.08.002 PG 16 WC Statistics & Probability SC Mathematics GA 018DD UT WOS:000235743100002 ER PT J AU Ehrlich, A Koch, T Amin, B Liewehr, DJ Steinberg, SM Turner, ML Blauvelt, A AF Ehrlich, A Koch, T Amin, B Liewehr, DJ Steinberg, SM Turner, ML Blauvelt, A TI Development and reliability testing of a standardized questionnaire to assess psoriasis phenotype SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article AB Background: Psoriasis genetics researchers have utilized separate and widely differing survey instruments to capture clinical data to be utilized in genotype-phenotype studies, which make comparison mid collaboration studies among these researchers difficult. Objective: The purpose of this study was to develop and validate a clinical survey instrument to facilitate lies among psoriasis genetics researchers. Methods: The Delphi method was employed to obtain international consensus on components of the novel survey instrument. The survey was pretested for acceptability purposes, and then formally tested for reliability using 3 independent raters interviewing 48 subjects with psoriasis. Results: Data showed high or moderately high agreement for questions relating to place of birth (85% to 100% in agreement), family origin (kappa = 0.48 -1.0) psoriasis history (kappa = 0.66-1.0) patient medical history (kappa = 0.76-1.0). distribution of lesions (kappa = 0.73-1.0), precipitating factors (kappa = 0.79-1.0), joint involvement (kappa = 0.74-91), and treatment history. including use of oral retinoids, methotrexate, and etanercept (kappa = 0.73-1.0). Other parameters had lower degrees of agreement. Limitations: The time involved and the need for the rater to be a clinician with knowledge of psoriasis may preclude widespread use of this survey instrument. Conclusion: We developed a novel reliable survey instrument that can be used to gather clinical information in a standardized manner from Psoriasis patients participating in clinical and genetics research studies. C1 George Washington Univ, Dept Dermatol, Washington, DC 20037 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NCI, Off Clin Director, Dermatol Branch, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Ehrlich, A (reprint author), George Washington Univ, Dept Dermatol, 2150 Penn Ave NW,Ste 6A-404, Washington, DC 20037 USA. EM aehrlich@mfa.gwu.edu OI Ehrlich, Alison/0000-0002-4062-5289 NR 6 TC 8 Z9 8 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUN PY 2006 VL 54 IS 6 BP 987 EP 991 DI 10.1016/j.jaad.2006.02.003 PG 5 WC Dermatology SC Dermatology GA 047WH UT WOS:000237908900003 ER PT J AU Braun, M Giri, N Alter, BP Cowen, EW AF Braun, M Giri, N Alter, BP Cowen, EW TI Thrombocytopenia, multiple mucosal squamous cell carcinomas, and dyspigmentation SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID FANCONI-ANEMIA; CANCER C1 NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Clin Genet Branch, Div Canc Epidemiol & Res, NIH, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10 Room 12N238,10 Center Dr,MSC 1908, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov FU Intramural NIH HHS NR 11 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUN PY 2006 VL 54 IS 6 BP 1056 EP 1059 DI 10.1016/j.jaad.2006.02.065 PG 4 WC Dermatology SC Dermatology GA 047WH UT WOS:000237908900013 PM 16713462 ER PT J AU Walston, J Hadley, EC Ferrucci, L Guralnik, JM Newman, AB Studenski, SA Ershler, WB Harris, T Fried, LP AF Walston, J Hadley, EC Ferrucci, L Guralnik, JM Newman, AB Studenski, SA Ershler, WB Harris, T Fried, LP TI Research agenda for frailty in older adults: Toward a better understanding of physiology and etiology: Summary from the American Geriatrics Society/National institute on aging research conference on frailty in older adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE frailty; multisystem decline; pathophysiology ID GROWTH-FACTOR-I; SERUM INTERLEUKIN-6; SARCOPENIC OBESITY; FUNCTIONAL DECLINE; PHYSICAL FRAILTY; OXIDATIVE STRESS; BODY-COMPOSITION; GENE-EXPRESSION; ELDERLY PERSONS; WOMEN AB Evolving definitions of frailty, and improved understanding of molecular and physiological declines in multiple systems that may increase vulnerability in frail, older adults has encouraged investigators from many disciplines to contribute to this emerging field of research. This article reports on the results of the 2004 American Geriatrics Society/National Institute on Aging conference on a Research Agenda on Frailty in Older Adults, which brought together a diverse group of clinical and basic scientists to encourage further investigation in this area. This conference was primarily focused on physical and physiological aspects of frailty. Although social and psychological aspects of frailty are critically important and merit future research, these topics were largely beyond the scope of this meeting. Included in this article are sections on the evolving conceptualization and definitions of frailty; physiological underpinnings of frailty, including the potential contributions of inflammatory, endocrine, skeletal muscle, and neurologic system changes; potential molecular and genetic contributors; proposed animal models; and integrative, system biology approaches that may help to facilitate future frailty research. In addition, several specific recommendations as to future directions were developed from suggestions put forth by participants, including recommendations on definition and phenotype development, methodological development to perform clinical studies of individual-system and multiple-system vulnerability to stressors, development of animal and cellular models, application of population-based studies to frailty research, and the development of large collaborative networks in which populations and resources can be shared. This meeting and subsequent article were not meant to be a comprehensive review of frailty research; instead, they were and are meant to provide a more-targeted research agenda-setting process. C1 Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. NIA, Bethesda, MD 20892 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. Ctr Geriatr Res Educ & Clin, Dept Vet Affairs Pittsburgh Healthcare Ctr, Pittsburgh, PA USA. Natl Geriatr Resource Consortium, Inst Adv Studies Aging & Geriatr Med, Washington, DC USA. RP Walston, J (reprint author), John R Burton Pavil,5505 Hopkins Bayview Circle, Baltimore, MD 21224 USA. EM jwalston@jhmi.edu RI Newman, Anne B./C-6408-2013 OI Newman, Anne B./0000-0002-0106-1150 FU Intramural NIH HHS [Z99 AG999999] NR 52 TC 541 Z9 557 U1 6 U2 38 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUN PY 2006 VL 54 IS 6 BP 991 EP 1001 DI 10.1111/j.1532-5415.2006.00745.x PG 11 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 049EX UT WOS:000237999800018 PM 16776798 ER PT J AU Kovacik, V Bekesova, S Tvaroska, I Kovac, P AF Kovacik, V Bekesova, S Tvaroska, I Kovac, P TI Positive electrospray ion trap multistage mass spectrometric fragmentation of synthetic analogs of saccharide part of lipopolysaccharides of Vibrio cholerae O : 1 SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article ID METHYL ALPHA-GLYCOSIDES; O-ANTIGEN; SEROTYPES OGAWA; INABA; VIBRIO-CHOLERAE-O-1; POLYSACCHARIDE; TRISACCHARIDE; DISACCHARIDE; MIMICKING; TERMINUS AB Oligosaccharides (mono- to hexamers) that mimic the terminal epitopes of O-antigens of Vibrio cholerae O:1, serotypes Ogawa and Inaba, have been studied by electrospray ion trap (ESI IT) mass spectrometry. Sodium or potassium-cationized adducts are characteristic ions under the conditions of ESI-MS analysis. The tentative pathways of fragmentation have been proven by multistage ion trap MS (MSn, n = 1-3). The predominant pathway of fragmentation of the oligomers is the neutral loss of monosaccharide residue shortening the length of the oligosaccharide. In this way, conversion of the Ogawa to Inaba fragments takes place under the conditions of measurement. ESI MS/MS provided sufficient information about molecular mass, the number of saccharide residues, and the structure of saccharides, about the C (4)-amide of 3-deoxy-L-glycero-tetronic acid (DGT) of the compounds investigated, and allows to distinguish between Ogawa and Inaba serotypes. (J Am Soc Mass Spectrom 2006, 17, 749-756) (C) 2006 American Society for Mass Spectrometry. C1 Slovak Acad Sci, Inst Chem, Bratislava 84538, Slovakia. NIDDK, NIH, Bethesda, MD USA. RP Kovacik, V (reprint author), Slovak Acad Sci, Inst Chem, Dubravska Cesta 9, Bratislava 84538, Slovakia. EM chemvkov@savba.sk NR 18 TC 4 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1044-0305 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD JUN PY 2006 VL 17 IS 6 BP 749 EP 756 DI 10.1016/j.jasms.2006.02.006 PG 8 WC Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 047YC UT WOS:000237913600001 PM 16600622 ER PT J AU Mark, SD Katki, HA AF Mark, SD Katki, HA TI Specifying and implementing nonparametric and semiparametric survival estimators in two-stage (nested) cohort studies with missing case data SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE absolute risk; auxiliary covariate; case cohort; case control; cox proportional hazard; cumulative hazard; efficiency; missing covariates; nested cohort; Nonparametric; robust estimation; semiparametric; standardized survival; survival; two-stage study; weighted estimating equation ID SQUAMOUS-CELL CARCINOMA; GASTRIC CARDIA CANCER; HELICOBACTER-PYLORI; ESOPHAGEAL; RISK; CHINA; LINXIAN; DISEASE; TRIALS AB Since 1986, we have been studying a cohort of individuals from a region in China with epidemic rates of gastric cardia cancer and have conducted numerous two-stage studies to assess the association of various exposures with this cancer. Two-stage studies are a commonly used statistical design. Stage one involves observing the outcomes and accessible baseline covariate information on all cohort members, and stage two involves using the stage one observations to select a subset of the cohort for measurements of exposures that are difficult to obtain. When the outcomes are censored failure times, such as in our studies, the most common designs used are the case-cohort and nested case-control designs. One limitation of both these designs is that the estimators of the cumulative hazards, and hence survivals and absolute risks, are biased when some cases are missing the stage two measurements. In our experience, such missingness is present in virtually all two-stage studies that (like ours) use biological specimens to obtain exposure measurements. In earlier work we derived and characterized the efficiency of a class of nonparametric and a class of semiparametric cumulative hazard estimators that are unbiased regardless of whether or not all cases are measured. In this article we limit the presentation of the mathematical derivation of these two classes to aspects important to study design and analysis. We analyze data from a two-stage study that we conducted on the association of Helicobacter pylori infection with incident gastric cardia cancers. We discuss the substantive reasons why we deliberately sampled only 25% of the available cancer cases. Through simulations, we demonstrate that substantial variation in precision exists between unbiased estimators within each class, and express the origin of these differences in terms of parameters familiar to investigators. We describe how preexistent knowledge about these parameters can be used to increase estimator precision, and detail specific strategies for constructing such estimators. Computer code in R that implements these estimators is available from the authors on request. C1 Univ Colorado, Sch Med, Dept Prevent Med & Biometr, Denver, CO 80262 USA. NCI, Div Canc Epidemiol & Genet, Biostat Branch, Rockville, MD 20852 USA. RP Mark, SD (reprint author), Univ Colorado, Sch Med, Dept Prevent Med & Biometr, Denver, CO 80262 USA. EM Steven.Mark@uchsc.edu RI Katki, Hormuzd/B-4003-2015 NR 32 TC 16 Z9 16 U1 1 U2 11 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 1429 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD JUN PY 2006 VL 101 IS 474 BP 460 EP 471 DI 10.1198/016214505000000952 PG 12 WC Statistics & Probability SC Mathematics GA 049RD UT WOS:000238033200005 ER PT J AU Reiner, AP Carty, CL Carlson, CS Wan, JY Rieder, MJ Smith, JD Rice, K Fornage, M Jaquish, CE Williams, OD Tracy, RP Lewis, CE Siscovick, DS Boerwinkle, E Nickerson, DA AF Reiner, AP Carty, CL Carlson, CS Wan, JY Rieder, MJ Smith, JD Rice, K Fornage, M Jaquish, CE Williams, OD Tracy, RP Lewis, CE Siscovick, DS Boerwinkle, E Nickerson, DA TI Association between patterns of nucleotide variation across the three fibrinogen genes and plasma fibrinogen levels: the Coronary Artery Risk Development in Young Adults (CARDIA) study SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE fibrinogen; haplotype; polymorphism ID THR312ALA POLYMORPHISM; MYOCARDIAL-INFARCTION; HEART-DISEASE; PROMOTER; LOCI AB Background: Previous genotype-phenotype association studies of fibrinogen have been limited by incomplete knowledge of genomic sequence variation within and between major ethnic groups in FGB, FGA, and FGG. Methods: We characterized the linkage disequilibrium patterns and haplotype structure across the human fibrinogen gene locus in European- and African-American populations. We analyzed the association between common polymorphisms in the fibrinogen genes and circulating levels of both 'functional' fibrinogen (measured by the Clauss clotting rate method) and total fibrinogen (measured by immunonephelometry) in a large, multi-center, bi-racial cohort of young US adults. Results: A common haplotype tagged by the A minor allele of the well-studied FGB-455 G/A promoter polymorphism (FGB 1437) was confirmed to be strongly associated with increased plasma fibrinogen levels. Two non-coding variants specific to African-American chromosomes, FGA 3845 A and FGG 5729 G, were each associated with lower plasma fibrinogen levels. In European-Americans, a common haplotype tagged by FGA Thr312Ala and several other variant alleles across the fibrinogen gene locus was strongly associated with decreased fibrinogen levels as measured by functional assay, but not by immunoassay. Overall, common polymorphisms within the three fibrinogen genes explain < 2% of the variability in plasma fibrinogen concentration. Conclusions: In young adults, fibrinogen multi-locus genotypes are associated with plasma fibrinogen levels. The specific single nucleotide polymorphism and haplotype patterns for these associations differ according to population and also according to phenotypic assay. It is likely that a substantial proportion of the heritable component of plasma fibrinogen concentration is due to genetic variation outside the three fibrinogen genes. C1 Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA. Univ Washington, Dept Genome Sci, Seattle, WA 98101 USA. Univ Texas, Houston, TX USA. NHLBI, Bethesda, MD 20892 USA. Univ Alabama, Birmingham, AL USA. Univ Vermont, Burlington, VT USA. RP Reiner, AP (reprint author), Univ Washington, Dept Epidemiol, Box 358085, Seattle, WA 98101 USA. EM apreiner@u.washington.edu RI Rice, Kenneth/A-4150-2013; Carty, Cara/B-8683-2013 OI Rice, Kenneth/0000-0001-5779-4495; FU NHLBI NIH HHS [HL66642, HL66682, HL71017, N01-HC-05187, N01-HC-45134, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-95095] NR 25 TC 37 Z9 38 U1 0 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1538-7933 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUN PY 2006 VL 4 IS 6 BP 1279 EP 1287 DI 10.1111/j.1538-7836.2006.01907.x PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 043JS UT WOS:000237597900019 PM 16706972 ER PT J AU Simak, J Gelderman, MP Yu, H Wright, V Baird, AE AF Simak, J Gelderman, MP Yu, H Wright, V Baird, AE TI Circulating endothelial microparticles in acute ischemic stroke: a link to severity, lesion volume and outcome SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE acute stroke; endoglin; endothelial microparticles; flow cytometry; VE-cadherin ID CELL-DERIVED MICROPARTICLES; MEMBRANE MICROPARTICLES; PROCOAGULANT ACTIVITY; APOPTOSIS; ENDOGLIN; PLASMA; BRAIN; INFILTRATION; GENERATION; MOLECULES AB Background: Endothelial membrane microparticles (EMP) in plasma are elevated in several vascular diseases. Objectives: To test the hypothesis that EMP would be increased in patients with acute ischemic stroke and would correlate with stroke severity, brain lesion volume and outcome. Patients and methods: Forty-one patients were studied and divided into two groups based on the National Institutes of Health Stroke Scale (NIHSS) score: 20 patients with mild stroke (NIHSS score < 5) and 21 patients with moderate-severe stroke (NIHSS score >= 5). Lesion volume was measured using diffusion-weighted magnetic resonance imaging and discharge outcome was based on the discharge Barthel and Rankin scores. Twenty-three age-matched control subjects were also studied. Using flow cytometry, endoglin-positive EMP: CD105(+) CD41a(-)CD45(-) (E+EMP), specific endothelial EMP expressing VE-cadherin and endoglin: CD105(+)CD144(+) (C+EMP), EMP expressing phosphatidylserine: CD105(+)PS(+) CD41a(-) (PS+EMP) and EMP expressing ICAM-1: CD105(+)CD54(+) CD45(-) (I+EMP) were analyzed. Results: Significantly higher PS+EMP counts were observed in the group of acute ischemic stroke patients [median 59 (25th-75th percentile: 28-86) MP mu L-1] relative to the controls [28 (14-36) MP mu L-1] (P = 0.002). All four EMP phenotypes studied were elevated in the subgroup of moderate-severe stroke patients relative to the controls (all P < 0.05). In the patients with acute ischemic stroke three EMP phenotypes (E+EMP, PS+EMP and I+EMP) correlated significantly with brain lesion volume, with I+EMP (P = 0.002) showing the strongest correlation. Admission counts of C+EMP (P = 0.0003) and E+EMP (P = 0.003) correlated significantly with discharge clinical outcome. Conclusions: Certain circulating EMP phenotypes may be associated with severity, lesion volume and outcome of acute ischemic stroke. EMP analysis shows promising contribution to understanding stroke pathophysiology. C1 US FDA, CBER, Lab Cellular Hematol, Rockville, MD 20852 USA. NINDS, Struct Neurosci Unit, NIH, Bethesda, MD 20892 USA. RP Simak, J (reprint author), US FDA, CBER, Lab Cellular Hematol, HFM-335,1401 Rockville Pike, Rockville, MD 20852 USA. EM jan.simak@fda.hhs.gov RI Simak, Jan/C-1153-2011 NR 34 TC 121 Z9 129 U1 0 U2 6 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1538-7933 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUN PY 2006 VL 4 IS 6 BP 1296 EP 1302 DI 10.1111/j.1538-7836.2006.01911.x PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 043JS UT WOS:000237597900021 PM 16706974 ER PT J AU Goncalves, LF Nien, JK Espinoza, J Kusanovic, JP Lee, W Swope, B Soto, E Treadwell, MC Romero, R AF Goncalves, LF Nien, JK Espinoza, J Kusanovic, JP Lee, W Swope, B Soto, E Treadwell, MC Romero, R TI What does 2-dimensional Imaging add to 3-and 4-dimensional obstetric ultrasonography? SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE accuracy; congenital anomalies; fetus; 4-dimensional ultrasonography; prenatal diagnosis; sonographic tomography; spatiotemporal image correlation; 3-dimensional ultrasonography ID 3-DIMENSIONAL FETAL ECHOCARDIOGRAPHY; VENTRICULAR SEPTAL-DEFECTS; PRENATAL-DIAGNOSIS; WEIGHT ESTIMATION; ULTRASOUND; SONOGRAPHY; VOLUME; HEART; FETUS; US AB Objective. The purpose of this study was to determine whether 2-dimensional (2D) ultrasonography adds diagnostic information to that provided by the examination of 3-dimensional/4-dimensional (3D/4D) volume data sets alone. Methods. Ninety-nine fetuses were examined by 3D/4D volume ultrasonography. Volume data sets were evaluated by a blinded independent examiner who, after establishing an initial diagnostic impression by 3D/4D ultrasonography, performed a 2D ultrasonographic examination. The frequency of agreement and diagnostic accuracy of each modality to detect congenital anomalies were calculated and compared. Results. Fifty-four fetuses with no abnormalities and 45 fetuses with 82 anomalies diagnosed by 2D ultrasonography were examined. Agreement between 3D/4D and 2D ultrasonography occurred for 90.4% of the findings (123/136; intraclass correlation coefficient, 0.834; 95% confidence interval, 0.774-0.879). Six anomalies were missed by 3D/4D ultrasonography when compared to 2D ultrasonography (ventricular septal defect [n = 2], interrupted inferior vena cava with azygous continuation [n = 1], tetralogy of Fallot (n = 1], horseshoe kidney [n = 11, and cystic adenomatoid malformation [n = 1]). There were 2 discordant diagnoses: transposition of the great arteries diagnosed as a double-outlet right ventricle and pulmonary atresia misinterpreted as tricuspid atresia on 3D/4D ultrasonography. One case of occult spinal dysraphism was suspected on 3D ultrasonography but not confirmed by 2D ultrasonography. When compared to diagnoses performed after delivery (n = 106), the sensitivity and specificity of 3D/4D ultrasonography (92.2% [47/51] and 76.4% [42/55], respectively) and 2D ultrasonography (96.1 % [49/51] and 72.7% [40/55]) were not significantly different (P =.233). Conclusions. Information provided by 2D ultrasonography is consistent, in most cases, with information provided by the examination of 3D/4D volume data sets alone. C1 Wayne State Univ, Hutzel Womens Hosp, Dept Hlth & Human Serv, NIH,NICHHD,Perinatol Res Branch, Detroit, MI 48201 USA. NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. William Beaumont Hosp, Div Fetal Imaging, Royal Oak, MI 48072 USA. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, Dept Hlth & Human Serv, NIH,NICHHD,Perinatol Res Branch, 3990 John R,Box 4, Detroit, MI 48201 USA. EM warfiela@mail.nih.gov FU Intramural NIH HHS; NICHD NIH HHS [Z01 HD002401-13] NR 35 TC 30 Z9 34 U1 0 U2 4 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 J9 J ULTRAS MED JI J. Ultrasound Med. PD JUN PY 2006 VL 25 IS 6 BP 691 EP 699 PG 9 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 050DY UT WOS:000238068900002 PM 16731885 ER PT J AU Goncalves, LF Espinoza, J Kusanovic, JP Lee, W Nien, JK Santolaya-Forgas, J Mari, G Treadwell, MC Romero, R AF Goncalves, LF Espinoza, J Kusanovic, JP Lee, W Nien, JK Santolaya-Forgas, J Mari, G Treadwell, MC Romero, R TI Applications of 2-dimensional matrix array for 3-and 4-dimensional examination of the fetus - A pictorial essay SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE anomalies; fetal echocardiography; fetus; 4-dimensional ultrasonography; prenatal diagnosis; 3-dimensional ultrasonography; 2-dimensional matrix array; ultrasonography ID 3-DIMENSIONAL FETAL ECHOCARDIOGRAPHY; REAL-TIME; HEART-DISEASE; ULTRASOUND; VOLUME; FEASIBILITY; DISPLAY; ACQUISITION; OBSTETRICS AB Objectives. Two-dimensional (2D) matrix array is a new technology for the performance of 3-dimensional and 4-dimensional (4D) ultrasonography. In this study, we report the use of a 2D matrix array transducer for examination of fetal structures including the fetal heart. Methods. Thirty-four fetuses without abnormalities and 19 fetuses with congenital anomalies were examined with a 2D matrix array transducer (x3-1, IE-33; Philips Medical Systems, Bothell, WA). Median gestational age was 25 6/7 weeks (range, 13 0/7-40 1/7 weeks). Results. (1) A 3601 rotation and examination of selected structures was possible in the second trimester. (2) Structures were examined by maintaining the transducer in a fixed position and rotating the volume using the system trackball. (3) Dorsal and ventral parts of the hands and feet were visualized in a single volume data set, in real time, without moving the transducer. (4) Real-time en face visualization of atrioventricular valves was possible from the ventricular or atrial chambers. (5) Four-dimensional images of bones were obtained by decreasing gain settings only, with no need for cropping. (6) Four-dimensional reconstruction of vascular structures was possible with color Doppler imaging. Two limitations were identified: (1) lower resolution than mechanical volumetric transducers, and (2) narrow volume display. Conclusions. Real-time direct 4D imaging with 360 degrees rotation for examination of fetal anatomic structures is feasible. This technology allows examination of fetal structures from multiple perspectives, in real time, without the need to move the transducer in the maternal abdomen. Further technological developments may overcome the limitations identified in this study. C1 Wayne State Univ, Hutzel Womens Hosp, Dept Hlth & Human Serv, NIH,NICHHD,Perinatol Res Branch, Detroit, MI 48201 USA. NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Wayne State Univ, Hutzel Womens Hosp, Dept Obstet & Gynecol, Detroit, MI USA. William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, Royal Oak, MI 48072 USA. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, Dept Hlth & Human Serv, NIH,NICHHD,Perinatol Res Branch, 3990 John R,Box 4, Detroit, MI 48201 USA. EM warfiela@mail.nih.gov FU Intramural NIH HHS; NICHD NIH HHS [Z01 HD002401-13] NR 28 TC 19 Z9 19 U1 0 U2 1 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 J9 J ULTRAS MED JI J. Ultrasound Med. PD JUN PY 2006 VL 25 IS 6 BP 745 EP 755 PG 11 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 050DY UT WOS:000238068900008 PM 16731891 ER PT J AU Goodman, PJ Thompson, IM Tangen, CM Crowley, JJ Ford, LG Coltman, CA AF Goodman, PJ Thompson, IM Tangen, CM Crowley, JJ Ford, LG Coltman, CA TI The prostate cancer prevention trial: Design, biases and interpretation of study results SO JOURNAL OF UROLOGY LA English DT Article DE prostate; prostatic neoplasms; biopsy; bias (epidemiology); research design ID FINASTERIDE; ANTIGEN; BIOPSY; GLAND; PCPT AB Purpose: We describe the complexities of the study design of the PCPT and how they influenced the end point chosen, trial implementation, analysis and interpretation of the results. Materials and Methods: Data from the PCPT are provided to evaluate and quantify the potential biases of this trial design. Results: Six potential sources of bias, including prostate specific antigen, digital rectal examination, prostate biopsy technique, study medication nonadherence and contamination, and transurethral prostate resection are presented. These biases resulted in the need for the end of study biopsy to evaluate the trial objectives. Conclusions: There were a large number of known and potential biases that worked for and against finasteride. Because of the trial design and inherent biases, it is imperative that interim biopsy results should be interpreted with caution. While the period prevalence end point that relied on an end of study biopsy was perhaps not the most clinically relevant, it was the only way to remove as much bias as possible and meet the study objective of determining if finasteride could decrease the risk of prostate cancer. The success of the PCPT depended on constant scrutiny by the Data and Safety Monitoring Committee to monitor these biases. The design and biopsy assumptions outlined at the inception of the trial were met, including adherence and contamination rates, the for-cause biopsy rate and the final percent of men with study end points. C1 SW Oncol Grp, Stat Ctr, Seattle, WA 98109 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. SW Oncol Grp Operat Off, San Antonio, TX USA. NCI, Bethesda, MD USA. RP Goodman, PJ (reprint author), SW Oncol Grp, Stat Ctr, 1100 Fairview Ave,N M3-C102,POB 19024, Seattle, WA 98109 USA. EM pgoodman@fhcrc.org FU NCI NIH HHS [CA37429] NR 12 TC 20 Z9 20 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUN PY 2006 VL 175 IS 6 BP 2234 EP 2242 DI 10.1016/S0022-5347(06)00284-9 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 043FJ UT WOS:000237585100069 PM 16697846 ER PT J AU McDermott, MM Criqui, MH Ferrucci, L Guralnik, JM Tian, L Liu, K Greenland, P Tan, J Schneider, JR Clark, E Pearce, WH AF McDermott, MM Criqui, MH Ferrucci, L Guralnik, JM Tian, L Liu, K Greenland, P Tan, J Schneider, JR Clark, E Pearce, WH TI Obesity, weight change, and functional decline in peripheral arterial disease SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT Annual Meeting of the Midwest-Society-of-General-Internal-Medicine CY SEP 30, 2005 CL Chicago, IL SP Midwest Soc Gen Internal Med ID BODY-MASS INDEX; DISABILITY; HEALTH; WOMEN; CLASSIFICATION; OSTEOARTHRITIS; ASSOCIATION; CRITERIA; RISK; FAT AB Background: Our objectives were to determine whether obesity is associated with a greater functional decline compared with the ideal body mass index (BMI) among persons with peripheral arterial disease (PAD) and to determine the associations between weight gain and loss and functional declines in PAD. We hypothesized that baseline obesity and weight gain during follow-up would each be associated with functional declines in persons with PAD. Methods. The design was a prospective cohort study. The subjects were 389 men and women with PAD (mean ankle-brachial index, 0.65 +/- 0.14) who were followed up prospectively for a median of 48 months. The main outcome measures were functional assessments (6-minute walk, usual- and rapid-paced 4-m walking speed, and summary performance score). Weight and height were measured at baseline and annually. Results were adjusted for age, sex, race, comorbidities, ankle-brachial index, education, leg symptoms, exercise status, depressive symptoms, pack-years of cigarette smoking, prior-year functioning, and patterns of missing data. Results. Compared with those with a baseline BMI between 20 and 25 kg/m(2), PAD participants with baseline BMI greater than 30 kg/m(2) had a significantly greater average annual decline in 6-minute walk performance (- 13.1 vs -26.5 m/y; P =.004), usual-paced 4-m walking velocity (-0.028 vs -0.055 m/s per year; P =.024), and fast-paced 4-m walking velocity (-0.053 vs -0.086 m/s per year; P =.012). Persons with weight gain between 5 and 10 pounds after baseline who walked for exercise regularly had significantly less decline in the 6-minute walk than persons without significant weight change who did not walk for exercise (P =.04). Conclusions. Obesity is associated with functional decline in persons with PAD. Walking exercise may protect against functional decline in PAD persons with modest weight gain. C1 Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Dept Surg, Chicago, IL 60611 USA. Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. Evanston Northwestern Hosp, Longitudinal Studies Sect, Clin Res Branch, NIA,Div Vasc Surg,Dept Surg, Chicago, IL USA. Evanston Northwestern Hosp, Lab Epidemiol Demog & Biometry, NIA, Div Vasc Surg,Dept Surg, Chicago, IL USA. Mt Sinai Hosp, Dept Surg, Div Vasc Surg, Chicago, IL USA. RP McDermott, MM (reprint author), 675 N St Clair,Suite 18-200, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU Intramural NIH HHS [Z99 AG999999]; NCRR NIH HHS [M01 RR000048, RR-00048]; NHLBI NIH HHS [R01 HL064739, R01 HL073351, R01-HL073351, R01-HL58099, R01-HL64739] NR 24 TC 17 Z9 17 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD JUN PY 2006 VL 43 IS 6 BP 1198 EP 1204 DI 10.1016/j.jvs.2006.02.036 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 049VW UT WOS:000238046700025 PM 16765239 ER PT J AU Teterina, NL Levenson, E Rinaudo, MS Egger, D Bienz, K Gorbalenya, AE Ehrenfeld, E AF Teterina, NL Levenson, E Rinaudo, MS Egger, D Bienz, K Gorbalenya, AE Ehrenfeld, E TI Evidence for functional protein interactions required for poliovirus RNA replication SO JOURNAL OF VIROLOGY LA English DT Article ID NEGATIVE-STRAND RNA; 2C PROTEIN; VIRAL-RNA; AMPHIPATHIC HELIX; MEMBRANE-BINDING; LINKAGE MAP; ENDOPLASMIC-RETICULUM; HYDROPHOBIC DOMAIN; 2B; REGIONS AB Poliovirus protein 2C contains a predicted N-terminal amphipathic helix that mediates association of the protein with the membranes of the viral RNA replication complex. A chimeric virus that contains sequences encoding the 18-residue core from the orthologous amphipathic helix from human rhinovirus type 14 (HRV14) was constructed. The chimeric virus exhibited defects in viral RNA replication and produced minute plaques on HeLa cell monolayers. Large plaque variants that contained mutations within the 2C-encoding region were generated upon subsequent passage. However, the majority of viruses that emerged with improved growth properties contained no changes in the region encoding 2C. Sequence analysis and reconstruction of genomes with individual mutations revealed changes in 3A or 2B sequences that compensated for the HRV14 amphipathic helix in the polio 2C-containing proteins, implying functional interactions among these proteins during the replication process. Direct binding between these viral proteins was confirmed by mammalian cell two-hybrid analysis. C1 NIAID, LID, NIH, Bethesda, MD 20892 USA. Univ Basel, Inst Med Microbiol, Basel, Switzerland. Leiden Univ, Med Ctr, Dept Med Microbiol, Leiden, Netherlands. RP Ehrenfeld, E (reprint author), NIAID, LID, NIH, Bldg 50,Room 6120,50 S Dr, Bethesda, MD 20892 USA. EM eehrenfeld@niaid.nih.gov RI Levenson, Eric/A-7963-2008; Gorbalenya, Alexander/J-4818-2012 OI Levenson, Eric/0000-0002-3896-3908; Gorbalenya, Alexander/0000-0002-4967-7341 FU Intramural NIH HHS NR 43 TC 28 Z9 29 U1 0 U2 2 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 JUN PY 2006 VL 80 IS 11 BP 5327 EP 5337 DI 10.1128/JVI.02684-05 PG 11 WC Virology SC Virology GA 045PG UT WOS:000237753400023 PM 16699013 ER PT J AU Schmidt, M Chiorini, JA AF Schmidt, M Chiorini, JA TI Gangliosides are essential for bovine adeno-associated virus entry SO JOURNAL OF VIROLOGY LA English DT Article ID ERYTHROCYTE-P-ANTIGEN; HEPARAN-SULFATE; PARVOVIRUS B19; POLYOMA-VIRUS; SIALIC-ACID; CELLS; RECEPTORS; TRANSDUCTION; ROTAVIRUS; BINDING AB Recombinant adeno-associated viruses (AAV) are promising gene therapy vectors. We have recently identified a bovine adeno-associated virus (BAAV) that demonstrates unique tropism and transduction activity compared to primate AAVs. To better understand the entry pathway and cell tropism of BAAV, we have characterized the initial cell surface interactions required for transduction with BAAV vectors. Like a number of AAVs, BAAV requires cell surface sialic acid groups for transduction and virus attachment. However, glycosphingolipids (GSLs), not cell surface proteins, were required for vector entry and transduction. Incorporation of gangliosides, ceramide-based glycolipids containing one or more sialic acid groups, into the cytoplasmic cell membranes of GSL-depleted COS cells partially reconstituted BAAV transduction. The dependency of BAAV on gangliosides for transduction was further confirmed by studies with C6 cells, a rat glioma cell line that is deficient in the synthesis of complex gangliosides. C6 cells were resistant to transduction by BAAV. Addition of gangliosides to C6 cells prior to transduction rendered the cells susceptible to transduction by BAAV. Therefore, gangliosides are a likely receptor for BAAV. C1 NIH, Gene Therapy & Therapeut Branch, Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. RP Chiorini, JA (reprint author), NIH, Gene Therapy & Therapeut Branch, Natl Inst Dent & Craniofacial Res, 10,1N113,10 Ctr Dr,MSC1190, Bethesda, MD 20892 USA. EM jchiorini@dir.nidcr.nih.gov FU Intramural NIH HHS NR 28 TC 28 Z9 28 U1 1 U2 1 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 JUN PY 2006 VL 80 IS 11 BP 5516 EP 5522 DI 10.1128/JVI.02393-05 PG 7 WC Virology SC Virology GA 045PG UT WOS:000237753400042 PM 16699032 ER PT J AU Nishigaki, K Hanson, C Ohashi, T Spadaccini, A Ruscetti, S AF Nishigaki, K Hanson, C Ohashi, T Spadaccini, A Ruscetti, S TI Erythroblast transformation by the friend spleen focus-forming virus is associated with a block in erythropoietin-induced STAT1 phosphorylation and DNA binding and correlates with high expression of the hematopoietic phosphatase SHP-1 SO JOURNAL OF VIROLOGY LA English DT Article ID PROTEIN-TYROSINE-PHOSPHATASE; COLONY-STIMULATING FACTOR; CYCLIN-DEPENDENT KINASES; ERYTHROLEUKEMIA-CELLS; SIGNAL-TRANSDUCTION; CONSTITUTIVE ACTIVATION; LEUKEMIA-VIRUS; INDUCIBLE GENE; GROWTH-HORMONE; SH2 DOMAIN AB Infection of mice with Friend spleen focus-forming virus (SFFV) results in a multistage erythroleukemia. In the first stage, the SFFV envelope glycoprotein interacts with the erythropoietin receptor and a short form of the receptor tyrosine kinase sf-Stk, resulting in constitutive activation of signal transducing molecules and the development of erythropoietin (Epo)-independent erythroid hyperplasia and polycythemia. The second stage results from the outgrowth of a rare virus-infected erythroid cell that expresses nonphysiological levels of the myeloid transcription factor PU.1. These cells exhibit a differentiation block and can be grown as murine erythroleukemia (MEL) cell lines. In this study, we examined SFFV MEL cells to determine whether their transformed phenotype was associated with a block in the activation of any Epo signal-transducing molecules. Our studies indicate that Epo- or SFFV-induced activation of STAT1/3 DNA binding activity is blocked in SFFV MEL cells. The block is at the level of tyrosine phosphorylation of STAT1, although Jak2 phosphorylation is not blocked in these cells. In contrast to Epo, alpha interferon can induce STAT1 phosphorylation and DNA binding in SFFV MEL cells. The SFFV-transformed cells were shown to express elevated levels of the hematopoietic phosphatase SHP-1, and treatment of the cells with a phosphatase inhibitor restored STAT1 tyrosine phosphorylation. MEL cells derived from Friend murine leukemia virus (MuLV) or ME26 MuLV-infected mice, which do not express PUA, express lower levels of SHP-1 and are not blocked in STAT1/3 DNA-binding activity. Our studies suggest that SFFV-infected erythroid cells become transformed when differentiation signals activated by STAT1/3 are blocked due to high SHP-1 levels induced by inappropriate expression of the PUA protein. C1 NCI, Lab Canc Prevent, Ft Detrick, MD 21702 USA. RP Ruscetti, S (reprint author), NCI, Lab Canc Prevent, Bldg 469,Room 205, Ft Detrick, MD 21702 USA. EM ruscetti@ncifcrf.gov RI Ohashi, Takashi/C-4671-2012 OI Ohashi, Takashi/0000-0002-3769-4224 FU Intramural NIH HHS; NCI NIH HHS [Z01 BC005657-16] NR 64 TC 12 Z9 13 U1 0 U2 1 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 JUN PY 2006 VL 80 IS 12 BP 5678 EP 5685 DI 10.1128/JVI.02651-05 PG 8 WC Virology SC Virology GA 050QV UT WOS:000238103900003 PM 16731906 ER PT J AU Govindarajan, D Buchholz, UJ Samal, SK AF Govindarajan, D Buchholz, UJ Samal, SK TI Recovery of avian metapneumovirus subgroup C from cDNA: Cross-recognition of avian and human metapneumovirus support proteins SO JOURNAL OF VIROLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; TURKEY RHINOTRACHEITIS VIRUS; NEWCASTLE-DISEASE VIRUS; SWOLLEN HEAD SYNDROME; SMALL HYDROPHOBIC SH; GROWTH IN-VITRO; REVERSE-GENETICS; G-GLYCOPROTEIN; G-GENES; PNEUMOVIRUS AB Avian metapneumovirus (AMPV) causes an acute respiratory disease in turkeys and is associated with "swollen head syndrome" in chickens, contributing to significant economic losses for the U.S. poultry industry. With a long-term goal of developing a better vaccine for controlling AMPV in the United States, we established a reverse genetics system to produce infectious AMPV of subgroup C entirely from cDNA. A cDNA clone encoding the entire 14,150-nucleotide genome of AMPV subgroup C strain Colorado (AMPV/CO) was generated by assembling five cDNA fragments between the T7 RNA polymerase promoter and the autocatalytic hepatitis delta virus rihozyme of a transcription plasmid, pBR 322. Transfection of this plasmid, along with the expression plasmids encoding the N, P, M2-1, and L proteins of AMPV/CO, into cells stably expressing T7 RNA polymerase resulted in the recovery of infectious AMPV/CO. Characterization of the recombinant AMPV/CO showed that its growth properties in tissue culture were similar to those of the parental virus. The potential of AMPV/CO to serve as a viral vector was also assessed by generating another recombinant virus, rAMPV/CO-GFP, that expressed the enhanced green fluorescent protein (GFP) as a foreign protein. Interestingly, GFP-expressing AMPV and GFP-expressing human metapneumovirus (HMPV) could be recovered using the support plasmids of either virus, denoting that the genome promoters are conserved between the two metapneumoviruses and can be cross-recognized by the polymerase complex proteins of either virus. These results indicate a close functional relationship between AMPV/CO and HMPV. C1 Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, 8075 Greenmead Dr, College Pk, MD 20742 USA. EM ssamal@umd.edu FU Intramural NIH HHS NR 42 TC 24 Z9 25 U1 0 U2 0 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 JUN PY 2006 VL 80 IS 12 BP 5790 EP 5797 DI 10.1128/JVI.00138-06 PG 8 WC Virology SC Virology GA 050QV UT WOS:000238103900015 PM 16731918 ER PT J AU Biacchesi, S Pham, QN Skiadopoulos, MH Murphy, BR Collins, PL Buchholz, UJ AF Biacchesi, S Pham, QN Skiadopoulos, MH Murphy, BR Collins, PL Buchholz, UJ TI Modification of the trypsin-dependent cleavage activation site of the human metapneumovirus fusion protein to be trypsin independent does not increase replication or spread in rodents or nonhuman primates SO JOURNAL OF VIROLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; F-PROTEIN; VACCINE CANDIDATE; MAJOR DETERMINANT; GENETIC DIVERSITY; G-GLYCOPROTEIN; AMINO-ACID; TYPE-3; EXPRESSION; INFECTION AB The contribution of cleavage activation of the fusion F protein of human metapneumovirus (HMPV) to replication and pathogenicity in rodents and nonhuman primates was investigated. Recombinant HMPVs were generated in which the naturally occurring trypsin-dependent cleavage sequence (R-Q-S-R down arrow) was replaced by each of three sequences whose cleavage in vitro does not depend upon added trypsin. Two of these were multibasic sequences derived from avian metapneumovirus type A (R-R-R-R) or type C (R-K-A-R), with the former containing the consensus furin protease cleavage motif (R-X-R/K-R down arrow). The third one (R-Q-P-R) was derived from a recently described trypsin independent HMPV isolate (J. H. Schickli, J. Kaur, N. Ulbrandt, R. R. Spaete, and R. S. Tang, J. Virol. 79:10678-10689, 2005). To preclude the possibility of conferring even greater virulence to this significant human pathogen, the modifications were done in an HMPV variant that was attenuated by the deletion of two of the three envelope glycoproteins, SH and G. Each of the introduced cleavage sequences conferred trypsin independent F cleavage and growth to HMPV in vitro. However, they differed in the efficiency of trypsin independent growth and plaque formation in vitro: R-R-R-R > R-K-A-R > R-Q-P-R > R-Q-S-R. The R-R-R-R mutant was the only one whose growth in vitro was not augmented by added trypsin, indicative of highly efficient trypsin independent cleavage. When inoculated intranasally into hamsters, there was essentially no difference in the magnitude of replication in the upper or lower respiratory tract between the mutants, and virus was not detected in organs outside of the respiratory tract. Evaluation of the most cleavage-efficient mutant, R-R-R-R, in African green monkeys showed that there was no detectable change in the magnitude of replication in the upper and lower respiratory tract or in immunogenicity and protective efficacy against HMPV challenge. These results suggest that cleavage activation is not a major determinant of HMPV virulence. C1 NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Buchholz, UJ (reprint author), Bldg 50,Room 6505,50 S Dr,MSC 8007, Bethesda, MD 20892 USA. EM ubuchholz@niaid.nih.gov RI Biacchesi, Stephane/A-6924-2010 FU Intramural NIH HHS NR 37 TC 28 Z9 30 U1 0 U2 0 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 JUN PY 2006 VL 80 IS 12 BP 5798 EP 5806 DI 10.1128/JVI.00294-06 PG 9 WC Virology SC Virology GA 050QV UT WOS:000238103900016 PM 16731919 ER PT J AU Bukreyev, A Serra, ME Laham, FR Melendi, GA Kleeberger, SR Collins, PL Polack, FP AF Bukreyev, A Serra, ME Laham, FR Melendi, GA Kleeberger, SR Collins, PL Polack, FP TI The cysteine-rich region and secreted form of the attachment G glycoprotein of respiratory syncytial virus enhance the cytotoxic T-lymphocyte response despite lacking major histocompatibility complex class I-restricted epitopes SO JOURNAL OF VIROLOGY LA English DT Article ID RECOMBINANT VACCINIA VIRUS; TOLL-LIKE RECEPTOR-4; G-PROTEIN; BALB/C MICE; PULMONARY EOSINOPHILIA; ANTIGENIC STRUCTURE; INNATE IMMUNITY; CELL RESPONSES; FUSION PROTEIN; RSV INFECTION AB The cytotoxic T-lymphocyte (CTL) response is important for the control of viral replication during respiratory syncytial virus (RSV) infection. The attachment glycoprotein (G) of RSV does not encode major histocompatibility complex class I-restricted epitopes in BALB/c mice (H-2(d)). Furthermore, studies to date have described an absence of significant CTL activity directed against this protein in humans. Therefore, G previously was not considered necessary for the generation of RSV-specific CTL responses. In this study, we demonstrate that, despite lacking H-2(d)-restricted epitopes, G enhances the generation of an effective CTL response against RSV. Furthermore, we show that this stimulatory effect is independent of virus titers and RSV-induced inflammation; that it is associated primarily with the secreted form of G; and that the effect depends on the cysteine-rich region of G (GCRR), a segment conserved in wild-type isolates worldwide. These findings reveal a novel function for the GCRR with potential implications for the generation of protective cellular responses and vaccine development. C1 NIAID, NIH, Bethesda, MD USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. INFANT Fundac, Buenos Aires, DF, Argentina. Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC USA. RP Polack, FP (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, 615 N Wolfe St,E5202, Baltimore, MD 21205 USA. EM fpolack@jhsph.edu FU Intramural NIH HHS; NIAID NIH HHS [AI-054952, R01 AI054952, R21 AI054952] NR 49 TC 23 Z9 24 U1 0 U2 0 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 JUN PY 2006 VL 80 IS 12 BP 5854 EP 5861 DI 10.1128/JVI.02671-05 PG 8 WC Virology SC Virology GA 050QV UT WOS:000238103900021 PM 16731924 ER PT J AU Graff, J Torian, U Nguyen, H Emerson, SU AF Graff, J Torian, U Nguyen, H Emerson, SU TI A bicistronic subgenornic mRNA encodes both the ORF2 and ORF3 proteins of hepatitis E virus SO JOURNAL OF VIROLOGY LA English DT Article ID HEV; TRANSLATION; INFECTION; IDENTIFICATION; REPLICATION; INTERACTS; DOMAINS; GENOME; CELLS; BINDS AB Hepatitis E virus replicons containing the neomycin resistance gene expressed from open reading frames (ORFs) 2 and 3 were transfected into Huh-7 cells, and stable cell lines containing functional replicons were selected by constant exposure to G418 sulfate. Northern blot analyses detected full-length replicon RNA and a single subgenomic RNA. This subgenomic RNA, which was capped, initiated at nucleotide 5122 downstream of the first two methionine codons in ORF3 and was bicistronic; two closely spaced methionine codons in different reading frames were used for the initiation of ORF3 and ORF2 translation. C1 NIH, NIAID, LID, Mol Hepatitis Sect, Bethesda, MD 20892 USA. RP Graff, J (reprint author), NIH, NIAID, LID, Mol Hepatitis Sect, Bldg 50,Room 6535, Bethesda, MD 20892 USA. EM jgraff@niaid.nih.gov FU Intramural NIH HHS NR 25 TC 106 Z9 110 U1 0 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 JUN PY 2006 VL 80 IS 12 BP 5919 EP 5926 DI 10.1128/JV1.00046-06 PG 8 WC Virology SC Virology GA 050QV UT WOS:000238103900027 PM 16731930 ER PT J AU Zhi, N Mills, IP Lu, J Wong, S Filippone, C Brown, KE AF Zhi, Ning Mills, Ian P. Lu, Jun Wong, Susan Filippone, Claudia Brown, Kevin E. TI Molecular and functional analyses of a human parvovirus B19 infectious clone demonstrates essential roles for NS1, VP1, and the 11-kilodalton protein in virus replication and infectivity SO JOURNAL OF VIROLOGY LA English DT Article ID MINOR CAPSID PROTEIN; SICKLE-CELL-ANEMIA; UNIQUE REGION; IN-VITRO; NONSTRUCTURAL PROTEIN; PHOSPHOLIPASE A(2); IDENTIFICATION; TRANSCRIPTION; SURFACE; PROMOTER AB In an attempt to experimentally define the roles of viral proteins encoded by the B19 genome in the viral life cycle, we utilized the B19 infectious clone constructed in our previous study to create two groups of B19 mutant genomes: (i) null mutants, in which either a translational initiation codon for each of these viral genes was substituted by a translational termination codon or a termination codon was inserted into the open reading frame by a frameshift; and (ii) a deletion mutant, in which half of the hairpin sequence was deleted at both the 5' and the 3' termini. The impact of these mutations on viral infectivity, DNA replication, capsid protein production, and distribution was systematically examined. Null mutants of the NS and VP1 proteins or deletion of the terminal hairpin sequence completely abolished the viral infectivity, whereas blocking expression of the 7.5-kDa protein or the putative protein X had no effect on infectivity in vitro. Blocking expression of the proline-rich 11-kDa protein significantly reduced B19 viral infectivity, and protein studies suggested that the expression of the 11-kDa protein was critical for VP2 capsid production and trafficking in infected cells. These findings suggest a previously unrecognized role for the 11-kDa protein, and together the results enhance our understanding of the key features of the B19 viral genome and proteins. C1 NIH, Hematol Branch, Heart Lung & Blood Inst, Bethesda, MD 20892 USA. RP Zhi, N (reprint author), NIH, Hematol Branch, Heart Lung & Blood Inst, Bldg 10-CRC,Rm 3E-5272,10 Ctr Dr, Bethesda, MD 20892 USA. EM zhin@nhlbi.nih.gov FU Intramural NIH HHS NR 43 TC 61 Z9 65 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUN PY 2006 VL 80 IS 12 BP 5941 EP 5950 DI 10.1128/JVI.02430-05 PG 10 WC Virology SC Virology GA 050QV UT WOS:000238103900029 PM 16731932 ER PT J AU Kotelkin, A Belyakov, IM Yang, LJ Berzofsky, JA Collins, PL Bukreyev, A AF Kotelkin, A Belyakov, IM Yang, LJ Berzofsky, JA Collins, PL Bukreyev, A TI The NS2 protein of human respiratory syncytial virus suppresses the cytotoxic T-cell response as a consequence of suppressing the type I interferon response SO JOURNAL OF VIROLOGY LA English DT Article ID DOUBLE-STRANDED-RNA; TARGETED DISRUPTION; ANTIVIRAL CYTOKINES; EPITHELIAL-CELLS; VIRAL-INFECTION; GENE-EXPRESSION; DENDRITIC CELLS; VACCINIA VIRUS; M2-2 PROTEIN; INHIBITION AB The NS1 and NS2 proteins of human respiratory syncytial virus (HRSV) have been shown to antagonize the type I interferon (IFN) response, an effect subject to host range constraints. We have now found that the HRSV NS2 protein strongly controls IFN induction in mouse cells in vitro, validating the use of the mouse model to study the consequences of these gene deletions on host immunity. We evaluated the effects of deleting the NS1 and/or NS2 gene on the induction of HRSV-specific pulmonary cytotoxic T lymphocytes (CTL) in BALB/c and 129S6 mice in response to intranasal infection with HRSV lacking the NS1 and/or NS2 gene and subsequent challenge with wild-type (wt) HRSV. In mice infected with HRSV lacking the NS2 gene (Delta NS2) or lacking the NS2 gene in combination with the NS1 gene (Delta NS1/2 HRSV), the magnitude of the pulmonary CTL response was substantially elevated compared to that of mice infected with wt HRSV or the Delta NS1 mutant, whether measured by binding of CD8(+) cells to an HRSV-specific major histocompatibility complex class I tetramer, by measurement of CD8(+) cells secreting gamma interferon (IFN-gamma) in response to specific in vitro stimulation, or by a standard chromium release cell-killing assay. In contrast, in STAT1 knockout mice, which lack responsiveness to type I IFN, the level of IFN-gamma-secreting CD8(+) cells was not significantly different for HRSV lacking the NS2 gene, suggesting that the increase in CTL observed in IFN-responsive mice is type I IFN dependent. Thus, the NS2 protein of HRSV suppresses the CTL component of the adaptive immune response, and this appears to be a consequence of its suppression of type I IFN. C1 NIAID, NIH, Infect Dis Lab, Bethesda, MD 20892 USA. NIH, Mol Immunogenet & Vaccine Res Sect, Vaccine Branch, Natl Canc Inst, Bethesda, MD 20892 USA. RP Bukreyev, A (reprint author), NIAID, NIH, Infect Dis Lab, Bldg 50,Room 6505,50 South Dr,MSC 8007, Bethesda, MD 20892 USA. EM AB176v@nih.gov FU Intramural NIH HHS NR 52 TC 24 Z9 25 U1 0 U2 0 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 JUN PY 2006 VL 80 IS 12 BP 5958 EP 5967 DI 10.1128/JVI.00181-06 PG 10 WC Virology SC Virology GA 050QV UT WOS:000238103900031 PM 16731934 ER PT J AU Iwatani, Y Takeuchi, H Strebel, K Levin, JG AF Iwatani, Y Takeuchi, H Strebel, K Levin, JG TI Biochemical activities of highly purified, catalytically active human APOBEC3G: Correlation with antiviral effect SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; B MESSENGER-RNA; VIF PROTEIN; REVERSE TRANSCRIPTION; CYTIDINE DEAMINASE; DNA-SYNTHESIS; HIV-1 VIF; RETROVIRAL INFECTION; NUCLEOCAPSID PROTEIN; SOR GENE AB APOBEC3G (APO3G), a cytidine deaminase with two zinc finger domains, inhibits human immunodeficiency virus type I replication in the absence of Vif. Here, we provide a comprehensive molecular analysis of the deaminase and nucleic acid binding activities of human APO3G using a pure system containing only one protein component, i.e., highly purified, catalytically active enzyme expressed in a baculovirus system. We demonstrate that APO3G deaminates cytosines in single-stranded DNA (ssDNA) only, whereas it binds efficiently to ssDNA and ssRNA, about half as well to a DNA/RNA hybrid, and poorly to double-stranded DNA and RNA. In addition, the base specificities for deamination and binding of ssDNA are not correlated. The minimum length required for detection of APO3G binding to an ssDNA oligonucleotide in an electrophoretic mobility shift assay is 16 nucleotides. Interestingly, if nucleocapsid protein and APO3G are present in the same reaction, we find that they do not interfere with each other's binding to RNA and a complex containing the RNA and both proteins is formed. Finally, we also identify the functional activities of each zinc finger domain. Thus, although both zinc finger domains have the ability to bind nucleic acids, the first zinc finger contributes more to binding and APO3G encapsidation into virions than finger two. In contrast, deamination is associated exclusively with the second zinc finger. Moreover, zinc finger two is more important than finger one for the antiviral effect, demonstrating a correlation between deaminase and antiviral activities. C1 NICHD, Mol Genet Lab, NIH, NICHHD,Natl Inst Allergy & Infect Dis, Bethesda, MD 20892 USA. NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. RP Levin, JG (reprint author), NICHD, Mol Genet Lab, NIH, NICHHD,Natl Inst Allergy & Infect Dis, Bldg 6B,Room 216, Bethesda, MD 20892 USA. EM levinju@mail.nih.gov RI Takeuchi, Hiroaki/F-9728-2012 FU Intramural NIH HHS NR 54 TC 109 Z9 112 U1 0 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 JUN PY 2006 VL 80 IS 12 BP 5992 EP 6002 DI 10.1128/JVI.02680-05 PG 11 WC Virology SC Virology GA 050QV UT WOS:000238103900035 PM 16731938 ER PT J AU Brann, TW Dewar, RL Jiang, MK Shah, A Nagashima, K Metcalf, JA Falloon, J Lane, HC Imamichi, T AF Brann, TW Dewar, RL Jiang, MK Shah, A Nagashima, K Metcalf, JA Falloon, J Lane, HC Imamichi, T TI Functional correlation between a novel amino acid insertion at codon 19 in the protease of human immunodeficiency virus type 1 and polymorphism in the p1/p6 gag cleavage site in drug resistance and replication fitness SO JOURNAL OF VIROLOGY LA English DT Article ID REVERSE-TRANSCRIPTASE; VIRAL FITNESS; PHENOTYPIC ANALYSIS; NUCLEOSIDE ANALOGS; TREATMENT FAILURE; PAIR INSERTION; HIV-1 PROTEASE; IN-VITRO; INHIBITOR; MUTATIONS AB Population-based sequence analysis revealed the presence of a variant of human immunodeficiency virus type 1 (HIV-1) containing an insertion of amino acid Ile in the protease gene at codon 19 (191) and amino acid substitutions in the protease at codons 21 (E21D) and 22 (A22V) along with multiple mutations associated with drug resistance, M46I/P63L/A7IV/I84V/I93L, in a patient who had failed protease inhibitor (PI) therapy. Longitudinal analysis revealed that the P63L/A71V/I93L changes were present prior to PI therapy. Polymorphisms in the Gag sequence were only seen in the p1/p6 cleavage site at the P1' position (Len to Pro) and the P5' position (Pro to Leu). To characterize the role of these mutations in drug susceptibility and replication capacity, a chimeric HIV-1 strain containing the 19I/E21D/A22V mutations with the M46I/P63L/A71V/I84V/ 193L and p16 mutations was constructed. The chimera displayed high-level resistance to multiple PIs, but not to lopinavir, and grew to 30% of that of the wild type. To determine the relative contribution of each mutation to the phenotypic characteristic of the virus, a series of mutants was constructed using site-directed mutagenesis. A high level of resistance was only seen in mutants containing the 19IA22V and p1p6 mutations. The E21D mutation enhanced viral replication. These results suggest that the combination of the 19I/E21D/A22V mutations may emerge and lead to high-level resistance to multiple PIs. The combination of the 19I/A22V mutations may be associated with PI resistance; however, the drug resistance may be caused by the presence of a unique set of mutations in the p1/p6 mutations. The E21D mutation contributes to replication fitness rather than drug resistance. C1 SAIC Frederick Inc, Lab Human Retrovirol, Appl & Dev Res Directorate, Clin Serv Program, Ft Detrick, MD 21702 USA. SAIC Frederick Inc, Virus Isolat & Serol Lab, Ft Detrick, MD 21702 USA. SAIC Frederick Inc, Image Anal Lab, Ft Detrick, MD 21702 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Imamichi, T (reprint author), SAIC Frederick Inc, Lab Human Retrovirol, Appl & Dev Res Directorate, Clin Serv Program, Bldg 550,Room 126, Ft Detrick, MD 21702 USA. EM timamichi@niaid.nih.gov FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 45 TC 14 Z9 14 U1 0 U2 0 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 JUN PY 2006 VL 80 IS 12 BP 6136 EP 6145 DI 10.1128/JVI.02212-05 PG 10 WC Virology SC Virology GA 050QV UT WOS:000238103900049 PM 16731952 ER PT J AU Massad, LS Evans, CT Minkoff, H Watts, DH Greenblatt, RM Levine, AM Anastos, K Young, M Seifer, DB Golub, E Cohen, M AF Massad, L. Stewart Evans, Charlesnika T. Minkoff, Howard Watts, D. Heather Greenblatt, Ruth M. Levine, Alexandra M. Anastos, Kathryn Young, Mary Seifer, David B. Golub, Elizabeth Cohen, Mardge TI Effects of HIV infection and its treatment on self-reported menstrual abnormalities in women SO JOURNAL OF WOMENS HEALTH LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; INTERAGENCY HIV; DISORDERS; CYCLE AB Objective: To describe menstrual abnormalities among women with HIV. Methods: Women in a multicenter prospective cohort study of HIV natural history reported menstrual abnormalities every 6-months between October 1994 and September 2002. Logistic regression and Cox proportional-hazards models were applied. Results: The prevalence and incidence of menstrual abnormalities were < 20%. HIV serostatus was not associated with prevalent menstrual abnormalities, but in HIV-seropositive women, higher CD4 counts were associated with fewer problems: compared with women with CD4 counts < 200/mm(3), in women with counts 200-500/mm(3), odds ratio (OR) for amenorrhea was 0.55, p = 0.02, and for oligomenorrhea was 0.54, p = 0.0003; for women with counts > 500/mm(3), OR for amenorrhea was 0.67, p = 0.14, and for oligomenorrhea was 0.55, p = 0.001. HIV serostatus was not associated with incident abnormalities. Highly active anti-retroviral therapy (HAART) use was not associated with prevalent abnormalities, but both HAART use and higher CD4 counts were linked to lower rates of incident menstrual problems. Conclusions: Compared with seronegative women, HIV-seropositive women are at increased risk for some menstrual changes, although the absolute frequency of most abnormalities is low. Higher CD4 counts and HAART protect against incident abnormalities. C1 So Illinois Univ, Sch Med, Dept Obstet & Gynecol, Springfield, IL 62794 USA. Univ Illinois, Sch Publ Hlth, Chicago, IL USA. SUNY, Maimonides Med Ctr, Brooklyn, NY USA. NICHHD, Bethesda, MD 20892 USA. Univ Calif San Francisco, Sch Med, San Francisco, CA 94143 USA. Univ So Calif, Keck Sch Med, Los Angeles, CA USA. Montefiore Med Ctr, Bronx, NY 10467 USA. Georgetown Univ, Sch Med, Washington, DC USA. Maimonides Hosp, New York, NY USA. Mt Sinai Sch Med, New York, NY USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. Cook Cty Hosp, Chicago, IL 60612 USA. RP Massad, LS (reprint author), So Illinois Univ, Sch Med, Dept Obstet & Gynecol, POB 19640, Springfield, IL 62794 USA. EM LSMASSAD@ameritech.net OI Seifer, David/0000-0003-3950-9341 FU NCRR NIH HHS [M01-RR-00079, M-01-RR-00083]; NIAID NIH HHS [U01-AI-34993, U01-AI-31834, U01-AI-34994, U01-AI-35004, U01-AI-42590]; NICHD NIH HHS [U01-HD-32632] NR 18 TC 21 Z9 21 U1 0 U2 1 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 JUN PY 2006 VL 15 IS 5 BP 591 EP 598 DI 10.1089/jwh.2006.15.591 PG 8 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 061PZ UT WOS:000238886000013 PM 16796486 ER PT J AU Sierra, F AF Sierra, F TI Is (your cellular response to) stress killing you? SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Editorial Material ID ENDOPLASMIC-RETICULUM STRESS; LIFE-SPAN; OXIDATIVE STRESS; MICE; CELLS; CANCER; TRANSCRIPTION; INSTABILITY; MECHANISMS; SENESCENCE AB Free radicals provide a generally accepted explanation for age-related decline in tissue function. However, the free radical hypothesis does not provide a mechanistic course of action to explain exactly how damage to macromolecules translates into the recognizable pathophysiology of aged organisms. Recent advances in the fields of DNA damage and cellular senescence point towards a substantial role for the DNA damage response, rather than DNA mutations per se, in the genesis of cellular and/or tissue damage. Furthermore, several studies suggest that protein damage can be at least as important as DNA damage in bringing about the aging phenotype. Here we propose that a "protein damage response," namely the ER/UPR (endoplasmic reticulum/unfolded protein) stress response is likely to play an important role in the aging process. C1 NIA, NIH, Bethesda, MD 20892 USA. RP Sierra, F (reprint author), NIA, NIH, 7201 Wisonsin Ave,Suite 2C231, Bethesda, MD 20892 USA. EM sierraf@nia.nih.gov NR 35 TC 10 Z9 11 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUN PY 2006 VL 61 IS 6 BP 557 EP 561 PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 056GY UT WOS:000238511400005 PM 16799136 ER PT J AU Maggio, M Guralnik, JM Longo, DL Ferrucci, L AF Maggio, M Guralnik, JM Longo, DL Ferrucci, L TI Interleukin-6 in aging and chronic disease: A magnificent pathway SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Review ID C-REACTIVE PROTEIN; ANTI-INTERLEUKIN-6 RECEPTOR ANTIBODY; SOLUBLE IL-6 RECEPTOR; NF-KAPPA-B; INFLAMMATORY-BOWEL-DISEASE; POTENT ANTITUMOR-ACTIVITY; MULTIPLE-MYELOMA CELLS; NECROSIS-FACTOR-ALPHA; GROWTH-FACTOR-I; SERUM INTERLEUKIN-6 AB The human interleukin IL-6 was originally cloned in 1986. In 1993, William Ershler, in his article "IL-6: A Cytokine for Gerontologists," indicated IL-6 as one of the main signaling pathways modulating the complex relationship between aging and chronic morbidity. Over the last 12 years, our understanding of the role of IL-6 in human physiology and pathology has substantially grown, although some of the questions originally posed by Ershler are still debated. In this review, we will focus on IL-6 structure, IL-6 signaling, and trans signaling pathways, and the role of IL-6 in geriatric syndromes and chronic disease. In the final section of this review, we dissect the critical elements of the IL-6 signaling pathway and point out targets for intervention that are targeted by emerging drugs, some still on the horizon and others already being tested in clinical trials. C1 NIA, Clin Res Branch, Longitudinal Studies Sect, NIH, Baltimore, MD USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD USA. RP Ferrucci, L (reprint author), NIA ASTRA, Unit Harbor Hosp, NIA, NIH, 3001 S Hanover St, Baltimore, MD 21225 USA. EM ferruccilu@grc.nia.nih.gov FU Intramural NIH HHS [Z99 AG999999] NR 162 TC 188 Z9 194 U1 1 U2 6 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUN PY 2006 VL 61 IS 6 BP 575 EP 584 PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 056GY UT WOS:000238511400008 PM 16799139 ER PT J AU Bartali, B Frongillo, EA Bandinelli, S Lauretani, F Semba, RD Fried, LP Ferrucci, L AF Bartali, B Frongillo, EA Bandinelli, S Lauretani, F Semba, RD Fried, LP Ferrucci, L TI Low nutrient intake is an essential component of frailty in older persons SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID MUSCLE; AGE; DISABILITY; INCHIANTI; DECLINE AB Background. Poor nutrient intake is conceptualized to be a component of frailty, but this hypothesis has been little investigated. We examined the association between low energy and nutrient intake and frailty. Methods. We used data from 802 persons aged 65 years or older participating to the InCHIANTI (Invecchiare in Chianti, aging in the Chianti area) study. Frailty was defined by having at least two of the following criteria: low muscle strength, feeling of exhaustion, low walking speed, and reduced physical activity. The European Prospective Investigation into Cancer and nutrition (EPIC) questionnaire was used to estimate the daily intake of energy and nutrients. Low intake was defined using the value corresponding to the lowest sex-specific intake quintile of energy and specific nutrients. Adjusted logistic regression analyses were used to study the association of frailty and frailty criteria with low intakes of energy and nutrients. Results. Daily energy intake <= 21 kcal/kg was significantly associated with frailty (odds ratio [OR]: 1.24; 95% Cl: 1.02-1.5). After adjusting for energy intake, a low intake of protein (OR: 1.98; 95% Cl: 1.18-3.31); vitamins D (OR: 2.35; 95% Cl: 1.48-3.73), E (OR: 2.06; 95% Cl: 1.28-3.33), C (OR: 2.15; 95% Cl: 1.34-3.45), and folate (OR: 1.84; 95% Cl: 1.14-2.98); and having a low intake of more than three nutrients (OR: 2.12; 95% Cl: 1.29-3.50) were significantly and independently related to frailty. Conclusions. This study provides evidence that low intakes of energy and selected nutrients are independently associated with frailty. C1 Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. Italina Natl Res Council Aging, Geriatr Dept, Lab Clin Epidemiol, Florence, Italy. Johns Hopkins Med Inst, Baltimore, MD USA. Natl Inst Aging, Longitudinal Studies Sect Clin Res Branch, NIH, Baltimore, MD USA. RP Bartali, B (reprint author), Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. EM bb232@cornell.edu RI Lauretani, Fulvio/K-5115-2016 OI Lauretani, Fulvio/0000-0002-5287-9972 FU Intramural NIH HHS [Z99 AG999999]; NIA NIH HHS [R01 AG027012, R37 AG019905]; NIMHD NIH HHS [263 MD 821336, 263 MD 9164 13, R01 MD009164] NR 26 TC 149 Z9 154 U1 7 U2 23 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUN PY 2006 VL 61 IS 6 BP 589 EP 593 PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 056GY UT WOS:000238511400010 PM 16799141 ER PT J AU Hu, PF Bretsky, P Crimmins, EM Guralnik, JM Reuben, DB Seeman, TE AF Hu, PF Bretsky, P Crimmins, EM Guralnik, JM Reuben, DB Seeman, TE TI Association between serum beta-carotene levels and decline of cognitive function in high-functioning older persons with or without apolipoprotein E 4 alleles: MacArthur studies of successful aging SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID ALZHEIMERS-DISEASE; PLASMA ANTIOXIDANTS; NUTRITIONAL-STATUS; ALPHA-TOCOPHEROL; OXIDATIVE DAMAGE; ELDERLY PERSONS; APOE GENOTYPE; E TYPE-4; RISK; DEMENTIA AB Background. Growing evidence from animal studies suggests an interaction between antioxidants and apolipoprotein E (APOE) alleles on cognitive functioning. We used data from a 7-year cohort study of high-functioning older persons to explore whether the associations between serum beta-carotene level and subsequent decline of cognitive function differed by APOE 4 genotype. Methods. Baseline information on sociodemographic characteristics, serum beta-carotene level, inflammation markers, APOE genotype, and cognitive functioning measured by a 9-item Short Portable Mental Status Questionnaire (SPMSQ) was obtained in 455 survivors. Multivariable logistic regression analyses were used to examine the relation between high serum beta-carotene level and risk of SPMSQ score decline in participants with or without APOE 4 alleles, while adjusting for age, sex, race, baseline SPMSQ score, and other covariates. Results. Nine (2%) study participants had homozygous and 97 (21%) had heterozygous APOE 4 alleles. Two hundred forty-nine (55%) had decline of SPMSQ scores during the follow-up. The presence of an APOE 4 allele was associated with higher risk and larger magnitude of SPMSQ score decline. The adjusted odds ratio of high beta-carotene level for cognitive decline was 0.11 (95% confidence interval, 0.02-0.57) in participants with at least one APOE 4 allele and 0.89 (95% confidence interval, 0.54-1.47) among those who were APOE 4 negative. Conclusion. Among high-functioning older persons, antioxidants and beta-carotene in particular may offer protection from cognitive decline in persons with greater genetic susceptibility as evidenced by the presence of the A-POE 4 allele. C1 Univ Calif Los Angeles, Sch Med, Program Geriatr Med & Gerontol, Los Angeles, CA 90095 USA. Univ So Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD USA. Univ So Calif, Andrus Gerontol Ctr, Los Angeles, CA USA. RP Hu, PF (reprint author), Univ Calif Los Angeles, Sch Med, Program Geriatr Med & Gerontol, 10945 Le Conte Ave,Suite 2339, Los Angeles, CA 90095 USA. EM phu@mednet.ucla.edu FU NIA NIH HHS [P06 AG10415-11, AG-17056, AG-17265] NR 39 TC 27 Z9 28 U1 0 U2 2 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUN PY 2006 VL 61 IS 6 BP 616 EP 620 PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 056GY UT WOS:000238511400014 PM 16799145 ER PT J AU Fox, CS Larson, MG Hwang, SJ Leip, EP Rifai, N Levy, D Benjamin, EJ Murabito, JM Meigs, JB Vasan, RS AF Fox, C. S. Larson, M. G. Hwang, S-J Leip, E. P. Rifai, N. Levy, D. Benjamin, E. J. Murabito, J. M. Meigs, J. B. Vasan, R. S. TI Cross-sectional relations of serum aldosterone and urine sodium excretion to urinary albumin excretion in a community-based sample SO KIDNEY INTERNATIONAL LA English DT Article DE urinary albumin excretion; aldosterone; urine sodium; Framingham Heart Study; epidemiology ID PRONE HYPERTENSIVE-RATS; NITRIC-OXIDE; BLOOD-PRESSURE; GLOMERULAR HYPERFILTRATION; ENDOTHELIAL DYSFUNCTION; CARDIOVASCULAR-DISEASE; DIABETES-MELLITUS; NONDIABETIC INDIVIDUALS; VASCULAR INJURY; RENAL-DISEASE AB Experimental models suggest that increased aldosterone and sodium intake are associated with renovascular damage and resultant proteinuria. We hypothesized that serum aldosterone and urinary sodium would be associated with urinary albumin excretion, an indicator of kidney damage. We evaluated 2700 participants (53% women, mean age 58 years) from the Framingham Offspring Study who attended a routine examination between 1995 and 1998, who were free of heart failure and renal failure, and underwent testing for serum aldosterone, spot urinary sodium, and urinary albumin excretion (urine albumin/ creatinine ratio, UACR), the latter two indexed to urinary creatinine. Stepwise multivariable linear regression was used to evaluate the relations between UACR with urinary sodium index and serum aldosterone. In multivariable regression, log urinary sodium index was associated positively with log-UACR (P < 0.0001). UACR levels in the fourth and fifth quintiles of urinary sodium index were 24% (95% confidence interval (Cl) 3-49%), and twofold higher (95% Cl 72-150%), respectively, relative to the lowest quintile (P-value for trend across quintiles < 0.001). In multivariable models, log-transformed aldosterone was not related to log-UACR. The top quintile of serum aldosterone levels was associated with a 21% higher (95% 1-44%) UACR levels relative to the lowest quintile. Urinary albumin excretion was strongly and positively associated in a continuous fashion with urinary sodium excretion, whereas a weaker nonlinear positive relation with serum aldosterone was noted. Our cross-sectional observations raise the possibility that dietary salt intake may be associated with early renovascular damage. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. Harvard Univ, Brigham & Womens Hosp, LeDucq Ctr Cardiovasc Res, Dept Med,Med Sch, Boston, MA 02115 USA. Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02118 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Larson, Martin/0000-0002-9631-1254; Murabito, Joanne/0000-0002-0192-7516; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [1R01HL67288, 2K24HL04334, N01-HC-25195] NR 58 TC 33 Z9 34 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUN PY 2006 VL 69 IS 11 BP 2064 EP 2069 DI 10.1038/sj.ki.5000378 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 050TS UT WOS:000238112100027 PM 16572107 ER PT J AU Gipson, C Wigglesworth, C AF Gipson, Chester Wigglesworth, Carol TI A word from USDA and OLAW SO LAB ANIMAL LA English DT Editorial Material C1 NIH, OLAW, OER, OD,HHS, Bethesda, MD 20892 USA. RP Gipson, C (reprint author), NIH, OLAW, OER, OD,HHS, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD JUN PY 2006 VL 35 IS 6 BP 17 EP 17 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 070TG UT WOS:000239546500005 PM 16582893 ER PT J AU Yang, J Yang, MQ AF Yang, J. Yang, M. Q. TI Data mining and knowledge discovery methodology development using predicting transmembrane proteins by synergy of computational and molecule biophysics approaches as an example SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY JUL 30-AUG 03, 2006 CL Orlando, FL SP Amer Assoc Physicists Med C1 Harvard Univ, Sch Med, Boston, MA USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 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 JUN PY 2006 VL 33 IS 6 BP 2009 EP 2009 DI 10.1118/1.2240295 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 058TW UT WOS:000238688500155 ER PT J AU Li, G Xie, H Ning, H Citrin, D Capala, J Arora, B Coleman, C Camphausen, K Miller, R AF Li, G. Xie, H. Ning, H. Citrin, D. Capala, J. Arora, B. Coleman, C. Camphausen, K. Miller, R. TI High accuracy of volumetric image registration of CT, NIR and PET images SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY JUL 30-AUG 03, 2006 CL Orlando, FL SP Amer Assoc Physicists Med C1 NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 2006 VL 33 IS 6 BP 2037 EP 2037 DI 10.1118/1.2240851 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 058TW UT WOS:000238688500271 ER PT J AU Ning, H Chin, B Karimpour, S Li, G Xie, H Miller, R AF Ning, H. Chin, B. Karimpour, S. Li, G. Xie, H. Miller, R. TI A pesudo-IMRT method for improving the dose uniformity in the spine in cranial-spinal irradaition SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY JUL 30-AUG 03, 2006 CL Orlando, FL SP Amer Assoc Physicists Med C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 2006 VL 33 IS 6 BP 2059 EP 2059 DI 10.1118/1.2240943 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 058TW UT WOS:000238688501061 ER PT J AU Deye, J AF Deye, J. TI Shielding I: New NCRP report: General report background and formulation SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY JUL 30-AUG 03, 2006 CL Orlando, FL SP Amer Assoc Physicists Med C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 JUN PY 2006 VL 33 IS 6 BP 2157 EP 2157 DI 10.1118/1.2241398 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 058TW UT WOS:000238688501471 ER PT J AU Hazle, J Clarke, L Jackson, E Humm, J AF Hazle, J. Clarke, L. Jackson, E. Humm, J. TI Molecular Imaging II - Applications SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY JUL 30-AUG 03, 2006 CL Orlando, FL SP Amer Assoc Physicists Med C1 UT MD Anderson Canc Ctr, Houston, TX USA. NCI, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 2006 VL 33 IS 6 BP 2197 EP 2197 DI 10.1118/1.2241554 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 058TW UT WOS:000238688502107 ER PT J AU Deye, J AF Deye, J. TI NCI talk on funding SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY JUL 30-AUG 03, 2006 CL Orlando, FL SP Amer Assoc Physicists Med C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 2006 VL 33 IS 6 BP 2226 EP 2226 DI 10.1118/1.2241669 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 058TW UT WOS:000238688502216 ER PT J AU Deye, J AF Deye, J. TI NCI perspective on clinical trials for emerging RT SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 48th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY JUL 30-AUG 03, 2006 CL Orlando, FL SP Amer Assoc Physicists Med C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 2006 VL 33 IS 6 BP 2238 EP 2238 DI 10.1118/1.2241735 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 058TW UT WOS:000238688502263 ER PT J AU Lohman, TG Ring, K Schmitz, KH Treuth, MS Loftin, M Yang, S Sothern, M Going, S AF Lohman, TG Ring, K Schmitz, KH Treuth, MS Loftin, M Yang, S Sothern, M Going, S TI Associations of body size and composition with physical activity in adolescent girls SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE exercise; fat mass; fat-free mass; body weight; physical activity ID NUTRITION EXAMINATION SURVEY; SOCIOECONOMIC-STATUS; ENERGY-EXPENDITURE; NATIONAL-HEALTH; WEIGHT STATUS; US CHILDREN; OBESITY; OVERWEIGHT; CHILDHOOD; FAT AB Purpose: To examine whether components of body composition (size, fat mass, and fat-free mass) were related to physical activity. Methods: A random sample of 60 eligible sixth grade girls at each of 36 schools (six schools per region and six regions in total sample); complete measurements on 1553 girls. Physical activity was assessed over 6 d in each girl using an accelerometer, and body composition was assessed using a multiple regression equation using body mass index and triceps skinfold. Minutes of moderate-to-vigorous and vigorous physical activity were estimated from accelerometer counts per 30 s above threshold values determined from a previous study. Results: Significant inverse relationships were found for all measures of body size and composition and all physical activity indices. The combination of fat and fat-free mass expressed as a weight and as an index (divided by height squared) along with race, SES, site, and school were most highly associated with physical activity in multiple regression analysis, accounting for 14-15% of the variance in physical activity. Fat mass was more closely related to moderate-to-vigorous physical activity (MVPA) and vigorous physical activity (VPA) than fat-free mass with higher standardized regression coefficients. Conclusion: We conclude that both fat mass or fat mass index as well as fat-free mass or fat-free mass index make independent contributions in association with physical activity levels. These indices are recommended for future studies. C1 Univ Arizona, Dept Physiol, Tucson, AZ 85721 USA. Univ Arizona, Dept Nutr Sci, Tucson, AZ 85721 USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. Univ Minnesota, Div Epidemiol, Minneapolis, MN 55455 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Human Nutr, Baltimore, MD USA. Univ New Orleans, Dept Human Performance & Hlth Promot, New Orleans, LA 70148 USA. Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. NHLBI, Bethesda, MD 20892 USA. RP Lohman, TG (reprint author), Univ Arizona, Dept Physiol, 1713 E Univ Blvd,93, Tucson, AZ 85721 USA. EM lohman@u.arizona.edu RI Schmitz, Kathryn/B-7154-2011 FU NHLBI NIH HHS [U01HL66857, U01 HL066845, U01 HL066852, U01 HL066853, U01 HL066855, U01 HL066856, U01 HL066857, U01 HL066858, U01 HL066858-04, U01HL66845, U01HL66852, U01HL66853, U01HL66855, U01HL66856, U01HL66858] NR 30 TC 21 Z9 21 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD JUN PY 2006 VL 38 IS 6 BP 1175 EP 1181 DI 10.1249/01.mss.0000222846.27380.61 PG 7 WC Sport Sciences SC Sport Sciences GA 052BI UT WOS:000238205200021 PM 16775560 ER PT J AU Fernandez, WG Hartman, R Olshaker, J AF Fernandez, WG Hartman, R Olshaker, J TI Brief interventions to reduce harmful alcohol use among military personnel: Lessons learned from the civilian experience SO MILITARY MEDICINE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; BRIEF PHYSICIAN ADVICE; EMERGENCY-DEPARTMENT; PRIMARY-CARE; SUBSTANCE-ABUSE; DRINKERS; METAANALYSIS; CONSUMPTION; VETERANS; DRINKING AB Unhealthy alcohol use is among the leading causes of morbidity and mortality in the United States. Among military personnel, service members between the ages 18 and 25 had a 27.3% prevalence of heavy drinking in the previous 30 days, compared to 15.3% among civilians in the same age group. In the civilian world, >100 million patients are treated in U.S. emergency departments (ED) annually; 7.9% of these visits are alcohol related. Alcohol is associated with a broad range of health consequences that may ultimately present in the ED setting: traumatic injuries (e.g., motor vehicle crashes, intentional violence, falls); environmental injuries (e.g., frostbite); cardiovascular problems (e.g., hypertension, dilated cardiomyopathy); gastrointestinal disorders (e.g., hepatitis, pancreatitis, gastrointestinal bleeding); neurological problems (e.g., encephalopathy, alcohol withdrawal, withdrawal seizures), as well as psychological problems (e.g., depression, suicide). Seminal work has been done to create behavioral interventions for at-risk drinkers. These motivational interventions have been found to be successful in encouraging clients to change their risky behaviors. We present such a technique, called the Brief Negotiated Interview as performed in a civilian ED setting, in hopes of adapting it for use in the military context. Military health care providers could easily adapt this technique to help reduce risky levels of alcohol consumption among service members, retirees, or military dependents. C1 Fleet Marine Forces Reserve, Med Battal 4, Surg Co Bravo, Detachment 5,Marine Logist Grp 4, Brooklyn, NY 11234 USA. NIAAA, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Boston Med Ctr, Dept Emergency Med, Boston, MA 02118 USA. RP Fernandez, WG (reprint author), Fleet Marine Forces Reserve, Med Battal 4, Surg Co Bravo, Detachment 5,Marine Logist Grp 4, Brooklyn, NY 11234 USA. NR 38 TC 10 Z9 10 U1 3 U2 4 PU ASSN MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 J9 MIL MED JI Milit. Med. PD JUN PY 2006 VL 171 IS 6 BP 538 EP 543 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 058IH UT WOS:000238658200022 PM 16808138 ER PT J AU Liepinsh, DJ Grivennikov, SI Klarmann, KD Lagarkova, MA Drutskaya, MS Lockett, SJ Tessarollo, L McAuliffe, M Keller, JR Kuprash, DV Nedospasov, SA AF Liepinsh, DJ Grivennikov, SI Klarmann, KD Lagarkova, MA Drutskaya, MS Lockett, SJ Tessarollo, L McAuliffe, M Keller, JR Kuprash, DV Nedospasov, SA TI Novel lymphotoxin alpha (LT alpha) knockout mice with unperturbed tumor necrosis factor expression: Reassessing LT alpha biological functions SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID LISTERIA-MONOCYTOGENES INFECTION; SECONDARY LYMPHOID-TISSUES; DEFICIENT MICE; GENE-EXPRESSION; IN-VIVO; ABNORMAL-DEVELOPMENT; TNF SUPERFAMILY; FACTOR-RECEPTOR; HOST-DEFENSE; BETA AB Lymphotoxin alpha (LT alpha) can exist in soluble form and exert tumor necrosis factor (TNF)-like activity through TNF receptors. Based on the phenotypes of knockout (KO) mice, the physiological functions of LT alpha and TNF are considered partly redundant, in particular, in supporting the microarchitecture of the spleen and in host defense. We exploited Cre-LoxP technology to generate a novel neomycin resistance gene (neo) cassette-free LT alpha-deficient mouse strain (neo-free LT alpha KO [LT alpha(Delta/Delta)]). Unlike the "conventional" LT alpha(-/-) mice, new LT alpha(Delta/Delta) animals were capable of producing normal levels of systemic TNF upon lipopolysaccharide (LPS) challenge and were susceptible to LPS/D-galactosamine (D-GaIN) toxicity. Activated neutrophils, monocytes, and macrophages from LT alpha(Delta/Delta) mice expressed TNF normally at both the mRNA and protein levels as opposed to conventional LT alpha KO mice, which showed substantial decreases in TNF. Additionally, the spleens of the neo-free LT alpha KO mice displayed several features resembling those of LT beta KO mice rather than conventional LT alpha KO animals. The phenotype of the new LT alpha(Delta/Delta) mice indicates that LT alpha plays a smaller role in lymphoid organ maintenance than previously thought and has no direct role in the regulation of TNF expression. C1 Russian Acad Sci, VA Engelhardt Mol Biol Inst, Lab Mol Immunol, Moscow 119991, Russia. Moscow MV Lomonosov State Univ, Belozerksy Inst Physicochem Biol, Lab Mol Immunol, Moscow 119991, Russia. NIH, Ctr Informat Technol, DCB, ISL,BIRSS, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Frederick, MD 21702 USA. NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. NCI, Image Anal Lab, Frederick, MD 21702 USA. NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. NCI, Basic Res Lab, Frederick, MD 21702 USA. NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. RP Nedospasov, SA (reprint author), Russian Acad Sci, VA Engelhardt Mol Biol Inst, Lab Mol Immunol, 32 Vavilov St, Moscow 119991, Russia. EM snedos@online.ru RI Nedospasov, Sergei/J-5936-2013; Nedospasov, Sergei/L-1990-2015; Kuprash, Dmitry/O-4899-2015; Nedospasov, Sergei/Q-7319-2016 OI Kuprash, Dmitry/0000-0002-1488-4148; FU Intramural NIH HHS; NCI NIH HHS [N01CO12400] NR 50 TC 25 Z9 25 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2006 VL 26 IS 11 BP 4214 EP 4225 DI 10.1128/MCB.01751-05 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 046CU UT WOS:000237789800019 PM 16705172 ER PT J AU Pilon, AM Nilson, DG Zhou, DW Sangerman, J Townes, TM Bodine, DM Gallagher, PG AF Pilon, AM Nilson, DG Zhou, DW Sangerman, J Townes, TM Bodine, DM Gallagher, PG TI Alterations in expression and chromatin configuration of the alpha hemoglobin-stabilizing protein gene in erythroid Kuppel-like factor-deficient mice SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID KRUPPEL-LIKE FACTOR; HUMAN GAMMA-GLOBIN; LOCUS-CONTROL REGION; TRANSCRIPTION FACTOR EKLF; CACCC PROMOTER ELEMENT; BETA-THALASSEMIA; BINDING-PROTEIN; MOUSE MODEL; REMODELING COMPLEX; ZINC-FINGER AB Erythroid Kriippel-like factor (EKLF) is an erythroid zinc finger protein identified by its interaction with a CACCC sequence in the beta-globin promoter, where it establishes local chromatin structure permitting P-globin gene transcription. We sought to identify other EKLF target genes and determine the chromatin status of these genes in the presence and absence of EKLF. We identified alpha hemoglobin-stabilizing protein (AHSP) by subtractive hybridization and demonstrated a 95 to 99.9% reduction in AHSP mRNA and the absence of AHSP in EKLF-deficient cells. Chromatin at the AHSP promoter from EKLF-deficient cells lacked a DNase I hypersensitive site and exhibited histone hypoacetylation across the locus compared to hyperacetylation of wild-type chromatin. Wild-type chromatin demonstrated a peak of EKLF binding over a promoter region CACCC box that differs from the EKLF consensus by a nucleotide. In mobility shift assays, the AHSP promoter CACCC site bound EKLF in a manner comparable to the beta-globin promoter CACCC site, indicating a broader recognition sequence for the EKLF consensus binding site. The AHSP promoter was transactivated by EKLF in K562 cells, which lack EKLF. These results support the hypothesis that EKLF acts as a transcription factor and a chromatin modulator for the AHSP and beta-globin genes and indicate that EKLF may play similar roles for other erythroid genes. C1 Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA. NHGRI, Hematopoiesis Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Univ Alabama, Sch Med & Dent, Dept Biochem & Mol Genet, Birmingham, AL 35294 USA. RP Gallagher, PG (reprint author), Yale Univ, Sch Med, Dept Pediat, 333 Cedar St,POB 208064, New Haven, CT 06520 USA. EM patrick.gallagher@yale.edu FU Intramural NIH HHS; NHLBI NIH HHS [HL65488, HL68965, R01 HL065448, R01 HL068965]; NIDDK NIH HHS [DK/HL62039] NR 77 TC 40 Z9 42 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2006 VL 26 IS 11 BP 4368 EP 4377 DI 10.1128/MCB.02216-05 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 046CU UT WOS:000237789800033 PM 16705186 ER PT J AU Boyer, L Turchi, L Desnues, B Doye, A Ponzio, G Mege, JL Yamashita, M Zhang, YE Bertoglio, J Flatau, G Boquet, P Lemichez, E AF Boyer, L Turchi, L Desnues, B Doye, A Ponzio, G Mege, JL Yamashita, M Zhang, YE Bertoglio, J Flatau, G Boquet, P Lemichez, E TI CNF1-induced ubiquitylation and proteasome destruction of activated RhoA is impaired in Smurf1(-/-) cells SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID NECROTIZING FACTOR-I; NUCLEOTIDE EXCHANGE FACTORS; BINDING PROTEIN-RHO; GROWTH-FACTOR-BETA; N-TERMINAL KINASE; ACTIN CYTOSKELETON; GTPASES; DEGRADATION; RAC; BIOLOGY AB Ubiquitylation of RhoA has emerged as an important aspect of both the virulence of Escherichia coli producing cytotoxic necrotizing factor (CNF) 1 toxin and the establishment of the polarity of eukaryotic cells. Owing to the molecular activity of CNF1, we have investigated the relationship between permanent activation of RhoA catalyzed by CNF1 and subsequent ubiquitylation of RhoA by Smurf1. Using Smurf1-deficient cells and by RNA interference (RNAi)-mediated Smurf1 knockdown, we demonstrate that Smurf1 is a rate-limiting and specific factor of the ubiquitin-mediated proteasomal degradation of activated RhoA. We further show that the cancer cell lines HEp-2, human embryonic kidney 293 and Vero are specifically deficient in ubiquitylation of either activated Rac, Cdc42, or Rho, respectively. In contrast, CNF1 produced the cellular depletion of all three isoforms of Rho proteins in the primary human cell types we have tested. We demonstrate that ectopic expression of Smurf1 in Vero cells, deficient for RhoA ubiquitylation, restores ubiquitylation of the activated forms of RhoA. We conclude here that Smurf1 ubiquitylates activated RhoA and that, in contrast to human primary cell types, some cancer cell lines have a lower ubiquitylation capacity of specific Rho proteins. Thus, both CNF1 and transforming growth factor-P trigger activated RhoA ubiquitylation through Smurf1 ubiquitin-ligase. C1 INSERM, Fac Med, U627, F-06107 Nice 2, France. INSERM, Fac Med, U634, F-06107 Nice, France. Univ Mediterranee, Fac Med, CNRS, Unite Rickettsies,Unite Mixte Rech 6020, F-13385 Marseille, France. NCI, Cellular & Mol Biol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. Univ Paris 11, Fac Pharm, INSERM, F-92290 Chatenay Malabry, France. RP Lemichez, E (reprint author), INSERM, Fac Med, U627, F-06107 Nice 2, France. EM lemichez@unice.fr RI Lemichez, Emmanuel/G-3559-2013; Zhang, Ying/G-3657-2015; Boyer, laurent/F-8921-2015; MEGE, JEAN-LOUIS/O-6063-2016; Desnues, Benoit/P-4725-2016; Ponzio, Gilles/Q-1256-2016 OI Lemichez, Emmanuel/0000-0001-9080-7761; Zhang, Ying/0000-0003-2753-7601; Boyer, laurent/0000-0002-1375-1706; Desnues, Benoit/0000-0003-1422-4294; Ponzio, Gilles/0000-0003-2741-0248 FU Intramural NIH HHS NR 34 TC 43 Z9 44 U1 0 U2 4 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUN PY 2006 VL 17 IS 6 BP 2489 EP 2497 DI 10.1091/mbc.E05-09-0876 PG 9 WC Cell Biology SC Cell Biology GA 049HJ UT WOS:000238006700001 PM 16540523 ER PT J AU Zhang, ZQ Wang, Y Yao, RS Lubet, RA You, M AF Zhang, ZQ Wang, Y Yao, RS Lubet, RA You, M TI p53 transgenic mice are highly susceptible to 4-nitroquinoline-1-oxide-induced oral cancer SO MOLECULAR CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; TUMOR-SUPPRESSOR GENE; CHEMOPREVENTIVE AGENTS; NECK-CANCER; A/J MICE; MUTATIONS; HEAD; OVEREXPRESSION; CARCINOGENESIS; PROGRESSION AB In this study, we did a bioassay employing mice with a dominant-negative p53 mutation (p53(Val135/WT)) to assess whether a germ-line p53 mutation predisposed mice toward the development of squamous cell carcinomas (SCC) in the oral cavity. Treatment of the mouse oral cavity with 4-nitroquinoline-1-oxide produced a 66%, 91%, and 20% tumor incidence in the oral cavity, esophagus, and forestomach/stomach, respectively, in p53(Val135/WT) mice. In contrast, only a 25%, 58%, and 4% tumor incidence was observed in oral cavity, esophagus, and forestomach/stomach, respectively, in wild-type littermates (p53(WT/WT)). The most striking difference between p53 (Val135/WT) and p53 WIT mice following the carcinogen treatment was the higher prevalence and more rapid development of SSC in p53(Val135/WT) mice than in wild-type mice. To identify the precise genes or pathways involved in these differences during tumor development, we examined gene expression profiles of 4-nitroquinoline-1-oxide-treated normal tongues as well as tongue SCC in p53(Val135/WT) and p53(WT/WT) mice. Microarray and GenMAPP analysis revealed that dominant-negative p53 ((135)Valp53) affects several cellular processes involved in SCC development. Affected processes included apoptosis and cell cycle arrest pathways, which were modulated in both tumor and normal epithelium. These results showed that reduction of p53-dependent apoptosis and increases in cell proliferation might contribute to the observed increase in oral cavity and gastroesophageal malignancies in p53(Val135/WT) mice as well as to the more rapid growth and progression of tumors. C1 Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. NCI, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. RP You, M (reprint author), Washington Univ, Sch Med, Dept Surg, 660 S Euclid Ave, St Louis, MO 63110 USA. EM youm@wustl.edu FU NCI NIH HHS [N01CN25104, R01CA58554] NR 31 TC 14 Z9 14 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD JUN PY 2006 VL 4 IS 6 BP 401 EP 410 DI 10.1158/1541-7786 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 054UC UT WOS:000238403100006 PM 16778087 ER PT J AU de la Pena, L Burgan, WE Carter, DJ Hollingshead, MG Satyamitra, M Camphausen, K Tofilon, PJ AF de la Pena, Lorena Burgan, William E. Carter, Donna J. Hollingshead, Melinda G. Satyamitra, Merriline Camphausen, Kevin Tofilon, Philip J. TI Inhibition of Akt by the alkylphospholipid perifosine does not enhance the radiosensitivity of human glioma cells SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID PROTEIN-KINASE-B; TUMOR-SUPPRESSOR GENES; IONIZING-RADIATION; SIGNALING PATHWAYS; VASCULAR ENDOTHELIUM; SURVIVAL PATHWAY; HUMAN CANCER; DNA-DAMAGE; IN-VIVO; PHASE-I AB Akt has been implicated as a molecular determinant of cellular radiosensitivity. Because it is often constitutively activated or overexpressed in malignant gliomas, it has been suggested as a target for brain tumor radiosensitization. To evaluate the role of Akt in glioma radioresponse, we have determined the effects of perifosine, a clinically relevant alkylphospholipid that inhibits Akt activation, on the radiosensitivity of three human glioma cell lines (U87, U251, and LN229). Each of the glioma cell lines expressed clearly detectable levels of phosphorylated Akt indicative of constitutive Akt activity. Exposure to a perifosine concentration that reduced survival by -50% significantly reduced the level of phosphorylated Akt as well as Akt activity. Cell survival analysis using a clonogenic assay, however, revealed that this Akt-inhibiting perifosine treatment did not enhance the radiosensitivity of the glioma cell lines. This evaluation was then extended to an in vivo model using U251 xenografts. Perifosine delivered to mice bearing U251 xenografts substantially reduced tumor phosphorylated Akt levels and inhibited tumor growth rate. However, the combination of perifosine and radiation resulted in a less than additive increase in tumor growth delay. Thus, in vitro and in vivo data indicate that the perifosine-mediated decrease in Akt activity does not enhance the radiosensitivity of three genetically disparate glioma cell lines. These results suggest that, although Akt may influence the radiosensitivity of other tumor types, it does not seem to be a target for glioma cell radio-sensitization. C1 NCI, Radiat Res Program, Mol Radiat Therapeut Branch, EPN 6004, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. NCI, Sci Applicat Int Corp, Frederick, MD 21701 USA. RP Tofilon, PJ (reprint author), NCI, Radiat Res Program, Mol Radiat Therapeut Branch, EPN 6004, 6130 Execut Blvd,MSC 7440, Bethesda, MD 20892 USA. EM tofilonp@mail.nih.gov FU NCI NIH HHS [N01-CO-12400] NR 53 TC 36 Z9 37 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 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUN PY 2006 VL 5 IS 6 BP 1504 EP 1510 DI 10.1158/1535-7163.MCT-06-0091 PG 7 WC Oncology SC Oncology GA 063OR UT WOS:000239029700015 PM 16818509 ER PT J AU Kar, S Wang, MF Yao, W Michejda, CJ Carr, BI AF Kar, Siddhartha Wang, Meifang Yao, Wei Michejda, Christopher J. Carr, Brian I. TI PM-20, a novel inhibitor of Cdc25A, induces extracellular signal-regulated kinase 1/2 phosphorylation and inhibits hepatocellular carcinoma growth in vitro and in vivo SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID PROTEIN-TYROSINE PHOSPHORYLATION; VITAMIN-K; CELL-GROWTH; PHOSPHATASE CDC25A; ACTIVATION; SPECIFICITY; CANCER; CYCLE; ANALOGS AB We have synthesized several new phenyl maleimide compounds, which are potent growth inhibitors of several human tumor cell lines. Among these, PM-20 was the most potent with an IC50 of 700 nmol/L for Hep3B human hepatoma cell growth. Two other derivatives, PM-26 and PM-38, did not inhibit Hep3B cell growth even at 100 [mu mol/L. Interestingly, under identical experimental conditions, PM-20 inhibited DNA synthesis of primary cultures of normal hepatocytes at a 10-fold higher concentration than that needed to inhibit the DNA synthesis of the Hep3B hepatoma cells. PM-20 affected two cellular signaling pathways in Hep3B cells: Cdc25 phosphatase and extracellular signal-regulated kinase (ERK) 1/2. It competitively inhibited the activity of Cdc25 (preferentially Cdc25A) by binding to the active site, likely through the catalytic cysteine, but did not inhibit PTP1B, CD45, or MKP-1 phosphatases. As a result of its action, tyrosine phosphorylation of the cellular Cdc25A substrates Cdk2 and Cdk4 was induced. It also induced strong and persistent phosphorylation of the Cdc25A substrate ERK 1/2. Hep3B cell lysates were found to contain ERK2 phosphatase(s) activity, which was inhibited by the actions of PM-20. However, activity of exogenous dual-specificity ERK2 phosphatase MKP1 was not inhibited. Induction of ERK1/2 phosphorylation correlated with the potency of growth inhibition in tumor cell lines and inhibition of ERK1/2 phosphorylation by the mitogen-activated protein kinase (MAPK)/ERK kinase 1/2 inhibitor U0126 or overexpression of the cdc25A gene in Hep3B cells antagonized the growth inhibitory actions of PM-20. Growth of transplantable rat hepatoma cells in vivo was also inhibited by PM-20 action with a concomitant induction of pERK in the tumors. The mechanism(s) of growth inhibition of Hep3B hepatoma cells by the phenyl maleimide PM-20 involves prolonged ERK1/2 phosphorylation, likely resulting from inhibition of the ERK phosphatase Cdc25A. PM-20 thus represents a novel class of tumor growth inhibitor that inhibits mainly Cdc25A, is dependent on ERK activation, and has a considerable margin of selectivity for tumor cells compared with normal cells. C1 Univ Pittsburgh, Liver Canc Ctr, Starzl Transplantat Inst, Pittsburgh, PA 15260 USA. NCI, Struct Biophys Lab, Frederick, MD 21701 USA. RP Carr, BI (reprint author), Univ Pittsburgh, Liver Canc Ctr, Starzl Transplantat Inst, E 1552 BST,200 Lothrop St, Pittsburgh, PA 15260 USA. EM carrbi@upmc.edu FU NCI NIH HHS [CA82723] NR 35 TC 33 Z9 34 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 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUN PY 2006 VL 5 IS 6 BP 1511 EP 1519 DI 10.1158/1535-7163.MCT-05-0485 PG 9 WC Oncology SC Oncology GA 063OR UT WOS:000239029700016 PM 16818510 ER PT J AU Rao, CV Reddy, BS Steele, VE Wang, CX Liu, XP Ouyang, NT Patlolla, JMR Simi, B Kopelovich, L Rigas, B AF Rao, Chinthalapally V. Reddy, Bandaru S. Steele, Vernon E. Wang, C-X Liu, Xiaoping Ouyang, Nengtai Patlolla, Jagan M. R. Simi, Barbara Kopelovich, Levy Rigas, Basil TI Nitric oxide-releasing aspirin and indomethacin are potent inhibitors against colon cancer in azoxymethane-treated rats: effects on molecular targets SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ABERRANT CRYPT FOCI; IN-VITRO METABOLISM; DONATING ASPIRIN; BETA-CATENIN; NITROASPIRIN NCX-4016; POSITIONAL ISOMERISM; TRADITIONAL NSAIDS; GROWTH-INHIBITION; CELL-GROWTH AB Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAID) are promising chemoprevention agents; unlike conventional NSAIDs, they seem free of appreciable adverse effects, while they retain beneficial activities of their parent compounds. Their effect on colon carcinogenesis using carcinoma formation as an end point is unknown. We assessed the chemopreventive properties of NO-indomethacin (NCX 530) and NO-aspirin (NCX 4016) against azoxymethane-induced colon cancer. Seven-week-old male F344 rats were fed control diet, and 1 week later, rats received two weekly s.c. injections of azoxymethane (15 mg/kg body weight). Two weeks after azoxymethane treatment, rats (48 per group) were fed experimental diets containing NO-indomethacin (0, 40, or 80 ppm), or NO-aspirin (1,500 or 3,000 ppm), representing 40% and 80% of the maximum tolerated dose. All rats were killed 48 weeks after azoxymethane treatment and assessed for colon tumor efficacy and molecular changes in colonic tumors and normally appearing colonic mucosa of different dietary groups. Our results suggest that NO-indomethacin at 40 and 80 ppm and NO-aspirin at 3,000 ppm significantly suppressed both tumor incidence (P < 0.01) and multiplicity (P < 0.001). The degree of inhibition was more pronounced with NO-indomethacin at both dose levels (72% and 76% inhibition) than with NO-aspirin (43% and 67%). NO-indomethacin at 40 and 80 ppm and NO-aspirin at 3,000 ppm significantly inhibited the colon tumors' [P < 0.01 to P < 0.001) total cyclooxygenase (COX), including COX-2 activity (5275% inhibition) and formation of prostaglandin E-2 (PGE(2)), PGF(2 alpha), and 6-keto-PGF(1 alpha), and TxB(2) from arachidonic acid (53-77% inhibition). Nitric oxide synthase 2 (NOS-2) activity and beta-catenin expression were suppressed in animals given NO-NSAID. In colonic crypts and tumors of animals fed these two NO-NSAIDs, there was a significant decrease in proliferating cell nuclear antigen labeling when compared with animals fed the control diet. The results of this study provide strong evidence that NO-NSAIDs possess strong inhibitory effect against colon carcinogenesis; their effect is associated with suppression of COX and NOS-2 activities and beta-catenin levels in colon tumors. These results pave the way for the rational design of human clinical trials. C1 Univ Oklahoma, Hlth Sci Ctr, Dept Med, Hem Onc Sect, Oklahoma City, OK 73104 USA. Rutgers State Univ, Coll Pharm, Dept Biol Chem, Piscataway, NJ 08855 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. SUNY Stony Brook, Div Canc Prevent, Stony Brook, NY 11794 USA. RP Rao, CV (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Med, Hem Onc Sect, Oklahoma City, OK 73104 USA. EM cv-rao@ouhsc.edu; brigas@notes.cc.suny.edu RI Chinthalapally, Rao/B-3633-2010 FU NCI NIH HHS [CA-92423, CA-94962, CA109247, N0-CN-05112] NR 46 TC 62 Z9 66 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUN PY 2006 VL 5 IS 6 BP 1530 EP 1538 DI 10.1158/1535-7163.MCT-06-0061 PG 9 WC Oncology SC Oncology GA 063OR UT WOS:000239029700018 PM 16818512 ER PT J AU Huang, BX Kim, HY AF Huang, BX Kim, HY TI Interdomain conformational changes in Akt activation revealed by chemical cross-linking and tandem mass spectrometry SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID PROTEIN-KINASE-B; PLECKSTRIN HOMOLOGY DOMAIN; LINKED PEPTIDES; SERUM-ALBUMIN; SURVIVAL; PHOSPHORYLATION; IDENTIFICATION; MECHANISM; ONCOGENE; PKB/AKT AB Akt, a serine/threonine kinase, plays a critical role in cell survival. Upon growth factor receptor stimulation, cytosolic Akt is recruited to the plasma membrane by phospholipid binding and activated through phosphorylation at Thr(308) and Ser(473). Although crystal structures for the parts of Akt have been reported, neither the three-dimensional structure of the whole molecule nor sequential conformational changes during activation have been demonstrated. In this study, we demonstrated that Akt undergoes dramatic interdomain conformational changes during activation processes by probing the three-dimensional structure of full-length Akt in solution using chemical cross-linking and tandem mass spectrometry. The cross-linking results not only provided new structural information but also revealed distinctive spatial arrangements of individual domains in the Akt molecule in resting, membrane-interacted, phosphorylated, and substrate-bound states. Our data allowed a new model for stepwise interdomain conformational changes in Akt activation sequence, setting a stage for the further investigation on Akt-membrane, Akt-protein, and/or Akt-drug interactions in solution to understand molecular mechanisms involved in physiological and pathophysiological processes of cell survival. C1 NIAAA, Sect Mass Spectrometry, Lab Membrane Biophys & Biochem, NIH, Bethesda, MD 20892 USA. RP Kim, HY (reprint author), NIAAA, Sect Mass Spectrometry, Lab Membrane Biophys & Biochem, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM hykim@nih.gov NR 34 TC 34 Z9 34 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD JUN PY 2006 VL 5 IS 6 BP 1045 EP 1053 DI 10.1074/mcp.M600026-MCP200 PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 053EM UT WOS:000238288100007 PM 16531397 ER PT J AU Cidlowski, JA AF Cidlowski, JA TI Molecular Endocrinology: Today and tomorrow SO MOLECULAR ENDOCRINOLOGY LA English DT Editorial Material C1 Natl Inst Environm Hlth Sci, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), Natl Inst Environm Hlth Sci, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUN PY 2006 VL 20 IS 6 BP 1200 EP 1200 DI 10.1210/me.2006-1115 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 046JC UT WOS:000237806900005 ER PT J AU Zemkova, H Balik, A Jiang, YH Kretschmannova, K Stojilkovic, SS AF Zemkova, H Balik, A Jiang, YH Kretschmannova, K Stojilkovic, SS TI Roles of purinergic P2X receptors as pacemaking channels and modulators of calcium-mobilizing pathway in pituitary gonadotrophs SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID INDUCED CA2+ OSCILLATIONS; ENDOPLASMIC-RETICULUM; MOLECULAR PHYSIOLOGY; CYTOPLASMIC CALCIUM; HORMONE RECEPTORS; PROLACTIN-RELEASE; ATP RECEPTORS; CELLS; EXPRESSION; DESENSITIZATION AB Anterior pituitary cells release ATP and express several subtypes of purinergic P2 receptors, but their biophysical properties and roles in spontaneous and receptor-controlled electrical activity have not been characterized. Here we focused on extracellular ATP actions in gonadotrophs from embryonic, neonatal, and adult rats. In cells from all three age groups, the Ca2+- mobilizing agonist GnRH induced oscillatory, hyperpolarizing, nondesensitizing, and slow deactivating currents. In contrast, ATP induced nonoscillatory, depolarizing, slowly desensitizing, and rapidly deactivating current, indicating that these cells express cation-conducting P2X channels but not Ca2+-mobilizing P2Y receptors. The amplitudes of P2X current response and the rates of receptor desensitization were dependent on ATP concentration. The biophysical and pharmacological properties of P2X currents were consistent with the expression of P2X(2) subtype of channels in these cells. ATP-induced rapid depolarization of gonadotrophs lead to initiation of firing in quiescent cells, an increase in the frequency of action potentials in spontaneously active cells, and a transient stimulation of LH release. ATP also influenced GnRH-induced current and membrane potential oscillations and LH release in an extracellular Ca2+- dependent manner. These inositol 1,4,5- triphosphate-dependent oscillations were facilitated, slowed, or stopped, depending of ATP concentration, the time of its application, and the level of Ca2+ content in intracellular stores. These results indicate that, in gonadotrophs, P2X receptors could operate as pacemaking channels and modulators of GnRH- controlled electrical activity and secretion. C1 NICHHD, Sect Cellular Signaling, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. Acad Sci Czech Republ, Inst Physiol, Prague 14220, Czech Republic. RP Stojilkovic, SS (reprint author), NICHHD, Sect Cellular Signaling, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. EM stojilks@mail.nih.gov RI Zemkova, Hana/C-1844-2012; Balik, Ales/C-1900-2012 FU Intramural NIH HHS NR 57 TC 20 Z9 20 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUN PY 2006 VL 20 IS 6 BP 1423 EP 1436 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 046JC UT WOS:000237806900022 PM 16543406 ER PT J AU Held, PK AF Held, PK TI Disorders of tyrosine catabolism SO MOLECULAR GENETICS AND METABOLISM LA English DT Article ID HEREDITARY TYROSINEMIA; FUMARYLACETOACETATE HYDROLASE; DIOXYGENASE; GENE; ALKAPTONURIA; MODEL; ACID; MICE C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Held, PK (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM heldp@mail.nih.gov NR 23 TC 15 Z9 15 U1 3 U2 76 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 JUN PY 2006 VL 88 IS 2 BP 103 EP 106 DI 10.1016/j.ymgme.2006.04.002 PG 4 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 048JW UT WOS:000237944400001 PM 16773741 ER PT J AU Dean, M AF Dean, M TI Cancer stem cells - Redefining the paradigm of cancer treatment strategies SO MOLECULAR INTERVENTIONS LA English DT Review ID ACUTE MYELOID-LEUKEMIA; BREAST-CANCER; HEPATOCELLULAR-CARCINOMA; MULTIDRUG-RESISTANCE; COLORECTAL-CANCER; HUMAN HOMOLOG; LUNG-CANCER; HEPATITIS-B; HEDGEHOG; NEOPLASIA AB Cancer has been known to arise from long-lived cells in the body and to possess properties in common with undifferentiated, embryonic cells. Recent findings of a population of cells in solid tumors resembling stem cells supports a stem cell model of cancer. A scheme in which all cancers initiate from "activated" stem cells helps bring together data from genetic, cell biology, and epidemiology studies. Cancer can arise from embryonic cells in the case of childhood tumors; hormone-activated stem cells in the case of breast cancer; and following chronic activation of stem cells caused by tissue damage. This scheme helps explain the failure of many cancer therapies, points out deficiencies in certain research approaches, and focuses the problem on a subset of cells that can be explicitly targeted, leading to more efficient therapy. C1 NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Dean, M (reprint author), NCI, Frederick Canc Res & Dev Ctr, Bldg 560, Frederick, MD 21702 USA. EM dean@ncifcrf.gov RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 NR 64 TC 39 Z9 44 U1 1 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 1534-0384 J9 MOL INTERV JI Mol. Interv. PD JUN PY 2006 VL 6 IS 3 BP 140 EP 148 DI 10.1124/mi.6.3.5 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 058UL UT WOS:000238690000004 PM 16809475 ER PT J AU Dai, QY Restrepo, BI Porcella, SF Raffel, SJ Schwan, TG Barbour, AG AF Dai, QY Restrepo, BI Porcella, SF Raffel, SJ Schwan, TG Barbour, AG TI Antigenic variation by Borrelia hermsii occurs through recombination between extragenic repetitive elements on linear plasmids SO MOLECULAR MICROBIOLOGY LA English DT Article ID LYME-DISEASE SPIROCHETE; BORNE RELAPSING FEVER; CIRCULAR PLASMIDS; AFRICAN TRYPANOSOMES; NORTH-AMERICA; BURGDORFERI; AGENT; SEQUENCE; GENES; BACTERIUM AB The relapsing fever agent Borrelia hermsii undergoes multiphasic antigenic variation through gene conversion of a unique expression site on a linear plasmid by an archived variable antigen gene. To further characterize this mechanism we assessed the repertoire and organization of archived variable antigen genes by sequencing similar to 85% of plasmids bearing these genes. Most archived genes shared with the expressed gene a <= 62 nucleotide (nt) region, the upstream homology sequence (UHS), that surrounded the start codon. The 59 archived variable antigen genes were arrayed in clusters with 13 repetitive, 214 nt long downstream homology sequence (DHS) elements distributed among them. A fourteenth DHS element was downstream of the expression locus. Informative nucleotide polymorphisms in UHS regions and DHS elements were applied to the analysis of the expression site of relapse serotypes from 60 infected mice in a prospective study. For most recombinations, the upstream crossover occurred in the UHS's second half, and the downstream crossover was in the DHS's second half. Usually the closest archival DHS element was used, but occasionally a more distant DHS was employed. The downstream extragenic crossover site in B. hermsii contrasts with the downstream extragenic crossover site for antigenic variation in African trypanosomes. C1 Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USA. Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. Univ Texas, Hlth Sci Ctr, Dept Microbiol, San Antonio, TX 78284 USA. Univ Texas, Sch Publ Hlth, Hlth Sci Ctr Houston, Brownsville, TX USA. NIAID, Rocky Mt Labs, Lab Zooton Pathogens, NIH, Hamilton, MT 59840 USA. RP Barbour, AG (reprint author), Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USA. EM abarbour@uci.edu RI Barbour, Alan/B-3160-2009 OI Barbour, Alan/0000-0002-0719-5248 FU Intramural NIH HHS; NIAID NIH HHS [AI24424] NR 47 TC 66 Z9 68 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUN PY 2006 VL 60 IS 6 BP 1329 EP 1343 DI 10.1111/j.1365-2958.2006.05177.x PG 15 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 046LG UT WOS:000237812500004 PM 16796672 ER PT J AU Rickard, AH Palmer, RJ Blehert, DS Campagna, SR Semmelhack, MF Egland, PG Bassler, BL Kolenbrander, PE AF Rickard, AH Palmer, RJ Blehert, DS Campagna, SR Semmelhack, MF Egland, PG Bassler, BL Kolenbrander, PE TI Autoinducer 2: a concentration-dependent signal for mutualistic bacterial biofilm growth SO MOLECULAR MICROBIOLOGY LA English DT Article ID QUORUM-SENSING SIGNAL; STREPTOCOCCUS-GORDONII; SALMONELLA-TYPHIMURIUM; INTERSPECIES COMMUNICATION; PORPHYROMONAS-GINGIVALIS; ACTINOMYCES-VISCOSUS; LUXS; COAGGREGATION; IDENTIFICATION; COLONIZATION AB 4,5-dihydroxy-2,3-pentanedione (DPD), a product of the LuxS enzyme in the catabolism of S-ribosylhomocysteine, spontaneously cyclizes to form autoinducer 2 (AI-2). AI-2 is proposed to be a universal signal molecule mediating interspecies communication among bacteria. We show that mutualistic and abundant biofilm growth in flowing saliva of two human oral commensal bacteria, Actinomyces naeslundii T14V and Streptococcus oralis 34, is dependent upon production of AI-2 by S. oralis 34. A luxS mutant of S. oralis 34 was constructed which did not produce AI-2. Unlike wild-type dual-species biofilms, A. naeslundii T14V and an S. oralis 34 luxS mutant did not exhibit mutualism and generated only sparse biofilms which contained a 10-fold lower biomass of each species. Restoration of AI-2 levels by genetic or chemical (synthetic AI-2 in the form of DPD) complementation re-established the mutualistic growth and high biomass characteristic for the wild-type dual-species biofilm. Furthermore, an optimal concentration of DPD was determined, above and below which biofilm formation was suppressed. The optimal concentration was 100-fold lower than the detection limit of the currently accepted AI-2 assay. Thus, AI-2 acts as an interspecies signal and its concentration is critical for mutualism between two species of oral bacteria grown under conditions that are representative of the human oral cavity. C1 NIH, NIDCR, Bethesda, MD 20892 USA. Princeton Univ, Dept Mol Biol, Dept Chem, Princeton, NJ 08544 USA. Princeton Univ, Howard Hughes Med Inst, Dept Biol Mol, Princeton, NJ 08544 USA. RP Kolenbrander, PE (reprint author), NIH, NIDCR, Bethesda, MD 20892 USA. EM pkolenbrander@dir.nidcr.nih.gov OI Campagna, Shawn/0000-0001-6809-3862 FU Intramural NIH HHS NR 34 TC 192 Z9 204 U1 5 U2 41 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUN PY 2006 VL 60 IS 6 BP 1446 EP 1456 DI 10.1111/j.1365-2958.2006.05202.x PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 046LG UT WOS:000237812500012 PM 16796680 ER PT J AU Franco, R Casado, V Mallol, J Ferrada, C Ferre, S Fuxe, K Cortes, A Ciruela, F Lluis, C Canela, EI AF Franco, R Casado, V Mallol, J Ferrada, C Ferre, S Fuxe, K Cortes, A Ciruela, F Lluis, C Canela, EI TI The two-state dimer receptor model: A general model for receptor dimers SO MOLECULAR PHARMACOLOGY LA English DT Article ID A(1) ADENOSINE RECEPTORS; CARDIAC MUSCARINIC RECEPTORS; PROTEIN-COUPLED RECEPTORS; TERNARY COMPLEX MODEL; OCCUPANCY MODEL; HIGH-AFFINITY; BINDING-PROPERTIES; ESTROGEN-RECEPTOR; LINKED RECEPTORS; CELL-MEMBRANE AB Nonlinear Scatchard plots are often found for agonist binding to G-protein-coupled receptors. Because there is clear evidence of receptor dimerization, these nonlinear Scatchard plots can reflect cooperativity on agonist binding to the two binding sites in the dimer. According to this, the "two-state dimer receptor model" has been recently derived. In this article, the performance of the model has been analyzed in fitting data of agonist binding to A 1 adenosine receptors, which are an example of receptor displaying concave downward Scatchard plots. Analysis of agonist/ntagonist competition data for dopamine D-1 receptors using the two-state dimer receptor model has also been performed. Although fitting to the two-state dimer receptor model was similar to the fitting to the "two-independent-site receptor model", the former is simpler, and a discrimination test selects the two-state dimer receptor model as the best. This model was also very robust in fitting data of estrogen binding to the estrogen receptor, for which Scatchard plots are concave upward. On the one hand, the model would predict the already demonstrated existence of estrogen receptor dimers. On the other hand, the model would predict that concave upward Scatchard plots reflect positive cooperativity, which can be neither predicted nor explained by assuming the existence of two different affinity states. In summary, the two-state dimer receptor model is good for fitting data of binding to dimeric receptors displaying either linear, concave upward, or concave downward Scatchard plots. C1 Univ Barcelona, Dept Bioquim & Biol Mol, E-08028 Barcelona, Spain. NIDA, NIH, Dept Hlth & Human Serv, Baltimore, MD USA. Karolinska Inst, Dept Neurosci, Div Cellular & Mol Neurochem, Stockholm, Sweden. RP Franco, R (reprint author), Univ Barcelona, Dept Bioquim & Biol Mol, Av Diagonal 645, E-08028 Barcelona, Spain. EM rfranco@ub.edu RI Canela, Enric I./M-8726-2013; Ferre, Sergi/K-6115-2014; Ciruela, Francisco/A-5096-2013; Franco, Rafael/C-3694-2015; Casado, Vicent/K-1660-2014; OI Canela, Enric I./0000-0003-4992-7440; Ferre, Sergi/0000-0002-1747-1779; Ciruela, Francisco/0000-0003-0832-3739; Franco, Rafael/0000-0003-2549-4919; Fuxe, Kjell/0000-0001-8491-4288; Casado, Vicent/0000-0002-1764-3825 NR 41 TC 56 Z9 57 U1 0 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUN PY 2006 VL 69 IS 6 BP 1905 EP 1912 DI 10.1124/mol.105.020685 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 044QU UT WOS:000237688100016 PM 16501032 ER PT J AU Ueda, R Iketaki, H Nagata, K Kimura, S Gonzalez, FJ Kusano, K Yoshimura, T Yamazoe, Y AF Ueda, R Iketaki, H Nagata, K Kimura, S Gonzalez, FJ Kusano, K Yoshimura, T Yamazoe, Y TI A common regulatory region functions bidirectionally in transcriptional activation of the human CYP1A1 and CYP1A2 genes SO MOLECULAR PHARMACOLOGY LA English DT Article ID AH-RECEPTOR; CYTOCHROME P4501A1; MICE LACKING; INDUCTION; EXPRESSION; 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN; 3-METHYLCHOLANTHRENE; ORGANIZATION; VARIABILITY; BINDING AB The human CYP1A1 and CYP1A2 genes on chromosome 15 are orientated head-to-head and are separated by a 23-kilobase (kb) intergenic spacer region. Thus, the possibility exists for sharing common regulatory elements contained in the spacer region responsible for transcriptional activation and regulation of the CYP1A1 and CYP1A2 genes. In the present study, a reporter gene construct containing -22.4 kb of the 5'-flanking region of the CYP1A2 gene was found to support beta-naphthoflavone (BNF) and 3-methylchoranthrene (3-MC)-mediated transcriptional activation. The responsive region was also functional in directing activation of the CYP1A1 promoter, indicating that the region works bidirectionally to govern transcriptional activation of both CYP1A1 and CYP1A2. To simultaneously evaluate transcriptional activation of both genes, a dual reporter between two different reporter genes, firefly luciferase and secreted alkaline phosphatase. Transient transfection of the dual reporter vector in HepG2 cells revealed increases in both reporter activities after exposure of the cells to BNF and 3-MC. Deletion studies of the spacer region indicated that a region from -464 to -1829 of the CYP1A1 gene works bidirectionally to enhance the transcriptional activation of not only CYP1A1 but also CYP1A2. In addition, a negative bidirectional regulatory region was found to exist from -18,989 to -21,992 of the CYP1A1 gene. These data established that induction of human CYP1A1 and CYP1A2 is simultaneously controlled through bidirectional and common regulatory elements. C1 Tohoku Univ, Div Drug Metab & Mol Toxicol, Grad Sch Pharmaceut Sci, Aoba Ku, Sendai, Miyagi 9808578, Japan. Tohoku Univ 21st Century, Comprehens Res & Educ Ctr Planning Drug Dev & Cli, Ctr Excellence Program, Sendai, Miyagi, Japan. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Eisai & Co Ltd, Drug Metab & Pharmacokinet Res, Tsukuba Res Labs, Tsukuba, Ibaraki, Japan. RP Nagata, K (reprint author), Tohoku Univ, Div Drug Metab & Mol Toxicol, Grad Sch Pharmaceut Sci, Aoba Ku, Aramaki Aoba 6-3, Sendai, Miyagi 9808578, Japan. EM nagataki@mail.tains.tohoku.ac.jp NR 25 TC 55 Z9 57 U1 2 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUN PY 2006 VL 69 IS 6 BP 1924 EP 1930 DI 10.1124/mol.105.021220 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 044QU UT WOS:000237688100018 PM 16505155 ER PT J AU Ben-Aharon, I Brown, PR Shalgi, R Eddy, EM AF Ben-Aharon, I Brown, PR Shalgi, R Eddy, EM TI Calpain 11 is unique to mouse spermatogenic cells SO MOLECULAR REPRODUCTION AND DEVELOPMENT LA English DT Article DE calcium-dependent proteases; signaling; gene expression; gene families ID MUSCULAR-DYSTROPHY; CALPASTATIN; PROTEINS; PROTEASE; TESTIS; EXPRESSION; SYSTEM; MYOBLASTS; MEMBRANE; CAPN11 AB The calpains are a family of calcium-dependent thiol proteases involved in intracellular processing of proteins. They occur as heterodimers containing one of various large subunits and a common small subunit. Some of the large subunits are expressed ubiquitously and others are expressed in a restricted set of tissues. We have cloned the cDNA for mouse calpain 11 and demonstrated that it is expressed specifically in the mouse testis. The mRNA begins to accumulate in the testis between days 14 and 16 after birth, corresponding to the period of pachytene spermatocyte development. The protein is detected by day 18 after birth, during mid to late pachytene spermatocyte development, and is present in the acrosomal region of spermatozoa from the cauda epididymis. The expression of calpain 11 during spermatogenesis and its localization in spermatozoa suggest that it is involved in regulating calcium-dependent signal transduction events during meiosis and sperm functional processes. C1 NIEHS, LRDT, Gamete Biol Grp, NIH, Res Triangle Pk, NC 27709 USA. Tel Aviv Univ, Sackler Sch Med, Dept Cell & Dev Biol, IL-69978 Tel Aviv, Israel. RP Eddy, EM (reprint author), NIEHS, LRDT, Gamete Biol Grp, NIH, C4-01,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM eddy@niehs.nih.gov FU Intramural NIH HHS; NIEHS NIH HHS [Z01 ES070076-19] NR 33 TC 11 Z9 12 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1040-452X J9 MOL REPROD DEV JI Mol. Reprod. Dev. PD JUN PY 2006 VL 73 IS 6 BP 767 EP 773 DI 10.1002/mrd.20466 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology SC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology GA 037DZ UT WOS:000237128200011 PM 16541461 ER PT J AU Nienhuis, AW Dunbar, CE Sorrentino, BP AF Nienhuis, Arthur W. Dunbar, Cynthia E. Sorrentino, Brian P. TI Genotoxicity of retroviral integration in hematopoietic cells SO MOLECULAR THERAPY LA English DT Review DE insertional mutagenesis; proto-oncogene activation; neoplasia; retroviral vectors; gene therapy ID SEVERE COMBINED IMMUNODEFICIENCY; CHRONIC GRANULOMATOUS-DISEASE; ACUTE LYMPHOBLASTIC-LEUKEMIA; TRANSCRIPTION START REGIONS; MEDIATED GENE-TRANSFER; BETA-GLOBIN INSULATOR; STEM-CELLS; INSERTIONAL MUTAGENESIS; IN-VIVO; PROGENITOR CELLS AB The experience of the past 3 years, since the first case of leukemia was reported in a child cured of X-linked severe combined immunodeficiency (X-SCID) by gene therapy, indicates that the potential genotoxicity of retroviral integration in hematopoietic cells will remain a consideration in evaluating the relative risks versus benefits of gene therapy for specific blood disorders. Although many unique variables may have contributed to an increased risk in X-SCID patients, clonal dominance or frank neoplasia in animal models, clonal dominance in humans with chronic granulomatous disease, and the ability of retroviral integration to immortalize normal bone marrow cells or convert factor-dependent cells to factor independence suggest that transduction of cells with an integrating retrovirus has the potential for altering their subsequent biologic behavior. The selective pressure imposed during in vitro culture or after engraftment may uncover a growth or survival advantage for cells in which an integration event has affected gene expression. Such cells then carry the risk that subsequent mutations may lead to neoplastic evolution of individual clones. Balancing that risk is that the vast majority of integration events seem to be neutral and that optimizing vector design may diminish the probability of altering gene expression by an integrated vector genome. Several cell culture systems and animal models designed to empirically evaluate the safety of vector systems are being developed and should provide useful data for weighing the relative risks and benefits for specific diseases and patient populations. Gene therapy interventions continue to have enormous potential for the treatment of disorders of the hematopoietic system. The future of such efforts seems bright as we continue to evolve and improve various strategies to make such interventions both effective and as safe as possible. C1 St Jude Childrens Hosp, Dept Hematol Oncol, Div Expt Hematol, Memphis, TN 38103 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Nienhuis, AW (reprint author), St Jude Childrens Hosp, Dept Hematol Oncol, Div Expt Hematol, Memphis, TN 38103 USA. EM Arthur.nienhuis@stjude.org NR 139 TC 183 Z9 189 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD JUN PY 2006 VL 13 IS 6 BP 1031 EP 1049 DI 10.1016/j.ymthe.2006.03.001 PG 19 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 054TR UT WOS:000238402000005 PM 16624621 ER PT J AU Schneider, SA Edwards, MJ Grill, SE Goldstein, S Kanchana, S Quinn, NP Bhatia, KP Hallett, M Reich, SG AF Schneider, SA Edwards, MJ Grill, SE Goldstein, S Kanchana, S Quinn, NP Bhatia, KP Hallett, M Reich, SG TI Adult-onset primary lower limb dystonia SO MOVEMENT DISORDERS LA English DT Article DE foot dystonia; dystonia; parkinsonism ID EXERCISE-INDUCED DYSTONIA; SPINOCEREBELLAR ATAXIA TYPE-3; PARKINSONS-DISEASE; FOOT DYSTONIA; CORTICOBASAL DEGENERATION; PRESENTING FEATURE; NATURAL-HISTORY; PHENOTYPE; FEATURES AB The lower extremity is affected infrequently in adult-onset primary dystonia in contrast to childhood-onset dystonia, which typically begins in the foot. When dystonia affects the foot in an adult, it is usually on a secondary basis. We present findings on 17 patients (11 women, 6 men; average age of onset 48.4 years; average time to diagnosis 2.7 years) with adult-onset primary foot dystonia. Prior to diagnosis, most patients underwent extensive testing and treatment, including unnecessary surgeries. Only the left lower extremity was involved in 8 patients, only the right in 7, and both in 2. The most common patterns were plantar flexion of all toes and inversion of the foot, typically activated with standing or walking. Only 2 patients had dystonia elsewhere. There was a family history of possible dystonia in 2 patients. One of five tested for DYT1 was positive, in the absence of a family history. One of eight patients treated with levodopa experienced mild improvement. Six of eight treated with botulinum toxin improved. No patient has been observed to have a secondary cause of dystonia. The prognosis, with regard to progression or spread to other body parts, has been favorable. Although uncommon, foot dystonia on a primary basis, not due to DYT1, can begin in adulthood. In this series of patients, the diagnosis was often not recognized, leading to extensive and unnecessary testing and treatment and emphasizing the need for wider recognition. (c) 2006 Movement Disorder Society. C1 Univ Maryland, Sch Med, Baltimore, MD 21201 USA. NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Parkinson Dis & Movement Disorders Ctr Maryland, Columbia, MD USA. Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London WC1N 3BG, England. RP Reich, SG (reprint author), Univ Maryland, Sch Med, 22 S Greene St,N4W46, Baltimore, MD 21201 USA. EM sreich@som.umaryland.edu RI Edwards, Mark/F-1052-2012 NR 38 TC 32 Z9 33 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUN PY 2006 VL 21 IS 6 BP 767 EP 771 DI 10.1002/mds.20794 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 056YJ UT WOS:000238560700005 PM 16456826 ER PT J AU Logroscino, G Chen, HL Wing, A Ascherio, A AF Logroscino, G Chen, HL Wing, A Ascherio, A TI Blood donations, iron stores, and risk of Parkinson's disease SO MOVEMENT DISORDERS LA English DT Article DE iron; blood donation; Parkinson's disease; risk cohort studies ID SUBSTANTIA-NIGRA; HEART-DISEASE; BRAIN; SERUM; MEN AB Iron overload and systemic iron stores may be important in the pathogenesis of Parkinson's disease (PD). We therefore examined the association between blood donations, which reduce body iron stores, and risk of PD in the Health Professionals Follow-Up Study, a large cohort investigation of U.S. men. Our hypothesis was that blood donation reduces the risk of PD by lowering systemic iron stores. Although the number of blood donations was inversely related to the ferritin levels in a subsample of the study population, no association was found between the number of blood donations and risk of PD (P for trend = 0.6). Unexpectedly, the risk of PD was higher among men who reported recent multiple blood donations (P for trend = 0.05). The results of this study do not support the hypothesis that reduced systemic iron stores lower the risk of PD. (c) 2006 Movement Disorder Society. C1 Harvard Univ, Dept Epidemiol, Sch Publ Hlth, Boston, MA 02115 USA. Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. Harvard Univ, Dept Nutr, Sch Publ Hlth, Boston, MA 02115 USA. Harvard Univ, Sch Med, Channing Lab, Boston, MA 02115 USA. RP Logroscino, G (reprint author), Harvard Univ, Dept Epidemiol, Sch Publ Hlth, HSPG 3-819,677 Huntington Ave, Boston, MA 02115 USA. EM glogrosc@hsph.harvard.edu RI LOGROSCINO, GIANCARLO/K-5148-2016; OI LOGROSCINO, GIANCARLO/0000-0003-0423-3242; Chen, Honglei/0000-0003-3446-7779 NR 20 TC 18 Z9 18 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUN PY 2006 VL 21 IS 6 BP 835 EP 838 DI 10.1002/mds.20826 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 056YJ UT WOS:000238560700015 PM 16453313 ER PT J AU Fung, HC Chen, CM Hardy, J Hernandez, D Singleton, A Wu, YR AF Fung, Hon-Chung Chen, Chiung-Mei Hardy, John Hernandez, Dena Singleton, Andrew Wu, Yih-Ru TI Lack of G2019S LRRK2 mutation in a cohort of Taiwanese with sporadic Parkinson's disease SO MOVEMENT DISORDERS LA English DT Article DE LRRK2; Parkinson's disease; Taiwan; mutation ID AUTOSOMAL-DOMINANT PARKINSONISM AB Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been shown to cause autosomal dominant and sporadic Parkinson's disease (PD). We report here the frequency of a common heterozygous mutation, 2877510G > A, which produces a glycine-to-serine amino acid substitution at codon 2019 in idiopathic Taiwanese PD. The extreme rarity of the G2019S mutation in our population suggests the occurrence of this mutation resulted from a common European founder. (c) 2006 Movement Disorder Society. C1 Chang Gung Mem Hosp, Dept Neurol, Taipei 10591, Taiwan. NIA, Neurogenet Lab, Bethesda, MD USA. UCL, Reta Lila Weston Inst Neurol Studies, London, England. Chang Gung Univ, Coll Med, Taipei, Taiwan. RP Wu, YR (reprint author), Chang Gung Mem Hosp, Dept Neurol, 199 Tung Hwa N Rd, Taipei 10591, Taiwan. EM yihruwu@adm.cgmh.org.tw RI Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009 FU Medical Research Council [G0701075] NR 7 TC 34 Z9 36 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUN PY 2006 VL 21 IS 6 BP 880 EP 881 DI 10.1002/mds.20814 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 056YJ UT WOS:000238560700027 PM 16511860 ER PT J AU Nijhara, R Balakrishnan, K AF Nijhara, Ruchika Balakrishnan, Ktishna TI Bringing nanomedicines to market: regulatory challenges, opportunities, and uncertainties SO NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE LA English DT Article AB Scientists and entrepreneurs who contemplate developing nanomedicine products face several unique challenges in addition to many of the traditional hurdles of product development. In this review we analyze the major physicochemical, biologic and functional characteristics of several nanomedicine products on the market and explore the question of what made them unique. What made them successful? We also focus on the regulatory challenges faced by nanomedicine product developers. Based on these analyses, we propose the factors that are most likely to contribute to the success of nanomedicine products. (c) 2006 Elsevier Inc. All rights reserved. RP Balakrishnan, K (reprint author), Fdn Adv Educ Sci, NIH, Bethesda, MD 20814 USA. EM balki@nih.gov NR 14 TC 37 Z9 37 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1549-9634 EI 1549-9642 J9 NANOMED-NANOTECHNOL JI Nanomed.-Nanotechnol. Biol. Med. PD JUN PY 2006 VL 2 IS 2 BP 127 EP 136 DI 10.1016/j.nano.2006.04.005 PG 10 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA 069WP UT WOS:000239480200010 PM 17292125 ER PT J AU Li, M Craigie, R AF Li, M Craigie, R TI Virology - HIV goes nuclear SO NATURE LA English DT Editorial Material ID TO-AUTOINTEGRATION FACTOR; INTEGRATION; LAMINA; ROLES; DNA; BAF C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Li, M (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM bobc@helix.nih.gov NR 8 TC 2 Z9 2 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 1 PY 2006 VL 441 IS 7093 BP 581 EP 582 DI 10.1038/441581a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 048AU UT WOS:000237920800028 PM 16738646 ER PT J AU Laugel, B Price, DA Sewell, AK AF Laugel, B Price, DA Sewell, AK TI On the path to TCR-directed therapeutics SO NATURE BIOTECHNOLOGY LA English DT Letter ID T-CELL-RECEPTOR; EVOLUTION; ANTIGEN; ANTIBODIES; SELECTION; AFFINITY; DISPLAY; LIBRARY C1 Tcell Modul, Oxford OX1 3SY, England. NIAID, NIH, Vaccine Res Ctr, Human Immunol Sect, Bethesda, MD 20892 USA. RP Laugel, B (reprint author), Tcell Modul, Peter Medawar Bldg Pathogen Res,S Pk Rd, Oxford OX1 3SY, England. RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 FU Medical Research Council [G108/441] NR 11 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUN PY 2006 VL 24 IS 6 BP 615 EP 616 DI 10.1038/nbt0606-615b PG 3 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 051UQ UT WOS:000238187300013 PM 16763581 ER PT J AU Kunkel, TA Van Houten, B AF Kunkel, TA Van Houten, B TI Survival choices SO NATURE CELL BIOLOGY LA English DT Editorial Material ID DNA-POLYMERASE-KAPPA; HUMAN DINB1 GENE; PCNA AB The recent discovery of many new mammalian DNA polymerases has left researchers trying to assign their biological functions. Surprising evidence has just emerged indicating that DNA polymerase., an enzyme implicated in the bypass of replication blocks, has a role in gap-filling synthesis during nucleotide excision repair (NER) of DNA adducts. C1 NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov NR 16 TC 4 Z9 4 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD JUN PY 2006 VL 8 IS 6 BP 547 EP 549 DI 10.1038/ncb0606-547 PG 4 WC Cell Biology SC Cell Biology GA 049PR UT WOS:000238029000005 PM 16738701 ER PT J AU Yanovski, SZ AF Yanovski, SZ TI Can we predict treatment response to antiobesity medication? SO NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material DE diet; obesity; orlistat; weight loss ID OBESITY AB BACKGROUND A sedentary lifestyle coupled with increased caloric intake has led to an obesity epidemic in the developed world. Individuals who are overweight have an increased risk of developing diabetes and cardiovascular disease. Targeted weight loss with orlistat can be clinically beneficial; however, the role of dietary restriction in this setting remains unclear. OBJECTIVE To determine the effect of mild and moderate energy restriction on the efficacy of orlistat treatment. DESIGN The Xenical(R) Prospective Evaluation in Real Practice Treatment (X-PERT) study-a 1 -year, multicenter, open-label, randomized, parallel-group trial-enrolled patients aged 18-70 years, with a BM I of 30-43 kg/m(2) and a body weight >= 90 kg. Additional inclusion criteria included a waist circumference >= 88 cm (women) or >= 102 cm (men). Patients with diabetes mellitus, hypertension, or a history of myocardial infarction were excluded. Patients who had lost 3 kg before screening, had undertaken surgical treatment for obesity, or had participated in a weight-loss program within the previous 6 months were also excluded. INTERVENTION Patients were randomly allocated to receive 120 mg orlistat three times daily plus a diet providing a daily deficit of 500 or 1,000 kcal. The diet provided 30% of calories from fat, 50% from carbohydrate and 20% from protein; energy intake was calculated as 1.3 x basal metabolic rate. Patients completed a daily food diary and were encouraged to participate in physical exercise. OUTCOME MEASURE The primary outcome measure was change in body weight from baseline at week 52. RESULTS In total, 215 patients received orlistat plus the 500 kcal deficit per day diet (500 kcal group) and 215 patients received orlistat plus the 1,000 kcal deficit per day diet (1,000 kcal group). By 3 months, 322 out of 430 (75%) patients had achieved a weight loss >= 5%; of these 322 patients, 295 (92%) had achieved a weight loss >= 5% at 6 months. Patients with <5% weight loss at either timepoint were excluded from further participation. The efficacy analysis at week 52 comprised the remaining patients: 141 in the 500 kcal group and 154 in the 1,000 kcal group. The greatest weight loss was observed in weeks 1-4; after 1 year of treatment weight loss ranged from >= 5% to >= 20%. Mean weight loss from baseline at week 52 was 11.4 +/- 6.2 kg in the 500 kcal group and 11.8 +/- 7.1 kg in the 1,000 kcal group (P=0.778). Patients in both groups also displayed similar, marked improvements in blood pressure, lipid levels, and waist circumference. The lack of difference between the results of the two groups might be explained by insufficient compliance with the dietary regimen. The difference in prescribed energy intake at week 0 was 428 kcal/day; however, the reported difference after 1 year was only 95 kcal/day (P= 0.058). CONCLUSION Orlistat was associated with weight loss, regardless of the level of dietary restriction prescribed. C1 NIDDKD, Off Obes Res, Bethesda, MD 20892 USA. NIDDKD, Obes & Eating Disorders Program, Bethesda, MD 20892 USA. RP Yanovski, SZ (reprint author), NIDDKD, Off Obes Res, 6707 Democracy Blvd,Room 675, Bethesda, MD 20892 USA. EM sy29f@nih.gov NR 4 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1745-8366 J9 NAT CLIN PRACT ENDOC JI Nat. Clin. Pract. Endocrinol. Metab. PD JUN PY 2006 VL 2 IS 6 BP 314 EP 315 DI 10.1038/ncpendmet0192 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 048RX UT WOS:000237965300007 PM 16932307 ER PT J AU Arking, DE Pfeufer, A Post, W Kao, WHL Newton-Cheh, C Ikeda, M West, K Kashuk, C Akyol, M Perz, S Jalilzadeh, S Illig, T Gieger, C Guo, CY Larson, MG Wichmann, HE Marban, E O'Donnell, CJ Hirschhorn, JN Kaab, S Spooner, PM Meitinger, T Chakravarti, A AF Arking, DE Pfeufer, A Post, W Kao, WHL Newton-Cheh, C Ikeda, M West, K Kashuk, C Akyol, M Perz, S Jalilzadeh, S Illig, T Gieger, C Guo, CY Larson, MG Wichmann, HE Marban, E O'Donnell, CJ Hirschhorn, JN Kaab, S Spooner, PM Meitinger, T Chakravarti, A TI A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization SO NATURE GENETICS LA English DT Article ID NITRIC-OXIDE SYNTHASE; CORONARY-HEART-DISEASE; FACTOR-H POLYMORPHISM; ALL-CAUSE MORTALITY; QT-INTERVAL; MACULAR DEGENERATION; CARDIOVASCULAR MORTALITY; QUANTITATIVE TRAIT; ELDERLY-MEN; K+ CHANNEL AB Extremes of the electrocardiographic QT interval, a measure of cardiac repolarization, are associated with increased cardiovascular mortality. We identified a common genetic variant influencing this quantitative trait through a genome-wide association study on 200 subjects at the extremes of a population-based QT interval distribution of 3,966 subjects from the KORA cohort in Germany, with follow-up screening of selected markers in the remainder of the cohort. We validated statistically significant findings in two independent samples of 2,646 subjects from Germany and 1,805 subjects from the US Framingham Heart Study. This genome-wide study identified NOS1AP ( CAPON), a regulator of neuronal nitric oxide synthase, as a new target that modulates cardiac repolarization. Approximately 60% of subjects of European ancestry carry at least one minor allele of the NOS1AP genetic variant, which explains up to 1.5% of QT interval variation. C1 Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Tech Univ Munich, Inst Human Genet, D-81675 Munich, Germany. GSF, Natl Res Ctr Environm & Hlth, Inst Human Genet, D-85764 Neuherberg, Germany. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Harvard Univ, Broad Inst, Cambridge, MA 02139 USA. MIT, Cambridge, MA 02139 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. GSF, Natl Res Ctr Environm & Hlth, Inst Epidemiol, D-85764 Neuherberg, Germany. Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. Univ Munich, Inst Informat Management Biometry & Epidemiol, D-81377 Munich, Germany. Childrens Hosp, Div Genet, Boston, MA 02115 USA. Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. Childrens Hosp, Program Genom, Boston, MA 02115 USA. Univ Munich, Dept Med 1, D-81377 Munich, Germany. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Chakravarti, A (reprint author), Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. EM aravinda@jhmi.edu RI Kaab, Stefan/H-3915-2012; Pfeufer, Arne/B-6634-2013; Meitinger, Thomas/O-1318-2015; AKYOL, Mahmut/C-2490-2016; OI Gieger, Christian/0000-0001-6986-9554; Larson, Martin/0000-0002-9631-1254 FU NHLBI NIH HHS [N01-HC-25195, 5U01HL066582, K23HL080025] NR 45 TC 330 Z9 340 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUN PY 2006 VL 38 IS 6 BP 644 EP 651 DI 10.1038/ng1790 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 048NW UT WOS:000237954800017 PM 16648850 ER PT J AU Ochando, JC Homma, C Yang, Y Hidalgo, A Garin, A Tacke, F Angeli, V Li, YS Boros, P Ding, YZ Jessberger, R Trinchieri, G Lira, SA Randolph, GJ Bromberg, JS AF Ochando, JC Homma, C Yang, Y Hidalgo, A Garin, A Tacke, F Angeli, V Li, YS Boros, P Ding, YZ Jessberger, R Trinchieri, G Lira, SA Randolph, GJ Bromberg, JS TI Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts SO NATURE IMMUNOLOGY LA English DT Article ID REGULATORY T-CELLS; HIGH-ENDOTHELIAL VENULES; TRANSCRIPTION FACTOR FOXP3; SECONDARY LYMPHOID-TISSUE; ACTIVATION IN-VIVO; ALLOGRAFT-REJECTION; L-SELECTIN; BLOOD-TRANSFUSION; ANTIGEN; CD4(+) AB The induction of alloantigen-specific unresponsiveness remains an elusive goal in organ transplantation. Here we identify plasmacytoid dendritic cells (pDCs) as phagocytic antigen-presenting cells essential for tolerance to vascularized cardiac allografts. Tolerizing pDCs acquired alloantigen in the allograft and then moved through the blood to home to peripheral lymph nodes. In the lymph node, alloantigen-presenting pDCs induced the generation of CCR4(+)CD4(+)CD25(+)Foxp3(+) regulatory T cells (T-reg cells). Depletion of pDCs or prevention of pDC lymph node homing inhibited peripheral Treg cell development and tolerance induction, whereas adoptive transfer of tolerized pDCs induced Treg cell development and prolonged graft survival. Thus, alloantigen-presenting pDCs home to the lymph nodes in tolerogenic conditions, where they mediate alloantigen-specific Treg cell development and allograft tolerance. C1 CUNY Mt Sinai Sch Med, Dept Gene & Cell Med, New York, NY 10029 USA. CUNY Mt Sinai Sch Med, Hematol Ctr, New York, NY 10029 USA. CUNY Mt Sinai Sch Med, Immunobiol Ctr, New York, NY 10029 USA. CUNY Mt Sinai Sch Med, Recanati Miller Transplantat Inst, New York, NY 10029 USA. Dresden Univ Technol, Dept Physiol Chem, D-8027 Dresden, Germany. NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. CUNY Mt Sinai Sch Med, Dept Surg, New York, NY 10029 USA. RP Ochando, JC (reprint author), CUNY Mt Sinai Sch Med, Dept Gene & Cell Med, New York, NY 10029 USA. EM jordi.ochando@mssm.edu; jon.bromberg@msnyuhealth.org RI Ochando, Jordi/B-6219-2008; Hidalgo, Andres/L-5643-2014 OI Hidalgo, Andres/0000-0001-5513-555X FU NIAID NIH HHS [AI44929, AI62765, R01 AI41428] NR 56 TC 409 Z9 425 U1 1 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUN PY 2006 VL 7 IS 6 BP 652 EP 662 DI 10.1038/ni1333 PG 11 WC Immunology SC Immunology GA 045OK UT WOS:000237751200021 PM 16633346 ER PT J AU Kunos, G Osei-Hyiaman, D Batkai, S Gao, B AF Kunos, G Osei-Hyiaman, D Batkai, S Gao, B TI Cannabinoids hurt, heal in cirrhosis SO NATURE MEDICINE LA English DT Editorial Material ID LIVER; FIBROSIS; ENDOCANNABINOIDS; RAT C1 NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Kunos, G (reprint author), NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. EM gkunos@mail.nih.gov RI Batkai, Sandor/G-3889-2010; Batkai, Sandor/H-7983-2014 NR 15 TC 1 Z9 1 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUN PY 2006 VL 12 IS 6 BP 607 EP 610 DI 10.1038/nm0606-608 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 051GI UT WOS:000238149200014 ER PT J AU Arumugam, TV Chan, SL Jo, DG Yilmaz, G Tang, SC Cheng, AW Gleichmann, M Okun, E Dixit, VD Chigurupati, S Mughal, MR Ouyang, X Miele, L Magnus, T Poosala, S Granger, DN Mattson, MP AF Arumugam, TV Chan, SL Jo, DG Yilmaz, G Tang, SC Cheng, AW Gleichmann, M Okun, E Dixit, VD Chigurupati, S Mughal, MR Ouyang, X Miele, L Magnus, T Poosala, S Granger, DN Mattson, MP TI Gamma secretase-mediated notch signaling worsens brain damage and functional outcome in ischemic stroke SO NATURE MEDICINE LA English DT Article ID ACTIVATION; DISEASE C1 NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. Louisiana State Univ, Hlth Sci Ctr, Dept Mol & Cellular Physiol, Shreveport, LA 71130 USA. Natl Taiwan Univ Hosp, Dept Neurol, Stroke Ctr, Taipei, Taiwan. NIA, Immunol Lab, Intramural Res Program, Baltimore, MD 21224 USA. NIA, Res Resources Branch, Intramural Res Program, Baltimore, MD 21224 USA. Univ Illinois, Dept Biopharmaceut Sci, Chicago, IL 60612 USA. Univ Illinois, Ctr Canc, Chicago, IL 60612 USA. Johns Hopkins Med Inst, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Arumugam, Thiruma/C-7969-2009; Arumugam, Thiruma/B-4898-2011; Mattson, Mark/F-6038-2012; OI Tang, Sung-Chun/0000-0003-3731-5973 FU Intramural NIH HHS NR 15 TC 136 Z9 147 U1 0 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUN PY 2006 VL 12 IS 6 BP 621 EP 623 DI 10.1038/nm1403 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 051GI UT WOS:000238149200021 PM 16680150 ER PT J AU Venkatesha, S Toporsian, M Lam, C Hanai, J Mammoto, T Kim, YM Bdolah, Y Lim, KH Yuan, HT Libermann, TA Stillman, IE Roberts, D D'Amore, PA Epstein, FH Sellke, FW Romero, R Sukhatme, VP Letarte, M Karumanchi, SA AF Venkatesha, S Toporsian, M Lam, C Hanai, J Mammoto, T Kim, YM Bdolah, Y Lim, KH Yuan, HT Libermann, TA Stillman, IE Roberts, D D'Amore, PA Epstein, FH Sellke, FW Romero, R Sukhatme, VP Letarte, M Karumanchi, SA TI Soluble endoglin contributes to the pathogenesis of preeclampsia SO NATURE MEDICINE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; NITRIC-OXIDE SYNTHASE; HEREDITARY HEMORRHAGIC TELANGIECTASIA; PREGNANCY-INDUCED HYPERTENSION; ELEVATED LIVER-ENZYMES; BETA BINDING-PROTEIN; HUMAN CYTOTROPHOBLASTS; ENDOVASCULAR INVASION; CELLS; PLASMA AB Preeclampsia is a pregnancy-specific hypertensive syndrome that causes substantial maternal and fetal morbidity and mortality. Maternal endothelial dysfunction mediated by excess placenta-derived soluble VEGF receptor 1 ( sVEGFR1 or sFlt1) is emerging as a prominent component in disease pathogenesis. We report a novel placenta-derived soluble TGF-beta coreceptor, endoglin ( sEng), which is elevated in the sera of preeclamptic individuals, correlates with disease severity and falls after delivery. sEng inhibits formation of capillary tubes in vitro and induces vascular permeability and hypertension in vivo. Its effects in pregnant rats are amplified by coadministration of sFlt1, leading to severe preeclampsia including the HELLP ( hemolysis, elevated liver enzymes, low platelets) syndrome and restriction of fetal growth. sEng impairs binding of TGF-beta 1 to its receptors and downstream signaling including effects on activation of eNOS and vasodilation, suggesting that sEng leads to dysregulated TGF-beta signaling in the vasculature. Our results suggest that sEng may act in concert with sFlt1 to induce severe preeclampsia. C1 Beth Israel Deaconess Med Ctr, Dept Med, Ctr Vasc Biol, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Obstet & Gynecol, Ctr Vasc Biol, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Surg, Ctr Vasc Biol, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Pathol, Ctr Vasc Biol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. Hosp Sick Children, Canc Res Program, Toronto, ON M5G 1X8, Canada. Univ Toronto, Heart & Stroke Fdn, Richard Lewar Ctr Excellence, Toronto, ON M5G 1X8, Canada. NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Wayne State Univ, Sch Med, Detroit, MI 48201 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Schepens Eye Res Inst, Boston, MA 02114 USA. RP Karumanchi, SA (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Ctr Vasc Biol, Boston, MA 02215 USA. EM sananth@bidmc.harvard.edu RI Libermann, Towia/F-9866-2010; OI Libermann, Towia/0000-0002-4006-8179; Toporsian, Mourad/0000-0002-8430-2094 FU NHLBI NIH HHS [HL079594]; NIDDK NIH HHS [DK064255] NR 51 TC 821 Z9 859 U1 7 U2 43 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUN PY 2006 VL 12 IS 6 BP 642 EP 649 DI 10.1038/nm1429 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 051GI UT WOS:000238149200025 PM 16751767 ER PT J AU Yaniv, K Isogai, S Castranova, D Dye, L Hitomi, J Weinstein, BM AF Yaniv, K Isogai, S Castranova, D Dye, L Hitomi, J Weinstein, BM TI Live imaging of lymphatic development in the zebrafish SO NATURE MEDICINE LA English DT Article ID ENDOTHELIAL-GROWTH-FACTOR; EMBRYONIC VASCULAR DEVELOPMENT; TRANSGENIC ZEBRAFISH; MOUSE EMBRYOS; FACTOR-C; IN-VIVO; EXPRESSION; SYSTEM; PROX1; GENE AB The lymphatic system has become the subject of great interest in recent years because of its important role in normal and pathological processes. Progress in understanding the origins and early development of this system, however, has been hampered by difficulties in observing lymphatic cells in vivo and in performing defined genetic and experimental manipulation of the lymphatic system in currently available model organisms. Here, we show that the optically clear developing zebrafish provides a useful model for imaging and studying lymphatic development, with a lymphatic system that shares many of the morphological, molecular and functional characteristics of the lymphatic vessels found in other vertebrates. Using two-photon time-lapse imaging of transgenic zebrafish, we trace the migration and lineage of individual cells incorporating into the lymphatic endothelium. Our results show lymphatic endothelial cells of the thoracic duct arise from primitive veins through a novel and unexpected pathway. C1 NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. Iwate Med Univ, Sch Med, Dept Anat, Morioka, Iwate 0208505, Japan. NICHHD, Microscopy & Imaging Core, NIH, Bethesda, MD 20892 USA. RP Weinstein, BM (reprint author), NICHHD, Mol Genet Lab, NIH, 6B-309,6 Ctr Dr, Bethesda, MD 20892 USA. EM bw96w@nih.gov FU Intramural NIH HHS NR 31 TC 218 Z9 223 U1 3 U2 19 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUN PY 2006 VL 12 IS 6 BP 711 EP 716 DI 10.1038/nm1427 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 051GI UT WOS:000238149200036 PM 16732279 ER PT J AU Fields, RD Burnstock, G AF Fields, R. Douglas Burnstock, Geoffrey TI Purinergic signalling in neuron-glia interactions SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID RAT HIPPOCAMPAL SLICES; FROG NEUROMUSCULAR-JUNCTION; MYELINATING SCHWANN-CELLS; FIBROBLAST GROWTH-FACTORS; LONG-TERM POTENTIATION; CENTRAL-NERVOUS-SYSTEM; FACTOR-ALPHA RELEASE; PROTEIN-KINASE-C; EXTRACELLULAR ATP; SYNAPTIC-TRANSMISSION AB Activity-dependent release of ATP from synapses, axons and glia activates purinergic membrane receptors that modulate intracellular calcium and cyclic AMP. This enables glia to detect neural activity and communicate among other glial cells by releasing ATP through membrane channels and vesicles. Through purinergic signalling, impulse activity regulates glial proliferation, motility, survival, differentiation and myelination, and facilitates interactions between neurons, and vascular and immune system cells. Interactions among purinergic, growth factor and cytokine signalling regulate synaptic strength, development and responses to injury. We review the involvement of ATP and adenosine receptors in neuron-glia signalling, including the release and hydrolysis of ATP, how the receptors signal, the pharmacological tools used to study them, and their functional significance. C1 NICHHD, NIH, Bethesda, MD 20892 USA. UCL Royal Free & Univ Coll, Sch Med, Auton Neurosci Ctr, London NW3 2PF, England. RP Fields, RD (reprint author), NICHHD, NIH, Bldg 35,Room 2A211,MSC 3713,35 Lincoln Dr, Bethesda, MD 20892 USA. EM fieldsd@mail.nih.gov FU Intramural NIH HHS [Z01 HD000713-13] NR 168 TC 440 Z9 453 U1 5 U2 27 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD JUN PY 2006 VL 7 IS 6 BP 423 EP 436 DI 10.1038/nrn1928 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 053EK UT WOS:000238287900012 PM 16715052 ER PT J AU Yin, HH Knowlton, BJ AF Yin, HH Knowlton, BJ TI The role of the basal ganglia in habit formation SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID MULTIPLE MEMORY-SYSTEMS; PAVLOVIAN-INSTRUMENTAL TRANSFER; PRIMATE PREFRONTAL CORTEX; CAUDATE-NUCLEUS LESIONS; MEDIAL TEMPORAL-LOBE; DORSOLATERAL STRIATUM; DORSOMEDIAL STRIATUM; REINFORCER DEVALUATION; DRUG-ADDICTION; DOUBLE DISSOCIATION AB Many organisms, especially humans, are characterized by their capacity for intentional, goal-directed actions. However, similar behaviours often proceed automatically, as habitual responses to antecedent stimuli. How are goal-directed actions transformed into habitual responses? Recent work combining modern behavioural assays and neurobiological analysis of the basal ganglia has begun to yield insights into the neural basis of habit formation. C1 Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA USA. NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. RP Knowlton, BJ (reprint author), Univ Calif Los Angeles, Dept Psychol, Franz Hall, Los Angeles, CA USA. EM knowlton@psych.ucla.edu FU Intramural NIH HHS NR 114 TC 851 Z9 862 U1 22 U2 115 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD JUN PY 2006 VL 7 IS 6 BP 464 EP 476 DI 10.1038/nrn1919 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 053EK UT WOS:000238287900015 PM 16715055 ER PT J AU Shi, H Rojas, R Bonifacino, JS Hurley, JH AF Shi, H Rojas, R Bonifacino, JS Hurley, JH TI The retromer subunit Vps26 has an arrestin fold and binds Vps35 through its C-terminal domain SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID MANNOSE 6-PHOSPHATE RECEPTORS; TRANS-GOLGI NETWORK; CRYSTAL-STRUCTURE; SORTING NEXIN-1; SACCHAROMYCES-CEREVISIAE; MAMMALIAN RETROMER; BETA-ARRESTIN; PHOX DOMAIN; PX-DOMAIN; PROTEINS AB The mammalian retromer complex consists of SNX1, SNX2, Vps26, Vps29 and Vps35, and retrieves lysosomal enzyme receptors from endosomes to the trans-Golgi network. The structure of human Vps26A at 2.1-angstrom resolution reveals two curved beta-sandwich domains connected by a polar core and a flexible linker. Vps26 has an unpredicted structural relationship to arrestins. The Vps35-binding site on Vps26 maps to a mobile loop spanning residues 235-246, near the tip of the C-terminal domain. The loop is phylogenetically conserved and provides a mechanism for Vps26 integration into the complex that leaves the rest of the structure free for engagements with membranes and for conformational changes. Hydrophobic residues and a glycine in this loop are required for integration into the retromer complex and endosomal localization of human Vps26, and for the function of yeast Vps26 in carboxypeptidase Y sorting. C1 NIDDKD, Mol Biol Lab, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NICHHD, Cell Biol & Metab Branch, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 FU Intramural NIH HHS; NIDDK NIH HHS [Z01 DK036118-12] NR 50 TC 101 Z9 104 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JUN PY 2006 VL 13 IS 6 BP 540 EP 548 DI 10.1038/nsmb1103 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 050XG UT WOS:000238122500019 PM 16732284 ER PT J AU Ziauddin, MF Yeow, WS Maxhimer, JB Baras, A Chua, A Reddy, RM Tsai, W Cole, GW Schrump, DS Nguyen, DM AF Ziauddin, M. Firdos Yeow, Wen-Shuz Maxhimer, Justin B. Baras, Aris Chua, Alex Reddy, Rishindra M. Tsai, Wilson Cole, George W., Jr. Schrump, David S. Nguyen, Dao M. TI Valproic acid, an antiepileptic drug with histone deacetylase inhibitory activity, potentiates the cytotoxic effect of Apo2L/TRAIL on cultured thoracic cancer cells through mitochondria-dependent caspase activation SO NEOPLASIA LA English DT Article DE histone deacetylase inhibitor; Apo2L/ TRAIL; lung cancer; esophageal cancer; malignant pleural mesothelioma; mitochondria; Bcl2; caspases ID APOPTOSIS-INDUCING LIGAND; TRAIL-INDUCED APOPTOSIS; LUNG-CANCER; HDAC INHIBITORS; MEDIATED APOPTOSIS; CYTOCHROME-C; IN-VIVO; DEPSIPEPTIDE FR901228; EXTRINSIC PATHWAYS; ANTITUMOR-ACTIVITY AB Inhibitors of histone deacetylases have been shown to enhance the sensitivity of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand TRAIL-mediated cytotoxicity. Valproic acid (VA), a commonly used antiepileptic agent whose pharmacokinetics and toxicity profiles are well described, is a histone deacetylase inhibitor. This project aims to evaluate if VA can potentiate Apo2L/TRAIL-mediated cytotoxicity in cultured thoracic cancer cells and to elucidate the underlying molecular mechanism responsible for this effect. VA sensitized cultured thoracic cancer cells to Apo2L/TRAIL, as indicated by a 4-fold to a > 20- fold reduction of Apo2L/TRAIL IC50 values in combination-treated cells. Although VA (0.5-5 mM) or Apo2L/TRAIL (20 ng/ml) induced less than 20% cell death, VA + Apo2L/TRAIL combinations caused 60% to 90% apoptosis of cancer cells. Moreover, substantial activation of caspases 8, 9, and 3, which was observed only in cells treated with the drug combinations, was completely suppressed by Bcl2 overexpression or by the caspase 9 inhibitor. Both the caspase 9 inhibitor and Bcl2 completely abrogated the substantial cytotoxicity and apoptosis induced by this combination, thus highlighting the pivotal role of the type II pathway in this process. These findings provide a rationale for the development of VA and Apo2L/TRAIL combination as a novel molecular therapeutic regimen for thoracic cancers. C1 NIH, Clin Res Ctr, Sect Thorac Oncol, NCI, Bethesda, MD 20892 USA. RP Nguyen, DM (reprint author), NIH, Clin Res Ctr, Sect Thorac Oncol, NCI, Room 4W-4-3940,10 Ctr Dr, Bethesda, MD 20892 USA. EM dao_nguyen@nih.gov FU Intramural NIH HHS NR 72 TC 38 Z9 38 U1 0 U2 4 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD JUN PY 2006 VL 8 IS 6 BP 446 EP 457 DI 10.1593/neo.05823 PG 12 WC Oncology SC Oncology GA 067DY UT WOS:000239283100003 PM 16820090 ER PT J AU Lerchner, A Sterner, G Hertz, J Ahmadi, M AF Lerchner, Alexander Sterner, Gustaf Hertz, John Ahmadi, Mandana TI Mean field theory for a balanced hypercolumn model of orientation selectivity in primary visual cortex SO NETWORK-COMPUTATION IN NEURAL SYSTEMS LA English DT Article DE mean-field theory; primary visual cortex; Fano factor; orientation tuning; contrast invariance ID CORTICAL NETWORK MODEL; RESPONSE VARIABILITY; SPIKING NEURONS; STRIATE CORTEX; STIMULUS CONTRAST; SINGLE CELLS; DYNAMICS; CAT; DISCRIMINATION; MONKEY AB We present a complete mean field theory for a balanced state of a simple model of an orientation hypercolumn, with a numerical procedure for solving the mean-field equations quantitatively. With our treatment, one can determine self-consistently both the firing rates and the firing correlations, without being restricted to specific neuron models. Here, we solve the mean-field equations numerically for integrate-and-fire neurons. Several known key properties of orientation selective cortical neurons emerge naturally from the description: Irregular firing with statistics close to - but not restricted to Poisson statistics; an almost linear gain function (firing frequency as a function of stimulus contrast) of the neurons within the network; and a contrast-invariant tuning width of the neuronal firing. We find that the irregularity in firing depends sensitively on synaptic strengths. If the Fano factor is considerably larger (smaller) than I at some stimulus orientation, then it is also larger (resp. maller) than 1 for all other stimulus orientations that elicit firing. We also find that the tuning of the noise in the input current is the same as the tuning of the external input, while that for the mean input current depends on both the external input and the intracortical connectivity. C1 Tech Univ Denmark, DK-2800 Lyngby, Denmark. NORDITA, DK-2100 Copenhagen O, Denmark. Univ Rochester, Dept Phys, Rochester, NY USA. RP Lerchner, A (reprint author), NIH, Neuropsychol Lab, Bldg 49 Rm 1B80,49 Convent Dr, Bethesda, MD 20892 USA. EM LerchnerA@mail.nih.gov NR 26 TC 6 Z9 6 U1 0 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0954-898X J9 NETWORK-COMP NEURAL JI Netw.-Comput. Neural Syst. PD JUN PY 2006 VL 17 IS 2 BP 131 EP 150 DI 10.1080/09548980500444933 PG 20 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic; Neurosciences SC Computer Science; Engineering; Neurosciences & Neurology GA 072ZR UT WOS:000239712400002 PM 16818394 ER PT J AU Clarimon, J Eerola, J Hellstrom, O Peuralinna, T Tienari, PJ Singleton, AB AF Clarimon, J Eerola, J Hellstrom, O Peuralinna, T Tienari, PJ Singleton, AB TI Assessment of PINK1 (PARK6) polymorphisms in Finnish PD SO NEUROBIOLOGY OF AGING LA English DT Article DE Parkinson's disease; PINK1; PARK6; case-control; genetics AB Recent data has demonstrated that mutations in PINK], encoding PTEN-induced kinase 1, are a cause of early onset recessive parkinsonism (PARK6 locus). Common variability in genes implicated in hereditary forms of parkinsonism may be a predisposing factor in sporadic Parkinson's disease (PD). We analyzed whether six different genetic variants within and surrounding PINK] contribute to the risk of sporadic PD in a Finnish case-control series. Our results indicate that this gene does not play a major role in the genetic predisposition to PD in this population. (c) 2005 Elsevier Inc. All rights reserved. C1 NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. Univ Helsinki, Helsinki, Finland. Univ Helsinki, Cent Hosp, Dept Neurol, Helsinki, Finland. Biomedicum, Neurosci Programme, Helsinki, Finland. Seinajoki Cent Hosp, Dept Neurol, Seinajoki, Finland. RP Clarimon, J (reprint author), NIA, Lab Neurogenet, NIH, Bldg 35 Room 1A1000,MSC 3707, Bethesda, MD 20892 USA. EM clarimon@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Tienari, Pentti/A-4893-2012; OI Clarimon, Jordi/0000-0002-6824-6942 NR 0 TC 7 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUN PY 2006 VL 27 IS 6 BP 906 EP 907 DI 10.1016/j.neurobiolaging.2005.03.028 PG 2 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 045WW UT WOS:000237774400016 PM 16046032 ER PT J AU Pacheco-Quinto, J de Turco, EBR DeRosa, S Howard, A Cruz-Sanchez, F Sambamurti, K Refolo, L Petanceska, S Pappolla, MA AF Pacheco-Quinto, J de Turco, EBR DeRosa, S Howard, A Cruz-Sanchez, F Sambamurti, K Refolo, L Petanceska, S Pappolla, MA TI Hyperhomocysteinemic Alzheimer's mouse model of amyloidosis shows increased brain amyloid beta peptide levels SO NEUROBIOLOGY OF DISEASE LA English DT Article DE A beta 40; A beta 42; Alzheimer's disease; amyloidosis; brain; hyperhomocysteinemia ID TRANSGENIC MICE; PRECURSOR-PROTEIN; PLASMA HOMOCYSTEINE; OXIDATIVE STRESS; VASCULAR-DISEASE; RISK FACTOR; NEUROTOXICITY; PRESENILIN-1; DEPOSITION; TOXICITY AB Recent epidemiological and clinical data suggest that elevated serum homocysteine levels may increase the risk of developing Alzheimer's disease (AD), but the underlying mechanisms are unknown. We tested the hypothesis that high serum homocysteine concentration may increase amyloid beta-peptide (A) levels in the brain and could therefore accelerate AD neuropathology. For this purpose, we mated a hyperhomocysteinemic CBStm1Unc mouse carrying a heterozygous dominant mutation in cystathionine-beta-synthase (CBS*) with the APP*/PS1* mouse model of brain amyloidosis. The APP*/PS1*/CBS* mice showed significant elevations of serum homocysteine levels compared to the double transgenic APP*/PS1* model of amyloidosis. Results showed that female (but not male) APP*/PS1*/CBS* mice exhibited significant elevations of A beta 40 and A beta 42 levels in the brain. Correlations between homocysteine levels in serum and brain A beta levels were statistically significant. No increases in beta secretase activity or evidence of neuronal cell loss in the hyperhomocysteinemic mice were found. C1 LSU, Hlth Sci Ctr, Neurosci Ctr Excellence, New Orleans, LA 70112 USA. Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. Univ Catalunya, Barcelona, Spain. Med Univ S Carolina, Charleston, SC 29425 USA. NINDS, Bethesda, MD 20892 USA. RP Pappolla, MA (reprint author), LSU, Hlth Sci Ctr, Neurosci Ctr Excellence, 2020 Gravier St,Suite D, New Orleans, LA 70112 USA. EM memorycenter@aol.com FU NIA NIH HHS [AG449905135, AG44905140]; NINDS NIH HHS [NS045913] NR 22 TC 58 Z9 63 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD JUN PY 2006 VL 22 IS 3 BP 651 EP 656 DI 10.1016/j.nbd.2006.01.005 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 055PL UT WOS:000238462600019 PM 16516482 ER PT J AU Mitchell, DGV Avny, SB Blair, RJR AF Mitchell, DGV Avny, SB Blair, RJR TI Divergent patterns of aggressive and neurocognitive characteristics in acquired versus developmental psychopathy SO NEUROCASE LA English DT Review ID ORBITOFRONTAL CORTEX DYSFUNCTION; VENTROMEDIAL PREFRONTAL CORTEX; POSITRON-EMISSION-TOMOGRAPHY; FRONTAL-LOBE DAMAGE; FACIAL EXPRESSIONS; RESPONSE REVERSAL; PASSIVE-AVOIDANCE; DECISION-MAKING; HUMAN AMYGDALA; SELECTIVE IMPAIRMENT AB An analogy is often drawn between patients with personality changes following orbitofrontal cortex lesions and individuals with developmental psychopathy. We present patient CL, who had acquired psychopathy following an orbitofrontal cortex lesion. Unlike previous studies, CL was assessed on a valid and reliable measure of psychopathy and was compared with controls and patients with developmental psychopathy on measures of instrumental (re)learning, extinction, emotional processing, and social cognition. The results provide further support for the notion that acquired and developmental forms of psychopathy are associated with dissociable neurocognitive deficits that leave each at different levels of risk for reactive and instrumental aggression. C1 NIMH, Mood & Anviety Disorders Program, NIH, US Dept HHS, Bethesda, MD 20892 USA. Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. RP Mitchell, DGV (reprint author), NIMH, Mood & Anviety Disorders Program, NIH, US Dept HHS, 15K N Dr,MSC 2670, Bethesda, MD 20892 USA. EM mitchelld@mail.nih.gov FU Intramural NIH HHS NR 112 TC 26 Z9 26 U1 8 U2 15 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1355-4794 J9 NEUROCASE JI Neurocase PD JUN PY 2006 VL 12 IS 3 BP 164 EP 178 DI 10.1080/13554790600611288 PG 15 WC Clinical Neurology; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 055LH UT WOS:000238451700005 PM 16801152 ER PT J AU Ma, KZ Deutsch, J Villacreses, NE Rosenberger, TA Rapoport, SI Shetty, HU AF Ma, Kaizong Deutsch, Joseph Villacreses, Nelly E. Rosenberger, Thad A. Rapoport, Stanley I. Shetty, H. Umesha TI Measuring brain uptake and incorporation into brain phosphatidylinositol of plasma myo-[H-2(6)]inositol in unanesthetized rats: An approach to estimate in vivo brain phosphatidylinositol turnover SO NEUROCHEMICAL RESEARCH LA English DT Article DE myo-inositol; phosphatidylinositol turnover; brain uptake; GC-MS; stable isotope; osmotic pump; Na+/myo-inositol cotransporter ID NA+/MYO-INOSITOL COTRANSPORTER; CEREBROSPINAL-FLUID; ALZHEIMERS-DISEASE; BIPOLAR DISORDER; H-1 MRS; MYOINOSITOL; LITHIUM; PHOSPHOLIPIDS; SPECTROSCOPY; HYPOTHESIS AB The in vivo rate of turnover of phosphatidylinositol (PtdIns) in brain is not known. In brain, certain receptor-mediated signal transduction involves metabolism of PtdIns and a method to measure its turnover in awake animals is useful in studying the effect of lithium and other therapeutic agents. In a method described here, rats were infused subcutaneously with myo-[[H-2(6)]inositol (Ins*) using an osmotic pump and, at I and 8 weeks, concentrations of free myo-inositol (Ins) and Ins* in plasma and brain were measured by GC-MS (chemical ionization). Also, PtdIns and PtdIns* together in brain were isolated, and Ins and Ins* from their headgroups were released enzymatically and specific activity of incorporated inositol was measured. The specific activity of inositol reached a steady state in plasma within I week of infusion, but not in brain even at 8 weeks. However, in brain, the specific activity of phosphatidylinositol was same as that of inositol at both time-points, suggestive of fast turnover of PtdIns. The animal experiment and the analytical methodology described here should be useful for measuring the rate of turnover of brain PtdIns in pathological and drug treatment conditions. C1 NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Shetty, HU (reprint author), NIMH, Mol Imaging Branch, NIH, 10 Ctr Dr,Room B3C351,MSC 1003, Bethesda, MD 20892 USA. EM shettyu@mail.nih.gov FU Intramural NIH HHS NR 30 TC 3 Z9 3 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD JUN PY 2006 VL 31 IS 6 BP 759 EP 765 DI 10.1007/s11064-006-9080-4 PG 7 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 071VC UT WOS:000239631000006 PM 16791473 ER PT J AU Kansaku, K Johnson, A Grillon, ML Garraux, G Sadato, N Hallett, M AF Kansaku, K Johnson, A Grillon, ML Garraux, G Sadato, N Hallett, M TI Neural correlates of counting of sequential sensory and motor events in the human brain SO NEUROIMAGE LA English DT Article ID HUMAN PARIETAL LOBE; HUMAN INFANTS; NUMBER REPRESENTATION; NUMERICAL COGNITION; FINGER MOVEMENTS; CORTICAL AREAS; CORTEX; CONJUNCTION; LANGUAGE; MONKEYS AB Little is known about the ability to enumerate small numbers of successive stimuli and movements. It is possible that there exist neural substrates that are consistently recruited both to count sensory stimuli from different modalities and for counting movements executed by different effectors. Here, we identify a network of areas that was involved in enumerating small numbers of auditory, visual, and somatosensory stimuli, and in enumerating sequential movements of hands and feet, in the bilateral premotor cortex, presupplementary motor area, posterior temporal cortex, and thalamus. The most significant consistent activation across sensory and motor counting conditions was found in the lateral premotor cortex. Lateral premotor activation was not dependent on movement preparation, stimulus presentation timing, or number word verbalization. Movement counting, but not sensory counting, activated the anterior parietal cortex. This anterior parietal area may correspond to an area recruited for movement counting identified by recent single-neuron studies in monkeys. These results suggest that overlapping but not identical networks of areas are involved in counting sequences of sensory stimuli and sequences of movements in the human brain. (c) 2005 Elsevier Inc. All rights reserved. C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Natl Inst Nat Sci, Natl Inst Physiol Sci, Div Cerebral Integrat, Okazaki, Aichi 4448585, Japan. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr MSC 1428, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov RI Garraux, Gaetan/G-9050-2011 NR 57 TC 6 Z9 6 U1 2 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUN PY 2006 VL 31 IS 2 BP 649 EP 660 DI 10.1016/j.neuroimage.2005.12.023 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 052KH UT WOS:000238232100019 PM 16460961 ER PT J AU Schaefer, M Berens, H Heinze, HJ Rotte, M AF Schaefer, Michael Berens, Harald Heinze, Hans-Jochen Rotte, Michael TI Neural correlates of culturally familiar brands of car manufacturers SO NEUROIMAGE LA English DT Article DE medial prefrontal cortex; somatic markers; self-reflection; fMRI ID PREFRONTAL CORTEX; DECISION-MAKING; SELF; FMRI; JUDGMENT AB Brands have a high impact on people's economic decisions. People may prefer products of brands even among almost identical products. Brands can be defined as cultural-based symbols, which promise certain advantages of a product. Recent studies suggest that the prefrontal cortex may be crucial for the processing of brand knowledge. The aim of this study was to examine the neural correlates of culturally based brands. We confronted subjects with logos of car manufactures during an fMR1 session and instructed them to imagine and use a car of these companies. As a control condition, we used graphically comparable logos of car manufacturers that were unfamiliar to the culture of the subjects participating in this study. If they did not know the logo of the brand, they were told to imagine and use a generic car. Results showed activation of a single region in the medial prefrontal cortex related to the logos of the culturally familiar brands. We discuss the results as self-relevant processing induced by the imagined use of cars of familiar brands and suggest that the prefrontal cortex plays a crucial role for processing culturally based brands. (c) 2006 Elsevier Inc. All rights reserved. C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. Univ Magdeburg, Dept Neurol 2, D-39120 Magdeburg, Germany. Icon Added Value, D-90491 Nurnberg, Germany. RP Schaefer, M (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bldg 10,Room 5N-234, Bethesda, MD 20892 USA. EM schaefem@ninds.nih.gov NR 27 TC 41 Z9 42 U1 1 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JUN PY 2006 VL 31 IS 2 BP 861 EP 865 DI 10.1016/j.neuroimage.2005.12.047 PG 5 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 052KH UT WOS:000238232100040 PM 16487728 ER PT J AU Fischer, D Clemen, CS Olive, M Ferrer, I Goudeau, B Roth, U Badorf, P Wattjes, MP Lutterbey, G Kral, T van der Ven, PFM Furst , DO Vicart, P Goldfarb, LG Moza, M Carpen, O Reichelt, J Schroder, R AF Fischer, Dirk Clemen, Christoph S. Olive, Montse Ferrer, Isidro Goudeau, Bertrand Roth, Udo Badorf, Petra Wattjes, Mike P. Lutterbey, Goetz Kral, Thomas van der Ven, Peter F. M. Fuerst, Dieter O. Vicart, Patrick Goldfarb, Lev G. Moza, Monica Carpen, Olli Reichelt, Julia Schroeder, Rolf TI Different early pathogenesis in myotilinopathy compared to primary desminopathy SO NEUROMUSCULAR DISORDERS LA English DT Article DE myotilin; titin; limb-girdle muscular dystrophy; distal myopathy; tibial muscular dystrophy; myofibrillar myopathy; inclusion body myopathy; desmin ID GIRDLE MUSCULAR-DYSTROPHY; DISTAL MYOPATHY; MYOFIBRILLAR MYOPATHY; MUTATION; PROTEIN; GENE; 1A; EXPRESSION; FILAMENTS; FILAMIN AB Mutations in the human myotilin gene may cause limb-girdle muscular dystrophy 1A and myofibrillar myopathy. Here, we describe a German patient with the clinically distinct disease phenotype of late adult onset distal anterior leg myopathy caused by a heterozygous S55F myotilin mutation. In addition to a thorough morphological and clinical analysis, we performed for the first time a protein chemical analysis and transient transfections. Morphological analysis revealed an inclusion body myopathy with myotilin- and desmin-positive aggregates. The clinical and pathological phenotype considerably overlaps with late onset distal anterior leg myopathy of the Markesbery-Griggs type. Interestingly, all three analyzed myotilin missense mutations (S55F, S60F and S60C) do not lead to gross changes in the total amount of myotilin or to aberrant posttranslational modifications in diseased muscle, as observed in a number of muscular dystrophies. Transiently transfected wild-type and S55F mutant myotilin similarly colocalised with actin-containing stress fibers in BHK-21 cells. Like the wild-type protein, mutated myotilin did not disrupt the endogenous desmin cytoskeleton or lead to pathological protein aggregation in these cells. This lack of an obvious dominant negative effect sharply contrasts to transfections with, for instance, the disease-causing A357P desmin mutant. In conclusion our data indicate that the disorganization of the extrasarcomeric cytoskeleton and the presence of desmin-positive aggregates are in fact late secondary events in the pathogenesis of primary myotilinopathies, rather than directly related. These findings suggest that unrelated molecular pathways may result in seemingly similar disease phenotypes at late disease stages. (C) 2006 Elsevier B.V. All rights reserved. C1 Univ Bonn, Dept Neurol, Muskellab, D-53105 Bonn, Germany. Univ Paris 06, CNRS, UMR 7000, Paris, France. Univ Bonn, Dept Mol Cell Biol, D-5300 Bonn, Germany. Univ Cologne, Fac Med, Ctr Biochem, Inst Biochem 1, Cologne, Germany. Hosp Llobregat, Inst Neuropatol, IDIBELL, Barcelona, Spain. Univ Cologne, Fac Med, Ctr Mol Med Cologne, Cologne, Germany. Univ Bonn, Dept Radiol, D-5300 Bonn, Germany. Univ Bonn, Dept Neurosurg, D-5300 Bonn, Germany. Univ Paris 07, UFR Biochem, Paris, France. NINDS, Clin Neurogenet Unit, NIH, Bethesda, MD 20892 USA. Univ Helsinki, Dept Pathol, Helsinki, Finland. Univ Helsinki, Neurosci Program, Helsinki, Finland. Univ Helsinki, Cent Hosp, Helsinki, Finland. Turku Univ, Cent Hosp, FIN-20520 Turku, Finland. Univ Turku, Dept Pathol, Turku, Finland. RP Fischer, D (reprint author), Univ Bonn, Dept Neurol, Muskellab, Sigmund Freud Str 25, D-53105 Bonn, Germany. EM dirk.fischer@ukb.uni-bonn.de RI Schroder, Rolf/B-2774-2011; Clemen, Christoph/B-2761-2011; OI Clemen, Christoph/0000-0002-1291-4219; Olive, Montse/0000-0001-5727-0165 NR 25 TC 15 Z9 16 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD JUN PY 2006 VL 16 IS 6 BP 361 EP 367 DI 10.1016/j.nmd.2006.03.007 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 064ZT UT WOS:000239129900002 PM 16684602 ER PT J AU Shalin, SC Hernandez, CM Dougherty, MK Morrison, DK Sweatt, JD AF Shalin, SC Hernandez, CM Dougherty, MK Morrison, DK Sweatt, JD TI Kinase suppressor of Ras1 compartmentalizes hippocampal signal transduction and subserves synaptic plasticity and memory formation SO NEURON LA English DT Article ID ACTIVATED PROTEIN-KINASE; LONG-TERM POTENTIATION; DENDRITIC K+ CHANNELS; ERK MAP KINASE; AREA CA1; PRESYNAPTIC PLASTICITY; DORSAL HIPPOCAMPUS; CONTEXTUAL FEAR; ERK/MAP KINASE; NMDA RECEPTOR AB The ERK/MAP kinase cascade is important for long-term memory formation and synaptic plasticity, with a myriad of upstream signals converging upon ERK activation. Despite this convergence of signaling, neurons routinely activate appropriate biological responses to different stimuli. Scaffolding proteins represent a mechanism to achieve compartmentalization of signaling and the appropriate targeting of ERK-dependent processes. We report that kinase suppressor of Ras (KSR1) functions biochemically in the hippocampus to scaffold the components of the ERK cascade, specifically regulating the cascade when a membrane fraction of ERK is activated via a PKC-dependent pathway but not via a cAMP/PKA-dependent pathway. Specificity of KSR1-dependent signaling also extends to specific downstream targets of ERK. Behaviorally and physiologically, we found that the absence of KSR1 leads to deficits in associative learning and theta burst stimulation-induced LTP. Our report provides novel insight into the endogenous scaffolding role of KSR1 in controlling kinase activation within the nervous system. C1 Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA. NCI, Lab Prot Dynam & Signaling, Ft Detrick, MD 21702 USA. RP Sweatt, JD (reprint author), Baylor Coll Med, Dept Neurosci, 1 Baylor Pl, Houston, TX 77030 USA. EM dsweatt@nrc.uab.edu OI Sweatt, J. David/0000-0003-3567-485X FU NIMH NIH HHS [F31MH071014, MH57014]; NINDS NIH HHS [NS13546, NS37444] NR 51 TC 57 Z9 59 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUN 1 PY 2006 VL 50 IS 5 BP 765 EP 779 DI 10.1016/j.neuron.2006.04.029 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 051MK UT WOS:000238165000011 PM 16731514 ER PT J AU Saavedra, JM Armando, I Bregonzio, C Juorio, A Macova, M Pavel, J Sanchez-Lemus, E AF Saavedra, JM Armando, I Bregonzio, C Juorio, A Macova, M Pavel, J Sanchez-Lemus, E TI A centrally acting, anxiolytic angiotensin II AT(1) receptor antagonist prevents the isolation stress-induced decrease in cortical CRF1 receptor and benzodiazepine binding SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE GABA(A) complex; anxiety; isolation; tyrosine hydroxylase; locus coeruleus; angiotensin receptor types ID CORTICOTROPIN-RELEASING-FACTOR; HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; MESSENGER-RNA EXPRESSION; ANXIETY-LIKE BEHAVIOR; RAT CEREBRAL-CORTEX; PLUS-MAZE; PREFRONTAL CORTEX; PASTE STANDARDS; HORMONE NEURONS; LOCUS COERULEUS AB Long-term pretreatment with an angiotensin II AT(1) antagonist blocks angiotensin II effects in brain and peripheral organs and abolishes the sympathoadrenal and hypothalamic-pituitary-adrenal responses to isolation stress. We determined whether AT(1) receptors were also important for the stress response of higher regulatory centers. We studied angiotensin II and corticotropin-releasing factor (CRF) receptors and benzodiazepine binding sites in brains of Wistar Hannover rats. Animals were pretreated for 13 days with vehicle or a central and peripheral AT(1) antagonist (candesartan, 0.5 mg/kg/day) via osmotic minipumps followed by 24 h of isolation in metabolic cages, or kept grouped throughout the study ( grouped controls). In another study, we determined the influence of a similar treatment with candesartan on performance in an elevated plus-maze. AT(1) receptor blockade prevented the isolation-induced increase in brain AT1 receptors and decrease in AT(2) binding in the locus coeruleus. AT(1) receptor antagonism also prevented the increase in tyrosine hydroxylase mRNA in the locus coeruleus. Pretreatment with the AT(1) receptor antagonist completely prevented the decrease in cortical CRF1 receptor and benzodiazepine binding produced by isolation stress. In addition, pretreatment with candesartan increased the time spent in and the number of entries to open arms of the elevated plus-maze, measure of decreased anxiety. Our results implicate a modulation of upstream neurotransmission processes regulating cortical CRF1 receptors and the GABA(A) complex as molecular mechanisms responsible for the anti-anxiety effect of centrally acting AT(1) receptor antagonists. We propose that AT(1) receptor antagonists can be considered as compounds with possible therapeutic anti-stress and anti-anxiety properties. C1 NIMH, Pharmacol Sect, DIRP, NIH,DHHS, Bethesda, MD 20892 USA. RP Saavedra, JM (reprint author), NIMH, Pharmacol Sect, DIRP, NIH,DHHS, 10 Ctr Dr,MSC 1514,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. EM Saavedrj@mail.nih.gov FU Intramural NIH HHS NR 80 TC 52 Z9 52 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2006 VL 31 IS 6 BP 1123 EP 1134 DI 10.1038/sj.npp.1300921 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 047SS UT WOS:000237899600003 PM 16205776 ER PT J AU Major, EO Yousry, TA Clifford, DB AF Major, EO Yousry, TA Clifford, DB TI Natalizumab for relapsing multiple sclerosis - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NINDS, Bethesda, MD 20892 USA. Inst Neurol, London WC1N 3BG, England. Washington Univ, St Louis, MO 63110 USA. RP Major, EO (reprint author), NINDS, Bethesda, MD 20892 USA. EM majorg@ninds.nih.gov RI Yousry, Tarek/B-3417-2009 NR 4 TC 2 Z9 2 U1 0 U2 0 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 JUN 1 PY 2006 VL 354 IS 22 BP 2388 EP 2389 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 047ZZ UT WOS:000237918500018 ER PT J AU Lindberg, DAB AF Lindberg, DAB TI Searching the medical literature SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Lindberg, DAB (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. NR 1 TC 2 Z9 2 U1 0 U2 0 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 JUN 1 PY 2006 VL 354 IS 22 BP 2393 EP 2393 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 047ZZ UT WOS:000237918500027 PM 16738283 ER PT J AU Robinson, ML Schroeder, JR Moolchan, ET AF Robinson, Miqun L. Schroeder, Jennifer R. Moolchan, Eric T. TI Adolescent smokers screened for a nicotine replacement treatment trial: Correlates of eligibility and enrollment SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID FAGERSTROM TOLERANCE QUESTIONNAIRE; SMOKING CESSATION PROGRAM; DEPENDENCE; FTND AB The enrollment process determines the study sample and external validity of clinical trial results; however, few reports describe the process and outcome of screening efforts for smoking cessation studies among adolescents. We describe and evaluate a screening protocol to enroll adolescent smokers for a randomized clinical trial of nicotine replacement therapy. Adolescent smokers obtained the recruitment call-in number (1-800-NO-SMOKE) via media and other advertisements. Trained recruitment staff collected information using an internally developed, targeted telephone screening interview, which was used to determine pre-eligibility for the clinical trial. Correlates of qualification and of study enrollment were determined. Among 1,347 adolescents screened, 329 (24.4%) were eligible to participate in the trial. Light smoking (39.1%) and lack of parental support (14.8%) were the biggest contributors to ineligibility. Eligible adolescents were more likely to be female (66.9% vs. 58.2%, p=.0052) and more likely to be European American (63.5% vs. 52.2%, p=.0003). The higher rates of ineligibility for African Americans and boys were partly explained by lower scores on the Fagerstrom Test for Nicotine Dependence. Of those eligible to participate in the trial, 159 (48.3%) enrolled. Results underscore the need for screening instruments that are measurement-invariant across ethnicities and gender, and for enrollment strategies that maximize inclusion of eligible participants. C1 DHHS, NIH, NIDA IRP,US Dept Hlth & Human Serv, Teen Tobacco Addict Res Clin,Clin Pharmacol & The, Baltimore, MD 21224 USA. RP Moolchan, ET (reprint author), DHHS, NIH, NIDA IRP,US Dept Hlth & Human Serv, Teen Tobacco Addict Res Clin,Clin Pharmacol & The, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM emoolcha@intra.nida.nih.gov FU Intramural NIH HHS NR 25 TC 11 Z9 11 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD JUN PY 2006 VL 8 IS 3 BP 447 EP 454 DI 10.1080/14622200600670413 PG 8 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 064GN UT WOS:000239077300012 PM 16801302 ER PT J AU Inami, K Nims, RW Srinivasan, A Citro, ML Saavedra, JE Cederbaum, AI Keefer, LK AF Inami, K Nims, RW Srinivasan, A Citro, ML Saavedra, JE Cederbaum, AI Keefer, LK TI Metabolism of a liver-selective nitric oxide-releasing agent, V-PYRRO/NO, by human microsomal cytochromes P450 SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Article DE cytochrome P450; nitric oxide; diazeniumdiolate; prodrug ID CAPILLARY-ZONE-ELECTROPHORESIS; INDUCED HEPATOTOXICITY; DONOR; PROTECTS; APOPTOSIS; TOXICITY; MICE; NECROSIS; NITRATE; OXIDATION AB Endogenously generated nitric oxide (NO) mediates a host of important physiological functions, playing roles in the vascular, immunological, and neurological systems. As a result, exogenous agents that release NO have become important therapeutic interventions and research tools. O-2-Vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO) is a prodrug designed with the hypothesis that it might release nitric oxide via epoxidation of the vinyl group by cytochrome P450, followed by enzymatic and/or spontaneous epoxide hydration to release the ultimate NO-donating moiety,1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (PYRRO/NO) ion. In this study, we investigated this hypothetical activation mechanism quantitatively for V-PYRRO/NO using cDNA-expressed human cytochrome P450 (CYP)2E1. Incubation with CYP2E1 and an NADPH-regenerating system resulted in a time-dependent decomposition of V-PYRRO/ NO, with a turnover rate of 2.0 nmol/min/pmol CYP2E1. Nitrate and nitrite were detected in high yield as metabolites of NO. The predicted organic metabolites pyrrolidine and glycolaldehyde were also detected in near-quantitative yields. The enzymatic decomposition of V-PYRRO/NO was also catalyzed, albeit at lower rates, by CYP2A6 and CYP2B6. We conclude that the initial step in the metabolism of V-PYRRO/NO NO in the liver is catalyzed efficiently but not exclusively by the alcohol-inducible form of cytochrome P450 (CYP2E1). The results confirm the proposed activation mechanism involving enzymatic oxidation of the vinyl group in V-PYRRO/NO followed by epoxide hydration and hydrolytic decomposition of the resulting PYRRO/NO ion to generate nitric oxide. (c) 2006 Elsevier Inc. All rights reserved. C1 NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. Natl Canc Inst, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. CUNY Mt Sinai Sch Med, Dept Pharmacol & Biol Chem, New York, NY 10029 USA. RP Keefer, LK (reprint author), NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. EM keefer@ncifcrf.gov RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 29 TC 12 Z9 12 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP 309 EP 315 DI 10.1016/j.niox.2006.01.003 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500004 PM 16545970 ER PT J AU Berg, AM Tremonti, CK Vasquez, VM Shiva, S Gladwin, MT Sack, MN AF Berg, AM Tremonti, CK Vasquez, VM Shiva, S Gladwin, MT Sack, MN TI Nitrite augments post-ischemic vascular function - A putative therapeutic preconditioning mimetic SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NHLBI, Vasc Med Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Ctr Clin, NIH, Bethesda, MD 20892 USA. RI Duran, Antonio/H-2244-2015 OI Duran, Antonio/0000-0002-8351-7392 NR 0 TC 0 Z9 0 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A54 EP A55 DI 10.1016/j.niox.2006.04.182 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500172 ER PT J AU Colton, C Wink, D Weinberg, JB Van Nostrand, W Dawson, H Vitek, M AF Colton, C Wink, D Weinberg, JB Van Nostrand, W Dawson, H Vitek, M TI Nitric oxide is neuroprotective in a mouse model of A beta-mediated chronic neurodegeneration SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 Duke Univ, Med Ctr, Durham, NC 27706 USA. NIH, Bethesda, MD 20892 USA. SUNY Stony Brook, Stony Brook, NY 11794 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A9 EP A9 DI 10.1016/j.niox.2006.04.033 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500036 ER PT J AU d'Agostino, C Dejam, A Schechter, AN AF d'Agostino, C Dejam, A Schechter, AN TI Nitrite ions fluxes in human erythrocytes SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A71 EP A72 DI 10.1016/j.niox.2006.04.235 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500222 ER PT J AU Donzelli, S Switzer, CH Espey, MG Thomas, DD Ridnour, LA Miranda, KM Tocchetti, CG Lazzarino, G Paolocci, N Wink, DA AF Donzelli, S Switzer, CH Espey, MG Thomas, DD Ridnour, LA Miranda, KM Tocchetti, CG Lazzarino, G Paolocci, N Wink, DA TI Nitroxyl formation from NH2OH and NOHA oxidation SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NIH, Bethesda, MD 20892 USA. Univ Arizona, Tucson, AZ 85721 USA. Univ Catania, I-95124 Catania, Italy. RI Miranda, Katrina/B-7823-2009 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A32 EP A32 DI 10.1016/j.niox.2006.04.105 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500102 ER PT J AU Espey, MG Wink, D AF Espey, MG Wink, D TI Nitrite reduction is an innate survival adaptation of cancer cells to hypoxia SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NCI, NIH, Radiol Biol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A13 EP A14 DI 10.1016/j.niox.2006.04.047 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500050 ER PT J AU Huang, Z Shiva, S Ringwood, LA Gladwin, MT AF Huang, Z Shiva, S Ringwood, LA Gladwin, MT TI Novel function of myoglobin as a nitrite reductase modulates mitochondrial respiration SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NHLBI, Vasc Med Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A72 EP A72 DI 10.1016/j.niox.2006.04.236 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500223 ER PT J AU Hussain, SP Harris, CC AF Hussain, SP Harris, CC TI p53 is a key molecular node in the inflammatory stress response network SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A15 EP A15 DI 10.1016/j.niox.2006.04.053 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500056 ER PT J AU Isenberg, JS Hyodo, F Matsumoto, K Krishna, MC Wink, DA Roberts, DD AF Isenberg, JS Hyodo, F Matsumoto, K Krishna, MC Wink, DA Roberts, DD TI Thrombospondin-1 and CD36 antagonize nitric oxide-stimulated vascular smooth muscle responses SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NCI, Bethesda, MD 20892 USA. RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A27 EP A27 DI 10.1016/j.niox.2006.04.089 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500086 ER PT J AU Keefer, LK Davies, KM Saavedra, JE Schleicher, U Showalter, BM Valdez, C Bogdan, C AF Keefer, LK Davies, KM Saavedra, JE Schleicher, U Showalter, BM Valdez, C Bogdan, C TI Targeting nitric oxide to macrophages with prodrugs of the O-2-glycosylated diazenitandiolate family SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NCI, SAIC Frederick, Frederick, MD 21702 USA. Univ Freiburg, D-79104 Freiburg, Germany. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A50 EP A50 DI 10.1016/j.niox.2006.04.169 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500159 ER PT J AU Keefer, LK Kong, L Saavedra, JE Buzard, GS Xu, X Hood, BL Conrads, TP Veenstra, TD AF Keefer, LK Kong, L Saavedra, JE Buzard, GS Xu, X Hood, BL Conrads, TP Veenstra, TD TI Deamidation of peptides in aerobic nitric oxide solution by a nitrosative pathway SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NCI, SAIC Frederick, Frederick, MD 21702 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A41 EP A41 DI 10.1016/j.niox.2006.04.140 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500134 ER PT J AU Malik, M Lee, J Saavedra, J Stuart, Y AF Malik, M Lee, J Saavedra, J Stuart, Y TI Nitric oxide regulated nuclear translocation of the intracellular chloride channel CLIC4 SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NCI, Lab Cellular Carcinogenesis & Tumor Promot, Bethesda, MD 20892 USA. SAIC Frederick, Basic Res Program, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A34 EP A34 DI 10.1016/j.niox.2006.04.113 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500110 ER PT J AU Nagababu, E Rifkind, JM AF Nagababu, E Rifkind, JM TI Measurement of plasma nitrite and S-nitrosothiols by chemiluminescence method SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NIA, Mol Dynam Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A73 EP A73 DI 10.1016/j.niox.2006.04.240 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500227 ER PT J AU Piknova, B Keszler, A Hogg, N Schechter, AN AF Piknova, B Keszler, A Hogg, N Schechter, AN TI Reaction of oxyhemoglobin with nitrite SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NIDDK, NIH, Bethesda, MD 20892 USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A70 EP A70 DI 10.1016/j.niox.2006.04.229 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500216 ER PT J AU Rifkind, JM Nagababu, E Ramasamy, S AF Rifkind, JM Nagababu, E Ramasamy, S TI Spectroscopic evidence for the formation of stable intermediates during nitrite reduction by hemoglobin SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NIA, Mol Dynam Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A70 EP A70 DI 10.1016/j.niox.2006.04.230 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500217 ER PT J AU Shiva, S Sack, MN Duranski, M Ringwood, LA Kirby, L Lefer, DJ Gladwin, MT AF Shiva, S Sack, MN Duranski, M Ringwood, LA Kirby, L Lefer, DJ Gladwin, MT TI Nitrite mediates cytoprotection following ischemia/reperfusion injury at the mitochondrial level SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NHLBI, Vasc Med Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. Albert Einstein Coll Med, Dept Med, Div Cardiol, Bronx, NY 10461 USA. NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A73 EP A74 DI 10.1016/j.niox.2006.04.242 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500229 ER PT J AU Shiva, S Wang, XD Ringwood, L Yuditskaya, S Miyajima, H Hoehn, G Harris, ZL Gladwin, MT AF Shiva, S Wang, XD Ringwood, L Yuditskaya, S Miyajima, H Hoehn, G Harris, ZL Gladwin, MT TI Ceruloplasmin is an NO oxidase that regulates nitrite homeostasis SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NHLBI, Vasc Med Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Sch Med, Baltimore, MD 21205 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A71 EP A71 DI 10.1016/j.niox.2006.04.234 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500221 ER PT J AU Sibmooh, N Piknova, B D'agostino, C Schechter, AN AF Sibmooh, N Piknova, B D'agostino, C Schechter, AN TI Mechanisms of erythrocytic reduction of nitrite to nitric oxide SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A69 EP A70 DI 10.1016/j.niox.2006.04.228 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500215 ER PT J AU Switzer, CH Ridnour, L Isenberg, J Roberts, D Wink, D AF Switzer, CH Ridnour, L Isenberg, J Roberts, D Wink, D TI The role of NO, HNO and H2S on NSAID-based cancer therapeutics SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. NCI, Biochem Pathol Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A54 EP A54 DI 10.1016/j.niox.2006.04.181 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500171 ER PT J AU Switzer, CH Fukuto, JM Farmer, P AF Switzer, CH Fukuto, JM Farmer, P TI Synthesis, isolation, and characterization of nitroxyl anion SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NCI, NIH, Radiat Biol Branch, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. Univ Calif Irvine, Irvine, CA 92717 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A25 EP A25 DI 10.1016/j.niox.2006.04.082 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500080 ER PT J AU Thomas, DD Ridnour, L Eepey, MG Roberts, D Mitchell, JB Wink, DA AF Thomas, DD Ridnour, L Eepey, MG Roberts, D Mitchell, JB Wink, DA TI Superoxide fluxes limit nitric oxide-induced signaling SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A29 EP A30 DI 10.1016/j.niox.2006.04.097 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500094 ER PT J AU Velazquez, CA Knaus, EE Perampali, PR AF Velazquez, CA Knaus, EE Perampali, PR TI Novel NONO-NSAIDs possessing a nitric oxide donor diazeniumdiolate moiety SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NCI, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2M7, Canada. RI Velazquez, Carlos/C-4224-2008 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A50 EP A50 DI 10.1016/j.niox.2006.04.170 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500160 ER PT J AU Wilde, TC Saavedra, JE Shami, PJ Findlay, VF Townsend, DM Tew, KD Ji, XH Keefer, LK AF Wilde, TC Saavedra, JE Shami, PJ Findlay, VF Townsend, DM Tew, KD Ji, XH Keefer, LK TI Development of arylated nitric oxide-releasing prodrugs as anticancer agents SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 4th International Conference on Biology, Chemistry and Therapeutic Applications of Nitric Oxide CY JUN 25-29, 2006 CL Monterey, CA SP NitroMed Inc, INO Therapeut, Ajinomoto AminoSci LLC, Bayer HealthCare, BioMarin Pharmaceut Inc, Nitr Oxide Soc Japan, Pfizer Inc, Schering AG, ALEXIS Biochem, Altana Pharma AG, BioLegend Ing, BIOMOL Int LP, Boehringer Ingelheim, Cognosci Inc, ECO PHYS INC, Med Coll Georgia C1 NCI, SAIC Frederick, Frederick, MD 21702 USA. Univ Utah, Salt Lake City, UT 84112 USA. Med Univ S Carolina, Charleston, SC 29425 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2006 VL 14 IS 4 BP A16 EP A16 DI 10.1016/j.niox.2006.04.265 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054TC UT WOS:000238400500060 ER PT J AU Johnson-Taylor, WL Everhart, JE AF Johnson-Taylor, Wendy L. Everhart, James E. TI Modifiable environmental and behavioral determinants of overweight among children and adolescents: Report of a workshop SO OBESITY LA English DT Review ID BODY-MASS INDEX; RANDOMIZED CONTROLLED-TRIAL; CARDIOVASCULAR RISK-FACTORS; SOFT DRINK CONSUMPTION; X-RAY ABSORPTIOMETRY; FOR-DISEASE-CONTROL; AIR DISPLACEMENT PLETHYSMOGRAPHY; FOOD FREQUENCY QUESTIONNAIRES; RESTRICTIVE FEEDING PRACTICES; PREVENTING CHILDHOOD OBESITY AB The number of children at risk for overweight and the number of overweight children are increasing and have become a serious public health concern. Interventions that could be applied at the population level have not been proven effective. The development of effective strategies is thought to be hampered by the lack of understanding of which behavioral and environmental factors need to be modified. On June 14 and 15, 2004, the NIH held a meeting of experts to discuss the issue of modifiable determinants of obesity in children and adolescents. Included were presentations on interventions among children that have been proven effective. dietary and physical activity behavioral determinants, physical, social, and family environmental determinants, and the quality of measures of determinants and correlates of overweight. C1 NIH, Div Nutr Res Coordinat, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIDDK, Clin Trials Branch, Div Digest Dis & Nutr, Bethesda, MD USA. RP Johnson-Taylor, WL (reprint author), NIH, Div Nutr Res Coordinat, Dept Hlth & Human Serv, 2 Democracy Plaza,Room 635,6707 Democracy Blvd,MS, Bethesda, MD 20892 USA. EM wj50v@nih.gov RI Loureiro, Nuno/I-6400-2012 OI Loureiro, Nuno/0000-0002-1166-3219 NR 220 TC 41 Z9 43 U1 8 U2 16 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBESITY JI Obesity PD JUN PY 2006 VL 14 IS 6 BP 929 EP 966 DI 10.1038/oby.2006.109 PG 38 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 071NP UT WOS:000239609200001 PM 16861599 ER PT J AU Silver, RM Landon, MB Rouse, DJ Leveno, KJ Spong, CY Thom, EA Moawad, AH Caritis, SN Harper, M Wapner, RJ Sorokin, Y Miodovnik, M Carpenter, M Peaceman, AM O'Sullivan, MJ Sibai, B Langer, O Thorp, JM Ramin, SM Mercer, BM AF Silver, Robert M. Landon, Mark B. Rouse, Dwight J. Leveno, Kenneth J. Spong, Catherine Y. Thom, Elizabeth A. Moawad, Atef H. Caritis, Steve N. Harper, Margaret Wapner, Ronald J. Sorokin, Yoram Miodovnik, Menachem Carpenter, Marshall Peaceman, Alan M. O'Sullivan, Mary J. Sibai, Baha Langer, Oded Thorp, John M. Ramin, Susan M. Mercer, Brian M. CA Natl Inst Child Hlth Human Dev Mat TI Maternal morbidity associated with multiple repeat cesarean deliveries SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID PLACENTA PREVIA; SECTION; OUTCOMES; PARITY AB Although repeat cesarean deliveries often are associated with serious morbidity, they account for only a portion of abdominal deliveries and are overlooked when evaluating morbidity. Our objective was to estimate the magnitude of increased maternal morbidity associated with increasing number of cesarean deliveries. METHODS: Prospective observational cohort of 30,132 women who had cesarean delivery without labor in 19 academic centers over 4 years (1999-2002). RESULTS: There were 6,201 first (primary), 15,808 second, 6,324 third, 1,452 fourth, 258 fifth, and 89 sixth or more cesarean deliveries. The risks of placenta accreta, cystotomy, bowel injury, ureteral injury, and ileus, the need for postoperative ventilation, intensive care unit admission, hysterectomy, and blood transfusion requiring 4 or more units, and the duration of operative time and hospital stay significantly increased with increasing number of cesarean deliveries. Placenta accreta was present in 15 (0.24%), 49 (0.31%), 36 (0.57%), 31 (2.13%), 6 (2.33%), and 6 (6.74%) women undergoing their first, second, third, fourth, fifth, and sixth or more cesarean deliveries, respectively. Hysterectomy was required in 40 (0.65%) first, 67 (0.42%) second, 57 (0.90%) third, 35 (2.41%) fourth, 9 (3.49%) fifth, and 8 (8-99%) sixth or more cesarean deliveries. In the 723 women with previa, the risk for placenta accreta was 3%, 11%, 40%, 61%, and 67% for first, second, third, fourth, and fifth or more repeat cesarean deliveries, respectively. CONCLUSION: Because serious maternal morbidity increases progressively with increasing number of cesarean deliveries, the number of intended pregnancies should be considered during counseling regarding elective repeat cesarean operation versus a trial of labor and when debating the merits of elective primary cesarean delivery. C1 Univ Utah, Sch Med, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Alabama, Birmingham, AL USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Univ Chicago, Chicago, IL 60637 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. Wayne State Univ, Detroit, MI 48202 USA. Univ Cincinnati, Cincinnati, OH 45221 USA. Brown Univ, Providence, RI 02912 USA. Northwestern Univ, Chicago, IL 60611 USA. Univ Miami, Miami, FL 33152 USA. Univ Tennessee, Memphis, TN USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Univ N Carolina, Chapel Hill, NC 27515 USA. Univ Texas, Hlth Sci Ctr, Houston, TX USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. George Washington Univ, Ctr Biostat, Washington, DC USA. NICHHD, Bethesda, MD 20892 USA. RP Silver, RM (reprint author), Univ Utah, Sch Med, Dept Obstet & Gynecol, 30 North 1900 East,Room 308, Salt Lake City, UT 84132 USA. EM Bob.Silver@hsc.utah.edu OI caritis, steve/0000-0002-2169-0712; Peaceman, Alan/0000-0002-4515-4850 FU NICHD NIH HHS [HD40500, HD21410, HD21414, HD27860, HD27861, HD27869, HD27905, HD27915, HD27917, HD34116, HD34122, HD34136, HD34208, HD34210, HD36801, HD40485, HD40512, HD40544, HD40545, HD40560] NR 20 TC 465 Z9 496 U1 8 U2 30 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUN PY 2006 VL 107 IS 6 BP 1226 EP 1232 DI 10.1097/01.AOG.0000219750.79480.84 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 095GS UT WOS:000241296800003 PM 16738145 ER PT J AU Hankins, GDV MacLennan, AH Speer, ME Strunk, A Nelson, K AF Hankins, Gary D. V. MacLennan, Alastair H. Speer, Michael E. Strunk, Albert Nelson, Karin TI Obstetric litigation is asphyxiating our maternity services SO OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material ID CEREBRAL-PALSY; INFANTS AB Obstetric care in the United States, as judged by maternal mortality, neonatal mortality, stillbirth rates, or any other metric, has never been better. Despite this, litigation over "bad outcomes" is threatening the specialty, not only now, but into the future. Despite damage to our specialty, the injured party often benefits little, if at all, from the process. Potential solutions include an emphasis on evidence-based medicine, a qualification and review process for medical experts, and a more rational and fair health court system. C1 Univ Texas, Med Branch, Dept Obstet & Gynecol, Div Maternal Fetal Med, Galveston, TX 77550 USA. Univ Adelaide, Dept Obstet & Gynaecol, Adelaide, SA 5001, Australia. Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. Amer Coll Obstetricians & Gynecologists, Washington, DC 20024 USA. NINDS, Neuroepidemiol Branch, NIH, Bethesda, MD 20892 USA. RP Hankins, GDV (reprint author), 301 Univ Blvd, Galveston, TX 77555 USA. EM ghankins@utmb.edu NR 29 TC 24 Z9 24 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUN PY 2006 VL 107 IS 6 BP 1382 EP 1385 DI 10.1097/01.AOG.0000220531.25707.27 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 095GS UT WOS:000241296800025 PM 16738167 ER PT J AU Nussenblatt, RB Chan, CC Wilson, WH Hochman, J Gottesman, M AF Nussenblatt, RB Chan, CC Wilson, WH Hochman, J Gottesman, M CA CNRS Ocular Lymphoma Worksh TI International central nervous system and ocular lymphoma workshop: Recommendations for the future SO OCULAR IMMUNOLOGY AND INFLAMMATION LA English DT Review DE intraocular lymphoma; imaging; masquerade syndrome; microarray ID B-CELL LYMPHOMA; PRIMARY CNS LYMPHOMA; ANTI-CD20 ANTIBODY RITUXIMAB; CHEMOTHERAPY; METHOTREXATE; INVOLVEMENT; DIAGNOSIS; REGIMEN; EPOCH; PILOT AB Purpose : To bring together multidisciplinary experts to discuss primary central nervous system lymphoma (PCNSL) and primary intraocular lymphoma (PIOL). Methods : NIH campus workshop discussion focusing on future work in both clinical and basic lymphoma research. Results : The discussion lead to recommendations on elucidating disease pathobiology, improving diagnostic accuracy and sensitivity, and novel therapeutic strategies. Conclusions : Approaches which have been successfully applied to other neoplasms, such as microarray, may be applied to improve diagnostic accuracy and sensitivity of PCNSL and PIOL and should be systematically incorporated into clinical trials of both. Development of animal models of PCNSL and PIOL may be useful in understanding the unique ocular and CNS milieu. Disease detection by radiological, nuclear medicine, molecular and flow cytometric approaches should be systematically studied to improve early diagnosis, accurate staging, and response evaluation. Improved therapy remains the ultimate goal. Efforts in these arenas should be coordinated on a national and international level. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, CCR, NIH, Bethesda, MD 20892 USA. Hebrew Univ Jerusalem, Inst Life Sci, Dept Cell & Anim Biol, IL-91904 Jerusalem, Israel. RP Nussenblatt, RB (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Room 10S219, Bethesda, MD 20892 USA. EM DrBob@nei.nih.gov FU Intramural NIH HHS [Z01 EY000222-22] NR 35 TC 24 Z9 25 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0927-3948 J9 OCUL IMMUNOL INFLAMM JI Ocul. Immunol. Inflamm. PD JUN PY 2006 VL 14 IS 3 BP 139 EP 144 DI 10.1080/09273940600630170 PG 6 WC Ophthalmology SC Ophthalmology GA 051WV UT WOS:000238193300002 PM 16827214 ER PT J AU Cochrane, G Bates, K Apweiler, R Tateno, Y Mashima, J Kosuge, T Mizrachi, IK Schafer, S Fetchko, M AF Cochrane, Guy Bates, Kirsty Apweiler, Rolf Tateno, Yoshio Mashima, Jun Kosuge, Takehide Mizrachi, Ilene Karsch Schafer, Susan Fetchko, Michael TI Evidence standards in experimental and inferential INSDC Third Party Annotation data SO OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY LA English DT Article ID NUCLEOTIDE-SEQUENCE DATABASE AB The Third Party Annotation (TPA) project collects and presents high-quality annotation of nucleotide sequence. Annotation is submitted by researchers who have not themselves generated novel nucleotide sequence. In its first few years, the resource has proven to be popular with submitters from a range of biological research areas. Central to the project is the requirement for high-quality data, resulting from experimental and inferred analysis discussed in peer-reviewed publications. The data are divided into two tiers: those with experimental evidence and those with inferential evidence. Standards for TPA are detailed and illustrated with the aid of case studies. This paper is part of the special issue of OMICS on data standards. C1 EMBL Nucleotide Sequence Database, European Bioinformat Inst, Cambridge CB10 1SD, England. Natl Inst Genet, DNA Data Bank Japan, CIB, DDBJ, Shizuoka, Japan. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Cochrane, G (reprint author), EMBL Nucleotide Sequence Database, European Bioinformat Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England. EM cochrane@ebi.ac.uk RI Mashima, Jun/F-3706-2010 OI Mashima, Jun/0000-0003-4138-1893 FU Intramural NIH HHS NR 9 TC 17 Z9 17 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1536-2310 J9 OMICS JI OMICS PD JUN PY 2006 VL 10 IS 2 BP 105 EP 113 DI 10.1089/omi.2006.10.105 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 079XJ UT WOS:000240210900004 PM 16901214 ER PT J AU Morrison, N Cochrane, G Faruque, N Tatusova, T Tateno, Y Hancock, D Field, D AF Morrison, Norman Cochrane, Guy Faruque, Nadeem Tatusova, Tatiana Tateno, Yoshio Hancock, David Field, Dawn TI Concept of sample in OMICS technology SO OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY LA English DT Article ID NUCLEOTIDE-SEQUENCE DATABASE; GENOME COLLECTION; INFORMATION; PHENOTYPES; ONTOLOGIES AB Fundamental biological processes can now be studied by applying the full range of OMICS technologies (genomics, transcriptomics, proteomics, metabolomics, and beyond) to the same biological sample. Clearly, it would be desirable if the concept of sample were shared among these technologies, especially as up until the time a biological sample is prepared for use in a specific OMICS assay, its description is inherently technology independent. Sharing a common informatic representation would encourage data sharing (rather than data replication), thereby reducing redundant data capture and the potential for error. This would result in a significant degree of harmonization across different OMICS data standardization activities, a task that is critical if we are to integrate data from these different data sources. Here, we review the current concept of sample in OMICS technologies as it is being dealt with by different OMICS standardization initiatives and discuss the special role that the newly formed Genomic Standards Consortium (GSC) might have to play in this domain. This paper is part of the special issue of OMICS on data standards. C1 Oxford Ctr Ecol & Hydrol, Mol Evolut & Bioinformat Sect, Oxford OX1 3SR, England. Oxford Ctr Ecol & Hydrol, NERC, Environm Bioinformat Ctr, Oxford OX1 3SR, England. Univ Manchester, Sch Comp Sci, Manchester, Lancs, England. EMBL Outstn, European Bioinformat Inst, Cambridge, England. NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. Natl Inst Genet, Ctr Informat Biol & DNA Data Bank, Res Organ Informat & Syst, Shizuoka, Japan. RP Field, D (reprint author), Oxford Ctr Ecol & Hydrol, Mol Evolut & Bioinformat Sect, Oxford OX1 3SR, England. EM dfield@ceh.ac.uk RI Field, Dawn/C-1653-2010; Smith, Barry/A-9525-2011 OI Smith, Barry/0000-0003-1384-116X NR 15 TC 23 Z9 24 U1 2 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1536-2310 J9 OMICS JI OMICS PD JUN PY 2006 VL 10 IS 2 BP 127 EP 137 DI 10.1089/omi.2006.10.127 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 079XJ UT WOS:000240210900007 PM 16901217 ER PT J AU Sansone, SA Rocca-Serra, P Tong, WD Fostel, J Morrison, N Jones, AR AF Sansone, Susanna-Assunta Rocca-Serra, Philippe Tong, Weida Fostel, Jennifer Morrison, Norman Jones, Andrew R. CA RSBI Members TI A strategy capitalizing on synergies: The Reporting Structure for Biological Investigation (RSBI) working group SO OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY LA English DT Article ID TOXICOGENOMICS; STANDARDS; SYSTEMS AB In this article we present the Reporting Structure for Biological Investigation (RSBI), a working group under the Microarray Gene Expression Data (MGED) Society umbrella. RSBI brings together several communities to tackle the challenges associated with integrating data and representing complex biological investigations, employing multiple OMICS technologies. Currently, RSBI includes environmental genomics, nutrigenomics and toxicogenomics communities, where independent activities are underway to develop databases and establish data communication standards within their respective domains. The RSBI working group has been conceived as a "single point of focus" for these communities, conforming to general accepted view that duplication and incompatibility should be avoided where possible. This endeavour has aimed to synergize insular solutions into one common terminology between biologically driven standardisation efforts and has also resulted in strong collaborations and shared understanding between those in the technological domain. Through extensive liaisons with many standards efforts, several threads have been woven with the hope that ultimately technology-centered standards and their specific extensions into biological domains of interest will not only stand alone, but will also be able to function together, as interchangeable modules. This paper is part of the special issue of OMICS on data processing. C1 EBI, EMBL, NuGO, Cambridge CB10 1SD, England. US FDA, Natl Ctr Toxicol Res, Ctr Toxicoinformat, Jefferson, AR 72079 USA. NIEHS, Natl Ctr Toxicogen, Res Triangle Pk, NC 27709 USA. NERC, Bioinformat Ctr, Oxford Ctr Ecol & Hydrol, Oxford OX1 3SR, England. Univ Manchester, Sch Comp Sci, Manchester, Lancs, England. RP Sansone, SA (reprint author), EBI, EMBL, NuGO, Wellcome Trust Gen Campus, Cambridge CB10 1SD, England. EM sansone@ebi.ac.uk OI Sansone, Susanna-Assunta/0000-0001-5306-5690; Jones, Andrew/0000-0001-6118-9327 FU Intramural NIH HHS NR 10 TC 19 Z9 20 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1536-2310 J9 OMICS JI OMICS PD JUN PY 2006 VL 10 IS 2 BP 164 EP 171 DI 10.1089/omi.2006.10.164 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 079XJ UT WOS:000240210900012 PM 16901222 ER PT J AU Whetzel, PL Brinkman, RR Causton, HC Fan, L Field, D Fostel, J Fragoso, G Gray, T Heiskanen, M Hernandez-Boussard, T Morrison, N Parkinson, H Rocca-Serra, P Sansone, SA Schober, D Smith, B Stevens, R Stoeckert, CJ Taylor, C White, J Wood, A AF Whetzel, Patricia L. Brinkman, Ryan R. Causton, Helen C. Fan, Liju Field, Dawn Fostel, Jennifer Fragoso, Gilberto Gray, Tanya Heiskanen, Mervi Hernandez-Boussard, Tina Morrison, Norman Parkinson, Helen Rocca-Serra, Philippe Sansone, Susanna-Assunta Schober, Daniel Smith, Barry Stevens, Robert Stoeckert, Christian J. Taylor, Chris White, Joe Wood, Andrew CA FuGO Working Grp TI Development of FuGO: An ontology for Functional Genomics Investigations SO OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY LA English DT Article AB The development of the Functional Genomics Investigation Ontology (FuGO) is a collaborative, international effort that will provide a resource for annotating functional genomics investigations, including the study design, protocols and instrumentation used, the data generated and the types of analysis performed on the data. FuGO will contain both terms that are universal to all functional genomics investigations and those that are domain specific. In this way, the ontology will serve as the "semantic glue" to provide a common understanding of data from across these disparate data sources. In addition, FuGO will reference out to existing mature ontologies to avoid the need to duplicate these resources, and will do so in such a way as to enable their ease of use in annotation. This project is in the early stages of development; the paper will describe efforts to initiate the project, the scope and organization of the project, the work accomplished to date, and the challenges encountered, as well as future plans. This paper is part of the special issue of OMICS on data standards. C1 Univ Penn, Sch Med, Ctr Bioinformat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. British Columbia Canc Res Ctr, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada. Univ London Imperial Coll Sci Technol & Med, Fac Med, MRC, Ctr Clin Sci, London, England. Ontol Workshop LLC, Columbia, MD USA. Oxford Ctr Ecol & Hydrol, Mol Evolut & Bioinformat Sect, Oxford, England. NIEHS, Res Triangle Pk, NC 27709 USA. NCI, Ctr Bioinformat, NCICB, Rockville, MD USA. Stanford Univ, Med Ctr, Dept Genet, Stanford, CA 94305 USA. Univ Manchester, Dept Comp Sci, Manchester, Lancs, England. Oxford Ctr Ecol & Hydrol, NERC, Environm Bioinformat Ctr, Oxford, England. European Bioinformat Inst, Cambridge, England. SUNY Buffalo, Dept Philosophy, Ctr Excellence Bioinformat & Life Sci, Buffalo, NY USA. SUNY Buffalo, Natl Ctr Biomed Oncol, Buffalo, NY USA. Inst Formal Ontol & Med Sci, Saarbrucken, Germany. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Whetzel, PL (reprint author), Univ Penn, Sch Med, Ctr Bioinformat, Philadelphia, PA 19104 USA. EM whetzel@pcbi.upenn.edu RI Field, Dawn/C-1653-2010; Brinkman, Ryan/B-1108-2008; Smith, Barry/A-9525-2011; OI Brinkman, Ryan/0000-0002-9765-2990; Smith, Barry/0000-0003-1384-116X; Sansone, Susanna-Assunta/0000-0001-5306-5690 FU Intramural NIH HHS; NHGRI NIH HHS [1 U 54 HG004028, P41 HG003619, P41 HG003619-01]; NIBIB NIH HHS [R01 EB005034-02, EB-5034, R01 EB005034]; NIGMS NIH HHS [U01 GM061374, U01GM61374] NR 14 TC 35 Z9 36 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1536-2310 J9 OMICS JI OMICS PD JUN PY 2006 VL 10 IS 2 BP 199 EP 204 DI 10.1089/omi.2006.10.199 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 079XJ UT WOS:000240210900016 PM 16901226 ER PT J AU Leebens-Mack, J Vision, T Brenner, E Bowers, JE Cannon, S Clement, MJ Cunningham, CW Depamphilis, C Desalle, R Doyle, JJ Eisen, JA Gu, X Harshman, J Jansen, RK Kellogg, EA Koonin, EV Mishler, BD Philippe, H Pires, JC Qiu, YL Rhee, SY Sjolander, K Soltis, DE Soltis, PS Stevenson, DW Wall, K Warnow, T Zmasek, C AF Leebens-Mack, Jim Vision, Todd Brenner, Eric Bowers, John E. Cannon, Steven Clement, Mark J. Cunningham, Clifford W. dePamphilis, Claude deSalle, Rob Doyle, Jeff J. Eisen, Jonathan A. Gu, Xun Harshman, John Jansen, Robert K. Kellogg, Elizabeth A. Koonin, Eugene V. Mishler, Brent D. Philippe, Herve Pires, J. Chris Qiu, Yin-Long Rhee, Seung Y. Sjoelander, Kimmen Soltis, Douglas E. Soltis, Pamela S. Stevenson, Dennis W. Wall, Kerr Warnow, Tandy Zmasek, Christian TI Taking the first steps towards a standard for reporting on phylogenies: Minimum information about a phylogenetic analysis (MIAPA) SO OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY LA English DT Article ID SEQUENCE ALIGNMENT; COMPARATIVE GENOMICS; EXPRESSION PROFILES; DUPLICATION EVENTS; GENE-EXPRESSION; MICROARRAY DATA; EVOLUTION; LIFE; TREE; DATABASE AB In the eight years since phylogenomics was introduced as the intersection of genomics and phylogenetics, the field has provided fundamental insights into gene function, genome history and organismal relationships. The utility of phylogenomics is growing with the increase in the number and diversity of taxa for which whole genome and large transcriptome sequence sets are being generated. We assert that the synergy between genomic and phylogenetic perspectives in comparative biology would be enhanced by the development and refinement of minimal reporting standards for phylogenetic analyses. Encouraged by the development of the Minimum Information About a Microarray Experiment (MIAME) standard, we propose a similar roadmap for the development of a Minimal Information About a Phylogenetic Analysis (MIAPA) standard. Key in the successful development and implementation of such a standard will be broad participation by developers of phylogenetic analysis software, phylogenetic database developers, practitioners of phylogenomics, and journal editors. This paper is part of the special issue of OMICS on data standards. C1 Univ Georgia, Dept Plant Biol, Athens, GA 30602 USA. Penn State Univ, Dept Biol, Inst Mol Evolut Genet, University Pk, PA 16802 USA. Penn State Univ, Huck Inst Life Sci, University Pk, PA 16802 USA. Univ N Carolina, Dept Biol, Chapel Hill, NC USA. New York Bot Garden, Bronx, NY 10458 USA. Univ Georgia, Athens, GA 30602 USA. Appl Genet Technol Ctr, Dept Crop & Soil Sci, Athens, GA USA. Appl Genet Technol Ctr, Dept Bot, Athens, GA USA. Appl Genet Technol Ctr, Dept Genet, Athens, GA USA. Iowa State Univ, USDA ARS, Ames, IA USA. Iowa State Univ, Dept Agron, Ames, IA USA. Brigham Young Univ, Dept Comp Sci, Networked Comp Lab, Provo, UT 84602 USA. Duke Univ, Dept Biol, Durham, NC USA. Amer Museum Nat Hist, Div Invertebrate Zool, New York, NY 10024 USA. Cornell Univ, LH Bailey Hortorium, Ithaca, NY USA. Univ Calif Davis, UC Davis Gen Ctr, Sect Evolut & Ecol, Davis, CA 95616 USA. Univ Calif Davis, Dept Med Microbiol & Immunol, Davis, CA 95616 USA. Iowa State Univ, Dept Genet Dev & Cell Biol, Ames, IA USA. Pepperwood Way, San Jose, CA USA. Univ Texas, Sect Integrat Biol, Austin, TX 78712 USA. Univ Texas, Inst Cellular & Mol Biol, Austin, TX 78712 USA. Univ Missouri, Dept Biol, St Louis, MO 63121 USA. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. Univ Herbarium, Berkeley, CA USA. Univ Montreal, Canadian Inst Adv Res, Ctr Robert Cedergren, Dept Biochim, Montreal, PQ, Canada. Univ Missouri, Div Biol Sci, Columbia, MO USA. Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. Carnegie Inst, Dept Plant Biol, Stanford, CA USA. Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA. Univ Florida, Dept Bot, Gainesville, FL USA. Univ Florida, Genet Inst, Gainesville, FL USA. Univ Florida, Florida Museum Nat Hist, Gainesville, FL USA. Univ Texas, Dept Comp Sci, Austin, TX 78712 USA. Burnham Inst Med Res, La Jolla, CA USA. RP Leebens-Mack, J (reprint author), Univ Georgia, Dept Plant Biol, Athens, GA 30602 USA. EM jleebensmack@plantbio.uga.edu RI Bowers, John/B-9245-2009; Vision, Todd/B-4867-2010; Jansen, Robert/F-6272-2011; Cunningham, Clifford/B-9807-2014; Soltis, Pamela/L-5184-2015; Kellogg, Elizabeth/M-2845-2013; dePamphilis, Claude/P-6652-2016; OI Vision, Todd/0000-0002-6133-2581; Kellogg, Elizabeth/0000-0003-1671-7447; Pires, J Chris/0000-0001-9682-2639 FU NIGMS NIH HHS [R01 GM067012-01] NR 57 TC 34 Z9 35 U1 0 U2 9 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1536-2310 J9 OMICS JI OMICS PD JUN PY 2006 VL 10 IS 2 BP 231 EP 237 DI 10.1089/omi.2006.10.231 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 079XJ UT WOS:000240210900021 PM 16901231 ER PT J AU Wang, S Zhan, M Yin, J Abraham, JM Mori, Y Sato, F Xu, Y Olaru, A Berki, AT Li, H Schulmann, K Kan, T Hamilton, JP Paun, B Yu, MM Jin, Z Cheng, Y Ito, T Mantzur, C Greenwald, BD Meltzer, SJ AF Wang, S Zhan, M Yin, J Abraham, JM Mori, Y Sato, F Xu, Y Olaru, A Berki, AT Li, H Schulmann, K Kan, T Hamilton, JP Paun, B Yu, MM Jin, Z Cheng, Y Ito, T Mantzur, C Greenwald, BD Meltzer, SJ TI Transcriptional profiling suggests that Barrett's metaplasia is an early intermediate stage in esophageal adenocarcinogenesis SO ONCOGENE LA English DT Article DE Barrett's esophagus; esophageal adenocarcinoma; transcriptional profiling; bioinformatics; early detection ID OVARIAN ENDOMETRIOID ADENOCARCINOMAS; GENE-EXPRESSION PROFILE; MICROSATELLITE INSTABILITY; INTESTINAL METAPLASIA; TUMOR PROGRESSION; OXIDATIVE DAMAGE; GASTRIC-CANCER; BETA-CATENIN; CARCINOMA; DIAGNOSIS AB To investigate the relationship between Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), we determined gene expression profiles of discrete pathological stages of esophageal neoplasia using a sequence-verified human cDNA microarray. Fifty one RNAs, comprising 24 normal esophagi ( NE), 18 BEs, and nine EACs were hybridized to cDNA microarrays. Five statistical analyses were used for the data analysis. Genes showing significantly different expression levels among the three sample groups were identified. Genes were grouped into functional categories based on the Gene Ontology Consortium. Surprisingly, the expression pattern of BE was significantly more similar to EAC than to NE, notwithstanding the known histopathologic differences between BE and EAC. The pattern of NE was clearly distinct from that of EAC. Thirty-six genes were the most differentially modulated, according to these microarray data, in BE-associated neoplastic progression. Twelve genes were significantly differentially expressed in cancer-associated BE's plus EAC (as a single combined tissue group) vs noncancer-associated BE's. These genes represent potential biomarkers to diagnose EAC at its early stages. Our results demonstrate that molecular events at the transcriptional level in BE are remarkably similar to BE's-associated adenocarcinoma of the esophagus. This finding alarmingly implies that BE is biologically closer to cancer than to normal esophagus, and that the cancer risk of BE is perhaps higher than we had imagined. These findings suggest that changes modulated at the molecular biologic level supervene earlier than histologic changes, and that BE is an early intermediate stage in the process of EAC. C1 Univ Maryland, Sch Med, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. Univ Maryland, Div Gastroenterol, Dept Med, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. Baltimore VA Hosp, Baltimore, MD USA. NIA, Bioinformat Unit, NIH, Baltimore, MD 21224 USA. RP Meltzer, SJ (reprint author), Univ Maryland, Sch Med, Greenebaum Canc Ctr, 22 S Greene St,Rm N3W62, Baltimore, MD 21201 USA. EM smeltzer@medicine.umaryland.edu RI Schulmann, Karsten/N-2230-2016 FU NCI NIH HHS [CA95323, CA10676, CA01808, CA85069]; NIDDK NIH HHS [DK67872] NR 53 TC 79 Z9 80 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 1 PY 2006 VL 25 IS 23 BP 3346 EP 3356 DI 10.1038/sj.onc.1209357 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 048MM UT WOS:000237951200013 PM 16449976 ER PT J AU Seeff, LB Hoofnagle, JH AF Seeff, L. B. Hoofnagle, J. H. TI Epidemiology of hepatocellular carcinoma in areas of low hepatitis B and hepatitis C endemicity SO ONCOGENE LA English DT Review DE hepatocellular carcinoma; hepatitis B; hepatitis C ID CHRONIC LIVER-DISEASE; UNITED-STATES; WORLDWIDE INCIDENCE; VIRAL-HEPATITIS; VIRUS; CANCER; TRENDS; POPULATION; BURDEN; PREVALENCE AB Hepatocellular carcinoma (HCC) ranks among the 10 most common cancers worldwide. It evolves from several chronic liver diseases, most of which culminate in cirrhosis. As the most common causes, other than alcoholic cirrhosis, are chronic hepatitis B and C infections, its prevalence worldwide is linked to the prevalence of these two viruses. Thus, the highest rates are in southeast Asia and sub-Saharan Africa, the world's most populous nations, where hepatitis B virus infection is endemic. In most western countries, hepatitis C virus infection is the predominant cause, and hepatitis B-related liver cancer occurs largely among immigrants from countries of high hepatitis B endemicity. In most western countries, the incidence and mortality from HCC is increasing as a consequence of the chronic sequelae of the 'epidemic' of hepatitis C of the 1960 - 1980s. In the US, modeling of this infection predicts a continued rise in liver cancer over the next decade. Surveillance by the National Cancer Institute and the Centers for Disease Control confirms the increasing incidence of and mortality from HCC to the year 2000, although subsequent analyses suggest a slowing or possibly decline in the rate of increase. Whether this trend will continue requires further evaluation. C1 NIDDK, Liver Dis Res Branch, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. RP Seeff, LB (reprint author), NIDDK, Liver Dis Res Branch, Div Digest Dis & Nutr, NIH, 27A Ctr Dr,Room 9A27, Bethesda, MD 20892 USA. EM seeffL@EXTRA.NIDDK.NIH.GOV RI Jepsen, Peter/A-2593-2010 OI Jepsen, Peter/0000-0002-6641-1430 NR 33 TC 102 Z9 110 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN PY 2006 VL 25 IS 27 BP 3771 EP 3777 DI 10.1038/sj.onc.1209560 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 056XY UT WOS:000238559600004 PM 16799618 ER PT J AU Lee, JS Thorgeirsson, SS AF Lee, J-S Thorgeirsson, S. S. TI Comparative and integrative functional genomics of HCC SO ONCOGENE LA English DT Review DE DNA microarray; gene expression profile; hepatocellular carcinoma (HCC); comparative functional genomics; integrative functional genomics ID GENE-EXPRESSION PROFILES; ACTIVATED RECEPTOR-ALPHA; HEPATITIS-B-VIRUS; ACUTE MYELOID-LEUKEMIA; HEPATOCELLULAR-CARCINOMA; BETA-CATENIN; PEROXISOME PROLIFERATOR; BREAST-CANCER; MOLECULAR-FEATURES; NATURAL-HISTORY AB Global gene expression pro. ling of hepatocellular carcinoma (HCC) is a promising new technology that has already refined the diagnosis and prognostic predictions of HCC patients. This has been accomplished by identifying genes whose expression pattern is associated with clinicopathological features of HCC tumors. Molecular characterization of HCC from gene expression pro. ling studies will undoubtedly improve the prediction of treatment responses, selection of treatments for specific molecular subtypes of HCC and ultimately the clinical outcome of HCC patients. The research focus is now shifting toward the identification of genetic determinants that are components of the specific regulatory pathways altered in cancers, and that may constitute novel therapeutic targets. Here we review the recent advances in gene expression pro. ling of HCC and discuss the future strategies for analysing large and complicated data sets from microarray studies and how to integrate these with diverse genomic data. C1 NCI, Lab Expt Carcinogenesis, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NCI, Lab Expt Carcinogenesis, Ctr Canc Res, NIH, 37 Convent Dr,Bldg 37,Room 4146, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov NR 69 TC 82 Z9 84 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN PY 2006 VL 25 IS 27 BP 3801 EP 3809 DI 10.1038/sj.onc.1209561 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 056XY UT WOS:000238559600007 PM 16799621 ER PT J AU Hashiramoto, A Mizukami, H Yamashita, T AF Hashiramoto, A Mizukami, H Yamashita, T TI Ganglioside GM3 promotes cell migration by regulating MAPK and c-Fos/AP-1 SO ONCOGENE LA English DT Article DE GM3; MAPK; cell cycle; c-Fos; AP-1 ID GROWTH-FACTOR RECEPTOR; SIGNAL-TRANSDUCTION; MICE LACKING; C-FOS; KINASE; PROLIFERATION; EXPRESSION; ACTIVATION; APOPTOSIS; PHOSPHORYLATION AB Gangliosides have been proposed as modulators of transmembrane signaling. Recently, GM3, a glycosphingolipid containing monosaialic acids, is thought to be one of the key molecules of signal transduction in mammalian cells. In this study, we used mouse embryonic fibroblast cell lines (MEFs) established from sialyltransferase-I knockout mice (GM3 synthase KO mice) to evaluate the regulation of mitogenic signals by gangliosides. Cell proliferation assay revealed a higher growth potential of GM3 KO MEFs. Immunoblots showed upregulation of Ras/Raf/MEK/ERK pathway in GM3 KO MEFs, and these signals resulted in enhanced translocation of ERK into the nuclei. Further, both exogenous and endogenous add-back of GM3 decreased the activities of MAPK in GM3 KO MEFs. In addition, GM3 KO MEFs formed foci in high-density culture condition, and analyses of cell cycle modulators revealed the resistance of GM3 KO MEFs for entering cell cycle arrest. Finally, sustained expressions of c-Fos in GM3 KO MEFs were shown to correlate with DNA-binding activity between c-Fos and AP-1. These results demonstrate that the deletion of sialyltransferase-I changes the character of MEFs to a highly activated state of the MAPK pathway, indicating the critical role of GM3 as a regulator of membrane-transmitted signals. C1 Kobe Univ, Dept Rheumatol, FHS Sch Med, Kobe, Hyogo 6540142, Japan. NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. Hirosaki Univ, Sch Med, Dept Pathol, Hirosaki, Aomori 036, Japan. Univ Tokyo, Inst Med Sci, Dept Cell Proc, Tokyo, Japan. RP Hashiramoto, A (reprint author), Kobe Univ, Dept Rheumatol, FHS Sch Med, 7-10-2 Tomogaoka, Kobe, Hyogo 6540142, Japan. EM hash@kobe-u.ac.jp NR 45 TC 29 Z9 29 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN PY 2006 VL 25 IS 28 BP 3948 EP 3955 DI 10.1038/sj.onc.1209416 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 058MJ UT WOS:000238668800008 PM 16491123 ER PT J AU Widemann, BC Adamson, PC AF Widemann, Brigitte C. Adamson, Peter C. TI Understanding and managing methotrexate nephrotoxicity SO ONCOLOGIST LA English DT Article DE methotrexate toxicity; renal dysfunction; carboxypeptidase-G(2); hemodialysis; hemoperfusion; thymidine; high-dose chemotherapy; rescue agents ID HIGH-DOSE METHOTREXATE; CITROVORUM FACTOR NSC-3590; HIGH-FLUX HEMODIALYSIS; CLINICAL PHARMACOLOGY; RENAL-FAILURE; CARBOXYPEPTIDASE-G(2) RESCUE; OSTEOGENIC-SARCOMA; LEUCOVORIN RESCUE; RHESUS-MONKEYS; PHASE-II AB Methotrexate (MTX) is one of the most widely used anticancer agents, and administration of high-dose methotrexate (HDMTX) followed by leucovorin (LV) rescue is an important component in the treatment of a variety of childhood and adult cancers. HDMTX can be safely administered to patients with normal renal function by the use of alkalinization, hydration, and pharmacokinetically guided LV rescue. Despite these measures, HDMTX-induced renal dysfunction continues to occur in approximately 1.8% of patients with osteosarcoma treated on clinical trials. Prompt recognition and treatment of MTX-induced renal dysfunction are essential to prevent potentially life-threatening MTX-associated toxicities, especially myelosuppression, mucositis, and dermatitis. In addition to conventional treatment approaches, dialysis-based methods have been used to remove MTX with limited effectiveness. More recently carboxypeptidase-G(2) (CPDG(2)), a recombinant bacterial enzyme that rapidly hydrolyzes MTX to inactive metabolites, has become available for the treatment of HDMTX-induced renal dysfunction. CPDG2 administration has been well tolerated and resulted in consistent and rapid reductions in plasma MTX concentrations by a median of 98.7% (range, 84%-99.5%). The early administration of CPDG(2) in addition to LV may be beneficial for patients with MTX-induced renal dysfunction and significantly elevated plasma MTX concentrations. C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. Childrens Hosp Philadelphia, Div Clin Pharmacol & Therapeut, Philadelphia, PA 19104 USA. RP Widemann, BC (reprint author), NCI, Pediat Oncol Branch, 10 Ctr Dr,Bldg 10 CRC Room 1-5750, Bethesda, MD 20892 USA. EM widemanb@mail.nih.gov FU Intramural NIH HHS NR 79 TC 193 Z9 201 U1 1 U2 11 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PD JUN PY 2006 VL 11 IS 6 BP 694 EP 703 DI 10.1634/theoncologist.11-6-694 PG 10 WC Oncology SC Oncology GA 085TO UT WOS:000240627500015 PM 16794248 ER PT J AU Goldman, JM AF Goldman, John M. TI The Savona/Talpaz article reviewed SO ONCOLOGY-NEW YORK LA English DT Editorial Material C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Goldman, JM (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NR 16 TC 0 Z9 0 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD JUN PY 2006 VL 20 IS 7 BP 712 EP + PG 2 WC Oncology SC Oncology GA V44BF UT WOS:000202977500006 ER PT J AU Ershler, WB AF Ershler, William B. TI Management of colorectal cancer in older patients - The Xiao/Lichtman article reviewed SO ONCOLOGY-NEW YORK LA English DT Editorial Material C1 Inst Adv Studies Aging, Washington, DC USA. NIA, Clin Res Branch, NIH, Baltimore, MD 21224 USA. RP Ershler, WB (reprint author), Inst Adv Studies Aging, Washington, DC USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD JUN PY 2006 VL 20 IS 7 BP 750 EP + PG 2 WC Oncology SC Oncology GA V44BF UT WOS:000202977500010 ER PT J AU Roth, MJ Abnet, CC Hu, N Wang, QH Wei, WQ Green, L D'Alelio, M Qiao, YL Dawsey, SM Taylor, PR Woodson, K AF Roth, MJ Abnet, CC Hu, N Wang, QH Wei, WQ Green, L D'Alelio, M Qiao, YL Dawsey, SM Taylor, PR Woodson, K TI p16, MGMT, RAR beta 2, CLDN3, CRBP and MT1G gene methylation in esophageal squamous cell carcinoma and its precursor lesions SO ONCOLOGY REPORTS LA English DT Article DE esophagus; squamous cell carcinoma; dysplasia; methylation; p16; MGMT; RAR beta 2; CLDN3; CRBP; MT1G ID HYPERMETHYLATION-ASSOCIATED INACTIVATION; PROMOTER HYPERMETHYLATION; DNA METHYLATION; CANCER; CHINA; LINXIAN; DYSPLASIA; DISEASE AB Esophageal squamous cell carcinoma (ESCC) is a common cancer with a very poor prognosis. New methods are needed to screen high-risk populations and identify curable tumors and precursor lesions early. Molecular markers may be useful in such screening efforts. This study was designed to determine the prevalence of p16, MGMT, RAR beta 2, CLDN3, CRBP and MT1G gene methylation in patients with ESCC to evaluate the variation of gene methylation across a spectrum of preneoplastic lesions, and assess the feasibility of using gene methylation in a primary screening test utilizing frozen esophageal cells collected by balloon cytology samplers. Samples were obtained from high-risk subjects from north central China. These samples included I I foci of histologically normal mucosa, 8 foci of low-grade squamous dysplasia, 7 foci of high-grade squamous dysplasia, and 13 foci of ESCC from 6 fully embedded resection specimens; endoscopic biopsies from 6 individuals with no histological evidence of disease; and frozen esophageal balloon samples from 12 asymptomatic subjects. Promoter CpG site-specific hypermethylation status was determined for each gene using realtime methylation-specific PCR (qMS-PCR) based on Taqman chemistry. Of the 6 ESCC patients, 5 showed methylation of at least one gene. For most genes, methylation occurred with increasing frequency during neoplastic progression, with the largest increase found between low- and high-grade dysplasia. There was considerable variation in methylation patterns among different foci of the same histological grade, even within individual patients, but 16/20 (80%) of high-grade dysplastic and cancer foci had >= 2 methylated genes, while 17/19 (89%) of normal and low-grade dysplastic foci had < 2 methylated genes. These genes were rarely methylated in histologically normal mucosa from patients with or without ESCC. Gene methylation was common and easily detectable in the frozen esophageal cells collected by balloon cytology samplers. Our data suggest that methylation of p16, MGMT, RAR beta 2, CLDN3, CRBP, and MT1G is common in the esophageal mucosa of patients with ESCC in this high-risk population, and tends to increase in prevalence in foci with increasing histological severity of disease. Methylation data from panels of genes may be able to identify patients with high-grade lesions. Balloon cytology may be able to screen the length of the esophagus effectively for a subset of cells with abnormal methylation, and may be useful in a primary screening test for ESCC and its precursor lesions. C1 NCI, Ctr Canc Res, Nutrit Epidemiol Branch, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Canc Genet Branch, Bethesda, MD 20892 USA. Shanxi Canc Hosp & Inst, Shanxi, Peoples R China. Chinese Acad Med Sci, Inst Canc, Dept Canc Epidemiol, Beijing 100037, Peoples R China. RP Roth, MJ (reprint author), NCI, Ctr Canc Res, Nutrit Epidemiol Branch, 6120 Execut Blvd,EPS-320,MSC 7232, Bethesda, MD 20892 USA. EM mr166i@nih.gov RI Qiao, You-Lin/B-4139-2012; Abnet, Christian/C-4111-2015 OI Qiao, You-Lin/0000-0001-6380-0871; Abnet, Christian/0000-0002-3008-7843 FU Intramural NIH HHS; NCI NIH HHS [N01-SC-91019] NR 27 TC 33 Z9 37 U1 0 U2 2 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD JUN PY 2006 VL 15 IS 6 BP 1591 EP 1597 PG 7 WC Oncology SC Oncology GA 047IP UT WOS:000237873300028 PM 16685400 ER PT J AU Tsilou, ET Rubin, BI Reed, G Caruso, RC Iwata, F Balog, J Gahl, WA Kaiser-Kupfer, MI AF Tsilou, ET Rubin, BI Reed, G Caruso, RC Iwata, F Balog, J Gahl, WA Kaiser-Kupfer, MI TI Nephropathic cystinosis - Posterior segment manifestations and effects of cysteamine therapy SO OPHTHALMOLOGY LA English DT Article ID LONG-TERM; OCULAR MANIFESTATIONS; CORNEAL CRYSTALS; POPULATION; EVOLUTION; APOPTOSIS; DEPLETION; CHILDREN; PROTEIN AB Purpose: Cystinosis is a rare autosomal recessive lysosomal storage disorder characterized by the intracellular accumulation of cystine. Treatment involves intracellular cystine depletion with oral cysteamine. A wide spectrum of ocular pathologic features has been associated with nephropathic cystinosis. We used the largest documented cohort of patients in the world to study the posterior segment manifestations associated with infantile nephropathic cystinosis and to determine retrospectively the effect of chronic oral cysteamine therapy on the frequency of these abnormalities. Design: Cross-sectional study of a series of patients. Participants: Two hundred eight patients with infantile nephropathic cystinosis were studied at the National Institutes of Health between 1976 and 2004. Methods: All patients underwent an ophthalmic evaluation. Patients older than 11 years also underwent Humphrey static perimetry, and electrophysiological testing was performed when possible. Main Outcome Measures: Visual acuity, retina findings, visual fields, and electroretinographic (ERG) findings. Results: Pigmentary changes with retinal pigment epithelial mottling, seen as early as infancy, were the most common posterior segment manifestations. Moderate to severe constriction of the visual fields, as well as moderate to severe reduction of rod- and cone-mediated ERG responses, was seen in older patients. The frequency of retinopathy correlated directly with time not receiving oral cysteamine therapy and inversely with time receiving oral cysteamine therapy. Conclusions: Infantile nephropathic cystinosis has posterior segment complications that can contribute to significant visual handicap. Early initiation of oral cysteamine therapy can reduce the frequency of posterior segment complications in cystinosis patients. C1 NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. NEI, Div Biometry & Epidemiol, NIH, Bethesda, MD 20892 USA. Juntendo Univ, Sch Med, Dept Ophthalmol, Tokyo 113, Japan. NIH, Dept Nursing, Ctr Clin, Bethesda, MD 20892 USA. NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Tsilou, ET (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, 10 Ctr Dr,MSC 1860,Bldg 10,Room 10N226, Bethesda, MD 20892 USA. EM tsiloue@nei.nih.gov FU Intramural NIH HHS NR 30 TC 23 Z9 24 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 JUN PY 2006 VL 113 IS 6 BP 1002 EP 1009 DI 10.1016/j.ophtha.2005.12.026 PG 8 WC Ophthalmology SC Ophthalmology GA 050KI UT WOS:000238085900020 PM 16603246 ER PT J AU Sher, A AF Sher, A TI Alan Sher's crystal ball SO PARASITE IMMUNOLOGY LA English DT Article C1 NIAID, Lab Parasite Dis, NIH, Bethesda, MD 20892 USA. RP Sher, A (reprint author), NIAID, Lab Parasite Dis, NIH, Bldg 50,Room 6140,50 S Dr, Bethesda, MD 20892 USA. EM asher@niaid.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0141-9838 J9 PARASITE IMMUNOL JI Parasite Immunol. PD JUN PY 2006 VL 28 IS 6 BP 242 EP 242 DI 10.1111/j.1365-3024.2006.00877.x PG 1 WC Immunology; Parasitology SC Immunology; Parasitology GA 043JN UT WOS:000237597400010 ER PT J AU Nutman, TB AF Nutman, TB TI Multidimensional profiling of host- and parasite-encoded genes and molecules SO PARASITE IMMUNOLOGY LA English DT Article C1 Lab Parasit Dis, Helminth Immunol Sect, NIH, Bethesda, MD 20892 USA. RP Nutman, TB (reprint author), Lab Parasit Dis, Helminth Immunol Sect, NIH, 4 Ctr Dr, Bethesda, MD 20892 USA. EM tnutman@niaid.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0141-9838 J9 PARASITE IMMUNOL JI Parasite Immunol. PD JUN PY 2006 VL 28 IS 6 BP 255 EP 256 DI 10.1111/j.1365-3024.2006.00868.x PG 2 WC Immunology; Parasitology SC Immunology; Parasitology GA 043JN UT WOS:000237597400027 ER PT J AU Duggal, P Peterson, K Petri, WA AF Duggal, P Peterson, K Petri, WA TI The international hapmap project as a tool to probe human susceptibility to parasitic diseases SO PARASITE IMMUNOLOGY LA English DT Article C1 Univ Virginia, Dept Med, Charlottesville, VA 22908 USA. Natl Human Genome, Inherited Dis Res Branch, NIH, Baltimore, MD 21224 USA. RP Petri, WA (reprint author), Univ Virginia, Dept Med, Charlottesville, VA 22908 USA. EM wap3g@virginia.edu NR 2 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0141-9838 J9 PARASITE IMMUNOL JI Parasite Immunol. PD JUN PY 2006 VL 28 IS 6 BP 257 EP 258 PG 2 WC Immunology; Parasitology SC Immunology; Parasitology GA 043JN UT WOS:000237597400029 ER PT J AU Wynn, TA AF Wynn, TA TI Understanding immune suppression - Multiple mediators, including Tregs, B cells, alternatively-activated macrophages, and decoy receptors SO PARASITE IMMUNOLOGY LA English DT Article DE suppression ID SCHISTOSOMIASIS C1 Natl Inst Allergy & Infect Dis, Lab Parasit Dis, Immunopathogenesis Sect, NIH, Bethesda, MD 20892 USA. RP Wynn, TA (reprint author), Natl Inst Allergy & Infect Dis, Lab Parasit Dis, Immunopathogenesis Sect, NIH, 50 South Dr,Room 6154, Bethesda, MD 20892 USA. EM twynn@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 NR 2 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0141-9838 J9 PARASITE IMMUNOL JI Parasite Immunol. PD JUN PY 2006 VL 28 IS 6 BP 267 EP 268 DI 10.1111/j.1365-3024.2006.00878.x PG 2 WC Immunology; Parasitology SC Immunology; Parasitology GA 043JN UT WOS:000237597400037 ER PT J AU Belkaid, Y AF Belkaid, Y TI Design of vaccines against parasitic infections: Understanding the nature of the antigens recognized by T-REG SO PARASITE IMMUNOLOGY LA English DT Article ID CELLS C1 NIAID, Mucosal Immunol Unit, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. RP Belkaid, Y (reprint author), NIAID, Mucosal Immunol Unit, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. EM ybelkaid@niaid.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0141-9838 J9 PARASITE IMMUNOL JI Parasite Immunol. PD JUN PY 2006 VL 28 IS 6 BP 268 EP 268 DI 10.1111/j.1365-3024.2006.00871.x PG 1 WC Immunology; Parasitology SC Immunology; Parasitology GA 043JN UT WOS:000237597400038 ER PT J AU Sacks, D AF Sacks, D TI Notch control of antigen-induced Treg differentiation in leishmaniasis SO PARASITE IMMUNOLOGY LA English DT Article C1 NIAID, Lab Parasit Dis, Intracellular Parasite Biol Sect, Bethesda, MD 20892 USA. RP Sacks, D (reprint author), NIAID, Lab Parasit Dis, Intracellular Parasite Biol Sect, Bldg 4,Rm 126,4 Ctr Dr MSC 0425, Bethesda, MD 20892 USA. EM dsacks@nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0141-9838 J9 PARASITE IMMUNOL JI Parasite Immunol. PD JUN PY 2006 VL 28 IS 6 BP 268 EP 269 DI 10.1111/j.1365-3024.2006.00864.x PG 2 WC Immunology; Parasitology SC Immunology; Parasitology GA 043JN UT WOS:000237597400039 ER PT J AU Roberts, SM Freeman, AF Harrington, SM Holland, SM Murray, PR Zelazny, AM AF Roberts, SM Freeman, AF Harrington, SM Holland, SM Murray, PR Zelazny, AM TI Linezolid-resistant Staphylococcus aureus in two pediatric patients receiving low-dose linezolid therapy SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE linezolid resistance; Staphylococcus aureus; hyper-IgE syndrome ID PERIPHERAL NEUROPATHY; PROGRAM AB We report 2 sisters with hyper-IgE syndrome treated with daily suppressive dosages of linezolid (LZD) who developed LZD-resistant Staphylococcus aureus carrying the G2576T mutation in the 23S rRNA gene. Molecular typing suggested transmission of the resistant strain from one sister to the other. LZD-susceptible S. aureus was isolated 2 months after LZD discontinuation. LZD-resistant S. aureus remains rare but may occur while receiving suppressive therapy. C1 NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. NIAID, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Freeman, AF (reprint author), NIH, Ctr Clin, Dept Lab Med, Bldg 10,Room 10S255,9000 Rockville Pike, Bethesda, MD 20892 USA. EM freemaal@mail.nih.gov FU Intramural NIH HHS NR 15 TC 38 Z9 41 U1 0 U2 0 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 JUN PY 2006 VL 25 IS 6 BP 562 EP 564 DI 10.1097/01.inf.0000219401.70804.1a PG 3 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 055EH UT WOS:000238432300019 PM 16732160 ER PT J AU Eisenstein, EM Choi, M AF Eisenstein, EM Choi, M TI Analysis of a uteroglobin gene polymorphism in childhood Henoch-Schonlein purpura SO PEDIATRIC NEPHROLOGY LA English DT Article DE uteroglobin; Henoch-Schonlein purpura; IgA nephropathy; polymorphism ID IGA NEPHROPATHY; RENAL SEQUELAE; ASSOCIATION; CHILDREN; NEPHRITIS; PROGRESSION AB Uteroglobin (UG) is a pleiotropic protein with anti-inflammatory properties. Mice rendered genetically incapable of expressing UG develop a form of renal disease that closely resembles human IgA nephropathy (IgAN). Furthermore, a single nucleotide polymorphism in the UG gene (A38G) has been associated with rapid progression of human IgAN. We examined whether the A38G polymorphism is associated with childhood Henoch-Schonlein purpura (HSP), a form of vasculitis associated with IgAN-like renal disease. We examined the prevalence of the A38G polymorphism in 34 children with HSP and in 38 ethnically matched controls. Only one patient had clinically evident renal involvement. As compared with controls, the prevalence of the 38G allele was slightly increased in children with HSP, but this increase was not statistically significant. Our results do not support a role for UG in susceptibility to childhood HSP in the population studied. Larger studies involving more patients with renal disease will be necessary to define whether UG is associated with increased risk for HSP nephritis. C1 Hadassah Hebrew Univ, Med Ctr, Dept Pediat, IL-91240 Jerusalem, Israel. NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Eisenstein, EM (reprint author), Hadassah Hebrew Univ, Med Ctr, Dept Pediat, POB 24035,Mt Scopus, IL-91240 Jerusalem, Israel. EM eisenstein173@yahoo.com NR 24 TC 3 Z9 4 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD JUN PY 2006 VL 21 IS 6 BP 782 EP 784 DI 10.1007/s00467-006-0094-6 PG 3 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 042XG UT WOS:000237563300008 PM 16703373 ER PT J AU Pavlakis, SG Hirtz, DG deVeber, G AF Pavlakis, SG Hirtz, DG deVeber, G TI Pediatric stroke: Opportunities and challenges in planning clinical trials SO PEDIATRIC NEUROLOGY LA English DT Editorial Material AB A conference entitled "Towards the establishment of clinical trials in pediatric and newborn stroke" assembled stroke animal model researchers, pediatric stroke researchers, adult stroke trialists, and members of the Food and Drug Administration and National Institute of Neurological Disorders and Stroke to focus on the obstacles and opportunities for conducting randomized trials in pediatric stroke. The need for good prospective clinical data in newborn and pediatric stroke in regard to outcome and recurrence risk was stressed. For clinical trials, there should be a scientific rationale. Preclinical data should be as promising and as complete as possible. Adult data should be explored, both positive and negative. For medication trials, reasonable safety and bioavailability data for the agent in question should be available. Commitment of researchers, collaboration with colleagues in primary care, emergency rooms, and intensive care units, and most importantly the willingness to participate of children and their families will all be crucial. Most children with cancer in the United States are enrolled in clinical trials and have an outcome superior to the adult patient with cancer, who is less likely to be enrolled in a trial. We should strive for enrollment and outcome results in pediatric stroke similar to those found in pediatric oncology trials. (c) 2006 by Elsevier Inc. All rights reserved. C1 Maimonides Infants & Chilrens Hosp, Brooklyn, NY 11219 USA. Mt Sinai Sch Med, New York, NY USA. NINDS, Bethesda, MD 20892 USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. Univ Toronto, Toronto, ON, Canada. RP Pavlakis, SG (reprint author), Maimonides Infants & Chilrens Hosp, Brooklyn, NY 11219 USA. EM spavlakis@maimonidesmed.org NR 3 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD JUN PY 2006 VL 34 IS 6 BP 433 EP 435 DI 10.1016/j.pediatrneurol.2005.09.009 PG 3 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 059PU UT WOS:000238745500002 PM 16765819 ER PT J AU Hirtz, DG Gilbert, PR Terrill, CM Buckman, SY AF Hirtz, DG Gilbert, PR Terrill, CM Buckman, SY TI Clinical trials in children - How are they implemented? SO PEDIATRIC NEUROLOGY LA English DT Article; Proceedings Paper CT Workshop Towards the Establishment of Clinical Trials in Pediatric and Newborn Stroke CY DEC, 2004 CL New York, NY AB Drug metabolism in children may differ from adults and adverse events may occur that are not predictable from the adult experience. Clinical trials of safety and efficacy are needed both for new treatments and those that may already be in use but have not been tested in infants and children. The role and responsibilities of different participants in a trial are discussed, including the steering committee, the clinical and statistical co-ordinating centers, and the data and safety monitoring board. Advantages of external vs internal pilot studies are reviewed. Information that is available on the websites of the Food and Drug Administration and the National Institute of Neurological Disorders and Stroke may be helpful to those planning clinical trials of interventions in children. (c) 2006 by Elsevier Inc. All rights reserved. C1 NINDS, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, St Louis, MO USA. US FDA, OCTAP, Div Pediat Drug Dev, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. RP Hirtz, DG (reprint author), NINDS, NIH, 6001 Execut Blvd,Room 2212, Bethesda, MD 20892 USA. EM hirtzd@ninds.nih.gov NR 9 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD JUN PY 2006 VL 34 IS 6 BP 436 EP 438 DI 10.1016/j.pediatrneurol.2005.09.011 PG 3 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 059PU UT WOS:000238745500003 PM 16765820 ER PT J AU Sofronas, M Ichord, RN Fullerton, HJ Lynch, JK Massicotte, MP Willan, AR deVeber, G AF Sofronas, M Ichord, RN Fullerton, HJ Lynch, JK Massicotte, MP Willan, AR deVeber, G TI Pediatric stroke initiatives and preliminary studies: What is known and what is needed? SO PEDIATRIC NEUROLOGY LA English DT Article; Proceedings Paper CT Workshop Towards the Establishment of Clinical Trials in Pediatric and Newborn Stroke CY DEC, 2004 CL New York, NY ID MOLECULAR-WEIGHT HEPARIN; ARTERIAL ISCHEMIC-STROKE; RANDOMIZED CONTROLLED-TRIAL; CHILDREN; CHILDHOOD; REGISTRY; RISK AB Cerebrovascular disorders are increasingly recognized as important causes of mortality and morbidity in the pediatric population. However, there have been no clinical trials performed to assess the safety and tolerability of acute interventions or secondary preventative treatments. In 2002, the International Pediatric Stroke Study was launched to create a network of investigators, with an interest in developing standards of practice, as well as design and implement the first-ever clinical trials in pediatric stroke. This article reviews existing studies in pediatric stroke epidemiology, risk factors, outcomes, as well as experience with antithrombotic trials in children. From there, current and future initiatives in the development of clinical trials in pediatric stroke are evaluated. (c) 2006 by Elsevier Inc. All rights reserved. C1 Hosp Sick Children, Div Neurol, Toronto, ON M5G 1E2, Canada. Hosp Sick Children, Dept Populat Hlth Sci, Toronto, ON M5G 1E2, Canada. Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA. Univ Calif San Francisco, Div Neurol, San Francisco, CA 94143 USA. NINDS, Bethesda, MD 20892 USA. Stollery Childrens Hosp, Div Haematol Oncol, Edmonton, AB, Canada. Univ Alberta, Edmonton, AB, Canada. Univ Toronto, Toronto, ON, Canada. Hosp Sick Children, Dept Populat Hlth Sci, Toronto, ON M5G 1X8, Canada. RP deVeber, G (reprint author), Hosp Sick Children, Div Neurol, 555 Univ Ave, Toronto, ON M5G 1E2, Canada. EM deveber@sickkids.ca NR 23 TC 24 Z9 25 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD JUN PY 2006 VL 34 IS 6 BP 439 EP 445 DI 10.1016/j.pediatrneurol.2005.10.016 PG 7 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 059PU UT WOS:000238745500004 PM 16765821 ER PT J AU Chodick, G Ronckers, C Ron, E Shalev, V AF Chodick, Gabriel Ronckers, Cecile Ron, Elaine Shalev, Varda TI The utilization of pediatric computed tomography in a large Israeli Health Maintenance Organization SO PEDIATRIC RADIOLOGY LA English DT Article DE CT; radiation; Israel; children ID HELICAL CT; CANCER-RISKS; RADIATION; SEDATION; BODY; FREQUENCY; CHILDREN AB Background: Concern has been raised about the potential risks related to radiation exposure from CT scans, particularly among children. However, to date, there are few data available describing the magnitude of pediatric CT utilization. Objective: The aim of the study was to explore patterns of CT use in pediatric patients, with respect to time, use of multiple scans, body regions imaged, and medical diagnoses. Materials and methods: Records of 22,223 scans performed on 18,075 people aged <= 18 years over the period 1999-2003, including diagnoses recorded within 21 days after the examination, were obtained from a large Israeli Health Maintenance Organization (1,600,000 members). Results: The highest annual CT examination rate (per 1,000) was recorded in 2001 (10.1) compared to 7.0 and 6.3 in 1999 and 2003, respectively. The lowest rate (three scans per 1,000) was found for 3-year-old children, with increasing rates with age. The head was the most frequently scanned region, both in young children (78%) and adolescents (39%). Symptoms of ill-defined conditions and injuries were documented in 22% and 10% of all scans, respectively. Conclusions: Although the results suggest that children comprise only 3% of all patients undergoing CT, this important modality must be carefully used because of their increased radiosensitivity, higher effective radiation doses, and longer life expectancy. C1 NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. Maccabi Healthcare Serv, IL-68125 Tel Aviv, Israel. RP Chodick, G (reprint author), NCI, Radiat Epidemiol Branch, 6120 Execut Blvd,MSC 7238,Execut Plaza S,Room 704, Bethesda, MD 20892 USA. EM Chodickg@mail.nih.gov FU Intramural NIH HHS NR 26 TC 16 Z9 16 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-0449 EI 1432-1998 J9 PEDIATR RADIOL JI Pediatr. Radiol. PD JUN PY 2006 VL 36 IS 6 BP 485 EP 490 DI 10.1007/s00247-005-0091-0 PG 6 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA 044FP UT WOS:000237658100002 PM 16552588 ER PT J AU Cotton, RB Hazinski, TA Morrow, JD Roberts, LJ Zeldin, DC Lindstrom, DP Lappalainen, U Law, AB Steele, S AF Cotton, RB Hazinski, TA Morrow, JD Roberts, LJ Zeldin, DC Lindstrom, DP Lappalainen, U Law, AB Steele, S TI Cimetidine does not prevent lung injury in newborn premature infants SO PEDIATRIC RESEARCH LA English DT Article ID ARACHIDONIC-ACID METABOLISM; PULMONARY CYTOCHROME-P450; DUCTUS-ARTERIOSUS; OXYGEN; RATS; MECHANISM; 1-AMINOBENZOTRIAZOLE; PHARMACOKINETICS; PROSTANOIDS; INHIBITION AB Animal studies have shown that induction of cytochrome P450 (CYP) in the lung by oxygen exposure may result in the release of free radical oxidants and arachidonic acid metabolites, which can cause lung injury that is reduced by treatment with cimetidine, a CYP inhibitor. To determine whether cimetidine would reduce lung injury in human infants at risk for chronic lung disease, we conducted a randomized clinical trial in which we administered either cimetidine or a placebo for 10 d beginning < 24 h after birth to 84 newborn infants weighing <= 1250 g who were receiving O-2 and mechanical ventilation. Cimetidine had no significant effect on severity of respiratory insufficiency assessed at 10 d postnatal age. F-2-isoprostane levels (a marker of oxidant injury) in tracheal aspirates were significantly higher in the cimetidine group at 4 d and at 10 d. There were no significant differences between the groups in tracheal aspirate levels of inflammatory markers (leukotriene B-4, IL-8, and nucleated cell count) or arachidonic acid metabolites. We conclude that cimetidine does not reduce lung injury in newborn premature infants receiving O-2 and mechanical ventilation. It is possible that cimetidine was not an adequate CYP inhibitor in this context. C1 Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA. Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA. NIH, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Cotton, RB (reprint author), Vanderbilt Univ, Med Ctr, Dept Pediat, 11111 Doctors Off Tower,2200 Childrens Way, Nashville, TN 37232 USA. EM robert.cotton@vanderbilt.edu FU Intramural NIH HHS [Z01 ES025034-13]; NHLBI NIH HHS [HL56697]; NIDDK NIH HHS [DK26657, P30 DK026657]; NIGMS NIH HHS [GM42056, P01 GM015431, R37 GM042056, GM15431, R01 GM042056, P50 GM015431] NR 34 TC 17 Z9 18 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD JUN PY 2006 VL 59 IS 6 BP 795 EP 800 DI 10.1203/01.pdr.0000219397.35473.5f PG 6 WC Pediatrics SC Pediatrics GA 047CW UT WOS:000237858400009 PM 16641218 ER PT J AU Garmany, TH Moxley, MA White, FV Dean, M Hull, WM Whitsett, JA Nogee, LM Hamvas, A AF Garmany, TH Moxley, MA White, FV Dean, M Hull, WM Whitsett, JA Nogee, LM Hamvas, A TI Surfactant composition and function in patients with ABCA3 mutations SO PEDIATRIC RESEARCH LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-for-Pediatric-Research CY MAY 11, 2004 CL San Francisco, CA SP Soc Pediat Res ID THIN-LAYER CHROMATOGRAPHY; PROTEIN-B; PULMONARY SURFACTANT; DISATURATED PHOSPHATIDYLCHOLINE; MEMBRANE-PROTEIN; AMNIOTIC-FLUID; MAMMALIAN LUNG; II CELLS; GENE; DEFICIENCY AB Mutations in the gene encoding the ATP binding cassette transporter member A3 (ABCA3) are associated with fatal surfactant deficiency. ABCA3 lines the limiting membrane of lamellar bodies within alveolar type-II cells, suggesting a role in surfactant metabolism. The objective of this study was to determine the surfactant phospholipid composition and function in patients with mutations in the ABCA3 gene. Bronchoalveolar lavage (BAL) fluid was analyzed from three groups of infants: 1) Infants with ABCA3 mutations, 2) infants with inherited surfactant protein-B deficiency (SP-B), and 3) patients without parenchymal lung disease (CON). Surfactant phospholipid profile was determined using two-dimensional thin-layer chromatography, and surface tension was measured with a pulsating bubble surfactometer. Phosphatidylcholine comprised 41 +/- 19% of the total phospbolipid in the BAL fluid of the ABCA3 group compared with 78 +/- 3% and 68 +/- 18%, p = 0.008 and 0.05, of the CON and SP-B groups, respectively. Surface tension was 31.5 +/- 9.3 mN/m and was significantly greater than CON but no different from SP-B. We conclude that mutations in ABCA3 are associated with surfactant that is deficient in phosphatidylcholine and has decreased function, suggesting that ABCA3 plays an important role in pulmonary surfactant phospholipid homeostasis. C1 Washington Univ, St Louis Childrens Hosp, Div Newborn Med, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. St Louis Univ, Sch Med, EA Doisy Dept Biochem & Mol Biol, St Louis, MO 63104 USA. Washington Univ, Sch Med, Dept Pathol, St Louis, MO 63110 USA. NCI, Lab Genom Divers, Human Genet Sect, Ft Detrick, MD 21702 USA. Cincinnati Childrens Hosp, Med Ctr, Div Pulm Biol, Cincinnati, OH 45229 USA. Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21287 USA. RP Garmany, TH (reprint author), Washington Univ, St Louis Childrens Hosp, Div Newborn Med, 1 Childrens Pl,Suite 5S20, St Louis, MO 63110 USA. EM garmany_t@kids.wustl.edu RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU Intramural NIH HHS; NHLBI NIH HHS [HL 38859, HL54703]; NICHD NIH HHS [T32 HD41925]; PHS HHS [R01 65174, R01 65385] NR 31 TC 69 Z9 71 U1 0 U2 3 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD JUN PY 2006 VL 59 IS 6 BP 801 EP 805 DI 10.1203/01.pdr.0000219311.14291.df PG 5 WC Pediatrics SC Pediatrics GA 047CW UT WOS:000237858400010 PM 16641205 ER PT J AU Peerzada, JM Schollin, J Hakansson, S AF Peerzada, JM Schollin, J Hakansson, S TI Delivery room decision-making for extremely preterm infants in Sweden SO PEDIATRICS LA English DT Article DE prematurity; neonatal intensive care; ethics; extremely low birth weight ID BIRTH-WEIGHT INFANTS; ACTIVE PERINATAL MANAGEMENT; EXTREMELY PREMATURE-INFANTS; NEONATAL MORBIDITY; BABY-DOE; VIABILITY; CARE; RESUSCITATION; GESTATION; ATTITUDES AB OBJECTIVE. To assess neonatologists' attitudes and practices regarding treatment of extremely preterm infants in the delivery room, particularly in response to parental wishes. STUDY DESIGN. Cross-sectional survey of all neonatologists in Sweden registered with the Swedish Pediatric Society. RESULTS. The response rate was 71% ( 88 of 124 neonatologists). At 24[1/7] to 24[6/7] weeks of gestation, 68% of neonatologists considered treatment clearly beneficial; at 25[1/7] to 25[6/7] weeks of gestation, 93% considered it clearly beneficial. When respondents consider treatment clearly beneficial, 97% reported that they would resuscitate in the delivery room despite parental requests to withhold treatment. At or below 23[0/7] weeks of gestation, 94% of neonatologists considered treatment futile. Nineteen percent reported that they would provide what they consider futile treatment at parental request. When respondents consider treatment to be of uncertain benefit, 99% reported that they would resuscitate when parents request it, 99% reported that they would resuscitate when parents are unsure, and 25% reported that they would follow parental requests to withhold treatment. CONCLUSION. Although neonatologists' attitudes and practices varied, respondents to our survey in general envisioned little parental role in delivery room decision-making for extremely preterm infants. C1 Univ Umea Hosp, Dept Pediat, SE-90185 Umea, Sweden. Univ Hosp Orebro, Dept Pediat, Orebro, Sweden. NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Hakansson, S (reprint author), Univ Umea Hosp, Dept Pediat, SE-90185 Umea, Sweden. EM stellan.hakansson@vll.se FU BHP HRSA HHS [T32 PE10018] NR 41 TC 23 Z9 23 U1 2 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 J9 PEDIATRICS JI Pediatrics PD JUN PY 2006 VL 117 IS 6 BP 1988 EP 1995 DI 10.1542/peds.2005-1885 PG 8 WC Pediatrics SC Pediatrics GA 048XE UT WOS:000237979000016 PM 16740840 ER PT J AU Ernst, M Luckenbaugh, DA Moolchan, ET Leff, MK Allen, R Eshel, N London, ED Kimes, A AF Ernst, M Luckenbaugh, DA Moolchan, ET Leff, MK Allen, R Eshel, N London, ED Kimes, A TI Behavioral predictors of substance-use initiation in adolescents with and without attention-deficit/hyperactivity disorder SO PEDIATRICS LA English DT Article DE experimentation; externalizing behavior disorders; tobacco; alcohol; marijuana; conduct disorder; aggression; impulsivity ID DEFICIT HYPERACTIVITY DISORDER; ALCOHOL-USE DISORDERS; ANXIETY DISORDERS; CIGARETTE-SMOKING; YOUNG-ADULTS; DRUG-USE; PSYCHIATRIC COMORBIDITY; PERSONALITY-DISORDER; NICOTINE DEPENDENCE; SOMATIC COMPLAINTS AB OBJECTIVE. Our goal was to examine substance-use initiation in healthy adolescents and in adolescents who have been diagnosed with attention-deficit/hyperactivity disorder. METHODS. Seventy-eight adolescents (28 healthy and 50 with attention-deficit/hyperactivity disorder) participated in an ongoing longitudinal study of predictors of substance use. The substances most commonly reported were tobacco, alcohol, and marijuana. Aggression, conduct problems, hyperactivity, impulsivity, inattention, anxiety/depression, social difficulties, and somatic complaints were assessed at study entry and tested as predictors for later substance use. RESULTS. With an average of 4 years into the study, 37 adolescents had not used any substances, 41 had experimented with at least 1 substance, and 29 experimented with > 1 substance. Psychiatric diagnoses (attention-deficit/hyperactivity disorder, attention-deficit/hyperactivity disorder and conduct disorder, and attention-deficit/hyperactivity disorder and depression/anxiety) did not influence reports of substance use. Distinct behavioral measures collected at study entry predicted use of different substances. In a multivariate analysis, aggression had the greatest association with tobacco smoking and marijuana use. Impulsivity was associated with alcohol use. Severity of drug exposure, indexed by the number of substances used, was predicted by aggression. CONCLUSIONS. This 4-year longitudinal study captured the onset of substance use, not abuse. Behavioral predictors differed with the type of substance used. These behavioral characteristics may raise suspicion among pediatricians for enhanced risk for substance-use initiation. C1 NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. NIDA, Intramural Res Program, Neuroimaging Branch, Baltimore, MD 21224 USA. NIDA, Intramural Res Program, Clin Pharmacol & Treatment Res Branch, Baltimore, MD 21224 USA. Univ Calif Los Angeles, Inst Neuropsychiat, Los Angeles, CA 90024 USA. RP Ernst, M (reprint author), NIMH, Mood & Anxiety Disorders Program, NIH, 15K North Dr,Room 118,MSC 2670, Bethesda, MD 20892 USA. EM ernstm@mail.nih.gov OI Eshel, Neir/0000-0002-5976-2013 FU Intramural NIH HHS NR 74 TC 72 Z9 73 U1 5 U2 12 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUN PY 2006 VL 117 IS 6 BP 2030 EP 2039 DI 10.1542/peds.2005-0704 PG 10 WC Pediatrics SC Pediatrics GA 048XE UT WOS:000237979000021 PM 16740845 ER PT J AU Taylor, ED Theim, KR Mirch, MC Ghorbani, S Tanofsky-Kraff, M Adler-Wailes, DC Brady, S Reynolds, JC Calis, KA Yanovski, JA AF Taylor, ED Theim, KR Mirch, MC Ghorbani, S Tanofsky-Kraff, M Adler-Wailes, DC Brady, S Reynolds, JC Calis, KA Yanovski, JA TI Orthopedic complications of overweight in children and adolescents SO PEDIATRICS LA English DT Article DE obesity; fractures; valgus deformity; child; quality of life ID METAPHYSEAL-DIAPHYSEAL ANGLE; BONE-MINERAL DENSITY; QUALITY-OF-LIFE; TIBIA VARA; TIBIOFEMORAL ANGLE; US CHILDREN; OBESITY; CHILDHOOD; PREVALENCE; QUESTIONNAIRE AB OBJECTIVE. Few studies have quantified the prevalence of weight-related orthopedic conditions in otherwise healthy overweight children. The goal of the present investigation was to describe the musculoskeletal consequences of pediatric overweight in a large pediatric cohort of children that included severely overweight children. METHODS. Medical charts from 227 overweight and 128 nonoverweight children and adolescents who were enrolled in pediatric clinical studies at the National Institutes of Health from 1996 to 2004 were reviewed to record pertinent orthopedic medical history and musculoskeletal complaints. Questionnaire data from 183 enrollees (146 overweight) documented difficulties with mobility. In 250, lower extremity alignment was determined by bilateral metaphyseal-diaphyseal and anatomic tibiofemoral angle measurements made from whole-body dual-energy x-ray absorptiometry scans. RESULTS. Compared with nonoverweight children, overweight children reported a greater prevalence of fractures and musculoskeletal discomfort. The most common self-reported joint complaint among those who were questioned directly was knee pain (21.4% overweight vs 16.7% nonoverweight). Overweight children reported greater impairment in mobility than did nonoverweight children (mobility score: 17.0 +/- 6.8 vs 11.6 +/- 2.8). Both metaphyseal-diaphyseal and anatomic tibiofemoral angle measurements showed greater malalignment in overweight compared with nonoverweight children. CONCLUSIONS. Reported fractures, musculoskeletal discomfort, impaired mobility, and lower extremity malalignment are more prevalent in overweight than nonoverweight children and adolescents. Because they affect the likelihood that children will engage in physical activity, orthopedic difficulties may be part of the cycle that perpetuates the accumulation of excess weight in children. C1 NICHHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH,CRC, Bethesda, MD 20892 USA. Duke Univ, Sch Med, Durham, NC USA. NICHHD, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Hatfield Clin Ctr, Dept Hlth & Human Serv, Bethesda, MD USA. NIH, Dept Pharm, Hatfield Clin Ctr, Dept Hlth & Human Serv, Bethesda, MD USA. RP Yanovski, JA (reprint author), NICHHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH,CRC, Room 1-3330,10 Ctr Dr MSC 1103, Bethesda, MD 20892 USA. EM jy15i@nih.gov FU Intramural NIH HHS [Z01 HD000641-12, Z99 HD999999]; NICHD NIH HHS [Z01 HD000641] NR 31 TC 162 Z9 176 U1 4 U2 14 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUN PY 2006 VL 117 IS 6 BP 2167 EP 2174 DI 10.1542/peds.2005-1832 PG 8 WC Pediatrics SC Pediatrics GA 048XE UT WOS:000237979000037 PM 16740861 ER PT J AU Wright, LL AF Wright, LL TI What will it take to improve very low birth weight follow-up care? SO PEDIATRICS LA English DT Editorial Material ID HEALTH-CARE; QUALITY C1 NICHHD, Ctr Res Mothers & Children, NIH, Bethesda, MD 20815 USA. RP Wright, LL (reprint author), NICHHD, Ctr Res Mothers & Children, NIH, Bldg 6100,Room 4B05, Bethesda, MD 20815 USA. EM wrightl@mail.nih.gov NR 14 TC 1 Z9 1 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUN PY 2006 VL 117 IS 6 BP 2277 EP 2278 DI 10.1542/peds.2005-2886 PG 2 WC Pediatrics SC Pediatrics GA 048XE UT WOS:000237979000050 PM 16740874 ER PT J AU Kattan, M Crain, EF Steinbach, S Visness, CM Walter, M Stout, JW Evans, R Smartt, E Gruchalla, RS Morgan, WJ O'Connor, GT Mitchell, HE AF Kattan, M Crain, EF Steinbach, S Visness, CM Walter, M Stout, JW Evans, R Smartt, E Gruchalla, RS Morgan, WJ O'Connor, GT Mitchell, HE TI A randomized clinical trial of clinician feedback to improve quality of care for inner-city children with asthma SO PEDIATRICS LA English DT Article DE asthma; clinical trial; provider feedback; access to care; inner city ID EVIDENCE BASED GUIDELINES; LOW-INCOME CHILDREN; EMERGENCY-DEPARTMENT; EDUCATION; MANAGEMENT; ACCESS; INTERVENTIONS; MEDICATIONS; OUTCOMES; DISEASE AB CONTEXT. Barriers impede translating recommendations for asthma treatment into practice, particularly in inner cities where asthma morbidity is highest. METHODS. The purpose of this study was to test the effectiveness of timely patient feedback in the form of a letter providing recent patient-specific symptoms, medication, and health service use combined with guideline-based recommendations for changes in therapy on improving the quality of asthma care by inner-city primary care providers and on resultant asthma morbidity. This was a randomized, controlled clinical trial in 5- to 11-year-old children (n = 937) with moderate to severe asthma receiving health care in hospital- and community-based clinics and private practices in 7 inner-city urban areas. The caretaker of each child received a bimonthly telephone call to collect clinical information about the child's asthma. For a full year, the providers of intervention group children received bimonthly computer-generated letters based on these calls summarizing the child's asthma symptoms, health service use, and medication use with a corresponding recommendation to step up or step down medications. We measured the number and proportion of scheduled visits resulting in stepping up of medications, asthma symptoms (2-week recall), and health care use (2-month recall). RESULTS. In this population, only a modest proportion of children whose symptoms warranted a medication increase actually had a scheduled visit to reevaluate their asthma treatment. However, in the 2-month interval after receipt of a step-up letter, 17.1% of the letters were followed by scheduled visits in the intervention group compared with scheduled visits 12.3% of the time by the control children with comparable clinical symptoms. Asthma medications were stepped up when indicated after 46.0% of these visits in the intervention group compared with 35.6% in the control group, and when asthma symptoms warranted a step up in therapy, medication changes occurred earlier among the intervention children. Among children whose medications were stepped up at any time during the 12-month study period, those in the intervention group experienced 22.1% fewer symptom days and 37.9% fewer school days missed. The intention-to-treat analysis showed no difference over the intervention year in the number of symptom days, yet there was a trend toward fewer days of limited activity and a significant decrease in emergency department visits by the intervention group compared with controls. This 24% drop in emergency department visits resulted in an intervention that was cost saving in its first year. CONCLUSIONS. Patient-specific feedback to inner-city providers increased scheduled asthma visits, increased asthma visits in which medications were stepped up when clinically indicated, and reduced emergency department visits. C1 CUNY Mt Sinai Sch Med, Dept Pediat, New York, NY 10029 USA. Albert Einstein Coll Med, Jacobi Med Ctr, Dept Pediat Emergency Med, Bronx, NY 10467 USA. Boston Univ, Sch Med, Boston, MA 02215 USA. Rho Inc, Chapel Hill, NC USA. Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. Northwestern Univ, Sch Med, Dept Pediat, Chicago, IL 60611 USA. Northwestern Univ, Sch Med, Dept Med, Chicago, IL 60611 USA. NIAID, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dept Med, Dallas, TX 75230 USA. Univ Texas, SW Med Ctr, Dept Pediat, Dallas, TX 75230 USA. Univ Arizona, Coll Med, Resp Sci Ctr, Tucson, AZ USA. RP Kattan, M (reprint author), CUNY Mt Sinai Sch Med, Dept Pediat, Box 1202B,1 Gustave L Levy Pl, New York, NY 10029 USA. EM meyer.kattan@mssm.edu OI O'Connor, George/0000-0002-6476-3926 FU NCRR NIH HHS [M01 RR00533]; NIAID NIH HHS [AI-39901, AI-39769, AI-39789, AI-39785, AI-39900, AI-39761, AI-39776, AI-39902] NR 36 TC 32 Z9 33 U1 0 U2 8 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUN PY 2006 VL 117 IS 6 BP E1095 EP E1103 DI 10.1542/peds.2005-2160 PG 9 WC Pediatrics SC Pediatrics GA 048XE UT WOS:000237979000087 PM 16740812 ER PT J AU Chen, D Song, SH Wientjes, MG Yeh, TK Zhao, L Villalona-Calero, M Otterson, GA Jensen, R Grever, M Murgo, AJ Au, JLS AF Chen, D Song, SH Wientjes, MG Yeh, TK Zhao, L Villalona-Calero, M Otterson, GA Jensen, R Grever, M Murgo, AJ Au, JLS TI Nontoxic suramin as a chemosensitizer in patients: Dosing nomogram development SO PHARMACEUTICAL RESEARCH LA English DT Article DE chemosensitization; dosing nomogram; neoplasms; suramin ID LOW-DOSE SURAMIN; CELL LUNG-CANCER; PHASE-I; PROSTATE-CANCER; MITOMYCIN-C; OVARIAN-CANCER; ADAPTIVE-CONTROL; ENHANCE ACTIVITY; COMBINATION; PACLITAXEL AB Purpose. We reported that suramin produced chemosensitization at nontoxic doses. This benefit was lost at the similar to 10-fold higher, maximally tolerated doses (MTD). The aim of the current study was to identify in patients the chemosensitizing suramin dose that delivers 10-50 mu M plasma concentrations over 48 h. Methods. Nonsmall cell lung cancer patients were given suramin, paclitaxel, and carboplatin, every 3 weeks. The starting chemosensitizing suramin dose was estimated based on previous results on MTD suramin in patients, and adjusted by using real-time pharmacokinetic monitoring. A dosing nomogram was developed by using population-based pharmacokinetic analysis of phase I results (15 patients, 85 treatment cycles), and evaluated in phase II patients (19 females, 28 males, 196 treatment cycles). Results. The chemosensitizing suramin dose showed a terminal half-life of 202 h and a total body clearance of 0.029 L h(-1) m(-2) (higher than the 0.013 L h(-1) m(-2) value for MTD of suramin). The dosing nomogram, incorporating body surface area as the major covariate of intersubject variability and the time elapsed since the previous dose (to account for the residual concentrations due to the slow elimination), delivered the target concentrations in > 95% of treatments. Conclusions. The present study identified and validated a dosing nomogram and schedule to deliver low and nontoxic suramin concentrations that produce chemosensitization in preclinical models. C1 Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. Ohio State Univ, James Canc Hosp, Columbus, OH 43210 USA. Ohio State Univ, Solove Res Inst, Columbus, OH 43210 USA. Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA. Natl Canc Inst, Bethesda, MD USA. RP Wientjes, MG (reprint author), Ohio State Univ, Coll Pharm, 496 W 12th Ave, Columbus, OH 43210 USA. EM wientjes.1@osu.edu FU NCI NIH HHS [R21CA91547, R01CA78577, U01CA76576, R37CA49816]; NCRR NIH HHS [M01-RR00034] NR 43 TC 6 Z9 6 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 J9 PHARM RES JI Pharm. Res. PD JUN PY 2006 VL 23 IS 6 BP 1265 EP 1274 DI 10.1007/s11095-006-0165-1 PG 10 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 056SW UT WOS:000238546400018 PM 16715360 ER PT J AU Lamba, JK Chen, X Lan, LB Kim, JW Wang, XW Relling, MV Kazuto, Y Watkins, PB Strom, S Sun, DX Schuetz, JD Schuetz, EG AF Lamba, Jatinder K. Chen, Xin Lan, Lu-Bin Kim, Jin Woo Wang, Xin Wei Relling, Mary V. Kazuto, Yasuda Watkins, Paul B. Strom, Stephen Sun, Daxi Schuetz, John D. Schuetz, Erin G. TI Increased CYP3A4 copy number in TONG/HCC cells but not in DNA from other humans SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE chemoresistance; CYP3A; copy number; gene amplification ID COMPARATIVE GENOMIC HYBRIDIZATION; DRUG-METABOLIZING-ENZYMES; HUMAN HEPATOCELLULAR-CARCINOMA; HIGH-RESOLUTION ANALYSIS; CYTOCHROME-P450; EXPRESSION; CANCER; GENE; AMPLIFICATION; VARIANTS AB Two recent screens for copy-number variations in the entire human genome found 12.4 gene copy number variations per person, including 2.5% of individuals with gains between 7q21.1 and 7q22.1, the chromosomal location of CYP3A4. CYP3A4 is involved in the metabolism of approximately 50% of all drugs, including many cancer chemotherapeutic agents. CYP3A4 gene copy was determined in DNA from 143 individuals: normal human livers, primary and secondary liver tumors, human hepatic cell lines, and immortalized cell lines representing eight ethnically diverse populations. CYP3A4 gene copy was normal in all but one sample, a primary human hepatocellular carcinoma cell line (TONG/HCC). Southern blots of TONG/HCC DNA revealed an approximate 10-fold increase in CYP3A and a corresponding increase in CYP3A mRNA expression and catalytic activity. Fluorescent in situ hybridization of TONG/HCC revealed specific amplification of the CYP3A4 gene on chromosome 7q21 but no amplification of the MDR1 gene that localizes 11.9 Mb upstream of CYP3A4. High resolution analysis of DNA copy number by comparative genomic hybridization confirmed amplification at 7q21.3-7q22. The amplicon spanned 1.7 Mb and contained 30 known genes, including the entire CYP3A locus. To determine whether CYP3A4 expression affected chemotherapeutic toxicity, LLC-PK1 cells were transduced with adenoviruses expressing CYP3A4 and P450 reductase. CYP3A4 conferred resistance to taxol, vinblastine and topotecan. These studies demonstrate that CYP3A4 copy number differences do not contribute to the normal variation in CYP3A4 expression. Tumors with increased CYP3A copy number (via amplification or increased chromosome 7q) would be expected to show reduced cytotoxicity to some chemotherapeutic drugs and potentially an increase in the outgrowth of drug resistant tumors. (C) 2006 Lippincott Williams & Wilkins. C1 St Jude Childrens Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. Univ Calif San Francisco, Dept Biopharmaceut Sci, San Francisco, CA 94143 USA. NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. Univ N Carolina, Chapel Hill, NC USA. Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15260 USA. RP Schuetz, EG (reprint author), St Jude Childrens Hosp, Dept Pharmaceut Sci, 332 N Lauderdale St,Mail Stop 313, Memphis, TN 38105 USA. EM erin.schuetz@stjude.org RI Wang, Xin/B-6162-2009 FU NCI NIH HHS [P30 CA21765, K01 CA 096774]; NIGMS NIH HHS [GM38149, GM60346, U01GM61374, U01GM61393] NR 38 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1744-6872 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD JUN PY 2006 VL 16 IS 6 BP 415 EP 427 DI 10.1097/01.fpc.0000194421.35641.70 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 162ZD UT WOS:000246127100004 PM 16708050 ER PT J AU Han, WH Kasai, S Hata, H Takahashi, T Takamatsu, Y Yamamoto, H Uhl, GR Sora, I Ikeda, K AF Han, Wenhua Kasai, Shinya Hata, Harumi Takahashi, Takehiro Takamatsu, Yukio Yamamoto, Hideko Uhl, George R. Sora, Ichiro Ikeda, Kazutaka TI Intracisternal A-particle element in the 3 ' noncoding region of the mu-opioid receptor gene in CXBK mice: a new genetic mechanism underlying differences in opioid sensitivity SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE CXBK mouse; mu-opoid receptor; 3 ' untranslated region; intracisternal A-particle; morphine; analgesia ID MORPHINE-INDUCED ANALGESIA; MESSENGER-RNA STABILITY; 3'-UNTRANSLATED REGION; UNTRANSLATED REGION; HEMATOPOIETIC-CELLS; OPIATE RECEPTOR; MOUSE; EXPRESSION; RESPONSES; SEQUENCE AB Objectives CXBK mice, recombinant inbred mice derived from C57BL/6By and BALB/cBy progenitors, display reduced morphine-induced analgesia. Earlier we reported that CXBK mice expressed a reduced amount of the major transcript, MOR-1 mRNA, of the mu-opioid receptor gene. The CXBK MOR-1 mRNA contains a normal coding region and an abnormally long untranslated region. Methods and results To identify the nucleotide-sequence difference between the CXBK MOR-1 mRNA and that of the progenitors, we first characterized the 3' untranslated region of the MOR-1 mRNA, which was largely unknown. A 3' rapid amplification of cDNA ends-PCR analysis revealed that the 3' untranslated region of the C57BL/6By MOR-1 mRNA was 10 181 nuclecitides transcribed from an exon. Next, we compared the MOR-1 genes in C57BL/6By, CXBK, and BALB/cBy mice, and found a 5293 nucleotide insertion only in CXBK mice. The inserted sequence was a variant of the intracisternal A-particle elements that exist in the mouse genome at approximately 1000 sites. Reverse transcription-PCR analyses revealed that the intracisternal A-particle element was transcribed as a part of the CXBK MOR-1 mRNA. No other differences were found in the MOR-1 mRNA between CXBK and BALB/cBy mice, whereas 100 nucleotides differed between C57BL/6By and CXBK mice aside from the intracisternal A-particle insertion. Finally, CXBK mice displayed reduced morphine responses compared with BALB/cBy mice. Conclusions Our data suggest that differences in the MOR-1 3' untranslated region appear to cause the CXBK phenotype. This genetic mechanism underlying the CXBK phenotype may provide good insight into the possible genetic mechanisms underlying individual differences in opioid sensitivity in humans. Pharmacogenetics (C) 2006 Lippincott Williams & Wilkins. C1 Psychiat Res Inst Tokyo, Div Psychobiol, Setagaya Ku, Tokyo 1568585, Japan. Tohoku Univ, Grad Sch Med, Dept Psychobiol, Sendai, Miyagi 980, Japan. NIDA, Int Res Program, Mol Neurobiol Branch, NIH, Baltimore, MD 21224 USA. RP Ikeda, K (reprint author), Psychiat Res Inst Tokyo, Div Psychobiol, Setagaya Ku, 2-1-8 Kamikitazawa, Tokyo 1568585, Japan. EM ikedak@prit.go.jp RI Ikeda, Kazutaka/I-4694-2013 OI Ikeda, Kazutaka/0000-0001-8342-0278 NR 40 TC 17 Z9 19 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1744-6872 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD JUN PY 2006 VL 16 IS 6 BP 451 EP 460 DI 10.1097/01.fpc.0000215072.36965.8d PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 162ZD UT WOS:000246127100007 PM 16708053 ER PT J AU Dallas, S Miller, DS Bendayan, R AF Dallas, Shannon Miller, David S. Bendayan, Reina TI Multidrug resistance-associated proteins: Expression and function in the central nervous system SO PHARMACOLOGICAL REVIEWS LA English DT Review ID BLOOD-BRAIN-BARRIER; ORGANIC ANION TRANSPORTER; CONJUGATE EXPORT PUMP; HUMAN-IMMUNODEFICIENCY-VIRUS; BINDING CASSETTE TRANSPORTER; P-GLYCOPROTEIN EXPRESSION; GAMMA-GLUTAMYLCYSTEINE SYNTHETASE; CAPILLARY ENDOTHELIAL-CELLS; ATP-DEPENDENT TRANSPORT; KIDNEY PROXIMAL TUBULES AB Drug delivery to the brain is highly restricted, since compounds must cross a series of structural and metabolic barriers to reach their final destination, often a cellular compartment such as neurons, microglia, or astrocytes. The primary barriers to the central nervous system are the blood-brain and blood-cerebrospinal fluid barriers. Through structural modifications, including the presence of tight junctions that greatly limit paracellular transport, the cells that make up these barriers restrict diffusion of many pharmaceutically active compounds. In addition, the cells that comprise the blood-brain and blood-cerebrospinal fluid barriers express multiple ATP-dependent, membrane-bound, efflux transporters, such as members of the multidrug resistance-associated protein (MRP) family, which contribute to lowered drug accumulation. A relatively new concept in brain drug distribution just beginning to be explored is the possibility that cellular components of the brain parenchyma could act as a "second" barrier to brain permeation of pharmacological agents via expression of many of the same transporters. Indeed, efflux transporters expressed in brain parenchyma may facilitate the overall export of xenobiotics from the central nervous system, essentially handing them off to the barrier tissues. We propose that these primary and secondary barriers work in tandem to limit overall accumulation and distribution of xenobiotics in the central nervous system. The present review summarizes recent knowledge in this area and emphasizes the clinical significance of MRP transporter expression in a variety of neurological disorders. C1 Univ Toronto, Leslie Dan Fac Pharm, Dept Pharmaceut Sci, Toronto, ON M5S 2S2, Canada. Natl Inst Environm Hlth Sci, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC USA. RP Dallas, S (reprint author), Univ Toronto, Leslie Dan Fac Pharm, Dept Pharmaceut Sci, 19 Russell St, Toronto, ON M5S 2S2, Canada. EM r.bendayan@utoronto.ca FU Intramural NIH HHS NR 281 TC 145 Z9 154 U1 0 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 J9 PHARMACOL REV JI Pharmacol. Rev. PD JUN PY 2006 VL 58 IS 2 BP 140 EP 161 DI 10.1124/pr.58.2.3 PG 22 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 044QQ UT WOS:000237687700004 PM 16714484 ER PT J AU Panlilio, LV Thorndike, EB Schindler, CW AF Panlilio, Leigh V. Thorndike, Eric B. Schindler, Charles W. TI Cocaine self-administration under variable-dose schedules in squirrel monkeys SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE within-session dose-response curve; interresponse time; regulation of drug intake; lever press; squirrel monkey ID NUCLEUS-ACCUMBENS DOPAMINE; RHESUS-MONKEYS; D-AMPHETAMINE; DRUG INTAKE; INTRAVENOUS COCAINE; SATIETY THRESHOLD; RAPID ASSESSMENT; FIXED-RATIO; SET-POINT; HEROIN AB Squirrel monkeys self-administered cocaine under a variable-dose schedule, with the dose varied from injection to injection. As in earlier studies with rats, post-injection pauses varied as a monotonic function of dose, allowing a cocaine dose-effect curve to be obtained during each session. These curves were shifted by pretreatment with dopamine antagonists, demonstrating that this procedure may provide an efficient means of evaluating treatments that affect drug self-administration. However, drug intake eventually became "dysregulated" after extensive training (100-300 sessions), with relatively short pauses following all doses. Dose-sensitivity was restored by adding a 60-s timeout period after each injection, suggesting that dysregulation occurred because the monkeys developed a tendency to self-administer another injection before the previous injection had been adequately distributed. Finally, when the response requirement under the variable-dose schedule was increased from 1 to 10, both the post-injection pause and the rate of responding following the pause ("run rates") were found to vary with dose. The dose-dependency of run rates suggests that post-injection pauses reflect not only motivational factors, such as satiety, but also the direct effects of cocaine on leverpressing. Published by Elsevier Inc. C1 Natl Inst Drug Abuse, Preclin Pharmacol Sect, Behav Neurosci Branch, Intramural Res Program,NIH,DHHS, Baltimore, MD 21224 USA. RP Panlilio, LV (reprint author), Natl Inst Drug Abuse, Preclin Pharmacol Sect, Behav Neurosci Branch, Intramural Res Program,NIH,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM lpanlili@intra.nida.nih.gov FU Intramural NIH HHS NR 46 TC 8 Z9 8 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD JUN PY 2006 VL 84 IS 2 BP 235 EP 243 DI 10.1016/j.pbb.2006.05.002 PG 9 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 075BF UT WOS:000239856400007 PM 16814853 ER PT J AU Jinsmaa, Y Marczak, E Fujita, Y Shiotani, K Miyazaki, A Li, TY Tsuda, Y Arnbo, A Sasaki, Y Bryant, SD Okada, Y Lazarus, LH AF Jinsmaa, Yunden Marczak, Ewa Fujita, Yoshio Shiotani, Kirnitaka Miyazaki, Anna Li, Tingyou Tsuda, Yuko Arnbo, Akihiro Sasaki, Yusuke Bryant, Sharon D. Okada, Yoshio Lazarus, Lawrence H. TI Potent in vivo antinociception and opioid receptor preference of the novel analogue [Dmt(1)]endomorphin-1 SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE antinociception; dimethyltyrosine; endomorphin; opioid receptor subtypes; spinal; supraspinal ID DIPEPTIDYL PEPTIDASE-IV; SPINAL-CORD; ENDOMORPHIN-1; MOUSE; ANALGESIA; MICE; DMT; ANTAGONIST; AGONISTS; RAT AB [Dmt(1)]Endomorphin-1 is a novel analogue of the potent mu-opioid agonist endomorphin-1. Given the physiological role of endomorphin-1 in vivo, this compound was investigated to determine if the antinociception occurred through systemic, supraspinal or in a combination of both neuronal pathways. This compound exhibited a potent dose-dependent effect intracerebroventricularly in both spinal and supraspinal regions, and was blocked by opioid antagonist naloxone, which verified the involvement of opioid receptors. Specific opioid antagonists characterized the apparent receptor type: beta-funaltrexamine (mu(1)/mu(2)-irreversible antagonist) equally inhibited spinal- and central-mediated antinociception; on the other hand, naloxonazine (mu(1)-subtype) was ineffective in both neural pathways and naltrindole (delta-selective antagonist) partially (26%), though not significantly, blocked only the spinal-mediated antinociception. Therefore, spinal antinociception was primarily triggered by mu(2)-subtypes without involvement of mu(1)-opioid receptors; however, although a slight enhancement of antinociception by delta-receptors cannot be completely ruled out since functional bioactivity indicated mixed mu-agonism/delta-antagonism. In terms of the CNS action, [Dmt(1)]endomorphin-1 appears to act through mu(2)-opioid receptor subtypes. (c) 2006 Elsevier Inc. All rights reserved. C1 NIEHS, Med Chem Grp, LPC, Res Triangle Pk, NC 27709 USA. Kobe Gakuin Univ, Grad Sch Food & Med Sci, Kobe, Hyogo 6512180, Japan. Kobe Gakuin Univ, Dept Med Chem, Nishi Ku, Kobe, Hyogo 6512180, Japan. Kobe Gakuin Univ, Fac Pharmaceut Sci, High Technol Res Ctr, Nishi Ku, Kobe, Hyogo 6512180, Japan. Tohoku Pharmaceut Univ, Dept Biochem, Aoba Ku, Sendai, Miyagi 9818558, Japan. RP Jinsmaa, Y (reprint author), NIEHS, Med Chem Grp, LPC, POB 12233,C304,111 S TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM yunden@niehs.nih.gov FU Intramural NIH HHS NR 32 TC 16 Z9 16 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD JUN PY 2006 VL 84 IS 2 BP 252 EP 258 DI 10.1016/j.pbb.2006.05.005 PG 7 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 075BF UT WOS:000239856400009 PM 16782179 ER PT J AU Figg, WD Dunn, L Liewehr, DJ Steinberg, SM Thurman, PW Barrett, JC Birkinshaw, J AF Figg, WD Dunn, L Liewehr, DJ Steinberg, SM Thurman, PW Barrett, JC Birkinshaw, J TI Scientific collaboration results in higher citation rates of published articles SO PHARMACOTHERAPY LA English DT Article DE impact factor; authorship; journals; collaborations; publishing; network; business alliances; strategy; cooperation ID MULTIPLE AUTHORSHIP AB Study Objective. The primary objective was to analyze the relationship between the citation rate of an article and the extent of collaboration. The secondary objective was to analyze the relationship between the number of authors/article and the number of institutions/article for the period of study Methods. We counted the number of original research articles published in six leading journals-Cell, Science, Nature, New England Journal of Medicine, The Lancet, and Journal of the American Medical Association-for the years 1975, 1985, and 1995. For each article, we determined the number of authors and the number of separate institutions. We also determined the number of times each article that was published in 1995 was cited in future scientific articles from the Science Citation Index database. Results. Science, Cell, Nature, New England Journal of Medicine, The Lancet, and Journal of the American Medical Association had 2014, 868, 3856, 643, 785, and 465 total articles published/3-year study period, respectively. There was a median of 2, 2, 2, 3, 3, and 3 institutions/article, respectively All of the final models had a significant linear author component for which all of the parameter estimates were positive, yet variable. Thus, the number of times an article was cited correlated significantly with the number of authors and the number of institutions. Conclusion. A correlation exists between the number of authors and the number of times an article is cited in other articles. investigators who are open to collaborations and those who seem to adequately manage those collaborations produce a superior product that results in a higher impact. C1 NCI, Mol Pharmacol Sect, Canc Therapeut Branch, Biostat Data Management Sect, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Bethesda, MD 20892 USA. Columbia Univ, Joseph L Mailman Sch Publ Hlth, New York, NY USA. Columbia Univ, Sch Int & Publ Affairs, New York, NY USA. London Business Sch, London NW1 4SA, England. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Canc Therapeut Branch, Biostat Data Management Sect, Bldg 10,Room 5A10,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Birkinshaw, Julian/C-9113-2014; Figg Sr, William/M-2411-2016 NR 19 TC 88 Z9 89 U1 2 U2 26 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD JUN PY 2006 VL 26 IS 6 BP 759 EP 767 DI 10.1592/phco.26.6.759 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 049JA UT WOS:000238011100003 PM 16716129 ER PT J AU Malley, JD Fine, A AF Malley, JD Fine, A TI Reply to "Comment on 'All quantum observables in a hidden-variable model must commute simultaneously'" [Phys. Rev. A 73, 066101 (2006)] SO PHYSICAL REVIEW A LA English DT Letter AB Nagata [Phys. Rev. A 73, 066101 (2006)] questions whether a general no-go theorem of Malley [Phys. Rev. A 69, 022118 (2004)] applies to local hidden variables and outlines a "counterexample." In fact this is not a counterexample at all, but in seeing why it fails we clarify the significance of Malley's result and its relation to other no-go theorems. C1 NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. Univ Washington, Dept Philosophy, Seattle, WA 98195 USA. RP Malley, JD (reprint author), NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. NR 4 TC 2 Z9 2 U1 0 U2 1 PU AMERICAN PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1050-2947 J9 PHYS REV A JI Phys. Rev. A PD JUN PY 2006 VL 73 IS 6 AR 066102 DI 10.1103/PhysRevA.73.066102 PG 1 WC Optics; Physics, Atomic, Molecular & Chemical SC Optics; Physics GA 058WI UT WOS:000238694900201 ER PT J AU Doerr, TP Yu, YK AF Doerr, T. P. Yu, Yi-Kuo TI Electrostatics of charged dielectric spheres with application to biological systems SO PHYSICAL REVIEW E LA English DT Article ID SOLVATION; PROTEINS; DYNAMICS; SOLVENT; ENERGY; MODELS AB Because electrostatic forces are crucial in biological systems, molecular dynamics simulations of biological systems require a method of computing electrostatic forces that is accurate and rapid. We propose a surface charge method, apply it to a system of arbitrary number of charged dielectric spheres, and obtain an exact solution for an arbitrary configuration of the spheres. The precision depends only on the number of terms kept in a series expansion and can therefore be controlled at will. It appears that the first few terms are usually adequate. The exact result exhibits a phenomenon that we call asymmetric screening. Namely, the magnitude of attractive interactions is decreased (relative to point charges in an infinite solvent) while the magnitude of repulsive interactions is increased (again, relative to point charges in an infinite solvent). This effect might aid in the adoption of correct conformations and in intermolecular recognition. Evaluation of the energy involves only matrix inversion. The surface charge method can be transformed easily to a numerical method for use with arbitrary surfaces. With modest additions, the model also describes an electrorheological fluid. Such a system provides the cleanest opportunity to apply the model. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Doerr, TP (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, 8600 Rockville Pike MSC 6075, Bethesda, MD 20894 USA. EM doerr@ncbi.nlm.nih.gov; yyu@ncbi.nlm.nih.gov FU Intramural NIH HHS NR 24 TC 16 Z9 16 U1 1 U2 3 PU AMERICAN PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD JUN PY 2006 VL 73 IS 6 AR 061902 DI 10.1103/PhysRevE.73.061902 PN 1 PG 14 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 058VX UT WOS:000238693800066 PM 16906859 ER PT J AU Hammond, RW Aebig, JA Hsu, H AF Hammond, R. W. Aebig, J. A. Hsu, H. TI Ectopic expression of single-chain antibodies and evaluation of resistance to Cucumber mosaic virus SO PHYTOPATHOLOGY LA English DT Meeting Abstract C1 [Aebig, J. A.] NIAID, NIH, Rockville, MD 20852 USA. [Hsu, H.] USDA ARS, FNPRU, Beltsville, MD 20705 USA. [Hammond, R. W.] USDA ARS, MPPL, Beltsville, MD 20705 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER PHYTOPATHOLOGICAL SOC PI ST PAUL PA 3340 PILOT KNOB ROAD, ST PAUL, MN 55121 USA SN 0031-949X J9 PHYTOPATHOLOGY JI Phytopathology PD JUN PY 2006 VL 96 IS 6 SU S BP S45 EP S45 PG 1 WC Plant Sciences SC Plant Sciences GA V44GP UT WOS:000202991500289 ER PT J AU Maroon-Lango, CJ Aebig, J Hammond, J Hsu, H AF Maroon-Lango, C. J. Aebig, J. Hammond, J. Hsu, H. TI Molecular and biological characterization of a novel ilarvirus in bacopa SO PHYTOPATHOLOGY LA English DT Meeting Abstract C1 [Hammond, J.; Hsu, H.] USDA ARS, US Natl Arboretum, Floral & Nursery Plants Res Unit, Beltsville, MD USA. [Aebig, J.] MVDU, NIAID, NIH, Rockville, MD USA. [Maroon-Lango, C. J.] USDA, APHIS, PPQ, PHP,Plant Germplasm Quarantine Program, Beltsville, MD 20705 USA. NR 0 TC 6 Z9 6 U1 0 U2 1 PU AMER PHYTOPATHOLOGICAL SOC PI ST PAUL PA 3340 PILOT KNOB ROAD, ST PAUL, MN 55121 USA SN 0031-949X J9 PHYTOPATHOLOGY JI Phytopathology PD JUN PY 2006 VL 96 IS 6 SU S BP S73 EP S73 PG 1 WC Plant Sciences SC Plant Sciences GA V44GP UT WOS:000202991500466 ER PT J AU Schneider, KT Choi, JJ Alkharouf, NW Lum, NL Munroe, DJ Mattews, BF Frederick, RD AF Schneider, K. T. Choi, J. J. Alkharouf, N. W. Lum, N. L. Munroe, D. J. Mattews, B. F. Frederick, R. D. TI Microarray analysis of genes expressed in Rpp1-mediated resistance to Asian soybean rust SO PHYTOPATHOLOGY LA English DT Meeting Abstract C1 [Alkharouf, N. W.] Genome Sci Ctr, Vancouver, BC, Canada. [Lum, N. L.; Munroe, D. J.] NCI LMT, Frederick, MD USA. [Mattews, B. F.] USDA, Beltsville, MD 20705 USA. [Schneider, K. T.; Choi, J. J.; Frederick, R. D.] USDA, Ft Detrick, MD USA. RI Moreira, Eder/B-2309-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER PHYTOPATHOLOGICAL SOC PI ST PAUL PA 3340 PILOT KNOB ROAD, ST PAUL, MN 55121 USA SN 0031-949X J9 PHYTOPATHOLOGY JI Phytopathology PD JUN PY 2006 VL 96 IS 6 SU S BP S104 EP S105 PG 2 WC Plant Sciences SC Plant Sciences GA V44GP UT WOS:000202991501013 ER PT J AU Valencia, JC Hoashi, T Pawelek, JM Solano, F Hearing, VJ AF Valencia, JC Hoashi, T Pawelek, JM Solano, F Hearing, VJ TI Pmel17: controversial indeed but critical to melanocyte function SO PIGMENT CELL RESEARCH LA English DT Letter ID SILVER LOCUS; TYROSINASE; PROTEIN; MELANOSOMES; IDENTIFICATION; TRAFFICKING; COMPARTMENT; MUTATION; CELLS; MODEL C1 NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06510 USA. Univ Murcia, Sch Med, Dept Biochem & Mol Biol & Immunol B, Murcia, Spain. RP Hearing, VJ (reprint author), NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, 9000 Rockville Pike,Bldg 31,Rm 10A03, Bethesda, MD 20892 USA. EM hearingv@nih.gov RI Solano, Francisco/G-5001-2013 OI Solano, Francisco/0000-0001-9612-761X NR 24 TC 9 Z9 9 U1 0 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0893-5785 J9 PIGM CELL RES JI Pigm. Cell. Res. PD JUN PY 2006 VL 19 IS 3 BP 250 EP 252 DI 10.1111/j.1600-0749.2006.00308.x PG 3 WC Cell Biology; Dermatology SC Cell Biology; Dermatology GA 043JP UT WOS:000237597600011 PM 16704461 ER PT J AU Romero, R Tarca, AL Tromp, G AF Romero, Roberto Tarca, Adi L. Tromp, Gerard TI Insights into the physiology of childbirth using transcriptomics SO PLOS MEDICINE LA English DT Editorial Material ID SUPPRESSION SUBTRACTIVE HYBRIDIZATION; GENE-EXPRESSION; HUMAN MYOMETRIUM; FUNCTIONAL GENOMICS; RAT MYOMETRIUM; LABOR; PRETERM; PREGNANCY; TERM; PARTURITION C1 NICHD, Perinatol Res Branch, Intramural Div, NIH DHHS, Bethesda, MD USA. NICHD, Perinatol Res Branch, Intramural Div, NIH DHHS, Detroit, MI USA. Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48202 USA. Wayne State Univ, Dept Comp Sci, Detroit, MI 48202 USA. RP Romero, R (reprint author), NICHD, Perinatol Res Branch, Intramural Div, NIH DHHS, Bethesda, MD USA. EM warfiela@mail.nih.gov RI Tromp, Gerard/B-2677-2017 OI Tromp, Gerard/0000-0002-7761-0806 NR 23 TC 14 Z9 14 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD JUN PY 2006 VL 3 IS 6 BP 739 EP 742 AR e276 DI 10.1371/journal.pmed.0030276 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 069WK UT WOS:000239479600010 PM 16752954 ER PT J AU Kramer, BS Wilentz, J Alexander, D Burklow, J Friedman, LM Hodes, R Kirschstein, R Patterson, A Rodgers, G Straus, SE AF Kramer, Barnett S. Wilentz, Joan Alexander, Duane Burklow, John Friedman, Lawrence M. Hodes, Richard Kirschstein, Ruth Patterson, Amy Rodgers, Griffin Straus, Stephen E. TI Getting it right: Being smarter about clinical trials SO PLOS MEDICINE LA English DT Editorial Material ID CARDIAC-INSUFFICIENCY BISOPROLOL; RANDOMIZED CONTROLLED-TRIAL; CONGESTIVE-HEART-FAILURE; BETA-CAROTENE; CARDIOVASCULAR-DISEASE; WOMENS HEALTH; LUNG-CANCER; INTERVENTION; MORTALITY; SUPPLEMENTATION C1 NIH, Rockville, MD USA. RP Kramer, BS (reprint author), NIH, Rockville, MD USA. EM kramerb@od.nih.gov NR 39 TC 7 Z9 8 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD JUN PY 2006 VL 3 IS 6 BP 756 EP 761 AR e144 DI 10.1371/journal.pmed.0030144 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 069WK UT WOS:000239479600014 PM 16608383 ER PT J AU Gross, CP Krumholz, HM Van Wye, G Emanuel, EJ Wendler, D AF Gross, Cary P. Krumholz, Harlan M. Van Wye, Gretchen Emanuel, Ezekiel J. Wendler, David TI Does random treatment assignment cause harm to research participants? SO PLOS MEDICINE LA English DT Article ID NONRANDOMIZED CLINICAL-TRIALS; ACUTE MYOCARDIAL-INFARCTION; PATIENT PREFERENCE; INFORMED-CONSENT; CANCER-PATIENTS; BREAST-CANCER; THERAPEUTIC MISCONCEPTION; COMPREHENSIVE COHORT; PRIMARY-CARE; SURVIVAL AB Background Some argue that by precluding individualized treatment, randomized clinical trials (RCTs) provide substandard medical care, while others claim that participation in clinical research is associated with improved patient outcomes. However, there are few data to assess the impact of random treatment assignment on RCT participants. We therefore performed a systematic review to quantify the differences in health outcomes between randomized trial participants and eligible non-participants. Methods and Findings Studies were identified by searching Medline, the Web of Science citation database, and manuscript references. Studies were eligible if they documented baseline characteristics and clinical outcomes of RCT participants and eligible non-participants, and allowed nonparticipants access to the same interventions available to trial participants. Primary study outcomes according to patient group (randomized trial participants versus eligible nonparticipants) were extracted from all eligible manuscripts. For 22 of the 25 studies (88%) meeting eligibility criteria, there were no significant differences in clinical outcomes between patients who received random assignment of treatment (RCT participants) and those who received individualized treatment assignment (eligible non-participants). In addition, there was no relation between random treatment assignment and clinical outcome in 15 of the 17 studies (88%) in which randomized and nonrandomized patients had similar health status at baseline. Conclusions These findings suggest that randomized treatment assignment as part of a clinical trial does not harm research participants. C1 Yale Univ, Sch Med, Sect Gen Internal Med, New Haven, CT 06520 USA. Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT 06520 USA. Yale Univ, Sch Med, Robert Wood Johnson Clin Scholars Program, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, Sect Hlth Policy & Adm, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, Sect Chron Dis Epidemiol, New Haven, CT 06520 USA. NIH, Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Gross, CP (reprint author), Yale Univ, Sch Med, Sect Gen Internal Med, New Haven, CT 06520 USA. EM cary.gross@yale.edu FU NCI NIH HHS [1K07CA-90402, K07 CA090402]; NIA NIH HHS [P30 AG021342, P30AG21342] NR 68 TC 21 Z9 21 U1 2 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD JUN PY 2006 VL 3 IS 6 BP 800 EP 808 AR e188 DI 10.1371/journal.pmed.0030188 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 069WK UT WOS:000239479600021 PM 16719548 ER PT J AU Sullivan, NJ Geisbert, TW Geisbert, JB Shedlock, DJ Xu, L Lamoreaux, L Custers, JHHV Popernack, PM Yang, ZY Pau, MG Roederer, M Koup, RA Goudsmit, J Jahrling, PB Nabel, GJ AF Sullivan, Nancy J. Geisbert, Thomas W. Geisbert, Joan B. Shedlock, Devon J. Xu, Ling Lamoreaux, Laurie Custers, Jerome H. H. V. Popernack, Paul M. Yang, Zhi-Yong Pau, Maria G. Roederer, Mario Koup, Richard A. Goudsmit, Jaap Jahrling, Peter B. Nabel, Gary J. TI Immune protection of nonhuman primates against Ebola virus with single low-dose adenovirus vectors encoding modified GPs SO PLOS MEDICINE LA English DT Article ID HEMORRHAGIC-FEVER; GLYCOPROTEIN; INFECTION; CELLS; ENTRY; VACCINE; MARBURG AB Background Ebola virus causes a hemorrhagic fever syndrome that is associated with high mortality in humans. In the absence of effective therapies for Ebola virus infection, the development of a vaccine becomes an important strategy to contain outbreaks. Immunization with DNA and/or replication-defective adenoviral vectors (rAd) encoding the Ebola glycoprotein ( GP) and nucleoprotein (NP) has been previously shown to confer specific protective immunity in nonhuman primates. GP can exert cytopathic effects on transfected cells in vitro, and multiple GP forms have been identified in nature, raising the question of which would be optimal for a human vaccine. Methods and Findings To address this question, we have explored the efficacy of mutant GPs from multiple Ebola virus strains with reduced in vitro cytopathicity and analyzed their protective effects in the primate challenge model, with or without NP. Deletion of the GP transmembrane domain eliminated in vitro cytopathicity but reduced its protective efficacy by at least one order of magnitude. In contrast, a point mutation was identified that abolished this cytopathicity but retained immunogenicity and conferred immune protection in the absence of NP. The minimal effective rAd dose was established at 10(10) particles, two logs lower than that used previously. Conclusions Expression of specific GPs alone vectored by rAd are sufficient to confer protection against lethal challenge in a relevant nonhuman primate model. Elimination of NP from the vaccine and dose reductions to 10(10) rAd particles do not diminish protection and simplify the vaccine, providing the basis for selection of a human vaccine candidate. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. USA, Med Res Inst Infect Dis, Ft Detrick, MD USA. Crucell Holland BV, Leiden, Netherlands. NIAID, Integrated Res Facil, NIH, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gnabel@nih.gov FU Intramural NIH HHS NR 26 TC 120 Z9 124 U1 1 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD JUN PY 2006 VL 3 IS 6 BP 865 EP 873 AR e177 DI 10.1371/journal.pmed.0030177 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 069WK UT WOS:000239479600028 PM 16683867 ER PT J AU Halperin, I Wolfson, H Nussinov, R AF Halperin, Inbal Wolfson, Haim Nussinov, Ruth TI Correlated mutations: Advances and limitations. A study on fusion proteins and on the cohesin-dockerin families SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE binding site; correlated mutations; residue covariation; fusion proteins; protein-protein interactions ID MULTIPLE SEQUENCE ALIGNMENTS; RNA SECONDARY STRUCTURE; LIGAND-RECEPTOR PAIRS; RESIDUE CONTACTS; CLOSTRIDIUM-THERMOCELLUM; ALLOSTERIC COMMUNICATION; CRYSTAL-STRUCTURE; GENE CONVERSION; NEURAL NETWORKS; CONSERVATION AB Correlated mutations have been repeatedly exploited for intramolecular contact map prediction. Over the last decade these efforts yielded several methods for measuring correlated mutations. Nevertheless, the application of correlated mutations for the prediction of intermolecular interactions has not yet been explored. This gap is due to several obstacles, such as 3D complexes availability, paralog discrimination, and the availability of sequence pairs that are required for inter- but not intramolecular analyses. Here we selected for analysis fusion protein families that bypass some of these obstacles. We find that several correlated mutation measurements yield reasonable accuracy for intramolecular contact map prediction on the fusion dataset. However, the accuracy level drops sharply in intermolecular contacts prediction. This drop in accuracy does not occur always. In the Cohesin-Dockerin family, reasonable accuracy is achieved in the prediction of both intra- and intermolecular contacts. The Cohesin-Dockerin family is well suited for correlated mutation analysis. Because, however, this family constitutes a special case (it has radical mutations, has domain repeats, within each species each Dockerin domain interacts with each Cohesin domain, see below), the successful prediction in this family does not point to a general potential in using correlated mutations for predicting intermolecular contacts. Overall, the results of our study indicate that current methodologies of correlated mutations analysis are not suitable for large-scale intermolecular contact prediction, and thus cannot assist in docking. With current measurements, sequence availability, sequence annotations, and underdeveloped sequence pairing methods, correlated mutations can yield reasonable accuracy only for a handful of families. C1 NCI, Ctr Canc Res, Nanobiol Program, Basic Res Program,SAIC Frederick Inc, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sch Comp Sci, Fac Exact Sci, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Ctr Canc Res, Nanobiol Program, Basic Res Program,SAIC Frederick Inc, Bldg 469,Room 151, Frederick, MD 21702 USA. EM ruthn@ncifcrf.gov RI Wolfson, Haim/A-1837-2011 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 69 TC 79 Z9 83 U1 0 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD JUN 1 PY 2006 VL 63 IS 4 BP 832 EP 845 DI 10.1002/prot.20933 PG 14 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 047ER UT WOS:000237863100012 PM 16508975 ER PT J AU Prasanna, MD Vondrasek, J Wlodawer, A Rodriguez, H Bhat, TN AF Prasanna, MD Vondrasek, J Wlodawer, A Rodriguez, H Bhat, TN TI Chemical compound navigator: A web-based chem-BLAST, chemical taxonomy-based search engine for browsing compounds SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE semantic Web; Chem-BIAST; HIV; AIDS; chemical ontology; chemical taxonomy; chemical knowledge base; InChI; drug discovery; mix and match method for drug design; chemical structural neighbor; substructure search; chemical datatree ID PROTEIN DATA-BANK; HIV-1 PROTEASE; DRUG DESIGN; DISCOVERY; SYSTEM AB A novel technique to annotate, query, and analyze chemical compounds has been developed and is illustrated by using the inhibitor data on HIV protease-inhibitor complexes. In this method, all chemical compounds are annotated in terms of standard chemical structural fragments. These standard fragments are defined by using criteria, such as chemical classification; structural, chemical, or functional groups; and commercial, scientific or common names or synonyms. These fragments are then organized into a data tree based on their chemical substructures. Search engines have been developed to use this data tree to enable query on inhibitors of HIV protease (http://xpdb.nist. gov/hivsdb/hivsdb.html). These search engines use a new novel technique, Chemical Block Layered Alignment of Substructure Technique (Chem-BILAST) to search on the fragments of an inhibitor to look for its chemical structural neighbors. This novel technique to annotate and query compounds lays the foundation for the use of the Semantic Web concept on chemical compounds to allow end users to group, sort, and search structural neighbors accurately and efficiently. During annotation, it enables the attachment of "meaning" (i.e., semantics) to data in a manner that far exceeds the current practice of associating "metadata" with data by creating a knowledge base (or ontology) associated with compounds. Intended users of the technique are the research community and pharmaceutical industry, for which it will provide a new tool to better identify novel chemical structural neighbors to aid drug discovery. C1 NIST, Biochem Sci Div 831, Gaithersburg, MD 20899 USA. Acad Sci Czech Republ, Inst Organ Chem & Biochem, Prague, Czech Republic. NCI, Macromol Crystallog Lab, Frederick, MD 21701 USA. RP Bhat, TN (reprint author), NIST, Biochem Sci Div 831, 100 Bur Dr, Gaithersburg, MD 20899 USA. EM bhat@nist.gov RI Vondrasek, JIri/A-4244-2008 FU Intramural NIH HHS NR 22 TC 13 Z9 13 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD JUN 1 PY 2006 VL 63 IS 4 BP 907 EP 917 DI 10.1002/prot.20914 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 047ER UT WOS:000237863100017 PM 16508960 ER PT J AU Minzenberg, MJ Xu, K Mitropoulo, V Harvey, PD Finch, T Flory, JD New, AS Goldman, D Siever, LJ AF Minzenberg, MJ Xu, K Mitropoulo, V Harvey, PD Finch, T Flory, JD New, AS Goldman, D Siever, LJ TI Catechol-O-methyltransferase VaI(158)Met genotype variation is associated with prefrontal-dependent task performance in schizotypal personality disorder patients and comparison groups6 SO PSYCHIATRIC GENETICS LA English DT Article DE cognition; catechol-O-methyltransferase; genetics; prefrontal cortex; schizotypal personality disorder ID WORKING-MEMORY; COGNITIVE-PROCESSES; GENE POLYMORPHISM; MET GENOTYPE; COMT GENE; SCHIZOPHRENIA; DOPAMINE; DYSFUNCTION; MODULATION; SPECTRUM AB Objective A sing le-nucleotide polymorphism of the gene coding for catechol-O-methyltransferase (COMT Val(158)Met) is associated with prefrontal-dependent task performance in schizophrenia. We evaluated the relationship of the COMT genotype with diagnostic status and cognitive performance in schizotypal personality disorder. Methods Unmedicated outpatients with schizotypal personality disorder (SPD; n=67) and non-schizotypal personality disorder (NSPD; n=154) by DSM-III-R, and normal control (NC; n=60) participants were genotyped at the COMT Val(158)Met locus. Of these, 98 Caucasians (23 SPD, 52 NSPD and 23 NC) performed a brief neurocognitive battery: Wisconsin Card Sorting Test (WCST), Paced Auditory Serial Addition Test (PASAT), California Verbal Learning Test (CVLT), Visuospatial Working Memory (DOT) and Visual Delayed Recall (Wechsler Memory Scale Visual Reproduction, WMS-VR). Results Allele distribution was not significantly different in the full sample (by chi(2)) for the SPD group compared with either the NC or combined NC/NSPD groups. In analyses of variance of Caucasian individuals, the SPD group performance met or approached significantly worse performance than NC, NSPD or both groups, on the PASAT, CVLT and WMS-VR. In regression analyses of cognitive performance, the COMT genotype was significantly associated with performance on WCST and PASAT, independent of diagnosis, with the Val/Val genotype associated with the worse performance. Conclusions (1) Allelic variation in COMT activity is unrelated to the diagnosis of SPD in this sample. (2) Individuals with SPD exhibit multiple deficits in prefrontal and temporal lobe-dependent tasks. (3) The COMT genotype is related to performance on prefrontal cortex-dependent tasks and may contribute to the deficit in prefrontal-dependent memory processes in SPD as it does in schizophrenia. C1 Vet Adm Med Ctr, Dept Psychiat, OOMH, Bronx, NY 10468 USA. Mt Sinai Sch Med, New York, NY USA. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. Univ Calif Davis, Med Ctr, Sacramento, CA 95817 USA. RP Minzenberg, MJ (reprint author), Vet Adm Med Ctr, Dept Psychiat, OOMH, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM michael.minzenberg@mssm.edu RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU NCRR NIH HHS [M01-RR-00071]; NIMH NIH HHS [MH R01-MH 56140] NR 44 TC 26 Z9 26 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8829 J9 PSYCHIAT GENET JI Psychiatr. Genet. PD JUN PY 2006 VL 16 IS 3 BP 117 EP 124 DI 10.1097/01.ypg.0000199448.00163.e6 PG 8 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 053QC UT WOS:000238318900005 PM 16691129 ER PT J AU Grillon, C Pine, DS Baas, JMP Lawley, M Ellis, V Charney, DS AF Grillon, C Pine, DS Baas, JMP Lawley, M Ellis, V Charney, DS TI Cortisol and DHEA-S are associated with startle potentiation during aversive conditioning in humans SO PSYCHOPHARMACOLOGY LA English DT Article DE fear conditioning; fear-potentiated startle; cortisol; DHEA-S; stress; HPA ID CORTICOTROPIN-RELEASING-FACTOR; CENTRAL-NERVOUS-SYSTEM; MENSTRUAL-CYCLE PHASE; ACOUSTIC STARTLE; DEHYDROEPIANDROSTERONE-SULFATE; MAJOR DEPRESSION; PARAVENTRICULAR NUCLEUS; PLASMA-CORTICOSTERONE; EXPLORATORY-BEHAVIOR; PSYCHOLOGICAL STRESS AB Fear conditioning reliably increases the startle reflex and stress hormones, yet very little is known about the effect of stress hormones on fear-potentiated startle. Cortisol and the sulfate ester of dehydroepiandrosterone (DHEA-S) are involved in stress and anxiety. Evidence suggests that low cortisol/DHEA-S ratio has a buffering effect on stress and anxiety in preclinical and clinical studies, suggesting that there may be a relationship between fear-potentiated startle and cortisol and DHEA-S activity. The aim of the study was to examine whether there is a relationship between cortisol/DHEA-S ratio and fear-potentiated startle. Thirty healthy subjects participated in a differential aversive conditioning experiment during which one of two stimuli (CS+) was paired with a shock, and the other was not (CS-). Conditioned responses were assessed with the startle reflex, defined as startle potentiation during CS+ compared to CS-. DHEA-S and cortisol levels were assayed from blood samples collected in both a baseline and an aversive conditioning session. Subjective state anxiety, arousal, and valence were assessed at various times during testing. Fear-potentiated startle was larger in individuals with high compared to low cortisol/DHEA-S ratio. Multiple regression analyses revealed that fear-potentiated startle was positively associated with cortisol and negatively associated with DHEA-S. There was no significant correlation between DHEA-S and cortisol levels. These data suggest that cortisol and DHEA-S are involved in fear conditioning. C1 NIMH, DHHS, Mood & Anxiety Disorder Program, NIH, Bethesda, MD 20892 USA. Univ Utrecht, Dept Psychonom, NL-3508 TC Utrecht, Netherlands. Mt Sinai Hosp, New York, NY 10029 USA. RP Grillon, C (reprint author), NIMH, DHHS, Mood & Anxiety Disorder Program, NIH, 15K N Dr,MSC 2670, Bethesda, MD 20892 USA. EM Christian.Grillon@nih.gov OI Baas, Johanna/0000-0001-6267-8712 FU Intramural NIH HHS [Z01 MH002798-06] NR 61 TC 29 Z9 30 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUN PY 2006 VL 186 IS 3 BP 434 EP 441 DI 10.1007/s00213-005-0124-2 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 047CI UT WOS:000237857000017 PM 16052364 ER PT J AU Doherty, KM Sharma, S Gupta, R Brosh, RM AF Doherty, Kevin M. Sharma, Sudha Gupta, Rigu Brosh, Robert M., Jr. TI Tetraplex binding molecules as anti-cancer agents SO RECENT PATENTS ON ANTI-CANCER DRUG DISCOVERY LA English DT Review DE tetraplex; G4; quadruplex; anti-cancer drug; chemotherapy; telomere; oncogene; helicase; RecQ; transcription; telomerase ID G-QUADRUPLEX DNA; SUBSTRATE-SPECIFIC INHIBITION; HUMAN TELOMERASE ACTIVITY; WERNER-SYNDROME PROTEIN; C-MYC PROMOTER; G4 DNA; HUMAN-CELLS; IN-VIVO; SACCHAROMYCES-CEREVISIAE; SGS1 HELICASE AB Increasing evidence suggests that four-stranded tetraplex structures spontaneously form under physiological conditions and these alternate DNA structures are likely to form in vivo. Alternate G-quadruplex DNA structures that may form in regulatory elements of oncogenes or G-rich telomere sequences are potential targets for cancer therapy since these sequence-specific structures are proposed to affect gene expression and telomerase activation, respectively. Small molecule compounds that specifically bind tetraplexes may be used to regulate cell cycle progression by modulating promotor activation or disrupting telomere maintenance, important processes of cellular transformation. In this review, we summarize the current research developments and associated patents that bear relevance to understanding the mechanism and clinical application of tetraplex binding molecules as anti-cancer agents. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Stock Dr, Baltimore, MD 21224 USA. EM BroshR@grc.nia.nih.gov OI Sharma, Sudha/0000-0003-2765-2482 FU Intramural NIH HHS NR 142 TC 12 Z9 12 U1 0 U2 8 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1574-8928 J9 RECENT PAT ANTI-CANC JI Recent Patents Anti-Canc. Drug Discov. PD JUN PY 2006 VL 1 IS 2 BP 185 EP 200 DI 10.2174/157489206777442232 PG 16 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 168ZZ UT WOS:000246563800004 PM 18221036 ER PT J AU Brady, RO AF Brady, RO TI Emerging strategies for the treatment of hereditary metabolic storage disorders SO REJUVENATION RESEARCH LA English DT Article ID ENZYME REPLACEMENT THERAPY; NEURONOPATHIC GAUCHERS-DISEASE; MEDIATED GENE-TRANSFER; LARGE-SCALE; FABRY MICE; ALPHA-GALACTOSIDASE; AAV VECTORS; GLUCOCEREBROSIDASE; DEFICIENCY; TUMORIGENESIS AB Metabolic storage disorders are caused by mutations in genes that result in insufficient activity of enzymes required for the catabolism of substances that arise from the turnover of senescent cells in the body. Among the most prevalent of these conditions are Gaucher disease and Fabry disease, which are caused by reduced activity of the housekeeping enzymes glucocerebrosidase and a-galactosidase A, respectively. Enzyme replacement therapy is extraordinarily effective for patients with Gaucher disease. It is under examination in patients with Fabry disease, and improvement of various clinical aspects in these patients has been documented. The blood-brain barrier prevents systemically administered enzymes from reaching the central nervous system. This limitation is a major impediment for the treatment of patients with enzyme deficiency disorders in whom the brain is involved. Alternatives to enzyme replacement therapy that have been initiated to treat systemic manifestations and brain involvement in patients with metabolic disorders include substrate reduction therapy, active site-specific chaperone therapy, and gene therapy. The present status and anticipated advances in the application of these therapeutic approaches are examined here. C1 NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Brady, RO (reprint author), NINDS, Dev & Metab Neurol Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 3D04, Bethesda, MD 20892 USA. EM bradyr@ninds.nih.gov NR 35 TC 22 Z9 22 U1 2 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1549-1684 J9 REJUV RES JI Rejuv. Res. PD SUM PY 2006 VL 9 IS 2 BP 237 EP 244 DI 10.1089/rej.2006.9.237 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 046RE UT WOS:000237827900014 PM 16706651 ER PT J AU Berrigan, D Dodd, K Troiano, RP Reeve, BB Ballard-Barbash, R AF Berrigan, David Dodd, Kevin Troiano, Richard P. Reeve, Bryce B. Ballard-Barbash, Rachel TI Physical activity and acculturation among adult Hispanics in the United States SO RESEARCH QUARTERLY FOR EXERCISE AND SPORT LA English DT Article DE Latino; leisure time; nonleisure time; occupational ID PUBLIC-HEALTH; US ADULTS; RISK; WOMEN; ASSOCIATION; POPULATION; MORTALITY; PATTERNS; CANCER AB Understanding the prevalence and demographic correlates of physical activity is important for public health and epidemiological research. This analysis examines the association between acculturation and physical activity in a large (similar to 5,000) sample of Hispanic adults from the 2000 National Health Interview Survey. Scores for eight questions concerning language use were summed to produce an acculturation index. Factor analysis indicated that these questions assessed a single underlying construct. Self-reparted adherence to recommendations concerning leisure time physical activity increased from 22.6% in the least acculturated tertile to 47% in the most acculturated tertile. In contrast, prevalence of walking or bicycling for errands decreased from 25.2 to 18.2%, and prevalence of standing or walking during most of the day decreased from 82.8 to 65.6% as acculturation increased. Thus, patterns of physical activity associated with leisure versus nonleisure time differed among Hispanics with varying acculturation levels. Alternatively, cultural factors may have differential effects an responses to questions concerning Leisure and nonleisure time physical activity, In either case. assessing both types of activity is important for monitoring and understanding Hispanic health behaviors and interpreting epidemiological studies that involve physical activity in Hispanics. C1 NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Surveillance Res Program, Bethesda, MD 20892 USA. RP Berrigan, D (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, Room 4095B,6130 Execut Plaza N MSC 7344, Bethesda, MD 20892 USA. EM berrigad@mail.nih.gov OI Troiano, Richard/0000-0002-6807-989X NR 41 TC 73 Z9 73 U1 2 U2 5 PU AMER ALLIANCE HEALTH PHYS EDUC REC & DANCE PI RESTON PA 1900 ASSOCIATION DRIVE, RESTON, VA 22091 USA SN 0270-1367 J9 RES Q EXERCISE SPORT JI Res. Q. Exerc. Sport PD JUN PY 2006 VL 77 IS 2 BP 147 EP 157 PG 11 WC Hospitality, Leisure, Sport & Tourism; Psychology, Applied; Psychology; Sport Sciences SC Social Sciences - Other Topics; Psychology; Sport Sciences GA 065IW UT WOS:000239154400001 PM 16898271 ER PT J AU Liang, HY Badano, A AF Liang, HY Badano, A TI Precision of gray level response time measurements of medical liquid crystal display SO REVIEW OF SCIENTIFIC INSTRUMENTS LA English DT Article AB We characterized the instrumentation needed for accurate measurements of temporal response of liquid crystal displays for medical imaging applications. We investigated the effect of display and detector noise on the minimum measurable gray level (or luminance) difference. For a typical display, a gray level difference of 5 at high gray levels and 20 at low gray levels is needed to obtain an accurate measurement. A less noisy light emitting diode light source is employed to study the smallest measurable luminance difference at different luminance levels. We found that luminance differences of the order of 0.5 cd/m(2) can be measured with an uncertainty of 10%. (c) 2006 American Institute of Physics. C1 US FDA, NIBIB, CDRH, Joint Lab Anal Med Images, Rockville, MD 20852 USA. RP Liang, HY (reprint author), US FDA, CDRH, NIBIB,Off Sci & Engn Labs, Lab Assessment Med Imaging Syst,Dept Imaging & Ap, 12720 Twinbrook Pkwy, Rockville, MD 20852 USA. EM aldo.badano@fda.hhs.gov OI badano, aldo/0000-0003-3712-6670 NR 7 TC 7 Z9 7 U1 0 U2 2 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 JUN PY 2006 VL 77 IS 6 AR 065104 DI 10.1063/1.2205151 PG 5 WC Instruments & Instrumentation; Physics, Applied SC Instruments & Instrumentation; Physics GA 059KX UT WOS:000238732800060 ER PT J AU Reynolds, HY Peavy, HH Gail, DB Kiley, JP AF Reynolds, Hebert Y. Peavy, Hannah H. Gail, Dorothy B. Kiley, James P. TI Past achievements and future directions of sarcoidosis research: a NHLBI perspective SO SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES LA English DT Review DE granuloma; cellular immunity; bronchoscopy ID LUNG LYMPHOCYTES-T; ACTIVE PULMONARY SARCOIDOSIS; I-CONVERTING ENZYME; HUMAN ALVEOLAR MACROPHAGES; BRONCHOALVEOLAR LAVAGE; BRONCHIAL LAVAGE; CORTICOSTEROID TREATMENT; CLINICAL-FEATURES; DISEASE-ACTIVITY; SECRETING CELLS AB This history of research on sarcoidosis is largely from the perspective of the National Heart, Lung, and Blood Institute of the National Insititutes of Health which has had an interest in this disease since the inception of the Lung Program in 1969. Background: Cutaneous sarcoidosis was described over 130 years ago and, subsequently, many reports have documented this illness affecting many organs or body sites. But a definitive cause has remained elusive. Multiple research stimuli converged in the early 1970s to begin an era of active investigation into the immunopathogensis of this granulomatous disease that included: new insights into host cellular immunity and lymphocytes; program analysis of lung research in 1971-72; new technology, especially the fiberoptic bronchoscope; and a focus by the NIH Intramural Pulmonary Branch to conduct research on interstitial lung diseases begun in 1974. During the mid 1970-80s, research into lung cellular immunity of sarcoidosis patients developed rapidly at NIH and at many other centers across the US, England, Europe, and Asia. Present and Future Directions: NHLBI has continued active support of research in sarcoidosis, both basic and clinical, such as the A Case Control Etiologic Study of Sarcoidosis (ACCESS) program, 1995-2003, whose conclusions are continuing to be published. A workshop on "Future Directions in Sarcoidosis Research" provided new research ideas to explore basic immunity mechanisms in human sarcoidosis tissue and search for latent microbial agents in tissue. The organization of sarcoidosis patient support groups has heightened awareness of the need for research on multiple organs affected by the disease in addition to the respiratory tract. In response, a trans-NIH sarcoidosis working group has been formed to assess this need and to better coordinate NIH research efforts. C1 NHLBI, Div Lung Dis, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Reynolds, HY (reprint author), 6701 Rockledge Dr,Suite 10018, Bethesda, MD 20892 USA. EM reynoldh@nhibi.nih.gov NR 83 TC 3 Z9 3 U1 0 U2 1 PU FONDAZIONE PNEUMOLOGIA U I P ONLUS PI MILANO PA VIA FRUA 15, MILANO, ITALY SN 1124-0490 J9 SARCOIDOSIS VASC DIF JI Sarcoidosis Vasc. Diffus. Lung Dis. PD JUN PY 2006 VL 23 IS 2 BP 83 EP 91 PG 9 WC Respiratory System SC Respiratory System GA 212RZ UT WOS:000249615800001 PM 17937103 ER PT J AU Ortaldo, JR Young, HA AF Ortaldo, John R. Young, Howard A. TI IL-18 as critical co-stimulatory molecules in modulating the immune response of ITAM bearing lymphocytes SO SEMINARS IN IMMUNOLOGY LA English DT Review DE ITAM; tyrosine-based activating motif; NK; natural killer; IFN; interferon ID IFN-GAMMA; T-CELLS; INHIBITORY RECEPTORS; NK RECEPTORS; LY-49D; MHC; EXPRESSION; PROTEINS AB NK cells responses are controlled by inhibitory and activating cell surface receptors. Inhibitory receptors serve to moderate NK activity by dampening cytokine release and cytotoxicity if activating ligands are also triggered by interaction with their receptors on the NK cells. This dampening effect is critical to prevent wide scale self destruction. These studies have focused on cytokine signaling in the context of an environment where ITAM bearing receptors are triggered on NK, NKT and T cells. Our findings indicate that cytokines are an important co-stimulatory signal that is needed to maximize the host innate immune response. (C) 2006 Elsevier Ltd. All rights reserved. C1 NCI Frederick, Expt Immunol Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Young, HA (reprint author), NCI Frederick, Expt Immunol Lab, Ctr Canc Res, Bldg 560,Rm 31-93, Frederick, MD 21702 USA. EM Ortaldo@ncifcrf.gov; Youngh@ncifcrf.gov RI Young, Howard/A-6350-2008 OI Young, Howard/0000-0002-3118-5111 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 18 TC 10 Z9 11 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD JUN PY 2006 VL 18 IS 3 BP 193 EP 196 DI 10.1016/j.smim.2006.03.014 PG 4 WC Immunology SC Immunology GA 065SF UT WOS:000239178900008 PM 16678434 ER PT J AU Marosy, B Justice, CM Nzegwu, N Kumar, G Wilson, AF Miller, NH AF Marosy, B Justice, CM Nzegwu, N Kumar, G Wilson, AF Miller, NH TI Lack of association between the aggrecan gene and familial idiopathic scoliosis SO SPINE LA English DT Article DE familial idiopathic scoliosis; aggrecan; polymorphism; chromosome 15q25-26 ID MATRIX DEFICIENCY CMD; CORE PROTEIN; SIB-PAIR; POLYMORPHISM; OSTEOARTHRITIS; IDENTIFICATION; LOCALIZATION; DEGENERATION; PREVALENCE; LINKAGE AB Study Design. A study was conducted to determine the potential association between a specific aggrecan gene polymorphism and familial idiopathic scoliosis (FIS). Objectives. To determine the allelic distribution of the exon 12 polymorphism within a sample of families with FIS. Summary of Background Data. FIS is a structural curvature of the spine where the underlying genetic etiology has not been established. The aggrecan locus has been linked to multiple skeletal disorders. A polymorphism, within the aggrecan gene, was previously reported to be associated with curve severity in individuals with scoliosis. Methods. Fifty-eight families with FIS were genotyped for the aggrecan exon 12 polymorphism using a polymerase chain reaction method. Model-independent sib-pair linkage analyses and tests of association were performed to analyze the genetic effects of the exon 12 polymorphism. Results. Linkage analyses of a genomic screen performed on a subgroup of 48 families with a most likely to be X-linked dominant mode of inheritance of FIS showed marginally significant results on chromosome 15q25-26 (P < 0.05). The overall distribution of the alleles was consistent with previously reported literature; no evidence of association and marginal significance of linkage was found between the polymorphism and FIS or the degree of lateral curvature. Conclusions. Despite the negative association reported here, further investigation of the gene and its potential association to FIS is required. C1 Johns Hopkins Univ, Baltimore, MD USA. NHGRI, IDRB, Genometr Sect, NIH, Baltimore, MD USA. RP Marosy, B (reprint author), 720 Rutland Ave,Ross 232, Baltimore, MD 21205 USA. EM bmarosy@jhmi.edu RI Wilson, Alexander/C-2320-2009 NR 45 TC 13 Z9 20 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD JUN 1 PY 2006 VL 31 IS 13 BP 1420 EP 1425 DI 10.1097/01.brs.0000219944.18223.52 PG 6 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 048YO UT WOS:000237982700004 PM 16741449 ER PT J AU Derfoul, A Perkins, GL Hall, DJ Tuan, RS AF Derfoul, Assia Perkins, Geraldine L. Hall, David J. Tuan, Rocky S. TI Glucocorticoids promote chondrogenic differentiation of adult human mesenchymal stem cells by enhancing expression of cartilage extracellular matrix genes SO STEM CELLS LA English DT Article DE differentiation; human mesenchymal stem cells; glucocorticoid; cartilage ID RECEPTOR BETA ISOFORM; HUMAN TRABECULAR BONE; 11-BETA-HYDROXYSTEROID DEHYDROGENASE; IN-VITRO; HORMONE-RECEPTORS; GROWTH; CHONDROCYTES; OSTEOBLASTS; MARROW; RAT AB In the adult human, mesenchymal stem cells (hMSCs) resident in the bone marrow retain the capacity to proliferate and differentiate along multiple connective tissue lineages, including cartilage. Glucocorticoids (GCs) are required for chondrogenic differentiation of hMSCs in vitro; however, the exact role of GCs in this process is not known. In this study, we examined the effects of dexamethasone (DEX) on chondrogenic differentiation of hMSCs in the presence or absence of DEX, transforming growth factor-beta (TGF-beta), or DEX plus TGF-beta. GC treatment upregulated gene expression of cartilage matrix components aggrecan, dermatopontin, and collagen type XI; enhanced TGF-beta-mediated upregulation of collagen type II and cartilage oligomeric matrix protein; and increased aggrecan and collagen type II production as well as cartilage matrix-sulfated proteoglycans as assessed by inummohistochemistry and alcian blue staining. Inclusion of an antagonist of GCs inhibited expression of chondrogenic differentiation markers, suggesting that the GC effects during chondrogenesis are mediated by the GC receptor (GR). Steady levels of the major active form of GR, GR alpha, were detected in both undifferentiated and differentiating hMSCs, whereas the dominant-negative isoform GR beta, present at low levels in undifferentiated hMSCs, was downregulated during chondrogenesis. In the presence of DEX and TGF-beta, expression of a collagen type II gene promoter luciferase reporter construct in hMSCs was upregulated. However, coexpression of GR beta dramatically inhibited promoter activity, suggesting that GR alpha is required for GC-mediated modulation of chondrogenesis and that GCs may play an important role in the maintenance of cartilage homeostasis. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIAMSD, Cartilage Genet Grp, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, 50 Ctr Dr,Room 1523,MSC 8022, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov FU Intramural NIH HHS NR 42 TC 114 Z9 133 U1 3 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD JUN PY 2006 VL 24 IS 6 BP 1487 EP 1495 DI 10.1634/stemcells.2005-0415 PG 9 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 085YC UT WOS:000240639300012 PM 16469821 ER PT J AU Lore, K Seggewiss, R Guenaga, FJ Pittaluga, S Donahue, RE Krouse, A Metzger, ME Koup, RA Reilly, C Douek, DC Dunbar, CE AF Lore, Karin Seggewiss, Ruth Guenaga, F. Javier Pittaluga, Stefania Donahue, Robert E. Krouse, Allen Metzger, Mark E. Koup, Richard A. Reilly, Cavan Douek, Daniel C. Dunbar, Cynthia E. TI In vitro culture during retroviral transduction improves thymic repopulation and output after total body irradiation and autologous peripheral blood progenitor cell transplantation in rhesus macaques SO STEM CELLS LA English DT Article DE T-cell immune reconstitution; in vitro expansion; retroviral gene transfer; autologous; transplantation; peripheral blood progenitor cell; rhesus macaque; thymus ID BONE-MARROW-TRANSPLANTATION; HUMAN CORD BLOOD; EX-VIVO CULTURE; SEVERE COMBINED IMMUNODEFICIENCY; HEMATOPOIETIC STEM-CELLS; HIGH-DOSE CHEMOTHERAPY; GENE-THERAPY; CD34(+) CELLS; FLT3 LIGAND; T-CELLS AB Immunodeficiency after peripheral blood progenitor cell (PBPC) transplantation may be influenced by graft composition, underlying disease, and/or pre-treatment. These factors are difficult to study independently in humans. Ex vivo culture and genetic manipulation of PBPC grafts may also affect immune reconstitution, with relevance to gene therapy applications. We directly compared the effects of three clinically relevant autologous graft compositions on immune reconstitution after myeloblative total body irradiation in rhesus macaques, the first time these studies have been performed in a large animal model with direct clinical relevance. Animals received CD34(+) cell dose-matched grafts of either peripheral blood mononuclear cells, purified CD34(+) PBPCs, or purified CD34(+) PBPCs expanded in vitro and retrovirally transduced. We evaluated the reconstitution of T, B, natural killer, dendritic cells, and monocytes in blood and lymph nodes for up to 1 year post-transplantation. Animals receiving selected-transduced CD34(+) cells had the fastest recovery of T-cell numbers, along with the highest T-cell-receptor gene rearrangement excision circles levels, the fewest proliferating Ki-67(+) T-cells in the blood, and the best-preserved thymic architecture. Selected-transduced CD34(+) cells may therefore repopulate the thymus more efficiently and promote a higher output of naive T-cells. These results have implications for the design of gene therapy trials, as well as for the use of expanded PBPCs for improved T-cell immune reconstitution after transplantation. C1 NHLBI, Hematol Branch, NIH, Dept Hlth & Human Serv,Clin Res Ctr, Bethesda, MD 20892 USA. NIAID, Human Immunol Sect, Vaccine Res Ctr, Bethesda, MD 20892 USA. NCI, Hematopathol Sect, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Minnesota, Div Biostat, St Paul, MN USA. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, NIH, Dept Hlth & Human Serv,Clin Res Ctr, Bldg 10,Room 4-5140,10 Ctr Dr,Mail Stop Code 1202, Bethesda, MD 20892 USA. EM dunbarc@nhlbi.nih.gov FU Intramural NIH HHS [Z99 AI999999, Z99 HL999999] NR 51 TC 6 Z9 6 U1 0 U2 0 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD JUN PY 2006 VL 24 IS 6 BP 1539 EP 1548 DI 10.1634/stemcells.2005.0455 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 085YC UT WOS:000240639300018 PM 16497945 ER PT J AU Player, A Wang, YH Bhattacharya, B Rao, M Puri, RK Kawasaki, ES AF Player, Audrey Wang, Yonghong Bhattacharya, Bhaskar Rao, Mahendra Puri, Raj K. Kawasaki, Ernest S. TI Comparisons between transcriptional regulation and RNA expression in human embryonic stem cell lines SO STEM CELLS AND DEVELOPMENT LA English DT Article ID GENE-EXPRESSION; GROWTH ARREST; MOLECULAR SIGNATURE; CANCER; SOX2; DIFFERENTIATION; OCT4; NETWORKS; COMPLEX; BIOLOGY AB Recent studies have focused on transcriptional regulation and gene expression profiling of human embryonic stem cells (hESCs). However, little information is available regarding the relationship between RNA expression and transcriptional regulation, which is critical in the complete understanding of pluripotency and differentiation of hESCs. In the current study, we determined RNA expression of three different hESC lines compared to Human universal reference RNA expression (HuU-RNA) using a full genome expression microarray, and compared our results to target genes previously identified using ChIP-on-chip analysis. The objective was to identify genes common between the two methods, and generate a more reliable list of embryonic signature genes. Even though hESCs were obtained from different sources and maintained under different conditions, a considerable number of genes could be identified as common between RNA expression and transcriptional regulation analyses. As an example, results from ChIP-on-chip studies show that OCT4, SOX2, and NANOG co-occupy SOX2, OCT4, TDGF1, GJA1, SET, and DPPA4 genes. The results are consistent with RNA expression analyses that demonstrate these genes as differently expressed in our hESC lines, further substantiating their role across cell types and confirming their importance as embryonic signatures. In addition, we report the differential expression of growth arrest-specific ( GAS) family of genes in hESC. GAS2L1 and GAS3 members of this family appear to be transcriptionally regulated by OCT4, SOX2, or NANOG, whereas GAS5 and GAS6 are not; all of the -genes are differentially expressed, as determined by microarray and validated via quantitative (Q)-PCR. Collectively, these data provide insight into the relationship between gene expression and transcriptional regulation, resulting in a reliable list of genes associated with hESCs. C1 NCI, Ctr Adv Technol, NIH, Microarray Facil, Bethesda, MD 20892 USA. SAIC Frederick Inc, NCI Frederick, Frederick, MD 21702 USA. US FDA, Ctr Biol & Evaluat & Res, Tumor Vaccines & Biotechnol Branch, Bethesda, MD 20892 USA. NIA, Neurosci Lab, Baltimore, MD 21224 USA. RP Player, A (reprint author), NCI, Ctr Adv Technol, NIH, Microarray Facil, 8717 Grovemont Circle, Bethesda, MD 20892 USA. EM playera@mail.nih.gov FU Intramural NIH HHS; PHS HHS [N01-C)-12400] NR 35 TC 23 Z9 25 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 J9 STEM CELLS DEV JI Stem Cells Dev. PD JUN PY 2006 VL 15 IS 3 BP 315 EP 323 DI 10.1089/scd.2006.15.315 PG 9 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA 064VO UT WOS:000239118100004 PM 16846370 ER PT J AU Kim, YH You, SH Ko, MH Park, JW Lee, KH Jang, SH Yoo, WK Hallett, M AF Kim, YH You, SH Ko, MH Park, JW Lee, KH Jang, SH Yoo, WK Hallett, M TI Repetitive transcranial magnetic stimulation-induced corticomotor excitability and associated motor skill acquisition in chronic stroke SO STROKE LA English DT Article DE motor activity; stroke; transcranial magnetic stimulation ID CORTICOSPINAL EXCITABILITY; CORTICAL STIMULATION; CORTEX EXCITABILITY; MODULATION; PLASTICITY; HAND; REPRESENTATIONS; REORGANIZATION; IMPROVEMENT; PULSES AB Background and Purpose - Although there is some early evidence showing the value of repetitive transcranial magnetic stimulation ( rTMS) in stroke rehabilitation, the therapeutic effect of high-frequency rTMS, along with the physiology of rTMS-induced corticomotor excitability supporting motor learning in stroke, has not been established. This study investigated high-frequency rTMS-induced cortical excitability and the associated motor skill acquisition in chronic stroke patients. Methods - Fifteen patients with chronic hemiparetic stroke ( 13 men; mean age 53.5 years) practiced a complex, sequential finger motor task using their paretic fingers either after 10 Hz or sham rTMS over the contralateral primary motor cortex ( M1). Both the changes in the behavior and corticomotor excitability before and after the intervention were examined by measuring the movement accuracy, the movement time, and the motor-evoked potential ( MEP) amplitude. A separate repeated-measures ANOVA and correlation statistics were used to determine the main and interaction effects as well as relationship between the changes in the behavioral and corticomotor excitability. Results - High-frequency rTMS resulted in a significantly larger increase in the MEP amplitude than the sham rTMS ( P < 0.01), and the plastic change was positively associated with an enhanced motor performance accuracy ( P < 0.05). Conclusions - High-frequency rTMS of the affected motor cortex can facilitate practice-dependent plasticity and improve the motor learning performance in chronic stroke victims. C1 Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Phys Med & Rehabil,Stroke & Cerebrovasc Ctr, Seoul 135710, South Korea. Hampton Univ, Phys Therapy Program, Hampton, VA 23668 USA. Chonbuk Natl Univ, Sch Med, Res Inst Clin Med, Dept Phys Med & Rehabil, Jeonju, South Korea. Catholic Univ Daegu, Coll Hlth Sci, Dept Phys Therapy, Taegu, South Korea. Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Neurol,Stroke & Cerebrovasc Ctr, Seoul 135710, South Korea. Yeungnam Univ, Sch Med, Dept Phys Med & Rehabil, Taegu, South Korea. Hallym Univ, Sacred Heart Hosp, Dept Phys Med & Rehabil, Anyang, South Korea. Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, NIH, Med Neurol Branch, Bethesda, MD USA. RP Kim, YH (reprint author), Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Phys Med & Rehabil,Stroke & Cerebrovasc Ctr, 50 Ilwon Dong, Seoul 135710, South Korea. EM yunkim@smc.samsung.co.kr RI Kim, Yun Hee/F-4600-2014; OI Ko, Myoung-Hwan/0000-0002-0566-3677; Yoo, Woo-Kyoung/0000-0002-1273-0647 NR 26 TC 224 Z9 246 U1 0 U2 22 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUN PY 2006 VL 37 IS 6 BP 1471 EP 1476 DI 10.1161/01.STR.0000221233.55497.51 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 048CK UT WOS:000237925000034 PM 16675743 ER PT J AU Iadecola, C Goldman, SS Harder, DR Heistad, DD Katusic, ZS Moskowitz, MA Simard, JM Sloan, MA Traystman, RJ Velletri, PA AF Iadecola, C Goldman, SS Harder, DR Heistad, DD Katusic, ZS Moskowitz, MA Simard, JM Sloan, MA Traystman, RJ Velletri, PA TI Recommendations of the National Heart, Lung, and Blood Institute working group on cerebrovascular biology and disease SO STROKE LA English DT Article DE cerebrovascular disease; microcirculation ID ALZHEIMERS-DISEASE; STROKE; GENE; ISCHEMIA; BRAIN AB The National Heart, Lung, and Blood Institute (NHLBI) convened a conference call working group, consisting of experts in stroke and cerebrovascular biology on January 28, 2005. The purpose of this working group was to develop a prioritized set of recommendations for NHLBI to establish a focused and comprehensive set of research activities in cerebrovascular biology and disease. Three thematic areas of research emerged: (1) molecular and cellular neurobiology of cerebral blood vessels, focusing on genomics and proteomics, neurovascular signaling and cerebrovascular embryogenesis, development and plasticity; (2) resource development, involving the development of new methodological approaches for normal and altered function of the neurovascular unit, collaborative research, and training in cerebrovascular pathobiology; and (3) cerebrovascular diseases and translational approaches, addressing vascular mechanisms of disease, the role of risk factors, importance of biomarkers with the ultimate goal of developing new treatments. C1 NHLBI, Bethesda, MD 20892 USA. Weill Cornell Med Coll, New York, NY USA. Med Coll Wisconsin, Milwaukee, WI USA. Univ Iowa, Iowa City, IA USA. Mayo Clin Coll Med, Rochester, MN USA. Massachusetts Gen Hosp, Charlestown, MA USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Carolinas Med Ctr, Charlotte, NC 28203 USA. Oregon Hlth Sci Univ, Sch Med, Portland, OR 97201 USA. RP Goldman, SS (reprint author), NHLBI, 6701 Rockledge Dr,MSC 7956,Suite 10192, Bethesda, MD 20892 USA. EM goldmans@nhlbi.nih.gov RI Moskowitz, Michael/D-9916-2011 FU NHLBI NIH HHS [R01 HL082517-01, R01 HL082517] NR 17 TC 26 Z9 27 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUN PY 2006 VL 37 IS 6 BP 1578 EP 1581 DI 10.1161/01.STR.0000221297.57305.8a PG 4 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 048CK UT WOS:000237925000054 PM 16627792 ER PT J AU Sun, PD AF Sun, PD TI Human CD23: Is it a lectin in disguise? SO STRUCTURE LA English DT Editorial Material ID BINDING; IGE AB The crystal structure of a low-affinity human IgE receptor, CD23, is reported by Wurzburg et al. (2006) in this issue of Structure. This, together with a similar NMR structure by Hibbert et al. (2005) provide some insights into the function of the receptor. C1 NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Sun, PD (reprint author), NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD JUN PY 2006 VL 14 IS 6 BP 950 EP 951 DI 10.1016/j.str.2006.05.009 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 059JY UT WOS:000238730300002 PM 16765887 ER PT J AU Tsai, HH Gunasekaran, K Nussinov, R AF Tsai, HH Gunasekaran, K Nussinov, R TI Sequence and structure analysis of parallel beta helices: Implication for constructing amyloid structural models SO STRUCTURE LA English DT Article ID SOLID-STATE NMR; SHEET STRUCTURE; SECONDARY STRUCTURE; MOLECULAR-DYNAMICS; ANTIFREEZE PROTEIN; ENERGY LANDSCAPE; FIBRIL FORMATION; PRION PROTEIN; PEPTIDE; AGGREGATION AB Increasing evidence suggests that amyloids and parallel beta helices may share similar motifs. A systemic analysis of beta helices is performed to examine their sequence and structural characteristics. lie prefers to occur in beta strands. In contrast, Pro is disfavored, compatible with the underlying assumption in Pro-scanning mutagenesis. Cys, Asn, and Phe form significant homostacking (identical amino acid interactions). Asn is highly conserved in the high-energy, left-handed alpha-helical conformation, where it frequently forms amide stacking. Based on the observed prominent stacking of chemically similar residues in parallel beta helices, we propose that within the "cross-beta" framework, amyloids with longer peptide chains may have common structural features of in-register, parallel alignment, with the side chains forming identical amino acid ladders. The requirement of ladder formation limits the combinations of side chain interactions. Such a limit combined with environmental conditions (e.g., pH, concentration) could be a major reason for the ability of most polypeptides to form amyloids. C1 Natl Cent Univ, Dept Chem, Chungli 32001, Taiwan. NCI, Ctr Canc Res Nanobiol Program, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, Dept Human Genet, IL-69978 Tel Aviv, Israel. RP Tsai, HH (reprint author), Natl Cent Univ, Dept Chem, Chungli 32001, Taiwan. EM hhtsai@cc.ncu.edu.tw; guna@ncifcrf.gov; ruthn@ncifcrf.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 64 TC 32 Z9 32 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD JUN PY 2006 VL 14 IS 6 BP 1059 EP 1072 DI 10.1016/j.str.2006.03.015 PG 14 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 059JY UT WOS:000238730300014 PM 16765899 ER PT J AU Primack, A Bloch, M Haverkos, L Gust, S Hare, M Smith, R AF Primack, A Bloch, M Haverkos, L Gust, S Hare, M Smith, R TI Launching the Fogarty International Center international tobacco control research and training program SO TOBACCO CONTROL LA English DT Editorial Material ID SMOKING C1 Fogarty Int Ctr, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NICHHD, Bethesda, MD 20892 USA. NHLBI, Bethesda, MD 20892 USA. RP Primack, A (reprint author), Fogarty Int Ctr, Bldg 31,Room B2C39, Bethesda, MD 20892 USA. EM primacka@mail.nih.gov NR 8 TC 4 Z9 4 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0964-4563 J9 TOB CONTROL JI Tob. Control PD JUN PY 2006 VL 15 SU 1 BP I1 EP I2 DI 10.1136/tc.2006.015677 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 046IK UT WOS:000237804800001 PM 16723668 ER PT J AU Sheets, RL Stein, J Manetz, TS Duffy, C Nason, M Andrews, C Kong, WP Nabel, GJ Gomez, PL AF Sheets, RL Stein, J Manetz, TS Duffy, C Nason, M Andrews, C Kong, WP Nabel, GJ Gomez, PL TI Biodistribution of DNA plasmid vaccines against HIV-1, Ebola, severe acute respiratory syndrome, or West Nile virus is similar, without integration, despite differing plasmid backbones or gene inserts SO TOXICOLOGICAL SCIENCES LA English DT Article DE DNA vaccines; HIV/AIDS; SARS; WNV; Ebola; DNA vaccine biodistribution; DNA vaccine integration; plasmid vaccines ID ANTIBODY-RESPONSES; IMMUNIZATION; IMMUNOGENICITY; EXPRESSION; INJECTION; IMMUNITY; SAFETY; TOLERABILITY; INFECTION AB The Vaccine Research Center has developed a number of vaccine candidates for different diseases/infectious agents (HIV-1, Severe Acute Respiratory Syndrome virus, West Nile virus, and Ebola virus, plus a plasmid cytokine adjuvant-IL-2/Ig) based on a DNA plasmid vaccine platform. To support the clinical development of each of these vaccine candidates, preclinical studies have been performed in mice or rabbits to determine where in the body these plasmid vaccines would biodistribute and how rapidly they would clear. In the course of these studies, it has been observed that regardless of the gene insert (expressing the vaccine immunogen or cytokine adjuvant) and regardless of the promoter used to drive expression of the gene insert in the plasmid backbone, the plasmid vaccines do not biodistribute widely and remain essentially in the site of injection, in the muscle and overlying subcutis. Even though similar to 10(14) molecules are inoculated in the studies in rabbits, by day 8 or 9 (similar to 1 week postinoculation), already all but on the order of 10(4)-10(6) molecules per microgram of DNA extracted from tissue have been cleared at the injection site. Over the course of 2 months, the plasmid clears from the site of injection with only a small percentage of animals (generally 10-20%) retaining a small number of copies (generally around 100 copies) in the muscle at the injection site. This pattern of biodistribution (confined to the injection site) and clearance (within 2 months) is consistent regardless of differences in the promoter in the plasmid backbone or differences in the gene insert being expressed by the plasmid vaccine. In addition, integration has not been observed with plasmid vaccine candidates inoculated i.m. by Biojector 2000 or by needle and syringe. These data build on the repeated-dose toxicology studies performed (see companion article, Sheets et al., 2006) to demonstrate the safety and suitability for investigational human use of DNA plasmid vaccine candidates for a variety of infectious disease prevention indications. C1 NIAID, Vaccine Res Ctr, US Publ Hlth Serv, Vaccine Product Program,NIH, Bethesda, MD 20892 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Gene Log Inc, Dept Toxicol, Gaithersburg, MD 20879 USA. Althea Technol Inc, Analyt Serv, San Diego, CA 92121 USA. RP Sheets, RL (reprint author), NIAID, Vaccine Res Ctr, US Publ Hlth Serv, Vaccine Product Program,NIH, Room 5145,6700B Rockledge Dr MSC-7628, Bethesda, MD 20892 USA. EM rsheets@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 18 TC 52 Z9 53 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUN PY 2006 VL 91 IS 2 BP 610 EP 619 DI 10.1093/toxsci/kfj169 PG 10 WC Toxicology SC Toxicology GA 044UG UT WOS:000237697300031 PM 16569729 ER PT J AU Sheets, RL Stein, J Manetz, TS Andrews, C Bailer, R Rathmann, J Gomez, PL AF Sheets, RL Stein, J Manetz, TS Andrews, C Bailer, R Rathmann, J Gomez, PL TI Toxicological safety evaluation of DNA plasmid vaccines against HIV-1, Ebola, severe acute respiratory syndrome, or West Nile virus is similar despite differing plasmid backbones or gene-inserts SO TOXICOLOGICAL SCIENCES LA English DT Article DE DNA vaccines; HIV/AIDS; SARS; WNV; Ebola; DNA vaccine toxicology; plasmid vaccines ID UVEITIS AB The Vaccine Research Center has developed a number of vaccine candidates for different diseases/infectious agents (HIV-1, Severe Acute Respiratory Syndrome virus, West Nile virus, and Ebola virus, plus a plasmid cytokine adjuvant-IL-2/Ig) based on a DNA plasmid vaccine platform. To support the clinical development of each of these vaccine candidates, preclinical studies were performed to screen for potential toxicities (intrinsic and immunotoxicities). All treatment-related toxicities identified in these repeated-dose toxicology studies have been confined primarily to the sites of injection and seem to be the result of both the delivery method (as they are seen in both control and treated animals) and the intended immune response to the vaccine (as they occur with greater frequency and severity in treated animals). Reactogenicity at the site of injection is generally seen to be reversible as the frequency and severity diminished between doses and between the immediate and recovery termination time points. This observation also correlated with the biodistribution data reported in the companion article (Sheets et al., 2006), in which DNA plasmid vaccine was shown to remain at the site of injection, rather than biodistributing widely, and to clear over time. The results of these safety studies have been submitted to the Food and Drug Administration to support the safety of initiating clinical studies with these and related DNA plasmid vaccines. Thus far, standard repeated-dose toxicology studies have not identified any target organs for toxicity (other than the injection site) for our DNA plasmid vaccines at doses up to 8 mg per immunization, regardless of disease indication (i.e., expressed gene-insert) and despite differences (strengths) in the promoters used to drive this expression. As clinical data accumulate with these products, it will be possible to retrospectively compare the safety profiles of the products in the clinic to the results of the repeated-dose toxicology studies, in order to determine the utility of such toxicology studies for signaling potential immunotoxicities or intrinsic toxicities from DNA vaccines. These data build on the biodistribution studies performed (see companion article, Sheets et al., 2006) to demonstrate the safety and suitability for investigational human use of DNA plasmid vaccine candidates for a variety of infectious disease prevention indications. C1 NIAID, Vaccine Res Ctr, Vaccine Prod Program, US Publ Hlth Serv,NIH, Bethesda, MD 20892 USA. Gene Log Inc, Gaithersburg, MD 20879 USA. NIAID, Vaccine Res Ctr, Immunol Core Lab Sect, NIH, Bethesda, MD 20892 USA. RP Sheets, RL (reprint author), NIAID, Vaccine Res Ctr, Vaccine Prod Program, US Publ Hlth Serv,NIH, Room 5145,6700B Rockledge Dr,MSC-7628, Bethesda, MD 20892 USA. EM rsheets@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 11 TC 24 Z9 25 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUN PY 2006 VL 91 IS 2 BP 620 EP 630 DI 10.1093/toxsci/kfj170 PG 11 WC Toxicology SC Toxicology GA 044UG UT WOS:000237697300032 PM 16569728 ER PT J AU Venkata, NG Robinson, JA Cabot, PJ Davis, B Monteith, GR Roberts-Thomson, SJ AF Venkata, NG Robinson, JA Cabot, PJ Davis, B Monteith, GR Roberts-Thomson, SJ TI Mono(2-ethylhexyl)phthalate and mono-n-butyl phthalate activation of peroxisome proliferator activated-receptors alpha and gamma in breast SO TOXICOLOGY LETTERS LA English DT Article DE MEHP; MBP; PPAR; human; breast ID CANCER CELL-LINES; PPAR-ALPHA; RETINOIC ACID; IN-VITRO; DELTA; EXPRESSION; MCF-7; RATS; METABOLITES; MONOESTERS AB The phthalates di(2-ethylhexyl)phthalate (DEHP) and di-n-butyl phthalate (DBP) are environmental contaminants with significant human exposures. Both compounds are known reproductive toxins in rodents and DEHP also induces rodent hepatocarcinogenesis in a process believed to be mediated via the peroxisome proliferator-activated receptor alpha (PPAR alpha). DEHP and DBP are metabolised to their respective monoesters, mono-(2-ethylhexyl)phthalate (MEHP) and mono-n-butyl phthalate (MBP), which are the active metabolites. MEHP also activates another member of the PPAR subfamily, PPAR gamma. The effects of PPAR alpha and PPAR gamma activation in human breast cells appears to be opposing; PPAR alpha activators in breast cells cause an increase in proliferation, while PPAR gamma activation in breast cells is associated with differentiation and an inhibition of cell proliferation. Further to this the activation of the PPARs is cell and ligand specific, suggesting the importance of examining the effect of MEHP and MBP on the activation of PPAR alpha, PPAR beta and PPAR gamma in human breast. We used the common model of human breast cancer MCF-7 and examined the ability of MEHP and MBP to activate human PPARs in this system. The ability of MBP and MEHP to block PPAR responses was also assessed. We found that both human PPAR alpha and PPAR gamma were activated by MEHP whereas MEHP could not activate PPAR beta. MBP was unable to activate any PPAR isoforms in this breast model, despite being a weak peroxisome proliferator in liver, although MBP was an antagonist for both PPAR gamma and PPAR beta. Our results suggest that the toxicological consequences of MEHP in the breast could be complex given the opposing effects of PPAR alpha and PPAR gamma in human breast cells. (c) 2005 Elsevier Ireland Ltd. All rights reserved. C1 Univ Queensland, Sch Pharm, St Lucia, Qld 4072, Australia. Natl Inst Environm Hlth Sci, Lab Womens Hlth, Res Triangle Pk, NC 27709 USA. RP Roberts-Thomson, SJ (reprint author), Univ Queensland, Sch Pharm, Steele Bldg 03, St Lucia, Qld 4072, Australia. EM S.Roberts-Thomson@pharmacy.uq.edu.au RI Monteith, Gregory/B-1626-2008; Roberts-Thomson, Sarah/B-4282-2011; Cabot, Peter/B-2424-2013 OI Monteith, Gregory/0000-0002-4345-530X; Roberts-Thomson, Sarah/0000-0001-8202-5786; Cabot, Peter/0000-0003-1778-3753 NR 49 TC 26 Z9 28 U1 2 U2 6 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 JUN 1 PY 2006 VL 163 IS 3 BP 224 EP 234 DI 10.1016/j.toxlet.2005.11.001 PG 11 WC Toxicology SC Toxicology GA 037EM UT WOS:000237129500007 PM 16326050 ER PT J AU Fattakhova, G Masilamani, M Borrego, F Gilfillan, AM Metcalfe, DD Coligan, JE AF Fattakhova, G Masilamani, M Borrego, F Gilfillan, AM Metcalfe, DD Coligan, JE TI The high-affinity immunoglobulin-E receptor (Fc epsilon RI) is endocytosed by an AP-2/clathrin-independent, dynamin-dependent mechanism SO TRAFFIC LA English DT Article DE AP-2; clathrin heavy chain; dynamin; endocytosis; Fc epsilon RI; siRNA ID BASOPHILIC LEUKEMIA-CELLS; CLATHRIN HEAVY-CHAIN; DETERGENT-RESISTANT MEMBRANES; COATED VESICLE FORMATION; LIPID RAFTS; SIGNAL-TRANSDUCTION; MEDIATED ENDOCYTOSIS; TRANSFERRIN RECEPTOR; IGE RECEPTOR; MAST-CELLS AB Aggregation of the high-affinity immunoglobulin E (IgE) receptor (Fc epsilon RI), expressed on mast cells and basophils, initiates the immediate hypersensitivity reaction. Aggregated Fc epsilon RI has been reported to rapidly migrate to lipid rafts in RBL-2H3 cells. We confirmed that aggregated Fc epsilon RI is found in the lipid raft fractions of cellular lysates. Furthermore, we show that the cross-linked Fc epsilon RI remains associated with detergent-resistant structures upon internalization. Previous morphological studies have reported that aggregated Fc epsilon RI is endocytosed via clathrin-coated pits, which in general are not lipid raft associated. To address this apparent discrepancy, we employed siRNA to suppress expression of components of the clathrin-mediated internalization machinery, namely, clathrin heavy chain, and the AP-2 (alpha-adaptin or mu 2-subunit). Transferrin receptor (TfR) is endocytosed by a clathrin-mediated process and, as expected, each transfected siRNA caused a two to threefold elevation of TfR surface expression and almost completely inhibited its endocytosis. In contrast, there was no effect on surface expression levels of Fc epsilon RI nor on the endocytosis of the dinitrophenyl-human serum albumin (DNP-HSA)/IgE/Fc epsilon RI complex. On the contrary, internalization of DNP-HSA/IgE/Fc epsilon RI was inhibited by overexpression of a dominant-negative dynamin mutant. We conclude that internalization of cross-linked Fc epsilon RI does not require the AP-2/clathrin complex but is dynamin-dependent and may be lipid raft mediated. C1 NIAID, Lab Allerg Dis, Receptor Cell Biol Sect, NIH, Rockville, MD 20852 USA. NIAID, Lab Allerg Dis, Mast Cell Biol Sect, NIH, Rockville, MD 20852 USA. RP Coligan, JE (reprint author), NIAID, Lab Allerg Dis, Receptor Cell Biol Sect, NIH, Rockville, MD 20852 USA. EM jcoligan@niaid.nih.gov OI Masilamani, Madhan/0000-0001-8181-8848 FU Intramural NIH HHS NR 71 TC 38 Z9 39 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1398-9219 J9 TRAFFIC JI Traffic PD JUN PY 2006 VL 7 IS 6 BP 673 EP 685 DI 10.1111/j.1600-0854.2006.00423.x PG 13 WC Cell Biology SC Cell Biology GA 040BK UT WOS:000237353800005 PM 16637889 ER PT J AU Vergarajauregui, S San Miguel, A Puertollano, R AF Vergarajauregui, S San Miguel, A Puertollano, R TI Activation of p38 mitogen-activated protein kinase promotes epidermal growth factor receptor internalization SO TRAFFIC LA English DT Article DE anisomycin; EGFR; endocytosis; p38; UV ID INDUCED ERYTHROID-DIFFERENTIATION; TERNARY COMPLEX FACTORS; TUMOR-NECROSIS-FACTOR; MAP-KINASE; EGF RECEPTOR; SIGNAL-TRANSDUCTION; TYROSINE KINASES; DOWN-REGULATION; MEDIATED ENDOCYTOSIS; COATED PITS AB Endocytic trafficking plays an important role in the regulation of the epidermal growth factor receptor (EGFR). To address if cellular kinases regulate EGFR internalization, we used anisomycin, a potent activator of kinase cascades in mammalian cells, especially the stress-activated mitogen-activated protein (MAP) kinase subtypes. Here, we report that activation of p38 MAP kinase by anisomycin is sufficient to induce internalization of EGFR. Anisomycin and EGF employ different mechanisms to promote EGFR endocytosis as anisomycin-induced internalization does not require tyrosine kinase activity or ubiquitination of the receptor. In addition, anisomycin treatment did not result in delivery and degradation of EGFR at lysosomes. Incubation with a specific inhibitor of p38, or depletion of endogenous p38 by small interfering RNAs, abolished anisomycin-induced internalization of EGFR while having no effect on transferrin endocytosis, indicating that the effect of p38 activation on EGFR endocytosis is specific. Interestingly, inhibition of p38 activation also abolished endocytosis of EGFR induced by UV radiation. Our results reveal a novel role for p38 in the regulation of EGFR endocytosis and suggest that stimulation of EGFR internalization by p38 might represent a general mechanism to prevent generation of proliferative or anti-apoptotic signals under stress conditions. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Puertollano, R (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM puertolr@mail.nih.gov FU Intramural NIH HHS NR 76 TC 53 Z9 57 U1 0 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1398-9219 J9 TRAFFIC JI Traffic PD JUN PY 2006 VL 7 IS 6 BP 686 EP 698 DI 10.1111/j.1600-0854.2006.00420.x PG 13 WC Cell Biology SC Cell Biology GA 040BK UT WOS:000237353800006 PM 16683917 ER PT J AU Klein, HG AF Klein, HG TI Transfusion-associated graft-versus-host disease: less fresh blood and more gray (Gy) for an aging population SO TRANSFUSION LA English DT Editorial Material ID IMMUNOCOMPETENT RECIPIENTS; TRAUMA PATIENTS; DONOR CELLS; MICROCHIMERISM; SURVIVAL; IMMUNITY; COMPONENTS; PREGNANCY; PATIENT C1 NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Klein, HG (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. NR 29 TC 10 Z9 11 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUN PY 2006 VL 46 IS 6 BP 878 EP 880 DI 10.1111/j.1537-2995.2006.00853.x PG 3 WC Hematology SC Hematology GA 045KQ UT WOS:000237741400003 PM 16734801 ER PT J AU Lu, NZ Cidlowski, JA AF Lu, Nick Z. Cidlowski, John A. TI Glucocorticoid receptor isoforms generatetranscription specificity SO TRENDS IN CELL BIOLOGY LA English DT Review ID GENE-EXPRESSION PROFILE; INDUCED APOPTOSIS; TRANSCRIPTIONAL ACTIVITY; 11-BETA-HYDROXYSTEROID DEHYDROGENASE; OLIGONUCLEOTIDE ARRAYS; EVOKED APOPTOSIS; LEUKEMIC-CELLS; BETA ISOFORM; TARGET GENES; PROTEIN AB Glucocorticoids are necessary for life and are essential in all aspects of health and disease as they regulate processes from mitosis to apoptosis, from metabolism to growth and development. However, responses to glucocorticoids vary among individuals, cells and tissues. Recent evidence indicates that multiple glucocorticoid receptor (GR) isoforms are generated from one single GR gene by alternative splicing and alternative translation initiation. These isoforms all have unique tissue distribution patterns and transcriptional regulatory profiles. Furthermore, each is subject to various post-translational modifications that affect receptor function. Thus, increasing evidence suggests that unique GR isoform compositions within cells could determine the cell-specific response to glucocorticoids. Here, we discuss a new molecular model potentially underlying tissue-specific glucocorticoid resistance and selectivity. C1 NIEHS, Mol Endocrinol Grp, Lab Signal Transduct, Mol Endocrinol Grp,NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Mol Endocrinol Grp, Lab Signal Transduct, Mol Endocrinol Grp,NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. EM cidlowski@niehs.nih.gov NR 47 TC 121 Z9 124 U1 0 U2 4 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD JUN PY 2006 VL 16 IS 6 BP 301 EP 307 DI 10.1016/j.tcb.2006.04.005 PG 7 WC Cell Biology SC Cell Biology GA 062ZQ UT WOS:000238986000005 PM 16697199 ER PT J AU Rivera, J AF Rivera, J TI Adaptors discriminate mast-cell cytokine production from eicosanoid production and degranulation SO TRENDS IN IMMUNOLOGY LA English DT Article ID KAPPA-B ACTIVATION; T-CELL; MALT LYMPHOMA; CARMA1; RECEPTOR; COMPLEX; PHOSPHORYLATION; STIMULATION; INDUCTION; BCL10 AB The Fc epsilon RI-dependent activation of nuclear factor (NF)kappa B is key for mast-cell cytokine production. The CAR-MA1-Bcl10-Malt1 adaptor complex regulates NF kappa B activation by antigen receptors in lymphocytes. A recent study reveals that the Bcl10-Malt1 complex promotes mast-cell interleukin-6 and tumor necrosis factor production, independent of degranulation, eicosanoid secretion or survival. The new findings place this complex at the forefront in discriminating between signals required for cytokine production and those required for mast-cell degranulation and eicosanoid production. C1 NIAMSD, Mol Inflammat Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Rivera, J (reprint author), NIAMSD, Mol Inflammat Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM juan_rivera@nih.gov NR 20 TC 16 Z9 16 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD JUN PY 2006 VL 27 IS 6 BP 251 EP 253 DI 10.1016/j.it.2006.04.001 PG 3 WC Immunology SC Immunology GA 060HU UT WOS:000238794100001 PM 16647297 ER PT J AU Xiao, RP Zhu, WZ Zheng, M Cao, CM Zhang, YY Lakatta, EG Han, Q AF Xiao, RP Zhu, WZ Zheng, M Cao, CM Zhang, YY Lakatta, EG Han, Q TI Subtype-specific alpha(1)- and beta-adrenoceptor signaling in the heart SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID PROTEIN-KINASE-A; IDIOPATHIC DILATED CARDIOMYOPATHY; ADRENERGIC-RECEPTOR KINASE; RAT VENTRICULAR MYOCYTES; BETA(2)-ADRENERGIC RECEPTOR; CARDIAC MYOCYTES; TRANSGENIC MICE; ADENYLYL-CYCLASE; BETA(1)-ADRENERGIC RECEPTOR; ALPHA(1D)-ADRENERGIC RECEPTORS AB Recent studies of adrenoceptors have revealed subtype-specific signaling, promiscuous G-protein coupling, time-dependent switching of intracellular signaling pathways, intermolecular interactions within or between adrenoceptor subfamilies, and G-protein-independent signaling pathways. These findings have extended the classical linear paradigm of G-protein-coupled receptor signaling to a complex 'signalome' in which an individual adrenoceptor initiates multiple signaling pathways in a temporally and spatially regulated manner. In particular, persistent stimulation of beta-adrenoceptor subtypes causes a time-dependent switch of signaling pathways and elicits different, even opposing, functional roles of these receptors in regulating cardiac structure and function. Recent progress in the understanding of subtype-specific functions and signaling mechanisms of cardiac adrenoceptor subtypes, particularly beta(1)-adrenoceptors, beta(2)-adrenoceptors, alpha(1A)-adrenoceptors and alpha(1B)-adrenoceptors, might have important pathogenic and therapeutic implications for heart disease. C1 Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. Peking Univ, Inst Cardiovasc Sci, Beijing 100083, Peoples R China. NIA, Ctr Gerontol Res, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Xiao, RP (reprint author), Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. EM xiaor@grc.nia.nih.gov; hanqd@bjmu.edu.cn NR 84 TC 101 Z9 106 U1 1 U2 7 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 JUN PY 2006 VL 27 IS 6 BP 330 EP 337 DI 10.1016/j.tips.2006.04.009 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 060HS UT WOS:000238793900008 PM 16697055 ER PT J AU Carabin, H Krecek, RC Cowan, LD Michael, L Foyaca-Sibat, H Nash, T Willingham, AL AF Carabin, H. Krecek, R. C. Cowan, L. D. Michael, L. Foyaca-Sibat, H. Nash, T. Willingham, A. L. TI Estimation of the cost of Taenia solium cysticercosis in Eastern Cape Province, South Africa SO TROPICAL MEDICINE & INTERNATIONAL HEALTH LA English DT Article DE Taenia solium; cysticercosis; zoonosis; South Africa; cost of illness ID EPILEPSY; NEUROCYSTICERCOSIS; CHILDREN; BURUNDI; BURDEN; BENIN; INDIA; RISK AB OBJECTIVES To provide a comprehensive estimate of the societal costs of Taenia solium cysticercosis for the Eastern Cape Province (ECP), South Africa, as an objective measure of its impact in this endemic area. METHODS Epidemiological data on the prevalence of epilepsy, proportion of epilepsy cases due to neurocysticercosis (NCC) and consequences of cysticercosis were gathered from published and unpublished sources. Economical data were mostly obtained from governmental source. Three methods were used for estimating productivity losses. Monte Carlo sampling was used to represent the uncertainty Of the estimates with 95% Credible Intervals (95% CI). The estimation is for I year Using a Societal approach. All costs are reported in 2004 US$. RESULTS Overall, there were an estimated 34 662 (95% CI: 17 167-54 068) NCC-associated cases of epilepsy in ECP in 2004. The overall monetary burden (in million of US$) was estimated to vary from US$18.6 (95% CI: US$9.0-32.9) to US$34.2 (95% Cl: US$12.8-70.0) depending on the method used to estimate productivity losses. The agricultural sector contributed an average Of $5.0 million. The prevalence of epilepsy, proportion of productivity reduction and the proportion of epilepsy cases attributable to NCC had the largest impact on the overall estimates, CONCLUSION This preliminary estimate suggests that T. solium cysticercosis results in considerable monetary costs to a region that is already economically constrained. Because this infection is preventable, these results could guide stakeholders in deciding where to invest scarce health and agricultural resources in their countries. C1 Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Dept Biostat & Epidemiol, Oklahoma City, OK USA. Ross Univ, Sch Vet Med, Basseterre, St Kitts, W Ind Assoc St. Univ Johannesburg, Dept Zool, Johannesburg, South Africa. Walter Sisulu Univ, Fac Hlth Sci, Mthathaa, Eastern Cape, South Africa. NIAID, Gastrointestinal Parasites Sect Lab Parasit Dis, Bethesda, MD 20892 USA. Royal Vet & Agr Univ, Int Cysticercosis Coordinat Ctr, Frederiksberg, Denmark. Int Livestock Res Inst, People Livestock & Environm Themat Programme, Nairobi, Kenya. RP Carabin, H (reprint author), Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Dept Biostat & Epidemiol, 801 NE 13th St, Oklahoma City, OK USA. EM helene-carabin@ouhsc.edu RI Carabin, Helene/B-7600-2016 NR 34 TC 51 Z9 52 U1 0 U2 12 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1360-2276 J9 TROP MED INT HEALTH JI Trop. Med. Int. Health PD JUN PY 2006 VL 11 IS 6 BP 906 EP 916 DI 10.1111/j.1365-3156.2006.01627.x PG 11 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 061II UT WOS:000238864500017 PM 16772013 ER PT J AU Kim, H Arakawa, H Hatae, N Sugimoto, Y Matsumoto, O Osada, T Ichikawa, A Ikai, A AF Kim, Hyonchol Arakawa, Hideo Hatae, Noriyuki Sugimoto, Yukihiko Matsumoto, Osamu Osada, Toshiya Ichikawa, Atsushi Ikai, Atsushi TI Quantification of the number of EP3 receptors on a living CHO cell surface by the AFM SO ULTRAMICROSCOPY LA English DT Article; Proceedings Paper CT 7th International Conferene on Scanning Probe Microscopy, Sensors and Nanostructures CY JUN 05-08, 2005 CL Cancun, MEXICO DE atomic force microscope; EP3 receptor; GFP; microbead; compression-free force spectroscopy; separation work ID ATOMIC-FORCE MICROSCOPY; PLASMA FIBRONECTIN; FIBROBLASTIC CELLS; ADHESION; BINDING; SPECTROSCOPY; MOLECULES; PROTEINS AB The distribution of EP3 receptors on a living cell surface was quantitatively studied by atomic force microscopy (AFM). Green fluorescent protein (GFP) was introduced to the extracellular region of the EP3 receptor on a CHO cell. A microbead was Used as a probe to ensure certain contact area, whose surface was coated with anti-GFP antibody. The interactions between the antibodies and GFP molecules on the cell surface were recorded to observe the distribution of the receptors. The result indicated that EP3 receptors were distributed on the CHO cell surface not uniformly but in small patches coincident with immunohistochemical observation. Repeated measurements on the same area of cell surface gave confirmation that it was unlikely that the receptors were extracted from the cell membrane during the experiments. The measurement of single molecular interaction between GFP and the anti-GFP antibody was succeeded on the cell surface using compression-free force spectroscopy. The value of separation work required to break a single molecular pair was estimated to be about 1.5 x 10(-18) J. The number of EP3 receptor on the CHO cell surface was estimated using this value to be about I X 10(4) under the assumption that the area of the cell surface was about 5000 mu m(2). These results indicated that the number of receptors on a living cell surface could be quantified through the force measurement by the AFM. (c) 2006 Elsevier B.V. All rights reserved. C1 Tokyo Inst Technol, Grad Sch Biosci & Biotechnol, Dept Life Sci, Midori Ku, Yokohama, Kanagawa 2268501, Japan. NICHHD, Sect Cellular Signaling, NIH, Bethesda, MD 20892 USA. Kyoto Univ, Fac Pharmaceut Sci, Grad Sch Pharmaceut Sci, Dept Physiol Chem,Sakyo Ku, Kyoto 6068501, Japan. Chiba Inst Sci, Fac Pharmaceut Sci, Dept Phys Chem, Choshi, Chiba 2880025, Japan. Mukogawa Womens Univ, Sch Pharmaceut Sci, Nishinomiya, Hyogo 6638179, Japan. RP Kim, H (reprint author), Tokyo Med & Dent Univ, Inst Biomat & Bioengn, Dept Biomed Informat, Div Biosyst,Chiyoda Ku, 2-3-10 Kanda Surugadai, Tokyo 1010062, Japan. EM kim.bmi@tmd.ac.jp NR 32 TC 25 Z9 30 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3991 J9 ULTRAMICROSCOPY JI Ultramicroscopy PD JUN-JUL PY 2006 VL 106 IS 8-9 BP 652 EP 662 DI 10.1016/j.ultramic.2005.12.007 PG 11 WC Microscopy SC Microscopy GA 066LI UT WOS:000239230600004 PM 16677763 ER PT J AU Uyama, R Nakagawa, T Hong, SH Mochizuki, M Nishimura, R Sasaki, N AF Uyama, R. Nakagawa, T. Hong, S.-H. Mochizuki, M. Nishimura, R. Sasaki, N. TI Establishment of four pairs of canine mammary tumour cell lines derived from primary and metastatic origin and their E-cadherin expression SO VETERINARY AND COMPARATIVE ONCOLOGY LA English DT Article DE dog; E-cadherin; mammary tumour; primary and metastatic origin cells ID HUMAN-BREAST-CANCER; ADHESION MOLECULES; EPITHELIAL-CELLS; INTERMEDIATE FILAMENTS; CARCINOMA; INVASIVENESS; VIMENTIN; PROTEINS; INVASION; INVITRO AB Four new pairs of canine mammary carcinoma cell lines derived from both primary and metastatic lesions were established. The cells were cultured in RPMI-1640 with 10% fetal bovine serum and they showed stable growth for more than 120 passages. Using these cell lines, the expression of E-cadherin was measured by flow cytometry and the function of E-cadherin was evaluated by cell aggregation assay and results from the primary and metastatic lesions were compared statistically. E-cadherin was strongly expressed in all of the cell lines, without a notable difference between cells of primary and metastatic origin. In the cell aggregation assay, the function of E-cadherin was significantly weaker in the cells of primary origin (p < 0.05), as compared with cells of metastatic origin. The present results suggest that a reduction in E-cadherin function may be implicated in the invasive and metastatic potential of canine mammary tumour cells; however, further study will be needed to clarify E-cadherin function in the context of the metastasis of canine mammary carcinoma. C1 Univ Tokyo, Dept Vet Surg, Grad Sch Agr & Life Sci, Bunkyo Ku, Tokyo 1138657, Japan. NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, Canc Res Ctr,NIH, Bethesda, MD 20892 USA. RP Sasaki, N (reprint author), Univ Tokyo, Dept Vet Surg, Grad Sch Agr & Life Sci, Bunkyo Ku, 1-1-1 Yayoi, Tokyo 1138657, Japan. EM asasaki@mail.ecc.u-tokyo.ac.jp NR 47 TC 18 Z9 20 U1 1 U2 9 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1476-5810 J9 VET COMP ONCOL JI Vet. Comp. Oncol. PD JUN PY 2006 VL 4 IS 2 BP 104 EP 113 DI 10.1111/j.1476-5810.2006.00098.x PG 10 WC Veterinary Sciences SC Veterinary Sciences GA 172IX UT WOS:000246798700005 PM 19754820 ER PT J AU Sheliga, BM Kodaka, Y FitzGibbon, EJ Miles, FA AF Sheliga, BM Kodaka, Y FitzGibbon, EJ Miles, FA TI Human ocular following initiated by competing image motions: Evidence for a winner-take-all mechanism SO VISION RESEARCH LA English DT Article DE visual motion; energy-based mechanisms; missing fundamental; spatio-temporal filtering ID PURSUIT EYE-MOVEMENTS; VISUAL AREA MT; SPATIAL-FREQUENCY CHANNELS; SUPERIOR TEMPORAL SULCUS; CAT STRIATE CORTEX; SHORT-LATENCY; TRANSPARENT MOTION; BINOCULAR DISPARITY; MACAQUE MONKEY; CORTICAL AREA AB The initial ocular following responses (OFRs) elicited by 1/4-wavelength steps applied to the missing fundamental (mf) stimulus are in the backward direction and largely determined by the principal Fourier component, the 3rd harmonic [Sheliga, B. M., Chen, K. J., FitzGibbon, E. J., & Miles, F. A. (2005). Initial ocular following in humans: A response to first-order motion energy. Vision Research, 45, 3307-3321]. When the contrast of the 3rd harmonic was selectively reduced below that of the next most prominent harmonic-the 5th, which moves in the opposite (forward) direction-then the OFR reversed direction and the 3rd harmonic effectively lost all of its influence as the OFR was now largely determined by the 5th harmonic. Restricting the stimulus to just two sine waves (of equal efficacy when of equal contrast and presented singly) with the spatial frequencies of the 3rd and 5th harmonics of the mf stimulus indicated that the critical factor was the ratio of their two contrasts: when of similar contrast both were effective (vector sum/averaging), but when the contrast of one was < 1/2 that of the other then the one with the lower contrast became ineffective (winner-take-all). This nonlinear dependence on the contrast ratio was attributed to mutual inhibition and was well described by a weighted-average model with just two free parameters. Further experiments with broadband and dual-grating stimuli indicated that nonlinear interactions occur not only in the neural processing of stimuli moving in opposite directions but also of stimuli that share the same direction and differ only in their spatial frequency and speed. Clearly, broad-band and dual-grating stimuli can uncover significant nonlinearities in visual information processing that are not evident with single sine-wave stimuli. Published by Elsevier Ltd. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Sheliga, BM (reprint author), NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. EM bms@lsr.nei.nih.gov FU Intramural NIH HHS [Z01 EY000153-24] NR 75 TC 27 Z9 28 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PD JUN PY 2006 VL 46 IS 13 BP 2041 EP 2060 DI 10.1016/j.visres.2005.11.033 PG 20 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 052QW UT WOS:000238249400005 PM 16487988 ER PT J AU Miller, DL Scheffler, R Lam, S Rosenberg, R Rupp, A AF Miller, Douglas L. Scheffler, Richard Lam, Suong Rosenberg, Rhonda Rupp, Agnes TI Social capital and health in Indonesia SO WORLD DEVELOPMENT LA English DT Article DE health; Indonesia; Indonesian Family Life Survey (IFLS); social capital AB This paper empirically examines the role of community social capital in the individual's health production function. We focus on health measures relating to physical as well as mental health. In addition to exploring the relationship between social capital and health, we test for interrelationships between social and human capital in the production of health. Data come from more than 10,000 adults surveyed in the Indonesian Family Life Surveys of 1993 and 1997. We identify a robust positive empirical association between community-level social capital and good health. We find weak evidence for an interrelationship between human and social capital and mental health. (c) 2006 Elsevier Ltd. All rights reserved. C1 Univ Calif Davis, Davis, CA 95616 USA. Univ Calif Berkeley, Berkeley, CA 94720 USA. Florida Int Univ, Miami, FL 33199 USA. NIMH, Bethesda, MD USA. RP Miller, DL (reprint author), Univ Calif Davis, Davis, CA 95616 USA. NR 17 TC 19 Z9 19 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0305-750X J9 WORLD DEV JI World Dev. PD JUN PY 2006 VL 34 IS 6 BP 1084 EP 1098 DI 10.1016/j.worlddev.2005.11.006 PG 15 WC Economics; Planning & Development SC Business & Economics; Public Administration GA 062JT UT WOS:000238941100009 ER PT J AU Chen, LJ Lebetkin, EH Sanders, JM Burka, LT AF Chen, L. -J. Lebetkin, E. H. Sanders, J. M. Burka, L. T. TI Metabolism and disposition of 2,2 ',4,4 ',5-pentabromodiphenyl ether (BDE99) following a single or repeated administration to rats or mice SO XENOBIOTICA LA English DT Article DE 2,2 ',4,4 ',5-pentabromodiphenyl ether (BDE99); polybrominated diphenyl ether ( PBDE); glutathione conjugation; glucuronide conjugation; sulfate conjugation ID POLYBROMINATED DIPHENYL ETHERS; BROMINATED FLAME RETARDANTS; IN-VITRO; EXCRETION; EXPOSURE; BINDING; BDE-99; PBDES; TREND; MILK AB The metabolism and disposition of C-14-labelled 2,2',4,4',5-pentabromodiphenyl ether ( BDE99) were studied in F344 rats and B6C3F1 mice. Approximately 85% of a 1 mu mol kg(-1) oral dose was absorbed by male rats and mice. Within 24 h following oral doses ranging from 0.1 to 1000 mmol kg(-1) to rats, 39 - 47% of the dose was excreted in the faeces ( including 16% unabsorbed), up to 2% was excreted in the urine, and 34 - 38% remained in the tissues, mostly in adipose tissue. Mice excreted more in the urine and less in the faeces than rats. Tissue accumulation was observed following repeated dosing to rats. Two dihydrohydroxy-S-glutathionyl and two S-glutathionyl conjugates of BDE99, 2,4,5-tribromophenol glucuronide, two mono-hydroxylated BDE99 glucuronides, and three mono-hydroxylated tetrabromodiphenyl ether glucuronides were identified in male rat bile. 2,4,5-Tribromophenol and its glucuronide and sulfate conjugates, were identified in male rat urine. 2,4,5-Tribromophenol, one mono-hydroxylated tetrabromodiphenyl ether, and two monohydroxylated BDE99 were characterized in male rat faeces. BDE99 undergoes more extensive metabolism than does BDE47. Half of the absorbed oral dose in male rats was excreted in 10 days mostly as metabolites derived from arene oxide intermediates. C1 NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Chen, LJ (reprint author), NIEHS, Lab Pharmacol & Chem, POB 12233, Res Triangle Pk, NC 27709 USA. EM ferguso2@niehs.nih.gov FU Intramural NIH HHS NR 26 TC 55 Z9 56 U1 1 U2 20 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0049-8254 J9 XENOBIOTICA JI Xenobiotica PD JUN PY 2006 VL 36 IS 6 BP 515 EP 534 DI 10.1080/00498250600674477 PG 20 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 060XI UT WOS:000238834800004 PM 16769647 ER PT J AU Weerasinghe, GR Coon, SL Bhattacharjee, AK Harry, GJ Bosetti, F AF Weerasinghe, GR Coon, SL Bhattacharjee, AK Harry, GJ Bosetti, F TI Regional protein levels of cytosolic phospholipase A(2) and cyclooxygenase-2 in Rhesus monkey brain as a function of age SO BRAIN RESEARCH BULLETIN LA English DT Article DE arachidonic acid; cyclooxygenase; cytosolic phospholipase A(2); brain; aging; rhesus monkey; post-synaptic ID CENTRAL-NERVOUS-SYSTEM; HUMAN SUBSTANTIA-NIGRA; ARACHIDONIC-ACID; RAT-BRAIN; INDUCIBLE CYCLOOXYGENASE; SIGNAL-TRANSDUCTION; HIPPOCAMPAL NEURON; PREFRONTAL CORTEX; CEREBRAL-CORTEX; EXPRESSION AB Limited evidence suggests that brain cytosolic phospholipase A(2) (cPLA(2)), which selectively releases arachidonic acid (AA) from membrane phospholipids, and cyclooxygenase-2 (COX-2), the rate-limiting enzyme for AA metabolism to prostanoids, change as a function of normal aging. In this study, we examined the protein levels of cPLA2 and COX-2 enzymes in hippocampus, frontal pole and cerebellum from young (2-5 years old), middle-aged (8-11 years old) and old (23 years old) male and female Rhesus monkeys. In the cerebellum, cPLA2 protein level was higher in the young brain as compared to levels seen at both middle-aged and old. Similarly, in the frontal pole, the young brain showed a higher level of COX-2 protein as compared to the levels seen at both older ages. For both, once an animal reached 8-11 years of age the levels appeared to remain relatively constant over the next decade. Immunohistochemistry of COX-2 protein within the brain demonstrated no significant change in the localization to neurons within the frontal pole. Qualitatively, a greater number of neurons were positively stained for COX-2 in the young brain than in the aged brain. Based on the previous reports of localization of cPLA2 and COX-2 at post-synaptic sites in neurons results from the current study suggest that the elevated protein levels of the two enzymes seen in the younger brain is related to the greater potential for synaptic plasticity across multiple neurons as a function of age and that cPLA2 and COX-2 may be considered as post-synaptic markers. Published by Elsevier Inc. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. NICHHD, Sect Neuroendocrinol, NIH, Bethesda, MD 20892 USA. NIEHS, Neurotoxicol Grp, NIH, Res Triangle Pk, NC 27709 USA. RP Bosetti, F (reprint author), NIA, Brain Physiol & Metab Sect, NIH, 9 Mem Dr,Bldg 9 Rm ISI26, Bethesda, MD 20892 USA. EM frances@mail.nih.gov FU Intramural NIH HHS; NIA NIH HHS [Z01 AG000424-02] NR 56 TC 6 Z9 6 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD MAY 31 PY 2006 VL 69 IS 6 BP 614 EP 621 DI 10.1016/j.brainresbull.2006.03.006 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 051SF UT WOS:000238180400003 PM 16716827 ER PT J AU Jeang, KT AF Jeang, Kuan-Teh TI Retrovirology: 3 at age 2 SO RETROVIROLOGY LA English DT Editorial Material AB Retrovirology announces new editorial board members and reprises progress over the first two years of publishing. C1 NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM kjeang@niaid.nih.gov RI Jeang, Kuan-Teh/A-2424-2008 NR 7 TC 2 Z9 2 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD MAY 31 PY 2006 VL 3 AR 30 DI 10.1186/1742-4690-3-30 PG 3 WC Virology SC Virology GA 067OV UT WOS:000239313400001 ER PT J AU Goldschmidt-Clermont, PJ Lam, GKW Dzau, VJ Dong, CM Kurtzberg, J Creager, MA Losordo, DW Wassef, M AF Goldschmidt-Clermont, Pascal J. Lam, Gregory K. W. Dzau, Victor J. Dong, Chunming Kurtzberg, Joanne Creager, Mark A. Losordo, Douglas W. Wassef, Momtaz TI Response to letter regarding article "Atherosclerosis 2005: Recent discoveries and novel hypotheses" SO CIRCULATION LA English DT Letter ID ENDOTHELIAL PROGENITOR CELLS C1 Duke Univ, Med Ctr, Dept Med, Div Cardiol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Pediat Blood & Marrow Transplantat Program, Durham, NC USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc, Boston, MA 02115 USA. Tufts Univ, Sch Med, St Elizabeths Med Ctr, Div Cardiovasc Res, Boston, MA 02111 USA. NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. RP Goldschmidt-Clermont, PJ (reprint author), Duke Univ, Med Ctr, Dept Med, Div Cardiol, Durham, NC 27710 USA. NR 6 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 30 PY 2006 VL 113 IS 21 BP E783 EP E783 DI 10.1161/CIRCULATIONHA.106.176126 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 048RQ UT WOS:000237964600021 ER PT J AU Cha, SC Kwak, LW Ruffini, PA Qin, H Neelapu, S Biragyn, A AF Cha, SC Kwak, LW Ruffini, PA Qin, H Neelapu, S Biragyn, A TI Cloning of B cell lymphoma-associated antigens using modified phage-displayed expression cDNA library and immunized patient sera SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE phage display; tumor antigen discovery; B cell lymphoma; epitope spreading ID CYTOLYTIC T-LYMPHOCYTES; CANCER-PATIENTS; IDENTIFICATION; IMMUNOTHERAPY; REPERTOIRE; ANTIBODIES; CARCINOMA; PROSTATE; VACCINE; PROTEIN AB Active immunization of follicular lymphoma patients with idiotypic vaccines elicits antigen-specific antibody responses, T-cell responses, and antitumor effects. We hypothesized that these vaccinated patients could generate tumor-specific immune responses, not only against idiotype, but also against other tumor-associated antigens (TAA) by a mechanism of epitope spreading. To identify potential antigens, a phage surface expressed cDNA library derived from primary tumor cells was screened with sera from idiotype-vaccinated patients. Consistent with our hypothesis, we identified two immunogenic peptides (FL-aa-7 and 18), unrelated to idiotype, which were recognized by postvaccine sera but not by prevaccine or normal human sera. These peptide sequences derived from the 5'-untranslated regions of the human GTPase, IMAP family member 7 gene (FL-aa-7) and an alternative reading frame of U1-snRNP 70 (FL-aa-18), respectively, suggesting that epitope spreading had occurred. (c) 2006 Elsevier B.V. All rights reserved. C1 Univ Texas, MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Div Canc Med,Ctr Canc Immunol Res, Houston, TX 77030 USA. Osped Niguarda Ca Granda, Div Oncol Med Falck, Milan, Italy. NIA, Gerontol Res Ctr, Immunol Lab, Baltimore, MD 21224 USA. RP Kwak, LW (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Div Canc Med,Ctr Canc Immunol Res, 1515 Holcombe Blvd,Unit 0903, Houston, TX 77030 USA. EM lkwak@mdanderson.org FU Intramural NIH HHS [Z01 AG000770-04] NR 25 TC 2 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD MAY 30 PY 2006 VL 312 IS 1-2 BP 79 EP 93 DI 10.1016/j.jim.2006.02.013 PG 15 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 057OL UT WOS:000238605000011 PM 16631194 ER PT J AU Piquemal, JP Pilme, J AF Piquemal, Jean-Philip Pilme, Julien TI Comments on the nature of the bonding in oxygenated dinuclear copper enzyme models SO JOURNAL OF MOLECULAR STRUCTURE-THEOCHEM LA English DT Article DE copper; ELF; QTAIM; topological analysis; tyrosinase; hemocyanin; DFT; CASSCF ID ELECTRON LOCALIZATION FUNCTION; TOPOLOGICAL ANALYSIS; DIOXYGEN BINDING; ACTIVE-SITE; MOLECULAR-SYSTEMS; CRYSTAL-STRUCTURE; CATECHOL OXIDASE; CHEMICAL-BONDS; COMPLEXES; TYROSINASE AB The nature of the bonding in model complexes of di-copper metalloenzymes has been analyzed by means of the electronic localization function (ELF) and by the quantum theory of atoms in molecules (QTAIM). The constrained space orbital variations (CSOV) approach has also been used. Density functional theory (DFT) and CASSCF calculations have been carried out on several models of tyrosinase such as the sole Cu(2)O(2)(2+) central core, the Cu(2)O(2)(NE(3))(6)(2+) complex and the Cu(2)O(2)(Imidazol)(6)(2+) complex. The influence on the central Cu(2)O(2) Moiety of both levels of calculation and ligand environment have been discussed. The distinct bonding modes have been characterized for the two major known structures: [Cu(2)(mu-eta(2):eta(2)-O(2))](2+) and [Cu(2)(mu-O(2))](2+). Particular attention has been given to the analysis of the O-O and Cu-O bonds and the nature of the bonding modes has also been analyzed in terms of mesomeric structures. The ELF topological approach shows a significant conservation of the topology between the DFT and CASSCF approaches. Particularly, three-center Cu-O-Cu bonds are observed when the ligands are attached to the central core. At the DFT level, the importance of self interaction effects are emphasized. Although, the DFT approach does not appear to be suitable for the computation of the electronic structure of the isolated Cu(2)O(2) central core, competitive self interaction mechanisms lead to an imperfect but acceptable model when using imidazol ligands. Our results confirm to a certain extent the observations of [M.F. Rode, H.J. Werner, Theoretical Chemistry Accounts 4-5 (2005) 247.] who found a qualitative agreement between B3LYP and localized MRCI calculations when dealing with the Cu(2)O(2) central core with six ammonia ligands. (c) 2006 Elsevier B.V. All rights reserved. C1 Natl Inst Environm Hlth Sci, Struct Biol Lab, Computat Chem Grp, Res Triangle Pk, NC 27709 USA. Ecole Normale Super Lyon, Chim Lab, CNRS, UMR 5182, F-69364 Lyon 07, France. RP Piquemal, JP (reprint author), Natl Inst Environm Hlth Sci, Struct Biol Lab, Computat Chem Grp, Mail Drop F0-08,111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM piquemalj@niehs.nih.gov; julien.pilme@ens-lyon.fr RI Piquemal, Jean-Philip/B-9901-2009; Pilme, Julien/G-4858-2012 OI Piquemal, Jean-Philip/0000-0001-6615-9426; FU Intramural NIH HHS [NIH0011886371] NR 56 TC 18 Z9 18 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-1280 J9 J MOL STRUC-THEOCHEM JI Theochem-J. Mol. Struct. PD MAY 30 PY 2006 VL 764 IS 1-3 BP 77 EP 86 DI 10.1016/j.theochem.2006.02.013 PG 10 WC Chemistry, Physical SC Chemistry GA 067IX UT WOS:000239296400010 PM 17893747 ER PT J AU Roberts, JE Kukielczak, B Chignell, C Sik, B Hu, DN Principato, M AF Roberts, JE Kukielczak, B Chignell, C Sik, B Hu, DN Principato, M TI Simulated microgravity induced damage in human retinal pigment epithelial cells SO MOLECULAR VISION LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 30-MAY 05, 2005 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol ID WALL VESSEL BIOREACTOR; FACTOR-H POLYMORPHISM; MACULAR DEGENERATION; UVEAL MELANOCYTES; T-LYMPHOCYTES; LIGHT DAMAGE; RAT RETINA; IN-VITRO; ENVIRONMENT; EYE AB Purpose: The goal of this study was to determine the potential damage to the human retina that may occur from weightlessness during space flight using simulated microgravity. Methods: Human retinal pigment epithelial (hRPE) cells were cultured for 24 h in a National Aeronautics and Space Administration-designed rotating wall bioreactor vessel to mimic the microgravity environment of space. Single-stranded breaks in hRPE DNA induced by simulated gravity were measured using the comet assay. In addition, the production of the inflammatory mediator prostaglandin E2 (PGE2) was measured in these cells 48 h after recovery from simulated microgravity exposure. Results: Simulated microgravity induced single-stranded breaks in the hRPE DNA that were not repaired within 48 h. Furthermore, PG E2 production was dramatically increased 48 h after the initial microgravity-induced damage, indicating the induction of an inflammatory response. There was less DNA damage and no PGE2 release in hRPE cells pretreated with the antiinflammatory agent cysteine during their exposure to microgravity. Conclusions: We have demonstrated that the microgravity environment generated by a NASA-designed rotating wall bioreactor vessel induces an inflammatory response in hRPE cells. This system thus constitutes a new model system for the study of inflammation in the retina, a system that does not involve the introduction of an exogenous chemical agent or supplementary irradiation. This in vitro method may also be useful for testing novel therapeutic approaches for suppression of retinal inflammation. Furthermore, we suggest a safe prophylactic treatment for prevention of acute, transitory, or enhanced age-related permanent blindness in astronauts or flight personnel engaged in long-haul flights. C1 Fordham Univ, Dept Nat Sci, New York, NY 10023 USA. Natl Inst Environm Hlth Sci, Lab Chem & Pharmacol, Res Triangle Pk, NC USA. New York Eye & Ear Infirm, Tissue Culture Ctr, New York, NY 10003 USA. New York Eye & Ear Infirm, Dept Pathol & Lab Med, New York, NY 10003 USA. New York Eye & Ear Infirm, Dept Ophthalmol, New York, NY 10003 USA. US FDA, Laurel, MD USA. RP Roberts, JE (reprint author), Fordham Univ, Dept Nat Sci, 113 W 60th St, New York, NY 10023 USA. EM jroberts@fordham.edu FU Intramural NIH HHS NR 46 TC 8 Z9 9 U1 0 U2 4 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD MAY 30 PY 2006 VL 12 IS 70 BP 633 EP 638 PG 6 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 050PB UT WOS:000238099300001 PM 16760899 ER PT J AU Young, HA Tovey, MG AF Young, HA Tovey, MG TI TL1A: A mediator of gut inflammation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID ACTIVE CROHNS-DISEASE; IFN-GAMMA PRODUCTION; DR3; COSTIMULATOR; NATALIZUMAB; RECEPTOR-3; EXPRESSION; INDUCTION; CYTOKINE; CELLS C1 NCI, Ctr Canc Res, Lab Expt Immunol, Frederick, MD 21702 USA. CNRS, FRE 2942, Inst Andre Lwoff, Lab Viral Oncol, F-94801 Villejuif, France. RP Young, HA (reprint author), NCI, Ctr Canc Res, Lab Expt Immunol, Frederick, MD 21702 USA. EM youngh@mail.ncifcrf.gov NR 18 TC 16 Z9 16 U1 0 U2 3 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 MAY 30 PY 2006 VL 103 IS 22 BP 8303 EP 8304 DI 10.1073/pnas.0602655103 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 052BX UT WOS:000238206800001 PM 16717188 ER PT J AU Farci, P Quinti, I Farci, S Alter, HJ Strazzera, R Palomba, E Coiana, A Cao, D Casadei, AM Ledda, R Iorio, R Vegnente, A Diaz, G Tovo, PA AF Farci, P Quinti, I Farci, S Alter, HJ Strazzera, R Palomba, E Coiana, A Cao, D Casadei, AM Ledda, R Iorio, R Vegnente, A Diaz, G Tovo, PA TI Evolution of hepatitis C viral quasispecies and hepatic injury in perinatally infected children followed prospectively SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE perinatal hepatitis C virus infection; genetic variability; alanine aminotransferase levels ID VIRUS-INFECTION; NATURAL-HISTORY; VERTICAL TRANSMISSION; HYPERVARIABLE REGION; LIVER-DISEASE; RISK-FACTORS; PERSISTENCE; INFANTS; MOTHERS; HCV AB Perinatal infection with hepatitis C virus (HCV) is characterized by a wide range of alanine aminotransferase (ALT) levels. The mechanisms responsible for this variability are unknown. We examined whether the evolution of the HCV quasispecies was associated with different ALT profiles in perinatally infected children. Sequences within HCV envelope 1 and 2 genes, inclusive of the hypervariable region 1, the viral load, and the nascent humoral immunity were analyzed in serial serum samples from 12 perinatally infected children prospectively followed for a median of 53 months. These patients were selected to represent two different ALT patterns during the first year of life: 6 had high levels (maximum values ranging from 4.2 to 30 times the normal upper limit), and 6 had normal or slightly elevated levels (< 2 times the normal upper limit). Two patterns of viral evolution were identified according to the ALT profiles. Biochemical evidence of hepatic injury was invariably associated with a mono- or oligoclonal viral population, whereas mild or no liver damage correlated with the early emergence of a heterogeneous viral quasispecies. Consistent with selective immune pressure, amino acid changes occurred almost exclusively within the hypervariable region 1 and were temporally associated with antibody seroconversion; at this time, the difference in genetic diversity between the two groups was highly significant (P = 0.002). The two patterns of viral evolution persisted over time and did not correlate with viral load or genotype. Our study demonstrates that, in perinatally infected children, the evolution of HCV quasispecies correlates with hepatic injury. C1 Univ Cagliari, Dept Med Sci, I-09042 Cagliari, Italy. Univ Cagliari, Dept Cytomorphol, I-09042 Cagliari, Italy. Univ Roma La Sapienza, Dept Clin Med, I-00185 Rome, Italy. NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Univ Turin, Dept Pediat, I-10126 Turin, Italy. Univ Roma La Sapienza, Dept Gynecol Sci & Perinatol, I-00185 Rome, Italy. Univ Cagliari, Inst Neonatol, I-09124 Cagliari, Italy. Univ Naples Federico II, Dept Pediat, I-80131 Naples, Italy. RP Farci, P (reprint author), Univ Cagliari, Dept Med Sci, SS 554 Bivio Sestu, I-09042 Cagliari, Italy. EM farcip@pacs.unica.it OI Coiana, Alessandra/0000-0002-1039-5486; Tovo, Pier Angelo/0000-0002-0192-3240 NR 38 TC 53 Z9 58 U1 0 U2 2 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 MAY 30 PY 2006 VL 103 IS 22 BP 8475 EP 8480 DI 10.1073/pnas.0602546103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 052BX UT WOS:000238206800033 PM 16707577 ER PT J AU Hassan, SA Hummer, G Lee, YS AF Hassan, Sergio A. Hummer, Gerhard Lee, Yong-Sok TI Effects of electric fields on proton transport through water chains SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID CYTOCHROME-C-OXIDASE; MOLECULAR-DYNAMICS SIMULATIONS; TRANSFER PATHWAYS; ION-TRANSPORT; LIQUID WATER; CHANNEL; ENERGY; CONDUCTION; AQUAPORIN; DENSITY AB Molecular dynamics simulations on quantum energy surfaces are carried out to study the effects of perturbing electric fields on proton transport (PT) in protonated water chains. As an idealized model of a hydrophobic cavity in the interior of a protein the water molecules are confined into a carbon nanotube (CNT). The water chain connects a hydrated hydronium ion (H3O+) at one end of the CNT and an imidazole molecule at the other end. Without perturbing electric fields PT from the hydronium proton donor to the imidazole acceptor occurs on a picosecond time scale. External perturbations to PT are created by electric fields of varying intensities, normal to the CNT axis, generated by a neutral pair of charges on the nanotube wall. For fields above similar to 0.5 V/A, the hydronium ion is effectively trapped at the CNT center, and PT blocked. Fields of comparable strength are generated inside proteins by nearby polar/charged amino acids. At lower fields the system displays a rich dynamic behavior, where the excess charge shuttles back and forth along the water chain before reaching the acceptor group on the picosecond time scale. The effects of the perturbing field on the proton movement are analyzed in terms of structural and dynamic properties of the water chain. The implications of these observations on PT in biomolecular systems and its control by external perturbing fields are discussed. (c) 2006 American Institute of Physics. C1 US DHHS, DCB, Ctr Mol Modeling, NIH,CIT, Bethesda, MD 20892 USA. US DHHS, NIDDK, Phys Chem Lab, NIH,CIT, Bethesda, MD 20892 USA. RP Hassan, SA (reprint author), US DHHS, DCB, Ctr Mol Modeling, NIH,CIT, Bethesda, MD 20892 USA. EM mago@helix.nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU CIT NIH HHS [Z01 CT000265-09]; Intramural NIH HHS NR 56 TC 18 Z9 18 U1 2 U2 28 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD MAY 28 PY 2006 VL 124 IS 20 AR 204510 DI 10.1063/1.2198820 PG 8 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 048JX UT WOS:000237944500053 PM 16774356 ER PT J AU Lopez, AD Mathers, CD Ezzati, M Jamison, DT Murray, CJL AF Lopez, Alan D. Mathers, Colin D. Ezzati, Majid Jamison, Dean T. Murray, Christopher J. L. TI Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data SO LANCET LA English DT Article ID DEATH AB Background Our aim was to calculate the global burden of disease and risk factors for 2001, to examine regional trends from 1990 to 2001, and to provide a starting point for the analysis of the Disease Control Priorities Project (DCPP). Methods We calculated mortality, incidence, prevalence, and disability adjusted life years (DALYs) for 136 diseases and injuries, for seven income/geographic country groups. To assess trends, we re-estimated all-cause mortality for 1990 with the same methods as for 2001. We estimated mortality and disease burden attributable to 19 risk factors. Findings About 56 million people died in 2001. Of these, 10.6 million were children, 99% of whom lived in low-and-middle-income countries. More than half of child deaths in 2001 were attributable to acute respiratory infections, measles, diarrhoea, malaria, and HIV/AIDS. The ten leading diseases for global disease burden were perinatal conditions, lower respiratory infections, ischaemic heart disease, cerebrovascular disease, HIV/AIDS, diarrhoeal diseases, unipolar major depression, malaria, chronic obstructive pulmonary disease, and tuberculosis. There was a 20% reduction in global disease burden per head due to communicable, maternal, perinatal, and nutritional conditions between 1990 and 2001. Almost half the disease burden in low-and-middle-income countries is now from non-communicable diseases (disease burden per head in Sub-Saharan Africa and the low-and-middle-income countries of Europe and Central Asia increased between 1990 and 2001). Undernutrition remains the leading risk factor for health loss. An estimated 45% of global mortality and 36% of global disease burden are attributable to the joint hazardous effects of the 19 risk factors studied. Uncertainty in all-cause mortality estimates ranged from around 1% in high-income countries to 15-20% in Sub-Saharan Africa. Uncertainty was larger for mortality from specific diseases, and for incidence and prevalence of non-fatal outcomes. Interpretation Despite uncertainties about mortality and burden of disease estimates, our findings suggest that substantial gains in health have been achieved in most populations, countered by the HIV/AIDS epidemic in Sub-Saharan Africa and setbacks in adult mortality in countries of the former Soviet Union. our results on major disease, injury, and risk factor causes of loss of health, together with information on the cost-effectiveness of interventions, can assist in accelerating progress towards better health and reducing the persistent differentials in health between poor and rich countries. C1 Univ Queensland, Sch Populat Hlth, Brisbane, Qld 4006, Australia. WHO, Dept Measurement & Hlth Informat Syst, CH-1211 Geneva, Switzerland. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Harvard Univ, Initiat Global Hlth, Cambridge, MA 02138 USA. NIH, Fogarty Int Ctr, Washington, DC USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Lopez, AD (reprint author), Univ Queensland, Sch Populat Hlth, Brisbane, Qld 4006, Australia. EM a.lopez@sph.uq.edu.au RI Lopez, Alan/F-1487-2010; OI Lopez, Alan/0000-0001-5818-6512; Muengtaweepongsa, Sombat/0000-0003-3715-4428 FU NIA NIH HHS [P01-AG17625] NR 32 TC 2533 Z9 2637 U1 25 U2 444 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 MAY 27 PY 2006 VL 367 IS 9524 BP 1747 EP 1757 DI 10.1016/S0140-6736(06)68770-9 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 047BE UT WOS:000237854000030 PM 16731270 ER PT J AU Fagundes, RB Abnet, CC Strickland, PT Kamangar, F Roth, MJ Taylor, PR Dawsey, SM AF Fagundes, Renato B. Abnet, Christian C. Strickland, Paul T. Kamangar, Farin Roth, Mark J. Taylor, Philip R. Dawsey, Sanford M. TI Higher urine 1-hydroxy pyrene glucuronide (1-OHPG) is associated with tobacco smoke exposure and drinking mate in healthy subjects from Rio Grande do Sul, Brazil SO BMC CANCER LA English DT Article ID POLYCYCLIC AROMATIC-HYDROCARBONS; ESOPHAGEAL CANCER; HIGH-RISK; HOT BEVERAGES; CHINA; URUGUAY; DIET; LINXIAN; CONSUMPTION; CONTRIBUTE AB Background: The highest rates of esophageal squamous cell carcinoma ( ESCC) in Brazil occur in Rio Grande do Sul, the most southern state, which has incidence rates of 20.4/ 100,000/ year for men and 6.5/ 100,000/ year for women. Exposure to carcinogenic polycyclic aromatic hydrocarbons ( PAHs) through tobacco smoke and other sources may increase the risk of ESCC. The aims of the current study were to investigate the degree and sources of PAH exposure of the inhabitants of this region of southern Brazil. Methods: Two hundred healthy adults ( half smokers, half non smokers, half male and half female) were recruited, given a standardized questionnaire, and asked to provide a urine sample for measurement of 1- hydroxypyrene glucuronide ( 1- OHPG), a PAH metabolite). Urine 1- OHPG concentrations were measured using immunoaffinity chromatography and synchronous fluorescence spectroscopy and urine cotinine was measured using a dipstick test. We examined factors associated with 1- OHPG concentration using Wilcoxon tests and multiple linear regression. Results: Urine 1- hydroxypyrene glucuronide ( 1- OHPG) was successfully measured on 199 subjects. The median ( interquartile range) of urine 1- OHPG in the 199 participants was 2.09 pmol/ mL ( 0.51, 5.84). Tobacco smoke exposure and mate drinking were statistically significantly associated with higher urine 1- OHPG concentrations in the multivariate linear regression model. Conclusion: Tobacco smoke and mate both contribute to high levels of benzo[ a] pyrene exposure in the people of southern Brazil. This high PAH exposure may contribute to the high rates of ESCC observed in this population. The increased urine 1- OHPG concentrations associated with mate suggest that contaminants, not just thermal injury, may help explain the increased risk of ESCC previously reported for mate consumption. C1 Univ Fed Santa Maria, Dept Clin Med, Ctr Ciencias Saude, BR-97119900 Santa Maria, RS, Brazil. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Fed Rio Grande Sul, Gastroenterol Postgrad Course, Porto Alegre, RS, Brazil. RP Fagundes, RB (reprint author), Univ Fed Santa Maria, Dept Clin Med, Ctr Ciencias Saude, BR-97119900 Santa Maria, RS, Brazil. EM rfagundes@pro.viars.com.br; abnetc@mail.nih.gov; pstrickl@jhsph.edu; kamangaf@mail.nih.gov; rothm@mail.nih.gov; taylorp@dcpcepn.nci.nih.gov; dawseys@dcpcepn.nci.nih.gov RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 FU Intramural NIH HHS; NIEHS NIH HHS [P01 ES006052, P01-ES06052] NR 34 TC 39 Z9 40 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD MAY 26 PY 2006 VL 6 AR 139 DI 10.1186/1471-2407-6-139 PG 7 WC Oncology SC Oncology GA 073KO UT WOS:000239741900001 PM 16729889 ER PT J AU Johnson, KR Zheng, QY Noben-Trauth, K AF Johnson, Kenneth R. Zheng, Qing Yin Noben-Trauth, Konrad TI Strain background effects and genetic modifiers of hearing in mice SO BRAIN RESEARCH LA English DT Article; Proceedings Paper CT Meeting on the Mouse as an Instrument for Ear Research II CY OCT 01-04, 2005 CL Jackson Lab, Bar Harbor, ME HO Jackson Lab DE modifier gene; genetic background; inbred mouse strain; age-related hearing loss; digenic inheritance; AHL; QTL ID MATERNALLY INHERITED DEAFNESS; QUANTITATIVE TRAIT LOCI; MYOSIN-VIIA GENE; INBRED STRAINS; MOUSE MODELS; DIGENIC INHERITANCE; RECESSIVE DEAFNESS; COMPLEX TRAITS; MUTATION; HUMANS AB Genetic modifiers can be detected in mice by looking for strain background differences in inheritance or phenotype of a mutation. They can be mapped by analyses of appropriate linkage crosses and congenic lines, and modifier genes of large effect can be identified by positional-candidate gene testing. Inbred strains of mice vary widely in onset and severity of age-related hearing loss (AHL), an important consideration when assessing hearing in mutant mice. At least 8 mapped loci and a mitochondrial variant (mt-Tr) are known to contribute to AHL in mouse strains; one locus (ahl) has been identified as a variant of the cadherin 23 gene (Cdh23(753A/G)). This variant also was shown to modify hearing loss associated with the Atp2b2(dfw center dot 2J) and Mass1(frings) mutations. The hearing modifier (Moth1) of tubby (Tub(tub)) mutant mice was shown to be a strain variant of the Mtap1a gene. Human hearing modifiers include DFNM1, which suppresses recessive deafness DFNB26, and a nuclear gene that modulates the severity of hearing loss associated with a mitochondrial mutation. Recently, a valiant of the human ATP2B2 gene was shown to exacerbate hearing loss in individuals homozygous for a CDH23 mutation, similar to the Atp2b2(dfw-2J)-Cdh23(753A/G) interaction affecting hearing in mice. Because modifier genes and digenic inheritance are not always distinguishable, we also include in this review several examples of digenic inheritance of hearing loss that have been reported in both mice and humans. (c) 2006 Elsevier B.V. All rights reserved. C1 Jackson Lab, Bar Harbor, ME 04609 USA. NIDCD, Neurogenet Sect, NIH, Rockville, MD 20850 USA. RP Johnson, KR (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM krj@jax.org RI Zheng, Qing/C-1731-2012 FU Intramural NIH HHS; NIDCD NIH HHS [DC62108, R01 DC005827, R01 DC005827-03, R21 DC005846-02, R21 DC005846, R01 DC007392-01A1, R01 DC007392, R01 DC005827-02, DC005827] NR 73 TC 61 Z9 62 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 26 PY 2006 VL 1091 SI SI BP 79 EP 88 DI 10.1016/j.brainres.2006.02.021 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 068DE UT WOS:000239351500011 PM 16579977 ER PT J AU Kelley, MW AF Kelley, Matthew W. TI Hair cell development: Commitment through differentiation SO BRAIN RESEARCH LA English DT Article; Proceedings Paper CT Meeting on the Mouse as an Instrument for Ear Research II CY OCT 01-04, 2005 CL Jackson Lab, Bar Harbor, ME HO Jackson Lab DE cochlea; hearing; ear; stereocilia; thyroid hormone; bHLH transcription factors ID NEURAL-TUBE DEFECTS; MAMMALIAN INNER-EAR; TYPE-2 IODOTHYRONINE DEIODINASE; AUTOSOMAL RECESSIVE DEAFNESS; THYROID-HORMONE RECEPTORS; NOTCH SIGNALING PATHWAY; SYNDROME TYPE 1D; HEARING-LOSS; UNCONVENTIONAL MYOSIN; LOOP-TAIL AB The perceptions of sound, balance and acceleration are mediated through the vibration of stereociliary bundles located on the lumenal surfaces of mechanosensory hair cells located within the inner ear. In mammals, virtually all hair cells are generated during a relatively brief period in embryogenesis with any subsequent hair cell loss leading to a progressive and permanent loss of sensitivity. In light of the importance of these cells, considerable effort has been focused on understanding the molecular genetic pathways that regulate their development. The results of these studies have begun to elucidate the signaling molecules that regulate several key events in hair cell development. In particular, significant progress has been made in the understanding of hair cell commitment, survival and differentiation. In addition, several aspects of the development of the stereociliary bundle, including its elongation and orientation, have recently been examined. This review will summarize results from each of these developmental events and describe the molecular signaling pathways involved. (c) 2006 Elsevier B.V. All rights reserved. C1 Natl Inst Deafness & Other Commun Disorders, Sect Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Kelley, MW (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Dev Neurosci, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM kelleymt@nidcd.nih.gov NR 118 TC 27 Z9 29 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 26 PY 2006 VL 1091 SI SI BP 172 EP 185 DI 10.1016/j.brainres.2006.02.062 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 068DE UT WOS:000239351500019 PM 16626654 ER PT J AU Harrington, PD Vieira, NE Chen, P Espinoza, J Nien, JK Romero, R Yergey, AL AF Harrington, PD Vieira, NE Chen, P Espinoza, J Nien, JK Romero, R Yergey, AL TI Proteomic analysis of amniotic fluids using analysis of variance-principal component analysis and fuzzy rule-building expert systems applied to matrix-assisted laser desorption/ionization mass spectrometry SO CHEMOMETRICS AND INTELLIGENT LABORATORY SYSTEMS LA English DT Article; Proceedings Paper CT International Conference on Chemometrics and Bioinformatics in Asia CY OCT 16-20, 2004 CL Shanghai, PEOPLES R CHINA SP Natl Nat Sci Fdn China, Near-Infrared Comm Japan, Chinese Chem Soc, Comp Chem Comm, Tongi Univ, Cent S Univ, Hunan Univ DE amniotic fluid; premature delivery; chorioamniotic infection; MALDI-MS; proteomic biomarker; hotelling T-2 confidence interval; Latin partition ID NEURAL-NETWORKS AB Amniotic fluids from 36 women who had premature or at term deliveries were studied using matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) [F. Hillenkamp, M. Karas, R.C. Beavis, B.T. Chait, Matrix-assisted laser desorption ionization mass-spectrometry of biopolymers, Analytical Chemistry 63 (1991) A1193-A1202. (1)]. The effects of experimental factors of patient, uterine infection, sample preparation, sample handling, three different days and four different studies, were examined using analysis of variance-principal component analysis (ANOVA-PCA) [P.B. Harrington, N.E. Vieira, J. Espinoza, J.K. Nien, R. Romero, A.L. Yergey, Analysis of variance-principal component analysis: a soft tool for proteomic discovery, Analytica Chimica Acta (in press)]. Hotelling T-2 95% confidence intervals were introduced as a graphical tool for evaluating the statistical significance of the levels for each factor. ANOVA-PCA gave biomarkers that distinguished amniotic fluids with evidence of chorioamniotic infection from the other amniotic fluids. All women with intrauterine infection, except for one were identified from the MALDI-MS spectra of their amniotic fluids. After querying the clinic, it was discovered that the amniotic fluid of the misclassified patient was incorrectly identified as infected. The biomarkers obtained from ANOVA-PCA corresponded to those obtained from a fuzzy rule-building system (FuRES) [P.B. Harrington, Fuzzy multivariate rule-building expert systems-minimal neural networks. Journal of Chemometrics 5 (1991) 467-486]. The FuRES model was evaluated using 10 Latin-partitions that yielded a sensitivity of 92% and specificity of 100% for detecting patients with uterine inflammation from MALI-WS measurements of the amniotic fluids. The specificity value contains a patient that was clinically misidentified as infected that was disclosed by querying the FuRES results. An ANOVA-PCA indicated that the solid phase extraction improved the precision of the analysis, but FuRES analysis showed that this procedure resulted in a lower prediction rate. Using the MALDI-MS data obtained from the amniotic fluids of patients who delivered at term or preterm without evidence of infection in the patients, could not be classified by ANOVA-PCA or predicted by FuRES into these groups. (c) 2005 Elsevier B.V. All rights reserved. C1 Ohio Univ, Ctr Intelligent Chem Instrumentat, Dept Chem & Biochem, Clippinger Labs, Athens, OH 45701 USA. NICHHD, Sect Mass Sepct & Metab, Bethesda, MD 20892 USA. NICHHD, Perinatol Res Branch, CS Mott Ctr 1580, Detroit, MI 48201 USA. RP Harrington, PD (reprint author), Ohio Univ, Ctr Intelligent Chem Instrumentat, Dept Chem & Biochem, Clippinger Labs, Athens, OH 45701 USA. EM Peter.Harrington@Ohio.edu OI Harrington, Peter/0000-0003-0268-8630 NR 16 TC 35 Z9 35 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-7439 J9 CHEMOMETR INTELL LAB JI Chemometrics Intell. Lab. Syst. PD MAY 26 PY 2006 VL 82 IS 1-2 SI SI BP 283 EP 293 DI 10.1016/j.chemolab.2005.05.011 PG 11 WC Automation & Control Systems; Chemistry, Analytical; Computer Science, Artificial Intelligence; Instruments & Instrumentation; Mathematics, Interdisciplinary Applications; Statistics & Probability SC Automation & Control Systems; Chemistry; Computer Science; Instruments & Instrumentation; Mathematics GA 043GL UT WOS:000237588100038 ER PT J AU Patino, WD Kang, JG Matoba, S Mian, OY Gochuico, BR Hwang, PM AF Patino, WD Kang, JG Matoba, S Mian, OY Gochuico, BR Hwang, PM TI Atherosclerotic plaque macrophage transcriptional regulators are expressed in blood and modulated by tristetraprolin SO CIRCULATION RESEARCH LA English DT Article DE serial analysis of gene expression; macrophage; monocyte; transcription ID GENE-EXPRESSION; C-FOS; HUMAN MONOCYTES; SERIAL ANALYSIS; DIFFERENTIATION; CELLS; P21(WAF1/CIP1); MECHANISMS; CANCER; AP-1 AB Circulating monocytes and plaque macrophages mediate inflammation in the pathogenesis of atherosclerosis. We purified these cells from patients undergoing carotid endarterectomy for advanced atherosclerosis and examined their in vivo transcriptomes using the serial analysis of gene expression (SAGE) technique. We observed striking differences in transcriptional regulators as monocytes transformed into plaque macrophages in contrast to monocytes and lung macrophages from normal subjects. Consistent with its role in moderating inflammation, tristetraprolin (TTP, ZFP36) was among the most highly expressed macrophage transcriptional regulators. Interestingly, the mRNAs of a subset of the macrophage transcriptional regulators specifically interacted with TTP, revealing a network of genes that may be important in controlling macrophage inflammatory activity. Giving functional significance to this interaction, the knockdown of TTP increased both cognate macrophage gene mRNAs and inflammatory tumor necrosis factor protein release. In contrast, transient overexpression of TTP resulted in decreased levels of the same genes supporting its role in regulating macrophage gene expression. Together, our results indicate that the in vivo gene expression analyses of cells involved in pathogenesis can provide biological insights for functional studies with potential clinical implications. C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD USA. RP Hwang, PM (reprint author), NHLBI, Cardiovasc Branch, NIH, Bldg 10-CRC,Rm 5-5330,10 Ctr Dr, Bethesda, MD 20892 USA. OI Mian, Omar/0000-0002-8133-8120 FU Intramural NIH HHS NR 40 TC 21 Z9 23 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD MAY 26 PY 2006 VL 98 IS 10 BP 1282 EP 1289 DI 10.1161/01.RES.0000222284.48288.28 PG 8 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 046LD UT WOS:000237812200010 PM 16614304 ER PT J AU Wang, H Charles, PC Wu, YX Ren, RQ Pi, XC Moser, M Barshishat-Kupper, M Rubin, JS Perou, C Bautch, V Patterson, C AF Wang, H Charles, PC Wu, YX Ren, RQ Pi, XC Moser, M Barshishat-Kupper, M Rubin, JS Perou, C Bautch, V Patterson, C TI Gene expression profile signatures indicate a role for wnt signaling in endothelial commitment from embryonic stem cells SO CIRCULATION RESEARCH LA English DT Article DE hemangioblast; angiogenesis; microarray; signaling ID VASCULAR ENDOTHELIUM; COMMON PRECURSOR; GROWTH-FACTOR; YOLK-SAC; DIFFERENTIATION; ANGIOGENESIS; RECEPTOR; VASCULOGENESIS; PROLIFERATION; HEMATOPOIESIS AB We have used global gene expression analysis to establish a comprehensive list of candidate genes in the developing vasculature during embryonic (ES) cell differentiation in vitro. A large set of genes, including growth factors, cell surface molecules, transcriptional factors, and members of several signal transduction pathways that are known to be involved in vasculogenesis or angiogenesis, were found to have expression patterns as expected. Some unknown or functionally uncharacterized genes were differentially regulated in flk1(+) cells compared with flk1(+) cells, suggesting possible roles for these genes in vascular commitment. Particularly, multiple components of the Wnt signaling pathway were differentially regulated in flk1(+) cells, including Wnt proteins, their receptors, downstream transcriptional factors, and other components belonging to this pathway. Activation of the Wnt signal was able to expand vascular progenitor populations whereas suppression of Wnt activity reduced flk1(+) populations. Suppression of Wnt signaling also inhibited the formation of matured vascular capillary-like structures during late stages of embryoid body differentiation. These data indicate a requisite and ongoing role for Wnt activity during vascular development, and the gene expression profiles identify candidate components of this pathway that participate in vascular cell differentiation. C1 Univ N Carolina, Div Cardiol, Chapel Hill, NC 27599 USA. Univ N Carolina, Cardiovasc Biol Ctr, Chapel Hill, NC USA. Univ N Carolina, Dept Med, Chapel Hill, NC USA. Univ N Carolina, Dept Biol, Chapel Hill, NC USA. Univ N Carolina, Dept Genet, Chapel Hill, NC USA. Natl Canc Inst, Cellular & Mol Biol Lab, Bethesda, MD USA. RP Patterson, C (reprint author), Univ N Carolina, Div Cardiol, 8200 Med Biomol Res Bldg, Chapel Hill, NC 27599 USA. EM cpatters@med.unc.edu OI Perou, Charles/0000-0001-9827-2247 FU NHLBI NIH HHS [HL 03658, HL 072347, HL 61656] NR 31 TC 43 Z9 44 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD MAY 26 PY 2006 VL 98 IS 10 BP 1331 EP 1339 DI 10.1161/01.RES.0000220650.26555.1d PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 046LD UT WOS:000237812200016 PM 16601226 ER PT J AU Baba, D Maita, N Jee, JG Uchimura, Y Saitoh, H Sugasawa, K Hanaoka, F Tochio, H Hiroaki, H Shirakawa, M AF Baba, D Maita, N Jee, JG Uchimura, Y Saitoh, H Sugasawa, K Hanaoka, F Tochio, H Hiroaki, H Shirakawa, M TI Crystal structure of SUMO-3-modified thymine-DNA glycosylase SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE post-translational protein modification; SUMO; DNA repair ID SUMO-BINDING MOTIF; TRANSCRIPTIONAL REPRESSION; PROTEIN; NUCLEAR; MODIFIER; IDENTIFICATION; RECOGNITION; SITES AB Modification of cellular proteins by the small ubiquitin-like modifier SUMO is important in regulating various cellular events. Many different nuclear proteins are targeted by SUMO, and the functional consequences of this modification are diverse. For most proteins, however, the functional and structural consequences of modification by specific SUMO isomers are unclear. Conjugation of SUMO to thymine-DNA glycosylase (TDG) induces the dissociation of TDG from its product DNA. Structure determination of the TDG central region conjugated to SUMO-1 previously suggested a mechanism in which the SUMOylation-induced conformational change in the C-terminal region of TDG releases TDG from tight binding to its product DNA. Here, we have determined the crystal structure of the central region of TDG conjugated to SUMO-3. The overall structure of SUMO-3-conjugated TDG is similar to the previously reported structure of TDG conjugated to SUMO-1, despite the relatively low level of amino acid sequence similarity between SUMO-3 and SUMO-1. The two structures revealed that the sequence of TDG that resembles the SUMO-binding motif (SBM) can form an intermolecular beta-sheet with either SUMO-1 or SUMO-3. Structural comparison with the canonical SBM shows that this SBM-like sequence of TDG retains all of the characteristic interactions of the SBM, indicating sequence diversity in the SBM. (c) 2006 Elsevier Ltd. All rights reserved. C1 Yokohama City Univ, Grad Sch Integrated Sci, Yokohama, Kanagawa 2300045, Japan. Kyoto Univ, Grad Sch Engn, Kyoto 6158510, Japan. Kyushu Univ, Grad Sch Syst Life Sci, Fukuoka 8128582, Japan. NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. Kumamoto Univ, Inst Mol Embryol & Genet, Dept Regenerat Med, Kumamoto 8600811, Japan. RIKEN, Discovery Res Inst, Cellular Physiol Lab, Wako, Saitama 3510198, Japan. Japan Sci & Technol Agcy, SORST, Kawaguchi, Saitama 3320012, Japan. Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka 5650871, Japan. RIKEN, Genom Sci Ctr, Yokohama, Kanagawa 2300045, Japan. Japan Sci & Technol Corp, CREST, Kawaguchi, Saitama 3320012, Japan. RP Shirakawa, M (reprint author), Yokohama City Univ, Grad Sch Integrated Sci, Yokohama, Kanagawa 2300045, Japan. EM shirakawa@moleng.kyoto-u.ac.jp RI Tochio, Hidehito/F-6109-2011; Hiroaki, Hidekazu /G-9564-2012; Maita, Nobuo/J-1443-2012; OI Tochio, Hidehito/0000-0003-3843-3330; Maita, Nobuo/0000-0003-2260-5783; Hiroaki, Hidekazu/0000-0003-1621-5893 NR 38 TC 30 Z9 32 U1 0 U2 3 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 26 PY 2006 VL 359 IS 1 BP 137 EP 147 DI 10.1016/j.jmb.2006.03.036 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 044HU UT WOS:000237663800013 PM 16626738 ER PT J AU Wheeler, AP Bernard, GR Thompson, BT Schoenfeld, D Wiedemann, HP deBoisblanc, B Connors, AF Hite, D Harabin, AL AF Wheeler, AP Bernard, GR Thompson, BT Schoenfeld, D Wiedemann, HP deBoisblanc, B Connors, AF Hite, D Harabin, AL CA Natl Heart Lung Blood Inst TI Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RIGHT-HEART CATHETERIZATION; CRITICALLY-ILL PATIENTS; RESPIRATORY-DISTRESS-SYNDROME; ACUTE MYOCARDIAL-INFARCTION; RANDOMIZED CONTROLLED-TRIAL; RISK SURGICAL PATIENTS; PATIENT SAFETY; PRESSURE; OUTCOMES; CARE AB Background: The balance between the benefits and the risks of pulmonary-artery catheters (PACs) has not been established. Methods: We evaluated the relationship of benefits and risks of PACs in 1000 patients with established acute lung injury in a randomized trial comparing hemodynamic management guided by a PAC with hemodynamic management guided by a central venous catheter (CVC) using an explicit management protocol. Mortality during the first 60 days before discharge home was the primary outcome. Results: The groups had similar baseline characteristics. The rates of death during the first 60 days before discharge home were similar in the PAC and CVC groups (27.4 percent and 26.3 percent, respectively; P=0.69; absolute difference, 1.1 percent; 95 percent confidence interval, -4.4 to 6.6 percent), as were the mean (+/-SE) numbers of both ventilator-free days (13.2+/-0.5 and 13.5+/-0.5; P=0.58) and days not spent in the intensive care unit (12.0+/-0.4 and 12.5+/-0.5; P=0.40) to day 28. PAC-guided therapy did not improve these measures for patients in shock at the time of enrollment. There were no significant differences between groups in lung or kidney function, rates of hypotension, ventilator settings, or use of dialysis or vasopressors. Approximately 90 percent of protocol instructions were followed in both groups, with a 1 percent rate of crossover from CVC- to PAC-guided therapy. Fluid balance was similar in the two groups, as was the proportion of instructions given for fluid and diuretics. Dobutamine use was uncommon. The PAC group had approximately twice as many catheter-related complications (predominantly arrhythmias). Conclusions: PAC-guided therapy did not improve survival or organ function but was associated with more complications than CVC-guided therapy. These results, when considered with those of previous studies, suggest that the PAC should not be routinely used for the management of acute lung injury. C1 Vanderbilt Univ, Med Ctr, Nashville, TN 37232 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Cleveland Clin, Cleveland, OH 44106 USA. Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. Case Western Reserve Univ, Metrohlth Med Ctr, Cleveland, OH USA. Wake Forest Univ Hlth Sci, Winston Salem, NC USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Wheeler, AP (reprint author), Vanderbilt Univ, Med Ctr, T-1217 MCN, Nashville, TN 37232 USA. EM art.wheeler@vanderbilt.edu OI Wiedemann, Herbert/0000-0002-4587-4401 NR 47 TC 459 Z9 475 U1 2 U2 7 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 MAY 25 PY 2006 VL 354 IS 21 BP 2213 EP 2224 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 045RF UT WOS:000237758900003 ER PT J AU Bonville, CA Bennett, NJ Koehnlein, M Haines, DM Ellis, JA DelVeechio, AM Rosenberg, HF Domachowske, JB AF Bonville, CA Bennett, NJ Koehnlein, M Haines, DM Ellis, JA DelVeechio, AM Rosenberg, HF Domachowske, JB TI Respiratory dysfunction and proinflammatory chemokines in the pneumonia virus of mice (PVM) model of viral bronchiolitis SO VIROLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-for-Pediatric-Research CY MAY 11, 2004 CL San Francisco, CA SP Soc Pediat Res DE pneumovirus; chemokine; bronchiolitis; inflammation ID MACROPHAGE-INFLAMMATORY PROTEIN-1-ALPHA; INDUCED AIRWAY DYSFUNCTION; HELPER TYPE-2 CYTOKINES; SYNCYTIAL VIRUS; SENDAI VIRUS; INTERFERON-GAMMA; F344 RATS; IN-VIVO; PNEUMOVIRUS INFECTIONS; EXPRESSION AB We explore relationships linking clinical symptoms, respiratory dysfunction, and local production of proinflammatory chemokines in the pneumonia virus of mice (PVM) model of viral bronchiolitis. With a reduced inoculum of this natural rodent pathogen, we observe virus clearance by day 9, while clinical symptoms and respiratory dysfunction persist through days 14 and 17 postinoculation, respectively. Via microarray and ELISA, we identify expression profiles of proinflammatory mediators MIP-1 alpha, MCP-1, and MIP-2 that correlate with persistent respiratory dysfunction. MIP-1 alpha is localized in bronchial epithelium, which is also the major site of PVM replication. Interferon-gamma was detected in lung tissue, but at levels that do not correlate with respiratory dysfunction. Taken together, we present a modification of our pneumovirus infection model that results in improved survival and data that stand in support of a connection between local production of specific mediators and persistent respiratory dysfunction in the setting of acute viral bronchiolitis. (c) 2006 Elsevier Inc. All rights reserved. C1 SUNY Upstate Med Univ, Syracuse, NY 13210 USA. Centocor Inc, Infect Dis Res, Radnor, PA 19087 USA. Univ Saskatchewan, Western Coll Vet Med, Dept Vet Microbiol, Saskatoon, SK S7N 0W0, Canada. NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Domachowske, JB (reprint author), SUNY Upstate Med Univ, Syracuse, NY 13210 USA. EM domachoj@upstate.edu FU Intramural NIH HHS NR 45 TC 48 Z9 48 U1 1 U2 1 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 MAY 25 PY 2006 VL 349 IS 1 BP 87 EP 95 DI 10.1016/j.virol.2006.02.017 PG 9 WC Virology SC Virology GA 047ET UT WOS:000237863300009 PM 16563455 ER PT J AU Dar, DE Metzger, TG Vandenbergh, DJ Uhl, GR AF Dar, DE Metzger, TG Vandenbergh, DJ Uhl, GR TI Dopamine uptake and cocaine binding mechanisms: The involvement of charged amino acids from the transmembrane domains of the human dopamine transporter SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE dopamine transporter; cocaine; charged amino acid; mutant; glutamate ID H-3 WIN 35,428; NEUROTRANSMITTER TRANSPORTERS; ANALOG RECOGNITION; EXPRESSION; MUTATIONS; MUTANTS; CLONING; CDNA AB The wild type human dopamine transporter (DAT) and five DAT mutants were transfected into COS-7 cells and their ability to uptake dopamine or to bind cocaine was examine three days later. In each mutant, a single charged amino acid, located in areas that initial hydrophobic analysis had indicated were DAT transmembrane domains was substituted by alanine. Mutants used in this study were lysines 257 and 525 (termed K257A and K525A), arginines 283 and 521 (termed R283A and R521A), and glutamate 491 (termed E491A). Dopamine affinity was significantly enhanced in the K257A and R283A mutants, and the IC50 for displacement of the radioactive cocaine analog 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane (CFT) by cocaine was significantly elevated in the E491A mutant. All mutants displayed a reduction or complete loss of the maximal velocity (V-m) of dopamine transport. (c) 2006 Elsevier B.V. All rights reserved. C1 Natl Inst Drug Abuse, Mol Neurobiol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Dar, DE (reprint author), Weizmann Inst Sci, Dept Neurobiol, Arison Bldg,Room 204, IL-76100 Rehovot, Israel. EM dalit.dar@weizmann.ac.il OI Vandenbergh, David/0000-0002-5620-2870 NR 20 TC 7 Z9 8 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD MAY 24 PY 2006 VL 538 IS 1-3 BP 43 EP 47 DI 10.1016/j.ejphar.2006.03.048 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 049ED UT WOS:000237997800007 PM 16674939 ER PT J AU Qiu, J Bosch, MA Tobias, SC Krust, A Graham, SM Murphy, SJ Korach, KS Chambon, P Scanlan, TS Ronnekleiv, OK Kelly, MJ AF Qiu, J Bosch, MA Tobias, SC Krust, A Graham, SM Murphy, SJ Korach, KS Chambon, P Scanlan, TS Ronnekleiv, OK Kelly, MJ TI A G-protein-coupled estrogen receptor is involved in hypothalamic control of energy homeostasis SO JOURNAL OF NEUROSCIENCE LA English DT Article DE GPCR; body weight; GABA(B) receptor; intracellular signaling; potassium channels; POMC neurons ID CENTRAL-NERVOUS-SYSTEM; REPRODUCTIVE PHENOTYPES; ARCUATE NEURONS; RHESUS-MONKEYS; GUINEA-PIGS; KINASE-A; PATHWAYS; BETA; HYPERPOLARIZATION; ACTIVATION AB Estrogens are involved in the hypothalamic control of multiple homeostatic functions including reproduction, stress responses, energy metabolism, sleep cycles, temperature regulation, and motivated behaviors. The critical role of 17 ss-estradiol (E-2) is evident in hypoestrogenic states ( e. g.,postmenopause) in which many of these functions go awry. The actions of E-2 in the brain have been attributed to the activation of estrogen receptors alpha and ss through nuclear, cytoplasmic, or membrane actions. However, we have identified a putative membrane- associated estrogen receptor that is coupled to desensitization of GABAB and mu-opioid receptors in guinea pig and mouse hypothalamic proopiomelanocortin neurons. We have synthesized a new nonsteroidal compound, STX, which selectively targets the G alpha q-coupled phospholipase C-protein kinase C-protein kinase A pathway, and have established that STX is more potent than E2 in mediating this desensitization in an ICI 182, 780-sensitive manner in both guinea pig and mouse neurons. Both E-2 and STX were fully efficacious in estrogen receptor alpha, ss knock-out mice. Moreover, in vivo treatment with STX, similar to E-2, attenuated the weight gain in hypoestrogenic female guinea pigs. Therefore, this membrane- delimited signaling pathway plays a critical role in the control of energy homeostasis and may provide a novel therapeutic target for treatment of postmenopausal symptoms and eating disorders in females. C1 Oregon Hlth Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97239 USA. Oregon Hlth Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97239 USA. Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Mol & Cellular Pharmacol, San Francisco, CA 94143 USA. NIH, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. Univ Strasbourg 1, Inst Genet & Biol Mol & Cellulaire, CNRS, Inst Natl Sante & Rech Med, F-67404 Illkirch Graffenstaden, France. RP Kelly, MJ (reprint author), Oregon Hlth Sci Univ, Dept Physiol & Pharmacol, L334, Portland, OR 97239 USA. EM ronnekle@ohsu.edu; kellym@ohsu.edu OI Korach, Kenneth/0000-0002-7765-418X FU NIDDK NIH HHS [DK68098, DK57574, R01 DK057574, R01 DK068098]; NINDS NIH HHS [NS38809, NS43330, NS49210, P01 NS049210, P01 NS049210-01A19002, R01 NS038809, R01 NS043330, R56 NS038809] NR 43 TC 136 Z9 140 U1 1 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 24 PY 2006 VL 26 IS 21 BP 5649 EP 5655 DI 10.1523/JNEURSCI.0327-06.2006 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 046KG UT WOS:000237809900007 PM 16723521 ER PT J AU Izquierdo, A Wellman, CL Holmes, A AF Izquierdo, A Wellman, CL Holmes, A TI Brief uncontrollable stress causes dendritic retraction in infralimbic cortex and resistance to fear extinction in mice SO JOURNAL OF NEUROSCIENCE LA English DT Article DE stress; infralimbic cortex; fear extinction; mPFC; PTSD; dendritic arborization ID MEDIAL PREFRONTAL CORTEX; LONG-TERM POTENTIATION; PYRAMIDAL NEURONS; CONDITIONED FEAR; SPINE DENSITY; SENSORIMOTOR NEOCORTEX; LAYER-V; AMYGDALA; RAT; DISORDER AB Extinction of conditioned fear responses is an active learning process resulting from the repeated presentation of a conditioned stimulus in the absence of the unconditioned aversive stimulus. Recent research implicates the medial prefrontal cortex (mPFC) in the mediation of fear extinction in rodents and the pathophysiology of posttraumatic stress disorder. However, there is currently little understanding of precisely how stress can impact fear extinction and the neural circuitry subserving this behavior. The present study examined the effects of brief exposure to an uncontrollable stressor on (1) fear conditioning and fear extinction, and ( 2) dendritic morphology of pyramidal neurons in the infralimbic (IL) and prelimbic (PL) regions of the mPFC in mice. Exposure to three episodes of stress ending 24 h before fear conditioning significantly attenuated the rate of cued fear extinction relative to nonstressed controls, but did not affect fear conditioning or cue or context recall. Analysis of Golgi-stained neurons showed that one or three exposures to daily swim stress caused significant retraction of terminal branches of apical, but not basilar, dendrites of IL neurons. In contrast, PL neuronal morphology was unaltered by stress. These data demonstrate that IL, but not PL, neurons are highly sensitive to even brief exposure to stress, and that this same form of stress impairs fear extinction. Present findings suggest that trauma may compromise the functional integrity of the mPFC with implications for the pathophysiology of certain neuropsychiatric disorders. C1 NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN 47405 USA. Indiana Univ, Program Neurosci, Bloomington, IN 47405 USA. RP Izquierdo, A (reprint author), Calif State Univ Los Angeles, Coll Nat & Social Sci, Dept Psychol, 1515 State Univ Dr, Los Angeles, CA 90032 USA. EM Alzquie@calstatela.edu FU Intramural NIH HHS; NIMH NIH HHS [MH067607] NR 56 TC 216 Z9 223 U1 4 U2 18 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 24 PY 2006 VL 26 IS 21 BP 5733 EP 5738 DI 10.1523/JNEUROSCI.0474-06.2006 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 046KG UT WOS:000237809900016 PM 16723530 ER PT J AU Sharp, JS Sullivan, DM Cavanagh, J Tomer, KB AF Sharp, JS Sullivan, DM Cavanagh, J Tomer, KB TI Measurement of multisite oxidation kinetics reveals an active site conformational change in Spo0F as a result of protein oxidation SO BIOCHEMISTRY LA English DT Article ID SUBTILIS RESPONSE REGULATOR; HIGH-RESOLUTION NMR; BACILLUS-SUBTILIS; MOLECULAR RECOGNITION; SIGNAL-TRANSDUCTION; MASS-SPECTROMETRY; SPORULATION; PHOSPHORELAY; SPOOF; RADIOLYSIS AB When most proteins undergo oxidative damage, they yield a variety of products containing oxidative damage at a large number of sites, most of which are modified substoichiometrically. The resulting complex mixture of products is not amenable to high-resolution structural analyses. The previous methods of structural analysis have relied upon either very generalized structural analyses such as circular dichroism or the creation of a battery of mutants to try to isolate single-residue damage effects. We present a methodology using mass spectrometry to measure the kinetics of oxidation at many sites simultaneously. Previous studies have shown that these kinetics are determined by the chemical nature of the damage site and by the accessibility of that site to the radical. By measuring deviations in the rate of oxidation from the expected pseudo-zero-order kinetics, we can detect and characterize local structural changes due to the oxidative damage. We demonstrate the application of this new technique to the Spo0F protein, a regulator of sporulation in Bacillus subtilis. Circular dichroism studies suggest a partial loss of helical structure of Spo0F as a result of oxidative damage. We report that oxidation causes a three-stage conformational change in Spo0F. Furthermore, we find the dramatic structural changes affect only the region surrounding the active site, while the remainder of the structure remains relatively unperturbed. Finally, we are able to determine that the specific oxidation event that triggers the conformational change at the active site of Spo0F occurs at Met81, a partially conserved methionine in the CheY superfamily. C1 N Carolina State Univ, Dept Mol & Sruct Biochem, Raleigh, NC 27695 USA. NIEHS, Struct Biol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Cavanagh, J (reprint author), N Carolina State Univ, Dept Mol & Sruct Biochem, Raleigh, NC 27695 USA. RI Tomer, Kenneth/E-8018-2013 FU Intramural NIH HHS NR 27 TC 24 Z9 24 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 23 PY 2006 VL 45 IS 20 BP 6260 EP 6266 DI 10.1021/bi060470r PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 043TS UT WOS:000237625200003 PM 16700537 ER PT J AU Chowdhury, MA Kuivaniemi, H Romero, R Edwin, S Chaiworapongsa, T Tromp, G AF Chowdhury, Mahboob A. Kuivaniemi, Helena Romero, Roberto Edwin, Samuel Chaiworapongsa, Tinnakorn Tromp, Gerard TI Identification of novel functional sequence variants in the gene for peptidase inhibitor 3 SO BMC MEDICAL GENETICS LA English DT Article ID ELASTASE-SPECIFIC INHIBITOR; EPITHELIAL-CELLS; DIFFERENTIAL EXPRESSION; ANTIMICROBIAL ACTIVITY; BRONCHIAL-SECRETIONS; NUCLEOTIDE-SEQUENCE; ELAFIN GENE; HUMAN SKIN; ANTILEUKOPROTEASE; KERATINOCYTES AB Background: Peptidase inhibitor 3 (PI3) inhibits neutrophil elastase and proteinase-3, and has a potential role in skin and lung diseases as well as in cancer. Genome-wide expression profiling of chorioamniotic membranes revealed decreased expression of PI3 in women with preterm premature rupture of membranes. To elucidate the molecular mechanisms contributing to the decreased expression in amniotic membranes, the PI3 gene was searched for sequence variations and the functional significance of the identified promoter variants was studied. Methods: Single nucleotide polymorphisms (SNPs) were identified by direct sequencing of PCR products spanning a region from 1,173 bp upstream to 1,266 bp downstream of the translation start site. Fourteen SNPs were genotyped from 112 and nine SNPs from 24 unrelated individuals. Putative transcription factor binding sites as detected by in silico search were verified by electrophoretic mobility shift assay ( EMSA) using nuclear extract from Hela and amnion cell nuclear extract. Deviation from Hardy-Weinberg equilibrium (HWE) was tested by chi(2) goodness-of-fit test. Haplotypes were estimated using expectation maximization (EM) algorithm. Results: Twenty-three sequence variations were identified by direct sequencing of polymerase chain reaction (PCR) products covering 2,439 nt of the PI3 gene (-1,173 nt of promoter sequences and all three exons). Analysis of 112 unrelated individuals showed that 20 variants had minor allele frequencies (MAF) ranging from 0.02 to 0.46 representing "true polymorphisms", while three had MAF <= 0.01. Eleven variants were in the promoter region; several putative transcription factor binding sites were found at these sites by database searches. Differential binding of transcription factors was demonstrated at two polymorphic sites by electrophoretic mobility shift assays, both in amniotic and HeLa cell nuclear extracts. Differential binding of the transcription factor GATA1 at -689C > G site was confirmed by a supershift. Conclusion: The promoter sequences of PI3 have a high degree of variability. Functional promoter variants provide a possible mechanism for explaining the differences in PI3 mRNA expression levels in the chorioamniotic membranes, and are also likely to be useful in elucidating the role of PI3 in other diseases. C1 Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48202 USA. NICHHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD 20892 USA. Wayne State Univ, Dept Obstet & Gynecol, Sch Med, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, Sch Med, Ctr Mol Med & Genet, 6050 Cass Ave, Detroit, MI 48202 USA. EM mchowdh@med.wayne.edu; kuivan@sanger.med.wayne.edu; warfiela@mail.nih.gov; sedwin@med.wayne.edu; Tchaiwor@med.wayne.edu; gerard.tromp@sanger.med.wayne.edu RI Tromp, Gerard/B-2677-2017; OI Tromp, Gerard/0000-0002-7761-0806; Kuivaniemi, Helena/0000-0001-5753-8766 NR 30 TC 12 Z9 12 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD MAY 23 PY 2006 VL 7 AR 49 DI 10.1186/1471-2350-7-49 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 064EP UT WOS:000239072300001 PM 16719916 ER PT J AU Hendrix, SL Wassertheil-Smoller, S Johnson, KC Howard, BV Kooperberg, C Rossouw, JE Trevisan, M Aragaki, A Baird, AE Bray, PF Buring, JE Criqui, MH Herrington, D Lynch, JK Rapp, SR Torner, J AF Hendrix, SL Wassertheil-Smoller, S Johnson, KC Howard, BV Kooperberg, C Rossouw, JE Trevisan, M Aragaki, A Baird, AE Bray, PF Buring, JE Criqui, MH Herrington, D Lynch, JK Rapp, SR Torner, J CA WHI Investigators TI Effects of conjugated equine estrogen on stroke in the Women's Health Initiative SO CIRCULATION LA English DT Article DE women; stroke; hormones; estrogen ID HORMONE REPLACEMENT THERAPY; RANDOMIZED CONTROLLED-TRIAL; CORONARY HEART-DISEASE; INDUCED CELL-DEATH; POSTMENOPAUSAL WOMEN; FOLLOW-UP; CLINICAL-TRIAL; PLUS PROGESTIN; RISK; MORTALITY AB Background - The Women's Health Initiative (WHI) Estrogen Alone trial assessed the balance of benefits and risks of hormone use in healthy postmenopausal women. The trial was stopped prematurely because there was no benefit for coronary heart disease and an increased risk of stroke. This report provides a thorough analysis of the stroke finding using the final results from the completed trial database. Methods and Results - The WHI Estrogen Alone hormone trial is a multicenter, double-blind, placebo-controlled, randomized clinical trial in 10 739 women aged 50 to 79 years who were given daily conjugated equine estrogen (CEE; 0.625 mg; n = 5310) or placebo (n = 5429). During an average follow-up of 7.1 years, there were 168 strokes in the CEE group and 127 in the placebo group; 80.3% of strokes were ischemic. For all stroke the intention-to-treat hazard ratio [HR] (95% CI) for CEE versus placebo was 1.37 (1.09 to 1.73). The HR (95% CI) was 1.55 (1.19 to 2.01) for ischemic stroke and 0.64 (0.35, 1.18) for hemorrhagic stroke. The HRs indicate excess risk of ischemic stroke was apparent in all categories of baseline stroke risk, including younger and more recently menopausal women and in women with prior or current use of statins or aspirin. Conclusions - CEE increases the risk of ischemic stroke in generally healthy postmenopausal women. The excess risk appeared to be present in all subgroups of women examined, including younger and more recently menopausal women. There was no convincing evidence to suggest that CEE had an effect on the risk of hemorrhagic stroke. C1 Wayne State Univ, Sch Med, Hutzel Womens Hosp, Dept Obstet & Gynecol, Detroit, MI 48201 USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. MedStar Res Inst, Washington, DC USA. Fred Hutchinson Canc Res Ctr, Seattle, WA USA. Natl Heat Lung & Blood Inst, Bethesda, MD USA. SUNY Buffalo, Buffalo, NY USA. Natl Inst Neurol, Disorders & Stroke Stroke Neurosci Unit, Bethesda, MD USA. Neuroepidemiol Branch, Bethesda, MD USA. Baylor Coll Med, Houston, TX 77030 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Calif San Diego, San Diego, CA 92103 USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. RP Hendrix, SL (reprint author), Wayne State Univ, Sch Med, Hutzel Womens Hosp, Dept Obstet & Gynecol, 3990 John R,7 Brush N, Detroit, MI 48201 USA. EM shendrix@med.wayne.edu NR 34 TC 181 Z9 185 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 23 PY 2006 VL 113 IS 20 BP 2425 EP 2434 DI 10.1161/CIRCULATIONAHA.105.594077 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 044YW UT WOS:000237710700012 PM 16702472 ER PT J AU Seidner, GA Ye, YH Faraday, MM Alvord, WG Fortini, ME AF Seidner, GA Ye, YH Faraday, MM Alvord, WG Fortini, ME TI Modeling clinically heterogeneous presenilin mutations with transgenic Drosophila SO CURRENT BIOLOGY LA English DT Article ID FAMILIAL ALZHEIMERS-DISEASE; AMYLOID PRECURSOR PROTEIN; NOTCH; GENE; POLYMORPHISM; ONSET AB To assess the potential of Drosophila to analyze clinically graded aspects of human disease, we developed a transgenic fly model to characterize Presenilin (PS) gene mutations that cause early-onset familial Alzheimer's disease (FAD). FAD exhibits a wide range in severity defined by ages of onset from 24 to 65 years [1]. PS FAD mutants have been analyzed in mammalian cell culture, but conflicting data emerged concerning correlations between age of onset and PS biochemical activity [2-4]. Choosing from over 130 FAD mutations in Presenilin-1, we introduced 14 corresponding mutations at conserved residues in Drosophila Presenilin (Psn) and assessed their biological activity in transgenic flies by using genetic, molecular, and statistical methods. Psn FAD mutant activities were tightly linked to their age-of-onset values, providing evidence that disease severity in humans primarily reflects differences in PS mutant lesions rather than contributions from unlinked genetic or environmental modifiers. Our study establishes a precedent for using transgenic Drosophila to study clinical heterogeneity in human disease. C1 NCI, Data Management Serv, NIH, Frederick, MD 21702 USA. Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM fortini@ncifcrf.gov FU NCI NIH HHS [N01-CO12400]; NIA NIH HHS [AG14583] NR 26 TC 28 Z9 28 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD MAY 23 PY 2006 VL 16 IS 10 BP 1026 EP 1033 DI 10.1016/j.cub.2006.04.004 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 047JB UT WOS:000237874500031 PM 16713961 ER PT J AU Lesser, RP Theodore, WH AF Lesser, RP Theodore, WH TI If not pharmacology, maybe physics SO NEUROLOGY LA English DT Editorial Material ID VAGUS NERVE-STIMULATION; INTRACTABLE EPILEPSY; ELECTRICAL-STIMULATION; NEUROSTIMULATOR C1 Johns Hopkins Med Inst, Dept Neurol, Baltimore, MD 21287 USA. Johns Hopkins Med Inst, Dept Neurosurg, Baltimore, MD 21287 USA. Johns Hopkins Med Inst, Zanvyl Krieger Mind & Brain Inst, Baltimore, MD 21287 USA. NINDS, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. RP Lesser, RP (reprint author), Johns Hopkins Med Inst, Dept Neurol, 2-147 Meyer Bldg,600 N Wolfe St, Baltimore, MD 21287 USA. NR 14 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAY 23 PY 2006 VL 66 IS 10 BP 1468 EP 1469 DI 10.1212/01.wnl.0000221746.07489.21 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 044XM UT WOS:000237706900003 PM 16717203 ER PT J AU Jordan, IK AF Jordan, I. King TI Evolutionary tinkering with transposable elements SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID GENOME; SEQUENCES C1 NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Jordan, IK (reprint author), NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM jordan@ncbi.nlm.nih.gov NR 14 TC 17 Z9 19 U1 0 U2 2 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 MAY 23 PY 2006 VL 103 IS 21 BP 7941 EP 7942 DI 10.1073/pnas.0602656103 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 047BD UT WOS:000237853900002 PM 16705033 ER PT J AU Petrache, HI Zemb, T Belloni, L Parsegian, VA AF Petrache, Horia I. Zemb, Thomas Belloni, Luc Parsegian, V. Adrian TI Salt screening and specific ion adsorption determine neutral-lipid membrane interactions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE electrostatics; halides; ion binding; van der waals; hydration ID THERMAL-MECHANICAL FLUCTUATIONS; MOLECULAR-DYNAMICS SIMULATIONS; LECITHIN BILAYERS; X-RAY; PHOSPHATIDYLCHOLINE BILAYERS; MULTILAYER SYSTEMS; HYDRATION FORCES; FLUID MEMBRANES; LAMELLAR PHASES; DOUBLE-LAYER AB The simplest, single-component biological membrane challenges accepted models of macromolecular interactions: lipid lamellar phases swell when immersed in monovalent salt solutions. Moreover, typical of a Hofmeister series, Br salts swell multilayers more than Cl salts, offering an excellent opportunity to investigate long-standing questions of ionic specificity. In accord with earlier measurements of liposome mobilities in electric fields, we find an added electrostatic repulsion of membranes due to anion binding, with a much stronger Br binding compared with Cl. However, contrary to the expectation that electrostatic repulsion should vanish in high salinity, swelling of lipid multilayers is monotonic with increasing salt concentration for both Br and Cl salts. The apparent contradiction is resolved by recognizing that although the electrostatic repulsion is progressively screened by increasing salt concentration, so is the van der Waals (vdW) attraction. Negligible in low salt, weakening of vdW forces becomes significant by the time electrostatic forces vanish. The result is a smooth monotonic swelling curve with no apparent distinction between low and high salt concentration regimes. Furthermore, when compared with theoretical predictions, measured vdW forces decay much too slowly with added salt. However, by accounting for the recently measured salt deficit near lipid bilayers, the expected scaling with Debye screening length is recovered. The combination of ion-specific binding and nonspecific ionic screening of low-frequency fluctuations explains salt effects on lipid membrane interactions and, by extension, explains specific (Hofmeister) effects at macromolecular interfaces between low and high dielectric. C1 NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. CEA, Dept Rech Etat Condensee Atomes & Mol, Serv Chim Mol, Lab Interdisciplinaire Org Nanometr & Supramol, F-91191 Gif Sur Yvette, France. CEA, CNRS, Lab Claude Frejacques, Unite Rech Associee 331, F-91191 Gif Sur Yvette, France. RP Petrache, HI (reprint author), Indiana Univ, Dept Phys, 402 N Blackford St, Indianapolis, IN 46202 USA. EM hpetrach@iupui.edu RI ZEMB, Thomas/E-5958-2010 NR 45 TC 171 Z9 172 U1 12 U2 57 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 MAY 23 PY 2006 VL 103 IS 21 BP 7982 EP 7987 DI 10.1073/pnas.0509967103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 047BD UT WOS:000237853900011 PM 16702553 ER PT J AU Pangas, SA Choi, Y Ballow, DJ Zhao, YG Westphal, H Matzuk, MM Rajkovic, A AF Pangas, SA Choi, Y Ballow, DJ Zhao, YG Westphal, H Matzuk, MM Rajkovic, A TI Oogenesis requires germ cell-specific transcriptional regulators Sohlh1 and Lhx8 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE infertility; oocyte; ovary; reproduction; folliculogenesis ID LIM-HOMEOBOX GENE; CHOLINERGIC NEURONS; FOLLICLE FORMATION; FIG-ALPHA; EXPRESSION; DIFFERENTIATION; FOLLICULOGENESIS; FOREBRAIN; FERTILITY; MSY2 AB Mammalian oogenesis requires oocyte-specific transcriptional regulators. The full complement of oocyte-specific transcription factors is unknown. Here, we describe the finding that Sohlh1, a spermatogenesis and oogenesis basic helix-loop-helix transcription factor in females, is preferentially expressed in oocytes and required for oogenesis. Sohlh1 disruption perturbs follicular formation in part by causing down-regulation of two genes that are known to disrupt folliculogenesis: newborn ovary homeobox gene (Nobox) and factor in the germ-line alpha (Figla). In addition, we show that Lhx8 is downstream of Sohlh1 and critical in fertility. Thus, Sohlh1 and Lhx8 are two germ cell-specific, critical regulators of oogenesis. C1 Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. RP Rajkovic, A (reprint author), Baylor Coll Med, Dept Obstet & Gynecol, 1709 Dryden Rd,Suite 1100, Houston, TX 77030 USA. EM rajkovic@bcm.tmc.edu FU NICHD NIH HHS [5F32 HD46335-01A1, F32 HD046335, HD42500, HD44858, R01 HD042500, R01 HD044858] NR 22 TC 122 Z9 134 U1 1 U2 7 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 MAY 23 PY 2006 VL 103 IS 21 BP 8090 EP 8095 DI 10.1073/pnas.0601083103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 047BD UT WOS:000237853900029 PM 16690745 ER PT J AU Chen, Z Laurence, A Kanno, Y Pacher-Zavisin, M Zhu, BM Tato, C Yoshimura, A Hennighausen, L O'Shea, JJ AF Chen, Z Laurence, A Kanno, Y Pacher-Zavisin, M Zhu, BM Tato, C Yoshimura, A Hennighausen, L O'Shea, JJ TI Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE signal transducer and activator of transcription 3; T lymphocytes ID PHYSIOLOGICAL NEGATIVE REGULATOR; COLONY-STIMULATING FACTOR; CYTOKINE SIGNALING SOCS; TYROSINE PHOSPHORYLATION; INTERLEUKIN-17 FAMILY; HELPER TYPE-1; BOX MOTIF; IN-VIVO; EXPRESSION; GENE AB Suppressor of cytokine signaling (Socs) 3 is a cytokine-inducible inhibitor with critical but selective cell-specific effects. We show that deficiency of Socs3 in T cells had minimal effects on differentiation of T cells to the T helper (Th) 1 or Th2 subsets; accordingly, Socs3 had no effect on IL-12-dependent signal transducer and activator of transcription (Stat) 4 phosphorylation or IL-4-dependent Stat6 phosphorylation. By contrast, Socs3 was found to be a major regulator of IL-23-mediated Stat3 phosphorylation and Th17 generation, and Stat3 directly binds to the IL-17A and IL-17F promoters. We conclude that Socs3 is an essential negative regulator of IL-23 signaling, inhibition of which constrains the generation of Th17 differentiation. C1 NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. Kyushu Univ, Div Mol & Cellular Immunol, Med Inst Bioregulat, Fukuoka 8128582, Japan. RP Laurence, A (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bldg 10,Room 9N262,10 Ctr Dr,MSC-1820, Bethesda, MD 20892 USA. EM laurencea@mail.nih.gov RI Laurence, Arian/A-8770-2009; Kanno, Yuka/B-5802-2013; Yoshimura, Akihiko/K-5515-2013; OI Laurence, Arian/0000-0003-0942-8292; Kanno, Yuka/0000-0001-5668-9319 NR 60 TC 374 Z9 411 U1 0 U2 10 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 MAY 23 PY 2006 VL 103 IS 21 BP 8137 EP 8142 DI 10.1073/pnas.0600666103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 047BD UT WOS:000237853900037 PM 16698929 ER PT J AU Sohn, HW Tolar, P Jin, T Pierce, SK AF Sohn, HW Tolar, P Jin, T Pierce, SK TI Fluorescence resonance energy transfer in living cells reveals dynamic membrane changes in the initiation of B cell signaling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE B cell receptor; lipid rafts; initiation of signaling; CD19/CD21 coreceptor complex; Lyn-based reporter ID LIPID RAFTS; ANTIGEN RECEPTOR; LIVE CELLS; FRET; ORGANIZATION; ACTIVATION; PROTEINS; SYNAPSE AB B cell responses are initiated by the clustering of the B cell receptor (BCR) by the binding of multivalent antigens. Clustering leads to phosphorylation of tyrosines in the cytoplasmic domains of the BCR by the inner plasma membrane leaf let-associated Src-family kinase Lyn. At present, little is known about the earliest events after BCR clustering that precede the BCR's phosphorylation by Lyn. Here we use fluorescence resonance energy transfer (FRET) in living cells to detect the interaction of the BCR with a Lyn-based membrane-targeted reporter in the first several seconds after BCR clustering. The results showed that, within seconds of antigen binding, the BCR selectively and transiently associated with the Lyn construct and that this association preceded by several seconds the triggering of Ca2+ fluxes and could be prolonged by the engagement of the B cell coreceptor complex, CD19/CD21. Thus, FRET measurements in living B cells revealed highly dynamic and regulated antigen-induced changes in the plasma membrane, allowing association of the BCR with the earliest components of its signaling cascade. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Pierce, SK (reprint author), NIAID, Immunogenet Lab, NIH, Twinbrook 2,12441 Parklawn Dr,Room 200B,MSC 8180, Rockville, MD 20852 USA. EM spierce@niaid.nih.gov FU Intramural NIH HHS NR 29 TC 67 Z9 70 U1 0 U2 5 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 MAY 23 PY 2006 VL 103 IS 21 BP 8143 EP 8148 DI 10.1073/pnas.0509858103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 047BD UT WOS:000237853900038 PM 16690746 ER PT J AU Yin, HH Lovinger, DM AF Yin, HH Lovinger, DM TI Frequency-specific and D-2 receptor-mediated inhibition of glutamate release by retrograde endocannabinoid signaling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE anandamide; cannabinoid; dopamine ID LONG-TERM DEPRESSION; EXCITATORY SYNAPTIC TRANSMISSION; RAT CAUDATE-PUTAMEN; STRIATAL NEURONS; BASAL GANGLIA; CORTICOSTRIATAL TERMINALS; CHOLINERGIC INTERNEURONS; CANNABINOID RECEPTORS; CALCIUM-CHANNELS; DORSAL STRIATUM AB The mechanisms underlying modulation of corticostriatal synaptic transmission by D-2-like receptors (D(2)Rs) have been controversial. A recent study suggested that D(2)Rs inhibit glutamate release at this synapse, but only during high-frequency synaptic activation. Because the release of postsynaptic endocannabinoids (eCBs), which act as retrograde messengers to inhibit presynaptic glutamate release, can be triggered by D2R activation and intense synaptic activation, such a mechanism could mediate dopaminergic modulation of corticostriatal transmission. Here, we show that D2R activation reduces excitatory transmission onto striatal medium spiny neurons at a stimulation frequency of 20 Hz but not at 1 Hz. This form of inhibition requires CB1 receptor activation, as evidenced by the fact that it is blocked by AM251 [N-(piperidin-1-yl)1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide], a CB1 antagonist, and is absent in CB1 knockout mice. It is also blocked by postsynaptic intracellular calcium chelation, by group I metabotropic glutamate receptor antagonism, and by inhibition of postsynaptic phospholipase C. These results demonstrate a previously unrecognized role for retrograde eCB signaling in reversible and frequency-specific inhibition of glutamate release by the activation of striatal D(2)Rs. C1 NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. RP Lovinger, DM (reprint author), NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, NIH, 5625 Fishers Lane,TS-13, Bethesda, MD 20892 USA. EM lovindav@mail.nih.gov FU Intramural NIH HHS NR 47 TC 98 Z9 101 U1 0 U2 3 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 MAY 23 PY 2006 VL 103 IS 21 BP 8251 EP 8256 DI 10.1073/pnas.0510797103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 047BD UT WOS:000237853900056 PM 16698932 ER PT J AU do Nascimento, GC de Melo, CP Souto-Maior, R AF do Nascimento, GC de Melo, CP Souto-Maior, R TI Sensors of volatile compounds based on the dielectric relaxation of organic molecules SO SENSORS AND ACTUATORS B-CHEMICAL LA English DT Article DE gas sensors; chemical sensors; dielectric sensors; electronic nose ID SPECTROSCOPY; POLYPYRROLE; POLYMERS AB Organic molecules can have their dielectric relaxation characteristics altered by their exposition to volatile substances and when immobilized in a porous silica substrate, they exhibit a very large number of active sites available for interaction with molecules of volatile organic compounds (VOCs). Here, we propose to exploit these properties for the development of chemical sensors by showing that the changes in the total capacitance of the system resulting from the adsorption of the VOCs can be unequivocally associated to the nature of the compound tested, so that the overall characteristics of any one of sensors constructed in this manner can be closely related to the corresponding molecules that were immobilized. Considering the stability of the electrical response of the system, its sensitivity towards different volatile compounds and the simplicity of the procedure for immobilizing molecules, this technique appears a promising manner of manufacturing devices that could be used in the development of competitive chemical sensors. (c) 2005 Elsevier B.V. All rights reserved. C1 Univ Fed Pernambuco, Dept Fis, BR-50670901 Recife, PE, Brazil. NIH, Bethesda, MD 20892 USA. Univ Fed Pernambuco, Dept Quim Fundamental, BR-50670901 Recife, PE, Brazil. RP de Melo, CP (reprint author), Univ Fed Pernambuco, Dept Fis, BR-50670901 Recife, PE, Brazil. EM celso@df.ufpe.br NR 14 TC 2 Z9 2 U1 3 U2 4 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 MAY 23 PY 2006 VL 115 IS 1 BP 542 EP 546 DI 10.1016/j.snb.2005.10.020 PG 5 WC Chemistry, Analytical; Electrochemistry; Instruments & Instrumentation SC Chemistry; Electrochemistry; Instruments & Instrumentation GA 034KY UT WOS:000236929100077 ER PT J AU Levy, D DePalma, SR Benjamin, EJ O'Donnell, CJ Parise, H Hirschhorn, JN Vasan, RS Izumo, S Larson, MG AF Levy, Daniel DePalma, Steven R. Benjamin, Emelia J. O'Donnell, Christopher J. Parise, Helen Hirschhorn, Joel N. Vasan, Ramachandran S. Izumo, Seigo Larson, Martin G. TI Phenotype-genotype association grid: a convenient method for summarizing multiple association analyses SO BMC GENETICS LA English DT Article ID HAPLOTYPE BLOCKS; HUMAN GENOME; MAP AB Background: High-throughput genotyping generates vast amounts of data for analysis; results can be difficult to summarize succinctly. A single project may involve genotyping many genes with multiple variants per gene and analyzing each variant in relation to numerous phenotypes, using several genetic models and population subgroups. Hundreds of statistical tests may be performed for a single SNP, thereby complicating interpretation of results and inhibiting identification of patterns of association. Results: To facilitate visual display and summary of large numbers of association tests of genetic loci with multiple phenotypes, we developed a Phenotype-Genotype Association ( PGA) grid display. A database-backed web server was used to create PGA grids from phenotypic and genotypic data ( sample sizes, means and standard errors, P-value for association). HTML pages were generated using Tcl scripts on an AOLserver platform, using an Oracle database, and the ArsDigita Community System web toolkit. The grids are interactive and permit display of summary data for individual cells by a mouse click (i.e. least squares means for a given SNP and phenotype, specified genetic model and study sample). PGA grids can be used to visually summarize results of individual SNP associations, gene-environment associations, or haplotype associations. Conclusion: The PGA grid, which permits interactive exploration of large numbers of association test results, can serve as an easily adapted common and useful display format for large-scale genetic studies. Doing so would reduce the problem of publication bias, and would simplify the task of summarizing large-scale association studies. C1 NHLBI, Bethesda, MD 20892 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. Boston Univ, Sch Med, Div Cardiol, Boston, MA 02215 USA. Boston Univ, Sch Med, Dept Prevent Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Howard Hughes Med Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Boston Univ, Dept Math & Stat, Boston, MA USA. Childrens Hosp, Div Genet, Boston, MA 02115 USA. Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. Harvard Univ, Broad Ctr, Cambridge, MA USA. MIT, Cambridge, MA USA. Novartis Res Inst, Cambridge, MA USA. RP Levy, D (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM levyd@nih.gov; depalma@receptor.med.harvard.edu; Emelia@bu.edu; codonnell@nih.gov; hparise@bu.edu; joelh@broad.mit.edu; vasan@bu.edu; seigoizumo@bidmc.harvard.edu; mlarson@bu.edu FU NHLBI NIH HHS [N01HC25195, N01-HC-25195] NR 6 TC 5 Z9 5 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD MAY 22 PY 2006 VL 7 AR 30 DI 10.1186/1471-2156/7/30 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 071WR UT WOS:000239635100001 PM 16716207 ER PT J AU Yeow, WS Ziauddin, MF Maxhimer, JB Shamimi-Noori, S Baras, A Chua, A Schrump, DS Nguyen, DM AF Yeow, W. -S. Ziauddin, M. F. Maxhimer, J. B. Shamimi-Noori, S. Baras, A. Chua, A. Schrump, D. S. Nguyen, D. M. TI Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01 SO BRITISH JOURNAL OF CANCER LA English DT Article DE histone deacetylase inhibitor; valproic acid; UCN-01; Staurosporine; protein kinase C; Parthenolide; NF-kappa B; apoptosis ID HUMAN LEUKEMIA-CELLS; SUBEROYLANILIDE HYDROXAMIC ACID; NF-KAPPA-B; SYNERGISTICALLY INDUCES APOPTOSIS; ESOPHAGEAL CANCER-CELLS; SIGNALING PATHWAY; SODIUM-BUTYRATE; SESQUITERPENE LACTONE; MEDIATED APOPTOSIS; LUNG-CANCER AB Histone deacetylase inhibitors (HDACIs) are novel anticancer agents with potent cytotoxicity against a wide range of malignancies. We have previously demonstrated that either Calphostin C (CC) (a protein kinase C (PKC) inhibitor) or Parthenolide (an NF-kappa B inhibitor) abrogates HDACI-induced transcriptional activation of NF-kappa B and p21, which is associated with profound potentiation of HDACI-mediated induction of apoptosis. Valproic acid (VA), a commonly used antiepileptic agent, has recently been shown to be an HDACI. This study was aimed to evaluate the anticancer property of VA in thoracic cancer cells and the development of clinically relevant strategies to enhance VA-mediated induction of apoptosis using kinase inhibitors Staurosporine (STP) or its analogue UCN-01. Treating cultured thoracic cancer cells with VA (0.62 - 10.0 mM) resulted in significant cell line- and dose- dependent growth inhibition (IC50 values: 4.1 - 6.0 mM) and cell cycle arrest at G1/S checkpoint with profound accumulation of cells at G0/G1 phase but little induction of apoptosis. Valproic acid, being an HDACI, caused significant dose- dependent accumulation of hyperacetylated histones, following 24 h of treatment. Valproic acid-mediated 5-20-fold upregulation of transcriptional activity of NF-kappa B was substantially (50 - 90%) suppressed by cotreatment with CC, STP or UCN-01. Whereas minimal death (< 20%) was observed in cells treated with either VA (1.0 or 5.0 mM) alone or kinase inhibitors alone, 60 - 90% of cells underwent apoptosis following exposure to combinations of VA + kinase inhibitors. Kinase inhibitor-mediated suppression of NF-kappa B transcriptional activity played an important role in sensitising cancer cells to VA as direct inhibition of NF-kappa B by Parthenolide drastically synergised with VA to induce apoptosis (VA + Parthenolide: 60 - 90% compared to < 20% following single-drug treatments). In conclusion, VA, a well-known antiepileptic drug, has mild growth-inhibitory activity on cultured cancer cells. The weak VA-mediated induction of apoptosis of thoracic cancer cells can be profoundly enhanced either by Parthenolide, a pharmacologic inhibitor of NF-kappa B, or by UCN-01 a kinase inhibitor that has already undergone phase I clinical development. Combinations of VA with either a PKC inhibitor or an NF-kappa B inhibitor are promising novel molecularly targeted therapeutics for thoracic cancers. C1 NCI, Ctr Canc Res, Sect Thorac Oncol, Surg Branch,NIH, Bethesda, MD 20892 USA. RP Nguyen, DM (reprint author), NCI, Ctr Canc Res, Sect Thorac Oncol, Surg Branch,NIH, Room 4W-4-3940,10 Ctr Dr, Bethesda, MD 20892 USA. EM Dao_Nguyen@nih.gov FU Intramural NIH HHS NR 44 TC 33 Z9 33 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD MAY 22 PY 2006 VL 94 IS 10 BP 1436 EP 1445 DI 10.1038/sj.bjc.663132 PG 10 WC Oncology SC Oncology GA 044BX UT WOS:000237648200013 PM 16705314 ER PT J AU Kim, PK Mullen, RT Schumann, U Lippincott-Schwartz, J AF Kim, PK Mullen, RT Schumann, U Lippincott-Schwartz, J TI The origin and maintenance of mammalian peroxisomes involves a de novo PEX16-dependent pathway from the ER SO JOURNAL OF CELL BIOLOGY LA English DT Article ID SIGNAL RECOGNITION PARTICLE; ENDOPLASMIC-RETICULUM; YARROWIA-LIPOLYTICA; FLUORESCENT PROTEIN; MEMBRANE-PROTEINS; BIOGENESIS; TOPOGENESIS; INTEGRATION; SUBDOMAIN; MECHANISM AB Peroxisomes are ubiquitous organelles that proliferate under different physiological conditions and can form de novo in cells that lack them. The endoplasmic reticulum ( ER) has been shown to be the source of peroxisomes in yeast and plant cells. It remains unclear, however, whether the ER has a similar role in mammalian cells and whether peroxisome division or outgrowth from the ER maintains peroxisomes in growing cells. We use a new in cellula pulse-chase imaging protocol with photoactivatable GFP to investigate the mechanism underlying the biogenesis of mammalian peroxisomes. We provide direct evidence that peroxisomes can arise de novo from the ER in both normal and peroxisome-less mutant cells. We further show that PEX16 regulates this process by being cotranslationally inserted into the ER and serving to recruit other peroxisomal membrane proteins to membranes. Finally, we demonstrate that the increase in peroxisome number in growing wild-type cells results primarily from new peroxisomes derived from the ER rather than by division of preexisting peroxisomes. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Univ Guelph, Dept Cellular & Mol Biol, Guelph, ON N1G 2W1, Canada. RP Lippincott-Schwartz, J (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM jlippin@helix.nih.gov NR 40 TC 168 Z9 171 U1 1 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD MAY 22 PY 2006 VL 173 IS 4 BP 521 EP 532 DI 10.1083/jcb.200601036 PG 12 WC Cell Biology SC Cell Biology GA 044ZI UT WOS:000237712000008 PM 16717127 ER PT J AU Vanita, V Singh, JR Hejtmancik, JF Nurnberg, P Hennies, HC Singh, D Sperling, K AF Vanita, V Singh, JR Hejtmancik, JF Nurnberg, P Hennies, HC Singh, D Sperling, K TI A novel fan-shaped cataract-microcornea syndrome caused by a mutation of CRYAA in an Indian family SO MOLECULAR VISION LA English DT Article ID CONGENITAL CATARACT; ALPHA-A; HEREDITARY CATARACTS; KNOBLOCH-SYNDROME; GENE; LINKAGE; DOMAIN; MYOPIA AB PURPOSE: The molecular characterization of an Indian family having 10 members in four generations affected with a unique fan-shaped cataract-microcornea syndrome. METHODS: Detailed family history and clinical data were recorded. A genome-wide screening by two-point linkage analysis using more than 400 microsatellite markers in combination with multipoint lod score and haplotype analysis was carried out. Mutation screening was performed in the candidate gene by bi-directional sequencing of amplified products. RESULTS: The cataract-microcornea locus in this family was mapped to a 23.5 cM region on chromosome 21q22.3. Direct sequencing of the candidate gene CRYAA revealed a heterozygous C > T transition resulting in the substitution of the highly conserved arginine at position 116 by cysteine (R116C). CONCLUSIONS: This study provides the report of mapping a locus for syndromal cataract (cataract-microcornea syndrome) on 21q22.3. The mutation observed in CRYAA in the present family highlights the phenotypic heterogeneity of the disorder in relation to the genotype, as an identical mutation has previously been reported in an American family with a different type of cataract. The "fan-shaped cataract" observed in the present family has not been reported before. C1 Guru Nanak Dev Univ, Ctr Genet Disorders, Amritsar 143005, Punjab, India. NEI, NIH, Bethesda, MD 20892 USA. Univ Cologne, Cologne Ctr Genom, Cologne, Germany. Univ Cologne, Inst Genet, Cologne, Germany. Max Delbruck Ctr Mol Med, Gene Mapping Ctr, Berlin, Germany. Dr Daljit Singh Eye Hosp, Amritsar, Punjab, India. Humboldt Univ, Inst Human Genet, Berlin, Germany. RP Vanita, V (reprint author), Guru Nanak Dev Univ, Ctr Genet Disorders, Amritsar 143005, Punjab, India. EM vanita_kumar@yahoo.com NR 28 TC 39 Z9 41 U1 0 U2 0 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD MAY 22 PY 2006 VL 12 IS 60-62 BP 518 EP 522 PG 5 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 048HW UT WOS:000237939200002 PM 16735993 ER PT J AU Egan, MA Megati, S Roopchand, V Garcia-Hand, D Luckay, A Chong, SY Rosati, M Sackitey, S Weiner, DB Felber, BK Pavlakis, GN Israel, ZR Eldridge, JH Sidhu, MK AF Egan, MA Megati, S Roopchand, V Garcia-Hand, D Luckay, A Chong, SY Rosati, M Sackitey, S Weiner, DB Felber, BK Pavlakis, GN Israel, ZR Eldridge, JH Sidhu, MK TI Rational design of a plasmid DNA vaccine capable of eliciting cell-mediated immune responses to multiple HIV antigens in mice SO VACCINE LA English DT Article DE plasmid DNA vaccine; triple promoter plasmid; HIV-1; mice ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD8 T-CELLS; REVERSE-TRANSCRIPTASE; RHESUS-MONKEYS; GAG; EXPRESSION; INFECTION; PROTEIN; IMMUNIZATION; MUTAGENESIS AB Given the importance of the HIV-specific cell-mediated immune response in the early control and resolution of HIV infection and the observed correlation between pre-challenge vaccine elicited CTL responses and post challenge outcome in SHIV/rhesus macaque experiments, we sought to identify several candidate plasmid DNA (pDNA) vaccine designs capable of eliciting robust and balanced cell-mediated immune responses to multiple HIV-1 derived antigens in mice for further vaccine development. To rationally construct candidate vaccines for immunogenicity testing, we determined the relative immunogenicity of the individual HIV-derived vaccine antigens (env, gag, pol, nef, tat and vif) and the relative strength of various transcriptional control elements (HCMV, SCMV, HSV Lap1) in Balb/c mice. Next, a number of 1-, 2-, 3- and 4-vector pDNA vaccine designs were tested for their ability to elicit HIV-1 antigen-specific CMI responses. For these studies, Balb/c mice were immunized with a fixed total pDNA vaccine dose of 100mcg in combination with 25 mcg plasmid-based murine IL-12 and tested for the induction of HIV-1 antigen-specific CMI responses by IFN-gamma ELISpot analysis. The results of this study indicate that all pDNA vaccine designs were capable of eliciting CMI responses to multiple HIV-1 antigens. As a result of this iterative comparative analysis, we have identified a number of pDNA vaccine candidates capable of eliciting potent, balanced CMI responses to multiple HIV-1 derived antigens. These results have important implications for the design and development of an efficacious vaccine for the prevention of HIV-1 infection. (c) 2005 Elsevier Ltd. All rights reserved. C1 Vaccine Discovery, Wyeth Vaccine Res, Pearl River, NY 10965 USA. NCI, Basic Res Labs, Human Retrovirus Sect, Ft Detrick, MD 21702 USA. Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Sidhu, MK (reprint author), Vaccine Discovery, Wyeth Vaccine Res, 401 N Middletown Rd,Bldg 180-216-10, Pearl River, NY 10965 USA. EM sidhum@wyeth.com RI Weiner, David/H-8579-2014 FU NIAID NIH HHS [N01-AI-05397] NR 40 TC 22 Z9 23 U1 0 U2 1 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 MAY 22 PY 2006 VL 24 IS 21 BP 4510 EP 4523 DI 10.1016/j.vaccine.2005.08.024 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 056JI UT WOS:000238518400010 PM 16140439 ER PT J AU Schadeck, EB Sidhu, M Egan, MA Chong, SY Piacente, P Masood, A Garcia-Hand, D Cappello, S Roopchand, V Megati, S Quiroz, J Boyer, JD Felber, BK Pavlakis, GN Weiner, DB Eldridge, JH Israel, ZR AF Schadeck, EB Sidhu, M Egan, MA Chong, SY Piacente, P Masood, A Garcia-Hand, D Cappello, S Roopchand, V Megati, S Quiroz, J Boyer, JD Felber, BK Pavlakis, GN Weiner, DB Eldridge, JH Israel, ZR TI A dose sparing effect by plasmid encoded IL-12 adjuvant on a SlVgag-plasmid DNA vaccine in rhesus macaques SO VACCINE LA English DT Article DE AIDS; vaccination; cytokines; adjuvant ID CELLULAR IMMUNE-RESPONSES; HIV-1-INFECTED PATIENTS; INTERLEUKIN-12 IL-12; NITRIC-OXIDE; ANTIGEN; EXPRESSION; INDUCTION; MALARIA; SAFETY; HIV-1 AB An experimental pDNA vaccine adjuvant expressing IL-12 was evaluated for its ability to augment the humoral and cellular immune responses elicited by a SIVmac239 gag p39 expressing pDNA vaccine. To determine the effect of vaccine dose on the immune response, rhesus macaques were immunized with 1.5 mg or 5.0 mg of SIVmac239 gag pDNA, with or without co-immunization of IL-12 pDNA at 1.5 mg and 5.0 mg, respectively. Serum antibody responses to simian immunodeficiency virus (SIV) gag were increased 10-fold (p = 0.044, 0.002) in macaques receiving IL-12 pDNA. Cellular immune responses, monitored by SIV gag-specific IFN-gamma ELISpot assay, were also significantly higher (p = 0.007 0.019) when the pDNA vaccine was co-immunized with IL-12 pDNA at high and low doses. There was no statistical difference between the immune responses elicited by the high and low dose of IL-12 pDNA (p=0.221, 0.917), a finding which could allow a dose reduction of vaccine without the concomitant loss of imunogenicity. Furthermore, analysis of the breadth of the T-cell response during the vaccination schedule, using overlapping peptides to SIV gag, demonstrated a significant correlation (p = 0.0002) between the magnitude and breadth of the immune responses in the vaccines. These results have important implications for the continuing development of an effective, safe low dose pDNA vaccine adjuvant suitable for human use. (c) 2005 Elsevier Ltd. All rights reserved. C1 Wyeth Vaccines Res, Pearl River, NY 10965 USA. Wyeth Res, Pearl River, NY 10965 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. NCI, Basic Res Lab, Human Retrovirus Sect, Frederick, MD 21702 USA. RP Israel, ZR (reprint author), Wyeth Vaccines Res, 401 N,Middletown Rd,Bldg 180-258-12, Pearl River, NY 10965 USA. EM israelz@wyeth.com RI Weiner, David/H-8579-2014 FU NIAID NIH HHS [N01-AI-05397] NR 41 TC 55 Z9 57 U1 0 U2 0 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 MAY 22 PY 2006 VL 24 IS 21 BP 4677 EP 4687 DI 10.1016/j.vaccine.2005.10.035 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 056JI UT WOS:000238518400041 PM 16288822 ER PT J AU Paravastu, AK Tycko, R AF Paravastu, AK Tycko, R TI Frequency-selective homonuclear dipolar recoupling in solid state NMR SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID ANGLE-SPINNING NMR; NUCLEAR-MAGNETIC-RESONANCE; CHEMICAL-SHIFT ANISOTROPIES; TILTED ROTATING-FRAME; BETA-AMYLOID PEPTIDE; CORRELATION SPECTROSCOPY; DISTANCE MEASUREMENTS; POLARIZATION TRANSFER; STRUCTURAL MODEL; PULSE SEQUENCES AB We introduce a new approach to frequency-selective homonuclear dipolar recoupling in solid state nuclear magnetic resonance (NMR) with magic-angle spinning (MAS). This approach, to which we give the acronym SEASHORE, employs alternating periods of double-quantum recoupling and chemical shift evolution to produce phase modulations of the recoupled dipole-dipole interactions that average out undesired couplings, leaving only dipole-dipole couplings between nuclear spins with a selected pair of NMR frequencies. In principle, SEASHORE is applicable to systems with arbitrary coupling strengths and arbitrary sets of NMR frequencies. Arbitrary MAS frequencies are also possible, subject only to restrictions imposed by the pulse sequence chosen for double-quantum recoupling. We demonstrate the efficacy of SEASHORE in experimental C-13 NMR measurements of frequency-selective polarization transfer in uniformly N-15, C-13-labeled L-valine powder and frequency-selective intermolecular polarization transfer in amyloid fibrils formed by a synthetic decapeptide containing uniformly N-15, C-13-labeled residues. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU Intramural NIH HHS; NIDDK NIH HHS [Z01 DK029029-09] NR 59 TC 36 Z9 36 U1 2 U2 8 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD MAY 21 PY 2006 VL 124 IS 19 AR 194303 DI 10.1063/1.2192516 PG 8 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 044OY UT WOS:000237683200015 PM 16729810 ER PT J AU Hopenfeld, B AF Hopenfeld, B TI A mathematical analysis of the action potential plateau duration of a human ventricular myocyte SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE myocyte; action potential duration; computer model; repolarization ID TRANSIENT OUTWARD CURRENT; LOCAL-CONTROL; CA2+ RELEASE; CALCIUM; MODEL; HETEROGENEITY; INACTIVATION; MUSCLE; I(KS) AB The plateau phase of a human ventricular myocyte is analysed. The plateau duration is a function of the time required for a myocyte's transmembrane voltage to decrease by a certain voltage, Delta V. The timing of the plateau is shown to be controlled by two slowly changing gate variables, the inactivation gate that controls the inward/depolarizing L-type calcium current and the inactivation gate that controls the outward/repolarizing slow rectifier potassium current. The amount of current controlled by these variables is a function of the net conductivity of the corresponding sodium and potassium channels. An equation is derived that relates action potential duration to these net conductivities and the time dependence of the slowly moving variables. This equation is used to estimate plateau duration for a given value of Delta V. The initial conditions of the slowly moving inactivation variables are shown to affect plateau duration. These initial conditions depend on the amount of time that has elapsed between a previous repolarization and a current depolarization (diastolic interval). The analysis thus helps to quantify the characteristics of action potential duration restitution. (c) 2005 Elsevier Ltd. All rights reserved. C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Hopenfeld, B (reprint author), NHLBI, NIH, 10 Ctr Dr,MSC 1061, Bethesda, MD 20892 USA. EM hopenfeldb@mail.nih.gov FU Intramural NIH HHS NR 19 TC 3 Z9 3 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 J9 J THEOR BIOL JI J. Theor. Biol. PD MAY 21 PY 2006 VL 240 IS 2 BP 311 EP 322 DI 10.1016/j.jtbi.2005.09.021 PG 12 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 046RH UT WOS:000237828200015 PM 16303142 ER PT J AU Hu, KF Vogeli, B Clore, GM AF Hu, KF Vogeli, B Clore, GM TI Interference between transverse cross-correlated relaxation and longitudinal relaxation affects apparent J-coupling and transverse cross-correlated relaxation SO CHEMICAL PHYSICS LETTERS LA English DT Article ID HUMAN UBIQUITIN; PROTON; DEPENDENCE; CONSTANTS; NITROGEN; PROTEIN AB The apparent value of the measured J-coupling is affected by transverse cross-correlated relaxation between dipolar interaction and chemical shift anisotropy. This effect counteracts the decrease in the apparent value of J resulting from self-decoupling caused by longitudinal relaxation, thereby bringing the measured J-coupling closer to its true value. In addition to the dynamic frequency shift and self-decoupling, interference between transverse cross-correlated and longitudinal relaxation processes may serve as a complementary explanation for the deviation between the measured and true J-couplings for small size scalar couplings. The apparent cross-correlated relaxation rate between coupled spins may also be affected by this interference. Published by Elsevier B.V. C1 NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Phys Chem Lab, NIH, Bldg 5,Rm B1-301,900 Rockville Pike, Bethesda, MD 20892 USA. EM mariusc@intra.niddk.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 10 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-2614 J9 CHEM PHYS LETT JI Chem. Phys. Lett. PD MAY 20 PY 2006 VL 423 IS 1-3 BP 123 EP 125 DI 10.1016/j.cplett.2006.03.051 PG 3 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 044RJ UT WOS:000237689700025 ER PT J AU Beck, KE Blansfield, JA Tran, KQ Feldman, AL Hughes, MS Royal, RE Kammula, US Topalian, SL Sherry, RM Kleiner, D Quezado, M Lowy, I Yellin, M Rosenberg, SA Yang, JC AF Beck, KE Blansfield, JA Tran, KQ Feldman, AL Hughes, MS Royal, RE Kammula, US Topalian, SL Sherry, RM Kleiner, D Quezado, M Lowy, I Yellin, M Rosenberg, SA Yang, JC TI Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID VERSUS-HOST-DISEASE; CTLA-4 BLOCKADE; METASTATIC MELANOMA; CROHNS-DISEASE; AUTOIMMUNITY; CELLS; REGRESSION; GENE; POLYENDOCRINOPATHY; TRANSPLANTATION AB Purpose Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) is an inhibitory receptor on T cells. Knocking out CTLA4 in mice causes lethal lymphoproliferation, and polymorphisms in human CTLA4 are associated with autoimmune disease. Trials of the anti-CTLA4 antibody ipilimumab (MDX-010) have resulted in durable cancer regression and immune-mediated toxicities. A report on the diagnosis, pathology, treatment, clinical outcome, and significance of the immune-mediated enterocolitis seen with ipilimumab is presented. Patients and Methods We treated 198 patients with metastatic melanoma (MM) or renal cell carcinoma (RCC) with ipilimumab. Results The overall objective tumor response rate was 14%. We observed several immune mediated toxicities including dermatitis, enterocolitis, hypophysitis, uveitis, hepatitis, and nephritis. Enterocolitis, defined by grade 3/4 clinical presentation and/or biopsy documentation, was the most common major toxicity (21% of patients). It presented with diarrhea, and biopsies showed both neutrophilic and lymphocytic inflammation. Most patients who developed enterocolitis responded to high-dose systemic corticosteroids. There was no evidence that steroid administration affected tumor responses. Five patients developed perforation or required colectomy. Four other patients with steroid-refractory enterocolitis appeared to respond promptly to tumor necrosis factor alpha blockade with infliximab. Objective tumor response rates in patients with enterocolitis were 36% for MM and 35% for RCC, compared with 11% and 2% in patients without enterocolitis, respectively (P =.0065 for MM and P =.0016 for RCC). Conclusion CTLA4 seems to be a significant component of tolerance to tumor and in protection against immune mediated enterocolitis and these phenomena are significantly associated in cancer patients. C1 NCI, Surg Branch, NIH, CRC, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Medarex Inc, Princeton, NJ USA. RP Yang, JC (reprint author), NCI, Surg Branch, NIH, CRC, Room 3W,10 Ctr Dr, Bethesda, MD 20892 USA. EM James_Yang@nih.gov RI Feldman, Andrew/D-5028-2012; OI Kleiner, David/0000-0003-3442-4453 FU Intramural NIH HHS [Z01 SC003811-32] NR 30 TC 347 Z9 354 U1 0 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2006 VL 24 IS 15 BP 2283 EP 2289 DI 10.1200/JCO.2005.04.5716 PG 7 WC Oncology SC Oncology GA 046RK UT WOS:000237828500012 PM 16710025 ER PT J AU Diamond, JS AF Diamond, JS TI Astrocytes put down the broom and pick up the baton SO CELL LA English DT Editorial Material ID D-SERINE; NEURONS; GLYCINE; RELEASE AB In this issue of Cell, Panatier et al. (2006) show that D-serine released by astrocytes, a type of glial cell in the brain, promotes NMDA receptor activity at synapses in the hypothalamus. These results confirm that glial cells participate in synaptic signaling and show that they can dictate the tenor of synaptic plasticity. C1 NINDS, NIH, Bethesda, MD 20892 USA. RP Diamond, JS (reprint author), NINDS, NIH, Bethesda, MD 20892 USA. EM diamondj@ninds.nih.gov RI Diamond, Jeffrey/C-1835-2015 OI Diamond, Jeffrey/0000-0002-1770-2629 NR 9 TC 5 Z9 5 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD MAY 19 PY 2006 VL 125 IS 4 BP 639 EP 641 DI 10.1016/j.cell.2006.05.006 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 047NM UT WOS:000237886000006 PM 16713554 ER PT J AU Knight, ZA Gonzalez, B Feldman, ME Zunder, ER Goldenberg, DD Williams, O Loewith, R Stokoe, D Balla, A Toth, B Balla, T Weiss, WA Williams, RL Shokat, KM AF Knight, Zachary A. Gonzalez, Beatriz Feldman, Morri E. Zunder, Eli R. Goldenberg, David D. Williams, Olusegun Loewith, Robbie Stokoe, David Balla, Andras Toth, Balazs Balla, Tamas Weiss, William A. Williams, Roger L. Shokat, Kevan M. TI A pharmacological map of the PI3-K family defines a role for p110 alpha in insulin signaling SO CELL LA English DT Article ID PHOSPHOINOSITIDE 3-KINASE INHIBITORS; DEPENDENT PROTEIN-KINASE; P85 REGULATORY SUBUNIT; CATALYTIC SUBUNIT; EMBRYONIC LETHALITY; TYROSINE KINASE; MICE; ACTIVATION; ATM; INSIGHTS AB Phosphoinositide 3-kinases (PI3-Ks) are an important emerging class of drug targets, but the unique roles of PI3-K isoforms remain poorly defined. We describe here an approach to pharmacologically interrogate the PI3-K family. A chemically diverse panel of PI3-K inhibitors was synthesized, and their target selectivity was biochemically enumerated, revealing cryptic homologies across targets and chemotypes. Crystal structures of three inhibitors bound to p110 gamma identify a conformationally mobile region that is uniquely exploited by selective compounds. This chemical array was then used to define the PI3-K isoforms required for insulin signaling. We find that p110 alpha is the primary insulin-responsive PI3-K in cultured cells, whereas p110 beta is dispensable but sets a phenotypic threshold for p110 alpha activity. Compounds targeting p110 alpha block the acute effects of insulin treatment in vivo, whereas a p110 beta inhibitor has no effect. These results illustrate systematic target validation using a matrix of inhibitors that span a protein family. C1 Univ Calif San Francisco, Howard Hughes Med Inst, Dept Mol & Cellular Pharmacol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. Univ Calif San Francisco, Brain Tumor Res Ctr, San Francisco, CA 94143 USA. Univ Calif San Francisco, Ctr Comprehens Canc, San Francisco, CA 94143 USA. MRC, Mol Biol Lab, Cambridge CB2 2QH, England. Univ Geneva, Dept Mol Biol, CH-1211 Geneva 4, Switzerland. NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Shokat, KM (reprint author), Univ Calif San Francisco, Howard Hughes Med Inst, Dept Mol & Cellular Pharmacol, San Francisco, CA 94143 USA. EM shokat@cmp.ucsf.edu RI Toth, Balazs/B-4252-2012; Gonzalez, Beatriz /M-1219-2014; Loewith, Robbie/S-6289-2016; OI Gonzalez, Beatriz /0000-0002-0710-0202; Loewith, Robbie/0000-0002-2482-603X; Knight, Zachary/0000-0001-7621-1478; Balla, Tamas/0000-0002-9077-3335; Balla, Andras/0000-0002-6450-2793 FU Howard Hughes Medical Institute; Intramural NIH HHS; Medical Research Council [MC_U105184308]; NIAID NIH HHS [AI44009, R01 AI044009, R01 AI044009-06] NR 50 TC 716 Z9 734 U1 5 U2 40 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD MAY 19 PY 2006 VL 125 IS 4 BP 733 EP 747 DI 10.1016/j.cell.2006.03.035 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 047NM UT WOS:000237886000018 PM 16647110 ER PT J AU Jeong, W Park, SJ Chang, TS Lee, DY Rhee, SG AF Jeong, W Park, SJ Chang, TS Lee, DY Rhee, SG TI Molecular mechanism of the reduction of cysteine sulfinic acid of peroxiredoxin to cysteine by mammalian sulfiredoxin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID THIOL-SPECIFIC ANTIOXIDANT; HYDROGEN-PEROXIDE; 2-CYS PEROXIREDOXIN; ACTIVE-SITE; SACCHAROMYCES-CEREVISIAE; CRYSTAL-STRUCTURE; PROTEIN; INACTIVATION; OXIDATION; CATALYSIS AB Among many proteins with cysteine sulfinic acid (Cys-SO2H) residues, the sulfinic forms of certain peroxiredoxins (Prxs) are selectively reduced by sulfiredoxin (Srx) in the presence of ATP. All Srx enzymes contain a conserved cysteine residue. To elucidate the mechanism of the Srx-catalyzed reaction, we generated various mutants of Srx and examined their interaction with PrxI, their ATPase activity, and their ability to reduce sulfinic PrxI. Our results suggest that three surface-exposed amino acid residues, corresponding to Arg(50), Asp(57), and Asp(79) of rat Srx, are critical for substrate recognition. The presence of the sulfinic form (but not the reduced form) of PrxI induces the conserved cysteine of Srx to take the gamma-phosphate of ATP and then immediately transfers the phosphate to the sulfinic moiety of PrxI to generate a sulfinic acid phosphoryl ester (Prx-Cys-S(=O)OPO32-). This ester is reductively cleaved by a thiol molecule (RSH) such as GSH, thioredoxin, and dithiothreitol to produce a disulfide-S-monoxide (Prx-Cys-S(=O)-S-R). The disulfide-S-monoxide is further reduced through the oxidation of three thiol equivalents to complete the catalytic cycle and regenerate Prx-Cys-SH. C1 Ewha Womans Univ, Ctr Cell Signaling Res, Seoul 120750, South Korea. Ewha Womans Univ, Div Mol Life Sci, Seoul 120750, South Korea. NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. RP Rhee, SG (reprint author), Ewha Womans Univ, Ctr Cell Signaling Res, Sci Bldg C,Rm 211,11 Daehyun Dong, Seoul 120750, South Korea. EM rheesg@ewha.ac.kr NR 34 TC 97 Z9 104 U1 1 U2 11 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 19 PY 2006 VL 281 IS 20 BP 14400 EP 14407 DI 10.1074/jbc.M511082200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 042FC UT WOS:000237512300067 PM 16565085 ER PT J AU Wei, Y Ito, Y AF Wei, Yun Ito, Yoichiro TI Preparative isolation of imperatorin, oxypeucedanin and isoimperatorin from traditional Chinese herb "bai zhi" Angelica dahurica (Fisch ex Hoffm) Benth. et Hook using multidimensional high-speed counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE multidimensional counter-current chromatography; isolation and purification; imperatorin; oxypeucedanin and isoimperatorin; Angelico dahurica (Fisch ex Hoffm) Benth. et Hook; bai zhi ID SEPARATION AB Preparative high-speed counter-current chromatography (CCC) was successfully used for isolation and purification of imperatorin, oxypeucedanin and isoimperatorin from traditional Chinese herb "bai zhi" Angelica dahurica (Fisch. ex Hoffm) Benth. et Hook using multidimensional countercurrent chromatography with a pair of two-phase solvent systems composed of n-hexane-ethyl acetate-methanol-water at volume ratios of 1: 1: 1: 1 (v/v) and 5:5:4.5:5.5 (v/v), which had been selected by analytical high-speed counter-current chromatography (HSCCC). Using two preparative units of the CCC centrifuge, which are connected by a column switching valve, about a 300 mg amount of the crude extract was separated, yielding 19.9 mg of imperatorin, 8.6 mg of oxypeucedanin and 10.4 mg of isoimperatorin all at a high purity of over 98%. Published by Elsevier B.V. C1 NHLBI, Ctr Biochem & Biophys, NIH, Bethesda, MD 20892 USA. Beijing Univ Chem Technol, Dept Appl Chem, Fac Sci, Beijing 100029, Peoples R China. RP Ito, Y (reprint author), NHLBI, Ctr Biochem & Biophys, NIH, Bldg 50,Room 3334, Bethesda, MD 20892 USA. EM itoy2@mail.nih.gov NR 13 TC 66 Z9 76 U1 2 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD MAY 19 PY 2006 VL 1115 IS 1-2 BP 112 EP 117 DI 10.1016/j.chroma.2006.02.081 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 041UJ UT WOS:000237481400012 PM 16542667 ER PT J AU Liu, FL Kovalevsky, AY Louis, JM Boross, PI Wang, YF Harrison, RW Weber, IT AF Liu, FL Kovalevsky, AY Louis, JM Boross, PI Wang, YF Harrison, RW Weber, IT TI Mechanism of drug resistance revealed by the crystal structure of the unliganded HIV-1 protease with F53L mutation SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE aspartic protease; catalysis; unliganded; flap mutant; non-active site mutant ID IMMUNODEFICIENCY-VIRUS PROTEASE; ELECTRON-DENSITY MAPS; INHIBITOR BINDING; KINETIC-ANALYSIS; ACTIVE-SITE; RESOLUTION; MUTANTS; FLAP; INTERFACE; COMPLEX AB Mutations in HIV-1 protease (PR) that produce resistance to antiviral PR inhibitors are a major problem in AIDS therapy The mutation F53L arising from antiretroviral therapy was introduced into the flexible flap region of the wild-type PR to study its effect and potential role in developing drug resistance. Compared to wild-type PR, PRF53L showed lower (15%) catalytic efficiency, 20-fold weaker inhibition by the clinical drug indinavir, and reduced dimer stability, while the inhibition constants of two peptide analog inhibitors were slightly lower than those for PR. The crystal structure of PRF53L was determined in the unliganded form at 1.35 angstrom resolution in space group P4(1)2(1)2. The tips of the flaps in PRF53L had a wider separation than in unliganded wild-type PR, probably due to the absence of hydrophobic interactions of the side-chains of Phe53 and Ile50'. The changes in interactions between the flaps agreed with the reduced stability of PRF53L relative to wild-type PR. The altered flap interactions in the unliganded form of PRF53L suggest a distinct mechanism for drug resistance, which has not been observed in other common drug-resistant mutants. (c) 2006 Elsevier Ltd. All rights reserved. C1 Georgia State Univ, Dept Biol, Mol Basis Dis Program, Atlanta, GA 30303 USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Univ Debrecen, Fac Med, Dept Biochem & Mol Biol, H-4012 Debrecen, Hungary. Georgia State Univ, Dept Comp Sci, Atlanta, GA 30302 USA. Georgia State Univ, Mol Basis Dis Program, Dept Chem, Atlanta, GA 30302 USA. RP Weber, IT (reprint author), Georgia State Univ, Dept Biol, Mol Basis Dis Program, Atlanta, GA 30303 USA. EM iweber@gsu.edu OI Kovalevsky, Andrey/0000-0003-4459-9142 FU FIC NIH HHS [TW01001]; NIGMS NIH HHS [GM062920, R01 GM062920] NR 43 TC 37 Z9 37 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 19 PY 2006 VL 358 IS 5 BP 1191 EP 1199 DI 10.1016/j.jmb.2006.02.076 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 044RI UT WOS:000237689600001 PM 16569415 ER PT J AU Yoshioka, K Yoshioka, Y Hsieh, P AF Yoshioka, Ken-Ichi Yoshioka, Yoshiko Hsieh, Peggy TI ATR kinase activation mediated by MutS alpha and MutL alpha in response to cytotoxic O(6)-methylguanine adducts SO MOLECULAR CELL LA English DT Article ID DNA MISMATCH REPAIR; REPLICATION PROTEIN-A; SINGLE-STRANDED-DNA; SACCHAROMYCES-CEREVISIAE; CHECKPOINT ACTIVATION; METHYLATING AGENTS; DEFICIENT CELLS; DAMAGE; REQUIRES; BINDING AB SO-type alkylating agents that produce cytotoxix O(6)- methyl-G (O(6)-meG) DNA adducts induce cell cycle arrest and apoptosis in a manner requiring the DNA mismatch repair (MMR) proteins MutS alpha and MutL alpha. Here, we show that checkpoint signaling in response to DNA methylation occurs during S phase and requires DNA replication that gives rise to O(6)-meG/T mispairs. DNA binding studies reveal that MutSa specifically recognizes O(6_)meG/T mispairs, but not O(6)-meG/C. In an in vitro assay, ATR-ATRIP, but not RPA, is preferentially recruited to O(6)-meG/T mismatches in a MutS alpha and MutL alpha-dependent manner. Furthermore, ATR kinase is activated to phosphorylate Chk1 in the presence of O(6)-meG/T mispairs and MMR proteins. These results suggest that MMR proteins can act as direct sensors of methylation damage and help recruit ATR-ATRIP to sites of cytotoxic O(6)-meG adducts to initiate ATR checkpoint signaling. C1 NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Hsieh, P (reprint author), NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM ph52x@nih.gov FU Intramural NIH HHS [Z01 DK052029-01] NR 48 TC 167 Z9 173 U1 1 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD MAY 19 PY 2006 VL 22 IS 4 BP 501 EP 510 DI 10.1016/j.molcel.2006.04.023 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 046LO UT WOS:000237813300011 PM 16713580 ER PT J AU Close, P Hawkes, N Cornez, I Creppe, C Lambert, CA Rogister, B Siebenlist, U Merville, MP Slaugenhaupt, SA Bours, V Svejstrup, JQ Chariot, A AF Close, P Hawkes, N Cornez, I Creppe, C Lambert, CA Rogister, B Siebenlist, U Merville, MP Slaugenhaupt, SA Bours, V Svejstrup, JQ Chariot, A TI Transcription impairment and cell migration defects in elongator-depleted cells: Implication for familial dysautonomia SO MOLECULAR CELL LA English DT Article ID POLYMERASE-II HOLOENZYME; B KINASE COMPLEX; HISTONE ACETYLTRANSFERASE; IN-VIVO; RNA; MOTILITY; PROTEIN; GENES; IKAP; FIBROBLASTS AB Mutations in IKBKAP, encoding a subunit of Elongator, cause familial dysautonomia (FD), a severe neuro-developmental disease with complex clinical characteristics. Elongator was previously linked not only with transcriptional elongation and histone acetylation but also with other cellular processes. Here, we used RNA interference (RNAi) and fibroblasts from FD patients to identify Elongator target genes and study the role of Elongator in transcription. Strikingly, whereas Elongator is recruited to both target and nontarget genes, only target genes display histone H3 hypoacetylation and progressively lower RNAPII density through the coding region in FD cells. Interestingly, several target genes encode proteins implicated in cell motility. Indeed, characterization of IKAP/hELP1 RNAi cells, FD fibroblasts, and neuronal cell-derived cells uncovered defects in this cellular function upon Elongator depletion. These results indicate that defects in Elongator function affect transcriptional elongation of several genes and that the ensuing cell motility deficiencies may underlie the neuropathology of FD patients. C1 Canc Res UK, London Res Inst, Clare Hall Labs, S Mimms EN6 3LD, Herts, England. Univ Liege, Lab Med Chem & Human Genet, Ctr Biomed Integrat Genoproteom, B-4000 Liege, Belgium. Univ Liege, Lab Connect Tissues Biol, Ctr Biomed Integrat Genoproteom, B-4000 Liege, Belgium. Univ Liege, Ctr Cellular & Mol Neurobiol, B-4000 Liege, Belgium. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Svejstrup, JQ (reprint author), Canc Res UK, London Res Inst, Clare Hall Labs, S Mimms EN6 3LD, Herts, England. EM j.svejstrup@cancer.org.uk; alain.chariot@ulg.ac.be OI Svejstrup, Jesper/0000-0003-4964-6147 NR 31 TC 118 Z9 122 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD MAY 19 PY 2006 VL 22 IS 4 BP 521 EP 531 DI 10.1016/j.molcel.2006.04.017 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 046LO UT WOS:000237813300013 PM 16713582 ER PT J AU Youle, M Emery, S Fisher, M Nelson, M Fosdick, L Janossy, G Loveday, C Sullivan, A Herzmann, C Wand, H Davey, RT Johnson, MA Tavel, JA Lane, HC AF Youle, Mike Emery, Sean Fisher, Martin Nelson, Mark Fosdick, Lisa Janossy, George Loveday, Clive Sullivan, Ann Herzmann, Christian Wand, Handan Davey, Richard T., Jr. Johnson, Margaret A. Tavel, Jorge A. Lane, H. Clifford TI A randomised trial of subcutaneous intermittent interleukin-2 without antiretroviral therapy in HIV-infected patients: The UK-Vanguard study SO PLOS CLINICAL TRIALS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; DNA SIGNAL AMPLIFICATION; CD4(+) CELL COUNTS; INTRAVENOUS INTERLEUKIN-2; HUMAN PLASMA; IMPACT; RATIONALE; EXPANSION; BURDEN; SYSTEM AB Objective: The objective of the trial was to evaluate in a pilot setting the safety and efficacy of interleukin-2 (IL-2) therapy when used without concomitant antiretroviral therapy as a treatment for HIV infection. Design and Setting: This was a multicentre randomised three-arm trial conducted between September 1998 and March 2001 at three clinical centres in the United Kingdom. Participants: Participants were 36 antiretroviral treatment naive HIV-1-infected patients with baseline CD4 T lymphocyte counts of at least 350 cells/mm(3). Interventions: Participants were randomly assigned to receive IL-2 at 15 million international units (MIU) per day ( 12 participants) or 9 MIU/day ( 12 participants) or no treatment ( 12 participants). IL-2 was administered by twice-daily subcutaneous injections for five consecutive days every 8 wk. Outcome Measures: Primary outcome was the change from baseline CD4 T lymphocyte count at 24 wk. Safety and plasma HIV RNA levels were also monitored every 4 wk through 24 wk. The two IL-2 dose groups were combined for the primary analysis. Results: Area under curve (AUC) for change in the mean CD4 T lymphocyte count through 24 wk was 129 cells/mm(3) for those assigned IL-2 ( both dose groups combined) and 13 cells/mm(3) for control participants (95% CI for difference, 51.3 - 181.2 cells/mm(3); p = 0.0009). Compared to the control group, significant increases in CD4 cell count were observed for both IL-2 dose groups: 104.2/mm(3) ( p = 0.008) and 128.4 cells/mm(3) ( p = 0.002) for the 4.5 and 7.5 MIU dose groups, respectively. There were no significant differences between the IL-2 (0.13 log(10) copies/ ml) and control (0.09 log(10) copies/ml) groups for AUC of change in plasma HIV RNA over the 24-wk period of follow- up ( 95% CI for difference, - 0.17 to 0.26; p = 0.70). Grade 4 and dose-limiting side effects were in keeping with those previously reported for IL-2 therapy. Conclusions: In participants with HIV infection and baseline CD4 T lymphocyte counts of at least 350 cells/mm(3), intermittent subcutaneous IL-2 without concomitant antiretroviral therapy was well tolerated and produced significant increases in CD4 T lymphocyte counts and did not adversely affect plasma HIV RNA levels. C1 Univ New S Wales, Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW, Australia. Royal Free Ctr HIV Med, London, England. Brighton Healthcare Trust, Brighton, E Sussex, England. Kobler Ctr, London, England. Univ Minnesota, Div Biostat, Minneapolis, MN USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Emery, S (reprint author), Univ New S Wales, Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW, Australia. EM semery@nchecr.unsw.edu.au; clane@niaid.nih.gov NR 32 TC 21 Z9 21 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1555-5887 J9 PLOS CLIN TRIALS JI PLos Clin. Trials PD MAY 19 PY 2006 VL 1 IS 1 AR e3 DI 10.1371/journal.pctr.0010003 PG 7 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 150HJ UT WOS:000245206100001 PM 16871325 ER PT J AU Lan, Q Vermeulen, R Zhang, LP Li, GL Rosenberg, PS Alter, BP Shen, M Rappaport, SM Weinberg, RS Chanock, S Waidyanatha, S Rabkin, C Hayes, RB Linet, M Kim, S Yin, S Rothman, N Smith, MT AF Lan, Q Vermeulen, R Zhang, LP Li, GL Rosenberg, PS Alter, BP Shen, M Rappaport, SM Weinberg, RS Chanock, S Waidyanatha, S Rabkin, C Hayes, RB Linet, M Kim, S Yin, S Rothman, N Smith, MT TI Benzene exposure and hematotoxicity - Response SO SCIENCE LA English DT Letter ID WORKERS C1 NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China. Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC 27599 USA. New York Blood Ctr, Clin Serv, White Plains, NY 10605 USA. NCI, Ctr Canc Res, NIH, DHHS, Bethesda, MD 20892 USA. RP Lan, Q (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. RI Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 NR 6 TC 15 Z9 15 U1 0 U2 2 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 MAY 19 PY 2006 VL 312 IS 5776 BP 998 EP 999 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 043UX UT WOS:000237628800019 ER PT J AU Scaffidi, P Misteli, T AF Scaffidi, P Misteli, T TI Lamin A-dependent nuclear defects in human aging SO SCIENCE LA English DT Article ID HUTCHINSON-GILFORD-PROGERIA; ARCHITECTURE; ZMPSTE24 AB Mutations in the nuclear structural protein lamin A cause the premature aging syndrome Hutchinson-Gilford progeria (HGPS). Whether lamin A plays any role in normal aging is unknown. We show that the same molecular mechanism responsible for HGPS is active in healthy cells. Cell nuclei from old individuals acquire defects similar to those of HGPS patient cells, including changes in histone modifications and increased DNA damage. Age-related nuclear defects are caused by sporadic use, in healthy individuals, of the same cryptic splice site in lamin A whose constitutive activation causes HGPS. Inhibition of this splice site reverses the nuclear defects associated with aging. These observations implicate lamin A in physiological aging. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [Z01 BC010309-07] NR 14 TC 486 Z9 510 U1 7 U2 43 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 MAY 19 PY 2006 VL 312 IS 5776 BP 1059 EP 1063 DI 10.1126/science.1127168 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 043UX UT WOS:000237628800047 PM 16645051 ER PT J AU Gummesson, C Ward, MM Atroshi, I AF Gummesson, Christina Ward, Michael M. Atroshi, Isam TI The shortened disabilities of the arm, shoulder and hand questionnaire (QuickDASH): validity and reliability based on responses within the full-length DASH SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article ID LONGITUDINAL CONSTRUCT-VALIDITY; OUTCOME QUESTIONNAIRE; INSTRUMENTS; PLOTS AB Background: The 30-item disabilities of the arm, shoulder and hand ( DASH) questionnaire is increasingly used in clinical research involving upper extremity musculoskeletal disorders. From the original DASH a shorter version, the 11-item QuickDASH, has been developed. Little is known about the discriminant ability of score changes for the QuickDASH compared to the DASH. The aim of this study was to assess the performance of the QuickDASH and its cross-sectional and longitudinal validity and reliability. Methods: The study was based on extracting QuickDASH item responses from the responses to the full-length DASH questionnaire completed by 105 patients with a variety of upper extremity disorders before surgery and at follow-up 6 to 21 months after surgery. The DASH and QuickDASH scores were compared for the whole population and for different diagnostic groups. For longitudinal construct validity the effect size and standardized response mean were calculated. Analyses with ROC curves were performed to compare the ability of the DASH and QuickDASH to discriminate among patients classified according to the magnitude of self-rated improvement. Cross-sectional and test-retest reliability was assessed. Results: The mean DASH score was 34 (SD 22) and the mean QuickDASH score was 39 ( SD 24) at baseline. For the different diagnostic groups the mean and median QuickDASH scores were higher than the corresponding DASH scores. For the whole population, the mean difference between the QuickDASH and DASH baseline scores was 4.2 (95% CI 3.2 - 5.3), follow-up scores was 2.6 (1.7 - 3.4), and change scores was 1.7 (0.6 - 2.8). The overall effect size and standardized response mean measured with the DASH and the QuickDASH were similar. In the ROC analysis of change scores among patients who rated their arm status as somewhat or much better and those who rated it as unchanged the difference in the area under the ROC curve for the DASH and QuickDASH was 0.01 ( 95% CI - 0.05 - 0.07) indicating similar discriminant ability. Cross-sectional and test-retest reliability of the DASH and QuickDASH were similar. Conclusion: The results indicate that the QuickDASH can be used instead of the DASH with similar precision in upper extremity disorders. C1 NIAMSD, NIH, Bethesda, MD 20892 USA. Lund Univ, Dept Hlth Sci, Div Physiotherapy, SE-22185 Lund, Sweden. Hassleholm Kristianstad, Dept Orthoped, SE-28125 Hassleholm, Sweden. RP Gummesson, C (reprint author), NIAMSD, NIH, Bethesda, MD 20892 USA. EM christina.gummesson@med.lu.se; wardm1@mail.nih.gov; Isam.Atroshi@skane.se FU Intramural NIH HHS NR 15 TC 197 Z9 199 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD MAY 18 PY 2006 VL 7 AR 44 DI 10.1186/1471-2474-7-44 PG 7 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 069HD UT WOS:000239436100001 PM 16709254 ER PT J AU Nguyen, P Awwad, RT Smart, DDK Spitz, DR Gius, D AF Nguyen, P Awwad, RT Smart, DDK Spitz, DR Gius, D TI Thioredoxin reductase as a novel molecular target for cancer therapy SO CANCER LETTERS LA English DT Review DE molecular targets; thioredoxin reductase; anticancer agents ID GLUTATHIONE-S-TRANSFERASE; DNA-BINDING ACTIVITY; NF-KAPPA-B; OXIDATIVE STRESS RESISTANCE; DEPENDENT PROTEIN-KINASE; HUMAN TUMOR-CELLS; IONIZING-RADIATION; FREE-RADICALS; REDOX REGULATION; GENE-EXPRESSION AB Tumor cell proliferation, de-differentiation, and progression depend on a complex combination of altered cell cycle regulation, excessive growth factor pathway activation, and decreased apoptosis. The understanding of these complex mechanisms should lead to the identification of potential targets for therapeutic intervention. Redox-sensitive signaling factors also regulate multiple cellular processes including proliferation, cell cycle, and pro-survival signaling cascades, suggesting their potential as molecular targets for anticancer agents. These observations suggest that redox-sensitive signaling factors may be potential novel molecular markers. We hypothesized that thioredoxin reductase-1 (TR), a component of several redox-regulated pathways, may represent a potential molecular target candidate in response to agents that induce oxidative stress. There have been numerous biological studies over the last decade investigating the cell biological, biochemical, and genetic properties of TR both in culture and in in vivo models. In addition, using a series of permanent cell lines that express either a wild-type TR or a dominant mutant TR gene or a chemical agent that inhibits TR we demonstrated that TR meets most criteria that would identify a molecular target. Based on these results we believe TR is a potential molecular target and discuss potential clinical possibilities. (c) 2005 Elsevier Ireland Ltd. All rights reserved. C1 NCI, Mol Radiat Oncol Sect, Radiat Oncol Branch, Radiat Oncol Sci Program,Ctr Canc Res,NIH, Bethesda, MD 20892 USA. Univ Iowa, Free Rad & Radiat Biol Program, Dept Radiat Oncol, Holden Comprehens Canc Ctr, Iowa City, IA 52242 USA. RP Gius, D (reprint author), NCI, Mol Radiat Oncol Sect, Radiat Oncol Branch, Radiat Oncol Sci Program,Ctr Canc Res,NIH, Bldg 10,Room B3B69,9000 Rockville Pike, Bethesda, MD 20892 USA. EM giusd@mail.nih.gov NR 87 TC 86 Z9 91 U1 2 U2 9 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 MAY 18 PY 2006 VL 236 IS 2 BP 164 EP 174 DI 10.1016/j.canlet.2005.04.028 PG 11 WC Oncology SC Oncology GA 053IQ UT WOS:000238299200002 PM 15955621 ER PT J AU Grantham, JJ Torres, VE Chapman, AB Guay-Woodford, LM Bae, KT King, BF Wetzel, LH Baumgarten, DA Kenney, PJ Harris, PC Klahr, S Bennett, WM Hirschman, GN Meyers, CM Zhang, XL Zhu, F Miller, JP AF Grantham, JJ Torres, VE Chapman, AB Guay-Woodford, LM Bae, KT King, BF Wetzel, LH Baumgarten, DA Kenney, PJ Harris, PC Klahr, S Bennett, WM Hirschman, GN Meyers, CM Zhang, XL Zhu, F Miller, JP CA CRISP Investigators TI Volume progression in polycystic kidney disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID AUTOSOMAL-DOMINANT; RENAL-FUNCTION; MANAGEMENT; CONSORTIUM; SEVERITY; CRISP; ADPKD; CYST AB Background: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of cyst-filled kidneys. Methods: In a three-year study, we measured the rates of change in total kidney volume, total cyst volume, and iothalamate clearance in patients with ADPKD. Of a total of 241 patients, in 232 patients without azotemia who were 15 to 46 years old at baseline we used magnetic-resonance imaging to correlate the total kidney volume and total cyst volume with iothalamate clearance. Statistical methods included analysis of variance, Pearson correlation, and multivariate regression analysis. Results: Total kidney volume and total cyst volume increased exponentially, a result consistent with an expansion process dependent on growth. The mean (+/-SD) total kidney volume was 1060+/-642 ml at baseline and increased by a mean of 204+/-246 ml (5.27+/-3.92 percent per year, P < 0.001) over a three-year period among 214 patients. Total cyst volume increased by 218+/-263 ml (P < 0.001) during the same period among 210 patients. The baseline total kidney volume predicted the subsequent rate of increase in volume, independently of age. A baseline total kidney volume above 1500 ml in 51 patients was associated with a declining glomerular filtration rate (by 4.33+/-8.07 ml per minute per year, P < 0.001). Total kidney volume increased more in 135 patients with PKD1 mutations (by 245+/-268 ml) than in 28 patients with PKD2 mutations (by 136+/-100 ml, P=0.03). Conclusions: Kidney enlargement resulting from the expansion of cysts in patients with ADPKD is continuous and quantifiable and is associated with the decline of renal function. Higher rates of kidney enlargement are associated with a more rapid decrease in renal function. C1 Univ Kansas, Med Ctr, Dept Internal Med, Kidney Inst, Kansas City, KS 66160 USA. Mayo Clin Coll Med, Dept Radiol, Rochester, MN USA. Mayo Clin Coll Med, Div Nephrol & Hypertens, Rochester, MN USA. Emory Univ, Sch Med, Div Nephrol, Atlanta, GA USA. Univ Alabama, Sch Med, Dept Med, Div Renal, Birmingham, AL USA. Univ Alabama, Sch Med, Dept Radiol, Birmingham, AL USA. Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Biostat, St Louis, MO 63110 USA. Legacy Good Samaritan Hosp, Portland, OR USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Grantham, JJ (reprint author), Univ Kansas, Med Ctr, Dept Internal Med, Kidney Inst, Maildrop 3018,3901 Rainbow Blvd, Kansas City, KS 66160 USA. EM jgrantha@kumc.edu OI Miller, J Philip/0000-0003-4568-6846 FU NCRR NIH HHS [M01-RR00039, M01-RR00052, M01-RR00585]; NIDDK NIH HHS [DK56943, DK56956, DK56957, DK56961] NR 29 TC 305 Z9 320 U1 1 U2 7 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 MAY 18 PY 2006 VL 354 IS 20 BP 2122 EP 2130 DI 10.1056/NEJMoa054341 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 043BX UT WOS:000237575400006 PM 16707749 ER PT J AU Quimby, BB Yong-Gonzalez, V Anan, T Strunnikov, AV Dasso, M AF Quimby, BB Yong-Gonzalez, V Anan, T Strunnikov, AV Dasso, M TI The promyelocytic leukemia protein stimulates SUMO conjugation in yeast SO ONCOGENE LA English DT Article DE promyelocytic leukemia protein (PML); SUMO-1; budding yeast; SUMO ligase; PML : RAR alpha ID NUCLEAR-BODY FORMATION; RAR-ALPHA; PML; ENZYME; LOCALIZATION; PATHOGENESIS; DEGRADATION; HOMOLOG; LIGASE; GENE AB The promyelocytic leukemia gene was first identified through its fusion to the gene encoding the retinoic acid receptor alpha (RAR alpha) in acute promyelocytic leukemia (APL) patients. The promyelocytic leukemia gene product (PML) becomes conjugated in vivo to the small ubiquitin-like protein SUMO-1, altering its behavior and capacity to recruit other proteins to PML nuclear bodies (PML-NBs). In the NB4 cell line, which was derived from an APL patient and expresses PML: RARa, we observed a retinoic acid-dependent change in the modi. cation of specific proteins by SUMO-1. To dissect the interaction of PML with the SUMO-1 modi. cation pathway, we used the budding yeast Saccharomyces cerevisiae as a model system through expression of PML and human SUMO-1 (hSUMO-1). We found that PML stimulated hSUMO-1 modi. cation in yeast, in a manner that was dependent upon PML's RING-finger domain. PML: RARa also stimulated hSUMO-1 conjugation in yeast. Interestingly, however, PML and PML: RARa differentially complemented yeast Smt3p conjugation pathway mutants. These findings point toward a potential function of PML and PML: RARa as SUMO E3 enzymes or E3 regulators, and suggest that fusion of RARa to PML may affect this activity. C1 NICHD, Lab Gene Regulat & Dev, Sect Cell Cycle Regulat, NIH, Bethesda, MD 20892 USA. NICHD, Unit Chromosome Struct & Funct, Lab Gene Regulat & Dev, NIH, Bethesda, MD USA. RP Dasso, M (reprint author), NICHD, Lab Gene Regulat & Dev, Sect Cell Cycle Regulat, NIH, Bldg 18T,Room 106,18 Lib Dr, Bethesda, MD 20892 USA. EM mdasso@helix.nih.gov OI Strunnikov, Alexander/0000-0002-9058-2256; Dasso, Mary/0000-0002-5410-1371 FU Intramural NIH HHS [Z01 HD001902-13] NR 31 TC 32 Z9 33 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 18 PY 2006 VL 25 IS 21 BP 2999 EP 3005 DI 10.1038/sj.onc.1209335 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 048MI UT WOS:000237950800004 PM 16501610 ER PT J AU Geho, D Cheng, MMC Killian, K Lowenthal, M Ross, S Frogale, K Nijdam, J Lahar, N Johann, D Herrmann, P Whiteley, G Ferrari, M Petricoin, E Liotta, L AF Geho, D Cheng, MMC Killian, K Lowenthal, M Ross, S Frogale, K Nijdam, J Lahar, N Johann, D Herrmann, P Whiteley, G Ferrari, M Petricoin, E Liotta, L TI Fractionation of serum components using nanoporous substrates SO BIOCONJUGATE CHEMISTRY LA English DT Article ID PROTEOMIC PATTERNS; MASS-SPECTROMETRY; OVARIAN-CANCER; ADSORPTION; PEPTIDES; PROTEINS; NITROGEN AB Numerous previously uncharacterized molecules resident within the low molecular weight circulatory proteome may provide a picture of the ongoing pathophysiology of an organism. Recently, proteomic signatures composed of low molecular weight molecules have been identified using mass spectrometry combined with bioinformatic algorithms. Attempts to sequence and identify the molecules that underpin the fingerprints are currently underway. The finding that many of these low molecular weight molecules may exist bound to circulating carrier proteins affords a new opportunity for fractionation and separation techniques prior to mass spectrometry-based analysis. In this study we demonstrate a method whereby nanoporous substrates may be used for the facile and reproducible fractionation and selective binding of the serum-based biomarker material, including subcellular proteins found within the serum. Aminopropyl-coated nanoporous silicon, when exposed to serum, can deplete serum of proteins and yield a serum with a distinct, altered MS profile. Additionally, aminopropyl-coated, nanoporous controlled-pore glass beads are able to bind a subset of serum proteins and release them with stringent elution. The eluted proteins have distinct MS profiles, gel electrophoresis profiles, and differential peptide sequence identities, which vary based on the size of the nanopores. These material surfaces could be employed in strategies for the harvesting and preservation of labile and carrier-protein-bound molecules in the blood. C1 NCI, Pathol Lab, US FDA, Clin Proteom Program,NIH, Bethesda, MD 20892 USA. NCI, US FDA, Ctr Biol Evaluat & Res, Clin Proteom Program,Food & Drug Adm, Bethesda, MD 20892 USA. Ohio State Univ, Davis Heart & Lung Res Inst, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43212 USA. SAIC Frederick Inc, Clin Proteom Lab, Gaithersburg, MD 20878 USA. RP Geho, D (reprint author), NCI, Pathol Lab, US FDA, Clin Proteom Program,NIH, Rm 2A33,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM herrmanp@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 23 TC 30 Z9 31 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD MAY 17 PY 2006 VL 17 IS 3 BP 654 EP 661 DI 10.1021/bc0503364 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 043CD UT WOS:000237576000012 PM 16704202 ER PT J AU Koch, CA Brouwers, FM Vortmeyer, AO Tannapfel, A Libutti, SK Zhuang, ZP Pacak, K Neumann, HPH Paschke, R AF Koch, CA Brouwers, FM Vortmeyer, AO Tannapfel, A Libutti, SK Zhuang, ZP Pacak, K Neumann, HPH Paschke, R TI Somatic VHL gene alterations in MEN2-associated medullary thyroid carcinoma SO BMC CANCER LA English DT Article ID MULTIPLE ENDOCRINE NEOPLASIA; RET PROTOONCOGENE MUTATIONS; HIPPEL-LINDAU-DISEASE; TUMOR-SUPPRESSOR GENE; MOLECULAR PATHOGENESIS; GERMLINE MUTATIONS; MUTANT RET; TYPE-2; PHEOCHROMOCYTOMAS; HETEROZYGOSITY AB Background: Germline mutations in RET are responsible for multiple endocrine neoplasia type 2 ( MEN2), an autosomal dominantly inherited cancer syndrome that is characterized by medullary thyroid carcinoma ( MTC), pheochromocytoma, and parathyroid hyperplasia/adenoma. Recent studies suggest a "second hit" mechanism resulting in amplification of mutant RET. Somatic VHL gene alterations are implicated in the pathogenesis of MEN2 pheochromocytomas. We hypothesized that somatic VHL gene alterations are also important in the pathogenesis of MEN2-associated MTC. Methods: We analyzed 6 MTCs and 1 C-cell hyperplasia ( CCH) specimen from 7 patients with MEN2A and RET germline mutations in codons 609, 618, 620, or 634, using microdissection, microsatellite analysis, phosphorimage densitometry, and VHL mutation analysis. Results: First, we searched for allelic imbalance between mutant and wild-type RET by using the polymorphic markers D10S677, D10S1239, and RET on thyroid tissue from these patients. Evidence for RET amplification by this technique could be demonstrated in 3 of 6 MTCs. We then performed LOH analysis using D3S1038 and D3S1110 which map to the VHL gene locus at 3p25/26. VHL gene deletion was present in 3 MTCs. These 3 MTCs also had an allelic imbalance between mutant and wildtype RET. Mutation analysis of the VHL gene showed a somatic frameshift mutation in 1 MTC that also demonstrated LOH at 3p25/26. In the 2 other MTCs with allelic imbalance of RET and somatic VHL gene deletion, no somatic VHL mutation could be detected. The CCH specimen did neither reveal RET imbalance nor somatic VHL gene alterations. Conclusion: These data suggest that a RET germline mutation is necessary for development of CCH, that allelic imbalance between mutant and wild-type RET may set off tumorigenesis, and that somatic VHL gene alterations may not play a major role in tumorigenesis of MEN2A-associated MTC. C1 Univ Leipzig, Div Endocrinol & Nephrol, D-04103 Leipzig, Germany. Univ Mississippi, Med Ctr, Div Endocrinol, Jackson, MS 39216 USA. NICHHD, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Ruhr Univ Bochum, BG Kliniken Bergmannsheil, Inst Pathol, D-44789 Bochum, Germany. NCI, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Freiburg, Div Nephrol & Hypertens, D-79106 Freiburg, Germany. RP Koch, CA (reprint author), Univ Leipzig, Div Endocrinol & Nephrol, Philipp Rosenthalstr 27, D-04103 Leipzig, Germany. EM ckoch@medicine.umsmed.edu; brouwerf@mail.nih.gov; vortmeyera@ninds.nih.gov; andrea.tannapfel@rub.de; libuttis@mail.nih.gov; zhuangz@ninds.nih.gov; karel@mail.nih.gov; neumann@Medizin.Ukl.Uni-Freiburg.De; ralf.paschke@medizin.uni-leipzig.de RI Koch, Christian/A-4699-2008; OI Koch, Christian/0000-0003-3127-5739; Koch, Christian/0000-0003-0678-1242 NR 44 TC 20 Z9 21 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD MAY 17 PY 2006 VL 6 AR 131 DI 10.1186/1471-2407-6-131 PG 7 WC Oncology SC Oncology GA 055SC UT WOS:000238469700002 PM 16707008 ER PT J AU Dissanayake, SN Marinotti, O Ribeiro, JMC James, AA AF Dissanayake, Sumudu N. Marinotti, Osvaldo Ribeiro, Jose Marcos C. James, Anthony A. TI angaGEDUCI: Anopheles gambiae gene expression database with integrated comparative algorithms for identifying conserved DNA motifs in promoter sequences SO BMC GENOMICS LA English DT Article AB Background: The completed sequence of the Anopheles gambiae genome has enabled genome-wide analyses of gene expression and regulation in this principal vector of human malaria. These investigations have created a demand for efficient methods of cataloguing and analyzing the large quantities of data that have been produced. The organization of genome-wide data into one unified database makes possible the efficient identification of spatial and temporal patterns of gene expression, and by pairing these findings with comparative algorithms, may offer a tool to gain insight into the molecular mechanisms that regulate these expression patterns. Description: We provide a publicly-accessible database and integrated data-mining tool, angaGEDUCI, that unifies 1) stage- and tissue-specific microarray analyses of gene expression in An. gambiae at different developmental stages and temporal separations following a bloodmeal, 2) functional gene annotation, 3) genomic sequence data, and 4) promoter sequence comparison algorithms. The database can be used to study genes expressed in particular stages, tissues, and patterns of interest, and to identify conserved promoter sequence motifs that may play a role in the regulation of such expression. The database is accessible from the address http://www.angaged.bio.uci.edu. Conclusion: By combining gene expression, function, and sequence data with integrated sequence comparison algorithms, angaGEDUCI streamlines spatial and temporal pattern-finding and produces a straightforward means of developing predictions and designing experiments to assess how gene expression may be controlled at the molecular level. C1 Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. NIAID, NIH, Lab Malaria & Vector Res, Rockville, MD 20852 USA. Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92697 USA. RP James, AA (reprint author), Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. EM sdissana@uci.edu; omarinot@uci.edu; jribeiro@niaid.nih.gov; aajames@uci.edu OI Marinotti, Osvaldo/0000-0002-7173-7160; Ribeiro, Jose/0000-0002-9107-0818 FU NIAID NIH HHS [AI29746, R01 AI029746, R37 AI029746] NR 9 TC 10 Z9 11 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD MAY 17 PY 2006 VL 7 AR 116 DI 10.1186/1471-2164-7-116 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 068AK UT WOS:000239343800001 PM 16707020 ER PT J AU Wang, HB Yang, CF Leskow, FC Sun, J Canagarajah, B Hurley, JH Kazanietz, MG AF Wang, HongBin Yang, Chengfeng Leskow, Federico Coluccio Sun, Jing Canagarajah, Bertram Hurley, James H. Kazanietz, Marcelo G. TI Phospholipase C gamma/diacylglycerol-dependent activation of beta 2-chimaerin restricts EGF-induced Rac signaling SO EMBO JOURNAL LA English DT Article DE beta 2-chimaerin; diacylglycerol; EGF; phorbol esters; Rac ID EPIDERMAL-GROWTH-FACTOR; CELL-SURFACE RECEPTORS; PHORBOL ESTER RECEPTOR; PROTEIN-KINASE-C; SUBCELLULAR-LOCALIZATION; TYROSINE PHOSPHORYLATION; EXCHANGE FACTOR; RHO-GTPASES; BINDING; DOMAIN AB Although receptor-mediated regulation of small G-proteins and the cytoskeleton is intensively studied, the mechanisms for attenuation of these signals are poorly understood. In this study, we have identified the Rac-GAP beta 2-chimaerin as an effector of the epidermal growth factor receptor (EGFR) via coupling to phospholipase C gamma (PLC gamma) and generation of the lipid second messenger diacylglycerol (DAG). EGF redistributes beta 2-chimaerin to promote its association with the small GTPase Rac1 at the plasma membrane, as determined by FRET. This relocalization and association with Rac1 were impaired by disruption of the beta 2-chimaerin C1 domain as well as by PLC gamma 1 RNAi, thus defining beta 2-chimaerin as a novel DAG effector. On the other hand, GAP-deficient beta 2-chimaerin mutants show enhanced translocation and sustained Rac1 association in the FRET assays. Remarkably, RNAi depletion of beta 2-chimaerin significantly extended the duration of Rac activation by EGF, suggesting that beta 2-chimaerin serves as a mechanism that self-limits Rac activity in response to EGFR activation. Our results represent the first direct evidence of divergence in DAG signaling downstream of a tyrosine-kinase receptor via a PKC-independent mechanism. C1 Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD USA. RP Kazanietz, MG (reprint author), Univ Penn, Sch Med, Dept Pharmacol, 816 BRB II-III,421 Curie Blvd, Philadelphia, PA 19104 USA. EM marcelo@spirit.gcrc.upenn.edu RI wang, hongbin/E-5541-2011 FU NCI NIH HHS [R01 CA074197, CA74197] NR 34 TC 36 Z9 36 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD MAY 17 PY 2006 VL 25 IS 10 BP 2062 EP 2074 DI 10.1038/sj.emboj.7601098 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 043HC UT WOS:000237590000003 PM 16628218 ER PT J AU Yang, Y Stopka, T Golestaneh, N Wang, Y Wu, KM Li, A Chauhan, BK Gao, CY Cveklova, K Duncan, MK Pestell, RG Chepelinsky, AB Skoultchi, AI Cvekl, A AF Yang, Ying Stopka, Tomas Golestaneh, Nady Wang, Yan Wu, Kongming Li, Anping Chauhan, Bharesh K. Gao, Chun Y. Cveklova, Kveta Duncan, Melinda K. Pestell, Richard G. Chepelinsky, Ana B. Skoultchi, Arthur I. Cvekl, Ales TI Regulation of alpha A-crystallin via Pax6, c-Maf, CREB and a broad domain of lens-specific chromatin SO EMBO JOURNAL LA English DT Article DE c-Maf; chromatin remodeling; histone acetylation and methylation; lens differentiation; Pax6 ID FIBER CELL-DIFFERENTIATION; TRANSCRIPTIONAL REGULATION; GENE-EXPRESSION; BINDING PROTEIN; B-CRYSTALLIN; MOUSE LENS; IN-VIVO; COMPLEXES; PROMOTER; DNA AB Pax6 and c-Maf regulate multiple stages of mammalian lens development. Here, we identified novel distal control regions (DCRs) of the alpha A-crystallin gene, a marker of lens fiber cell differentiation induced by FGF-signaling. DCR1 stimulated reporter gene expression in primary lens explants treated with FGF2 linking FGF-signaling with alpha A-crystallin synthesis. A DCR1/alpha A-crystallin promoter ( including DCR2) coupled with EGFP virtually recapitulated the expression pattern of alpha A-crystallin in lens epithelium and fibers. In contrast, the DCR3/alpha A/EGFP reporter was expressed only in 'late' lens fibers. Chromatin immunoprecipitations showed binding of Pax6 to DCR1 and the alpha A-crystallin promoter in lens chromatin and demonstrated that high levels of alpha A-crystallin expression correlate with increased binding of c-Maf and CREB to the promoter and of CREB to DCR3, a broad domain of histone H3K9-hyper-acetylation extending from DCR1 to DCR3, and increased abundance of chromatin remodeling enzymes Brg1 and Snf2h at the alpha A-crystallin locus. Our data demonstrate a novel mechanism of Pax6, c-Maf and CREB function, through regulation of chromatin-remodeling enzymes, and suggest a multistage model for the activation of alpha A-crystallin during lens differentiation. C1 Albert Einstein Coll Med, Dept Ophthalmol & Visual Sci & Mol Genet, Bronx, NY 10461 USA. Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY USA. Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY USA. LMDB, NEI, Bethesda, MD USA. Univ Delaware, Dept Biol Sci, Newark, DE USA. Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA USA. RP Cvekl, A (reprint author), Albert Einstein Coll Med, Dept Ophthalmol & Visual Sci & Mol Genet, 123 Ullmann,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM cvekl@aecom.yu.edu RI Cvekl, Ales/B-2427-2013; Stopka, Tomas/D-5864-2017; OI Stopka, Tomas/0000-0001-7236-6894; Duncan, Melinda/0000-0003-1570-322X FU NCRR NIH HHS [P20 RR016472, P20 RR16472]; NEI NIH HHS [R01 EY012200, EY12200, EY12221, EY14237, R01 EY012221, R01 EY014237] NR 56 TC 65 Z9 67 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD MAY 17 PY 2006 VL 25 IS 10 BP 2107 EP 2118 DI 10.1038/sj.emboj.7601114 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 043HC UT WOS:000237590000007 PM 16675956 ER PT J AU Liu, JH Kouzine, F Nie, ZQ Chung, HJ Zichrini, EF Weber, A Zhao, K Levens, D AF Liu, Juhong Kouzine, Fedor Nie, Zuqin Chung, Hye-Jung Elisha-Feil, Zichrini Weber, Achim Zhao, Keji Levens, David TI The FUSE/FBP/FIR/TFIIH system is a molecular machine programming a pulse of c-myc expression SO EMBO JOURNAL LA English DT Article ID RNA-POLYMERASE-II; XERODERMA-PIGMENTOSUM; TARGET GENES; TRANSCRIPTION; DNA; PROMOTER; CHROMATIN; BINDING; DOMAIN; COMPLEX AB FarUpStream Element ( FUSE) Binding Protein (FBP) binds the human c-myc FUSE in vitro only in single-stranded or supercoiled DNA. Because transcriptionally generated torsion melts FUSE in vitro even in linear DNA, and FBP/FBP Interacting Repressor ( FIR) regulates transcription through TFIIH, these components have been speculated to be the mechanosensor (FUSE) and effectors (FBP/FIR) of a real-time mechanism controlling c-myc transcription. To ascertain whether the FUSE/FBP/FIR system operates according to this hypothesis in vivo, the flux of activators, repressors and chromatin remodeling complexes on the c-myc promoter was monitored throughout the serum-induced pulse of transcription. After transcription was switched on by conventional factors and chromatin regulators, FBP and FIR were recruited and established a dynamically remodeled loop with TFIIH at the P2 promoter. In XPB cells carrying mutant TFIIH, loop formation failed and the serum response was abnormal; RNAi depletion of FIR similarly disabled c-myc regulation. Engineering FUSE into episomal vectors predictably re-programmed metallothionein-promoter-driven reporter expression. The in vitro recruitment of FBP and FIR to dynamically stressed c-myc DNA paralleled the in vivo process. C1 NCI, Pathol Lab, CCR, Bethesda, MD 20892 USA. Univ Mainz, Inst Pathol, D-6500 Mainz, Germany. NHLBI, Lab Mol Immunol, Bethesda, MD USA. RP Levens, D (reprint author), NCI, Pathol Lab, CCR, Bldg 10,Room 2N106, Bethesda, MD 20892 USA. EM levens@helix.nih.gov RI Levens, David/C-9216-2009 OI Levens, David/0000-0002-7616-922X FU Intramural NIH HHS NR 47 TC 85 Z9 87 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD MAY 17 PY 2006 VL 25 IS 10 BP 2119 EP 2130 DI 10.1038/sj.emboj.7601101 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 043HC UT WOS:000237590000008 PM 16628215 ER PT J AU Cao, L Kim, S Xiao, CY Wang, RH Coumoul, X Wang, XY Li, WM Xu, XL De Soto, JA Takai, H Mai, S Elledge, SJ Motoyama, N Deng, CX AF Cao, Liu Kim, Sangsoo Xiao, Cuiying Wang, Rui-Hong Coumoul, Xavier Wang, Xiaoyan Li, Wen Mei Xu, Xiao Ling De Soto, Joseph A. Takai, Hiroyuki Mai, Sabine Elledge, Stephen J. Motoyama, Noboru Deng, Chu-Xia TI ATM-Chk2-p53 activation prevents tumorigenesis at an expense of organ homeostasis upon Brca1 deficiency SO EMBO JOURNAL LA English DT Article DE aging; apoptosis; breast cancer; cell senescence; G1/S cell cycle checkpoint ID DNA-DAMAGE CHECKPOINT; CELL-CYCLE; GENOMIC INSTABILITY; GENETIC INSTABILITY; BREAST-CANCER; HISTONE H2AX; REPAIR; MICE; P53; SENESCENCE AB BRCA1 is a checkpoint and DNA damage repair gene that secures genome integrity. We have previously shown that mice lacking full-length Brca1 (Brca1(Delta 11/Delta 11)) die during embryonic development. Haploid loss of p53 completely rescues embryonic lethality, and adult Brca1(Delta 11/Delta 11)p53(+/-) mice display cancer susceptibility and premature aging. Here, we show that reduced expression and/or the absence of Chk2 allow Brca1(Delta 11/Delta 11) mice to escape from embryonic lethality. Compared to Brca1(Delta 11/Delta 11)p53(+/-) mice, lifespan of Brca1(Delta 11/Delta 11)Chk2(-/-) mice was remarkably extended. Analysis of Brca1(Delta 11/Delta 11)Chk2(-/-) mice revealed that p53-dependent apoptosis and growth defect caused by Brca1 deficiency are significantly attenuated in rapidly proliferating organs. However, in later life, Brca1(Delta 11/Delta 11)Chk2(-/-) female mice developed multiple tumors. Furthermore, haploid loss of ATM also rescued Brca1 deficiency-associated embryonic lethality and premature aging. Thus, in response to Brca1 deficiency, the activation of the ATM-Chk2-p53 signaling pathway contributes to the suppression of neoplastic transformation, while leading to compromised organismal homeostasis. Our data highlight how accurate maintenance of genomic integrity is critical for the suppression of both aging and malignancy, and provide a further link between aging and cancer. C1 NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Longevity Sci, Dept Geriatr Res, Morioka, Iwate, Japan. Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. Univ Manitoba, Inst Cell Biol, Winnipeg, MB, Canada. RP Deng, CX (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, 10-9N105, Bethesda, MD 20892 USA. EM chuxiad@bdg10.niddk.nih.gov RI Takai, Hiroyuki/B-8352-2011; deng, chuxia/N-6713-2016; Mai, Sabine/E-5667-2017 OI Mai, Sabine/0000-0002-5797-2201 FU Intramural NIH HHS NR 45 TC 57 Z9 60 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD MAY 17 PY 2006 VL 25 IS 10 BP 2167 EP 2177 DI 10.1038/sj.emboj.7601115 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 043HC UT WOS:000237590000012 PM 16675955 ER PT J AU Nakamura, K Hikosaka, O AF Nakamura, K Hikosaka, O TI Role of dopamine in the primate caudate nucleus in reward modulation of saccades SO JOURNAL OF NEUROSCIENCE LA English DT Article DE basal ganglia; caudate; saccade; dopamine; reward; primate ID SUPPLEMENTARY EYE FIELD; DORSOLATERAL PREFRONTAL CORTEX; BASAL GANGLIA; NEURONAL-ACTIVITY; DORSAL STRIATUM; CORTICOSTRIATAL PROJECTIONS; ANTICIPATORY ACTIVITY; SYNAPTIC PLASTICITY; NEOSTRIATAL NEURONS; PARKINSONS-DISEASE AB Expected reward impacts behavior and neuronal activity in brain areas involved in sensorimotor processes. However, where and how reward signals affect sensorimotor signals is unclear. Here, we show evidence that reward-dependent modulation of behavior depends on normal dopamine transmission in the striatum. Monkeys performed a visually guided saccade task in which expected reward gain was different depending on the position of the target. Saccadic reaction times were reliably shorter on large-reward trials than on small-reward trials. When position-reward contingency was switched, the reaction time difference changed rapidly. Injecting dopamine D-1 antagonist into the caudate significantly attenuated the reward- dependent saccadic reaction time changes. Conversely, injecting D-2 antagonist into the same region enhanced the reward-dependent changes. These results suggest that reward-dependent changes in saccadic eye movements depend partly on dopaminergic modulation of neuronal activity in the caudate nucleus. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Nakamura, K (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50,49 Convent Dr, Bethesda, MD 20892 USA. EM kae@lsr.nei.nih.gov FU Intramural NIH HHS NR 76 TC 91 Z9 96 U1 1 U2 9 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 17 PY 2006 VL 26 IS 20 BP 5360 EP 5369 DI 10.1523/JNEUROSCI.4853-05.2006 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 043NR UT WOS:000237608400009 PM 16707788 ER PT J AU Spaulding, AC Weinbaum, CM Lau, DTY Sterling, R Seeff, LB Margolis, HS Hoofnagle, JH AF Spaulding, AC Weinbaum, CM Lau, DTY Sterling, R Seeff, LB Margolis, HS Hoofnagle, JH TI A framework for management of hepatitis C in prisons SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID VIRUS-INFECTION; UNITED-STATES; THERAPY; INMATES; ALCOHOL AB The prevalence of chronic hepatitis C virus (HCV) infection in prisons ranges from 12% to 31%. There are generally accepted - albeit still evolving - guidelines for identification and treatment of hepatitis C in the community. However, there is less agreement among health professionals caring for prisoners about best practices for identification, medical management, and treatment of hepatitis C. inmates often lack health care before incarceration. In prisons, infected persons could be identified and the management of infection initiated; however, the high prevalence of HCV infection among prisoners would impose a disproportionate cost for hepatitis C care on the correctional system. The optimal solution is for prison and public health systems in the United States to jointly provide targeted HCV testing and standard-of-care hepatitis C medical management, treatment, and prevention programs to prison inmate populations. The authors report on a January 2003 meeting of experts in prison health, public health, hepatology, and infectious diseases and explore the clinical care, prevention, and collaboration needed to provide hepatitis C management in prisoners. C1 Ctr Dis Control & Prevent, Atlanta, GA USA. Univ Texas, Med Branch, Galveston, TX 77555 USA. Virginia Commonwealth Univ Hlth Syst, Richmond, VA USA. Natl Inst Hlth, Bethesda, MD USA. RP Spaulding, AC (reprint author), Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, 1518 Clifton Rd NE, Atlanta, GA 30322 USA. EM aspauld@emory.edu NR 67 TC 49 Z9 49 U1 1 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD MAY 16 PY 2006 VL 144 IS 10 BP 762 EP 769 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 043XO UT WOS:000237636400007 PM 16702592 ER PT J AU D'Souza, VM Foraker, AB Free, RB Ray, A Shapiro, PS Swaan, PW AF D'Souza, VM Foraker, AB Free, RB Ray, A Shapiro, PS Swaan, PW TI cAMP-coupled riboflavin trafficking in placental trophoblasts: A dynamic and ordered process SO BIOCHEMISTRY LA English DT Article ID PERFUSED HUMAN-PLACENTA; TRANSFERRIN RECEPTOR; IN-VITRO; CELLULAR TRANSLOCATION; COATED PITS; CELLS; TRANSPORT; NANOPARTICLES; INVOLVEMENT; ENDOCYTOSIS AB Riboflavin (RF, vitamin B-2), an essential micronutrient central to cellular metabolism through formation of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) cofactors, is internalized, at least in part, via a proposed receptor-mediated endocytic (RME) process. The purpose of this study was to delineate the cellular RF distribution using human placental trophoblasts and evaluate the regulatory role of cAMP in this process. Subcellular fractionation and three-dimensional confocal microscopy analyses were carried out to define the RF accumulation profile. Biochemical assays evaluating the cAMP dependence of this pathway were also performed. This study records an intracellular RF distribution pattern that shows dynamic accumulation of the ligand predominantly in the endosomal and lysosomal compartments and to a lesser extent in the Golgi and mitochondria. In contrast, transferrin (TF) colocalizes rapidly within endosomes with minimal accumulation in the other organelles. The temporal and spatial distribution of RF and TF colocalized with unique markers of the endocytic machinery provides added morphological evidence in support of the RME process with ultimate translocation to the mitochondrial domain. Colocalized staining with the Golgi also suggests a possible recycling or exocytic mechanism for this ligand. Furthermore, this study demonstrates cAMP regulation of the putative ligand-bound RF receptor and its association into endocytic vesicles. Delineating the dynamics of the process governing cellular RF homeostasis presents an untapped resource that can be further exploited in improving our current understanding of nutritional biology and fetal growth and development, and perhaps in targeting the endogenous system for developing novel therapeutic approaches. C1 Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. Natl Inst Neurol Disorders & Stroke, Mol Neuropharmacol Sect, NIH, Bethesda, MD 20852 USA. RP Swaan, PW (reprint author), Univ Maryland, Dept Pharmaceut Sci, 20 Penn St, Baltimore, MD 21201 USA. EM pswaan@rx.umaryland.edu OI Swaan, Peter/0000-0003-1767-1487 FU NIDDK NIH HHS [DK56631, R01 DK056631, R01 DK056631-04] NR 48 TC 9 Z9 9 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 16 PY 2006 VL 45 IS 19 BP 6095 EP 6104 DI 10.1021/bi060138f PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 043DG UT WOS:000237579000019 PM 16681382 ER PT J AU Skinner, PJ Abbassi, H Chesebro, B Race, RE Reilly, C Haase, AT AF Skinner, PJ Abbassi, H Chesebro, B Race, RE Reilly, C Haase, AT TI Gene expression alterations in brains of mice infected with three strains of scrapie SO BMC GENOMICS LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES; UP-REGULATED GENES; MOUSE BRAINS; ALZHEIMERS-DISEASE; PRION DISEASES; IDENTIFICATION; PROTEIN; CELLS; PATHOGENESIS AB Background: Transmissible spongiform encephalopathies (TSEs) or prion diseases are fatal neurodegenerative disorders which occur in humans and various animal species. Examples include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in deer and elk, and scrapie in sheep, and experimental mice. To gain insights into TSE pathogenesis, we made and used cDNA microarrays to identify disease-associated alterations in gene expression. Brain gene expression in scrapie-infected mice was compared to mock-infected mice at pre-symptomatic and symptomatic time points. Three strains of mouse scrapie that show striking differences in neuropathology were studied: ME7, 22L, and Chandler/RML. Results: In symptomatic mice, over 400 significant gene expression alterations were identified. In contrast, only 22 genes showed significant alteration in the pre-symptomatic animals. We also identified genes that showed significant differences in alterations in gene expression between strains. Genes identified in this study encode proteins that are involved in many cellular processes including protein folding, endosome/lysosome function, immunity, synapse function, metal ion binding, calcium regulation and cytoskeletal function. Conclusion: These studies shed light on the complex molecular events that occur during prion disease, and identify genes whose further study may yield new insights into strain specific neuropathogenesis and ante-mortem tests for TSEs. C1 Univ Minnesota, Dept Vet & Biomed Sci, Minneapolis, MN 55455 USA. NIH, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. Univ Minnesota, Dept Biostat, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA. RP Skinner, PJ (reprint author), Univ Minnesota, Dept Vet & Biomed Sci, Minneapolis, MN 55455 USA. EM skinn002@umn.edu; abbas004@umn.edu; BCHESEBRO@niaid.nih.gov; RRACE@niaid.nih.gov; reill017@umn.edu; haase001@umn.edu OI Skinner, Pamela/0000-0003-3388-1687 FU NIAID NIH HHS [T32 AI007421, T32 AI07421] NR 47 TC 68 Z9 69 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD MAY 16 PY 2006 VL 7 AR 114 DI 10.1186/1471-2164-7-114 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 053FW UT WOS:000238292000001 PM 16700923 ER PT J AU Vasan, RS AF Vasan, Ramachandran S. TI Biomarkers of cardiovascular disease - Molecular basis and practical considerations SO CIRCULATION LA English DT Review DE atherosclerosis; epidemiology; genetics; genomics; proteins ID CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; LEFT-VENTRICULAR HYPERTROPHY; PUBLIC-HEALTH PRACTICE; BRAIN NATRIURETIC PEPTIDE; DENSITY-LIPOPROTEIN CHOLESTEROL; MIDDLE-AGED MEN; SOLUBLE CD40 LIGAND; APOLIPOPROTEIN-A-I; EDUCATION-PROGRAM RECOMMENDATIONS C1 Framingham Heart Dis Epidemiol Study, NHLBI, Framingham, MA 01702 USA. Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02215 USA. Boston Univ, Sch Med, Dept Epidemiol & Prevent Med, Boston, MA 02215 USA. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, NHLBI, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM vasan@bu.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [1R01HL67288, 1R01HL71039, 2K24HL04334, N01-HC-25195, N01-HV-28178, U01 HL 66585] NR 412 TC 513 Z9 535 U1 5 U2 56 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 MAY 16 PY 2006 VL 113 IS 19 BP 2335 EP 2362 DI 10.1161/CIRCULATIONAHA.104.482570 PG 28 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 042TB UT WOS:000237551300014 PM 16702488 ER PT J AU Chan, WY Lee, TL Wu, SM Ruszczyka, L Alba, D Baxendale, V Rennert, OM AF Chan, WY Lee, TL Wu, SM Ruszczyka, L Alba, D Baxendale, V Rennert, OM TI Transcriptome analyses of male germ cells with serial analysis of gene expression (SAGE) SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE germ cells; transcriptome; promoter; network; apoptosis; splicing ID MAMMALIAN SPERMATOGENIC CELLS; CYTOCHROME-C RELEASE; MOUSE SPERMATOGENESIS; FUNCTIONAL-ANALYSIS; FAS SYSTEM; RAT TESTIS; IDENTIFICATION; APOPTOSIS; MICE; DIFFERENTIATION AB Serial analysis of gene expression (SAGE) provides an alternative with additional advantages to microarrays for studying gene expression during spermatogenesis. The digitized transcriptome provided by SAGE of purified mouse germ cells identified 27,504 species of transcripts expressed in type A spermatogonia, pachytene spermatocytes, and round spermatids. Over 2700 of these transcripts were novel. Computational analyses allowed the identification of clusters of co-regulated genes, cell-specific promoter modules, cell-specific biological processes, as well as "preferential" biological networks in different cell types. These analyses provided potential drug targets for interference of specific pathways at different stages of spermatogenesis. Analyses of the transcriptomes revealed the prominent role of cytochrome c oxidase in germ cells and suggest a novel role for this enzyme in cytochrome c-mediated apoptosis in spermatogonia. A number of genes were shown to undergo differential splicing during spermatogenesis giving rise to cell-specific splice variants. Published by Elsevier Ireland Ltd. C1 NICHHD, Lab Clin Genom, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Pediat, Washington, DC 20007 USA. RP Chan, WY (reprint author), NICHHD, Lab Clin Genom, NIH, 49 Convent Dr,MSC 4429, Bethesda, MD 20892 USA. EM chanwy@mail.nih.gov RI Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 FU Intramural NIH HHS NR 68 TC 23 Z9 25 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD MAY 16 PY 2006 VL 250 IS 1-2 BP 8 EP 19 DI 10.1016/j.mce.2005.12.018 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 049MP UT WOS:000238020900003 PM 16413108 ER PT J AU Liu, H Ippolito, GC Wall, JK Niu, T Probst, L Lee, BS Pulford, K Banham, AH Stockwin, L Shaffer, AL Staudt, LM Das, C Dyer, MJS Tucker, PW AF Liu, Hui Ippolito, Gregory C. Wall, Jason K. Niu, Teresa Probst, Loren Lee, Baeck-Seung Pulford, Karen Banham, Alison H. Stockwin, Luke Shaffer, Arthur L. Staudt, Louis M. Das, Chhaya Dyer, Martin J. S. Tucker, Philip W. TI Functional studies of BCLIIA: characterization of the conserved BCLIIA-XL splice variant and its interaction with BCL6 in nuclear paraspeckles of germinal center B cells SO MOLECULAR CANCER LA English DT Article ID ZINC-FINGER PROTEIN; GENE-EXPRESSION PROGRAM; LYMPHOCYTE DIFFERENTIATION; HODGKIN LYMPHOMA; T-LYMPHOCYTES; BCL11A; PROMOTER; COMPLEX; FOG; DNA AB Background: Chromosomal aberrations of BCL11A at 2p16.1 have been reported in a variety of B-cell malignancies and its deficiency in mice leads to a profound block in B-cell development. Results: Alternative pre-mRNA splicing of BCL11A produces multiple isoforms sharing a common N-terminus. The most abundant isoform we have identified in human lymphoid samples is BCL11AXL, the longest transcript produced at this locus, and here we report the conservation of this major isoform and its functional characterization. We show that BCL11A-XL is a DNA-sequence-specific transcriptional repressor that associates with itself and with other BCL11A isoforms, as well as with the BCL6 proto-oncogene. Western blot data for BCL11A-XL expression coupled with data previously published for BCL6 indicates that these genes are expressed abundantly in germinal-center-derived B cells but that expression is extinguished upon terminal differentiation to the plasma cell stage. Although BCL11A-XL/BCL6 interaction can modulate BCL6 DNA binding in vitro, their heteromeric association does not alter the homomeric transcriptional properties of either on model reporter activity. BCL11A-XL partitions into the nuclear matrix and colocalizes with BCL6 in nuclear paraspeckles. Conclusion: We propose that the conserved N-terminus of BCL11A defines a superfamily of C2HC zinc-finger transcription factors involved in hematopoietic malignancies. C1 Univ Texas, Sect Mol Genet & Microbiol, Austin, TX 78712 USA. Univ Texas, Inst Cellular & Mol Biol, Austin, TX 78712 USA. John Radcliffe Hosp, Nuffield Dept Clin Lab Sci, Oxford OX3 9DU, England. NCI, Metab Branch, Div Clin Sci, Bethesda, MD 20892 USA. Univ Leicester, MRC, Toxicol Unit, Leicester LE1 9HN, Leics, England. RP Tucker, PW (reprint author), Univ Texas, Sect Mol Genet & Microbiol, 1 Univ Stn,A5000, Austin, TX 78712 USA. EM hui.liu@zimmer.com; gci@mail.utexas.edu; jkwnavbandnerd@mail.utexas.edu; teresaniu@gmail.com; loren@mail.utexas.edu; bslee@mail.utexas.edu; karen.pulford@ndcls.ox.ac.uk; ahbanham@ndcls.ox.ac.uk; lstockwin@hotmail.com; artman@box-a.nih.gov; lstaudt@mail.nih.gov; cdas@mail.utexas.edu; mjsd1@leicester.ac.uk; philtucker@mail.utexas.edu RI Banham, Alison/B-2966-2009; Pulford, Karen/B-3609-2009; Dyer, Martin/F-2691-2014 OI Pulford, Karen/0000-0002-2989-789X; Dyer, Martin/0000-0002-5033-2236 FU Intramural NIH HHS; Medical Research Council [MC_U132670597]; NCI NIH HHS [F32 CA110624, 1F32CA110624-01A1, CA092318, R01 CA092318] NR 40 TC 33 Z9 38 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD MAY 16 PY 2006 VL 5 AR 18 DI 10.1186/1476-4598-5-18 PG 16 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 076OY UT WOS:000239968800001 PM 16704730 ER PT J AU Yuen, PST Jo, SK Holly, MK Hu, XZ Star, RA AF Yuen, Peter S. T. Jo, Sang-Kyung Holly, Mikaela K. Hu, Xuzhen Star, Robert A. TI Ischemic and nephrotoxic acute renal failure are distinguished by their broad transcriptomic responses SO PHYSIOLOGICAL GENOMICS LA English DT Article DE microarray; principal component analysis; TaqMan; western blots; immunohistochemistry ID GELATINASE-ASSOCIATED LIPOCALIN; MERCURIC-CHLORIDE; GENE-EXPRESSION; PROTEOMIC ANALYSIS; ADHESION MOLECULE; ENDOTHELIAL-CELLS; PROXIMAL TUBULE; C-FOS; KIDNEY; INJURY AB Acute renal failure (ARF) has a high morbidity and mortality. In animal ARF models, effective treatments must be administered before or shortly after the insult, limiting their clinical potential. We used microarrays to identify early biomarkers that distinguish ischemic from nephrotoxic ARF or biomarkers that detect both injury types. We compared rat kidney transcriptomes at 2 and 8 h after ischemia/reperfusion and after mercuric chloride. Quality control and statistical analyses were necessary to normalize microarrays from different lots, eliminate outliers, and exclude unaltered genes. Principal component analysis revealed distinct ischemic and nephrotoxic trajectories and clear array groupings. Therefore, we used supervised analysis, t-tests, and fold changes to compile gene lists for each group, exclusive or nonexclusive, alone or in combination. There was little network connectivity, even in the largest group. Some microarray-identified genes were validated by TaqMan assay, ruling out artifacts. Western blotting confirmed that heme oxygenase-1 (HO-1) and activating transcription factor-3 (ATF3) proteins were upregulated; however, unexpectedly, their localization changed within the kidney. HO-1 staining shifted from cortical (early) to outer stripe of the outer medulla (late), primarily in detaching cells, after mercuric chloride but not ischemia/reperfusion. ATF3 staining was similar, but with additional early transient expression in the outer stripe after ischemia/reperfusion. We conclude that microarray-identified genes must be evaluated not only for protein levels but also for anatomical distribution among different zones, nephron segments, or cell types. Although protein detection reagents are limited, microarray data lay a rich foundation to explore biomarkers, therapeutics, and the pathophysiology of ARF. C1 NIDDK, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD 20892 USA. RP Yuen, PST (reprint author), NIDDK, Renal Diagnost & Therapeut Unit, NIH, 10 Ctr Dr,Rm 3N108, Bethesda, MD 20892 USA. EM py@nih.gov RI Yuen, Peter/B-1954-2008 OI Yuen, Peter/0000-0001-9557-3909 FU Intramural NIH HHS; NIDDK NIH HHS [Z01 DK043400-06] NR 44 TC 42 Z9 44 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD MAY 16 PY 2006 VL 25 IS 3 BP 375 EP 386 DI 10.1152/physiolgenomics.00223.2005. PG 12 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 054KN UT WOS:000238375600003 PM 16507785 ER PT J AU Zheng, WJ Brooks, BR Thirumalai, D AF Zheng, WJ Brooks, BR Thirumalai, D TI Low-frequency normal modes that describe allosteric transitions in biological nanomachines are robust to sequence variations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE DNA polymerase; myosin; GroEL; elastic network model; robustness ID ELASTIC-NETWORK MODEL; DNA-POLYMERASE-I; CONFORMATIONAL TRANSITIONS; SINGLE-PARAMETER; LARGE FRAGMENT; PROTEINS; MYOSIN; NUCLEOTIDE; RESIDUES; DYNAMICS AB By representing the high-resolution crystal structures of a number of enzymes using the elastic network model, it has been shown that only a few low-frequency normal modes are needed to describe the large-scale domain movements that are triggered by ligand binding. Here we explore a link between the nearly invariant nature of the modes that describe functional dynamics at the mesoscopic level and the large evolutionary sequence variations at the residue level. By using a structural perturbation method (SPM), which probes the residue-specific response to perturbations (or mutations), we identify a sparse network of strongly conserved residues that transmit allosteric signals in three structurally unrelated biological nanomachines, namely, DNA polymerase, myosin motor, and the Escherichia coli chaperonin. Based on the response of every mode to perturbations, which are generated by interchanging specific sequence pairs in a multiple sequence alignment, we show that the functionally relevant low-frequency modes are most robust to sequence variations. Our work shows that robustness of dynamical modes at the mesoscopic level is encoded in the structure through a sparse network of residues that transmit allosteric signals. C1 NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. Univ Maryland, Inst Phys Sci & Technol, Biophys Program, College Pk, MD 20742 USA. RP Thirumalai, D (reprint author), NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. EM zhengwj@helix.nih.gov; brb@nih.gov; thirum@glue.umd.edu OI Zheng, Wenjun/0000-0002-6236-9765 FU Intramural NIH HHS; NIGMS NIH HHS [1R01GM067851-01, R01 GM067851] NR 33 TC 147 Z9 147 U1 3 U2 13 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 MAY 16 PY 2006 VL 103 IS 20 BP 7664 EP 7669 DI 10.1073/pnas.0510426103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 046UF UT WOS:000237835900026 PM 16682636 ER PT J AU Vietri, NJ Purcell, BK Lawler, JV Leffel, EK Rico, P Gamble, CS Twenhafel, NA Ivins, BE Heine, HS Sheeler, R Wright, ME Friedlander, AM AF Vietri, NJ Purcell, BK Lawler, JV Leffel, EK Rico, P Gamble, CS Twenhafel, NA Ivins, BE Heine, HS Sheeler, R Wright, ME Friedlander, AM TI Short-course postexposure antibiotic prophylaxis combined with vaccination protects against experimental inhalational anthrax SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Bacillus anthracis; treatment; vaccine ID CIPROFLOXACIN; PATHOGENESIS; ANTIBODIES; EFFICACY; ANTIGEN AB Prevention of inhalational anthrax after Bacillus anthracis spore exposure requires a prolonged course of antibiotic prophylaxis. In response to the 2001 anthrax attack in the United States, approximate to 10,000 people were offered 60 days of antibiotic prophylaxis to prevent inhalational anthrax, but adherence to this regimen was poor. We sought to determine whether a short course of antibiotic prophylaxis after exposure could protect non-human primates from a high-dose spore challenge if vaccination was combined with antibiotics. Two groups of 10 rhesus macaques were exposed to approximate to 1,600 LD50 of spores by aerosol. Both groups were given ciprofloxacin by orogastric tube twice daily for 14 days, beginning 1-2 h after exposure. One group also received three doses of the licensed human anthrax vaccine (anthrax vaccine adsorbed) after exposure. In the ciprofloxacin-only group, four of nine monkeys (44%) survived the challenge. In contrast, all 10 monkeys that received 14 days of antibiotic plus anthrax vaccine adsorbed survived (P = 0.011). Thus postexposure vaccination enhanced the protection afforded by 14 days of antibiotic prophylaxis alone and completely protected animals against inhalational anthrax. These data provide evidence that postexposure vaccination can shorten the duration of antibiotic prophylaxis required to protect against inhalational anthrax and may impact public health management of a bioterrorism event. C1 USA, Med Res Inst Infect Dis, Div Headquarters, Ft Detrick, MD 21702 USA. USA, Med Res Inst Infect Dis, Div Bacteriol, Ft Detrick, MD 21702 USA. USA, Med Res Inst Infect Dis, Div Med, Ft Detrick, MD 21702 USA. USA, Med Res Inst Infect Dis, Div Vet Med, Ft Detrick, MD 21702 USA. USA, Med Res Inst Infect Dis, Div Pathol, Ft Detrick, MD 21702 USA. USA, Med Res Inst Infect Dis, Ctr Aerobiol Sci, Ft Detrick, MD 21702 USA. Bayer Pharmaceut Corp, West Haven, CT 06516 USA. NIAID, Biodefense Clin Res Branch, NIH, Bethesda, MD 20892 USA. RP Friedlander, AM (reprint author), USA, Med Res Inst Infect Dis, Div Headquarters, 1425 Porter St, Ft Detrick, MD 21702 USA. EM arthur.friedlander@amedd.army.mil OI Gamble, Christopher/0000-0002-2094-205X NR 16 TC 40 Z9 42 U1 1 U2 4 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 MAY 16 PY 2006 VL 103 IS 20 BP 7813 EP 7816 DI 10.1073/pnas.0602748103 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 046UF UT WOS:000237835900051 PM 16672361 ER PT J AU Balansky, R D'Agostini, F Ganchev, G Izzotti, A Di Marco, B Lubet, RA Zanesi, N Croce, CM De Flora, S AF Balansky, R D'Agostini, F Ganchev, G Izzotti, A Di Marco, B Lubet, RA Zanesi, N Croce, CM De Flora, S TI Influence of FHIT on benzo[a]pyrene-induced tumors and alopecia in mice: Chemoprevention by budesonide and N-acetylcysteine SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE alopecia areata; lung tumors; stomach tumors ID FEMALE A/J MICE; DEFICIENT MICE; CIGARETTE-SMOKE; LUNG-CANCER; PULMONARY CARCINOGENESIS; AEROSOLIZED BUDESONIDE; GENE-THERAPY; PREVENTION; PROGRESSION; MODULATION AB The FHIT gene has many ha I I marks of a tumor-suppressor gene and is involved in a large variety of cancers. We treated A/J mice and (C57BL/6J x 129/SvJ)F-1 (B6/129 F-1) mice, either wild-type or FHIT+/-, with multiple doses of benzo[a]pyrene (B[a]P) by gavage. B[a]P caused a time-related increase of micronuclei in peripheral blood erythrocytes. Both A/J and B6/129 F, mice, irrespective of their FHIT status, were sensitive to induction of forestomach tumors, whereas B[a]P induced glandular stomach hyperplasia and a high multiplicity of lung tumors in A/J mice only. Preneoplastic lesions of the uterus were more frequent in FHIT+/- mice. B6/129 F-1 mice underwent spontaneous alopecia areata and hair bulb cell apoptosis, which were greatly accelerated either by FHIT heterozygosity or by B[a]P treatment, thus suggesting that FHIT plays a role in the pathogenesis of alopecia areata. The oral administration of either budesonide or N-acetyl-L-cysteine (NAC) inhibited the occurrence of this inflammatory skin disease. In addition, these agents prevented B[a]P-induced glandular stomach hyperplasia and decreased the size of both forestomach tumors and lung tumors in A/J mice. Budesonide also attenuated lung tumor multiplicity. In 136/129 F-1 mice, NAC significantly decreased the proliferating cell nuclear antigen in lung tumors. Both budesonide and NAC inhibited B[a]P-induced forestomach tumors and preneoplastic lesions of the respiratory tract in 136/129 F, mice. In conclusion, heterozygosity for FHIT affects susceptibility of mice to spontaneous alopecia areata and B[a]P-induced preneoplastic lesions of the uterus and does not alter responsiveness to budesonide and NAC. C1 Univ Genoa, Dept Hlth Sci, I-16132 Genoa, Italy. NCI, Rockville, MD 20899 USA. Natl Oncol Ctr, Sofia 1756, Bulgaria. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Via A Pastore 1, I-16132 Genoa, Italy. EM sdf@unige.it OI izzotti, alberto/0000-0002-8588-0347 NR 38 TC 15 Z9 15 U1 0 U2 1 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 MAY 16 PY 2006 VL 103 IS 20 BP 7823 EP 7828 DI 10.1073/pnas.0601412103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 046UF UT WOS:000237835900053 PM 16672365 ER PT J AU Fox, CS Guo, CY Larson, MG Vasan, RS Parise, H O'Donnell, CJ D'Agostino, RB Keaney, JF Benjamin, EJ AF Fox, CS Guo, CY Larson, MG Vasan, RS Parise, H O'Donnell, CJ D'Agostino, RB Keaney, JF Benjamin, EJ TI Relations of inflammation and novel risk factors to valvular calcification SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID NONRHEUMATIC AORTIC-STENOSIS; CARDIAC-VALVE CALCIFICATION; T-LYMPHOCYTE INFILTRATION; CORONARY HEART-DISEASE; STAGE RENAL-DISEASE; ASSOCIATION; EXPRESSION AB Investigators have suggested that inflammation may play a role in the pathogenesis of valve calcium. Participants in the Framingham Heart Study's offspring cohort had systemic levels of C-reactive protein, intercellular adhesion molecule-1, interleukin-6, and monocyte chemoattractant protein-1 measured at examination cycle 7. Mitral annular calcium, aortic annular calcium, aortic sclerosis, and aortic stenosis were assessed by echocardiography at examination cycle 6. Logistic regression was used to examine the odds of valvular calcium per 1 unit increase in inflammation (ISUM), a summary statistic of all normalized deviates of the individual markers. Two thousand six hundred eighty-three participants (mean age 61 +/- 10 years; 52% women) were analyzed: 8.2% (n = 216) had 1 calcified valve or annulus; 89 had mitral annular calcium, 78 had aortic annular calcium, 135 had aortic sclerosis, and 33 had aortic stenosis. Participants with valvular calcium were older and were more likely to have hypertension and diabetes mellitus. Participants with valve calcium had higher median levels of all markers. For each log unit increase in ISUM, after adjustment for age and gender, there was an associated 1.1-fold increased odds of >= 1 calcified valve (p = 0.02); the odds ratios were no longer significant after adjustment for cardiovascular disease risk factors (odds ratio 1.0, 95% confidence interval 0.9 to 1.1). Similar results were obtained for the individual markers and the odds of >= 1 calcified valve. In conclusion, inflammatory markers were elevated in patients with valvular calcium. Our findings suggest that much of the observed association between systemic inflammatory markers and valvular calcium may be due to shared risk factors. (c) 2006 Elsevier Inc. All rights reserved. C1 Framingham Heart Dis Epidemiol Study, NHLBI, Framingham, MA USA. Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02118 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Diabet Endocrinol & Metab, Boston, MA 02115 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Fox, CS (reprint author), Framingham Heart Dis Epidemiol Study, NHLBI, Framingham, MA USA. EM foxca@nhlbi.nih.gov OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [R01 HL076784, K24-HL-04334, N01-HC-25195, R01 HL64753]; NINDS NIH HHS [6R01-NS-17950] NR 20 TC 30 Z9 33 U1 0 U2 1 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAY 15 PY 2006 VL 97 IS 10 BP 1502 EP 1505 DI 10.1016/j.amjcard.2005.11.086 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 044YC UT WOS:000237708600018 PM 16679093 ER PT J AU Maggio, M Ceda, GP Lauretani, F Pahor, M Bandinelli, S Najjar, SS Ling, SM Basaria, S Ruggiero, C Luigi, G Ferrucci, L AF Maggio, M Ceda, GP Lauretani, F Pahor, M Bandinelli, S Najjar, SS Ling, SM Basaria, S Ruggiero, C Luigi, G Ferrucci, L TI Relation of angiotensin-converting enzyme inhibitor treatment to insulin-like growth factor-1 serum levels in subjects > 65 years of age (the InCHIANTI study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID MUSCLE STRENGTH; SKELETAL-MUSCLE; HEART-FAILURE; OLDER PERSONS; RECEPTOR; HEALTH; WOMEN; ACE AB Observational studies have shown that the use of angiotensin-converting enzyme (ACE) inhibitors is associated with the maintenance of greater muscle strength and physical performance in older subjects. However, the mechanism that underlies these beneficial effects remains poorly understood. Because ACE inhibitors block the production of angiotensin 11, which is a potent inhibitor of insulin-like growth factor-1 (IGF-1) production, it was hypothesized that treatment with ACE inhibitors is associated with higher levels of IGF-1. This hypothesis was tested in 745 subjects (417 women, 328 men) enrolled in the Invecchiare in Chianti study. Of these, 160 were receiving ACE inhibitors. The association between ACE inhibitor use and serum IGF-1 was tested by linear regression models, After adjusting for multiple potential confounders, serum levels of total IGF-1 were significantly higher in participants receiving ACE inhibitors (mean +/- SD 129.0 +/- 56.1 ng/ml) compared with the rest of the study population (mean +/- SD 116.5 +/- 54.8 ng/ml) (p < 0.001). Participants with short (< 3 years) and long (3 to 9 years) treatment durations had higher serum IGF-1 levels than participants who were not receiving ACE inhibitor treatment, but the difference was statistically significant only for the short-duration group (p < 0.05). In conclusion, in older subjects, treatment with ACE inhibitors for < 3 years is associated with significantly higher levels of IGF-1. This may be 1 of the mechanisms by which ACE inhibitors might slow the decreases in muscle strength and physical function that are often observed in older subjects. (c) 2006 Elsevier Inc. All rights reserved. C1 NIA, Clin Res Branch, Intramural Res Program, Longitudinal Studies Sect,NIH, Bethesda, MD 20892 USA. NIA, Clin Res Branch, Intramural Res Program, Adv Studies Translat Res Aging Unit,NIH, Bethesda, MD 20892 USA. Univ Parma, Dept Internal Med & Biomed Sci, Sct Geriatr, I-43100 Parma, Italy. Tuscany REg Hlth Agcy, Florence, Italy. Univ Florida, Coll Med, Dept Aging & Geriat Res, Gainesville, FL USA. Azienda Sanitaria Firenze, Geriatr Rehabil Unit, Florence, Italy. NIA, Cardiovasc Sci Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Baystate Med Ctr, Dept Med,Div Endocrinol, Baltimore, MD USA. RP Ferrucci, L (reprint author), NIA, Clin Res Branch, Intramural Res Program, Longitudinal Studies Sect,NIH, Bethesda, MD 20892 USA. EM ferruccilu@grc.nia.nih.gov RI Lauretani, Fulvio/K-5115-2016; OI Lauretani, Fulvio/0000-0002-5287-9972; Ceda, Gian Paolo/0000-0002-9648-8295 FU Intramural NIH HHS [Z99 AG999999]; NIMHD NIH HHS [263 MD 821336, 263 MD 916413] NR 19 TC 25 Z9 26 U1 0 U2 1 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAY 15 PY 2006 VL 97 IS 10 BP 1525 EP 1529 DI 10.1016/j.amjcard.2005.11.089 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 044YC UT WOS:000237708600023 PM 16679098 ER PT J AU Friedenreich, CM Courneya, KS Neilson, HK Matthews, CE Willis, G Irwin, M Troiano, R Ballard-Barbash, R AF Friedenreich, CM Courneya, KS Neilson, HK Matthews, CE Willis, G Irwin, M Troiano, R Ballard-Barbash, R TI Reliability and validity of the past year total physical activity questionnaire SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE data collection; exercise; physical fitness; questionnaires; reproducibility of results ID ENERGY-EXPENDITURE; COMPUTER-SCIENCE; CANCER RISK; REPRODUCIBILITY; ACCELEROMETER; CALIBRATION; HEALTH; VALIDATION; VARIANCE; ADULTS AB The authors determined the validity and reliability of their Past Year Total Physical Activity Questionnaire (PYTPAQ), which assesses the frequency, duration, and intensity of occupational, household, and recreational activities performed over the past year. The PYTPAQ was completed twice at baseline, 9 weeks apart (on average), by 154 healthy Canadian men and women aged 35-65 years for assessment of reliability. The PYTPAQ was completed again 1 year later as a self-administered questionnaire. Four times during the year, participants wore an accelerometer for 7 days and completed 7-day physical activity logs. The authors assessed validity by comparing PYTPAQ summary values with 1-year averages of the physical activity logs and accelerometer data and with physical fitness and anthropometric data measured at baseline and 1 year. Spearman correlations for reliability (metabolic equivalent-hours/week) were 0.64 for total activity, 0.70 for occupational activity, 0.73 for recreational activity, and 0.65 for household activity. For total activity, the intraclass correlation coefficient for correlation between the PYTPAQ and the 7-day physical activity logs was 0.42 (95% confidence interval: 0.28, 0.54), and for the accelerometer data it was 0.18 (95% confidence interval: 0.03, 0.32). Spearman correlations between PYTPAQ hours/week of vigorous activity and maximal oxygen uptake were 0.37 and 0.32 at baseline and follow-up, respectively. In general, the PYTPAQ has acceptable reliability and validity for measurement of past-year physical activity that is comparable to that of similar questionnaires. C1 Alberta Canc Board, Div Populat Hlth & Informat, Calgary, AB T2N 4N2, Canada. Univ Alberta, Fac Phys Educ & Recreat, Edmonton, AB, Canada. Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Dept Med,Div Gen Internal Med, Nashville, TN 37212 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Yale Univ, Sch Publ Hlth, Dept Epidemiol, New Haven, CT USA. RP Friedenreich, CM (reprint author), Alberta Canc Board, Div Populat Hlth & Informat, 1331 29 St NW, Calgary, AB T2N 4N2, Canada. EM chrisf@cancerboard.ab.ca RI matthews, Charles/E-8073-2015; OI matthews, Charles/0000-0001-8037-3103; Troiano, Richard/0000-0002-6807-989X FU NCI NIH HHS [K07 CA109363] NR 35 TC 98 Z9 99 U1 1 U2 15 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 MAY 15 PY 2006 VL 163 IS 10 BP 959 EP 970 DI 10.1093/aje/kwj112 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 039PQ UT WOS:000237319100011 PM 16524954 ER PT J AU Montello, MJ Tarosky, M Pincock, L Montello, N Hess, WA Velazquez, L Patel, A Krzyworzeka, J Hay, E AF Montello, MJ Tarosky, M Pincock, L Montello, N Hess, WA Velazquez, L Patel, A Krzyworzeka, J Hay, E TI Dosing cards for treatment of children exposed to weapons of mass destruction SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article C1 NCI, Protocol & Informat Off, Rockville, MD 20852 USA. US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. Costco Pharm, Southbury, CT USA. Capital Technol Informat Syst, Global Hlth Dev, Rockville, MD USA. Philadelphia Coll Pharm, Philadelphia, PA USA. RP Montello, MJ (reprint author), NCI, Protocol & Informat Off, 6130 Execut Blvd,Suite 6118, Rockville, MD 20852 USA. EM montellom@ctep.nci.nih.gov NR 14 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD MAY 15 PY 2006 VL 63 IS 10 BP 944 EP 949 DI 10.2146/ajhp050372 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 042HB UT WOS:000237517600012 PM 16675651 ER PT J AU Bookman, EB Langehorne, AA Eckfeldt, JH Glass, KC Jarvik, GP Klag, M Koski, G Motulsky, A Wilfond, B Manolio, TA Fabsitz, RR Luepker, RV AF Bookman, EB Langehorne, AA Eckfeldt, JH Glass, KC Jarvik, GP Klag, M Koski, G Motulsky, A Wilfond, B Manolio, TA Fabsitz, RR Luepker, RV TI Reporting genetic results in research studies: Summary and recommendations of an NHLBI working group SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Editorial Material DE research results; genetic testing; reporting research results ID CHILDRENS ONCOLOGY GROUP; RESEARCH PARTICIPANTS; INFORMED-CONSENT; ATTITUDES; POPULATION; TRIAL; ASSOCIATION; ISSUES; NEEDS AB Prospective epidemliologic studies aid in identifying genetic variants associated with diseases, health risks, and phhysiologic traits. These genetic variants may eventually be measured clinically for purposes of diagnosis, prognosis, and treatment. As evidence of the Potential clinical value of such information accrues, research studies face growing pressure to report these results to study participants or their physicians, even before sufficient evidence is available to support widespread screening of asymptomatic persons. There is thus a need to begin to develop consensus on whether and when genetic findings should be reported to participants in research studies. The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group on Reporting Genetic Resuls in Research Studies to discuss if, when, and how genetic information should be reported to study participants. The Working Group concluded that genetic test results should he reported to study participants when the associated risk for the disease is significant; the disease has important health inifilications such as premature death or substantial morbidity or has significant reproductive implications and proven therapeutic or preventive interventions are available. Finally, the working group recommended procedures for reporting genetic research results and encouraged increased efforts to create uniform guidelines for this activity. Published 2006 Wiley-Liss, Inc. C1 NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. NHLBI, Biomed Res Training Program Underrepresented Mino, Bethesda, MD 20892 USA. Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. McGill Univ, Dept Human Genet & Pediat, Montreal, PQ, Canada. Univ Washington, Med Ctr, Dept Med, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. Johns Hopkins Univ, Dept Internal Med, Baltimore, MD USA. Massachusetts Gen Hosp, Dept Anesthesia, Boston, MA 02114 USA. NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. Univ Minnesota, Div Epidemiol, Minneapolis, MN 55455 USA. RP Bookman, EB (reprint author), NHLBI, Div Epidemiol & Clin Applicat, 6701 Rockledge Dr,Room 8166, Bethesda, MD 20892 USA. EM bookmane@mail.nih.gov RI Jarvik, Gail/N-6476-2014 OI Jarvik, Gail/0000-0002-6710-8708 FU Intramural NIH HHS [Z99 HG999999] NR 34 TC 121 Z9 121 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD MAY 15 PY 2006 VL 140A IS 10 BP 1033 EP 1040 DI 10.1002/ajmg.a.31195 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 037TW UT WOS:000237171100001 PM 16575896 ER PT J AU Miller, NH Marosy, B Justice, CM Novak, SM Tang, EY Boyce, P Pettengil, J Doheny, KF Pugh, EW Wilson, AF AF Miller, NH Marosy, B Justice, CM Novak, SM Tang, EY Boyce, P Pettengil, J Doheny, KF Pugh, EW Wilson, AF TI Linkage analysis of genetic loci for kyphoscoliosis on chromosomes 5q13, 13q13.3, and 13q32 SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE kyphoscoliosis; single nucleotide polymorphism; linkage analysis ID ADOLESCENT IDIOPATHIC SCOLIOSIS; SAGITTAL CONFIGURATION; SEGREGATION ANALYSIS; SCHEUERMANN-DISEASE; FIBRILLIN GENES; PROTEIN; IDENTIFICATION; KYPHOSIS; MUTATION; CLONING AB Kyphoscoliosis, a three-dimensional deformity of spinal growth, is characterized by a curvature in the coronal plane (scoliosis) in conjunction with thoracic kyphosis in excess of the normal range in the sagittal plane. We identified kyphoscoliosis within members of seven families (53 individuals) originally ascertained as part of a large collaborative study of familial idiopathic scoliosis. Model-independent linkage analysis of a genome-wide microsatellite screen identified areas suggestive of linkage on chromosomes 2q22, 5p13, 13q, and 17q11. Single-point and multipoint analyses of an additional 25 flanking microsatellite markets corroborated linkage to these regions, with areas on chromosomes 5p13, 13q13, and 13q32 being the most: significant (P < 0.005). Analyses of single nucleotide polymorphism (SNP) markers in the candidate region oil chromosome 5 narrowed the region to approximately 3.5 Mb (p < 0.05), with the "lost significant P values (P < 0.01) occurring ill approximately a 1.3-Mb region. Candidate loci in this region include IRX1, IRX2, and IRX4 of the Iroquois Homeobox protein family. On chromosome 13, single-point and multipoint analyses resulted in multiple SNPs having P values < 0.05 within five candidate genes: Osteoblast-specific factor 2 or periostin, forkhead box O1A, A-kinase anchor protein 11, TBC1 domain family member 4, and glypican 5, thus supporting the potential relevance of this region in the pathogenesis of kyphoscoliosis. (c) 2006 Wiley-Liss, Inc. C1 Johns Hopkins Univ, Sch Med, Dept Orthopaed Surg, Inst Med Genet, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Ctr Inherited Dis Res, Inst Med Genet, Baltimore, MD USA. NHGRI, Genometr Sect, NIH, Baltimore, MD USA. RP Miller, NH (reprint author), Johns Hopkins Outpatient Ctr, Dept Orthopaed Surg, 601 N Caroline St, Baltimore, MD 21287 USA. EM nmillerb@jhmi.edu RI Wilson, Alexander/C-2320-2009 FU NCRR NIH HHS [P41 RR03655]; NHGRI NIH HHS [N01-HG-65403] NR 60 TC 19 Z9 19 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD MAY 15 PY 2006 VL 140A IS 10 BP 1059 EP 1068 DI 10.1002/ajmg.a.31211 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 037TW UT WOS:000237171100004 PM 16596674 ER PT J AU Borgaonkar, D AF Borgaonkar, D TI Literature searches of double trisomy citations are inadequate SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Letter C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Borgaonkar, D (reprint author), NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM borgaonk@mail.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD MAY 15 PY 2006 VL 140A IS 10 BP 1126 EP 1126 DI 10.1002/ajmg.a.31206 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 037TW UT WOS:000237171100016 PM 16596672 ER PT J AU Thorne, PS Arbes, SJ Zeldin, DC AF Thorne, PS Arbes, SJ Zeldin, DC TI Endotoxin and asthma - Reply SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Letter C1 Univ Iowa, Iowa City, IA 52240 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Thorne, PS (reprint author), Univ Iowa, Iowa City, IA 52240 USA. NR 4 TC 1 Z9 1 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAY 15 PY 2006 VL 173 IS 10 BP 1177 EP 1177 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 042MD UT WOS:000237531200021 ER PT J AU Xiao, BL Zhong, GF Obayashi, M Yang, DM Chen, KY Walsh, MP Shimoni, Y Cheng, HP ter Keurs, H Chen, SRW AF Xiao, BL Zhong, GF Obayashi, M Yang, DM Chen, KY Walsh, MP Shimoni, Y Cheng, HP ter Keurs, H Chen, SRW TI Ser-2030, but not Ser-2808, is the major phosphorylation site in cardiac ryanodine receptors responding to protein kinase A activation upon beta-adrenergic stimulation in normal and failing hearts SO BIOCHEMICAL JOURNAL LA English DT Article DE heart failure (HF); beta-adrenergic stimulation; protein kinase A (PKA); ryanodine receptor (RyR) phosphorylation; phospho-specific antibodies ID SARCOPLASMIC-RETICULUM CA2+; PKA PHOSPHORYLATION; BETA(1)-ADRENERGIC STIMULATION; DEFECTIVE REGULATION; CALCIUM CHANNELS; FAILURE; RELEASE; CONTRACTILITY; PHOSPHATASES; SERINE-2808 AB We have recently shown that RyR2 (cardiac ryanodine receptor) is phosphorylated by PKA (protein kinase A/cAMP-dependent protein kinase) at two major sites, Ser-2030 and Ser-2808. In the present study, ye examined the properties and physiological relevance of phosphorylation of these two sites. Using site- and phospho-specific antibodies, we demonstrated that Ser-2030 of both recombinant and native RyR2 from a number of species was phosphorylated by PKA, indicating that Ser-2030 is a highly conserved PKA site. Furthermore, we found that the phosphorylation of Ser-2030 responded to isoproterenol (isoprenaline) stimulation in rat cardiac myocytes in a concentration- and time-dependent manner, whereas Ser-2808 was already substantially phosphorylated before beta-adrenergic stimulation, and the extent of the increase in Ser-2808 phosphorylation after P-adrenergic stimulation was much less than that for Ser-2030. Interestingly, the isoproterenol-induced phosphorylation of Ser-2030, but not of Ser-2808, was markedly inhibited by PKI, a specific inhibitor of PKA. The basal phosphorylation of Ser-2808 was also insensitive to PKA inhibition. Moreover, Ser-2808, but not Ser-2030, was stoichiometrically phosphorylated by PKG (protein kinase G). In addition, we found no significant phosphorylation of RyR2 at the Ser-2030 PKA site in failing rat hearts. Importantly, isoproterenol stimulation markedly increased the phosphorylation of Ser-2030, but not of Ser-2808, in failing rat hearts. Taken together, these observations indicate that Ser-2030, but not Ser-2808, is the major PKA phosphorylation site in RyR2 responding to PKA activation upon P-adrenergic stimulation in both normal and failing hearts,. and that RyR2 is not hyperphosphorylated by PKA in heart failure. Our results also suggest that phosphorylation of RyR2 at Ser-2030 may be an important event associated with altered Ca2+ handling and cardiac arrhythmia that is commonly observed in heart failure upon P-adrenergic stimulation. C1 Univ Calgary, Cardiovasc Res Grp, Dept Physiol & Biophys, Calgary, AB, Canada. NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. Univ Calgary, Smooth Muscle Res Grp, Dept Biochem & Mol Biol, Calgary, AB, Canada. RP Chen, SRW (reprint author), Univ Calgary, Cardiovasc Res Grp, Dept Physiol & Biophys, Calgary, AB, Canada. EM swchen@ucalgary.ca RI Xiao, Bailong/B-6187-2012 NR 32 TC 82 Z9 87 U1 1 U2 4 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD MAY 15 PY 2006 VL 396 BP 7 EP 16 DI 10.1042/BJ20060116 PN 1 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 047KJ UT WOS:000237877900002 PM 16483256 ER PT J AU Seto, B McLaughlin, A Li, K Menkens, N Sullivan, D Pettigrew, R AF Seto, B McLaughlin, A Li, K Menkens, N Sullivan, D Pettigrew, R TI Advancing the boundaries of molecular imaging SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material C1 Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Seto, B (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, 6707 Democracy Blvd Suite 202,MSC 5477, Bethesda, MD 20892 USA. EM setob@mail.nih.gov FU Intramural NIH HHS 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 15 PY 2006 VL 59 IS 10 BP 881 EP 882 DI 10.1016/j.biopsych.2005.07.037 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 044MH UT WOS:000237676100001 PM 16165101 ER PT J AU Shen, J AF Shen, J TI C-13 magnetic resonance spectroscopy studies of alterations in glutamate neurotransmission SO BIOLOGICAL PSYCHIATRY LA English DT Review DE glutamate-glutamine cycle; in vivo C-13 magnetic resonance spectroscopy; glucose metabolism; acetate metabolism; GABA ID TRICARBOXYLIC-ACID CYCLE; GAMMA-AMINOBUTYRIC ACID; IN-VIVO; RAT-BRAIN; METABOLIC COMPARTMENTATION; GABA-TRANSAMINASE; TCA CYCLE; GLUCOSE-METABOLISM; PREFRONTAL CORTEX; ENERGY-METABOLISM AB Over the past a few years, significant progresas has been made in refining the in vivo C-13 magnetic resonance spectroscopy technique and in applying it to studying the alterations in the glutamate-glutamine cycling flux. Meanwhile, the details of the metabolic modeling are being rigorously debated. Recent exidence against fast alpha-ketoglutarate-glutamate exchange across the motochondrial membrane is examined. Previous reports have indicated that glutamate release or C-13 label incorporation into glutamine is attenuated at elevated concentrations of endogenous gamma-aminobutyric acid (GABA). A recent study has shown that phenelzine administration reduces the glutamate-glutamine cycling flux while raising endogenous GABA levels in vivo. Effects of several metabotropic glutamate receptor agonists and antagonists and brain disorders on the glutamate-glutamine cycle are also summarized. C1 NIMH, Mol Imaging Branch, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Shen, J (reprint author), NIMH, Mol Imaging Branch, Mood & Anxiety Disorders Program, Bldg 10,Rm 2D51A,9000 Rockville Pike, Bethesda, MD 20892 USA. EM shenj@intra.nimh.nih.gov NR 62 TC 20 Z9 21 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 15 PY 2006 VL 59 IS 10 BP 883 EP 887 DI 10.1016/j.biopsych.2005.07.042 PG 5 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 044MH UT WOS:000237676100002 PM 16199016 ER PT J AU Hariri, AR Drabant, EM Weinberger, DR AF Hariri, Ahmad R. Drabant, Emily M. Weinberger, Daniel R. TI Imaging genetics: Perspectives from studies of genetically driven variation in serotonin function and corticolimbic affective processing SO BIOLOGICAL PSYCHIATRY LA English DT Review DE emotion; mood disorders; serotonin; amygdala; prefrontal cortex; neuroimaging; genetics ID TRANSPORTER PROMOTER POLYMORPHISM; ANXIETY-RELATED TRAITS; HUMAN AMYGDALA; PERSONALITY-TRAITS; TRYPTOPHAN DEPLETION; PREFRONTAL CORTEX; MAJOR DEPRESSION; 5-HTTLPR POLYMORPHISM; BEHAVIORAL-RESPONSES; REGION POLYMORPHISM AB Advances in molecular biology and neuroimaging have provided a unique opportunity to explore the relationships between genes, brain, and behavior. In this review, we will briefly outline the rationale for studying genetic effects on brain Junction with neuroimaging. We will then use studies of genetically driven variation in serotonin transporter function on corticolimbic structure and function to highlight the effectiveness of this strategy to delineate biological pathways and mechanisms by which individual differences in brain function emerge and potentially bias behavior and risk for psychiatric illness. In a series of studies, a relatively frequent regulatory variant of the human serotonin transporter gene (5-HTTLPR) has been demonstrated to bias the reactivity of the amygdala to salient environmental cues. Moreover, the 5-HTTLPR affects the development of a broader corticolimbic circuit and alters the Junctional integration of emotional information between the amygdala and, medial prefrontal cortex. In turn, corticolimbic circuit reflect a predictive,function Predicts individual differences in an experimental index of temperamental anxiety and, thus, might re biological marker of increased risk for mood disorders associated with the 5-HTTLPR. C1 Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Dev Imaging Genom Program,Dept Psychiat, Pittsburgh, PA 15213 USA. NIMH, Genet Cognit & Psychosis Program, IRP, NIH,DHHS, Bethesda, MD 20892 USA. RP Hariri, AR (reprint author), Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Dev Imaging Genom Program,Dept Psychiat, 3811 O'Hara St,Room E-729, Pittsburgh, PA 15213 USA. RI Hariri, Ahmad/D-5761-2011 FU Intramural NIH HHS; NIMH NIH HHS [K01MH072837] NR 106 TC 210 Z9 216 U1 6 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 15 PY 2006 VL 59 IS 10 BP 888 EP 897 DI 10.1016/j.biopsych.2005.11.005 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 044MH UT WOS:000237676100003 PM 16442081 ER PT J AU Cropley, VL Fujita, M Innis, RB Nathan, PJ AF Cropley, VL Fujita, M Innis, RB Nathan, PJ TI Molecular imaging of the dopaminergic system and its association with human cognitive function SO BIOLOGICAL PSYCHIATRY LA English DT Review DE PET; SPECT; dopamine; cognition; Parkinson's disease; schizophrenia ID POSITRON-EMISSION-TOMOGRAPHY; SPATIAL WORKING-MEMORY; EARLY PARKINSONS-DISEASE; D-2 RECEPTOR-BINDING; IN-VIVO BINDING; PREFRONTAL CORTEX; BASAL GANGLIA; ENDOGENOUS DOPAMINE; HUMAN BRAIN; CATECHOLAMINE DEPLETION AB Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) has recently been used to examine dopamine (DA)Junction and its relationship with cognition in human subjects. This article will review PET and SPECT studies that have explored the relationship between cognitive processes and components of the DA system (pre-, intra-, and postsynaptic) in healthy and patient populations such as Parkinsons disease (PD), schizophrenia, Huntington's disease, and aging. it is demonstrated that DA activity modulates a range of frontal executive-type cognitive processes such as working memory, attentional functioning, and sequential organization, and alterations of DA within the fronto-striato-thalamic circuits might contribute to the cognitive impairments observed in PD, schizophrenia, and normal aging. Although associations between DA and cognitive measures need to be considered within the context of fronto-striato-thalamic circuitry, it is suggested that striatal (especially caudate) DA receptors, might be important for response inhibition, temporal organization of material, and motor activity, particularly via D-2 receptors might be important for response inhibition, temporal organization of material, and motor performance, whereas conical DA transmission via D-1 receptors might be important for maintaining and representing on-going behavior. C1 Monash Univ, Monash Ctr Brain & Behav, Dept Physiol, Behav Neurosci Lab, Clayton, Vic 3800, Australia. NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. RP Cropley, VL (reprint author), Monash Univ, Monash Ctr Brain & Behav, Dept Physiol, Behav Neurosci Lab, Clayton, Vic 3800, Australia. EM cropleyv@mail.nih.gov NR 91 TC 158 Z9 160 U1 4 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 15 PY 2006 VL 59 IS 10 BP 898 EP 907 DI 10.1016/j.biopsych.2006.03.004 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 044MH UT WOS:000237676100004 PM 16682268 ER PT J AU Nichols, L Pike, VW Cai, LS Innis, RB AF Nichols, L Pike, VW Cai, LS Innis, RB TI Imaging and in vivo quantitation of beta-amyloid: An exemplary biomarker for Alzheimer's disease? SO BIOLOGICAL PSYCHIATRY LA English DT Review DE Alzheimer's disease; imaging; amyloid; biomarker; PET; MRI ID MILD COGNITIVE IMPAIRMENT; POSITRON-EMISSION-TOMOGRAPHY; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; APOLIPOPROTEIN-E EPSILON-4; PITTSBURGH COMPOUND-B; A-BETA; NEUROFIBRILLARY TANGLES; CASCADE HYPOTHESIS; PROTEIN-PRECURSOR; TRANSGENIC MICE AB Alzheimer's disease (AD) is characterized pathologically by the presence of beta-amyloid plaques in the brain. A substantial body of research indicates that the presence of increased beta-amyloid peptide (A beta) is neurotoxic and may initiate the further pathology observed in AD, including neurofibrillary tangles, synaptic loss and dysfunction, and neurodegeneration. The use of brain imaging in patients with or at risk for AD has increased our understanding of pathophysiology of the disease and may potentially aid in diagnosis. The development of new therapeutics that reduce A beta in the brain has also indicated a potential use for amyloid imaging in monitoring response to treatment. This review explores the utility of amyloid as a biomarker and the use of positron emission tomography and magnetic resonance imaging in the diagnosis and treatment of AD. C1 NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. RP Innis, RB (reprint author), NIMH, Mol Imaging Branch, 1 Ctr Dr MSC 0135,Bldg 1,Room B3-10, Bethesda, MD 20892 USA. EM robert.innis@nih.gov NR 66 TC 19 Z9 20 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 15 PY 2006 VL 59 IS 10 BP 940 EP 947 DI 10.1016/j.biopsych.2005.12.004 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 044MH UT WOS:000237676100008 PM 16487944 ER PT J AU Lafite, P Dijols, S Buisson, D Macherey, AC Zeldin, DC Dansette, PM Mansuy, D AF Lafite, P Dijols, S Buisson, D Macherey, AC Zeldin, DC Dansette, PM Mansuy, D TI Design and synthesis of selective, high-affinity inhibitors of human cytochrome P450 2J2 SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE cardiovascular system; terfenadine; ebastine; hydroxylation; suicide substrates; monooxygenases ID POTENTIAL FUNCTIONAL-SIGNIFICANCE; ARACHIDONIC-ACID; EPOXYEICOSATRIENOIC ACIDS; ENDOTHELIAL-CELLS; METABOLISM; EXPRESSION; CYP2J2; LIVER; P450S; LOCALIZATION AB The active site topology, substrate specificity, and biological roles of the human cytochrome P450 CYP2J2, which is mainly expressed in the cardiovascular system, are poorly known even though recent data suggest that it Could be a novel biomarker and potential target for therapy of human cancer. This paper reports a first series of high-affinity, selective CYP2J2 inhibitors that are related to terfenadine, with K-i values as low as 160 nM, that should be useful tools to determine the biological roles of CYP2J2. (C) 2006 Elsevier Ltd. All rights reserved. C1 Univ Paris 05, CNRS, UMR 8601, Chim & Biochim Pharmacol & Toxicol Lab, F-75270 Paris 06, France. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Mansuy, D (reprint author), Univ Paris 05, CNRS, UMR 8601, Chim & Biochim Pharmacol & Toxicol Lab, 45 Rue St Peres, F-75270 Paris 06, France. EM daniel.mansuy@univ-paris5.fr RI DANSETTE, Patrick/B-8384-2014; Lafite, Pierre/F-6806-2011 OI Lafite, Pierre/0000-0003-1637-4966 FU Intramural NIH HHS [Z99 ES999999] NR 29 TC 24 Z9 28 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD MAY 15 PY 2006 VL 16 IS 10 BP 2777 EP 2780 DI 10.1016/j.bmcl.2006.02.004 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 033IE UT WOS:000236839700044 PM 16495056 ER PT J AU Seggewiss, R Pittaluga, S Adler, RL Guenaga, FJ Ferguson, C Pilz, IH Ryu, B Sorrentino, BP Young, WS Donahue, RE von Kalle, C Nienhuis, AW Dunbar, CE AF Seggewiss, Ruth Pittaluga, Stefania Adler, Rima L. Guenaga, F. Javier Ferguson, Cole Pilz, Ingo H. Ryu, Byoung Sorrentino, Brian P. Young, W. Scott, III Donahue, Robert E. von Kalle, Christof Nienhuis, Arthur W. Dunbar, Cynthia E. TI Acute myeloid leukemia is associated with retroviral gene transfer to hematopoietic progenitor cells in a rhesus macaque SO BLOOD LA English DT Article ID INSERTIONAL MUTAGENESIS; ONCORETROVIRAL VECTOR; CLONAL HEMATOPOIESIS; IN-VIVO; STEM; IDENTIFICATION; INTEGRATION; SELECTION; MARKING; PROTEIN AB We report, for the first time, a replication-defective retroviral vector-associated neoplasia in a nonhuman primate. Five years after transplantation with CD34(+) cells transduced with a retroviral vector expressing enhanced green fluorescent protein (eGFP) and a drug-resistant variant of the dihydrofolate reductase gene (L22Y), a rhesus macaque developed a fatal myeloid sarcoma, a type of acute myeloid leukemia. Tumor cells contained 2 clonal vector insertions. One insertion was found in BCL2-A1, an antiapoptotic gene. This event suggests that currently available retroviral vectors may have long-term side effects, particularly in hematopoietic stem and progenitor cells. C1 NHLBI, Hematol Branch, NIH, DHHS, Bethesda, MD 20892 USA. NCI, Hematopathol Sect, Bethesda, MD 20892 USA. NIMH, Sect Neural Gene Express, NIH, DHHS, Bethesda, MD 20892 USA. St Jude Childrens Hosp, Div Expt Hematol Hematol Oncol, Memphis, TN 38105 USA. Univ Freiburg, Dept Med 1, Freiburg, Germany. Childrens Hosp Res Fdn, Mol & Gene Therapy Program, Cincinnati, OH 45229 USA. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, NIH, DHHS, Bldg 10,CRC,Rm 4-5130,10 Ctr Dr,MSC 1202, Bethesda, MD 20892 USA. EM dunbarc@nhlbi.nih.gov RI Young, W Scott/A-9333-2009 OI Young, W Scott/0000-0001-6614-5112 FU Intramural NIH HHS NR 16 TC 90 Z9 97 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 15 PY 2006 VL 107 IS 10 BP 3865 EP 3867 DI 10.1182/blood-2005-10-4108 PG 3 WC Hematology SC Hematology GA 043FD UT WOS:000237584500017 PM 16439674 ER PT J AU Narazaki, M Tosato, G AF Narazaki, M Tosato, G TI Ligand-induced internalization selects use of common receptor neuropilin-1 by VEGF(165) and semaphorin3A SO BLOOD LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; AXON GUIDANCE; HEMATOPOIETIC-CELLS; DENDRITIC CELLS; NERVOUS-SYSTEM; TUMOR-CELLS; FACTOR VEGF; FACTOR-2; BINDING; MORPHOGENESIS AB Neuropilin-1 (Npn-1) is a receptor shared by class 3 semaphorins and heparin-binding forms of vascular endothelial growth factor (VEGF), protein families that regulate endothelial and neuronal-cell function. Ligand interaction with Npn-1 dictates the choice of signal transducer; plexins transduce semaphorin signals, and VEGF receptors transduce VEGF signals. It is not clear how class 3 semaphorins affect endothelial-cell function and how the shared receptor Npn-1 selects its ligand. We report that semaphorin3A (Sema3A) inhibits endothelial-cell lamellipodia formation, adhesion, survival, proliferation, and cord formation. VEGF(165), but not VEGF(121), could block all these effects of Sema3A. VEGF(165) competed with Sema3A for binding to endothelial cells, effectively reduced cell-surface Npn-1, and promoted its internalization. Use of soluble forms of Npn-1 or VEGF receptor-1 to block VEGF(165) binding to Npn-1 or to VEGF receptors provided evidence that surface Npn-1 and VEGF receptors are required for VEGF(165)-induced Npn-1 internalization. Sema3A also reduced cell-surface Npn-1 in endothelial cells and promoted its internalization, but required a higher concentration than VEGF(165). These results demonstrate that preferential receptor binding and internalization by a ligand are mechanisms by which the common receptor Npn-1 can play an essential role in prioritizing conflicting signals. C1 NCI, Basic Res Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Narazaki, M (reprint author), NCI, Basic Res Lab, Canc Res Ctr, NIH, 10 Ctr Dr 12N226, Bethesda, MD 20892 USA. EM narazakm@mail.nih.gov OI narazaki, masashi/0000-0002-5613-4409 FU Intramural NIH HHS NR 55 TC 57 Z9 62 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 15 PY 2006 VL 107 IS 10 BP 3892 EP 3901 DI 10.1182/blood-2005-10-4113 PG 10 WC Hematology SC Hematology GA 043FD UT WOS:000237584500021 PM 16424390 ER PT J AU Zhao, DM Thornton, AM DiPaolo, RJ Shevach, EM AF Zhao, DM Thornton, AM DiPaolo, RJ Shevach, EM TI Activated CD4(+)CD25(+) T cells selectively kill B lymphocytes SO BLOOD LA English DT Article ID GROWTH-FACTOR-BETA; CUTTING EDGE; FAS-LIGAND; GRANZYME-B; REGULATORY CELLS; LYMPHOPROLIFERATIVE DISEASE; MEDIATED CYTOTOXICITY; TARGET-CELLS; IN-VITRO; MICE AB The suppressive capacity of naturally occurring mouse CD4(+)CD25(+) T cells on T-cell activation has been well documented. The present study is focused on the interaction of CD4(+)CD25(+) T cells and B cells. By coculturing preactivated CD4(+)CD25(+) T cells with B cells in the presence of polyclonal B-cell activators, we found that B-cell proliferation was significantly suppressed. The suppression of B-cell proliferation was due to increased cell death caused by the CD4(+)CD25(+) T cells in a cell-contact-dependent manner. The induction of B-cell death is not mediated by Fas-Fas ligand pathway, but surprisingly, depends on the up-regulation of perforin and granzymes in the CD4(+)CD25(+) T cells. Furthermore, activated CD4(+)CD25(+) T cells preferentially killed antigen-presenting but not bystander B cells. Our results demonstrate that CD4(+)CD25(+) T cells can act directly on B cells and suggest that the prevention of autoimmunity by CD4(+)CD25(+) T cells can be explained, at least in part, by the direct regulation of B-cell function. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Rm 11N315, Bethesda, MD 20892 USA. EM eshevach@niaid.nih.gov NR 43 TC 253 Z9 276 U1 1 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 15 PY 2006 VL 107 IS 10 BP 3925 EP 3932 DI 10.1182/blood-2005-11-4502 PG 8 WC Hematology SC Hematology GA 043FD UT WOS:000237584500026 PM 16418326 ER PT J AU Solomou, EE Keyvanfar, K Young, NS AF Solomou, EE Keyvanfar, K Young, NS TI T-bet, a Th1 transcription factor, is up-regulated in T cells from patients with aplastic anemia SO BLOOD LA English DT Article ID PROTEIN-KINASE-C; INTERFERON-GAMMA PROMOTER; BONE-MARROW FAILURE; TEC-FAMILY KINASES; LINEAGE COMMITMENT; IMMUNE-RESPONSES; LYMPHOCYTES-T; ACTIVATION; THETA; EXPRESSION AB In aplastic anemia, immune destruction of hematopoietic cells results in bone marrow failure. Type 1 cytokines, especially IFN-gamma, have been implicated in the pathophysiology of T-cell-mediated, Fas-mediated stem cell apoptosis of hematopoietic cells. Here, we show that the transcription factor T-bet (T-box expressed in T cells) is increased in T cells from patients with aplastic anemia. Patients' T-bet bound directly to the proximal site of the IFN-gamma promoter without any prior stimulation, in contrast to healthy controls. Increased levels of Itk kinase participated in T-bet up-regulation and active transcription of the IFN-gamma gene observed in these patients. Blocking PKC-theta, a kinase that lies downstream of Itk kinase, decreased T-bet protein and IFN-gamma intracellular levels. These data suggest that the increased IFN-gamma levels observed in aplastic anemia patients are the result of active transcription of the IFN-gamma gene by T-bet. Blocking the transcription of the IFN-gamma gene with kinase inhibitors might lead to the development of novel therapeutic agents for patients with aplastic anemia and other autoimmune diseases. C1 NIH, Hematol Branch, NHLBI, Bethesda, MD 20892 USA. RP Solomou, EE (reprint author), NIH, Hematol Branch, NHLBI, Bldg 10,Rm 3E5216,10 Ctr Dr, Bethesda, MD 20892 USA. EM elenasolomou@hotmail.com FU Intramural NIH HHS NR 55 TC 56 Z9 74 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 15 PY 2006 VL 107 IS 10 BP 3983 EP 3991 DI 10.1182/blood-2005-10-4201 PG 9 WC Hematology SC Hematology GA 043FD UT WOS:000237584500033 PM 16434488 ER PT J AU Steiner, AA Chakravarly, S Ruclaya, AY Herkenham, M Romanovsky, AA AF Steiner, AA Chakravarly, S Ruclaya, AY Herkenham, M Romanovsky, AA TI Bacterial lipopolysaccharide fever is initiated via Toll-like receptor 4 on hematopoietic cells SO BLOOD LA English DT Article ID INDUCIBLE CYCLOOXYGENASE EXPRESSION; BRAIN; RECEPTORS; ENDOTOXIN; RESPONSES; MOUSE; RATS; MICE; LPS AB Lipopolysaccharide (LPS), a well-known bacterial pyrogen, is recognized by several receptors, including the Toll-like receptor 4 (TLR4), on various cells. Which of these receptors and cells are linked to fever production is unknown. By constructing 4 mouse chimeras and studying their thermoregulatory responses, we found that all 3 phases of the typical LIPS fever depend on TLR4 signaling. The first phase is triggered via the TLR4 on hematopoietic cells. The second and third phases involve TLR4 signaling in both hematopoietic and nonhematopoietic cells. C1 St Josephs Hosp, Systemat Inflammat Lab, Phoenix, AZ 85013 USA. Med Ctr, Phoenix, AZ USA. NIMH, Funct Neuroanat Sect, NIH, Bethesda, MD 20892 USA. RP Romanovsky, AA (reprint author), St Josephs Hosp, Systemat Inflammat Lab, 350 W Thomas Rd, Phoenix, AZ 85013 USA. EM aromano@chw.edu RI Steiner, Alexandre/G-1288-2012; OI Steiner, Alexandre/0000-0002-0802-4619; Herkenham, Miles/0000-0003-2228-4238 FU NINDS NIH HHS [NS 41233] NR 19 TC 46 Z9 47 U1 3 U2 10 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 15 PY 2006 VL 107 IS 10 BP 4000 EP 4002 DI 10.1182/blood-2005-11-4743 PG 3 WC Hematology SC Hematology GA 043FD UT WOS:000237584500035 PM 16403908 ER PT J AU Lan, Q Zheng, TZ Rothman, N Zhang, YW Wang, SS Shen, M Berndt, SI Zahm, SH Holford, TR Leaderer, B Yeager, M Welch, R Boyle, P Zhang, B Zou, KY Zhu, Y Chanock, S AF Lan, Q Zheng, TZ Rothman, N Zhang, YW Wang, SS Shen, M Berndt, SI Zahm, SH Holford, TR Leaderer, B Yeager, M Welch, R Boyle, P Zhang, B Zou, KY Zhu, Y Chanock, S TI Cytokine polymorphisms in the Tb1/Th2 pathway and susceptibility to non-Hodgkin lymphoma SO BLOOD LA English DT Article ID SINGLE NUCLEOTIDE POLYMORPHISMS; INTERLEUKIN-10 GENE PROMOTER; SYSTEMIC-LUPUS-ERYTHEMATOSUS; PERIPHERAL-BLOOD CELLS; CANDIDATE GENES; T-CELLS; ASSOCIATION; IL4; HAPLOTYPES; POPULATION AB Studies have demonstrated that common polymorphisms in Th1 and Th2 cytokine genes can alter gene expression, modulate the balance between Th1/Th2 responsiveness, and influence susceptibility for autoimmune disorders, infectious diseases, and cancer. We analyzed one or more single nucleotide polymorphisms (SNPs) in 20 candidate Th1/Th2 genes in a population-based case-control study of non-Hodgkin lymphoma (NHL; n = 518 cases, 597 controls) among women in Connecticut. SNPs in critical genes, IL4, IL5, IL6, and 100, were associated with risk for NHL and in some instances with a specific histologic subtype. Analysis of 4 SNPs in the IL10 promoter (-3575T > A, -1082A > G, -819C > T, and -592C > A) revealed that both the AGCC haplotype (odds ratio [OR] = 1.54, 95% confidence interval [CI] = 1.21-1.96, P < .001) and the TATA haplotype (OR = 1.37, 95% CI = 1.05-1.79, P = .02) were associated with increased risk for B-cell lymphomas. In contrast, the IL4-1098G allele was associated with increased risk of T-cell lymphomas (OR = 3.84; 95% C1 = 1.79-8.22; P < .001). Further, the IL10 and IL4 SNP associations remained significant after adjusting for multiple comparisons. These results suggest that SNPs in Th2 cytokine genes may be associated with risk of NHL. C1 NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, Canc Res Ctr, NIH,DHHS, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT USA. Int Agcy Res Canc, Lyon, France. McGill Univ, Dept Epidemiol & Biostat, Montreal, PQ, Canada. RP Lan, Q (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, MSC 7240,6120 Execut Blvd,EPS 8109, Bethesda, MD 20892 USA. EM qingl@mail.nih.gov RI Zahm, Shelia/B-5025-2015; Boyle, Peter/A-4380-2014 OI Boyle, Peter/0000-0001-6251-0610 FU Intramural NIH HHS; NCI NIH HHS [CA 62006] NR 58 TC 137 Z9 143 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 15 PY 2006 VL 107 IS 10 BP 4101 EP 4108 DI 10.1182/blood-2005-10-4160 PG 8 WC Hematology SC Hematology GA 043FD UT WOS:000237584500047 PM 16449530 ER PT J AU Kaeda, J O'Shea, D Szydlo, RM Olavarria, E Dazzi, F Marin, D Saunders, S Khorashad, JS Cross, NCP Goldman, JM Apperley, JF AF Kaeda, J O'Shea, D Szydlo, RM Olavarria, E Dazzi, F Marin, D Saunders, S Khorashad, JS Cross, NCP Goldman, JM Apperley, JF TI Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplantation for chronic myeloid leukemia: an attempt to define patients who may not require further therapy SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; POLYMERASE-CHAIN-REACTION; CHRONIC MYELOGENOUS LEUKEMIA; MINIMAL RESIDUAL DISEASE; VERSUS-HOST-DISEASE; CHRONIC PHASE; RELAPSE; DONOR; GRAFT; TRANSFUSIONS AB We identified 243 patients with Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) who had BCR-ABL transcripts monitored by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) after allogeneic stem cell transplantation for a median of 84.3 months. Individual patients were regarded as having achieved molecular relapse (MR) if the BCR-ABL/ABL ratio exceeded 0.02% on 3 occasions or reached 0.05% on 2 occasions. Patients were allocated to 1 of 4 categories: (1) 36 patients were "persistently negative" or had a single low-level positive result; (2) 51 patients, "fluctuating positive, low level," had more than 1 positive result but never more than 2 consecutive positive results; (3) 27 patients, "persistently positive, low level," had persisting low levels of BCR-ABL transcripts but never more than 3 consecutive positive results; and (4) 129 patients relapsed. In 107 of these, relapse was based initially only on molecular criteria; in 72 (67.3%) patients the leukemia progressed to cytogenetic or hematologic relapse either prior to or during treatment with donor lymphocyte infusions. We conclude that the pattern of BCR-ABL transcript levels after allograft is variable; only a minority of patients with fluctuating or persistent low levels of BCR-ABL transcripts satisfied our definitions of MR, whereas the majority of patients who did so were likely to progress further. C1 Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Haematol, London, England. Univ Southampton, Natl Genet Reference Lab, Salisbury, Wilts, England. RP Goldman, JM (reprint author), NHLBI, Hematol Branch, Bldg 10,Room 3-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM goldmanj2@nhlbi.nih.gov RI Szydlo, Richard/C-6678-2012; Cross, Nicholas/B-4817-2009 OI Szydlo, Richard/0000-0003-1102-8298; Cross, Nicholas/0000-0001-5481-2555 NR 28 TC 84 Z9 87 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 15 PY 2006 VL 107 IS 10 BP 4171 EP 4176 DI 10.1182/blood-2005-08-3320 PG 6 WC Hematology SC Hematology GA 043FD UT WOS:000237584500057 PM 16449534 ER PT J AU Blank, TO Bellizzi, KM AF Blank, TO Bellizzi, KM TI After prostate cancer: Predictors of well-being among long-term prostate cancer survivors SO CANCER LA English DT Article DE prostatic neoplasms; quality of life; psychology; psychologic adaptation; coping behavior; affect; personality; well-being ID QUALITY-OF-LIFE; RADICAL PROSTATECTOMY; CARCINOMA PATIENTS; NEGATIVE AFFECT; BREAST-CANCER; HEALTH; SYMPTOMS; OUTCOMES; VALIDATION; OPTIMISM AB BACKGROUND. Despite growing numbers of prostate cancer (PCa) survivors, to the authors' knowledge there is little research regarding how personality, coping, and treatment influence men's psychologic well-being, as distinct from the often-studied functional, health-related quality of life. The purpose of this study was to examine how hope, optimism, use of coping strategies, and primary treatment predict well-being, positive and negative affect, impact, depression, and adaptive changes among PCa survivors. METHODS. A questionnaire tapping personality, primary treatment, and coping strategy predictor variables and outcome variables of both positive and negative aspects of well-being was sent to 1-8-year PCa survivors. The final sample included 490 men. RESULTS. Basic univariate analyses demonstrated that the men reported being happy, hopeful, and positive, with low levels of negative outcomes. Regression analyses demonstrated that positive outcomes were influenced primarily by personality. Negative outcomes were found to be affected by both personality and coping strategies. Adaptive changes were the only ones found to be significantly affected by primary treatment. CONCLUSIONS. Although longer-term survivorship of PCa does not appear to be a highly traumatic experience, personality factors and the use of coping strategies years after treatment were found to introduce variability to well-being in complex ways, differing in relation to positive and negative outcomes. Clinical attention should be given to how the experience of cancer fits within the larger context of an individual's attitudes, choices, and coping strategy orientation. C1 Univ Connecticut, Sch Family Studies, Unit 2058, Storrs, CT 06269 USA. NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Blank, TO (reprint author), Univ Connecticut, Sch Family Studies, Unit 2058, Storrs, CT 06269 USA. EM thomas.blank@uconn.edu FU PHS HHS [1-R03177288] NR 45 TC 46 Z9 46 U1 0 U2 11 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD MAY 15 PY 2006 VL 106 IS 10 BP 2128 EP 2135 DI 10.1002/cncr.21865 PG 8 WC Oncology SC Oncology GA 039CR UT WOS:000237278300006 PM 16607648 ER PT J AU Nunez, NP Oh, WJ Rozenberg, J Perella, C Anver, M Barrett, JC Perkins, SN Berrigan, D Moitra, J Varticovski, L Hursting, SD Vinson, C AF Nunez, Nomeli P. Oh, Won-Jun Rozenberg, Julian Perella, Chris Anver, Miriam Barrett, J. Carl Perkins, Susan N. Berrigan, David Moitra, Jaideep Varticovski, Lyuba Hursting, Stephen D. Vinson, Charles TI Accelerated tumor formation in a fatless mouse with type 2 diabetes and inflammation SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-I; ADIPOSE-TISSUE; BREAST-CANCER; INSULIN-RESISTANCE; COLORECTAL-CANCER; OBESITY; OVERWEIGHT; RECEPTOR; MECHANISMS; RISK AB Epidemiologic studies show a positive association between obesity and cancer risk. In addition to increased body adiposity and secretion of fat-derived hormones, obesity is also linked to insulin resistance, type 2 diabetes, and chronic inflammation. We used the fatless A-ZIP/F-1 transgenic mouse to dissociate the relative role of each of these underlying factors in the development of cancer. These mice are unique in that they do not have white fat but do develop type 2 diabetes. In two cancer models, the classic two-stage skin carcinogenesis protocol and the C3(1)/T-Ag transgenic mouse mammary tumor model, A-ZIP/F-1 mice displayed higher tumor incidence, tumor multiplicity, and decreased tumor latency than wild-type mice. We examined circulating levels of adipokines, growth factors, and cytokines. As expected, adipokines (i.e., leptin, adiponectin, and resistin) were undetectable or found at very low levels in the blood of fatless mice. However, insulin, insulin-like growth factor-I, growth hormone, vascular endothelial growth factor, and proinflammatory Th2 cytokines, such as interleukin (IL)-1 beta, IL-4, and IL-6, were elevated in A-ZIP/F-1 mice. Additionally, we examined multiple phosphorylated proteins (i.e., protein kinase B/Akt and ErbB2/HER-2 kinase) associated with cancer development. Results show that many of these phosphorylated proteins were activated specifically in the A-ZIP/ F-1 skin but not in the wild-type skin. These findings suggest that adipokines are not required for the promotion of tumor development and thus contradict the epidemiologic data linking obesity to carcinogenesis. We postulate that insulin resistance and inflammation are responsible for the positive correlation with cancer observed in A-ZIP/F-1 mice. C1 Natl Canc Inst, Div Canc Control & Populat Sci, Appl Res Program, NIH, Bldg 37,Room 3128, Bethesda, MD 20892 USA. Natl Canc Inst, Div Canc Control & Populat Sci, Lab Biosyst & Canc, NIH, Bethesda, MD 20892 USA. Natl Canc Inst, Div Canc Control & Populat Sci, Lab Metab, NIH, Bethesda, MD 20892 USA. Natl Canc Inst, Div Canc Control & Populat Sci, Lab Human Carcinogenesis, NIH, Bethesda, MD 20892 USA. Sci Applicat Int Corp Frederick Inc, NCI, Basic Res Program, Frederick, MD USA. RP Vinson, C (reprint author), Natl Canc Inst, Div Canc Control & Populat Sci, Appl Res Program, NIH, Bldg 37,Room 3128, Bethesda, MD 20892 USA. EM vinsonc@mad.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 43 TC 57 Z9 62 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2006 VL 66 IS 10 BP 5469 EP 5476 DI 10.1158/0008-5472.CAN-05-4102 PG 8 WC Oncology SC Oncology GA 044NS UT WOS:000237679900061 PM 16707476 ER PT J AU Cunningham, SC Gallmeier, E Hucl, T Dezentje, DA Abdelmohsen, K Gorospe, M Kern, SE AF Cunningham, SC Gallmeier, E Hucl, T Dezentje, DA Abdelmohsen, K Gorospe, M Kern, SE TI Theoretical proposal: Allele dosage of MAP2K4/MKK4 could rationalize frequent 17p loss in diverse human cancers SO CELL CYCLE LA English DT Article DE Mkk4; p53; targeted disruption; gene dosage; haploinsufficiency; human ID TUMOR-SUPPRESSOR; C-JUN; SIGNALING PATHWAY; GENE; JNK; P53; CELLS; EXPRESSION; MUTATIONS; CARCINOMA AB Although aneuploidy is a global genomic abnormality present in most human cancers, the clonal selection model best explains the action of select activating mutations in oncogenes and homozygous losses of tumor-suppressor genes. Simple gene dosage changes are difficult however, to incorporate into this model, in part due to negative feedback loops that govern major cancer mutational targets ( e. g., TP53, PTCH, SMAD4) and essentially preclude a haploinsufficient phenotype. The 17p conundrum may offer a clue to reconciling this difficulty: In comparison to the moderate mutation rate of TP53, many tumors have a disproportionately high frequency of loss of 17p. This discrepancy, and similar discrepancies at other sites of LOH, has long been thought to be due to the presence of undiscovered yet frequently mutated tumor-suppressor genes. However, over 15 years of searching for this grail has distributed bountiful disappointment. It is perhaps time to seriously consider an alternative explanation. Located on 17p adjacent to the TP53 gene, MKK4 is one of the most consistently mutated genes across tumor types, and is located on one of the most frequently lost arms in the human genome. We theorized that a gene dosage-dependent phenotype of MKK4 could plausibly promote the emergence of 17p LOH and thereby the probability of evolving the biallelic inactivation of TP53. Using MKK4 somatic human knockout cancer cells, we observed the proof of principle in the downstream gene dosage-dependent phenotypes: heterozygous and homozygous knockouts were progressively deficient in Mkk4 protein, in stress-induced phosphorylation of Jnk, and the resultant upregulation of JUN mRNA. These observations highlight a lack of compensatory regulation when gene dosage changes perturb the Jnk-Jun relationship. Consideration of gene dosage changes specifically affecting members of positive feedback loops may permit integration of the aneuploidy process into a conventional model of clonal selection in tumorigenesis. C1 Johns Hopkins Univ, Sch Med, Dept Oncol, Sidney Kimmel Canc Res Ctr, Baltimore, MD 21231 USA. NIA, Cellular & Mol Biol Lab, IRP, NIH, Baltimore, MD 21224 USA. Univ Maryland, Dept Surg, Med Ctr, Baltimore, MD 21201 USA. RP Kern, SE (reprint author), Johns Hopkins Univ, Sch Med, Dept Oncol, Sidney Kimmel Canc Res Ctr, Canc Res Bldg 464,1650 Orleans St, Baltimore, MD 21231 USA. EM sk@jhmi.edu OI abdelmohsen, Kotb/0000-0001-6240-5810 FU NCI NIH HHS [CA 62924] NR 30 TC 7 Z9 7 U1 0 U2 0 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAY 15 PY 2006 VL 5 IS 10 BP 1090 EP 1093 DI 10.4161/cc.5.10.2805 PG 4 WC Cell Biology SC Cell Biology GA 057DD UT WOS:000238575300016 PM 16721048 ER PT J AU Ramaswamy, B Elias, AD Kelbick, NT Dodley, A Morrow, M Hauger, M Allen, J Rhoades, C Kendra, K Chen, HX Eckhardt, SG Shapiro, CL AF Ramaswamy, B Elias, AD Kelbick, NT Dodley, A Morrow, M Hauger, M Allen, J Rhoades, C Kendra, K Chen, HX Eckhardt, SG Shapiro, CL TI Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT San Antonio Breast Cancer Meetings CY 2003 CL San Antonio, TX ID ENDOTHELIAL GROWTH-FACTOR; SOLUBLE E-SELECTIN; HUMANIZED MONOCLONAL-ANTIBODY; COLORECTAL-CANCER; SERUM-LEVELS; ADHESION MOLECULE-1; PROGNOSTIC VALUE; SOLID TUMORS; IN-VITRO; ANGIOGENESIS AB Purpose: To evaluate the safety and efficacy of bevacizumab and weekly docetaxel as first- or second-line therapy in patients with metastatic breast cancer (MBC). Patients and Methods: Twenty-seven MBC patients received i.v. bevacizumab at 10 mg/kg on days 1 and 15 in combination with i.v. docetaxel 35 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. Primary end points were to assess toxicity, overall response rate, and progression-free survival. A secondary end point was to assess the relationship between plasma endothelial and cell adhesion markers and clinical outcomes. Results: One-hundred fifty-eight treatment cycles were administered with a median of six cycles (range 1-15 cycles) per patient. The most common grade 4 toxicities per patient were as follows: 2 (7%)-pulmonary embolus, 1 (4%)-febrile neutropenia, and 1 (4%)-infection; grade 3 toxicities were 4 (15%)-neutropenia, 4 (15%)-fatigue, 2 (7%)-neuropathy, 2 (7%)-athralgias, 2 (7%)-stomatitis, 1 (7%)-pleural effusion, and 1 (4%)-hypertension. The overall response rate was 52% [95% confidence interval (95% CI), 32-71%], median response duration was 6.0 months (95% Cl, 4.6-6.5 months), and the median progression-free survival was 7.5 months (95% Cl, 6.2-8.3 months). In hypothesis-generating univariate and limited multivariate analyses, E-selectin was statistically significantly associated with response to the combination. Conclusion: Bevazicumab in combination with weekly docetaxel is active with acceptable toxicities in MBC. Additional studies evaluating E-selectin as a marker of response to bevacizumab-containing chemotherapy are warranted. C1 Ohio State Univ, Med Ctr, Div Hematol Oncol, Columbus, OH 43210 USA. Ohio State Univ, Med Ctr, Comprehens Breast Hlth Serv, Columbus, OH 43210 USA. Ohio State Univ, Med Ctr, Ctr Biostat, Ctr Comprehens Canc, Columbus, OH 43210 USA. Univ Colorado, Ctr Canc, Aurora, CO USA. NCI, Canc Treatment Evaluat Program, Bethesda, MD 20892 USA. RP Shapiro, CL (reprint author), B 405 Starling Loving,320 W 10th Ave, Columbus, OH 43210 USA. EM shapiro-1@medctr.osu.edu RI Ramaswamy, Bhuvaneswari/E-3919-2011 NR 39 TC 97 Z9 100 U1 0 U2 1 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 MAY 15 PY 2006 VL 12 IS 10 BP 3124 EP 3129 DI 10.1158/1078-0432.CCR.05-2603 PG 6 WC Oncology SC Oncology GA 044PX UT WOS:000237685800025 PM 16707611 ER PT J AU Murad, GJA Walbridge, S Morrison, PF Garmestani, K Degen, JW Brechbiel, MW Oldfield, EH Lonser, RR AF Murad, GJA Walbridge, S Morrison, PF Garmestani, K Degen, JW Brechbiel, MW Oldfield, EH Lonser, RR TI Real-time, image-guided, convection-enhanced delivery of interleukin 13 bound to Pseudomonas exotoxin SO CLINICAL CANCER RESEARCH LA English DT Article ID BRAIN-STEM GLIOMAS; GROUP PHASE-I/II; HYPERFRACTIONATED RADIATION-THERAPY; MALIGNANT GLIOMA; TARGETED CYTOTOXIN; PONTINE GLIOMAS; PRIMATE BRAIN; COMPUTERIZED-TOMOGRAPHY; INTERSTITIAL INFUSION; CHILDREN AB Purpose: To determine if the tumor-targeted cytotoxin interleukin 13 bound to Pseudomonas exotoxin (IL13-PE) could be delivered to the brainstem safely at therapeutic doses while monitoring its distribution in real-time using a surrogate magnetic resonance imaging tracer, we used convection-enhanced delivery to perfuse rat and primate brainstems with IL13-PE and gadolinium-bound albumin (Gd-albumin). Experimental Design: Thirty rats underwent convective brainstem perfusion of IL13-PE (0.25, 0.5, or 10 mu g/mL) or vehicle. Twelve primates underwent convective brainstem perfusion of either IL13-PE (0.25, 0.5, or 10 mu g/mL; n = 8), co-infusion of I-125-IL13-PE and Gd-albumin (n = 2), or co-infusion of IL13-PE (0.5 mu g/mL) and Gd-albumin (n = 2). The animals were permitted to survive for up to 28 days before sacrifice and histologic assessment. Results: Rats showed no evidence of toxicity at all doses. Primates showed no toxicity at 0.25 or 0.5 mu g/mL but showed clinical and histologic toxicity at 10 mu g/mL. Quantitative autoradiography confirmed that Gd-albumin precisely tracked IL13-PE anatomic distribution and accurately showed the volume of distribution. Conclusions: IL13-PE can be delivered safely and effectively to the primate brainstem at therapeutic concentrations and over clinically relevant volumes using convection-enhanced delivery. Moreover, the distribution of IL13-PE can be accurately tracked by co-infusion of Gd-albumin using real-time magnetic resonance imaging. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Div Bioengn & Phys Sci, Off Res Serv, NIH, Bethesda, MD 20892 USA. NINDS, Radioimmune & Inorgan Chem Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Univ Florida, Dept Neurosurg, Gainesville, FL USA. Georgetown Univ, Dept Neurosurg, Washington, DC USA. RP Lonser, RR (reprint author), NINDS, Surg Neurol Branch, NIH, Room 5D37,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM lonserr@ninds.nih.gov FU Intramural NIH HHS NR 56 TC 38 Z9 39 U1 0 U2 0 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 MAY 15 PY 2006 VL 12 IS 10 BP 3145 EP 3151 DI 10.1158/1078-0432.CCR-05-2583 PG 7 WC Oncology SC Oncology GA 044PX UT WOS:000237685800028 PM 16707614 ER PT J AU Waters, ST Lewandoski, M AF Waters, ST Lewandoski, M TI A threshold requirement for Gbx2 levels in hindbrain development SO DEVELOPMENT LA English DT Article DE cerebellum; Fgf8; Gbx2; rhombomere; vermis ID DEVELOPING NERVOUS-SYSTEM; ISTHMIC ORGANIZER; MID/HINDBRAIN ORGANIZER; NEURAL PLATE; REGULATORY INTERACTIONS; CEREBELLAR DEVELOPMENT; INT-1 PROTOONCOGENE; ANTERIOR HINDBRAIN; EXPRESSION DOMAINS; VISCERAL ENDODERM AB Gbx2 is a homeobox gene that plays a crucial role in positioning the mid/hindbrain organizer ( isthmus), which regulates midbrain and cerebellar development primarily through the secreted factor FGF8. In Gbx2 null homozygotes, rhombomeres (r) 1-3 fail to develop and the isthmic expression of Fgf8 is reduced and disorganized. These mutants fail to form a cerebellum, as it is derived from r1. Here, we analyze mice homozygous for a Gbx2 hypomorphic allele (Gbx2(neo)). Quantitative RT-PCR and RNA in situ analyses indicate that the presence of a neo-resistance cassette impairs normal Gbx2 splicing thus reducing wild-type Gbx2 mRNA levels to 6-10% of normal levels in all domains and stages examined. In Gbx2 hypomorphic mutants, gene marker and neuronal patterning analyses indicate that reduced Gbx2 expression is sufficient to support the development of r3 but not r2. The posterior region of r1, from which the lateral cerebellum develops, is unaffected in these mutants. However, the anterior region of r1 is converted to an isthmus-like tissue. Hence, instead of expressing r1 markers, this region displays robust expression of Fgf8 and Fgf17, as well as the downstream FGF targets Spry1 and Spry4. Additionally, we demonstrate that the cell division regulator cyclin D2 is downregulated, and that cellular proliferation is reduced in both the normal isthmus and in the mutant anterior r1. As a result of this transformation, the cerebellar midline fails to form. Thus, our studies demonstrate different threshold requirements for the level of Gbx2 gene product in different regions of the hindbrain. C1 NIH, Lab Canc Dev Biol, NCI, Frederick, MD 21702 USA. RP Lewandoski, M (reprint author), NIH, Lab Canc Dev Biol, NCI, Frederick, MD 21702 USA. EM mlewandoski@mail.ncifcrf.gov FU Intramural NIH HHS NR 83 TC 17 Z9 17 U1 1 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD MAY 15 PY 2006 VL 133 IS 10 BP 1991 EP 2000 DI 10.1242/dev.02364 PG 10 WC Developmental Biology SC Developmental Biology GA 038GX UT WOS:000237208300013 PM 16651541 ER PT J AU Buono, KD Robinson, GW Martin, C Shi, SL Stanley, P Tanigaki, K Honjo, T Hennighausen, L AF Buono, KD Robinson, GW Martin, C Shi, SL Stanley, P Tanigaki, K Honjo, T Hennighausen, L TI The canonical Notch/RBP-J signaling pathway controls the balance of cell lineages in mammary epithelium during pregnancy SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Notch; myoepithelium; basal cells; Pofut1; RBP-J; mammary epithelium; cytokeratins ID STEM-CELLS; RBP-J; MYOEPITHELIAL CELLS; FATE DETERMINATION; GLAND DEVELOPMENT; KNOCKOUT MICE; GENE; MOUSE; DIFFERENTIATION; PROLIFERATION AB Mammary alveoli are composed of luminal (secretory) and basal (myoepithelial) cells, which are descendants of a common stem cell. This study addressed the role of RBP-J-dependent Notch signaling in the formation, maintenance and cellular composition of alveoli during pregnancy. For this purpose, tire genes encoding RBP-J, the shared transcriptional mediator of Notch receptors, and Pofut1, a fucosyltransferase required for the activity of Notch receptors, were deleted in mammary progenitor cells in the mouse using Cre-mediated recombination. Loss of RBP-J and Pofut1 led to an accumulation of basal cell clusters characterized by the presence of cytokeratins (K5) and K14 and smooth muscle actin (SMA) during pregnancy. Hormonal stimulation of mutant tissue induced the expression of the basal cell transcription factor p63 in luminal cells and excessive proliferation of basal cells. A transient enrichment of K6-positive luminal cells was observed upon hormonal treatment suggesting a temporary arrest at an immature stage prior to transdifferentiation and expansion as basal cells. Despite the extensive proliferation of RBP-J-null basal cells during pregnancy, hormonal withdrawal during involution resulted in complete remodeling and the restoration of normal tissue architecture. We propose that the Notch-RBP-J pathway regulates alveolar development during pregnancy by maintaining luminal cell fate and preventing uncontrolled basal cell proliferation. (c) 2006 Elsevier Inc. All rights reserved. C1 NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. Kyoto Univ, Grad Sch Med, Dept Med Chem, Kyoto 6068501, Japan. RP Hennighausen, L (reprint author), NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. EM lotharh@mail.nih.gov RI Robinson, Gertraud/I-2136-2012; Honjo, Tasuku/N-4470-2016; OI Stanley, Pamela/0000-0001-5704-3747 FU Intramural NIH HHS; PHS HHS [R01 30645] NR 54 TC 84 Z9 86 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD MAY 15 PY 2006 VL 293 IS 2 BP 565 EP 580 DI 10.1016/j.ydbio.2006.02.043 PG 16 WC Developmental Biology SC Developmental Biology GA 045BF UT WOS:000237716900024 PM 16581056 ER PT J AU Zhang, XY Hu, Y Cui, YP Miao, XP Tian, F Xia, YJ Wu, YQ Liu, XJ AF Zhang, XY Hu, Y Cui, YP Miao, XP Tian, F Xia, YJ Wu, YQ Liu, XJ TI Integrated genome-wide gene expression map and high-resolution analysis of aberrant chromosomal regions in squamous cell lung cancer SO FEBS LETTERS LA English DT Article DE microarray; aberrant chromosomal region; squamous cell carcinoma; gene expression map; moving-median method ID HYBRIDIZATION ANALYSIS; ALLELIC IMBALANCE; DISTINCT PATTERNS; HIGH-LEVEL; ADENOCARCINOMA; CARCINOMAS; HETEROZYGOSITY; IDENTIFICATION; MICROARRAYS; FREQUENT AB The recognition of recurrent aberrant regions in cancer is important to the discovery of candidate cancer related genes. Here we first constructed a genome-wide gene expression map of squamous lung carcinoma from the Stanford Microarray Database. High-resolution detection of aberrant chromosomal regions was performed by using moving-median method. 84% (27 of 32) of our results were consistent with the previous studies of comparative genomic hybridization or loss of heterozygosity. One overrepresented region in Xq28 was newly discovered to be related to squamous cell lung carcinoma. These observations could be of great interest for further studies. (c) 2006 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 Tsing Hua Univ, Dept Biol Sci & Biotechnol, Beijing 100084, Peoples R China. Tsing Hua Univ, Inst Biomed, Beijing 100084, Peoples R China. Tsing Hua Univ, Minist Educ Key Lab Bioinformat, Beijing 100084, Peoples R China. NCI, Lab Populat Genet, Ctr Bioinformat, Bethesda, MD 20892 USA. Chinese Acad Med Sci, Beijing 100021, Peoples R China. Peking Union Med Coll, Dept Etiol & Carcinogenesis, Beijing 100021, Peoples R China. RP Liu, XJ (reprint author), Tsing Hua Univ, Dept Biol Sci & Biotechnol, Beijing 100084, Peoples R China. EM frankliu@mail.tsinghua.edu.cn RI miao, xiaoping/C-4336-2011; Zhang, Xinyu/S-4946-2016 OI miao, xiaoping/0000-0002-6818-9722; Zhang, Xinyu/0000-0001-8154-9334 NR 39 TC 3 Z9 4 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD MAY 15 PY 2006 VL 580 IS 11 BP 2774 EP 2778 DI 10.1016/j.febslet.2006.04.043 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 044QD UT WOS:000237686400038 PM 16674950 ER PT J AU Kim, SJ Zhang, ZJ Lee, YC Mukherjee, AB AF Kim, SJ Zhang, ZJ Lee, YC Mukherjee, AB TI Palmitoyl-protein thioesterase-1 deficiency leads to the activation of caspase-9 and contributes to rapid neurodegeneration in INCL SO HUMAN MOLECULAR GENETICS LA English DT Article ID NEURONAL CEROID-LIPOFUSCINOSIS; ENDOPLASMIC-RETICULUM STRESS; CELL-DEATH; APOPTOSIS; PATHWAYS; BRAIN; DISEASE; DAMAGE; BETA AB The infantile neuronal ceroid lipofuscinosis (INCL), a rare (one in 100 000 births) but one of the most lethal inherited neurodegenerative storage disorders of childhood, is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 cleaves thioester linkages in s-acylated (palmitoylated) proteins and facilitates their degradation and/or recycling. Thus, PPT1-deficiency leads to an abnormal intracellular accumulation of s-acylated proteins causing INCL pathogenesis. Although neuronal apoptosis is the suggested cause of neurodegeneration in this disease, the molecular mechanism(s) remains poorly understood. We recently reported that one of the major pathways of neuronal apoptosis in PPT1-knockout (PPT1-KO) mice that mimic INCL, is mediated by endoplasmic reticulum (ER) stress-induced caspase-12 activation. ER stress also increases the production of reactive oxygen species (ROS), disrupts Ca(2+) homeostasis and increases the potential for destabilizing mitochondrial membrane. Mitochondrial membrane destabilization activates caspase-9 present in this organelle, and can mediate apoptosis. We report here that the levels of superoxide dismutase (SOD), most likely induced by ROS, in human INCL as well as PPT1-KO mouse brain tissues are markedly elevated. Moreover, we demonstrate that activated caspase-3 and cleaved-PARP, indicative of apoptosis, are also increased in these tissues. Using cultured neurospheres from PPT1-KO and wild-type mouse fetuses, we further demonstrate that the levels of ROS, SOD-2, cleaved-caspase-9, activated caspase-3 and cleaved-PARP are elevated. We propose that: (i) ER stress due to PPT1-deficiency increases ROS and disrupts calcium homeostasis activating caspase-9 and (ii) caspase-9 activation mediates caspase-3 activation and apoptosis contributing to rapid neurodegeneration in INCL. C1 NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Mukherjee, AB (reprint author), NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. EM mukherja@exchange.nih.gov FU Intramural NIH HHS NR 33 TC 35 Z9 35 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 15 PY 2006 VL 15 IS 10 BP 1580 EP 1586 DI 10.1093/hmg/ddi078 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 039QB UT WOS:000237320200003 PM 16571600 ER PT J AU Lee, CR North, KE Bray, MS Fornage, M Seubert, JM Newman, JW Hammock, BD Couper, DJ Heiss, G Zeldin, DC AF Lee, CR North, KE Bray, MS Fornage, M Seubert, JM Newman, JW Hammock, BD Couper, DJ Heiss, G Zeldin, DC TI Genetic variation in soluble epoxide hydrolase (EPHX2) and risk of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) study SO HUMAN MOLECULAR GENETICS LA English DT Article ID EPOXYGENASE-DERIVED EICOSANOIDS; OXIDE SYNTHASE GENE; EPOXYEICOSATRIENOIC ACIDS; BLOOD-PRESSURE; HAPLOTYPE RECONSTRUCTION; ENDOTHELIAL DYSFUNCTION; LINKAGE DISEQUILIBRIUM; CIGARETTE-SMOKING; YOUNG-ADULTS; POLYMORPHISM AB Endothelial dysfunction contributes to the development of coronary heart disease (CHD). Soluble epoxide hydrolase metabolizes epoxyeicosatrienoic acids in the vasculature and regulates endothelial function. We sought to determine whether genetic variation in soluble epoxide hydrolase (EPHX2) was associated with the risk of CHD. We genotyped 2065 Atherosclerosis Risk in Communities study participants (1085 incident CHD cases, 980 non-cases) for 10 previously identified polymorphisms in EPHX2. Using a case-cohort design, associations between incident CHD risk and both non-synonymous EPHX2 polymorphisms and phase-reconstructed haplotypes were evaluated using proportional hazards regression. Individuals carrying the K55R polymorphism variant allele demonstrated higher apparent soluble epoxide hydrolase activity in vivo. Presence of the K55R variant allele was significantly more common among Caucasian CHD cases when compared with non-cases (20.8% versus 15.3%, respectively, P=0.012), and was associated with significantly higher risk of incident CHD (adjusted hazard rate ratio 1.45, 95% confidence interval 1.05-2.01, P=0.026). A significant association between the K55R variant allele and risk of CHD was not observed in African-Americans. The distribution of reconstructed haplotypes were significantly different in Caucasian cases when compared with non-cases (P=0.021). Significant differences in haplotype distribution were not observed in African-Americans (P=0.315). Genetic variation in EPHX2 was significantly associated with risk of incident CHD in Caucasians, implicating EPHX2 as a potential cardiovascular disease-susceptibility gene. C1 Natl Inst Environm Hlth Sci, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Sch Publ Hlth, Div Pharmacol & Expt Therapeut, Sch Pharm, Chapel Hill, NC USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Univ N Carolina, Sch Publ Hlth, Dept Biostat, Chapel Hill, NC USA. Baylor Coll Med, Dept Pediat, Childrens Nutr Res Ctr, Houston, TX 77030 USA. Univ Texas, Ctr Hlth Sci, Inst Mol Med Prevent Human Dis, Houston, TX USA. Univ Calif Davis, Canc Res Ctr, Dept Entomol, Davis, CA 95616 USA. RP Zeldin, DC (reprint author), Natl Inst Environm Hlth Sci, Div Intramural Res, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM zeldin@niehs.nih.gov OI Lee, Craig/0000-0003-3595-5301 FU Intramural NIH HHS [Z01 ES025034-13]; NHLBI NIH HHS [N01-HC-55018, HL073366, HL69126, N01-HC-55015, N01-HC-55016, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01HC55015, N01HC55016, N01HC55018, N01HC55019, N01HC55020, N01HC55021, N01HC55022, R01 HL069126, R01 HL073366]; NIEHS NIH HHS [ES012856, ES02710, ES04699, F32 ES012856, P42 ES004699, R01 ES002710, R37 ES002710]; NINDS NIH HHS [NS41466, R01 NS041466]; PHS HHS [NL59699-06A1] NR 43 TC 96 Z9 100 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 15 PY 2006 VL 15 IS 10 BP 1640 EP 1649 DI 10.1093/hmg/ddl085 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 039QB UT WOS:000237320200009 PM 16595607 ER PT J AU Barsov, EV Andersen, H Coalter, VJ Carrington, M Lifson, JD Ott, DE AF Barsov, EV Andersen, H Coalter, VJ Carrington, M Lifson, JD Ott, DE TI Capture of antigen-specific T lymphocytes from human blood by selective immortalization to establish long-term T-cell lines maintaining primary cell characteristics SO IMMUNOLOGY LETTERS LA English DT Article DE T cell response; antigen-specific T cells; immortalization; telomerase ID HTLV-I TAX; MURINE LEUKEMIA-VIRUS; HERPESVIRUS-SAIMIRI; INDUCED APOPTOSIS; CYCLE DEPENDENCE; STABLE GROWTH; TELOMERASE; CLONES; TRANSFORMATION; INFECTION AB To establish long-term, antigen-specific T-cell lines and clones, we selectively immortalized antigen-responsive T cells from human peripheral blood mononuclear cells (PBMCs). PBMCs were stimulated with either alloantigen or soluble antigen, then infected with a murine leukemia virus-based retroviral vectorcarrying an immortalizing gene, either the Taxgene from human T-cell leukemia virus type 1, or the human telomerase-reverse transcriptase gene. Since such vectors can only integrate in dividing cells, only antigen-activated T cells are efficiently transduced. This approach generated immortalized antigen-specific CD4(+) and CD8(+) T-cell lines that maintained strictly IL-2-dependent growth and HLA-restricted, antigen-specific responsiveness, some of which have been in continuous culture for longer than 1 year, far in excess of the survival of parallel control non-immortalized cultures. Clones derived from these lines showed antigen-specific proliferation with induced cytokine and chemokine production, and, in the case of a CD8(+) T-cell clone, antigen-specific cytolytic activity. This approach provides a convenient, reproducible means for generating a stable, continuously renewable source of antigen-specific T lymphocytes for a variety of studies of T cell biology. Published by Elsevier B.V. C1 NCI, SAIC Frederick Inc, AIDS Vaccine Program, Frederick, MD 21702 USA. NCI, SAIC Frederick Inc, Basic Res Program, Lab Genom Divers, Frederick, MD 21702 USA. RP Barsov, EV (reprint author), NCI, SAIC Frederick Inc, AIDS Vaccine Program, POB B, Frederick, MD 21702 USA. EM barsov@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 60 TC 8 Z9 9 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 J9 IMMUNOL LETT JI Immunol. Lett. PD MAY 15 PY 2006 VL 105 IS 1 BP 26 EP 37 DI 10.1016/j.imlet.2005.11.029 PG 12 WC Immunology SC Immunology GA 050RN UT WOS:000238105700005 PM 16442639 ER PT J AU Kovarova, M Wassif, CA Odom, S Liao, K Porter, FD Rivera, J AF Kovarova, Martina Wassif, Christopher A. Odom, Sandra Liao, Katherine Porter, Forbes D. Rivera, Juan TI Cholesterol deficiency in a mouse model of Smith-Lemli-Opitz syndrome reveals increased mast cell responsiveness SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID FC-EPSILON-RI; HIGH-AFFINITY; LYN KINASE; MEMBRANE DOMAINS; LIPID RAFTS; TYROSINE PHOSPHORYLATION; SIGNAL-TRANSDUCTION; CYTOKINE PRODUCTION; ALLERGIC RESPONSE; REDUCTASE GENE AB Mutation of the 3 beta-hydroxysterol Delta(7)-reductase gene (Dhcr7(-/-)) results in Smith-Lemli-Opitz syndrome ( SLOS). Patients, and genetically altered mice, are unable to produce cholesterol and accumulate 7-dehydrocholesterol (DHC) in serum and tissue. This causes multiple growth and developmental abnormalities as well as immune system anomalies including allergy. Because cholesterol is a key component of liquid-ordered membranes ( lipid rafts) and these domains have been implicated in regulating mast cell activation, we examined whether mast cell responsiveness is altered in this model. Mast cells derived from Dhcr7(-/-) mice (DHCR KO) showed constitutive cytokine production and hyper-degranulation after stimulation of the high affinity IgE receptor (Fc epsilon RI). DHCR KO mast cells, but not wild-type mast cells, accumulated DHC in lipid rafts. DHC partially disrupted lipid raft stability and displaced Lyn kinase protein and activity from lipid rafts. This led to down-regulation of some Lyn-dependent signaling events but increased Fyn kinase activity and Akt phosphorylation. The Lyn-dependent phosphorylation of Csk-binding protein, which negatively regulates Fyn activity, was decreased. This phenotype reproduces some of the characteristics of Lyn-null mast cells, which also demonstrate hyper-degranulation. These findings provide the first evidence of lipid raft dysfunction in SLOS and may explain the observed association of allergy with SLOS. C1 NIAMSD, Mol Inflammat Sect, Mol Immunol & Inflammat Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NICHHD, Unit Mol Dysmorphol, Heritable Disorders Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Rivera, J (reprint author), NIAMSD, Mol Inflammat Sect, Mol Immunol & Inflammat Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM juan_rivera@nih.gov OI Wassif, Christopher/0000-0002-2524-1420 FU Intramural NIH HHS NR 45 TC 42 Z9 42 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD MAY 15 PY 2006 VL 203 IS 5 BP 1161 EP 1171 DI 10.1084/jem.20051701 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 046IA UT WOS:000237803700006 PM 16618793 ER PT J AU Khakoo, AY Pati, S Anderson, SA Reid, W Elshal, MF Rovira, II Nguyen, AT Malide, D Combs, CA Hall, G Zhang, JH Raffeld, M Rogers, TB Stetler-Stevenson, W Frank, JA Reitz, M Finkel, T AF Khakoo, AY Pati, S Anderson, SA Reid, W Elshal, MF Rovira, II Nguyen, AT Malide, D Combs, CA Hall, G Zhang, JH Raffeld, M Rogers, TB Stetler-Stevenson, W Frank, JA Reitz, M Finkel, T TI Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID MARROW STROMAL CELLS; NF-KAPPA-B; HEMATOLOGIC MALIGNANCY; MYOCARDIAL-INFARCTION; PARACRINE MECHANISMS; BRAIN-TUMORS; E-CADHERIN; CANCER; FIBROBLASTS; AKT AB Emerging evidence suggests that both human stem cells and mature stromal cells can play an important role in the development and growth of human malignancies. In contrast to these tumor-promoting properties, we observed that in an in vivo model of Kaposi's sarcoma (KS), intravenously (i.v.) injected human mesenchymal stem cells (MSCs) home to sites of tumorigenesis and potently inhibit tumor growth. We further show that human MSCs can inhibit the in vitro activation of the Akt protein kinase within some but not all tumor and primary cell lines. The inhibition of Akt activity requires the MSCs to make direct cell-cell contact and can be inhibited by a neutralizing antibody against E-cadherin. We further demonstrate that in vivo, Akt activation within KS cells is potently downregulated in areas adjacent to MSC infiltration. Finally, the in vivo tumor-suppressive effects of MSCs correlates with their ability to inhibit target cell Akt activity, and KS tumors engineered to express a constitutively activated Akt construct are no longer sensitive to i.v. MSC administration. These results suggest that in contrast to other stem cells or normal stromal cells, MSCs possess intrinsic antineoplastic properties and that this stem cell population might be of particular utility for treating those human malignancies characterized by dysregulated Akt. C1 NHLBI, Mol Biol Lab, Cardiovasc Branch, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NIH, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Biochem, Baltimore, MD 21201 USA. Univ Maryland, Inst Biotechnol, Inst Human Virol, Baltimore, MD 21201 USA. Univ Texas, MD Anderson Canc Ctr, Dept Cardiol, Houston, TX 77030 USA. RP Khakoo, AY (reprint author), NHLBI, Mol Biol Lab, Cardiovasc Branch, Bldg 10, Bethesda, MD 20892 USA. EM aykhakoo@mdanderson.org RI Stetler-Stevenson, William/H-6956-2012; Elshal, Mohamed/H-7953-2012 OI Stetler-Stevenson, William/0000-0002-5500-5808; FU Intramural NIH HHS; NCI NIH HHS [1R01 CA09905-01] NR 60 TC 395 Z9 447 U1 3 U2 23 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD MAY 15 PY 2006 VL 203 IS 5 BP 1235 EP 1247 DI 10.1084/jem.20051921 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 046IA UT WOS:000237803700012 PM 16636132 ER PT J AU Wille-Reece, U Flynn, BJ Lore, K Koup, RA Miles, AP Saul, A Kedl, RM Mattapallil, JJ Weiss, WR Roederer, M Seder, RA AF Wille-Reece, U Flynn, BJ Lore, K Koup, RA Miles, AP Saul, A Kedl, RM Mattapallil, JJ Weiss, WR Roederer, M Seder, RA TI Toll-like receptor agonists infl uence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primates SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID COMPARATIVE IMMUNOGENICITY; CD8-T-CELL MEMORY; CD4-T-CELL HELP; RHESUS-MONKEYS; VACCINE; IMMUNITY; VIRUS; PROLIFERATION; INFECTION AB There is a remarkable heterogeneity in the functional profile (quality) of T cell responses. Importantly, the magnitude and/or quality of a response required for protection may be different depending on the infection. Here, we assessed the capacity of different Toll like receptor (TLR)-binding compounds to influence T helper cell (Th) 1 and CD8(+) T cell responses when used as adjuvants in nonhuman primates (NHP) with HIV Gag as a model antigen. NHP were immunized with HIV Gag protein emulsified in Montanide ISA 51, an oil-based adjuvant, with or without a TLR7/8 agonist, a TLR8 agonist, or the TLR9 ligand cytosine phosphate guanosine oligodeoxynucleotides (CpG ODN), and boosted 12 wk later with a replication-defective adenovirus-expressing HIV-Gag (rAD-Gag). Animals vaccinated with HIV Gag protein/Montanide and CpG ODN or the TLR7/8 agonist had higher frequencies of Th1 responses after primary immunization compared to all other vaccine groups. Although the rAD-Gag boost did not elevate the frequency of Th1 memory cytokine responses, there was a striking increase in HIV Gag-specifi c CD8(+) T cell responses after the boost in all animals that had received a primary immunization with any of the TLR adjuvants. Importantly, the presence and type of TLR adjuvant used during primary immunization conferred stability and dramatically influenced the magnitude and quality of the Th1 and CD8(+) T cell responses after the rAD-Gag boost. These data provide insights for designing prime-boost immunization regimens to optimize Th1 and CD8(+) T cell responses. C1 NIH, Cellular Immunol Sect, Bethesda, MD 20892 USA. NIH, Immunol Lab, Bethesda, MD 20892 USA. NIH, ImmunoTechnol Sect, Vaccine Res Ctr, Bethesda, MD 20892 USA. NIH, Malaria Vaccine Dev Branch, Rockville, MD 20852 USA. 3M Pharmaceut, St Paul, MN 55144 USA. Natl Naval Med Res Inst, Malaria Program, Silver Spring, MD 20910 USA. RP Seder, RA (reprint author), NIH, Cellular Immunol Sect, Bldg 10, Bethesda, MD 20892 USA. EM rseder@mail.nih.gov RI Roederer, Mario/G-1887-2011; Saul, Allan/I-6968-2013 OI Saul, Allan/0000-0003-0665-4091 NR 27 TC 184 Z9 192 U1 0 U2 10 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD MAY 15 PY 2006 VL 203 IS 5 BP 1249 EP 1258 DI 10.1084/jem.20052433 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 046IA UT WOS:000237803700013 PM 16636134 ER PT J AU Reits, EA Hodge, JW Herberts, CA Groothuis, TA Chakraborty, M Wansley, EK Camphausen, K Luiten, RM de Ru, AH Neijssen, J Griekspoor, A Mesman, E Verreck, FA Spits, H Schlom, J van Veelen, P Neefjes, JJ AF Reits, EA Hodge, JW Herberts, CA Groothuis, TA Chakraborty, M Wansley, EK Camphausen, K Luiten, RM de Ru, AH Neijssen, J Griekspoor, A Mesman, E Verreck, FA Spits, H Schlom, J van Veelen, P Neefjes, JJ TI Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID NEWLY SYNTHESIZED PROTEINS; IONIZING-RADIATION; ANTIGEN PRESENTATION; T-LYMPHOCYTES; TUMOR-CELLS; ENDOTHELIAL-CELLS; MELANOMA PATIENTS; IRRADIATION; DEGRADATION; MOLECULES AB Radiotherapy is one of the most successful cancer therapies. Here the effect of irradiation on antigen presentation by MHC class I molecules was studied. Cell surface expression of MHC class I molecules was increased for many days in a radiation dose-dependent manner as a consequence of three responses. Initially, enhanced degradation of existing proteins occurred which resulted in an increased intracellular peptide pool. Subsequently, enhanced translation due to activation of the mammalian target of rapamycin pathway resulted in increased peptide production, antigen presentation, as well as cytotoxic T lymphocyte recognition of irradiated cells. In addition, novel proteins were made in response to gamma-irradiation, resulting in new peptides presented by MHC class I molecules, which were recognized by cytotoxic T cells. We show that immunotherapy is successful in eradicating a murine colon adenocarcinoma only when preceded by radiotherapy of the tumor tissue. Our findings indicate that directed radiotherapy can improve the efficacy of tumor immunotherapy. C1 Netherlands Canc Inst, Div Tumor Biol, NL-1066 CX Amsterdam, Netherlands. Netherlands Canc Inst, Div Immunol, NL-1066 CX Amsterdam, Netherlands. NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Leiden State Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2333 AA Leiden, Netherlands. Ctr Med Syst Biol, NL-2333 AA Leiden, Netherlands. RP Neefjes, JJ (reprint author), Netherlands Canc Inst, Div Tumor Biol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. EM j.neefjes@nki.nl RI Hodge, James/D-5518-2015; OI Hodge, James/0000-0001-5282-3154; Luiten, Rosalie/0000-0002-0800-0721; van Veelen, Peter/0000-0002-7898-9408; Groothuis, Tom/0000-0002-1751-4783; Wansley, Elizabeth/0000-0002-0110-7550 FU Intramural NIH HHS NR 51 TC 390 Z9 402 U1 3 U2 27 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD MAY 15 PY 2006 VL 203 IS 5 BP 1259 EP 1271 DI 10.1084/jem.20052494 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 046IA UT WOS:000237803700014 PM 16636135 ER PT J AU Allam, A Kabelitz, D AF Allam, A Kabelitz, D TI TCR trans-rearrangements: Biological significance antigen recognition vs the role as lymphoma biomarker SO JOURNAL OF IMMUNOLOGY LA English DT Review ID CELL RECEPTOR GENE; INTERMOLECULAR V(D)J RECOMBINATION; NIJMEGEN BREAKAGE SYNDROME; COMBINED IMMUNE-DEFICIENCY; DEPENDENT PROTEIN-KINASE; ATAXIA-TELANGIECTASIA; INTERLOCUS RECOMBINATION; SURFACE EXPRESSION; CHROMOSOME-14 INVERSION; MURINE MODEL AB V(D)J rearrangements occur within loci of TCRandBCR genes, thus generating the diversity of the AgR repertoire. In addition, interlocus V(D)J rearrangements occur, giving rise to so-called "trans-rearrangements. " Such transrearrangements increase the diversity of the immune receptor repertoire and can be expressed as functional chimeric TCRproteins on the surface of T cells. Although chimeric receptors are notpathogenicper se, the frequency of AgR trans-rearrangements correlates with the level of genetic instability and thus could be used as a predictive biomarkerforlymphoma risk. C1 Univ Hosp Schleswig Holstein, Inst Immunol, D-24105 Kiel, Germany. NIH, Lab Immune Cell Biol, NCI, Bethesda, MD 20892 USA. RP Kabelitz, D (reprint author), Univ Hosp Schleswig Holstein, Inst Immunol, Campus Kiel,Michaelisstr 5, D-24105 Kiel, Germany. EM kabelitz@immunologie.uni-kiel.de RI Kabelitz, Dieter/A-2757-2010 NR 61 TC 11 Z9 11 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2006 VL 176 IS 10 BP 5707 EP 5712 PG 6 WC Immunology SC Immunology GA 044WW UT WOS:000237705200003 PM 16670273 ER PT J AU Choi, H Cho, SY Schwartz, RH Choi, K AF Choi, H Cho, SY Schwartz, RH Choi, K TI Dual effects of Sprouty1 on TCR signaling depending on the differentiation state of the T cell SO JOURNAL OF IMMUNOLOGY LA English DT Article ID E3 UBIQUITIN LIGASE; NEGATIVE REGULATION; ANTIGEN RECEPTOR; CBL-B; ADAPTER PROTEIN; TYROSINE PHOSPHORYLATION; PROLIFERATIVE RESPONSE; DROSOPHILA-SPROUTY; MAMMALIAN-CELLS; ERK ACTIVATION AB Sprouty (Spry) is known to be a negative feedback inhibitor of growth factor receptor signaling through inhibition of the Ras/MAPK pathway. Several groups, however, have reported a positive role for Spry involving sequestration of the inhibitory protein c-Cbl. Thus, Spry may have various functions in the regulation of receptor-mediated signaling depending on the context. In the immune system, the function of Spry is unknown. In this study, we investigated the role of Spry1 in T cell activation. Spry1, among the four mammalian homologs, was specifically induced by TCR signaling of CD4(+) murine T cells. In fully differentiated Th1 clones, overexpressed Spry1 inhibited TCR signaling and decreased IL-2 production while reducing expression with specific siRNA transfection had the opposite effect, increasing IL-2 production. In contrast, in naive T cells, Spry1 overexpression enhanced TCR signaling, and increased proliferation and IL-2 production, while siRNA transfection again had the opposite effect, reducing IL-2 production following activation. The enhancing effect in naive cells was abrogated by preactivation of the T cells with Ag and APC, indicating that the history of exposure to Ag is correlated with a hierarchy of T cell responsiveness to Spry1. Furthermore, both the NF-AT and MAPK pathways were influenced by Spry1, implying a different molecular mechanism from that for growth factor receptor signaling. Thus, Spry1 uses a novel mechanism to bring about differential effects on TCR signaling through the same receptor, depending on the differentiation state of the T cell. C1 NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. Seoul Natl Univ, Coll Med, Dept Biochem & Mol Biol, Aging & Apoptosis Res Ctr, Seoul, South Korea. RP Choi, K (reprint author), Natl Canc Ctr, Res Inst, 809 Madu I Dong, Goyang 410769, Gyeonggi Do, South Korea. EM kchoi@ncc.re.kr RI Choi, Kyungho/J-5685-2012 FU Intramural NIH HHS NR 63 TC 17 Z9 18 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2006 VL 176 IS 10 BP 6034 EP 6045 PG 12 WC Immunology SC Immunology GA 044WW UT WOS:000237705200042 PM 16670312 ER PT J AU Khan, T Stauffer, JK Williams, R Hixon, JA Salcedo, R Lincoln, E Back, TC Powell, D Lockett, S Arnold, AC Sayers, TJ Wigginton, JM AF Khan, T Stauffer, JK Williams, R Hixon, JA Salcedo, R Lincoln, E Back, TC Powell, D Lockett, S Arnold, AC Sayers, TJ Wigginton, JM TI Proteasome inhibition to maximize the apoptotic potential of cytokine therapy for murine neuroblastoma tumors SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERFERON-GAMMA RECEPTOR; MULTIPLE-MYELOMA CELLS; PHASE-I TRIAL; NF-KAPPA-B; IFN-GAMMA; MEDIATED APOPTOSIS; MALIGNANT-MELANOMA; ANTITUMOR EFFICACY; CLINICAL-RESPONSE; INDUCE APOPTOSIS AB Human neuroblastomas possess several mechanisms of self-defense that may confer an ability to resist apoptosis and contribute to the observed difficulty in treating these tumors in the clinical setting. These molecular alterations may include defects in proapoptotic genes as well as the overexpression of prosurvival factors, such as Akt among others. As a key regulator of the turnover of proteins that modulate the cell cycle and mechanisms of apoptosis, the proteasome could serve as an important target for the treatment of neuroblastoma. The present studies provide the first evidence that bortezomib, a newly approved inhibitor of proteasome function, inhibits phosphorylation of Akt, induces the translocation of proapoptotic Bid, and potently enhances the apoptosis of murine neuroblastoma tumor cells in vitro. Furthermore, in that inhibitors of the Akt pathway can sensitize otherwise resistant TBJ/Neuro-2a cells to apoptosis induced by IFN-gamma plus TNF-alpha, we hypothesized that bortezomib also could sensitize these cells to IFN-gamma plus TNF-alpha. We demonstrate for the first time that bortezomib not only up-regulates the expression of receptors for IFN-gamma and TNF-alpha on both TBJ neuroblastoma and EOMA endothelial cell lines, but also markedly enhances the sensitivity of these cells to apoptosis induced by IFN-gamma plus TNF-alpha in vitro. Furthermore, bortezomib enhances the in vivo antitumor efficacy of IFN-gamma/TNF-alpha-inducing cytokines, including both IL-2 and IL-12 in mice bearing well-established primary and/or metastatic TBJ neuroblastoma tumors. Collectively, these studies suggest that bortezomib could be used therapeutically to enhance the proapoptotic and overall antitumor activity of systemic cytokine therapy in children with advanced neuroblastoma. C1 NCI, Pediat Oncol Branch, Ctr Canc Res, Frederick, MD 21702 USA. SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. Sci Applicat Int Corp, Image Anal Lab, Ft Detrick, MD 21702 USA. NCI, Data Management Serv, Frederick, MD 21702 USA. RP Wigginton, JM (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, Bldg 560,Room 31-93, Frederick, MD 21702 USA. EM jw121b@nih.gov RI Sayers, Thomas/G-4859-2015 FU NCI NIH HHS [N01 CO 12400] NR 58 TC 27 Z9 27 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2006 VL 176 IS 10 BP 6302 EP 6312 PG 11 WC Immunology SC Immunology GA 044WW UT WOS:000237705200072 PM 16670342 ER PT J AU Prophete, C Maciejczyk, P Salnikow, K Gould, T Larson, T Koenig, J Jaques, P Sioutas, C Lippmann, M Cohen, M AF Prophete, C Maciejczyk, P Salnikow, K Gould, T Larson, T Koenig, J Jaques, P Sioutas, C Lippmann, M Cohen, M TI Effects of select PM-associated metals on alveolar macrophage phosphorylated ERK1 and-2 and iNOS expression during ongoing alteration in iron homeostasis SO JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A-CURRENT ISSUES LA English DT Article ID NITRIC-OXIDE SYNTHASE; KAPPA-B ACTIVATION; LEVEL MANGANESE EXPOSURE; LIPID-PEROXIDATION; SIGNALING PATHWAYS; BINDING PROPERTIES; KINASE ACTIVATION; MESSENGER-RNA; RAT; CELLS AB It was hypothesized that relative mass relationships among select constituent metals and iron (Fe3+) govern the pulmonary immunotoxic potential of any PM2.5 sample, as these determine the extent to which Fe3+ binding by transferrin is affected ( resulting in altered alveolar macrophage [AM] Fe status and subsequent antibacterial function). Iron response protein (IRP) binding activity is a useful indirect measurement of changes in Fe status, as reductions in cell Fe levels lead to increases in IRP binding. However, AM IRP activity can be affected by an increased presence of nitric oxide generated by inducible nitric oxide synthase ( iNOS). This study sought to determine if any changes in AM IRP activity induced by PM2.5 constituents V, Mn, or Al were independent from effects of the metals on cell NO formation. NR8383 rat AM were exposed to Fe3+ alone or combined with V, Mn, or Al at metal: Fe ratios representative of those in PM2.5 collected in New York City, Los Angeles, and Seattle during fall 2001. Cells were then assessed for changes in IRP activity and iNOS expression. Phosphorylated extracellular signal-regulated kinase (ERK) 1 and 2 levels were also measured since activated ERKs are involved in signaling pathways that lead to increased iNOS expression. The results indicate that V and Al, and to a lesser extent Mn, altered IRP activity, though the effects were not consistently concentration dependent. Furthermore, while V and Mn treatments did not induce iNOS expression, Al did. These results confirmed our hypothesis that certain metals associated with PM2.5 might alter the pulmonary immunocompetence of exposed hosts by affecting the Fe status of AM, a major class of deep lung defense cells. C1 NYU, Sch Med, Nelson Inst Environm Med, NYU EPA Particulate Matter Hlth Res Ctr, Tuxedo Pk, NY 10987 USA. NCI, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. Univ Washington, NW Ctr Particulate Matter & Hlth, Seattle, WA 98195 USA. Clarkson Univ, Ctr Air Resources Engn & Sci, Dept Biol, Potsdam, NY 13676 USA. Univ So Calif, Los Angeles, CA 90089 USA. RP Cohen, M (reprint author), NYU, Sch Med, Nelson Inst Environm Med, NYU EPA Particulate Matter Hlth Res Ctr, Tuxedo Pk, NY 10987 USA. EM cohenm@env.med.nyu.edu OI Jaques, Peter/0000-0002-4714-4082 FU NIEHS NIH HHS [ES00260] NR 51 TC 19 Z9 20 U1 0 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1528-7394 J9 J TOXICOL ENV HEAL A JI J. Toxicol. Env. Health Part A PD MAY 15 PY 2006 VL 69 IS 10 BP 935 EP 951 DI 10.1080/15287390500362030 PG 17 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 046IO UT WOS:000237805300004 PM 16728372 ER PT J AU Ohara, S Ikeda, A Matsuhashi, M Satow, T Kunieda, T Mikuni, N Baba, K Mihara, T Miyamoto, S Shibasaki, H AF Ohara, S Ikeda, A Matsuhashi, M Satow, T Kunieda, T Mikuni, N Baba, K Mihara, T Miyamoto, S Shibasaki, H TI Bereitschaftspotentials recorded from the lateral part of the superior frontal gyrus in humans SO NEUROSCIENCE LETTERS LA English DT Article DE Bereitschaftspotential; supplementary motor area; superior frontal gyrus; epicortical recording ID SUPPLEMENTARY MOTOR AREA; PACED HAND MOVEMENTS; PREMOTOR CORTEX; VOLUNTARY MOVEMENTS; CEREBRAL-CORTEX; POTENTIALS; MONKEY; TOPOGRAPHY AB To demonstrate the Bereitschaftspotentials (BPs) over the high lateral convexity in the superior frontal gyrus, movement-related cortical potentials with respect to the middle finger extension were recorded in seven patients with refractory epilepsy who underwent subdural implantation of platinum electrode grids and/or strips covering the high lateral frontal convexity. In two out of the seven patients, BPs were recorded from the electrodes placed on the Superior frontal gyrus in the vicinity of the border between the medial and lateral frontal lobes, which were distinct from those recorded from the primary sensorimotor cortex. The results suggest the possible contribution of either the lateral dorsal non-primary motor area or the SMA to the generation of the BPs. (c) 2005 Elsevier Ireland Ltd. All rights reserved. C1 Kyoto Univ, Grad Sch Med, Human Brain Res Ctr, Kyoto 6068507, Japan. Kyoto Univ, Grad Sch Med, Dept Neurol, Kyoto 6068507, Japan. Kyoto Univ, Grad Sch Med, Dept Neurosurg, Kyoto 6068507, Japan. Shizuoka Med Inst Neurol Disorders, Natl Epilepsy Ctr, Shizuoka 4208688, Japan. NINDS, NIH, Bethesda, MD 20892 USA. RP Ikeda, A (reprint author), Kyoto Univ, Grad Sch Med, Human Brain Res Ctr, Kyoto 6068507, Japan. EM akio@kuhp.kyoto-u.ac.jp RI Frank, David/E-8213-2012; OI Ikeda, Akio/0000-0002-0790-2598 NR 27 TC 3 Z9 4 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAY 15 PY 2006 VL 399 IS 1-2 BP 1 EP 5 DI 10.1016/j.neulet.2005.06.062 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 042KL UT WOS:000237526700001 PM 16600501 ER PT J AU Nam, J AF Nam, J TI Assessment on homogeneity tests for kappa statistics under equal prevalence across studies in reliability SO STATISTICS IN MEDICINE LA English DT Article DE distortion of p-value; equal prevalence; homogeneity of kappas; reliability; sample size ID SAMPLE-SIZE DETERMINATION; ESTIMATING EQUATIONS; INTERVAL ESTIMATION; INTRACLASS VERSION; AGREEMENT; COEFFICIENTS; SCORE AB In this paper, we assess the performance of homogeneity tests for two or more kappa statistics when prevalence rates across reliability studies are assumed to be equal. The likelihood score method and the chi-square goodness-of-fit (GOF) test provide type I error rates that are satisfactorily close to the nominal level, but a Fleiss-like test is not satisfactory for small or moderate sample sizes. Simulations show that the score test is more powerful than the chi-square GOF test and the approximate sample size required for a specific power of the former is substantially smaller than the latter. In addition, the score test is robust to deviations from the equal prevalence assumption, while the GOF test is highly sensitive and it may give a grossly misleading type I error rate when the assumption of equal prevalence is violated. We conclude that the homogeneity score test is the preferred method. Published (c) 2005 by John Wiley & Sons, Ltd. C1 NCI, Div Canc Epidemiol & Genet, Biostat Branch, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. RP Nam, J (reprint author), NCI, Div Canc Epidemiol & Genet, Biostat Branch, Dept Hlth & Human Serv,NIH, Execut Pl South Room 8028,6120 Execut Blvd,MSC 72, Bethesda, MD 20892 USA. EM namj@mail.nih.gov NR 23 TC 4 Z9 4 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD MAY 15 PY 2006 VL 25 IS 9 BP 1521 EP 1531 DI 10.1002/sim.2321 PG 11 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 040GC UT WOS:000237366000006 PM 16220477 ER EF