FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Harada, ND Pourat, N AF Harada, ND Pourat, N TI Does membership in veterans' service organizations influence use of the Department of Veterans Affairs as the usual source of care? SO MILITARY MEDICINE LA English DT Article ID HEALTH-CARE; REGULAR SOURCE; MEDICAL-CARE; DIFFERENCE; PHYSICIAN AB Veterans' service organizations (VSOs) provide outreach regarding veterans' benefits. Medical care provided by the Department of Veterans Affairs (VA) is one such benefit that has improved health and quality of life. This study evaluates the characteristics of veterans who report VSO membership and who use the VA as their usual source of care, and it determines whether VSO membership influences the choice of a VA or non-VA facility as the usual source of care. The findings reveal that VSO members, compared with nonmembers, are Caucasian, older, retired, of lower income, and more functionally impaired. Veterans who use the VA, compared with non-VA users, are African American, of lower income, unemployed, and more functionally impaired. VSO members are more likely to use the VA as the usual source of care than are VSO nonmembers, with the effects varying according to race/ethnicity. Policy recommendations include increasing the diversity of VSO membership, because VSOs play an important outreach and informational role for veterans. C1 VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Ctr Hlth Policy Res, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90095 USA. RP Harada, ND (reprint author), VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 18 TC 2 Z9 2 U1 0 U2 1 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 SEP PY 2004 VL 169 IS 9 BP 735 EP 740 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 019JB UT WOS:000235830300019 PM 15495731 ER PT J AU Dadras, SS North, PE Bertoncini, J Mihm, MC Detmar, M AF Dadras, SS North, PE Bertoncini, J Mihm, MC Detmar, M TI Infantile hemangiomas are arrested in an early developmental vascular differentiation state SO MODERN PATHOLOGY LA English DT Article DE infantile hemangioma; LYVE-1; Prox1; lymphangiogenesis ID ENDOTHELIAL-CELLS; CUTANEOUS HEMANGIOMAS; JUVENILE HEMANGIOMAS; LYMPHATIC-SYSTEM; EXPRESSION; INFANCY; GROWTH; LYMPHANGIOGENESIS; MALFORMATIONS; ANGIOGENESIS AB Infantile hemangiomas, the most common tumors of infancy, are vascular tumors characterized by rapid proliferation of endothelial cells during the first few months of postnatal life followed by slow spontaneous involution, whose molecular pathogenesis remains unclear. The recent identification of developmental expression of vascular lineage-specific markers prompted us to characterize infantile hemangiomas for the expression of lymphatic endothelial hyaluronan receptor-1 (LYVE-1), Prox-1, CD31 and CD34. We found that LYVE-1, a specific marker for normal and tumor-associated lymphatic vessels, was strongly expressed in tumor cells of infantile hemangiomas (n=28), but not in other vascular tumors including pyogenic granulomas (n=19, P<0.0001) or intramuscular hemangiomas (n=9), using LYVE-1/CD31 double immunostains. Whereas LYVE-1 expression was detected on the endothelial cells of all proliferating infantile hemangiomas, this lymphatic marker was absent from the lesional capillaries during involution in the majority of cases (P=0.0009). The majority of LYVE-1(+) endothelial cells also expressed CD34, but were negative for the lymphatic-specific homeobox protein Prox-1. Based on coexpression of both LYVE-1 and the blood vascular marker CD34, we propose that the endothelial cells in proliferating infantile hemangioma are arrested in an early developmental stage of vascular differentiation. The immature, incompletely differentiated immunophenotype of proliferating infantile hemangiomas may contribute to their rapid growth during the first few months of life. C1 Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Dept Dermatol, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Arkansas Med Sci, Dept Pathol, Little Rock, AR 72205 USA. Arkansas Childrens Hosp, Little Rock, AR 72202 USA. RP Dadras, SS (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Bldg 149,13th St, Charlestown, MA 02129 USA. EM sam.dadras@cbrc2.mgh.harvard.edu FU NCI NIH HHS [CA91861, CA69184, CA86410] NR 30 TC 62 Z9 74 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD SEP PY 2004 VL 17 IS 9 BP 1068 EP 1079 DI 10.1038/modpathol.3800153 PG 12 WC Pathology SC Pathology GA 848BZ UT WOS:000223443400006 PM 15143338 ER PT J AU Schlaeger, TM Schuh, A Flitter, S Fisher, A Mikkola, H Orkin, SH Vyas, P Porcher, C AF Schlaeger, TM Schuh, A Flitter, S Fisher, A Mikkola, H Orkin, SH Vyas, P Porcher, C TI Decoding hematopoietic specificity in the helix-loop-helix domain of the transcription factor SCL/Tal-1 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID T-CELL LEUKEMIA; C-KIT EXPRESSION; DNA-BINDING; CRYSTAL-STRUCTURE; TRANSGENIC MICE; BASIC REGION; STEM-CELLS; PROTEINS; SCL; GENE AB The helix-loop-helix (HLH) domain is employed by many transcription factors that control cell fate choice in multiple developmental settings. Previously, we demonstrated that the HLH domain of the class 11 basic HLH (bHLH) protein SCL/Tal-1 is critical for hematopoietic specification. We have now identified residues in this domain that are essential for restoring hematopoietic development to SCL-/- embryonic stem cells and sufficient to convert a muscle-specific HLH domain to one able to rescue hematopoiesis. Most of these critical residues are distributed in the loop of SCL, with one in helix 2. This is in contrast to the case for MyoD, the prototype of class II bHLH proteins, where the loop seems to serve mainly as a linker between the two helices. Among the identified residues, some promote heterodimerization with the bHLH partners of SCL (E12/E47), while others, unimportant for this property, are still crucial for the biological function of SCL. Importantly, the residue in helix 2 specifically promotes interaction with a known partner of SCL, the LIM-only protein LMO2, a finding that strengthens genetic evidence that these proteins interact. Our data highlight the functional complexity of bHLH proteins, provide mechanistic insight into SCL function, and strongly support the existence of an active SCL/LMO2-containing multiprotein complex in early hematopoietic cells. C1 Harvard Univ, Sch Med, Dept Hematol Oncol, Childrens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Howard Hughes Med Inst, Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Oxford, MRC, Mol Haematol Unit, Oxford OX1 2JD, England. Univ Oxford, Weatherall Inst Mol Med, Dept Haematol, Oxford OX1 2JD, England. RP Porcher, C (reprint author), John Radcliffe Hosp, Weatherall Inst Mol Med, MRC, Mol Haematol Unit, Oxford OX3 9DS, England. EM catherine.porcher@imm.ox.ac.uk RI Schuh, Anna/D-8954-2014; Porcher, Catherine/D-7026-2016; OI Vyas, Paresh/0000-0003-3931-0914 NR 45 TC 26 Z9 28 U1 0 U2 6 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 SEP PY 2004 VL 24 IS 17 BP 7491 EP 7502 DI 10.1128/MCB.24.17.7491-7502.2004 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 848CD UT WOS:000223443800016 PM 15314159 ER PT J AU Friedrich, EB Liu, E Sinha, S Cook, S Milstone, DS MacRae, CA Mariotti, M Kuhlencordt, PJ Force, T Rosenzweig, A St-Arnaud, R Dedhar, S Gerszten, RE AF Friedrich, EB Liu, E Sinha, S Cook, S Milstone, DS MacRae, CA Mariotti, M Kuhlencordt, PJ Force, T Rosenzweig, A St-Arnaud, R Dedhar, S Gerszten, RE TI Integrin-linked kinase regulates endothelial cell survival and vascular development SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PROTEIN-KINASE; EXTRACELLULAR-MATRIX; EXPRESSION INCREASES; MONOCLONAL-ANTIBODY; IN-VITRO; ADHESION; ILK; APOPTOSIS; ANGIOGENESIS; ACTIVATION AB Integrin-linked kinase (ILK) is a phosphoinositide 3-kinase-dependent serine/threonine kinase that interacts with beta integrins. Here we show that endothelial cell (EC)-specific deletion of ILK in mice confers placental insufficiency with decreased labyrinthine vascularization, yielding no viable offspring. Deletion of ILK in zebra fish using antisense morpholino oligonucleotides results in marked patterning abnormalities of the vasculature and is similarly lethal. To dissect potential mechanisms responsible for these phenotypes, we performed ex vivo deletion of ILK from purified EC of adult mice. We observed downregulation of the active-conformation of beta1 integrins with a striking increase in EC apoptosis associated with activation of caspase 9. There was also reduced phosphorylation of the ILK kinase substrate, Akt. However, phenotypic rescue of ILK-deficient EC by wild-type ILK, but not by a constitutively active mutant of Akt, suggests regulation of EC survival by ILK in an Akt-independent manner. Thus, endothelial ILK plays a critical role in vascular development through integrin-matrix interactions and EC survival. These data have important implications for both physiological and pathological angiogenesis. C1 Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, Dept Pathol, Div Vasc Res, Boston, MA 02115 USA. Tufts Univ, Sch Med, New England Med Ctr, Mol Cardiol Res Inst, Boston, MA 02111 USA. Univ Wurzburg, Dept Med, Wurzburg, Germany. McGill Univ, Montreal, PQ, Canada. Shriners Hosp Children, Montreal, PQ, Canada. Univ British Columbia, Dept Biochem & Mol Biol, Vancouver, BC V5Z 1M9, Canada. Vancouver Gen Hosp & Hlth Serv Ctr, BC Canc Agcy, Jack Bell Res Ctr, Vancouver, BC, Canada. RP Gerszten, RE (reprint author), Massachusetts Gen Hosp E, Ctr Immunol & Inflammatory Dis, 8307,149 13th St, Charlestown, MA 02129 USA. EM rgerszten@partners.org RI Cook, Stuart/G-9567-2011; OI Force, Thomas/0000-0002-0450-8659; Cook, Stuart/0000-0001-6628-194X FU NHLBI NIH HHS [K08 HL068711]; NIGMS NIH HHS [R21 GM075946] NR 42 TC 87 Z9 96 U1 0 U2 2 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 SEP PY 2004 VL 24 IS 18 BP 8134 EP 8144 DI 10.1128/MCB.24.18.8134-8144.2004 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 852MY UT WOS:000223760600029 PM 15340074 ER PT J AU Huamani, J McMahan, CA Herbert, DC Reddick, R McCarrey, JR MacInnes, MI Chen, DJ Walter, CA AF Huamani, J McMahan, CA Herbert, DC Reddick, R McCarrey, JR MacInnes, MI Chen, DJ Walter, CA TI Spontaneous mutagenesis is enhanced in Apex heterozygous mice SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID BASE EXCISION-REPAIR; DNA-POLYMERASE-BETA; GERM-CELL APOPTOSIS; APURINIC APYRIMIDINIC SITES; SPONTANEOUS MUTATION; TRANSGENIC MICE; MEIOTIC RECOMBINATION; SPERMATOGENIC CELLS; SECTORED PLAQUES; BINDING ACTIVITY AB Germ line DNA directs the development of the next generation and, as such, is profoundly different from somatic cell DNA. Spermatogenic cells obtained from young adult lacI transgenic mice display a lower spontaneous mutant frequency and greater in vitro base excision repair activity than somatic cells and tissues obtained from the same mice. However, spermatogenic cells from old lacI mice display a 10-fold higher mutant frequency. This increased spontaneous mutant frequency occurs coincidentally with decreased in vitro base excision repair activity for germ cell and testicular extracts that in turn corresponds to a decreased abundance of AP endonuclease. To directly test whether a genetic diminution of AP endonuclease results in increased spontaneous mutant frequencies in spermatogenic cell types, AP endonuclease heterozygous (Apex(+/-)) knockout mice were crossed with lacI transgenic mice. Spontaneous mutant frequencies were significantly elevated (approximately twofold) for liver and spleen obtained from 3-month-old Apex(+/-) lacI(+) mice compared to frequencies from Apex(+/+) lacI(+) littermates and were additionally elevated for somatic tissues from 9-month-old mice. Spermatogenic cells from 9-month-old Apex(+/+) lacI(+) mice were significantly elevated twofold compared to levels for 9-month-old Apex(+/+) lacI(+) control mice. These data indicate that diminution of AP endonuclease has a significant effect on spontaneous mutagenesis in somatic and germ line cells. C1 Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78229 USA. Univ Texas, Dept Biol, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, Div Res, San Antonio, TX USA. Los Alamos Natl Lab, Biosci Div, Los Alamos, NM USA. Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA. RP Walter, CA (reprint author), Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, Mail Code 7762,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM walter@uthscsa.edu FU NCI NIH HHS [R01 CA086936, CA86936]; NIA NIH HHS [P01 AG019316, AG19316, R01 AG021163, AG21163]; NIEHS NIH HHS [ES09136, R01 ES009136] NR 67 TC 40 Z9 43 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 SEP PY 2004 VL 24 IS 18 BP 8145 EP 8153 DI 10.1128/MCB.24.18.8145-8153 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 852MY UT WOS:000223760600030 PM 15340075 ER PT J AU Zhu, BM Gulick, T AF Zhu, BM Gulick, T TI Phosphorylation and alternative Pre-mRNA splicing converge to regulate myocyte enhancer factor 2C activity SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TRANSCRIPTION FACTOR MEF2C; MYOSIN HEAVY-CHAIN; SKELETAL-MUSCLE; GENE-EXPRESSION; DNA-BINDING; MADS-BOX; NONMUSCLE CELLS; MYOGENIC BHLH; DIFFERENTIATION; PROTEINS AB Myocyte enhancer factor 2 (MEF2) transcription factors play pivotal roles in cardiac, muscle, and neuron gene expression. All products of MEF2 genes have a common amino-terminal DNA binding and dimerization domain, but the four vertebrate MEF2 gene transcripts are alternatively spliced among coding exons to produce splicing isoforms. In MEF2C alone, alternative splice acceptors in the last exon give forms that include or exclude a short domain that we designate gamma. We show that MEF2C is expressed exclusively as gamma- isoforms in heart tissue and predominantly as gamma- in other adult tissues and in differentiating myocytes. MEF2C gamma-isoforms are much more robust than gamma+ forms in activating MEF2-responsive reporters in transfected fibroblasts despite indistinguishable expression levels, and they better synergize with MyoD in promoting myogenic conversion. One-hybrid transcription assays using Gal4-MEF2C fusions give similar distinctions between gamma- and gamma+ isoforms in all cell types tested, including myocytes. Cis effects of gamma on MEF2C DNA binding, dimerization, protein stability, or response to CaM or p38 mitogen-activated protein kinase signaling are not apparent, and the isolated gamma domain represses transcription when fused to Gal4. One phosphoserine residue is present within the gamma domain according to tandem mass spectrometry, and mutation of this residue abolishes gamma-mediated transrepression. A similar activity is present in the constitutive gamma domain and serine phosphoacceptor of MEF2A. Our findings indicate that gamma functions autonomously as a phosphoserine-dependent transrepressor to downregulate transactivation function of MEF2 factors and that alternative splicing and serine phosphorylation converge to provide complex combinatorial control of MEF2C activity. C1 Massachusetts Gen Hosp, Diabet Res Lab, Dept Med, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Gulick, T (reprint author), Massachusetts Gen Hosp, Diabet Res Lab, Dept Med, MGH E,CNY 149 8219, Charlestown, MA 02129 USA. EM gulick@helix.mgh.harvard.edu FU NHLBI NIH HHS [HL72713, R01 HL072713]; NIDDK NIH HHS [DK02461, DK55875, R01 DK055875] NR 53 TC 44 Z9 47 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 SEP PY 2004 VL 24 IS 18 BP 8264 EP 8275 DI 10.1128/MCB.24.18.8264-8275.2004 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 852MY UT WOS:000223760600041 PM 15340086 ER PT J AU Tang, W Chang, SB Hemler, ME AF Tang, W Chang, SB Hemler, ME TI Links between CD147 function, glycosylation, and caveolin-1 SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID MATRIX-METALLOPROTEINASE INDUCER; COLLAGENASE-STIMULATORY FACTOR; IMMUNOGLOBULIN SUPERFAMILY MEMBER; LYSOSOMAL MEMBRANE-GLYCOPROTEINS; HAMSTER OVARY CELLS; EMMPRIN CD147; MELANOMA-CELLS; GOLGI-COMPLEX; CYCLOPHILIN-A; BREAST-CANCER AB Cell surface CD147 shows remarkable variations in size (31-65 kDa) because of heterogeneous N-glycosylation, with the most highly glycosylated forms functioning to induce matrix metalloproteinase (MMP) production. Here we show that all three CD147 N-glycosylation sites make similar contributions to both high and low glycoforms (HG- and LG-CD147). L-Phytohemagglutinin lectin binding and swainsonine inhibition experiments indicated that HG-CD147 contains N-acetylglucosaminyltransferase V-catalyzed, beta1,6-branched, polylactosamine-type sugars, which account for its excess size. Therefore, CD147, which is itself elevated on invasive tumor cells, may make a major contribution to the abundance of beta1,6-branched polylactosamine sugars that appear on invasive tumor cells. It was shown previously that caveolin-1 associates with CD147, thus inhibiting CD147 self-aggregation and MMP induction; now we show that caveolin-1 associates with LG-CD147 and restricts the biosynthetic conversion of LG-CD147 to HG-CD147. In addition, HG-CD147 (but not LG-CD147) was preferentially captured as a multimer after treatment of cells with a homobifunctional cross-linking agent and was exclusively recognized by monoclonal antibody AAA6, a reagent that selectively recognizes self-associated CD147 and inhibits CD147-mediated MMP induction. In conclusion, we have 1) determined the biochemical basis for the unusual size variation in CD147, 2) established that CD147 is a major carrier, of beta1,6-branched polylactosamine sugars on tumor cells, and 3) determined that caveolin-1 can inhibit the conversion of LG-CD147 to HG-CD147. Because it is HG-CD147 that self-aggregates and stimulates MMP induction, we now have a mechanism to explain how caveolin-1 inhibits these processes. These results help explain the previously established tumor suppressor functions of caveolin-1. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Hemler, ME (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. EM martin_hemler@dfci.harvard.edu FU NCI NIH HHS [R01 CA086712, CA-86712] NR 53 TC 142 Z9 154 U1 2 U2 11 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 SEP PY 2004 VL 15 IS 9 BP 4043 EP 4050 DI 10.1091/mbc.E04-05-0402 PG 8 WC Cell Biology SC Cell Biology GA 849US UT WOS:000223567100009 PM 15201341 ER PT J AU Kim, TG Gruber, A Ruprecht, RM Langridge, WHR AF Kim, TG Gruber, A Ruprecht, RM Langridge, WHR TI Synthesis and assembly of SIVmac Gag p27 capsid protein cholera toxin B subunit fusion protein in transgenic potato SO MOLECULAR BIOTECHNOLOGY LA English DT Article DE SIV; Solarium tuberosum; edible vaccine; AIDS; Gag ID T-LYMPHOCYTE RESPONSES; VIRUS TYPE-1 INFECTION; SURFACE-ANTIGEN; HEAT-LABILE; IMMUNIZATION; EXPRESSION; PLANTS; IMMUNOGENICITY; OLIGOMERS; INDUCTION AB A deoxyribonucleic acid (DNA) fragment encoding the cholera toxin B subunit (CTB) was linked 5' to the simian immunodeficiency virus (SIVmac) Gag p27 capsid gene (CTB-Gag). The fusion gene was transferred into Solanum tuberosum cells by Agrobacterium tumefaciens-mediated transformation methods and transformed plants regenerated. The CTB-Gag gene fusion was detected in transformed potato leaf genomic DNA by polymerase chain reaction-mediated DNA amplification. The results of immunoblot analysis with anti-CTB and anti-Gag antibodies verified the synthesis of biologically active CTB-Gag fusion protein in transformed leaf and tuber tissues. Synthesis and assembly of the CTB-Gag fusion protein into oligomeric structures of pentamer size was confirmed by G(MI)-ganglioside-enzyme-linked immunosorbent assay (G(MI)-ELISA) of transformed potato tuber tissue extracts. The binding of CTB-Gag fusion protein oligomers to intestinal epithelial cell membrane receptors quantified by G(MI)-ELISA showed that CTB-Gag fusion protein made up approx 0.016-0.022% of the total soluble tuber protein. The synthesis of CTB-Gag monomers and their assembly into biologically active CTB-Gag fusion protein oligomers in potato tuber tissues provides the opportunity for employment of the carrier and adjuvant properties of CTB for the development of edible plant-based subunit mucosal vaccines for enhanced mucosal immunity against SIV in macaques. C1 Loma Linda Univ, Sch Med, Dept Biochem & Microbiol, Loma Linda, CA 92350 USA. Loma Linda Univ, Sch Med, Ctr Mol Biol & Gene Therapy, Loma Linda, CA 92350 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Langridge, WHR (reprint author), Loma Linda Univ, Sch Med, Dept Biochem & Microbiol, Loma Linda, CA 92350 USA. EM blangridge@som.llu.edu FU NIAID NIH HHS [P01 AI 48240] NR 31 TC 16 Z9 18 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1073-6085 J9 MOL BIOTECHNOL JI Mol. Biotechnol. PD SEP PY 2004 VL 28 IS 1 BP 33 EP 40 DI 10.1385/MB:28:1:33 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 855ZF UT WOS:000224012700004 PM 15456961 ER PT J AU Krop, I Player, A Tablante, A Taylor-Parker, M Lahti-Domenici, J Fukuoka, J Batra, SK Papadopoulos, N Richards, WG Sugarbaker, DJ Wright, RL Shim, J Stamey, TA Sellers, WR Loda, M Meyerson, M Hruban, R Jen, J Polyak, K AF Krop, I Player, A Tablante, A Taylor-Parker, M Lahti-Domenici, J Fukuoka, J Batra, SK Papadopoulos, N Richards, WG Sugarbaker, DJ Wright, RL Shim, J Stamey, TA Sellers, WR Loda, M Meyerson, M Hruban, R Jen, J Polyak, K TI Frequent HIN-1 promoter methylation and lack of expression in multiple human tumor types SO MOLECULAR CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; NORMAL-1 HIN-1; PCR ASSAY; GENE; HYPERMETHYLATION; ADENOCARCINOMA; MORPHOGENESIS; PROTEIN AB HIN-1 (high in normal-1) is a candidate tumor suppressor identified as a gene silenced by methylation in the majority of breast carcinomas. HIN-1 is highly expressed in the mammary gland, trachea, lung, prostate, pancreas, and salivary gland, and in the lung, its expression is primarily restricted to bronchial epithelial cells. In this report, we show that, correlating with the secretory nature of HIN-1, high levels of HIN-1 protein are detected in bronchial lavage, saliva, plasma, and serum. To determine if, similar to breast carcinomas, HIN-1 is also silenced in tumors originating from other organs with high HIN-1 expression, we analyzed its expression and promoter methylation status in lung, prostate, and pancreatic carcinomas. Nearly all prostate and a significant fraction of lung and pancreatic carcinomas showed HIN-1 hypermethylation, and the majority of lung and prostate tumors lacked HIN-1 expression. In lung carcinomas, the degree of HIN-1 methylation differed among tumor subtypes (P = 0.02), with the highest level of HIN-1 methylation observed in squamous cell carcinomas and the lowest in small cell lung cancer. In lung adenocarcinomas, the expression of HIN-1 correlated with cellular differentiation status. Hypermethylation of the HIN-1 promoter was also frequently observed in normal tissue adjacent to tumors but not in normal tissue from noncancer patients, implying that HIN-1 promoter methylation may be a marker of premalignant changes. Thus, silencing of HIN-1 expression and methylation of its promoter occurs in multiple human cancer types, suggesting that elimination of HIN-1 function may contribute to several forms of epithelial tumorigenesis. C1 Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. NCI, Lab Populat Genet, Bethesda, MD 20892 USA. Univ Nebraska, Med Ctr, Omaha, NE USA. Columbia Univ, Dept Pathol, Inst Canc Genet, New York, NY USA. Stanford Univ, Stanford, CA 94305 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. RP Polyak, K (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St,D740C, Boston, MA 02115 USA. EM Kornelia_Polyak@dfci.harvard.edu RI Meyerson, Matthew/E-7123-2012; Papadopoulos, Nickolas/K-7272-2012 FU NCI NIH HHS [CA89393, CA94787-01, R01 CA94074-01A1] NR 20 TC 35 Z9 36 U1 0 U2 1 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 SEP PY 2004 VL 2 IS 9 BP 489 EP 494 PG 6 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 857AM UT WOS:000224087600001 PM 15383627 ER PT J AU Lopez, CA Kimchi, ET Mauceri, HJ Park, JO Mehta, N Murphy, KT Beckett, MA Hellman, S Posner, MC Kufe, DW Weichselbaum, RR AF Lopez, CA Kimchi, ET Mauceri, HJ Park, JO Mehta, N Murphy, KT Beckett, MA Hellman, S Posner, MC Kufe, DW Weichselbaum, RR TI Chemoinducible gene therapy: A strategy to enhance doxorubicin antitumor activity SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID TUMOR-NECROSIS-FACTOR; ALPHA TNF-ALPHA; PHASE-II TRIAL; IONIZING-RADIATION; CARCINOMA-CELLS; CONTINUOUS INFUSION; HYDROGEN-PEROXIDE; ANTICANCER DRUGS; PROSTATE-CANCER; BREAST-CANCER AB A replication-defective adenoviral vector, Ad.Egr-TNF.11D, was engineered by ligating the CArG (CC(A/T)(6)GG) elements of the Egr-1 gene promoter upstream to a cDNA encoding human tumor necrosis factor-alpha. We report here that Ad.Egr-TNF.11D is activated by the clinically important anticancer agents cisplatin, cyclophosphamide, doxorubicin, 5-fluorouracil, gemcitabine, and paclitaxel. N-acetylcysteine, a free radical scavenger, blocked induction of tumor necrosis factor-alpha by anticancer agents, supporting a role for reactive oxygen intermediates in activation of the CArG sequences. Importantly, resistance of PC-3 human prostate carcinoma and PROb rat colon carcinoma tumors to doxorubicin in vivo was reversed by combining doxorubicin with Ad.Egr-TNF and resulted in significant antitumor effects. Treatment with Ad.Egr-TNF.11D has been associated with inhibition of tumor angiogenesis. In this context, a significant decrease in tumor microvessel density was observed following combined treatment with doxorubicin and Ad.Egr-TNF.11 D as compared with either agent alone. These data show that Ad.Egr-TNF.11 D is activated by diverse anticancer drugs. C1 Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL USA. Univ Chicago, Dept Surg, Chicago, IL USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Weichselbaum, RR (reprint author), Univ Chicago Hosp, Dept Radiat & Cellular Oncol, Ctr Adv Med, Room 1329,Mail Code 9006,5758 S Maryland Ave, Chicago, IL 60637 USA. EM rrw@rover.uchicago.edu NR 57 TC 23 Z9 37 U1 0 U2 1 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 SEP PY 2004 VL 3 IS 9 BP 1167 EP 1175 PG 9 WC Oncology SC Oncology GA 854MM UT WOS:000223907300014 PM 15367711 ER PT J AU Yurkovetskiy, AV Hiller, A Syed, S Yin, M Lu, XM Fischman, AJ Papisov, MI AF Yurkovetskiy, A. V. Hiller, A. Syed, S. Yin, M. Lu, X. M. Fischman, A. J. Papisov, M. I. TI Synthesis of a macromolecular camptothecin conjugate with dual phase drug release SO MOLECULAR PHARMACEUTICS LA English DT Article DE drug release; drug delivery; cancer; camptothecin; polyals; polyacetals; biodegradable polymers AB A water soluble macromolecular conjugate of camptothecin (CPT) with a new, dual phase hydrolytic drug release mechanism was prepared on the basis of a 60 kDa biodegradable hydrophilic "stealth" polyacetal, poly(1-hydroxymethylethylene hydroxy-methyl formal). Succinamido-glycinate was used as a prodrug releasing group. A model preparation with 7.5% CPT content w/w was water soluble. The lipophilic camptothecin prodrug, camptothecin-(O20)-succinimidoglycinate, was released from the conjugate with t(1/2) = 2.2 +/- 0.1 h in rodent plasma. The blood clearance in a rodent model as measured by CPT was release limited, t(1/2) = 2.1 +/- 0.2 h, while the conjugate half-life was 14.2 +/- 1.7 h. In a xenograft tumor model, the conjugate demonstrated higher antineoplastic efficacy than CPT at a less than equitoxic dose. This improved therapeutic window is in line with the modified drug pharmacokinetics and with camptothecin release in a stabilized lipophilic prodrug form. Regulation of prodrug release and hydrolysis rates through linker structure modification will open the way to further improve both pharmacokinetics and pharmacodynamics. C1 [Yurkovetskiy, A. V.; Hiller, A.; Syed, S.; Lu, X. M.; Fischman, A. J.; Papisov, M. I.] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med, Lab Mol Bioengn, Boston, MA 02114 USA. [Yurkovetskiy, A. V.; Hiller, A.; Syed, S.; Lu, X. M.; Fischman, A. J.; Papisov, M. I.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Yin, M.] Nanopharma Corp, Boston, MA 02116 USA. RP Papisov, MI (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med, Lab Mol Bioengn, MGH Bartlett Hall 500R,55 Fruit St, Boston, MA 02114 USA. EM papisov@helix.mgh.harvard.edu OI Papisov, Mikhail/0000-0003-4716-2122 FU NIH/NCRR [R21-RRI4221, T32 GM07035]; Nanopharma Corp FX This work was supported in part by NIH/NCRR Grants R21-RRI4221 and T32 GM07035 and by Nanopharma Corp. NR 17 TC 28 Z9 30 U1 3 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD SEP-OCT PY 2004 VL 1 IS 5 BP 375 EP 382 DI 10.1021/mp0499306 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA V52IY UT WOS:000203538400007 PM 16026008 ER PT J AU Hafler, D O'Connor, KC Cherry, S Viglietta, V Boecher-Allan, C Wucherpfennig, K AF Hafler, D O'Connor, KC Cherry, S Viglietta, V Boecher-Allan, C Wucherpfennig, K TI Defective immunity in multiple sclerosis SO MULTIPLE SCLEROSIS LA English DT Meeting Abstract CT 20th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple- Sclerosis/9th Annual Meeting of Rehabilitation in MS CY OCT 06-09, 2004 CL Vienna, AUSTRIA C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD SEP PY 2004 VL 10 IS 7032 SU 2 BP S103 EP S104 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 875YS UT WOS:000225459800026 ER PT J AU Weir, GC Bonner-Weir, S AF Weir, GC Bonner-Weir, S TI beta-cell precursors - a work in progress SO NATURE BIOTECHNOLOGY LA English DT Editorial Material ID STEM-CELLS; MARROW C1 Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. RP Weir, GC (reprint author), Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, 1 Joslin Pl, Boston, MA 02215 USA. EM gordon.weir@joslin.harvard.edu NR 9 TC 15 Z9 16 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD SEP PY 2004 VL 22 IS 9 BP 1095 EP 1096 DI 10.1038/nbt0904-1095 PG 2 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 850ZR UT WOS:000223653400024 PM 15340475 ER PT J AU Austin, CP Battey, JF Bradley, A Bucan, M Capecchi, M Collins, FS Dove, WF Duyk, G Dymecki, S Eppig, JT Grieder, FB Heintz, N Hicks, G Insel, TR Joyner, A Koller, BH Lloyd, KCK Magnuson, T Moore, MW Nagy, A Pollock, JD Roses, AD Sands, AT Seed, B Skarnes, WC Snoddy, J Soriano, P Stewart, DJ Stewart, F Stillman, B Varmus, H Varticovski, L Verma, IM Vogt, TF von Melchner, H Witkowski, J Woychik, RP Wurst, W Yancopoulos, GD Young, SG Zambrowicz, B AF Austin, CP Battey, JF Bradley, A Bucan, M Capecchi, M Collins, FS Dove, WF Duyk, G Dymecki, S Eppig, JT Grieder, FB Heintz, N Hicks, G Insel, TR Joyner, A Koller, BH Lloyd, KCK Magnuson, T Moore, MW Nagy, A Pollock, JD Roses, AD Sands, AT Seed, B Skarnes, WC Snoddy, J Soriano, P Stewart, DJ Stewart, F Stillman, B Varmus, H Varticovski, L Verma, IM Vogt, TF von Melchner, H Witkowski, J Woychik, RP Wurst, W Yancopoulos, GD Young, SG Zambrowicz, B CA Comprehensive Knockout Mouse Proje TI The knockout mouse project SO NATURE GENETICS LA English DT Article ID EMBRYONIC STEM-CELLS; GENE-TRAP MUTAGENESIS; GENOME; MICE; SEQUENCE; IDENTIFICATION; DEFICIENCY; PHENOTYPE; INSIGHTS; RESOURCE AB Mouse knockout technology provides a powerful means of elucidating gene function in vivo, and a publicly available genome-wide collection of mouse knockouts would be significantly enabling for biomedical discovery. To date, published knockouts exist for only about 10% of mouse genes. Furthermore, many of these are limited in utility because they have not been made or phenotyped in standardized ways, and many are not freely available to researchers. It is time to harness new technologies and efficiencies of production to mount a high-throughput international effort to produce and phenotype knockouts for all mouse genes, and place these resources into the public domain. C1 NHGRI, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. Univ Utah, Eccles Inst Human Genet, Salt Lake City, UT 85112 USA. Univ Wisconsin, McArdle Lab Canc Res, Madison, WI 53706 USA. TPG Ventures, San Francisco, CA 94104 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Jackson Lab, Bar Harbor, ME 04609 USA. NIH, Natl Ctr Res Resources, Bethesda, MD 20817 USA. Rockefeller Univ, Mol Biol Lab, New York, NY 10021 USA. Manitoba Inst Cell Biol, Winnipeg, MB R3E 0V9, Canada. NIMH, Bethesda, MD 20892 USA. Skirball Inst Biomol Med, New York, NY 10016 USA. Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. Univ Calif Davis, Sch Vet Med, Davis, CA 95616 USA. Deltagen, Redwood City, CA 94063 USA. Univ Toronto, Samuel Lumenfeld Res Inst, Toronto, ON M5G 1X5, Canada. Natl Inst Drug Abuse, Bethesda, MD 20892 USA. GlaxoSmithKline Inc, Res Triangle Pk, NC 27709 USA. Lexicon Genet, The Woodlands, TX 77381 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Oak Ridge Natl Lab, Univ Tennessee ORNL Grad Sch Genome Sci & Technol, Oak Ridge, TN 37831 USA. Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. Cold Spring Harbor Lab, Banbury Ctr, Cold Spring Harbor, NY 11724 USA. Univ Technol, Bioz, MPI CBG, D-1307 Dresden, Germany. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NCI, NIH, Bethesda, MD 20892 USA. Salk Inst Biol Studies, Mol Biol & Virol Lab, La Jolla, CA 92037 USA. Merck Res Labs, West Point, PA 19486 USA. Goethe Univ Frankfurt, Sch Med, Lab Mol Hematol, D-60590 Frankfurt, Germany. Jackson Lab, Bar Harbor, ME 04609 USA. Max Planck Inst Psychiat, GSF Res Ctr, Inst Dev Genet, D-85764 Munich, Germany. Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA. Univ Calif San Francisco, Gladstone Fdn Cardiovasc Dis, San Francisco, CA 94143 USA. RP Austin, CP (reprint author), NHGRI, NIH, Bldg 31,Room 4B09,31 Ctr Dr, Bethesda, MD 20892 USA. EM austinc@mail.nih.gov RI Pollock, Jonathan/B-1554-2009; Stewart, A. Francis/E-7789-2010; Nagy, Andras/G-6465-2013; Soriano, Philippe/E-5797-2015; OI Soriano, Philippe/0000-0002-0427-926X; Witkowski, Jan/0000-0002-8159-2874; Stillman, Bruce/0000-0002-9453-4091 FU Wellcome Trust [077188] NR 25 TC 359 Z9 385 U1 4 U2 30 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD SEP PY 2004 VL 36 IS 9 BP 921 EP 924 DI 10.1038/ng0904-921 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 851AY UT WOS:000223658100005 PM 15340423 ER PT J AU DePinho, RA Polyak, K AF DePinho, RA Polyak, K TI Cancer chromosomes in crisis SO NATURE GENETICS LA English DT Editorial Material ID TELOMERE DYSFUNCTION; BREAST; CARCINOMA; MICE AB The benign-to-malignant transition in human breast cancer is associated with a marked increase in chromosomal aberrations. A new study suggests that telomere dysfunction and its associated bridge-fusion-breakage cycles may drive this episodic instability, thereby providing aspiring cancer cells with the multiple genetic aberrations needed to achieve a fully malignant state. C1 Dana Farber Canc Inst, Ctr Appl Canc Sci, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP DePinho, RA (reprint author), Dana Farber Canc Inst, Ctr Appl Canc Sci, Boston, MA 02115 USA. EM ron_depinho@dfci.harvard.edu NR 11 TC 67 Z9 69 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD SEP PY 2004 VL 36 IS 9 BP 932 EP 934 DI 10.1038/ng0904-932 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 851AY UT WOS:000223658100008 PM 15340427 ER PT J AU Iafrate, AJ Feuk, L Rivera, MN Listewnik, ML Donahoe, PK Qi, Y Scherer, SW Lee, C AF Iafrate, AJ Feuk, L Rivera, MN Listewnik, ML Donahoe, PK Qi, Y Scherer, SW Lee, C TI Detection of large-scale variation in the human genome SO NATURE GENETICS LA English DT Article ID SEGMENTAL DUPLICATIONS; SEQUENCE; DISEASE AB We identified 255 loci across the human genome that contain genomic imbalances among unrelated individuals. Twenty-four variants are present in >10% of the individuals that we examined. Half of these regions overlap with genes, and many coincide with segmental duplications or gaps in the human genome assembly. This previously unappreciated heterogeneity may underlie certain human phenotypic variation and susceptibility to disease and argues for a more dynamic human genome structure. C1 Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Hosp Sick Children, Dept Genet & Genom Biol, Toronto, ON M5G 1X8, Canada. Univ Toronto, Toronto, ON, Canada. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. RP Lee, C (reprint author), Brigham & Womens Hosp, Dept Pathol, 20 Shattuck St,Thorn 6-28, Boston, MA 02115 USA. EM clee@rics.bwh.harvard.edu RI Howe, Jennifer/I-9013-2012; Scherer, Stephen /B-3785-2013 OI Scherer, Stephen /0000-0002-8326-1999 NR 12 TC 1635 Z9 1701 U1 4 U2 54 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD SEP PY 2004 VL 36 IS 9 BP 949 EP 951 DI 10.1038/ng1416 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 851AY UT WOS:000223658100018 PM 15286789 ER PT J AU Crittenden, JR Bergmeier, W Zhang, YY Piffath, CL Liang, YQ Wagner, DD Housman, DE Graybiel, AM AF Crittenden, JR Bergmeier, W Zhang, YY Piffath, CL Liang, YQ Wagner, DD Housman, DE Graybiel, AM TI CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation SO NATURE MEDICINE LA English DT Article ID DIACYLGLYCEROL-BINDING MOTIFS; NUCLEOTIDE-RELEASING PROTEIN; SMALL GTPASE RAP1; MOUSE PLATELETS; GLYCOPROTEIN VI; EXCHANGE FACTOR; CELL-ADHESION; R-RAS; ACTIVATION; MEGAKARYOCYTES AB Signaling through the second messengers calcium and diacylglycerol (DAG) is a critical element in many biological systems. Integration of calcium and DAG signals has been suggested to occur primarily through protein kinase C family members, which bind both calcium and DAG. However, an alternative pathway may involve members of the CalDAG-GEF/ RasGRP protein family, which have structural features (calcium-binding EF hands and DAG-binding C1 domains) that suggest they can function in calcium and DAG signal integration(1,2). To gain insight into the signaling systems that may be regulated by CalDAG-GEF/ RasGRP family members, we have focused on CalDAG-GEFI, which is expressed preferentially in the brain and blood(1). Through genetic ablation in the mouse, we have found that CalDAG-GEFI is crucial for signal integration in platelets. Mouse platelets that lack CalDAG-GEFI are severely compromised in integrin-dependent aggregation as a consequence of their inability to signal through CalDAG-GEFI to its target, the small GTPase Rap1. These results suggest that analogous signaling defects are likely to occur in the central nervous system when CalDAG-GEFI is absent or compromised in function. C1 MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, CBR Inst Biomed Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Univ Washington, Dept Immunol, Seattle, WA 98195 USA. MIT, Ctr Canc Res, Cambridge, MA 02139 USA. RP Graybiel, AM (reprint author), MIT, Dept Brain & Cognit Sci, 45 Carleton St,E25-618, Cambridge, MA 02139 USA. EM graybiel@mit.edu FU NHLBI NIH HHS [P01-HL56949, HL66105, P01 HL056949]; NICHD NIH HHS [R01 HD028341, R01-HD28341]; NIMH NIH HHS [F32-MH065815] NR 25 TC 225 Z9 232 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD SEP PY 2004 VL 10 IS 9 BP 982 EP 986 DI 10.1038/1098 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 851AZ UT WOS:000223658400036 PM 15334074 ER PT J AU Luster, AD Tager, AM AF Luster, AD Tager, AM TI T-CELL trafficking in asthma: Lipid mediators grease the way SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID PROSTAGLANDIN-D SYNTHASE; HUMAN POLYMORPHONUCLEAR LEUKOCYTES; ACTIVATION-REGULATED CHEMOKINE; BRONCHOALVEOLAR LAVAGE FLUID; MONOCYTE-DERIVED CHEMOKINE; ALLERGIC AIRWAY DISEASE; LUNG MAST-CELLS; HUMAN TYPE-2 TH; LEUKOTRIENE B-4; ARACHIDONIC-ACID AB Recruitment of T cells to the airways is crucial in the pathogenesis of asthma, and it is thought to be mediated mainly by peptide chemokines. By contrast, lipid mediators such as leukotrienes and prostaglandins have classically been thought to contribute to asthma pathogenesis by other mechanisms. However, as we discuss here, the recent molecular identification of leukotriene and prostaglandin receptors, as well as the generation of mice that are genetically deficient in them, has revealed that two of these lipids-leukotriene B-4 and prostaglandin D-2- also direct T-cell migration and seem to cooperate with chemokines in a non-redundant, sequential manner to recruit T cells to the airways in asthma. C1 Massachusetts Gen Hosp, Ctr immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Charlestown, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. RP Luster, AD (reprint author), Massachusetts Gen Hosp, Ctr immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Bldg 149-8301,13th St, Charlestown, MA 02129 USA. EM aluster@partners.org NR 118 TC 141 Z9 145 U1 1 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD SEP PY 2004 VL 4 IS 9 BP 711 EP 724 DI 10.1038/nri1438 PG 14 WC Immunology SC Immunology GA 851AW UT WOS:000223657900015 PM 15343370 ER PT J AU Benn, SC Woolf, CJ AF Benn, SC Woolf, CJ TI Adult neuron survival strategies - Slamming on the brakes SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID TUMOR-NECROSIS-FACTOR; N-TERMINAL KINASE; ENDOPLASMIC-RETICULUM STRESS; PROGRAMMED CELL-DEATH; CYTOCHROME-C RELEASE; BCL-2 FAMILY-MEMBERS; NERVE GROWTH-FACTOR; KAPPA-B ACTIVATION; SPINAL-CORD-INJURY; X-LINKED INHIBITOR AB Developing neurons are programmed to die by an apoptotic pathway unless they are rescued by extrinsic growth factors that generate an anti-apoptotic response. By contrast, adult neurons need to survive for the lifetime of the organism, and their premature death can cause irreversible functional deficits. The default apoptotic pathway is shut down when development is complete, and consequently growth factors are no longer required to prevent death. To protect against accidental apoptotic cell death, anti-apoptotic mechanisms are activated in mature neurons in response to stress. Loss or reduced activity of these intrinsic anti-apoptotic 'brakes' might contribute to or accelerate neurodegeneration, whereas their activation might rescue neurons from injury or genetic abnormalities. C1 Massachusetts Gen Hosp, Dept Anaesthesia & Crit Care, Neural Plast Res Grp, Boston, MA 02129 USA. Massachusetts Gen Hosp, Dept Neurol, Day Neuromuscular Res Lab, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Woolf, CJ (reprint author), Massachusetts Gen Hosp, Dept Anaesthesia & Crit Care, Neural Plast Res Grp, Boston, MA 02129 USA. EM cwoolf@partners.org NR 206 TC 151 Z9 160 U1 0 U2 9 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 SEP PY 2004 VL 5 IS 9 BP 686 EP 700 DI 10.1038/nrn1477 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 850QO UT WOS:000223627700012 PM 15322527 ER PT J AU Park, HJ Westin, CF Kubicki, M Maier, SE Niznikiewicz, M Baer, A Frumin, M Kikinis, R Jolesz, FA McCarley, RW Shenton, ME AF Park, HJ Westin, CF Kubicki, M Maier, SE Niznikiewicz, M Baer, A Frumin, M Kikinis, R Jolesz, FA McCarley, RW Shenton, ME TI White matter hemisphere asymmetries in healthy subjects and in schizophrenia: a diffusion tensor MRI study SO NEUROIMAGE LA English DT Article DE hemisphere asymmetry; diffusion tensor MRI; fractional anisotropy ID CORPUS-CALLOSUM; HUMAN-BRAIN; CEREBRAL LATERALIZATION; BIOLOGICAL MECHANISMS; PLANUM TEMPORALE; UNCINATE FASCICULUS; ANATOMIC ASYMMETRY; FIBER TRACTS; GRAY-MATTER; IN-VIVO AB Hemisphere asymmetry was explored in normal healthy subjects and in patients with schizophrenia using a novel voxel-based tensor analysis applied to fractional anisotropy (FA) of the diffusion tensor. Our voxel-based approach, which requires precise spatial normalization to remove the misalignment of fiber tracts, includes generating a symmetrical group average template of the diffusion tensor by applying nonlinear elastic warping of the demons algorithm. We then normalized all 32 diffusion tensor MRIs from healthy subjects and 23 from schizophrenic subjects to the symmetrical average template. For each brain, six channels of tensor component images and one T2-weighted image were used for registration to match tensor orientation and shape between images. A statistical evaluation of white matter asymmetry was then conducted on the normalized FA images and their flipped images. In controls, we found left-higher-than-right anisotropic asymmetry in the anterior part of the corpus callosum, cingulum bundle, the optic radiation, and the superior cerebellar peduncle, and right-higher-than-left anisotropic asymmetry in the anterior limb of the internal capsule and the anterior limb's prefrontal regions, in the uncinate fasciculus, and in the superior longitudinal fasciculus. In patients, the asymmetry was lower, although still present, in the cingulum bundle and the anterior corpus callosum, and not found in the anterior limb of the internal capsule, the uncinate fasciculus, and the superior cerebellar peduncle compared to healthy subjects. These findings of anisotropic asymmetry pattern differences between healthy controls and patients with schizophrenia are likely related to neurodevelopmental abnormalities in schizophrenia. Published by Elsevier Inc. C1 Harvard Med Sch, VA Boston Healthcare Syst, Brockton Div, Dept Psychiat,Lab Neurosci,Clin Neurosci Div, Boston, MA 02301 USA. Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, Lab Math Imaging, Boston, MA 02301 USA. Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, Surg Planning Lab, Boston, MA 02301 USA. Yonsei Univ, Coll Med, Dept Diagnost Radiol, Div Nucl Med, Seoul 120752, South Korea. Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, MRI Div, Boston, MA 02301 USA. RP Shenton, ME (reprint author), Harvard Med Sch, VA Boston Healthcare Syst, Brockton Div, 940 Belmont St, Brockton, MA 02301 USA. EM martha-shenton@hms.harvard.edu RI McCarley, Robert/N-5562-2014 OI McCarley, Robert/0000-0001-5705-7495 FU NCRR NIH HHS [R01 RR011747, P41 RR013218, P41 RR013218-020001, P41-RR13218, R01 RR011747-02]; NIMH NIH HHS [K02 MH 01110, K02 MH001110, K02 MH001110-10, K05 MH070047, K05 MH070047-01, R01 MH 40799, R01 MH 50747, R01 MH040799, R01 MH040799-17, R01 MH050740, R01 MH050740-12, R01 MH050740-15, R03 MH068464, R03 MH068464-01]; NINDS NIH HHS [R01 NS 39335, R01 NS039335, R01 NS039335-02]; PHS HHS [11747] NR 68 TC 175 Z9 179 U1 3 U2 20 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 SEP PY 2004 VL 23 IS 1 BP 213 EP 223 DI 10.1016/j.neuroimage.2004.04.036 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 850WL UT WOS:000223645000023 PM 15325368 ER PT J AU Nguyen, PT Holschneider, DP Maarek, JMI Yang, J Mandelkern, MA AF Nguyen, PT Holschneider, DP Maarek, JMI Yang, J Mandelkern, MA TI Statistical parametric mapping applied to an autoradiographic study of cerebral activation during treadmill walking in rats SO NEUROIMAGE LA English DT Article DE statistical parametric mapping; autoradiography; cerebral blood flow; rats ID BLOOD-FLOW; INDICATOR FRACTIONATION; BRAIN; SECTIONS; RECONSTRUCTION; INFORMATION; ALIGNMENT; IMAGES AB Autoradiographs are conventionally analyzed by a region-of-interest (ROI) analysis. However, definition of ROIs on an image set is labor intensive, is subject to potential inter-rater bias, and is not well suited for anatomically variable structures that may not consistently correspond to specific ROIs. Most importantly, the ROI method is poorly suited for whole-brain analysis, where one wishes to detect all activations resulting from an experimental paradigm. A system developed for analysis of imaging data in humans, Statistical Parametric Mapping (SPM), avoids some of these limitations but has not previously been adapted as a toot for the analysis of autoradiographs. Here, we describe the application of SPM to an autoradiographic data set mapping cerebral activation in rats during treadmill walking. We studied freely moving, non-tethered rats that received injections of the cerebral blood flow tracer [C-14]-iodoantipyrine, while they were performing a treadmill task (n=7) or during a quiescent control condition (n=6). Results obtained with SPM were compared to those previously reported using a standard ROI-based method of analysis [J. Cereb. Blood Flow Metab. 23(2003) 925]. The SPM method confirmed most areas detected as significant using the ROI approach. However, in the subcortex, SPM detected additional significant regions that, because of their irregular structures, fell short of statistical significance when analyzed by ROI. The SPM approach offers the ability to perform a semi-automated whole-brain analysis, and coupled with autoradiography, provides an effective means to globally localize functional activity in small animals. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ So Calif, Keck Sch Med, Dept Cell & Neurobiol, Los Angeles, CA 90089 USA. Univ Calif Irvine, Dept Phys & Astron, Irvine, CA USA. Univ So Calif, Dept Psychiat & Behav Sci, Los Angeles, CA USA. Univ So Calif, Dept Neurol, Los Angeles, CA USA. Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Holschneider, DP (reprint author), Univ So Calif, Keck Sch Med, Dept Cell & Neurobiol, 1333 San Pablo St,BMT 401,MC 9112, Los Angeles, CA 90089 USA. EM holschne@usc.edu FU NIBIB NIH HHS [R01 EB-00300-03, R01 EB000300] NR 25 TC 42 Z9 42 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2004 VL 23 IS 1 BP 252 EP 259 DI 10.1016/j.neuroimage.2004.05.014 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 850WL UT WOS:000223645000027 PM 15325372 ER PT J AU Venna, N AF Venna, N TI Mitochondrial neurological diseases: A clinician's perspective SO NEUROLOGY INDIA LA English DT Editorial Material C1 Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Venna, N (reprint author), Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02114 USA. EM nvenna1@partners.org NR 4 TC 2 Z9 2 U1 0 U2 0 PU NEUROL SOC INDIA PI CHANDIGARH PA C/O J S CHOPRA, PGIMER, DEPT NEUROLOGY, CHANDIGARH 160 012, INDIA SN 0028-3886 J9 NEUROL INDIA JI Neurol. India PD SEP PY 2004 VL 52 IS 3 BP 305 EP 306 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 865QE UT WOS:000224716800001 PM 15472416 ER PT J AU Finkel, RS Medne, L Seltzer, WK Hedley-Whyte, ET AF Finkel, RS Medne, L Seltzer, WK Hedley-Whyte, ET TI Novel myelin protein zero mutation in a kindred with hypomyelinating motor and sensory polyneuropathy type 1b - a clinicopathologic study SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 9th International Congress of the World-Muscle-Society CY SEP 01-04, 2004 CL Goteborg, SWEDEN SP World Muscle Soc C1 Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Athena Diagnost Inc, Genet Lab, Worcester, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 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 SEP PY 2004 VL 14 IS 8-9 BP 570 EP 571 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 847ZQ UT WOS:000223437000053 ER PT J AU Zhang, KH Grady, CJ Tsapakis, EM Andersen, SL Tarazi, FI Baldessarini, RJ AF Zhang, KH Grady, CJ Tsapakis, EM Andersen, SL Tarazi, FI Baldessarini, RJ TI Regulation of working memory by dopamine D-4 receptor in rats SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE cognition; delayed alternation; dopamine; D-4 receptor; L-745,870; working memory ID NEONATAL 6-HYDROXYDOPAMINE LESIONS; SPATIAL DELAYED ALTERNATION; PREFRONTAL CORTEX; MOTOR HYPERACTIVITY; COGNITIVE PERFORMANCE; RHESUS-MONKEY; AGED MONKEYS; ANTAGONIST; D1; LOCALIZATION AB Working memory is regulated by neurotransmitters in prefrontal cortex (PFC), including dopamine and norepinephrine. Previous studies of dopamine function in working memory have focused on the D-1 and D-2 receptors, with most evidence suggesting a dominant role for the D-1 receptor. Since the dopamine D-4 receptor is highly expressed in PFC, we hypothesize that it may also contribute to working memory. To test this hypothesis, we examined behavioral effects of L-745,870, a highly selective, centrally active, D-4 antagonist, using a delayed alternation task in rats. Task performance was dose-dependently affected by the D-4 antagonist, depending on individual baseline functional status of working memory. In rats with good baseline performance, the D-4 antagonist had no effects at low doses, whereas high doses disrupted working memory. In rats with poor baseline working memory, the D-4 antagonist significantly improved working memory at low doses, and higher doses were not distinguishable from vehicle controls. Effects of the D-4 antagonist among poor performers were most robust when task demand for working memory was high, with lesser effects at lower demand level, suggesting that such effects were selective for working memory. The present findings indicate a significant role of the D-4 receptor in working memory, and suggest innovative, D-4-based, treatment of cognitive deficits associated with neuropsychiatric disorders. C1 Massachusetts Gen Hosp, McLean Div, Mailman Res Ctr, Belmont, MA USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. RP Zhang, KH (reprint author), McLean Hosp, Mailman Res Ctr, 115 Mill St, Belmont, MA 02478 USA. EM kz@mclean.harvard.edu NR 60 TC 51 Z9 52 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD SEP PY 2004 VL 29 IS 9 BP 1648 EP 1655 DI 10.1038/sj.npp.1300491 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 848LD UT WOS:000223468100007 PM 15138447 ER PT J AU Holschneider, DP Maarek, JMI AF Holschneider, DP Maarek, JMI TI Mapping brain function in freely moving subjects SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE brain mapping; nontethered; freely moving; positron emission tomography; single photon emission computed tomography; behavior; Tc-99m-HMPAO; Tc-99m-bicisate; Cu-64-PTSM ID CEREBRAL BLOOD-FLOW; POSITRON-EMISSION-TOMOGRAPHY; CYTOCHROME-OXIDASE ACTIVITY; POSTTRAUMATIC-STRESS-DISORDER; PREFRONTAL ACTIVATION PROBE; SURFACE-AREA PRODUCT; GLUCOSE-UTILIZATION; PARKINSONS-DISEASE; NEURONAL-ACTIVITY; DYNAMIC EXERCISE AB Expression of many fundamental mammalian behaviors such as, for example, aggression, mating, foraging or social behaviors, depend on locomotor activity. A central dilemma in the functional neuroimaging of these behaviors has been the fact that conventional neuroimaging techniques generally rely on immobilization of the subject, which extinguishes all but the simplest activity. Ideally, imaging could occur in freely moving subjects, while presenting minimal interference with the subject's natural behavior. Here we provide an overview of several approaches that have been undertaken in the past to achieve this aim in both tethered and freely moving animals, as well as in nonrestrained human subjects. Applications of specific radiotracers to single photon emission computed tomography and positron emission tomography are discussed in which brain activation is imaged after completion of the behavioral task and capture of the tracer. Potential applications to clinical neuropsychiatry are discussed, as well as challenges inherent to constraint-free functional neuroimaging. Future applications of these methods promise to increase our understanding of the neural circuits underlying mammalian behavior in health and disease. (C) 2004 Elsevier Ltd. All rights reserved. C1 Univ So Calif, Dept Psychiat & Behav Sci, Los Angeles, CA 90089 USA. Univ So Calif, Dept Neurol, Los Angeles, CA 90089 USA. Univ So Calif, Dept Cell & Neurobiol, Los Angeles, CA 90089 USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. RP Holschneider, DP (reprint author), Univ So Calif, Dept Psychiat & Behav Sci, 1333 San Pablo St,BMT 401,MC 9112, Los Angeles, CA 90089 USA. EM holschne@usc.edu FU NIBIB NIH HHS [R01 EB000300, R01 EB-00300-03] NR 136 TC 14 Z9 14 U1 3 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD SEP PY 2004 VL 28 IS 5 BP 449 EP 461 DI 10.1016/j.neubiorev.2004.06.007 PG 13 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 864LM UT WOS:000224635000001 PM 15465134 ER PT J AU Barker, FG Amin-Hanjani, S AF Barker, FG Amin-Hanjani, S TI Changing neurosurgical workload in the United States, 1988-2001: Craniotomy other than trauma in adults SO NEUROSURGERY LA English DT Article DE centralization; craniotomy; length of stay; workload ID IN-HOSPITAL MORTALITY; UNRUPTURED INTRACRANIAL ANEURYSMS; CAROTID-ENDARTERECTOMY; SURGEON VOLUME; PROGRESSIVE CENTRALIZATION; GEOGRAPHIC-VARIATION; OPERATIVE MORTALITY; MEDICARE POPULATION; SURGICAL-PROCEDURES; PRACTICE PATTERNS AB OBJECTIVE: Changes in neurosurgical workload can justify requests for hospital resources and guide planning by neurosurgical training programs. Most previous studies have used non-population-based data sources, such as surveys of professional society members, to explore the neurosurgical workload in the United States. METHODS: This is a retrospective cohort study of patients in Diagnosis Related Group (DRG) 1 ("Craniotomy other than trauma, age > 17") using the Nationwide Inpatient Sample. Statistical methods were adjusted for complex survey methodology to generate total United States caseload estimates. RESULTS: The total United States DRG 1 caseload increased from 70,800 admissions in 1988 to 105,300 admissions in 2001, a 50% relative increase (P < 0.001). For most diagnostic categories, the relative caseload increase was similar to that for the whole group. Patient age and sex distributions remained stable over time. Medical comorbidities, such as hypertension, chronic pulmonary disease, diabetes, and obesity, became more frequent. Elective admissions increased and in-hospital mortality rates decreased. Length of hospital stay decreased during the first half of the study period and then stabilized. Combined with increasing caseload, this caused total annual inpatient DRG 1 days to increase progressively after 1996. The number of United States hospitals with DRG 1 admissions decreased over time. Per-hospital annual DRG 1 caseloads increased, especially at high-volume centers. For the largest 100 hospitals by DRG 1 caseload, total admissions increased from 8.5% of all United States admissions 0 988) to 9.4% (2001), whereas DRG 1 caseload increased disproportionately, from 27% to 38% of the United States aggregate caseload. This is evidence that progressive centralization of DRG 1 admissions took place during the study period. CONCLUSION: We documented an increase in total caseload and centralization of care for DRG 1 in the United States during the period 1988 to 2001. Defining the reasons for the changes in neurosurgical workload we observed will require further research. C1 Massachusetts Gen Hosp, Neurosurg Serv, Brain Tumor Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Surg Neurosurg, Boston, MA USA. Univ Illinois, Dept Neurosurg, Chicago, IL USA. RP Barker, FG (reprint author), Massachusetts Gen Hosp, Neurosurg Serv, Brain Tumor Ctr, Fruit St, Boston, MA 02114 USA. EM barker@helix.mgh.harvard.edu NR 79 TC 10 Z9 10 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD SEP PY 2004 VL 55 IS 3 BP 506 EP 517 DI 10.1227/01.NEU.0000134284.47965.71 PG 12 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 860AH UT WOS:000224309000011 PM 15335418 ER PT J AU Wolfberg, AJ Feltmate, C Goldstein, DP Berkowitz, RS Lieberman, E AF Wolfberg, AJ Feltmate, C Goldstein, DP Berkowitz, RS Lieberman, E TI Low risk of relapse after achieving undetectable hCG levels in women with complete molar pregnancy SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID GESTATIONAL TROPHOBLASTIC DISEASE; HUMAN CHORIONIC-GONADOTROPIN; HYDATIDIFORM MOLE; FOLLOW-UP; EVACUATION; MANAGEMENT; LONG AB OBJECTIVE: Complete hydatidiform molar pregnancies occur in approximately 1 of 1,000 conceptions. After uterine evacuation of the trophoblastic tissue, women are followed up with serial serum human chorionic gonadotropin (hCG) measurements. Patients are considered to have attained remission when their hCG level spontaneously declines to an undetectable level and remains there during a 6-month follow-up period. This standard effectively detects all disease recurrence; however, it is resource intensive, delays child bearing, and is subject to significant noncompliance. Our objective was to determine the risk of disease recurrence after hCG spontaneously declines to undetectable levels. METHODS: We used a database from the New England Trophoblastic Disease Center to analyze hCG levels in patients with complete molar pregnancies. RESULTS: Among 1,029 women with complete molar pregnancy and complete data, 15% developed persistent gestational trophoblastic neoplasia. The rate of persistent neoplasm among those whose hCG level fell spontaneously to undetectable levels was 0.2% (2/876, 95% confidence interval 0 - 0.8%). No women developed persistent gestational trophoblastic neoplasia after their hCG level fell to undetectable levels using an assay with a sensitivity of 5 mIU/mL (n = 82, 95% confidence interval 0 - 4.5%). CONCLUSION: Based on our experience with women with complete hydatidiform molar pregnancies whose hCG values spontaneously fell to undetectable levels after molar evacuation, we conclude that the risk of recurrent neoplasm after hCG levels fall to less than 5 mIU/mL approaches zero. (C) 2004 by The American College of Obstetricians and Gynecologists. C1 Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Maternal Fetal Med, Boston, MA 02115 USA. RP Wolfberg, AJ (reprint author), Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, 75 Francis St, Boston, MA 02115 USA. EM awolfberg@partners.org NR 18 TC 47 Z9 51 U1 0 U2 0 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 SEP PY 2004 VL 104 IS 3 BP 551 EP 554 DI 10.1097/01.AOG.0000136099.21216.45 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 875JB UT WOS:000225415200020 PM 15339768 ER PT J AU Perez, VL Papaliodis, GN Chu, D Anzaar, F Christen, W Foster, CS AF Perez, VL Papaliodis, GN Chu, D Anzaar, F Christen, W Foster, CS TI Elevated levels of interleukin 6 in the vitreous fluid of patients with pars planitis and posterior uveitis: The Massachusetts eye & ear experience and review of previous studies SO OCULAR IMMUNOLOGY AND INFLAMMATION LA English DT Article DE uveitis; IL-6; cytokines; vitreous ID GROWTH-FACTOR-BETA; IMMUNE PRIVILEGE; AQUEOUS-HUMOR; INTRAOCULAR INFLAMMATION; IL-6; CYTOKINES AB Introduction: Although the exact mechanisms that lead to uveitis are not entirely known, the role of cytokines in the pathogenesis of this disease has been shown to be important. Prior studies described the presence of an array of cytokines in the intraocular fluid of patients with uveitis. Review of these studies indicate that Interleukin-6 (IL-6) is present, and animal data suggest the important role of IL-6 in the regulation of ophthalmologic immune responses. Purpose: We investigated whether IL-6, TNF-alpha, IL-I alpha, beta, IL-2 are present in the vitreous of patients with active intermediate and posterior uveitis. Methods: Vitreous specimens were collected from 23 eyes of patients with active intermediate and posterior uveitis who underwent diagnostic or therapeutic vitrectomies. TNF-alpha, IL-I alpha and beta, IL-2 and IL-6 were measured by enzyme-linked immunosorbent assay. Eight vitreous fluid samples from eye bank eyes were used as control. Results: IL-6 was higher in the vitreous of patients with uveitis compared to control samples (p = 0.0119). No TNF-alpha, IL-2, ILI-alpha or beta was detected. The levels of IL-6 did not correlate with a specific clinical diagnosis, but patients with pars planitis and panuveitis had the highest levels (P = 0.58) Conclusions: IL-6 is elevated in the vitreous of patients with active intermediate and posterior uveitis. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Immunol & Uveitis Serv, Boston, MA 02114 USA. Cleveland Clin Fdn, Cole Eye Inst, Cleveland, OH 44195 USA. Univ Med & Dent New Jersey, Coll Med, Newark, NJ 07103 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Foster, CS (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Immunol & Uveitis Serv, 243 Charles St, Boston, MA 02114 USA. EM fosters@uveitis.org NR 20 TC 28 Z9 29 U1 1 U2 2 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 0927-3948 J9 OCUL IMMUNOL INFLAMM JI Ocul. Immunol. Inflamm. PD SEP PY 2004 VL 12 IS 3 BP 193 EP 201 DI 10.1080/092739490500282 PG 9 WC Ophthalmology SC Ophthalmology GA 865BI UT WOS:000224677100003 PM 15385196 ER PT J AU Lu, QY Sartippour, MR Brooks, MN Zhang, QF Hardy, M Go, VL Li, FP Heber, D AF Lu, QY Sartippour, MR Brooks, MN Zhang, QF Hardy, M Go, VL Li, FP Heber, D TI Ganoderma lucidum spore extract inhibits endothelial and breast cancer cells in vitro SO ONCOLOGY REPORTS LA English DT Article DE Ganoderma lucidum; angiogenesis; breast cancer; cancer prevention; alternative medicine ID ANTITUMOR-ACTIVITY; FUNGAL POLYSACCHARIDES; STRUCTURAL EXAMINATION; TRITERPENES; MECHANISM; KARST AB This study was conducted to investigate the anti-proliferative activities of medicinal mushroom Ganoderma lucidum (Rei-shi or Mannentake). We have identified an alcohol extract from the spore of Ganoderma lucidum that inhibits the in vitro proliferation of human umbilical vein endothelial cells and MDA-MB231 human breast cancer cells. Further fractionation of the alcohol extract revealed that the ethyl acetate fraction inhibited both cell lines in a dose-dependent manner from 2 to 40 mug/ml. Our results suggest that the alcohol extract from the spore of Ganoderma lucidum may possess potential anti-tumor and anti-angiogenic activities. C1 Univ Calif Los Angeles, Ctr Human Nutr, Dept Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Surg, Div Oncol, Los Angeles, CA 90095 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Brooks, MN (reprint author), Univ Calif Los Angeles, Ctr Human Nutr, Dept Med, Box 951782, Los Angeles, CA 90095 USA. EM maibrooks@mednet.ucla.edu FU NCCIH NIH HHS [AT 00151] NR 29 TC 16 Z9 21 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 SEP PY 2004 VL 12 IS 3 BP 659 EP 662 PG 4 WC Oncology SC Oncology GA 844LB UT WOS:000223158600026 PM 15289852 ER PT J AU Rubin, PAD Chang, E Bernardino, CR Hatton, MP Dohlrnan, CH AF Rubin, PAD Chang, E Bernardino, CR Hatton, MP Dohlrnan, CH TI Oculoplastic technique of connecting a glaucoma valve shunt to extraorbital locations in cases of severe glaucoma SO OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID AQUEOUS-HUMOR; FLOW; KERATOPROSTHESIS; IMPLANTS AB Purpose: To describe a technique for inserting glaucoma shunts to the sinuses or the lacrimal sac as a means of lowering intraocular pressure in patients with refractory glaucoma associated with severe ocular surface disease. Methods: Nineteen patients with severe ocular surface disease necessitating a keratoprosthesis and with intractable glaucoma underwent placement of a modified Ahmed shunt to direct aqueous in the maxillary or ethmoid sinus or lacrimal sac. Results: Intraocular pressure is presently well controlled without glaucoma medications in two thirds of patients. None of the patients had endophthalmitis. Conclusions. Established oculoplastic surgery techniques may be used to redirect aqueous to extraorbital locations and effectively lower intraocular pressure in patients with severe ocular surface disease and refractory glaucoma. This procedure has not been associated with endophthalmitis. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. RP Rubin, PAD (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. NR 10 TC 10 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0740-9303 J9 OPHTHAL PLAST RECONS JI Ophthalmic Plast. Reconstr. Surg. PD SEP PY 2004 VL 20 IS 5 BP 362 EP 367 DI 10.1097/01.IOP.0000139520.72137.0A PG 6 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 856KW UT WOS:000224045100006 PM 15377903 ER PT J AU Thakker, MM Fay, AM Pieroth, L Rubin, PAD AF Thakker, MM Fay, AM Pieroth, L Rubin, PAD TI Fibrovascular ingrowth into hydroxyapatite and porous polyethylene orbital implants wrapped with acellular dermis SO OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID CELLS; ALLOGRAFTS; ANTIGENS; GAMMA AB Purpose: Acellular dermis is a frequently used wrapping material for hydroxyapatite (HA) and porous polyethylene (PP) orbital implants. In an animal model, we determined by histology the extent of fibrovascular ingrowth within orbital implants wrapped in acellular dermis at 6 and 12 weeks after surgery. Methods: Four Yucatan minipigs were used for the study. Two minipigs had HA implants and two had PP implants. Implants were harvested at 6 or 12 weeks after surgery and were examined histologically for fibrovascular ingrowth. Results: There was complete fibrovascularization of HA implants harvested at both 6 and 12 weeks after surgery. The PP implant harvested at 6 weeks had incomplete fibrovascularization, whereas the PP implant harvested at 12 weeks had complete fibrovascular ingrowth. There was no histologic evidence of inflammation seen in any of the orbital implants. On gross and histologic examination, the wraps were found to persist on the surface of all orbital implants, with little histologic evidence of inflammation localized to the acellular dermis. Conclusions: Acellular dermis wraps support fibrovascularization of both HA and PP orbital implants. Additionally, acellular dermis does not incite significant inflammation in association with HA and PP orbital implants and can persist in situ for at least 12 weeks after surgery. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Oculoplast & Orbital Surg, Oculoplast & Orbital Surg Serv,Dept Ophthalmol, Boston, MA 02114 USA. RP Fay, AM (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Oculoplast & Orbital Surg, Oculoplast & Orbital Surg Serv,Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM aaron_fay@meei.harvard.edu NR 23 TC 7 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0740-9303 J9 OPHTHAL PLAST RECONS JI Ophthalmic Plast. Reconstr. Surg. PD SEP PY 2004 VL 20 IS 5 BP 368 EP 373 DI 10.1097/01.IOP.0000134247.29702.90 PG 6 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 856KW UT WOS:000224045100007 PM 15377904 ER PT J AU Collignon-Robe, NJ Feke, GT Rizzo, JF AF Collignon-Robe, NJ Feke, GT Rizzo, JF TI Optic nerve head circulation in nonarteritic anterior ischemic optic neuropathy and optic neuritis SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY MAY 05-10, 2002 CL FT LAUDERDALE, FL SP Assoc Res Vis & Ophthalmol ID LASER-DOPPLER FLOWMETRY; MULTIPLE-SCLEROSIS; INTERFERON BETA-1A; BLOOD-FLOW; FLUORESCEIN ANGIOGRAPHY; TREATMENT TRIAL; EXPERIENCE; COUNTY; EDEMA; DEPTH AB Purpose: To quantify optic nerve head circulatory abnormalities in patients with unilateral nonarteritic anterior ischemic optic neuropathy (NAION) or optic neuritis (ON), and to assess the potential of such measurements to differentiate NAION from ON. Design: Prospective, cross-sectional, observational study. Participants: Thirty consecutive patients with unilateral NAION, 22 consecutive patients with unilateral ON, and 50 healthy control subjects. Methods: All subjects underwent a complete neuro-ophthalmologic evaluation. The widths of Doppler-broadened frequency spectra, which are directly proportional to the speed of blood cells flowing through the capillaries of the optic nerve head, were measured at multiple sites in both eyes of each subject. The variation of Doppler broadening (DB) with age was determined in the control subjects. Doppler broadening values in the patients were compared between similar sites in affected and contralateral eyes, and between both affected and contralateral eyes and the age-adjusted values determined in the control subjects. Main Outcome Measures: The differences in DB between (1) the affected and contralateral eyes of the patients, (2) the patients and the control subjects, and (3) the patients with NAION and those with ON. Results: In NAION, DB was decreased at both temporal (-20.2% and -18.5%) and nasal (-12.8% and -12.4%) sites of the nerve head in affected eyes compared with contralateral eyes or eyes of control subjects. In ON, DB was also decreased at temporal sites (-11.3% and -9.2%) in affected eyes compared with contralateral or control eyes. At nasal sites, there were no significant differences in DB in affected eyes of ON patients compared with contralateral or control eyes. The DB decreases were significantly greater in NAION patients than in ON patients. Conclusions: Optic nerve head circulatory abnormalities are present in patients with NAION or ON. This is the first demonstration of such abnormalities in ON, a finding consistent with the recent attention given to the phenomenon of axonal loss in this disease. Although there are differences in the circulatory abnormalities between the 2 diseases that provide insights into the pathophysiological mechanisms at play, they are not large enough to enable the clinician to distinguish between ON and NAION in an individual patient. (C) 2004 by the American Academy of Ophthalmology. C1 Schepens Retina Associates Fdn, Boston, MA 02215 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. Univ Liege, Dept Ophthalmol, Liege, Belgium. RP Feke, GT (reprint author), Schepens Retina Associates Fdn, 1 Autumn St, Boston, MA 02215 USA. EM feke@schepens.com NR 40 TC 22 Z9 22 U1 0 U2 0 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 SEP PY 2004 VL 111 IS 9 BP 1663 EP 1672 DI 10.1016/j.ophtha.2004.05.020 PG 10 WC Ophthalmology SC Ophthalmology GA 850JD UT WOS:000223606300009 PM 15350320 ER PT J AU Yaroslavsky, AN Neel, V Anderson, RR AF Yaroslavsky, AN Neel, V Anderson, RR TI Fluorescence polarization imaging for delineating nonmelanoma skin cancers SO OPTICS LETTERS LA English DT Article ID SPECTROSCOPY; EXCISIONS; TISSUES; LIGHT AB We present a method for detecting nonmelanoma skin cancers using exogenous fluorescence polarization. We built an automated system that permits exogenous fluorescence polarization imaging. It includes a tunable linearly polarized monochromatic light source and a CCD camera equipped with a rotating linear polarizer and a filter to reject excitation light. Two fluorophores that are retained in tumors, toluidine blue and methylene blue, are employed. We demonstrate that fluorescence polarization imaging can be used for accurate delineation of nonmelanoma cancers. The results suggest that this optical technique may be suitable for real-time noninvasive demarcation of epithelial cancers. (C) 2004 Optical Society of America. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Labs Photomed, Boston, MA 02114 USA. RP Yaroslavsky, AN (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Labs Photomed, Boston, MA 02114 USA. EM yaroslav@helix.mgh.harvard.edu FU NIBIB NIH HHS [R01 EB002423-01] NR 12 TC 35 Z9 35 U1 1 U2 4 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 0146-9592 J9 OPT LETT JI Opt. Lett. PD SEP 1 PY 2004 VL 29 IS 17 BP 2010 EP 2012 DI 10.1364/OL.29.002010 PG 3 WC Optics SC Optics GA 848QB UT WOS:000223481100016 PM 15455763 ER PT J AU Sah, AR Eisler, T Karrholm, J Malchau, H AF Sah, AR Eisler, T Karrholm, J Malchau, H TI Is there still a role fop the cemented stem? SO ORTHOPEDICS LA English DT Article ID TOTAL HIP-ARTHROPLASTY; FEMORAL COMPONENT; 2ND-GENERATION; REVISIONS C1 Massachusetts Gen Hosp, Dept Orthoped Surg, Boston, MA 02114 USA. Karolinska Inst, Stockholm Soder Hosp, Dept Orthoped Surg, S-10401 Stockholm, Sweden. Gothenburg Univ, Sahlgrenska Univ Hosp, Inst Surg Sci, Dept Orthoped Surg, S-41124 Gothenburg, Sweden. RP Malchau, H (reprint author), Sahlgrenska Univ Hosp, Dept Orthoped, SE-41345 Gothenburg, Sweden. NR 8 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0147-7447 J9 ORTHOPEDICS JI Orthopedics PD SEP PY 2004 VL 27 IS 9 BP 963 EP 964 PG 2 WC Orthopedics SC Orthopedics GA 853LU UT WOS:000223829900023 PM 15487417 ER PT J AU Sindwani, R Metson, R AF Sindwani, R Metson, R TI Impact of image guidance on complications during osteoplastic frontal sinus surgery SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Academy-of-Otolaryngology-Head-and-Neck-Surgery CY 2003 CL Orlando, FL SP Amer Acad Otolaryngol Head Neck Surg ID EXPERIENCE; OPERATIONS; FLAP AB OBJECTIVES: To evaluate the impact of image-guidance technology on intraoperative complications during frontal sinus obliteration surgery. STUDY DESIGN AND SETTING: Retrospective case control. Twenty-four patients underwent frontal sinus obliteration with image-guidance technology (n = 15) or conventional instrumentation (n = 9) between 1992 and 2003. The image-guidance system was used to delineate the frontal sinus perimeter and direct cuts through the frontal bone. RESULTS: Intraoperative complications occurred in none of the patients in the image-guidance group and in 3 patients in the control group (P = 0.042). Adverse events included dural tear with CSF leak in 2 patients and exposure of orbital fat in I patient. The incidence of postoperative complications was similar between groups (P = 0.326). No patients required revision surgery. Mean follow-up was 5.2 years. CONCLUSIONS: The use of surgical navigation during frontal sinus obliteration appears to improve intraoperative safety. SIGNIFICANCE: This is the first report to document a reduction in the rate of intraoperative complications when image guidance is utilized for frontal sinus surgery. C1 Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Cambridge, MA 02138 USA. RP Metson, R (reprint author), Zero Emerson Pl, Boston, MA 02114 USA. EM ralph_metson@meei.harvard.edu NR 14 TC 29 Z9 29 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD SEP PY 2004 VL 131 IS 3 BP 150 EP 155 DI 10.1016/j.otohns.2004.03.034 PG 6 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 860PS UT WOS:000224356100002 PM 15365529 ER PT J AU Peltomaa, M McHugh, G Steere, AC AF Peltomaa, M McHugh, G Steere, AC TI The VlsE (IR6) peptide ELISA in the serodiagnosis of Lyme facial paralysis SO OTOLOGY & NEUROTOLOGY LA English DT Article DE facial paralysis; Lyme disease; serology; VIsE (IR6) peptide; whole cell sonicate; Borrelia burgdorferi; ELISA ID LINKED-IMMUNOSORBENT-ASSAY; BORRELIA-BURGDORFERI; NEUROLOGIC MANIFESTATIONS; ANTIBIOTIC-TREATMENT; ANTIBODY-RESPONSE; DISEASE; PALSY; REGION; NEUROBORRELIOSIS; PERSISTENCE AB Objective: Facial paralysis is a manifestation of early disseminated Lyme neuroborreliosis. In the current study, we compared the immunoglobutin G (IgG) VlsE (sixth invariant region) peptide enzyme-linked immunosorbent assay (ELISA) with the current two-tier approach of sonicate ELISA and Western blot in the serodiagnosis of Lyme facial paralysis. Study design: Retrospective. Setting: Tertiary referral center. Patients: Serum samples from 47 Lyme patients with facial paralysis and 86 control subjects were analyzed for IgG antibodies to VlsE peptide of Borrelia burgdorferi and for immunoglobulin M (IgM) and IgG antibodies to sonicate antigens of B. burgdorferi using the two-tier approach. Intervention: Diagnostic. Main outcome measure: Serum IgG antibody responses to VIsE (IR6) peptide. Results: All 47 (100%) patients with facial paralysis and 4 (5%) of 86 controls had positive antibody responses to the VlsE peptide. In the two-tier test, 41 (87%) patients had positive IgM, 31 (66%) had positive IgG, and all 47 patients had positive IgM or IgG responses. Of the 86 control subjects, 2 (2%) had positive results with the two-tier test. Thus, the sensitivities of the VlsE and the two-tier tests were 100%; the specificity of the VlsE ELISA was 95% and the specificity of the two-tier test was 98%. Conclusions: The VlsE peptide ELISA showed a high sensitivity and specificity in the serological diagnosis of Lyme facial paralysis, similar to the two-tier test. The principal advantage of the VlsE peptide ELISA is that it requires only one test rather than four tests. However, the specificity of the VlsE test may not be as high as that of the two-tier test. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA USA. Univ Helsinki, Cent Hosp, Dept Otolaryngol, Helsinki, Finland. RP Peltomaa, M (reprint author), Univ Helsinki, Haartman Inst, Dept Bacteriol & Immunol, Haartmaninkatu 3,POB 21, FIN-00014 Helsinki, Finland. EM miikka.peltomaa@iki.fi NR 25 TC 19 Z9 19 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 J9 OTOL NEUROTOL JI Otol. Neurotol. PD SEP PY 2004 VL 25 IS 5 BP 838 EP 841 DI 10.1097/00129492-200409000-00031 PG 4 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 853ML UT WOS:000223831600033 PM 15354020 ER PT J AU Zehnder, A Merchant, SN AF Zehnder, A Merchant, SN TI Transverse fracture of the temporal bone SO OTOLOGY & NEUROTOLOGY LA English DT Article C1 Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Otolaryngol,Otopathol Lab, Boston, MA 02114 USA. RP Merchant, SN (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Otolaryngol,Otopathol Lab, 243 Charles St, Boston, MA 02114 USA. EM snm@epl.meei.harvard.edu NR 7 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 J9 OTOL NEUROTOL JI Otol. Neurotol. PD SEP PY 2004 VL 25 IS 5 BP 852 EP 853 DI 10.1097/00129492-200409000-00034 PG 2 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 853ML UT WOS:000223831600037 PM 15354023 ER PT J AU Fishman, SM Gallagher, RM Carr, DB Sullivan, LW AF Fishman, SM Gallagher, RM Carr, DB Sullivan, LW TI The case for pain medicine SO PAIN MEDICINE LA English DT Editorial Material DE pain medicine; specialty; primary specialty; classification ID PRIMARY-CARE; RHEUMATOID-ARTHRITIS; PALLIATIVE CARE; PUBLIC-HEALTH; RHEUMATOLOGISTS; DISABILITY; EDUCATION; OUTCOMES; DISEASE; BURDEN AB Pain Medicine has its roots in multiple primary specialties and has developed into a discrete specialty with disparate practice styles. Its identity is in flux and is threatened by forces that may fragment this new field before it can set firm roots. The public health crisis of under treated pain parallels medicine's struggle to adequately classify Pain Medicine as a specialty. We review the case for Pain Medicine as a discrete discipline, with specialized knowledge, treatments, training and education. Without recognition of the specialty of Pain Medicine, and resolution of the fragmentation of the field throughout healthcare, medicine's approach to the current problem of under treated pain is likely to continue to be inadequate. C1 Univ Calif Davis, Sch Med, Dept Anesthesiol & Pain Med, Div Pain Med, Sacramento, CA 95817 USA. Philadelphia VA Med Ctr, Dept Anesthesia, Pain Med Serv, Philadelphia, PA USA. Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. Univ Penn, Dept Anesthesiol, Philadelphia, PA 19104 USA. Tufts Univ, Sch Med, Dept Anesthesiol, Boston, MA 02111 USA. Tufts Univ, Sch Med, Dept Internal Med, Boston, MA 02111 USA. Morehouse Coll Sch Med, Off President Emeritus, Atlanta, GA USA. RP Fishman, SM (reprint author), Univ Calif Davis, Sch Med, Dept Anesthesiol & Pain Med, Div Pain Med, 4860 Y St,Suite 3200, Sacramento, CA 95817 USA. EM smfishman@ucdavis.edu NR 52 TC 16 Z9 16 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1526-2375 J9 PAIN MED JI Pain Med. PD SEP PY 2004 VL 5 IS 3 BP 281 EP 286 DI 10.1111/j.1526-4637.2004.04050.x PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 852UJ UT WOS:000223781700009 PM 15367306 ER PT J AU Redline, RW Ariel, I Baergen, RN DeSa, DJ Kraus, FT Roberts, DJ Sander, CM AF Redline, RW Ariel, I Baergen, RN DeSa, DJ Kraus, FT Roberts, DJ Sander, CM CA Soc Pediat Pathology Preinatal Sec TI Fetal vascular obstructive lesions: Nosology and reproducibility of placental reaction patterns SO PEDIATRIC AND DEVELOPMENTAL PATHOLOGY LA English DT Article DE avascular villi; fetal thrombotic vasculopathy; hemorrhagic endovasculitis; nomenclature; placenta; reproducibility; villitis of unknown etiology ID THROMBOTIC VASCULOPATHY; CEREBRAL-PALSY; HEMORRHAGIC ENDOVASCULITIS; NEUROLOGIC IMPAIRMENT; RELIABILITY; PATHOLOGY; VILLITIS; DIAGNOSES; HISTOLOGY; VESSELS AB The purpose of this study was to assemble and test the reliability of a complete set of the placental reaction patterns seen with chronic fetal vascular obstruction in the hope that this might provide a standardized diagnostic framework useful for practicing pathologists. Study cases (14 with fetal vascular obstructive lesions, 6 controls) were reviewed blindly by seven pathologists after agreement on a standard set of diagnostic criteria. Majority vote served as the gold standard and 80% of the 180 diagnoses rendered (9 diagnoses each for 20 cases) were agreed upon by at least six of the seven scores. The sensitivity of individual diagnosis relative to the group consensus averaged 83% (range, 69-100%) and specificity averaged 91% (range, 86-100%). Reproducibility was measured by unweighted kappa-values and interpreted as follows: < 0.2, poor; 0.2-0.6, fair/moderate; > 0.6, substantial. Kappa values for lesions of distal villi were generally superior to those for lesions involving large fetal vessels: avascular villi (0.49), villous stromal-vascular karyorrhexis (0.58), and villitis of unknown etiology (VUE) with stem villitis and avascular villi (0.65) versus large vessel thrombi (any vessel, 0.34; chorionic plate vessel, 0.40) and intimal fibrin cushions (recent, 0.47; remote, 0.78). Reproducibility for a global impression of any villous change consistent with chronic fetal vascular obstruction was substantial (0.63), while that for a more severe subgroup was moderate (0.44). Three points are worthy of emphasis. Our system separately recognizes, but later combines, uniformly avascular villi and villous stromal-vascular karyorrhexis as manifestations of the same underlying process. We propose that this combined group of villous lesions be dichotomized with the terms fetal thrombotic vasculopathy or extensive avascular villi (and/or villous stromal-vascular karyorrhexis) being reserved for the group with 15 or more affected terminal villi per section. Scattered foci of avascular villi (and/or villous stromal-vascular karyorrhexis) could be used to describe less severe cases. Finally, we distinguish VUE with stem villitis and avascular villi (obliterative fetal vasculopathy) as a distinct process with substantial perinatal morbidity. C1 Univ Hosp Cleveland, Dept Pathol, Cleveland, OH 44106 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Hadassah Univ Hosp, Dept Pathol, IL-91120 Jerusalem, Israel. New York Presbyterian Hosp, Weill Cornell Med Ctr, Dept Pathol, New York, NY USA. British Columbia Childrens Hosp, Dept Pathol, Vancouver, BC V6H 3V4, Canada. Washington Univ, Sch Med, Dept Obstet & Gynecol, St Louis, MO 63110 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Michigan State Univ, Placental Tissue Registry, E Lansing, MI 48824 USA. RP Redline, RW (reprint author), Univ Hosp Cleveland, Dept Pathol, 11100 Euclid Ave, Cleveland, OH 44106 USA. EM raymond.redline@uhhs.com NR 42 TC 138 Z9 140 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1093-5266 J9 PEDIATR DEVEL PATHOL JI Pediatr. Dev. Pathol. PD SEP-OCT PY 2004 VL 7 IS 5 BP 443 EP 452 DI 10.1007/s10024-004-2020-x PG 10 WC Pathology; Pediatrics SC Pathology; Pediatrics GA 871LE UT WOS:000225134400007 PM 15547768 ER PT J AU Solky, BA Yang, FC Xu, X Levins, P AF Solky, BA Yang, FC Xu, X Levins, P TI Transient myeloproliferative disorder causing a vesiculopustular eruption in a phenotypically normal neonate SO PEDIATRIC DERMATOLOGY LA English DT Article ID DOWN-SYNDROME; LEUKEMOID REACTION; NORMAL NEWBORN; TRISOMY-21 MOSAICISM; CONGENITAL LEUKEMIA; INFANT; MANIFESTATION; PATIENT; CUTIS AB We report an unusual congenital vesiculopustular eruption arising in a neonate as the result of the transient myeloproliferative disorder (TMD) associated with trisomy 21. In this instance, the neonate was phenotypically normal, making the diagnosis more elusive. Initially the lesions were clinically suspicious for herpetic infection. The clinical scenario quickly became highly suggestive of leukemia cutis, given the infant's extremely high white blood cell count. Further examination revealed trisomy 21 in the leukemic cells and disomy 21 in the buccal keratinocytes, and a diagnosis of self-resolving TMD was made. Biopsy specimens of the lesions showed a sparse, perivascular, atypical, mononuclear infiltrate. We suggest that examination for a TMD be undertaken in neonates with a vesiculopustular eruption and leukemic white blood cell counts. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA 02114 USA. Hosp Univ Penn, Dept Pathol, Philadelphia, PA 19104 USA. RP Solky, BA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Bartlett Hall,6th Floor,55 Fruit St, Boston, MA 02114 USA. EM bsolky@partners.org NR 27 TC 12 Z9 12 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0736-8046 J9 PEDIATR DERMATOL JI Pediatr. Dermatol. PD SEP-OCT PY 2004 VL 21 IS 5 BP 551 EP 554 DI 10.1111/j.0736-8046.2004.21505.x PG 4 WC Dermatology; Pediatrics SC Dermatology; Pediatrics GA 858JK UT WOS:000224187900006 PM 15461760 ER PT J AU James, CA Arauz, AD AF James, CA Arauz, AD TI Abdominal pain from an unusual source SO PEDIATRIC EMERGENCY CARE LA English DT Article DE abdominal pain; hematocolpos; mullerian anomalies ID ANOMALIES; TRACT C1 Childrens Hosp, Div Emergency Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. RP James, CA (reprint author), Childrens Hosp, Div Emergency Med, 300 Longwood Ave, Boston, MA 02115 USA. EM Catherine.James@childrens.harvard.edu NR 10 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0749-5161 J9 PEDIATR EMERG CARE JI Pediatr. Emerg. Care PD SEP PY 2004 VL 20 IS 9 BP 607 EP 609 DI 10.1097/01.pec.0000139744.77085.89 PG 3 WC Emergency Medicine; Pediatrics SC Emergency Medicine; Pediatrics GA 855GF UT WOS:000223960500009 PM 15599264 ER PT J AU Chamlin, SL Frieden, IJ Williams, ML Chren, MM AF Chamlin, SL Frieden, IJ Williams, ML Chren, MM TI Effects of atopic dermatitis on young American children and their families SO PEDIATRICS LA English DT Article DE atopic dermatitis; quality of life; child-family relationships ID SLEEP; ECZEMA; DERMATOLOGY; IMPACT; INFANT; INDEX AB Objective. The psychologic, physical, and social impact of atopic dermatitis is complex and varies among children of different ages, and the effects of atopic dermatitis on the quality of life of very young American children and their families are not well understood. This study was conducted to document these effects of atopic dermatitis on young children and their families. Methods. Directed focus sessions were performed with parents of 26 young children with atopic dermatitis and 6 expert clinicians. Specific mentions of the ways in which atopic dermatitis affected the children and parents were reviewed, rank ordered, and categorized according to similarity in content. The categories were examined to determine the domains represented, and the domains were used to compose a conceptual framework of all of the ways that atopic dermatitis affects children and their families. Results. Parents and experts mentioned a total of 181 specific quality-of-life effects. A conceptual framework, developed from the 181 effects, contains the domains of physical health, emotional health, physical functioning, and social functioning; each domain includes effects on both the child and the parents. Conclusions. Atopic dermatitis greatly affects the quality of life of afflicted children and their families. The comprehensive conceptual framework summarizes the ways in which atopic dermatitis affects the quality of life in young American children. This conceptual framework forms the basis from which quality-of-life instruments can be developed. C1 Childrens Mem Hosp, Div Pediat Dermatol, Chicago, IL 60614 USA. Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. San Francisco Vet Affairs Med Ctr, Dermatol Serv, San Francisco, CA USA. San Francisco Vet Affairs Med Ctr, Hlth Serv Res Enhancement Award Program, San Francisco, CA USA. RP Chamlin, SL (reprint author), 2300 Childrens Plaza,Box 107, Chicago, IL 60614 USA. EM schamlin@childrensmemorial.org OI Frieden, Ilona/0000-0001-7305-5940 NR 16 TC 126 Z9 133 U1 1 U2 3 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 SEP PY 2004 VL 114 IS 3 BP 607 EP 611 DI 10.1542/peds.2004-0374 PG 5 WC Pediatrics SC Pediatrics GA 851AU UT WOS:000223657600005 PM 15342828 ER PT J AU Bass, JL Corwin, M Gozal, D Moore, C Nishida, H Parker, S Schonwald, A Wilker, RE Stehle, S Kinane, TB AF Bass, JL Corwin, M Gozal, D Moore, C Nishida, H Parker, S Schonwald, A Wilker, RE Stehle, S Kinane, TB TI The effect of chronic or intermittent hypoxia on cognition in childhood: A review of the evidence SO PEDIATRICS LA English DT Review DE hypoxia; cognition; development; behavior; academic achievement ID OBSTRUCTIVE SLEEP-APNEA; CONGENITAL HEART-DISEASE; DEFICIT-HYPERACTIVITY DISORDER; OXYGEN-SATURATION; TERM INFANTS; RESPIRATORY INSTABILITY; ACADEMIC-PERFORMANCE; SCHOOL PERFORMANCE; PROSPECTIVE COHORT; MOTOR DEVELOPMENT AB Objective. A review of the evidence concerning the effect of chronic or intermittent hypoxia on cognition in childhood was performed by using both a systematic review of the literature and critical appraisal criteria of causality. Because of the significant impact of behavioral disorders such as attention-deficit/hyperactivity disorder on certain cognitive functions as well as academic achievement, the review also included articles that addressed behavioral outcomes. Methods. Both direct and indirect evidence were collected. A structured Medline search was conducted from the years 1966-2000 by using the OVID interface. Both English- and non - English- language citations were included. Significant articles identified by the reviewers up to 2003 were also included. To be included as direct evidence, an article needed to be an original report in a peer-reviewed journal with data on cognitive, behavioral, or academic outcomes in children up to 14 years old, with clinical conditions likely to be associated with exposure to chronic or intermittent hypoxia. Indirect evidence from other reviews and publications in closely related fields, including experimental studies in adults, was used to help formulate conclusions. Two reviewers screened abstracts and titles. Each article included as direct evidence received a structured evaluation by 2 reviewers. Adjudication of differences was performed by a group of 2 reviewers and a research consultant. After this review, tables of evidence were constructed that were used as the basis for group discussion and consensus development. Indirect evidence assigned by topic to specific reviewers was also presented as part of this process. A formal procedure was used to rank the studies by design strength. The critical appraisal criteria for causation described in Evidence Based Pediatrics and Child Health (Moyer V, Elliott E, Davis R, et al, eds. London, United Kingdom: BMJ Books; 2000: 46 - 55) were used to develop consensus on causality. Results. A total of 788 literature citations were screened. For the final analysis, 55 articles met the criteria for inclusion in the direct evidence. Of these, 43 (78.2%) reported an adverse effect. Of the 37 controlled studies, 31 (83.8%) reported an adverse effect. Adverse effects were noted at every level of arterial oxygen saturation and for exposure at every age level except for premature newborns. The studies were classified into 5 clinical categories: congenital heart disease (CHD), sleep-disordered breathing (SDB), asthma, chronic ventilatory impairment, and respiratory instability in infants. Two of these categories, CHD and SDB, which accounted for 42 (76.4%) of the included articles, fulfilled the Evidence Based Pediatrics and Child Health criteria for causation. The indirect evidence included 8 reviews, 1 meta-analysis, and 10 original reports covering the fields of adult anoxia, animal research, SDB in adults, natural and experimental high-altitude studies, perinatal hypoxic-ischemic encephalopathy, anemia, and carbon-monoxide poisoning. The studies of high-altitude and carbon-monoxide poisoning provided evidence for causality. Conclusions. Adverse impacts of chronic or intermittent hypoxia on development, behavior, and academic achievement have been reported in many well-designed and controlled studies in children with CHD and SDB as well as in a variety of experimental studies in adults. This should be taken into account in any situation that may expose children to hypoxia. Because adverse effects have been noted at even mild levels of oxygen desaturation, future research should include precisely defined data on exposure to all levels of desaturation. C1 Harvard Univ, Sch Med, MassGen Hosp Children, Newton Wellesley Hosp,Dept Pediat, Newton, MA 02462 USA. Boston Univ, Sch Med, CareStat Inc, Boston Med Ctr,Dept Pediat, Newton, MA USA. Univ Louisville, Kosair Childrens Hosp Res Inst, Dept Pediat, Louisville, KY 40292 USA. Tokyo Womens Med Univ, Maternal & Perinatal Ctr, Tokyo, Japan. Boston Univ, Sch Med, Boston Med Ctr, Dept Pediat, Boston, MA 02118 USA. Harvard Univ, Sch Med, Childrens Hosp, Med Ctr,Dev Med Ctr, Boston, MA USA. Greater Lawrence Family Hlth Ctr, Lawrence, MA USA. Harvard Univ, Sch Med, MassGen Hosp Children, Boston, MA USA. RP Bass, JL (reprint author), Harvard Univ, Sch Med, MassGen Hosp Children, Newton Wellesley Hosp,Dept Pediat, 2014 Washington St, Newton, MA 02462 USA. EM jbass@partners.org OI Corwin, Michael/0000-0002-6591-209X NR 103 TC 222 Z9 230 U1 6 U2 41 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 SEP PY 2004 VL 114 IS 3 BP 805 EP 816 DI 10.1542/peds.2004-0227 PG 12 WC Pediatrics SC Pediatrics GA 851AU UT WOS:000223657600034 PM 15342857 ER PT J AU Mital, S Fried, LF Piraino, B AF Mital, S Fried, LF Piraino, B TI Bleeding complications associated with peritoneal dialysis catheter insertion SO PERITONEAL DIALYSIS INTERNATIONAL LA English DT Article DE Tenckhoff catheter; bleeding; insertion; placement; complications; anticoagulation ID PLACEMENT; ACCESS AB Objective: To identify the incidence of bleeding complications associated with peritoneal dialysis catheter insertion. Design: Retrospective review at a tertiary-care center of all double-cuffed Tenckhoff catheters placed surgically from 1 January 1992 to 1 October 2003 to identify the incidence of major bleeding complications occurring with catheter insertion. Major bleeding episodes were defined as greater than or equal to3% decline in hematocrit, or the need for surgical intervention or blood transfusion within 2 weeks of insertion. Results: 292 catheters had been inserted in 263 patients. Six patients satisfied the criteria for a major bleeding event, for a major bleeding complication rate of 2%. Bleeding was associated with perioperative anticoagulation in 3 patients, uremia and thrombocytopenia in 1 patient, aspirin use and thrombocytopenia in 1 patient, and I patient experienced intraoperative bleeding. Coagulation parameters were not obtained prior to the procedure in 2 of the 6 patients. Conclusion:The rate of serious bleeding complications related to catheter insertion is low and usually associated with anticoagulation. Holding anticoagulation therapy for a minimum of 24 hours during the postoperative period should eliminate much of the risk. Coagulation parameters should also be obtained and corrected preoperatively. C1 Univ Pittsburgh, Sch Med, Div Renal & Electrolyte, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Mital, S (reprint author), A915 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. EM mitals@upmc.edu OI Piraino, Beth/0000-0001-5061-0841 NR 12 TC 10 Z9 11 U1 0 U2 0 PU MULTIMED INC PI TORONTO PA 66 MARTIN ST, TORONTO, ON L9T 2R2, CANADA SN 0896-8608 J9 PERITON DIALYSIS INT JI Perit. Dial. Int. PD SEP-OCT PY 2004 VL 24 IS 5 BP 478 EP 480 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 861KP UT WOS:000224415700014 PM 15490989 ER PT J AU Lee, IO Yukhananov, R Standaert, DG Crosby, G AF Lee, IO Yukhananov, R Standaert, DG Crosby, G TI NMDA-RI antisense oligodeoxynucleotides modify formalin-induced nociception and spinal c-Fos expression in rat spinal cord SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE nociception; hyperalgesia; N-methyl-D-aspartate; antisense oligodeoxynucleotide; formalin test; c-Fos; spinal cord; intrathecal ID ASPARTATE RECEPTOR SUBUNITS; SUBCUTANEOUS FORMALIN; PAIN; OLIGONUCLEOTIDES; INFLAMMATION; HYPERALGESIA; ANALGESIA; PROTEIN; NEURONS; TRANSMISSION AB Noxious peripheral stimuli (thermal, mechanical, or chemical) produce long-term adaptations in the sensitivity of central nociceptive neurons to subsequent noxious stimuli. The mechanisms responsible for this central sensitization are multifactorial, but the activation of spinal N-methyl-D-aspartate (NMDA) receptors plays a pivotal role. Using antisense oligodeoxynucleotides, we tested the role of the NR1 subunit of the NMDA receptor in the nociception and expression of the immediate early gene c-fos following formalin-induced pain. Rats received NMDA-R1 antisense, sense, or missense oligodeoxynucleotides intrathecally three times over a 48-h interval. The day after the last injection of the oligodeoxynucleotide, the formalin test was performed. Pain-related behavior was quantified by counting the incidence of flinching of the injected paw for 60 min, and the animals were perfused and the spinal cord removed for c-Fos immunohistochemistry 60 min later. Immunopositive cells were counted in the laminae I/II0 and V of the lumbar enlargement. Treatment with NR1 antisense oligodeoxynucleotide resulted in a marked decrease in flinching. Similarly, the antisense oligodeoxynucleotide virtually abolished formalin-induced expression of c-Fos-like immunoreactivity (Fos-IR) in the spinal cord dorsal horn ipsilateral to injection. In contrast, the corresponding sense or missense oligodeoxynucleotides had no effect on either formalin-evoked behavior or c-Fos immunoreactivity. We conclude that an NR1 antisense oligodeoxynucleotide inhibits both nociceptive behavior and c-fos expression following formalin injection in rats, demonstrating that NR1 plays an important role in the development of noxious stimulation induced c-fos expression in this model. (C) 2004 Elsevier Inc. All rights reserved. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Anesthesiol, Boston, MA 02115 USA. Korea Univ, Guro Hosp, Dept Anesthesiol, Seoul 425020, South Korea. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Yukhananov, R (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Anesthesiol, 75 Francis St, Boston, MA 02115 USA. EM ryyukhan@zeus.bwh.harvard.edu FU NIGMS NIH HHS [R01 GM 42466]; NINDS NIH HHS [R01 NS34361] NR 32 TC 17 Z9 18 U1 0 U2 0 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 SEP PY 2004 VL 79 IS 1 BP 183 EP 188 DI 10.1016/j.pbb.2004.07.003 PG 6 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 860IU UT WOS:000224336700022 PM 15388298 ER PT J AU Anderson, RR AF Anderson, RR TI Shedding some light on tattoos? SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Editorial Material C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatol,Wellman Ctr Photomed, Boston, MA 02114 USA. RP Anderson, RR (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatol,Wellman Ctr Photomed, 55 Fruit St, Boston, MA 02114 USA. EM rranderson@partners.org NR 2 TC 3 Z9 3 U1 1 U2 2 PU AMER SOC PHOTOBIOLOGY PI AUGUSTA PA BIOTECH PARK, 1021 15TH ST, SUITE 9, AUGUSTA, GA 30901-3158 USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD SEP-OCT PY 2004 VL 80 IS 2 BP 155 EP 156 DI 10.1562/2004-09-10-IR-313.1 PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 871UE UT WOS:000225158400001 PM 15362953 ER PT J AU Mansury, Y Deisboeck, TS AF Mansury, Y Deisboeck, TS TI Simulating the time series of a selected gene expression profile in an agent-based tumor model SO PHYSICA D-NONLINEAR PHENOMENA LA English DT Article DE time series; tumor modeling; malignant brain tumors; gliomas; agent-based model; gene expression profile; pattern formation ID PROLIFERATION MARKERS; BRAIN-TUMORS; HYPOXIA; ANGIOGENESIS; MIGRATION; PATTERNS; IMPACT; CELLS; PCNA AB To elucidate the role of environmental conditions in molecular-level dynamics and to study their impact on macroscopic brain tumor growth patterns, the expression of the genes Tenascin C and PCNA in a 2D agent-based model for the migratory trait is calibrated using experimental data from the literature, while the expression of these genes for the proliferative trait is obtained as the model output. Numerical results confirm that the gene expression of Tenascin C is indeed consistently higher in the migratory glioma cell phenotype and show that the expression of PCNA is consistently higher among proliferating tumor cells. Intriguingly, the time series of the tumor cells' gene expression exhibit a sudden change in behavior during the invasion of the tumor into a nutrient-abundant region, showing a robust positive correlation between the expression of Tenascin C and the tumor's diameter, yet a strong negative correlation between the expression of PCNA and the diameter. These molecular-level dynamics correspond to the emergence of a structural asymmetry in the form of a bulging tumor rim in the nutrient-abundant region. The simulated time series thus supports the critical role of the migratory cell phenotype during both the tumor system's overall macroscopic expansion and the evolvement of regional growth patterns, particularly in the later stages. Furthermore, detrended fluctuation analysis (DFA) suggests that for prediction purposes, the simulated gene expression profiles of Tenascin C and PCNA that were determined separately for the migrating and proliferating phenotypes exhibit lesser predictability than those of the phenotypic mixture combining all viable tumor cells typically found in clinical biopsies. Finally, partitioning the tumor into distinct geographic regions of interest (ROI) reveals that the gene expression profile of tumor cells in the quadrant close to the nutrient-abundant region is representative for the entire tumor whereas the expression profile of tumor cells in the geographically opposite ROI is not. Potential implications of these modeling results for experimental and clinical cancer research are discussed. (C) 2004 Elsevier B.V. All rights reserved. C1 MIT, HST Biomed Engn Ctr, Harvard MIT HST Athinoula A Martinos Ctr Biomed I, Complex Biosyst Modeling Lab, Cambridge, MA 02139 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurooncol Lab, Charlestown, MA 02129 USA. Harvard Univ, Div Engn & Appl Sci, Cambridge, MA 02138 USA. RP Deisboeck, TS (reprint author), MIT, HST Biomed Engn Ctr, Harvard MIT HST Athinoula A Martinos Ctr Biomed I, Complex Biosyst Modeling Lab, Cambridge, MA 02139 USA. EM deisboec@helix.mgh.harvard.edu NR 26 TC 11 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-2789 J9 PHYSICA D JI Physica D PD SEP 1 PY 2004 VL 196 IS 1-2 BP 193 EP 204 DI 10.1016/j.physd.2004.04.008 PG 12 WC Mathematics, Applied; Physics, Multidisciplinary; Physics, Mathematical SC Mathematics; Physics GA 849GL UT WOS:000223526600009 ER PT J AU Gonzalez-Perrett, S Montalbetti, N Semprine, J Cantiello, HF AF Gonzalez-Perrett, S Montalbetti, N Semprine, J Cantiello, HF TI Effect of hydrostatic and osmotic pressure on cation channel activation in human syncytiotrophoblast SO PLACENTA LA English DT Meeting Abstract CT Conference of the Placenta-Association-of-the-Americas/10th Meeting of the International-Federation-of-Placenta CY SEP 25-29, 2004 CL Asilomar, CA SP Placenta Assoc Amer, Int Fed Placenta C1 Fac Farm & Bioquim, Lab Canales Ion, Buenos Aires, DF, Argentina. Fac Med, Dept Fisiol, Buenos Aires, DF, Argentina. Massachusetts Gen Hosp, Renal Unit, Charlestown, MA 02129 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD SEP-OCT PY 2004 VL 25 IS 8-9 BP A42 EP A42 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 854JG UT WOS:000223898300167 ER PT J AU Montalbetti, N Timpanaro, GA Gonzalez-Perrett, S Cantiello, HF AF Montalbetti, N Timpanaro, GA Gonzalez-Perrett, S Cantiello, HF TI Calcium-gelsolin feedback mechanism for channel regulation in human syncytiotrophoblast SO PLACENTA LA English DT Meeting Abstract CT Conference of the Placenta-Association-of-the-Americas/10th Meeting of the International-Federation-of-Placenta CY SEP 25-29, 2004 CL Asilomar, CA SP Placenta Assoc Amer, Int Fed Placenta C1 Fac Farm & Bioquim, Lab Canales Ion, Buenos Aires, DF, Argentina. Fac Med, Dept Fisiol, Buenos Aires, DF, Argentina. Massachusetts Gen Hosp, Renal Unit, Charlestown, MA 02129 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD SEP-OCT PY 2004 VL 25 IS 8-9 BP A42 EP A42 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 854JG UT WOS:000223898300168 ER PT J AU Montalbetti, N Timpanaro, GA Semprine, J Gonzalez-Perrett, S Cantiello, HF AF Montalbetti, N Timpanaro, GA Semprine, J Gonzalez-Perrett, S Cantiello, HF TI PKA activates cation channel activity in human syncytiotrophoblast SO PLACENTA LA English DT Meeting Abstract CT Conference of the Placenta-Association-of-the-Americas/10th Meeting of the International-Federation-of-Placenta CY SEP 25-29, 2004 CL Asilomar, CA SP Placenta Assoc Amer, Int Fed Placenta C1 Fac Farm & Bioquim, Lab Canales Ion, Buenos Aires, DF, Argentina. Fac Med, Dept Fisiol, Buenos Aires, DF, Argentina. Massachusetts Gen Hosp, Renal Unit, Charlestown, MA 02129 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD SEP-OCT PY 2004 VL 25 IS 8-9 BP A33 EP A33 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 854JG UT WOS:000223898300132 ER PT J AU Rajakumar, A Brandon, HM Rajakumar, PA Shibata, E Hubel, CA Karumanchi, A Thadhani, R Harger, G Markovic, N AF Rajakumar, A Brandon, HM Rajakumar, PA Shibata, E Hubel, CA Karumanchi, A Thadhani, R Harger, G Markovic, N TI Peripheral blood mononuclear cells (PBMCs) of pregnant women are the potential extraplacental source of soluble VEGF receptor, sFLT-1 contributing to preeclampsia: Regulation by hypoxia SO PLACENTA LA English DT Meeting Abstract CT Conference of the Placenta-Association-of-the-Americas/10th Meeting of the International-Federation-of-Placenta CY SEP 25-29, 2004 CL Asilomar, CA SP Placenta Assoc Amer, Int Fed Placenta C1 Univ Pittsburgh, Magee Womens Res Inst, Pittsburgh, PA 15260 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 4 Z9 5 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD SEP-OCT PY 2004 VL 25 IS 8-9 BP A11 EP A11 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 854JG UT WOS:000223898300044 ER PT J AU Blackshaw, S Harpavat, S Trimarchi, J Cai, L Huang, HY Kuo, WP Weber, G Lee, K Fraioli, RE Cho, SH Yung, R Asch, E Ohno-Machado, L Wong, WH Cepko, CL AF Blackshaw, S Harpavat, S Trimarchi, J Cai, L Huang, HY Kuo, WP Weber, G Lee, K Fraioli, RE Cho, SH Yung, R Asch, E Ohno-Machado, L Wong, WH Cepko, CL TI Genomic analysis of mouse retinal development SO PLOS BIOLOGY LA English DT Review ID ROD PHOTORECEPTOR DEVELOPMENT; CILIARY NEUROTROPHIC FACTOR; CELL-FATE DETERMINATION; HOMEOBOX GENE CHX10; IN-VITRO; RAT RETINA; STEM-CELLS; TRANSCRIPTION FACTORS; NEURAL RETINA; MICROARRAY ANALYSIS AB The vertebrate retina is comprised of seven major cell types that are generated in overlapping but well-defined intervals. To identify genes that might regulate retinal development, gene expression in the developing retina was profiled at multiple time points using serial analysis of gene expression (SAGE). The expression patterns of 1,051 genes that showed developmentally dynamic expression by SAGE were investigated using in situ hybridization. A molecular atlas of gene expression in the developing and mature retina was thereby constructed, along with a taxonomic classification of developmental gene expression patterns. Genes were identified that label both temporal and spatial subsets of mitotic progenitor cells. For each developing and mature major retinal cell type, genes selectively expressed in that cell type were identified. The gene expression profiles of retinal Muller glia and mitotic progenitor cells were found to be highly similar, suggesting that Miller glia might serve to produce multiple retinal cell types under the right conditions. In addition, multiple transcripts that were evolutionarily conserved that did not appear to encode open reading frames of more than 100 amino acids in length ("noncoding RNAs") were found to be dynamically and specifically expressed in developing and mature retinal cell types. Finally, many photoreceptor-enriched genes that mapped to chromosomal intervals containing retinal disease genes were identified. These data serve as a starting point for functional investigations of the roles of these genes in retinal development and physiology. C1 Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Calif Berkeley, Dept Stat, Berkeley, CA 94720 USA. Childrens Hosp Informat Program, Boston, MA USA. Brigham & Womens Hosp, Decis Syst Grp, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Cepko, CL (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM cepko@genetics.med.harvard.edu OI Weber, Griffin/0000-0002-2597-881X; Ohno-Machado, Lucila/0000-0002-8005-7327; Trimarchi, Jeffrey/0000-0001-7923-1538 FU NCI NIH HHS [P20 CA96470, P20 CA096470]; NEI NIH HHS [EY08064, R01 EY008064] NR 117 TC 309 Z9 314 U1 0 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD SEP PY 2004 VL 2 IS 9 BP 1411 EP 1431 AR e247 DI 10.1371/journal.pbio.0020247 PG 21 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 857HW UT WOS:000224108100020 PM 15226823 ER PT J AU Bhidayasiri, R Truong, DD AF Bhidayasiri, R Truong, DD TI Chorea and related disorders SO POSTGRADUATE MEDICAL JOURNAL LA English DT Review ID DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY; SYSTEMIC LUPUS-ERYTHEMATOSUS; BENIGN HEREDITARY CHOREA; HUNTINGTONS-DISEASE; SYDENHAMS CHOREA; TRINUCLEOTIDE REPEAT; MOVEMENT-DISORDERS; GENE CARRIERS; ACANTHOCYTOSIS; TETRABENAZINE AB Chorea refers to irregular, flowing, non-stereotyped, random, involuntary movements that often possess a writhing quality referred to as choreoathetosis. When mild, chorea can be difficult to differentiate from restlessness. When chorea is proximal and of large amplitude, it is called ballism. Chorea is usually worsened by anxiety and stress and subsides during sleep. Most patients attempt to disguise chorea by incorporating it into a purposeful activity. Whereas ballism is most often encountered as hemiballism due to contralateral structural lesions of the subthalamic nucleus and/or its afferent or efferent projections, chorea may be the expression of a wide range of disorders, including metabolic, infectious, inflammatory, vascular, and neurodegenerative, as well as drug induced syndromes. In clinical practice, Sydenham's chorea is the most common form of childhood chorea, whereas Huntington's disease and drug induced chorea account for the majority of adult onset cases. The aim of this review is to provide an up to date discussion of this disorder, as well as a practical approach to its management. C1 Parkinsons & Movement Disorders Inst, Fountain Valley, CA 92708 USA. Univ Calif Los Angeles, Med Ctr, Dept Neurol, David Geffen UCLA Sch Med, Los Angeles, CA 90024 USA. W Los Angeles Vet Affairs Med Ctr, Parkinsons Dis Res Educ & Clin Ctr PADRECC, Los Angeles, CA 90073 USA. RP Truong, DD (reprint author), Parkinsons & Movement Disorders Inst, 9940 Talbert Ave,204, Fountain Valley, CA 92708 USA. EM dtruong@pmdi.org OI Bhidayasiri, Roongroj/0000-0002-6901-2064 NR 64 TC 37 Z9 42 U1 1 U2 7 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0032-5473 J9 POSTGRAD MED J JI Postgrad. Med. J. PD SEP PY 2004 VL 80 IS 947 BP 527 EP 534 DI 10.1136/pgmj.2004.019356 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 852KF UT WOS:000223753500005 PM 15356354 ER PT J AU Sorensen, G Linnan, L Hunt, MK AF Sorensen, G Linnan, L Hunt, MK TI Worksite-based research and initiatives to increase fruit and vegetable consumption SO PREVENTIVE MEDICINE LA English DT Article; Proceedings Paper CT Fruit and Vegetable Environment, Policy, and Pricing Workshop CY SEP 26-27, 2002 CL Atlanta, GA DE worksites; environment; nutrition ID HEALTH PROMOTION PROGRAMS; RANDOMIZED CONTROLLED-TRIAL; TOBACCO PREVENTION PROGRAM; BLUE-COLLAR WORKERS; NUTRITION EDUCATION; TREATWELL 5-A-DAY; PHYSICAL-ACTIVITY; SYSTEMATIC REVIEWS; INTERVENTIONS; DIFFUSION AB Background. Worksite initiatives to promote increased consumption of fruits and vegetables include a wide range of programs. Some initiatives focus on the physical and informational environments, with the dual aim of increasing the availability of healthful food options and providing education and support through point-of-choice labeling and signage. Methods. Authors reviewed recent literature on comprehensive worksite health promotion programs that have addressed some type of environmental/organizational intervention to increase fruit/vegetable consumption. Results. This review revealed that environmental/organizational initiatives rely on management commitment, supervisory support, and supportive organizational structures to sustain policy efforts over time. Program effectiveness is enhanced when they are based on social ecological approaches; include worker participation in program planning and implementation (e.g. employee advisory boards and peer-delivered interventions); address multiple (vs. single) risk factors for change; and integrate workers' broader social context (e.g. families, neighborhoods, etc.). Conclusions. Priorities for future worksite-based interventions include identifying and reducing barriers to organizational and environmental change, addressing social disparities in fruit and vegetable consumption, addressing social contextual factors driving behaviors, and building expanded networks of community partnerships. Future research is needed to identify key policy and program components that will yield meaningful increases in fruit and vegetable consumption; bartiers/facilitators of organizational and environmental change within worksites; effective community-based participatory methods; and methods to disseminate cost-effective interventions for all worksites. (C) 2004 The Institute For Cancer Prevention and Elsevier Inc. All rights reserved. C1 Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. Harvard Univ, Sch Hlth, Dept Hlth & Social Behav, Boston, MA 02115 USA. Univ N Carolina, Sch Publ Hlth, Dept Hlth Educ & Hlth Behav, Boston, MA 02115 USA. RP Sorensen, G (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 44 Binney St, Boston, MA 02115 USA. EM glorian_sorensen@dfci.harvard.edu NR 75 TC 52 Z9 53 U1 3 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD SEP PY 2004 VL 39 SU 2 BP S94 EP S100 DI 10.1016/j.ypmed.2003.12.020 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 853SI UT WOS:000223847600005 PM 15313078 ER PT J AU Yao, JK Magan, S Sonel, AF Gurklis, JA Sanders, R Reddy, RD AF Yao, JK Magan, S Sonel, AF Gurklis, JA Sanders, R Reddy, RD TI Effects of omega-3 fatty acid on platelet serotonin responsivity in patients with schizophrenia SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article; Proceedings Paper CT 1st Brain Phospholipids Conference CY AUG-SEP -, 2003 CL Aviemore, SCOTLAND ID MAGNETIC-RESONANCE SPECTROSCOPY; CELL MEMBRANE DYNAMICS; FATTY-ACIDS; EICOSAPENTAENOIC ACID; DIETARY SUPPLEMENTATION; HUMAN ERYTHROCYTES; SYMPTOM REMISSION; RECEPTOR-BINDING; FRONTAL-CORTEX; POSTMORTEM AB Studies suggest that the omega-3 fatty acid supplementation may be beneficial in reducing symptom severity in schizophrenia. The mechanism(s) underlying the clinical effect is not known. Serotonin (5-HT) has been implicated in the pathophysiology of schizophrenia and in the mechanism of some antipsychotic agents. 5-HT receptors are known to be modified by omega-3 fatty acids. We examined whether supplementation with the omega-3 fatty acid eicosapentaenoic acid (EPA)-modified 5-HT amplified ADP-induced platelet aggregation in patients with schizophrenia. Two grams of ethyl-EPA was administered daily for 6 months supplementally to ongoing antipsychotic treatment in 12 patients with chronic schizophrenia, using an open-label design. Red blood cell membrane fatty acids and platelet functions (platelet aggregation and dense granule secretion) were monitored at baseline, 1-, 3- and 6-months. The EPA levels were elevated more than five-fold in RBC membranes of all patients after 3 months supplementation, indicating a high degree of compliance. Consistent with previous reports, there was inhibition of ADP-induced platelet aggregation by EPA supplementation. Moreover, EPA markedly enhanced the 5-HT responsivity as measured by the magnitude of 5-HT amplification on ADP-induced platelet aggregation. Previously, we have demonstrated a significant inverse correlation between 5-HT responsivity and psychosis severity in unmedicated patients with schizophrenia. Taken together, the present data support the notion that EPA may be mediating its therapeutic effects in schizophrenia via modulation of the 5-HT2 receptor complex. Published by Elsevier Ltd. C1 VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Dept Psychiat, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Sch Nursing, Pittsburgh, PA 15261 USA. VA Med Ctr, Dayton, OH USA. RP Yao, JK (reprint author), VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. EM jkyao@pitt.edu NR 42 TC 36 Z9 38 U1 2 U2 5 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD SEP PY 2004 VL 71 IS 3 BP 171 EP 176 DI 10.1016/j.plefa.2004.03.011 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 842JZ UT WOS:000223001600006 PM 15253886 ER PT J AU Ziada, A Barqawi, A Glode, LM Varella-Garcia, M Crighton, F Majeski, S Rosenblum, M Kane, M Chen, L Crawford, ED AF Ziada, A Barqawi, A Glode, LM Varella-Garcia, M Crighton, F Majeski, S Rosenblum, M Kane, M Chen, L Crawford, ED TI The use of trastuzumab in the treatment of hormone refractory prostate cancer; phase II trial SO PROSTATE LA English DT Article DE prostate; cancer; trastuzumab; HER-2 receptor ID METASTATIC BREAST-CANCER; IN-SITU HYBRIDIZATION; HER-2/NEU ONCOGENE AMPLIFICATION; MONOCLONAL-ANTIBODIES; PLUS TRASTUZUMAB; NEU ONCOGENE; RECEPTOR; CHEMOTHERAPY; DOCETAXEL; PROGRESSION AB PURPOSE. To investigate the efficacy and toxicity of the antibody to the HER-2/neu receptor (trastuzumab, Herceptin(R)) in the treatment of advanced hormone-refractory prostate cancer (HRPC). MATERIALS AND METHODS. Eighteen patients with HRPC were recruited for this phase 11 trial in which they received trastuzumab for 12 weeks or until disease progression or unacceptable toxicity was documented. HER-2 receptor overexpression was evaluated using immunohistochemistry (IHC) and dual-color fluorescence in-situ hybridization (FISH) assays. RESULTS. Trastuzumab as a single agent demonstrated little efficacy in treating HRPC. Two patients demonstrated stable disease based on a decrease in PSA level to less than 50% of baseline. No patient demonstrated a regression of radiographic bony or soft tissue metastatic disease. The medication was well tolerated in 16 patients (89%), and 2 patients (11%) had to be hospitalized for cardiac complications. CONCLUSIONS. Trastuzumab (Herceptin(R)) as a single agent demonstrated poor efficacy in treating HRPC. Based on promising results in treating breast cancer with regimens using Herceptin(R) and cytotoxic agents, a similar combination approach might demonstrate better efficacy in treating HRPC. (C) 2004 Wiley-Liss, Inc. C1 Univ Colorado, Hlth Sci Ctr, Dept Med, Div Med Oncol, Denver, CO 80262 USA. Anschutz Canc Pavil, Aurora, CO USA. Denver VA Med Ctr, Denver, CO USA. RP Barqawi, A (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Med, Div Med Oncol, 4200 E 9th Ave C-319, Denver, CO 80262 USA. EM al.barqawi@uchsc.edu RI Barqawi, Al/A-3002-2008 NR 25 TC 105 Z9 112 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-4137 J9 PROSTATE JI Prostate PD SEP 1 PY 2004 VL 60 IS 4 BP 332 EP 337 DI 10.1002/pros.20065 PG 6 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 845DJ UT WOS:000223215700009 PM 15264245 ER PT J AU Kim, TG Gruber, A Langridge, WHR AF Kim, TG Gruber, A Langridge, WHR TI HIV-1 gp120 V3 cholera toxin B subunit fusion gene expression in transgenic potato SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE HIV-1; Solanum tuberosum; edible vaccine; gp 120 V3 loop ID HUMAN-IMMUNODEFICIENCY-VIRUS; RECEPTOR-BINDING; SURFACE-ANTIGEN; CCR5 CORECEPTOR; TYPE-1 GP120; PROTEIN; GLYCOPROTEIN; ENVELOPE; PLANTS; IMMUNOGENICITY AB A cDNA fragment encoding the V3 loop of human immunodeficiency virus type-1 (HIV-1) envelope glycoprotein gp120 was fused to the cholera toxin B subunit gene (CTB-gp120) and transferred into Solanum tuberosum cells by Agrobacterium tumefaciens-mediated transformation. The CTB-gp 120 fusion gene was detected in genomic DNA from transformed potato leaves by PCR DNA amplification. Synthesis and assembly of the CTB-gp120 fusion protein into oligomeric structures of pentamer size was detected in transformed tuber extracts by immunoblot analysis. The binding of CTB-gp120 fusion protein pentamers to intestinal epithelial cell membrane glycolipid receptors was quantified by G(M1)-ganglioside enzyme-linked immunosorbent assay (G(M1)-ELISA). The ELISA results indicated that CTB-gp120 fusion protein made up 0.002-0.004% of the total soluble tuber protein. Synthesis of CTB-gp120 monomers and their assembly into biologically active oligomers in transformed potato tuber tissues demonstrates for the first time the expression of HIV-1 gp120 in plants and emphasizes the feasibility of using edible plant-based vaccination for protection against HIV-1 infection. (C) 2004 Elsevier Inc. All rights reserved. C1 Loma Linda Univ, Sch Med, Ctr Mol Biol & Gene Therapy, Dept Biochem & Microbiol, Loma Linda, CA 92350 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Langridge, WHR (reprint author), Loma Linda Univ, Sch Med, Ctr Mol Biol & Gene Therapy, Dept Biochem & Microbiol, Loma Linda, CA 92350 USA. EM blangridge@som.llu.edu NR 41 TC 26 Z9 31 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 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD SEP PY 2004 VL 37 IS 1 BP 196 EP 202 DI 10.1016/j.pep.2004.04.014 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 847RR UT WOS:000223413100025 PM 15294298 ER PT J AU Butterfield, RM Park, ER Puleo, E Mertens, A Gritz, ER Li, FP Emmons, K AF Butterfield, RM Park, ER Puleo, E Mertens, A Gritz, ER Li, FP Emmons, K TI Multiple risk behaviors among smokers in the childhood cancer survivors study cohort SO PSYCHO-ONCOLOGY LA English DT Article ID LONG-TERM SURVIVORS; ACUTE LYMPHOBLASTIC-LEUKEMIA; SMOKING-CESSATION; HEALTH BEHAVIORS; PHYSICAL-ACTIVITY; CIGARETTE-SMOKING; ADULT SURVIVORS; EXERCISE; WORKING; TRIAL AB The literature on health behaviors of young adult cancer survivors is very limited, and thus little is known about preventable risk factors in this population. This paper describes the prevalence of five behavioral risk factors among 541 young adult survivors of childhood cancers from the CCSS cohort who were identified as smokers and enrolled in a randomized controlled trial of a smoking cessation intervention. The relationship between presence of multiple risk factors and a number of smoking-related factors was examined. About 31% of the sample engaged in zero or one health-risk behavior in addition to smoking; 63% engaged in 2 or 3, and 6% engaged in 4 or 5. There were positive linear relationships between number of risk factors and smoking rate and nicotine dependence. Number of risk factors was not associated with self-efficacy for quitting, but was related to readiness to quit. This study demonstrated that childhood cancer survivors who smoke have a number of other risk factors for the development of preventable disease and the presence of these risks was associated with factors that decrease the likelihood of quitting smoking. Attention to other health behaviors may be an important strategy for helping smokers quit. In particular, helping childhood cancer survivors who smoke to reduce other risk behaviors might also encourage them to quit smoking. Copyright (C) 2003 John Wiley Sons, Ltd. C1 Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cambridge, MA 02138 USA. Univ Minnesota, Minneapolis, MN 55455 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX USA. RP Butterfield, RM (reprint author), Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Ctr Community Based Res, 44 Binney St, Boston, MA 02115 USA. EM rita_butterfield@dfci.harvard.edu FU NCI NIH HHS [U24-CA55727]; PHS HHS [R01-GA77780] NR 55 TC 35 Z9 35 U1 1 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD SEP PY 2004 VL 13 IS 9 BP 619 EP 629 DI 10.1002/pon.764 PG 11 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 854AA UT WOS:000223871100003 PM 15334530 ER PT J AU DuHamel, KN Ostroff, J Ashman, T Winkel, G Mundy, EA Keane, TM Morasco, BJ Vickberg, SMJ Hurley, K Burkhalter, J Chhabra, R Scigliano, E Papadopoulos, E Moskowitz, C Redd, W AF DuHamel, KN Ostroff, J Ashman, T Winkel, G Mundy, EA Keane, TM Morasco, BJ Vickberg, SMJ Hurley, K Burkhalter, J Chhabra, R Scigliano, E Papadopoulos, E Moskowitz, C Redd, W TI Construct validity of the posttraumatic stress disorder checklist in cancer survivors: Analyses based on two samples SO PSYCHOLOGICAL ASSESSMENT LA English DT Article ID BONE-MARROW-TRANSPLANTATION; CONFIRMATORY FACTOR-ANALYSIS; MALE VIETNAM VETERANS; PTSD CHECKLIST; BREAST-CANCER; SCREENING INSTRUMENT; CIVILIAN VERSION; SYMPTOMS; PREDICTORS; PREVALENCE AB The measurement of posttraumatic stress disorder (PTSD) is critically important for the identification and treatment of this disorder. The PTSD Checklist (PCL; F. W. Weathers & J. Ford, 1996) is a self-report measure that is increasingly used. In this study, the authors investigated the factorial validity of the PCL with data from 236 cancer survivors who received a bone marrow or stem cell transplantation. The authors examined the fit of these data with the clinical model of 3 symptom clusters for PTSD, as proposed in the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association. 1994), and alternative models tested in prior research. By using confirmatory factor analysis the authors found that a 4-first-order-factor model of PTSD provided the best fit. The relations of PTSD symptoms with sociodemographic and medical variables were also explored. C1 Mt Sinai Sch Med, Dept Oncol Sci, Mt Sinai Med Ctr, New York, NY 10029 USA. Univ Wisconsin, Hosp & Clin, Madison, WI 53792 USA. Boston Healthcare Syst, Natl Ctr PTSD, Dept Vet Affairs, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. RP DuHamel, KN (reprint author), Mt Sinai Sch Med, Dept Oncol Sci, Mt Sinai Med Ctr, 1 Gustave L Levy Pl,Box 1130, New York, NY 10029 USA. EM Katherine.duhamel@mssm.edu RI Ashman, Teresa/B-1621-2013; OI Ostroff, Jamie/0000-0003-2671-5680 FU NCI NIH HHS [CA-81137-05, T32-CA09461]; NIMH NIH HHS [MH-1900] NR 53 TC 85 Z9 87 U1 6 U2 9 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1040-3590 J9 PSYCHOL ASSESSMENT JI Psychol. Assess. PD SEP PY 2004 VL 16 IS 3 BP 255 EP 266 DI 10.1037/1040-3590.16.3.255 PG 12 WC Psychology, Clinical SC Psychology GA 854QE UT WOS:000223917600004 PM 15456381 ER PT J AU Cook, JM Orvaschel, H Simco, E Hersen, M Joiner, T AF Cook, JM Orvaschel, H Simco, E Hersen, M Joiner, T TI A test of the tripartite model of depression and anxiety in older adult psychiatric outpatients SO PSYCHOLOGY AND AGING LA English DT Article ID COGNITIVE CONTENT-SPECIFICITY; LATE-LIFE ANXIETY; NEGATIVE AFFECTIVITY; PSYCHOMETRIC PROPERTIES; MOOD DISORDERS; INVENTORY; SYMPTOMS; HYPERAROUSAL; RELIABILITY; ADOLESCENTS AB This study examined the tripartite model of depression and anxiety in 131 psychiatric outpatients, ages 55-87. Confirmatory factor analyses revealed that a 3-factor model provided an adequate fit to the observed data, that the 3-factor model was empirically superior to 1- or 2-factor models, and that the 3-factor structure obtained in the current sample of older adult outpatients converged with that obtained on a separate, younger sample. Negative affect was significantly related to depression and anxiety symptoms and syndromes, and positive affect was more highly related to depression than anxiety symptoms and syndromes. Ways for taking into account possible age-associated differences in emotion in older adults and thus improving the conceptual model of anxiety and depression are briefly noted. C1 Univ Penn, Treatment Res Ctr, Dept Psychiat, Sch Med, Philadelphia, PA 19104 USA. Univ Penn, Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. Nova SE Univ, Ctr Psychol Studies, Ft Lauderdale, FL 33314 USA. Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. RP Cook, JM (reprint author), Univ Penn, Treatment Res Ctr, Dept Psychiat, Sch Med, 3900 Chestnut St, Philadelphia, PA 19104 USA. EM cook_j@mail.trc.upenn.edu NR 55 TC 21 Z9 22 U1 1 U2 3 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0882-7974 J9 PSYCHOL AGING JI Psychol. Aging PD SEP PY 2004 VL 19 IS 3 BP 444 EP 451 DI 10.1037/0882-7974.19.3.444 PG 8 WC Gerontology; Psychology, Developmental SC Geriatrics & Gerontology; Psychology GA 850QH UT WOS:000223627000007 PM 15382995 ER PT J AU Dien, J Spencer, KM Donchin, E AF Dien, J Spencer, KM Donchin, E TI Parsing the late positive complex: Mental chronometry and the ERP components that inhabit the neighborhood of the P300 SO PSYCHOPHYSIOLOGY LA English DT Article DE event-related potentials; P300; novelty P3; PCA; information processing ID EVENT-RELATED POTENTIALS; CHOICE-REACTION-TIME; BRAIN POTENTIALS; STIMULUS EVALUATION; SCALP DISTRIBUTIONS; SELECTIVE ATTENTION; EVOKED POTENTIALS; PROCESSING STAGES; NOVELTY P3; INFORMATION AB Falkenstein, Hohnsbein, and Hoorman (1994) suggested that common measures of P300 latency confound a "P-SR" component whose latency corresponds to stimulus evaluation time and a "P-CR" component whose latency varies with response-selection time, thus casting doubt on work in mental chronometry that relies on P300 latency. We report here a replication and extension of Falkenstein et al. (1994) using a high-density 129-electrode montage with 11 subjects. Spatiotemporal PCA was used to extract the components of the ER-P. A centroid measure is also introduced for detecting waveform-timing changes beyond just peak latency. In terms of componentry, we argue that the P-SR and the P-CR, correspond to the P3a/Novelty P3 and the P300, respectively. Conceptually, we dispute the proposed distinction between stimulus evaluation and response selection. We suggest a four-stage ERP model of information processing and place the P3a and the P300 in this framework. C1 Univ Kansas, Dept Psychol, Lawrence, KS 66045 USA. Univ Illinois, Dept Psychol, Urbana, IL 61801 USA. Univ S Florida, Dept Psychol, Tampa, FL USA. Harvard Univ, Sch Med, Dept Psychiat, VA Boston Healthcare Syst, Boston, MA 02115 USA. RP Dien, J (reprint author), Univ Kansas, Dept Psychol, 1415 Jayhawk Blvd, Lawrence, KS 66045 USA. EM jdien@ku.edu OI Spencer, Kevin/0000-0002-5500-7627 FU NIMH NIH HHS [MH11751, MH19554] NR 94 TC 184 Z9 185 U1 2 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2004 VL 41 IS 5 BP 665 EP 678 DI 10.1111/j.1469-8986.2004.00193.x PG 14 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 849RH UT WOS:000223557800001 PM 15318873 ER PT J AU Bankier, B Januzzi, JL Littman, AB AF Bankier, B Januzzi, JL Littman, AB TI The high prevalence of multiple psychiatric disorders in stable outpatients with coronary heart disease SO PSYCHOSOMATIC MEDICINE LA English DT Article DE coronary heart disease; stable outpatients; multiple psychiatric disorders ID POSTTRAUMATIC-STRESS-DISORDER; MYOCARDIAL-INFARCTION; PANIC DISORDER; ARTERY-DISEASE; CHEST-PAIN; MAJOR DEPRESSION; RISK-FACTORS; MORTALITY; PROGNOSIS; ALCOHOL AB Objecetive: There is accumulating evidence of high prevalence of comorbid psychiatric disorders in patients with coronary heart disease (CHD). However, most of these studies focused on one psychiatric disorder or one set of psychological symptoms and detected psychiatric disorders in acutely ill CHD patients. To date, no systematic comprehensive psychiatric diagnostic evaluation has been performed in a consecutive sample of stable CHD outpatients. Methods: One hundred stable CHD outpatients of the Cardiology Division outpatient clinic at the Massachusetts General Hospital were included in the study. Psychiatric diagnoses were established by using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (axes IN). Results: Frequent comorbid psychiatric diagnoses were detected, including single past major depressive episode (29%), current dysthymic disorder (15%), recurrent major depressive disorder with current major depressive episode (31%), current alcohol abuse (19%), posttraumatic stress disorder (29%), current generalized anxiety disorder (24%), current binge-eating disorder (10%), and current primary insomnia (13%). The mean number of comorbid clinical psychiatric disorders per Subject was 1.7. Conclusion: The findings suggest high prevalence rates of comorbid psychiatric disorders as well as a broad spectrum of psychiatric disorders in stable CHD outpatients. However, larger epidemiological studies are needed in order to determine the true prevalence of these disorders in CHD patients. C1 Massachusetts Gen Hosp, Dept Psychiat, Behav Med Div Prevent Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Bankier, B (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Behav Med Div Prevent Cardiol, 50 Stanford St,Suite 401, Boston, MA 02114 USA. EM bbankier@partners.org NR 29 TC 58 Z9 63 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD SEP-OCT PY 2004 VL 66 IS 5 BP 645 EP 650 DI 10.1097/01.psy.0000138126.90551.62 PG 6 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 856UJ UT WOS:000224070300004 PM 15385686 ER PT J AU Cohen, LS Scares, CN Yonkers, KA Bellew, KM Bridges, IM Steiner, M AF Cohen, LS Scares, CN Yonkers, KA Bellew, KM Bridges, IM Steiner, M TI Paroxetine controlled release for premenstrual dysphoric disorder: A double-blind, placebo-controlled trial SO PSYCHOSOMATIC MEDICINE LA English DT Article DE premenstrual dysphoric disorder; premenstrual syndrome; selective serotonin reuptake inhibitors; controlled release; Clinical Global Impression severity; last-observation-carried forward; visual analog scale ID INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; SEROTONIN-REUPTAKE INHIBITORS; DSM-IV; WOMEN; FLUOXETINE; PREVALENCE; DISABILITY; SERTRALINE; SYMPTOMS; EFFICACY AB Background: Better characterization of safety and efficacy of multiple doses of selective serotonin reuptake inhibitors for the treatment of a wider range of symptoms of premenstrual dysphoric disorder (PMDD) will provide clinicians with flexibility to provide symptom relief along with acceptable tolerability. This study was designed to assess the efficacy and tolerability of multiple doses of paroxetine controlled release (CR) in PMDD. Methods: In a multicenter (43 outpatient U.S. sites), placebo-controlled trial, 327 females aged 18 to 45 years, with regular menstrual cycles, meeting DSM-IV criteria for PMDD, were randomly assigned to receive paroxetine CR 12.5 mg; paroxetine CR 25 mg; or placebo, once daily, for up to three treatment cycles. The primary efficacy outcome was change from baseline to end point in mean luteal phase Visual Analogue Scale-Mood (irritability, tension, affective lability, depressed mood) score. Results: At end point, subjects treated with paroxetine CR (12.5 mg and 25 mg) demonstrated significant improvement in VAS-Mood scores compared with those who received placebo (paroxetine CR 12.5 mg mean treatment difference vs. placebo, -8.7 mm; 95% CI, -15.7, -1.7; p = .015; paroxetine CR 25 mg mean treatment difference vs. placebo, -12.1 mm; 95% CI, -18.9, -5.3; p <.001). Results were also significant across measures of physical symptoms and social functioning. Paroxetine CR was well tolerated; 9.5% of subjects treated with 12.5 mg and 13.5% of subjects treated with 25 mg withdrew from the trial due to adverse events, compared with 6.5% of subjects in the placebo group. Conclusions: Both doses of paroxetine CR 12.5 mg and 25 mg daily are effective and well tolerated in patients who suffer from PMDD. Efficacy with both doses affords greater flexibility to the prescribing physician. C1 Massachusetts Gen Hosp, Clin Res Program, Perinatal & Reprod Psychiat Program, Boston, MA 02114 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. GlaxoSmithKline Clin Dev & Med Affairs, King Of Prussia, PA USA. GlaxoSmithKline Biostat & Data Sci, Harlow, Essex, England. St Josephs Hosp, Womens Hlth Concerns Clin, Hamilton, ON, Canada. RP Cohen, LS (reprint author), Massachusetts Gen Hosp, Clin Res Program, Perinatal & Reprod Psychiat Program, 15 Parkman St,WACC 812, Boston, MA 02114 USA. EM Lcohen2@partners.org RI Steiner, Meir /B-2121-2016; OI Steiner, Meir/0000-0001-7838-2246 NR 27 TC 36 Z9 40 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD SEP-OCT PY 2004 VL 66 IS 5 BP 707 EP 713 DI 10.1097/01.psy.0000140005.94790.9c PG 7 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 856UJ UT WOS:000224070300013 PM 15385695 ER PT J AU Chang, G Orav, EJ Tong, MY Antin, JH AF Chang, G Orav, EJ Tong, MY Antin, JH TI Predictors of 1-year survival assessed at the time of bone marrow transplantation SO PSYCHOSOMATICS LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; ABL TYROSINE KINASE; LIVER-TRANSPLANTATION; CIGARETTE-SMOKING; UNRELATED DONORS; CANCER-PATIENTS; ALCOHOL-ABUSE; INTERFERON; DISORDERS AB The purpose of this prospective cohort study was to identify pretransplant and transplant predictors of 1-year survival after allogeneic hematopoietic stem cell transplantation (HSCT) for chronic myelogenous leukemia. Psychosocial and behavioral variables such as alcohol abuse and cigarette smoking were systematically assessed at the time of HSCT with structured diagnostic instruments. A total of 114 patients participated, with an overall 1-year survival rate of 66%. Lifetime alcohol and other substance use, cigarette smoking, depression, and quality of life prior to transplant were not found to affect 1-year survival. However, other clinical variables prior to transplant and once transplant occurred were found to predict survival. C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med Biostat, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Chang, G (reprint author), Brigham & Womens Hosp, 221 Longwood Ave, Boston, MA 02115 USA. EM Gchang@partners.org FU PHS HHS [K2400289] NR 45 TC 19 Z9 20 U1 1 U2 2 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD SEP-OCT PY 2004 VL 45 IS 5 BP 378 EP 385 DI 10.1176/appi.psy.45.5.378 PG 8 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 851OX UT WOS:000223695500002 PM 15345782 ER PT J AU Iosifescu, DV Nierenberg, AA Alpert, JE Papakostas, GI Perlis, RH Sonawalla, S Fava, M AF Iosifescu, DV Nierenberg, AA Alpert, JE Papakostas, GI Perlis, RH Sonawalla, S Fava, M TI Comorbid medical illness and relapse of major depressive disorder in the continuation phase of treatment SO PSYCHOSOMATICS LA English DT Article; Proceedings Paper CT 155th Annual Meeting of the American-Psychiatric-Association CY MAY 18-23, 2002 CL PHILADELPHIA, PA SP Amer Psychiat Assoc ID RATING-SCALE; ILL PATIENTS; SYMPTOMS; POPULATION; FLUOXETINE; RECOVERY; OUTCOMES; IMPACT AB The authors examined the impact of comorbid medical illness on the rate of relapse of major depressive disorder during continuation therapy. Subjects (N = 128) with major depressive disorder (according to DSM-III-R criteria) achieved clinical remission (a 17-item Hamilton Depression Rating Scale score less than or equal to 7) after 8 weeks of treatment with fluoxetine and entered the continuation phase of antidepressant treatment. They used the Cumulative Illness Rating Scale to measure the severity of comorbid medical illness. Eight patients (63%) relapsed during the 28-week continuation phase. With logistic regression, the total burden and the severity of comorbid medical illness significantly predicted the relapse of major depressive disorder during continuation therapy with fluoxetine. Greater medical comorbidity was also associated with higher increases in setf-reported symptoms of depression, anxiety, and anger during the follow-up. C1 Massachusetts Gen Hosp, Dept Psychiat, Depress Clin & Res Program, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Iosifescu, DV (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Depress Clin & Res Program, 50 Staniford St,Suite 401, Boston, MA 02114 USA. EM diosifescu@partners.org RI Papakostas, George/I-6905-2013; OI Papakostas, George/0000-0002-2465-5103; Alpert, Jonathan/0000-0002-4332-908X FU NIMH NIH HHS [R01-MH48483] NR 29 TC 28 Z9 28 U1 1 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD SEP-OCT PY 2004 VL 45 IS 5 BP 419 EP 425 DI 10.1176/appi.psy.45.5.419 PG 7 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 851OX UT WOS:000223695500007 PM 15345787 ER PT J AU Cramer, MA AF Cramer, MA TI Imaginary gardens with real toads: Attachment to others, attachment to the market SO PSYCHOTHERAPY LA English DT Article ID SECURITY AB Although the treatment alliance has been shown to be important to successful outcome in psychotherapy, there has been an erosion of the conditions that encourage its development. It is proposed that cultural and economic changes in the perceived worth of relationship have created a kind of ambient trauma in the treatment environment for the therapeutic dyad. The cultural encouragement of a substitution of relationships with the market for relationships with others and with one's own internal affects is explored. Consequences for the patient, therapist, and treatment are discussed. Case examples are included. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Psychoanal Studies, Cambridge, MA 02138 USA. RP Cramer, MA (reprint author), 40 Beacon St, Melrose, MA 02176 USA. EM margaretacramer@aol.com NR 41 TC 2 Z9 2 U1 0 U2 1 PU AMER PSYCHOLOGICAL ASSOC, DIV PSYCHOTHERAPY PI CORAL GABLES PA 1390 SOUTH DIXIE HIGHWAY, STE 2222, CORAL GABLES, FL 33146-2946 USA SN 0033-3204 J9 PSYCHOTHERAPY JI Psychotherapy PD FAL PY 2004 VL 41 IS 3 BP 208 EP 216 DI 10.1037/0033-3204.41.3.208 PG 9 WC Psychology, Clinical SC Psychology GA 906OO UT WOS:000227651700002 ER PT J AU Hawkins, EJ Lambert, MJ Vermeersch, DA Slade, KL Tuttle, KC AF Hawkins, EJ Lambert, MJ Vermeersch, DA Slade, KL Tuttle, KC TI The therapeutic effects of providing patient progress information to therapists and patients SO PSYCHOTHERAPY RESEARCH LA English DT Article ID CLINICAL-SIGNIFICANCE; GROUP-PSYCHOTHERAPY; TREATMENT FAILURE; FEEDBACK; OUTCOMES; METAANALYSIS; INVENTORY AB Patient-focused research systems have been developed to monitor and inform therapists of patients' treatment progress in psychotherapy as a method of enhancing outcome. The current study examined the effects of providing treatment progress information to only therapists and to both patients and therapists during the course of psychotherapy. Outpatients (N = 201) at a hospital-based psychotherapy clinic were randomly assigned to 1 of 3 treatment groups: treatment as usual, therapist feedback, and patient-therapist feedback. Patients in the 2 feedback conditions demonstrated significantly greater improvement at termination than those in the treatment-as-usual condition, with no average increase in sessions attended. These findings suggest that providing feedback to patients and therapists may be a viable approach to enhancing patient outcomes. C1 Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. VA Puget Sound Hlth Care Syst, Seattle, WA USA. Loma Linda Univ, Loma Linda, CA 92350 USA. RP Lambert, MJ (reprint author), Brigham Young Univ, Dept Psychol, 272 TLRB, Provo, UT 84602 USA. EM michael_lambert@byu.edu NR 38 TC 93 Z9 93 U1 1 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1050-3307 J9 PSYCHOTHER RES JI Psychother. Res. PD FAL PY 2004 VL 14 IS 3 BP 308 EP 327 DI 10.1093/ptr/kph027 PG 20 WC Psychology, Clinical SC Psychology GA 844GA UT WOS:000223144700003 ER PT J AU Wittram, C Maher, MM Yoo, AJ Kalra, MK Shepard, JAO McLoud, TC AF Wittram, C Maher, MM Yoo, AJ Kalra, MK Shepard, JAO McLoud, TC TI CT angiography of pulmonary embolism: Diagnostic criteria and causes of misdiagnosis SO RADIOGRAPHICS LA English DT Article DE computed tomography (CT), angiography; embolism, pulmonary; pulmonary angiography; pulmonary arteries, CT; pulmonary arteries, stenosis or obstruction ID DEEP-VEIN THROMBOSIS; HELICAL CT; SPIRAL CT; COMPUTED-TOMOGRAPHY; MEDICAL-CENTER; TUMOR EMBOLI; PITFALLS; FEATURES; DISEASE AB Computed tomographic (CT) pulmonary angiography is becoming the standard of care at many institutions for the evaluation of patients with suspected pulmonary embolism. This pathologic condition, whether acute or chronic, causes both partial and complete intraluminal filling defects, which should have a sharp interface with intravascular contrast material. In acute pulmonary embolism that manifests as complete arterial occlusion, the affected artery may be enlarged. Partial filling defects due to acute pulmonary embolism are often centrally located, but when eccentrically located they form acute angles with the vessel wall. Chronic pulmonary embolism can manifest as complete occlusive disease in vessels that are smaller than adjacent patent vessels. Other CT pulmonary angiographic findings in chronic pulmonary embolism include evidence of recanalization, webs or flaps, and partial filling defects that form obtuse angles with the vessel wall. Factors that cause misdiagnosis of pulmonary embolism may be patient related, technical, anatomic, or pathologic. The radiologist needs to determine the quality of a CT pulmonary angiographic study and whether pulmonary embolism is present. If the quality of the study is poor, the radiologist should identify which pulmonary arteries have been rendered indeterminate and whether additional imaging is necessary. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Wittram, C (reprint author), Massachusetts Gen Hosp, Dept Radiol, Founders Bldg 202,55 Fruit St, Boston, MA 02114 USA. EM cwittram@partners.org NR 45 TC 124 Z9 142 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD SEP-OCT PY 2004 VL 24 IS 5 BP 1219 EP 1238 DI 10.1148/rg.245045008 PG 20 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 853DX UT WOS:000223807800001 PM 15371604 ER PT J AU Sahani, D Mehta, A Blake, M Prasad, S Harris, G Saini, S AF Sahani, D Mehta, A Blake, M Prasad, S Harris, G Saini, S TI Preoperative hepatic vascular evaluation with CT and MR angiography: Implications for surgery SO RADIOGRAPHICS LA English DT Article; Proceedings Paper CT 87th Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America CY NOV 25-30, 2001 CL CHICAGO, IL SP Radiol Soc N Amer ID DONOR LIVER-TRANSPLANTATION; HELICAL COMPUTED-TOMOGRAPHY; RIGHT LOBE GRAFTS; COLORECTAL-CANCER; ARTERIAL INFUSION; RESECTION; CHEMOTHERAPY; CANDIDATES; HEPATECTOMY; CARCINOMA AB Partial liver resection for living donor transplantations and treatment of hepatic tumors is a major surgical undertaking, and detailed knowledge of the hepatic angioarchitecture is essential to ensure safe and successful liver surgery. Noninvasive imaging techniques such as computed tomographic (CT) and magnetic resonance (MR) angiography have begun to replace conventional catheter angiography for evaluation of the hepatic vascular anatomy. Multisection CT angiography and MR angiography are complementary modalities that permit comprehensive, accurate preoperative delineation of the hepatic vascular anatomy and evaluation of the parenchyma in patients undergoing liver surgery, thereby obviating multiple invasive studies including catheter angiography. Understanding a surgeon's perspective on liver surgery is critical so that the required information can be provided accurately with imaging. Both CT angiography and MR angiography have had a significant impact on the selection of candidates for liver surgery as well as on surgical technique. C1 Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent, Dept Radiol, Boston, MA 02114 USA. RP Sahani, D (reprint author), Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent, Dept Radiol, Boston, MA 02114 USA. EM dsahani@partners.org NR 27 TC 72 Z9 85 U1 1 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD SEP-OCT PY 2004 VL 24 IS 5 BP 1367 EP 1380 DI 10.1148/rg.245035224 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 853DX UT WOS:000223807800012 PM 15371614 ER PT J AU Kalra, MK Maher, MM Blake, MA Lucey, BC Karau, K Toth, TL Avinash, G Halpern, EF Saini, S AF Kalra, MK Maher, MM Blake, MA Lucey, BC Karau, K Toth, TL Avinash, G Halpern, EF Saini, S TI Detection and characterization of lesions on low-radiation-dose abdominal CT images postprocessed with noise reduction filters SO RADIOLOGY LA English DT Article ID COMPUTED-TOMOGRAPHY; CANCER-RISKS; TUBE CURRENT; HELICAL CT; RADIOLOGY; SCANNERS AB PURPOSE: To assess the effect of noise reduction filters on detection and characterization of lesions on low-radiation-close abdominal computed tomographic (CT) images. MATERIALS AND METHODS: Low-dose CT images of abdominal lesions in 19 consecutive patients (11 women, eight men; age range, 32-78 years) were obtained at reduced tube currents (120-144 mAs). These baseline low-dose CT images were postprocessed with six noise reduction filters; the resulting postprocessed images were then randomly assorted with baseline images. Three radiologists performed independent evaluation of randomized images for presence, number, margins, attenuation, conspicuity, calcification, and enhancement of lesions, as well as image noise. Side-by-side comparison of baseline images with postprocessed images was performed by using a five-point scale for assessing lesion conspicuity and margins, image noise, beam hardening, and diagnostic acceptability. Quantitative noise and contrast-to-noise ratio were obtained for all liver lesions. Statistical analysis was performed by using the Wilcoxon signed rank test, Student t test, and kappa test of agreement. RESULTS: Significant reduction of noise was observed in images postprocessed with filter F compared with the noise in baseline nonfiltered images (P = 004). Although the number of lesions seen on baseline images and that seen on postprocessed images were identical, lesions were less conspicuous on postprocessed images than on baseline images. A decrease in quantitative image noise and contrast-to-noise ratio for liver lesions was noted with all noise reduction filters. There was good interobserver agreement (kappa = 0.7). CONCLUSION: Although the use of currently available noise reduction filters improves image noise and ameliorates beam-hardening artifacts at low-dose CT, such filters are limited by a compromise in lesion conspicuity and appearance in comparison with lesion conspicuity and appearance on baseline low-dose CT images. (C) RSNA 2004. C1 Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. GE Med Syst, Waukesha, WI USA. RP Saini, S (reprint author), Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent, 55 Fruit St,White 270E, Boston, MA 02114 USA. EM ssaini@partners.org NR 16 TC 63 Z9 65 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD SEP PY 2004 VL 232 IS 3 BP 791 EP 797 DI 10.1148/radiol.2323031563 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 848GG UT WOS:000223455000021 PM 15333797 ER PT J AU Sahani, DV Kalva, SP Tanabe, KK Hayat, SM O'Neill, MJ Halpern, EF Saini, S Mueller, PR AF Sahani, DV Kalva, SP Tanabe, KK Hayat, SM O'Neill, MJ Halpern, EF Saini, S Mueller, PR TI Intraoperative US in patients undergoing surgery for liver neoplasms: Comparison with MR imaging SO RADIOLOGY LA English DT Article; Proceedings Paper CT 87th Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America CY NOV 25-30, 2001 CL CHICAGO, IL SP Radiol Soc N Amer ID HEPATIC METASTASES; CONTRAST AGENTS; MN-DPDP; ULTRASONOGRAPHY; RESECTION; IMPACT; ULTRASOUND; SONOGRAPHY; TUMORS; CANCER AB PURPOSE: To retrospectively compare intraoperative ultrasonography (US) and preoperative magnetic resonance (MR) imaging with contrast material enhancement for the depiction of liver lesions in patients undergoing hepatic resection. MATERIALS AND METHODS: A radiologist (D.V.S.) and a surgeon (K.K.T.) retrospectively identified 79 patients (36 female and 43 male patients; age range, 10-78 years; mean age, 57 years) who had undergone surgical resection for primary liver tumor or metastasis and had also undergone preoperative contrast-enhanced MR imaging within 6 weeks before surgery. MR imaging was performed with a 1.5-T system. Dedicated intraoperative US of the liver was performed or supervised by a gastrointestinal radiologist using a 7.5-MHz linear-array transducer, after adequate hepatic mobilization by the surgeon. Histopathologic evaluation of the 159 resected hepatic lesions served as the reference standard. The lesion distribution included colon cancer metastasis (n = 122), hepatocellular carcinoma (n = 23), cholangiocarcinoma (n = 6), cavernous hemangioma (n = 4), focal nodular hyperplasia (n 2), hamartoma (n = 1), and metastatic embryonal sarcoma (n = 1). RESULTS: Of 159 lesions, 138 (86.7%) were identified at both MR imaging and intraoperative US. Twelve additional lesions (7.5%) in 10 patients were detected only at intraoperative US (eight metastases, one hepatocellular carcinoma, one cholangiocarcinoma, one hemangioma, and one biliary hamartoma). Both modalities failed to depict nine lesions (5.6%) (four metastases, four hepatocellular carcinomas, and one cholangiocarcinoma). The sensitivities of MR imaging and intraoperative US for liver lesion depiction were 86.7% and 94.3%. respectively. Surgical management was altered on the basis of the intraoperative US findings in only three of 10 patients (4%). CONCLUSION: Contrast-enhanced MR imaging is as sensitive as intraoperative US in depicting liver lesions before hepatic resection. (C) RSNA 2004. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Sahani, DV (reprint author), Massachusetts Gen Hosp, Dept Radiol, White 270,55 Fruit St, Boston, MA 02114 USA. EM dsahani@partners.org NR 19 TC 65 Z9 69 U1 1 U2 5 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD SEP PY 2004 VL 232 IS 3 BP 810 EP 814 DI 10.1148/radiol.2323030896 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 848GG UT WOS:000223455000023 PM 15273336 ER PT J AU Binkert, CA Baker, PD Petersen, BD Szumowski, J Kaufman, JA AF Binkert, CA Baker, PD Petersen, BD Szumowski, J Kaufman, JA TI Peripheral vascular disease: Blinded study of dedicated calf MR angiography versus standard bolus-chase MR angiography and film hard-copy angiography SO RADIOLOGY LA English DT Article DE angiography, comparative studies; arteries, extremities; arteries, MR; arteries, stenosis or obstruction; magnetic resonance (MR), vascular studies ID DIGITAL-SUBTRACTION-ANGIOGRAPHY; LOWER-EXTREMITY; ARTERIES; AORTA; VESSELS AB PURPOSE: To compare the accuracy of contrast material-enhanced three-dimensional (3D) dedicated calf magnetic resonance (MR) angiography with that of bolus-chase MR angiography, with conventional angiography as the reference standard, in patients with symptomatic peripheral vascular disease (PVD). MATERIALS AND METHODS: Thirty men with symptomatic PVD were examined. MR angiography was performed at 1.5 T before conventional angiography. MR angiographic examination included 3D contrast-enhanced dedicated calf MR angiography and three-station bolus-chase MR angiography. Two radiologists blinded to conventional angiographic results evaluated the MR angiograms independently. Two angiographers evaluated the conventional angiograms in consensus. Calf artery segments were graded as having 50% or less stenosis, greater than 50% stenosis, or occlusion or as being nondiagnostic. Statistical analyses were performed with paired permutation testing. RESULTS: Analyses of 472 calf segments and 420 pelvic and thigh segments were performed. Of the 472 calf segments, three and 75 segments (reader 1) and seven and 91 segments (reader 2) were graded as nondiagnostic at dedicated calf MR angiography and bolus-chase MR angiography, respectively. Differences in diagnostic grade between the two examinations were significant (P < .001), accounting for within-subject correlations, with a mean estimated difference of -17.1% (95% confidence interval [CI]: -25.8%, -8.4%). In the calf arteries, the dedicated and bolus-chase MR angiographic sequences had diagnostic accuracies, respectively, of 81.5% (reader 1) and 79.1% (reader 2) and of 67.8% (reader 1) and 63.4% (reader 2). The dedicated calf sequence was significantly more accurate than the bolus-chase sequence (P = .001). The point estimate of the difference was 14.7%, with estimated correct diagnosis rates of 80.3% and 65.6% for the dedicated calf and bolus-chase examinations, respectively (95% CI for difference: 4.0%, 25.4%). The diagnostic accuracy of bolus-chase MR angiography at the pelvis-thigh level was slightly higher when it was performed first: 81.9% (reader 1) and 83.8% (reader 2) versus 74.3% (reader 1) and 80.0% (reader 2) when it was performed last. The difference was not significant (P = .21). CONCLUSION: Use of dedicated calf MR angiography led to significantly increased diagnostic accuracy in the calf arteries compared with standard bolus-chase MR angiography. Use of the dual-bolus technique did not jeopardize the diagnostic accuracy in the pelvic and thigh arteries. (C) RSNA, 2004. C1 Oregon Hlth Sci Univ, Dotter Intervent Inst, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Diagnost Radiol, Portland, OR 97201 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. Portland VA Med Ctr, Imaging Serv, Portland, OR USA. RP Binkert, CA (reprint author), Oregon Hlth Sci Univ, Dotter Intervent Inst, Portland, OR 97201 USA. EM cbinkert@partners.org NR 14 TC 25 Z9 27 U1 1 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD SEP PY 2004 VL 232 IS 3 BP 860 EP 866 DI 10.1148/radiol.2323030244 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 848GG UT WOS:000223455000030 PM 15333800 ER PT J AU Stone, ME AF Stone, ME TI Encyclopedia of lesbian, gay, bisexual, and transgender history in America. SO REFERENCE & USER SERVICES QUARTERLY LA English DT Book Review C1 Massachusetts Gen Hosp, Treadwell Lib, Boston, MA 02114 USA. RP Stone, ME (reprint author), Massachusetts Gen Hosp, Treadwell Lib, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER LIBRARY ASSOC PI CHICAGO PA 50 E HURON ST, CHICAGO, IL 60611 USA SN 1094-9054 J9 REF USER SERV Q JI Ref. User Serv. Q. PD FAL PY 2004 VL 44 IS 1 BP 84 EP 85 PG 2 WC Information Science & Library Science SC Information Science & Library Science GA 939LR UT WOS:000230074800018 ER PT J AU Sudoh, Y Desai, SP Haderer, AE Sudoh, S Gerner, P Anthony, DC De Girolami, U Wang, GK AF Sudoh, Y Desai, SP Haderer, AE Sudoh, S Gerner, P Anthony, DC De Girolami, U Wang, GK TI Neurologic and histopathologic evaluation after high-volume intrathecal amitriptyline SO REGIONAL ANESTHESIA AND PAIN MEDICINE LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Society-of-Anesthesiologists CY OCT 12-16, 2002 CL ORLANDO, FL SP Amer Soc Anesthesiologists DE amitriptyline; spinal block; long-acting; local anesthetic; neurotoxicity ID RAT SCIATIC-NERVE; TRICYCLIC ANTIDEPRESSANTS; ANTINOCICEPTIVE MECHANISM; DIABETIC-NEUROPATHY; LOCAL-ANESTHETICS; SODIUM-CHANNELS; RECEPTORS; BLOCK; DRUGS; INVOLVEMENT AB Background and Objectives: Accumulating evidence indicates that amitriptyline decreases pain sensation when administered orally, intraperitoneally, or for sciatic nerve block. Previous reports of intrathecal administration of amitriptyline have yielded inconsistent results. The failure of amitriptyline to provide antinociception may partly be related to its high logP (octanol-water partition coefficient) and consequent poor spread within the cerebrospinal fluid. We evaluated spinal block after various concentrations of amitriptyline administered intrathecally in a fixed high volume. Methods: We administered 100 muL of 5, 10, 15.9 (0.5%), 25, 50, or 100 mmol/L amitriptyline hydrochloride solution or 100 muL of 15.4 mmol/L (0.5%) bupivacaine hydrochloride solution intrathecally to rats. The neurologic deficit was evaluated by antinociceptive, motor, and proprioceptive responses, and the spinal cord was examined for histopathologic changes. Results: Doses of 100 muL amitriptyline at 15.9 mmol/L (0.5%) and 25 mmol/L produced longer complete nerve block than did bupivacaine at 15.4 mmol/L (0.5%); 5 and 10 mmol/L amitriptyline produced only partial nerve block. However, with 100 muL intrathecal amitriptyline at 50 and 100 mmol/L, many rats did not fully recover from spinal block. Severe axonal degeneration, myelin breakdown, and replacement of neuronal structures by vacuoles were seen in the spinal root section of animals injected with concentrations higher than 25 mmol/L amitriptyline. Conclusions: At lower doses, intrathecal injection of high volumes of amitriptyline results in long-acting spinal block. At higher doses, intrathecal amitriptyline results in irreversible neurologic deficit. Therefore, we do not recommend the use of intrathecal amitriptyline because of a very low therapeutic index. C1 Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Desai, SP (reprint author), Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, 75 Francis St, Boston, MA 02115 USA. EM sdesai@partners.org OI Anthony, Douglas/0000-0002-3815-2240 FU NIGMS NIH HHS [GM48090, GM35401] NR 24 TC 29 Z9 30 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 1098-7339 J9 REGION ANESTH PAIN M JI Region. Anesth. Pain Med. PD SEP-OCT PY 2004 VL 29 IS 5 BP 434 EP 440 DI 10.1016/j.rapm.2004.06.008 PG 7 WC Anesthesiology SC Anesthesiology GA 856WF UT WOS:000224075400008 PM 15372388 ER PT J AU Preutthipan, S Chen, SH Tilly, JL Kugu, K Lareu, RR Dharmarajan, AM AF Preutthipan, S Chen, SH Tilly, JL Kugu, K Lareu, RR Dharmarajan, AM TI Inhibition of nitric oxide synthesis potentiates apoptosis in the rabbit corpus luteum SO REPRODUCTIVE BIOMEDICINE ONLINE LA English DT Article DE apoptosis; corpus luteum; nitric oxide; progesterone; rabbit ID PROGRAMMED CELL-DEATH; CORPORA-LUTEA; CHORIONIC-GONADOTROPIN; PSEUDOPREGNANT RABBITS; MATERNAL RECOGNITION; DNA FRAGMENTATION; OVULATORY PROCESS; RELAXING FACTOR; BLOOD-FLOW; RAT AB To determine if nitric oxide (NO) plays a role in corpus luteum (CL) physiology by affecting progesterone secretion or luteal apoptosis, an in-vitro pseudopregnant rabbit ovarian perfusion system was used to measure the effects of an inhibitor of NO synthesis, N-G-nitro-L-arginine methyl ester (L-NAME), on progesterone secretion and corpus luteal apoptosis as measured by internucleosomal DNA breakdown. Pseudopregnant rabbit ovaries perfused in vitro with L-NAME did not demonstrate any significant differences compared with control ovaries in progesterone secretion. However, apoptosis, as measured by internucleosomal breakdown, was significantly increased in L-NAME-perfused CL compared with controls. While NO does not appear to directly affect progesterone secretion, there does appear to be a role for NO in CL maintenance, or a role for inhibition of NO production in CL regression. C1 Johns Hopkins Univ, Sch Med, Dept Gynecol & Obstet, Baltimore, MD 21205 USA. Mahidol Univ, Ramathibodi Hosp, Dept Obstet & Gynecol, Bangkok 10400, Thailand. St Barnabas Hosp, Dept Obstet & Gynecol, Livingston, NJ 07039 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Ob Gyn,Vincent Ctr Reprod Biol, Boston, MA 02114 USA. Univ Tokyo, Fac Med, Dept Obstet Gynecol, Bunkyo Ku, Tokyo 113, Japan. Univ Western Australia, Sch Anat & Human Biol, Crawley, WA 6009, Australia. RP Dharmarajan, AM (reprint author), Johns Hopkins Univ, Sch Med, Dept Gynecol & Obstet, Baltimore, MD 21205 USA. EM dharma@anhb.uwa.edu.au RI Lareu, Ricky/D-2713-2011 FU NICHD NIH HHS [HD-19430] NR 49 TC 7 Z9 8 U1 0 U2 0 PU REPRODUCTIVE HEALTHCARE LTD PI CAMBRIDGE PA DUCK END FARM, DRY DRAYTON, CAMBRIDGE, CB3 8DB, ENGLAND SN 1472-6483 J9 REPROD BIOMED ONLINE JI Reprod. Biomed. Online PD SEP PY 2004 VL 9 IS 3 BP 264 EP 270 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 888QG UT WOS:000226388700004 PM 15353073 ER PT J AU Zeggini, E Reginato, AM Prais, A Thomson, W McLean, W Donn, R AF Zeggini, E Reginato, AM Prais, A Thomson, W McLean, W Donn, R CA BPRG Study Grp TI Linkage and association studies of discoidin domain receptor 1 (DDR1) single nucleotide polymorphisms (SNPs) in juvenile oligoarthritis SO RHEUMATOLOGY LA English DT Article DE juvenile oligoarthritis; DDR1; MHC; linkage; association; SNP; haplotype ID RHEUMATOID-ARTHRITIS; TRANSMISSION/DISEQUILIBRIUM TEST; IDIOPATHIC ARTHRITIS; GENETIC DISSECTION; HLA-A; HAPLOTYPES; COLLAGEN; REGION; LOCI; MHC AB Objectives. Multiple independent juvenile oligoarthritis susceptibility loci have been identified within the major histocompatibility complex (MHC), including HLA-A, HLA-DRB1 and an as yet unlocalized effect in the centromeric class I region. The discoidin domain receptor 1 (DDR1) gene resides within this region and codes for a receptor tyrosine kinase that plays an important role in regulating cell attachment to collagen, chemotaxis, proliferation and matrix metalloproteinase (MMP) production. DDR1 expression in chondrocytes has not been investigated. The objectives of this study were to investigate expression of DDR1 in healthy chondrocytes and to identify linkage and association of this candidate gene with juvenile oligoarthritis. Methods. A set of 135 simplex juvenile idiopathic arthritis families consisting of one affected child and healthy parent(s) and 199 healthy unrelated individuals were genotyped for six single nucleotide polymorphisms (SNPs) within the DDR1 gene using the primer extension SNaPshot(TM) method. Single-point and multipoint transmission disequilibrium tests were carried out with the ETDT and TDTPHASE packages. Allele frequency comparisons between cases and controls were carried out with the chi(2) test. DDR1 expression was investigated in normal articular cartilage by RT-PCR and immunofluorescence methods. Results. No linkage and association with any of the six SNPs or their haplotypic combinations were observed in the families studied. No significant differences were observed in allele frequencies between patients and controls. DDR1 expression was found in normal articular cartilage by RT-PCR and by immunofluorescence. Conclusions. The DDR1 SNPs examined are not involved in susceptibility to juvenile oligoarthritis. C1 Univ Manchester, CIGMR, Manchester, Lancs, England. Univ Manchester, ARC Epidemiol Unit, Manchester, Lancs, England. Univ Manchester, Sch Biol Sci, Manchester, Lancs, England. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. Massachusetts Gen Hosp, Dept Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Univ Oxford, WTCHG, Roosevelt Rd, Oxford OX3 7BN, England. EM elez@well.ox.ac.uk OI Zeggini, Eleftheria/0000-0003-4238-659X; Herrick, Ariane/0000-0003-4941-7926; Thomson, Wendy/0000-0002-9022-5179; Donn, Rachelle/0000-0001-6976-9828 NR 20 TC 4 Z9 5 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 EI 1462-0332 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD SEP PY 2004 VL 43 IS 9 BP 1138 EP 1141 DI 10.1093/rheumatology/keh261 PG 4 WC Rheumatology SC Rheumatology GA 850CK UT WOS:000223588600012 PM 15213330 ER PT J AU Schneider, A Barmada, MM Slivka, A Martin, JA Whitcomb, DC AF Schneider, A Barmada, MM Slivka, A Martin, JA Whitcomb, DC TI Clinical characterization of patients with idiopathic chronic pancreatitis and SPINK1 mutations SO SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID SERINE-PROTEASE INHIBITOR; KAZAL TYPE-1; DISEASE C1 Univ Pittsburgh, VA Pittsburgh Hlth Care Syst, Dept Med, Pittsburgh, PA 15101 USA. Univ Pittsburgh, VA Pittsburgh Hlth Care Syst, Dept Human Genet, Pittsburgh, PA 15101 USA. Univ Pittsburgh, VA Pittsburgh Hlth Care Syst, Dept Cell Biol & Physiol, Pittsburgh, PA 15101 USA. Univ Pittsburgh, Ctr Genome Sci, Pittsburgh, PA 15101 USA. RP Whitcomb, DC (reprint author), Univ Pittsburgh, VA Pittsburgh Hlth Care Syst, Dept Med, 571 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15101 USA. EM whitcomb@pitt.edu OI Barmada, M Michael/0000-0002-3604-6460 NR 5 TC 17 Z9 17 U1 1 U2 1 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0036-5521 J9 SCAND J GASTROENTERO JI Scand. J. Gastroenterol. PD SEP PY 2004 VL 39 IS 9 BP 903 EP 904 DI 10.1080/00365520410006710 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 854NL UT WOS:000223910500016 PM 15513391 ER PT J AU Mitropoulou, V Goodman, M Sevy, S Elman, I New, AS Iskander, EG Silverman, JM Breier, A Siever, LJ AF Mitropoulou, V Goodman, M Sevy, S Elman, I New, AS Iskander, EG Silverman, JM Breier, A Siever, LJ TI Effects of acute metabolic stress on the dopaminergic and pituitary-adrenal axis activity in patients with schizotypal personality disorder SO SCHIZOPHRENIA RESEARCH LA English DT Article DE 2-DG; schizophrenia spectrum; HPA; dopamine; glycopyruvic ID PREFRONTAL CORTEX; SCHIZOPHRENIA; VOLUNTEERS; FEATURES AB Background: Stress has been associated with the onset of schizophrenia and exacerbation of psychotic symptoms. Patients with schizotypal personality disorder (SPD), the prototypic schizophrenia spectrum disorder, do not develop the frank psychosis of schizophrenia and appear clinically to be less reactive to stress than schizophrenic patients. Schizophrenic patients demonstrate increased dopaminergic (DA) and hypothalamic-pituitary-adrenal-axis (HPA) activation following 2-deoxyglucose (2-DG), an acute metabolic (glycopyruvic) stressor, compared to healthy volunteers (HV). We hypothesized that SPD patients would demonstrate comparable or lower DA and HPA responses after 2-DG to HV. Methods: Fifteen SPD patients and 13 HV were administered 2-DG (40 mg/kg, i.v.) in a double-blind, placebo-controlled, randomized protocol. The area under the curve (AUC) was determined for plasma HVA, ACTH and cortisol (utilizing baseline and post infusion indices). Results: 2-DG induced significant increases in ACTH, cortisol and HVA concentrations in both groups and cortisol elevations were significantly lower in patients with SPD, than in HV. Conclusions: Patients with SPD have a blunted cortisol and a normal dopaminergic response to 2-DG. These results are consistent with the hypothesis that SPD patients are better buffered against DA and HPA overactivation in response to stress. (C) 2003 Elsevier B.V. All rights reserved. C1 CUNY Mt Sinai Sch Med, Clin Res Ctr, Dept Psychiat, New York, NY 10029 USA. Vet Adm Med Ctr, Bronx, NY 10468 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Mitropoulou, V (reprint author), CUNY Mt Sinai Sch Med, Clin Res Ctr, Dept Psychiat, 1 Gustave Levy Pl,Box 1027, New York, NY 10029 USA. EM vivian.mitropoulou@mssm.edu FU NCRR NIH HHS [M01-RR-00071]; NIMH NIH HHS [R01-MH 56140] NR 24 TC 22 Z9 22 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP 1 PY 2004 VL 70 IS 1 BP 27 EP 31 DI 10.1016/j.schres.2003.10.008 PG 5 WC Psychiatry SC Psychiatry GA 841VD UT WOS:000222958800003 PM 15246460 ER PT J AU Shaner, A Miller, G Mintz, J AF Shaner, A Miller, G Mintz, J TI Schizophrenia as one extreme of a sexually selected fitness indicator SO SCHIZOPHRENIA RESEARCH LA English DT Article DE schizophrenia; genetics; evolution; sexual selection; mate choice; fitness indicator ID MATE CHOICE; LEK PARADOX; GENETIC EPIDEMIOLOGY; REPRODUCTIVE RATES; ELABORATE TRAINS; MENSTRUAL-CYCLE; EVOLUTION; PSYCHOSIS; RESOLUTION; DISORDER AB Schizophrenia remains an evolutionary paradox. Its delusions, hallucinations and other symptoms begin in adolescence or early adulthood and so devastate sexual relationships and reproductive success that selection should have eliminated the disorder long ago. Yet it persists as a moderately heritable disorder at a global 1% prevalence-too high for new mutations at a few genetic loci. We suggest that schizophrenia persists and involves many loci because it is the unattractive, low-fitness extreme of a highly variable mental trait that evolved as a fitness ("good genes") indicator through mutual mate choice. Here we show that this hypothesis explains many key features of schizophrenia and predicts that some families carry modifier alleles that increase the indicator's neurodevelopmental sensitivity to heritable fitness and condition. Such alleles increase the extent to which high-fitness family members develop impressive courtship abilities and achieve high reproductive success, but also increase the extent to which low-fitness family members develop schizophrenia. Here we introduce this fitness indicator model of schizophrenia, discuss its explanatory power, explain how it resolves the evolutionary paradox, discuss its implications for gene hunting, and identify some empirically testable predictions as directions for further research. (C) 2003 Elsevier B.V. All rights reserved. C1 Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. RP Shaner, A (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM Andrew.Shaner@med.va.gov; gfmiller@unm.edu RI Miller, Geoffrey/C-4145-2008 NR 68 TC 24 Z9 26 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP 1 PY 2004 VL 70 IS 1 BP 101 EP 109 DI 10.1016/j.schres.2003.09.014 PG 9 WC Psychiatry SC Psychiatry GA 841VD UT WOS:000222958800012 PM 15246469 ER PT J AU Kraut, JA Madias, NE AF Kraut, JA Madias, NE TI What unique acid-base considerations exist in dialysis patients? SO SEMINARS IN DIALYSIS LA English DT Editorial Material ID HEMODIALYSIS-PATIENTS; METABOLIC-ACIDOSIS; POTASSIUM BICARBONATE; POSTMENOPAUSAL WOMEN; RENAL-DISEASE; BALANCE; INCREASES; ALBUMIN; RISK C1 Univ Calif Los Angeles, Sch Med, VA Greater Los Angeles Hlth Care Syst, Nephrol Sect 691 111L, Los Angeles, CA 90073 USA. Tufts Univ, Sch Med, Caritas St Elizabeths Med Ctr, Dept Med, Boston, MA 02111 USA. RP Kraut, JA (reprint author), Univ Calif Los Angeles, Sch Med, VA Greater Los Angeles Hlth Care Syst, Nephrol Sect 691 111L, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM jkraut@ucla.edu NR 20 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0894-0959 J9 SEMIN DIALYSIS JI Semin. Dial. PD SEP-OCT PY 2004 VL 17 IS 5 BP 358 EP 360 DI 10.1111/j.0894-0959.2004.17344.x PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 856TK UT WOS:000224067700009 ER PT J AU Roy-Byrne, P Arguelles, L Vitek, ME Goldberg, J Keane, TM True, WR Pitman, RK AF Roy-Byrne, P Arguelles, L Vitek, ME Goldberg, J Keane, TM True, WR Pitman, RK TI Persistence and change of PTSD symptomatology - A longitudinal co-twin control analysis of the Vietnam Era Twin Registry SO SOCIAL PSYCHIATRY AND PSYCHIATRIC EPIDEMIOLOGY LA English DT Article DE PTSD; genetics; twins; combat ID POSTTRAUMATIC-STRESS-DISORDER; RISK-FACTORS; URBAN-POPULATION; COMBAT EXPOSURE; YOUNG-ADULTS; PREDICTORS; CHRONICITY; RESPONSES; LIABILITY; VETERANS AB Introduction Previous twin studies have demonstrated a strong association between the degree of combat exposure and PTSD, and the continued presence of PTSD, almost two decades after combat. Independent genetic effects have also been demonstrated for both combat exposure and PTSD vulnerability in Vietnam veterans. The current study, involving a subset of male-male twin pairs discordant for service in Southeast Asia (SEA), is a follow-up to an earlier study conducted in 1987. The purpose of this study is to examine the changes in the combat exposure-PTSD relationship over an additional decade of time. Methods The Mississippi Scale for Combat-Related or Civilian PTSD was administered by telephone in 1997 during a follow-up survey of the Vietnam Era Twin Registry. Only twins discordant for service in Southeast Asia who originally participated in the 1987 study were included. Results of this scale and the original 1987 PTSD symptom scale were separately standardized using z-score transformations and used as dependent variables in a random effects regression model with zygosity, time and combat exposure as independent variables. Main effects and interactions were estimated to address whether there were differential effects of combat on PTSD over time, and whether there was evidence of genetic covariation between combat exposure and PTSD in 1987 that persisted to 1997. Results Combat exposure was strongly associated with PTSD in both 1987 and 1997. Although still highly significant, the effect sharply diminished over time. There is little evidence for a shared genetic vulnerability between combat and PTSD in either 1987 or 1997. Conclusion This analysis documents the continuing role of combat exposure (i.e., trauma severity) on the persistence and chronicity of PTSD. Nearly 25 years after the end of hostilities, PTSD symptoms continue to be elevated in those exposed to the highest levels of combat. There is no evidence that genetic influences on exposure to combat are shared with those inducing a genetic vulnerability to PTSD. Clinicians need to be aware of the persistent and long-term residual effects of trauma exposure C1 VAPSHCS, Seattle ERIC VET Registry MS 152E, Seattle, WA 98108 USA. Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. Univ Illinois, Epidemiol Biostat Div, Chicago, IL USA. VA Cooperat Studies Program Coordinating Ctr, Hines, IL USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. VAMC, Psychol Serv, Boston, MA USA. St Louis Univ, Hlth Sci Ctr, Sch Publ Hlth, St Louis, MO 63103 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Goldberg, J (reprint author), VAPSHCS, Seattle ERIC VET Registry MS 152E, 1660 S Columbian Way, Seattle, WA 98108 USA. EM goldie1@u.washington.edu FU NIMH NIH HHS [R01MH054636] NR 26 TC 18 Z9 19 U1 2 U2 3 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PO BOX 10 04 62, D-64204 DARMSTADT, GERMANY SN 0933-7954 J9 SOC PSYCH PSYCH EPID JI Soc. Psychiatry Psychiatr. Epidemiol. PD SEP PY 2004 VL 39 IS 9 BP 681 EP 685 DI 10.1007/s00127-004-0810-0 PG 5 WC Psychiatry SC Psychiatry GA 860ZT UT WOS:000224386600001 PM 15672287 ER PT J AU Beninato, M O'Kane, KS Sullivan, PE AF Beninato, M O'Kane, KS Sullivan, PE TI Relationship between motor FIM and muscle strength in lower cervical-level spinal cord injuries SO SPINAL CORD LA English DT Article DE functional independence measure; manual muscle test; impairments; rehabilitation; spinal cord injury; tetraplegia ID FUNCTIONAL INDEPENDENCE MEASURE; QUADRIPLEGIA INDEX; REHABILITATION OUTCOMES; TRAUMATIC QUADRIPLEGIA; NEUROLOGICAL LEVEL; FUNCTION QIF; RECOVERY; RELIABILITY; TETRAPLEGIA; SENSITIVITY AB Study design: Retrospective analysis. Objectives: The objectives of this research were to, in subjects with lower cervical spinal cord injury (SCI), examine the relationship between strength of muscle groups as measured by the manual muscle test (MMT) and function (reflected as burden of care) as measured by individual functional independence measure (FIM) motor tasks, and investigate the extent to which MMT scores explain the variance of the motor FIM scores. Setting: Acute rehabilitation hospitals, Boston, MA, USA. Methods: Retrospective pilot study of 20 in-patients, age 18 - 62 years, with an SCI between C5 and C7. Discharge demographic variables, MMT and motor FIM scores were analyzed. Descriptive statistics, Spearman's rank correlation coefficients, stepwise regressions were performed. Results: MMT scores for elbow flexion followed by shoulder flexion and wrist extension correlated with the greatest number of FIM tasks. MMT scores explained some part of the variance in the eight of 12 motor FIM tasks. In six of eight tasks, one key muscle explained a large portion of the variance. Conclusion: Key muscles relative to FIM tasks can be identified. These findings may help focus therapeutic interventions aimed at achievement in these tasks. C1 Massachusetts Gen Hosp, Inst Hlth Profess, Grad Programs Phys Therapy, Boston, MA 02129 USA. Visiting Nurses Assoc Greater Salem, Partners Home Care, Beverly, MA USA. RP Beninato, M (reprint author), Massachusetts Gen Hosp, Inst Hlth Profess, Grad Programs Phys Therapy, Charlestown Navy Yard,36 1st Ave, Boston, MA 02129 USA. NR 45 TC 15 Z9 17 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1362-4393 J9 SPINAL CORD JI Spinal Cord PD SEP PY 2004 VL 42 IS 9 BP 533 EP 540 DI 10.1038/sj.sc.3101635 PG 8 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 851CT UT WOS:000223663700005 PM 15224086 ER PT J AU Atochin, DN Murciano, JC Gursoy-Ozdemir, Y Krasik, T Noda, F Ayata, C Dunn, AK Moskowitz, MA Huang, PL Muzykantov, VR AF Atochin, DN Murciano, JC Gursoy-Ozdemir, Y Krasik, T Noda, F Ayata, C Dunn, AK Moskowitz, MA Huang, PL Muzykantov, VR TI Mouse model of microembolic stroke and reperfusion SO STROKE LA English DT Article DE animal models; fibrinolysis; microemboli; stroke; stroke, embolic ID FOCAL CEREBRAL-ISCHEMIA; TPA-DEFICIENT MICE; PLASMINOGEN-ACTIVATOR; ARTERY OCCLUSION; WILD-TYPE; INJURY; DAMAGE; RAT AB Background and Purpose - To test the role of fibrinolysis in stroke, we used a mouse model in which preformed 2.5- to 3-mum-diameter fibrin microemboli are injected into the cerebral circulation. The microemboli lodge in the downstream precapillary vasculature and are susceptible to fibrinolysis. Methods - We injected various doses of microemboli into the internal carotid artery in mice and characterized their distribution, effects on cerebral blood flow, neurological deficit, infarct area, and spontaneous dissolution. By comparing wild-type and tissue plasminogen activator (tPA) knockout (tPA(-/-)) mice, we analyzed the role of endogenous tPA in acute thrombotic stroke. Results - Microemboli cause dose-dependent brain injury. Although moderate doses of microemboli are followed by spontaneous reperfusion, they result in reproducible injury. Gene knockout of tPA markedly delays dissolution of cerebral emboli and restoration of blood flow and aggravates ischemic thrombotic infarction in the brain. Conclusions - We describe a microembolic model of stroke, in which degree of injury can be controlled by the dose of microemboli injected. Unlike vessel occlusion models, this model can be modulated to allow spontaneous fibrinolysis. Application to tPA(-/-) mice supports a key role of endogenous tPA in restoring cerebral blood flow and limiting infarct size after thrombosis. C1 Massachusetts Gen Hosp, Div Cardiol, Charlestown, MA USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. Massachusetts Gen Hosp, Dept Radiol, Stroke & Neurovasc Regulat Lab, Charlestown, MA USA. Massachusetts Gen Hosp, Athinoula A Martinos Ctr, Charlestown, MA USA. Univ Penn, Sch Med, Inst Environm Med, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA. RP Huang, PL (reprint author), Massachusetts Gen Hosp E, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. EM phuang1@partners.org RI Moskowitz, Michael/D-9916-2011; Dunn, Andrew/I-9527-2014; Atochin, Dmitriy/Q-3150-2016 FU NHLBI NIH HHS [R01-HL66442]; NINDS NIH HHS [P50-NS10828, R01-NS33335] NR 17 TC 27 Z9 35 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD SEP PY 2004 VL 35 IS 9 BP 2177 EP 2182 DI 10.1161/01.STR.0000137412.35700.0e PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 849KH UT WOS:000223537000034 PM 15256680 ER PT J AU Matros, E Wang, ZGC Richardson, AL Iglehart, JD AF Matros, E Wang, ZGC Richardson, AL Iglehart, JD TI Genomic approaches in cancer biology SO SURGERY LA English DT Editorial Material ID GENE-EXPRESSION PROFILES; HUMAN BREAST-CANCER; SOLID TUMORS; HETEROZYGOSITY; HYBRIDIZATION; PROGRESSION; PREDICTION; SUBCLASSES; SIGNATURE; PATTERNS C1 Dana Farber Canc Inst, Dept Surg, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA USA. RP Iglehart, JD (reprint author), Dana Farber Canc Inst, Dept Surg, 44 Binney St,Smith Bldg 822, Boston, MA 02115 USA. NR 28 TC 2 Z9 2 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0039-6060 J9 SURGERY JI Surgery PD SEP PY 2004 VL 136 IS 3 BP 511 EP 518 DI 10.1016/j.surg.2004.05.040 PG 8 WC Surgery SC Surgery GA 853RE UT WOS:000223844300004 PM 15349094 ER PT J AU Long, JA Gomez, A Asch, DA Shea, JA AF Long, JA Gomez, A Asch, DA Shea, JA TI Effect of race on ratings of hypothetical candidates for a research scholarship/research assistant position SO TEACHING AND LEARNING IN MEDICINE LA English DT Article; Proceedings Paper CT 26th Annual Meeting of the Society-of-General-Internal-Medicine CY APR 30-MAY 03, 2003 CL VANCOUVER, CANADA SP Soc Gen Internal Med ID MEDICAL-STUDENTS; CULTURAL COMPETENCE; CARE; AWARENESS; SCHOOL; SEX AB Background: Study of the racial-ethnic biases of medical students is necessary to further understand health disparities. The objectives of this study were to (a) determine if medical students exhibit racial biases, (b) assess whether there are differences in racial biases among medical students who have and have not received a curriculum in cultural sensitivity, and (c) determine if these findings vary by student race-ethnicity. Description: We evaluated medical students' preferences in hiring hypothetical candidates for a research scholarship and a research assistant position. Each student received a packet containing four curricula vitae (CVs) with attached photographs. Three CVs and photographs were identical. The fourth CV was identical, but in half the packets the photograph was of an African American man and in the other half of a White man. Students were asked to provide ratings of suitability. Evaluation: The African American candidate received better ratings than the White candidate. There were no differences in the ratings by student curriculum receipt or race-ethnicity. Conclusion: We found no evidence that an African American candidate was discriminated against by medical students. Teaching and Learning in Medicine, 16(4), 355-360 Copyright (C) 2004 by Lawrence Erlbaum Associates, Inc. C1 Univ Penn, Sch Med, Leonard Davis Inst Hlth Econ, Philadelphia VA Ctr Hlth Equ Res & Promot, Philadelphia, PA 19104 USA. Univ Penn, Sch Arts & Sci, Philadelphia, PA 19104 USA. RP Long, JA (reprint author), 1201 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19146 USA. EM jalon@mail.med.upenn.edu NR 31 TC 1 Z9 1 U1 4 U2 7 PU LAWRENCE ERLBAUM ASSOC INC PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430-2262 USA SN 1040-1334 J9 TEACH LEARN MED JI Teach. Learn. Med. PD FAL PY 2004 VL 16 IS 4 BP 355 EP 360 DI 10.1207/s15328015tlm1604_8 PG 6 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 868GG UT WOS:000224901500008 PM 15582872 ER PT J AU Johnson, TS Xu, JW Zaporojan, VV Mesa, JM Weinand, C Randolph, MA Bonassar, LJ Winograd, JM Yaremchuk, MJ AF Johnson, TS Xu, JW Zaporojan, VV Mesa, JM Weinand, C Randolph, MA Bonassar, LJ Winograd, JM Yaremchuk, MJ TI Integrative repair of cartilage with articular and nonarticular chondrocytes SO TISSUE ENGINEERING LA English DT Article; Proceedings Paper CT Annua Meeting of the New-England-Society-of-Plastic-and-Reconstructive-Surgeons CY MAY 30-JUN 01, 2003 CL Plymouth, MA SP New England Soc Plastic & Reconstruct Surg ID TISSUE-ENGINEERED CARTILAGE; PERIOSTEAL GRAFTS; EXPERIMENTAL-MODEL; FOLLOW-UP; DEFECTS; RECONSTRUCTION; DURABILITY; PHENOTYPE; POLYMER AB Articular chondrocytes can synthesize new cartilaginous matrix in vivo that forms functional bonds with native cartilage. Other sources of chondrocytes may have a similar ability to form new cartilage with healing capacity. This study evaluates the ability of various chondrocyte sources to produce new cartilaginous matrix in vivo and to form functional bonds with native cartilage. Disks of articular cartilage and articular, auricular, and costal chondrocytes were harvested from swine. Articular, auricular, or costal chondrocytes suspended in fibrin glue ( experimental), or fibrin glue alone ( control), were placed between disks of articular cartilage, forming trilayer constructs, and implanted subcutaneously into nude mice for 6 and 12 weeks. Specimens were evaluated for neocartilage production and integration into native cartilage with histological and biomechanical analysis. New matrix was formed in all experimental samples, consisting mostly of neocartilage integrating with the cartilage disks. Control samples developed fibrous tissue without evidence of neocartilage. Ultimate tensile strength values for experimental samples were significantly increased ( p < 0.05) from 6 to 12 weeks, and at 12 weeks they were significantly greater ( p < 0.05) than those of controls. We conclude that articular, auricular, and costal chondrocytes have a similar ability to produce new cartilaginous matrix in vivo that forms mechanically functional bonds with native cartilage. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Plast Surg,WACC 453, Boston, MA 02130 USA. Zhongshan Hosp, Dept Plast & Reconstruct Surg, Shanghai, Peoples R China. Fudan Univ, Shanghai 200433, Peoples R China. Univ Massachusetts, Med Ctr, Ctr Tissue Engn, Worcester, MA USA. Cornell Univ, Sibley Sch Mech & Aerosp Engn, Ithaca, NY 14853 USA. RP Randolph, MA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Plast Surg,WACC 453, 15 Parkman St, Boston, MA 02130 USA. EM mrandolph@partners.org RI Bonassar, Lawrence/C-2103-2016 OI Bonassar, Lawrence/0000-0003-1094-6433 NR 30 TC 45 Z9 46 U1 0 U2 3 PU MARY ANN LIEBERT INC PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1076-3279 J9 TISSUE ENG JI Tissue Eng. PD SEP PY 2004 VL 10 IS 9-10 BP 1308 EP 1315 DI 10.1089/1076327042500445 PG 8 WC Cell & Tissue Engineering SC Cell Biology GA 875CC UT WOS:000225396300002 PM 15588391 ER PT J AU Chaiswing, L Cole, MP St Clair, DK Ittarat, W Szweda, LI Oberley, TD AF Chaiswing, L Cole, MP St Clair, DK Ittarat, W Szweda, LI Oberley, TD TI Oxidative damage precedes nitrative damage in adriamycin-induced cardiac mitochondrial injury SO TOXICOLOGIC PATHOLOGY LA English DT Article DE adriamycin; 4-hydroxy-2-nonenal protein adducts; nitrotyrosine; reactive oxygen species; reactive nitrogen species; cardiac injury ID MANGANESE SUPEROXIDE-DISMUTASE; LIPID-PEROXIDATION PRODUCTS; NITRIC-OXIDE; SKELETAL-MUSCLE; TRANSGENIC MICE; 4-HYDROXY-2-NONENAL-MODIFIED PROTEINS; ANTHRACYCLINE ANTIBIOTICS; IMMUNOCHEMICAL DETECTION; PEROXYNITRITE FORMATION; ELECTRON-TRANSPORT AB The purpose of the present study was to determine if elevated reactive oxygen (ROS)/nitrogen species (RNS) reported to be present in adriamycin (ADR)-induced cardiotoxicity actually resulted in cardiomyocyte oxidative/nitrative damage, and to quantitatively determine the time course and subcellular localization of these postulated damage products using an in vivo approach. B6C3 mice were treated with a single dose of 20 mg/kg ADR. Ultrastructural damage and levels of 4-hydroxy-2-nonenal (4HNE)-protein adducts and 3-nitrotyrosine (3NT) were analyzed. Quantitative ultrastructural damage using computerized image techniques showed cardiomyocyte injury as early as 3 hours, with mitochondria being the most extensively and progressively injured subcellular organelle. Analysis of 4HNE protein adducts by immunogold electron microscopy showed appearance of 4HNE protein adducts in mitochondria as early as 3 hours, with a peak at 6 hours and subsequent decline at 24 hours. 3NT levels were significantly increased in all subcellular compartments at 6 hours and subsequently declined at 24 hours. Our data showed ADR induced 4HNE-protein adducts in mitochondria at the same time point as when mitochondrial injury initially appeared. These results document for the first time in vivo that mitochondrial oxidative damage precedes nitrative damage. The progressive nature of mitochondrial injury suggests that mitochondria, not other subcellular organelles, are the major site of intracellular injury. C1 William S Middleton Mem Vet Adm Med Ctr, Dept Pathol & Lab Med, Madison, WI 53705 USA. Univ Wisconsin, Sch Med, Madison, WI 53705 USA. Mahidol Univ, Fac Med Technol, Bangkok 10700, Thailand. Univ Kentucky, Dept Toxicol, Lexington, KY 40506 USA. Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 44106 USA. RP Oberley, TD (reprint author), William S Middleton Mem Vet Adm Med Ctr, Dept Pathol & Lab Med, Rm A-35,2500 Overlook Terrace, Madison, WI 53705 USA. EM dstc100@pop.uky.edu FU NCI NIH HHS [CA 49797, CA 59835]; NIDDK NIH HHS [T32DK07778] NR 64 TC 51 Z9 58 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD SEP-OCT PY 2004 VL 32 IS 5 BP 536 EP 547 DI 10.1080/01926230490502601 PG 12 WC Pathology; Toxicology SC Pathology; Toxicology GA 887GF UT WOS:000226293000006 PM 15605432 ER PT J AU Fehr, T Sykes, M AF Fehr, T Sykes, M TI Tolerance induction in clinical transplantation SO TRANSPLANT IMMUNOLOGY LA English DT Review DE tolerance; non-human primate; human; clinical; bone marrow transplantation ID BONE-MARROW-TRANSPLANTATION; TOTAL LYMPHOID IRRADIATION; RENAL-ALLOGRAFT RECIPIENTS; MIXED HEMATOPOIETIC CHIMERISM; STEM-CELL TRANSPLANTATION; REFRACTORY HEMATOLOGIC MALIGNANCIES; BRONCHIOLITIS OBLITERANS SYNDROME; ANTIGEN-SPECIFIC HYPOREACTIVITY; DOSE CYCLOSPORINE MONOTHERAPY; NONLETHAL PREPARATIVE REGIMEN AB Introduction of modern immunosuppressive agents has led to great success of allotransplantation in humans, and survival rates for all solid organs have been dramatically improved. However, a constant proportion of organs is lost every year due to chronic allograft rejection and immunosuppressive drug toxicity. This has led to a situation where, despite the donor organ shortage, about one third of the patients on the kidney transplant waiting list are listed for a retransplant. The induction of donor-specific tolerance has the potential of at least partially resolving this problem, since it might prevent chronic rejection and drug toxicity at the same time. For a variety of protocols, successful tolerance induction has been demonstrated in rodent models. However, translation of such protocols to large animal models and on clinical trials has turned out to be very difficult. This review briefly describes mechanisms and barriers to transplantation tolerance, and then focuses on pre-clinical and clinical studies in non-human primates and humans. We have divided the strategies into two groups, based on the principle mechanisms of tolerance induction: the first group are protocols not using hematopoietic stem cell transplantation (HCT) as part of there regimen. They rely mainly on intensive T cell depletion (either by total body irradiation, total lymphoid irradiation or treatment with T cell-depleting agents such as anti-thymocyte globulin, anti-CD52 antibody or CD3 immunotoxin), which have been combined with costimulatory blockade, signaling blockade or donor antigen infusion. The second group are HCT-based protocols combining HCT with T cell-depleting agents and cytoreductive treatment. So far, only two protocols (one with total lymphoid irradiation and anti-thymocyte globulin, but no HCT; one with HCT, cyclophosphamide, anti-thymocyte globulin and thymic irradiation) have been translated into successful human studies. We summarize and discuss the results of these trials and suggest goals for further studies for the development of tolerance protocols applicable for a broad population of allograft recipients. (C) 2004 Elsevier B.V. All rights reserved. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr,Bone Marrow Transplant, Boston, MA 02129 USA. RP Fehr, T (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr,Bone Marrow Transplant, MGH E CNY 149,13th St, Boston, MA 02129 USA. EM thomas.fehr@tbrc.mgh.harvard.edu FU NCI NIH HHS [R01 CA79989, R01 CA79986]; NHLBI NIH HHS [R01 HL49915, R01 HL6347] NR 119 TC 69 Z9 73 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0966-3274 J9 TRANSPL IMMUNOL JI Transpl. Immunol. PD SEP-OCT PY 2004 VL 13 IS 2 BP 117 EP 130 DI 10.1016/j.trim.2004.05.009 PG 14 WC Immunology; Transplantation SC Immunology; Transplantation GA 859QJ UT WOS:000224282700006 PM 15380542 ER PT J AU Levine, SS King, IFG Kingston, RE AF Levine, SS King, IFG Kingston, RE TI Division of labor in Polycomb group repression SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID HISTONE METHYLTRANSFERASE ACTIVITY; IMPRINTED X-INACTIVATION; H3 LYSINE-27 METHYLATION; DROSOPHILA-ZESTE PROTEIN; GROUP-COMPLEXES; GENE-EXPRESSION; DNA-BINDING; GAGA FACTOR; TRANSCRIPTIONAL REPRESSION; SELF-ASSOCIATION AB The epigenetic maintenance of gene expression patterns is essential for developing and maintaining the diverse types of cell that cooperate to form the larger organism. Recent data suggest that proteins of the Polycomb group (PcG) use a combination of posttranslational modifications and structural changes to the underlying chromatin structure to maintain silenced epigenetic states. We are now beginning to understand the mechanisms by which the PcG proteins are able to silence genes and to maintain this silencing over many cell divisions. C1 Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Kingston, RE (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM kingston@frodo.mgh.harvard.edu NR 80 TC 171 Z9 175 U1 0 U2 8 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD SEP PY 2004 VL 29 IS 9 BP 478 EP 485 DI 10.1016/j.tibs.2004.07.007 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 856LB UT WOS:000224045600006 PM 15337121 ER PT J AU Bajetta, E Vercammen, E Reinhardt, U Janmohamed, R da Costa, RM Matulonis, U Guastalla, JP AF Bajetta, E Vercammen, E Reinhardt, U Janmohamed, R da Costa, RM Matulonis, U Guastalla, JP CA Epoetin Alfa Study Grp TI Efficacy of epoetin alfa in a retrospective non-stratified subgroup analysis of a breast cancer cohort receiving non-platinum chemotherapy SO TUMORI LA English DT Article DE anemia; breast cancer; epoetin alfa; non-platinum chemotherapy; quality of life ID QUALITY-OF-LIFE; RECOMBINANT-HUMAN-ERYTHROPOIETIN; PLACEBO-CONTROLLED TRIAL; CELL LUNG-CANCER; ADJUVANT CHEMOTHERAPY; DOUBLE-BLIND; TRANSFUSION REQUIREMENTS; COMMUNITY ONCOLOGY; HEMOGLOBIN LEVEL; MULTIPLE-MYELOMA AB Aims and background: More than 60% of patients with metastatic breast cancer receiving non-platinum-based chemotherapy experience anemia, which is associated with fatigue and impaired quality of life. Epoetin alfa treatment in patients with a variety of malignancies has been shown to decrease transfusion requirements and improve hemoglobin levels and quality-of-life efficacy parameters. Patients: Retrospective subgroup analyses were performed in patients with breast cancer who were part of a multinational, randomized (2 : 1), double-blind, placebo-controlled trial of anemic cancer patients (n = 375) undergoing non-platinum-based chemotherapy. Results: In the breast cancer subpopulation (n = 114, 48% with stage IV disease at baseline), the hemoglobin increase was greater for epoetin alfa patients than placebo patients (2.3 versus 0.9 g/dL). Epoetin alfa patients had lower transfusion requirements (28.2% versus 33.3%), improvement or preservation versus deterioration of quality of life, and a higher proportion of responders (patients achieving a greater than or equal to2 g/dL increase in hemoglobin levels unrelated to transfusion) (68.0% versus 22.9% for placebo). The results were similar to those observed in the full study cohort, where statistical analyses showed the differences to be significant (P < 0.05 for all). Epoetin alfa treatment was well tolerated. Although the study was not designed or powered for survival as an endpoint, Kaplan-Meier estimates for the full cohort showed a trend in overall survival favoring epoetin alfa treatment (P = 0.13, log rank test); a similar benefit was seen in the breast cancer subpopulation. Conclusions: In the full study cohort and the breast cancer subpopulation, epoetin alfa effectively treated anemia (increased hemoglobin levels and decreased transfusion requirements) and improved or preserved quality of life. Results concerning potential survival benefits support further study of epoetin alfa in anemic cancer patients. C1 Ist Nazl Studio & Cura Tumori, Med Oncol Unit 2, I-20133 Milan, Italy. Klinikum Bayreuth, Bayreuth, Germany. Hillingdon Hosp, Uxbridge, Middx, England. Hosp Distrital Leiria, Leiria, Portugal. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Bajetta, E (reprint author), Ist Nazl Studio & Cura Tumori, Med Oncol Unit 2, Via Venezian 1, I-20133 Milan, Italy. EM emilio.bajetta@istitutotumori.mi.it NR 34 TC 2 Z9 2 U1 0 U2 1 PU PENSIERO SCIENTIFICO EDITOR PI ROME PA VIA PANAMA 48, 00198 ROME, ITALY SN 0300-8916 J9 TUMORI JI Tumori PD SEP-OCT PY 2004 VL 90 IS 5 BP 449 EP 457 PG 9 WC Oncology SC Oncology GA 874HJ UT WOS:000225341200001 PM 15656327 ER PT J AU Kaufman, DS Carducci, MA Kuzel, TM Todd, MB Oh, WK Smith, MR Ye, ZS Nicol, SJ Stadle, WM AF Kaufman, DS Carducci, MA Kuzel, TM Todd, MB Oh, WK Smith, MR Ye, ZS Nicol, SJ Stadle, WM TI A multi-institutional phase II trial of gemcitabine plus paclitaxel in patients with locally advanced or metastatic urothelial cancer SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE urothelial cancer; bladder cancer; clinical trial; gemcitabine; paclitaxel ID TRANSITIONAL-CELL CARCINOMA; LONG-TERM SURVIVAL; CISPLATIN; CHEMOTHERAPY; METHOTREXATE; DOXORUBICIN; VINBLASTINE; THERAPY; COMBINATION; REGIMEN AB The purpose of the study was to evaluate response and survival in patients with metastatic urothelial cancer treated with combination gemcitabine and paclitaxel administered on a biweekly schedule at doses of 3000 mg/m(2) and 150 mg/m(2), respectively. Patients with adequate organ function and performance status were accrued through 7 institutions, stratified by prior therapy status, and treated as noted. Response was evaluated by 1979 bi-dimensional World Health Organization (WHO) criteria. Of 55 eligible patients, 17 had a partial and 5 had a complete response rate for an overall response rate of 40% (27-54%). One complete response and one partial response were observed in the 6 previously treated patients. Overall median survival was 11.8 months (11.9 months in the chemonaive cohort). Grade 3 or 4 myelosuppression occurred in 56%, but only 4 serious infections were observed. We conclude that because of a lower than expected complete response rate. even when corrected for prognostic groupings, this regimen is not recommended for routine use in patients with metastatic urothelial cancer. Insufficient patients with poor renal function or prior therapy were accrued to reach conclusions regarding its utility in these subgroups. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Chicago, Chicago, IL 60637 USA. Lilly Res Labs, Indianapolis, IN USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Canc Inst New Jersey, New Brunswick, NJ USA. Northwestern Univ, Sch Med, Evanston, IL 60208 USA. Johns Hopkins Oncol Ctr, Baltimore, MD USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Stadle, WM (reprint author), Univ Chicago, Chicago, IL 60637 USA. EM wstadler@medicine.bsd.uchicago.edu RI Oh, William/B-9163-2012 OI Oh, William/0000-0001-5113-8147 NR 16 TC 40 Z9 41 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD SEP-OCT PY 2004 VL 22 IS 5 BP 393 EP 397 DI 10.1016/j.urolonc.2004.01.002 PG 5 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 863FW UT WOS:000224547400002 PM 15464919 ER PT J AU Siebert, U Bornschein, B Walbert, T Dodel, RC AF Siebert, U Bornschein, B Walbert, T Dodel, RC TI Systematic assessment of decision models in Parkinson's disease SO VALUE IN HEALTH LA English DT Article DE cost-effectiveness analysis; decision analysis; Parkinson's disease; systematic review ID QUALITY-OF-LIFE; COST-EFFECTIVENESS ANALYSIS; RANDOMIZED CONTROLLED-TRIAL; DEEP BRAIN-STIMULATION; SUBTHALAMIC NUCLEUS; MOTOR FLUCTUATIONS; DOPAMINE AGONISTS; ECONOMIC-IMPACT; UNITED-STATES; LEVODOPA AB Objective: To give an insight into the structural and methodological approaches used in published decision-analytic models evaluating interventions in Parkinson's disease (PD) and to derive recommendations for future comprehensive PD decision models. Methods: A systematic literature review was performed to identify studies that evaluated PD interventions using mathematical decision models. Using a standardized assessment form, information on the study design, methodological framework, and data sources was extracted from each publication and systematically reported. Strengths and limitations were assessed. Results: We identified eight studies that used mathematical models to evaluate different pharmaceutical (n = 7) and surgical (n = 1) treatment options in PD. All models included economic evaluations. Modeling approaches comprised mathematical equations, decision trees, and Markov models with a time horizon ranging from 5 years to lifetime. All based progression on the evolution of clinical surrogate endpoints. Treatment effects were either modeled via reduction of symptomatic progression and/or initial symptomatic improvement or via reduction of adverse effect rates. No model is currently available that encompasses both the underlying biologic disease progression and the spectrum of all relevant complications and also links them to patient preferences and economic outcomes. Conclusions: Models have been successfully applied to evaluate PD treatments. However, currently available models have substantial limitations. We recommend that a comprehensive, generic, and flexible decision model for PD that can be applied to different treatment strategies should consider a large spectrum of clinically relevant outcomes and complications of the disease during a sufficiently long time horizon, include PD-specific mortality, systematically evaluate uncertainty including heterogeneity effects, and should be validated by independent data or other models. Approaches to model treatment effects included reduction of symptomatic progression, initial symptomatic improvement, or reduction of adverse effects. We believe that structural bias could be avoided if underlying disease progression and treatment effects on symptoms are modeled separately. C1 Univ Bonn, Dept Neurol, D-53105 Bonn, Germany. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. Harvard Univ, Sch Med, Inst Technol Assessment, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Harvard Ctr Risk Anal, Boston, MA 02115 USA. Univ Munich, Bavarian Publ Hlth Res & Coordinating Ctr, Inst Med Informat Biometry & Epidemiol, Munich, Germany. RP Dodel, RC (reprint author), Univ Bonn, Dept Neurol, Sigmund Freud Str 25, D-53105 Bonn, Germany. EM richard.dodel@ukb.uni-bonn.de NR 73 TC 14 Z9 14 U1 0 U2 2 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1098-3015 J9 VALUE HEALTH JI Value Health PD SEP-OCT PY 2004 VL 7 IS 5 BP 610 EP 626 DI 10.1111/j.1524-4733.2004.75012.x PG 17 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 852TQ UT WOS:000223779700012 PM 15367256 ER PT J AU Gerharz, EW McDougal, WS AF Gerharz, EW McDougal, WS TI Metabolic and functional consequences of urinary diversion through intestinal segments SO WORLD JOURNAL OF UROLOGY LA English DT Editorial Material C1 Univ Wurzburg, Sch Med, Dept Urol, D-97080 Wurzburg, Germany. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA USA. RP Gerharz, EW (reprint author), Univ Wurzburg, Sch Med, Dept Urol, Oberdurrbacher Str 6, D-97080 Wurzburg, Germany. EM Gerharz_E@klinik.uni-wuerzburg.de NR 5 TC 5 Z9 8 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0724-4983 J9 WORLD J UROL JI World J. Urol. PD SEP PY 2004 VL 22 IS 3 BP 155 EP 156 DI 10.1007/s00345-004-0428-6 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 868LR UT WOS:000224915600001 PM 15300392 ER PT J AU Tanrikut, C McDougal, WS AF Tanrikut, C McDougal, WS TI Acid-base and electrolyte disorders after urinary diversion SO WORLD JOURNAL OF UROLOGY LA English DT Article DE urinary diversion; urinary reservoir; neobladder; metabolic complications; metabolic acidosis ID CHRONIC METABOLIC ACIDOSIS; INTESTINAL SEGMENTS; HYPERAMMONEMIC ENCEPHALOPATHY; COMPLICATIONS; URETEROSIGMOIDOSTOMY; RECONSTRUCTION; HEMATURIA; TRANSPORT; STOMACH; DYSURIA AB The use of bowel in urologic reconstructive procedures may result in numerous short and long-term complications, including well-described acid-base and electrolyte disorders. Many of these metabolic alterations are influenced by how solute absorption occurs across the particular bowel segment chosen for reconstruction. Solute absorption is impacted by: (1) the segment of bowel used, (2) the surface area of bowel used, (3) the time of retention of urine, (4) the concentration of solutes in the urine, (5) renal function, and (6) the pH and osmolality of the urine. These factors affect the type and amount of solutes absorbed, as well as the severity of metabolic complications that develop. C1 Massachusetts Gen Hosp, Dept Urol GRB1102, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Tanrikut, C (reprint author), Massachusetts Gen Hosp, Dept Urol GRB1102, 55 Fruit St, Boston, MA 02114 USA. EM ctanrikut@partners.org NR 26 TC 17 Z9 18 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0724-4983 J9 WORLD J UROL JI World J. Urol. PD SEP PY 2004 VL 22 IS 3 BP 168 EP 171 DI 10.1007/s00345-004-0430-z PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 868LR UT WOS:000224915600003 PM 15290206 ER PT J AU Houser, SL Kuwaki, K Knosalla, C Dor, FJMF Gollackner, B Cheng, J Shimizu, A Schuurman, HJ Cooper, DKC AF Houser, SL Kuwaki, K Knosalla, C Dor, FJMF Gollackner, B Cheng, J Shimizu, A Schuurman, HJ Cooper, DKC TI Thrombotic microangiopathy and graft arteriopathy in pig hearts following transplantation into baboons SO XENOTRANSPLANTATION LA English DT Article DE baboons; hDAF pig; heart; thrombotic microangiopathy; xenotransplantation ID HUMORAL XENOGRAFT REJECTION; KIDNEY-TRANSPLANTATION; CARDIAC XENOGRAFT; ANTIBODIES; COAGULATION; ACTIVATION; DEPLETION; SURVIVAL; ORGAN AB Background: Acute humoral xenograft rejection (AHXR) is an immunologic barrier in pig-to-baboon organ transplantation (Tx). We report microvascular thrombosis and myocardial necrosis in a series of cardiac xenografts. Methods: Ten baboons underwent heterotopic heart Tx from pigs transgenic for human decay-accelerating factor. Recipients were treated with soluble Gal glycoconjugates and multiple immunosuppressive agents. Grafts were removed when palpable contractions stopped. Stained tissue sections from harvested grafts were analyzed by light and fluorescence microscopy. Results: Xenograft survival ranged from 4 to 139 (mean 37, median 27) days. Some histology was typical for AHXR (n = 4; median survival 22 days). Hemorrhage and edema were only focal in the longer-surviving grafts (n = 4, median survival 54 days). All grafts had multiple platelet-rich fibrin thrombi occluding myocardial vessels. Ischemic damage was manifested by contraction band necrosis in four grafts, myocytolysis in eight, coagulative necrosis in nine, and patchy myocyte dropout in all grafts. A notable paucity of interstitial mononuclear cells was observed in all grafts. Marked intimal thickening resembling that of allograft vasculopathy was observed in one graft. Immunofluorescence showed immunoglobulin (Ig)G and/or IgM deposition in five grafts. Multivessel C4d deposition appeared in seven grafts. Significant C3 deposition was absent. Conclusions: Cardiac xenograft survival in the pig-to-baboon model can be significantly prolonged by vigorous immunosuppressive treatment of recipient animals. Additional efforts to block humoral activation of graft endothelial cells and/or to overcome species-specific molecular coagulation pathway incompatibilities may prevent the development of microvascular thrombosis and myocardial infarction. Cardiac xenograft vasculopathy (chronic rejection) can occur with prolonged graft survival. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02114 USA. Immerge BioTherapeut, Cambridge, MA USA. RP Houser, SL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Warren 2,55 Fruit St,Warren 225, Boston, MA 02114 USA. EM houser.stuart@mgh.harvard.edu RI Dor, Frank/E-1032-2013 OI Dor, Frank/0000-0001-7845-3075 FU PHS HHS [1P01 A145897] NR 30 TC 81 Z9 83 U1 1 U2 2 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP PY 2004 VL 11 IS 5 BP 416 EP 425 DI 10.1111/j.1399-3089.2004.00155.x PG 10 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 845EE UT WOS:000223218000006 PM 15303978 ER PT J AU Brennan, FX Beck, KD Servatius, RJ AF Brennan, FX Beck, KD Servatius, RJ TI Proinflammatory cytokines differentially affect leverpress avoidance acquisition in rats SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE IL-1 beta; IL-6; TNF alpha; escape/avoidance conditioning ID NECROSIS-FACTOR-ALPHA; BEHAVIORAL VARIATIONS; CENTRAL MONOAMINE; IMMUNE-SYSTEM; INTERLEUKIN-1-BETA; MEMORY; PERFORMANCE; BRAIN; CORTICOSTERONE; HIPPOCAMPUS AB Recent evidence indicates that the pro-inflammatory cytokines (PICs) can affect learning and memory processes. To examine the effect of the PICs on leverpress escape/avoidance conditioning, we injected male Sprague-Dawley rats with IL-1beta, IL-6 (both 3.0 mug/kg, i.p.), TNFalpha (6.0 mug/kg, i.p.) or vehicle, 24 h before a single 4-h session of leverpress escape/avoidance conditioning. The TNFalpha-treated animals made more avoidance responses and fewer escape responses than controls during the last hour of the session. Further, both TNFalpha- and IL-1beta-treated animals had a higher percent avoidance than controls during the 4th hour of the session. None of the cytokines had an effect on the number of leverpresses during safety, a putative measure of anxiety. Results are discussed in terms of the differential central effects of the pro-inflammatory cytokines and the possible relationship to avoidance conditioning. (C) 2004 Elsevier B.V. All rights reserved. C1 Philadelphia VA Med Ctr, Med Res Serv 151, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. VA Med Ctr, Neurobehav Res Lab, E Orange, NJ 07018 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Neurosci, Newark, NJ 07103 USA. RP Brennan, FX (reprint author), Philadelphia VA Med Ctr, Med Res Serv 151, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM francis.brennan@med.va.gov NR 25 TC 21 Z9 22 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD AUG 31 PY 2004 VL 153 IS 2 BP 351 EP 355 DI 10.1016/j.bbr.2003.12.025 PG 5 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 845JX UT WOS:000223239800005 PM 15265629 ER PT J AU Lloyd-Jones, DM Wang, TJ Leip, EP Larson, MG Levy, D Vasan, RS D'Agostino, RB Massaro, JM Beiser, A Wolf, PA Benjamin, EJ AF Lloyd-Jones, DM Wang, TJ Leip, EP Larson, MG Levy, D Vasan, RS D'Agostino, RB Massaro, JM Beiser, A Wolf, PA Benjamin, EJ TI Lifetime risk for development of atrial fibrillation - The Framingham Heart Study SO CIRCULATION LA English DT Article DE atrial fibrillation; epidemiology; risk factors ID QUALITY-OF-LIFE; RHYTHM CONTROL; FOLLOW-UP; TRENDS; POPULATION; DISEASE; HYPERTENSION; PREVALENCE; COMMUNITY; FAILURE AB Background-Atrial fibrillation (AF) is the most common cardiac dysrhythmia and a source of considerable morbidity and mortality, but lifetime risk for AF has not been estimated. Methods and Results-We included all participants in the Framingham Heart Study who were free of AF at index ages of 40 years and older. We estimated lifetime risks for AF (including atrial flutter) to age 95 years, with death free of AF as a competing event. We followed 3999 men and 4726 women from 1968 to 1999 (176166 person-years); 936 participants had development of AF and 2621 died without prior AF. At age 40 years, lifetime risks for AF were 26.0% (95% CI, 24.0% to 27.0%) for men and 23.0% (21.0% to 24.0%) for women. Lifetime risks did not change substantially with increasing index age despite decreasing remaining years of life because AF incidence rose rapidly with advancing age. At age 80 years, lifetime risks for AF were 22.7% (20.1% to 24.1%) in men and 21.6% (19.3% to 22.7%) in women. In further analyses, counting only those who had development of AF without prior or concurrent congestive heart failure or myocardial infarction, lifetime risks for AF were approximately 16%. Conclusions-Lifetime risks for development of AF are 1 in 4 for men and women 40 years of age and older. Lifetime risks for AF are high (1 in 6), even in the absence of antecedent congestive heart failure or myocardial infarction. These substantial lifetime risks underscore the major public health burden posed by AF and the need for further investigation into predisposing conditions, preventive strategies, and more effective therapies. C1 Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. NHLBI, Framingham Heart Study, NIH, Framingham, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. Boston Univ, Sch Med, Dept Epidemiol & Prevent Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Cardiol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA 02118 USA. RP Lloyd-Jones, DM (reprint author), Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, 680 N Lake Shore Dr,Suite 1102, Chicago, IL 60611 USA. EM dlj@northwestern.edu RI Lloyd-Jones, Donald/C-5899-2009; OI Massaro, Joseph/0000-0002-2682-4812; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336; Beiser, Alexa/0000-0001-8551-7778 FU NHLBI NIH HHS [K23 HL04253, N01-HC-25195] NR 41 TC 820 Z9 874 U1 3 U2 29 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 31 PY 2004 VL 110 IS 9 BP 1042 EP 1046 DI 10.1161/01.CIR.0000140263.20897.42 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 850FD UT WOS:000223595700004 PM 15313941 ER PT J AU Bermejo, J Rojo-Alvarez, JL Antoranz, JC Abel, M Burwash, IG Yotti, R Moreno, M Garcia-Fernandez, MA Lehmann, KG Otto, CM AF Bermejo, J Rojo-Alvarez, JL Antoranz, JC Abel, M Burwash, IG Yotti, R Moreno, M Garcia-Fernandez, MA Lehmann, KG Otto, CM TI Estimation of the end of ejection in aortic stenosis - An unreported source of error in the invasive assessment of severity SO CIRCULATION LA English DT Article; Proceedings Paper CT Scientific Sessions of the American-Heart-Association CY NOV 11-14, 2001 CL Anaheim, CA SP Amer Heart Assoc DE valves; stenosis; catheterization; hemodynamics; animal experimentation ID LEFT-VENTRICULAR EJECTION; PRESSURE DIFFERENCE; VALVE; FLOW; GRADIENTS; DYNAMICS; CATHETER; RECOVERY; DISEASE; VOLUME AB Background-All indices of aortic stenosis (AS) rely on measurements of mean transvalvular pressure gradient ((&UDelta;P) over bar) and flow rate. Because the gradient is reversed during late ejection, the late systolic left ventricular (LV)-aortic pressure crossover may be an erroneous landmark of end-ejection. The aortic incisura should be a better reference to calculate indices of AS invasively. Methods and Results-The accuracy of the pressure crossover and the incisura to define end-ejection was assessed in a chronic AS experimental model (9 dogs) with the use of an implantable flowmeter and Doppler echocardiography as reference. In 288 hemodynamic recordings analyzed (aortic valve area [AVA]: 0.74+/-0.46 cm(2)), ejection ended 37+/-29 ms after the pressure crossover but almost simultaneously with the incisura (2+/-17 ms). Pressure crossover error accounted for significant errors in the measurement of (&UDelta;P) over bar (95% limits of agreement, +0 to +7 mm Hg) and AVA (-0.1 to +0.2 cm(2)). These errors were reduced to less than half with the use of the incisura to define end-ejection. Additionally, the agreement with Doppler-derived AS indices was best with use of the incisura. Pressure crossover error was maximal in situations of higher output, moderate orifice narrowing, higher arterial compliance, and lower vascular resistance. In 32 consecutive patients undergoing cardiac catheterization for AS, the pressure crossover induced a clinically important overestimation of the (&UDelta;P) over bar from +22 to +50%. Errors in AVA estimation were considerably smaller (-2% to +6%) because of simultaneous and offsetting errors in the measurements of (&UDelta;P) over bar and flow. Conclusions-The aortic incisura and not the second pressure crossover should be used to obtain invasive indices of AS. C1 Hosp Gen Gregorio Maranon, Lab Echocardiog, Dept Cardiol, Madrid 28007, Spain. Univ Carlos III Madrid, Dept Signal Theory & Commun, Madrid, Spain. Univ Nacl Educ Distancia, Dept Math Phys & Fluids, Fac Ciencias, E-28040 Madrid, Spain. Univ Washington, Div Cardiol, Sch Med, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. Providence Hlth Grp, Seattle, WA USA. Univ Ottawa, Inst Heart, Ottawa, ON, Canada. Univ Washington, Div Cardiol, Seattle, WA 98195 USA. RP Bermejo, J (reprint author), Hosp Gen Gregorio Maranon, Lab Echocardiog, Dept Cardiol, Dr Esquerdo 46, Madrid 28007, Spain. EM javbermejo@jet.es RI Antoranz, Carlos/A-5414-2009; OI Antoranz, Carlos/0000-0003-2925-3629; Garcia Fernandez, Miguel Angel/0000-0001-7010-0830; Otto, Catherine/0000-0002-0527-9392 NR 28 TC 15 Z9 15 U1 1 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 AUG 31 PY 2004 VL 110 IS 9 BP 1114 EP 1120 DI 10.1161/01.CIR.0000139846.66047.62 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 850FD UT WOS:000223595700015 PM 15326077 ER PT J AU Im, SH Rao, A AF Im, SH Rao, A TI Activation and deactivation of gene expression by Ca2+/calcineurin-NFAT-mediated signaling SO MOLECULES AND CELLS LA English DT Article DE AP-1; Ca2+/calcineurin; HDAC; MEF-2; nuclear factor of activated T cell (NFAT); T cell anergy ID TRANSCRIPTION FACTOR NFAT1; T-CELL DEVELOPMENT; MUSCLE FIBER-TYPE; T(H)2 DIFFERENTIATION; SELECTIVE-INHIBITION; DEFICIENT MICE; IMMUNE-SYSTEM; TH1 CELLS; NF-ATC; CALCINEURIN AB Ca2+/calcineurin-NFAT-mediated signaling pathways are involved in diverse cellular reactions by regulating gene expression either positively or negatively. The transcriptional activity of NFAT proteins can be either activating or deactivating depending on which binding partners are involved. Interaction of NFAT with AP-1 turns on the genes involved in active immune responses, while NFAT without cooperative binding of AP-1 turns on a T cell anergy program and blocks T cell activation and proliferation. In addition, interaction of NFAT with histone deacetylase (HDAC) proteins induces gene silencing. In this review we focus on the dual function, activator or deactivator, of NFAT and the binding partners that determine the role of NFAT in gene expression. C1 Gwangju Inst Sci & Technol, Dept Life Sci, Kwangju 500712, South Korea. Harvard Univ, Sch Med, CBR Inst Biomed Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Im, SH (reprint author), Gwangju Inst Sci & Technol, Dept Life Sci, Kwangju 500712, South Korea. EM imsh@gist.ac.kr RI Im, Sin-Hyeog/E-6811-2013 OI Im, Sin-Hyeog/0000-0002-3173-1856 FU NCI NIH HHS [R01-CA42471]; PHS HHS [R01-A148213] NR 69 TC 132 Z9 137 U1 1 U2 1 PU SPRINGER SINGAPORE PTE LTD PI SINGAPORE PA #04-01 CENCON I, 1 TANNERY RD, SINGAPORE 347719, SINGAPORE SN 1016-8478 J9 MOL CELLS JI Mol. Cells PD AUG 31 PY 2004 VL 18 IS 1 BP 1 EP 9 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 850YA UT WOS:000223649100001 PM 15359117 ER PT J AU McLean, PJ Klucken, J Shin, Y Hyman, BT AF McLean, PJ Klucken, J Shin, Y Hyman, BT TI Geldanamycin induces Hsp70 and prevents alpha-synuclein aggregation and toxicity in vitro SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Parkinson's disease; Lewy body; heat shock protein; protein folding; aggregation ID PARKINSONS-DISEASE; LEWY BODIES; CHAPERONE SUPPRESSION; SYNPHILIN-1; DROSOPHILA; INCLUSIONS; MUTATIONS; NEURONS; MODEL; FORM AB Geldanamycin (GA) is a naturally occurring benzoquinone ansamycin that induces heat shock protein 70 (Hsp70). GA has been shown to reduce alpha-synuclein induced neurotoxicity in a fly model of Parkinson's disease. We have previously shown that heat shock proteins can prevent a-synuclein aggregation and protect against alpha-synuclein induced toxicity in human H4 neuroglioma cells. Here, we hypothesize that GA treatment will reduce alpha-synuclein aggregation and prevent alpha-synuclein induced toxicity and we show that GA can induce Hsp70 in a time- and concentration-dependent manner in H4 cells. Pretreatment with 200 nM GA 24 h prior to transfection prevented alpha-synuclein aggregation and protected against toxicity. Treatment of cells with pre-existing inclusions with GA did not result in a reduction in the number of cells containing inclusions, suggesting that upregulation of Hsp70 is not sufficient to remove established inclusions. Similarly, Western blot analysis demonstrated that GA treatment could dramatically reduce both total of-synuclein and high molecular weight alpha-synuclein aggregates. Taken together, these data suggest that GA is effective in preventing alpha-synuclein aggregation and may represent a pharmacological intervention to therapeutically increase expression of molecular chaperone proteins to treat neurodegenerative diseases where aggregation is central to the pathogenesis. (C) 2004 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Dept Neurol, Charlestown, MA 02129 USA. RP McLean, PJ (reprint author), Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Dept Neurol, 114 16th St, Charlestown, MA 02129 USA. EM pmclean@partners.org NR 18 TC 96 Z9 103 U1 1 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 27 PY 2004 VL 321 IS 3 BP 665 EP 669 DI 10.1016/j.bbrc.2004.07.021 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 845XC UT WOS:000223277600021 PM 15358157 ER PT J AU Monticelli, S Solymar, DC Rao, A AF Monticelli, S Solymar, DC Rao, A TI Role of NFAT proteins in IL13 gene transcription in mast cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MUSCLE-SPECIFIC TRANSCRIPTION; EMBRYONIC STEM-CELLS; T-CELLS; FACTOR GATA-1; ERYTHROID-DIFFERENTIATION; HEMATOPOIETIC-CELLS; CYTOKINE PRODUCTION; IN-VIVO; EXPRESSION; IL-4 AB Th2 and mast cells are participants in the asthmatic response to allergens, and both cell types produce the cytokines interleukin (IL)-4 and IL-13. IL-13 in particular is both necessary and sufficient for experimental models of asthma. The transcription factor NFAT plays a central role in cytokine transcriptional regulation in both cell types. Here, we analyze the molecular basis of IL13 gene transcription in Th2 and mast cells. We show that NFAT1 is the major NFAT protein involved in regulating IL13 transcription in mast cells. Although NFAT2 is correctly expressed and regulated in mast cells, it does not contribute to IL13 gene transcription as shown by analysis of cells lacking NFAT2 and cells expressing a constitutively active version of NFAT2. The difference between NFAT1 and NFAT2 appears to be due to a preferential synergistic interaction of NFAT1 with GATA proteins at the IL13 promoter. We suggest that mast cells lack a co-activator protein that stabilizes the binding of NFAT2 to the IL13 promoter by interacting either with NFAT2 itself or with a DNA-bound complex of NFAT2 and GATA proteins. C1 Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. CBR Inst Biomed Res, Boston, MA 02115 USA. Univ Milan, Div Biotechnol Appl Med Sci, I-20133 Milan, Italy. Harvard Univ, Sch Med, Div Med Sci, Grad Program Immunol, Boston, MA 02115 USA. RP Rao, A (reprint author), Harvard Univ, Sch Med, Dept Pathol, Warren Alpert Bldg,Rm 152,200 Longwood Ave, Boston, MA 02115 USA. EM arao@cbr.med.harvard.edu FU NIAID NIH HHS [AI 44432] NR 61 TC 61 Z9 62 U1 1 U2 2 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 AUG 27 PY 2004 VL 279 IS 35 BP 36210 EP 36218 DI 10.1074/jbc.M406354200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 848FS UT WOS:000223453600008 PM 15229217 ER PT J AU Chaudhuri, J Khuong, C Alt, FW AF Chaudhuri, J Khuong, C Alt, FW TI Replication protein A interacts with AID to promote deamination of somatic hypermutation targets SO NATURE LA English DT Article ID CLASS-SWITCH RECOMBINATION; SINGLE-STRANDED-DNA; B-CELLS; IMMUNOGLOBULIN GENES; ANTIBODY DIVERSIFICATION; V(D)J RECOMBINATION; RNA-POLYMERASE; IG GENES; TRANSCRIPTION; CYTIDINE AB Activation-induced cytidine deaminase ( AID) is a single-stranded ( ss) DNA deaminase required for somatic hypermutation (SHM) and class switch recombination of immunoglobulin genes. Class switch recombination involves transcription through switch regions, which generates ssDNA within R loops. However, although transcription through immunoglobulin variable region exons is required for SHM, it does not generate stable ssDNA, which leaves the mechanism of AID targeting unresolved. Here we characterize the mechanism of AID targeting to in-vitro-transcribed substrates harbouring SHM motifs. We show that the targeting activity of AID is due to replication protein A (RPA), a ssDNA-binding protein involved in replication, recombination and repair. The 32-kDa subunit of RPA interacts specifically with AID from activated B cells in a manner that seems to be dependent on post-translational AID modification. Thus, our study implicates RPA as a novel factor involved in immunoglobulin diversification. We propose that B-cell-specific AID-RPA complexes preferentially bind to ssDNA of small transcription bubbles at SHM 'hotspots', leading to AID-mediated deamination and RPA-mediated recruitment of DNA repair proteins. C1 Childrens Hosp, Ctr Blood Res, Howard Hughes Med Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Alt, FW (reprint author), Childrens Hosp, Ctr Blood Res, Howard Hughes Med Inst, 300 Longwood Ave, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu NR 50 TC 251 Z9 256 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 26 PY 2004 VL 430 IS 7003 BP 992 EP 998 DI 10.1038/nature02821 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 849CD UT WOS:000223514900034 PM 15273694 ER PT J AU Rassenti, LZ Huynh, L Toy, TL Chen, L Keating, MJ Gribben, JG Neuberg, DS Flinn, IW Rai, KR Byrd, JC Kay, NE Greaves, A Weiss, A Kipps, TJ AF Rassenti, LZ Huynh, L Toy, TL Chen, L Keating, MJ Gribben, JG Neuberg, DS Flinn, IW Rai, KR Byrd, JC Kay, NE Greaves, A Weiss, A Kipps, TJ TI ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID VARIABLE-REGION MUTATIONS; V-H GENES; CD38 EXPRESSION; B-CELLS; PHENOTYPE AB BACKGROUND: The course of chronic lymphocytic leukemia (CLL) is variable. In aggressive disease, the CLL cells usually express an unmutated immunoglobulin heavy-chain variable-region gene (IgV(sub H)) and the 70-kD zeta-associated protein (ZAP-70), whereas in indolent disease, the CLL cells usually express mutated IgV(sub H) but lack expression of ZAP-70. METHODS: We evaluated the CLL B cells from 307 patients with CLL for ZAP-70 and mutations in the rearranged IgV(sub H) gene. We then investigated the association between the results and the time from diagnosis to initial therapy. RESULTS: We found that ZAP-70 was expressed above a defined threshold level in 117 of the 164 patients with an unmutated IgV(sub H) gene (71 percent), but in only 24 of the 143 patients with a mutated IgV(sub H) gene (17 percent, P<0.001). Among the patients with ZAP-70-positive CLL cells, the median time from diagnosis to initial therapy in those who had an unmutated IgV(sub H) gene (2.8 years) was not significantly different from the median time in those who had a mutated IgV(sub H) gene (4.2 years, P=0.07). However, the median time from diagnosis to initial treatment in each of these groups was significantly shorter than the time in patients with ZAP-70-negative CLL cells who had either mutated or unmutated IgV(sub H) genes (P<0.001). The median time from diagnosis to initial therapy among patients who did not have ZAP-70 was 11.0 years in those with a mutated IgV(sub H) gene and 7.1 years in those with an unmutated IgV(sub H) gene (P<0.001). CONCLUSIONS: Although the presence of an unmutated IgV(sub H) gene is strongly associated with the expression of ZAP-70, ZAP-70 is a stronger predictor of the need for treatment in B-cell CLL. C1 Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. Chron Lymphocyt Leukemia Res Consortium, La Jolla, CA USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Johns Hopkins, Kimmel Canc Ctr, Baltimore, MD USA. Long Isl Jewish Med Ctr, New Hyde Pk, NY 11042 USA. Ohio State Univ, Columbus, OH 43210 USA. Mayo Clin, Rochester, MN USA. Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA. RP Kipps, TJ (reprint author), Univ Calif San Diego, Sch Med, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM tkipps@ucsd.edu FU NCI NIH HHS [P01-CA81534] NR 27 TC 597 Z9 618 U1 1 U2 13 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 26 PY 2004 VL 351 IS 9 BP 893 EP 901 DI 10.1056/NEJMoa040857 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 849BM UT WOS:000223512500011 PM 15329427 ER PT J AU Schlossmacher, MG Hamann, C Cole, AG Gonzalez, RG Frosch, MP AF Schlossmacher, MG Hamann, C Cole, AG Gonzalez, RG Frosch, MP TI A 79-year-old woman with disturbances in gait, cognition, and autonomic function - Multiple-system atrophy. Cerebral arteriolar sclerosis. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID GLIAL CYTOPLASMIC INCLUSIONS; ALPHA-SYNUCLEIN; PARKINSONS-DISEASE; STRIATONIGRAL DEGENERATION; ALZHEIMERS-DISEASE; DEMENTIA; LEUKOENCEPHALOPATHY; MUTATION; CARE C1 Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Geriatr Med Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Div Neuropathol, Boston, MA 02114 USA. MetroW Med Ctr, Dept Med, Natick, MA USA. RP Schlossmacher, MG (reprint author), Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. NR 42 TC 6 Z9 6 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 26 PY 2004 VL 351 IS 9 BP 912 EP 922 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 849BM UT WOS:000223512500015 PM 15329430 ER PT J AU Chandan, VS Wilbur, D Faquin, WC Khurana, KK AF Chandan, VS Wilbur, D Faquin, WC Khurana, KK TI Is c-kit (CD117) immunolocalization in cell block preparations useful in the differentiation of adenoid cystic carcinoma from pleomorphic adenoma? SO CANCER CYTOPATHOLOGY LA English DT Editorial Material ID LOW-GRADE ADENOCARCINOMA; EXPRESSION; NEOPLASMS; PROTEIN C1 SUNY Upstate Med Univ, Dept Pathol, Syracuse, NY 13210 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA. RP Khurana, KK (reprint author), SUNY Upstate Med Univ, Dept Pathol, 750 E Adams St, Syracuse, NY 13210 USA. EM khuranak@upstate.edu RI Chandan, Vishal/K-8860-2015 NR 7 TC 14 Z9 14 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD AUG 25 PY 2004 VL 102 IS 4 BP 207 EP 209 DI 10.1002/cncr.20301 PG 3 WC Oncology; Pathology SC Oncology; Pathology GA 847LG UT WOS:000223393400002 PM 15368311 ER PT J AU Rajadhyaksha, A Husson, I Satpute, SS Kuppenbender, KD Ren, JQ Guerriero, RM Standaert, DG Kosofsky, BE AF Rajadhyaksha, A Husson, I Satpute, SS Kuppenbender, KD Ren, JQ Guerriero, RM Standaert, DG Kosofsky, BE TI L-type Ca2+ channels mediate adaptation of extracellular signal-regulated kinase 1/2 phosphorylation in the ventral tegmental area after chronic amphetamine treatment SO JOURNAL OF NEUROSCIENCE LA English DT Article DE amphetamine; L-type Ca2+ channels; VTA; ERK1/2 phosphorylation; Ca(v)1.2; addiction ID GATED CALCIUM-CHANNELS; LONG-TERM POTENTIATION; DEPENDENT PROTEIN-KINASE; BEHAVIORAL SENSITIZATION; GENE-EXPRESSION; CREB PHOSPHORYLATION; MAP KINASE; NUCLEUS-ACCUMBENS; DOPAMINE NEURONS; NMDA RECEPTORS AB L-type Ca2+ channels (LTCCs) play an important role in chronic psychostimulant-induced behaviors. However, the Ca2+ second messenger pathways activated by LTCCs after acute and recurrent psychostimulant administration that contribute to drug-induced molecular adaptations are poorly understood. Using a chronic amphetamine treatment paradigm in rats, we have examined the role of LTCCs in activating the mitogen-activated protein ( MAP) kinase pathway in the ventral tegmental area (VTA), a primary target for the reinforcing properties of psychostimulants. Using immunoblot and immunohistochemical analyses, we find that in chronic saline-treated rats a challenge injection of amphetamine increases phosphorylation of MAP[ extracellular signal-regulated kinase 1/2 (ERK1/2)] kinase in the VTA that is independent of LTCCs. However, in chronic amphetamine-treated rats there is no increase in amphetamine-mediated ERK1/2 phosphorylation unless LTCCs are blocked, in which case there is robust phosphorylation in VTA dopamine neurons. Examination of the expression of phosphatases reveals an increase in calcineurin [ protein phosphatase 2B (PP2B)] and MAP kinase phosphatase-1 (MKP-1) in the VTA. Using in situ hybridization histochemistry and immunoblot analyses, we further examined the mRNA and protein expression of the LTCC subtypes Ca(v)1.2 and Ca(v)1.3 in VTA dopamine neurons in drug-naive animals and in rats after chronic amphetamine treatment. We found an increase in Ca(v)1.2 mRNA and protein levels, with no change in Ca(v)1.3. Together, our results suggest that one aspect of LTCC-induced changes in second messenger pathways after chronic amphetamine exposure involves activation of the MAP kinase phosphatase pathway by upregulation of Ca(v)1.2 in VTA dopaminergic neurons. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,NMR Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. RP Rajadhyaksha, A (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,NMR Ctr, Room 2415,Bldg 149,13th St, Charlestown, MA 02129 USA. EM rajadhan@helix.mgh.harvard.edu OI Standaert, David/0000-0003-2921-8348 FU NIDA NIH HHS [K01 DA014057, K02 DA000354, K02DA00354, KO1DA14057] NR 94 TC 37 Z9 39 U1 0 U2 5 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 AUG 25 PY 2004 VL 24 IS 34 BP 7464 EP 7476 DI 10.1523/JNEUROSCI.0612-04.2004 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 849EJ UT WOS:000223521200006 PM 15329393 ER PT J AU Yaffe, K Blackwell, T Kanaya, AM Davidowitz, N Barrett-Connor, E Krueger, K AF Yaffe, K Blackwell, T Kanaya, AM Davidowitz, N Barrett-Connor, E Krueger, K TI Diabetes, impaired fasting glucose, and development of cognitive impairment in older women SO NEUROLOGY LA English DT Article ID INSULIN-DEGRADING ENZYME; ALZHEIMERS-DISEASE; RISK-FACTORS; POSTMENOPAUSAL WOMEN; DEMENTIA; POPULATION; MELLITUS; DECLINE; HEALTH; PERFORMANCE AB Objective: To investigate the association between diabetes and impaired fasting glucose (IFG) and cognition and risk of developing both dementia and mild cognitive impairment (MCI) in older women. Methods: The authors analyzed data from a 4-year randomized trial of raloxifene among 7,027 osteoporotic postmenopausal women (mean age, 66.3 years) at 178 sites. Diabetes was defined by history, fasting blood glucose greater than or equal to7.0 mmol/L (greater than or equal to126 mg/dL), or use of hypoglycemic agents; IFG was defined as fasting glucose <7.0 mmol/L but >6.11 mmol/ L (110 mg/dL); all others were considered to have normal glucose (NG). The main outcome was baseline and 4-year change on five standardized cognitive tests (z scores with lower scores indicating worse performance) and risk of developing clinically significant impairment (dementia, mild cognitive impairment, or very low cognitive score). Results: A total of 267 (3.8%) women had diabetes and 297 (4.2%) had IFG. Women with IFG had worse baseline cognitive scores compared to women with NG but better scores than diabetics (age-adjusted composite z score based on five tests: NG 0.40, 95% CI 0.30 to 0.49; IFG 0.14, 95% CI -0.36 to 0.64; diabetics -0.78, 95% CI -1.23 to -0.33; p<0.001). There was greater 4-year decline among diabetics (age and treatment-adjusted composite z score: NG -0.05, 95% CI -0.16 to 0.05; IFG 0.11, 95% CI -0.53 to 0.75; diabetics -1.00, 95% CI -1.50 to -0.50; p=0.001). Further adjustment for education, race, and depression led to similar results. Risk of developing cognitive impairment among women with IFG or diabetes was increased by almost twofold (age and treatment-adjusted OR=1.64; 95% CI 1.03 to 2.61 for IFG; OR=1.79; 95% CI 1.14 to 2.81 for diabetics). Conclusions: Diabetic as well as pre-diabetic women have impaired cognitive performance and greater risk of developing cognitive impairment. C1 Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA. San Francisco VA Med Ctr, San Francisco, CA USA. Univ Calif San Diego, Dept Community & Family Med, La Jolla, CA 92093 USA. Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Yaffe, K (reprint author), Univ Calif San Francisco, Dept Psychiat, Box 181 4150 Clement St, San Francisco, CA 94121 USA. EM kyaffe@itsa.ucsf.edu FU NIA NIH HHS [R01 AG021918-01] NR 34 TC 256 Z9 266 U1 2 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 24 PY 2004 VL 63 IS 4 BP 658 EP 663 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 848UP UT WOS:000223493800012 PM 15326238 ER PT J AU Gottlieb, DJ DeStefano, AL Foley, DJ Mignot, E Redline, S Givelber, RJ Young, T AF Gottlieb, DJ DeStefano, AL Foley, DJ Mignot, E Redline, S Givelber, RJ Young, T TI APOE epsilon 4 is associated with obstructive sleep apnea/hypopnea - The Sleep Heart Health Study SO NEUROLOGY LA English DT Article ID APOLIPOPROTEIN-E GENOTYPE; CARDIOVASCULAR-DISEASE; ALZHEIMERS-DISEASE; RISK-FACTORS; APNEA; PATHOGENESIS; POPULATION; ADULTS; GENE; AGE AB Background: Obstructive sleep apnea/hypopnea (OSAH) has a strong heritable component, although its genetic basis remains largely unknown. One epidemiologic study found a significant association between the APOE epsilon4 allele and OSAH in middle-aged adults, a finding that was not replicated in a cohort of elderly adults. The objective of this study was to further examine the association of the APOE epsilon4 allele with OSAH in a community-dwelling cohort, exploring age dependency of the association. Methods: A genetic association study was performed, nested within a prospective cohort study of the cardiovascular consequences of OSAH. Unattended, in-home nocturnal polysomnography was used to measure apnea-hypopnea index (AHI) in 1,775 participants age 40 to 100 years. OSAH was defined as an AHIgreater than or equal to15. The relation of APOE genotype to prevalent OSAH was analyzed using generalized estimating equations to account for non-independent observations of individuals from the same sibship. Results: At least one APOE epsilon4 allele was present in 25% of subjects, with 1.3% epsilon4/epsilon4 homozygotes. The prevalence of OSAH was 19%. After adjustment for age, sex, and BMI, the presence of any APOE epsilon4 allele was associated with increased odds of OSAH (OR 1.41, 95% CI 1.06 to 1.87, p=0.02). The effect was approximately twice as great in subjects <75 (OR 1.61, CI 1.02 to 2.54) as in those &GE;75 years old ( OR 1.32, CI 0.91 to 1.90). Exploratory analyses revealed that the strongest effect of APOE ε4 was in subjects age <65 (OR 3.08, CI 1.43 to 6.64), and was stronger in those with hypertension or cardiovascular disease than in those without. Conclusion: The APOE epsilon4 allele is associated with increased risk of OSAH, particularly in individuals under age 65. The mechanisms underlying this association are uncertain. Age-dependency of the APOE-OSAH association may explain previous conflicting results. C1 Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. VA Boston Healthcare Syst, Boston, MA USA. Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. NIA, Bethesda, MD 20892 USA. Stanford Univ, Stanford, CA 94305 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Univ Wisconsin, Madison, WI USA. RP Gottlieb, DJ (reprint author), Boston Univ, Sch Med, Ctr Pulm, 715 Albany St,R-304, Boston, MA 02118 USA. EM dgottlieb@lung.bumc.bu.edu FU NHLBI NIH HHS [U01 HL53934, R01 HL71515, U01 HL53916, U01 HL53931, U01 HL53937, U01 HL53938, U01 HL53940, U01 HL53941, U01 HL63429, U01 HL63463, U01 HL64360] NR 27 TC 91 Z9 95 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 24 PY 2004 VL 63 IS 4 BP 664 EP 668 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 848UP UT WOS:000223493800013 PM 15326239 ER PT J AU Oaklander, AL AF Oaklander, AL TI Progression of dystonia in complex regional pain syndrome SO NEUROLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Oaklander, AL (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Clin 3, Boston, MA 02114 USA. EM aoaklander@partners.org NR 2 TC 12 Z9 12 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 AUG 24 PY 2004 VL 63 IS 4 BP 751 EP 751 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 848UP UT WOS:000223493800036 PM 15326262 ER PT J AU Jager, S Schwartz, HT Horvitz, HR Conradt, B AF Jager, S Schwartz, HT Horvitz, HR Conradt, B TI The Caenorhabditis elegans F-box orotein SEL-10 promotes female development and may target FEM-1 and FEM-3 for degradation by the proteasome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SEX-DETERMINING GENE; PROTEIN-PROTEIN INTERACTION; C-ELEGANS; INTRACELLULAR DOMAIN; CELL-INTERACTIONS; DISEASE GENE; TRA-1; INTERACTS; LIN-12; HERMAPHRODITE AB The Caenorhabditis elegans F-box protein SEL-10 and its human homolog have been proposed to regulate LIN-12 Notch signaling by targeting for ubiquitin-mediated proteasomal degradation LIN-12 Notch proteins and SEL-12 PS1 presenilins, the latter of which have been implicated in Alzheimer's disease. We found that sel-10 is the same gene as egl-41, which previously had been defined by gain-of-function mutations that semidominantly cause masculinization of the hermaphrodite soma. Our results demonstrate that mutations causing loss-of-function of sel-10 also have masculinizing activity, indicating that sel-10 functions to promote female development. Genetically, sel-10 acts upstream of the genes fern-1, fem-2, and fem-3 and downstream of her-1 and probably tra-2. When expressed in mammalian cells, SEL-10 protein coimmunoprecipitates with FEM-1, FEM-2, and FEM-3, which are required for masculinization, and FEM-1 and FEM-3 are targeted by SEL-10 for proteasomal degradation. We propose that SEL-10-mediated proteolysis of FEM-1 and FEM-3 is required for normal hermaphrodite development. C1 Max Planck Inst Neurobiol, D-82152 Planegg Martinsried, Germany. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. Dartmouth Coll Sch Med, Dept Genet, Hanover, NH 03755 USA. RP Max Planck Inst Neurobiol, Klopferspitz 18A, D-82152 Planegg Martinsried, Germany. EM barbara.conradt@dartmouth.edu RI Conradt, Barbara/K-2665-2014 FU NIGMS NIH HHS [R01 GM024663, GM 24663, R37 GM024663] NR 48 TC 29 Z9 42 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 AUG 24 PY 2004 VL 101 IS 34 BP 12549 EP 12554 DI 10.1073/pnas.0405087101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 850FI UT WOS:000223596200029 PM 15306688 ER PT J AU Denis, MC Mahmood, U Benoist, C Mathis, D Weissleder, R AF Denis, MC Mahmood, U Benoist, C Mathis, D Weissleder, R TI Imaging inflammation of the pancreatic islets in type 1 diabetes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DENDRITIC CELLS; IRON-OXIDE; NOD MOUSE; IN-VIVO; MICE; PERMEABILITY; MACROPHAGES; INSULITIS; STREPTOZOTOCIN; PROGRESSION AB Type 1 diabetes is the clinical manifestation of aberrant leukocytic infiltration of the pancreatic islets; it is usually diagnosed only very late in disease progression, after the critical autoimmune phenomena have mostly played out. A noninvasive means of directly monitoring the evolution of islet infiltrates would have important research and clinical applications. We have exploited fluorescence and MRI of long-circulating magnetofluorescent nanoparticles to visualize microvascular leakage, as an indicator of inflammation, in pancreata of mouse models of type 1 diabetes ex vivo or in vivo. We could detect the onset and evolution of insulitis in vivo and in real time, permitting us to study the natural history of diabetes in individual animals. C1 Joslin Diabet Ctr, Sect Immunol & Immunogenet, Boston, MA 02215 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. RP Mathis, D (reprint author), Joslin Diabet Ctr, Sect Immunol & Immunogenet, 1 Joslin Pl, Boston, MA 02215 USA. EM dm@joslin.harvard.edu FU NCI NIH HHS [P50 CA086355, R24 CA 92782, P50 CA 86355, R24 CA092782]; NIAID NIH HHS [P01 AI054904, P01 AI 54904]; NIDDK NIH HHS [F32 DK063886, 1F32 DK 63886, 5R01 DK 059658, R01 DK059658, 2P30 DK 36836-17, P30 DK036836, 2P30 DK 36836] NR 30 TC 115 Z9 121 U1 1 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 24 PY 2004 VL 101 IS 34 BP 12634 EP 12639 DI 10.1073/pnas.040437101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 850FI UT WOS:000223596200044 PM 15304647 ER PT J AU Iftimia, NV Bouma, BE de Boer, JF Park, BH Cense, B Tearney, GJ AF Iftimia, NV Bouma, BE de Boer, JF Park, BH Cense, B Tearney, GJ TI Adaptive ranging for optical coherence tomography SO OPTICS EXPRESS LA English DT Article ID ATHEROSCLEROTIC PLAQUES; CORONARY-ARTERY; RESOLUTION; MICROSCOPY; CATHETER; POWER AB At present, optical coherence tomography systems have a limited imaging depth or axial scan range, making diagnosis of large diameter arterial vessels and hollow organs difficult. Adaptive ranging is a feedback technique where image data is utilized to adjust the coherence gate offset and range. In this paper, we demonstrate an adaptive optical coherence tomography system with a 7.0 mm range. By matching the imaging depth to the approximately 1.5 mm penetration depth in tissue, a 3 dB sensitivity improvement over conventional imaging systems with a 3.0 mm imaging depth was realized. (C) 2004 Optical Society of America. C1 Massachusetts Gen Hosp, Wellman Labs Photomed, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Iftimia, NV (reprint author), Phys Sci Inc, 20 New England Business Ctr, Andover, MA 01810 USA. EM gtearney@partners.org RI de Boer, Johannes/B-7590-2012 OI de Boer, Johannes/0000-0003-1253-4950 FU NCI NIH HHS [R01 CA103769, R01 CA103769-02]; NEI NIH HHS [R24 EY012877, R24 EY012877-02]; NHLBI NIH HHS [R01 HL076398-03, R01 HL076398] NR 24 TC 26 Z9 26 U1 0 U2 2 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD AUG 23 PY 2004 VL 12 IS 17 BP 4025 EP 4034 DI 10.1364/OPEX.12.004025 PG 10 WC Optics SC Optics GA 848LL UT WOS:000223469000020 PM 19483942 ER PT J AU Chen, JW Pham, W Weissleder, R Bogdanov, AA AF Chen, JW Pham, W Weissleder, R Bogdanov, AA TI Imaging of human myeloperoxidase activity using MR signal amplification. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Massachusetts Gen Hosp, Ctr Mol Imaging Res Radiol, Charlestown, MA 02129 USA. EM chenjo@helix.mgh.harvard.edu; abogdanov@helix.mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 302-INOR BP U824 EP U824 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712803346 ER PT J AU Hanczyc, MM Szostak, JW AF Hanczyc, MM Szostak, JW TI Experimental. models of primitive cellular compartments. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Harvard Univ, Dept Mol Biol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM hanczyc@molbio.mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 046-GEOC BP U697 EP U698 PN 1 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712802900 ER PT J AU Jenkins, BG AF Jenkins, BG TI Mapping dopamine receptor function with iron MRI techniques. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, NMR Ctr, Charlestown, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM bgj@nmr.mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 348-INOR BP U831 EP U831 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712803392 ER PT J AU Litovchick, A Salehi-Ashtiani, K Szostak, JW AF Litovchick, A Salehi-Ashtiani, K Szostak, JW TI Ribozymes from human genome. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 MGH, HHMI, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM sasha@molbio.mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 012-BIOL BP U172 EP U173 PN 1 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712800706 ER PT J AU Scholz, C Sweitzer, R Stewart, P Gingerich, M Shire, D Montezuma, S Rizzo, J AF Scholz, C Sweitzer, R Stewart, P Gingerich, M Shire, D Montezuma, S Rizzo, J TI Surface modification of retinal implants. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Univ Alabama, Dept Chem, Huntsville, AL 35899 USA. Cornell Univ, Ithaca, NY 14853 USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Boston Vet Adm Hosp, Boston, MA USA. EM cscholz@chemistry.uah.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 393-POLY BP U384 EP U384 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851VJ UT WOS:000223713802068 ER PT J AU Kozar, K Ciemerych, MA Rebel, VI Shigematsu, H Zagozdon, A Sicinska, E Geng, Y Yu, QY Bhattacharya, S Bronson, RT Akashi, K Sicinski, P AF Kozar, K Ciemerych, MA Rebel, VI Shigematsu, H Zagozdon, A Sicinska, E Geng, Y Yu, QY Bhattacharya, S Bronson, RT Akashi, K Sicinski, P TI Mouse development and cell proliferation in the absence of D-cyclins SO CELL LA English DT Article ID HEMATOPOIETIC STEM-CELLS; RETINOBLASTOMA PROTEIN; DEPENDENT KINASES; CDK INHIBITORS; MICE; PROGRESSION; PROGENITOR; P27(KIP1); BMI-1; PHOSPHORYLATION AB D-type cyclins (cyclins D1, D2, and D3 are regarded as essential links between cell environment and the core cell cycle machinery. We tested the requirement for D-cyclins in mouse development and in proliferation by generating mice lacking all D-cyclins. We found that these cyclin D1(-/-)D2(-/-)D3(-/-) mice develop until mid/late gestation and die due to heart abnormalities combined with a severe anemia. Our analyses revealed that the D-cyclin; are critically required for the expansion of hematopoietic stem cells. In contrast, cyclin D-deficient fibroblasts proliferate nearly normally but show increased requirement for mitogenic stimulation in cell cycle re-entry. We found that the proliferation of cyclin D1(-/-)D2(-/-)D3(-/-) cells is resistant to the inhibition by p16(INK4a), but it critically depends on CDK2. Lastly, we found that cells lacking D-cyclins display reduced susceptibility to the oncogenic transformation. Our results reveal the presence of alternative mechanisms that allow cell cycle progression in a cyclin D-indeperdent fashion. C1 Harvard Univ, Sch Med, Dept Canc Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. Univ Oxford, Dept Cardiovasc Med, Oxford OX3 7BN, England. Tufts Univ, Sch Vet Med, North Grafton, MA 01536 USA. RP Sicinski, P (reprint author), Harvard Univ, Sch Med, Dept Canc Biol, Boston, MA 02115 USA. EM peter_sicinski@dfci.harvard.edu RI Bhattacharya, Shoumo/F-4127-2010 FU NCI NIH HHS [CA85296, CA108420] NR 38 TC 409 Z9 427 U1 1 U2 14 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD AUG 20 PY 2004 VL 118 IS 4 BP 477 EP 491 DI 10.1016/j.cell.2004.07.025 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 850YS UT WOS:000223650900010 PM 15315760 ER PT J AU Irie, M Homma, S Komita, H Zeniya, M Kufe, D Ohno, T Toda, G AF Irie, M Homma, S Komita, H Zeniya, M Kufe, D Ohno, T Toda, G TI Inhibition of spontaneous development of liver tumors by inoculation with dendritic cells loaded with hepatocellular carcinoma cells in C3H/HeNCRJ mice SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE dendritic cell; hepatocellular carcinoma; cancer vaccine; macrophage; IFN-gamma; CD4(+) T cell ID MONOCYTE-MEDIATED IMMUNOTHERAPY; CYTOTOXIC T-LYMPHOCYTES; CHRONIC HEPATITIS-C; RESPONSES IN-VITRO; INTERFERON-ALPHA; CANCER-IMMUNOTHERAPY; ANTITUMOR-ACTIVITY; ANTIGEN; THERAPY; VIVO AB We attempted to prevent spontaneous development of liver tumors by s.c. inoculation with DCs loaded with syngeneic HCC cells in C3H/HeNCrj mice. A new cell line, MIH-2, was established from an HCC that had developed spontaneously in a C3H/HeNCrj mouse. Bone marrow-derived DCs were loaded with irradiated MIH-2 cells by treatment with PEG. Fluorescence microscopy and flow-cytometric analysis showed that about 45% of PEG-treated DCs and MIH-2 cells (DC/MIH-2) were DCs loaded with MIH-2 cells. Thirteen-month-old mice received inoculations of DC/MIH-2 (9 X 10(5)/ mouse) 4 times at 6-day intervals and were killed at 16 months of age to assess liver tumors. The incidence of liver tumors in these mice was significantly lower than that in mice not receiving inoculations (p < 0.05) but similar to that in 13-month-old mice (the age at which inoculation started), indicating that inoculation inhibited the development of new tumors. Splenocytes from inoculated mice, but not those from uninoculated mice, showed cytotoxic activity against MIH-2 cells. Cytotoxic activity was not elicited by CD4(+) T cells, CD8(+) T cells, or DX5(+) cells isolated from splenocytes but was elicited by adherent cells, identified as CDIIb(+) macrophages. CD4(+) T cells, but not CD8(+) T cells, from inoculated mice produced IFN-gamma by incubation with DC/MIH-2. Cytotoxicity by splenocytes was attenuated by anti-IFN-gamma antibody. Immunization with DCs loaded with syngeneic HCC cells induces CD4(+) T cells that produce IFN-gamma by response to antigen of HCC, which would lead to macrophage activation to kill liver tumor cells at an early stage. (C) 2004 Wiley-Liss, Inc. C1 Jikei Univ, Sch Med, Inst DNA Med, Dept Oncol,Minato Ku, Tokyo 1058461, Japan. Jikei Univ, Sch Med, Dept Internal Med, Div Gastroenterol & Hepatol, Tokyo, Japan. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Homma, S (reprint author), Jikei Univ, Sch Med, Inst DNA Med, Dept Oncol,Minato Ku, 3-25-8 Nishi Shimbashi, Tokyo 1058461, Japan. EM sahya@jikei.ac.jp NR 50 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 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD AUG 20 PY 2004 VL 111 IS 2 BP 238 EP 245 DI 10.1002/ijc.20247 PG 8 WC Oncology SC Oncology GA 837PA UT WOS:000222646400011 PM 15197777 ER PT J AU Werner, ED Lee, JS Hansen, L Yuan, MS Shoelson, SE AF Werner, ED Lee, JS Hansen, L Yuan, MS Shoelson, SE TI Insulin resistance due to phosphorylation of insulin receptor substrate-1 at Serine 302 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR-NECROSIS-FACTOR; PROTEIN-KINASE-C; PHOSPHATIDYLINOSITOL 3-KINASE ACTIVITY; TYROSINE PHOSPHORYLATION; SERINE/THREONINE PHOSPHORYLATION; FACTOR-ALPHA; METABOLIC SYNDROME; TARGETED DISRUPTION; DIABETES-MELLITUS; SIGNALING CASCADE AB Inhibitory serine phosphorylation is a potential molecular mechanism for insulin resistance. We have developed a new variant of the yeast two-hybrid method, referred to as disruptive yeast tri-hybrid (Y3H), to identify inhibitory kinases and sites of phosphorylation in insulin receptors (IR) and IR substrates, IRS-1. Using IR and IRS-1 as bait and prey, respectively, and c-Jun NH2-terminal kinase (JNK1) as the disruptor, we now show that phosphorylation of IRS-1 Ser-307, a previously identified site, is necessary but not sufficient for JNK1-mediated disruption of IR/IRS-1 binding. We further identify a new phosphorylation site, Ser-302, and show that this too is necessary for JNK1-mediated disruption. Seven additional kinases potentially linked to insulin resistance similarly block IR/IRS-1 binding in the disruptive Y3H, but through distinct Ser-302- and Ser-307-independent mechanisms. Phosphospecific antibodies that recognize sequences surrounding Ser(P)-302 or Ser(P)-307 were used to determine whether the sites were phosphorylated under relevant conditions. Phosphorylation was promoted at both sites in Fao hepatoma cells by reagents known to promote Ser/Thr phosphorylation, including the phorbol ester phorbol 12-myristate 13-acetate, anisomycin, calyculin A, and insulin. The antibodies further showed that Ser(P)-302 and Ser(P)-307 are increased in animal models of obesity and insulin resistance, including genetically obese ob/ob mice, diet-induced obesity, and upon induction of hyperinsulinemia. These findings demonstrate that phosphorylation at both Ser-302 and Ser-307 is necessary for JNK1-mediated inhibition of the IR/IRS-1 interaction and that Ser-302 and Ser-307 are phosphorylated in parallel in cultured cells and in vivo under conditions that lead to insulin resistance. C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Lee, JS (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM Jongsoon.Lee@joslin.harvard.edu; Steven.Shoelson@joslin.harvard.edu FU NIDDK NIH HHS [DK09393, DK36836, DK43123, DK45943, DK63225] NR 80 TC 139 Z9 142 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 20 PY 2004 VL 279 IS 34 BP 35298 EP 35305 DI 10.1074/jbc.M405203200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 846GJ UT WOS:000223303400021 PM 15199052 ER PT J AU Patenge, N Elkin, SK Oettinger, MA AF Patenge, N Elkin, SK Oettinger, MA TI ATP-dependent remodeling by SWI/SNF and ISWI proteins stimulates V(D)J cleavage of 5 S arrays SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HISTONE ACETYLTRANSFERASE COMPLEXES; T-CELL DEVELOPMENT; IN-VITRO; NUCLEOSOMAL DNA; CHROMATIN-STRUCTURE; TRANSCRIPTION FACTORS; PROMOTER NUCLEOSOMES; RAG2 PROTEINS; PHD FINGER; RECOMBINATION AB Control of V(D)J recombination is critical for the generation of a fully developed immune repertoire. The molecular mechanisms underlying the regulation of antigen receptor gene assembly are beginning to be revealed. Here we studied the influence of chromatin modifications on V(D)J cleavage of a polynucleosomal substrate, in which V(D)J cleavage is greatly reduced compared with naked DNA. ATP-dependent remodeling by human SWI/SNF (hSWI/SNF) in the presence of HMG1 led to a substantial increase of cleavage by the recombination activation gene (RAG) proteins. Either BRG1, the ATPase subunit of hSWI/SNF, or SNF2h, the ATPase of human ISWI complexes, was capable of stimulating V(D)J cleavage of the array, although these remodelers act by different mechanisms. No effect of histone hyperacetylation was detectable in this system. As is observed on naked DNA, in the presence of core RAG1, the full-length RAG2 protein proved to be more active than core RAG2 on these polynucleosomal arrays, reinforcing the importance of the RAG2 C-terminal domain for efficient recombination. Comparison of 5 S array cleavage by the RAG proteins or by the restriction enzyme HhaI after remodeling by hSWI/SNF suggested that RAG proteins and HhaI might have different requirements for maximal accessibility of the substrate. C1 Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Oettinger, MA (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Wellman 10,50 Blossom St, Boston, MA 02114 USA. EM oettinger@frodo.mgh.harvard.edu FU NIGMS NIH HHS [R01 GM48026] NR 70 TC 35 Z9 35 U1 0 U2 0 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 AUG 20 PY 2004 VL 279 IS 34 BP 35360 EP 35367 DI 10.1074/jbc.M405790200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 846GJ UT WOS:000223303400029 PM 15201272 ER PT J AU Sordella, R Bell, DW Haber, DA Settleman, J AF Sordella, R Bell, DW Haber, DA Settleman, J TI Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways SO SCIENCE LA English DT Article ID GROWTH-FACTOR RECEPTOR; CELL-CYCLE PROGRESSION; RAS/RAF/MEK/ERK PATHWAY; TYROSINE KINASE; INHIBITOR; TRIAL; THERAPY; ZD1839 AB Gefitinib (Iressa, AstraZeneca Pharmaceuticals) is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR) and induces dramatic clinical responses in nonsmall. cell lung cancers (NSCLCs) with activating mutations within the EGFR kinase domain. We report that these mutant EGFRS selectively activate Akt and signal transduction and activator of transcription (STAT) signaling pathways, which promote cell survival, but have no effect on extracellular signal-regulated kinase signaling which induces proliferation. NSCLC cells expressing mutant EGFRs underwent extensive apoptosis after small interfering RNA-mediated knockdown of the mutant EGFR or treatment with pharmacological inhibitors of Akt and STAT signaling and were relatively resistant to apoptosis induced by conventional chemotherapeutic drugs. Thus, mutant EGFRs selectively transduce survival signals on which NSCLCs become dependent, inhibition of those signals by gefitinib may contribute to the drug's efficacy. C1 Massachusetts Gen Hosp, Ctr Canc, Ctr Mol Therapeut, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Settleman, J (reprint author), Massachusetts Gen Hosp, Ctr Canc, Ctr Mol Therapeut, Bldg 149,13th St, Charlestown, MA 02129 USA. EM settleman@helix.mgh.harvard.edu FU PHS HHS [P01 95281] NR 19 TC 1037 Z9 1088 U1 12 U2 80 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 AUG 20 PY 2004 VL 305 IS 5687 BP 1163 EP 1167 DI 10.1126/science.1101637 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 849RD UT WOS:000223557400051 PM 15284455 ER PT J AU Lin, B Wang, SW Masland, RH AF Lin, B Wang, SW Masland, RH TI Retinal ganglion cell type, size, and spacing can be specified independent of homotypic dendritic contacts SO NEURON LA English DT Article ID DOMAIN FACTOR BRN-3B; MAMMALIAN RETINA; SENSORY NEURONS; MOUSE RETINA; CAT RETINA; SPATIAL-ORGANIZATION; RECEPTIVE-FIELDS; NERVOUS-SYSTEM; AXON OUTGROWTH; VISUAL-SYSTEM AB In Brn3b(-/-) mice, where 80% of retinal ganglion cells degenerate early in development, the remaining 20% include most or all ganglion cell types. Cells of the same type cover the retinal surface evenly but tile it incompletely, indicating that a regular mosaic and normal dendritic field size can be maintained in the absence of contact among homotypic cells. In Math5(-/-) mice, where only similar to5% of ganglion cells are formed, the dendritic arbors of at least two types among the residual ganglion cells are indistinguishable from normal in shape and size, even though throughout development they are separated by millimeters from the nearest neighboring ganglion cell of the same type. It appears that the primary phenotype of retinal ganglion cells can develop without homotypic contact; dendritic repulsion may be an end-stage mechanism that fine-tunes the dendritic arbors for more efficient coverage of the retinal surface. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Howard Hughes Med Inst, Boston, MA 02114 USA. Univ Texas, MD Anderson Canc Ctr, Dept Biochem & Mol Biol, Houston, TX 77030 USA. RP Masland, RH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Howard Hughes Med Inst, Boston, MA 02114 USA. EM masland@helix.mgh.harvard.edu RI Lin, Bin/E-9871-2010 NR 53 TC 114 Z9 115 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG 19 PY 2004 VL 43 IS 4 BP 475 EP 485 DI 10.1016/j.neuron.2004.08.002 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 847ZK UT WOS:000223436400007 PM 15312647 ER PT J AU Temel, J Aquino, SL Lynch, TJ Wright, CD Mark, EJ Choi, NC AF Temel, J Aquino, SL Lynch, TJ Wright, CD Mark, EJ Choi, NC TI Case 26-2004: A 56-year-old woman with cough and a lung nodule - Large-cell undifferentiated carcinoma of the lung, stage IIIA (T1N2M0) SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID POSITRON-EMISSION-TOMOGRAPHY; INTENSITY-MODULATED RADIOTHERAPY; SOLITARY PULMONARY NODULES; RANDOMIZED-TRIAL; FLUORINE-18-FLUORODEOXYGLUCOSE UPTAKE; ADJUVANT CHEMOTHERAPY; COMPUTED-TOMOGRAPHY; FDG PET; CANCER; SURGERY C1 Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Thorac Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Surg, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Radiat Oncol, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Temel, J (reprint author), Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. NR 41 TC 4 Z9 4 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 AUG 19 PY 2004 VL 351 IS 8 BP 809 EP 817 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 847CY UT WOS:000223367900015 ER PT J AU Hass, C Lohrmann, J Albrecht, V Sweere, U Hummel, F Yoo, SD Hwang, I Zhu, T Schafer, E Kudla, J Harter, K AF Hass, C Lohrmann, J Albrecht, V Sweere, U Hummel, F Yoo, SD Hwang, I Zhu, T Schafer, E Kudla, J Harter, K TI The response regulator 2 mediates ethylene signalling and hormone signal integration in Arabidopsis SO EMBO JOURNAL LA English DT Article DE expression profiling; phosphorelay; phytohormone signalling; response regulator; two-component system ID TRANSCRIPTION FACTOR; RECEPTOR ETR1; TRANSDUCTION; EXPRESSION; PROTEIN; KINASE; GENES; CYTOKININS; MUTATIONS; STABILITY AB Hormones are important regulators of plant growth and development. In Arabidopsis, perception of the phytohormones ethylene and cytokinin is accomplished by a family of sensor histidine kinases including ethylene-resistant (ETR) 1 and cytokinin-response (CRE) 1. We identified the Arabidopsis response regulator 2 (ARR2) as a signalling component functioning downstream of ETR1 in ethylene signal transduction. Analyses of loss-of-function and ARR2-overexpressing lines as well as functional assays in protoplasts indicate an important role of ARR2 in mediating ethylene responses. Additional investigations indicate that an ETR1-initiated phosphorelay regulates the transcription factor activity of ARR2. This mechanism may create a novel signal transfer from endoplasmic reticulum-associated ETR1 to the nucleus for the regulation of ethylene-response genes. Furthermore, global expression profiling revealed a complex ARR2-involving two-component network that interferes with a multitude of different signalling pathways and thereby contributes to the highly integrated signal processing machinery in higher plants. C1 Univ Munster, Inst Bot & Botanischer Garten, D-48149 Munster, Germany. Univ Cologne, Inst Bot, D-50931 Cologne, Germany. Univ Ulm, Ulm, Germany. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Pohang Univ Sci & Technol, Div Mol & Life Sci, Pohang, South Korea. Syngenta Biotechnol Inc, Res Triangle Pk, NC USA. RP Kudla, J (reprint author), Univ Munster, Inst Bot & Botanischer Garten, Schlossgarten 3, D-48149 Munster, Germany. EM jkudla@uni-muenster.de; klaus.harter@uni-koeln.de RI Kudla, Jorg/C-2174-2012; Zhu, Tong/G-5202-2011 OI Kudla, Jorg/0000-0002-8238-767X; Zhu, Tong/0000-0002-8732-3499 NR 34 TC 111 Z9 125 U1 1 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0261-4189 J9 EMBO J JI Embo J. PD AUG 18 PY 2004 VL 23 IS 16 BP 3290 EP 3302 DI 10.1038/sj.emboj.7600337 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 852CK UT WOS:000223732600011 PM 15282545 ER PT J AU D'Amico, AV Manola, J Loffredo, M Renshaw, AA DellaCroce, A Kantoff, PW AF D'Amico, AV Manola, J Loffredo, M Renshaw, AA DellaCroce, A Kantoff, PW TI 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer - A randomized controlled trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PHASE-III TRIAL; DEPRIVATION THERAPY; RADIOTHERAPY; NEOADJUVANT; CARCINOMA; MORTALITY; MEN AB Context Survival benefit in the management of high-grade clinically localized prostate cancer has been shown for 70 Gy radiation therapy combined with 3 years of androgen suppression therapy (AST), but long-term AST is associated with many adverse events. Objective To assess the survival benefit of 3-dimensional conformal radiation therapy (3D-CRT) alone or in combination with 6 months of AST in patients with clinically localized prostate cancer. Design, Setting, and Patients A prospective randomized controlled trial of 206 patients with clinically localized prostate cancer who were randomized to receive 70 Gy 3D-CRT alone (n=104) or in combination with 6 months of AST (n=102) from December 1, 1995, to April 15, 2001. Eligible patients included those with a prostate-specific antigen (PSA) of at least 10 ng/mL, a Gleason score of at least 7, or radiographic evidence of extraprostatic disease. Main Outcome Measures Time to PSA failure (PSA >11.0 ng/mL and increasing >0.2 ng/mL on 2 consecutive visits) and overall survival. Results After a median follow-up of 4.52 years, patients randomized to receive 3D-CRT plus AST had a significantly higher survival (P=.04), lower prostate cancer-specific mortality (P=.02), and higher survival free of salvage AST (P=.002). Kaplan-Meier estimates of 5-year survival rates were 88% (95% confidence interval [Cl], 80%-95%) in the 3D-CRT plus AST group vs 78% (95% Cl, 68%-88%) in the 3D-CRT group. Rates of survival free of salvage AST at 5 years were 82% (95% Cl, 73%-90%) in the 3D-CRT plus AST group vs 57% (95% Cl, 46%-69%) in the 3D-CRT group. Conclusion The addition of 6 months of AST to 70 Gy 3D-CRT confers an overall survival benefit for patients with clinically localized prostate cancer. C1 Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02215 USA. Brigham & Womens Hosp, Dept Biostat, Boston, MA 02215 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. Brigham & Womens Hosp, Dept Med Oncol, Boston, MA 02215 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP D'Amico, AV (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,L-2 Level, Boston, MA 02215 USA. EM adamico@lroc.harvard.edu NR 21 TC 516 Z9 523 U1 0 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 18 PY 2004 VL 292 IS 7 BP 821 EP 827 DI 10.1001/jama.292.7.821 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 847FO UT WOS:000223378300022 PM 15315996 ER PT J AU Wiviott, SD Morrow, DA Frederick, PD Giugliano, RP Gibson, CM McCabe, CH Cannon, CP Antman, EM Braunwald, E AF Wiviott, SD Morrow, DA Frederick, PD Giugliano, RP Gibson, CM McCabe, CH Cannon, CP Antman, EM Braunwald, E TI Performance of the thrombolysis in myocardial infarction risk index in the national registry of myocardial infarction-3 and-4 - A simple index that predicts mortality in ST-segment elevation myocardial infarction SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID ACUTE CORONARY SYNDROMES; COOPERATIVE CARDIOVASCULAR PROJECT; INTERNATIONAL TRIAL; ELDERLY-PATIENTS; INTRAVENOUS NPA; UNSTABLE ANGINA; TASK-FORCE; INTIME-II; SCORE; THERAPY AB OBJECTIVES We sought to evaluate a simple risk index based on age and vital signs in a community sample of patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND A simple risk index based on age and vital signs (heart rate X [age/10](2)/systolic blood pressure) developed from patients with STEMI accurately predicts mortality in clinical trials of fibrinolysis. The application of such a tool in an unselected population is necessary to evaluate its utility in clinical practice. METHODS To evaluate the Thrombolysis In Myocardial Infarction (TIMI) risk index for routine practice, we tested it in the National Registry of Myocardial Infarction (NRMI)-3 and -4. The risk index was evaluated as a continuous variable in patients with STEMI from NRMI and in subgroups based on age and reperfusion status. RESULTS A total of 153,486 patients with STEMI were eligible. As anticipated, STEMI patients in NRMI had a higher risk index profile, as compared with those in the clinical trial (median 26.9 vs. 20, p < 0.0001). Classification of NRMI patients with STEMI into risk groups revealed a significant graded relationship with mortality (0.9% to 53.2%, P-trend < 0.0001, c statistic 0.79). The discriminatory capacity of the risk index was particularly strong in the 81,679 patients receiving reperfusion therapy (0.6% to 60%, P-trend < 0.0001, c statistic 0.81). For the 71,807 patients not receiving reperfusion therapy, a strong graded relationship remained (1.9% to 52.2%, p(trend) < 0.0001, c statistic 0.71). Among the elderly, although the distribution of scores was shifted toward higher risk, the performance remained (0% to 53.1%, P-trend < 0.0001, c statistic 0.71). CONCLUSIONS A simple risk index from baseline clinical variables routinely obtained at the first patient encounter predicted mortality in a large unselected heterogeneous group of patients with STEMI. (C) 2004 by the American College of Cardiology Foundation. C1 Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. Ovat Res, Seattle, WA USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Wiviott, SD (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM swiviott@partners.org OI Frederick, Paul/0000-0002-7936-5488 NR 29 TC 61 Z9 61 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 18 PY 2004 VL 44 IS 4 BP 783 EP 789 DI 10.1016/j.jacc.2004.05.045 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 845XP UT WOS:000223279000009 PM 15312859 ER PT J AU Inglessis, I Shin, JT Lepore, JJ Palacios, IF Zapol, WM Bloch, KD Semigran, MJ AF Inglessis, I Shin, JT Lepore, JJ Palacios, IF Zapol, WM Bloch, KD Semigran, MJ TI Hernodynamic effects of inhaled nitric oxide in right ventricular myocardial infarction and cardiogenic shock SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID PATENT FORAMEN OVALE; SELECTIVE PULMONARY VASODILATOR; SYSTOLIC FUNCTION; HEART-FAILURE; HYPERTENSION; PRESSURE; LUNG; VASOCONSTRICTION; MANAGEMENT; DOBUTAMINE AB OBJECTIVES We sought to determine whether or not inhaled nitric oxide (NO) could improve hemodynamic function in patients with right ventricular myocardial infarction (RVMI) and cardiogenic shock (CS). BACKGROUND Inhaled NO is a selective pulmonary vasodilator that can decrease right ventricular afterload. METHODS Thirteen patients (7 males and 6 females, age 65 3 years) presenting with electrocardiographic, echocardiographic, and hemodynamic evidence of acute inferior myocardial infarction associated with RVMI and CS were studied. After administration of supplemental oxygen (inspired oxygen fraction [FiO2] = 1.0), hemodynamic measurements were recorded before, during inhalation of NO (80 ppm at FiO2 = 0.90) for 10 min, and 10 min after NO inhalation was discontinued (FiO2, = 1.0). RESULTS Breathing NO decreased the mean right atrial pressure by 12 +/- 3%, mean pulmonary arterial pressure by 13 +/- 2%, and pulmonary vascular resistance by 36 +/- 8% (all p < 0.05). Nitric oxide inhalation increased the cardiac index by 24 +/- 11% and the stroke volume index by 23 +/- 12% (p < 0.05). The NO administration did not change systemic arterial or pulmonary capillary wedge pressures. Contrast echocardiography identified three patients with a patent foramen ovale and right-to-left shunt flow while breathing at FiO2 = 1.0. Breathing NO decreased shunt flow by 56 +/- 5% (p < 0.05) and was associated with markedly improved systemic oxygen saturation. CONCLUSIONS Nitric oxide inhalation results in acute hemodynamic improvement when administered to patients with RVMI and CS. (C) 2004 by the American College of Cardiology Foundation. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Semigran, MJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Bigelow 842,32 Fruit St, Boston, MA 02114 USA. EM msemigran@partners.org FU NHLBI NIH HHS [HL-04021, HL-42397, HL-70896] NR 36 TC 36 Z9 40 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 18 PY 2004 VL 44 IS 4 BP 793 EP 798 DI 10.1016/j.jacc.2004.05.047 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 845XP UT WOS:000223279000011 PM 15312861 ER PT J AU Beausoleil, SA Jedrychowski, M Schwartz, D Elias, JE Villen, J Li, JX Cohn, MA Cantley, LC Gygi, SP AF Beausoleil, SA Jedrychowski, M Schwartz, D Elias, JE Villen, J Li, JX Cohn, MA Cantley, LC Gygi, SP TI Large-scale characterization of HeLa cell nuclear phosphoproteins SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE phosphorylation; mass spectrometry; strong cation exchange chromatography ID TANDEM MASS-SPECTROMETRY; PROTEIN-PHOSPHORYLATION; YEAST PROTEOME; PEPTIDES; KINASE; CHROMATOGRAPHY; IDENTIFICATION; ENRICHMENT; SUBSTRATE; EXPRESSION AB Determining the site of a regulatory phosphorylation event is often essential for elucidating specific kinase-substrate relationships, providing a handle for understanding essential signaling pathways and ultimately allowing insights into numerous disease pathologies. Despite intense research efforts to elucidate mechanisms of protein phosphorylation regulation, efficient, large-scale identification and characterization of phosphorylation sites remains an unsolved problem. In this report we describe an application of existing technology for the isolation and identification of phosphorylation sites. By using a strategy based on strong cation exchange chromatography, phosphopeptides were enriched from the nuclear fraction of HeLa cell lysate. From 967 proteins, 2,002 phosphorylation sites were determined by tandem MS. This unprecedented large collection of sites permitted a detailed accounting of known and unknown kinase motifs and substrates. C1 Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Taplin Biol Mass Spectrometry Facil, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Gygi, SP (reprint author), Harvard Univ, Sch Med, Dept Syst Biol, 240 Longwood Ave, Boston, MA 02115 USA. EM steven_gygi@hms.harvard.edu RI Cantley, Lewis/D-1800-2014; OI Cantley, Lewis/0000-0002-1298-7653; Cohn, Martin/0000-0002-2988-3009; Villen, Judit/0000-0002-1005-1739 FU NHGRI NIH HHS [HG00041, K22 HG000041, T32 HG000041]; NIGMS NIH HHS [GM67945, GMS6203, R01 GM056203, R01 GM067945] NR 34 TC 1006 Z9 1075 U1 7 U2 89 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 17 PY 2004 VL 101 IS 33 BP 12130 EP 12135 DI 10.1073/pnas.0404720101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 847QN UT WOS:000223410100041 PM 15302935 ER PT J AU Ntziachristos, V Schellenberger, EA Ripoll, J Yessayan, D Graves, E Bogdanov, A Josephson, L Weissleder, R AF Ntziachristos, V Schellenberger, EA Ripoll, J Yessayan, D Graves, E Bogdanov, A Josephson, L Weissleder, R TI Visualization of antitumor treatment by means of fluorescence molecular tomography with an annexin V-Cy5.5 conjugate SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE drug discovery; quantification; three-dimensional ID DIFFUSE OPTICAL TOMOGRAPHY; IN-VIVO; TURBID MEDIA; APOPTOSIS; BREAST; LIGHT; RECONSTRUCTION; SPECTROSCOPY; SYSTEM AB in vivo imaging of treatment responses at the molecular level could have a significant impact on the speed of drug discovery and ultimately lead to personalized medicine. Strong interest has been shown in developing quantitative fluorescence-based technologies with good molecular specificity and sensitivity for noninvasive 3D imaging through tissues and whole animals. We show herein that tumor response to chemotherapy can be accurately resolved by fluorescence molecular tomography (FMT) with a phosphaticlylserine-sensing fluorescent probe based on modified annexins. We observed at least a 10-fold increase of fluorochrome concentration in cyclophosphamide-sensitive tumors and a 7-fold increase of resistant tumors compared with control studies. FMT is an optical imaging technique developed to overcome limitations of commonly used planar illumination methods and demonstrates higher quantification accuracy validated by histology. It is further shown that a 3-fold variation in background absorption heterogeneity may yield 100% errors in planar imaging but only 20% error in FMT, thus confirming tomographic imaging as a preferred tool for quantitative investigations of fluorescent probes in tissues. Tomographic approaches are found essential for small-animal optical imaging and are potentially well suited for clinical drug development and monitoring. C1 Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Ntziachristos, V (reprint author), Massachusetts Gen Hosp, Ctr Mol Imaging Res, Bldg 149,13th St,5209, Charlestown, MA 02129 USA. EM vasilis@helix.mgh.harvard.edu RI Ripoll, Jorge/J-8134-2012 OI Ripoll, Jorge/0000-0001-8856-7738 FU NCI NIH HHS [R33 CA 91807, P50 CA 86355, P50 CA086355, R33 CA091807, T32 CA 79443, T32 CA079443]; NIBIB NIH HHS [R01 EB 00750-1, R01 EB000750] NR 31 TC 268 Z9 271 U1 1 U2 30 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 17 PY 2004 VL 101 IS 33 BP 12294 EP 12299 DI 10.1073/pnas.0401137101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 847QN UT WOS:000223410100070 PM 15304657 ER PT J AU Ni, X Zhang, W Huang, KC Wang, Y Ng, SK Mok, SC Berkowitz, RS Ng, SW AF Ni, X Zhang, W Huang, KC Wang, Y Ng, SK Mok, SC Berkowitz, RS Ng, SW TI Characterisation of human kallikrein 6 protease M expression in ovarian cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE serine protease; monoclonal antibody; ovarian cancer; biomarker; gene amplification ID PROSTATE-SPECIFIC ANTIGEN; TUMOR-MARKERS; CARCINOMA; ASSOCIATION; FUTURE; SERUM; CELLS AB Kallikrein 6 (hK6, also known as protease M/zyme/neurosin) is a member of the human kallikrein gene family. We have previously cloned the cDNA for this gene by differential display and shown the overexpression of the mRNA in breast and ovarian primary tumour tissues and cell lines. To thoroughly characterise the expression of this kallikrein in ovarian cancer, we have developed a novel monoclonal antibody specific to hK6 and employed it in immunohistochemistry with a wide range of ovarian tumour samples. The expression was found elevated in 67 of 80 cases of ovarian tumour samples and there was a significant difference in the expression levels between normal and benign ovarian tissues and the borderline and invasive tumours (P<0.001). There was no difference of expression level between different subtypes of tumours. More significantly, high level of kallikrein 6 expression was found in many early-stage and low-grade tumours, and elevated hK6 proteins were found in benign epithelia coexisting with borderline and invasive tissues, suggesting that overexpression of hK6 is an early phenomenon in the development of ovarian cancer. Quantitative real-time reverse transcription-polymerase chain reactions also showed elevated kallikrein 6 mRNA expression in ovarian tumours. Genomic Southern analysis of 19 ovarian tumour samples suggested that gene amplification is one mechanism for the overexpression of hK6 in ovarian cancer. C1 Brigham & Womens Hosp, Div Gynecol Oncol, Lab Gynecol Oncol, Boston, MA 02115 USA. Dana Farber Harvard Canc Ctr, Gillette Ctr Womens Canc, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Univ Queensland, Ctr Stat, Dept Math, Brisbane, Qld, Australia. RP Ng, SW (reprint author), Lab Gynecol Oncol, 221 Longwood Ave,BLI 449A, Boston, MA 02115 USA. EM sng@rics.bwh.harvard.edu FU NCI NIH HHS [U01 CA086381, CA86381] NR 32 TC 46 Z9 52 U1 0 U2 0 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 AUG 16 PY 2004 VL 91 IS 4 BP 725 EP 731 DI 10.1038/sj.bjc.6602041 PG 7 WC Oncology SC Oncology GA 844YT UT WOS:000223201600022 PM 15305183 ER PT J AU Wiviott, SD de Lemos, JA Morrow, DA AF Wiviott, SD de Lemos, JA Morrow, DA TI Pathophysiology, prognostic significance and clinical utility of B-type natriuretic peptide in acute coronary syndromes SO CLINICA CHIMICA ACTA LA English DT Review DE natriuretic peptides; BNP; ANP; NT-pro-BNP; acute coronary syndrome; myocardial infarction; unstable angina; review ID ACUTE MYOCARDIAL-INFARCTION; C-REACTIVE PROTEIN; INCREASED PLASMA-LEVELS; N-TERMINAL PROATRIAL; SERUM TROPONIN-T; UNSTABLE ANGINA; HEART-FAILURE; CARDIOVASCULAR-DISEASE; ARTERY-DISEASE; RISK STRATIFICATION AB The natriuretic hormones are a family of vasoactive peptides that can be measured circulating in the blood. Because they serve as markers of hemodynamic stress, the major focus of the use of natriuretic peptide levels [predominantly B-type natriuretic peptide (BNP) and N-terminal (NT)-pro-BNP] has been as an aid to the clinical diagnosis and management of congestive heart failure (CHF). Recently, however, the measurement of natriuretic peptides in the acute coronary syndromes (ACS) has been shown to provide information complementary to traditional biomarkers (of necrosis) such as cardiac troponins and creatine kinase (CK). Studies in several types of acute coronary syndromes [ST-segment elevation myocardial infarction (STEMI), non-ST elevation MI (NSTEMI) and unstable angina (UA)] have shown that elevated levels of natriuretic peptides are independently associated with adverse outcomes, particularly mortality. Additional information is obtained from the use natriuretic peptides in combination with other markers of risk including biomarkers of necrosis and inflammation. This review will summarize the scientific rationale and clinical evidence supporting measurement of natriuretic peptides for risk stratification in acute coronary syndromes. Future research is needed to identify therapies of particular benefit for patients with ACS and natriuretic peptide elevation. (C) 2004 Elsevier B.V. All rights reserved. C1 Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. RP Morrow, DA (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM dmorrow@partners.org NR 48 TC 25 Z9 34 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD AUG 16 PY 2004 VL 346 IS 2 BP 119 EP 128 DI 10.1016/j.cccn.2004.04.004 PG 10 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 842ZH UT WOS:000223042700002 PM 15256312 ER PT J AU Sonnenberg, A AF Sonnenberg, A TI Personal view: 'Don't ask, don't tell' - the undesirable consequences of incidental test results in gastroenterology SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID HELICOBACTER-PYLORI; GUIDELINES; THERAPY; ARTICLE AB A gastroenterologist is frequently approached to perform an endoscopic procedure after an incidental test has resulted in an unexpected positive finding. Should the incidental test result be ignored or automatically followed by an endoscopic procedure? The present analysis strives to characterize the common pattern of such scenarios and resolve their underlying dilemma. A model of game theory is used as a mathematical tool to develop general management strategies. Three clinical scenarios are used as examples to demonstrate this approach. The model is based on how doctors rank the various outcomes with which they are confronted by the incidental test results. The ranks of different outcomes are listed in a decision matrix that is converted into a two-by-two, non-zero, ordinal game. All scenarios of incidental test results emerge as a similar type of game that is best played by both parties adhering to the same set of strategies: 'Don't do the test' and 'don't respond to whatever test result it yields'. These two strategies lead to a Nash equilibrium for a non-zero game, where neither party can improve its payoff any further by choosing a different strategy. Although the equilibrium does not provide the individual players with their best possible payoff, it yields the best overall outcome available to both parties given the economic and medical constraints of the situation. C1 Portland VA Med Ctr, Gastroenterol Sect, Portland, OR 97239 USA. Oregon Hlth & Sci Univ, Portland, OR USA. RP Sonnenberg, A (reprint author), Portland VA Med Ctr, Gastroenterol Sect, P3-GI,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM sonnenbe@ohsu.edu NR 16 TC 5 Z9 5 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0269-2813 J9 ALIMENT PHARM THERAP JI Aliment. Pharmacol. Ther. PD AUG 15 PY 2004 VL 20 IS 4 BP 381 EP 387 DI 10.1111/j.1365-2036.2004.02087.x PG 7 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 844JK UT WOS:000223154000002 PM 15298631 ER PT J AU Chen, HL Zhang, SMM Schwarzschild, MA Hernan, MA Logroscino, G Willett, WC Ascherio, A AF Chen, HL Zhang, SMM Schwarzschild, MA Hernan, MA Logroscino, G Willett, WC Ascherio, A TI Folate intake and risk of Parkinson's disease SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cohort studies; diet; folic acid; homocysteine; Parkinson disease ID FOOD FREQUENCY QUESTIONNAIRE; CORONARY-HEART-DISEASE; TOTAL-ENERGY INTAKE; PLASMA HOMOCYSTEINE; ALZHEIMERS-DISEASE; VITAMIN STATUS; NURSES HEALTH; BREAST-CANCER; L-DOPA; WOMEN AB In clinical studies, individuals with Parkinson's disease have had higher concentrations of plasma homocysteine than did controls, and experimental evidence suggests that folate deficiency or focal administration of homocysteine sensitizes dopaminergic neurons to the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The authors thus prospectively investigated whether higher intake of folate, vitamin B-6, or vitamin B-12 was related to a lower risk of Parkinson's disease in the Health Professionals Follow-up Study (1986-2000) and the Nurses' Health Study (1980-1998). They documented Parkinson's disease diagnoses in 248 men and 167 women during the follow-up. Folate intake was not associated with the risk of Parkinson's disease; the relative risks for the highest compared with the lowest quintiles were 1.0 (95% confidence interval: 0.7, 1.5) in men and 1.3 (95% confidence interval: 0.8, 2.3) in women. Neither did they find significant associations in analyses stratified by age, smoking, alcohol consumption, or lactose intake. Intake of vitamin B-6 or vitamin B-12 also was not related to the risk of Parkinson's disease. The current study does not support the hypothesis that higher intake of folate or related B vitamins lowers the risk of Parkinson's disease. C1 Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Chen, HL (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. EM hchen@hsph.harvard.edu RI LOGROSCINO, GIANCARLO/K-5148-2016; OI LOGROSCINO, GIANCARLO/0000-0003-0423-3242; Chen, Honglei/0000-0003-3446-7779 FU NCI NIH HHS [CA87969]; NINDS NIH HHS [NS35624] NR 40 TC 35 Z9 36 U1 1 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2004 VL 160 IS 4 BP 368 EP 375 DI 10.1093/aje/kwh213 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 844EX UT WOS:000223141400009 PM 15286022 ER PT J AU Poorkaj, P Nutt, JG James, D Gancher, S Bird, TD Steinbart, E Schellenberg, GD Payami, H AF Poorkaj, P Nutt, JG James, D Gancher, S Bird, TD Steinbart, E Schellenberg, GD Payami, H TI parkin mutation analysis in clinic patients with early-onset Parkinson's disease SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Parkinson's disease; parkin; clinical testing; gene dosage ID RECESSIVE JUVENILE PARKINSONISM; PSEUDO-DOMINANT INHERITANCE; GENE-MUTATIONS; LEWY BODIES; 2 FAMILIES; PHENOTYPE; PATHWAY; ALLELES; EUROPE AB parkin mutations are the most common identified cause of Parkinson's disease (PD). It has been suggested that patients with young-onset PD be screened for parkin mutations as a part of their clinical work-up. The aim of this study was to assess parkin mutation frequency in a clinical setting, correlate genotype with phenotype, and evaluate the current justification for clinical parkin testing. Patients were selected from a movement disorder clinic based on diagnosis of PD and onset age less than or equal to 40 years.parkin was genotyped by sequence and dosage analysis for all 12 exons. Key relatives and controls were screened for identified mutations. Mutations were found in 7/ 39 patients. Two patients were compound heterozygous; five were heterozygous. Mutations included deletions in exons 2, 3, and 8, duplications in exons 2-4, and 9, and P437L substitution. Seventy-eight percent of mutations were deletions/multiplications. A novel substitution (R402W) was found in one patient and in one control. None of the point mutations found in patients were detected in 96 controls. parkin phenotypes were consistent with idiopathic PD. In conclusion, parkin mutations are common in the clinic setting: 10% of PD patients had early-onset and 18% of them had parkin mutations. However, if parkin is recessive, only 5% of early-onset cases who had compound mutations could be attributed to this locus. Mutation frequency was 0.12 (95% Cl 0.04-0.19). parkin cases can present as typical idiopathic PD, distinguishable only by molecular testing. Seventy percent of parkin cases were heterozygous. It is unclear whether heterozygous mutations are pathogenic. parkin-based diagnosis and counseling require a better understanding of the mode of inheritance, penetrance, and carrier frequencies. (C) 2004 Wiley-Liss, Inc. C1 Vet Affairs Puget Sound Hlth Care Syst, Seattle Div, Ctr Geriatr Res Educ & Clin, Seattle, WA USA. Univ Washington, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR USA. New York State Dept Hlth, Wadsworth Ctr, Genom Inst, Div Genet Disorders, Albany, NY 12208 USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. Univ Washington, Dept Neurol, Seattle, WA 98195 USA. Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. RP Payami, H (reprint author), New York State Dept Hlth, Wadsworth Ctr, Genom Inst, Div Genet Disorders, 120 New Scotland Ave, Albany, NY 12208 USA. EM hpayami@wadsworth.org FU NINDS NIH HHS [R01 NS36960] NR 32 TC 31 Z9 32 U1 1 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG 15 PY 2004 VL 129A IS 1 BP 44 EP 50 DI 10.1002/ajmg.a.30157 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 842AP UT WOS:000222975000010 PM 15266615 ER PT J AU Kolevzon, A Smith, CJ Schmeidler, J Buxbaum, JD Silverman, JM AF Kolevzon, A Smith, CJ Schmeidler, J Buxbaum, JD Silverman, JM TI Familial symptom domains in monozygotic siblings with autism SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE autism; monozygotic twins; concordance; genetics; heterogeneity; symptom domains ID PERVASIVE DEVELOPMENTAL DISORDERS; MULTIPLEX FAMILIES; CHROMOSOME 7Q; CHILDREN; LANGUAGE; HISTORY; TWINS; INDIVIDUALS; LINKAGE; PHENOTYPES AB Autism is characterized by a triad of symptom domains (impaired social interaction, communication deficits, and repetitive behaviors) that vary significantly in their clinical presentation across the population. Within families with more than one affected member, however, discrepant findings exist with regard to symptom variability. Reduced intrafamily variance is of particular importance because it supports an underlying model of genetic heterogeneity in the transmission of autism, and the identification of familial clinical subtypes can be used to select more homogeneous samples for linkage analysis in the future. This study examines whether there are specific features of autism that show decreased variance within 16 families with monozygotic siblings concordant for autism. Evidence for familiality was defined as significantly decreased variance of symptom levels within monozygotic siblingships as compared to between siblingships. Using regression analysis, we demonstrated Significant aggregation of symptoms within monozygotic siblingships for two of the three main symptom domains in autism: impairments in communication and social interaction showed significant familiality. Within the repetitive behavior domain, only the categories of circumscribed interests and preoccupation with part-objects showed reduced variance within siblingships. In addition, with the exception of a negative association between the social and behavior domains, partial correlation coefficients did not reveal significant associations between the levels of different symptom domains within families, suggesting that the levels of clinical features seen in autism may be a result of mainly independent genetic traits. Because of presumed genetic heterogeneity and the wide clinical variation seen in autism and other pervasive developmental disorders, selecting probands according to specific features known to show reduced variance within families may provide more homogeneous samples for genetic analysis and strengthen the power to detect the specific genes involved in autism. (C) 2004 Wiley-Liss, Inc. C1 Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. Bronx Vet Adm Med Ctr, Psychiat Serv, Bronx, NY USA. Mt Sinai Sch Med, Seaver Autism Res Ctr, New York, NY USA. RP Kolevzon, A (reprint author), Mt Sinai Sch Med, Dept Psychiat, Box 1230,1 Gustave L Levy Pl, New York, NY 10029 USA. EM alexander.kolevzon@mssm.edu OI Buxbaum, Joseph/0000-0001-8898-8313 FU NIMH NIH HHS [U54 MH 066673] NR 34 TC 35 Z9 35 U1 3 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD AUG 15 PY 2004 VL 129B IS 1 BP 76 EP 81 DI 10.1002/ajmg.b.30011 PG 6 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 842AW UT WOS:000222975700018 PM 15274045 ER PT J AU Wiest, FC Bryson, CL Burman, M McDonell, MB Henikoff, JG Fihn, SD AF Wiest, FC Bryson, CL Burman, M McDonell, MB Henikoff, JG Fihn, SD TI Suboptimal pharmacotherapeutic management of chronic stable angina in the primary care setting SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; CORONARY-ARTERY-DISEASE; CONGESTIVE-HEART-FAILURE; PRACTICE GUIDELINES; FUNCTIONAL STATUS; ELDERLY-PATIENTS; HEALTH-STATUS; PHYSICIAN SPECIALTY; MEDICAL-TREATMENT; BETA-BLOCKERS AB PURPOSE: To assess the adequacy of symptomatic treatment for chronic stable angina among primary care patients who receive care from the Department of Veterans Affairs (VA). METHODS: We conducted a cross-sectional analysis involving 7038 veterans with self-reported coronary heart disease who completed the Seattle Angina Questionnaire and who had made a primary care visit to one of seven VA general internal medicine clinics between May 1997 and January 2000. The main outcome measures included the anginal frequency scale of the questionnaire and receipt of prescriptions for antianginal medication in three classes (beta-blockers, calcium antagonists, and long-acting nitrates). RESULTS: Seventy percent of the patients experienced angina or took sublingual nitroglycerin preparations two or fewer times per week. Of the 30% of patients with more frequent symptoms, 22% were receiving no antianginal medications and 33% were receiving only one class of antianginal medication. Of the patients with frequent angina who were prescribed medications, 18% were taking no medications at the recommended therapeutic dose and 50% were receiving only one class of antianginal medication at the recommended therapeutic dose. CONCLUSION: A substantial proportion of patients with frequent episodes of chronic stable angina appeared to be receiving an inadequate antianginal regimen in terms of number of agents and dosages. While numerous studies have described inadequate treatment of asymptomatic conditions and risk factors, our results suggest similar deficiencies in addressing a serious and eminently treatable symptomatic problem. (C) 2004 by Elsevier Inc. C1 Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res & Dev Ctr Excellence, Seattle, WA 98108 USA. RP Bryson, CL (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res & Dev Ctr Excellence, 1660 S Columbian Way,Mail Stop 152, Seattle, WA 98108 USA. EM cbryson@u.washington.edu NR 44 TC 32 Z9 33 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD AUG 15 PY 2004 VL 117 IS 4 BP 234 EP 241 DI 10.1016/j.amjmed.2004.02.044 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 846NW UT WOS:000223323500003 PM 15308432 ER PT J AU Burton, EC Phillips, RS Covinsky, KE Sands, LP Goldman, L Dawson, NV Connors, AF Landefeld, CS AF Burton, EC Phillips, RS Covinsky, KE Sands, LP Goldman, L Dawson, NV Connors, AF Landefeld, CS TI The relation of autopsy rate to physicians' beliefs and recommendations regarding autopsy SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID ILL HOSPITALIZED ADULTS; QUALITY-ASSURANCE; CLINICIAN; ATTITUDES; SUPPORT; PATHOLOGIST; DIAGNOSES; MORTALITY; CONSENT; TRENDS AB PURPOSE: Multiple factors have affected the decline in autopsy rates. Our goal was to determine the relation of physicians' recommendations regarding autopsy, as well as patient and surrogate decision-maker characteristics, to autopsy performance. METHODS: We assessed measures related to autopsy performance using data from two teaching institutions in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments. We included patients who had died within 6 months of their index hospitalization and for whom information was available on autopsy performance,. physicians' response to questions about autopsy, and interviews with surrogate decision makers about autopsy performance. We assessed the association between autopsy performance and the strength of a physician's recommendation for autopsy, adjusting for patient, surrogate, and physician characteristics. RESULTS: Of the 680 patients who died, 59% (n = 402) met our inclusion criteria. Based on physician and surrogate responses, the expected autopsy rate was 42% while the actual autopsy rate was 23%. The autopsy rate was higher when the physician's recommendation for autopsy was strong or very strong at the time of death compared with when autopsy was not recommended strongly or not at all (P <0.001). The strength of the physician's postmortem recommendation was independently associated with autopsy performance after adjusting for patient, surrogate, and physician characteristics (P <0.001). CONCLUSION: Autopsies are less likely to be performed when not recommended strongly or not at all. Training physicians (or others) how to recommend autopsies may increase autopsy rates. (C) 2004 by Elsevier Inc. C1 Baylor Univ, Med Ctr, Dept Pathol, Dallas, TX 75246 USA. Beth Israel Deaconess Med Ctr, Dept Med, Div Gen Med & Primary Care, Boston, MA 02215 USA. San Francisco VA Med Ctr, Dept Vet Affairs, Natl Qual Scholars Fellowship Program, San Francisco, CA USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. Univ Calif San Francisco, Ctr Aging, San Francisco, CA 94143 USA. Purdue Univ, Dept Nursing, W Lafayette, IN 47907 USA. Case Western Reserve Univ, Ctr Hlth Care Res & Policy, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. Metro Hlth Med Ctr, Cleveland, OH USA. RP Burton, EC (reprint author), Baylor Univ, Med Ctr, Dept Pathol, 5th Floor,Y Wing,3500 Gaston Ave, Dallas, TX 75246 USA. EM LizBu@baylorhealth.edu RI Sands, Laura/E-8919-2015 OI Sands, Laura/0000-0003-2446-4486 NR 39 TC 28 Z9 28 U1 2 U2 3 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD AUG 15 PY 2004 VL 117 IS 4 BP 255 EP 261 DI 10.1016/j.amjmed.2004.01.028 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 846NW UT WOS:000223323500006 PM 15308435 ER PT J AU Gurubhagavatula, I Maislin, G Nkwuo, JE Pack, AI AF Gurubhagavatula, I Maislin, G Nkwuo, JE Pack, AI TI Occupational screening for obstructive sleep apnea in commercial drivers SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE nocturnal pulse oximetry; polysomnography; questionnaire ID POSITIVE AIRWAY PRESSURE; PROSPECTIVE PARALLEL TRIAL; DAYTIME SLEEPINESS; POPULATION; PERFORMANCE; ADULTS; RISK; CPAP; PREDICTION; DISORDERS AB Excluding the presence of obstructive sleep apnea in commercial drivers is valuable, as the syndrome may increase their risk of sleepiness-related accidents. Using polysomnography as the criterion standard, we prospectively compared accuracies of five strategies in excluding the presence of severe sleep apnea and, secondarily, any sleep apnea among 406 commercial drivers. These strategies were as follows: (1) symptoms; (2) body mass index; (3) symptoms plus body mass index; (4) a two-stage approach with symptoms plus body mass index for everyone, followed by oximetry for a subset; and (5) oximetry for all. For excluding severe apnea, the two-stage strategy was highly successful, with 91% sensitivity and specificity, and a negative likelihood ratio of 0.10. This strategy was comparable in accuracy to oximetry, which had a negative likelihood ratio of 0.12, and was 88% sensitive and 95% specific. If we avoided oximetry altogether, then symptoms together with body mass index were 81% sensitive and 73% specific, with a negative likelihood ratio of 0.26. On the other hand, excluding any apnea could not be done with reasonable accuracy unless oximetry was used. We conclude that two-stage screening is likely to be a viable means of excluding severe sleep apnea among commercial drivers. C1 Univ Penn, Neurobiol Hosp, Ctr Sleep & Resp, Philadelphia, PA 19104 USA. Univ Penn, Med Ctr, Ctr Sleep & Resp Neurobiol, Philadelphia, PA 19104 USA. Univ Penn, Med Ctr, Dept Med, Div Sleep Med, Philadelphia, PA 19104 USA. Philadelphia Vet Affairs Med Ctr, Pulm & Crit Care & Sleep Sect, Philadelphia, PA USA. RP Gurubhagavatula, I (reprint author), Univ Penn, Neurobiol Hosp, Ctr Sleep & Resp, 9th Floor,Maloney Bldg,3600 Spruce St, Philadelphia, PA 19104 USA. EM gurubhag@mail.med.upenn.edu FU NCRR NIH HHS [K23-RR16068-03, 3-M01-RR00040, K23 RR016068]; NHLBI NIH HHS [P01-HL60287] NR 42 TC 64 Z9 65 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 AUG 15 PY 2004 VL 170 IS 4 BP 371 EP 376 DI 10.1164/rccm.200307-968OC PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 845DY UT WOS:000223217300008 PM 15142866 ER PT J AU Stone, RM AF Stone, RM TI FLT3 target practice SO BLOOD LA English DT Editorial Material ID LEUKEMIA C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Stone, RM (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 5 TC 1 Z9 1 U1 0 U2 0 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 AUG 15 PY 2004 VL 104 IS 4 BP 915 EP 916 DI 10.1182/blood-2004-05-1929 PG 2 WC Hematology SC Hematology GA 844GK UT WOS:000223145800008 ER PT J AU Ebert, BL Golub, TR AF Ebert, BL Golub, TR TI Genomic approaches to hematologic malignancies SO BLOOD LA English DT Review ID B-CELL LYMPHOMA; ACUTE LYMPHOBLASTIC-LEUKEMIA; EXPRESSION PROFILING REVEALS; CHRONIC LYMPHOCYTIC-LEUKEMIA; HEMATOPOIETIC STEM-CELLS; ACUTE MYELOID-LEUKEMIA; MYELODYSPLASTIC BONE-MARROW; DNA MICROARRAY ANALYSIS; GENE-EXPRESSION; HODGKIN LYMPHOMA AB In the past several years, experiments using DNA microarrays have contributed to an increasingly refined molecular taxonomy of hematologic malignancies. In addition to the characterization of molecular profiles for known diagnostic classifications, studies have defined patterns of gene expression corresponding to specific molecular abnormalities, oncologic phenotypes, and clinical outcomes. Furthermore, novel subclasses with distinct molecular profiles and clinical behaviors have been identified. In some cases, specific cellular pathways have been highlighted that can be therapeutically targeted. The findings of microarray studies are beginning to enter clinical practice as novel diagnostic tests, and clinical trials are ongoing in which therapeutic agents are being used to target pathways that were identified by gene expression profiling. While the technology of DNA microarrays is becoming well established, genome-wide surveys of gene expression generate large data sets that can easily lead to spurious conclusions. Many challenges remain in the statistical interpretation of gene expression data and the biologic validation of findings. As data accumulate and analyses become more sophisticated, genomic technologies offer the potential to generate increasingly sophisticated insights into the complex molecular circuitry of hematologic malignancies. This review summarizes the current state of discovery and addresses key areas for future research. (C) 2004 by The American Society of Hematology. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. MIT, Broad Inst, Cambridge, MA 02139 USA. RP Golub, TR (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St,D640, Boston, MA 02115 USA. EM golub@broad.mit.edu FU NCI NIH HHS [T32 CA009172] NR 74 TC 83 Z9 90 U1 0 U2 4 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 AUG 15 PY 2004 VL 104 IS 4 BP 923 EP 932 DI 10.1182/blood-2004-01.0274 PG 10 WC Hematology SC Hematology GA 844GK UT WOS:000223145800011 PM 15155462 ER PT J AU Kunstfeld, R Hirakawa, S Hong, YK Schacht, V Lange-Asschenfeldt, B Velasco, P Lin, C Fiebiger, E Wei, XB Wu, Y Hicklin, D Bohlen, P Detmar, M AF Kunstfeld, R Hirakawa, S Hong, YK Schacht, V Lange-Asschenfeldt, B Velasco, P Lin, C Fiebiger, E Wei, XB Wu, Y Hicklin, D Bohlen, P Detmar, M TI Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia SO BLOOD LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; TUMOR LYMPHANGIOGENESIS; TYROSINE KINASE; ANGIOGENESIS; CELLS; RECEPTOR; OVEREXPRESSION; PSORIASIS; IDENTIFICATION; VASCULATURE AB Vascular endothelial growth factor-A (VEGF-A) expression is up-regulated in several inflammatory diseases including psoriasis, delayed-type hypersensitivity (DTH) reactions, and rheumatoid arthritis. To directly characterize the biologic function of VEGF-A in inflammation, we evaluated experimental DTH reactions induced in the ear skin of transgenic mice that overexpress VEGF-A specifically in the epidermis. VEGF-A transgenic mice underwent a significantly increased inflammatory response that persisted for more than 1 month, whereas inflammation returned to baseline levels within 7 days in wild-type mice. Inflammatory lesions in VEGF-A transgenic mice closely resembled human psoriasis and were characterized by epidermal hyperplasia, impaired epidermal differentiation, and accumulation of dermal CD4(+) T-lymphocytes and epidermal CD8(+) lymphocytes. Surprisingly, VEGF-A also promoted lymphatic vessel proliferation and enlargement, which might contribute to the increased inflammatory response, as lymphatic vessel enlargement was also detected in human psoriatic skin lesions. Combined systemic treatment with blocking antibodies against VEGF receptor-1 (VEGFR-1) and VEGFR-2 potently inhibited inflammation and also decreased lymphatic vessel size. Together, these findings reveal a central role of VEGF-A in promoting lymphatic enlargement, vascular hyperpermeability, and leukocyte recruitment, thereby leading to persistent chronic inflammation. They also indicate that inhibition of VEGF-A bioactivity might be a new approach to anti-inflammatory therapy. (C) 2004 by The American Society of Hematology. C1 Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Wellman Labs Photomed, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Dermatol, New York, NY USA. Harvard Univ, Sch Med, Dept Pathol, New York, NY USA. ImClone Syst Inc, New York, NY USA. RP Detmar, M (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Bldg 149,13th St, Charlestown, MA 02129 USA. EM michael.detmar@cbrc2.mgh.harvard.edu FU NCI NIH HHS [CA86410, CA69184, CA92644]; NIBIB NIH HHS [EB000664] NR 44 TC 187 Z9 194 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 AUG 15 PY 2004 VL 104 IS 4 BP 1048 EP 1057 DI 10.1182/blood-2003-08-2964 PG 10 WC Hematology SC Hematology GA 844GK UT WOS:000223145800028 PM 15100155 ER PT J AU Ho, VT Zahrieh, D Hochberg, E Micale, E Levin, J Reynolds, C Steckel, S Cutler, C Fisher, DC Lee, SJ Alyea, EP Ritz, J Soiffer, RJ Antin, JH AF Ho, VT Zahrieh, D Hochberg, E Micale, E Levin, J Reynolds, C Steckel, S Cutler, C Fisher, DC Lee, SJ Alyea, EP Ritz, J Soiffer, RJ Antin, JH TI Safety and efficacy of denileukin diftitox in patients with steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation SO BLOOD LA English DT Article ID MARROW TRANSPLANTATION; THERAPY AB Denileukin diftitox (Ontak), a recombinant protein composed of human interleukin 2 (IL-2) fused to diphtheria toxin, has selective cytotoxicity against activated lymphocytes expressing the high-affinity IL-2 receptor. We conducted a phase 1 study of denileukin diftitox in 30 patients with steroid refractory acute graft-versus-host disease (GVHD). Seven patients received 9 mug/kg intravenously on days 1 and 15; 18 received 9 mug/kg intravenously on days 1, 3, 5, 15, 17, and 19; and 5 received 9 mug/kg intravenously on days 1 to 5 and 15 to 19. Hepatic transaminase elevation was the dose-limiting toxicity (DLT), and dose level 2 was the maximum tolerated dose (MTD). Overall, 71% of patients responded with complete resolution (112 of 24; 50%) or partial resolution (5 of 24; 21%) of GVHD. Eight of 24 patients (33%) are alive at 6.3 to 24.6 months (median, 7.2 months). Denileukin diftitox is tolerable and has promising activity in steroid-refractory acute GVHD. (C) 2004 by The American Society of Hematology. C1 Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med, Div Med Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med, Div Biostat, Boston, MA 02115 USA. Ligand Pharmaceut Inc, San Diego, CA USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Ho, VT (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med, Div Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM vtho@partners.org RI Ritz, Jerome/C-7929-2009 OI Ritz, Jerome/0000-0001-5526-4669 FU NHLBI NIH HHS [HL070149-01]; NIAID NIH HHS [AI29530] NR 6 TC 99 Z9 102 U1 0 U2 0 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 AUG 15 PY 2004 VL 104 IS 4 BP 1224 EP 1226 DI 10.1182/blood-2004-01-0028 PG 3 WC Hematology SC Hematology GA 844GK UT WOS:000223145800051 PM 15113758 ER PT J AU Freedland, SJ Aronson, WJ Kane, CJ Terris, MK Presti, JC Trock, B Amling, CL AF Freedland, SJ Aronson, WJ Kane, CJ Terris, MK Presti, JC Trock, B Amling, CL TI Biochemical outcome after radical prostatectomy among men with normal preoperative serum prostate-specific antigen levels SO CANCER LA English DT Article DE prostate carcinoma; radical prostatectomy; prostate-specific antigen; prostate-specific antigen recurrence ID DISEASE RECURRENCE; RADIATION-THERAPY; CANCER; CUTOFF; SPECIMENS; NOMOGRAM; SURVIVAL; NG./ML.; NG/ML; STAGE AB BACKGROUND. Recent studies have shown that a significant number of men with normal prostate-specific antigen (PSA) levels have prostate carcinoma, Whether malignancies in such men are associated with better outcomes is unclear. The authors compared the risk of biochemical failure after radical prostatectomy (RP) between men with normal PSA levels and men with elevated PSA levels. METHODS. Data were examined from 1582 men who underwent RP between 1988 and 2002 at I of 5 equal-access medical centers. Patients were segregated into groups based on serum PSA levels (with stratification according to age-specific reference ranges). Clinical and pathologic characteristics and biochemical outcome data were compared across groups using analyses of variance, log-rank tests, and Cox proportional hazards analysis. RESULTS. Men who had normal PSA levels had significantly fewer high-grade tumors compared with men who had higher PSA levels (P < 0.001). The former group had a significantly decreased incidence of positive surgical margins, extracapsular disease, seminal vesicle invasion, and lymph node involvement (P < 0.001). On multivariate analysis, only serum PSA level (P < 0.001) and biopsy Gleason score (P < 0.001) predicted the time to disease recurrence. When only men with serum PSA levels < 10 ng/mL were examined, PSA level treated as a continuous variable remained a significant predictor of time to biochemical failure (P = 0.02). CONCLUSIONS. Men who had normal PSA levels had significantly fewer high-grade tumors and significantly better biochemical outcomes after undergoing RP compared with men who had elevated PSA levels. Overall, men with normal PSA levels who undergo RP represent a favorable risk group. Cancer 2004;101:748-53. (C) 2004 American Cancer Society. C1 Johns Hopkins Sch Med, Dept Urol, Baltimore, MD 21287 USA. Vet Adm Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Dept Urol, Los Angeles, CA USA. Vet Adm Med Ctr, Urol Sect, Dept Surg, San Francisco, CA 94121 USA. Univ Calif San Francisco, Sch Med, Dept Urol, San Francisco, CA 94143 USA. Med Coll Georgia, Dept Surg, Urol Sect, Augusta, GA 30912 USA. Stanford Univ, Sch Med, Dept Urol, Palo Alto, CA 94304 USA. San Diego Naval Hosp, Dept Urol, San Diego, CA USA. RP Freedland, SJ (reprint author), Johns Hopkins Sch Med, Dept Urol, 600 N Wolfe St, Baltimore, MD 21287 USA. EM sfreedl1@jhmi.edu OI Terris, Martha/0000-0002-3843-7270 NR 24 TC 14 Z9 14 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD AUG 15 PY 2004 VL 101 IS 4 BP 748 EP 753 DI 10.1002/cncr.20390 PG 6 WC Oncology SC Oncology GA 843UD UT WOS:000223111200011 PM 15305405 ER PT J AU Chang, G Orav, EJ McNamara, T Tong, MY Antin, JH AF Chang, G Orav, EJ McNamara, T Tong, MY Antin, JH TI Depression, cigarette smoking, and hematopoietic stem cell transplantation outcome SO CANCER LA English DT Article DE depression; cigarette smoking; chronic myelogenous leukemia; hematopoietic stem cell transplantation ID BONE-MARROW-TRANSPLANTATION; CHRONIC MYELOGENOUS LEUKEMIA; NATIONAL COMORBIDITY SURVEY; CHRONIC MYELOID-LEUKEMIA; UNRELATED DONORS; CANCER-PATIENTS; IMMUNE-SYSTEM; SURVIVAL; ABUSE; ONCOLOGISTS AB BACKGROUND. The relationships between psychological and behavioral variables and patient outcomes after hematopoietic stem cell transplantation (HSCT) are not known definitively but have great potential importance, since this lifesaving procedure is used increasingly to treat a variety of malignancies. The objective of this study was to evaluate psychosocial predictors of long-term survival and disease recurrence after patients underwent allogeneic HSCT for chronic myelogenous leukemia (CML). METHODS. in this prospective cohort study, 114 adults were admitted for allogeneic HSCT to the Brigham and Women's Hospital between July, 1997 and January, 2002. The median follow-up was 882 days, and serial measures were taken for mood and substance use 6 months and 12 months posttransplantation. RESULTS. With a 93% participation rate by all potentially eligible patients and with < 3% of patients loss to follow-up, univariate predictors of long-term survival and recurrence were identified. Cox proportional hazards regression models for survival and recurrence were developed. Depressive symptoms, as measured by the most recent Beck Depression Inventory (BDI), increased the risk of death by 7% for each point increase in the BDI score (P = 0.006). Fourteen of 17 patients who developed recurrent disease were cigarette smokers with an average of 22.3 pack-years. For each pack-year of cigarette smoking, the risk of recurrence increased by 1.7% (P = 0.01). CONCLUSIONS. This study assessed the role of psychosocial variables prospectively among a clinically homogeneous but representative cohort of patients who underwent allogeneic HSCT. Although additional confirmatory studies are pending, it appears that depressive symptoms posttransplantation and cigarette smoking prior to transplantation affect outcomes adversely and may represent opportunities to improve the morbidity and mortality associated with HSCT for patients with CML. (C) 2004 American Cancer Society. C1 Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Gen Med & Primary Care, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA. Dana Farber Partners Canc Inst, Dept Med Oncol, Boston, MA USA. RP Chang, G (reprint author), Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA. EM gchang@partners.org FU NIAAA NIH HHS [K24AA00289] NR 45 TC 22 Z9 22 U1 3 U2 6 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD AUG 15 PY 2004 VL 101 IS 4 BP 782 EP 789 DI 10.1002/cncr.20431 PG 8 WC Oncology SC Oncology GA 843UD UT WOS:000223111200016 PM 15305410 ER PT J AU Mullen, JT Donahue, JM Chandrasekhar, S Yoon, SS Liu, WB Ellis, LM Nakamura, H Kasuya, H Pawlik, TM Tanabe, KK AF Mullen, JT Donahue, JM Chandrasekhar, S Yoon, SS Liu, WB Ellis, LM Nakamura, H Kasuya, H Pawlik, TM Tanabe, KK TI Oncolysis by viral replication and inhibition of angiogenesis by a replication-conditional herpes simplex virus that expresses mouse endostatin SO CANCER LA English DT Article DE herpes simplex virus 1; oncolysis; angiogenesis; endostatin; colon carcinoma ID CANCER GENE-THERAPY; LIVER METASTASES; TUMOR-GROWTH; COLON-CARCINOMA; TRANSGENE; ADENOVIRUS; COMPETENT; DELIVERY; VECTORS; MUTANT AB BACKGROUND. in preclinical models, infection of tumors by oncolytic strains of herpes simplex virus 1 (HSV-1) resulted in the destruction of tumor cells by viral replication and release of progeny virion that infected and destroyed adjacent tumor cells. However, complete tumor regression was rarely observed. 2. METHODS. To augment the antitumor effect of viral oncolysis, a replication con ditional HSV-1 mutant (HSV-Endo) was constructed in which the murine endostatin gene was incorporated into the HSV-1 genome. RESULTS. Replication of HSV-Endo effectively destroyed several colon carcinoma cell lines in vitro. Secretion of endostatin by HSV-Endo-infected HT29 human colon carcinoma cells was confirmed by Western blot analysis. The secreted endostatin was biologically active as assessed in a chick chorioallantoic membrane assay. Importantly, endostatin production at the site of viral replication did not inhibit viral replication. Direct injection of HSV-Endo into flank tumors caused tumor destruction, and some of the HSV-Endo-treated flank tumors completely sloughed. Immunohistochemical staining of the tumors revealed a decreased number of blood vessels in the HSV-Endo-treated group versus the control group. CONCLUSIONS. The oncolytic HSV-1 mutant HSV-Endo provided a two-pronged therapy; namely, inhibition of angiogenesis and direct tumor cell destruction by viral replication. (C) 2004 American Cancer Society. C1 Massachusetts Gen Hosp, Div Surg Oncol, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Univ Texas, MD Anderson Canc Ctr, Dept Surg & Canc Biol, Houston, TX USA. RP Tanabe, KK (reprint author), Massachusetts Gen Hosp, Div Surg Oncol, Dept Surg, Cox Bldg 626, Boston, MA 02114 USA. EM ktanabe@partners.org RI Kasuya, hideki/I-7278-2014 FU NCI NIH HHS [CA76183, CA71345]; NIDDK NIH HHS [DK43552]; NIGMS NIH HHS [GM07035] NR 18 TC 29 Z9 30 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD AUG 15 PY 2004 VL 101 IS 4 BP 869 EP 877 DI 10.1002/cncr.20434 PG 9 WC Oncology SC Oncology GA 843UD UT WOS:000223111200027 PM 15305421 ER PT J AU Keith, RL Miller, YE Hudish, TM Girod, CE Sotto-Santiago, S Franklin, WA Nemenoff, RA March, TH Nana-Sinkam, SP Geraci, MW AF Keith, RL Miller, YE Hudish, TM Girod, CE Sotto-Santiago, S Franklin, WA Nemenoff, RA March, TH Nana-Sinkam, SP Geraci, MW TI Pulmonary prostacyclin synthase overexpression chemoprevents tobacco smoke lung carcinogenesis in mice SO CANCER RESEARCH LA English DT Article ID ACTIVATED RECEPTOR-GAMMA; CIGARETTE-SMOKE; GENE-EXPRESSION; BETA-CAROTENE; RESPIRATORY BRONCHIOLITIS; CARDIOVASCULAR-DISEASE; INTERSTITIAL PNEUMONIA; INDUCED EMPHYSEMA; TRANSGENIC MICE; ASPIRIN USE AB Increased pulmonary production of prostaglandin 12 (prostacyclin) by lung-specific overexpression of prostacyclin synthase decreases lung tumor incidence and multiplicity in chemically induced murine lung cancer models. We hypothesized that pulmonary prostacyclin synthase overexpression would prevent lung carcinogenesis in tobacco-smoke exposed mice. Murine exposure to tobacco smoke is an established model of inducing pulmonary adenocarcinomas and allows for the testing of potential chemopreventive strategies. Transgenic FVB/N mice with lung-specific prostacyclin synthase overexpression were exposed to mainstream cigarette smoke for 22 weeks and then held unexposed for an additional 20 weeks. All of the exposed animals developed bronchiolitis analogous to the respiratory bronchiolitis seen in human smokers. The transgenic mice, when compared with smoke-exposed transgene negative littermates, had significant decreases in tumor incidence and multiplicity. Significantly fewer transgenics (6 of 15; 40%) developed tumors compared with the tumor incidence in wild-type littermates (16 of 19; 84%; Fisher's exact test, P = 0.012). Tumor multiplicity was also significantly decreased in the transgenic animals (tg(+) = 0.4 +/- 0.5 versus wild-type = 1.2 +/- 0.86 tumors/mouse; P < 0.001). Targeted prostaglandin levels at the time of sacrifice revealed significantly elevated prostaglandin 12 levels in the transgenic animals, coupled with significantly decreased prostaglandin E-2 levels. Gene expression analysis of isolated type II pneumocytes suggests potential explanations for the observed chemoprevention, with Western blot analysis confirming decreased expression of cytochrome p450 2e1. These studies extend our previous studies and demonstrate that manipulation of prostaglandin production distal to cyclooxygenase significantly reduces lung carcinogenesis in a tobacco smoke exposure model, and gene expression studies show critical alterations in antioxidation, immune response, and cytokine pathways. C1 Univ Colorado, Hlth Sci Ctr, Dept Med, Div Pulm Sci & Crit Care Med, Denver, CO 80220 USA. Univ Colorado, Hlth Sci Ctr, Dept Pathol, Denver, CO 80220 USA. Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80220 USA. Univ Colorado, Hlth Sci Ctr, Dept Pharmacol, Denver, CO 80220 USA. Denver VA Med Ctr, Dept Med, Div Pulm Sci & Crit Care Med, Denver, CO USA. Univ Texas, SW Med Ctr, Dept Med, Div Pulm & Crit Care Med, Dallas, TX 75230 USA. Lovelace Resp Res Inst, Inhalat Toxicol Lab, Albuquerque, NM USA. RP Keith, RL (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Med, Div Pulm Sci & Crit Care Med, 1055 Clermont, Denver, CO 80220 USA. EM robert.keith@uchsc.edu NR 50 TC 69 Z9 72 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2004 VL 64 IS 16 BP 5897 EP 5904 DI 10.1158/0008-5472.CAN-04-1070 PG 8 WC Oncology SC Oncology GA 846NH UT WOS:000223321900051 PM 15313935 ER PT J AU Sekiguchi, K Li, X Coker, M Flesch, M Barger, PM Sivasubramanian, N Mann, DL AF Sekiguchi, K Li, X Coker, M Flesch, M Barger, PM Sivasubramanian, N Mann, DL TI Cross-regulation between the renin-angiotensin system and inflammatory mediators in cardiac hypertrophy and failure SO CARDIOVASCULAR RESEARCH LA English DT Review DE angiotensin II; renin-angiotensin system; heart failure; tumor necrosis factor; inflammation ID TUMOR-NECROSIS-FACTOR; ACTIVATED PROTEIN-KINASE; LEFT-VENTRICULAR DYSFUNCTION; CONVERTING ENZYME-INHIBITION; CONGESTIVE-HEART-FAILURE; KAPPA-B ACTIVATION; FACTOR-ALPHA; C-JUN; CARDIOMYOCYTE HYPERTROPHY; TRANSCRIPTION FACTOR AB One of the major conceptual advances ill Our understanding of the pathogenesis of heart failure has been the insight that heart failure may progress as the result of the sustained overexpression of biologically active "neurohormones", such as norepinephrine and angiotensin II, which by virtue of their deleterious effects are sufficient to contribute to disease progression by provoking worsening left ventricular (LV) remodeling and progressive LV dysfunction. Recently, a second class of biologically active molecules, termed cytokines, has also been identified in the setting of heart failure. Analogous to the situation with neurohormones, the overexpression of cytokines is sufficient to contribute to disease progression in heart failure phenotype. Although important interactions between proinflammatory cytokines and the adrenergic system have been recognized in the heart for over a decade, the nature of the important interactions between proinflammatory cytokines and the renin-angiotensin system has become apparent only recently. Accordingly, in the present review, we will discuss the evidence which suggests that there is a functionally significant cross-talk between neurohormonal and inflammatory cytokine signaling in cardiac hypertrophy and failure. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved. C1 Houston VAMC, Winters Ctr Heart Failure Res, Dept Med, Cardiol Sect, Houston, TX 77030 USA. Baylor Coll Med, Houston, TX 77030 USA. Univ Cologne, Innere Med Klin 3, Cologne, Germany. RP Mann, DL (reprint author), Houston VAMC, Winters Ctr Heart Failure Res, Dept Med, Cardiol Sect, 6565 Fannin,MS 524, Houston, TX 77030 USA. EM dmann@bcm.tmc.edu OI Mann, Douglas /0000-0002-2516-0145 NR 56 TC 44 Z9 51 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD AUG 15 PY 2004 VL 63 IS 3 BP 433 EP 442 DI 10.1016/j.cardiores.2004.02.005 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 845KP UT WOS:000223241600008 PM 15276468 ER PT J AU Martin, NE Brunner, TB Kiel, KD DeLaney, TF Regine, WF Mohiuddin, M Rosato, EF Haller, DG Stevenson, JP Smith, D Pramanik, B Tepper, J Tanaka, WK Morrison, B Deutsch, P Gupta, AK Muschel, RJ McKenna, WG Bernhard, EJ Hahn, SM AF Martin, NE Brunner, TB Kiel, KD DeLaney, TF Regine, WF Mohiuddin, M Rosato, EF Haller, DG Stevenson, JP Smith, D Pramanik, B Tepper, J Tanaka, WK Morrison, B Deutsch, P Gupta, AK Muschel, RJ McKenna, WG Bernhard, EJ Hahn, SM TI A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID TUMOR-CELL LINES; FARNESYL TRANSFERASE INHIBITOR; RADIATION-RESISTANCE; PROTEIN TRANSFERASE; RAS ONCOGENES; N-RAS; H-RAS; SIGNAL-TRANSDUCTION; CODON-12 MUTATIONS; NIH-3T3 CELLS AB Purpose: Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with activation of Ras and produce clinical response in patients with cancer. The aim of this study was to determine the maximally tolerated dose of the dual farnesyltransferase and geranylgeranyltransferase I inhibitor L-778,123 in combination with radiotherapy for patients with locally advanced pancreatic cancer. Experimental Design: L-778,123 was given by continuous intravenous infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778,123 dose levels were tested: 280 mg/m(2)/day over weeks 1, 2, 4, and 5 for dose level 1; and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2. Results: There were no dose-limiting toxicities observed in the eight patients treated on dose level 1. Two of the four patients on dose level 2 experienced dose-limiting toxicities consisting of grade 3 diarrhea in one case and grade 3 gastrointestinal hemorrhage associated with grade 3 thrombocytopenia and neutropenia in the other case. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. One patient on dose level I showed a partial response of 6 months in duration. Both reversible inhibition of HDJ2 farnesylation and radiosensitization of a study patient-derived cell line were demonstrated in the presence of L-773,123. K-RAS mutations were found in three of the four patients evaluated. Conclusions: The combination of L-778,123 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization of a patient-derived pancreatic cancer cell line was observed. C1 Univ Penn, Sch Med, Dept Radiat Oncol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Surg, Philadelphia, PA 19104 USA. Northwestern Mem Hosp, Dept Radiat Oncol, Chicago, IL USA. Boston Univ, Massachusetts Gen Hosp, Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. Univ Kentucky, Dept Radiat Med, Lexington, KY USA. Univ N Carolina, Dept Radiat Oncol, Chapel Hill, NC USA. Merck Res Lab, Rahway, NJ USA. RP Hahn, SM (reprint author), Hosp Univ Penn, Dept Radiat Oncol, 3400 Spruce St,2 Donner, Philadelphia, PA 19104 USA. EM hahn@xrt.upenn.edu RI Martin, Neil/E-2193-2014 OI Martin, Neil/0000-0002-8164-8516 FU NCI NIH HHS [CA75138, CA-73820]; NCRR NIH HHS [M01 RR00040] NR 49 TC 45 Z9 47 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 AUG 15 PY 2004 VL 10 IS 16 BP 5447 EP 5454 DI 10.1158/1078-0432.CCR-04-0248 PG 8 WC Oncology SC Oncology GA 848GC UT WOS:000223454600020 PM 15328183 ER PT J AU Andreassen, PR D'Andrea, AD Taniguchi, T AF Andreassen, PR D'Andrea, AD Taniguchi, T TI ATR couples FANCD2 monoubiquitination to the DNA-damage response SO GENES & DEVELOPMENT LA English DT Article DE Fanconi anemia; FANCD2; cancer susceptibility; check-point; replication stress ID FANCONI-ANEMIA PROTEINS; ATAXIA-TELANGIECTASIA; REPLICATION FORKS; CHECKPOINT; ACTIVATION; PATHWAY; BRCA1; CHROMATIN; CELLS; STRESS AB Fanconi anemia (FA) is a multigenic autosomal recessive cancer susceptibility syndrome. The FA pathway regulates the monoubiquitination of FANCD2 and the assembly of damage-associated FANCD2 nuclear foci. How FANCD2 monoubiquitination is coupled to the DNA-damage response has remained undetermined. Here, we demonstrate that the ATR checkpoint kinase and RPA1 are required for efficient FANCD2 monoubiquitination. Deficiency of ATR function, either in Seckel syndrome, which clinically resembles Fanconi anemia, or by siRNA silencing, results in the formation of radial chromosomes in response to the DNA cross-linker, mitomycin C (MMC), thus mimicking the chromosome instability of FA cells. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP D'Andrea, AD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. EM alan_dandrea@dfci.harvard.edu FU NHLBI NIH HHS [P01HL54785, R01 HL052725, P50 HL054785, R01HL52725]; NIDDK NIH HHS [R01 DK043889, R01DK43889] NR 29 TC 249 Z9 254 U1 3 U2 7 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD AUG 15 PY 2004 VL 18 IS 16 BP 1958 EP 1963 DI 10.1101/gad.1196104 PG 6 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 846GL UT WOS:000223303600005 PM 15314022 ER PT J AU Yu, MC Bachand, F McBride, AE Komili, S Casolari, JM Silver, PA AF Yu, MC Bachand, F McBride, AE Komili, S Casolari, JM Silver, PA TI Arginine methyltransferase affects interactions and recruitment of mRNA processing and export factors SO GENES & DEVELOPMENT LA English DT Article DE Hmt1; arginine methylation; genome-wide localization ID SACCHAROMYCES-CEREVISIAE; NUCLEAR EXPORT; BINDING PROTEINS; 3'-END FORMATION; COTRANSCRIPTIONAL RECRUITMENT; TRANSCRIPTION FACTOR; POLYMERASE-II; IN-VIVO; YEAST; METHYLATION AB Hmt1 is the major type I arginine methyltransferase in the yeast Saccharomyces cerevisiae and facilitates the nucleocytoplasmic transport of mRNA-binding proteins through their methylation. Here we demonstrate that Hmt1 is recruited during the beginning of the transcriptional elongation process. Hmt1 methylates Yra1 and Hrp1, two mRNA-binding proteins important for mRNA processing and export. Moreover, loss of Hmt1 affects interactions between mRNA-binding proteins and Tho2, a component of the TREX (transcription/export) complex that is important for transcriptional elongation and recruitment of mRNA export factors. Furthermore, RNA in situ hybridization analysis demonstrates that loss of Hmt1 results in slowed release of HSP104 mRNA from the sites of transcription. Genome-wide location analysis shows that Hmt1 is bound to specific functional gene classes, many of which are also bound by Tho2 and other mRNA-processing factors. These data suggest a model whereby Hmt1 affects transcriptional elongation and, as a result, influences recruitment of RNA-processing factors. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Syst Biol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Silver, PA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Syst Biol, Boston, MA 02115 USA. EM pamela_silver@dfci.harvard.edu FU NIGMS NIH HHS [F32 GM066450] NR 53 TC 95 Z9 97 U1 0 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD AUG 15 PY 2004 VL 18 IS 16 BP 2024 EP 2035 DI 10.1101/gad.1223204 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 846GL UT WOS:000223303600012 PM 15314027 ER PT J AU Dubinett, SM Elashoff, D Meyerson, M AF Dubinett, SM Elashoff, D Meyerson, M TI Assessing prognosis in non-small-cell lung cancer: Avenues to a more complete picture? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID ADENOCARCINOMA; EXPRESSION; INHIBITORS; METALLOPROTEINASES; CLASSIFICATION; MUTATIONS; GEFITINIB; SURVIVAL; THERAPY C1 Univ Calif Los Angeles, Sch Med, Lung Canc Res Program, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. RP Dubinett, SM (reprint author), Univ Calif Los Angeles, Sch Med, Lung Canc Res Program, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. RI Meyerson, Matthew/E-7123-2012 NR 22 TC 4 Z9 4 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 AUG 15 PY 2004 VL 22 IS 16 BP 3209 EP 3211 DI 10.1200/JCO.2004.05.931 PG 3 WC Oncology SC Oncology GA 846NY UT WOS:000223323700002 PM 15249586 ER PT J AU Richardson, P Anderson, K AF Richardson, P Anderson, K TI Immunomodulatory analogs of thalidomide: An emerging new therapy in myeloma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID RELAPSED MULTIPLE-MYELOMA; DRUG-RESISTANCE; CELLS; DEXAMETHASONE; DERIVATIVES; GROWTH C1 Harvard Univ, Sch Med, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Div Hematol Neoplasia, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. RP Richardson, P (reprint author), Harvard Univ, Sch Med, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. NR 16 TC 39 Z9 40 U1 0 U2 2 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 AUG 15 PY 2004 VL 22 IS 16 BP 3212 EP 3214 DI 10.1200/JCO.2004.05.984 PG 3 WC Oncology SC Oncology GA 846NY UT WOS:000223323700003 PM 15249587 ER PT J AU Sasaki, Y Casola, S Kutok, JL Rajewsky, K Schmidt-Supprian, M AF Sasaki, Y Casola, S Kutok, JL Rajewsky, K Schmidt-Supprian, M TI TNF family member B cell-activating factor (BAFF) receptor-dependent and -independent roles for BAFF in B cell physiology SO JOURNAL OF IMMUNOLOGY LA English DT Article ID APRIL-DEFICIENT MICE; MARGINAL ZONE; A/WYSNJ MICE; LYMPHOCYTE STIMULATOR; HUMORAL RESPONSE; IMMUNE-RESPONSES; CUTTING EDGE; MOUSE STRAIN; B-1 CELLS; SURVIVAL AB The cytokine TNF family member B cell-activating factor (BAFF; also termed BLyS) is essential for B cell generation and maintenance. Three receptors have been identified that bind to BAFF: transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI); B cell maturation Ag (BCMA); and BAFF-R. Recently, it was shown that A/WySnJ mice, which contain a dramatically reduced peripheral B cell compartment due to decreased B cell life span, express a mutant BAFF-R. This finding, together with normal or enhanced B cell generation in mice deficient for BCMA or TACI, respectively, suggested that the interaction of BAFF with BAFF-R triggers signals essential for the generation and maintenance of mature B cells. However, B cells in mice deficient for BAFF differ phenotypically and functionally from A/WySnJ B cells. Residual signaling through the mutant BAFF-R could account for these differences. Alternatively, dominant-negative interference by the mutant receptor could lead to an overestimation of the importance of BAFF-R. To resolve this issue, we generated BAFF-R-null mice. Baff-r(-/-) mice display strongly reduced late transitional and follicular B cell numbers and are essentially devoid of marginal zone B cells. Overexpression of Bcl-2 rescues mature B cell development in Baff-r(-/-) mice, suggesting that BAFF-R mediates a survival signal. CD21 and CD23 surface expression are reduced on mature Baff-r(-/-) B cells, but not to the same extent as on mature B cells in BAFF-deficient mice. In addition, we found that Baff-r(-/-) mice mount significant, but reduced, Ag-specific Ab responses and are able to form spontaneous germinal centers in mesenteric lymph nodes. The reduction in Ab titers correlates with the reduced B cell numbers in the mutant mice. C1 Harvard Univ, Inst Biomed Res, CBR, Sch Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Sasaki, Y (reprint author), Harvard Univ, Inst Biomed Res, CBR, Sch Med, 200 Longwood Ave, Boston, MA 02115 USA. EM sasaki@cbr.med.harvard.edu RI Schmidt-Supprian, Marc/F-5893-2011 OI Schmidt-Supprian, Marc/0000-0002-8543-6166 FU NIAID NIH HHS [1R37AI054636, AI057947] NR 56 TC 215 Z9 220 U1 1 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 AUG 15 PY 2004 VL 173 IS 4 BP 2245 EP 2252 PG 8 WC Immunology SC Immunology GA 845AV UT WOS:000223208900008 PM 15294936 ER PT J AU Haining, WN Anderson, DG Little, SR von Berwelt-Baildon, MS Cardoso, AA Alves, P Kosmatopoulos, K Nadler, LM Langer, R Kohane, DS AF Haining, WN Anderson, DG Little, SR von Berwelt-Baildon, MS Cardoso, AA Alves, P Kosmatopoulos, K Nadler, LM Langer, R Kohane, DS TI pH-triggered microparticles for peptide vaccination SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MHC CLASS-I; MAJOR HISTOCOMPATIBILITY COMPLEX; PROTEIN-SUGAR PARTICLES; T-LYMPHOCYTE RESPONSES; DENDRITIC CELLS; CROSS-PRESENTATION; EXOGENOUS ANTIGENS; HLA-A-ASTERISK-0201-RESTRICTED EPITOPES; ANTICANCER IMMUNOTHERAPY; HLA-A2.1-TRANSGENIC MICE AB Improving vaccine delivery to human APCs is a way to increase the CTL response to vaccines. We report the use of a novel pH-triggered microparticle that exploits the ability of APCs to cross-present MHC I-restricted Ags that have been engulfed in the low pH environment of the phagosome. A model MHC class I-restricted peptide Ag from the influenza A matrix protein was encapsulated in spray-dried microparticles composed of dipalmitoylphosphatidylcholine and the pH-sensitive polymethacrylate Eudragit E100. Release of the peptide from the particle was triggered by a drop in pH to the acidity normally found in the phagosome. The particles were efficiently phagocytosed by human monocytes and dendritic cells with minimal cellular toxicity and no functional impairment. Encapsulation of the peptide in the microparticles resulted in efficient presentation of the peptide to CD8(+) T cells by human dendritic cells in vitro, and was superior to unencapsulated peptide or peptide encapsulated in an analogous pH-insensitive particle. Vaccination of human HLA-A*0201 transgenic mice with peptide encapsulated in pH-triggering microparticles resulted in priming of CTL responses. These microparticles can be modified to coencapsulate a range of adjuvants along with the Ag of interest. Encapsulation of MHC I epitopes in pH-triggered microparticles increases Ag presentation and may improve CD8(+) T cell priming to peptide vaccines against viruses and cancer. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Inst Gustave Roussy, Inst Natl Sante & Rech Med 487, Paris, France. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Univ Cologne, Dept Hematol & Oncol, Cologne, Germany. MIT, Dept Chem Engn, Cambridge, MA 02139 USA. Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Kohane, DS (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Ellison 317, Boston, MA 02114 USA. EM dkohane@partners.org OI Little, Steven/0000-0002-7000-3931 FU NHLBI NIH HHS [HL72750]; NIGMS NIH HHS [GM00684, GM26698] NR 47 TC 52 Z9 54 U1 0 U2 12 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2004 VL 173 IS 4 BP 2578 EP 2585 PG 8 WC Immunology SC Immunology GA 845AV UT WOS:000223208900046 PM 15294974 ER PT J AU Birdsall, HH Porter, WJ Green, DM Rubio, J Trial, JA Rossen, RD AF Birdsall, HH Porter, WJ Green, DM Rubio, J Trial, JA Rossen, RD TI Impact of fibronectin fragments on the transendothelial migration of HIV-infected leukocytes and the development of subendothelial foci of infectious leukocytes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CELL-ADHESION MOLECULE-1; NECROSIS-FACTOR-ALPHA; TNF-ALPHA; DENDRITIC CELLS; HUMAN MONOCYTES; T-LYMPHOCYTES; HIV-1-INFECTED PATIENTS; FLOW CONDITIONS; NERVOUS-SYSTEM; P-SELECTIN AB Leukocyte infiltrates that can serve as viral reservoirs, and sites for viral replication are found in many organs of HIV-1-infected patients. Patients whose blood leukocytes migrate across confluent endothelial monolayers ex vivo and transmit infectious virus to mononuclear leukocytes (MNLs) lodged beneath this endothelial barrier have a worse prognosis. We evaluated the ability of 110- to 120-kDa fibronectin fragments (FNf), which are found in the blood of >60% of HIV-1-infected patients, to stimulate transendothelial migration and drive productively infected MNLs into a potential perivascular space. FNf induced MNLs to release TNF-alpha in a dose-dependent fashion; the resulting increase in lymphocyte and monocyte transendothelial migration could be blocked with soluble TNF receptor I. Rather than penetrate deeply into the subendothelial matrix, as is seen with untreated controls, FNf-treated MNLs clustered just below the endothelial monolayer. Treatment with FNf during migration increased subsequent recovery of HIV-infected cells from the subendothelial compartment. FNf treatment also significantly increased the numbers of HLA-DRbright, dendritic-type cells that reverse-migrated from the subendothelial depot to the apical endothelial surface 48 h after migration. Fibronectin fragments can be produced by viral and host proteases in the course of inflammatory conditions. The ability of FNf to stimulate transendothelial migration of HIV-1-infected MNLs may help to explain the dissemination of this infection into cardiac, renal, and CNS tissues. C1 Michael E DeBakey Vet Affairs Med Ctr, Res Ctr AIDS & HIV Infect, Immunol Res Lab, Houston, TX 77030 USA. Baylor Coll Med, Dept Otorhinolaryngol, Houston, TX 77030 USA. Baylor Coll Med, Dept Immunol, Houston, TX 77030 USA. Baylor Coll Med, Dept Orthoped, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. RP Birdsall, HH (reprint author), Houston Vet Affairs Med Ctr, Bldg 110,Room 328,2002 Holcombe Blvd, Houston, TX 77030 USA. EM birdsall@bcm.tmc.edu FU NIAID NIH HHS [R01AI46285, AI36211]; NIMH NIH HHS [R01MH63035]; NINDS NIH HHS [R01NS32583] NR 49 TC 14 Z9 14 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 AUG 15 PY 2004 VL 173 IS 4 BP 2746 EP 2754 PG 9 WC Immunology SC Immunology GA 845AV UT WOS:000223208900065 PM 15294993 ER PT J AU Anand, BS Velez, M AF Anand, Bhupinder S. Velez, Maria TI Assessment of correlation between serum titers of hepatitis c virus and severity of liver disease SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article AB AIM: The significance of hepatitis C virus (HCV) serum titers has been examined in several clinical situations. There is much evidence that patients with a lower viral load have better response rates to anti-viral therapy compared to those with higher levels. Moreover, a direct association has been observed between serum titers of HCV and transmission rates of the virus. The aim of the present study was to determine if there was any correlation between HCV viral load and the severity of liver disease. METHODS: Fifty patients with HCV infection were included in the study. These comprised of 34 subjects with a history of alcohol use and 16 non-alcoholics. Quantitative serum HCV RNA assay was carried out using the branched DNA (bDNA) technique. Linear regression analysis was performed between serum viral titers and liver tests. In addition, for the purpose of comparison, the subjects were divided into two groups: those with low viral titers (50 mEq/mL). RESULTS: All subjects were men, with a mean +/- SD age of 47 +/- 7.8 years. The mean HCV RNA level in the blood was 76.3x10(5) +/- 109.1 genome equivalents/mL. There was no correlation between HCV RNA levels and age of the patients (r = 0.181), and the history or amount (g/d) of alcohol consumption (r = 0.07). Furthermore, no correlation was observed between serum HCV RNA levels and the severity of liver disease as judged by the values of serum albumin (r = 0.175), bilirubin (r = 0.217), ALT (r = 0.06) and AST (r = 0.004) levels. Similarly, no significant difference was observed between patients with low viral titers and high titers with respect to any of the parameters. CONCLUSION: Our results indicate that the severity of liver disease is independent of serum levels of hepatitis C virus. These findings are important since they have a direct impact on the current debate regarding the role of direct cytopathic effect of hepatitis C virus versus immune-mediated injury in the pathogenesis of HCV-related liver damage. C1 [Anand, Bhupinder S.] VA Med Ctr, Digest Dis Sect 111D, Dept Med, Houston, TX 77030 USA. Baylor Coll Med, Houston, TX 77030 USA. RP Anand, BS (reprint author), VA Med Ctr, Digest Dis Sect 111D, Dept Med, 2002 Holcombe Blvd Houston, Houston, TX 77030 USA. EM ana0@flash.net NR 26 TC 20 Z9 23 U1 0 U2 0 PU BAISHIDENG PUBL GRP CO LTD PI BEIJING PA RM 903, BLDG D, OCEAN INTERNATIONAL CTR, NO 62 DONGSIHUAN ZHONGLU, BEIJING, CHAOYANG DISTRICT 100025, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD AUG 15 PY 2004 VL 10 IS 16 BP 2409 EP 2411 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA V23BF UT WOS:000208317600021 PM 15285030 ER PT J AU Matsushita, M Noguchi, H Lu, YF Tomizawa, K Michiue, H Li, ST Hirose, K Bonner-Weir, S Matsui, H AF Matsushita, M Noguchi, H Lu, YF Tomizawa, K Michiue, H Li, ST Hirose, K Bonner-Weir, S Matsui, H TI Photo-acceleration of protein release from endosome in the protein transduction system SO FEBS LETTERS LA English DT Article DE photo; FITC; endosomal release; protein transduction; protein transduction domain ID TAT-FUSION PROTEINS; BASIC DOMAIN; DELIVERY; PEPTIDES; MEMBRANE; CELLS; VP22; INTERNALIZATION; EFFICIENCY; THERAPY AB The protein transduction system has been employed for delivery of bioactive proteins into cells via an endocytotic mechanism. However, trapping of endocytosed proteins in the endosome may significantly attenuate biological actions in cells. The present investigation demonstrated that endosomal release of transduced protein could be artificially accelerated by exposure to fluorescent light. Exposure to light at 480 nm stimulated endosomal release of transduced FITC-11 arginine-protein transduction domain (11R-PTD), TAT-PTD and Antennapedia-PTD. Moreover, FITC-11R-p53 protein was released from endosomes following stimulation with light. These data suggest that photo-acceleration is a more efficient strategy in terms of the protein transduction system. (C) 2004 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 Okayama Univ, Grad Sch Med & Dent, Dept Physiol, Okayama 7008558, Japan. Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. Okayama Univ, Grad Sch Med & Dent, Japan Sci & Technol Corp, Off Technol Transfer,Preventure Program, Okayama 7008558, Japan. Univ Tokyo, Grad Sch Med, Dept Pharmacol, Bunkyo Ku, Tokyo 1130033, Japan. RP Matsushita, M (reprint author), Okayama Univ, Grad Sch Med & Dent, Dept Physiol, 2-5-1 Shikata Cho, Okayama 7008558, Japan. EM masayuki@cc.okayama-u.ac.jp RI Tomizawa, Kazuhito/F-2405-2015; OI Tomizawa, Kazuhito/0000-0002-5663-2627; Li, Sheng Tian/0000-0002-2836-3802 FU NIDDK NIH HHS [DK 61251] NR 24 TC 42 Z9 43 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD AUG 13 PY 2004 VL 572 IS 1-3 BP 221 EP 226 DI 10.1016/j.febslet.2004.07.033 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 849DQ UT WOS:000223519300040 PM 15304352 ER PT J AU Xie, ZC Romano, DM Kovacs, DM Tanzi, RE AF Xie, ZC Romano, DM Kovacs, DM Tanzi, RE TI Effects of RNA interference-mediated silencing of gamma-secretase complex components on cell sensitivity to caspase-3 activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AMYLOID PRECURSOR PROTEIN; PERTURBED CALCIUM HOMEOSTASIS; FAMILIAL ALZHEIMERS-DISEASE; BETA-PEPTIDE; IN-VIVO; PRESENILIN-1; NICASTRIN; CLEAVAGE; NOTCH; APH-1 AB Familial Alzheimer's disease mutations in the presenilin 1 gene (PSEN1) have been previously shown to potentiate caspase activation and apoptosis in transfected cells and transgenic mice. However, the mechanism underlying this effect is not known. We set out to determine whether cellular sensitivity to caspase activation could be affected by modulating presenilin 1 (PS1) processing. PS1 processing was altered using RNA interference (RNAi) aimed at silencing the expression of the genes encoding the four components of the gamma-secretase complex, PSEN1, APH-1, PEN-2, and nicastrin. RNAi for these genes was carried out in naive H4 human neuroglioma cells, as well as H4 cell lines overexpressing either wild-type PSEN1 or the Familial Alzheimer's disease mutant PSEN1-Delta9 (PS1-mutant), that were induced to undergo apoptosis. In wildtype PSEN1 cells, RNAi for PEN-2, as expected, increased levels of full-length PS1 (PS1-FL) and decreased PS1 endoproteolysis. This was accompanied by potentiated caspase-3 activation in response to an apoptotic stimulus. In contrast, nicastrin RNAi, which only decreased levels of PS1-amino-terminal fragment and did not affect PS1-FL levels, had no effect on caspase-3 activation during apoptosis. Surprisingly, in the PS1-mutant cells, RNAi for PEN-2 ( and APH-1) did not increase but instead reduced the levels of PS1-FL deleted for exon 9. In turn, this was accompanied by attenuated caspase-3 activation in response to an apoptotic stimulus. Finally, in naive H4 cells, PSEN1 RNAi also attenuated caspase-3 activation in response to an apoptotic stimulus. Collectively, these findings indicate that cellular sensitivity to caspase activation correlates with overall PS1 protein levels, particularly with levels of FL-PS1. C1 Massachusetts Gen Hosp, MassGen Inst Neurogenet Dis, Genet & Aging Res Unit, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Charlestown, MA 02129 USA. RP Tanzi, RE (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Genet & Aging Res Unit, 114 16th St,C3009, Charlestown, MA 02129 USA. EM tanzi@helix.mgh.harvard.edu FU NIA NIH HHS [AG 00294-17, AG 014713-07, P50 AG 05134]; NIGMS NIH HHS [T32 GM 07592]; NIMH NIH HHS [MH 60009-02] NR 47 TC 23 Z9 25 U1 1 U2 2 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 AUG 13 PY 2004 VL 279 IS 33 BP 34130 EP 34137 DI 10.1074/jbc.M401094200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 844CL UT WOS:000223134800010 PM 15184387 ER PT J AU Nadeau, KJ Leitner, JW Gurerich, I Draznin, B AF Nadeau, KJ Leitner, JW Gurerich, I Draznin, B TI Insulin regulation of sterol regulatory element-binding protein-1 expression in L-6 muscle cells and 3T3 L1 adipocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHATIDYLINOSITOL 3-KINASE ACTIVITY; GENE-EXPRESSION; SKELETAL-MUSCLE; PHOSPHOINOSITIDE 3-KINASE; DIABETES-MELLITUS; GLUCOSE-TRANSPORT; RECEPTOR SUBSTRATE-1; ADIPOSE-TISSUE; FATTY RATS; KINASE AB Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate enzymes required for cholesterol and fatty acid synthesis. Expression of SREBP-1 is enhanced by insulin; however, the actual insulin-signaling cascades employed are yet unclear. We determined the roles of the phosphatidylinositol (PI) 3-kinase and mitogen-activated protein (MAP) kinase-dependent pathways in the effect of mediating insulin on SREBP-1 in L-6 skeletal muscle cells and 3T3 L1 adipocytes, using wortmannin or LY294002 to inhibit the PI 3-kinase pathway, and PD98059 to inhibit the MAP kinase-dependent pathway. In myocytes, insulin increased SREBP-1 protein in a dose-dependent manner. 1 and 10 nM insulin significantly increased expression of total cellular SREBP-1 protein at 24 and 48 h, nuclear SREBP-1 protein at 24 h, and SREBP-1a mRNA at 24 h. Although wortmannin and LY294002 had no effect on this aspect of insulin action, PD98059 completely blocked each of these responses. Transfection of a dominant negative mutant of Ras similarly blocked the insulin effect on SREBP-1. In contrast, in adipocytes, the insulin effect on SREBP-1 was mediated via the PI 3-kinase and not the MAP kinase pathway. In conclusion, although insulin increases skeletal muscle SREBP-1 expression in a dose-dependent fashion via the MAP kinase-dependent signaling pathway, insulin action on adipocyte SREBP-1 is mediated via the PI 3-kinase signaling pathway. In the state of insulin resistance, characterized by selective inhibition of the PI 3-kinase pathway, the usual stimulation of lipogenesis by insulin in adipocytes may be inhibited, whereas intramyocellular lipogenesis via the MAP kinase pathway of insulin may continue unabated. C1 Univ Colorado, Hlth Sci Ctr, Dept Pediat, Div Pediat Endocrinol, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Med, Div Endocrinol Metab & Diabet, Denver, CO 80262 USA. Denver VA Med Ctr, Vet Affairs Res Serv, Denver, CO 80220 USA. RP Nadeau, KJ (reprint author), Pediat Endocrinol Box 256,1056 E 19th Ave, Denver, CO 80218 USA. EM kristen.nadeau@UCHSC.edu NR 40 TC 27 Z9 29 U1 0 U2 2 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 AUG 13 PY 2004 VL 279 IS 33 BP 34380 EP 34387 DI 10.1074/jbc.M403596200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 844CL UT WOS:000223134800038 PM 15187085 ER PT J AU Huang, SC Jagadeeswaran, R Liu, ES Benz, EJ AF Huang, SC Jagadeeswaran, R Liu, ES Benz, EJ TI Protein 4.1R, a microtubule-associated protein involved in microtubule aster assembly in mammalian mitotic extract SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SPECTRIN-ACTIN-BINDING; CYTOPLASMIC DYNEIN; FUNCTIONAL-CHARACTERIZATION; NONERYTHROID ISOFORM; MESSENGER-RNA; CELL-CYCLE; IN-VITRO; SPINDLE; TUBULIN; ORGANIZATION AB Non-erythroid protein 4.1R ( 4.1R) consists of a complex family of isoforms. We have shown that 4.1R isoforms localize at the mitotic spindle/spindle poles and associate in a complex with the mitotic-spindle organization proteins Nuclear Mitotic Apparatus protein ( NuMA), dynein, and dynactin. We addressed the mitotic function of 4.1R by investigating its association with microtubules, the main component of the mitotic spindles, and its role in mitotic aster assembly in vitro. 4.1R appears to partially co-localize with microtubules throughout the mitotic stages of the cell cycle. In vitro sedimentation assays showed that 4.1R isoforms directly interact with microtubules. Glutathione S-transferase (GST) pull-down assays using GST-4.1R fusions and mitotic cell extracts further showed that the association of 4.1R with tubulin results from both the membrane-binding domain and C-terminal domain of 4.1R. Moreover, 4.1R, but not actin, is a mitotic microtubule-associated protein; 4.1R associates with microtubules in the microtubule pellet of the mitotic asters assembled in mammalian cell-free mitotic extract. The organization of microtubules into asters depends on 4.1R in that immunodepletion of 4.1R from the extract resulted in randomly dispersed microtubules. Furthermore, adding a 135-kDa recombinant 4.1R reconstituted the mitotic asters. Finally, we demonstrated that a mitotic 4.1R isoform appears to form a complex in vivo with tubulin and NuMA in highly synchronized mitotic HeLa extracts. Our results suggest that a 135-kDa non-erythroid 4.1R is important to cell division, because it participates in the formation of mitotic spindles and spindle poles through its interaction with mitotic microtubules. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Childrens Hosp Boston, Dept Pediat, Boston, MA USA. RP Huang, SC (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, D610,44 Binney St, Boston, MA 02115 USA. EM shu-ching_huang@dfci.harvard.edu RI Jagadeeswaran, Ramasamy/C-9987-2013 FU NHLBI NIH HHS [HL 61295, HL 44985] NR 51 TC 16 Z9 16 U1 0 U2 0 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 AUG 13 PY 2004 VL 279 IS 33 BP 34595 EP 34602 DI 10.1074/jbc.M404051200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 844CL UT WOS:000223134800064 PM 15184364 ER PT J AU Vaquero, EC Edderkaoui, M Pandol, SJ Gukovsky, I Gukovskaya, AS AF Vaquero, EC Edderkaoui, M Pandol, SJ Gukovsky, I Gukovskaya, AS TI Reactive oxygen species produced by NAD(P)H oxidase inhibit apoptosis in pancreatic cancer cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CULTURED ENDOTHELIAL-CELLS; SMOOTH-MUSCLE-CELLS; NF-KAPPA-B; NADPH OXIDASE; HYDROGEN-PEROXIDE; SUPEROXIDE ANION; REGULATES GROWTH; MITOCHONDRIAL; ACTIVATION; DEATH AB One reason why pancreatic cancer is so aggressive and unresponsive to treatments is its resistance to apoptosis. We report here that reactive oxygen species (ROS) are a prosurvival, antiapoptotic factor in pancreatic cancer cells. Human pancreatic adenocarcinoma MIA PaCa-2 and PANC-1 cells generated ROS, which was stimulated by growth factors ( serum, insulin-like growth factor I, or fibroblast growth factor-2). Growth factors also stimulated membrane NAD(P) H oxidase activity in these cells. Both intracellular ROS and NAD( P) H oxidase activity were inhibited by antioxidants tiron and N-acetylcysteine and the inhibitor of flavoprotein-dependent oxidases, diphenylene iodonium, but not by inhibitors of various other ROS-generating enzymes. Using Rho(0) cells deficient in mitochondrial DNA, we showed that a nonmitochondrial NAD( P) H oxidase is a major source of growth factor-induced ROS in pancreatic cancer cells. Among proteins that have been implicated in NAD( P) H oxidase activity, MIA PaCa-2 and PANC-1 cells do not express the phagocytic gp91(phox) subunit but express several nonphagocytic oxidase (NOX) isoforms. Transfection with Nox4 antisense oligonucleotide inhibited NAD( P) H oxidase activity and ROS production in MIA PaCa-2 and PANC-1 cells. Inhibiting ROS with the antioxidants, Nox4 antisense, or MnSOD overexpression all stimulated apoptosis in pancreatic cancer cells as measured by internucleosomal DNA fragmentation, phosphatidylserine externalization, cytochrome c release, and effector caspase activation. The results show that growth factor-induced ROS produced by NAD( P) H oxidase ( probably Nox4) protect pancreatic cancer cells from apoptosis. This mechanism may play an important role in pancreatic cancer resistance to treatment and thus represent a novel therapeutic target. C1 Vet Affairs Greater Los Angeles Healthcare Syst, Dept Med, W Los Angeles Healthcare Ctr, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Los Angeles, CA 90073 USA. RP Gukovskaya, AS (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Dept Med, W Los Angeles Healthcare Ctr, Bldg 258,Rm 340,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM agukovsk@ucla.edu RI Bell, Tiffany/F-4403-2010 FU NIDDK NIH HHS [DK 59936] NR 57 TC 212 Z9 222 U1 1 U2 14 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 AUG 13 PY 2004 VL 279 IS 33 BP 34643 EP 34654 DI 10.1074/jbc.M400078200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 844CL UT WOS:000223134800069 PM 15155719 ER PT J AU Qiu, ZH Hyman, BT Rebeck, GW AF Qiu, ZH Hyman, BT Rebeck, GW TI Apolipoprotein E receptors mediate neurite outgrowth through activation of p44/42 mitogen-activated protein kinase in primary neurons SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BETA-AMYLOID PEPTIDE; METHYL-D-ASPARTATE; CULTURED HIPPOCAMPAL-NEURONS; RAT CORTICAL-NEURONS; GROWTH CONE MOTILITY; ALZHEIMERS-DISEASE; IN-VIVO; TRANSCRIPTIONAL ACTIVITY; CALCIUM TRANSIENTS; SIGNALING PATHWAY AB Several ligands of the endocytic low density lipoprotein receptor-related protein (LRP), such as apoE-containing lipoproteins and activated alpha2-macroglobulin (alpha2M*), promote neurite outgrowth, suggesting that LRP may have signaling functions. In this study, we found that the treatment of neurons with alpha2M* significantly increased the individual length (by 71%) and numbers (by 139%) of neurites of primary mouse cortical neurons. These effects were blocked by the LRP antagonist, the receptor-associated protein. We found similar neurite outgrowth with purified apoE3 and a tandem apoE peptide containing only the receptor-binding domain. To investigate the intracellular pathway of the LRP signaling involved in neurite outgrowth, we tested the effects of alpha2M* on the phosphorylation of the mitogen-activated protein (MAP) extracellular signal-regulated kinases 1 and 2 (ERK1/2). We found that 1) phospho-MAP kinase levels were altered within 30 min after treatment with alpha2M*, 2) the MAP kinase inhibitor, PD98059, specifically blocked the alpha2M*-induced neurite outgrowth, 3) manipulating intracellular calcium by BayK or BAPTA altered the neurite outgrowth and associated changes in the phospho-MAP kinase levels, which were blunted by alpha2M*, 4) alpha2M* promoted the phosphorylation of the transcription factor CREB through MAP kinase, and 5) LRP-specific antibodies increased levels of phosphorylated MAP kinase and phosphorylated CREB. The effects of alpha2M*, apoE3, and apoE peptides increased LRP levels in the cortical neurons, whereas LRP receptor-associated protein reduced dendritic LRP expression. These results demonstrate that p44/42 MAP kinase plays an important role in LRP-mediated neurite outgrowth with activation involving the effects on calcium homeostasis and downstream effects involving the activation of gene transcription through CREB. C1 Georgetown Univ, Dept Neurosci, Washington, DC 20057 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. RP Rebeck, GW (reprint author), Georgetown Univ, Dept Neurosci, Washington, DC 20057 USA. EM gwr2@georgetown.edu FU NIA NIH HHS [R01 AG 14773, R37 AG 12406] NR 64 TC 64 Z9 65 U1 0 U2 0 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 AUG 13 PY 2004 VL 279 IS 33 BP 34948 EP 34956 DI 10.1074/jbc.M401055200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 844CL UT WOS:000223134800106 PM 15169786 ER PT J AU Fricchione, G AF Fricchione, G TI Generalized anxiety disorder SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID COGNITIVE-BEHAVIORAL THERAPY; LONG-TERM TREATMENT; PRIMARY-CARE; CLINICAL-TRIALS; DOUBLE-BLIND; FOLLOW-UP; PLACEBO; PREVALENCE; PAROXETINE; EFFICACY C1 Massachusetts Gen Hosp, Div Psychiat & Med, Boston, MA 02114 USA. RP Fricchione, G (reprint author), Massachusetts Gen Hosp, Div Psychiat & Med, Warren 6,55 Fruit St, Boston, MA 02114 USA. EM gfricchione@partners.org NR 53 TC 42 Z9 46 U1 2 U2 9 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 12 PY 2004 VL 351 IS 7 BP 675 EP 682 DI 10.1056/NEJMcp022342 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 845FZ UT WOS:000223225500010 PM 15306669 ER PT J AU Pratt, JS Kaplan, LM Cummings, S Vineberg, DA Graeme-Cook, F Fernandez-del Castillo, C Vacanti, J AF Pratt, JS Kaplan, LM Cummings, S Vineberg, DA Graeme-Cook, F Fernandez-del Castillo, C Vacanti, J TI Case 25-2004: A 49-year-old woman with severe obesity, diabetes, and hypertension SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID Y GASTRIC BYPASS; QUALITY-OF-LIFE; BARIATRIC SURGERY; MORBID-OBESITY; DEPRESSION; OUTCOMES C1 Massachusetts Gen Hosp, Weight Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Gastrointestinal Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Surg, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. RP Pratt, JS (reprint author), Massachusetts Gen Hosp, Weight Ctr, Boston, MA 02114 USA. NR 24 TC 13 Z9 15 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 12 PY 2004 VL 351 IS 7 BP 696 EP 705 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 845FZ UT WOS:000223225500014 PM 15306672 ER PT J AU Lincoff, AM Kleiman, NS Kereiakes, DJ Feit, F Bittl, JA Jackman, JD Sarembock, IJ Cohen, DJ Spriggs, D Ebrahimi, R Keren, G Carr, J Cohen, EA Betriu, A Desmet, W Rutsch, W Wilcox, RG de Feyter, PJ Vahanian, A Topol, EJ AF Lincoff, AM Kleiman, NS Kereiakes, DJ Feit, F Bittl, JA Jackman, JD Sarembock, IJ Cohen, DJ Spriggs, D Ebrahimi, R Keren, G Carr, J Cohen, EA Betriu, A Desmet, W Rutsch, W Wilcox, RG de Feyter, PJ Vahanian, A Topol, EJ CA REPLACE-2 Investigators TI Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization - REPLACE-2 randomized trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID MYOCARDIAL-INFARCTION; ISCHEMIC EVENTS; RECEPTOR BLOCKADE; UNSTABLE ANGINA; ABCIXIMAB; INTERVENTION; ANGIOPLASTY; PREVENTION; COMPLICATIONS; EPTIFIBATIDE AB Context In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, bivalirudin with provisional glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibition was found to be noninferior to heparin plus planned Gp IIb/IIIa blockade in the prevention of acute ischemic end points and was associated with significantly less bleeding by 30 days after percutaneous coronary intervention (PCI). Objective To determine whether the efficacy of bivalirudin remains comparable with that of heparin plus Gp IIb/IIIa blockade over 6 months and 1 year. Design, Setting, and Participants Follow-up study to 1 year of a randomized, double-blind trial conducted among 6010 patients undergoing urgent or elective PCI at 233 community or referral hospitals in 9 countries from October 2001 through August 2002. Interventions Patients were randomly assigned to receive intravenously bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg per hour for the duration of PCI), with provisional Gp IIb/IIIa inhibition, or to receive heparin (65 U/kg bolus), with planned Gp IIb/IIIa inhibition (abciximab or eptifibatide). Both groups received daily aspirin and a thienopyridine for at least 30 days after PCI. Main Outcome Measures incidence of death, myocardial infarction, or repeat revascularization by 6 months and death by 12 months after enrollment. Results At 6 months, death occurred in 1.4% of patients in the heparin plus Gp IIb/IIIa group and in 1.0% of patients in the bivalirudin group (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.43-1.14; P=.15). Myocardial infarction occurred in 7.4% and 8.2% of patients, respectively (HR, 1.12; 95% CI, 0.93-1.34; P=.24), and repeat revascularization was required in 11.4% and 12.1% of patients, respectively (HR, 1.06; 95% CI, 0.91-1.23; P=.45). By 1 year, death occurred in 2.46% of patients treated with heparin plus Gp IIb/IIIa blockade and in 1.89% of patients treated with bivalirudin (HR, 0.78; 95% CI, 0.55-1.11; P=.16). Nonsignificant trends toward lower 1-year mortality with bivalirudin were present in all patient subgroups analyzed and were of greatest magnitude among high-risk patients. Conclusion Long-term clinical outcome with bivalirudin and provisional Gp IIb/IIIa blockade is comparable with that of heparin plus planned Gp IIb/IIIa inhibition during contemporary PCI. C1 Cleveland Clin Fdn, Dept Cardiovasc Med, Cleveland, OH 44195 USA. Baylor Coll Med, Houston, TX 77030 USA. Methodist Hosp, Houston, TX 77030 USA. Ohio Heart Hlth Ctr, Lindner Ctr, Cincinnati, OH USA. NYU, Sch Med, New York, NY USA. Ocala Heart Inst, Munroe Reg Med Ctr, Ocala, FL USA. Trinity Mother Frances Hosp, Tyler, TX USA. Univ Virginia Hlth Syst, Charlottesville, VA USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Clearwater Cardiovasc Consultants, Clearwater, FL USA. W Los Angeles VA, Los Angeles, CA USA. Tel Aviv Sourasky Med Ctr, Tel Aviv, Israel. E Texas Med Ctr, Tyler, TX USA. Sunnybrook & Womens Coll Hlth Sci Ctr, Toronto, ON, Canada. Univ Barcelona, Hosp Clin, Barcelona, Spain. Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. Univ Clin Charite Berlin, Berlin, Germany. Univ Nottingham Hosp, Nottingham NG7 2UH, England. Univ Hosp Dijkzigt, NL-3015 GD Rotterdam, Netherlands. Hop Bichat, F-75877 Paris, France. RP Lincoff, AM (reprint author), Cleveland Clin Fdn, Dept Cardiovasc Med, Desk F25,9500 Euclid Ave, Cleveland, OH 44195 USA. EM lincofa@ccf.org OI Topol, Eric/0000-0002-1478-4729 NR 23 TC 274 Z9 285 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 11 PY 2004 VL 292 IS 6 BP 696 EP 703 DI 10.1001/jama.292.6.696 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 844RM UT WOS:000223177300023 PM 15304466 ER PT J AU Hancock, KE Delgutte, B AF Hancock, KE Delgutte, B TI A physiologically based model of interaural time difference discrimination SO JOURNAL OF NEUROSCIENCE LA English DT Article DE auditory; binaural; hearing; inferior colliculus; localization; psychophysics ID INFERIOR COLLICULUS; SOUND LOCALIZATION; NERVE FIBERS; FREQUENCY; NEURONS; LATERALIZATION; RESPONSES; STIMULI; DELAYS; SENSITIVITY AB Interaural time difference (ITD) is a cue to the location of sounds containing low frequencies and is represented in the inferior colliculus (IC) by cells that respond maximally at a particular best delay ( BD). Previous studies have demonstrated that single ITD-sensitive cells contain sufficient information in their discharge patterns to account for ITD acuity on the midline (ITD = 0). If ITD discrimination were based on the activity of the most sensitive cell available ("lower envelope hypothesis"), then ITD acuity should be relatively constant as a function of ITD. In response to broadband noise, however, the ITD acuity of human listeners degrades as ITD increases. To account for these results, we hypothesize that pooling of information across neurons is an essential component of ITD discrimination. This report describes a neural pooling model of ITD discrimination based on the response properties of ITD-sensitive cells in the IC of anesthetized cats. Rate versus ITD curves were fit with a cross-correlation model of ITD sensitivity, and the parameters were used to constrain a population model of ITD discrimination. The model accurately predicts ITD acuity as a function of ITD for broadband noise stimuli when responses are pooled across best frequency (BF). Furthermore, ITD tuning based solely on a system of internal delays is not sufficient to predict ITD acuity in response to 500 Hz tones, suggesting that acuity is likely refined by additional mechanisms. The physiological data confirms evidence from the guinea pig that BD varies systematically with BF, generalizing the observation across species. C1 Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. MIT, Elect Res Lab, Cambridge, MA 02143 USA. RP Hancock, KE (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM keh@epl.meei.harvard.edu OI , /0000-0003-1349-9608 FU NIDCD NIH HHS [F32 DC005295, R03 DC007353-02, DC05295, R01 DC002258, R01 DC002258-10, DC00119, DC02258] NR 32 TC 95 Z9 95 U1 0 U2 5 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 AUG 11 PY 2004 VL 24 IS 32 BP 7110 EP 7117 DI 10.1523/JNEUROSCI.0762-04.2004 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 846QP UT WOS:000223331100008 PM 15306644 ER PT J AU Mortensen, EM Cornell, J Whittle, J AF Mortensen, EM Cornell, J Whittle, J TI Racial variations in processes of care for patients with community-acquired pneumonia SO BMC HEALTH SERVICES RESEARCH LA English DT Article ID ELDERLY PATIENTS; PULSE OXIMETRY; HEALTH-CARE; QUALITY; SYSTEM; ACCURACY; OUTCOMES; RACE AB Background: Patients hospitalized with community acquired pneumonia (CAP) have a substantial risk of death, but there is evidence that adherence to certain processes of care, including antibiotic administration within 8 hours, can decrease this risk. Although national mortality data shows blacks have a substantially increased odds of death due to pneumonia as compared to whites previous studies of short-term mortality have found decreased mortality for blacks. Therefore we examined pneumonia-related processes of care and short-term mortality in a population of patients hospitalized with CAP. Methods: We reviewed the records of all identified Medicare beneficiaries hospitalized for pneumonia between 10/1/1998 and 9/30/1999 at one of 101 Pennsylvania hospitals, and randomly selected 60 patients at each hospital for inclusion. We reviewed the medical records to gather process measures of quality, pneumonia severity and demographics. We used Medicare administrative data to identify 30-day mortality. Because only a small proportion of the study population was black, we included all 240 black patients and randomly selected 720 white patients matched on age and gender. We performed a resampling of the white patients 10 times. Results: Males were 43% of the cohort, and the median age was 76 years. After controlling for potential confounders, blacks were less likely to receive antibiotics within 8 hours (odds ratio with 95% confidence interval 0.6, 0.4-0.97), but were as likely as whites to have blood cultures obtained prior to receiving antibiotics (0.7, 0.3-1.5), to have oxygenation assessed within 24 hours of presentation (1.6, 0.9-3.0), and to receive guideline concordant antibiotics (OR 0.9, 0.6-1.7). Black patients had a trend towards decreased 30-day mortality (0.4, 0.2 to 1.0). Conclusion: Although blacks were less likely to receive optimal care, our findings are consistent with other studies that suggest better risk-adjusted survival among blacks than among whites. Further study is needed to determine why this is the case. C1 Audie L Murphy Mem Vet Adm Med Ctr, VERDICT, San Antonio, TX 78284 USA. Audie L Murphy Mem Vet Adm Med Ctr, Div Gen Internal Med, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Kansas City VA Med Ctr, Kansas City, MO USA. Univ Kansas, Sch Med, Div Gen Med & Geriatr, Lawrence, KS 66045 USA. RP Mortensen, EM (reprint author), Audie L Murphy Mem Vet Adm Med Ctr, VERDICT, 7400 Merton Minter Blvd, San Antonio, TX 78284 USA. EM mortensen@verdict.uthscsa.edu; jcornell@verdict.uthscsa.edu; JWHITTLE@kumc.edu OI Mortensen, Eric/0000-0002-3880-5563 FU AHRQ HHS [F32 HS000135] NR 19 TC 12 Z9 12 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD AUG 10 PY 2004 VL 4 AR 20 DI 10.1186/1472-6963-4-20 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 850HF UT WOS:000223601100001 PM 15304197 ER PT J AU Gibson, CM Jennings, LK Murphy, SA Lorenz, DP Giugliano, RP Harrington, RA Cholera, S Krishnan, R Califf, RM Braunwald, E AF Gibson, CM Jennings, LK Murphy, SA Lorenz, DP Giugliano, RP Harrington, RA Cholera, S Krishnan, R Califf, RM Braunwald, E CA INTEGRITI Study Grp TI Association between platelet receptor occupancy after eptifibatide (integrilin) therapy and patency, myocardial perfusion, and ST-segment resolution among patients with ST-segment-elevation myocardial infarction - An INTEGRITI Integrilin and tenecteplase in acute myocardial infarction) substudy SO CIRCULATION LA English DT Article DE platelets; receptors; perfusion; blood flow ID PERCUTANEOUS CORONARY INTERVENTION; TIMI FRAME COUNT; PLASMINOGEN-ACTIVATOR; ARTERY DISEASE; ESSENTIAL THROMBOCYTHEMIA; REPERFUSION THERAPY; GLYCOPROTEIN-IIIA; VOLUME; SIZE; PHARMACODYNAMICS AB Background-Paradoxically, fibrinolytic agents may systemically activate platelets, which in turn secrete plasminogen activator inhibitor (PAI-1), an antagonist of the fibrinolytic process in proportion to total body platelet mass. We hypothesized that improved epicardial patency, myocardial perfusion, and ST-segment resolution would be associated with higher levels of platelet receptor occupancy (RO) by a glycoprotein IIb/IIIa antagonist in ST-elevation MI (STEMI). Methods and Results-Patients were drawn from the low-dose tenecteplase plus eptifibatide arm of the INTEGRITI study. Angiographic and platelet RO data were analyzed at 2 independent core laboratories. To take into account the absolute platelet count and receptors available for cross-linking, absolute platelet count was multiplied by percent of available receptors to obtain the index of the absolute number of receptors available (IANRA). Percent RO was higher among patients with a patent artery (TIMI flow grade 2/3; 78.2+/-9.2, n=63 versus 63.9+/-29.7, n=7; P=0.005), those with TIMI myocardial perfusion grade 2/3 (79.6+/-9.5, n=40 versus 73.0+/-16.2, n=30; P=0.036), and those with complete (greater than or equal to70%) ST-segment resolution at 60 minutes (81.3+/-8.3%, n=27 versus 73.1+/-17.4%, n=24; P=0.034). The absolute number of glycoprotein IIb/IIIa receptors available for cross-linking was reduced (ie, the IANRA was lower) among patients with a patent artery (P=0.0015), patients with TIMI myocardial perfusion grade 2/3 (P=0.026), and patients with greater than or equal to70% ST-segment resolution (P=0.029). Conclusions-This study links restoration of epicardial flow, normal myocardial perfusion, and complete ST-segment resolution with higher levels of platelet glycoprotein IIb/IIIa receptor occupancy after therapy with eptifibatide administered with tenecteplase. C1 Harvard Univ, Sch Med, TIMI Study Grp, Boston, MA USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA USA. Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. Duke Clin Res Inst, Durham, NC USA. RP Gibson, CM (reprint author), 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. NR 37 TC 39 Z9 41 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 AUG 10 PY 2004 VL 110 IS 6 BP 679 EP 684 DI 10.1161/01.CIR.0000137912.11655.F6 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 844XP UT WOS:000223194700007 PM 15262838 ER PT J AU Song, YH Mirey, G Betson, M Haber, DA Settleman, J AF Song, YH Mirey, G Betson, M Haber, DA Settleman, J TI The Drosophila ATM ortholog, dATM, mediates the response to ionizing radiation and to spontaneous DNA damage during development SO CURRENT BIOLOGY LA English DT Article ID EARLY EMBRYONIC LETHALITY; CHROMOSOMAL FRAGMENTATION; ATAXIA-TELANGIECTASIA; TARGETED DISRUPTION; FUNCTIONAL HOMOLOG; GENOME SEQUENCE; MEI-41; LEADS; MELANOGASTER; GENE AB Cells of metazoan organisms respond to DNA damage by arresting their cell cycle to repair DNA, or they undergo apoplosis [1]. Two protein kinases, ataxia-telangiectasia mutated (ATM) and ATM and Rad-3 related (ATR), are sensors for DNA damage [2]. In humans, ATM is mutated in patients with ataxia-telangiectasia (A-T), resulting in hypersensitivity to ionizing radiation (IR) and increased cancer susceptibility. Cells from A-T patients exhibit chromosome aberrations and excessive spontaneous apoptosis. We used Drosophila as a model system to study ATM function. Previous studies suggest that mei-41 corresponds to ATM in Drosophila [3]; however, it appears that mei-41 is probably the ATR ortholog [4]. Unlike mei-41 mutants, flies deficient for the true ATM ortholog, dATM, die as pupae or eclose with eye and wing abnormalities. Developing larval discs exhibit substantially increased spontaneous chromosomal telomere fusions and p53-dependent apoptosis. These developmental phenotypes are unique to dATM, and both dATM and mei-41 have temporally distinct roles in G2 arrest after IR. Thus, ATM and ATR orthologs are required for different functions in Drosophila; the developmental defects resulting from absence of dATM suggest an important role in mediating a protective checkpoint against DNA damage arising during normal cell proliferation and differentiation. C1 Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Canc Ctr, Charlestown, MA 02129 USA. RP Settleman, J (reprint author), Massachusetts Gen Hosp, Ctr Canc, 149 13th St, Charlestown, MA 02129 USA. EM settleman@helix.mgh.harvard.edu RI Betson, Martha/D-3818-2014; OI Betson, Martha/0000-0002-4220-3290; Song, Young-Han/0000-0002-0758-3654; Mirey, Gladys/0000-0002-0095-1864 NR 25 TC 54 Z9 57 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD AUG 10 PY 2004 VL 14 IS 15 BP 1354 EP 1359 DI 10.1016/j.cub.2004.06.064 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 846HJ UT WOS:000223306200027 PM 15296752 ER PT J AU Cha, JH Cudkowicz, ME Gevorkian, S Young, A de Blieck, EA Kieburtz, K Marshall, F Oakes, D Shinaman, MA Shoulson, I Zhao, HW Friedlander, R AF Cha, JH Cudkowicz, ME Gevorkian, S Young, A de Blieck, EA Kieburtz, K Marshall, F Oakes, D Shinaman, MA Shoulson, I Zhao, HW Friedlander, R CA Huntington Study Grp TI Minocycline safety and tolerability in Huntington disease SO NEUROLOGY LA English DT Article ID NEURODEGENERATIVE DISEASES; MOUSE MODEL; CASPASE-1; GENE AB Minocycline is an antibiotic with anti-inflammatory and antiapoptotic properties that prolongs survival in a transgenic Huntington disease (HD) mouse model. In a double-blind, randomized, placebo-controlled study of minocycline in 60 HD patients, the authors determined that over 8 weeks, minocycline at 100 and 200 mg/day was well tolerated and safe in HD patients. Tolerability and adverse event frequency were similar between treatment and placebo groups. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Univ Rochester, Rochester, NY 14627 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Cudkowicz, ME (reprint author), Massachusetts Gen Hosp, Neurol Clin Trial Unit, 13 St,Bldg 149,Rm 2274, Charlestown, MA 02129 USA. EM mcudkowicz@partners.org RI Friedlander, Robert/A-2845-2016 OI Friedlander, Robert/0000-0003-4423-9219 NR 9 TC 53 Z9 54 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 10 PY 2004 VL 63 IS 3 BP 547 EP 549 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 845GK UT WOS:000223229100027 ER PT J AU Shao, WL Keeton, EK McDonnell, DP Brown, M AF Shao, WL Keeton, EK McDonnell, DP Brown, M TI Coactivator AIB1 links estrogen receptor transcriptional activity and stability SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BREAST-CANCER CELLS; 26S PROTEASOME; TAMOXIFEN RESISTANCE; DEPENDENT ACTIVATION; HUMAN PROGESTERONE; ANDROGEN RECEPTOR; NUCLEAR RECEPTORS; ER-ALPHA; PROTEIN; TURNOVER AB Agonist-mediated degradation of estrogen receptor alpha (ERalpha) has been associated with its transcriptional activity. However, the mechanism by which ERa is targeted for degradation and whether there is a direct functional link between ERa stability and ERalpha-mediated transactivation have not been elucidated. Here we provide evidence that the p160 coactivator, AIB1, uniquely mediates agonist-induced, but not antagonist-induced, ERalpha degradation. We show that AIB1 recruitment by ERalpha is not only necessary but also sufficient to promote degradation. Suppression of AIB1 levels leads to ERalpha stabilization in the presence of 17beta-estradiol and, despite increased ERalpha levels, reduced recruitment of ERalpha to enclogenous target gene promoters. In addition, association of RNA polymerase II with ERalpha target promoters is lost when AIB1 is suppressed, leading to inhibition of target gene transcription. AIB1 thus plays a dual role in regulating ERalpha activity, one in recruiting transcription factors including other coactivators involved in gene activation and the other in regulating ERalpha protein degradation mediated by the ubiquitin-proteosome machinery. C1 Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Mol Oncol, Div Mol & Cellular Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Duke Univ, Ctr Med, Dept Pharmacol & Canc Biol, Durham, NC USA. RP Brown, M (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Mol Oncol, Div Mol & Cellular Oncol, 75 Francis St, Boston, MA 02115 USA. EM myles_brown@dfci.harvard.edu RI Myles, Brown/B-6906-2008; OI Brown, Myles/0000-0002-8213-1658 FU NCI NIH HHS [P01 CA080111, P01CA080111]; NIDDK NIH HHS [DK48807, R01 DK048807, R37 DK048807] NR 48 TC 90 Z9 94 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 AUG 10 PY 2004 VL 101 IS 32 BP 11599 EP 11604 DI 10.1073/pnas.0402997101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 845WT UT WOS:000223276700015 PM 15289619 ER PT J AU Stern, JNH Illies, Z Reddy, J Keskin, DB Sheu, E Fridkis-Hareli, M Nishimura, H Brosnan, CF Santambrogio, L Kuchroo, VK Strominger, JL AF Stern, JNH Illies, Z Reddy, J Keskin, DB Sheu, E Fridkis-Hareli, M Nishimura, H Brosnan, CF Santambrogio, L Kuchroo, VK Strominger, JL TI Amerlioration of proteolipid protein 139-151-induced encephalomyelitis in SJL mice by modified amino acid copolymers and their mechanisms SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE multiple sclerosis; cytokines; peptides; T cells; autoimmunity ID MYELIN BASIC-PROTEIN; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; T-CELL RESPONSES; INDUCED DEMYELINATING DISEASE; ANTIGEN-PRESENTING CELLS; MULTIPLE-SCLEROSIS; GLATIRAMER ACETATE; BYSTANDER SUPPRESSION; RECEPTOR ANTAGONISM AB Copolymer 1 [Cop1, glatiramer acetate, Copaxone, poly(Y,E,A,K)n] is widely used in the treatment of relapsing/remitting multiple sclerosis in which it reduces the frequency of relapses by approximate to30%. In the present study, copolymers with modified amino acid compositions (based on the binding motif of myelin basic protein 85-99 to HLA-DR2) have been developed with the aim of suppressing multiple sclerosis more effectively. The enhanced efficacy of these copolymers in experimental autoimmune encephalomyelitis (EAE) induced in SJL/J mice with proteolipid protein 139-151 was demonstrated by using three protocols: (i) simultaneous administration of autoantigen and copolymer (termed prevention), (it) pretreatment with copolymers (vaccination), or (iii) administration of copolymers after disease onset (treatment). Strikingly, in the treatment protocol administration of soluble VWAK and FYAK after onset of disease led to stasis of its progression and suppression of histopathological evidence of EAE. The mechanisms by which these effects are achieved have been examined in several types of assays: binding of copolymers to I-As in competition with proteolipid protein 139-151 (blocking), cytokine production by T cells (T helper 2 polarization), and transfer of protection by CD3(+) splenocytes or, notably, by copolymer-specific T cell lines (induction of regulatory T cells). The generation of these copolymerspecific regulatory T cells that secrete IL-4 and IL-10 and are independent of the immunizing autoantigen is very prominent among the multiple mechanisms that account for the observed suppressive effect of copolymers in EAE. C1 Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. Harvard Univ, Inst Med, Ctr Neurol Dis, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA. RP Strominger, JL (reprint author), Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. EM jlstrom@fas.harvard.edu FU NIAID NIH HHS [AI 49524, R01 AI049524]; NINDS NIH HHS [R01 NS030843, P01 NS038037, P01 NS38037, R01 NS30843] NR 46 TC 32 Z9 33 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 AUG 10 PY 2004 VL 101 IS 32 BP 11743 EP 11748 DI 10.1073/pnas.0403832101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 845WT UT WOS:000223276700040 PM 15292514 ER PT J AU Illies, Z Stern, JNH Reddy, J Waldner, H Mycko, MP Brosnan, CF Ellmerich, S Altmann, DM Santambrogio, L Strominger, JL Kuchroo, VK AF Illies, Z Stern, JNH Reddy, J Waldner, H Mycko, MP Brosnan, CF Ellmerich, S Altmann, DM Santambrogio, L Strominger, JL Kuchroo, VK TI Modified amino acid copolymers suppress myelin basic protein 85-99-induced encephalomyelitis in humanized mice through different effects on T cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE multiple sclerosis; DRB1*1501; microglia; CNS; autoimmunity ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ALTERED PEPTIDE LIGAND; HLA-DR MOLECULES; MULTIPLE-SCLEROSIS; GLATIRAMER ACETATE; PROTEOLIPID PROTEIN; CEREBROSPINAL-FLUID; DOUBLE-BLIND; TRIAL; MECHANISMS AB A humanized mouse bearing the HLA-DR2 (DRA/DRB1*1501) protein associated with multiple sclerosis (MS) and the myelin basic protein (MBP) 85-99-specific HLA-DR2-restricted T cell receptor from an MS patient has been used to examine the effectiveness of modified amino acid copolymers poly(F,Y,A,K)n and poly(V,W,A,K)n in therapy of MBP 85-99-induced experimental autoimmune encephalomyelitis (EAE) in comparison to Copolymer 1 [Copaxone, poly(Y,E,A,K)n]. The copolymers were designed to optimize binding to HLA-DR2. Vaccination, prevention, and treatment of MBP-induced EAE in the humanized mice with copolymers FYAK and VWAK ameliorated EAE more effectively than Copolymer 1, reduced the number of pathological lesions, and prevented the up-regulation of human HLA-DR on CNS microglia. Moreover, VWAK inhibited MBIP 85-99-specific T cell proliferation more efficiently than either FYAK or Copolymer 1 and induced anergy of HLA-DR2-restricted transgenic T cells as its principle mechanism. in contrast, FYAK induced proliferation and a pronounced production of the anti inflammatory T helper 2 cytokines IL-4 and IL-10 from nontransgenic T cells as its principle mechanism of immunosuppression. Thus, copolymers generated by using different amino acids inhibited disease using different mechanisms to regulate T cell responses. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Inst Med,Ctr Neurol Dis, Boston, MA 02115 USA. Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA. Univ London Imperial Coll Sci Technol & Med, Dept Infect Dis, London WC1E 6BT, England. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Kuchroo, VK (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Inst Med,Ctr Neurol Dis, 75 Francis St, Boston, MA 02115 USA. EM vkuchroo@rics.bwh.harvard.edu RI Reddy, Jay/K-7200-2014; Mycko, Marcin Przemyslaw/S-9386-2016; OI Reddy, Jay/0000-0003-4082-9254; Stern, Joel N.H./0000-0002-1259-2256; Altmann, Daniel/0000-0002-2436-6192 NR 35 TC 31 Z9 31 U1 0 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 AUG 10 PY 2004 VL 101 IS 32 BP 11749 EP 11754 DI 10.1073/pnas.0403833101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 845WT UT WOS:000223276700041 ER PT J AU Perron, MJ Stremlau, M Song, B Ulm, W Mulligan, RC Sodroski, J AF Perron, MJ Stremlau, M Song, B Ulm, W Mulligan, RC Sodroski, J TI TRIM5 alpha mediates the postentry block to N-tropic murine leukemia viruses in human cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; ENDOGENOUS RETROVIRUS; RESTRICTION FACTORS; CYCLOPHILIN-A; REVERSE TRANSCRIPTION; HOST RESTRICTION; HIV-1 VIRIONS; MONKEY CELLS; REPLICATION; GENE AB Murine leukemia viruses (MLVs) have been classified as N-tropic (N-MLV) or B-tropic (B-MLV), depending on their ability to infect particular mouse strains. The early phase of N-MLV infection is blocked in the cells of several mammalian species, including humans. This block is mediated by a dominant host factor that targets the viral capsid soon after virus entry into the cell has been achieved. A similar block to HIV-1 in rhesus monkey cells is mediated by TRIM5alpha. Here we show that human TRIM5alpha is both necessary and sufficient for the restriction of N-MLV in human cells. Rhesus monkey TRIM5alpha, which potently blocks HIV-1 infection, exhibited only modest inhibition of N-MLV infection. B-MLV was resistant to the antiviral effects of both human and rhesus monkey TRIM5alpha susceptibility to TRIM5alpha-mediated restriction was conferred by alteration of residue 110 of the B-MLV capsid protein to the amino acid found in the N-MLV capsid. Our results demonstrate that species-specific variation in TRIM5alpha governs its ability to block infection by diverse retrovinuses. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS,Div AIDS, Boston, MA 02115 USA. Harvard Univ, Div Mol Med, Dept Genet, Childrens Hosp,Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Sodroski, J (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS,Div AIDS, Fund Bldg,Room 824,44 Binney St, Boston, MA 02115 USA. EM joseph-sodroski@dfci.harvard.edu FU NHLBI NIH HHS [HL54785, P50 HL054785]; NIAID NIH HHS [P30 AI028691, P30 AI28691] NR 42 TC 220 Z9 224 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 AUG 10 PY 2004 VL 101 IS 32 BP 11827 EP 11832 DI 10.1073/pnas.0403364101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 845WT UT WOS:000223276700054 PM 15280539 ER PT J AU Jagsi, R Lehmann, S AF Jagsi, R Lehmann, S TI The ethics of medical education SO BRITISH MEDICAL JOURNAL LA English DT Article ID LEGAL IMPLICATIONS; INFORMED CONSENT; STUDENT DOCTOR; CARE; RESIDENTS; ATTITUDES; PATIENT C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Gen Med & Primary Care, Boston, MA 02120 USA. RP Lehmann, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. EM llehmann1@partners.org OI Jagsi, Reshma/0000-0001-6562-1228 NR 19 TC 19 Z9 20 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD AUG 7 PY 2004 VL 329 IS 7461 BP 332 EP 334 DI 10.1136/bmj.329.7461.332 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 846FF UT WOS:000223300300024 PM 15297341 ER PT J AU Pham, W Kircher, MF Weissleder, R Tung, CH AF Pham, W Kircher, MF Weissleder, R Tung, CH TI Enhancing membrane permeability by fatty acylation of oligoarginine peptides SO CHEMBIOCHEM LA English DT Article DE arginine; lipids; membranes; peptides; Tat ID CELLULAR UPTAKE; ENDOPLASMIC-RETICULUM; PROTEIN; TOXICITY; ARGININE; CELLS C1 Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. RP Tung, CH (reprint author), Massachusetts Gen Hosp, Ctr Mol Imaging Res, 149 13th St,Room 5406, Charlestown, MA 02129 USA. EM tung@helix.mgh.harvard.edu OI Tung, Ching-Hsuan/0000-0001-6648-6195 FU NCI NIH HHS [R01-CA99385, P50-CA86355] NR 17 TC 40 Z9 40 U1 0 U2 3 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1439-4227 J9 CHEMBIOCHEM JI Chembiochem PD AUG 6 PY 2004 VL 5 IS 8 BP 1148 EP 1151 DI 10.1002/cbic.200400063 PG 4 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 846BY UT WOS:000223291000020 PM 15300843 ER PT J AU Maertens, G Cherepanov, P Debyser, Z Engelborghs, Y Engelman, A AF Maertens, G Cherepanov, P Debyser, Z Engelborghs, Y Engelman, A TI Identification and characterization of a functional nuclear localization signal in the HIV-1 integrase interactor LEDGF/p75 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 PREINTEGRATION COMPLEXES; CENTRAL DNA FLAP; LARGE-T-ANTIGEN; VIRAL MATRIX PROTEIN; STRESS-RELATED GENES; NONDIVIDING CELLS; IMPORTIN-BETA; SUBCELLULAR-LOCALIZATION; LENTIVIRAL VECTOR AB Human lens epithelium-derived growth factor ( LEDGF)/p75 protein forms a specific nuclear complex with human immunodeficiency virus type 1 (HIV-1) integrase and is essential for nuclear localization and chromosomal association of the viral protein. We now studied nuclear import of LEDGF/p75 in live and semipermeabilized cells. We show that nuclear import of LEDGF/p75 is GTP-, Ran-, importin-alpha/beta-, and energy-dependent and that the protein competes with the canonical SV40 large T antigen nuclear localization signal (NLS) for nuclear import receptors. We identified the NLS of LEDGF/p75 through deletion analysis and site-directed mutagenesis. The LEDGF/p75 NLS, (148)GRKR-KAEKQ(156), belongs to the canonical SV40-like family. Fusion of this short peptide to the amino terminus of Escherichia coli beta-galactosidase rendered the fusion protein nuclear, confirming that the LEDGF/p75 NLS is transferable. Moreover, a single amino acid change in the NLS was sufficient to exclude the mutant LEDGF/ p75 protein from the nucleus and abolish nuclear import of HIV-1 integrase. C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Katholieke Univ Leuven, Lab Biomol Dynam, B-3001 Heverlee, Belgium. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium. Katholieke Univ Leuven, KULAK, B-3000 Louvain, Belgium. RP Engelman, A (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM Alan_Engelman@dfci.harvard.edu RI Cherepanov, Peter/F-6859-2010; Maertens, Goedele/D-8628-2015 OI Cherepanov, Peter/0000-0002-0634-538X; Maertens, Goedele/0000-0002-1963-8026 FU NIAID NIH HHS [AI52014] NR 74 TC 77 Z9 81 U1 1 U2 3 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 AUG 6 PY 2004 VL 279 IS 32 BP 33421 EP 33429 DI 10.1074/jbc.M404700200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 842YD UT WOS:000223039700050 PM 15163664 ER PT J AU Wilens, E Faraone, SV Biederman, J AF Wilens, E Faraone, SV Biederman, J TI Attention-deficit/hyperactivity disorder in adults SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID DEFICIT HYPERACTIVITY DISORDER; CHILDHOOD-ONSET; DOPAMINE TRANSPORTER; YOUNG-ADULTS; DOUBLE-BLIND; HUMAN BRAIN; METHYLPHENIDATE; ADHD; PERFORMANCE; CHILDREN C1 Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Clin Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Wilens, E (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Clin Res Program Pediat Psychopharmacol, ACC 725,15 Parkman St, Boston, MA 02114 USA. EM twilens@partners.org OI Faraone, Stephen/0000-0002-9217-3982 NR 44 TC 21 Z9 23 U1 2 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 4 PY 2004 VL 292 IS 5 BP 619 EP 623 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 843AE UT WOS:000223045500020 ER PT J AU Sadanandan, S Cannon, CP Chekuri, K Murphy, SA DiBattiste, PM Morrow, DA de Lemos, JA Braunwald, E Gibson, CM AF Sadanandan, S Cannon, CP Chekuri, K Murphy, SA DiBattiste, PM Morrow, DA de Lemos, JA Braunwald, E Gibson, CM TI Association of elevated B-type natriuretic peptide levels with anglographic findings among patients with unstable angina and non-ST-segment elevation myocardial infarction SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID INCREASED PLASMA-LEVELS; CORONARY ANGIOPLASTY; HEART-FAILURE; ATRIAL; PREDICTION; STRATEGIES; BNP AB OBJECTIVES We hypothesized that elevated B-type natriuretic peptide (BNP) levels would be associated with a greater severity of angiographic disease and a greater extent of myocardium at risk. BACKGROUND Elevations of BNP have been associated with increased risk of adverse outcomes in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI). METHODS Of the 2,220 patients with UA/NSTEMI enrolled in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction-18 (TACTICS-TIMI-18) trial, 276 randomized to the invasive arm had both baseline BNP levels and angiographic core laboratory data. Patients were categorized according to their baseline BNP levels as less than or equal to80 or >80 pg/ml. RESULTS A total of 233 patients (84%) had BNP levels >80 pg/ml, and 43 (16%) had admission BNP levels >80 pg/ml. Patients with BNP >80 pg/ml had tighter culprit vessel stenosis on quantitative coronary angiography (median stenosis 76% vs. 67%, p = 0.004) and a higher (slower) corrected TIMI frame count (median CTFC 43 vs. 30, p = 0.018) in the culprit vessel. The median BNP level was higher in patients with a left anterior descending coronary artery (LAD) versus non-LAD culprit lesion location (median BNP level 40 vs. 24 pg/ml, p = 0.005), and the culprit artery was more often the LAD in patients with BNP >80 pg/ml compared with less than or equal to80 pg/ml (44% vs. 30%, p = 0.06). CONCLUSIONS Among patients with UA/NSTEMI, elevated BNP levels are associated with tighter culprit stenosis, higher CTFC, and LAD involvement. These findings suggest that elevated BNP may be associated with a greater severity and extent of myocardial ischemic territory during the index event and may partly explain the association between elevated BNP and adverse outcomes. (C) 2004 by the American College of Cardiology Foundation. C1 Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Merck & Co Inc, W Point, PA USA. Univ Texas, SW Med Ctr, Donald W Reynolds Cardiovasc Clin Res Ctr, Dallas, TX 75230 USA. RP Sadanandan, S (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Cardiol, 1 Deaconess Rd,Baker 4, Boston, MA 02215 USA. EM ssadanan@bidmc.harvard.edu NR 24 TC 80 Z9 89 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 4 PY 2004 VL 44 IS 3 BP 564 EP 568 DI 10.1016/j.jacc.2004.03.072 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 843AV UT WOS:000223047900012 PM 15358021 ER PT J AU Craig, WA AF Craig, WA TI Overview of newer antimicrobial formulations for overcoming pneumococcal resistance SO AMERICAN JOURNAL OF MEDICINE LA English DT Article; Proceedings Paper CT Roundtable Meeting on Streptococcus Pneumoniae - Resistance Patterns, Disease Trends and Cllinical Implications CY AUG 28, 2003 CL Rosemont, IL ID COMMUNITY-ACQUIRED PNEUMONIA; RESPIRATORY-TRACT INFECTIONS; STREPTOCOCCUS-PNEUMONIAE; AMOXICILLIN-CLAVULANATE; PHARMACODYNAMICS; PHARMACOKINETICS; MANAGEMENT; GUIDELINES; THERAPY; AMOXICILLIN/CLAVULANATE AB The pharmacokinetic (PK) and pharmacodynamic (PD) profile of an antimicrobial agent provides important information that can be used to maximize bacteriologic and clinical efficacy, minimize selective pressure for the development of antimicrobial resistance, and determine an optimal dosing regimen. Judicious selection of an antimicrobial based on local susceptibility data and PK and PD parameters is imperative in this era of increasing resistance among Streptococcus pneumoniae, a leading cause of community-acquired respiratory tract infections. The beta-lactam antimicrobials display time-dependent bacterial killing with minimal to no persistent effects. Ketolides and fluoroquinolones display concentration-dependent bacterial killing, and tetracyclines and macrolides display time-dependent killing. All have prolonged persistent effects (e.g., postantibiotic effect) that retard or prevent bacterial regrowth when free drug levels fall below the minimum inhibitory concentration (MIC). New high-dose and/or ex tended-release formulations of traditional antimicrobials have been added to the current armamentarium for treatment of community-acquired respiratory tract infections. These formulations include amoxicillin-clavulanate potassium powder for oral suspension 90/6.4 mg/kg per day divided every 12 hours (Augmentin ES-600; GlaxoSmithKline, Research Triangle Park, NC), amoxicillin-clavulanate potassium extended-release tablets 2 x 1,000 mg/62.5 mg every 12 hours (Augmentin XR; GlaxoSmithKline), clarithromycin extended-release tablets 2 x 500 mg once daily (Biaxin XL; Abbott Laboratories, North Chicago, IL), and cefaclor extended-release tablets 375 mg or 500 mg every 12 hours (Ceclor CD; Eli Lilly Pharmaceuticals, Indianapolis, IN). Of these agents, only amoxicillin-clavulanate potassium powder for oral suspension and amoxicillin-clavulanate potassium extended-release tablets were designed to treat infections caused by penicillin-resistant pneumococci (penicillin MIC less than or equal to 2 mug/mL). Extended-release clarithromycin does not provide higher daily doses than its immediate-release counterpart; rather, it allows for once-daily dosing of this agent because of its slower absorption following oral administration. Extended-release cefaclor is considered clinically equivalent to 250 mg of immediate-release cefaclor pulvules administered 3 times daily; it cannot be used interchangeably with 500 mg 3-times-daily dosages of other cefaclor formulations. Thus, despite providing a similar or higher total daily dose than its immediate-release counterpart, extended-release cefaclor is indicated only for the treatment of patients with mild to moderate infections caused by susceptible strains of certain organisms. (C) 2004 by Elsevier Inc. C1 Univ Wisconsin, William S Middleton Mem Vet Adm Hosp, Dept Med, Madison, WI 53705 USA. RP Craig, WA (reprint author), Univ Wisconsin, William S Middleton Mem Vet Adm Hosp, Dept Med, 2500 Overlook Terrace, Madison, WI 53705 USA. NR 39 TC 5 Z9 5 U1 0 U2 3 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD AUG 2 PY 2004 VL 117 SU 3A BP 16 EP 22 DI 10.1016/j.amjmed.2004.07.004 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 843RC UT WOS:000223101200003 ER PT J AU Meyer-Olson, D Shoukry, NH Brady, KW Kim, H Olson, DP Hartman, K Shintani, AK Walker, CM Kalams, SA AF Meyer-Olson, D Shoukry, NH Brady, KW Kim, H Olson, DP Hartman, K Shintani, AK Walker, CM Kalams, SA TI Limited T cell receptor diversity of HCV-specific T cell responses is associated with CTL escape SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE CD8(+) T lymphocytes; CD4(+) T lymphocytes; hepatitis C; antigenic variation; epitopes ID HEPATITIS-C VIRUS; ACUTE VIRAL-INFECTION; LYMPHOCYTE CLONES; IN-VIVO; DISEASE PROGRESSION; IMMUNE-RESPONSES; REPERTOIRE; VARIANTS; MEMORY; EPITOPE AB Escape mutations are believed to be important contributors to immune evasion by rapidly evolving viruses such as hepatitis C virus (HCV). We show that the majority of HCV-specific cytotoxic T lymphocyte (CTL) responses directed against viral epitopes that escaped immune recognition in HCV-infected chimpanzees displayed a reduced CDR3 amino acid diversity when compared with responses in which no CTL epitope variation was detected during chronic infection or with those associated with protective immunity. Decreased T cell receptor (TCR) CDR3 amino acid diversity in chronic infection could be detected long before the appearance of viral escape mutations in the plasma. In both chronic and resolved infection, identical T cell receptor clonotypes were present in liver and peripheral blood. These findings provide a deeper understanding of the evolution of CTL epitope variations in chronic viral infections and highlight the importance of the generation and maintenance of a diverse TCR repertoire directed against individual epitopes. C1 Vanderbilt Univ, Med Ctr, Dept Internal Med, Infect Dis Unit, Nashville, TN 37232 USA. Vanderbilt Univ, Med Ctr, Dept Microbiol & Immunol, Nashville, TN 37232 USA. Vanderbilt Univ, Med Ctr, Ctr Hlth Serv Res, Dept Gen Internal Med, Nashville, TN 37232 USA. Harvard Univ, Sch Med, Partners AIDS Res Ctr, Boston, MA 02129 USA. Massachusetts Gen Hosp, Boston, MA 02129 USA. Ohio State Univ, Coll Med & Publ Hlth, Columbus Childrens Res Inst, Ctr Vaccines & Immun, Columbus, OH 43205 USA. Ohio State Univ, Coll Med & Publ Hlth, Dept Pediat, Columbus, OH 43205 USA. RP Kalams, SA (reprint author), Vanderbilt Univ, Med Ctr, Dept Internal Med, Infect Dis Unit, MCN A4013, Nashville, TN 37232 USA. EM spyros.a.kalams@vanderbilt.edu FU NIAID NIH HHS [P30 AI054999, P30 AI54999, U19 AI048231, U19 AI48231, R01 AI039966, R01 AI39966, R01 AI47367] NR 64 TC 117 Z9 120 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 AUG 2 PY 2004 VL 200 IS 3 BP 307 EP 319 DI 10.1084/jem.20040638 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 844RX UT WOS:000223178500005 PM 15289502 ER PT J AU Sullivan, AM Warren, AG Lakoma, MD Liaw, KR Hwang, D Block, SD AF Sullivan, AM Warren, AG Lakoma, MD Liaw, KR Hwang, D Block, SD TI End-of-life care in the curriculum: A national study of medical education deans SO ACADEMIC MEDICINE LA English DT Article ID INCORPORATING PALLIATIVE CARE; SCHOOL; RESISTANCE; DEATH AB Purpose. To describe attitudes and practices of end-of-life care teaching in the undergraduate medical curriculum in the United States as reported by administrative leadership and identify opportunities for improvement. Method. A telephone survey of associate deans for medical education or curricular affairs at a random sample of 62 accredited U.S. medical schools was conducted in 2002. Results. Fifty-one deans participated (82% response rate). Most (84%) described end-of-life care education as "very important" and supported incorporating more end-of-life care teaching into the undergraduate curriculum. Sixty-seven percent reported that insufficient time is currently given to palliative care in their curriculum. Although a majority opposed required courses (59%) or clerkships (70%) that focused on end-of-life care, they did unanimously endorse integrating teaching end-of-life care into existing courses or clerkships. Key barriers to incorporating more end-of-life care into the curriculum included lack of time in the curriculum, lack of faculty expertise, and absence of a faculty leader. Conclusion. Associate deans for medical education or curricular affairs in the United States support integrating end-of-life care content into existing courses and clerkships throughout the undergraduate medical curriculum. Successful integration will require institutional investment in faculty development, including both the development of faculty leaders to drive change efforts, and the education of all faculty who teach students and exert influence as role models and mentors. The strong support for end-of-life care education expressed by academic leaders in this study, combined with the high level of interest expressed in the authors' 2001 national survey of students, provide evidence of the potential for meaningful change in the undergraduate medical curriculum. C1 Dana Farber Canc Inst, Div Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Sullivan, AM (reprint author), Dana Farber Canc Inst, Div Psychosocial Oncol & Palliat Care, 44 Binney St,Room G420D, Boston, MA 02115 USA. EM amy_sullivan@dfci.harvard.edu NR 35 TC 56 Z9 58 U1 0 U2 3 PU ASSOC AMER MEDICAL COLLEGES PI WASHINGTON PA 2450 N ST N W, WASHINGTON, DC 20037-1126 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD AUG PY 2004 VL 79 IS 8 BP 760 EP 768 DI 10.1097/00001888-200408000-00011 PG 9 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 842KD UT WOS:000223002000007 PM 15277133 ER PT J AU Alderson, PO Bresolin, LB Becker, GJ Thrall, JH Dunnick, NR Hillman, BJ Lee, JKT Nagy, EC AF Alderson, PO Bresolin, LB Becker, GJ Thrall, JH Dunnick, NR Hillman, BJ Lee, JKT Nagy, EC CA Consensus Conference Participants TI Enhancing research in academic radiology departments: Recommendations of the 2003 Consensus Conference SO ACADEMIC RADIOLOGY LA English DT Article AB Opportunities for funded radiological research are greater than ever, and the amount of federal funding coming to academic radiology departments is increasing. Even so, many medical school-based radiology departments have little or no research funding. Accordingly, a consensus panel was convened to discuss ways to enhance research productivity and broaden the base of research strength in as many academic radiology departments as possible. The consensus panel included radiologists who have leadership roles in some of the best-funded research departments, radiologists who direct other funded research programs, and radiologists with related expertise. The goals of the consensus panel were to identify the attributes associated with successful research programs and to develop an action plan for radiology research based on these characteristics. C1 Columbia Univ, New York, NY 10027 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Cincinnati, Cincinnati, OH 45221 USA. Univ Chicago, Chicago, IL 60637 USA. Univ Penn, Philadelphia, PA 19104 USA. Miami Cardiac & Vasc Inst, Miami, FL USA. Univ Michigan, Ann Arbor, MI 48109 USA. Harvard Univ, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. Univ N Carolina, Chapel Hill, NC 27515 USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. RP Nagy, EC (reprint author), 622 W 168 St, New York, NY 10032 USA. NR 8 TC 0 Z9 0 U1 0 U2 2 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD AUG PY 2004 VL 11 IS 8 BP 951 EP 956 DI 10.1016/j.acra.2004.02.005 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 844DN UT WOS:000223137600013 PM 15470808 ER PT J AU Arnsten, JH Reid, K Bierer, M Rigotti, N AF Arnsten, JH Reid, K Bierer, M Rigotti, N TI Smoking behavior and interest in quitting among homeless smokers SO ADDICTIVE BEHAVIORS LA English DT Article; Proceedings Paper CT 20th Annual Meeting of the Society-for-General-Internal-Medicine CY MAY, 1997 CL Washington, DC SP Soc Gen Internal Med DE self-efficacy; smoking cessation counseling; readiness to quit ID NEW-YORK-CITY; CESSATION; RESIDENTS; ADDICTION; URBAN AB Objectives: To examine smoking behavior in homeless persons, including the impact of self-reported tobacco-related health problems and drug and alcohol abuse on readiness to quit and interest in smoking cessation counseling. Methods: Cross-sectional survey of outpatients and inpatients on the homeless service at Massachusetts General Hospital. Results: Among 98 homeless smokers with a mean age of 44 years, tobacco-related medical diagnoses and symptoms and psychiatric illnesses were common, as were drug and alcohol abuse. One third of the smokers in this sample intended to quit smoking within the next 6 months, including 19% who planned to quit in the next 1 month. Forty-four percent of the participants were somewhat or very interested in smoking cessation counseling. In multivariate analyses, significant (P < .05) predictors of readiness to quit smoking were greater confidence in one's ability to quit (self-efficacy) and more social support for quitting. Multivariate predictors of interest in smoking cessation counseling were smoking-related symptoms and higher self-efficacy for quitting. Conclusions: Homeless smokers recruited from the inpatient and outpatient services of a large, urban teaching hospital reported interest in both stopping tobacco use and receiving assistance to quit smoking. Having an illness that a smoker believes is tobacco-related, having greater confidence in the ability to quit, and having more social support for quitting were associated with greater readiness to quit and more interest in smoking cessation counseling. Alcohol and drug abuse were not associated with reduced interest in quitting smoking. These findings suggest that homeless smokers may benefit from smoking cessation programs that are colocated in medical or drug treatment settings. (C) 2004 Elsevier Ltd. All rights reserved. C1 Albert Einstein Coll Med, AIDS Res Program, Dept Med, Montefiore Med Ctr, Bronx, NY 10467 USA. Albert Einstein Coll Med, Montefiore Med Ctr, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. Albert Einstein Coll Med, Montefiore Med Ctr, Div Subst Abuse, Dept Psychiat & Behav Sci, Bronx, NY 10467 USA. Univ Calif San Francisco, Sch Med, Dept Med, San Francisco, CA 94143 USA. Massachusetts Gen Hosp, Dept Med, Gen Internal Med Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Dept Med, Boston, MA 02114 USA. RP Arnsten, JH (reprint author), Albert Einstein Coll Med, AIDS Res Program, Dept Med, Montefiore Med Ctr, 111 E 210th St, Bronx, NY 10467 USA. EM jarnsten@montefiore.org FU BHP HRSA HHS [T32-PE11001]; NHLBI NIH HHS [K24-HL04440]; NIDA NIH HHS [R25 DA15302, R01-DA11869] NR 17 TC 46 Z9 47 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD AUG PY 2004 VL 29 IS 6 BP 1155 EP 1161 DI 10.1016/j.addbeh.2004.03.010 PG 7 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 840BT UT WOS:000222832700011 PM 15236817 ER PT J AU Wang, SW Bertley, FMN Kozlowski, PA Herrmann, L Manson, K Mazzara, G Piatak, M Johnson, RP Carville, A Mansfield, K Aldovini, A AF Wang, SW Bertley, FMN Kozlowski, PA Herrmann, L Manson, K Mazzara, G Piatak, M Johnson, RP Carville, A Mansfield, K Aldovini, A TI An SHIV DNA/MVA rectal vaccination in macaques provides systemic and mucosal virus-specific responses and protection against AIDS SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; CYTOTOXIC T-LYMPHOCYTES; POLYMERASE CHAIN-REACTION; IMMUNE-RESPONSES; VIRAL LOAD; TYPE-1 INFECTION; RHESUS MACAQUES; CELL RESPONSES; DISEASE PROGRESSION; HIV-1 INFECTION AB We explored the use of a simian-human immunodeficiency virus (SHIV) DNA vaccine as an effective mucosal priming agent to stimulate a protective immune response for AIDS prevention. Rhesus macaques were vaccinated rectally with a DNA construct producing replication-defective SHIV particles, and boosted with either the same DNA construct or recombinant modified vaccinia virus Ankara (MVA) expressing SIV Gag, SIV Pol, and HIV Env (MVA-SHIV). Virus-specific mucosal and systemic humoral and cell-mediated immune responses could be stimulated by this approach but were present inconsistently among the vaccinated animals. Rectal vaccination with either SHIV DNA alone or SHIV DNA followed by MVA-SHIV induced SIV Gag/Pol- or HIV gp120-specific IgA in rectal secretions of four of seven animals. However, the gp120-specific rectal IgA antibody responses were not durable and had become undetectable in all but one animal shortly before rectal challenge with pathogenic SHIV 89.6P. Only the macaques primed with SHIV DNA and boosted with MVA-SHIV demonstrated SHIV-specific IgG in plasma. In addition, these animals developed more consistent antiviral cell-mediated responses and had better preservation of CD4 T cells following challenge with SHIV 89.6P. Our study demonstrates the utility of a rectal DNA/MVA vaccination protocol for the induction of diverse responses in different immunological compartments. In addition, the immunity achieved with this mucosal vaccination regimen is sufficient to delay progression to AIDS. C1 Childrens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Therion, Cambridge, MA 02142 USA. NCI, Frederick Canc Res & Dev Ctr, Retroviral Pathogenesis Lab, AIDS Vaccine Program,SAIC Frederick, Frederick, MD 21702 USA. Harvard Univ, New England Primate Res Ctr, Sch Med, Southborough, MA 01772 USA. Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Infect Dis Unit, Charlestown, MA 02129 USA. RP Aldovini, A (reprint author), Childrens Hosp, Dept Med, Enders 861,300 Longwood Ave, Boston, MA 02115 USA. EM anna.aldovini@childrens.harvard.edu FU NCI NIH HHS [N01-CO-124000]; NIAID NIH HHS [AI41365] NR 82 TC 37 Z9 37 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD AUG PY 2004 VL 20 IS 8 BP 846 EP 859 DI 10.1089/0889222041725253 PG 14 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 852AF UT WOS:000223726900009 PM 15320989 ER PT J AU Lieber, CS AF Lieber, CS TI Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis SO ALCOHOL LA English DT Article; Proceedings Paper CT Symposium on Role of Fatty Liver Dietary Fatty Acid Supplements and Obesity in the Progression of Alcoholic Liver Disease CY OCT 03, 2003 CL Bethesda, MD DE alcoholic steatosis; alcoholic steatchepatitis; cytochrome P450 2E1; obesity; dilinoleoylphosphatidylcholine; S-adenosylmethionine; oxidative stress; TNF-alpha; acetaldehyde ID ETHANOL-OXIDIZING SYSTEM; ADENOSYL-L-METHIONINE; HEPATIC STELLATE CELLS; ACID-BINDING-PROTEIN; RAT-LIVER; CYTOCHROME P-4502E1; DOUBLE-BLIND; NONALCOHOLIC STEATOHEPATITIS; COLLAGEN-SYNTHESIS; MITOCHONDRIAL ABNORMALITIES AB Liver disease in the alcoholic is due not only to malnutrition but also to ethanol's hepatotoxicity linked to its metabolism by means of the alcohol dehydrogenase and cytochrome P450 2E1 (CYP2E1) pathways and the resulting production of toxic acetaldehyde. In addition, alcohol dehydrogenase-mediated ethanol metabolism generates the reduced form of nicotinamide adenine dinuclectide (NADH), which promotes steatosis by stimulating the synthesis of fatty acids and opposing their oxidation. Steatosis is also promoted by excess dietary lipids and can be attenuated by their replacement with medium-chain triglycerides. Through reduction of pyruvate, elevated NADH also increases lactate, which stimulates collagen synthesis in myofibroblasts. Furthermore, CYP2E1 activity is inducible by its substrates, not only ethanol but also fatty acids. Their excess and metabolism by means of this pathway generate release of free radicals, which cause oxidative stress, with peroxidation of lipids and membrane damage, including altered enzyme activities. Products of lipid peroxidation such as 4-hydroxynonenal stimulate collagen generation and fibrosis, which are further increased through diminished feedback inhibition of collagen synthesis because acetaldehyde forms adducts with the carboxyl-tertninal propeptide of procollagen in hepatic stellate cells. Acetaldehyde is also toxic to the mitochondria, and it aggravates their oxidative stress by binding to reduced glutathione and promoting its leak-age. Oxidative stress and associated cellular injury promote inflammation, which is aggravated by increased production of the proinflammatory cytokine tumor necrosis factor-alpha in the Kupffer cells. These are activated by induction of their CYP2E1 as well as by endotoxin. The endotoxin-stimulated tumor necrosis factor-alpha release is decreased by dilinoleoylphosphatidylcholine, the active phosphatidylcholine (PC) species of polyenylphosphatidlcholine (PPC). Moreover, defense mechanisms provided by peroxisome proliferator-activated receptor alpha and omega fatty acid oxidation are readily overwhelmed, particularly in female rats and also in women who have low hepatic induction of fatty acid-binding protein (L-FABPc). Accordingly, the intracellular concentration of free fatty acids may become high enough to injure membranes, thereby contributing to necrosis, inflammation, and progression to fibrosis and cirrhosis. Eventually, hepatic S-adenosylmethionine and PCs become depleted in the alcoholic, with impairment of their multiple cellular functions, which can be restored by PC replenishment. Thus, prevention and therapy opposing the development of steatosis and its progression to more severe injury can be achieved by a multifactorial approach: control of alcohol consumption, avoidance of obesity and of excess dietary long-chain fatty acids, or their replacement with medium-chain fatty acids, and replenishment of S-adenosylmethionine and PCs by using PPC. Progress in the understanding of the pathogenesis of alcoholic fatty liver and its progression to inflammation and fibrosis has resulted in prospects for their better prevention and treatment. (C) 2005 Elsevier Inc. All rights reserved. C1 Bronx Vet Affairs Med Ctr, Bronx, NY 10468 USA. Mt Sinai Sch Med, New York, NY 10029 USA. RP Lieber, CS (reprint author), Bronx Vet Affairs Med Ctr, 130 W Kingsbridge Rd 151-2, Bronx, NY 10468 USA. EM liebercs@aol.com FU NCCIH NIH HHS [AT001583]; NIAAA NIH HHS [AA11115] NR 115 TC 264 Z9 290 U1 2 U2 39 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0741-8329 J9 ALCOHOL JI Alcohol PD AUG PY 2004 VL 34 IS 1 BP 9 EP 19 DI 10.1016/j.alcohol.2004.07.008 PG 11 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 898KB UT WOS:000227074600003 PM 15670660 ER PT J AU Charness, ME Wilkemeyer, MF AF Charness, ME Wilkemeyer, MF TI Rational development of ethanol antagonists. SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 12th International Congress of the International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 29-OCT 02, 2004 CL Heidelberg, GERMANY SP Int Soc Biomed Res Alcoholism C1 VA Boston Healthcare Syst, W Roxbury, MA 02132 USA. Harvard Univ, Sch Med, W Roxbury, MA 02132 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 2004 VL 28 IS 8 SU S BP 61A EP 61A DI 10.1097/00000374-200408002-00326 PG 1 WC Substance Abuse SC Substance Abuse GA 850LS UT WOS:000223613600326 ER PT J AU Myrick, H Anton, RF Li, X Henderson, S George, M AF Myrick, H Anton, RF Li, X Henderson, S George, M TI Neuroimaging in alcoholism: Relationship to craving. SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 12th International Congress of the International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 29-OCT 02, 2004 CL Heidelberg, GERMANY SP Int Soc Biomed Res Alcoholism C1 Med Univ S Carolina, Alcohol Res Ctr, Charleston, SC 29425 USA. Ralph H Johnson Vet Adm Med Ctr, Charleston, SC 29425 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 2004 VL 28 IS 8 SU S BP 72A EP 72A DI 10.1097/00000374-200408002-00393 PG 1 WC Substance Abuse SC Substance Abuse GA 850LS UT WOS:000223613600392 ER PT J AU Hermos, JA Young, MM Gagnon, DR Fiore, LD AF Hermos, JA Young, MM Gagnon, DR Fiore, LD TI Patterns of dispensed disulfiram and naltrexone for alcoholism treatment in a veteran patient population SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE disulfiram; naltrexone; pharmacoepidemiology; alcoholism treatment ID MAINTENANCE TREATMENT; DEPENDENCE; DISORDERS; EFFICACY; RELAPSE; THERAPY; MODELS AB Background: Short-term treatment trials indicate that two Food and Drug Administration-approved agents, disulfiram and naltrexone, may each curtail alcohol consumption, but two large 1-year Veterans Administration cooperative studies showed no long-term benefits for these agents over placebo. To assess whether these agents are being prescribed for extended periods, as an indicator of long-term use in nonexperimental settings, we compared dispensing patterns in a veteran patient population. Methods: The New England Veterans Integrated Service Network outpatient pharmacy files between January 1, 1998, and June 30, 2001, were analyzed; only patients with prescriptions on or after March 1, 1998, were included. Measurements for each patient included data on new and refilled prescriptions of disulfiram, naltrexone, and control medications. Prescription survival curves with right censoring were constructed. Distinct treatment episodes were defined by having six or more months between the end date of a prior prescription and the start date of a new prescription. Results: From eight New England Veterans Integrated Service Network centers, 754 patients were dispensed disulfiram, and 971 were dispensed naltrexone, encompassing 873 and 1075 treatment episodes, respectively. Treatment episode durations were virtually identical for both drugs: more than 35% of episodes were 1 month or shorter, more than 50% were 2 months or shorter, and 75% were 5 months or shorter. Concurrently prescribed neuroleptic or statin medications predicted longer disulfiram and naltrexone treatment episodes. However, for patients newly prescribed common neuroleptic, antidepressant, or statin agents, the risks for discontinuing disulfiram or naltrexone were 1.4 to 2.3 times greater than for discontinuing these other agents. Conclusions: In clinical settings, veteran patients were likely to be dispensed either disulfiram or naltrexone for only several months or less. The contexts and reasons for these predominantly short-term treatment episodes or the benefits derived were not known and merit further study. C1 VA Boston Healthcare Syst, MAVERIC, Pharmacoepidemiol Res Project, Boston, MA 02130 USA. Boston Univ, Sch Publ Hlth, Boston, MA USA. RP Hermos, JA (reprint author), VA Boston Healthcare Syst, MAVERIC, Pharmacoepidemiol Res Project, 151MAV,150 S Huntington Ave, Boston, MA 02130 USA. EM john.hermos@med.va.gov OI Gagnon, David/0000-0002-6367-3179 NR 24 TC 13 Z9 13 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 2004 VL 28 IS 8 BP 1229 EP 1235 DI 10.1097/01.ALC.0000134234.39303.17 PG 7 WC Substance Abuse SC Substance Abuse GA 848PR UT WOS:000223480100012 PM 15318122 ER PT J AU Wiviott, SD Braunwald, E AF Wiviott, SD Braunwald, E TI Unstable angina and non-ST-segment elevation myocardial infarction: Part I. Initial evaluation and management, and hospital care SO AMERICAN FAMILY PHYSICIAN LA English DT Article ID ACUTE CORONARY SYNDROMES; C-REACTIVE PROTEIN; TIMI RISK SCORE; CONSERVATIVE STRATEGIES; NATRIURETIC PEPTIDE; RANDOMIZED TRIAL; PROGNOSTIC VALUE; TIROFIBAN; ASPIRIN; METAANALYSIS AB Each year, more than 1 million patients are admitted to U.S. hospitals because of unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI). To help standardize the assessment and treatment of these patients, the American College of Cardiology and the American Heart Association convened a task force to formulate a management guideline. This guideline, which was published in 2000 and updated in 2002, highlights recent medical advances and is a practical tool to help physicians provide medical care for patients with UA/NSTEMI. Management of suspected UA/NSTEMI has four components: initial evaluation and management; hospital care; coronary revascularization; and hospital discharge and post-hospital care. Part I of this two-part article discusses the first two components of management. During the initial evaluation, the history, physical examination, electrocardiogram, and cardiac biomarkers are used to determine the likelihood that the patient has UA/NSTEMI and to aid in risk assessment when the diagnosis is established. Hospital care consists of appropriate initial triage and monitoring. Medical treatment includes anti-ischemic therapy (oxygen, nitroglycerin, beta blocker), antiplatelet therapy (aspirin, clopidogrel, platelet glycoprotein IIb/IIIa inhibitor), and antithrombotic therapy (heparin, low-molecular-weight heparin). C1 Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Wiviott, SD (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM swiviott@partners.org NR 38 TC 13 Z9 14 U1 0 U2 2 PU AMER ACAD FAMILY PHYSICIANS PI KANSAS CITY PA 8880 WARD PARKWAY, KANSAS CITY, MO 64114-2797 USA SN 0002-838X J9 AM FAM PHYSICIAN JI Am. Fam. Physician PD AUG 1 PY 2004 VL 70 IS 3 BP 525 EP 532 PG 8 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 846AN UT WOS:000223287100010 PM 15317439 ER PT J AU Braunwald, E AF Braunwald, E TI Happy birthday, GISSI! SO AMERICAN HEART JOURNAL LA English DT Editorial Material C1 Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Braunwald, E (reprint author), TIMI Study Grp, 350 Longwood Ave, Boston, MA 02115 USA. NR 0 TC 3 Z9 4 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD AUG PY 2004 VL 148 IS 2 BP 187 EP 187 DI 10.1016/j.ahj.2004.03.057 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 848UR UT WOS:000223494000001 PM 15308983 ER PT J AU Gibson, CM Murphy, SA Morrow, DA Aroesty, JM Gibbons, RJ Gourlay, SG Barron, HV Giugliano, RP Antman, EM Braunwald, E AF Gibson, CM Murphy, SA Morrow, DA Aroesty, JM Gibbons, RJ Gourlay, SG Barron, HV Giugliano, RP Antman, EM Braunwald, E TI Angiographic perfusion score: An angiographic variable that integrates both epicardial and tissue level perfusion before and after facilitated percutaneous coronary intervention in acute myocardial infarction SO AMERICAN HEART JOURNAL LA English DT Article ID TIMI FRAME COUNT; RESCUE ANGIOPLASTY; ELECTROCARDIOGRAPHIC EVIDENCE; PLASMINOGEN ACTIVATOR; VENTRICULAR-FUNCTION; CLINICAL-OUTCOMES; RANDOMIZED-TRIAL; THROMBOLYSIS; ARTERY; THERAPY AB Background Both epicardial and myocardial perfusion have been associated with clinical outcomes in the setting of ST elevation myocardial infarction (STEMI), and the performance of adjunctive/rescue percutaneous coronary intervention (PCI) may further improve clinical outcomes after fibrinolytic administration. Methods The goal was to develop a simple, broadly applicable angiographic metric that takes into account indices of epicardial and myocardial perfusion both before and after PCI to arrive at a single perfusion grade in patients undergoing cardiac catheterization after fibrinolysis. The angiographic perfusion score (APS) is the sum of the Thrombolysis in Myocardial Infarction (TIMI) flow grade (TFG; 0-3) added to the TIMI myocardial perfusion grade (TMPG; 0-3) before and after PCI (total possible grade, 0-12). Failed perfusion was defined as an APS of 0 to 3, partial perfusion was defined as an APS of 4 to 9, and full perfusion was defined as an APS of 10 to 12. The APS was evaluated in patients from the Double-blind, Placebo-contolled, Multicenter Angiographic Trial of Rhumab CD18 in Acute Myocardial Infarction (LIMIT-AMI; n = 394) and Enoxaparin as Adjunctive Antithrombin Therapy for ST-Elevation Myocardial Infarction-Thrombolysis In Myocardial Infarction (ENTIRE-TIMI) 23 trials (n = 483), and infarct size (120-216 hours after AMI SPECT Technetium-99m Sestamibi data) was assessed in the LIMIT-AMI trial. Results The APS was associated with the incidence of death or myocardial infarction (failed, 16.7% [n = 18]; partial, 2.5% [n = 155]; full, 2.4% [n = 82]; P=.039 for trend) and larger SPECT infarct sizes (failed, median 39% [n = 10]; partial, 12% [n = 79]; and full, 8% [n 35]; P =.002). No patient with full APS died, whereas the mortality rate was 11.1% in patients with a failed APS (P=.03). Conclusions The APS combines grades of epicardial and tissue level perfusion before and after PCI or at the end of diagnostic cardiac catheterization to arrive at a single angiographic variable that is associated with infarct size and the rates of 30-day death or MI. Partial or full angiographic perfusion scores are associated with a halving of infarct size, and no patients with full angiographic perfusion died. C1 Brigham & Womens Hosp, Dept Med, TIMI Study Grp, Boston, MA 02115 USA. Mayo Clin, Div Cardiovasc, Rochester, MN USA. Univ Calif San Francisco, Div Cardiovasc, San Francisco, CA 94143 USA. RP Gibson, CM (reprint author), TIMI Data Coordinating Ctr, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. NR 23 TC 42 Z9 46 U1 0 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD AUG PY 2004 VL 148 IS 2 BP 336 EP 340 DI 10.1016/j.ahj.2003.12.044 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 848UR UT WOS:000223494000025 PM 15309006 ER PT J AU Cury, RC Ferencik, M Hoffmann, U Ferullo, A Moselewski, F Abbara, S Booth, SL O'Donnell, CJ Brady, TJ Achenbach, S AF Cury, RC Ferencik, M Hoffmann, U Ferullo, A Moselewski, F Abbara, S Booth, SL O'Donnell, CJ Brady, TJ Achenbach, S TI Epidemiology and association of vascular and valvular calcium quantified by multidetector computed tomography in elderly asymptomatic subjects SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-ARTERY-DISEASE; AORTIC-VALVE SCLEROSIS; MITRAL ANNULAR CALCIUM; ROW CT; CALCIFICATION; ATHEROSCLEROSIS; STENOSIS; MARKER AB The epidemiology of and association between vascular and valvular calcium as quantified by multidetector computed tomography (MDCT) were studied in 416 elderly subjects with no history of coronary artery disease. Coronary calcium (CC), descending thoracic aortic calcium (DTAC), aortic valve calcium (AVC), and mitral valve calcium [MVC] were present in 282 (68%), 214 (51%), 152 (37%), and 68 (16%) subjects, respectively. Multiple logistic regression analysis showed that after adjusting for age and gender, subjects with AVC (odds ratio [OR] 2.3), MVC (OR 2.81), and DTAC (OR 2.79) were independently and significantly more likely to have CC. Further evidence is provided for the notion that calcifications in those regions are associated and that MDCT can be used as a tool for the, global assessment of vascular and valvular calcium. (C) 2004 by Excerpta Medica, Inc. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Human Nutr Res Ctr Aging, Jean Mayer USDA, Boston, MA USA. NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA USA. RP Cury, RC (reprint author), Massachusetts Gen Hosp, Dept Radiol, 100 Charles River Plaza,Suite 400, Boston, MA 02114 USA. EM rcury@partners.org FU NHLBI NIH HHS [HL69272]; NIA NIH HHS [AG19147] NR 18 TC 10 Z9 10 U1 0 U2 0 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 AUG 1 PY 2004 VL 94 IS 3 BP 348 EP 351 DI 10.1016/j.amjcard.2004.04.032 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 843AK UT WOS:000223046300015 PM 15276102 ER PT J AU Januzzi, JL Marayati, F Mehta, RH Cooper, JV O'Gara, PT Sechtem, U Bossone, E Evangelista, A Oh, JK Nienaber, CA Eagle, KA Isselbacher, EM AF Januzzi, JL Marayati, F Mehta, RH Cooper, JV O'Gara, PT Sechtem, U Bossone, E Evangelista, A Oh, JK Nienaber, CA Eagle, KA Isselbacher, EM TI Comparison of aortic dissection in patients with and without Marfan's syndrome (Results from the international registry of aortic dissection) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID LONG-TERM SURVIVAL; ANEURYSM; IRAD AB Among 1,049 patients diagnosed with aortic dissection in a multinational registry, patients with Marfan's syndrome were typically younger and had unique presentations. Despite their younger age at presentation, patients with Marfan's syndrome and aortic dissection had a high mortality rate, similar to patients without Marfan's syndrome, an older patient cohort. Our data support the importance of aneurysm surveillance and prophylactic surgical intervention for patients with Marfan's syndrome to potentially reduce the risk of mortality. (C)2004 by Excerpta Medica, Inc. C1 Massachusetts Gen Hosp, Dept Cardiol Internal Med, Div Cardiol, Thorac Aorta Ctr, Boston, MA 02114 USA. Univ Michigan, Med Ctr, Div Cardiol, Ann Arbor, MI 48109 USA. Univ Michigan, Med Ctr, Coordinating Ctr IRAD Investigators, Ann Arbor, MI 48109 USA. Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA. Robert Bosch Krankenhaus, Div Cardiol, Stuttgart, Germany. Univ Vall Hebron, Gen Hosp, Div Cardiol, Barcelona, Spain. Mayo Clin, Rochester, MN USA. Univ Rostock, Div Cardiol, Rostock, Germany. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Dept Cardiol Internal Med, Div Cardiol, Thorac Aorta Ctr, Bulfinch 019, Boston, MA 02114 USA. EM jjanuzzi@portners.org NR 12 TC 30 Z9 31 U1 0 U2 0 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 AUG 1 PY 2004 VL 94 IS 3 BP 400 EP 402 DI 10.1016/j.amjcard.2004.04.049 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 843AK UT WOS:000223046300032 PM 15276119 ER PT J AU Johansen, KL Young, B Kaysen, GA Chertow, GM AF Johansen, KL Young, B Kaysen, GA Chertow, GM TI Association of body size with outcomes among patients beginning dialysis SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE end-stage renal disease; dialysis; body mass index; adiposity; survival; outcomes ID RENAL-TRANSPLANT OUTCOMES; HEMODIALYSIS-PATIENTS; RISK FACTOR; MASS INDEX; OBESITY; MORTALITY; WEIGHT; SURVIVAL; IMPACT; DEATH AB Background: Although obesity confers an increased risk of mortality in the general population, observational reports on the dialysis population have suggested that obesity is associated with improved survival. These reports have generally not examined extremely high values of body mass index (BMI; in kg/m(2)), survival >1 y, or alternative measures of adiposity. Objective: We sought to clarify the relation between body size and outcomes among a large cohort of patients beginning dialysis. Design: Data on 418 055 patients beginning dialysis between I April 1995 and 1 November 2000 were analyzed by using US Renal Data System data. BMI was divided into 8 categories in increments of 3 units, ranging from <19 to greater than or equal to37, and the relation between survival and BMI was examined by using proportional hazards regression with adjustment for demographic, laboratory, and comorbidity data. Results: High BMI was associated with increased survival in this cohort, even at extremely high BMI, after adjustment, and over a 2-y average follow-up time. This was true for whites, African Americans, and Hispanics but not for Asians. High BMI was also associated with a reduced risk of hospitalization and a lower rate of mortality in all mortality categories. Alternative estimates of adiposity, including the Berm index and estimated fat mass, yielded similar results, and adjustments for lean body mass did not substantially alter the findings. Conclusions: High BMI is not associated with increased mortality among patients beginning dialysis. This finding does not appear to be a function of lean body mass and, although modified by certain patient characteristics, it is a robust finding. C1 Univ Calif San Francisco, Dept Med Res, Div Nephrol, San Francisco, CA 94118 USA. San Francisco VA Med Ctr, San Francisco, CA USA. Univ Calif Davis, Div Nephrol, Davis, CA USA. RP Chertow, GM (reprint author), Univ Calif San Francisco, Dept Med Res, Div Nephrol, UCSF Laurel Heights Suite 430,3333 Calif St, San Francisco, CA 94118 USA. EM chertowg@medicine.ucsf.edu FU NIDDK NIH HHS [N01 DK 12450] NR 28 TC 163 Z9 166 U1 0 U2 2 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG PY 2004 VL 80 IS 2 BP 324 EP 332 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 841ET UT WOS:000222912800013 PM 15277152 ER PT J AU Devlin, PM Kazakin, J Adak, S Li, Y Norris, CM Tishler, RB Clark, JR Busse, PM Posner, MR AF Devlin, PM Kazakin, J Adak, S Li, Y Norris, CM Tishler, RB Clark, JR Busse, PM Posner, MR TI Prospective phase II trial of PFL-induction chemotherapy followed by definitive local treatment for advanced squamous cell carcinoma of the head and neck - 10-year follow-up SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE head and neck cancer/KW; combined modality therapy/KW; chemoradiotherapy; long-term survival ID HIGH-DOSE LEUCOVORIN; ADJUVANT CHEMOTHERAPY; RANDOMIZED-TRIAL; CONCOMITANT CHEMOTHERAPY; RADIATION-THERAPY; CANCER; FLUOROURACIL; CISPLATIN; RADIOTHERAPY; 5-FLUOROURACIL AB Reported is an analysis of overall survival at 10 years of 102 patients with advanced squamous cell carcinoma of the head and neck (SCCHN) who were enrolled in a prospective phase II trial of high-dose cisplatin, 5-fluorouracil (5-FU), and high-dose leucovorin (PFL) induction chemotherapy followed by surgery and/or definitive radiation therapy (RT) between 1987 and 1991. Initially, 14 patients underwent primary site (PS) and neck surgery irrespective of the clinical response to PFL. The high rate of clinical and pathologic complete response (CR) to PFL prompted a switch from PS surgery to definitive RT. Of 102 patients, 18 (17.6%) who completed PFL and local-regional treatment for SCCHN between 1988 to 1991 were alive in December 2000. Among these, 1 of 14 patients (7%) who had undergone PS resection and 17 of 85 (20%) who were treated after PFL with definitive RT but without PS surgery were alive at 10 years. Median survival time was higher in the nonsurgical group (98.9 vs. 51.9 months). Subset analysis suggested that patients with oropharyngeal PS had the longest median survival (108.6 months). The oropharyngeal patients represented the 61% (11/18) of the long-term survivors with organ preservation. An organ preservation approach for patients with advanced SCCHN who demonstrated PS CR to chemotherapy demonstrated a trend to improved overall survival. C1 Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Binney Radiat Oncol Fdn, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Otolaryngol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Devlin, PM (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM pdevlin@lroc.harvard.edu NR 40 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3732 J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD AUG PY 2004 VL 27 IS 4 BP 369 EP 375 DI 10.1097/01.COC.0000071518.80534.AD PG 7 WC Oncology SC Oncology GA 846YH UT WOS:000223355000009 PM 15289730 ER PT J AU Bellon, JR Livingston, RB Eubank, WB Gralow, JR Ellis, GK Dunnwald, LK Mankoff, DA AF Bellon, JR Livingston, RB Eubank, WB Gralow, JR Ellis, GK Dunnwald, LK Mankoff, DA TI Evaluation of the internal mammary lymph nodes by FDG-PET in locally advanced breast cancer (LABC) SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article; Proceedings Paper CT 23rd Annual San-Antonio Breast Cancer Symposium CY DEC 06-09, 2000 CL SAN ANTONIO, TX DE locally advanced breast cancer; internal mammary lymph nodes; PET ID PREMENOPAUSAL WOMEN; LUNG-CANCER; CHEMOTHERAPY; MASTECTOMY; DISSECTION; PATTERNS; RADIOTHERAPY; PERFORMANCE; METASTASES; SURGERY AB The presence of internal mammary (IM) lymph node metastases in breast cancer predicts outcome and may alter treatment. Standard imaging has limited usefulness for evaluation of the IM chain because of low sensitivity. Our preliminary studies suggested that [F-18]-2-fluoro-D-glucose positron emission tomography (FDG-PET) improves the detection of IM and mediastinal metastases. We therefore performed a retrospective review of women who underwent FDG-PET prior to treatment to determine the benefit of PET for imaging IM disease. The records of 28 consecutive patients undergoing FDG-PET prior to neoadjuvant chemotherapy for suspected locally advanced breast cancer (LABC) were reviewed. The presence of abnormal IM uptake on FDG-PET was noted. IM uptake on FDG PET was compared with standard radiographic imaging and was correlated with putative risk factors for IM involvement and with clinical patterns of failure. Patients did not undergo IM biopsy; however, patterns of failure were assessed to validate the FDG-PET findings. Clearly abnormal FDG uptake in the IM nodes was seen in 7 of 28 women (25%). Prospective conventional chest imaging failed to identify IM metastases in any patient. IM uptake on PET was associated with large size of the primary tumor (P = 0.03) and with inflammatory disease (P = 0.04). The presence of IM FDG uptake predicted failure by a pattern consistent with spread from IM lymph node metastasis. FDG-PET appears to be a useful noninvasive modality to detect IM metastases in LABC. Pathologic verification in a prospective study is necessary to confirm these findings. C1 Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. Univ Washington, Ctr Med, Dept Radiat Oncol, Seattle, WA 98195 USA. Univ Washington, Ctr Med, Dept Med Oncol, Seattle, WA 98195 USA. Univ Washington, Ctr Med, Dept Diagnost Radiol, Seattle, WA 98195 USA. Univ Washington, Ctr Med, Dept Nucl Med, Seattle, WA 98195 USA. RP Bellon, JR (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM jbellon@lroc.harvard.edu RI Mankoff, David/F-9576-2010 FU NCI NIH HHS [CA 42045, CA 72064] NR 25 TC 53 Z9 60 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3732 J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD AUG PY 2004 VL 27 IS 4 BP 407 EP 410 DI 10.1097/01.coc.0000128869.19357.9b PG 4 WC Oncology SC Oncology GA 846YH UT WOS:000223355000016 PM 15289736 ER PT J AU Henry, JB Hubbell, CA Davis, MC Fernandez-Vina, MA Yunis, EJ Shrimpton, AE AF Henry, JB Hubbell, CA Davis, MC Fernandez-Vina, MA Yunis, EJ Shrimpton, AE TI A new HLA-A1 mutation - A novel, null variant allele SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE HLA molecular DNA typing and sequencing; allele expression; null variant HLA "blanks"; novel alleles; HLA alleles and antigens ID ERROR RATE; INDIVIDUALS; SEQUENCE AB From an unusually informative family of 8 with near identical parental hoplotypes (a and c), which differed by a single nucleotide substitution, we identified a new HLA-A1 null variant. While serologic antigen typing initially showed a "blank" allele in maternal haplotype "c" and 2 male offspring, more sophisticated DNA molecular HLA typing subsequently revealed the presence of a novel HLA-A0101 allele. Sequence-based typing showed a point mutation consisting of a nucleotide substitution of a cytosine for a guanine at nucleotide 215 yielding an amino acid change of arginine to proline at codon 48 in exon 2 (R48P). The impact on the HLA and immunogenetics laboratory is the need to not assume that all blanks are homozygous, as well as the need for the availability of high-resolution DNA molecular typing to clarify new alleles and to detect HLA-A null variants. C1 SUNY, Upstate Med Univ, Dept Pathol, Syracuse, NY 13210 USA. Tepnel Lifecodes Corp, Stamford, CT USA. Georgetown Univ, CW Bill Young Dept Def Marrow, Donar Program, Kensington, MD USA. Harvard Univ, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Henry, JB (reprint author), SUNY, Upstate Med Univ, Dept Pathol, 750 E Adams St, Syracuse, NY 13210 USA. FU NHLBI NIH HHS [HL59838, HL29583] NR 16 TC 8 Z9 8 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD AUG PY 2004 VL 122 IS 2 BP 185 EP 192 DI 10.1309/8DE12YU65BKHHQW6 PG 8 WC Pathology SC Pathology GA 841RN UT WOS:000222949200004 PM 15323134 ER PT J AU Jiang, Z Woda, BA Wu, CL Yang, XMJ AF Jiang, Z Woda, BA Wu, CL Yang, XMJ TI Discovery and clinical application of a novel prostate cancer marker - alpha-Methylacyl CoA racemase (P504S) SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Review DE alpha-methylacyl-CoA racemase; AMACR; P504S; prostate carcinoma; cancer marker ID ATYPICAL ADENOMATOUS HYPERPLASIA; NEEDLE-BIOPSY SPECIMENS; INTRAEPITHELIAL NEOPLASIA; FOLLOW-UP; MONOCLONAL-ANTIBODIES; HISTOLOGIC FEATURES; RADIATION-THERAPY; ACID-PHOSPHATASE; MOLECULAR MARKER; CARCINOMA AB The recent discovery of the overexpression of P504S/alpha-methylacyl coenzyme A racemase (AMACR) in prostate cancer is a successful example of translating an advanced molecular finding into clinical practice. AMACR (P504S) has been proven to be one of the few biomarkers that can help distinguish cancer from benign cells, with high sensitivity and specificity for prostate carcinoma. It is the first gene identified by the analysis of complementary DNA microarray profiles from prostate tissue to be used as a tissue tumor marker in clinical practice and to improve the diagnosis of prostate cancer This review focuses on the study of AMACR (P504S) expression in prostate cancer, premalignant lesions, benign prostate tissues, and other normal and malignant tissues and a discussion of its clinical usefulness. We emphasize the interpretation of the AMACR immunohistochemical results in routine surgical pathology practice and also discuss the potential future applications of this marker and the possible role of AMACR in the pathogenesis of cancer development. C1 Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01655 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Northwestern Univ, Dept Pathol & Urol, Feinberg Sch Med, Chicago, IL 60611 USA. RP Jiang, Z (reprint author), Univ Massachusetts, Sch Med, Dept Pathol, 55 Lake Ave, Worcester, MA 01655 USA. NR 96 TC 62 Z9 67 U1 0 U2 1 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD AUG PY 2004 VL 122 IS 2 BP 275 EP 289 DI 10.1309/EJUYUQPEX1MG68MK PG 15 WC Pathology SC Pathology GA 841RN UT WOS:000222949200015 PM 15323145 ER PT J AU Skinner, HG Michaud, DS Giovannucci, EL Rimm, EB Stampfer, MJ Willett, WC Colditz, GA Fuchs, CS AF Skinner, HG Michaud, DS Giovannucci, EL Rimm, EB Stampfer, MJ Willett, WC Colditz, GA Fuchs, CS TI A prospective study of folate intake and the risk of pancreatic cancer in men and women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE adult; cohort studies; folic acid; human; nutrition assessment; pancreatic neoplasms; prospective studies ID SELF-ADMINISTERED QUESTIONNAIRE; FOOD FREQUENCY QUESTIONNAIRE; COLON-CANCER; DIETARY QUESTIONNAIRE; DIABETES-MELLITUS; MULTIVITAMIN USE; MALE SMOKERS; DNA; REPRODUCIBILITY; ALCOHOL AB Laboratory and human studies suggest that folate intake may influence the risk of some cancers. However, prospective information about the relation between folate intake and the risk of exocrine pancreatic cancer is limited. The authors examined the relation of dietary folate intake to the risk of pancreatic cancer in two large prospective US cohorts. Folate intake was assessed by food frequency questionnaire in 1984 in women and in 1986 in men. Multivariate relative risks were adjusted for age, energy intake, cigarette smoking, body mass index, diabetes, and height. During 14 years' follow-up in each cohort, 326 incident cases of pancreatic cancer were identified. Compared with participants in the lowest category of folate intake, participants in increasing 100-mug categories of total energy-adjusted folate intake had pooled multivariate relative risks for pancreatic cancer of 1.08, 1.10, and 1.03 (95% confidence interval: 0.74, 1.43; p(trend) = 0.99). For energy-adjusted folate from food, the pooled relative risks for increasing 100-mug categories of intake were 0.81, 0.89, and 0.66 (95% confidence interval: 0.42, 1.03; p(trend) = 0.12). There was no statistical interaction between folate intake and methionine, alcohol, fat, or caffeine. The results from these two large prospective cohorts do not support a strong association between energy-adjusted folate intake and the risk of pancreatic cancer. C1 Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Skinner, HG (reprint author), Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, 680 N Lake Shore Dr,Suite 1102, Chicago, IL 60611 USA. EM hskinner@northwestern.edu RI Skinner, Halcyon/A-1049-2009; Michaud, Dominique/I-5231-2014; Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NCI NIH HHS [CA46475, CA49449, CA55075, CA65725, CA67883, CA70817, CA75016, CA78293, CA82838, CA86102, CA86271, CA87969, CA89393, CA9001, CA93683]; NEI NIH HHS [EY09611]; NHLBI NIH HHS [HL03804, HL34594, HL57871, HL63841, HL64108, HL65582]; NIA NIH HHS [AG/CA14742, AG15424]; NIAMS NIH HHS [AR02074]; NIDCR NIH HHS [DE12102]; NIDDK NIH HHS [DK59583, DK52866, DK54900, DK58845]; NIEHS NIH HHS [ES08074] NR 45 TC 42 Z9 44 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 1 PY 2004 VL 160 IS 3 BP 248 EP 258 DI 10.1093/aje/kwh214 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 843FF UT WOS:000223063200011 PM 15257998 ER PT J AU Barbeau, EM McLellan, D Levenstein, C DeLaurier, GF Kelder, G Sorensen, G AF Barbeau, EM McLellan, D Levenstein, C DeLaurier, GF Kelder, G Sorensen, G TI Reducing occupation-based disparities related to tobacco: Roles for occupational health and organized Labor SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article; Proceedings Paper CT Meeting on Smoking in the Workplace - Science and Policy CY APR 11, 2003 CL New York, NY DE tobacco control; organized Labor; occupational health; health protection-health promotion ID WORKSITE CANCER PREVENTION; BLUE-COLLAR WORKERS; WORKING WELL TRIAL; CIGARETTE-SMOKING; UNITED-STATES; INTEGRATIVE PERSPECTIVE; BEHAVIOR-CHANGE; PUBLIC-HEALTH; WORKPLACE; PROMOTION AB Background Persistent and growing occupation-based disparities related to tobacco pose a serious public health challenge. Tobacco exacts a disproportionate toll on individuals employed in working class occupations, due to higher prevalence of smoking and exposure to secondhand smoke among these workers compared to others. Methods We provide an overview of recent advances that may help to reduce these disparities, including research findings on a successful social contextual intervention model that integrates smoking cessation and occupational health and safety, and a new national effort to link labor unions and tobacco control organizations around their shared interest in reducing tobacco's threat to workers' health. Conclusions Implications of these efforts for future research and action are discussed. (C) 2004 Wiley-Liss, Inc. C1 Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. Univ Massachusetts, Dept Work Environm, Lowell, MA USA. RP Barbeau, EM (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 44 Binney St, Boston, MA 02115 USA. EM elizabeth_barbeau@dfci.harvard.edu FU NCI NIH HHS [5 R01 CA68087, 5 P01 CA75308] NR 90 TC 30 Z9 31 U1 0 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD AUG PY 2004 VL 46 IS 2 BP 170 EP 179 DI 10.1002/ajim.20026 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 842NF UT WOS:000223010400011 PM 15273970 ER PT J AU Weissman, JS Bendavid, E AF Weissman, JS Bendavid, E TI Should US hospitals go 24/7? SO AMERICAN JOURNAL OF MEDICINE LA English DT Editorial Material ID MORTALITY; WEEKEND; QUALITY; RATES; CARE C1 Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Hosp Univ Penn, Dept Med, Philadelphia, PA 19104 USA. RP Weissman, JS (reprint author), Massachusetts Gen Hosp, Inst Hlth Policy, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM jweissman@partners.org NR 11 TC 2 Z9 2 U1 1 U2 1 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD AUG 1 PY 2004 VL 117 IS 3 BP 202 EP 203 DI 10.1016/j.amjmed.2004.04.005 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 843BG UT WOS:000223049500011 PM 15276598 ER PT J AU Hoh, BL Rabinov, JD Pryor, JC Hirsch, JA Dooling, EC Ogilvy, CS AF Hoh, BL Rabinov, JD Pryor, JC Hirsch, JA Dooling, EC Ogilvy, CS TI Persistent nonfused segments of the basilar artery: Longitudinal versus axial nonfusion SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID EXTREME FENESTRATION; DUPLICATION AB Embryologic development of the basilar artery occurs along two axis systems: longitudinal fusion and axial fusion. Longitudinal fusion consists of midline fusion of paired ventral arteries and reflects the simplified pattern of arterial anatomy found in the spinal cord. Axial fusion consists of fusion of the distal basilar artery, which arises from the caudal division of the internal carotid artery, to the midbasilar agenesis to the posterior inferior cerebellar artery termination of the vertebral arteries. Persistent longitudinal nonfusion (or complete duplication) of the basilar artery is very rare, and persistent axial nonfusion is even rarer. We report one case of persistent longitudinal nonfusion of the basilar artery in a 3-year-old boy and a case of persistent axial nonfusion of the basilar artery in a 43-year-old man. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Neurosurg, Endovasc Neurosurg & Intervent Neuroradiol Serv, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Radiol, Endovasc Neurosurg & Intervent Neuroradiol Serv, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Neurosurg, Cerebrovasc Surg Serv, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Neurol, Pediat Neurol Serv, Boston, MA 02114 USA. RP Hoh, BL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Neurosurg, Endovasc Neurosurg & Intervent Neuroradiol Serv, Gray 289,55 Fruit St, Boston, MA 02114 USA. NR 10 TC 7 Z9 7 U1 0 U2 1 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD AUG PY 2004 VL 25 IS 7 BP 1194 EP 1196 PG 3 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 846OY UT WOS:000223326400015 PM 15313708 ER PT J AU Poulaki, V Joussen, AM Mitsiades, N Mitsiades, CS Iliaki, EF Adamis, AP AF Poulaki, V Joussen, AM Mitsiades, N Mitsiades, CS Iliaki, EF Adamis, AP TI Insulin-like growth factor-I plays a pathogenetic role in diabetic retinopathy SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR-1; RETINAL BARRIER BREAKDOWN; INTERCELLULAR-ADHESION MOLECULE-1; MULTIPLE-MYELOMA CELLS; BREAST-CANCER CELLS; NF-KAPPA-B; FACTOR EXPRESSION; FACTOR GENE; IRIS NEOVASCULARIZATION; VASCULAR-PERMEABILITY AB Diabetic retinopathy is a leading cause of blindness in the Western world. Aberrant intercellular adhesion molecule-1 expression and leukocyte adhesion have been implicated in its pathogenesis, raising the possibility of an underlying chronic inflammatory mechanism. In the current study, the role of insulin-like growth factor (IGF)-I in these processes was investigated. We found that systemic inhibition of IGF-I signaling with a receptor-neutralizing antibody, or with inhibitors of PI-3 kinase (PI-3K), c-Jun kinase (JNK), or Akt, suppressed retinal Akt, JNK, HIF-1alpha, nuclear factor (NF)-kappaB, and AP-1 activity, vascular endothelial growth factor (VEGF) expression, as well as intercellular adhesion molecule-1 levels, leukostasis, and blood-retinal barrier breakdown, in a relevant animal model. Intravitreous administration of IGF-I increased retinal Akt, JNK, HIF-1alpha, NF-kappaB, and AP-1 activity, and VEGF levels. IGF-I stimulated VEGF promoter activity in vitro, mainly via HIF-1alpha, and secondarily via NF-kappaB and AP-1. In conclusion, IGF-I participates in the pathophysiology of diabetic retinopathy by inducing retinal VEGF expression via PI-3K/Akt, HIF-1alpha, NF-kappaB, and secondarily, JNK/AP-1 activation. Taken together, these in vitro and in vivo signaling studies thus identify potential targets for pharmacological intervention to preserve vision in patients with diabetes. C1 Eyetech Res Ctr, Eyetech Pharmaceut, Woburn, MA 01801 USA. Massachusetts Eye & Ear Infirm, Retina Res Inst, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Ctr Ophthalmol, Dept Vitreoretinal Surg, Cologne, Germany. Zentrum Mol Med, Cologne, Germany. Univ Cologne, Ctr Mol Med, Cologne, Germany. RP Adamis, AP (reprint author), Eyetech Res Ctr, Eyetech Pharmaceut, 42 Cummings Pk, Woburn, MA 01801 USA. EM tony.adamis@eyetk.com FU NEI NIH HHS [EY11627] NR 55 TC 91 Z9 101 U1 0 U2 3 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2004 VL 165 IS 2 BP 457 EP 469 DI 10.1016/S0002-9440(10)63311-1 PG 13 WC Pathology SC Pathology GA 840XL UT WOS:000222893400010 PM 15277220 ER PT J AU Yee, KO Streit, M Hawighorst, T Detmar, M Lawler, J AF Yee, KO Streit, M Hawighorst, T Detmar, M Lawler, J TI Expression of the type-1 repeats of thrombospondin-1 inhibits tumor growth through activation of transforming growth factor-beta SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID SQUAMOUS-CELL CARCINOMAS; N-TERMINAL DOMAIN; ENDOTHELIAL-CELLS; TRANSGENIC MICE; CANCER-CELLS; TGF-BETA; ANGIOGENESIS; SUPPRESSION; GROWTH-FACTOR-BETA-1; ATTACHMENT AB in the present study, the type-1 repeats of thrombospondin-1 (TSP-1) were transfected into A431 cells. Expression of all three type-1 repeats OTSR) and expression of just the second type-1 repeat containing the transforming growth factor (TGF)-beta activating sequence KRFK (TSR2 + IURFK) significantly inhibited in vivo tumor angiogenesis and growth in nude mice. These tumors expressed increased levels of both active and total TGF-beta. A431 cells expressing the second type-1 repeat without the KRFK sequence (TSR2 - KRFK) produced tumors that were slightly Larger than the 3TSR and TSR2 + KRFK tumors. These tumors expressed elevated levels of active TGF-beta but levels of total TGF-beta were not different from control tumors. injection of the peptide, LSKL, which blocks TSP-1 activation of TGF-beta, reversed the growth inhibition observed with cells expressing TSR2 + KRFK to a level comparable to controls. Various residues in the WSHWSPW region and the VTCG sequence of both TSR2+/- KRFK were mutated. Although mutation of the VTCG sequence had no significant effect on tumor growth, mutation of the WSHWSPW sequence reduced inhibition of tumor growth. These findings suggest that the inhibition of tumor angiogenesis and growth by endogenons TSP-1 involves regulation of both active and total TGF-beta and the sequences KRFK and WSHWSPW in the second type-1 repeat. C1 Beth Israel Deaconess Med Ctr, Dept Pathol, Div Tumor Biol & Angiogenesis, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. Univ Gottingen, Dept Gynecol & Obstet, Gottingen, Germany. RP Lawler, J (reprint author), Beth Israel Deaconess Med Ctr, Dept Pathol, Div Tumor Biol & Angiogenesis, 330 Brookline Ave,Res N 270C, Boston, MA 02215 USA. EM jlawler@bidmc.harvard.edu FU NCI NIH HHS [R01 CA069184, CA69184, CA86410, CA92644, F32 CA084618, F32 CA84618-01, P01 CA092644, R01 CA086410]; NHLBI NIH HHS [HL68003, R01 HL068003] NR 59 TC 37 Z9 41 U1 0 U2 0 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2004 VL 165 IS 2 BP 541 EP 552 DI 10.1016/S0002-9440(10)63319-6 PG 12 WC Pathology SC Pathology GA 840XL UT WOS:000222893400018 PM 15277228 ER PT J AU Kiaris, H Politi, K Grimm, LM Szabolcs, M Fisher, P Efstratiadis, A Artavanis-Tsakonas, S AF Kiaris, H Politi, K Grimm, LM Szabolcs, M Fisher, P Efstratiadis, A Artavanis-Tsakonas, S TI Modulation of notch signaling elicits signature tumors and inhibits Hras1-induced oncogenesis in the mouse mammary epithelium SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID CYCLIN D1; ACTIVATED NOTCH; NEOPLASTIC TRANSFORMATION; TRANSGENIC MICE; DROSOPHILA EYE; HUMAN BREAST; IN-VITRO; RAS; TUMORIGENESIS; EXPRESSION AB Deregulation of Notch signaling, which normally affects a broad spectrum of cell fates, has been implicated in various neoplastic conditions. Here we describe a transgenic mouse model, which demonstrates that expression of a constitutively active form of the Notch1 receptor in the mammary epithelium induces the rapid development of pregnancy/lactation-dependent neoplasms that consistently exhibit a characteristic histopathological pattern. These signature tumors retain the ability to respond to apoptotic stimuli and regress on initiation of mammary gland involution, but eventually appear to progress in subsequent pregnancies to nonregressing malignant adenocarcinomas. Additionally, we present evidence indicating that cyclin D1 is an in vivo target of Notch signals in die mammary glands and demonstrate that we can effectively inhibit Hras1-driven, cyclin D1-dependent mammary oncogenesis by transgenic expression of the Notch antagonist Deltex. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Canc Res Ctr,Dept Cell Biol, Charlestown, MA 02129 USA. Columbia Univ, Dept Genet & Dev, New York, NY USA. Columbia Univ, Dept Pathol, New York, NY USA. Columbia Univ, Inst Canc Genet, New York, NY USA. Coll France, F-75231 Paris, France. RP Artavanis-Tsakonas, S (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Canc Res Ctr,Dept Cell Biol, 13th St,Bldg 149, Charlestown, MA 02129 USA. EM tsakonas@helix.mgh.harvard.edu OI Kiaris, Hippokratis/0000-0002-8999-8289 FU NCI NIH HHS [P01 CA097403, R01 CA098402, T32 CA09503, CA098402, T32 CA009503, CA97403]; NIGMS NIH HHS [GM62931, R01 GM062931]; NINDS NIH HHS [R37 NS026084, NS26084, R01 NS026084] NR 53 TC 88 Z9 90 U1 0 U2 2 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2004 VL 165 IS 2 BP 695 EP 705 DI 10.1016/S0002-9440(10)63333-0 PG 11 WC Pathology SC Pathology GA 840XL UT WOS:000222893400032 PM 15277242 ER PT J AU Bryant, AE Genc, M Hurtado, RM Chen, KT AF Bryant, AE Genc, M Hurtado, RM Chen, KT TI Pulmonary Kaposi's sarcoma in pregnancy SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE Kaposi's sarcoma; pulmonary; HIV; pregnancy ID PNEUMOCYSTIS-CARINII-PNEUMONIA; HIV-INFECTION; HERPESVIRUS HUMAN-HERPESVIRUS-8; SEXUAL TRANSMISSION; GENDER-DIFFERENCES; NATURAL-HISTORY; BREAST-CANCER; DNA-SEQUENCES; AIDS; WOMEN AB Kaposi's sarcoma in human immunodeficiency virus (HIV) -infected women, often misdiagnosed, has an aggressive clinical course, with high rates of visceral involvement and decreased survival. We describe the first case of isolated pulmonary Kaposi's sarcoma in pregnancy. A nulliparous woman was diagnosed with AIDS after presenting at 25 weeks gestation with a cough and multiple pulmonary nodules. Extensive pulmonary evaluation was nondiagnostic until thorascopic lung biopsy revealed Kaposi's sarcoma. Despite combination antiretroviral therapy, her malignancy progressed. Labor was induced at 33.5 weeks gestation for nonreassuring fetal testing. She received chemotherapy postpartum and remains in remission. Pulmonary Kaposi's sarcoma should be considered in the differential diagnosis of HIV-infected obstetric patients with respiratory compromise. Definitive diagnosis is necessary given the aggressive clinical course that is potentially responsive to therapy. C1 Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Med, Boston, MA USA. Brigham & Womens Hosp, Dept Med, Div Infect Dis, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Infect Dis, Boston, MA USA. RP Bryant, AE (reprint author), Northwestern Univ, Feinberg Sch Med, Div Maternal Fetal Med, Suite 410,333 E Super St, Chicago, IL 60611 USA. NR 38 TC 10 Z9 10 U1 1 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 J9 AM J PERINAT JI Am. J. Perinatol. PD AUG PY 2004 VL 21 IS 6 BP 355 EP 363 DI 10.1055/s-2004-831880 PG 9 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 848UN UT WOS:000223493600009 PM 15311373 ER PT J AU Li, SX Gerrard, ER Balkovetz, DF AF Li, SX Gerrard, ER Balkovetz, DF TI Evidence for ERK1/2 phosphorylation controlling contact inhibition of proliferation in Madin-Darby canine kidney epithelial cells SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE cell density; cyclin D1; hepatocyte growth factor; cell cycle; extracellular signal-regulated kinases ID ACTIVATED PROTEIN-KINASE; HEPATOCYTE GROWTH-FACTOR; CYCLIN D1 EXPRESSION; PHOSPHATIDYLINOSITOL 3-KINASE; MAP KINASES; MDCK CELLS; E-CADHERIN; PATHWAY; PROGRESSION; TRANSLOCATION AB Increasing cell density arrests epithelial cell proliferation by a process termed contact inhibition. We investigated mechanisms of contact inhibition using a model of contact-inhibited epithelial cells. Hepatocyte growth factor (HGF) treatment of contact-inhibited Madin-Darby canine kidney (MDCK) cells stimulated cell proliferation and increased levels of phosphorylated ERK1/2 (phospho-ERK1/2) and cyclin D1. MEK inhibitors PD-98059 and U0126 inhibited these HGF-dependent changes, indicating the dependence on phosphorylation of ERK1/2 during HGF-induced loss of contact inhibition. In relation to contact-inhibited high-density cells, low-density MDCK cells proliferated and had higher levels of phospho-ERK1/2 and cyclin D1. PD-98059 and U0126 inhibited low-density MDCK cell proliferation. Trypsinization of high-density MDCK cells immediately increased phospho-ERK1/2 and was followed by a transient increase in cyclin D1 levels. Reformation of cell junctions after trypsinization led to decreases in phospho-ERK1/2 and cyclin D1 levels. High-density MDCK cells express low levels of both cyclin D1 and phospho-ERK1/2, and treatment of these cells with fresh medium containing HGF but not fresh medium alone for 6 h increased phospho-ERK1/2 and cyclin D1 levels compared with cells without medium change. These data provide evidence that HGF abrogates MDCK cell contact inhibition by increasing ERK1/2 phosphorylation and levels of cyclin D1. These results suggest that in MDCK cells, contact inhibition of cell proliferation in the presence of serum occurs by cell density-dependent regulation of ERK1/2 phosphorylation. C1 Univ Alabama, Dept Med, Birmingham, AL 35294 USA. Univ Alabama, Dept Cell Biol, Birmingham, AL 35294 USA. Univ Alabama, Dept Surg, Birmingham, AL 35294 USA. Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA. RP Balkovetz, DF (reprint author), Univ Alabama, Dept Med, 1530 3rd Ave S,LHRB 642, Birmingham, AL 35294 USA. EM balkovet@uab.edu NR 35 TC 15 Z9 15 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD AUG PY 2004 VL 287 IS 2 BP C432 EP C439 DI 10.1152/ajpcell.00020.2004 PG 8 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 835ED UT WOS:000222462400023 PM 15070810 ER PT J AU Cummings, DE Frayo, RS Marmonier, C Aubert, R Chapelot, D AF Cummings, DE Frayo, RS Marmonier, C Aubert, R Chapelot, D TI Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE appetite; insulin ID AGOUTI-RELATED PROTEIN; CIRCULATING GHRELIN; BODY-WEIGHT; INTERMEAL INTERVAL; ACYLATED PEPTIDE; GLUCOSE; SECRETION; APPETITE; INSULIN; RATS AB Ghrelin is an orexigenic hormone that is implicated in meal initiation, in part because circulating levels rise before meals. Because previous human studies have examined subjects fed on known schedules, the observed preprandial ghrelin increases could have been a secondary consequence of meal anticipation. A causal role for ghrelin in meal initiation would be better supported if preprandial increases occurred before spontaneously initiated meals not prompted by external cues. We measured plasma ghrelin levels among human subjects initiating meals voluntarily without cues related to time or food. Samples were drawn every 5 min between a scheduled lunch and a freely requested dinner, and hunger scores were obtained using visual analog scales. Insulin, glucose, fatty acids, leptin, and triglycerides were also measured. Ghrelin levels decreased shortly after the first meal in all subjects. A subsequent preprandial increase occurred over a wide range of intermeal intervals (IMI; 320-425 min) in all but one subject. Hunger scores and ghrelin levels showed similar temporal profiles and similar relative differences in magnitude between lunch and dinner. One subject displayed no preprandial ghrelin increase and was also the only individual whose insulin levels did not return to baseline between meals. This finding, along with a correlation between area-under-the-curve values of ghrelin and insulin, suggests a role for insulin in ghrelin regulation. The preprandial increase of ghrelin levels that we observed among humans initiating meals voluntarily, without time- or food-related cues, and the overlap between these levels and hunger scores are consistent with a role for ghrelin in meal initiation. C1 Univ Washington, VA Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98108 USA. Univ Paris 13, Lab Physiol Comportement Alimentaire, Unite Format & Rech Sante Med & Biol Humaine, F-93014 Bobigny, France. Univ Paris 07, Fac Xavier Bichat, Lab Nutr Humaine, F-75018 Paris, France. RP Cummings, DE (reprint author), Univ Washington, VA Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, 1660 S Columbian Way,S-111 Endo, Seattle, WA 98108 USA. EM davidec@u.washington.edu FU NIDDK NIH HHS [R01 DK-61516] NR 53 TC 230 Z9 232 U1 0 U2 15 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD AUG PY 2004 VL 287 IS 2 BP E297 EP E304 DI 10.1152/ajpendo.00582.2003 PG 8 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 839KQ UT WOS:000222784400016 PM 15039149 ER PT J AU Reeve, JR Liddle, RA McVey, DC Vigna, SR Solomon, TE Keire, DA Rosenquist, G Shively, JE Lee, TD Chew, P Green, GM Coskun, T AF Reeve, JR Liddle, RA McVey, DC Vigna, SR Solomon, TE Keire, DA Rosenquist, G Shively, JE Lee, TD Chew, P Green, GM Coskun, T TI Identification of nonsulfated cholecystokinin-58 in canine intestinal extracts and its biological properties SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE gallbladder; pancreas; gastric acid; receptor binding; CCKA; CCKB ID GASTRIC-ACID-SECRETION; SULFATION; TYROSINE; CCK-58; METABOLISM; RECEPTORS; FORMS; DEGRADATION; OCTAPEPTIDE; INHIBITION AB Nonsulfated CCK58 [CCK58(ns)] has not been considered to be of biological importance because CCK58(ns) binds poorly to the CCKA receptor and has only been identified once in intestinal extracts. In this work, a radioimmunoassay specific for the COOH-terminal region of gastrin and CCK (antibody 5135) was used to monitor the purification of CCK molecular forms from canine intestinal extracts. A minor immunoreactive peak was associated with a major absorbance peak during an ion-exchange, HPLC step. Characterization of this minor immunoreactive peak demonstrated that it was CCK58(ns). CCK58(ns) is 14% as immunoreactive as sulfated CCK8 [CCK8(s)]. Amino acid analysis demonstrated that CCK58(ns) was present at 50% the amount of CCK58(s). In addition, we found that CCK58(ns) does not potently displace an I-125-labeled CCK10 analog from the CCKA receptor in mouse pancreatic membranes and does not stimulate amylase release from isolated pancreatic acini, or stimulate pancreatic secretion in an anesthetized rat model. By contrast, CCK58(ns) does bind to CCKB receptors and stimulates gastric acid secretion via this receptor. The presence of CCK58(ns) and its ability to selectively stimulate the CCKB receptor without stimulation of the CCKA receptor suggest that CCK58(ns) may have unique physiological properties, especially tissues where the nonsulfated peptide can act as a paracrine or neurocrine agent. C1 Vet Affairs Greater Los Angeles Healthcare Syst, CURE, Digest Dis Res Ctr, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Div Digest Dis, Los Angeles, CA 90024 USA. Univ Calif Davis, Sect Neurobiol Physiol & Behav, Davis, CA 95616 USA. City Hope Natl Med Ctr, Beckman Res Inst, Div Immunol, Duarte, CA 91010 USA. Duke Univ, Med Ctr, Div Gastroenterol, Durham, NC USA. Durham Vet Affairs Med Ctr, Durham, NC USA. Univ Texas, Hlth Sci Ctr, Dept Physiol, San Antonio, TX 78229 USA. RP Reeve, JR (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, CURE, Digest Dis Res Ctr, Bldg 115,Rm 115, Los Angeles, CA 90073 USA. EM jreeve@ucla.edu FU NCI NIH HHS [CA-3572]; NCRR NIH HHS [R01-RR-06217]; NIDDK NIH HHS [R01-DK-37482, DK-41301, R01-DK-33580, R01-DK-38626] NR 44 TC 15 Z9 16 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD AUG PY 2004 VL 287 IS 2 BP G326 EP G333 DI 10.1152/ajpgi.00520.2003 PG 8 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 836JT UT WOS:000222552500005 PM 15064233 ER PT J AU Veal, N Hsieh, CL Xiong, SG Mato, JM Lu, S Tsukamoto, H AF Veal, N Hsieh, CL Xiong, SG Mato, JM Lu, S Tsukamoto, H TI Inhibition of lipopolysaccharide-stimulated TNF-alpha promoter activity by S-adenosylmethionine and 5 '-methylthioadenosine SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE Kupffer cells; macrophages; gene regulation; nuclear factor-kappa B ID NF-KAPPA-B; NECROSIS-FACTOR-ALPHA; ADENOSYL-L-METHIONINE; INDUCED HEPATIC-INJURY; INDUCED LIVER-INJURY; RAT-LIVER; TRANSCRIPTIONAL ACTIVATION; PRIMARY MACROPHAGES; PROTEIN-KINASE; METHYLATION AB S-adenosylmethionine (SAM) is the principal biological methyl donor and precursor for polyamines. SAM is known to be hepatoprotective in many liver disease models in which TNF-alpha is implicated. The present study investigated whether and how SAM inhibited LPS-stimulated TNF-alpha expression in Kupffer cells (hepatic macrophages). SAM downregulated TNF-alpha expression in LPS-stimulated Kupffer cells at the transcriptional level as suggested by a transfection experiment with a TNF-alpha promoter-reporter gene. This inhibition was not mediated through decreased NF-kappaB binding to four putative kappaB binding elements located within the promoter. The inhibited promoter activity was neither prevented by overexpression of p65 and/or its coactivator p300 nor enhanced by overexpression of coactivator-associated arginine methyltransferase-1, an enzyme that methylates p300 and inhibits a p65-p300 interaction. SAM did not lead to DNA methylation at the most common CpG target sites in the TNF-alpha promoter. Moreover, 5'-methylthioadenosine (MTA), which is derived from SAM but does not serve as a methyl donor, recapitulated SAM's effect with more potency. These data demonstrate that SAM inhibits TNF-alpha expression at the level downstream of NF-kappaB binding and at the level of the promoter activity via mechanisms that do not appear to involve the limited availability of p65 or p300. Furthermore, our study is the first to demonstrate a potent inhibitory effect on NF-kappaB promoter activity and TNF-alpha expression by a SAM's metabolite, MTA. C1 Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA. Univ So Calif, Res Ctr Alcohol Liver & Pancreat Dis, Los Angeles, CA 90033 USA. Univ So Calif, Res Ctr Liver Dis, Los Angeles, CA 90033 USA. Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. Univ So Calif, Keck Sch Med, Dept Urol, Div Gastrointestinal & Liver Dis, Los Angeles, CA 90033 USA. Univ So Calif, Keck Sch Med, Dept Med, Los Angeles, CA 90033 USA. CIC Biogune, Parque Tecnol, Bizkaia, Spain. Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP Tsukamoto, H (reprint author), Univ So Calif, Keck Sch Med, Dept Pathol, 1333 San Pablo St,MMR-402, Los Angeles, CA 90033 USA. EM htsukamo@usc.edu RI MATO, JOSE/A-5187-2011 FU NIAAA NIH HHS [R01-AA-12677, P50-AA-11999, R01-AA-013847, R24-AA12885, R37-AA-006603]; NIDDK NIH HHS [P30-DK-48522] NR 48 TC 42 Z9 45 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD AUG PY 2004 VL 287 IS 2 BP G352 EP G362 DI 10.1152/ajpgi.00316.2003 PG 11 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 836JT UT WOS:000222552500008 PM 15064230 ER PT J AU Sharafkhaneh, A Officer, TM Goodnight-White, S Rodarte, JR Boriek, AM AF Sharafkhaneh, A Officer, TM Goodnight-White, S Rodarte, JR Boriek, AM TI Innovative methodology - Novel method for measuring effects of gas compression on expiratory flow SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE flow-volume loop; chronic obstructive pulmonary disease; asthma; lung mechanics ID BODY PLETHYSMOGRAPH; VOLUME CURVE; LIMITATION; MECHANICS; PRESSURE AB During forced vital capacity maneuvers in subjects with expiratory flow limitation, lung volume decreases during expiration both by air flowing out of the lung (i.e., exhaled volume) and by compression of gas within the thorax. As a result, a flow-volume loop generated by using exhaled volume is not representative of the actual flow-volume relationship. We present a novel method to take into account the effects of gas compression on flow and volume in the first second of a forced expiratory maneuver (FEV1). In addition to oral and esophageal pressures, we measured flow and volume simultaneously using a volume-displacement plethysmograph and a pneumotachograph in normal subjects and patients with expiratory flow limitation. Expiratory flow vs. plethysmograph volume signals was used to generate a flow-volume loop. Specialized software was developed to estimate FEV1 corrected for gas compression (NFEV1). We measured reproducibility of NFEV1 in repeated maneuvers within the same session and over a 6-mo interval in patients with chronic obstructive pulmonary disease. Our results demonstrate that NFEV1 significantly correlated with FEV1, peak expiratory flow, lung expiratory resistance, and total lung capacity. During intrasession, maneuvers with the highest and lowest FEV1 showed significant statistical difference in mean FEV1 (P < 0.005), whereas NFEV1 from the same maneuvers were not significantly different from each other (P > 0.05). Furthermore, variability of NFEV1 measurements over 6 mo was <5%. We concluded that our method reliably measures the effect of gas compression on expiratory flow. C1 Baylor Coll Med, MEDVAMC, Houston, TX 77030 USA. Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. RP Sharafkhaneh, A (reprint author), Baylor Coll Med, MEDVAMC, Bldg 100 111I,2002 Holcombe Blvd, Houston, TX 77030 USA. EM amirs@bcm.tmc.edu FU NHLBI NIH HHS [HL-072839] NR 23 TC 5 Z9 5 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD AUG PY 2004 VL 287 IS 2 BP R479 EP R484 DI 10.1152/ajpregu.00573.2003 PG 6 WC Physiology SC Physiology GA 840CT UT WOS:000222835300034 PM 15117729 ER PT J AU Yehuda, R Golier, JA Halligan, SL Meaney, M Bierer, LM AF Yehuda, R Golier, JA Halligan, SL Meaney, M Bierer, LM TI The ACTH response to dexamethasone in PTSD SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; PITUITARY-ADRENAL AXIS; COMBAT VETERANS; PLASMA-CORTISOL; SUPPRESSION; CHILDHOOD; WOMEN; ABUSE; DEPRESSION; SURVIVORS AB Objective: Enhanced negative feedback and reduced adrenal output are two different models that have been put forth to explain the paradoxical observations of increased release of corticotropin-releasing factor in the face of low cortisol levels in posttraumatic stress disorder (PTSID). To discriminate between these models, the authors measured levels of adrenocorticopic hormone (ACTH) and cortisol at baseline and in response to dexamethasone in medically healthy subjects with and without PTSID. Under conditions of enhanced negative feedback inhibition, ACTH levels would not be altered relative to cortisol levels, but the ACTH response to dexamethasone would be augmented, in concert with the enhanced cortisol response to dexamethasone. In contrast, under conditions of reduced adrenal output, ACTH levels would be expected to be higher at baseline relative to cortisol levels, but the ACTH response to dexamethasone would be unchanged in PTSID relative to healthy comparison subjects. Method: The ACTH and cortisol responses to 0.50 mg of dexamethasone were assessed in 19 subjects (15 men and four women) with PTSID and 19 subjects (14 men and five women) without psychiatric disorder. Results: The ACTH-to-cortisol ratio did not differ between groups before or after dexamethasone, but the subjects with PTSD showed greater suppression of ACTH (as well as cortisol) in response to dexamethasone. Conclusions: The data support the hypothesis of enhanced cortisol negative feedback inhibition of ACTH secretion at the level of the pituitary in PTSD. Pituitary glucocorticoid receptor binding, rather than low adrenal output, is implicated as a likely mechanism for this effect. C1 Mt Sinai Sch Med, Dept Psychiat, Traumat Stress Studies Program, New York, NY USA. Bronx Vet Affairs Med Ctr, New York, NY USA. Univ Reading, Sch Psychol, Reading, Berks, England. Douglas Hosp, Res Ctr, Dept Neurosci, Montreal, PQ, Canada. RP Yehuda, R (reprint author), Bronx VA OOMH, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM rachel.yehuda@med.va.gov OI Halligan, Sarah/0000-0002-3436-3358 FU NIMH NIH HHS [R01 MH-49555] NR 30 TC 93 Z9 94 U1 2 U2 3 PU AMER PSYCHIATRIC PRESS, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2004 VL 161 IS 8 BP 1397 EP 1403 DI 10.1176/appi.ajp.161.8.1397 PG 7 WC Psychiatry SC Psychiatry GA 842BC UT WOS:000222976400012 PM 15285965 ER PT J AU Bartels, SJ Coakley, EH Zubritsky, C Ware, JH Miles, KM Arean, PA Chen, HT Oslin, DW Llorente, MD Costantino, G Quijano, L McIntyre, JS Linkins, KW Oxman, TE Maxwell, J Levkoff, SE AF Bartels, SJ Coakley, EH Zubritsky, C Ware, JH Miles, KM Arean, PA Chen, HT Oslin, DW Llorente, MD Costantino, G Quijano, L McIntyre, JS Linkins, KW Oxman, TE Maxwell, J Levkoff, SE CA PRISM-E investigators TI Improving access to geriatric mental health services: A randomized trial comparing treatment engagement with integrated versus enhanced referral care for depression, anxiety, and at-risk alcohol use SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 16th Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 01-04, 2003 CL HONOLULU, HI SP Amer Assoc Geriatr Psychiat ID OLDER; MANAGEMENT; VALIDATION; SYMPTOMS; ILLNESS AB Objective: The authors sought to determine whether integrated mental health services or enhanced referral to specialty mental health clinics results in greater engagement in mental health/substance abuse services by older primary care patients. Method: This multisite randomized trial included 10 sites consisting of primary care and specialty mental health/substance abuse clinics. Primary care patients 65 years old or older (N=24,930) were screened. The final study group consisted of 2,022 patients (mean age=73.5 years; 26% female; 48% ethnic minority) with depression (N=1,390), anxiety (N= 70), at-risk alcohol use (N=414), or dual diagnosis (N=1 48) who were randomly assigned to integrated care (mental health and substance abuse providers co-located in primary care; N=999) or enhanced referral to specialty mental health/substance abuse clinics (i.e., facilitated scheduling, transportation, payment; N=1,023). Results: Seventy-one percent of patients engaged in treatment in the integrated model compared with 49% in the enhanced referral model. Integrated care was associated with more mental health and substance abuse visits per patient (mean=3.04) relative to enhanced referral (mean=1.91). Overall, greater engagement was predicted by integrated care and higher mental distress. For depression, greater engagement was predicted by integrated care and more severe depression. For at-risk alcohol users, greater engagement was predicted by integrated care and more severe problem drinking. For all conditions, greater engagement was associated with closer proximity of mental health/substance abuse services to primary care. Conclusions: Older primary care patients are more likely to accept collaborative mental health treatment within primary care than in mental health/substance abuse clinics. These results suggest that integrated service arrangements improve access to mental health and substance abuse services for older adults who underuse these services. C1 Dartmouth Coll Sch Med, Dept Psychiat, Lebanon, NH USA. John Snow Inc, Boston, MA USA. Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Philadelphia VA Med Ctr, Philadelphia, PA USA. Miami VA Med Ctr, Ctr Geriatr Res Educ & Clin, Miami, FL USA. Univ Miami, Sch Med, Miami, FL USA. Lutheran Med Ctr, Sunset Pk Family Hlth Ctr Network, Brooklyn, NY USA. Baylor Coll Med, Baylor, TX USA. Unity Hlth Syst, Dept Psychiat & Hlth Behav, Rochester, NY USA. Lewin Grp, Falls Church, VA USA. RP Bartels, SJ (reprint author), New Hampshire Dartmouth Psychiat Res Ctr, 2 Whippleplace,Suite 202, Lebanon, NH 03766 USA. EM stephen.j.bartels@dartmouth.edu NR 26 TC 197 Z9 200 U1 5 U2 10 PU AMER PSYCHIATRIC PRESS, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2004 VL 161 IS 8 BP 1455 EP 1462 DI 10.1176/appi.ajp.161.8.1455 PG 8 WC Psychiatry SC Psychiatry GA 842BC UT WOS:000222976400020 PM 15285973 ER PT J AU Saliba, D Buchanan, J Kington, RS AF Saliba, D Buchanan, J Kington, RS TI Function and response of nursing facilities during community disaster SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID LOMA-PRIETA EARTHQUAKE; NORTHRIDGE EARTHQUAKE; NATURAL DISASTERS; HEALTH-CARE; HOME; LESSONS; NEEDS; RESIDENTS; SYSTEM; RECOMMENDATIONS AB Objectives. We sought to describe the role and function of nursing facilities after disaster. Methods. We surveyed administrators at 144 widely dispersed nursing facilities after the Los Angeles Northridge earthquake. Results. Of the 113 (78%) nursing facilities that responded (11365 beds), 23 sustained severe damage, 5 closed (625 beds), and 72 lost vital services. Of 87 nursing facilities implementing disaster plans, 56 cited problems that plans did not adequately address, including absent staff, communication problems, and insufficient water and generator fuel. Fifty-nine (52%) reported disaster-related admissions from hospitals, nursing facilities, and community residences. Nursing facilities received limited postdisaster assistance. Five months after the earthquake, only half of inadequate nursing facility disaster plans had been revised. Conclusions. Despite considerable disaster-related stresses, nursing facilities met important community needs. To optimize disaster response, community-wide disaster plans should incorporate nursing facilities. C1 RAND Corp, Santa Monica, CA 90407 USA. NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Cambridge, MA 02138 USA. Univ Calif Los Angeles, Vet Adm Med Ctr, Multicampus Program Geriatr, Los Angeles, CA USA. Vet Adm Greater Los Angeles Hlth Care Syst, Los Angeles, CA 91343 USA. RP Saliba, D (reprint author), RAND Corp, 1700 Main St M-28, Santa Monica, CA 90407 USA. EM saliba@rand.org NR 44 TC 21 Z9 22 U1 0 U2 7 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2004 VL 94 IS 8 BP 1436 EP 1441 DI 10.2105/AJPH.94.8.1436 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 843AT UT WOS:000223047600039 PM 15284056 ER PT J AU Alderson, PO Bresolin, LB Becker, GJ Thrall, JH Dunnick, NR Hillman, BJ Lee, JKI Nagy, EC AF Alderson, PO Bresolin, LB Becker, GJ Thrall, JH Dunnick, NR Hillman, BJ Lee, JKI Nagy, EC CA Consensus Conference Participants TI Enhancing research in academic radiology departments: Recommendations of the 2003 consensus conference SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article ID AMERICAN-COLLEGE; IMAGING NETWORK C1 Acad Radiol Res, Washington, DC 20005 USA. Columbia Univ, Med Ctr, Dept Radiol, New York, NY 10032 USA. Univ N Carolina, Chapel Hill, NC 27514 USA. Univ Virginia, Charlottesville, VA 22904 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02114 USA. Miami Cardiac & Vasc Inst, Miami, FL 33176 USA. Radiol Soc N Amer, Oak Brook, IL 60523 USA. RP Nagy, EC (reprint author), Acad Radiol Res, 1029 Vermont Ave NW,Ste 505, Washington, DC 20005 USA. NR 6 TC 3 Z9 3 U1 0 U2 2 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2004 VL 183 IS 2 BP 273 EP 276 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 840YF UT WOS:000222895600015 PM 15269010 ER PT J AU Guimaraes, AR Wain, JC Mark, EJ Wittram, C AF Guimaraes, AR Wain, JC Mark, EJ Wittram, C TI Mucinous cystadenoma of the lung SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article C1 Massachusetts Gen Hosp, Dept Radiol, Div Thorac Radiol, Boston, MA 02114 USA. Harvard Univ, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Thorac Surg Radiol, Boston, MA 02114 USA. RP Wittram, C (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Thorac Radiol, 55 Fruit St, Boston, MA 02114 USA. NR 4 TC 6 Z9 6 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2004 VL 183 IS 2 BP 282 EP 282 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 840YF UT WOS:000222895600017 PM 15269012 ER PT J AU Lucey, BC Gervais, DA Titton, RL O'Hare, F Hahn, PF Maher, M Mueller, PR AF Lucey, BC Gervais, DA Titton, RL O'Hare, F Hahn, PF Maher, M Mueller, PR TI Enteric feeding with gastric decompression: Management with separate gastric accesses SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article ID PERCUTANEOUS GASTROSTOMY AB OBJECTIVE. Our purpose is to describe our experience with combined enteral feeding and gastric decompression or drainage in debilitated patients with persistent gastroesophageal reflux using two separate catheters. CONCLUSION. The placement of two percutaneous catheters through separate skin sites is a feasible and successful approach to providing enteral feeding and gastric decompression or drainage in debilitated patients with persistent gastroesophageal reflux and aspiration pneumonia. C1 Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, Boston, MA 02114 USA. RP Mueller, PR (reprint author), Harvard Univ, Sch Med, Dept Radiol, White 270,55 Fruit St, Boston, MA 02114 USA. NR 11 TC 1 Z9 1 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2004 VL 183 IS 2 BP 387 EP 390 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 840YF UT WOS:000222895600035 PM 15269030 ER PT J AU Lerwill, MF AF Lerwill, MF TI Current practical applications of diagnostic immunohistochemistry in breast pathology SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Review ID THYROID TRANSCRIPTION FACTOR; CARCINOMA IN-SITU; SENTINEL LYMPH-NODE; MALIGNANT INTRADUCTAL PROLIFERATIONS; E-CADHERIN REACTIVITY; SMALL-CELL CARCINOMAS; ESTROGEN-RECEPTOR; DIFFERENTIAL-DIAGNOSIS; MYOEPITHELIAL CELLS; LOBULAR CARCINOMA AB In recent years, immunohistochemistry has assumed an increasingly prominent role in diagnostic breast pathology. Immunohistochemistry is now frequently used in the evaluation of many epithelial proliferations of the breast. Common applications include the use of myoepithelial markers to evaluate for stromal invasion, E-cadherin to distinguish between ductal and lobular neoplasia, high molecular weight cytokeratins to differentiate usual ductal hyperplasia from ductal carcinoma in situ, immunohistochemical profiles to characterize site of origin of metastatic carcinomas, and cytokeratin stains to detect metastases in sentinel lymph nodes. Recent advances, practical considerations, and potential pitfalls in the use of immunohistochemistry in these five diagnostic categories are discussed herein. C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Lerwill, MF (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM mlerwill@partners.org NR 117 TC 86 Z9 99 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD AUG PY 2004 VL 28 IS 8 BP 1076 EP 1091 DI 10.1097/01.pas.0000126780.10029.f0 PG 16 WC Pathology; Surgery SC Pathology; Surgery GA 840WU UT WOS:000222891400014 PM 15252316 ER PT J AU Nahar, A Akom, M Hanes, D Briglia, A Drachenberg, CB Weinman, EJ AF Nahar, A Akom, M Hanes, D Briglia, A Drachenberg, CB Weinman, EJ TI Pyelonephritis and acute renal failure SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article DE pyelonephritis; acute renal failure ID SECONDARY AB Bacterial invasion of the renal parenchyma, pyelonephritis, is rarely considered as a primary cause of acute renal failure, particularly in adults. We report two cases of acute renal failure occurring in absence of hypotension, urinary tract obstruction, or nephrotoxic medications that are likely the direct consequence of pyelonephritis. The first case involved a 48-year-old HIV-positive woman who presented with 3 days of nonspecific symptoms and was noted to have acute renal failure. Due to unremitting renal dysfunction, a renal biopsy was performed confirming the diagnosis of bacterial pyelonephritis. The second case, a 33-year-old man with HIV disease, presented with fever and was found to have pyelonephritis by urine culture and ultrasonography. These cases represented initial diagnostic dilemmas for the admitting physicians and demonstrate the varied clinical presentations of acute renal failure as a direct consequence of bacterial infiltration of the renal parenchyma. C1 Univ Maryland, Sch Med, Div Nephrol, Baltimore, MD 21201 USA. Univ Maryland, Ctr Med, Dept Pathol, Baltimore, MD 21201 USA. US Dept Vet Affairs, Med Ctr, Baltimore, MD USA. RP Weinman, EJ (reprint author), Univ Maryland, Sch Med, Div Nephrol, N3W143,UHM,22 S Greene St, Baltimore, MD 21201 USA. EM eweinman@medicine.umaryland.edu NR 10 TC 9 Z9 9 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-9629 J9 AM J MED SCI JI Am. J. Med. Sci. PD AUG PY 2004 VL 328 IS 2 BP 121 EP 123 DI 10.1097/00000441-200408000-00009 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 845QF UT WOS:000223258700009 PM 15311172 ER PT J AU Cho, PS Mueller, NJ Cameron, AM Cina, RA Coburn, RC Hettiaratchy, S Melendy, E Neville, DM Patience, C Fishman, JA Sachs, DH Huang, CA AF Cho, PS Mueller, NJ Cameron, AM Cina, RA Coburn, RC Hettiaratchy, S Melendy, E Neville, DM Patience, C Fishman, JA Sachs, DH Huang, CA TI Risk factors for the development of post-transplant lymphoproliferative disorder in a large animal model SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE hematopoietic cell transplantation; immunosuppression; miniature swine; porcine lymphotrophic herpes virus; post transplant lymphoproliferative disease ID EPSTEIN-BARR-VIRUS; HEMATOPOIETIC-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; MINIATURE SWINE; MIXED CHIMERISM; RECIPIENTS; LYMPHOMA; DISEASE; IMMUNOSUPPRESSION; TOLERANCE AB A high incidence of a post-transplant lymphoproliferative disorder (PTLD) is observed in miniature swine conditioned for allogeneic hematopoietic cell transplantation using a protocol involving T-cell depletion and cyclosporine therapy. This study was designed to assess contributing factors to disease development. Forty-six animals were studied including 12 (26%) that developed PTLD. A number of risk factors for PTLD were examined, including degree of immunosuppression, degree of MHC mismatch and infection by a porcine lymphotrophic herpesvirus (PLHV-1). Flow cytometry was used to measure host and donor T- and B-cell levels in the peripheral blood. Porcine lymphotrophic herpesvirus viral load was determined by quantitative PCR. Animals developing PTLD had significantly lower levels of T cells on the day of transplant. Cyclosporine levels did not differ significantly between animals with and without PTLD. Animals receiving transplants across a two-haplotype mismatch barrier showed an increased incidence of PTLD. All animals with PTLD had significant increases in PLHV-1 viral loads. Porcine lymphotrophic herpesvirus viral copy numbers remained at low levels in the absence of disease. The availability of a preclinical large-animal model with similarities to PTLD of humans may allow studies of the pathogenesis and treatment of that disorder. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Infect Dis, Boston, MA USA. NIMH, NIH, Bethesda, MD 20892 USA. Immerge BioTherapeut Inc, Cambridge, MA USA. RP Huang, CA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. EM huangc@helix.mgh.harvard.edu RI Mueller, Nicolas/B-6864-2013 OI Mueller, Nicolas/0000-0002-1059-3191 FU NCI NIH HHS [1R01 CA79989-01A1]; NHLBI NIH HHS [1R01 HL63430-01]; NIAID NIH HHS [5T3232-AI07529-04, P01-AI45897] NR 39 TC 15 Z9 15 U1 0 U2 2 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD AUG PY 2004 VL 4 IS 8 BP 1274 EP 1282 DI 10.1111/j.1600-6143.2004.00506.x PG 9 WC Surgery; Transplantation SC Surgery; Transplantation GA 838HZ UT WOS:000222705500010 PM 15268728 ER PT J AU Cardarelli, F Pascual, M Chung, RT Tolkoff-Rubin, N Wong, WC Cosimi, AB Saidman, SL AF Cardarelli, F Pascual, M Chung, RT Tolkoff-Rubin, N Wong, WC Cosimi, AB Saidman, SL TI Interferon-alpha therapy in liver transplant recipients: Lack of association with increased production of anti-HLA antibodies SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE acute rejection; donor-specific antibodies; ELISA; HLA antibodies; humoral rejection; interferon-alpha; IFN; liver transplantation ID CYTOMETRY CROSS-MATCH; HEPATITIS-C; REJECTION; INFECTION; PATIENT AB Interferon-alpha (IFN) is a useful treatment for active HCV infection. In kidney transplantation, IFN has been shown to trigger acute rejection with de novo anti-HLA antibodies. Interferon-alpha has not been reported to enhance the risk of acute rejection in HCV-positive liver transplant recipients (LTRs). Sera were collected from 44 LTRs greater than 6 months post-transplant. Sera were tested with ELISA for the presence and the specificity of anti-HLA antibodies. The prevalence of anti-HLA antibodies was 11% and was not significantly different in 13 HCV-positive recipients who received IFN, compared with 10 who did not receive IFN (8% vs. 20%), or with 21 HCV-negative recipients (10%). None of the patients had an acute rejection after starting IFN. In this study, LTRs receiving IFN did not have an increased frequency of anti-HLA antibodies. This may partially explain the safety of IFN previously reported in LTRs requiring antiviral therapy. C1 Massachusetts Gen Hosp, Dept Med, Renal Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Transplantat Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Renal Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Transplantat Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Histocompatibil Lab, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Gastrointestinal Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Parma, Clin Med & Nefrol, I-43100 Parma, Italy. CHU Vaudois, Transplantat Ctr, CH-1011 Lausanne, Switzerland. RP Cardarelli, F (reprint author), Massachusetts Gen Hosp, Dept Med, Renal Unit, Boston, MA 02114 USA. EM francesca.cardarelli@libero.it NR 18 TC 3 Z9 4 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD AUG PY 2004 VL 4 IS 8 BP 1352 EP 1356 DI 10.1111/j.1600-6143.2004.00497.x PG 5 WC Surgery; Transplantation SC Surgery; Transplantation GA 838HZ UT WOS:000222705500021 PM 15268739 ER PT J AU Finegold, SM St John, S Vu, AW Li, CM Molitoris, D Song, YL Liu, CX Wexler, HM AF Finegold, SM St John, S Vu, AW Li, CM Molitoris, D Song, YL Liu, CX Wexler, HM TI In vitro activity of ramoplanin and comparator drugs against anaerobic intestinal bacteria from the perspective of potential utility of pathology involving bowel flora SO ANAEROBE LA English DT Article ID RESISTANT ENTEROCOCCI; VANCOMYCIN; GLYCOLIPODEPSIPEPTIDE; GLYCOPEPTIDE; ANTIBIOTICS; MECHANISMS; INVITRO; COCCI AB Susceptibility of intestinal bacteria to various antimicrobial agents in vitro, together with levels of those agents achieved in the gut, provides information on the likely impact of the agents on the intestinal flora. Orally administered drugs that are poorly absorbed may be useful for treatment of intestinal infections and for certain other situations in which intestinal bacteria may play a role. The antimicrobial activity of ramoplanin (MDL 62,198) against 928 strains of intestinal anaerobic bacteria was determined using the NCCLS-approved Wadsworth brucella laked-blood agar dilution method. The activity of ramoplanin was compared with that of ampicillin, bacitracin, metronidazole, trimethoprim/sulfamethoxazole (TMP/SMX), and vancomycin. The organisms tested included Bacteroides fragilis group (n = 89), other Bacteroides species (n = 16), other anaerobic Gram-negative rods (n = 56) anaerobic cocci (n = 114), Clostridium species (n = 426), and non-sporeforming anaerobic Gram-positive rods (n = 227). The overall MIC(90)s of ramoplanin, ampicillin, bacitracin, metronidazole, and vancomycin were 256, 32, 128, 16, and 128 mcg/ml, respectively. Ramoplanin was almost always highly active vs. Gram-positive organisms and relatively poor in activity against Gram-negative organisms, particularly Bacteroides, Bilophila, Prevotella, and Veillonella. Vancomycin was quite similar to ramoplanin in its activity. Ampicillin was relatively poor in activity vs. organisms that often produce beta-lactamase, including most of the Gram-negative rods as well as Clostridium bolteae and C clostridioforme. Bacitracin was relatively poor in activity against most anaerobic Gram-negative rods, but better vs. most Gram-positive organisms. Metronidazole was very active against all groups other than bifidobacteria and some strains of other types of non-sporeforming Gram-positive bacilli. TMP/SMX was very poorly active, with an MIC90 of > 2048 mcg/ml. (C) 2004 Elsevier Ltd. All rights reserved. C1 VA Greater Los Angeles Healthcare Syst, Med Serv, Los Angeles, CA 90073 USA. VA Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90024 USA. RP Finegold, SM (reprint author), VA Med Ctr W Los Angeles, Infect Dis Sect, 111 F,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM sidfinegol@aol.com NR 25 TC 18 Z9 19 U1 1 U2 4 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1075-9964 J9 ANAEROBE JI Anaerobe PD AUG PY 2004 VL 10 IS 4 BP 205 EP 211 DI 10.1016/j.anaerobe.2004.04.003 PG 7 WC Microbiology SC Microbiology GA 848OU UT WOS:000223477800001 PM 16701520 ER PT J AU Han, TH Kim, H Bae, J Kim, K Martyn, JAJ AF Han, TH Kim, H Bae, J Kim, K Martyn, JAJ TI Neuromuscular pharmacodynamics of rocuronium in patients with major burns SO ANESTHESIA AND ANALGESIA LA English DT Article; Proceedings Paper CT 11th Annual Meeting of the European-Society-of-Anaesthesiologists CY MAY 31-JUN 03, 2003 CL GLASGOW, SCOTLAND SP European Soc Anaesthesiologists ID NICOTINIC ACETYLCHOLINE-RECEPTORS; RAPID-SEQUENCE INDUCTION; THERMAL-INJURY; CLINICAL-PHARMACOLOGY; TRACHEAL INTUBATION; MUSCLE MEMBRANE; D-TUBOCURARINE; DOSE-RESPONSE; SUCCINYLCHOLINE; PHARMACOKINETICS AB Rocuronium, which has a short onset time and is free of hyperkalemic effects, could be considered for rapid-sequence induction of anesthesia in patients with burns. In this study, we assessed the neuromuscular pharmacodynamics of rocuronium in patients with major burns. Adults aged 18-59 yr who had a major burn injury (n = 56) and a control group of 44 nonburned patients were included. Rocuronium was used at 3 times (0.9 mg/kg) or 4 times (1.2 mg/kg) the 95% effective dose. Anesthesia consisted of propofol and fentanyl with nitrous oxide and oxygen. Neuromuscular block was monitored with an acceleromyograph by using train-of-four stimulation. The onset time to 95% neuromuscular block was prolonged in burned compared with nonburned patients (115 +/- 58 s versus 68 +/- 16 s for 0.9 mg/kg; 86 +/- 20 s versus 57 +/- 11 s for 1.2 mg/kg). Dose escalation shortened the onset time, prolonged the duration of action, and improved intubating conditions in burned patients. All recovery profiles were significantly shorter in burned versus nonburned groups with both doses. Resistance to the neuromuscular effects of rocuronium was partially overcome by increasing the dose. A dose up to 1.2 mg/kg provides good tracheal intubating conditions after major burns. C1 Hallym Univ, Hangang Sacred Heart Hosp, Dept Anesthesiol & Pain Med, Sch Med, Seoul 150719, South Korea. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesiol & Crit Care, Boston, MA 02115 USA. Shriners Hosp Children, Boston, MA USA. RP Han, TH (reprint author), Hallym Univ, Hangang Sacred Heart Hosp, Dept Anesthesiol & Pain Med, Sch Med, 94-200 Yongdungpo Dong, Seoul 150719, South Korea. EM athan@unitel.co.kr NR 37 TC 19 Z9 21 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD AUG PY 2004 VL 99 IS 2 BP 386 EP 392 PG 7 WC Anesthesiology SC Anesthesiology GA 840YS UT WOS:000222897100016 PM 15271712 ER PT J AU Decosterd, I Allchornet, A Woolf, CJ AF Decosterd, I Allchornet, A Woolf, CJ TI Differential analgesic sensitivity of two distinct neuropathic pain models SO ANESTHESIA AND ANALGESIA LA English DT Article ID NERVE INJURY; SPINAL-CORD; ALLODYNIA; RAT; HYPERSENSITIVITY; AMITRIPTYLINE; HYPERALGESIA; MANAGEMENT; MECHANISMS; BEHAVIOR AB Progressive tactile hypersensitivity (PTH) manifesting after sciatic nerve crush and spared nerve injury (SNI) are two distinct rodent experimental models of neuropathic pain. PTH develops months after recovery from the nerve crush in response to repeated intermittent low-threshold mechanical stimulation of the reinnervated sciatic nerve skin territory and represents a model of stimulus-induced pain. SNI is characterized by an early and sustained increase in stimulus-evoked pain sensitivity in the intact skin territory of the spared sural nerve after sectioning of the two other terminal branches of the sciatic nerve. We examined the effects of morphine (0.5-10 mg/kg), gabapentin (30-200 mg/kg), MK801 (0.01-0.02 mg/kg), amitriptyline (1025 mg/kg), and carbamazepine (5-7.5 mg/kg) in both models. Morphine, gabapentin, and carbamazepine both reversed and prevented stimulus-induced PTH, whereas MK801 and amitriptyline reduced but did not prevent stimulus-induced PTH. In contrast, the stimulus-evoked behavioral hypersensitivity in the SNI model was poorly modified by these drugs. Independent neuropathic pain models show differential sensitivity to analgesic drug treatment. We suggest that this is due to the different mechanisms responsible for the neuropathic pain-related behavior. Multiple models are required, therefore, to study the mechanisms that contribute to neuropathic pain and to predict analgesic efficacy for different components of the neuropathic pain syndrome. C1 CHUV, Anesthesiol Pain Res Grp, Dept Anesthesiol, Lausanne, Switzerland. Univ Lausanne, Fac Biol & Med, Dept Cell Biol & Morphol, Lausanne, Switzerland. Massachusetts Gen Hosp, Neural Plast Res Grp, Dept Anesthesia & Crit Care, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. RP Decosterd, I (reprint author), Univ Lausanne, Dept Anesthesiol & DBCM, Bugnon 9, CH-1005 Lausanne, Switzerland. EM Isabelle.Decosterd@chuv.hospvd.ch NR 25 TC 56 Z9 59 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD AUG PY 2004 VL 99 IS 2 BP 457 EP 463 PG 7 WC Anesthesiology SC Anesthesiology GA 840YS UT WOS:000222897100029 PM 15271725 ER PT J AU Ahmed, SU Vallejo, R Hord, ED AF Ahmed, SU Vallejo, R Hord, ED TI Seizures after a bier block with clonidine and lidocaine SO ANESTHESIA AND ANALGESIA LA English DT Article ID INTRAVENOUS LIDOCAINE; RAT AB A 47-yr-old man with history of complex regional pain syndrome type 1 underwent an IV Bier block with a mixture of lidocame and clonidine. The tourniquet was deflated after 60 min, and approximately 10 min later he presented with complex partial seizures. The possible mechanisms for this are discussed, and the effects of clonidine, lidocaine, and the mixture of both are reviewed, as are four additional published cases reporting seizures after the administration of clonidine. C1 Massachusetts Gen Hosp, Pain Ctr, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Ahmed, SU (reprint author), Massachusetts Gen Hosp, Pain Ctr, Dept Anesthesia & Crit Care, WACC-324,15 Parkman St, Boston, MA 02114 USA. EM sahmed@partners.org NR 16 TC 11 Z9 12 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD AUG PY 2004 VL 99 IS 2 BP 593 EP 594 DI 10.1213/01.ANE.0000123011.00161.C9 PG 2 WC Anesthesiology SC Anesthesiology GA 840YS UT WOS:000222897100050 PM 15271746 ER PT J AU Markovitz, JH Matthews, KA Whooley, M Lewis, CE Greenlund, KJ AF Markovitz, JH Matthews, KA Whooley, M Lewis, CE Greenlund, KJ TI Increases in job strain are associated with incident hypertension in the CARDIA study SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article ID AMBULATORY BLOOD-PRESSURE; CORONARY HEART-DISEASE; RISK-FACTORS; YOUNG-ADULTS; FOLLOW-UP; DEPRESSION; UNEMPLOYMENT; SYMPTOMS; HEALTH; WOMEN AB Background: Job strain, defined as high job demands and low decision latitude, has been associated with increased blood pressure levels in some studies, but most of these studies have been cross-sectional. Purpose: We sought to determine whether changes in job strain during young adulthood were associated with the development of hypertension, using the Coronary Artery Risk Development in Young Adults cohort. Methods: A total of 3,200 employed, initially normotensive participants, aged 20 to 32 in 1987-1988, were followed for 8 years; the Job Content Questionnaire was completed twice: initially and 8 years later. Hypertension at follow-up was defined as systolic blood pressure (SBP) of 160 or higher and diastolic blood pressure of 95 mmHg or higher or reporting being on antihypertensive medication. Results: Job strain (based on job demands above the median and decision latitude below the median of the sample) was associated with hypertension incidence (ps <.05) for the entire cohort and among White women and men. Adjustment for baseline SBP education, body mass index (BMI), change in BMI, and age did not alter these relations. The ratio of increasing demands relative to decreasing decision latitude was also associated with greater incidence of hypertension in the entire cohort in the multivariate model (odds ratio = 2.06, 95% confidence interval = 1.01-4.26). Conclusions: An increase in job strain is associated with incident hypertension, particularly among Whites. C1 Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. Univ Alabama, Div Prevent Med, Birmingham, AL 35487 USA. San Francisco Vet Affairs Med Ctr, Div Gen Internal Med, San Francisco, CA USA. Univ Alabama, Div Prevent Med, Birmingham, AL 35487 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. RP Matthews, KA (reprint author), Univ Pittsburgh, Dept Psychiat, 3811 O Hara St, Pittsburgh, PA 15213 USA. EM matthewska@upmc.edu FU NHLBI NIH HHS [N01-HC-48050, N01-HC-48048, N01-HC-95100, N01-HC-48047, N01-HC-48049] NR 35 TC 51 Z9 55 U1 2 U2 12 PU LAWRENCE ERLBAUM ASSOC INC PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430-2262 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD AUG PY 2004 VL 28 IS 1 BP 4 EP 9 DI 10.1207/s15324796abm2801_2 PG 6 WC Psychology, Multidisciplinary SC Psychology GA 840DF UT WOS:000222836500002 PM 15249254 ER PT J AU Rosinski, M Yarmush, ML Berthiaume, F AF Rosinski, M Yarmush, ML Berthiaume, F TI Quantitative dynamics of in vivo bone marrow neutrophil production and egress in response to injury and infection SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE neutrophil dysfunction; cellular proliferation; hematopoiesis; bromodeoxyuridine ID T-CELL DEVELOPMENT; PULMONARY SEQUESTRATION; LYMPHOID ORGANS; BURN INJURY; GRANULOCYTE; KINETICS; DIFFERENTIATION; LYMPHOCYTES; TURNOVER; PROLIFERATION AB Production rates of blood cells from the bone marrow (BM) can be determined from pool size and residence time in the circulation only during steady state. We describe a method to evaluate changes in BM neutrophil production following severe injury. Male CD-1 mice underwent nonlethal cutaneous burn injury, a lethal burn injury with Pseudomonas aeruginosa infection, or sham treatment, and received bromodeoxyuridine (BrdU) to label proliferative cells. Rates of BM neutrophil production and release into the circulation were determined using a mathematical model that integrates BM neutrophil pool size and fraction of BrdU labeled cells as a function of time. Absolute rates could not be quantified without BrdU data for the neutrophil progenitor pool; however, relative rates could be determined. BM neutrophil production and release significantly increased after injury. After nonlethal burn, release transiently exceeded production, causing a temporary decrease in BM neutrophil stores followed by reestablishment of a steady-state BM neutrophil pool similar to sham controls. After lethal burn infection, release always exceeded production, causing complete depletion of BM neutrophils and suppression of BM neutrophil production. This method is generally applicable to estimating production rates of nonproliferating, terminally differentiated cells, arising from a stem cell pool in vivo. C1 Shriners Hosp Children, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA USA. RP Berthiaume, F (reprint author), Shriners Hosp Children, 51 Blossom St, Boston, MA 02114 USA. EM fberthiaume@hms.harvard.edu NR 38 TC 12 Z9 12 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0090-6964 EI 1573-9686 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD AUG PY 2004 VL 32 IS 8 BP 1108 EP 1119 PG 12 WC Engineering, Biomedical SC Engineering GA 851GQ UT WOS:000223674000008 PM 15446507 ER PT J AU Spacey, SD Hildebrand, ME Materek, LA Bird, TD Snutch, TP AF Spacey, SD Hildebrand, ME Materek, LA Bird, TD Snutch, TP TI Functional implications of a novel EA2 mutation in the P/Q-type calcium channel SO ANNALS OF NEUROLOGY LA English DT Article ID EPISODIC ATAXIA TYPE-2; FAMILIAL HEMIPLEGIC MIGRAINE; NEURONS AB Episodic ataxia type 2 (EA2) is an autosomal dominant condition characterized by paroxysmal attacks of ataxia, vertigo, and nausea, typically lasting minutes to days in duration. These symptoms can be prevented or significantly attenuated by the oral administration of acetazolamide; however, the mechanism by which acetazolamide ameliorates EA2 symptoms is unknown. EA2 typically results from nonsense mutations in the CACNA1A gene that encodes the alpha(1A) (Ca(v)2.1) subunit of the P/Q-type calcium (Ca2+) channel. We have identified a novel H1736L missense mutation in the CACNA1A gene associated with the EA2 phenotype. This mutation is localized near the pore-forming region of the P/Q-type Ca2+ channel. Functional analysis of P/Q-type channels containing the mutation show that the H1736L alteration affects several channel properties, including reduced current density, increased rate of inactivation, and a shift in the voltage dependence of activation to more positive values. Although these findings are consistent with an overall loss of P/Q-type channel function, the mutation also caused some biophysical changes consistent with a gain of function. We also tested the direct effect of acetazolamide on both wild-type and H1736L mutated P/Q-type channels and did not observe any direct action on channel properties of this pharmacological agent used to treat EA2 patients. C1 Univ British Columbia, Div Neurol, Vancouver, BC V5Z 1M9, Canada. Univ British Columbia, Biotechnol Lab, Vancouver, BC V5Z 1M9, Canada. Univ Washington, Dept Neurol, Seattle, WA 98195 USA. VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Spacey, SD (reprint author), UBC Hosp, Room S-127,2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada. EM spacey@interchange.ubc.ca RI Hildebrand, Michael/J-9102-2012 NR 14 TC 41 Z9 44 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD AUG PY 2004 VL 56 IS 2 BP 213 EP 220 DI 10.1002/ana.20169 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 847YT UT WOS:000223434700007 PM 15293273 ER PT J AU Heymach, JV Johnson, DH Khuri, FR Safran, H Schlabach, LL Yunus, F DeVore, RF De Porre, PM Richards, HM Jia, X Zhang, S Johnson, BE AF Heymach, JV Johnson, DH Khuri, FR Safran, H Schlabach, LL Yunus, F DeVore, RF De Porre, PM Richards, HM Jia, X Zhang, S Johnson, BE TI Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer SO ANNALS OF ONCOLOGY LA English DT Article DE farnesyl transferase inhibitor; RI 15777; Ras; small-cell lung cancer; tipifarnib ID COOPERATIVE-ONCOLOGY-GROUP; FARNESYLTRANSFERASE INHIBITOR; 2ND-LINE TREATMENT; TOPOTECAN; CISPLATIN; LINES; TRIAL; ACTIVATION; ETOPOSIDE; MUTATIONS AB Background: R115777 (tipifarnib, Zarnestra(TM)) is a farnesyl transferase inhibitor that blocks the farnesylation of proteins involved in signal transduction pathways critical for cell proliferation and survival. This multicenter phase II study was conducted to determine the efficacy, tolerability and pharmacokinetics of R115777 in patients with relapsed small-cell lung cancer (SCLC). Patients and methods: Patients who had a partial or complete response to their initial chemotherapy regimen, followed by at least 3 months off treatment before relapse (sensitive relapse) were eligible. R115777 was administered in 3-week cycles at a dose of 400 mg orally twice daily for 14 consecutive days followed by 7 days off treatment. Results: Twenty-two patients were enrolled. The median progression-free survival was 1.4 months and median overall survival was 6.8 months. Non-hematological toxicities were predominantly grade 1-2 and included nausea (64%) and fatigue (60%). Grade 3-4 granulocytopenia and thrombocytopenia occurred in 27% and 23% of patients, respectively. Febrile neutropenia was not observed. Pharmacokinetic studies demonstrated peak plasma concentrations of R115777 2.6-4.5 h after oral dosing and no significant drug accumulation. The trial was terminated because no objective responses were observed in 20 patients evaluable for response. Conclusions: R115777 showed no significant antitumor activity as a single agent in sensitive-relapse SCLC. C1 Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Brown Univ, Providence, RI 02912 USA. Erlanger Med Ctr, Chattanooga, TN USA. Univ Tennessee, Inst Canc, Memphis, TN USA. Johnson & Johnson Pharmaceut Res & Dev, Titusville, NJ USA. Johnson & Johnson Pharmaceut Res & Dev, Beerse, Belgium. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dana 1234,44 Binney St, Boston, MA 02115 USA. EM bejohnson@partners.org RI Johnson, David/A-7437-2009 NR 36 TC 57 Z9 60 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD AUG PY 2004 VL 15 IS 8 BP 1187 EP 1193 DI 10.1093/annonc/mdh315 PG 7 WC Oncology SC Oncology GA 846YK UT WOS:000223355400006 PM 15277257 ER PT J AU Kwek, BH Wain, JC Aquino, SL AF Kwek, BH Wain, JC Aquino, SL TI The radiologic appearance of intercostal muscle flap SO ANNALS OF THORACIC SURGERY LA English DT Article ID PEDICLE FLAP; HETEROTOPIC OSSIFICATION; BRONCHIAL ANASTOMOSES; CLINICAL PROBLEMS; REVASCULARIZATION; REPAIR AB Background. The intercostal muscle flap (ICMF) is commonly used in airway and esophageal surgery to reinforce an anastomosis or site of closure. These flaps undergo heterotopic ossification that may result in stenosis of adjacent airways or the esophagus. We evaluated the computer tomography (CT) scan, technetium-99mmethylene diphosphonate bone scan and positron emission tomography with 2-[(18)Fl-fluoro-2-deoxy-D-glucose (FDG-PET) findings of ICMF and the frequency of airway or esophageal stenosis. Methods. A retrospective review was made of the radiologic records of 23 patients (9 women, 14 men) who underwent ICMF. The CT scans were obtained a mean of 36 months (range, 1 week to 58 months) after surgery and the size, morphology, and density of the ICMFs were recorded. Correlative bone scan in 13 patients and FDGPET scans in 11 patients were reviewed. Results. A discontinuous, thin, linear calcified stripe or parallel stripes (mean thickness, 4 mm; mean density, 430 Houndsfield unit [HUI) were present in all patients on CT. The flap contained fat density (mean, -59 HU) in 18 patients and soft tissue density (mean, 41 HU) in 8 patients and measured about I cm in thickness. The appearance of ICMF is characteristic when the ossification extends from the posterolateral chest wall to an adjacent bronchial stump. There was no increased uptake on bone scan or FDG-PET scan. None of the patients had airway or esophageal stenosis. Conclusions. The ICMF manifests on CT as a thin, linear calcified stripe or parallel stripes with central fat or soft tissue density. Airway stenosis due to ICMF is likely quite rare. We did not detect any airway stenosis. (C) 2004 by The Society of Thoracic Surgeons. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Thorac Surg Unit, Boston, MA 02114 USA. RP Aquino, SL (reprint author), Massachusetts Gen Hosp, Dept Radiol, FND 202,55 Fruit St, Boston, MA 02114 USA. EM saquino@partners.org NR 16 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD AUG PY 2004 VL 78 IS 2 BP 432 EP 435 DI 10.1016/j.athorascular.2004.01.018 PG 4 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 842JE UT WOS:000222999300008 PM 15276491 ER PT J AU Mukhopadhyay, NK Gilchrist, D Gordon, GJ Chen, CJ Bueno, R Lu, ML Salgia, R Sugarbaker, DJ Jaklitsch, MT AF Mukhopadhyay, NK Gilchrist, D Gordon, GJ Chen, CJ Bueno, R Lu, ML Salgia, R Sugarbaker, DJ Jaklitsch, MT TI Integrin dependent protein tyrosine phosphorylation is a key regulatory event in collagen IV mediated adhesion and proliferation of human lung tumor cell line, Calu-1 SO ANNALS OF THORACIC SURGERY LA English DT Article ID FOCAL ADHESION; ENDOTHELIAL-CELLS; EXTRACELLULAR-MATRIX; CANCER CELLS; EXPRESSION; PAXILLIN; LOCALIZATION; ALPHA-1(IV); ACTIVATION; KINASE AB Background. The clinical phenomenon of lung cancer metastasis to specific target organs is believed to be a direct interaction between tumor cells and extracellular matrix components. During invasion, tumor cells attach to the basement membrane protein, collagen type IV, degrade it, migrate through blood vessels, and adhere to extracellular matrix proteins. Methods. Four nonsmall-cell lung cancer cells were tested for adhesion, proliferation, migration and morphologic alterations on collagen type IV matrix by immunoprecipitation, Western blotting, phase contrast and time lapse video microscopy. Results. Collagen type IV promoted Calu-1 cell adhesion (<15 minutes) and motility (<6 hours) without any significant effect on proliferation. beta(1)-integrin is essential for collagen type IV adhesion and 8 to 10 fold higher expression of beta(1)-integrin on the surface of Calu-1 cells was identified. A protein tyrosine phosphatase inhibitor, peroxyvanadate, caused 50% inhibition in the adhesion process within 5 minutes but exposure to 60 mumol/L genistein for 72 hours, a protein tyrosine kinase inhibitor, drastically inhibits Calu-1 cell proliferation (>70%). We examined the influence of beta(1)-integrin, peroxyvanadate and genistein on the spreading morphogenesis of Calu-1 cells on Collagen type IV. Use of either 1 mug of anti beta(1)-integrin inhibitory antibody (P5D2), 100 mumol/L peroxyvanadate or 60 mumol/L genistein had dramatic influence on the spreading of Calu-1 cells. Finally, Focal adhesion kinase was identified as a phosphoprotein target. Conclusions. We have characterized an in vitro model of matrix-specific binding of a lung cancer cell line, Calu-1 to Coll IV. Calu-1 cells use primarily a beta(1)-integrin mediated intracellular tyrosine phosphorylation phenomenon as the key regulatory mechanism for its binding advantage to Coll IV matrix. (C) 2004 by The Society of Thoracic Surgeons. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol,Div Thorac Surg, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Urol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Jaklitsch, MT (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol,Div Thorac Surg, 75 Francis St, Boston, MA 02115 USA. EM mjaklitsch@partners.org NR 25 TC 16 Z9 16 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD AUG PY 2004 VL 78 IS 2 BP 450 EP 457 DI 10.1016/j.athoracsur.2004.01.042 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 842JE UT WOS:000222999300011 PM 15276495 ER PT J AU Little, SJ Grant, RM Daar, ES Markowitz, M Hecht, FM Johnson, V Allen, T Frenkel, LM Benson, C Routy, JP Conway, B Sun, X Richman, DD Frost, SDW AF Little, SJ Grant, RM Daar, ES Markowitz, M Hecht, FM Johnson, V Allen, T Frenkel, LM Benson, C Routy, JP Conway, B Sun, X Richman, DD Frost, SDW TI Transmitted NNRTl drug resistance is associated with higher steady-state viral load measures in untreated subjects with primary HIV infection SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 13th International HIV Drug Resistance Workshop CY JUN 08-12, 2004 CL Tenerife, SPAIN C1 Univ Calif San Diego, San Diego, CA 92103 USA. Gladstone Inst Virol & Immunol, San Francisco, CA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Harbor UCLA Med Ctr, Torrance, CA 90509 USA. Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10021 USA. Birmingham VA Med Ctr, Birmingham, AL USA. Univ Alabama, Sch Med, Birmingham, AL USA. Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. Univ Washington, Seattle, WA 98195 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO 80202 USA. McGill Univ, Ctr Hlth, Montreal, PQ, Canada. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. VA San Diego Healthcare Syst, San Diego, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD AUG PY 2004 VL 9 IS 4 BP U53 EP U54 PG 2 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 960TH UT WOS:000231615600073 ER PT J AU Tremblay, CL Giguel, F Dong, H Chou, TC Hirsch, MS AF Tremblay, CL Giguel, F Dong, H Chou, TC Hirsch, MS TI In vitro antiviral interactions among tenofovir, abacavir, lamivudine and didanosine SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 13th International HIV Drug Resistance Workshop CY JUN 08-12, 2004 CL Tenerife, SPAIN C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. Univ Montreal, Ctr Rech, Ctr Hosp, Montreal, PQ H3C 3J7, Canada. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD AUG PY 2004 VL 9 IS 4 BP U46 EP U46 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 960TH UT WOS:000231615600065 ER PT J AU Dougherty, DD Rauch, SL Deckersbach, T Marci, P Loh, R Shin, LM Alpert, NM Fischman, A Fava, M AF Dougherty, DD Rauch, SL Deckersbach, T Marci, P Loh, R Shin, LM Alpert, NM Fischman, A Fava, M TI Ventromedial prefrontal cortex and amygdala dysfunction during an anger induction positron emission tomography study in patients with major depression disorder with anger attacks SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Review ID ANTISOCIAL PERSONALITY-DISORDER; POSTTRAUMATIC-STRESS-DISORDER; HEALTHY POSTMENOPAUSAL WOMEN; CORONARY-HEART-DISEASE; TEMPORAL-LOBE EPILEPSY; SCRIPT-DRIVEN IMAGERY; GLUCOSE-METABOLISM; BRAIN ACTIVITY; PSYCHOPATHIC TENDENCIES; MYOCARDIAL-INFARCTION AB Context: Although a variety of functional neuroimaging studies have used emotion induction paradigms to investigate the neural basis of anger in control subjects, no functional neuroimaging studies using anger induction have been conducted in patient populations. Objective: To study the neural basis of anger in unmedicated patients with major depressive disorder with anger attacks (MDD + A), unmedicated patients with MDD without anger attacks (MDD - A), and controls. Design: We used positron emission tomography, psychophysiologic measures, and autobiographical narrative scripts in the context of an anger induction paradigm. Setting: Academic medical center. Participants: Thirty individuals, evenly divided among the 3 study groups. Interventions: In separate conditions, participants were exposed to anger and neutral autobiographical scripts during the positron emission tomography study. Subjective self-report and psychophysiologic data were also collected. Main Outcome Measures: Voxelwise methods were used for analyses of regional cerebral blood flow changes for the anger vs neutral contrast within and between groups. Results: Controls showed significantly (P < .001) greater regional cerebral blood flow increases in the left ventromedial prefrontal cortex during anger induction than patients with MDD + A, whereas these differences were not present in other between-group analyses. Also, in controls, an inverse relationship was demonstrated between regional cerebral blood flow changes during anger induction in the left ventromedial prefrontal cortex and left amygdala, whereas in patients with MDD + A there was a positive correlation between these brain regions during anger induction. There was no significant relationship between these brain regions during anger induction in patients with MDD - A. Conclusion: These results suggest a pathophysiology of MDD + A that is distinct from that of MDD - A and that may be responsible for the unique clinical presentation of patients with MDD + A. C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Tufts Univ, Dept Psychol, Medford, MA 02155 USA. RP Dougherty, DD (reprint author), Massachusetts Gen Hosp E, CNY-2612,Bldg 149,13th St, Charlestown, MA 02129 USA. EM ddougherty@partners.org FU NIMH NIH HHS [MH01735] NR 122 TC 100 Z9 105 U1 9 U2 20 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD AUG PY 2004 VL 61 IS 8 BP 795 EP 804 DI 10.1001/archpsyc.61.8.795 PG 10 WC Psychiatry SC Psychiatry GA 844EN UT WOS:000223140400005 PM 15289278 ER PT J AU Tyler, KL AF Tyler, KL TI West Nile virus infection in the United States SO ARCHIVES OF NEUROLOGY LA English DT Review ID ACUTE FLACCID PARALYSIS; NEW-YORK; INTRAVENOUS IMMUNOGLOBULIN; ENCEPHALITIS; POLIOMYELITIS; PATHOLOGY; RIBAVIRIN; OUTBREAK; EFFICACY; WEAKNESS AB West Nile virus (WNV), an arthropod-borne flavivirus belonging to the Japanese encephalitis virus antigenic complex, first appeared as a cause of naturally acquired meningitis and encephalitis in the United States in the New York City area in the summer of 1999.(1) During succeeding years, the virus has spread rapidly throughout North America, becoming enzootic in bird and mosquito populations throughout much of the continental United States. In 2003, WNV was responsible for one of the largest arboviral encephalitis epidemics in US history (9858 cases; 2863 with meningoencephalitis and 262 deaths) and one of the largest WNV meningoencephalitis epidemics yet recorded.(2) C1 Univ Colorado, Hlth Sci Ctr, Dept Neurol, Denver, CO 80262 USA. Denver VA Med Ctr, Denver, CO 80262 USA. RP Tyler, KL (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Neurol, 4200 E 9th Ave,Campus Box B-182, Denver, CO 80262 USA. EM ken.tyler@uchsc.edu OI Tyler, Kenneth/0000-0003-3294-5888 NR 55 TC 26 Z9 29 U1 1 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD AUG PY 2004 VL 61 IS 8 BP 1190 EP 1195 DI 10.1001/archneur.61.8.1190 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 844SM UT WOS:000223180100006 PM 15313835 ER PT J AU Rodrigues, MI Dohlman, CH AF Rodrigues, MI Dohlman, CH TI Blindness in an American boy caused by unrecognized vitamin A deficiency SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID KERATOMALACIA C1 Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. RP Dohlman, CH (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM claes_dohlman@meei.harvard.edu NR 5 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD AUG PY 2004 VL 122 IS 8 BP 1228 EP 1229 DI 10.1001/archopht.122.8.1228 PG 2 WC Ophthalmology SC Ophthalmology GA 845AB UT WOS:000223206900019 PM 15302667 ER PT J AU White, WM Baldassano, M Rajadhyaksha, M Gonzalez, S Tearney, GJ Anderson, RR Fabian, RL AF White, WM Baldassano, M Rajadhyaksha, M Gonzalez, S Tearney, GJ Anderson, RR Fabian, RL TI Confocal reflectance Imaging of head and neck surgical specimens - A comparison with histologic analysis SO ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Article ID FROZEN-SECTION DIAGNOSIS; SCANNING LASER OPHTHALMOSCOPE; IN-VIVO; MICROSCOPY; ACCURACY; MARGINS; SURGERY; GLAND; SKIN AB Background: Confocal reflectance microscopy (CRM) is an optical method of imaging tissue noninvasively without the need for fixation, sectioning, and staining as in standard histopathologic analysis. Image contrast is determined by natural differences in refractive indices of organelles and other subcellular structures within the tissues. Gray-scale images are displayed in real time on a video monitor and represent horizontal (en face) optical sections through the tissue. We hypothesized that CRM is capable of discerning histologic characteristics of different tissues in the head and neck. Objectives: To examine the microscopic anatomy of freshly excised head and neck surgical specimens en bloc using CRM and to compare the findings with those generated by conventional histologic analysis. Design: This was a pilot observational cohort study. Bone, muscle, nerve, thyroid, parotid, and ethmoid mucosa from human surgical specimens were imaged immediately after excision. Confocal images were compared with corresponding routine paraffin-embedded, hematoxylin-eosin-stained sections obtained from the same tissue. Results: Characteristic histologic features of various tissues and cell types were readily discernible by CRM and correlated well with permanent sections. However, in all tissues examined, there was less microscopic detail visible in the CRM images than was appreciated in paraffin-embedded histologic sections. Conclusions: The CRM images revealed cytologic features without the artifacts of histologic processing and thus may have the potential for use as an adjunct to frozen-section analysis in intraoperative consultation. C1 Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Wellman Labs Photomed, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Fabian, RL (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. EM RFabian847@aol.com NR 22 TC 18 Z9 18 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0886-4470 J9 ARCH OTOLARYNGOL JI Arch. Otolaryngol. Head Neck Surg. PD AUG PY 2004 VL 130 IS 8 BP 923 EP 928 DI 10.1001/archotol.130.8.923 PG 6 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 844DY UT WOS:000223138800003 PM 15313861 ER PT J AU Melanson, SF Hsieh, B Flood, JG Lewandrowski, KB AF Melanson, SF Hsieh, B Flood, JG Lewandrowski, KB TI Evaluation of add-on testing in the clinical chemistry laboratory of a large academic medical center - Operational considerations SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article AB Context.-Physicians frequently request that additional tests be performed on an existing specimen (add-ons). In our institution, add-ons comprise approximately 1% of the specimen volume and require a disproportionate number of employees. Not only are add-on tests time-consuming and expensive, but storing routine specimens for 7 days in anticipation of add-ons consumes valuable laboratory space. Design.-One hundred sixty add-on tests during a 1-week period were reviewed. Objectives.-To analyze the pattern of add-on testing and determine methods to improve laboratory operations. Results.-All add-on tests were ordered within 24 hours of receipt of the original specimen, even though specimens were retained for 7 days. At our institution, 1.5 full-time equivalents are required to complete add-on testing, which accounts for less than 1% of the specimen volume. The most common add-on tests recorded during the study period were hepatic and electrolyte/renal/glucose panels. The medicine service ordered more than 60% of the add-on tests. Five percent of add-on tests were caused by a lack of order communication, 64.7% of cardiac marker add-ons were not ordered according to the chest pain protocol, and certain ordering patterns were present. Conclusions.-Routine specimens do not need to be retained for 7 days to accommodate add-on tests. Decreasing the storage time to 2 days would save space, while still maintaining regulatory compliance. Order communication with the laboratory, educating physicians about chest pain protocols, and instituting admission laboratory panels would decrease the number of add-ons in our hospital. This change would translate into a reduction in laboratory expenses and an improvement in operations. C1 Massachusetts Gen Hosp, Dept Pathol, Div Lab Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Lewandrowski, KB (reprint author), Massachusetts Gen Hosp, Dept Pathol, Div Lab Med, 55 Fruit St,GRJ 5, Boston, MA 02114 USA. EM klewandrowski@partners.org NR 5 TC 10 Z9 10 U1 0 U2 2 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD AUG PY 2004 VL 128 IS 8 BP 885 EP 889 PG 5 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 842IZ UT WOS:000222998800010 PM 15270614 ER PT J AU Wunder, A Tung, CH Muller-Ladner, U Weissleder, R Mahmood, U AF Wunder, A Tung, CH Muller-Ladner, U Weissleder, R Mahmood, U TI In vivo imaging of protease activity in arthritis - A novel approach for monitoring treatment response SO ARTHRITIS AND RHEUMATISM LA English DT Article ID RHEUMATOID-ARTHRITIS; CATHEPSIN-B; MATRIX METALLOPROTEINASES; RADIOGRAPHIC DATA; SYNOVIAL TISSUE; GENE-EXPRESSION; JOINT DAMAGE; PATHOGENESIS; METHOTREXATE AB Objective. Sensitive noninvasive strategies for monitoring treatment response in rheumatoid arthritis (RA) would be valuable for facilitating appropriate therapy and dosing, evaluating clinical outcome, and developing more effective drugs. Because different proteases are highly up-regulated in RA and contribute significantly to joint destruction, in the present study we investigated whether such enzymes are suitable in vivo imaging biomarkers for early evaluation of treatment response in a murine model of RA. Methods. Using a protease-activated near-infrared fluorescence (NIRF) imaging "smart" probe, we examined the presence and distribution of fluorescence in arthritic joints of mice with collagen-induced arthritis by both noninvasive fluorescence imaging and histology. Proteases that target the Lys-Lys cleavage site, including cathepsin B, activate probe fluorescence. Treatment monitoring data were obtained following methotrexate (MTX) therapy. Results. Twenty-four hours after intravenous injection of the protease sensor, affected toes and paws of arthritic mice showed significantly higher fluorescence intensity than did toes and paws of healthy mice. Fluorescence from the protease probe and cathepsin B antibody histologic staining were localized in the vast majority of cells in the inflamed synovium. In arthritic animals treated with MTX (35 mg of MTX/kg 48 hours prior to probe injection), a significantly lower fluorescent signal (inflamed paws 50%, inflamed toes 70%) was observed as compared with untreated arthritic animals. Conclusion. Protease-activated NIRF probes are sensitive means of imaging the presence of target enzymes in arthritic joints and can be used for early monitoring of treatment response to antirheumatic drugs such as MTX. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, CMIR 5408, Boston, MA 02129 USA. German Canc Res Ctr, D-6900 Heidelberg, Germany. Univ Regensburg, D-8400 Regensburg, Germany. RP Mahmood, U (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, CMIR 5408, Bldg 149,13th St, Boston, MA 02129 USA. EM mahmood@helix.mgh.harvard.edu OI Tung, Ching-Hsuan/0000-0001-6648-6195 FU NCI NIH HHS [P50-CA-86355, R224-CA-92782]; NIBIB NIH HHS [R01-EB-001872] NR 31 TC 112 Z9 113 U1 1 U2 9 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD AUG PY 2004 VL 50 IS 8 BP 2459 EP 2465 DI 10.1002/art.20379 PG 7 WC Rheumatology SC Rheumatology GA 844UG UT WOS:000223185500011 PM 15334458 ER PT J AU Jacobs, JP Pettit, AR Shinohara, ML Jansson, M Cantor, H Gravallese, EM Mathis, D Benoist, C AF Jacobs, JP Pettit, AR Shinohara, ML Jansson, M Cantor, H Gravallese, EM Mathis, D Benoist, C TI Lack of requirement of osteopontin for inflammation, bone erosion, and cartilage damage in the K/BxN model of autoantibody-mediated arthritis SO ARTHRITIS AND RHEUMATISM LA English DT Article ID ANTIBODY-INDUCED ARTHRITIS; COLLAGEN-INDUCED ARTHRITIS; AUTOIMMUNE-DISEASE; II COLLAGEN; OSTEOCLAST DIFFERENTIATION; MONOCLONAL-ANTIBODIES; RHEUMATOID-ARTHRITIS; IMMUNE-SYSTEM; MICE LACKING; IN-VITRO AB Objective. Osteopontin (OPN) is a secreted glycoprotein involved in a range of physiologic processes, including inflammation, immunity mediated by Th1 cells, and bone remodeling. It is expressed in the joints of rheumatoid arthritis patients and has been the subject of conflicting reports concerning its role in arthritis induced by antibodies against type II collagen. This study assessed the role of OPN in the K/BxN serum-transfer model of autoantibody-induced arthritis. Methods. Expression of OPN gene transcripts was assessed by microarray analysis of ankle RNA taken at 6 time points after transfer of K/BxN serum. OPN-sufficient or OPN-deficient littermates backcrossed for 10 generations onto the C57BL/6 genetic background were given K/BxN serum. Arthritis severity was measured by ankle thickening and a clinical index. Hind limb sections were stained with hematoxylin and eosin or toluidine blue and scored for inflammation, cartilage damage, and bone erosion. Results. OPN messenger RNA transcripts progressively increased in ankle joints during the course of K/BxN serum-transferred arthritis. OPN-deficient mice receiving K/BxN serum developed arthritis with kinetics and clinical severity comparable with those of OPN-sufficient littermates. Histologic assessment of arthritic joints from OPN-deficient mice revealed synovial hyperplasia, pannus formation, mononuclear cell infiltration, bone erosion, cartilage damage at sites adjacent to and distal from pannus invasion, and tartrate-resistant acid phosphatase-positive multinucleated cells at sites of bone erosion. Histopathologic scoring demonstrated comparable levels of inflammation, cartilage damage, and bone erosion in OPN-sufficient and OPN-deficient mice. Conclusion. OPN does not have a required role in inflammation, bone erosion, and cartilage damage in the K/BxN serum-transfer model. C1 Brigham & Womens Hosp, Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. Harvard Univ, Brigham & Womens Hosp, Inst Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Benoist, C (reprint author), Brigham & Womens Hosp, Joslin Diabet Ctr, 1 Joslin Pl,Room 475, Boston, MA 02215 USA. EM cbdm@joslin.harvard.edu RI Pettit, Allison/G-2591-2010; OI Pettit, Allison/0000-0003-4707-7892; Jacobs, Jonathan/0000-0003-4698-0254 FU NCI NIH HHS [CA 70083]; NIAID NIH HHS [AI-46580-04, AI-12184, AI-54904-01]; NIAMS NIH HHS [R01-AR-47665] NR 43 TC 18 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 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD AUG PY 2004 VL 50 IS 8 BP 2685 EP 2694 DI 10.1002/art.20381 PG 10 WC Rheumatology SC Rheumatology GA 844UG UT WOS:000223185500038 PM 15334485 ER PT J AU Kozel, FA Padgett, TM George, MS AF Kozel, FA Padgett, TM George, MS TI A replication study of the neural correlates of deception SO BEHAVIORAL NEUROSCIENCE LA English DT Article ID FUNCTIONAL MAGNETIC-RESONANCE; ORBITOFRONTAL CORTEX; INTERFERENCE TASK; STROOP; POLYGRAPH; FMRI AB The authors attempted to replicate prior group brain correlates of deception (F. Kozel et al., in press) and improve on the consistency of individual results. Healthy, right-handed adults were instructed to tell the truth or to lie while being imaged in a 3T magnetic resonance imaging (MRI) scanner. Blood oxygen level-dependent functional MRI significance maps were generated for subjects giving a deceptive answer minus a truthful answer (lie minus true) and the reverse (true minus lie). The lie minus true group analysis (n = 10) revealed significant activation in 5 regions, consistent with a previous study (right orbitofrontal, inferior frontal, middle frontal cortex, cingulate gyrus, and left middle frontal), with no significant activation for true minus lie. Individual results of the lie minus true condition were variable. Results show that functional MRI is a reasonable tool with which to study deception. C1 Med Univ S Carolina, Dept Psychiat, Ctr Adv Imaging Res, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Psychiat, Brain Stimulat Lab, Charleston, SC 29425 USA. Ralph H Johnson Vet Affairs Med Ctr, Mental Hlth Serv, Charleston, SC USA. RP Kozel, FA (reprint author), Med Univ S Carolina, Dept Psychiat, Ctr Adv Imaging Res, 67 President St,POB 250861, Charleston, SC 29425 USA. EM kozelfa@musc.edu RI Kozel, Frank/I-5366-2012 NR 22 TC 92 Z9 96 U1 0 U2 10 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD AUG PY 2004 VL 118 IS 4 BP 852 EP 856 DI 10.1037/0735-7044.118.4.852 PG 5 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 841IM UT WOS:000222923500018 PM 15301611 ER PT J AU Shin, M Ishii, O Sueda, T Vacanti, JP AF Shin, M Ishii, O Sueda, T Vacanti, JP TI Contractile cardiac grafts using a novel nanofibrous mesh SO BIOMATERIALS LA English DT Article DE cardiac tissue engineering; polycaprolactone; heart; electrospinning ID MYOCARDIUM; MUSCLE; MANIPULATION; CONSTRUCT AB Cardiomyoctes are terminally differentiated cells and therefore unable to regenerate after infarction. The use of autologous bioengineered cardiac grafts has been suggested to replace infarcted myocardium and enhance cardiac function. Here we report the development of an in vitro system for engineered myocardium. Cardiac nanofibrous meshes (CNM) were developed by culturing cardiomyocytes from neonatal Lewis rats on electrospun, nanofibrous polycaprolactone (PCL) meshes. The mesh had an ECM-like topography and was suspended across a wire ring that acted as a passive load to contracting cardiomyocytes. The cardiomyocytes started beating after 3 days and were cultured in vitro for 14 days. The cardiomyocytes attached well on the PCL meshes and expressed cardiac-specific proteins such as a-myosin heavy chain, connexin43 and cardiac troponin I. The results demonstrate the formation of contractile cardiac grafts in vitro. Using this technique, cardiac grafts can be matured in vitro to obtain sufficient function prior to implantation. It is conjectured that cardiac grafts with clinically relevant dimensions can be obtained by stacking CNMs and inducing vascularization with angiogenic factors. (C) 2003 Elsevier Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Hiroshima Univ, Sch Med, Dept Surg 1, Hiroshima 7368551, Japan. RP Shin, M (reprint author), Massachusetts Gen Hosp, Dept Surg, Wellman 627,55 Fruit St, Boston, MA 02114 USA. EM mshin@partners.org NR 21 TC 231 Z9 242 U1 4 U2 37 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD AUG PY 2004 VL 25 IS 17 BP 3717 EP 3723 DI 10.1016/j.biomaterials.2003.10.055 PG 7 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 808GS UT WOS:000220558200041 PM 15020147 ER PT J AU Im, GI Qureshi, SA Kenney, J Rubash, HE Shanbhag, AS AF Im, GI Qureshi, SA Kenney, J Rubash, HE Shanbhag, AS TI Osteoblast proliferation and maturation by bisphosphonates SO BIOMATERIALS LA English DT Article DE alendronate; risedronate; human trabecular bone cells; BMP-2; total joint replacements ID TOTAL HIP-ARTHROPLASTY; HUMAN-BONE-MARROW; CELLS IN-VITRO; NITROGEN-CONTAINING BISPHOSPHONATES; POSTMENOPAUSAL OSTEOPOROSIS; MEVALONATE PATHWAY; RANDOMIZED-TRIAL; OSTEOGENESIS IMPERFECTA; PAMIDRONATE TREATMENT; RHEUMATOID-ARTHRITIS AB Aseptic loosening and osteolysis are currently the most common causes of failure of total joint replacements. Osteolysis is initiated by a macrophage response to wear debris, resulting in localized, osteoclastic peri-implant bone loss. We have previously inhibited osteoclast-mediated bone resorption in a canine total hip arthroplasty model using oral bisphosphonate therapy. Based on serendipitous observations from our canine study, we hypothesized that bisphosphonates have an anabolic effect on osteoblasts, in a manner distinct from their inhibitory effect on osteoclastic bone resorption. We studied the anabolic effects of two FDA-approved bisphosphonates (alendronate and risedronate) on two in vitro models: a primary human trabecular bone cell culture and the MG-63 osteoblast-like cell line. Following treatment with bisphosphonates at varying concentrations and time periods. cells were assayed for proliferation effects and results were quantified using the methods of direct cell count, and the colorimetric MTT (3-dimethylthiazol-2,5-diphenyltetrazolium bromide) assay at 24, 48, and 72 It. The effect of bisphosphonates on the maturation of osteoblasts were tested with alkaline phosphatase bioassay and reverse transcription-polymerase chain reaction for markers of osteoblast differentiation. Results from both the primary human trabecular bone cell culture and the MG-63 osteoblast-like cell line showed that both bisphosphonates significantly increased the cell number over controls, attaining peak levels at a concentration of 10(-8) m. Alkaline phosphatase activity was also increased, representing earlier commitment of osteoprogenitor cells towards the osteoblastic phenotype. Bisphosphonates also enhanced gene expression of BMP-2, Type I collagen and osteocalcin. In summary, bisphosphonates, aside from their role as inhibitors of osteoclastic bone resorption, are promoters of osteoblast proliferation and maturation. (C) 2003 Elsevier Ltd. All rights reserved. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Biomat Lab, Boston, MA 02114 USA. RP Shanbhag, AS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Biomat Lab, GRJ 1115,55 Fruit St, Boston, MA 02114 USA. EM shanbhag@helix.mgh.harvard.edu FU NIAMS NIH HHS [AR-47465-02] NR 72 TC 221 Z9 245 U1 1 U2 33 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD AUG PY 2004 VL 25 IS 18 BP 4105 EP 4115 DI 10.1016/j.biomaterials.2003.11.024 PG 11 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 813ZQ UT WOS:000220945400019 PM 15046901 ER PT J AU Mazzucco, D Scott, R Spector, M AF Mazzucco, D Scott, R Spector, M TI Composition of joint fluid in patients undergoing total knee replacement and revision arthroplasty: correlation with flow properties SO BIOMATERIALS LA English DT Article DE arthroplasty; tribology; joint; synovial; fluid; composition ID ALPHA-TRYPSIN INHIBITOR; SYNOVIAL-FLUID; HYALURONIC-ACID; ARTICULAR-CARTILAGE; RHEUMATOID-ARTHRITIS; SODIUM HYALURONATE; BOUNDARY LUBRICANT; MOLECULAR-WEIGHT; LIPID-COMPOSITION; HIP-REPLACEMENT AB The protein, phospholipid and hyaluronic acid (HA) contents of joint fluid samples were determined in specimens obtained from patients undergoing total knee arthroplasty (TKA) and revision TKA. It was hypothesized that these components would vary widely among patients undergoing TKA, and that the composition of joint fluid in patients undergoing revision would differ from that in patients undergoing revision. It was further hypothesized that HA concentration and molecular weight would principally determine the flow properties previously reported. Biochemical assays were used to assess protein and phospholipid content, and size exclusion chromatography was used to determine HA concentration and molecular weight. Sixty samples were included in the study. HA, protein, and phospholipid concentrations all varied widely in patients undergoing index TKA and revision TKA. HA concentration was lower in patients undergoing revision arthroplasty due to wear-related failure compared to patients undergoing the index procedure (0.9+/-0.4mg/ml versus 1.3+/-0.5mg/ml, mean+/-standard deviation, p = 0.04). Other components were not different between the groups. Flow properties at high shear rates were correlated with HA concentration and, to a lesser extent, HA molecular weight. but neither protein nor phospholipid concentration. The composition of joint fluid is highly variable in the context of arthroplasty. Much of the variation in flow properties, especially at high shear rate, is explained by large variation in HA concentration and small variation in HA molecular weight. The variation in composition and lower HA concentration in joints necessitating revision may relate to variation in arthroplasty lubrication leading to highly variable wear rates and clinical outcomes. (C) 2003 Elsevier Ltd. All rights reserved. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Orthopaed Surg, Boston, MA 02115 USA. VA Boston Healthcare Syst, Boston, MA 02130 USA. MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Orthopaed Surg, 75 Francis St, Boston, MA 02115 USA. EM mspector@rics.bwh.harvard.edu NR 63 TC 59 Z9 60 U1 0 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD AUG PY 2004 VL 25 IS 18 BP 4433 EP 4445 DI 10.1016/j.biomaterials.2003.11.023 PG 13 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 813ZQ UT WOS:000220945400052 PM 15046934 ER PT J AU Greenbaum, ES Burroughs, BB Harris, WH Muratoglu, OK AF Greenbaum, ES Burroughs, BB Harris, WH Muratoglu, OK TI Effect of lipid absorption on wear and compressive properties of unirradiated and highly crosslinked UHMWPE: An in vitro experimental model SO BIOMATERIALS LA English DT Article DE total joint arthroplasty; UHMWPE; crosslinking; wear; compressive properties; lipid absorption ID MOLECULAR-WEIGHT POLYETHYLENE; VIVO AB Ultra-high molecular weight polyethylene (UHMWPE or polyethylene) components used in total joint arthroplasty absorb lipids in vivo. However, the effect, if any, of this lipid uptake on both the wear and the mechanical properties of polyethylene is not known. We contrasted the effects of lipid diffusion into the polyethylene on the wear and mechanical properties of unirradiated UHMWPE versus that into highly crosslinked UHMWPE preparation (a 95-kGy irradiated and melted UHMWPE). We doped test samples of both types of polyethylenes with either squalene alone or a 15% (w/v) solution of cholestene/squalene (CH/SQ) solution. The diffusion profiles were quantified using infrared microscopy as a function of depth away from free surfaces; we used the 1620 and 1680 cm(-1) absorbances characteristic of CH and SQ, respectively. There were no statistically significant changes in the bidirectional pin-on-disk wear rates of neither type of polyethylene after lipid absorption. On the other hand, compressive modulus and compressive strength of both polyethylenes decreased after doping with either lipid. (C) 2003 Elsevier Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Orthopaed Biomech & Biomat Lab, Boston, MA 02114 USA. RP Muratoglu, OK (reprint author), Massachusetts Gen Hosp, Orthopaed Biomech & Biomat Lab, Jackson GRJ 1206 55 Fruit St, Boston, MA 02114 USA. EM orhun@alum.mit.edu NR 8 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 0142-9612 J9 BIOMATERIALS JI Biomaterials PD AUG PY 2004 VL 25 IS 18 BP 4479 EP 4484 DI 10.1016/j.biomaterials.2003.11.049 PG 6 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 813ZQ UT WOS:000220945400056 PM 15046938 ER PT J AU Jia, XQ Colombo, G Padera, R Langer, R Kohane, DS AF Jia, XQ Colombo, G Padera, R Langer, R Kohane, DS TI Prolongation of sciatic nerve blockade by in situ cross-linked hyaluronic acid SO BIOMATERIALS LA English DT Article DE nerve; muscle; hyaluronic acid; biocompatibility; animal model ID DURATION LOCAL-ANESTHESIA; PROTEIN-SUGAR PARTICLES; CONTROLLED-RELEASE; BUPIVACAINE; LIDOCAINE; MICROSPHERES; RAT; TETRODOTOXIN; ADJUVANTS; HYDROGELS AB Controlled release technology has been applied extensively in providing prolonged duration local anesthesia. Here we used modified hyaluronic acids (HAs: hydrazide and aldehyde) that cross-link upon mixing, as the vehicle for bupivacaine. We assessed the formulations' efficacy and biocompatibility in a rat model of sciatic nerve blockade. We found that 2% (w/v) cross-linked HA doubled the duration of block of 0.1%. 0.25%, and 0.5% bupivacaine, without a statistically significant increase in myotoxicity. 1% (w/w) cross-linked HA also prolonged nerve block, but unmodified HA, and both modified HAs did not. HA itself was associated with a mild to moderate inflammatory response with macrophages and lymphocytes. Cross-linked HA is an effective and biocompatible vehicle for enhancing local anesthetic efficacy. (C) 2003 Elsevier Ltd. All rights reserved. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Pediat Intens Care Unit, Boston, MA 02114 USA. MIT, Dept Chem Engn, Cambridge, MA 02139 USA. Univ Parma, Dept Pharmaceut, Parma, Italy. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard MIT, Div Hlth Sci & Technol, Cambridge, MA USA. RP Kohane, DS (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Pediat Intens Care Unit, Ellison 7,55 Fruit St, Boston, MA 02114 USA. EM dkohane@partners.org RI Colombo, Gaia/G-6837-2012 OI Colombo, Gaia/0000-0001-9033-2305 FU NIGMS NIH HHS [GM00684, GM26698] NR 20 TC 105 Z9 106 U1 5 U2 31 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD AUG PY 2004 VL 25 IS 19 BP 4797 EP 4804 DI 10.1016/j.biomaterials.2003.12.012 PG 8 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 817XY UT WOS:000221211400031 PM 15120526 ER PT J AU Chen, IA Szostak, JW AF Chen, IA Szostak, JW TI A kinetic study of the growth of fatty acid vesicles SO BIOPHYSICAL JOURNAL LA English DT Article ID CRYOTRANSMISSION ELECTRON-MICROSCOPY; MURCHISON CARBONACEOUS CHONDRITE; MONOCARBOXYLIC ACIDS; FLIP-FLOP; PHOSPHOLIPID-BILAYERS; PHASE-SEPARATION; ENERGY-TRANSFER; MEMBRANES; TRANSITION; PHOSPHATIDYLCHOLINE AB Membrane vesicles composed of fatty acids can be made to grow and divide under laboratory conditions, and thus provide a model system relevant to the emergence of cellular life. Fatty acid vesicles grow spontaneously when alkaline micelles are added to buffered vesicles. To investigate the mechanism of this process, we used stopped-flow kinetics to analyze the dilution of non-exchanging FRET probes incorporated into preformed vesicles during growth. Oleate vesicle growth occurs in two phases ( fast and slow), indicating two pathways for the incorporation of fatty acid into preformed vesicles. We propose that the fast phase, which is stoichiometrically limited by the preformed vesicles, results from the formation of a "shell'' of fatty acid around a vesicle, followed by rapid transfer of this fatty acid into the preformed vesicle. The slower phase may result from incorporation of fatty acid which had been trapped in an intermediate state. We provide independent evidence for the rapid transformation of micelles into an aggregated intermediate form after transfer from high to low pH. Our results show that the most efficient incorporation of added oleate into oleic acid/oleate vesicles occurs under conditions that avoid a large transient increase in the micelle/vesicle ratio. C1 Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. EM szostak@molbio.mgh.harvard.edu FU NIGMS NIH HHS [T32 GM008313, T32 GM007753, T32-GM07753, T32-GM08313] NR 68 TC 103 Z9 103 U1 6 U2 47 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD AUG PY 2004 VL 87 IS 2 BP 988 EP 998 DI 10.1529/biophysj.104.039875 PG 11 WC Biophysics SC Biophysics GA 844XZ UT WOS:000223195700024 PM 15298905 ER PT J AU Faedda, GL Baldessarini, RJ Glovinsky, IP Austin, NB AF Faedda, GL Baldessarini, RJ Glovinsky, IP Austin, NB TI Pediatric bipolar disorder: phenomenology and course of illness SO BIPOLAR DISORDERS LA English DT Article DE bipolar disorder; children; course; diagnosis; DSM-criteria; pediatric psychiatry ID MAJOR DEPRESSIVE DISORDER; PROSPECTIVE FOLLOW-UP; MANIC SYMPTOMS; REFERRED CHILDREN; MOOD DISORDERS; ONSET MANIA; II DISORDER; ADOLESCENTS; COMORBIDITY; PREVALENCE AB Background: Specific features and diagnostic boundaries of childhood bipolar disorder (BD) remain controversial, and its differentiation from other disorders challenging, owing to high comorbidity with other common childhood disorders, and frequent lack of an episodic course typical of adult BD. Methods: We repeatedly examined children meeting DSM-IV criteria for BD (excluding episode-duration requirements) and analyzed their clinical records to evaluate age-at-onset, family history, symptoms, course, and comorbidity. Results: Of 82 juveniles (aged 10.6 +/- 3.6 years) diagnosed with BD, 90% had a family history of mood or substance-use disorders, but only 10% of patients had been diagnosed with BD. In 74%, psychopathology was recognized before age 3, usually as mood and sleep disturbances, hyperactivity, aggression, and anxiety. At onset, dysphoric-manic and mixed presentations were most common (48%), euphoric mania less (35%), and depression least (17%). Subtype diagnoses were: BP-I (52%) > BP-II (40%) > cyclothymia (7%). DSM episode-duration criteria were met in 52% of cases, and frequent shifts of mood and energy were common. Limitations: Partly retrospective study of clinically diagnosed referred outpatients without a comparison group. Conclusions: Pediatric BD is often mis- or undiagnosed, although it often manifests with mood lability and sleep disturbances early in life. DSM BD criteria inconsistent with clinical findings require revision for pediatric application. C1 Lucio Bini Mood Disorders Ctr, New York, NY USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA. Massachusetts Gen Hosp, McLean Div, Bipolar & Psychot Disorders Program, Belmont, MA USA. Massachusetts Gen Hosp, McLean Div, Psychiat Res Labs, Belmont, MA USA. Village Educ Ctr, Beverly Hills, MI USA. RP Faedda, GL (reprint author), 245 E 50th St, New York, NY 10022 USA. EM gianni.faedda@moodcenter.org OI Faedda, Gianni/0000-0001-6197-0543 NR 56 TC 106 Z9 109 U1 6 U2 9 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD AUG PY 2004 VL 6 IS 4 BP 305 EP 313 DI 10.1111/j.1399-5618.2004.00128.x PG 9 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 833RK UT WOS:000222356100005 PM 15225148 ER PT J AU Tamada, RS Issler, CK Amaral, JA Sachs, GS Lafer, B AF Tamada, RS Issler, CK Amaral, JA Sachs, GS Lafer, B TI Treatment emergent affective switch: a controlled study SO BIPOLAR DISORDERS LA English DT Article DE antidepressants; bipolar depression; spontaneous mania; treatment emergent affective switch ID ANTIDEPRESSANT-ASSOCIATED MANIA; BIPOLAR DEPRESSION; RATING-SCALE; DOUBLE-BLIND; IMIPRAMINE; BUPROPION AB Objective: To study the clinical features of treatment emergent affective switch (TEAS) in comparison with spontaneous mania. Methods: Twelve patients with TEAS within a 12-week period (average) of starting standard antidepressant medication were compared with 12 patients with spontaneous mania. Results: Patients with TEAS were older, had longer duration of illness, more previous episodes, higher prevalence of subclinical hypothyroidism, and reported more previous episodes of mania associated with antidepressant use. TEAS was less severe, with a lower incidence of psychotic symptoms, lower Young Mania Rating Scale index score and rarely required hospitalization. The interval from intervention to response and remission was similar in both groups. Conclusion: TEAS was less severe, but had similar duration when compared with spontaneous mania. These results cannot directly answer the question of whether there is a causal relationship between antidepressant use and TEAS. While it is also possible that patients with longer duration of illness and higher cycle frequencies are more likely to experience episodes, it is difficult to attribute lesser severity of TEAS episodes to these clinical factors. Our observations are consistent with the suggestion that patients with longer duration of illness and previous history of TEAS may be at a greater risk of switching to mania during the use of antidepressants. C1 Univ Sao Paulo, Sch Med, Dept Psychiat, Bipolar Disorder Res Program, Sao Paulo, Brazil. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Harvard Bipolar Res Program, Boston, MA USA. RP Tamada, RS (reprint author), R Alves Guimaraes 689-124, BR-05410001 Sao Paulo, Brazil. EM rstamada@uol.com.br RI Lafer, Beny/C-1055-2012; Lafer, Beny/F-9390-2015 OI Lafer, Beny/0000-0002-6132-9999; Lafer, Beny/0000-0002-6132-9999 NR 20 TC 18 Z9 18 U1 1 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD AUG PY 2004 VL 6 IS 4 BP 333 EP 337 DI 10.1111/j.1399-5618.2004.00124.x PG 5 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 833RK UT WOS:000222356100010 PM 15225153 ER PT J AU Horal, M Zhang, ZQ Stanton, R Virkamaki, A Loeken, MR AF Horal, M Zhang, ZQ Stanton, R Virkamaki, A Loeken, MR TI Activation of the hexosamine pathway causes oxidative stress and abnormal embryo gene expression: Involvement in diabetic teratogenesis SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Article; Proceedings Paper CT 60th Scientific Sessions of the American-Diabetes-Association CY JUN 09-13, 2000 CL San Antonio, TX SP Amer Diabet Assoc DE Pax-3; glucosamine; oxidative stress; neural tube; gene expression; glutathione ID NEURAL-TUBE DEFECTS; HIGH GLUCOSE; SIGNAL-TRANSDUCTION; INSULIN-RESISTANCE; REDOX REGULATION; MOUSE EMBRYOS; PAX-3 GENE; MALFORMATIONS; CELLS; RAT AB BACKGROUND: Oxidative stress is critical to the teratogenic effects of diabetic pregnancy, yet the specific biochemical pathways responsible for oxidative stress have not been fully elucidated. The hexosamine pathway is activated in many tissues during diabetes and could contribute to oxidative stress by inhibiting the pentose shunt pathway, thereby diminishing production of the cellular antioxidant, reduced glutathione (GSH). METHODS: To test the hypothesis that activation of the hexosamine pathway might contribute to the teratogenic effects of diabetic pregnancy, pregnant mice were injected with glucose, to induce hyperglycemia, or glucosamine, to directly activate the hexosamine pathway. Embryo tissue fragments were also cultured in physiological glucose, high glucose, or physiological glucose plus glucosamine, to test effects on oxidative stress and embryo gene expression. RESULTS: Glucosamine increased hexosamine synthesis and inhibited pentose shunt activity. There was a trend for transient hyperglycemia to have the same effects, but they did not reach statistical significance. However, both glucose and glucosamine significantly decreased GSH, and increased oxidative stress, as indicated by 2',7'-dichloro-dihydrofluorescein fluorescence. Glucose and glucosamine inhibited expression of Pax-3, a gene required for neural tube closure both in vivo and in vitro, and increased neural tube defects (NTDs) in vivo; these effects were prevented by GSH ethyl ester. High glucose and glucosamine inhibited Pax-3 expression by embryo culture, but culture in glutamine-free media to block the hexosamine pathway prevented the inhibition of Pax-3 expression by high glucose. CONCLUSIONS: Activation of the hexosamine pathway causes oxidative stress through depletion of GSH and consequent disruption of embryo gene expression. Activation of this pathway may contribute to diabetic teratogenesis. (C) 2004 Wiley-Liss, Inc. C1 Joslin Diabet Ctr, Sect Dev & Stem Cell Biol, Boston, MA 02215 USA. Joslin Diabet Ctr, Sect Cell Vasc Biol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Helsinki Univ Hosp, Dept Med, Helsinki, Finland. RP Loeken, MR (reprint author), Joslin Diabet Ctr, Sect Dev & Stem Cell Biol, 1 Joslin Pl, Boston, MA 02215 USA. EM mary.loeken@joslin.harvard.edu OI Loeken, Mary/0000-0002-8056-9816 FU NIDDK NIH HHS [DK54380, DK58300] NR 47 TC 43 Z9 47 U1 0 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-0752 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD AUG PY 2004 VL 70 IS 8 BP 519 EP 527 DI 10.1002/bdra.20056 PG 9 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 851IF UT WOS:000223678100003 PM 15329829 ER PT J AU Lin, AE Peller, AJ Westpate, MN Houde, K Franz, A Holmes, LB AF Lin, AE Peller, AJ Westpate, MN Houde, K Franz, A Holmes, LB TI Clonazepam use in pregnancy and the risk of malformations SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Article DE anticonvulsant; clonazepam; malformations; teratogen ID ANTICONVULSANT DRUGS; ABNORMALITIES AB BACKGROUND: Clonazepam (Klonopin) is a benzodiazepine that has been used widely to treat seizures and conditions such as panic attacks and anxiety disorder. However, the current findings about its use in pregnancy are derived from limited studies of small sample size. Because it is commonly prescribed during pregnancy, more information about its safety is needed. METHODS: The medical records of 28,565 infants were surveyed as part of a hospital-based malformation surveillance program to identify those who had been exposed prenatally to an anticonvulsant, including clonazepam. RESULTS: During a 32-month period, 166 anticonvulsant-exposed infants were identified; 52 had been exposed to clonazepam, 43 as monotherapy. A total of 33 (76.7%) of the monotherapy infants were exposed during the first trimester. One (3.0%) infant had dysmorphic features, growth retardation, and a heart malformation (tetralogy of Fallot). CONCLUSIONS: This study did not observe an increase in major malformations in births exposed to clonazepam monotherapy. However, this study is not large enough to have adequate power to determine whether or not the rate of major malformations is increased in clonazepam-exposed pregnancies. No increase has been identified in three other case series. Although the number of patients in this series was larger than previous reports, continued monitoring of pregnancies is needed to determine whether or not clonazepam is teratogenic. (C) 2004 Wiley-Liss, Inc. C1 Massachusetts Gen Hosp, Genet & Teratol Unit, Boston, MA 02114 USA. Brigham & Womens Hosp, Malformat Surveillance Program, Boston, MA 02115 USA. RP Lin, AE (reprint author), Massachusetts Gen Hosp, Genet & Teratol Unit, Warren 801,55 Fruit St, Boston, MA 02114 USA. EM lin.angela@mgh.harvard.edu NR 10 TC 23 Z9 24 U1 3 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-0752 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD AUG PY 2004 VL 70 IS 8 BP 534 EP 536 DI 10.1002/bdra.20051 PG 3 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 851IF UT WOS:000223678100006 PM 15329832 ER PT J AU Gribben, JG AF Gribben, JG TI Killing malignant but not normal B cells SO BLOOD LA English DT Editorial Material ID EPITOPES AB A major limitation of idiotype vaccination is the requirement for patient-specific reagents. This could be overcome using shared framework region peptides. Knowing that this does not lead to loss of normal B-cell responses is important in bringing this approach to clinical trials. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Gribben, JG (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 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 AUG 1 PY 2004 VL 104 IS 3 BP 601 EP 601 DI 10.1182/blood-2004-05-1776 PG 1 WC Hematology SC Hematology GA 840UW UT WOS:000222886400007 ER PT J AU Hideshima, T Bergsagel, PL Kuehl, WM Anderson, KC AF Hideshima, T Bergsagel, PL Kuehl, WM Anderson, KC TI Advances in biology of multiple myeloma: clinical applications SO BLOOD LA English DT Review ID NF-KAPPA-B; ENDOTHELIAL GROWTH-FACTOR; PROTEASOME INHIBITOR PS-341; BONE-MARROW MICROENVIRONMENT; OVERCOMES DRUG-RESISTANCE; NECROSIS-FACTOR-ALPHA; SOLUBLE INTERLEUKIN-6 RECEPTOR; CELL-DERIVED FACTOR-1-ALPHA; COOPERATIVE-ONCOLOGY-GROUP; GLOBAL GENE-EXPRESSION AB There appear to be 2 pathways involved in the early pathogenesis of premalignant monoclonal gammopathy of undetermined significance (MGUS) and malignant multiple myeloma (MM) tumors. Nearly half of these tumors are nonhyperdiploid and mostly have immunoglobulin H (IgH) translocations that involve 5 recurrent chromosomal loci, including 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (fibroblast growth factor receptor 3 [FGFR3] and multiple myeloma SET domain [MMSET]), 16q23 (c-maf), and 20q11 (mafB). The remaining tumors are hyperdiploid and contain multiple trisomies involving chromosomes 3, 5, 75 9,115 15, 19, and 21, but infrequently have IgH translocations involving the 5 recurrent loci. Dysregulated expression of cyclin D1, D2, or D3 appears to occur as an early event in virtually all of these tumors. This may render the cells more susceptible to proliferative stimuli, resulting in selective expansion as a result of interaction with bone marrow stromal cells that produce interleukin-6 (IL-6) and other cytokines. There are 5 proposed tumor groups, defined by IgH translocations and/or cyclin D expression, that appear to have differences in biologic properties, including interaction with stromal cells, prognosis, and response to specific therapies. Delineation of the mechanisms mediating MM cell proliferation, survival, and migration in the bone marrow (BM) microenvironment may both enhance understanding of pathogenesis and provide the framework for identification and validation of novel molecular targets. C1 Dana Farber Canc Inst, Dept Med Oncol, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Cornell Univ, Weill Med Coll, New York, NY USA. NCI, Genet Branch, Bethesda, MD 20892 USA. RP Anderson, KC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Jerome Lipper Multiple Myeloma Ctr, Mayer 557,44 Binney St, Boston, MA 02115 USA. EM kenneth_anderson@dfci.harvard.edu RI Bergsagel, Peter/A-7842-2011 OI Bergsagel, Peter/0000-0003-1523-7388 FU NCI NIH HHS [1P50 CA10070-01, R0-1 CA50947]; PHS HHS [P0-1 78378] NR 197 TC 420 Z9 440 U1 2 U2 28 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 AUG 1 PY 2004 VL 104 IS 3 BP 607 EP 618 DI 10.1182/blood-2004-01-0037 PG 12 WC Hematology SC Hematology GA 840UW UT WOS:000222886400012 PM 15090448 ER PT J AU Barton, JJS Cherkasova, MV Hefter, R Cox, TA O'Connor, M Manoach, DS AF Barton, JJS Cherkasova, MV Hefter, R Cox, TA O'Connor, M Manoach, DS TI Are patients with social developmental disorders prosopagnosic? Perceptual heterogeneity in the Asperger and socio-emotional processing disorders SO BRAIN LA English DT Article DE Asperger's disorder; autism; face recognition; prosopagnosia ID RIGHT-HEMISPHERE; FACE RECOGNITION; LEARNING-DISABILITIES; AUTISTIC SYNDROME; COVERT RECOGNITION; FACIAL EXPRESSIONS; CHILDHOOD AUTISM; VISUAL AGNOSIA; CHILDREN; DISCRIMINATION AB It has been hypothesized that social developmental disorders (SDD) like autism, Asperger's disorder and the social-emotional processing disorder may be associated with prosopagnosic-like deficits in face recognition. We studied the ability to recognize famous faces in 24 adults with a variety of SDD diagnoses. We also measured their ability to discriminate changes in internal facial configuration, a perceptual function that is important in face recognition, and their imagery for famous faces, an index of their facial memory stores. We contrasted their performance with both healthy subjects and prosopagnosic patients. We also performed a cluster analysis of the SDD patients. One group of eight SDD subjects performed normally on all tests of face perception and recognition. The other 16 subjects were impaired in recognition, though most were better than prosopagnosic patients. One impaired SDD subgroup had poor perception of facial structure but relatively preserved imagery, resembling prosopagnosic patients with medial occipitotemporal lesions. Another subgroup had better perception than imagery, resembling one prosopagnosic with bilateral anterior temporal lesions. Overall, SDD subgroup membership by face recognition did not correlate with a particular SDD diagnosis or subjective ratings of social impairment. We conclude that the social disturbance in SDD does not invariably lead to impaired face recognition. Abnormal face recognition in some SDD subjects is related to impaired perception of facial structure in a manner suggestive of occipitotemporal dysfunction. Heterogeneity in the perceptual processing of faces may imply pathogenetic heterogeneity, with important implications for genetic and rehabilitative studies of SDD. C1 Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Ophthalmol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Athinoula A Martinos Ctr, Boston, MA USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Boston Univ, Dept Bioengn, Boston, MA 02215 USA. NEI, NIH, Bethesda, MD 20892 USA. RP Barton, JJS (reprint author), Beth Israel Deaconess Med Ctr, Dept Neurol, KS 452,330 Brookline Ave, Boston, MA 02215 USA. EM jbarton@bidmc.harvard.edu RI Barton, Jason/A-6362-2012 FU NIMH NIH HHS [1R01 MH069898-01]; NINDS NIH HHS [1 K08 NS01920-01A1] NR 65 TC 53 Z9 53 U1 9 U2 21 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD AUG PY 2004 VL 127 BP 1706 EP 1716 DI 10.1093/brain/awh194 PN 8 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 845GJ UT WOS:000223228600003 PM 15215211 ER PT J AU Kessler, DA Kademani, D Feldman, RS Howlett, P AF Kessler, DA Kademani, D Feldman, RS Howlett, P TI Mesenchymoma: an unusual tumour of the lip SO BRITISH JOURNAL OF ORAL & MAXILLOFACIAL SURGERY LA English DT Article DE benign neoplasm; mouth neoplasm; head and neck neoplasm; mesenchymoma; mesenchymal hamartoma; oral pathology ID BENIGN MESENCHYMOMAS AB The purpose of this paper is to present a case report of a benign mesenchymoma involving the lip. A brief review of relevant literature is presented. (C) 2004 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. C1 Univ Penn, Hlth Syst, Dept Oral & Maxillofacial Surg, Philadelphia, PA USA. Univ Penn, Sch Dent Med, Dent Serv, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. Philadelphia Vet Affairs Med Ctr, Dept Pathol, Philadelphia, PA USA. Dept Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. RP Kessler, DA (reprint author), Univ Penn, Hlth Syst, Dept Oral & Maxillofacial Surg, 3400 Spruce St,White Bldg,5th Floor, Philadelphia, PA USA. EM kesslerd@uphs.upenn.edu; kademani@yahoo.com; roy.feldman@med.va.gov; paut.howlett@med.va.gov NR 7 TC 5 Z9 5 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0266-4356 J9 BRIT J ORAL MAX SURG JI Br. J. Oral Maxillofac. Surg. PD AUG PY 2004 VL 42 IS 4 BP 348 EP 350 DI 10.1016/j.bjoms.2004.03.002 PG 3 WC Dentistry, Oral Surgery & Medicine; Surgery SC Dentistry, Oral Surgery & Medicine; Surgery GA 839CE UT WOS:000222760100015 PM 15225956 ER PT J AU Giza, E Mithofer, K Matthews, H Vrahas, M AF Giza, E Mithofer, K Matthews, H Vrahas, M TI Hip fracture-dislocation in football: a report of two cases and review of the literature SO BRITISH JOURNAL OF SPORTS MEDICINE LA English DT Article ID PROFESSIONAL FOOTBALL; YOUTH SOCCER; INJURIES; PLAYERS AB Soccer is the world's most popular sport, with over 200 million participants world wide. Fractures account for only 4-9% of acute injuries, and hip fracture-dislocation is extremely uncommon. The potentially serious long term sequelae require that team physicians have an awareness of this injury. Two cases of traumatic hip fracture-dislocation are here reported in recreational soccer players sustained by low energy mechanisms. Prompt reduction and fixation are important to produce a stable and congruent joint. C1 Massachusetts Gen Hosp, Harvard Orthopaed Residency Program, Boston, MA 02114 USA. RP Giza, E (reprint author), Massachusetts Gen Hosp, Harvard Orthopaed Residency Program, 25 Fruit St,GRB 624, Boston, MA 02114 USA. EM egiza@partners.org NR 17 TC 18 Z9 19 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-3674 J9 BRIT J SPORT MED JI Br. J. Sports Med. PD AUG 1 PY 2004 VL 38 IS 4 AR e17 DI 10.1136/bjsm.2003.005736 PG 2 WC Sport Sciences SC Sport Sciences GA 840IL UT WOS:000222851200044 PM 15273210 ER PT J AU Shi, HN Walker, A AF Shi, HN Walker, A TI Bacterial colonization and the development of intestinal defences SO CANADIAN JOURNAL OF GASTROENTEROLOGY LA English DT Article; Proceedings Paper CT Canadian Digestive Disease Week CY FEB, 2004 CL Banff, CANADA DE bacterial-epithelial 'cross-talk'; inflammatory bowel disease; innate immunity; intestinal allergy; necrotizing enterocolitis; toll-like receptors ID TOLL-LIKE RECEPTORS; PLACEBO-CONTROLLED TRIAL; REGULATORY T-CELLS; INFLAMMATORY-BOWEL-DISEASE; ORAL TOLERANCE INDUCTION; DENDRITIC CELLS; EPITHELIAL-CELLS; IMMUNE-RESPONSE; DOWN-REGULATION; ATOPIC DISEASE C1 Massachusetts Gen Hosp, Mucosal Immunol Lab, Combined Program Pediat Gastroenterol, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Walker, A (reprint author), Massachusetts Gen Hosp, Mucosal Immunol Lab, Combined Program Pediat Gastroenterol, 114 16th St, Charlestown, MA 02129 USA. EM wwalker@partners.org FU NICHD NIH HHS [R01 HD31852, R37 HD12437]; NIDDK NIH HHS [DK59996, P30-DK40561, P01 DK35506] NR 60 TC 49 Z9 59 U1 1 U2 4 PU PULSUS GROUP INC PI OAKVILLE PA 2902 S SHERIDAN WAY, OAKVILLE, ONTARIO L6J 7L6, CANADA SN 0835-7900 J9 CAN J GASTROENTEROL JI Can. J. Gastroenterol. PD AUG PY 2004 VL 18 IS 8 BP 493 EP 500 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 846HM UT WOS:000223306500002 PM 15372112 ER PT J AU Blanchard, K Colbert, JA Puri, D Weissman, J Moy, B Kopans, DB Kaine, EM Moore, RH Halpern, EF Hughes, KS Tanabe, KK Smith, BL Michaelson, JS AF Blanchard, K Colbert, JA Puri, D Weissman, J Moy, B Kopans, DB Kaine, EM Moore, RH Halpern, EF Hughes, KS Tanabe, KK Smith, BL Michaelson, JS TI Mammographic screening: Patterns of use and estimated impact on breast carcinoma survival SO CANCER LA English DT Article DE breast carcinoma; mammography; screening; disparity AB BACKGROUND. Although many studies support the life-saving potential of. screening mammography, the actual utilization of screening and the impact of the actual pattern of screening use on the breast carcinoma death rate, remain incompletely understood. In the current report, the authors describe patterns of 2 screening use among women who were examined at a large screening and diagnostic service and estimate the added mortality associated with missed screening mammograms. METHODS. Mammography use was assessed in a population of 72,417 women who received a total of 254,818 screening mammograms at the Massachusetts General Hospital (MGH) Avon Comprehensive Breast Center (Boston, MA) between January 1, 1985, and February 19, 2002. A computer simulation of breast carcinoma growth, spread, and detection of breast carcinoma was used to estimate the likely health consequences of various types of screening use. RESULTS. Both prompt return for annual screening and full use of screening over extended periods of time were rare, and comparison of the MGH population with other populations revealed that the low level of use observed in the MGH population was not atypical. Only 6% of women who received a mammogram in 1992 received all annual mammograms that were available over the next 10 years; the mean number of mammograms received during this period was 5.06, or 51% of the number recommended by the American Cancer Society. Computer simulation results indicate that this underutilization of screening should result in higher mortality levels. Women from traditionally underserved socioeconomic, racial, and ethnic groups, women without insurance, and women who did not speak English had lower levels of use compared with other women. Lower levels of use also were observed among women receiving their first mammogram or who in the past had not returned promptly. Women ages 55-65 years had higher levels of use than did younger or older women. Women who previously had breast carcinoma also had higher levels of screening use. Nonetheless, none of the subpopulations of women stratified by age, race, ethnicity, zip code, income, language, insurance, status, previous screening use, or medical history exhibited a widespread propensity to promptly return for annual screening over an extended period of time. CONCLUSIONS. By many measures, the current analysis is one of the most detailed descriptions of screening use to date. The authors observed a level of screening use that was disappointingly low, with potentially negative health-related consequences, among women across categories defined by racial, ethnic, socioeconomic, and geographic characteristics; insurance status; language; age; medical history; and previous screening use. Improvements in the promptness with which women return to screening appear to have the potential to lead to considerable reductions in breast carcinoma death. (C) 2004 American Cancer Society. C1 Massachusetts Gen Hosp, Div Surg Oncol, Dept Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Michaelson, JS (reprint author), Massachusetts Gen Hosp, Div Surg Oncol, Dept Surg, Cox Bldg Room 626,100 Blossom St, Boston, MA 02114 USA. EM michaelj@helix.mgh.harvard.edu OI Hughes, Kevin/0000-0003-4084-6484 NR 0 TC 68 Z9 70 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD AUG 1 PY 2004 VL 101 IS 3 BP 495 EP 507 DI 10.1002/cncr.20392 PG 13 WC Oncology SC Oncology GA 839FX UT WOS:000222770100007 PM 15274062 ER PT J AU Krupski, TL Smith, MR Lee, WC Pashos, CL Brandman, J Wang, Q Botteman, M Litwin, MS AF Krupski, TL Smith, MR Lee, WC Pashos, CL Brandman, J Wang, Q Botteman, M Litwin, MS TI Natural history of bone complications in men with prostate carcinoma initiating androgen deprivation therapy SO CANCER LA English DT Article DE osteoporosis; fractures; androgen ablation; prostate carcinoma ID RADICAL PROSTATECTOMY; HORMONE AGONISTS; MINERAL DENSITY; OSTEOPOROSIS; CANCER; FRACTURES; ORCHIECTOMY; VALIDATION; LENGTH AB BACKGROUND. As evidence accumulates in favor of androgen deprivation therapy (ADT) in patients with recurrent or metastatic prostate carcinoma, concern has increased regarding bone loss associated with therapeutic hypogonadism. The current study described the natural history of bone complications in men with prostate carcinoma who have initiated ADT. METHODS. Using 1992-2001 claims data from a 5% national random sample of Medicare beneficiaries, the authors identified men with prostate carcinoma who initiated ADT between 1992 and 1994. They analyzed inpatient, outpatient, and physician claims for bone complications over 7 subsequent years. They stratified the quartile of patients who survived longest into 2 cohorts: those who had received ADT for longer than and those who had received ADT for shorter than the median of 697 days. They evaluated the cumulative proportions of patients in each cohort with claims for pathologic fractures, osteoporosis/osteopenia, and non-pathologic fractures. RESULTS. In the 1992-1994 sample, 4494 men with prostate carcinoma initiated ADT. Of these, 1126 survived > 2028 days (5.5 years). During the first 3 years of evaluation, the proportion of bone events was similar for men with shorter durations of ADT and men with longer durations of ADT. However, by 7 years, more men in the longer ADT cohort (45%) had sustained at least 1 pathologic or nonpathologic fracture compared with men in the shorter ADT cohort (40%). CONCLUSIONS. In the current study, men with prostate carcinoma were found to be at risk for adverse bone effects from both the disease and the treatment. These longitudinal data revealed that fractures are common in this patient population and appear to be linked to the duration of ADT. (C) 2004 American Cancer Society. C1 Univ Calif Los Angeles, Dept Urol, David Geffen Sch Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Hlth Serv, David Geffen Sch Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90095 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. Abt Assoc Clin Trials, Bethesda, MD USA. Nova Pharmaceut Corp, E Hanover, NJ USA. RP Litwin, MS (reprint author), Univ Calif Los Angeles, Dept Urol, David Geffen Sch Med, POB 951738, Los Angeles, CA 90095 USA. EM mlitwin@mednet.ucla.edu NR 34 TC 67 Z9 69 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD AUG 1 PY 2004 VL 101 IS 3 BP 541 EP 549 DI 10.1002/cncr.20388 PG 9 WC Oncology SC Oncology GA 839FX UT WOS:000222770100012 PM 15274067 ER PT J AU Oyen, W Massuger, L Verheijen, R Seiden, M Benigno, B Lopes, A Soper, J Markowska, J Vyzula, R Lambert, H Epenetos, A AF Oyen, W Massuger, L Verheijen, R Seiden, M Benigno, B Lopes, A Soper, J Markowska, J Vyzula, R Lambert, H Epenetos, A TI Consolidation therapy with intraperitoneal R1549 (yttrium-90-labeled HMFG1 murine monoclonal antibody) in epithelial ovarian cancer: A phase III trial SO CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS LA English DT Meeting Abstract CT 10th Conference on Cancer Therapy with Antibodies and Immunoconjugates CY OCT 20-23, 2004 CL Princeton, NJ SP Bristol Myers Squibb, Berlex, biogen idec, Immunomedics Inc, Ctr Mol Med & Immunol, NCI C1 Univ Nijmegen, Med Ctr, Nijmegen, Netherlands. Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands. Massachusetts Gen Hosp, Boston, MA 02114 USA. Ovarian Canc Inst, Atlanta, GA USA. Queen Elizabeth Hosp, Gateshead, England. Duke Univ, Med Ctr, Durham, NC USA. Poznan Tech Univ, Sch Med, PL-60965 Poznan, Poland. Univ Agr Brno, Ctr Oncol, Brno, Czech Republic. Hammersmith Hosp, London, England. St Bartholomews Hosp, London, England. RI Oyen, Wim/D-4178-2009; Massuger, Leon/H-8072-2014 OI Oyen, Wim/0000-0001-8235-7078; NR 0 TC 1 Z9 1 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1084-9785 J9 CANCER BIOTHER RADIO JI Cancer Biother. Radiopharm. PD AUG PY 2004 VL 19 IS 4 MA 36 BP 528 EP 528 PG 1 WC Oncology; Medicine, Research & Experimental; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Research & Experimental Medicine; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging GA 857KN UT WOS:000224115300049 ER PT J AU Golub, TR AF Golub, TR TI Toward a functional taxonomy of cancer SO CANCER CELL LA English DT Editorial Material ID ACUTE MYELOID-LEUKEMIA; SURVIVAL AB Interrogating the genomes of tumor cells with genomic and proteomic methods is becoming a mainstay of modern cancer classification efforts. This notion is brought to a new level by a paper in the July 23 issue of Cell, in which the dynamic responses of leukemia cells to perturbation are cataloged by flow cytometry, and the leukemias classified in terms of their functional responses. This study paves the way for more systematic attempts to bring functional genomics to the study of human cancer. C1 MIT, Broad Inst, Cambridge, MA 02141 USA. Harvard Univ, Broad Inst, Cambridge, MA 02141 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Howard Hughes Med Inst, Coconut Grove, FL 33133 USA. RP Golub, TR (reprint author), MIT, Broad Inst, Cambridge, MA 02141 USA. EM golub@broad.mit.edu NR 5 TC 9 Z9 10 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD AUG PY 2004 VL 6 IS 2 BP 107 EP 108 DI 10.1016/j.ccr.2004.08.007 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 850DR UT WOS:000223591900003 PM 15324692 ER PT J AU Nakamura, M Kikuchi, T Kufe, DW Ohno, T AF Nakamura, M Kikuchi, T Kufe, DW Ohno, T TI Antitumor effects of fusions composed of dendritic cells and fibroblasts transfected with genomic DNA from tumor cells SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE cancer; dendritic cells; fibroblasts; fusions; tumor immunity ID RECOMBINANT INTERLEUKIN-12; CARCINOMA-CELLS; CANCER-CELLS; GLIOMA-CELLS; IN-VIVO; EX-VIVO; ANTIGEN; GENE; ENHANCEMENT; INDUCTION AB Based on several previous studies indicating that transfection of genomic DNA can stably alter the character of the cells that take up the exogenous DNA, we investigated antitumor immunity conferred by fusions of syngeneic dendritic cells (DCs) and allogeneic fibroblasts (NIH3T3) transfected with genomic DNA from B16 tumor cells. Fusion cells (FCs) composed of dendritic and genetically engineered NIH3T3 cells were prepared with polyethylene glycol, and fusion efficiency was 30.3%. Prior immunization with FCs prevented tumor formation upon challenge with B16 tumor cells. Efficacy was reduced when studies were performed in mice depleted of NK cells. Vaccination with FCs containing DCs and fibroblasts transfected with denatured DNA did not inhibit tumor growth. Cytotoxic T cell (CTL) activity of spleen cells from immunized mice against both Yac-1 and tumor cells was also stimulated by administration of FCs compared with the activity observed for cells obtained from naive mice. These data demonstrate the therapeutic efficacy of fusion cell-based vaccine therapy using syngeneic DCs and allogeneic fibroblasts transfected with tumor-derived genomic DNA. C1 Jikei Univ, Inst DNA Med, Dept Oncol, Minato Ku, Tokyo 1058461, Japan. Jikei Univ, Dept Neurosurg, Tokyo 1058461, Japan. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Kikuchi, T (reprint author), Jikei Univ, Inst DNA Med, Dept Oncol, Minato Ku, 3-25-8 Nishishinbashi, Tokyo 1058461, Japan. EM tkikuchi@jikei.ac.jp NR 23 TC 6 Z9 6 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD AUG PY 2004 VL 53 IS 8 BP 690 EP 696 DI 10.1007/s00262-004-0511-2 PG 7 WC Oncology; Immunology SC Oncology; Immunology GA 832WI UT WOS:000222297900004 PM 15024501 ER PT J AU Georgakoudi, I Solban, N Novak, J Rice, WL Wei, XB Hasan, T Lin, CP AF Georgakoudi, I Solban, N Novak, J Rice, WL Wei, XB Hasan, T Lin, CP TI In vivo flow cytometry: A new method for enumerating circulating cancer cells SO CANCER RESEARCH LA English DT Article ID PROSTATE-CANCER; TUMOR-CELLS; METASTASIS; EXPRESSION; TOMOGRAPHY; BLOOD AB The fate of circulating tumor cells is an important determinant of their ability to form distant metastasis. Here, we demonstrate the use of in VIVO flow cytometry as a powerful new method for detecting quantitatively circulating cancer cells. We specifically examine the circulation kinetics of two prostate cancer cell lines with different metastatic potential in mice and rats. We find that the cell line and the host environment affect the circulation kinetics of prostate cancer cells, with the intrinsic cell line properties determining the initial rate of cell depletion from the circulation and the host affecting cell circulation at later time points. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Georgakoudi, I (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, 40 Blossom St,BHX630, Boston, MA 02114 USA. EM igeorgakoudi@partners.org FU NCI NIH HHS [P01 CA 84203]; NEI NIH HHS [EY 14106, R01 EY014106-01]; NIBIB NIH HHS [EB 00064] NR 19 TC 93 Z9 95 U1 2 U2 17 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2004 VL 64 IS 15 BP 5044 EP 5047 DI 10.1158/0008-5472.CAN-04-1058 PG 4 WC Oncology SC Oncology GA 842XO UT WOS:000223038200003 PM 15289300 ER PT J AU Duensing, A Joseph, NE Medeiros, F Smith, F Hornick, JL Heinrich, MC Corless, CL Demetri, GD Fletcher, CDM Fletcher, JA AF Duensing, A Joseph, NE Medeiros, F Smith, F Hornick, JL Heinrich, MC Corless, CL Demetri, GD Fletcher, CDM Fletcher, JA TI Protein kinase C theta (PKC theta) expression and constitutive activation in gastrointestinal stromal tumors (GISTs) SO CANCER RESEARCH LA English DT Article ID T-CELL SURVIVAL; INTERSTITIAL-CELLS; GENE-EXPRESSION; MUTATIONS; CAJAL; PHOSPHORYLATION; INACTIVATION; ISOFORMS; EFFICACY; SAFETY AB KIT expression is a key diagnostic feature of gastrointestinal stromal tumors (GISTs), and virtually all of the GISTs express oncogenic forms of the KIT or PDGFRA receptor tyrosine kinase proteins, which serve as therapeutic targets of imatinib mesylate (Gleevec; Novartis, Basel, Switzerland). However, KIT expression can be low in PDGFRA-mutant GISTs, increasing the likelihood of misdiagnosis as other types of sarcoma. We report that the signaling intermediate protein kinase C theta (PKCtheta) is a diagnostic marker in GISTs, including those that lack KIT expression and/or contain PDGFRA mutations. PKCtheta is strongly activated in most GISTs and hence may serve, along with KIT/PDGFRA, as a novel therapeutic target. C1 Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Oregon Hlth & Sci Univ, Dept Med, OHSU Canc Inst, Portland, OR USA. Portland VA Med Ctr, Portland, OR USA. Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Duensing, A (reprint author), Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, Res Pavil,Suite 1-8,5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM aduensin@pitt.edu; jfletcher@partners.org OI Duensing, Anette/0000-0002-0168-4067 NR 25 TC 75 Z9 80 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 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2004 VL 64 IS 15 BP 5127 EP 5131 DI 10.1158/0008-5472.CAN-04-0559 PG 5 WC Oncology SC Oncology GA 842XO UT WOS:000223038200018 PM 15289315 ER PT J AU Dimitroff, CJ Lechpammer, M Long-Woodward, D Kutok, JL AF Dimitroff, CJ Lechpammer, M Long-Woodward, D Kutok, JL TI Rolling of human bone-metastatic prostate tumor cells on human bone marrow endothelium under shear flow is mediated by E-selectin SO CANCER RESEARCH LA English DT Article ID CANCER-CELLS; ADHESION MOLECULE-1; PREFERENTIAL ADHESION; HUMAN BREAST; LINES; ANTIGEN; GLYCOPROTEINS; ESTABLISHMENT; MICROVESSELS; INTEGRINS AB Prostate tumor cells preferentially adhere to bone marrow endothelial cells (BMECs) compared with endothelial linings from other tissue microvessels, implicating the importance of BMEC adhesion in the predilection of prostate tumor metastasis to bone. E (endothelial)-sellectin, which functions as an initiator of leukocyte adhesion to target tissue endothelium, is constitutively expressed on BMECs, suggesting that prostate tumor cells could use this adhesive mechanism to initiate their migration into bone. In this report, we demonstrate for the first time that human bone-metastatic prostate tumor cells roll on human BMECs under physiological flow conditions. We show that these dynamic adhesive interactions are dependent on the expression of BMEC E-selectin and sialylated glycoconjugates on bone-metastatic prostate tumor cells. We also establish the importance of both glycoprotein(s) and glycosphingolipid structures displaying sialyl Lewis X epitopes as potential E-selectin ligands on bone-metastatic prostate tumor cells. Coexpression of sialylated glycoproteins and glycolipids on bone-metastatic prostate tumor cells triggers robust E-selectin binding activity, which is identical to that observed on human hematopoietic progenitor cells. By Western blot analysis, we identify candidate E-selectin glycoprotein ligand(s); distinct sialyl Lewis X (or HECA-452 antigen)-bearing membrane proteins were resolved at M, 130,000 and M-r 220,000 as well as others ranging from M-r 100,000 to M-r 220,000. Immunohistochemical analysis of HECA-452 antigen expression on normal prostate tissue and on low- and high-grade prostate adenocarcinoma shows that HECA-452 antigen expression is directly associated with prostate tumor progression and may indicate acquisition of E-selectin ligand expression. These findings provide novel insight into potential adhesive mechanisms promoting hematogenous dissemination of prostate tumor cells into bone. C1 Brigham & Womens Hosp, Harvard Skin Dis Res Ctr, Dept Dermatol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Dimitroff, CJ (reprint author), Harvard Inst Med, Room 650,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM edimitroff@rics.bwh.harvard.edu FU NCI NIH HHS [1R21 CA 102913-01, 1R21 CA 104828-01, CA 06516-37]; NIAMS NIH HHS [5P30 AR 42689-09 004, 5P30 AR 42689] NR 38 TC 84 Z9 86 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2004 VL 64 IS 15 BP 5261 EP 5269 DI 10.1158/0008-5472.CAN-04-0691 PG 9 WC Oncology SC Oncology GA 842XO UT WOS:000223038200035 PM 15289332 ER PT J AU Chauncey, TR AF Chauncey, TR TI Autologous bone marrow transplantation improves disease free survival but not overall survival in people with acute myeloid leukaemia SO CANCER TREATMENT REVIEWS LA English DT Editorial Material ID STEM-CELL TRANSPLANTATION; AML 10 TRIAL; INTENSIVE CHEMOTHERAPY; 1ST REMISSION; POSTREMISSION THERAPY; CURRENT CONTROVERSIES; RECEIVE; VIEW C1 Univ Washington, Sch Med, Fred Hutchinson Canc Res Ctr, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. RP Chauncey, TR (reprint author), Univ Washington, Sch Med, Fred Hutchinson Canc Res Ctr, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. EM tchaunce@u.washington.edu NR 13 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0305-7372 J9 CANCER TREAT REV JI Cancer Treat. Rev. PD AUG PY 2004 VL 30 IS 5 BP 483 EP 487 DI 10.1061/j.ctrv.2004.05.005 PG 5 WC Oncology SC Oncology GA 850NT UT WOS:000223619800009 PM 15245781 ER PT J AU Meyer, AM Dwyer-Nield, LD Hurteau, GJ Keith, RL O'Leary, E You, M Bonventre, JV Nemenoff, RA Malkinson, AM AF Meyer, AM Dwyer-Nield, LD Hurteau, GJ Keith, RL O'Leary, E You, M Bonventre, JV Nemenoff, RA Malkinson, AM TI Decreased lung tumorigenesis in mice genetically deficient in cytosolic phospholipase A(2) SO CARCINOGENESIS LA English DT Article ID PLATELET-ACTIVATING-FACTOR; A/J MICE; CANCER; TUMORS; CELLS; EXPRESSION; GENE; LIPOXYGENASE; INHIBITORS; ACID AB Epidemiological investigations suggest that chronic lung inflammation increases lung cancer risk. Pharmacologic and genetic evidence in mouse models indicates that lipid mediators released during pulmonary inflammation enhance lung tumor formation. Cytosolic phospholipase A(2) (cPLA(2)) catalyzes arachidonic acid (AA) release from membrane phospholipids. AA can then lead to the synthesis of several classes of lipid mediators, including prostaglandin (PG) biosynthesis through the cyclooxygenase (COX) pathway. We investigated a role for cPLA(2) in mouse lung tumorigenesis by using mice genetically deficient in cPLA(2). After multiple urethane injections into cPLA(2) null mice and wild-type littermates, the number of lung tumors was determined. cPLA(2) null mice developed 43% fewer tumors (from 16 +/- 2 to 9 +/- 2 tumors/mouse; P < 0.05) than wild-type littermates. cPLA(2), COX-1, COX-2 and microsomal prostaglandin E-2 synthase (mPGES), examined by immunohistochemistry, are present in alveolar and bronchiolar epithelia and in alveolar macrophages in lungs from naive mice and tumor-bearing mice. Tumors express higher levels of each of these four enzymes than control lungs, as determined by immunoblotting. No differences were detected in the contents of COX-1, COX-2 and mPGES between wild-type and cPLA(2) null mice. Although the steady-state levels of prostaglandin E-2 and prostaglandin I-2 in lung tissue extracts prepared from wild-type or cPLA(2) (-/-) mice were not significantly different, both prostaglandins markedly increased in tumors from wild-type mice, an increase that was significantly blunted in tumors from cPLA(2) (-/-) mice. These results demonstrate a role for cPLA(2) in mouse lung tumorigenesis that may be mediated by decreased prostaglandin synthesis. C1 Univ Colorado, Hlth Sci Ctr, Dept Pharmaceut Sci, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Pharmacol, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80262 USA. Denver VA Med Ctr, Dept Med, Div Pulm Sci & Crit Care Med, Denver, CO 80220 USA. Harvard Univ, Sch Med, Dept Med, Charlestown, MA 02129 USA. Harvard MIT Div Hlth Sci & Technol, Charlestown, MA 02129 USA. Washington Univ, Dept Surg, St Louis, MO 63110 USA. RP Malkinson, AM (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Pharmaceut Sci, 4200 E 9th Ave, Denver, CO 80262 USA. EM al.malkinson@uchsc.edu FU NCI NIH HHS [CA33497, CA58187, CA103618] NR 52 TC 57 Z9 58 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 2004 VL 25 IS 8 BP 1517 EP 1524 DI 10.1093/carcin/bgh150 PG 8 WC Oncology SC Oncology GA 844FJ UT WOS:000223142700024 PM 15033900 ER PT J AU Cai, GF Karni, A Oliveira, EML Weiner, HL Hafler, DA Freeman, GJ AF Cai, GF Karni, A Oliveira, EML Weiner, HL Hafler, DA Freeman, GJ TI PD-1 ligands, negative regulators for activation of naive, memory, and recently activated human CD4(+) T cells SO CELLULAR IMMUNOLOGY LA English DT Article DE PD-1; PD-1 ligand; costimulation; dendritic cells; human T cells; naive T cells; memory T cells; myelin basic protein ID MYELIN BASIC-PROTEIN; SYSTEMIC-LUPUS-ERYTHEMATOSUS; PROGRAMMED DEATH-1 GENE; DENDRITIC CELLS; B7 FAMILY; MULTIPLE-SCLEROSIS; RHEUMATOID-ARTHRITIS; RECEPTOR; COSTIMULATION; EXPRESSION AB We examined the role of the PD-1 pathway on the activation of naive, memory, and recently activated human CD4(+) T cells to test whether they responded differently. PD-1 ligand blockade modestly enhanced the percentage of responding T cells and production of IFN-gamma in a primary response to myelin basic protein (MBP) in normal donors. PD-1 ligand blockade strongly enhanced proliferation and cytokine production by memory or recently activated T cells (tetanus toxoid and MBP). Blockade of PD-L1 alone had more effect than PD-L2, consistent with its higher expression on ex vivo dendritic cells; furthermore, anti-PD-L1 plus anti-PD-L2 resulted in the greatest enhancement. Moreover, PD-L1-Ig inhibited anti-CD3 induced activation of naive, memory, and recently activated CD4+ T cells. Together, our data demonstrated PD-1 functioned as a negative regulatory pathway on naive T cells during a primary response, and more potently, on memory or recently activated T cells during a secondary response. (C) 2004 Elsevier Inc. All rights reserved. C1 Brigham & Womens Hosp, Dept Neurol, Lab Mol Immunol, Boston, MA 02115 USA. Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Freeman, GJ (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM gordon_freeman@dfci.harvard.edu FU NCI NIH HHS [CA84500]; NIAID NIH HHS [P01AI39671, AI39671]; NINDS NIH HHS [NS24247] NR 43 TC 45 Z9 49 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 0008-8749 J9 CELL IMMUNOL JI Cell. Immunol. PD AUG PY 2004 VL 230 IS 2 BP 89 EP 98 DI 10.1016/j.cellimm.2004.09.004 PG 10 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 884TX UT WOS:000226110400003 PM 15598424 ER PT J AU Muza-Moons, MM Schneeberger, EE Hecht, GA AF Muza-Moons, MM Schneeberger, EE Hecht, GA TI Enteropathogenic Escherichia coli infection leads to appearance of aberrant tight junctions strands in the lateral membrane of intestinal epithelial cells SO CELLULAR MICROBIOLOGY LA English DT Article ID MYOSIN LIGHT-CHAIN; TRANSEPITHELIAL ELECTRICAL-RESISTANCE; BINDING PROTEIN-RHO; BARRIER FUNCTION; CLOSTRIDIUM-DIFFICILE; TYROSINE PHOSPHORYLATION; SELECTIVE CHANNELS; SECRETED PROTEIN; CL-SECRETION; HOST-CELLS AB Infection of intestinal epithelial cells with enteropathogenic Escherichia coli (EPEC) disrupts tight junction (TJ) architecture and barrier function. The aim of this study was to determine the impact of EPEC on TJ protein interactions and localization. Human intestinal epithelial cells (T84) were infected for 1, 3 or 6 h with EPEC. To probe the TJ protein-protein interactions, co-immunoprecipitations were performed. The associations between ZO-1, occludin and claudin-1 progressively decreased after infection. Corresponding morphological changes were analysed by immunofluorescence confocal microscopy. Tight junction proteins progressively lost their apically restricted localization. Freeze-fracture electron microscopy revealed the appearance of aberrant strands throughout the lateral membrane that contained claudin-1 and occludin as determined by immunogold labelling. These structural alterations were accompanied by a loss of barrier function. Mutation of the gene encoding EspF, important in the disruption of TJs by EPEC, prevented the disruption of TJs. Tight junction structure normalized following eradication of EPEC with gentamicin and overnight recovery. This is the first demonstration that a microbial pathogen can cause aberrant TJ strands in the lateral membrane of host cells. We speculate that the disruption of integral and cytoplasmic TJ protein interactions following EPEC infection allows TJ strands to form or diffuse into the lateral plasma membrane. C1 Univ Illinois, Dept Med, Sect Digest Dis & Nutr, Chicago, IL 60680 USA. Univ Illinois, Dept Microbiol & Immunol, Chicago, IL 60680 USA. Vet Adm Med Ctr, Chicago, IL USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Hecht, GA (reprint author), Univ Illinois, Dept Med, Sect Digest Dis & Nutr, Chicago, IL 60680 USA. EM gahecht@uic.edu FU NHLBI NIH HHS [HL25822]; NIDDK NIH HHS [DK50694] NR 72 TC 84 Z9 90 U1 2 U2 10 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1462-5814 J9 CELL MICROBIOL JI Cell Microbiol. PD AUG PY 2004 VL 6 IS 8 BP 783 EP 793 DI 10.1111/j.1462-5822.2004.00404.x PG 11 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 835EB UT WOS:000222462200009 PM 15236645 ER PT J AU Barrett, MJ Lacey, CS Sekara, AE Linden, EA Gracely, EJ AF Barrett, MJ Lacey, CS Sekara, AE Linden, EA Gracely, EJ TI Mastering cardiac murmurs - The power of repetition SO CHEST LA English DT Article; Proceedings Paper CT Annual Meeting of the American-College-of-Chest-Physicians CY OCT 25-30, 2003 CL ORLAMDO, FL SP Amer Coll Chest Physicians DE cardiac murmurs; heart auscultation; medical students; teaching ID INTERNAL-MEDICINE; AUSCULTATION; DIAGNOSIS; PATIENT; SKILLS AB Background: The ability of medical students to recognize heart murmurs is poor (20%), and does not improve with subsequent years of training. A teaching method to improve this skill would be useful. Study objectives: To determine whether intensive repetition of four basic cardiac murmurs improves auscultatory proficiency in medical students. Design: Controlled intervention study. Subjects: Fifty-one second-year medical students in an east coast medical school. Interventions: Subjects were classified into three groups: (1) a monitored group, who listened to 500 repetitions of each murmur in a monitored setting, (2) an unmonitored group, who listened to 500 repetitions of each murmur in an unmonitored setting, and (3) a control group. All three groups were tested using a pretest and posttest methodology. Measurements and results: The 20 subjects in the monitored group improved from 13.5 +/- 9.8 to 85 +/- 17.6% following the intervention (mean +/- SD). Similarly, 21 students in the unmonitored group improved from 20.9 +/- 10.9 to 86.1 +/- 15.6%. Ten control students showed no significant improvement (24 +/- 21.7 to 32 +/- 22.5%). The differences between the two intervention groups and the control subjects was significant at p < 0.001 by analysis of variance. Conclusion: Five hundred repetitions of four basic cardiac murmurs significantly improved auscultatory proficiency in recognizing basic cardiac murmurs by medical students. These results suggest that cardiac auscultation is, in part, a technical skill. C1 USAF, Dept Cardiovasc Med & Surg, Travis Base Hosp, Fairfield, CA USA. USAF, Dept Internal Med, Travis Base Hosp, Fairfield, CA USA. USN Hosp, Dept Family Practice, Jacksonville, FL USA. Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. Drexel Univ, Dept Family & Community Med, Coll Med, Philadelphia, PA 19104 USA. RP Barrett, MJ (reprint author), 620 GSB Bldg,1 Belmont Ave, Bala Cynwyd, PA 19004 USA. EM mbarret55@yahoo.com NR 14 TC 31 Z9 32 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD AUG PY 2004 VL 126 IS 2 BP 470 EP 475 DI 10.1378/chest.126.2.470 PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 846CZ UT WOS:000223293900027 PM 15302733 ER PT J AU Harris, RS Hadian, M Hess, DR Chang, YH Venegas, JG AF Harris, RS Hadian, M Hess, DR Chang, YH Venegas, JG TI Pulmonary artery occlusion increases the ratio of diffusing capacity for nitric oxide to carbon monoxide in prone sheep SO CHEST LA English DT Article DE carbon monoxide; diffusing capacity of the lung for CO; diffusing capacity of the lung for nitric oxide; nitric oxide; pulmonary embolism ID CAPILLARY BLOOD-VOLUME; EMBOLISM; LUNGS; HEMOGLOBIN; PRESSURE; EXERCISE; DOGS; FLOW AB Objective: To test the hypothesis that the ratio of diffusing capacity of the lung for nitric oxide (DLNO) to diffusing capacity of the lung for carbon monoxide (DLCO) would be affected by occlusion of a fraction of the pulmonary vascular bed. Design: Interventional physiologic study. Setting: Animal laboratory of a university hospital. Subjects: Thirteen sheep. Interventions: We simultaneously measured single-breath DLNO and DLCO in anesthetized and mechanically ventilated sheep (fraction of inspired oxygen [FIO2] of 1.0) before and after pulmonary artery occlusion by inflation of a balloon (n = 6), and by autologous clot embolism (n = 4). To see if the effect also occurred on FIO2 of 0.21, four animals were studied during ventilation with room air, one of which was also in the FIO2 of 1.0 group (14 total experiments with 13 sheep). Results: On FIO2 of 1.0, the mean DLNO/DLCO ratio rose by 35% from 4.76 +/- 0.41 in control to 6.42 +/- 0.82 after balloon occlusion (p = 0.002), and by 54% from 7.55 +/- 2.09 to 11.6 +/- 2.61 (p = 0.005) after autologous clot embolism (+/- SD). An equivalent relative increase of 27% took place during ventilation with room air, but the DLNO/DLCO ratio was lower (3.14 +/- 0.22 in control and 3.98 +/- 0.38 after balloon occlusion). Independent of the method of obstruction or FIO2, the increase in DLNO/DLCO ratio was mostly due to a drop in DLCO. The DLNO/DLCO ratio reduced much of the intersubject variability of either DLNO or DLCO alone. Conclusion: The DLNO/DLCO ratio increased after pulmonary artery occlusion regardless of the method of occlusion or FIO2. This increase may be a result of a greater sensitivity of DLCO than DLNO to a regional reduction in capillary blood flow. C1 Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Clin Epidemiol Unit, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Harris, RS (reprint author), Massachusetts Gen Hosp, Pulm & Crit Care Unit, Bulfinch 148,55 Fruit St, Boston, MA 02114 USA. EM rharris@partners.org FU NHLBI NIH HHS [HL04501, HL68011] NR 20 TC 8 Z9 8 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD AUG PY 2004 VL 126 IS 2 BP 559 EP 565 DI 10.1378/chest.126.2.559 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 846CZ UT WOS:000223293900039 PM 15302745 ER PT J AU Dhillon, SS Roberto, A AF Dhillon, SS Roberto, A TI A 62-year-old man with shoulder pain SO CHEST LA English DT Editorial Material ID CHEST-WALL; PYOMYOSITIS C1 Baylor Coll Med, Houston Vet Affairs Med Ctr, Houston, TX 77030 USA. RP Dhillon, SS (reprint author), 85 Spring St,3rd Floor, Laconia, NH 03246 USA. EM samjot@yahoo.com OI Dhillon, Samjot/0000-0003-2955-2266 NR 9 TC 1 Z9 1 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD AUG PY 2004 VL 126 IS 2 BP 614 EP 616 DI 10.1378/chest.126.2.614 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 846CZ UT WOS:000223293900045 PM 15302751 ER PT J AU Zhou, W Gurubhagavatula, S Liu, G Park, S Neuberg, DS Wain, JC Lynch, TJ Su, L Christiani, DC AF Zhou, W Gurubhagavatula, S Liu, G Park, S Neuberg, DS Wain, JC Lynch, TJ Su, L Christiani, DC TI Excision repair cross-complementation group 1 polymorphism predicts overall survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy SO CLINICAL CANCER RESEARCH LA English DT Article ID MESSENGER-RNA LEVELS; FLUOROURACIL CHEMOTHERAPY; ERCC1 EXPRESSION; CISPLATIN; GENE; OXALIPLATIN; ASSOCIATION; CARCINOMA; RESISTANT; RISK AB DNA repair is a critical mechanism of resistance to platinum-based chemotherapy. Excision repair cross-complementation group 1 (ERCC1) is the lead enzyme in the nucleotide excision repair process. Increased ERCC1 mRNA levels are related directly to platinum resistance in various cancers. We examined the association between two polymorphisms of ERCC1, codon 118 C/T and C8092A, which are associated with altered ERCC1 mRNA levels and mRNA stability, and overall survival (OS) in 128 advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. The two polymorphisms were in linkage disequilibrium. There was a statistically significant association between the C8092A polymorphism and OS (P = 0.006, by log-rank test), with median survival times of 22.3 (C/C) and 13.4 (C/A or A/A) months, respectively, suggesting that any copies of the A allele were associated with poor outcome. No statistically significant association was found for the codon 118 polymorphism and OS (P = 0.41, by log-rank test), with median survival times of 19.9 (T/T), 16.1 (C/T), and 13.3 (C/C) months, respectively. In conclusion, the ERCC1 C8092A polymorphism may be a useful predictor of OS in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. C1 Harvard Univ, Sch Publ Hlth, Occupat Hlth Program, Dept Environm Hlth, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Occupat Hlth Program, Dept Biostat, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hematol Oncol Unit, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pulm & Crit Care Unit, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Thorac Surg Unit,Dept Surg, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. RP Christiani, DC (reprint author), Harvard Univ, Sch Publ Hlth, Occupat Hlth Program, Dept Environm Hlth, 665 Huntington Ave, Boston, MA 02115 USA. EM dchristi@hsph.harvard.edu RI Liu, Geoffrey/N-4421-2016 FU NCI NIH HHS [CA092824, CA74386, 5T32CA71345-07] NR 23 TC 204 Z9 229 U1 1 U2 4 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 AUG 1 PY 2004 VL 10 IS 15 BP 4939 EP 4943 DI 10.1158/1078-0432.CCR-04-0247 PG 5 WC Oncology SC Oncology GA 845PQ UT WOS:000223257200006 PM 15297394 ER PT J AU Deangelo, DJ Hochberg, EP Alyea, EP Longtine, J Lee, S Galinsky, I Parekkedon, B Ritz, J Antin, JH Stone, RM Soiffer, RJ AF Deangelo, DJ Hochberg, EP Alyea, EP Longtine, J Lee, S Galinsky, I Parekkedon, B Ritz, J Antin, JH Stone, RM Soiffer, RJ TI Extended follow-up of patients treated with imatinib mesylate (Gleevec) for chronic myelogenous leukemia relapse after allogeneic transplantation: Durable cytogenetic remission and conversion to complete donor chimerism without graft-versus-host disease SO CLINICAL CANCER RESEARCH LA English DT Article ID STEM-CELL TRANSPLANTATION; CHRONIC MYELOID-LEUKEMIA; BONE-MARROW TRANSPLANTATION; ABL TYROSINE KINASE; GLIVEC STI571; STI-571; CML; LYMPHOCYTES; INHIBITOR; EFFICACY AB Purpose: Over the last several years, donor lymphocyte infusions have become the standard approach for patients with chronic myelogenous leukemia (CML) who relapse after allogeneic stem cell transplantation (SCT). Recent reports indicate that imatinib mesylate (Gleevec) can induce remissions in these patients as well. Less is known about the extent and durability of these responses. Experimental Design: We studied 15 patients treated with imatinib for recurrent CML after SCT, 10 patients with stable phase CML (SP-CML), 1 with accelerated phase (AP-CML), and 4 with blast phase (BP-CML). The dose of imatinib was 600 mg (n = 10) or 400 mg (n = 5) daily. Patients were followed for hematological, cytogenetic, and molecular response. A susbset of responders was followed for changes in donor-derived hematopoietic chimerism. Results: Of the 10 patients with SP-CML, all achieved a hematological response. Within 3 months, five of these patients had achieved a complete cytogenetic response (CCR). By six months, 9 of 10 patients had achieved CCR. The BCR-ABL transcript could not be detected by reverse transcription-PCR in 7 of these 9 patients. Patients who achieved CCR showed evidence of conversion to complete donor chimerism. No patient developed graft-versus-host disease. With a median follow up of 25 months, all patients are alive and 9 of 10 patients remain in CCR. Only one of the 5 patients with AP/BP-CML achieved a complete cytogenetic response. Conclusions: We find that imatinib is well tolerated in patients with SP-CML who relapse after SCT. Responses were rapid, durable, and associated with conversion to full donor chimerism without graft-versus-host disease. Imantinib was far less effective in patients who relapsed with AP/BP-CML. Imatinib should be evaluated as either an alternative or as an adjunct to donor lymphocyte infusions for patients with SP-CML who relapse after SCT. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Soiffer, RJ (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. EM rsoiffer@partners.org RI Ritz, Jerome/C-7929-2009 OI Ritz, Jerome/0000-0001-5526-4669 NR 23 TC 51 Z9 59 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 AUG 1 PY 2004 VL 10 IS 15 BP 5065 EP 5071 DI 10.1158/1078-0432.CCR-03-0580 PG 7 WC Oncology SC Oncology GA 845PQ UT WOS:000223257200020 PM 15297408 ER PT J AU Chan, AT Tranah, GJ Giovannucci, EL Hunter, DJ Fuchs, CS AF Chan, Andrew T. Tranah, Gregory J. Giovannucci, Edward L. Hunter, David J. Fuchs, Charles S. TI A Prospective Study of Genetic Polymorphisms in the Cytochrome P-450 2C9 Enzyme and the Risk for Distal Colorectal Adenoma SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article AB Background & Aims: Regular aspirin use is associated with a reduced risk for colorectal adenoma, whereas smoking increases risk. The cytochrome P-450 (CYP) 2C9 (CYP2C9) enzyme is involved in the metabolism of several drugs, including possibly aspirin, and such carcinogens as smoking-related polycyclic aromatic hydrocarbons. Genetic variation in this enzyme may modulate the influence of aspirin and smoking on adenoma risk. Methods: We examined the risk for incident distal colorectal adenoma according to CYP2C9 genotype, aspirin use, and smoking in a prospective nested case-control study of women. Results: Among 394 cases and 396 controls, women with at least 1 variant CYP2C9 allele had a significantly greater risk for adenoma (multivariate odds ratio [OR], 1.56; 95% confidence interval [CI], 1.13-2.15; P = 0.007). Although women who used aspirin regularly (>= 2 standard tablets/wk) experienced a lower risk for adenoma compared with non-regular users, the effect was similar irrespective of genotype. Women who smoked >20 pack-years had an OR of adenoma of 1.50 (95% CI, 1.07-2.12; P = 0.02) compared with those who smoked <= 20 pack-years. Among women with at least 1 variant allele who smoked >20 pack-years, the OR of adenoma was 2.50 (95% CI, 1.44-4.38; P = 0.001) compared with women with no variant alleles who smoked <= 20 pack-years. Conclusions: Polymorphisms in the CYP2C9 enzyme are associated with elevated risk for colorectal adenoma. This observation does not appear to be related to modification of the effect of aspirin on adenoma risk, but may be associated with differential metabolism of environmental carcinogens. C1 [Chan, Andrew T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Chan, Andrew T.; Giovannucci, Edward L.; Hunter, David J.; Fuchs, Charles S.] Harvard Univ, Sch Med, Boston, MA USA. [Chan, Andrew T.; Tranah, Gregory J.; Giovannucci, Edward L.; Hunter, David J.; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Tranah, Gregory J.; Giovannucci, Edward L.; Hunter, David J.; Fuchs, Charles S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward L.; Hunter, David J.; Fuchs, Charles S.] Dana Farber Harvard Canc Ctr, Canc Epidemiol Program, Boston, MA USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Chan, AT (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, 55 Fruit St,GRJ-722, Boston, MA 02114 USA. FU National Institutes of Health [HL 34594, CA 87969, CA 55075, CA 09001-27]; National Colorectal Cancer Research Alliance; American Gastroenterological Association/Foundation for Digestive Health and Nutrition Research FX Supported in part by grants no. HL 34594, CA 87969, CA 55075, and CA 09001-27 (to G.J.T.) from the National Institutes of Health; and funds from the National Colorectal Cancer Research Alliance. A.T.C. is a recipient of the American Gastroenterological Association/Foundation for Digestive Health and Nutrition Research Scholar Award. NR 44 TC 31 Z9 32 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD AUG PY 2004 VL 2 IS 8 BP 704 EP 712 DI 10.1053/S1542-3565(04)00294-0 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA V19KT UT WOS:000208072000012 PM 15290664 ER PT J AU Bassett, IV Freedberg, KA Walensky, RP AF Bassett, IV Freedberg, KA Walensky, RP TI Two drugs or three? Balancing efficacy, toxicity, and resistance in postexposure prophylaxis for occupational exposure to HIV SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEALTH-CARE WORKERS; INFECTION; TOLERABILITY; PREVENTION; ADULTS AB Thousands of health care workers are potentially exposed to human immunodeficiency virus (HIV) each year via occupationally acquired needlesticks. The Centers for Disease Control and Prevention (Atlanta, GA) advise health care workers who experience a high-risk occupational exposure from an HIV-infected patient to begin receiving multidrug antiretroviral postexposure prophylaxis (PEP) as soon as possible, preferably within 36 h after exposure. Although the need to prescribe antiretroviral postexposure prophylaxis in a timely fashion is common, few data exist regarding the efficacy and optimal regimen for prophylaxis to prevent transmission. Our objectives were to examine the limited human and animal data on postexposure prophylaxis, to elucidate the factors that affect the choice of 2 versus 3 drugs as the optimal prophylactic drug regimen, and to place these findings within a mathematical framework to help guide the prescription of PEP. C1 Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. RP Bassett, IV (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 55 Fruit St,GRJ 504, Boston, MA 02114 USA. EM ibassett@partners.org OI Walensky, Rochelle P./0000-0002-8795-379X FU NIAID NIH HHS [P30 AI042851, K23 AI001794, 1K23AI01794, R01 AI042006, P30AI42851, R01AI42006] NR 37 TC 46 Z9 47 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 1 PY 2004 VL 39 IS 3 BP 395 EP 401 DI 10.1086/422459 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 839VR UT WOS:000222813500016 PM 15307008 ER PT J AU Jeffcoate, WJ Lipsky, BA AF Jeffcoate, WJ Lipsky, BA TI Controversies in diagnosing and managing osteomyelitis of the foot in diabetes SO CLINICAL INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 5th Annual Almelo Diabetic Foot Symposium CY 2001 CL Almelo, NETHERLANDS ID PERIPHERAL VASCULAR-DISEASE; UNDERLYING OSTEOMYELITIS; CONSERVATIVE MANAGEMENT; COST-EFFECTIVENESS; SOFT-TISSUE; INFECTIONS; ULCERS; FEET; MELLITUS; THERAPY AB The optimal approach to diagnosing and managing osteomyelitis of the foot in diabetes is unclear. Diagnosis is based on clinical signs, supplemented by a variety of imaging tests. Bone biopsy is the accepted criterion standard for diagnosis but is not used by many. Management traditionally involves surgical removal of infected bone, combined with antibiotic therapy. However, recent studies have shown that antibiotics alone may apparently eliminate bone infection in many cases. There is also evidence that early amputation of infected digits is frequently noncurative. Agreement on criteria for diagnosing osteomyelitis is required, and randomized trials are urgently needed, to determine the relative benefits of various surgical interventions and the optimal deployment of antibiotics. We review the microbiology of osteomyelitis of the foot in diabetes, the benefits and limitations of various diagnostic procedures, and the evidence for the effectiveness of both surgical and nonsurgical approaches to management. C1 City Hosp, Dept Endocrinol & Diabet, Nottingham NG5 1PB, England. Univ Washington, Sch Med, Dept Med, Gen Internal Med Clin, Seattle, WA 98195 USA. VA Puget Sound Hlth Care Syst, Antibiot Res Clin, Seattle, WA USA. RP Jeffcoate, WJ (reprint author), City Hosp, Dept Endocrinol & Diabet, Nottingham NG5 1PB, England. EM jeffcoate@bigfoot.com NR 64 TC 80 Z9 82 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 1 PY 2004 VL 39 SU 2 BP S115 EP S122 DI 10.1086/383272 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 839VU UT WOS:000222813800008 PM 15306989 ER PT J AU Lipsky, BA AF Lipsky, BA TI Medical treatment of diabetic foot infections SO CLINICAL INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 5th Annual Almelo Diabetic Foot Symposium CY 2001 CL Almelo, NETHERLANDS ID LOWER-EXTREMITY INFECTIONS; COLONY-STIMULATING FACTOR; HYPERBARIC-OXYGEN THERAPY; OPEN-LABEL TRIAL; STAPHYLOCOCCUS-AUREUS; CHRONIC OSTEOMYELITIS; ANTIBIOTIC-THERAPY; MELLITUS; CIPROFLOXACIN; MANAGEMENT AB Diabetic foot infections frequently cause morbidity, hospitalization, and amputations. Gram-positive cocci, especially staphylococci and also streptococci, are the predominant pathogens. Chronic or previously treated wounds often yield several microbes on culture, including gram-negative bacilli and anaerobes. Optimal culture specimens are wound tissue taken after debridement. Infection of a wound is defined clinically by the presence of purulent discharge or inflammation; systemic signs and symptoms are often lacking. Only infected wounds require antibiotic therapy, and the agents, route, and duration are predicated on the severity of infection. Mild to moderate infections can usually be treated in the outpatient setting with oral agents; severe infections require hospitalization and parenteral therapy. Empirical therapy must cover gram-positive cocci and should be broad spectrum for severe infections. Definitive therapy depends on culture results and the clinical response. Bone infection is particularly difficult to treat and often requires surgery. Several adjuvant agents may be beneficial in some cases. C1 VA Puget Sound Hlth Care Syst, Gen Internal Med Clin, Seattle, WA 98108 USA. Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. RP Lipsky, BA (reprint author), VA Puget Sound Hlth Care Syst, Gen Internal Med Clin, S-111-GIMC,1660 S Columbian Way, Seattle, WA 98108 USA. EM Benjamin.Lipsky@med.va.gov OI Lipsky, Benjamin A./0000-0001-9886-5114 NR 86 TC 62 Z9 65 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 1 PY 2004 VL 39 SU 2 BP S104 EP S114 DI 10.1086/383271 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 839VU UT WOS:000222813800007 PM 15306988 ER PT J AU van Baal, JG Harding, KG Lipsky, BA AF van Baal, JG Harding, KG Lipsky, BA TI Foot infections in diabetic patients: An overview of the problem SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material C1 Twenteborg Hosp, Dept Surg, Diabet Foot Unit, Almelo, Netherlands. Cardiff Medictr, Wound Healing Res Unit, Cardiff, S Glam, Wales. Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. Vet Affairs Puget Sound Hlth Care Syst, Gen Internal Med Clin, Seattle, WA USA. RP van Baal, JG (reprint author), Twenteborg Hosp, Dept Surg, Diabet Foot Unit, Almelo, Netherlands. EM Baal0020@wxs.nl RI Lipsky, Benjamin/B-4645-2013 NR 4 TC 1 Z9 1 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 1 PY 2004 VL 39 SU 2 BP S71 EP S72 DI 10.1086/383265 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 839VU UT WOS:000222813800001 ER PT J AU Leritz, E Loftis, C Crucian, G Friedman, W Bowers, D AF Leritz, E Loftis, C Crucian, G Friedman, W Bowers, D TI Self-awareness of deficits in Parkinson disease SO CLINICAL NEUROPSYCHOLOGIST LA English DT Article ID MINI-MENTAL-STATE; ALZHEIMERS-DISEASE; IMPAIRED AWARENESS; ANOSOGNOSIA; UNAWARENESS; NEUROPSYCHOLOGY; NEGLECT; DEPRESSION; DEMENTIA; SECTION AB Anosognosia is an unawareness or denial of deficits. While it has mainly been associated with damage to cortical brain regions, anosognosia has also been reported in patients with subcortical brain disease, The present study investigated whether anosognosia is a feature of Parkinson disease. Forty-eight Parkinson disease patients with predominantly left- (N = 16) or right-sided (N = 32) motor symptoms who eventually underwent right or left pallidotomies, and 48 individuals identified as caregivers completed questionnaires rating severity of PD. There was no discrepancy in report between patients and caregivers as a function of pallidotomy side. However, as a group, patients rated themselves as significantly less impaired on 2 measures of activities of daily living, indicating that basal ganglia dysfunction may alter insight into severity of illness. Patients and caregivers in the left-symptom PD group differed significantly on selected measures of functional independence. This suggests the potential interaction of laterality and handedness. The importance of future investigations in PD patients with more severe cognitive impairment is stressed. C1 Univ Florida, Inst Brain, Dept Clin & Hlth Psychol, Gainesville, FL USA. Univ Florida, Inst Brain, Dept Neurol, Gainesville, FL USA. Univ Florida, Inst Brain, Dept Neurosurg, Gainesville, FL USA. RP Leritz, E (reprint author), VA Boston Healthcare Syst, Ctr Geriatr Res Educ & Clin, 150 S Huntington Ave, Jamaica Plain, MA 02130 USA. EM bleritz@heartbrain.com NR 43 TC 35 Z9 35 U1 1 U2 3 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 0920-1637 J9 CLIN NEUROPSYCHOL JI Clin. Neuropsychol. PD AUG PY 2004 VL 18 IS 3 BP 352 EP 361 DI 10.1080/1385404049052412 PG 10 WC Psychology, Clinical; Clinical Neurology; Psychology SC Psychology; Neurosciences & Neurology GA 875QP UT WOS:000225437100002 PM 15739807 ER PT J AU Ring, D Kloen, P Kadzielski, J Helfet, D Jupiter, JB AF Ring, D Kloen, P Kadzielski, J Helfet, D Jupiter, JB TI Locking compression plates for osteoporotic nonunions of the diaphyseal humerus SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID ADJUNCTIVE BONE-CEMENT; INTERNAL-FIXATION; PATHOLOGICAL FRACTURES; UNUNITED FRACTURES; SCREW FIXATION; AUGMENTATION; OSTEOSYNTHESIS; SHAFT AB Poor bone quality increases the technical difficulty and complications of operative treatment of nonunions and delayed unions of the diaphyseal humerus in older patients. Plates with screws that lock to the plate (transforming each screw into a fixed blade) are intended to improve the fixation of poor quality bone. Twenty-four patients (20 women, four men) with an average age of 72 years (range, 52-86 years) were followed up for a minimum of 12 months after locking compression plate fixation of an osteopenic delayed union (nine patients) or nonunion (15 patients) of the diaphyseal humerus. Twelve patients had iliac crest cancellous bone grafts, two patients had local graft, and 13 patients had demineralized bone applied to the fracture site. All the fractures eventually healed; two healed after a second procedure for autogenous bone grafting in patients who initially received demineralized bone. Using a modification of the Constant and Murley shoulder score, the results were good or excellent in 22 patients, and fair in two patients. Locking compression plates provide stable fixation of poor quality bone in patients with delayed union or nonunion of the humerus. Successful union and restoration of function are achieved in most patients. We no longer consider osteoporosis a contraindication to operative fixation of an ununited fracture of the humeral diaphysis. C1 Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. Univ Amsterdam, Acad Med Ctr, Dept Orthopaed Surg, NL-1105 AZ Amsterdam, Netherlands. Hosp Special Surg, New York, NY 10021 USA. RP Ring, D (reprint author), ACC 525,15 Parkman St, Boston, MA 02114 USA. EM dring@partners.org NR 29 TC 79 Z9 91 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD AUG PY 2004 IS 425 BP 50 EP 54 DI 10.1097/01.blo.0000131484.27501.4b PG 5 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 845IU UT WOS:000223236800007 PM 15292787 ER PT J AU Mankin, HJ Hornicek, FJ Temple, HT Gebhardt, MC AF Mankin, HJ Hornicek, FJ Temple, HT Gebhardt, MC TI Malignant tumors of the pelvis SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID HINDQUARTER AMPUTATION; LIMB SALVAGE; RESECTION; HEMIPELVECTOMY; RECONSTRUCTION; SARCOMA; CHONDROSARCOMA; NEOPLASMS; SYSTEM; LIFE AB This is a report of outcomes after a review of the demographic, diagnostic, therapeutic, and survival data for patients with pelvic primary and secondary tumors treated during the past 28 years. Using a computerized system it has been possible to assess the results for 206 patients with bone and soft tissue sarcomas and metastatic carcinomas to define the variation in outcome and the factors which statistically show an effect on survival. The data were compared with data for other anatomic sites. Based on our study, it is apparent that the outcome for all the tumors was approximately 50% survival with only soft tissue sarcomas having a poorer result. There were only minimal to moderate differences in outcome on the basis of gender, age, type of surgery, or adjunctive therapy. Patients who had intralesional surgery did less well as did patients with higher Musculoskeletal Tumor Society stages. Comparing the results for these patients with results for patients with the same stage and diagnosis but with tumors located in other sites showed significant differences. Results for patients with pelvic allograft compared with results of patients who had femoral allografts for the same diagnoses showed a poorer outcome for the patients who had pelvic allografts. Several possible explanations are provided for these variations in results. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Orthopaed Oncol Serv, Boston, MA 02114 USA. Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02114 USA. RP Mankin, HJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Orthopaed Oncol Serv, Gray 6 Orthopaed, Boston, MA 02114 USA. EM hmankin@partners.org NR 42 TC 21 Z9 31 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD AUG PY 2004 IS 425 BP 212 EP 217 DI 10.1097/01.blo.0000137241.24906.bf PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 845IU UT WOS:000223236800030 PM 15292810 ER PT J AU Mithofer, K Lhowe, DW Vrahas, MS Altman, DT Altman, GT AF Mithofer, K Lhowe, DW Vrahas, MS Altman, DT Altman, GT TI Clinical spectrum of acute compartment syndrome of the thigh and its relation to associated injuries SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID SKELETAL-MUSCLE; CRUSH SYNDROME; BLUNT TRAUMA; FASCIOTOMY; PRESSURE; ISCHEMIA; LEG; ANTICOAGULATION; ARTHROPLASTY; DIAGNOSIS AB The reason for the described clinical variability of acute compartment syndrome of the thigh, with high morbidity and mortality in some patients and an uncomplicated clinical course in others, is not known. To better define the clinical spectrum and factors determining the clinical course of this rare clinical entity, we did a retrospective multicenter study of 28 patients with 29 thigh compartment syndromes. The leading cause of acute thigh compartment syndrome was blunt trauma from motor vehicle accidents (46%) or contusion (39%). Pain with passive motion was present in all patients who were conscious, followed by paresthesia (60%), and paralysis (42%). The anterior compartment was involved most frequently with mean compartment pressure of 58 3 mm Hg. Myonecrosis, sepsis, and need for skin grafting were observed more frequently in patients with ipsilateral femur fracture. Only 7% of patients with isolated thigh compartment syndromes had short-term complications compared with 57% of patients with ipsilateral femur fractures. The incidence of complications correlated with the time to fasciotomy. Mortality was limited to patients with high injury severity scores. The clinical spectrum of thigh compartment syndrome is comparable with that of other compartment syndromes and its clinical course is determined by its associated injuries. C1 Hosp Special Surg, Dept Orthoped Surg, New York, NY 10021 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Mithofer, K (reprint author), Hosp Special Surg, Dept Orthoped Surg, 535 E 70th St, New York, NY 10021 USA. EM mithoeferk@hss.edu NR 36 TC 38 Z9 40 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD AUG PY 2004 IS 425 BP 223 EP 229 DI 10.1097/01.blo.0000137291.48374.22 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 845IU UT WOS:000223236800032 PM 15292812 ER PT J AU Wong, WC Tolkoff-Rubin, N Delmonico, FL Cardarelli, F Saidman, SL Farrell, ML Shih, V Winkelmayer, WC Cosimi, AB Pascual, M AF Wong, WC Tolkoff-Rubin, N Delmonico, FL Cardarelli, F Saidman, SL Farrell, ML Shih, V Winkelmayer, WC Cosimi, AB Pascual, M TI Analysis of the cardiovascular risk profile in stable kidney transplant recipients after 50% cyclosporine reduction SO CLINICAL TRANSPLANTATION LA English DT Review DE cardiovascular disease; cyclosporine reduction; renal transplantation ID C-REACTIVE PROTEIN; IMPROVED RENAL-FUNCTION; MYCOPHENOLATE-MOFETIL; CHRONIC REJECTION; RANDOMIZED TRIAL; EARLY WITHDRAWAL; HEART-DISEASE; URIC-ACID; SIROLIMUS; PREDICTION AB Background: Long-term use of cyclosporine (CsA) contributes to post-transplant cardiovascular disease (CVD). Hence, a reduction in CsA dosage in kidney transplant recipients (KTR) may improve long-term outcomes. We analyzed the effects of 50% CsA dose reduction on the CVD risk profile in stable KTR. Method: Thirty-one KTR on a regimen of CsA, prednisone and mycophenolate mofetil (MMF) were studied. Patients were randomized to either a) continue their previously determined CsA dose (control group, n = 15) or b) lower their CsA dose by 50% (CsA reduction group, n = 16). Renal function, blood pressure, lipid profile, plasma homocysteine (HCY), C-reactive protein (CRP), fibrinogen, and uric acid were compared at baseline and at 6 months. Results: At 6 months, there was a significant improvement in allograft function, systolic blood pressure, number of anti-hypertensive medications and serum uric acid levels in the CsA reduction group. No significant decrease in plasma HCY, CRP, fibrinogen or improvement in lipid profile was found. In contrast, in the Control group, there was a significant increase in HCY, uric acid, and triglycerides. No acute rejection occurred in either group. Conclusions: A greater reduction in CsA dose could further improve CVD risk profiles, although this may increase the risk of acute or subclinical rejection. C1 Massachusetts Gen Hosp, Transplantat Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Amino Acid Disorder Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02115 USA. CHU Vaudois, CH-1011 Lausanne, Switzerland. Fac Biol & Med, Lausanne, Switzerland. RP Wong, WC (reprint author), Massachusetts Gen Hosp, Transplantat Unit, POB MZ 70,55 Fruit St, Boston, MA 02114 USA. EM wwong@partners.org NR 37 TC 15 Z9 17 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0902-0063 J9 CLIN TRANSPLANT JI Clin. Transplant. PD AUG PY 2004 VL 18 IS 4 BP 341 EP 348 DI 10.1111/j.1399-0012.2004.00171.x PG 8 WC Surgery; Transplantation SC Surgery; Transplantation GA 834NU UT WOS:000222418600001 PM 15233807 ER PT J AU Miller, KK AF Miller, KK TI Management of hyperprolactinemia in patients receiving antipsychotics SO CNS SPECTRUMS LA English DT Article; Proceedings Paper CT 2nd World Congress on Womens Mental Health CY MAR 17-20, 2004 CL Washington, DC ID RISPERIDONE-INDUCED HYPERPROLACTINEMIA; PROLACTIN LEVELS; BREAST-CANCER; SCHIZOPHRENIA; OLANZAPINE AB Hyperprolactinemia is increasingly prevalent in patients with common psychiatric disorders due to increasing prescriptions of antipsychotics, particularly newer atypical neuroleptics, in these patients. However, measurement of prolactin levels is indicated only in symptomatic patients. When hyper-prolactinemia is diagnosed, work-up should include exclusion of other causes of hyperprolactinemia, particularly those that might require treatment. Once such causes have been ruled out, a minority of patients with antipsychotic medication-induced hyperprolactinemia, including those with clinically significant signs and symptoms, will require treatment. When treatment is indicated, specifically when hyperprolactinemia results in amenorrhea in women or testosterone deficiency in men, dopamine agonist therapy is generally not advisable. Hormone-replacement therapy, which involves estrogen/progestogen in women and testosterone in men, can often prevent modification and interruption Of successful psychiatric medication regimens. C1 Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Miller, KK (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, 55 Fruit St,BUL457B, Boston, MA 02114 USA. NR 9 TC 20 Z9 21 U1 0 U2 1 PU M B L COMMUNICATIONS, INC PI NEW YORK PA 333 HUDSON ST, 7TH FLOOR, NEW YORK, NY 10013 USA SN 1092-8529 J9 CNS SPECTRUMS JI CNS Spectr. PD AUG PY 2004 VL 9 IS 8 SU 7 BP 28 EP 32 PG 5 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 896ZE UT WOS:000226972500004 PM 15303078 ER PT J AU Tabin, GC Gurung, R Paudyal, G Reddy, HS Hobbs, CL Wiedman, MS Ruit, S AF Tabin, GC Gurung, R Paudyal, G Reddy, HS Hobbs, CL Wiedman, MS Ruit, S TI Penetrating keratoplasty in Nepal SO CORNEA LA English DT Article DE penetrating keratoplasty; corneal blindness; Nepal; developing nations ID COLLABORATIVE CORNEAL TRANSPLANTATION; BLINDNESS; EPIDEMIOLOGY; PREVALENCE; DIAGNOSIS; OUTCOMES; INDIA AB Purpose: To identify indications and outcomes in a large series of penetrating keratoplasty surgeries performed in Nepal. Methods: A retrospective case series of 472 consecutive penetrating keratoplasty surgeries (408 patients) performed at Tilganga Eye Center, Kathmandu, Nepal from June 1994 to September 1999. Results: Mean recipient age was 39.2 years ( +/- 19.7 years). Main indications for PKP were corneal scar (37%), adherent leukoma (35%), perforation or impending perforation (9%), pseudophakic bultons keratopathy (6%), keratoconus (4%), and aphakic bullous keratopathy (3%). Mean duration of follow-up was 27.6 +/- 25.1 months. Sixty-five percent of available grafts were clear at 6 months, and 70% of available grafts were clear at 3 years. Six months postoperatively, 15% of patients had acuity better than 6/18, 37% had acuity between 6/18 and 6/60, and 17.7% had acuity between 6/60 and 3/60. Common causes of graft failure were endothelial failure (43%), increased intraocular pressure (15%), ulcer (14%), and trauma (7%). Conclusions: The corneal diseases and indications for transplant surgery in Nepal are different from those in the Western world. Despite these differences, penetrating keratoplasty is a successful and reasonable way to reduce corneal blindness in developing nations. Key Words: penetrating keratoplasty, corneal blindness, Nepal, developing nations C1 Univ Vermont, Coll Med, Dept Ophthalmol, Burlington, VT 05401 USA. Tilganga Eye Ctr, Kathmandu, Nepal. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Tabin, GC (reprint author), Univ Vermont, Coll Med, Dept Ophthalmol, 1 S Prospect St,4th Floor, Burlington, VT 05401 USA. EM geoffrey.tabin@vtmednet.org NR 33 TC 19 Z9 20 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3740 J9 CORNEA JI Cornea PD AUG PY 2004 VL 23 IS 6 BP 589 EP 596 DI 10.1097/01.ico.0000121712.36593.0d PG 8 WC Ophthalmology SC Ophthalmology GA 841BO UT WOS:000222904500011 PM 15256998 ER PT J AU Bellomo, R Ronco, C Kellum, JA Mehta, RL Palevsky, P AF Bellomo, R Ronco, C Kellum, JA Mehta, RL Palevsky, P CA ADQI Workgroup TI Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group SO CRITICAL CARE LA English DT Article DE acute renal failure; animal models; creatinine; glomerular filtration rate; information technology; intravenous fluids; kidney; outcome research; randomized controlled trials; urea ID CRITICALLY ILL PATIENTS; OCCULT HYPOPERFUSION; SEPTIC SHOCK; MAJOR TRAUMA; SOFA SCORE; MULTICENTER; PRESSURE; SEPSIS; TRIAL; CARE AB Introduction There is no consensus definition of acute renal failure (ARF) in critically ill patients. More than 30 different definitions have been used in the literature, creating much confusion and making comparisons difficult. Similarly, strong debate exists on the validity and clinical relevance of animal models of ARF; on choices of fluid management and of end-points for trials of new interventions in this field; and on how information technology can be used to assist this process. Accordingly, we sought to review the available evidence, make recommendations and delineate key questions for future studies. Methods We undertook a systematic review of the literature using Medline and PubMed searches. We determined a list of key questions and convened a 2-day consensus conference to develop summary statements via a series of alternating breakout and plenary sessions. In these sessions, we identified supporting evidence and generated recommendations and/or directions for future research. Results We found sufficient consensus on 47 questions to allow the development of recommendations. Importantly, we were able to develop a consensus definition for ARF. In some cases it was also possible to issue useful consensus recommendations for future investigations. We present a summary of the findings. (Full versions of the six workgroups' findings are available on the internet at http://www.ADQI.net) Conclusion Despite limited data, broad areas of consensus exist for the physiological and clinical principles needed to guide the development of consensus recommendations for defining ARF, selection of animal models, methods of monitoring fluid therapy, choice of physiological and clinical end-points for trials, and the possible role of information technology. C1 Austin Hlth, Dept Intens Care & Med, Melbourne, Vic, Australia. San Bortolo Hosp, Dept Nephrol, Vicenza, Italy. Univ Pittsburgh, Med Ctr, Dept Crit Care Med, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Dept Med, Pittsburgh, PA USA. VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. RP Bellomo, R (reprint author), Austin Hlth, Dept Intens Care & Med, Melbourne, Vic, Australia. EM rinaldo.bellomo@austin.org.au NR 45 TC 2598 Z9 2777 U1 23 U2 123 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1466-609X J9 CRIT CARE JI Crit. Care PD AUG PY 2004 VL 8 IS 4 BP R204 EP R212 DI 10.1186/cc2872 PG 9 WC Critical Care Medicine SC General & Internal Medicine GA 846GU UT WOS:000223304600007 PM 15312219 ER PT J AU Tung, RH Garcia, C Morss, AM Pino, RM Fifer, MA Thompson, BT Lewandrowski, K Lee-Lewandrowski, E Januzzi, JL AF Tung, RH Garcia, C Morss, AM Pino, RM Fifer, MA Thompson, BT Lewandrowski, K Lee-Lewandrowski, E Januzzi, JL TI Utility of B-type natriuretic peptide for the evaluation of intensive care unit shock SO CRITICAL CARE MEDICINE LA English DT Article DE congestive heart failure; B-type natriuretic peptide; cardiac hemodynamics; prognosis; shock; pulmonary artery catheterization ID LEFT-VENTRICULAR DYSFUNCTION; ACUTE MYOCARDIAL-INFARCTION; PULMONARY-ARTERY CATHETERS; ACUTE CORONARY SYNDROMES; HEART-FAILURE; CLASSIFICATION-SYSTEM; PROGNOSTIC VALUE; SEPTIC SHOCK; SEPSIS; TROPONIN AB Objectives: Among patients with congestive heart failure, B-type natriuretic peptide measurement is useful to estimate filling pressures and to prognosticate adverse outcome. However, among critically ill intensive care unit patients with shock, the utility of B-type natriuretic peptide to assess cardiac hemodynamics or prognosis has not been explored. Design: Clinical investigation. Setting: Hospital. Patients. Forty-nine patients with shock and indication for pulmonary artery catheterization. Interventions. Analysis for B-type natriuretic peptide was performed on blood obtained at the time of catheter placement. Measurements and Main Results: Correlations between B-type natriuretic peptide and pulmonary artery occlusion pressure as well as cardiac index were calculated using Spearman analysis. Mortality at the time of study completion was correlated with B-type natriuretic peptide values and Acute Physiology and Chronic Health Evaluation II scores, and logistic regression identified independent predictors of mortality. A wide range of B-type natriuretic peptide concentrations was seen in intensive care unit patients (<5 to >5000 pg/mL); only eight patients (16%) had normal B-type natriuretic peptide concentrations. Log-transformed B-type natriuretic peptide concentrations did not correlate with interpatient cardiac index or pulmonary artery occlusion pressure (all p = not significant); however, a B-type natriuretic peptide <350 pg/mL had a negative predictive value of 95% for the diagnosis of cardiogenic shock. Median B-type natriuretic peptide concentrations were higher in those who died than those who survived (943 pg/mL vs. 378 pg/mL, p < .001). In multivariable analysis, a B-type natriuretic peptide concentration in the highest log-quartile was the strongest predictor of mortality (odds ratio = 4.50, 95% confidence interval = 1.87-99.0, p < .001). Conclusion: B-type natriuretic peptide concentrations are frequently elevated among critically ill patients in the intensive care unit and cannot be used as a surrogate for pulmonary artery catheterization. B-type natriuretic peptide concentrations in intensive care unit shock may provide powerful information for use in mortality prediction. C1 Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Lab Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Pulm Crit Care, Boston, MA 02114 USA. RP Tung, RH (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 32 TC 86 Z9 88 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD AUG PY 2004 VL 32 IS 8 BP 1643 EP 1647 DI 10.1097/01.CCM.0000133694.28370.7F PG 5 WC Critical Care Medicine SC General & Internal Medicine GA 847QU UT WOS:000223410800002 PM 15286538 ER PT J AU Zeiher, BG Artigas, A Vincent, JL Dmitrienko, A Jackson, K Thompson, T Bernard, G AF Zeiher, BG Artigas, A Vincent, JL Dmitrienko, A Jackson, K Thompson, T Bernard, G CA STRIVE Study Grp TI Neutrophil elastase inhibition in acute lung injury: Results of the STRIVE study SO CRITICAL CARE MEDICINE LA English DT Article DE acute lung injury; acute respiratory distress syndrome; neutrophil elastase; sivelestat; ONO-5046; mechanical ventilation ID RESPIRATORY-DISTRESS-SYNDROME; VENTILATION; ARDS AB Objective: Neutrophil elastase is believed to be an important mediator of acute lung injury. Sivelestat (ONO-5046, Elaspol) is a small molecular weight inhibitor of neutrophil elastase. The primary objectives of this study were to determine whether sivelestat would reduce 28-day all-cause mortality or increase the number of ventilator-free days (days alive and free from mechanical ventilation from day 1 to day 28) compared with placebo in mechanically ventilated patients with acute lung injury. Design: Multiple-center, double-blind, placebo-controlled trial administering a continuous infusion of sivelestat at a dose of 0.16 mg(.)kg(-1.)hr(-1). Setting: One hundred and five institutions in the United States, Canada, Belgium, Spain, Australia, and New Zealand. Patients: A total of 492 mechanically ventilated patients with acute lung injury. Interventions. Patients were randomized in a 1:1 fashion to sivelestat or placebo. Study drug was administered as a continuous infusion for the duration of mechanical ventilation plus 24 hrs for a maximum of 14 days. All patients were managed using low tidal volume mechanical ventilation. Measurements and Main Results: The study was stopped prematurely at the recommendation of an external Data and Safety Monitoring Board, which noted a negative trend in long-term mortality rate. Final analysis revealed no effect of sivelestat on the primary end points of ventilator-free days (day 1-day 28) or 28-day all-cause mortality. There were 64 deaths in each treatment group within the 28-day study period, and the mean number of ventilator-free days was 11.4 and 11.9 in the sivelestat and placebo treatment groups, respectively (p = .536). There was no evidence of effect on measures of pulmonary function, including Pao(2)/Fi0(2), static lung compliance, and time to meeting weaning criteria. There was no difference in adverse events or serious adverse events between treatment groups. A comparison of the Kaplan-Meier 180-day survival curves showed no difference between treatment groups (p = .102), but there was an increase in 180-day all-cause mortality in the sivelestat treatment group compared with the placebo group (p = .006). Conclusions: Intravenous sivelestat had no effect on 28-day all-cause mortality or ventilator-free days in a heterogeneous acute lung injury patient population managed with low tidal volume mechanical ventilation. C1 Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA. Autonomous Univ Barcelona, Crit Care Ctr, Sabadell Hosp, Parc Tauli Univ Inst,Cellular Biol & Physiol Dept, Red Gira, Sabadell, Spain. Free Univ Brussels, Erasme Hosp, Dept Intens Care, B-1050 Brussels, Belgium. Massachusetts Gen Hosp, Dept Med, Pulm Crit Care Unit, Boston, MA 02114 USA. Vanderbilt Univ, Nashville, TN USA. RP Zeiher, BG (reprint author), Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA. EM bernie_zeiher@lilly.com NR 14 TC 128 Z9 137 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD AUG PY 2004 VL 32 IS 8 BP 1695 EP 1702 DI 10.1097/01.CCM.0000133332.48386.85 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA 847QU UT WOS:000223410800010 PM 15286546 ER PT J AU Sambamurti, K Granholm, AC Kindy, MS Bhat, NR Greig, NH Lahiri, DK Mintzer, JE AF Sambamurti, K Granholm, AC Kindy, MS Bhat, NR Greig, NH Lahiri, DK Mintzer, JE TI Cholesterol and Alzheimer's disease: Clinical and experimental models suggest interactions of different genetic, dietary and environmental risk factors SO CURRENT DRUG TARGETS LA English DT Review DE aging; cognition; diets; dementia; high fats; apolipoprotein E; secretase; myelin; memory ID AMYLOID PRECURSOR PROTEIN; APOLIPOPROTEIN-E GENOTYPE; LOW-DENSITY-LIPOPROTEIN; ALPHA-SECRETASE CLEAVAGE; INSOLUBLE MEMBRANE COMPARTMENT; BETA-PEPTIDE PRODUCTION; TRANSGENIC MOUSE MODEL; NECROSIS-FACTOR-ALPHA; NERVE GROWTH-FACTOR; HIGH-FAT DIETS AB Alzheimer's disease (AD) is a progressive senile dementia characterized by deposition of a 4 kDa peptide of 39-42 residues known as amyloid beta-peptide (AD) in the form of senile plaques and the microtubule associated protein tau as paired helical filaments. Genetic studies have identified mutations in the Abeta precursor protein (APP) as the key triggers for the pathogenesis of AD. Other genes such as presenilins 1 and 2 (PS1/2) and apolipoprotein E (APOE) also play a critical role in increased Abeta deposition. Severial biochemical and molecular studies using transfected cultured cells and transgenic animals point to mechanisms by which AD is generated and aggregated to trigger the neurodegeneration that may cause AD. Three important enzymes collectively known as 'secretases' participate in APP processing leading to the generation of either Abeta or non-amyloid proteins. However, the mechanisms of neurotoxicity of Abeta and the role of APP function in AD remain important unanswered questions. Although early studies recognized the loss of cholesterol and other lipids in the brain, these findings have been poorly connected with AD pathogenesis, despite the identification of the epsilon4 allele of APOE as a major risk factor in AD. The recent finding that cholesterol can modulate the yield of potentially toxic Abeta has boosted research on its role in AD. Consequently, several cholesterol-reducing drugs are currently being evaluated for the treatment of AD. The present review summarizes our current understanding of the relationship of AD pathogenesis with cholesterol, lipids and other genetic and environmental risk factors. C1 Med Univ S Carolina, Dept Physiol & Neurosci, Charleston, SC 29425 USA. Med Univ S Carolina, Ctr Aging, Charleston, SC 29425 USA. Ralph H Johnson VA Med Ctr, Charleston, SC USA. Med Univ S Carolina, Dept Neurol, Charleston, SC 29425 USA. NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. Indiana Univ, Sch Med, Dept Psychiat, Inst Psychiat Res, Indianapolis, IN 46202 USA. Dept Psychiat, N Charleston, SC USA. Ctr Aging, N Charleston, SC USA. RP Sambamurti, K (reprint author), Med Univ S Carolina, Dept Physiol & Neurosci, 173 Ashley Ave,BSB 403, Charleston, SC 29425 USA. EM sambak@musc.edu NR 165 TC 41 Z9 42 U1 1 U2 2 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 1389-4501 J9 CURR DRUG TARGETS JI Curr. Drug Targets PD AUG PY 2004 VL 5 IS 6 BP 517 EP 528 DI 10.2174/1389450043345335 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 836GG UT WOS:000222543200004 PM 15270198 ER PT J AU Mempel, TR Scimone, ML Mora, JR von Andrian, UH AF Mempel, TR Scimone, ML Mora, JR von Andrian, UH TI In vivo imaging of leukocyte trafficking in blood vessels and tissues SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID HIGH ENDOTHELIAL VENULES; GREEN FLUORESCENT PROTEIN; ENDOTOXIN-INDUCED UVEITIS; CELL-ADHESION MOLECULE-1; PERIPHERAL LYMPH-NODES; DENDRITIC CELLS; T-CELLS; P-SELECTIN; INTRAVITAL MICROSCOPY; INVIVO MICROSCOPY AB Selective recruitment of blood-borne leukocytes to tissues and their proper positioning within them is crucial for the many integrated functions of the immune system. Intravital microscopy (IVM) techniques have been employed for more than a century to study these events at the single-cell level in living animals. Conventional video-based IVM allows the visualization of extremely rapid adhesion events at the interface between blood and tissue. Multiphoton IVM is a relatively new tool for imaging the slower dynamics of cell migration and cell-cell interactions in the extravascular space in three dimensions. Fueled by the burgeoning development of sophisticated fluorescent markers and increasingly powerful imaging tools, we are currently witnessing the emergence of a new field in immuno-imaging, in which leukocyte function and cell-cell communication is explored in a truly physiological context. C1 Harvard Univ, Sch Med, CBR Inst Biomed Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Mempel, TR (reprint author), Harvard Univ, Sch Med, CBR Inst Biomed Res, Boston, MA 02115 USA. EM uva@cbr.med.harvard.edu RI von Andrian, Ulrich/A-5775-2008 NR 90 TC 110 Z9 116 U1 2 U2 7 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD AUG PY 2004 VL 16 IS 4 BP 406 EP 417 DI 10.1016/j.coi.2004.05.018 PG 12 WC Immunology SC Immunology GA 841GZ UT WOS:000222919200004 PM 15245733 ER PT J AU del Monte, F Kizana, E Tabchy, A Hajjar, RJ AF del Monte, F Kizana, E Tabchy, A Hajjar, RJ TI Targeted gene transfer in heart failure: Implications for novel gene identification SO CURRENT OPINION IN MOLECULAR THERAPEUTICS LA English DT Article DE adeno-associated virus vector; beta-adrenergic receptor; gene transfer; heart failure; vector delivery ID SEVERE COMBINED IMMUNODEFICIENCY; ADENOASSOCIATED VIRUS VECTORS; IN-VIVO; LENTIVIRAL VECTORS; SUSTAINED EXPRESSION; ADENOVIRAL VECTORS; ARTERIAL-WALL; VIRAL VECTORS; AAV VECTORS; THERAPY AB Heart failure remains an intractable disease with epidemic proportions in the Western World. While progress in conventional treatment modalities for congestive heart failure is making steady and incremental gains to reduce this disease burden, there remains a need to explore new potentially therapeutic approaches. Gene therapy, for example, was initially envisioned as a treatment strategy for inherited monogenic disorders. It is now apparent that gene therapy has broader potential that also includes acquired polygenic diseases, such as heart failure. Advances in the understanding of the molecular basis of congestive heart failure, together with the evolution of increasingly efficient gene transfer technology, has placed congestive heart failure within reach of gene-based therapy. In addition, gene-based reconstitution of a normal phenotype allows us to closely examine the behavior of a large number of transcripts as the heart fails and is rescued by genetic manipulations. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol,Cardiol Lab Integrat Physiol & Imagin, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. Westmead Hosp, Dept Cardiol, Westmead, NSW 2145, Australia. Westmead Hosp, Gene Therapy Res Unit, Westmead, NSW 2145, Australia. MIT, Dept Mech Engn, Cambridge, MA 02139 USA. RP Hajjar, RJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol,Cardiol Lab Integrat Physiol & Imagin, 55 Fruit St, Boston, MA 02115 USA. EM rhajjar@partners.org FU NHLBI NIH HHS [HL 071763, HL069842, HL-057623] NR 86 TC 5 Z9 5 U1 0 U2 2 PU CURRENT DRUGS LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1P 6LB, ENGLAND SN 1464-8431 J9 CURR OPIN MOL THER JI Curr. Opin. Mol. Ther. PD AUG PY 2004 VL 6 IS 4 BP 381 EP 394 PG 14 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 852KM UT WOS:000223754200005 PM 15468597 ER PT J AU van Tuyl, M Blommaart, PE de Boer, PAJ Wert, SE Ruijter, JM Islam, S Schnitzer, J Ellison, AR Tibboel, D Moorman, AFM Lamers, WH AF van Tuyl, M Blommaart, PE de Boer, PAJ Wert, SE Ruijter, JM Islam, S Schnitzer, J Ellison, AR Tibboel, D Moorman, AFM Lamers, WH TI Prenatal exposure to thyroid hormone is necessary for normal postnatal development of murine heart and lungs SO DEVELOPMENTAL BIOLOGY LA English DT Article DE maternal hypothyroidism; lung development; surfactant proteins; heart development; myosin heavy chain ID THYROTROPIN-RELEASING-HORMONE; SURFACTANT PROTEIN-B; FETAL-RAT LUNG; IN-SITU HYBRIDIZATION; ADULT TRANSGENIC MICE; MESSENGER-RNA; SARCOPLASMIC-RETICULUM; CONGENITAL HYPOTHYROIDISM; NA+/CA2+ EXCHANGER; MATERNAL THYROXINE AB Maternal hypothyroxinemia during early pregnancy poses an increased risk for poor neuropsychological development of the fetus. We tested the hypothesis that maternal hypothyroidism before the onset of fetal thyroid function also affects postnatal development of heart and lungs. This question was addressed in transgenic mice that express herpes simplex virus thymidine kinase in their thyroidal follicle cells. Treatment with ganciclovir rendered these mice severely hypothyroid because viral thymidine kinase converts ganciclovir into a cytotoxic nucleoside analog. Since ganciclovir crosses the placenta, it also destroyed the thyroid of transgenic embryos while leaving the thyroids of nontransgenic littermates unaffected. Hypothyroidism of both mother and fetus did not affect prenatal heart and lung development. However, the postnatal switch from beta-to alpha-myosin heavy chain (beta- and alpha-MHC, respectively) gene expression and the increase of SERCA-2a mRNA expression did not occur in the ventricular myocardium of either the transgenic (thyroid destroyed) or nontransgenic (intact thyroid) offspring of hypothyroid mothers. Similarly, postnatal animals of the latter two groups retained elevated surfactant protein (SP) -A, -B, and -C mRNA levels in their alveolar epithelium. In hypothyroid pups from hypothyroid mothers, these changes were accompanied by decreased alveolar septation. Our study shows that these effects of maternal hypothyroidism become manifest after birth and are aggravated by the concomitant existence of neonatal hypothyroidism. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Amsterdam, Acad Med Ctr, Dept Anat & Embryol, NL-1105 AZ Amsterdam, Netherlands. Sophia Chrildrens Hosp, Erasmus Med Ctr, Dept Pediat Surg, NL-3015 GJ Rotterdam, Netherlands. Childrens Hosp, Med Ctr, Div Pulm Biol, Cincinnati, OH 45229 USA. Childrens Hosp, Med Ctr, Div Neonatol, Cincinnati, OH 45229 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Surg Res Labs, Boston, MA 02114 USA. BitTech Inc, Westlake Village, CA 91361 USA. RP Lamers, WH (reprint author), Univ Amsterdam, Dept Anat & Embryol, Room S2-162,Meibergdreef 69-71, NL-1105 BK Amsterdam, Netherlands. EM w.h.lamers@amc.uva.nl RI Lamers, Wouter /D-2965-2012 FU NHLBI NIH HHS [HL56387] NR 69 TC 27 Z9 27 U1 0 U2 3 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 AUG 1 PY 2004 VL 272 IS 1 BP 104 EP 117 DI 10.1016/j.ydbio.2004.03.042 PG 14 WC Developmental Biology SC Developmental Biology GA 838EI UT WOS:000222695900009 PM 15242794 ER PT J AU Carr, DB Utzschneider, KM Hull, RL Kodama, K Retzlaff, BM Brunzell, JD Shofer, JB Fish, BE Knopp, RH Kahn, SE AF Carr, DB Utzschneider, KM Hull, RL Kodama, K Retzlaff, BM Brunzell, JD Shofer, JB Fish, BE Knopp, RH Kahn, SE TI Intra-abdominal fat is a major determinant of the national cholesterol education program adult treatment panel III criteria for the metabolic syndrome SO DIABETES LA English DT Article ID CORONARY-HEART-DISEASE; IMPAIRED GLUCOSE-TOLERANCE; NECROSIS-FACTOR-ALPHA; INSULIN-RESISTANCE; VISCERAL FAT; RISK-FACTORS; ABDOMINAL FAT; DIABETES-MELLITUS; JAPANESE-AMERICANS; ADIPOSE-TISSUE AB The underlying pathophysiology of the metabolic syndrome is the subject of debate, with both insulin resistance and obesity considered as important factors. We evaluated the differential effects of insulin resistance and central body fat distribution in determining the metabolic syndrome as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III. In addition, we determined which NCEP criteria were associated with insulin resistance and central adiposity. The subjects, 218 healthy men (n = 89) and women (n = 129) with a broad range of age (26-75 years) and BMI (18.4-46.8 kg/m(2)), underwent quantification of the insulin sensitivity index (S-i) and intraabdominal fat (IAF) and subcutaneous fat (SCF) areas. The metabolic syndrome was present in 34 (15.6%) of subjects who had a lower S-i [median:3.13 vs. 6.09 x 10(-5) min(-1)/(pmol/l)] and higher IAF (166.3 vs. 79.1 cm(2)) and SCF (285.1 vs. 179.8 cm(2)) areas compared with subjects without the syndrome (P < 0.001). Multivariate models including S-i, IAF, and SCF demonstrated that each parameter was associated with the syndrome. However, LAX was independently associated with all five of the metabolic syndrome criteria. In multivariable models containing the criteria as covariates, waist circumference and triglyceride levels were independently associated with S-i and IAF and SCF areas (P < 0.001). Although insulin resistance and central body fat are both associated with the metabolic syndrome, IAF is independently associated with all of the criteria, suggesting that it may have a pathophysiological role. Of the NCEP criteria, waist circumference and triglycerides may best identify insulin resistance and visceral adiposity in individuals with a fasting plasma glucose < 6.4 mmol/l. C1 Univ Washington, Dept Obstet & Gynecol, Div Maternal Fetal Med, Seattle, WA 98195 USA. Univ Washington, Vet Affairs Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. Univ Washington, Harborview Med Ctr, Seattle, WA 98195 USA. Univ Washington, Dept Rehabil Res & Dev, Seattle, WA 98195 USA. RP Carr, DB (reprint author), Univ Washington, Dept OB GYN, Box 356460, Seattle, WA 98195 USA. EM darcarr@u.washington.edu OI Kahn, Steven/0000-0001-7307-9002; Hull, Rebecca/0000-0001-9690-4087 FU NCRR NIH HHS [RR-16066, RR-37]; NHLBI NIH HHS [HL-30086]; NIDDK NIH HHS [DK-17047, DK-02456, DK-02654, DK-35747, DK-35816, DK-50129] NR 53 TC 471 Z9 518 U1 3 U2 20 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD AUG PY 2004 VL 53 IS 8 BP 2087 EP 2094 DI 10.2337/diabetes.53.8.2087 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 842TL UT WOS:000223027000022 PM 15277390 ER PT J AU Blake, DR Meigs, JB Muller, DC Najjar, SS Andres, R Nathan, DM AF Blake, DR Meigs, JB Muller, DC Najjar, SS Andres, R Nathan, DM TI Impaired glucose tolerance, but not impaired fasting glucose, is associated with increased levels of coronary heart disease risk factors - Results from the Baltimore Longitudinal Study on Aging SO DIABETES LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; INCIDENT CARDIOVASCULAR EVENTS; DEPENDENT DIABETES-MELLITUS; C-REACTIVE PROTEIN; MORTALITY; PROGRAM; ADULTS; ATHEROSCLEROSIS; DIAGNOSIS; PLASMA AB Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) identify individuals at high risk for progression to diabetes. Whether IFG and IGT have comparable coronary heart disease (CHD) risk factor profiles, independent of their progression to diabetes, is unclear. We determined CHD risk factor levels in 937 nondiabetic individuals at baseline and biannually over a mean follow-up period of 9.6 years. Subjects had no known CHD at baseline and had greater than or equal to 2 (mean 4.2) oral glucose tolerance tests during follow-up. We classified glucose tolerance categories using American Diabetes Association diagnostic criteria or modified criteria that redefined IFG as 100-126 mg/dl, creating a similar baseline prevalence of IFG and IGT. Subjects who developed diabetes during follow-up were excluded from our analysis. Baseline CHD risk factors were similar in subjects with normal glucose tolerance (NGT) and IFG, but significantly more atherogenic in those with IGT or IFG + IGT. These findings were unchanged when the modified criteria were used, suggesting that IGT is phenotypically different from IFG and is associated with increased levels of CHD risk factors. Subjects with isolated IFG had similar levels of CHD risk factors as NGT subjects, even when IFG was redefined with a lower threshold. Although CHD risk factors were increased in the IGT group, the incidence of CHD events was not significantly different among groups, perhaps owing to the limited number of events. The differences in CHD risk factors among prediabetic groups may have clinical implications for screening strategies and CHD risk stratification of individuals with IFG and IGT. C1 Massachusetts Gen Hosp, Diabet Unit, Ctr Diabet, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. NIA, Baltimore, MD 21224 USA. RP Nathan, DM (reprint author), Massachusetts Gen Hosp, Diabet Unit, Ctr Diabet, Bulfinch 408, Boston, MA 02114 USA. EM dnathan@partners.org NR 25 TC 92 Z9 102 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD AUG PY 2004 VL 53 IS 8 BP 2095 EP 2100 DI 10.2337/diabetes.53.8.2095 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 842TL UT WOS:000223027000023 PM 15277391 ER PT J AU Bacci, S Menzaghi, C Ercolino, T Ma, XW Rauseo, A Salvemini, L Vigna, C Fanelli, R Di Mario, U Doria, A Trischitta, V AF Bacci, S Menzaghi, C Ercolino, T Ma, XW Rauseo, A Salvemini, L Vigna, C Fanelli, R Di Mario, U Doria, A Trischitta, V TI The +276G/T single nucleotide polymorphism of the adiponectin gene is associated with coronary artery disease in type 2 diabetic patients SO DIABETES CARE LA English DT Article ID INSULIN-RESISTANCE; PLASMA-PROTEIN; CARDIOVASCULAR-DISEASE; RISK-FACTORS; HYPOADIPONECTINEMIA; ATHEROSCLEROSIS; EXPRESSION; MORTALITY; ADIPOSE; OBESITY AB OBJECTIVE- Two single nucleotide polymorphisms (SNPs) at the adiponectin locus (+45>G and +276G>T) have been associated with low circulating adiponectin levels, insulin resistance, and type 2 diabetes. We investigated whether these genetic markers are determinants of coronary artery disease (CAD) in type 2 diabetic patients. RESEARCH DESIGN AND METHODS- A total of 376 consecutive type 2 diabetic patients were studied: 142 case subjects with coronary stenosis >50% or previous myocardial infarction and 234 control subjects with no symptoms, no electrogram (ECG) signs of myocardial ischemia, and a normal ECG stress test (n = 189) and/or (n = 45) with coronary stenosis less than or equal to50%. RESULTS- No association with CAD was observed for the +45 SNP (P = 0.48). By contrast, a significant association was observed for the +276 SNP, with T/T homozygotes having a lower risk of CAD than carriers of other genotypes (adjusted odds ratio [OR] 0.13 [95% CI 0.037-0.46], P = 0.002) Serum adiponectin, although clearly related to several features of the proatherogenic/insulin-resistant phenotype, was not different between control subjects and CAD patients (26 +/- 17 vs. 25 +/- 13 mug/ml). CONCLUSIONS- In conclusion, the +276 G>T polymorphism is a determinant of CAD risk in type 2 diabetic patients. This marker may assist in the identification of diabetic individuals at especially high risk of CAD, so that preventive programs can be targeted at these subjects. C1 Inst Sci, Unit Endocrinol, Casa Sollievo Soffrenza, Cardiovasc & Endocrine Dept, I-71013 San Giovanni Rotondo, Italy. Univ Roma La Sapienza, Dept Clin Sci, Rome, Italy. Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. RP Bacci, S (reprint author), Inst Sci, Unit Endocrinol, Casa Sollievo Soffrenza, Cardiovasc & Endocrine Dept, Viale Cappuccini 1, I-71013 San Giovanni Rotondo, Italy. EM endocrino@operapadrepio.it RI Trischitta, Vincenzo/K-1487-2016; Salvemini, Lucia/K-2121-2016; OI Trischitta, Vincenzo/0000-0003-1174-127X; Salvemini, Lucia/0000-0001-8776-9477; Menzaghi, Claudia/0000-0002-7438-8955 FU NHLBI NIH HHS [HL73168] NR 26 TC 80 Z9 98 U1 0 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD AUG PY 2004 VL 27 IS 8 BP 2015 EP 2020 DI 10.2337/diacare.27.8.2015 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 842TD UT WOS:000223026200026 PM 15277433 ER PT J AU Farnier, M Freeman, M Macdonell, G Perevozskaya, I Davies, M Mitchel, Y Gumbiner, B AF Farnier, M Freeman, M Macdonell, G Perevozskaya, I Davies, M Mitchel, Y Gumbiner, B TI Efficacy and safety of coadministered ezetimibe and fenofibrate in patients with mixed hyperlipidemia SO DIABETOLOGIA LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Association-for-the-Study-of-Diabetes CY SEP 05-09, 2004 CL Munich, GERMANY SP European Assoc Study Diabetes C1 Point Med, Cabinet Endocrinol, Dijon, France. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Merck & Co Inc, Merck Res Labs, Rahway, NJ 07065 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2004 VL 47 SU 1 MA 1144 BP A408 EP A408 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 855CW UT WOS:000223951601142 ER PT J AU Jaeckel, E Manns, MP von Boehmer, H AF Jaeckel, E Manns, MP von Boehmer, H TI Preproinsulin is an important, yet not an essential autoantigen in the pathogenesis of Type 1 diabetes in the NOD mouse SO DIABETOLOGIA LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Association-for-the-Study-of-Diabetes CY SEP 05-09, 2004 CL Munich, GERMANY SP European Assoc Study Diabetes C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Hannover Med Sch, Hannover, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2004 VL 47 SU 1 MA 257 BP A99 EP A99 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 855CW UT WOS:000223951600258 ER PT J AU Kuhl, J Ruderman, NB Musi, N Goodyear, LJ Patti, ME Thorell, A Nygren, J Ljungkvist, O Degerblad, M Stahle, A Brismar, TB Saha, AK Efendic, S Bavenholm, PN AF Kuhl, J Ruderman, NB Musi, N Goodyear, LJ Patti, ME Thorell, A Nygren, J Ljungkvist, O Degerblad, M Stahle, A Brismar, TB Saha, AK Efendic, S Bavenholm, PN TI Exercise training increases activity and mRNA expression of malonyl CoA decarboxylase in human muscle SO DIABETOLOGIA LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Association-for-the-Study-of-Diabetes CY SEP 05-09, 2004 CL Munich, GERMANY SP European Assoc Study Diabetes C1 Karolinska Inst, Ersta Hosp, Stockholm, Sweden. Boston Univ Hosp, Diabet & Metab Unit, Boston, MA USA. Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02115 USA. Karolinska Hosp & Karolinska Inst, Dept Med, S-10401 Stockholm, Sweden. Karolinska Hosp & Karolinska Inst, Dept Diagnost Radiol, S-10401 Stockholm, Sweden. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2004 VL 47 SU 1 MA 679 BP A246 EP A246 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 855CW UT WOS:000223951600679 ER PT J AU Lechner, A Nolan, AL Blacken, RA Habener, JF AF Lechner, A Nolan, AL Blacken, RA Habener, JF TI Insulin-secreting cells differentiated in vitro from expanded human pancreatic islet progenitor cells SO DIABETOLOGIA LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Association-for-the-Study-of-Diabetes CY SEP 05-09, 2004 CL Munich, GERMANY SP European Assoc Study Diabetes C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Howard Hughes Med Inst,Lab Mol Endocrinol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2004 VL 47 SU 1 MA 421 BP A156 EP A156 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 855CW UT WOS:000223951600421 ER PT J AU Nolan, AL Lechner, A Blacken, RA Habener, JF AF Nolan, AL Lechner, A Blacken, RA Habener, JF TI Gene expression profiling of isolated islets of Langerhans treated with glucagon-like peptide-1 (7-36 amide) SO DIABETOLOGIA LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Association-for-the-Study-of-Diabetes CY SEP 05-09, 2004 CL Munich, GERMANY SP European Assoc Study Diabetes C1 Massachusetts Gen Hosp, Lab Mol Endocrinol, Boston, MA 02114 USA. Univ Munich, Klinikum Grosshadern, Munich, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2004 VL 47 SU 1 MA 438 BP A161 EP A162 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 855CW UT WOS:000223951600438 ER PT J AU Sheetz, MJ Aiello, LP Davis, MD Milton, RC Arora, V Hu, K Girach, A Vignati, L AF Sheetz, MJ Aiello, LP Davis, MD Milton, RC Arora, V Hu, K Girach, A Vignati, L TI Diabetic macular edema - relationship of visual acuity to involvement of the center of the macula SO DIABETOLOGIA LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Association-for-the-Study-of-Diabetes CY SEP 05-09, 2004 CL Munich, GERMANY SP European Assoc Study Diabetes C1 Lilly Res Labs, Ruboxistaurin Prod Team, Indianapolis, IN USA. Joslin Diabet Ctr, Sect Eye Res, Boston, MA 02215 USA. Univ Wisconsin, Fundus Photog Reading Ctr, Madison, WI USA. EMMES Corp, Certificat, Rockville, MD USA. Lilly Res Labs, Ruboxistaurin Prod Team, Erl Wood, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2004 VL 47 SU 1 MA 1060 BP A380 EP A380 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 855CW UT WOS:000223951601058 ER PT J AU Bassing, CH Alt, FW AF Bassing, CH Alt, FW TI The cellular response to general and programmed DNA double strand breaks SO DNA REPAIR LA English DT Review DE cellular response; DNA double strand breaks; eukaryotic cells ID CLASS-SWITCH RECOMBINATION; ATM-DEFICIENT MICE; HISTONE H2AX PHOSPHORYLATION; CYTIDINE DEAMINASE AID; V(D)J RECOMBINATION; B-CELLS; GENOMIC INSTABILITY; CHROMOSOMAL TRANSLOCATIONS; ATAXIA-TELANGIECTASIA; TARGETED DISRUPTION AB DNA double strand breaks (DSBs) are among the most dangerous lesions that can occur in the genome of eukaryotic cells. Proper repair of chromosomal DSBs is critical for maintaining cellular viability and genomic integrity and, in multi-cellular organisms, for suppression of tumorigenesis. Thus, eukaryotic cells have evolved specialized and redundant molecular mechanisms to sense, respond to, and repair DSBs. in this chapter, we provide an overview of the progress that has been made over the last decade in elucidating the identity and function of components that participate in the cellular response to chromosomal DSBs. Then, we discuss, in more depth, the response to DSBs that occur in the context of the V(D)J recombination and IgH class switch recombination reactions that occur in cells of the lymphocyte lineage. (C) 2004 Elsevier B.V. All rights reserved. C1 Harvard Univ, Sch Med, Dept Genet, CBR Inst Biomed Res,Childrens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Howard Hughes Med Inst,Childrens Hosp, Boston, MA 02115 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Dept Genet, CBR Inst Biomed Res,Childrens Hosp, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu NR 104 TC 198 Z9 207 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD AUG-SEP PY 2004 VL 3 IS 8-9 BP 781 EP 796 DI 10.1016/j.dnarep.2004.06.001 PG 16 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 850YQ UT WOS:000223650700002 PM 15279764 ER PT J AU Maser, RS DePinho, RA AF Maser, RS DePinho, RA TI Telomeres and the DNA damage response: why the fox is guarding the henhouse SO DNA REPAIR LA English DT Review DE telomeres; DNA damage; DNA repair; checkpoints ID DOUBLE-STRAND BREAKS; NORMAL HUMAN-CELLS; ATAXIA-TELANGIECTASIA FIBROBLASTS; SACCHAROMYCES-CEREVISIAE; LENGTH MAINTENANCE; YEAST KU; LIFE-SPAN; IN-VITRO; MAMMALIAN CHROMOSOMES; MRE11 COMPLEX AB DNA double strand breaks (DSBs) are repaired by an extensive network of proteins that recognize damaged DNA and catalyze its repair. By virtue of their similarity., the normal ends of linear chromosomes and internal DNA DSBs are both potential substrates for DSB repair enzymes. Thus, telomeres, specialized nucleo-protein complexes that cap chromosomal ends, serve a critical function to differentiate themselves from internal DNA strand breaks, and as a result prevent genomic instability that can result from their inappropriate involvement in repair reactions. Telomeres that become critically short due to failure of telomere maintenance mechanisms, or which become dysfunctional by loss of telomere binding proteins, elicit extensive checkpoint responses that in normal cells blocks proliferation. In this situation, the DNA DSB repair machinery plays a major role in responding to these "damaged" telomeres-creating chromosome fusions or capturing telomeres from other chromosomes in an effort to rid the cell of the perceived damage. However, a surprising aspect of telomere maintenance is that many of the same proteins that facilitate this repair of damaged telomeres are also necessary for their proper integrity. Here, we review recent work defining the roles for DSB repair machinery in telomere maintenance and in response to telomere dysfunction. (C) 2004 Elsevier B.V. All rights reserved. C1 Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Maser, RS (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM richard_maser@dfci.harvard.edu RI Maser, Richard/B-2970-2012 NR 100 TC 46 Z9 48 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD AUG-SEP PY 2004 VL 3 IS 8-9 BP 979 EP 988 DI 10.1016/j.dnarep.2004.05.009 PG 10 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 850YQ UT WOS:000223650700022 PM 15279784 ER PT J AU Wang, XZ D'Andrea, AD AF Wang, XZ D'Andrea, AD TI The interplay of Fanconi anemia proteins in the DNA damage response SO DNA REPAIR LA English DT Review DE Fanconi anemia; FANCD2; monoubiquitination; BRCA2; mitomycin C ID DOUBLE-STRAND BREAKS; ATM-DEPENDENT PHOSPHORYLATION; HOMOLOGY-DIRECTED REPAIR; NUCLEAR-COMPLEX; ATAXIA-TELANGIECTASIA; BRCA PATHWAY; CROSS-LINKS; BINDING; FANCD2; RECOMBINATION AB Fanconi anemia (FA) is a rare autosomal recessive disease characterized by chromosome instability and cancer predisposition. At least 11 complementation groups for FA have been identified, and eight FA genes have been cloned. Interestingly, the eight known FA proteins cooperate in a common pathway leading to the interaction of monoubiquitinated FANCD2 and BRCA2 in damaged chromatin. Disruption of this pathway results in the clinical and cellular abnormalities common to all FA subtypes. This review will examine the interaction of the cloned FA proteins with each other and with other DNA damage response proteins (i.e., ATM, ATR, and NBS1). Also, somatic (acquired) disruption of the FA pathway in human tumors appears to account for their chromosome instability and crosslinker hypersensitivity. (C) 2004 Elsevier B.V. All rights reserved. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP D'Andrea, AD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, 44 Binney St, Boston, MA 02115 USA. EM alan_dandrea@dfci.harvard.edu NR 41 TC 50 Z9 54 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD AUG-SEP PY 2004 VL 3 IS 8-9 BP 1063 EP 1069 DI 10.1016/j.dnarep.2004.04.005 PG 7 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 850YQ UT WOS:000223650700032 PM 15279794 ER PT J AU Mitin, T von Moltke, LL Demay, M Court, MH Greenblatt, DJ AF Mitin, T von Moltke, LL Demay, M Court, MH Greenblatt, DJ TI In vivo effect of vitamin D status on interindividual variability in cytochrome P450 3A4 activity SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 Tufts Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Boston, MA 02111 USA. Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 619 BP 309 EP 309 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200615 ER PT J AU von Boehmer, H Nussenzweig, MC AF von Boehmer, H Nussenzweig, MC TI The manipulation of immunity - Conference on From Allergy to Cancer: New Perspectives for Therapeutic Vaccination SO EMBO REPORTS LA English DT Editorial Material DE allergy; cancer; vaccination; tolerance; memory C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA. RP von Boehmer, H (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM harald_von_boehmer@dfci.harvard.edu; nussen@rockefeller.edu NR 7 TC 2 Z9 2 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1469-221X J9 EMBO REP JI EMBO Rep. PD AUG PY 2004 VL 5 IS 8 BP 765 EP 770 DI 10.1038/sj.embor.7400204 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 842LJ UT WOS:000223005400008 PM 15258616 ER PT J AU Noble, VE Brown, DFM AF Noble, VE Brown, DFM TI Renal ultrasound SO EMERGENCY MEDICINE CLINICS OF NORTH AMERICA LA English DT Article ID ACUTE FLANK PAIN; UNENHANCED HELICAL CT; INTRAVENOUS UROGRAPHY; EXCRETORY UROGRAPHY; BLADDER VOLUME; CELL CARCINOMA; EMPHYSEMATOUS PYELONEPHRITIS; INDUCED NEPHROTOXICITY; ULTRASONOGRAPHY; TRACT AB This article discusses the indications for renal ultrasonography and its advantages and disadvantages compared with other diagnostic modalities. In addition, the evidence that supports a role for bedside emergency physician-performed renal ultrasound is discussed. A clinical algorithm for its use in the emergency department is presented, along with a description of how it should be performed and examples of common findings. C1 Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Div Emergency Med, Boston, MA 02115 USA. RP Brown, DFM (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Bulfinch 105, Boston, MA 02114 USA. EM dbrown2@partners.org NR 50 TC 31 Z9 33 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0733-8627 J9 EMERG MED CLIN N AM JI Emerg. Med. Clin. N. Am. PD AUG PY 2004 VL 22 IS 3 BP 641 EP + DI 10.1016/j.emc.2004.04.014 PG 20 WC Emergency Medicine SC Emergency Medicine GA 849GI UT WOS:000223526300005 PM 15301843 ER PT J AU Yuan, BZ Xing, Y Horst, RL Drezner, MK AF Yuan, BZ Xing, Y Horst, RL Drezner, MK TI Evidence for abnormal translational regulation of renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity in the Hyp-mouse SO ENDOCRINOLOGY LA English DT Article ID LINKED HYPOPHOSPHATEMIC RICKETS; 25-HYDROXYVITAMIN D-1-ALPHA-HYDROXYLASE ACTIVITY; VITAMIN-D METABOLISM; SERUM 1,25-DIHYDROXYVITAMIN-D LEVELS; 1-ALPHA-HYDROXYLASE GENE-EXPRESSION; PARATHYROID-HORMONE; MESSENGER-RNA; D-3-1-ALPHA-HYDROXYLASE GENE; CALCITONIN STIMULATION; CALCITRIOL PRODUCTION AB Hyp-mice exhibit abnormal regulation of 25-hydroxyvitamin D [25(OH)D]-1alpha-hydroxylase activity. Previous observations suggest such aberrant modulation is posttranscriptional. To investigate this possibility further, we examined whether hypmice manifest abnormal translation of 25(OH) D-1alpha-hydroxylase mRNA. We compared phosphate, parathyroid, and calcitonin effects on renal 25(OH) D-1alpha-hydroxylase protein as well as mRNA and enzyme activity in normal and hyp-mice. We assayed protein by Western blots, mRNA by real-time RT-PCR, and enzyme activity by measuring 1,25-dihydroxyvitamin D production. Although phosphate-depleted mice exhibited enhanced enzyme function, with significantly increased mRNA and protein expression, hyp-mice comparably increased mRNA but failed to augment enzyme activity, concordant with an inability to increase protein expression. PTH stimulation increased mRNA and protein expression as well as enzyme activity in normal mice but in hyp-mice, despite effecting mRNA enhancement, did not increment enzyme function or protein. The inability of hypophosphatemia and PTH to increase 25(OH)D-1alpha-hydroxylase activity and protein expression in hyp-mice was not universal because calcitonin stimulation was normal, suggesting proximal convoluted tubule localization of the defect. These data, in accord with absent undue enhancement of protein expression in hyp-mice treated with protease inhibitors, establish that abberrant regulation of vitamin D metabolism results from abnormal translational activity. C1 Univ Wisconsin, Sch Med, Dept Med, Clin Sci Ctr H4 554, Madison, WI 53792 USA. Univ Wisconsin Hosp & Clin, William S Middleton Mem Vet Adm Hosp, Ctr Geriatr Res Educ & Clin, Madison, WI 53792 USA. ARS, Natl Anim Dis Ctr, USDA, Ames, IA 50010 USA. RP Drezner, MK (reprint author), Univ Wisconsin, Sch Med, Dept Med, Clin Sci Ctr H4 554, 600 Highland Ave, Madison, WI 53792 USA. EM mkd@medicine.wisc.edu NR 56 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 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD AUG PY 2004 VL 145 IS 8 BP 3804 EP 3812 DI 10.1210/en.2004-0192 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 837XB UT WOS:000222673500036 PM 15265826 ER PT J AU Gonzalez, RR Rueda, BR Ramos, MP Littell, RD Glasser, S Leavis, PC AF Gonzalez, RR Rueda, BR Ramos, MP Littell, RD Glasser, S Leavis, PC TI Leptin-induced increase in leukemia inhibitory factor and its receptor by human endometrium is partially mediated by interleukin 1 receptor signaling SO ENDOCRINOLOGY LA English DT Article ID EMBRYOS IN-VITRO; MENSTRUAL-CYCLE; FACTOR LIF; PREIMPLANTATION DEVELOPMENT; TARGETED DISRUPTION; EPITHELIAL-CELLS; INFERTILE WOMEN; EARLY-PREGNANCY; POTENTIAL ROLE; EXPRESSION AB Leptin and leukemia inhibitory factor (LIF) have been implicated as important mediators of implantation. The present study was designed to investigate whether leptin can directly regulate the expression of LIF and its receptor (LIF-R) in human endometrial cells and/or whether leptin-induced effects are linked to, or regulated in part by IL-1 signaling. Primary endometrial cells and endometrial epithelial cell lines (HES and Ishikawa cells) were cultured for 24 - 48 h in a medium containing insulin ( 5 mug/ml) and leptin ( 3, 10, and 62 nM) or IL-1beta (0.6, 3, and 10 nM) in the presence or absence of cytokines and/or receptor antagonists. The endpoints included phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the relative levels of LIF, LIF-R, IL-1beta, IL-1 receptor antagonist (IL-1Ra) and IL-1 receptor type I (IL-1R tI) as determined by ELISA or Western blotting techniques. Leptin treatment increases the level of phosphorylated STAT3, LIF-R, and LIF. Leptin also increases the levels of IL-1 ligand, receptor, and antagonist as was previously reported. Blockade of OB-R with antibodies or with a specific OB-R inhibitor ( leptin peptide antagonist-2) abrogated leptin-induced effects, suggesting that leptin binding to its receptor activates Janus kinase 2/STAT3 signaling. Treatment of endometrial cells with IL-1beta also results in elevated levels of LIF-R. Interestingly, the inhibition of IL-1R tI with a specific antibody or with IL-1Ra negatively affects both leptin-induced and IL-1-induced effects on LIF-R levels. Abnormal endometrial LIF expression has been associated with human infertility and leptin has profound effects on the levels of LIF, IL-1, and their cognate receptors in vitro. Thus, it is tempting to speculate that leptin's role in vivo could include the regulation of other key cytokines to be fundamental to endometrial receptivity during implantation (i.e. LIF and IL-1). C1 Boston Biomed Res Inst, Watertown, MA 02472 USA. Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. Tufts Univ, Sch Med, Dept Physiol, Boston, MA 02111 USA. RP Gonzalez, RR (reprint author), Boston Biomed Res Inst, 64 Grove St, Watertown, MA 02472 USA. EM gonzalezr@bbri.org NR 59 TC 40 Z9 42 U1 0 U2 2 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 AUG PY 2004 VL 145 IS 8 BP 3850 EP 3857 DI 10.1210/en.2004-0383 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 837XB UT WOS:000222673500041 PM 15142989 ER PT J AU Wang, L Coffinier, C Thomas, MK Gresh, L Eddu, G Manor, T Levitsky, LL Yaniv, M Rhoads, DB AF Wang, L Coffinier, C Thomas, MK Gresh, L Eddu, G Manor, T Levitsky, LL Yaniv, M Rhoads, DB TI Selective deletion of the Hnf1 beta (MODY5) gene in beta-cells leads to altered gene expression and defective insulin release SO ENDOCRINOLOGY LA English DT Article ID HEPATOCYTE NUCLEAR FACTOR-1-BETA; TYPE-2 DIABETES-MELLITUS; TRANSCRIPTION FACTOR; FRAMESHIFT MUTATION; RENAL DYSFUNCTION; MOUSE MODEL; HNF-1-ALPHA; VHNF1; MICE; HNF1 AB Hepatocyte nuclear factor 1alpha (HNF1alpha) and HNF1beta ( or vHNF1) are closely related transcription factors expressed in liver, kidney, gut, and pancreatic beta-cells. Many HNF1 target genes are involved in carbohydrate metabolism. Human mutations in HNF1alpha or HNF1beta lead to maturity-onset diabetes of the young (MODY3 and MODY5, respectively), and patients present with impaired glucose-stimulated insulin secretion. The underlying defect in MODY5 is not known. Analysis of HNF1beta deficiency in mice has not been possible because HNF1beta null mice die in utero. To examine the role of HNF1beta in glucose homeostasis, viable mice deleted for HNF1beta selectively in beta-cells (beta/H1beta-KO mice) were generated using a Cre-LoxP strategy. beta/H1beta-KO mice had normal growth, fertility, fed or fasted plasma glucose and insulin levels, pancreatic insulin content, and insulin sensitivity. However, beta/H1beta-KO mice exhibited impaired glucose tolerance with reduced insulin secretion compared with wild-type mice but preserved a normal insulin secretory response to arginine. Moreover, beta/H1beta-KO islets had increased HNF1alpha and Pdx-1, decreased HNF4 mRNA levels, and reduced glucose-stimulated insulin release. These results indicate that HNF1beta is involved in regulating the beta-cell transcription factor network and is necessary for glucose sensing or glycolytic signaling. C1 Harvard Univ, Sch Med, MassGen Hosp Children, Pediat Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Mol Endocrinol Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. Inst Pasteur, Unite Express Genet & Malad, Ctr Natl Rech Sci 1644, Unite Rech Associee, F-75724 Paris, France. RP Rhoads, DB (reprint author), Harvard Univ, Sch Med, MassGen Hosp Children, Pediat Endocrine Unit, 55 Fruit St BHX410, Boston, MA 02114 USA. EM drhoads@partners.org OI Gresh, Lionel/0000-0002-2333-1748 FU NICHD NIH HHS [HD31215]; NIDDK NIH HHS [DK54399, DK57521] NR 57 TC 47 Z9 47 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 AUG PY 2004 VL 145 IS 8 BP 3941 EP 3949 DI 10.1210/en.2004-0281 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 837XB UT WOS:000222673500051 PM 15142986 ER PT J AU Altshul, L Covaci, A Hauser, R AF Altshul, L Covaci, A Hauser, R TI The relationship between levels of PCBs and pesticides in human hair and blood: Preliminary results SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE exogenous and endogenous contaminants; organochlorines; pesticides; polychlorinated biphenyls (PCBs) ID POLYCHLORINATED-BIPHENYLS; INDOOR AIR; ORGANOCHLORINE PESTICIDES; CORD BLOOD; HUMAN-MILK; HEXACHLOROBENZENE; CONGENERS; POLLUTANTS; POLLUTION; EXPOSURE AB Human hair as a biologic measure of exposure to persistent organic pollutants (POPs) has some advantages over the more commonly used blood and adipose tissue samples. However, one of the primary limitations is the difficulty in distinguishing between exogenous and endogenous contamination. In addition, there are currently no standardized methods for hair sample collection, washing, and chemical analysis. There is also very limited information describing the correlation between levels of organic contaminants in hair and other body compartments. To explore levels of POPs in blood and hair, samples from 10 volunteers were collected and analyzed for select organochlorine pesticides and 57 individual polychlorinated biphenyl (PCB) congeners. We demonstrated that the method for analyzing organic contaminants in human hair was reliable and reproducible. Washing hair with shampoo decreased levels of PCBs, pesticides, and lipids by 25-33% on average and up to 62% for low-chlorinated congeners. The percentage of lipids and the levels of organochlorines in hair were higher than in serum. We found strong correlation (r = 0.8) between p,p'-DDE (dichlorodiphenyldichloroethylene) levels in hair and blood and moderate correlations for the more persistent PCB congeners, but no correlations or weak correlations for other organochlorines. The present study provides preliminary evidence on the utility of hair analysis for Pops; however, further larger studies are recommended before hair analysis can be successfully applied in epidemiologic studies on POPs. C1 Harvard Univ, Sch Publ Hlth, Exposure Epidemiol & Risk Program, Boston, MA 02115 USA. Univ Antwerp, Toxicol Ctr, Antwerp, Belgium. Harvard Univ, Sch Publ Hlth, Occupat Hlth Program, Dept Environm Hlth, Boston, MA USA. Massachusetts Gen Hosp, Androl Lab In Vitro Fertilizat Unit, Vincent Mem Obstet & Gynecol Serv, Boston, MA USA. RP Altshul, L (reprint author), Harvard Univ, Sch Publ Hlth, Exposure Epidemiol & Risk Program, Bldg 1,Room B28,665 Huntington Ave, Boston, MA 02115 USA. EM laltshul@hsph.harvard.edu RI Covaci, Adrian/A-9058-2008 OI Covaci, Adrian/0000-0003-0527-1136 FU NIEHS NIH HHS [5P42 ES 05947, ES 00002, ES 09718] NR 31 TC 79 Z9 81 U1 4 U2 32 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 AUG PY 2004 VL 112 IS 11 BP 1193 EP 1199 DI 10.1289/ehp.6916 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 852GN UT WOS:000223743700040 PM 15289166 ER PT J AU Lee, MLT Whitmore, GA Laden, F Hart, JE Garshick, E AF Lee, MLT Whitmore, GA Laden, F Hart, JE Garshick, E TI Assessing lung cancer risk in railroad workers using a first hitting time regression model SO ENVIRONMETRICS LA English DT Article; Proceedings Paper CT International Workshop on Environment and Health Related Quality of Life CY NOV 07-08, 2002 CL Vannes, FRANCE DE death; disease progression; environmetrics; exposure risk; first hitting time; health status; latent process; lung cancer; stochastic process; survival analysis; Wiener process; work environment ID DIESEL EXHAUST EXPOSURE; RETROSPECTIVE COHORT; MARKER AB This article examines the application of a first hitting time (FHT) model, using an operational time scale, to assess mortality risk differentials of the work environment. A major case application is presented that applies the model to three job categories of railroad workers. The data set involves a study of more than 50000 workers with mortality assessed from 1959 to 1996. Lung cancer mortality was assessed because of a suspected link to diesel exhaust exposure. Based on a model that stipulates that death occurs when the disease state of a subject first hits a threshold value, the FHT model provides insights into factors influencing disease progression. In this application, in particular, the findings suggest that a job category in 1959 alters the risk of death from lung cancer. Copyright (C) 2004 John Wiley Sons, Ltd. C1 Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. McGill Univ, Fac Management, Montreal, PQ, Canada. Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. VA Boston Healthcare Syst, Pulm & Crit Care Med Sect, Boston, MA USA. RP Lee, MLT (reprint author), Brigham & Womens Hosp, Channing Lab, 181 Longwood Ave, Boston, MA 02115 USA. EM stmei@channing.harvard.edu FU NCI NIH HHS [R01 CA079725-02, R01 CA079725, R01 CA079725-01A1, R01 CA079725-03] NR 15 TC 14 Z9 14 U1 0 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1180-4009 J9 ENVIRONMETRICS JI Environmetrics PD AUG PY 2004 VL 15 IS 5 BP 501 EP 512 DI 10.1002/env.683 PG 12 WC Environmental Sciences; Mathematics, Interdisciplinary Applications; Statistics & Probability SC Environmental Sciences & Ecology; Mathematics GA 842WK UT WOS:000223035000012 PM 16741563 ER PT J AU Khan, A Huerter, V Sheikh, SM Thiele, EA AF Khan, A Huerter, V Sheikh, SM Thiele, EA TI Treatments and perceptions of epilepsy in Kashmir and the United States: a cross-cultural analysis SO EPILEPSY & BEHAVIOR LA English DT Article DE epilepsy; cultured perspectives; developing countries; quality of life ID PUBLIC-ATTITUDES; INDIA; CARE; PREVALENCE; KNOWLEDGE; PAKISTAN; PATTERN; STIGMA AB Treatments and perceptions of epilepsy have been found to vary across cultures. This study draws on a comparison of two patient samples, one from the United States (n = 28), the other from Kashmir (n = 29), to gauge the similarities and differences in social perceptions of epilepsy, attitudes toward conventional and alternative treatments, practice of conventional and alternative treatments, and selected quality-of-life issues. While both the Kashmiri and American patients interviewed were prescribed a similar regimen of traditional antiepileptic drugs, a wider range of drugs and treatments were available to and used by the latter. The use of adjunctive spiritual therapies was more prevalent in the Kashmiri sample, and the use of alternative, nonpharmacological therapies was more prevalent in the American sample. Quality of life for the Kashmiri patients sampled was found to be poorer in terms of educational and occupational opportunities, feelings of stigmatization, and openness with others about the illness. Although the two patient populations interviewed differed in their access to resources and approaches to the disorder, both samples were found to be similar overall in many attitudes and practices relating to epilepsy and its treatment. (C) 2004 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Dept Neurol, Pediat Epilepsy Program, Boston, MA 02114 USA. Harvard Univ, Cambridge, MA 02138 USA. Sheri Kashmir Inst Med Sci, Srinagar, Jammu & Kashmir, India. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Thiele, EA (reprint author), Massachusetts Gen Hosp, Dept Neurol, Pediat Epilepsy Program, Boston, MA 02114 USA. EM ethiele@partners.org NR 30 TC 12 Z9 12 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-5050 J9 EPILEPSY BEHAV JI Epilepsy Behav. PD AUG PY 2004 VL 5 IS 4 BP 580 EP 586 DI 10.1016/j.yebeh.2004.04.014 PG 7 WC Behavioral Sciences; Clinical Neurology; Psychiatry SC Behavioral Sciences; Neurosciences & Neurology; Psychiatry GA 840WO UT WOS:000222890800021 PM 15256197 ER PT J AU Aretz, T Keane, D Ammer, R AF Aretz, T Keane, D Ammer, R TI Structural remodelling in atrial fibrillation - role of p38, Bcl2 and estrogen SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT ESC Congress 2004 CY AUG 28-SEP 01, 2004 CL Munich, GERMANY SP ESC C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Cardiol, Boston, MA 02114 USA. Univ Klinikum Muenster, Dept Cardiol, Munster, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG-SEP PY 2004 VL 25 SU S BP 64 EP 64 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 856PG UT WOS:000224056500245 ER PT J AU Wong, M Latini, R Staszewsky, L Masson, S Carretta, E Barlera, S Tognoni, G Cohn, JN AF Wong, M Latini, R Staszewsky, L Masson, S Carretta, E Barlera, S Tognoni, G Cohn, JN CA Val-HeFT Investigators TI Brain natriuretic peptide and symptoms as markers of severity in patients with chronic heart failure: Val-HeFT data SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT ESC Congress 2004 CY AUG 28-SEP 01, 2004 CL Munich, GERMANY SP ESC C1 VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Ist Ric Farmacol Mario Negri, Milan, Italy. Univ Minnesota, Minneapolis, MN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG-SEP PY 2004 VL 25 SU S BP 136 EP 137 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 856PG UT WOS:000224056500541 ER PT J AU Rodriguez, A Alemparte, MR Baldi, J Pereira, CF Vigo, C De la Casa, A Palacios, I Neill, WO AF Rodriguez, A Alemparte, MR Baldi, J Pereira, CF Vigo, C De la Casa, A Palacios, I Neill, WO CA ERAC II Study Investigators TI Five year follow-up of Argentine randomized study of coronary stents vs coronary bypass surgery in multiple vessels diasease SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT ESC Congress 2004 CY AUG 28-SEP 01, 2004 CL Munich, GERMANY SP ESC C1 Otamendi Hosp, Buenos Aires, DF, Argentina. Massachusetts Gen Hosp, Cardiac Unit, Boston, MA 02114 USA. William Beaumont, Cardiol, Ann Arbor, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG-SEP PY 2004 VL 25 SU S BP 309 EP 309 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 856PG UT WOS:000224056501235 ER PT J AU Uemura, T Otsuji, Y Nakashiki, K Yu, B Kisanuki, A Minagoe, S Levine, R Tei, C AF Uemura, T Otsuji, Y Nakashiki, K Yu, B Kisanuki, A Minagoe, S Levine, R Tei, C TI Ischaemic mitral regurgitation is independent of papillary muscle dysfunction: insights from tissue Doppler strain imaging SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT ESC Congress 2004 CY AUG 28-SEP 01, 2004 CL Munich, GERMANY SP ESC C1 Kagoshima Univ, Ctr Cardiovasc, Kagoshima 890, Japan. Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG-SEP PY 2004 VL 25 SU S BP 649 EP 649 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 856PG UT WOS:000224056502596 ER PT J AU Kuwahara, E Otsuji, Y Yuge, K Kisanuki, A Minagoe, M Sakata, R Levine, RA Tei, C AF Kuwahara, E Otsuji, Y Yuge, K Kisanuki, A Minagoe, M Sakata, R Levine, RA Tei, C TI Mechanism of late-onset ischaemic mitral regurgitation following Dors plasty: potential relation to increased left ventricular filling pressure inducing later remodeling SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT ESC Congress 2004 CY AUG 28-SEP 01, 2004 CL Munich, GERMANY SP ESC C1 Kagoshima Univ Hosp, Kagoshima, Japan. Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG-SEP PY 2004 VL 25 SU S BP 650 EP 650 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 856PG UT WOS:000224056502600 ER PT J AU Kathiresan, S Newton-Cheh, C Gerszten, RE AF Kathiresan, S Newton-Cheh, C Gerszten, RE TI On the interpretation of genetic association studies SO EUROPEAN HEART JOURNAL LA English DT Editorial Material ID POPULATION STRATIFICATION; ASP299GLY POLYMORPHISM; MICE C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. Harvard Univ, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02138 USA. MIT, Cambridge, MA 02139 USA. NHLBI, Frmingham Heart Study, Framingham, MA USA. RP Gerszten, RE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, 149 13th St, Charlestown, MA 02129 USA. EM rgerszten@partners.org NR 18 TC 19 Z9 19 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2004 VL 25 IS 16 BP 1378 EP 1381 DI 10.1016/j.ehj.2004.06.035 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 851IZ UT WOS:000223680100004 PM 15321696 ER PT J AU Maehr, R Kraus, M Ploegh, HL AF Maehr, R Kraus, M Ploegh, HL TI Mice deficient in invariant-chain and MHC class II exhibit a normal mature B2 cell compartment SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE B cell development; MHC class II; invariant chain ID MOLECULES; MATURATION; EXPRESSION; SURVIVAL; LACKING; TRAFFICKING; ACTIVATION; RESOLUTION; SELECTION; SUBSETS AB The role of the invariant chain (Ii), an MHC class II-associated chaperone, in B cell development is controversial. Ii deficient mice (Ii(-/-) mice) show a defect in B cell development. This defect has been attributed to the absence of a fragment liberated from the Ii by intramembranous proteolysis. It was proposed that this fragment is required for activation of the NF-kappa B pathway as a means of controlling B cell maturation. The opposing view holds that defects in the assembly of MHC class II molecules result in impaired B cell development. Here we demonstrate that a lack of Ii indeed causes defects in B cell development, with fewer mature B cells in the periphery as previously reported, but that in a compound-mutant from which both Ii and all MHC class II subunits are absent, B cell development is normal. We suggest that neither Ii itself, nor the MHC class II products are required for normal B cell development. C1 Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Ctr Blood Res, Inst Biomed Res, Boston, MA 02115 USA. RP Ploegh, HL (reprint author), Harvard Univ, Sch Med, Dept Pathol, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM ploegh@hms.harvard.edu NR 22 TC 10 Z9 10 U1 0 U2 0 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 AUG PY 2004 VL 34 IS 8 BP 2230 EP 2236 DI 10.1002/eji.200425246 PG 7 WC Immunology SC Immunology GA 844RR UT WOS:000223177800018 PM 15259020 ER PT J AU Karchewski, LA Bloechlinger, S Woolf, CJ AF Karchewski, LA Bloechlinger, S Woolf, CJ TI Axonal injury-dependent induction of the peripheral benzodiazepine receptor in small-diameter adult rat primary sensory neurons SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE axotomy; DBI; DRG; nerve injury; PBR; PK11195 ID DIAZEPAM-BINDING INHIBITOR; ENDOGENOUS LIGANDS; NERVE INJURY; SUBCELLULAR-LOCALIZATION; INDUCED APOPTOSIS; NEUROPATHIC PAIN; MESSENGER-RNA; SCIATIC-NERVE; ANION CHANNEL; DORSAL-ROOT AB The peripheral benzodiazepine receptor (PBR), a benzodiazepine but not gamma-aminobutyric acid-binding mitochondrial membrane protein, has roles in steroid production, energy metabolism, cell survival and growth. PBR expression in the nervous system has been reported in non-neuronal glial and immune cells. We now show expression of both PBR mRNA and protein, and the appearance of binding of a synthetic ligand, [H-3]PK11195, in dorsal root ganglion (DRG) neurons following injury to the sciatic nerve. In naive animals, PBR mRNA, protein expression and ligand binding are undetectable in the DRG. Three days after sciatic nerve transection, however, PBR mRNA begins to be expressed in injured neurons, and 4 weeks after the injury, expression and ligand binding are present in 35% of L4 DRG neurons. PBR ligand binding also appears after injury in the superficial dorsal horn of the spinal cord. The PBR expression in the DRG is restricted to small and medium-sized neurons and returns to naive levels if the injured peripheral axons are allowed to regrow and reinnervate targets. No non-neuronal PBR expression is detected, unlike its putative endogenous ligand the diazepam binding inhibitor (DBI), which is expressed only in non-neuronal cells, including the satellite cells that surround DRG neurons. DBI expression does not change with sciatic nerve transection. PBR acting on small-calibre neurons could play a role in the adaptive survival and growth responses of these cells to injury of their axons. C1 ULP, CNRS, UMR7104, Inst Genet & Biol Mol & Cellulaire, F-67404 Strasbourg, France. Massachusetts Gen Hosp, Neural Plast Res Grp, Dept Anaesthesia & Crit Care, Boston, MA 02129 USA. Harvard Univ, Sch Med, MGH E, Boston, MA 02129 USA. Univ Zurich, Brain Res Inst, Dept Biol, Swiss Fed Inst Technol, CH-8057 Zurich, Switzerland. RP Karchewski, LA (reprint author), ULP, CNRS, UMR7104, Inst Genet & Biol Mol & Cellulaire, Parc Innovat,1 Rue Laurent Fries BP 10142, F-67404 Strasbourg, France. EM lkarch@igbmc.u-strasbg.fr FU NINDS NIH HHS [NS038253] NR 68 TC 37 Z9 38 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD AUG PY 2004 VL 20 IS 3 BP 671 EP 683 DI 10.1111/j.1460-9568.2004.03530.x PG 13 WC Neurosciences SC Neurosciences & Neurology GA 838MA UT WOS:000222716200007 PM 15255978 ER PT J AU Seyedahmadia, BJ Rivolta, C Keene, JA Berson, EL Dryja, TP AF Seyedahmadia, BJ Rivolta, C Keene, JA Berson, EL Dryja, TP TI Comprehensive screening of the USH2A gene in Usher syndrome type II and non-syndromic recessive retinitis pigmentosa SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE Usher syndrome; retinitis pigmentosa; USH2A gene; mutation ID GENOMIC STRUCTURE; HEARING-LOSS; MUTATIONS; IDENTIFICATION; LOCALIZATION; PROTEIN; PERIPHERIN/RDS; CHROMOSOME-11; DOMINANT; MISSENSE AB A screen of the entire coding region of the USH2A gene in 129 unrelated patients with Usher syndrome type II (USH2) and in 146 unrelated patients with non-syndromic autosomal recessive retinitis pigmentosa (ARRP) uncovered 54 different sequence variations, including 18 likely pathogenic mutations (13 frameshift, three nonsense, and two missense), 12 changes of uncertain pathogenicity (II missense changes and one in-frame deletion), and 24 non-pathogenic rare variants or polymorphisms. Of the 18 likely pathogenic mutations, nine were novel. Among the USH2 patients, 50 (39%) had one or two likely pathogenic mutations. The most common mutant allele in USH2 patients was E767fs, which was found in 29 patients, including one homozygote. Among the ARRP patients, we found 17 (12%) with one or two likely pathogenic mutations. The most common mutant allele in ARRP patients was C759F and it was found in 10 patients. The C759F allele was also found in two USH2 patients; in neither of them was a change in the other allele found. The second most common mutant allele in both patient groups was L1447fs (found in 6/50 USH2 patients and 6/17 ARRP patients). Of the 50 + 17 = 67 patients with identified USH2A mutations, only one mutation in one allele was found in 41 + 12 = 53 (79%); the reason for the high proportion of patients with only one identified mutation is obscure. Our results indicate that USH2A mutations are found in about 7% of all cases of RP in North America, a frequency similar to the RPGR gene (8%) and the rhodopsin gene (10%). (C) 2004 Elsevier Ltd. All rights reserved. C1 Harvard Univ, Sch Med, Ocular Mol Genet Inst, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Harvard Univ, Sch Med, Berman Gund Lab Study Retinal Degenerat, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Dryja, TP (reprint author), Harvard Univ, Sch Med, Ocular Mol Genet Inst, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. EM thaddeus_dryja@meei.harvard.edu OI Rivolta, Carlo/0000-0002-0733-9950 FU NEI NIH HHS [EY00169, EY08683] NR 30 TC 49 Z9 56 U1 0 U2 2 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 AUG PY 2004 VL 79 IS 2 BP 167 EP 173 DI 10.1016/j.exer.2004.03.005 PG 7 WC Ophthalmology SC Ophthalmology GA 845CG UT WOS:000223212700003 PM 15325563 ER PT J AU Kevork, HA Ramsey, JJ Weindruch, R AF Kevork, HA Ramsey, JJ Weindruch, R TI Krebs cycle enzymes from livers of old mice are differentially regulated by caloric restriction SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE caloric restriction; Krebs cycle enzymes; liver; aging ID ALPHA-KETOGLUTARATE DEHYDROGENASE; ACETYL-COA CARBOXYLASE; FATTY-ACID SYNTHESIS; GENE-EXPRESSION; PYRUVATE-CARBOXYLASE; PHOSPHOENOLPYRUVATE CARBOXYKINASE; MITOCHONDRIAL ACONITASE; MULTIPLE TRANSCRIPTS; ALTERNATE PROMOTERS; OXIDATIVE DAMAGE AB Krebs cycle enzyme activities and levels of five metabolites were determined from livers of old mice (30 months) maintained either on control or on long-term caloric restriction (CR) diets (28 months). In CR mice, the cycle was divided into two major blocks, the first containing citrate synthase, aconitase and NAD-dependent isocitrate dehydrogenase which showed decreased activities, while the second block, containing the remaining enzymes, displayed increased activity (except for fumarase, which was unchanged). CR also resulted in decreased levels of citrate, glutamate and alpha-ketoglutarate, increased levels of malate, and unchanged levels of aspartate. The alpha-ketoglutarate/glutamate and malate/alpha-ketoglutarate ratios were higher in CR, in parallel with previously reported increases with CR in pyruvate carboxylase activity and glucagon levels, respectively. The results indicate that long-term CR induces a differential regulation of Krebs cycle in old mice and this regulation may be the result of changes in gene expression levels, as well as a complex interplay between enzymes. hormones and other effectors. Truncation of Krebs cycle by CR may be an important adaptation to utilize available substrates for the gluconeogenesis necessary to sustain glycolytic tissues, such as brain. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Calif Davis, Dept Mol Biosci, Sch Vet Med, Davis, CA 95616 USA. Univ Wisconsin, Sch Med, Dept Med, Madison, WI 53706 USA. William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI 53705 USA. Univ Wisconsin, Wisconsin Reg Primate Res Ctr, Madison, WI 53715 USA. RP Kevork, HA (reprint author), Univ Calif Davis, Dept Mol Biosci, Sch Vet Med, 1 Shields Ave, Davis, CA 95616 USA. EM khagopian@ucdavis.edu NR 58 TC 0 Z9 0 U1 0 U2 3 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 AUG PY 2004 VL 39 IS 8 BP 1145 EP 1154 DI 10.1016/j.exger.2004.04.009 PG 10 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 848VZ UT WOS:000223497500004 ER PT J AU Wen, PH Hof, PR Chen, XP Gluck, K Austin, G Younkin, SG Younkin, LH DeGasperi, R Sosa, MAG Robakis, NK Haroutunian, V Elder, GA AF Wen, PH Hof, PR Chen, XP Gluck, K Austin, G Younkin, SG Younkin, LH DeGasperi, R Sosa, MAG Robakis, NK Haroutunian, V Elder, GA TI The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice SO EXPERIMENTAL NEUROLOGY LA English DT Article DE presenilin 1; familial Alzheimer disease; bromodeoxyuridine ID AMYLOID-BETA-PROTEIN; GENERATED GRANULE CELLS; DENTATE GYRUS; TRANSGENIC MICE; SUBVENTRICULAR ZONE; GENETIC INFLUENCE; PROGENITOR CELLS; RAT HIPPOCAMPUS; SENILE PLAQUES; SPINAL-CORD AB The functions of presenilin 1 (PS1) and how PS1 mutations cause familial Alzheimer's disease (FAD) are incompletely understood. PS1 expression is essential for neurogenesis during embryonic development and may also influence neurogenesis in adult brain. We examined how increasing PS1 expression or expressing an FAD mutant would affect neurogenesis in the adult hippocampus. A neuron-specific enolase (NSE) promoter was used to drive neuronal overexpression of either wild-type human PS1 or the FAD mutant P117L in transgenic mice, and the animals were studied under standard-housing conditions or after environmental enrichment. As judged by bromodeoxyuridine (BrdU) labeling, neural progenitor proliferation rate was mostly unaffected by increasing expression of either wild-type or FAD mutant PS1. However, in both housing conditions, the FAD mutant impaired the survival of BrdU-Iabeled neural progenitor cells leading to fewer new beta-III-tubulin-immunoreactive neurons being generated in FAD mutant animals during the 4-week postlabeling period. The effect was FAD mutant specific in that neural progenitor survival and differentiation in mice overexpressing wild-type human PS1 were similar to nontransgenic controls. Two additional lines of PS1 wild-type and FAD mutant transgenic mice showed similar changes indicating that the effects were not integration site-dependent. These studies demonstrate that a PS1 FAD mutant impairs new neuron production in adult hippocampus by decreasing neural progenitor survival. They also identify a new mechanism whereby PS1 FAD mutants may impair normal neuronal function and may have implications for the physiological functioning of the hippocampus in FAD. (C) 2004 Elsevier Inc. All rights reserved. C1 Bronx Vet Adm Med Ctr, Psychiat Res Serv, Bronx, NY 10468 USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. Mt Sinai Sch Med, Kastor Neurobiol Aging Labs, New York, NY 10029 USA. Mt Sinai Sch Med, Fishberg Res Ctr Neurobiol, New York, NY 10029 USA. Mt Sinai Sch Med, Dept Geriatr & Adult Dev, New York, NY 10029 USA. Mayo Clin Jacksonville, Jacksonville, FL 32224 USA. RP Elder, GA (reprint author), Bronx Vet Adm Med Ctr, Psychiat Res Serv, 3F22,130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM gregory.elder@mssm.edu FU NIA NIH HHS [P50 AG05138, R01 AG17926, R01 AG20139] NR 79 TC 114 Z9 119 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD AUG PY 2004 VL 188 IS 2 BP 224 EP 237 DI 10.1016/j.expneurol.2004.04.002 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 838PX UT WOS:000222726500005 PM 15246822 ER PT J AU Ayasolla, K Khan, M Singh, AK Singh, I AF Ayasolla, K Khan, M Singh, AK Singh, I TI Inflammatory mediator and beta-amyloid (25-35)-induced ceramide generation and iNOS expression are inhibited by vitamin E SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Alzheimer disease; inducible nitric oxide synthase; vitamin E; amyloid peptide; ceramide; reactive oxygen species; CCAAT enhancer binding proteins; free radicals ID NITRIC-OXIDE SYNTHASE; NF-KAPPA-B; NECROSIS-FACTOR-ALPHA; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; NEUTRAL SPHINGOMYELINASE; SPHINGOLIPID METABOLISM; GENE-TRANSCRIPTION; GLIAL-CELLS; ASTROCYTES AB To investigate the putative role of beta-amyloid peptide (Abeta) in inducing oxidative stress damage in Alzheimer disease (AD), we studied the effects of proinflammatory cytokines and Abeta peptide on the induction of inducible nitric oxide synthase (iNOS). Abeta(25-35) upregulated the cytokine (TNF-alpha/IL-1beta)-induced expression of iNOS and the production of nitric oxide (NO) in astrocytes, which were inhibited by vitamin E. Abeta treatment of C6 glial cells (together with LPS and IFN-gamma), in addition to inducing iNOS, enhanced the oxidative stress as measured by increased expression of manganese superoxide dismutase and an increase in 2,7'-dichlorofluorescein diacetate fluorescence. We also observed that LPS, IFN-gamma, and Abeta(25-35) treatment led to the activation of the sphingomyelin-ceramide (SM-Cer) cascade with an increase in cellular ceramide. Inhibition of the SM-Cer cascade either by vitamin E treatment or by the neutral sphingomyelinase inhibitor 3-O-methyl sphingomyelin also resulted in alteration of the transcriptional binding activities of C/EBP, NFkappaB, AP-1, and CREB in C6 glial cells. Hence, these findings suggest a role for ceramide in iNOS induction and NO production in Abeta-induced AD pathobiology and provide a possible explanation for the beneficial effects of vitamin E therapy. (C) 2004 Elsevier Inc. All rights reserved. C1 Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Pathol, Charleston, SC 29425 USA. Ralph H Johnson VA Med Ctr, Charleston, SC 29425 USA. RP Singh, I (reprint author), Med Univ S Carolina, Childrens Hosp, 316 CSB,96 Jonathan Lucas St, Charleston, SC 29425 USA. EM singhi@muse.edu OI Ayasolla, kameshwar/0000-0002-4265-2168 FU NINDS NIH HHS [NS-34741, NS-22576, NS-37766, NS-40144] NR 50 TC 73 Z9 81 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG 1 PY 2004 VL 37 IS 3 BP 325 EP 338 DI 10.1016/j.freeadbiomed.2004.04.007 PG 14 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 838VG UT WOS:000222740800004 PM 15223066 ER PT J AU Spiegel, BMR Targownik, LE Kanwal, F Derosa, V Dulai, GS Gralnek, IM Chiou, CF AF Spiegel, BMR Targownik, LE Kanwal, F Derosa, V Dulai, GS Gralnek, IM Chiou, CF TI The quality of published health economic analyses in digestive diseases: A systematic review and quantitative appraisal SO GASTROENTEROLOGY LA English DT Review ID COST-EFFECTIVENESS; GASTROENTEROLOGY LITERATURE; STRATEGIES; IMPACT AB Background & Aims: Health economic analyses are increasingly common in the digestive diseases literature and often are cited to frame practice guidelines. Although clinical trials are subjected routinely to critical appraisal, there has been no attempt to appraise the quality of health economic analyses with a validated instrument. We sought to appraise the quality of health economic analyses in digestive diseases, and to identify predictors of study quality. Methods: We performed a systematic review to identify digestive disease health economic analyses published since 1980. We assessed these studies using the Quality of Health Economic Studies (QHES), a validated quality-scoring instrument (score range = 0-100; > 75 = high quality). We conducted regression analysis to identify predictors of high quality. Results: Of :186 identified analyses, 29% were high quality, 71% failed to address potential model biases, 52% failed to disclose conflicts of interest, and 74% failed to describe methods for deriving the model assumptions. Four factors predicted high quality in logistic regression: (1) one or more authors had an advanced degree in health services or a related field (odds ratio for high quality, 5.0; 95% confidence interval, 2.6-9.3); (2) the study used decision-analysis software package (odds ratio, 2.4; 95% confidence interval, :1.2-4.7); (3) the study was federally funded (odds ratio, 2.2; 95% confidence interval, 1.2-4.1); and (4) the study cited the National Panel on Cost Effectiveness guidelines (odds ratio, 2.1; 95% confidence interval, 1.1-4.2). Conclusions: Less than one third of health economic analyses in digestive diseases meet criteria for high quality. Study quality is limited by factors that potentially can be remedied. These data may be used to focus the attention of journal editors and peer reviewers to ensure the future high quality of health economic analyses in digestive diseases. C1 Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, CURE Digest Dis Res Ctr,Ctr Study Digest Healthca, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, Los Angeles, CA USA. Univ Manitoba, Winnipeg, MB, Canada. CURE Digest Dis Res Ctr, Los Angeles, CA USA. Ctr Study Digest Healthcare Qual & Outcomes, Los Angeles, CA USA. Zync Hlth, Cerner Co, Beverly Hills, CA USA. RP Spiegel, BMR (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, CURE Digest Dis Res Ctr,Ctr Study Digest Healthca, 11301 Wilshire Blvd,Bldg 115,Room 215C, Los Angeles, CA 90073 USA. EM bspiegel@ucla.edu FU NCRR NIH HHS [K23 RR-16188]; NIDDK NIH HHS [DK-07180] NR 15 TC 33 Z9 35 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2004 VL 127 IS 2 BP 403 EP 411 DI 10.1053/j.gastro.2004.04.020 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 847XK UT WOS:000223431200010 PM 15300571 ER PT J AU Shah, K Jacobs, A Breakefield, XO Weissleder, R AF Shah, K Jacobs, A Breakefield, XO Weissleder, R TI Molecular imaging of gene therapy for cancer SO GENE THERAPY LA English DT Review DE MRI; virus vectors; bioluminescence; PET; FIAU; fluorescence ID POSITRON-EMISSION-TOMOGRAPHY; ENDOTHELIAL GROWTH-FACTOR; NEURAL STEM-CELLS; GREEN FLUORESCENT PROTEIN; SODIUM-IODIDE SYMPORTER; HUMAN TUMOR XENOGRAFTS; IN-VIVO TRACKING; TRANSGENE EXPRESSION; LIVING ANIMALS; SODIUM/IODIDE SYMPORTER AB Gene therapy of cancer has been one of the most exciting and elusive areas of scientific and clinical research in the past decade. One of the most critical issues for ensuring success of this therapy is the development of technology for noninvasive monitoring of the location, magnitude and duration of vector-mediated gene expression, as well as the distribution and targeting of vector particles in vivo. In recent years many advances have been made in high-resolution, in vivo imaging methods, including: radionuclide imaging, such as positron emission tomography ( PET) and single photon emission tomography ( SPECT), magnetic resonance (MR) imaging and spectroscopy, bioluminescence imaging and various fluorescence imaging techniques, including fluorescence-mediated tomography (FMT) and near-infrared fluorescence (NIRF) reflectance imaging. A variety of factors determine the choice of specific imaging system, some of them are the imaging requirements ( single or repeated), intended use ( animal or human) and spatial requirements ( organs versus cellular resolution and depth). This review provides descriptions of modalities applicable to imaging different parameters of vector-mediated gene expression in tumors and stem cell tracking in vivo. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Imaging Res, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Neurosci Program,Mol Neurogenet Unit, Boston, MA USA. Max Planck Inst Neurol Res, Dept Neurol, Lab Gene Therapy & Mol Imaging, Cologne, Germany. CMMC, Cologne, Germany. RP Shah, K (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Imaging Res, 13th St,Bldg 149,Room 5421, Charlestown, MA 02129 USA. NR 90 TC 108 Z9 117 U1 2 U2 29 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD AUG PY 2004 VL 11 IS 15 BP 1175 EP 1187 DI 10.1038/sj.gt.3302278 PG 13 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 839NI UT WOS:000222791400001 PM 15141158 ER PT J AU Lopes, SMCD Roelen, BAJ Monteiro, RM Emmens, R Lin, HY Li, E Lawson, KA Mummery, CL AF Lopes, SMCD Roelen, BAJ Monteiro, RM Emmens, R Lin, HY Li, E Lawson, KA Mummery, CL TI BMP signaling mediated by ALK2 in the visceral endoderm is necessary for the generation of primordial germ cells in the mouse embryo SO GENES & DEVELOPMENT LA English DT Article DE primordial germ cells; mouse; embryo; visceral endoderm; ALK2; IMP signaling ID STEM-CELLS; GROWTH-FACTOR; EXTRAEMBRYONIC TISSUES; HEPATIC SPECIFICATION; TRANSCRIPTION FACTOR; KINASE RECEPTOR; II RECEPTOR; IN-VITRO; EXPRESSION; ACTIVIN AB Deletion of various bone morphogenetic proteins (BMPs) and their downstream Smads in mice have clearly shown that BMP signaling is essential for the formation of primordial germ cells (PGCs). However, the molecular mechanism through which this takes place is still unclear. Here, we demonstrate that BMP4 produced in the extraembryonic ectoderm signals through ALK2, a type I BMP receptor, in the visceral endoderm (VE) to induce formation of PGCs from the epiblast. Firstly, embryonic day 5.5-6.0 (E5.5-E6.0) embryos cultured on fibronectin formed PGCs in the presence of VE, but not in its absence. Secondly, Alk2-deficient embryos completely lacked PGCs and the heterozygotes had reduced numbers, resembling Bmp4-deficient phenotypes. Thirdly, expression of constitutively active ALK2 in the VE, but not in the epiblast, was sufficient to rescue the PGC phenotype in Bmp4-deficient embryos. In addition, we show that the requirement for the VE at E5.5-E6.0 can be replaced by culturing embryos stripped of VE on STO cells, indicating that STO cells provide or transduce signals necessary for PGC formation that are normally transmitted by the VE. We propose a model in which direct signaling to proximal epiblast is supplemented by an obligatory indirect BMP-dependent signal via the VE. C1 Netherlands Inst Dev Biol, Hubrecht Lab, NL-3584 CT Utrecht, Netherlands. Massachusetts Gen Hosp, Program Membrane Biol, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02129 USA. RP Mummery, CL (reprint author), Netherlands Inst Dev Biol, Hubrecht Lab, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands. EM christin@niob.knaw.nl RI Monteiro, Rui/J-2544-2013 OI Monteiro, Rui/0000-0002-4223-8506 FU NICHD NIH HHS [R01 HD035286, R01 HD35286]; NIDDK NIH HHS [DK-D02716, DK-19406, R37 DK019406] NR 57 TC 118 Z9 121 U1 2 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD AUG 1 PY 2004 VL 18 IS 15 BP 1838 EP 1849 DI 10.1101/gad.294004 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 843IZ UT WOS:000223073500006 PM 15289457 ER PT J AU Hochedlinger, K Blelloch, R Brennan, C Yamada, Y Kim, MJ Chin, L Jaenisch, R AF Hochedlinger, K Blelloch, R Brennan, C Yamada, Y Kim, MJ Chin, L Jaenisch, R TI Reprogramming of a melanoma genome by nuclear transplantation SO GENES & DEVELOPMENT LA English DT Article DE cancer; epigenetics; nuclear transfer; reprogramming; pluripotency; embryonic stem cells ID TETRAPLOID EMBRYO COMPLEMENTATION; ACUTE PROMYELOCYTIC LEUKEMIA; STEM-CELL; MOUSE ZYGOTES; DONOR CELLS; GERM-LINE; MICE; TUMORS; CANCER; GENE AB We have used nuclear transplantation to test whether the reprogramming activity of oocytes can reestablish developmental pluripotency of malignant cancer cells. We show here that the nuclei of leukemia, lymphoma, and breast cancer cells could support normal preimplantation development to the blastocyst stage but failed to produce embryonic stem (ES) cells. However, a blastocyst cloned from a RAS-inducible melanoma nucleus gave rise to ES cells with the potential to differentiate into multiple cell types in vivo including melanocytes, lymphocytes, and fibroblasts. Chimeras produced from these ES cells developed cancer with higher penetrance, shorter latency, and an expanded tumor spectrum when compared with the donor mouse model. These results demonstrate that the secondary changes of a melanoma nucleus are compatible with a broad developmental potential but predispose mice to melanomas and other malignant tumors on reactivation of RAS. Our findings serve as a paradigm for studying the tumorigenic effect of a given cancer genome in the context of a whole animal. C1 MIT, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. MIT, Dept Biol, Cambridge, MA 02142 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Dept Dermatol, Boston, MA 02115 USA. RP Chin, L (reprint author), MIT, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. EM Lynda_Chin@dfci.harvard.edu; jaenisch@wi.mit.edu OI Brennan, Cameron/0000-0003-4064-8891 FU NCI NIH HHS [R37 CA 84198-04, R01 CA093947, R01 CA93947, R350 CA 44339-13, R37 CA084198, T32 CA009382, T32 CA09382] NR 52 TC 202 Z9 218 U1 0 U2 10 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD AUG 1 PY 2004 VL 18 IS 15 BP 1875 EP 1885 DI 10.1101/gad.1213504 PG 11 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 843IZ UT WOS:000223073500009 PM 15289459 ER PT J AU Miley, GR Fantz, D Glossip, D Lu, XW Saito, RM Palmer, RE Inoue, T van den Heuvel, S Sternberg, PW Kornfeld, K AF Miley, GR Fantz, D Glossip, D Lu, XW Saito, RM Palmer, RE Inoue, T van den Heuvel, S Sternberg, PW Kornfeld, K TI Identification of residues of the Caenorhabditis elegans LIN-1 ETS domain that are necessary for DNA binding and regulation of vulval cell fates SO GENETICS LA English DT Article ID ERK MAP KINASE; TRANSCRIPTION FACTOR; C-ELEGANS; SIGNALING PATHWAYS; DOCKING SITES; PROTEIN; GENE; RAS; INDUCTION; SPECIFICITY AB LIN-1 is an ETS domain protein. A receptor tyrosine kinase/Ras/mitogen-activated protein kinase signaling pathway regulates LIN-1 in the P6.p cell to induce the primary vulval cell fate during Caenorhabditis elegans development. We identified 23 lin-1 loss-of-function mutations by conducting several genetic screens. We characterized the molecular lesions in these lin-1 alleles and in several previously identified lin-1 alleles. Nine missense mutations and 10 nonsense mutations were identified. All of these lin-1 missense mutations affect highly conserved residues in the ETS domain. These missense mutations can be arranged in an allelic series; the strongest mutations eliminate most or all lin-1 functions, and the weakest mutation partially reduces lin-1 function. An electrophoretic mobility shift assay was used to demonstrate that purified LIN-1 protein has sequence-specific DNA-binding activity that required the core sequence GGAA. LIN-1 mutant proteins containing the missense substitutions had dramatically reduced DNA binding. These experiments identify eight highly conserved residues of the ETS domain that are necessary for DNA binding. The identification of multiple imitations that reduce the function of lin-1 as an inhibitor of the primary vulval cell fate and also reduce DNA binding suggest that DNA binding is essential for LIN-1 function in an animal. C1 Washington Univ, Sch Med, Dept Mol Biol & Pharmacol, St Louis, MO 63110 USA. MIT, Dept Biol, Howard Hughes Med Inst, Cambridge, MA 02139 USA. Massachusetts Gen Hosp, Charlestown, MA 02129 USA. CALTECH, Howard Hughes Med Inst, Pasadena, CA 91125 USA. RP Kornfeld, K (reprint author), Washington Univ, Sch Med, Dept Mol Biol & Pharmacol, Campus Box 8103,660 S Euclid Ave, St Louis, MO 63110 USA. EM kornfeld@molecool.wustl.edu RI van den Heuvel, Sander/B-8892-2011 FU NCI NIH HHS [CA-84271]; NIGMS NIH HHS [GM20450-01] NR 52 TC 17 Z9 20 U1 0 U2 2 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD AUG PY 2004 VL 167 IS 4 BP 1697 EP 1709 DI 10.1534/genetics.104.029017 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 851XR UT WOS:000223720300015 PM 15342509 ER PT J AU Simmons, SF Cadogan, MP Cabrera, GR Al-Samarrai, NR Jorge, JS Levy-Storms, L Osterweil, D Schnelle, JF AF Simmons, SF Cadogan, MP Cabrera, GR Al-Samarrai, NR Jorge, JS Levy-Storms, L Osterweil, D Schnelle, JF TI The minimum data set depression quality indicator: Does it reflect differences in care processes? SO GERONTOLOGIST LA English DT Editorial Material DE nursing homes; quality of care; mental health ID NURSING-HOME; VULNERABLE ELDERS; RESIDENTS; SCORES AB Purpose. The objective of this work was to determine if nursing homes that score differently on prevalence of depression, according to the Minimum Data Set (MDS) quality indicator, also provide different processes of care related to depression. Design and Methods. A cross-sectional study with 396 long-term residents in 14 skilled nursing facilities was conducted: 10 homes in the lower (25th percentile: low prevalence 0-2%) quartile and 4 homes in the upper (75th percentile: high prevalence 12-14%) quartile on the MDS depression quality indicator. Ten care processes related to depression were defined and operationalized into clinical indicators. Measurement of nursing home staff implementation of each care process and the assessment of depressive symptoms were conducted by trained research staff during 3 consecutive 12-hr days (7 a.m. to 7 p.m.), which included resident interviews (Geriatric Depression Scale), direct observations, and medical record review using standardized protocols. Results. The prevalence of depressive symptoms according to independent assessments was significantly higher than prevalence based on the MDS quality indicator and comparable between homes reporting low versus high rates of depression (46% and 41%, respectively). Documentation of depressive symptoms was significantly more common in homes reporting a high prevalence rate; however, documentation of symptoms on the MDS did not result in better treatment or management of depression according to any care-process measure. Psychosocial prevention and intervention efforts, such as resident participation in organized social group activities, were not widely used within either group of homes. Implications. The MDS depression quality indicator underestimates the prevalence of depressive symptoms in all homes but, in particular, among those reporting low or nonexistent rates. The indicator may be more reflective of measurement processes related to detection of symptoms than of prevention, intervention, or management of depression outcomes. A depression quality indicator should not be eliminated from MDS reports because of the importance and prevalence of the condition. However, efforts to improve nursing home staff detection of depressive symptoms should be initiated prior to the use of any MDS-based depression indicator for improvement purposes. Homes that report a low prevalence of depression according to the nationally publicized MDS quality indicator should not be regarded as providing better care. C1 Univ Calif Los Angeles, Jewish Home Aging, Borun Ctr Gerontolog Res, Dept Geriatr,Sch Med, Reseda, CA 91335 USA. Vet Adm Greater Los Angeles Healthcare Syst, Sepulveda Geriatr Res Educ & Clin Ctr, Los Angeles, CA USA. RP Simmons, SF (reprint author), Univ Calif Los Angeles, Jewish Home Aging, Borun Ctr Gerontolog Res, Dept Geriatr,Sch Med, 7150 Tampa Ave, Reseda, CA 91335 USA. EM ssimmons@ucla.edu FU NIA NIH HHS [AG10415] NR 21 TC 26 Z9 26 U1 1 U2 2 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD AUG PY 2004 VL 44 IS 4 BP 554 EP 564 PG 11 WC Gerontology SC Geriatrics & Gerontology GA 850EZ UT WOS:000223595300012 PM 15331813 ER PT J AU Forcione, DG Rosen, MJ Kisiel, JB Sands, BE AF Forcione, DG Rosen, MJ Kisiel, JB Sands, BE TI Anti-Saccharomyces cerevisiae antibody (ASCA) positivity is associated with increased risk for early surgery in Crohn's disease SO GUT LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODIES; MARKER; CLASSIFICATION; PROGNOSIS; SMOKING AB Background: Anti-Saccharomyces cerevisiae antibodies (ASCA) are a specific but only moderately sensitive diagnostic marker for Crohn's disease. We sought to explore the role of ASCA as a prognostic marker for aggressive disease phenotype in Crohn's disease. Aims: To determine the role of ASCA status as a risk factor for early surgery in Crohn's disease. Subjects: We performed a case control study in a cohort of patients, newly diagnosed with Crohn's disease, between 1991 and 1999. All patients were followed for at least three years. Case subjects ( n = 35) included those who had major surgery for Crohn's disease within three years of diagnosis. Controls ( n = 35) included patients matched to cases for age, sex, disease location, and smoking status, and who did not undergo major surgery for Crohn's disease within three years of diagnosis. Methods: Blinded assays were performed on serum for ASCA ( immunoglobulin (Ig) A and IgG). A paired analysis of cases-controls was performed to test for the association between ASCA status and risk of early surgery. Results: ASCA IgA was strongly associated with early surgery (odds ratio (OR) 8.5 (95% confidence interval (CI) 2.0 - 75.9); p = 0.0013). ASCA IgG+ and ASCA IgG+/ IgA+ patients were also at increased risk for early surgery (OR 5.5 ( 95% CI 1.2 - 51.1), p = 0.0265; and OR 5.0 ( 95% CI 1.1 - 46.9), p = 0.0433, respectively). The association between ASCA and early surgery was evident in patients requiring surgery for ileal or ileocolonic disease. Conclusions: Patients with Crohn's disease who are positive for ASCA IgA, IgG, or both, may define a subset of patients with Crohn's disease at increased risk for early surgery. C1 Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Sands, BE (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, 55 Fruit St,GRJ7, Boston, MA 02114 USA. EM bsands@partners.org OI Rosen, Michael/0000-0002-5149-718X FU NIDDK NIH HHS [T32 DK007191, DK 07191, 5 K23 DK02850, K23 DK002850] NR 23 TC 80 Z9 86 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD AUG PY 2004 VL 53 IS 8 BP 1117 EP 1122 DI 10.1136/gut.2003.030734 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 836KN UT WOS:000222554600013 PM 15247177 ER PT J AU Moriyama, T Littell, RD Debernardo, R Oliva, E Lynch, MP Rueda, BR Duska, LR AF Moriyama, T Littell, RD Debernardo, R Oliva, E Lynch, MP Rueda, BR Duska, LR TI BAG-1 expression in normal and neoplastic endometrium SO GYNECOLOGIC ONCOLOGY LA English DT Article; Proceedings Paper CT 34th Annual Meeting of the Society-of-Gynecologic-Oncology CY 2003 CL New Orleans, LA SP Soc Gynecol Oncol DE BAG-1; endometrial cancer; steroid receptors ID ALTERNATIVE TRANSLATION INITIATION; CARCINOMA CELL-LINE; BCL-2 GENE FAMILY; BREAST-CANCER; MENSTRUAL-CYCLE; DEATH ACTIVITY; PROTEIN; APOPTOSIS; ISOFORMS; MEMBERS AB Objective. BAG-1 has anti-apoptotic actions and is known to bind BCL-2 and steroid receptors. High levels of BAG-1 have been implicated as a prognostic indicator in breast cancer. Whether this observation can be generalized to endometrial cancer remains unknown. Methods. IRB permission was obtained for use of human discarded tissue. Immunohistochemical analyses were performed on: proliferative endometrium (PEM, 6), secretory endometrium (SEM, 28), "low-grade" neoplastic lesions (complex atypical hyperplasia and grade 1 endometrial adenocarcinomas) (19), and "high-grade" cancers (grade 2 and 3 endometrial adenocarcinomas) (13). The level of total BAG-1 and its isoforms was evaluated by Western blot in lysates from Ishikawa cells (grade 1), MFE 296 cells (grade 2), and SK-UT2 cells (grade 3). Results. The proportion of "high-grade" cancers with positive cytoplasmic staining for BAG-1 was higher than that of secretory endometrium (P = 0.006). Additionally, the proportion of specimens with positive staining for nuclear BAG-1 expression was significantly higher among high-grade carcinoma specimens compared to secretory specimens (P = 0.009). A high proportion (91%) of all specimens were positive for BCL-2, limiting the ability to subcategorize the other variables analyzed. There was no relationship between positive nuclear BAG-1 expression and either estrogen receptor (ER) or progesterone receptor (PR) expression. BAG-1 was expressed in the three cell lines evaluated and total BAG-1 level was not different among the different cell lines. Conclusion. BAG-1 is expressed in the endometrium. High-grade cancers stain more frequently than secretory endometrium for both cytoplasmic and nuclear BAGA expression, perhaps indicating an association between expression of BAG-1 and prognosis. (C) 2004 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Gillette Ctr Womens Canc, Div Gynecol Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Duska, LR (reprint author), Massachusetts Gen Hosp, Gillette Ctr Womens Canc, Div Gynecol Oncol, 100 Blossom St,Cox 501, Boston, MA 02114 USA. EM Iduska@partners.org NR 28 TC 9 Z9 9 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 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD AUG PY 2004 VL 94 IS 2 BP 289 EP 295 DI 10.1016/j.ygyno.2004.04.026 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 846GG UT WOS:000223303100008 PM 15297164 ER PT J AU Penson, RT Dignan, F Seiden, MV Lee, H Gallagher, CJ AF Penson, RT Dignan, F Seiden, MV Lee, H Gallagher, CJ TI Attitudes to chemotherapy in patients with ovarian cancer SO GYNECOLOGIC ONCOLOGY LA English DT Article DE ovarian cancer; chemotherapy; remission ID CELL LUNG-CANCER; QUALITY-OF-LIFE; WOMEN; DOCTORS; FUTURE; NURSES; TRIAL; END AB Background. Recurrent ovarian cancer (OVCA) has become the model for cancer as a chronic disease, yet little is known about what motivates patients and physicians in treatment choices. Methods. We investigated the attitudes of patients with epithelial OVCA and staff towards palliative chemotherapy for recurrent OVCA with a cross-sectional questionnaire study. Results. Instruments were developed and piloted in 15 patients. This exploratory study reflects substantial bias in the sample populations. One hundred twenty-two patients and 37 staff were enrolled in the US and 39 patients and 25 staff were enrolled in the UK. UK patients had a lower educational status (P = 0.001), lower stage disease (P = 0.025), and less prior lines of chemotherapy (P < 0.001). 61% of patients had recurrent OVCA and 67% of staff were physicians. Seventy-three percent of patients recalled a discussion about prognosis and 74% wanted to know details of the prognosis for a typical patient (US = UK). Most patients (48%) thought that their physician was realistic, and 57% of staff felt that they were optimistic. The vast majority of both staff and patients thought that patients positively reinterpreted what they were told. Five percent of staff thought that palliative care was 'incompatible' when considering chemotherapy as an option for their second recurrence of OVCA, compared with 36% of US patients, significantly more than the 12% of UK patients (P = 0.007). Patients thought that standard chemotherapy for a second recurrence of OVCA produced remission in 50% and cure in 15% of patients. Staff reported 20% and 0%, respectively. Fifty percent of patients and 57% of staff would want chemotherapy as an asymptomatic patient with a normal CT and a rising CA-125. Patients generally appear to be very tolerant of grade II chemotherapy-induced toxicity with staff being less tolerant than patients of nausea, anorexia, diarrhea, and rash. Staff rated life prolongation by 3 months to 1 year very much less acceptable than patients (P < 0.001). Although possibly allowing comprehensive collection of sensitive data, the questionnaire was too distressing for some patients and made 11% of patients feel uncomfortably anxious. Conclusions. Patients are optimistic and in the US, may be more reluctant than staff to see the Palliative Care Team. These data challenge the assertion that the use of palliative chemotherapy is physician-driven. (C) 2004 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Dept Med, Div Hematol & Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Ctr Biostat, Boston, MA 02114 USA. St Bartholomews Hosp, London, England. Massachusetts Gen Hosp, Div Gynecol Oncol, Brigham & Womens Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Dana Farber Canc Inst, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Div Adult Oncol, Boston, MA 02114 USA. Harvard Univ, Royal Marsden Hosp, Ctr Canc, US Representing Members Gynecol Oncol Res Program, London, England. RP Penson, RT (reprint author), Massachusetts Gen Hosp, Dept Med, Div Hematol & Oncol, Cox 548,100 Blossom St, Boston, MA 02114 USA. EM rpenson@partners.org NR 27 TC 20 Z9 20 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD AUG PY 2004 VL 94 IS 2 BP 427 EP 435 DI 10.1016/j.ygyno.2004.05.034 PG 9 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 846GG UT WOS:000223303100028 PM 15297184 ER PT J AU Huang, PY Yano, EM Lee, ML Chang, BL Rubenstein, LV AF Huang, PY Yano, EM Lee, ML Chang, BL Rubenstein, LV TI Variations in nurse practitioner use in Veterans Affairs primary care practices SO HEALTH SERVICES RESEARCH LA English DT Article DE nurse practitioner; primary care staffing; practice characteristics; environmental characteristics ID IMPROVING PRIMARY-CARE; PHYSICIAN ASSISTANTS; MANAGED CARE; SETTINGS; ORGANIZATIONS; SATISFACTION; MIDWIVES; SYSTEM; IMPACT; MODEL AB Background. Increasingly, primary care practices include nurse practitioners (NPs) in their staffing mix to contain costs and expand primary care. To achieve these aims in U.S. Department of Veterans Affairs medical centers (VAMCs), national policy endorsed involvement of NPs as primary care (PC) providers. Objectives. To evaluate the degree to which VAMCs incorporated NPs into PC practices between 1996 and 1999, and to identify the internal and external practice environment features associated with NP use. Study Design. We surveyed 131 PC directors of all VAMCs in 1996 and 1999 to ascertain the staffing and characteristics of the PC practice and parent organization (e.g., academic affiliation, level of physician staffing, use of managed care arrangements), and drew on previously published studies and HRSA State Health Workforce Profiles to characterize each practice's regional health care environment (e.g., geographic region, state NP practice laws, state managed care penetration). Using multivariate linear regression, we evaluate the contribution of these environmental and organizational factors on the number of NPs/10,000 PC patients in 1999, controlling for the rate of NP use in 1996. Principal Findings. From 1996-1999, NP use increased from 75 percent to 90 percent in VA PC practices. The mean number of NPs per practice increased by about 60 percent (2.0 versus 3.2; p<.001), while the rate of NPs/10,000 PC patients trended upward (2.2 versus 2.7; p=.09). Staffing of other primary care clinicians (e.g., physicians and physician assistants per practice) remained stable, while the NP-per-physician rate increased (0.2 versus 0.4; p<.001). After multivariate adjustment, greater reliance on managed-care-oriented provider education programs (p=.02), the presence of NP training programs (p=.05), and more specialty-trained physicians/10,000 PC patients (p=.09) were associated with greater NP involvement in primary care. Conclusions. Staffing models in VA PC practices have, in fact, changed, with NPs having a greater presence. However, we found substantial practice-based variations in their use, suggesting that more research is needed to better understand how they have been integrated into practice and what impact their involvement has had on the VA's ability to achieve its restructuring goals. C1 VA Greater Los Angeles HSR&D Ctr Excellence, Sepulveda Ambulatory Care Ctr, Sepulveda, CA 91343 USA. So Calif Permanente Med Grp, Harbor City, CA USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Nursing, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. RAND Hlth Program, Santa Monica, CA USA. RP Yano, EM (reprint author), VA Greater Los Angeles HSR&D Ctr Excellence, Sepulveda Ambulatory Care Ctr, 16111 Plummer St 152, Sepulveda, CA 91343 USA. NR 60 TC 19 Z9 19 U1 1 U2 4 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0017-9124 J9 HEALTH SERV RES JI Health Serv. Res. PD AUG PY 2004 VL 39 IS 4 BP 887 EP 904 DI 10.1111/j.1475-6773.2004.00263.x PN 1 PG 18 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 893HT UT WOS:000226710600011 PM 15230933 ER PT J AU Toivola, DA Ku, NO Resurreccion, EZ Nelson, DR Wright, TL Omary, MB AF Toivola, DA Ku, NO Resurreccion, EZ Nelson, DR Wright, TL Omary, MB TI Keratin 8 and 18 hyperphosphorylation is a marker of progression of human liver disease SO HEPATOLOGY LA English DT Article ID HUMAN ALCOHOLIC HEPATITIS; INTERMEDIATE-FILAMENTS; EPITHELIAL-CELLS; TRANSGENIC MICE; CULTURED-CELLS; DESMIN PHOSPHORYLATION; NEUROFILAMENT PROTEINS; I KERATINS; APOPTOSIS; MUTATION AB Keratin 8 and 18 (K8/18) phosphorylation plays a significant and site-specific role in regulating keratin filament organization, association with binding proteins, and modulation of cell cycle progression. Keratin hyperphosphorylation correlates with exposure to a variety of stresses in cultured cells and in mouse models of liver, pancreatic, and gallbladder injury, and it is found in association with mouse and human Mallory bodies. We asked whether K8/18 phosphorylation correlates with human liver disease progression by analyzing liver explants and biopsies of patients with chronic noncirrhotic hepatitis C virus (HCV) or cirrhosis. We also examined the effect of HCV therapy with interleukin-10 on keratin phosphorylation. Using site-specific antiphosphokeratin antibodies we found keratin hyperphosphorylation on most K8/18 sites in all cirrhotic liver explants tested and in most liver biopsies from patients with chronic HCV infection. Immunofluorescence staining of precirrhotic HCV livers showed focal keratin hyperphosphorylation and limited reorganization of keratin filament networks. In cirrhotic livers, keratin hyperphosphorylation occurred preferentially in hepatic nodule cells adjacent to bridging fibrosis and associated with increased stress kinase activation and apoptosis. Histological and serological improvement after interleukin-10 therapy was accompanied by normalization of keratin hyperphosphorylation on some sites in 7 of 10 patients. In conclusion, site-specific keratin phosphorylation in liver disease is a progression marker when increased and a likely regression marker when decreased. C1 Palo Alto VA Med Ctr, Dept Med, Palo Alto, CA 94304 USA. Stanford Univ, Sch Med, Ctr Digest Dis, Palo Alto, CA 94304 USA. Univ Florida, Coll Med, Gainesville, FL USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. San Francisco VA Med Ctr, San Francisco, CA USA. RP Toivola, DA (reprint author), Palo Alto VA Med Ctr, Dept Med, 3801 Miranda Ave,Mail Code 1541, Palo Alto, CA 94304 USA. EM dtoivola@stanford.edu FU NIDDK NIH HHS [DK52951, DK56339] NR 49 TC 57 Z9 67 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD AUG PY 2004 VL 40 IS 2 BP 459 EP 466 DI 10.1002/hep.20277 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 848AN UT WOS:000223439400022 PM 15368451 ER PT J AU Berry, J Keebler, ME McGuire, DK AF Berry, J Keebler, ME McGuire, DK TI Diabetes mellitus and cardiovascular disease. Pandora's box has been opened SO HERZ LA English DT Article DE diabetes mellitus; cardiovascular disease; evidence-based medicine ID ACUTE MYOCARDIAL-INFARCTION; CORONARY-HEART-DISEASE; IMPAIRED GLUCOSE-TOLERANCE; INSULIN-RESISTANCE ATHEROSCLEROSIS; CONVERTING-ENZYME-INHIBITOR; ST-SEGMENT-ELEVATION; LIFE-STYLE; RANDOMIZED-TRIAL; GLYCEMIC CONTROL; DIAGNOSTIC-CRITERIA AB As a result of an aging, increasingly obese, and decreasingly physically active population, the global incidence and prevalence of type 2 diabetes mellitus (DM) is increasing. While little can be done to influence the contribution of aging to the increasing global prevalence of diabetes, opportunities abound to develop effective interventions with regard to diet, exercise and obesity to prevent type 2 DM and more importantly, diabetes-associated complications. The major cause of morbidity and mortality from diabetes is from atherosclerotic macrovascular disease - including peripheral, cerebrovascular, and coronary artery disease. The markedly increased risk for cardiovascular disease associated with diabetes compound medical and public health challenges in the face of the burgeoning global epidemic of diabetes and will inevitably strain healthcare resources. Although the cardiovascular benefits of glycemic control have yet to be clearly established, a number of therapeutic interventions improve cardiovascular risk among the high-risk cohort of patients with diabetes. The development of new strategies targeting both primary prevention of diabetes and the prevention of diabetic complications will remain important research and clinical objectives. Great advances are being made in the realm of diabetes and cardiovascular disease, and there is much optimism for the future. C1 Univ Texas, SW Med Ctr, Div Cardiol, Dept Internal Med, Dallas, TX 75235 USA. Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. Univ Texas, SW Med Ctr, Donald W Reynolds Cardiovasc Clin Res Ctr, Dallas, TX 75235 USA. RP McGuire, DK (reprint author), Univ Texas, SW Med Ctr, Div Cardiol, Dept Internal Med, 5323 Harry Hines Blvd,Rm HAg-133, Dallas, TX 75235 USA. EM darren.mcguire@utsouthwestern.edu NR 76 TC 12 Z9 12 U1 2 U2 2 PU URBAN & VOGEL PI MUNICH PA NEUMARKTER STRASSE 43, D-81673 MUNICH, GERMANY SN 0340-9937 J9 HERZ JI Herz PD AUG PY 2004 VL 29 IS 5 BP 456 EP 462 DI 10.1007/s00059-004-2605-1 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 852BP UT WOS:000223730500002 PM 15340730 ER PT J AU Liao, J Kochilas, L Nowotschin, S Arnold, JS Aggarwal, VS Epstein, JA Brown, MC Adams, J Morrow, BE AF Liao, J Kochilas, L Nowotschin, S Arnold, JS Aggarwal, VS Epstein, JA Brown, MC Adams, J Morrow, BE TI Full spectrum of malformations in velo-cardio-facial syndrome/DiGeorge syndrome mouse models by altering Tbx1 dosage SO HUMAN MOLECULAR GENETICS LA English DT Article ID DIGEORGE-SYNDROME PHENOTYPE; INNER-EAR MORPHOGENESIS; HOLT-ORAM SYNDROME; CHROMOSOME 22Q11; SYNDROME REGION; MICE DEFICIENT; OTITIS-MEDIA; GENE; MUTATIONS; DELETION AB Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is associated with de novo hemizygous 22q11.2 deletions and is characterized by malformations attributed to abnormal development of the pharyngeal arches and pouches. The main physical findings include aortic arch and outflow tract heart defects, thymus gland hypoplasia or aplasia and craniofacial anomalies. The disorder varies greatly in expressivity; while some patients are mildly affected with learning disabilities and subtle craniofacial malformations, others die soon after birth with major cardiovascular defects and thymus gland aplasia. In addition to the main clinical features, many other findings are associated with the disorder such as chronic otitis media and hypocalcemia. Tbx1, a gene encoding a T-box transcription factor, which is hemizygously deleted on chromosome 22q11.2, was found to be a strong candidate for the equivalent of human VCFS/DGS in mice. Mice hemizygous for a null allele of Tbx1 had mild malformations, while homozygotes had severe malformations in the affected structures; neither precisely modeling the syndrome. Interestingly, bacterial artificial chromosome (BAC) transgenic mice overexpressing human TBX1 and three other transgenes, had similar malformations as VCFS/DGS patients. By employing genetic complementation studies, we demonstrate that altered TBX1 dosage and not overexpression of the other transgenes is responsible for most of the defects in the BAC transgenic mice. Furthermore, the full spectrum of VCFS/DGS malformations was elicited in a Tbx1 dose dependent manner, thus providing a molecular basis for the pathogenesis and varied expressivity of the syndrome. C1 Yeshiva Univ Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USA. Brown Univ, Sch Med, Dept Pediat, Providence, RI 02912 USA. Univ Penn, Dept Med, Philadelphia, PA 19104 USA. Univ Penn, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. Harvard Univ, Sch Med, Eaton Peabody Lab,Dept Otol & Laryngol, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Morrow, BE (reprint author), Yeshiva Univ Albert Einstein Coll Med, Dept Mol Genet, Ullmann Bldg,Room 1217,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM morrow@aecom.yu.edu FU NICHD NIH HHS [HD34980-08]; NIDCD NIH HHS [DC05186-01] NR 50 TC 135 Z9 136 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 AUG 1 PY 2004 VL 13 IS 15 BP 1577 EP 1585 DI 10.1093/hmg/ddh176 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 836MB UT WOS:000222558800004 PM 15190012 ER PT J AU Silverberg, SG Bell, DA Kurman, RJ Seidman, JD Prat, J Ronnett, BM Copeland, L Silva, E Gorstein, F Young, RH AF Silverberg, SG Bell, DA Kurman, RJ Seidman, JD Prat, J Ronnett, BM Copeland, L Silva, E Gorstein, F Young, RH TI Borderline ovarian tumors: Key points and workshop summary SO HUMAN PATHOLOGY LA English DT Article DE ovary; borderline tumor; low malignant potential; atypical proliferative; serous; mucinous ID MICROPAPILLARY SEROUS CARCINOMA; K-RAS MUTATIONS; LYMPH-NODES; DIAGNOSTIC-CRITERIA; PERITONEAL IMPLANTS; MUCINOUS TUMORS; CRIBRIFORM PATTERNS; INTESTINAL-TYPE; MICROINVASION; MALIGNANCY AB This article documents major points of agreement and disagreement among experts invited to participate in a Borderline Ovarian Tumor Workshop held in Bethesda, MD, on August 27-28, 2003. It is suggested that controversies related to the diagnosis and management of these tumors are often related to lack of data in the literature (small numbers of cases, unreported or unclear criteria for diagnosis and follow-up, insufficient length of follow-up, etc), and specific recommendations are made for further investigation and for reporting of data in future studies. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Gynecol, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Obstet, Baltimore, MD USA. Washington Hosp Ctr, Dept Pathol, Washington, DC 20010 USA. Univ Autonoma Barcelona, Hosp Santa Creu Sant Pau, Dept Pathol, Barcelona, Spain. Ohio State Univ, James Canc Ctr, Dept Obstet & Gynecol, Columbus, OH USA. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. RP Silverberg, SG (reprint author), Univ Maryland, Sch Med, Dept Pathol, 22 S Greene St,Rm N2W50, Baltimore, MD 21201 USA. RI Prat, Jaime/G-4679-2011 NR 45 TC 63 Z9 68 U1 1 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD AUG PY 2004 VL 35 IS 8 BP 910 EP 917 DI 10.1016/j.humpath.2004.03.003 PG 8 WC Pathology SC Pathology GA 848AT UT WOS:000223440100002 PM 15297959 ER PT J AU Seidman, JD Soslow, RA Vang, R Berman, JJ Stoler, MH Sherman, ME Oliva, E Kajdacsy-Balla, A Berman, DM Copeland, LJ AF Seidman, JD Soslow, RA Vang, R Berman, JJ Stoler, MH Sherman, ME Oliva, E Kajdacsy-Balla, A Berman, DM Copeland, LJ TI Borderline ovarian tumors: Diverse contemporary viewpoints on terminology and diagnostic criteria with illustrative images SO HUMAN PATHOLOGY LA English DT Article DE ovary; ovarian neoplasms; serous borderline tumor; atypical proliferative serous tumor; mucinous borderline tumor; atypical proliferative mucinous tumor; pseudomyxoma peritonei ID TERM-FOLLOW-UP; DISSEMINATED PERITONEAL ADENOMUCINOSIS; MICROPAPILLARY SEROUS CARCINOMA; CLINICOPATHOLOGICAL ANALYSIS; PSEUDOMYXOMA-PERITONEI; MUCINOUS TUMORS; PAPILLARY CYSTADENOMAS; CRIBRIFORM PATTERNS; INTESTINAL-TYPE; MULLERIAN TYPE AB The National Cancer Institute sponsored a Borderline Ovarian Tumor Workshop held in August 2003 in Bethesda, MD. This report was developed from discussions at the Workshop. The participants acknowledged several areas of disagreement on basic terminology issues and agreed that a glossary with example images would help clarify many commonly misunderstood issues. This report defines terminology used in the pathological description of borderline tumors and their variants, and illustrates examples of each of the most common entities. It also addresses controversial aspects of the definitions and issues involving specimen handling and reporting. For those issues where there is disagreement, the terminology and diagnostic approaches reflecting the differing views are presented. (C) 2004 Elsevier Inc. All rights reserved. C1 Washington Hosp Ctr, Dept Pathol, Washington, DC 20010 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD USA. NCI, Div Canc Treatment & Diagnost, Bethesda, MD USA. Univ Virginia Hlth Syst, Dept Pathol, Charlottesville, VA USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Univ Illinois, Dept Pathol, Chicago, IL USA. NCI, Lab Pathol, Bethesda, MD USA. Ohio State Univ, Coll Med & Publ Hlth, James Canc Hosp, Cleveland, OH USA. Ohio State Univ, Coll Med & Publ Hlth, Solove Res Inst, Cleveland, OH USA. RP Seidman, JD (reprint author), Washington Hosp Ctr, Dept Pathol, 110 Irving St NW, Washington, DC 20010 USA. OI Soslow, Robert/0000-0002-7269-5898 NR 57 TC 65 Z9 77 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD AUG PY 2004 VL 35 IS 8 BP 918 EP 933 DI 10.1016/j.humpath.2004.03.004 PG 16 WC Pathology SC Pathology GA 848AT UT WOS:000223440100003 PM 15297960 ER PT J AU Bell, DA Longacre, TA Prat, J Kohn, EC Soslow, RA Ellenson, LH Malpica, A Stoler, MH Kurman, RJ AF Bell, DA Longacre, TA Prat, J Kohn, EC Soslow, RA Ellenson, LH Malpica, A Stoler, MH Kurman, RJ TI Serous borderline (low malignant potential, atypical proliferative) ovarian tumors: Workshop perspectives SO HUMAN PATHOLOGY LA English DT Article DE serous; ovary; borderline; low malignant potential; atypical proliferative ID K-RAS MUTATIONS; TERM FOLLOW-UP; MULLERIAN INCLUSION CYSTS; STAGE-I CARCINOMAS; EPITHELIAL TUMORS; PERITONEAL IMPLANTS; LOW-GRADE; CRIBRIFORM PATTERNS; HISTOLOGIC FEATURES; MICROPAPILLARY AB Although the category of serous borderline ovarian tumor (S-BOT) was established more than 30 years ago, the nomenclature and prognostic significance of various histological features of these neoplasms continues to engender controversy. The Borderline Ovarian Tumor Workshop was held in Bethesda, MD, in August 2003 in an attempt to examine the existing data, establish areas of agreement, and identify areas needing further investigation. This report addresses 6 areas of controversy regarding S-BOT: (1) tumors with and without a micropapillary architecture (typical vs micropapillary type), (2) peritoneal implants, (3) stromal microinvasion, (4) ovarian surface involvement, (5) lymph node involvement, and (6) recurrent tumors. Each of these issues is addressed by summarizing the data in the literature on which the discussions were based, areas of agreement that emerged, divergent opinions and the reasoning behind them, and the conclusions of the participants with recommended nomenclature. (C) 2004 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Stanford Univ, Ctr Med, Dept Pathol, Div Surg Pathol, Stanford, CA USA. Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Dept Pathol, Barcelona, Spain. Ctr Canc Res, Lab Pathol, NCI, Bethesda, MD USA. Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. Cornell Univ, Weill Med Coll, Dept Pathol, New York, NY USA. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX USA. Univ Virginia Hlth Syst, Robert E Fechner Lab Surg Pathol, Charlottesville, VA USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Gynecol & Obstet, Baltimore, MD USA. RP Bell, DA (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 105, Boston, MA 02114 USA. RI Prat, Jaime/G-4679-2011; OI Soslow, Robert/0000-0002-7269-5898 NR 76 TC 72 Z9 82 U1 1 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD AUG PY 2004 VL 35 IS 8 BP 934 EP 948 DI 10.1016/j.humpath.2004.03.005 PG 15 WC Pathology SC Pathology GA 848AT UT WOS:000223440100004 PM 15297961 ER PT J AU Wu, CL Yang, XMJ Tretiakova, M Patton, KT Halpern, EF Woda, BA Young, RH Jiang, Z AF Wu, CL Yang, XMJ Tretiakova, M Patton, KT Halpern, EF Woda, BA Young, RH Jiang, Z TI Analysis of alpha-methylacyl-CoA racemase (P504S) expression in high-grade prostatic intraepithelial neoplasia SO HUMAN PATHOLOGY LA English DT Article DE prostate; PIN; AMACR; P504S; immunohistochemistry ID NEEDLE-BIOPSY; MOLECULAR MARKER; SEVERE DYSPLASIA; REPEAT BIOPSY; CANCER; ADENOCARCINOMA; CARCINOMA; DIAGNOSIS; STRATEGY AB alpha-methylacyl-CoA racemase (AMACR), also known as P504S, is a recently identified molecular marker for prostate cancer. The expression of AMACR/P504S has also been observed in high-grade prostatic intraepithelial neoplasia (PIN), a precursor lesion of prostate cancer. However, a detailed study focusing on the analysis of AMACR/P504S expression in high-grade PIN has not been performed. In this study, we analyzed AMACR/P504S expression by immumohistochemisty in 3954 prostatic ducts and acini with high-grade PIN from 140 prostatectomy specimens. AMACR/P504S immunoreactivity was measured as negative (0), weakly positive (+1), moderately positive (+2), and strongly positive (+3). AMACR/P504S immunoreactivity was detected in 90.0% (126/140) of high-grade PIN cases, although only 41.5% (1642/3954) of prostatic glands involved by PIN showed AMACR/P504S immunoreactivity. A significantly higher AMACR/P504S-positive rate (56.0%) was found in isolated high-grade PIN glands adjacent to cancer (distance less than 5 turn) compared with those away from cancer (distance more than 5 mm; 14%, P < 0.0001). High-grade PIN glands adjacent to cancer also showed a higher (P < 0.0004) AMACR/P504S intensity (1.62) than did those away from cancer (1.11). Our results suggest that PIN strongly positive for AMACR/P504S might be more closely associated with cancer than PIN negative or weakly positive for AMACR/P504S. This study provides additional evidence to link high-grade PIN as a precursor lesion to prostatic adenocarcinoma. (C) 2004 Elsevier Inc. All rights reserved. C1 Northwestern Univ, Feinberg Sch Med, Dept Pathol, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Dept Urol, Chicago, IL 60611 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Urol, Boston, MA 02115 USA. Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA USA. Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01605 USA. RP Yang, XMJ (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Pathol, Feinberg 7-334,251 E Huron St, Chicago, IL 60611 USA. NR 25 TC 52 Z9 54 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD AUG PY 2004 VL 35 IS 8 BP 1008 EP 1013 DI 10.1016/j.humpath.2004.03.019 PG 6 WC Pathology SC Pathology GA 848AT UT WOS:000223440100011 PM 15297968 ER PT J AU Drapkin, R Crum, CP Hecht, JL AF Drapkin, R Crum, CP Hecht, JL TI Expression of candidate tumor markers in ovarian carcinoma and benign ovary: Evidence for a link between epithelial phenotype and neoplasia SO HUMAN PATHOLOGY LA English DT Article DE EMA/MUC1; EpCAM; mesothelin; CD9; calretinin; EMA; ovary; carcinoma ID GENE-EXPRESSION; SURFACE EPITHELIUM; CDNA MICROARRAY; CANCER; CELLS; IDENTIFICATION; MESOTHELIOMA; PERITONEAL; CALRETININ; DYSPLASIA AB EpCAM, epithelial membrane antigen (EMA)-mucin 1 (MUC1), mesothelin, and CD9 have been reported to be overexpressed at the RNA level in ovarian carcinomas. By using immunohistochemistry, we profiled the protein expression of these gene products in ovarian carcinoma tissues and compared them with benign ovarian surface epithelium (OSE) and cortical inclusion cysts (CICs). Immunoreactivity for EMA and calretinin were used to define epithelial and mesothelial differentiation in nontumor tissues, respectively. Papillary serous (n = 16) and endometrioid (n = 10) tumors were immunopositive for EMA/MUCI (100%), mesothelin (75% and 30%, respectively), CD9 (88% and 90%, respectively), and EpCAM (100%). All ovarian carcinomas and carcinoma cell lines tested were negative for calretinin. In nonneoplastic ovary, both OSE and CICs ranged from flat-to-cuboidal to stratified and ciliated in appearance. OSE with a cuboidal morphology had a similar immunoreactivity as omental peritoneum, expressing calretinin, mesothelin, and CD9. In contrast, CICS with stratified and ciliated epithelium show expression patterns similar to those in fallopian tubes. They frequently expressed EMA, EpCAM, mesothelin, and CD9. This immunophenotype is preserved in ovarian carcinomas, suggesting that Mullerian metaplasia signals the acquisition of these markers and that their expression is maintained in ovarian carcinomas that originate from this epithelium. (C) 2004 Elsevier Inc. All rights reserved. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA USA. RP Hecht, JL (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. RI Drapkin, Ronny/E-9944-2016 OI Drapkin, Ronny/0000-0002-6912-6977 NR 38 TC 49 Z9 52 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD AUG PY 2004 VL 35 IS 8 BP 1014 EP 1021 DI 10.1016/j.humpath.2004.04.014 PG 8 WC Pathology SC Pathology GA 848AT UT WOS:000223440100012 PM 15297969 ER PT J AU Bonmassar, G AF Bonmassar, G TI Resistive tapered stripline (RTS) in electroencephalogram recordings during MRI SO IEEE TRANSACTIONS ON MICROWAVE THEORY AND TECHNIQUES LA English DT Article DE cable; electrocardiography; electroencephalography (EEG); finite difference time domain (FDTD); magnetic resonance imaging (MRI); specific absorption rate (SAR) ID SAFETY; FIELD; EEG; IMPLANTS; EXPOSURE; WIRES AB A purely resistive stripline lead is introduced to reduce the specific absorption rate (SAR) increase due to the presence of leads in electroencephalography (EEG) measurements during magnetic resonance imaging. Discontinuities in the resistivity profile of the stripline introduce high-frequency inductive impedance that is not present in the low-frequency band of the EEG recordings. The changes in SAR introduced by the resistive tapered stripline (RTS) are studied using the finite-difference time-domain (FDTD) algorithm on a spherical phantom that models the human head. The FDTD simulations predict a reduction of the peak SAR when using RTS versus conventional resistive carbon fibers. Furthermore, our FDTD simulations have been validated on a simple prototype that exhibits no temperature increase on a spherical phantom. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, A Martinos Ctr, Charlestown, MA 02129 USA. RP Bonmassar, G (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, A Martinos Ctr, Charlestown, MA 02129 USA. EM giorgio@nmr.mgh.harvard.edu NR 22 TC 7 Z9 8 U1 0 U2 5 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0018-9480 J9 IEEE T MICROW THEORY JI IEEE Trans. Microw. Theory Tech. PD AUG PY 2004 VL 52 IS 8 BP 1992 EP 1998 DI 10.1109/TMTT.2004.832688 PN 2 PG 7 WC Engineering, Electrical & Electronic SC Engineering GA 843BW UT WOS:000223051400017 ER PT J AU Sharp, GC Lee, SW Wehe, DK AF Sharp, GC Lee, SW Wehe, DK TI Multiview registration of 3D scenes by minimizing error between coordinate frames SO IEEE TRANSACTIONS ON PATTERN ANALYSIS AND MACHINE INTELLIGENCE LA English DT Article DE registration; global registration; range images; multiple views; graph analysis ID MULTIPLE RANGE IMAGES; MOBILE ROBOTS; LOCALIZATION; ALIGNMENT; OBJECTS; VIEWS AB This paper addresses the problem of large-scale multiview registration of range images captured from unknown viewing directions. To reduce the computational burden, we separate the local problem of pairwise registration on neighboring views from the global problem of distribution of accumulated errors. We define the global problem as an optimization over the graph of neighboring views, and we show how the graph can be decomposed into a set of cycles such that the optimal transformation parameters for each cycle can be solved in closed form. We then describe an iterative procedure that can be used to integrate the solutions for the set of cycles across the graph of views. This method for error distribution does not require point correspondences between views, and can be used to integrate any method of pairwise registration or robot odometry. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Sogang Univ, Sch Media & Commun, Seoul 121742, South Korea. Univ Michigan, Dept Nucl Engn & Radiol Sci, Ann Arbor, MI 48109 USA. RP Massachusetts Gen Hosp, Dept Radiat Oncol, 55 Fruit St,FND5, Boston, MA 02114 USA. EM gcsharp@partners.org; slee@ccs.sogang.ac.kr; dkw@umich.edu NR 37 TC 54 Z9 57 U1 1 U2 9 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 0162-8828 EI 1939-3539 J9 IEEE T PATTERN ANAL JI IEEE Trans. Pattern Anal. Mach. Intell. PD AUG PY 2004 VL 26 IS 8 BP 1037 EP 1050 DI 10.1109/TPAMI.2004.49 PG 14 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 827BE UT WOS:000221872400007 PM 15641733 ER PT J AU Rooney, S Chaudhuri, J Alt, FW AF Rooney, S Chaudhuri, J Alt, FW TI The role of the non-homologous end-joining pathway in lymphocyte development SO IMMUNOLOGICAL REVIEWS LA English DT Review ID DEPENDENT PROTEIN-KINASE; DOUBLE-STRAND-BREAK; DNA-LIGASE-IV; CLASS-SWITCH RECOMBINATION; SEVERE COMBINED IMMUNODEFICIENCY; COMBINED IMMUNE-DEFICIENCY; SPEAKING NATIVE-AMERICANS; GERM-LINE TRANSCRIPTION; METALLO-BETA-LACTAMASE; B-CELL DIFFERENTIATION AB One of the most toxic insults a cell can incur is a disruption of its linear DNA in the form of a double-strand break (DSB). Left unrepaired, or repaired improperly, these lesions can result in cell death or neoplastic transformation. Despite these dangers, lymphoid cells purposely introduce DSBs into their genome to maximize the diversity and effector functions of their antigen receptor genes. While the generation of breaks requires distinct lymphoid-specific factors, their resolution requires various ubiquitously expressed DNA-repair proteins, known collectively as the non-homologous end-joining pathway. In this review, we discuss the factors that constitute this pathway as well as the evidence of their involvement in two lymphoid-specific DNA recombination events. C1 Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. Ctr Blood Res, Boston, MA 02115 USA. RP Alt, FW (reprint author), Childrens Hosp, Howard Hughes Med Inst, 300 Longwood Ave,New Res Bldg,9th Floor, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu FU NCI NIH HHS [CA92625]; NIAID NIH HHS [AI20047, AI31541, AI35714] NR 243 TC 148 Z9 150 U1 0 U2 5 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD AUG PY 2004 VL 200 BP 115 EP 131 DI 10.1111/j.0105-2896.2004.00165.x PG 17 WC Immunology SC Immunology GA 843RZ UT WOS:000223105500010 PM 15242400 ER PT J AU Oettinger, MA AF Oettinger, MA TI How to keep V(D)J recombination under control SO IMMUNOLOGICAL REVIEWS LA English DT Review ID B-CELL DEVELOPMENT; TCR-BETA LOCUS; ENHANCER-BLOCKING ACTIVITY; HISTONE H3 METHYLATION; RNA-POLYMERASE-II; HEAVY-CHAIN GENE; CHROMATIN-MODIFYING COMPLEXES; ALLELIC EXCLUSION; TARGETED RECRUITMENT; TRANSCRIPTIONAL REGULATION AB Breaking apart chromosomes is not a matter to be taken lightly. The possible negative outcomes are obvious: loss of information, unstable chromosomes, chromosomal translocations, tumorigenesis, or cell death. Utilizing DNA rearrangement to generate the desired diversity in the antigen receptor loci is a risky business, and it must be carefully controlled. In general, the regulation is so precise that the negative consequences are minimal or not apparent. They are visible only when the process of V(D)J recombination goes awry, as for example in some chromosomal translocations; associated with lymphoid tumors. Regulation is imposed not only to prevent the generation of random breaks in the DNA, but also to direct rearrangement to the appropriate locus or subregion of a locus in the appropriate cell at the appropriate time. Antigen receptor rearrangement is regulated essentially at four different levels: expression of the RAG1/2 recombinase, intrinsic biochemical 1 properties of the recombinase and the cleavage reaction, the post-cleavage/DNA repair stage of the process, and accessibility of the substrate to the recombinase. Within each of these broad categories, multiple mechanisms are used to achieve the desired aims. The major focus of this review is on accessibility control and the role of chromatin and nuclear architecture in achieving this regulation, although other issues are touched upon. C1 Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Oettinger, MA (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Wellman Bldg,10th Floor,50 Blossom St, Boston, MA 02114 USA. EM oettinger@frodo.mgh.harvard.edu NR 157 TC 33 Z9 33 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD AUG PY 2004 VL 200 BP 165 EP 181 DI 10.1111/j.0105-2896.2004.00172.x PG 17 WC Immunology SC Immunology GA 843RZ UT WOS:000223105500014 PM 15242404 ER PT J AU Chatterji, M Tsai, CL Schatz, DG AF Chatterji, M Tsai, CL Schatz, DG TI New concepts in the regulation of an ancient reaction: transposition by RAG1/RAG2 SO IMMUNOLOGICAL REVIEWS LA English DT Review ID RAG-MEDIATED TRANSPOSITION; HYBRID JOINT FORMATION; V(D)J RECOMBINATION; SIGNAL ENDS; CELL-CYCLE; CHROMOSOMAL TRANSLOCATIONS; IN-VITRO; DNA; PROTEINS; CLEAVAGE AB The lymphoid-specific factors, recombination-activating gene 1 (RAG1) and RAG2, initiate V(D)J recombination by introducing DNA double-stand breaks at specific sites in the genome. In addition to this critical endonuclease activity, the RAG proteins catalyze other chemical reactions that can affect the outcome of V(D)J recombination, one of which is transposition. While the transposition activity of the RAG proteins is thought to have been critical for the evolution of modern antigen-receptor loci, it has also been proposed to contribute to chromosomal translocations and lymphoid malignancy. A major challenge has been to determine how the transposition activity of the RAG proteins is regulated in vivo. Although a variety of mechanisms have been suggested by recent studies, a clear resolution of this issue remains elusive. C1 Yale Univ, Sch Med, Howard Hughes Med Inst, Immunol Sect, New Haven, CT 06510 USA. Massachusetts Gen Hosp, Dept Mol Biol, Howard Hughes Med Inst, Boston, MA 02114 USA. RP Schatz, DG (reprint author), Yale Univ, Sch Med, Howard Hughes Med Inst, Immunol Sect, 300 Cedar St, New Haven, CT 06510 USA. EM david.schatz@yale.edu RI Schatz, David/A-6748-2013 OI Schatz, David/0000-0002-5669-1176 FU NIAID NIH HHS [R01-AI32524] NR 71 TC 15 Z9 16 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD AUG PY 2004 VL 200 BP 261 EP 271 DI 10.1111/j.0105-2896.2004.00167.x PG 11 WC Immunology SC Immunology GA 843RZ UT WOS:000223105500021 PM 15242411 ER PT J AU Ince, MN Harnisch, B Xu, Z Lee, SK Lange, C Moretta, L Lederman, M Lieberman, J AF Ince, MN Harnisch, B Xu, Z Lee, SK Lange, C Moretta, L Lederman, M Lieberman, J TI Increased expression of the natural killer cell inhibitory receptor CD85j/ILT2 on antigen-specific effector CD8 T cells and its impact on CD8 T-cell function SO IMMUNOLOGY LA English DT Article DE NK receptor; CD8; CTL; interferon-gamma; HIV ID HUMAN-IMMUNODEFICIENCY-VIRUS; CLASS-I MOLECULES; HIV-1-INFECTED INDIVIDUALS; DISEASE PROGRESSION; SIGNALING MOLECULES; TRANSCRIPT-2 ILT2; IMPAIRED FUNCTION; HIV-1 INFECTION; NK CELLS; HLA-G AB We investigated whether inhibitory natural killer cell receptor (iNKR) expression contributes to impaired antigen-specific cytotoxicity and interferon-gamma (IFN-gamma) production by CD8 T cells during chronic infection. iNKR immunoglobulin-like transcript-2 (ILT2/CD85j) is expressed on 40-55% of cytomegalovirus (CMV)-, Epstein-Barr virus (EBV)- and human immunodeficiency virus (HIV)-specific CD8 T cells in both healthy and HIV-infected donors. Other iNKRs (CD158a, b1, e1/e2, k, CD94/NKG2A) are expressed on only a small minority of CD8 T cells and are not preferentially expressed on tetramer-staining virus-specific cells. In normal donors, ILT2 is expressed largely on perforin(+) CD27(-) effector cells. However, in HIV-infected donors, only a third of ILT2(+) cells are also perforin(+). In both normal and HIV-infected donors, ILT2(+) cells are prone to spontaneous apoptosis. Therefore, ILT2 is normally expressed during effector cytotoxic T-lymphocyte (CTL) differentiation, but can also be expressed when effector maturation is incomplete, as in HIV infection. The effect of ILT2 on CD8 cell function was assessed by preincubating effector cells with ILT2 antibody. While blocking ILT2 engagement has no appreciable effect on cytotoxicity, it increases antiviral IFN-gamma production by approximately threefold in both normal and HIV-infected donors. Thus, ILT2 expression, increased on antiviral CD8 cells in chronic infection, may interfere with protective CD8 T-cell function by suppressing IFN-gamma production. C1 Harvard Univ, Sch Med, CBR Inst Biomed Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Case Western Reserve Univ, Univ Hosp Cleveland, Ctr AIDS Res, Cleveland, OH 44106 USA. Univ Genoa, Dipartimento Med Sperimentale, Genoa, Italy. Univ Genoa, Ist Giannina Gaslini, Genoa, Italy. RP Lieberman, J (reprint author), Harvard Univ, Sch Med, CBR Inst Biomed Res, 200 Longwood Ave, Boston, MA 02115 USA. EM lieberman@cbr.med.harvard.edu RI Lange, Christoph/J-6289-2012; Lieberman, Judy/A-2717-2015 FU NIAID NIH HHS [R01 AI042519, AI 36219, AI 42519, P30 AI036219] NR 58 TC 32 Z9 32 U1 1 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD AUG PY 2004 VL 112 IS 4 BP 531 EP 542 DI 10.1046/j.1365-2567.2004.01907.x PG 12 WC Immunology SC Immunology GA 839RG UT WOS:000222801700003 PM 15270723 ER PT J AU Macedo, MF de Sousa, M Ned, RM Mascarenhas, C Andrews, NC Correia-Neves, M AF Macedo, MF de Sousa, M Ned, RM Mascarenhas, C Andrews, NC Correia-Neves, M TI Transferrin is required for early T-cell differentiation SO IMMUNOLOGY LA English DT Article DE transferrin; transferrin receptor; iron; T-cell differentiation; thymus ID ADAPTER PROTEIN SLP-76; LYMPHOCYTE DEVELOPMENT; RECEPTOR ANTIBODY; TYROSINE KINASES; MICE LACKING; THYMOCYTES; CD3-EPSILON; EXPRESSION; INDUCTION; MOUSE AB Transferrin, the major plasma iron carrier, mediates iron entry into cells through interaction with its receptor. Several in vitro studies have demonstrated that transferrin plays an essential role in lymphocyte division, a role attributed to its iron transport function. In the present study we used hypotransferrinaemic (Trf(hpx/hpx)) mice to investigate the possible involvement of transferrin in T lymphocyte differentiation in vivo. The absolute number of thymocytes was substantially reduced in Trf(hpx/hpx) mice, a result that could not be attributed to increased apoptosis. Moreover, the proportions of the four major thymic subpopulations were maintained and the percentage of dividing cells was not reduced. A leaky block in the differentiation of CD4(-) CD8(-) CD3(-) CD44(-) CD25(+) (TN3) into CD4(-) CD8(-) CD3(-) CD44(-) CD25(-) (TN4) cells was observed. In addition, a similar impairment of early thymocyte differentiation was observed in mice with reduced levels of transferrin receptor. The present study demonstrates, for the first time, that transferrin itself or a pathway triggered by the interaction of transferrin with its receptor is essential for normal early T-cell differentiation in vivo. C1 Inst Mol & Cell Biol, Div Human Genet & Genet Disorders, P-4150180 Oporto, Portugal. Inst Mol & Cell Biol, Immune Syst Lab, P-4150180 Oporto, Portugal. Inst Ciencias Biomed Abel Salazar, Oporto, Portugal. Childrens Hosp, Div Hematol Oncol, Boston, MA USA. Dana Farber Canc Inst, Boston, MA USA. Harvard Univ, Sch Med, Div Med Sci, Boston, MA USA. Howard Hughes Med Inst, Boston, MA USA. Inst Super Saude Alto Ave, Fontarcada, Portugal. RP de Sousa, M (reprint author), Inst Mol & Cell Biol, Div Human Genet & Genet Disorders, P-4150180 Oporto, Portugal. EM mdesousa@ibmc.up.pt RI Correia-Neves, Margarida/C-9122-2009; Ned, Renee/D-3746-2009; Macedo, Fatima/L-4623-2013; OI Correia-Neves, Margarida/0000-0002-2202-5431; Macedo, Fatima/0000-0002-2252-6105; de sousa, maria/0000-0002-4552-185X; Andrews, Nancy/0000-0003-0243-4462 FU NHLBI NIH HHS [R01 HL051057] NR 27 TC 26 Z9 28 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD AUG PY 2004 VL 112 IS 4 BP 543 EP 549 DI 10.1111/j.1365-2567.2004.01915.x PG 7 WC Immunology SC Immunology GA 839RG UT WOS:000222801700004 PM 15270724 ER PT J AU Asaduzzaman, M Ryan, ET John, M Hang, L Khan, AI Faruque, ASG Taylor, RK Calderwood, SB Qadri, F AF Asaduzzaman, M Ryan, ET John, M Hang, L Khan, AI Faruque, ASG Taylor, RK Calderwood, SB Qadri, F TI The major subunit of the toxin-coregulated pilus TcpA induces mucosal and systemic immunoglobulin A immune responses in patients with cholera caused by Vibrio cholerae O1 and O139 SO INFECTION AND IMMUNITY LA English DT Article ID RURAL EAST PAKISTAN; VACCINE FIELD-TRIAL; ANTIBODY TITRE; COLONIZATION FACTOR; CELL RESPONSES; INFECTION; PROTECTION; GENES; IMMUNOGENICITY; SUSCEPTIBILITY AB Diarrhea caused by Vibrio cholerae is known to give long-lasting protection against subsequent life-threatening illness. The serum vibriocidal antibody response has been well studied and has been shown to correlate with protection. However, this systemic antibody response may be a surrogate marker for mucosal immune responses to key colonization factors of this organism, such as the toxin-coregulated pilus (TCP) and other factors. Information regarding immune responses to TCP, particularly mucosal immune responses, is lacking, particularly for patients infected with the El Tor biotype of V. cholerae O1 or V cholerae O139 since highly purified TcpA from these strains has not been available previously for use in immune assays. We studied the immune responses to El Tor TcpA in cholera patients in Bangladesh. Patients had substantial and significant increases in TepA-specific antibody-secreting cells in the circulation on day 7 after the onset of illness, as well as similar mucosal responses as determined by an alternate technique, the assay for antibody in lymphocyte supernatant. Significant increases in antibodies to TcpA were also seen in sera and feces of patients on days 7 and 21 after the onset of infection. Overall, 93% of the patients showed a TcpA-specific response in at least one of the specimens compared with the results obtained on day 2 and with healthy controls. These results demonstrate that TcpA is immunogenic following natural V. cholerae infection and suggest that immune responses to this antigen should be evaluated for potential protection against subsequent life-threatening illness. C1 ICDDR B, Lab Sci Div, Dhaka 1212, Bangladesh. Massachusetts Gen Hosp, Div Infect Dis, Boston, MA USA. Dartmouth Coll Sch Med, Dept Microbiol & Immunol, Hanover, NH USA. RP Qadri, F (reprint author), ICDDR B, Lab Sci Div, Dhaka 1212, Bangladesh. EM fqadri@icddrb.org FU FIC NIH HHS [D43 TW005572, D43 TW05572]; NIAID NIH HHS [U01 AI058935, R01 AI040725, R01 AI40725, UO1 AI58935] NR 30 TC 27 Z9 31 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 AUG PY 2004 VL 72 IS 8 BP 4448 EP 4454 DI 10.1128/IAI.72.8.4448-4454.2004 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 841LW UT WOS:000222932600016 PM 15271902 ER PT J AU Moy, TI Mylonakis, E Calderwood, SB Ausubel, FM AF Moy, TI Mylonakis, E Calderwood, SB Ausubel, FM TI Cytotoxicity of hydrogen peroxide produced by Enterococcus faecium SO INFECTION AND IMMUNITY LA English DT Article ID CAENORHABDITIS-ELEGANS; STREPTOCOCCUS-PNEUMONIAE; PSEUDOMONAS-AERUGINOSA; NADH OXIDASE; STAPHYLOCOCCUS-AUREUS; EXTRACELLULAR-SUPEROXIDE; VIRULENCE FACTORS; MODEL HOST; FAECALIS; GENE AB Although the opportunistic bacterial pathogen Enterococcus faecium is a leading source of nosocomial infections, it appears to lack many of the overt virulence factors produced by other bacterial pathogens, and the underlying mechanism of pathogenesis is not clear. Using E. faecium-mediated killing of the nematode worm Caenorhabditis elegans as an indicator of toxicity, we determined that E. faecium produces hydrogen peroxide at levels that cause cellular damage. We identified E. faecium transposon insertion mutants with altered C elegans killing activity, and these mutants were altered in hydrogen peroxide production. Mutation of an NADH oxidase-encoding gene eliminated nearly all NADH oxidase activity and reduced hydrogen peroxide production. Mutation of an NADH peroxidase-encoding gene resulted in the enhanced accumulation of hydrogen peroxide. E. faecium is able to produce hydrogen peroxide by using glycerol-3-phosphate oxidase, and addition of glycerol to the culture medium enhanced the killing of C elegans. Conversely, addition of glucose, which leads to the down-regulation of glycerol metabolism, prevented both C. elegans killing and hydrogen peroxide production. Lastly, detoxification of hydrogen peroxide either by exogenously added catalase or by a C. elegans transgenic strain overproducing catalase prevented E. faecium-mediated killing. These results suggest that hydrogen peroxide produced by E. faecium has cytotoxic effects and highlight the utility of C. elegans pathogenicity models for identifying bacterial virulence factors. C1 Massachusetts Gen Hosp, Dept Biol Mol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. RP Ausubel, FM (reprint author), Massachusetts Gen Hosp, Dept Biol Mol, 55 Fruit St, Boston, MA 02114 USA. EM ausubel@molbio.mgh.harvard.edu FU NIGMS NIH HHS [GM48707, R37 GM048707, R01 GM048707] NR 62 TC 39 Z9 50 U1 1 U2 5 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 AUG PY 2004 VL 72 IS 8 BP 4512 EP 4520 DI 10.1128/IAI.72.8.4512-4520.2004 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 841LW UT WOS:000222932600024 PM 15271910 ER PT J AU Bhabhra, R Miley, MD Mylonakis, E Boettner, D Fortwendel, J Panepinto, JC Postow, M Rhodes, JC Askew, DS AF Bhabhra, R Miley, MD Mylonakis, E Boettner, D Fortwendel, J Panepinto, JC Postow, M Rhodes, JC Askew, DS TI Disruption of the Aspergillus fumigatus gene encoding nucleolar protein CgrA impairs thermotolerant growth and reduces virulence SO INFECTION AND IMMUNITY LA English DT Article ID PRE-RIBOSOMAL-RNA; INVASIVE PULMONARY ASPERGILLOSIS; SACCHAROMYCES-CEREVISIAE; CRYPTOCOCCUS-NEOFORMANS; HEAT-SHOCK; DROSOPHILA-MELANOGASTER; ESCHERICHIA-COLI; PSEUDOMONAS-AERUGINOSA; SUBUNIT BIOGENESIS; MOLECULAR ANALYSIS AB Aspergillus fumigatus CgrA is the ortholog of a yeast nucleolar protein that functions in ribosome synthesis. To determine how CgrA contributes to the virulence of A. fumigatus, a DeltacgrA mutant was constructed by targeted gene disruption, and the mutant was reconstituted to wild type by homologous introduction of a functional cgrA gene. The DeltacgrA mutant had the same growth rate as the wild type at room temperature. However, when the cultures were incubated at 37degreesC, a condition that increased the growth rate of the wild-type and reconstituted strains approximately threefold, the DeltacgrA mutant was unable to increase its growth rate. The absence of cgrA function caused a delay in both the onset and rate of germination at 37degreesC but had little effect on germination at room temperature. The DeltacgrA mutant was significantly less virulent than the wild-type or reconstituted strain in immunosuppressed mice and was associated with smaller fungal colonies in lung tissue. However, this difference was less pronounced in a Drosophila infection model at 25degreesC, which correlated with the comparable growth rates of the two strains at this temperature. To determine the intracellular localization of CgrA, the protein was tagged at the C terminus with green fluorescent protein, and costaining with propidium iodide revealed a predominantly nucleolar localization of the fusion protein in living hyphae. Together, these findings establish the intracellular localization of CgrA in A. fumigatus and demonstrate that cgrA is required for thermotolerant growth and wild-type virulence of the organism. C1 Univ Cincinnati, Coll Med, Dept Pathol & Lab Med, Cincinnati, OH 45267 USA. Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Askew, DS (reprint author), Univ Cincinnati, Coll Med, Dept Pathol & Lab Med, 231 Bethesda Ave, Cincinnati, OH 45267 USA. EM David.Askew@uc.edu RI Boettner, Douglas/I-3218-2012; OI Boettner, Douglas/0000-0002-0591-443X FU NIAID NIH HHS [R01 AI041119, R01 AI048746, R01 AI48746, R01AI41119] NR 70 TC 77 Z9 84 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 AUG PY 2004 VL 72 IS 8 BP 4731 EP 4740 DI 10.1128/IAI.72.8.4731-4740.2004 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 841LW UT WOS:000222932600049 PM 15271935 ER PT J AU Agarwal, S Giannoudis, PV Smith, RM AF Agarwal, S Giannoudis, PV Smith, RM TI Cruciate fracture of the distal femur: the double Hoffa fracture SO INJURY-INTERNATIONAL JOURNAL OF THE CARE OF THE INJURED LA English DT Article ID UNICONDYLAR FRACTURES; TIBIAL PLATEAU C1 Massachusetts Gen Hosp, Dept Orthopaed Surg, Orthopaed Trauma Serv, Boston, MA 02114 USA. St James Univ Hosp, Dept Orthopaed Surg, Leeds LS9 7TF, W Yorkshire, England. RP Smith, RM (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Orthopaed Trauma Serv, WACC 5-525,55 Fruit St, Boston, MA 02114 USA. EM msmith23@partners.org NR 6 TC 4 Z9 7 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0020-1383 J9 INJURY JI Injury-Int. J. Care Inj. PD AUG PY 2004 VL 35 IS 8 BP 828 EP 830 DI 10.1016/S0020-1383(02)00168-7 PG 3 WC Critical Care Medicine; Emergency Medicine; Orthopedics; Surgery SC General & Internal Medicine; Emergency Medicine; Orthopedics; Surgery GA 841LZ UT WOS:000222932900020 PM 15246811 ER PT J AU Niwa, K Perloff, JK Webb, GD Murphy, D Liberthson, R Warnes, CA Gatzoulis, MA AF Niwa, K Perloff, JK Webb, GD Murphy, D Liberthson, R Warnes, CA Gatzoulis, MA TI Survey of specialized tertiary care facilities for adults with congenital heart disease SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE adult congenital heart disease; specialized tertiary care facilities; congenital heart surgery ID CARDIAC-SURGERY; FOLLOW-UP; 2 PARTS; MANAGEMENT; PROGRAM; LIFE AB Background: Specialized tertiary care facilities developed in response to the increasing numbers of adults with congenital heart disease (CHD). Because this patient population comprises a relatively new area of specialized cardiovascular interest, the first facilities necessarily evolved without preexisting guidelines or interaction. Objectives: To characterize the major features of the six original and largest tertiary adults CHD facilities. Methods: Written questionnaire sent to six participating facilities in North America and Europe. Information was analyzed centrally. Results: All but one facilities was established over 20 years ago, and each cares for over 1500 patients. Hospital admissions ranged from 100 to 660 patients/unit/year. Of the total number of registered patients, 52-81% had undergone one or more reparative surgeries. Reoperations constituted 25-80% of the 50-170 operations/unit/year. Overall mean surgical mortality was 1.9%/year. Inpatient and outpatient care was provided in adult (n = 4) or both adult and pediatric (n = 2) settings. All six facilities enjoyed close collaboration between adult and pediatric cardiologists, cardiac surgeons, nurse specialists and cardiac and non-cardiac consultants. Training and research were pivotal activities. Conclusions: Provision of comprehensive care by multidisciplinary learns including adult and pediatric cardiologists, cardiac surgeons, specialized nurses and other cardiac and non-cardiac consultants was the unifying feature for all six tertiary care facilities reported here. There were minor differences among them based on available resources, local expertise and national health care policies. There appears to be a significant shortfall in tertiary care provision for the adult with CHD that requires further planning and resource allocation. These data may be useful for new and evolving adult CHD services. (C) 2003 Elsevier Ireland Ltd. All rights reserved. C1 Chiba Cardiovasc Ctr, Dept Pediat, Chiba 2900512, Japan. Ahmanson UCLA Adult Congenital Heart Dis Ctr, Los Angeles, CA USA. Univ Toronto, Congenital Cardias Ctr Adults, Toronto, ON, Canada. Cleveland Clin Fdn, Ctr Pediat & Congenital Heart Dis, Cleveland, OH 44195 USA. Massachusetts Gen Hosp, Massachussets Congenital Heart Dis Program, Boston, MA 02114 USA. Mayo Clin, Adult Congenital Heart Dis Clin, Rochester, MN USA. Royal Brompton Adult Congenital Heart Program, London, England. RP Niwa, K (reprint author), Chiba Cardiovasc Ctr, Dept Pediat, 575 Tsurumai, Chiba 2900512, Japan. EM KNIWA@aol.com NR 26 TC 46 Z9 46 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD AUG PY 2004 VL 96 IS 2 BP 211 EP 216 DI 10.1016/ijcard.2003.06.019 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 843WH UT WOS:000223117000014 PM 15262035 ER PT J AU Ren, JQ Malanga, CJ Tabit, E Kosofsky, BE AF Ren, JQ Malanga, CJ Tabit, E Kosofsky, BE TI Neuropathological consequences of prenatal cocaine exposure in the mouse SO INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE LA English DT Article DE cocaine; prenatal; gestation; brain growth; cortical lamination; cytoarchitecture; morphometry; dil; mouse drug abuse ID CEREBRAL-CORTEX; GANGLIONIC EMINENCE; BRAIN-DEVELOPMENT; FETAL GROWTH; BEHAVIOR; MODEL; DRUGS; RAT; BENZOYLECGONINE; DECREASES AB We have developed an animal model in Swiss Webster mice to identify mechanisms by which prenatal exposure to cocaine results in persistent alterations in brain structure and function. Clinical data suggests that children who demonstrate the largest impairments in prenatal brain growth, which are positively correlated with the highest level of prenatal cocaine exposure, are more likely to demonstrate selective impairment in postnatal brain growth, as well as postnatal impairments in motor function, attention and language skills. We conducted neuroanatomic studies to identify the postnatal evolution of structural changes in the primary somatosensory (SI) cortex of the developing mouse brain following prenatal exposure to cocaine. Our previous work, and that of others, provides evidence that many of the processes underlying corticogenesis are disrupted by gestational exposure of the developing mouse brain to cocaine, and that from the earliest phases of corticogenesis that there is an imprecision in the development of cortical lamination. We performed morphometric comparisons between the brains of animals prenatally exposed to varying amounts of cocaine with vehicle and malnutrition controls on postnatal (P) days P9 and P50. We found that on P50, but not P9, the relative number of cortical neurons in S I is significantly less in cocaine exposed animals as compared with controls. The significant decrease in the number of cells in cocaine exposed animals on P50 is evident as a decreased density of cells restricted to the infragranular compartment (layers V and VI). Those changes are not seen in malnourished animals. Taken together our findings support the conclusion that cocaine-induced alterations in SI cortical cytoarchitectonics are in part a consequence of altered postnatal survival of infragranular cortical neurons, which are lost during the interval between P9 and P50. Determining whether a similar process is evident in a subset of humans following in utero cocaine exposure is a high priority for future clinical brain imaging studies, because analogous structural changes could impact the brain function and behavioral repertoire of infants and children following significant prenatal exposures. (C) 2004 ISDN. Published by Elsevier Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Lab Mol & Dev Neurosci, Dept Neurol, Charlestown, MA 02129 USA. RP Kosofsky, BE (reprint author), Massachusetts Gen Hosp, Lab Mol & Dev Neurosci, Dept Neurol, Room 2508,149 13th St, Charlestown, MA 02129 USA. EM kosofsky@helix.mgh.harvard.edu OI Malanga, C.J./0000-0003-4808-3995 FU NIDA NIH HHS [DA008648, R29 DA008648, K08 DA015429-02, K08 DA015429, K02 DA000354, DA000354, R01 DA008648, DA015429] NR 51 TC 25 Z9 26 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0736-5748 J9 INT J DEV NEUROSCI JI Int. J. Dev. Neurosci. PD AUG-OCT PY 2004 VL 22 IS 5-6 BP 309 EP 320 DI 10.1016/j.ijdevneu.2004.05.003 PG 12 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 861XR UT WOS:000224452400007 PM 15380830 ER PT J AU Keogh, IJ Godinho, RN Wu, TP de Palacios, AMD Palacios, N de Alford, MB De Almada, MI MarPalacios, N Vazquez, A Mattei, R Seidman, C Seidman, J Eavey, RD AF Keogh, IJ Godinho, RN Wu, TP de Palacios, AMD Palacios, N de Alford, MB De Almada, MI MarPalacios, N Vazquez, A Mattei, R Seidman, C Seidman, J Eavey, RD TI Clinical and genetic linkage analysis of a large Venezuelan kindred with Usher syndrome SO INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the European-Society-of-Pediatric-Otolaryngology CY SEP 16, 2002 CL Oxford, ENGLAND SP European Soc Pediat Otolaryngol DE Usher syndrome 1B; myosin VIIA; linkage analysis; retinitis pigmentosa; sensorineural hearing loss ID MYOSIN-VIIA GENE; 1B SYNDROME; DEAFNESS; MUTATION; DIAGNOSIS; FAMILIES; SHAKER-1; MOUSE AB Objective: To undertake a comprehensive investigation into the very high incidence of congenital deafness on the Macano peninsula of Margarita Island, Venezuela. Methods: Numerous visits were made to the isolated island community over a 4-year-period. During these visits, it became apparent that a significant number of individuals complained of problems with hearing and vision. Socioeconomic assessments, family pedigrees and clinical histories were recorded on standard questionnaires. ALL individuals underwent thorough otolaryngotogic and ophthalmologic examinations. Twenty milliliters of peripheral venous blood was obtained from each participant. A Genome-wide linkage analysis study was performed. Polymorphic microsatellite markers were amplified by polymerase chain reaction and separated on polyacrylamide gets. An ABI 377XL sequencer was used to separate fragments and LOD scores were calculated by using published software. Results: Twenty-four families were identified, comprising 329 individuals, age range 1-80 years, including 184 children. All families were categorized in the lower two (least affluent) socioeconomic categories. A high incidence of consanguinity was detected. Fifteen individuals (11 adults, 4 children) had profound congenital sensorineurat hearing Loss, vestibular areflexia and retinitis pigmentosa. A maximum LOD score of 6.76 (Linkage > 3.0), between markers D11s4186 and D11s911, confirmed linkage to chromosome 11q13.5. The gene myosin VIIA (MYO7A) was confirmed in the interval. Clinical and genetic findings are consistent with a diagnosis of Usher syndrome 1 B for those with hearing and vision problems. Conclusions: We report 15 Usher syndrome 1B individuals from a newly detected Latin American socio-demographic origin, with a very high prevalence of 76 per 100,000 population. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Div Pediat Otolaryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. Hosp Luis Ortega, Porlamar, Margarita Isl, Venezuela. RP Keogh, IJ (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Div Pediat Otolaryngol, Boston, MA 02114 USA. EM ivankeogh@oceanfree.net RI KEOGH, IVAN/M-2704-2016 OI KEOGH, IVAN/0000-0001-6358-6377 NR 26 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0165-5876 J9 INT J PEDIATR OTORHI JI Int. J. Pediatr. Otorhinolaryngol. PD AUG PY 2004 VL 68 IS 8 BP 1063 EP 1068 DI 10.1016/j.ijporl.2004.04.005 PG 6 WC Otorhinolaryngology; Pediatrics SC Otorhinolaryngology; Pediatrics GA 845LM UT WOS:000223244200010 PM 15236894 ER PT J AU Dibart, S Capri, D Casavecchia, P Nunn, M Skobe, Z AF Dibart, S Capri, D Casavecchia, P Nunn, M Skobe, Z TI Comparison of the effectiveness of scaling and root planing in vivo using hand vs rotary instruments SO INTERNATIONAL JOURNAL OF PERIODONTICS & RESTORATIVE DENTISTRY LA English DT Article ID PERIODONTALLY DISEASED TEETH; HEALING FOLLOWING TREATMENT; DEMINERALIZED DENTIN; FIBER ATTACHMENT; RADICULAR DENTIN; CEMENTUM; ROUGHNESS; ENDOTOXIN; SURFACES; REMOVAL AB The purpose of the present investigation was to compare the effectiveness of a scaling bur and conventional Gracey curettes in vivo. Ten teeth scheduled for extraction were scaled and root planed thoroughly before extraction. The instrumented areas were observed using SEM. Scaling with a No. 12 fluted carbide bur was more effective in removing debris and plaque than were conventional Gracey curettes. Because of the aggressive nature of the process, a certain learning curve is necessary to get accustomed to bur scaling; otherwise, dentinal hypersensitivity and patient discomfort may be increased. C1 Boston Univ, Sch Dent Med, Dept Periodontol & Oral Biol, Boston, MA 02118 USA. Boston Univ, Sch Dent Med, Dept Hlth Policy & Hlth Serv Res, Boston, MA 02118 USA. Forsyth Inst, Dept Electron Microscopy, Boston, MA USA. RP Dibart, S (reprint author), Boston Univ, Sch Dent Med, Dept Periodontol & Oral Biol, 100 E Newton St, Boston, MA 02118 USA. NR 34 TC 0 Z9 0 U1 0 U2 2 PU QUINTESSENCE PUBL CO INC PI CAROL STREAM PA 551 NORTH KIMBERLY DR, CAROL STREAM, IL 60188-1881 USA SN 0198-7569 J9 INT J PERIODONT REST JI Int. J. Periodontics Restor. Dent. PD AUG PY 2004 VL 24 IS 4 BP 371 EP + PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 850XI UT WOS:000223647300007 ER PT J AU Delgado, JC Quinones-Berrocal, J Thim, S Miranda, LF Goldfeld, AE AF Delgado, JC Quinones-Berrocal, J Thim, S Miranda, LF Goldfeld, AE TI Diagnostic and clinical implications of response to tuberculin in two ethnically distinct populations from Peru and Cambodia SO INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE LA English DT Article DE tuberculosis diagnosis; tuberculin testing; BCG vaccination ID CALMETTE-GUERIN VACCINATION; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; ANERGY; REACTIVITY; PREVALENCE; VIRULENT; ADULTS AB BACKGROUND: Proper interpretation of the tuberculin skin test (TST) requires knowledge about prior vaccination with BCG and the results of epidemiological studies with the test. DESIGN: A TST survey was performed in patients with pulmonary tuberculosis (PTB) in two ethnically distinct populations from Cambodia and the Peruvian Andes. We examined interferon-gamma (IFN-gamma) production in whole blood cultures stimulated by ESAT-6, a Mycobacterium tuberculosis specific antigen in tuberculin-positive BCG-vaccinated Peruvians with no history of PTB. RESULTS: Of the 81 Peruvian PTB patients tested, none had a skin response to tuberculin that was <10 mm, whereas 98 of 364 Cambodian PTB patients (37%) did. Furthermore, TST skin reaction sizes were significantly larger in Peruvian (21.69 +/- 5.46 mm) than Cambodian patients (11.42 +/- 7.74 mm; P < 0.0001). IFN-gamma production in response to ESAT-6 correlated with a TST reaction size > 15 mm indicating previous infection with M. tuberculosis (kappa coefficient of agreement 0.66; 95%CI 0.29-1). CONCLUSION: Ethnicity is an important factor in the interpretation of TST results in both BCG-vaccinated and non-vaccinated individuals. A negative TST appears to be a useful indicator to rule out tuberculosis infection in Peruvians of Quechua origin. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Hosp Antonio Lorena, Cuzco, Peru. Cambodian Hlth Comm, Phnom Penh, Cambodia. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Goldfeld, AE (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. EM goldfeld@cbr.med.harvard.edu FU NHLBI NIH HHS [HL-59838, HL-67471] NR 21 TC 7 Z9 8 U1 0 U2 0 PU INT UNION AGAINST TUBERCULOSIS LUNG DISEASE (I U A T L D) PI PARIS PA 68 BOULEVARD SAINT-MICHEL,, 75006 PARIS, FRANCE SN 1027-3719 J9 INT J TUBERC LUNG D JI Int. J. Tuberc. Lung Dis. PD AUG PY 2004 VL 8 IS 8 BP 982 EP 987 PG 6 WC Infectious Diseases; Respiratory System SC Infectious Diseases; Respiratory System GA 842YJ UT WOS:000223040300010 PM 15305481 ER PT J AU Cense, B Chen, TC Park, BH Pierce, MC de Boer, JF AF Cense, B Chen, TC Park, BH Pierce, MC de Boer, JF TI Thickness and birefringence of healthy retinal nerve fiber layer tissue measured with polarization-sensitive optical coherence tomography SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID SCANNING LASER POLARIMETRY; COMPENSATION; GLAUCOMA AB PURPOSE. Thinning of the retinal nerve fiber layer and changes in retinal nerve fiber layer (RNFL) birefringence may both precede clinically detectable glaucomatous vision loss. Early detection of RNFL changes may enable treatment to prevent permanent loss of vision. Polarization-sensitive optical coherence tomography (PS-OCT) can provide objective information on RNFL thickness and birefringence. METHODS. PS-OCT scans around the optic nerve head (ONH) of two healthy young volunteers were made using 10 concentric circles of increasing radius. Both the mean RNFL thickness and mean retinal nerve fiber birefringence for each of 48 sectors on a circle were determined with data analysis. RESULTS. Both the RNFL thickness and birefringence varied as a function of sector around the ONH. The RNFL became thinner with increasing distance from the ONH. In contrast, the birefringence did not vary significantly as a function of radius. CONCLUSIONS. Birefringence of healthy RNFL is constant as a function of scan radius but varies as a function of position around the ONH, with higher thickness values occurring superior and inferior to the ONH. Measured double-pass phase retardation per unit depth around the ONH ranged between 0.10 and 0.35 deg/mum, equivalent to birefringences of 1.2 x 10(-4) and 4.1 x 10(-4) respectively, measured at a wavelength of 840 nm. Consequently, when a spatially constant birefringence around the ONH is assumed, the conversion of scanning laser polarimetry (SLP) phase-retardation measurements to RNFL thickness may yield incorrect values. The data do not invalidate the clinical value of a phase-retardation measurement, but affect the conversion of phase retardation to RNFL thickness. C1 Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP de Boer, JF (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Bartlett 726,50 Blossom St, Boston, MA 02114 USA. EM deboer@helix.mgh.harvard.edu RI de Boer, Johannes/B-7590-2012 OI de Boer, Johannes/0000-0003-1253-4950 FU NEI NIH HHS [1R 24 EY 12877] NR 20 TC 146 Z9 149 U1 1 U2 5 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 AUG PY 2004 VL 45 IS 8 BP 2606 EP 2612 DI 10.1167/iovs.03-1160 PG 7 WC Ophthalmology SC Ophthalmology GA 841DC UT WOS:000222908500022 PM 15277483 ER PT J AU Swarup, A Sachdeva, N Schumacher, HR AF Swarup, A Sachdeva, N Schumacher, HR TI Dosing of antirheumatic drugs in renal disease and dialysis SO JCR-JOURNAL OF CLINICAL RHEUMATOLOGY LA English DT Review DE rheumatoid arthritis; gout; renal insufficiency; drug dosing; hemodialysis ID ANTITUMOR NECROSIS FACTOR; URINARY PROSTAGLANDIN EXCRETION; LOW-DOSE METHOTREXATE; RHEUMATOID-ARTHRITIS; CLINICAL PHARMACOKINETICS; MYCOPHENOLATE-MOFETIL; PERITONEAL-DIALYSIS; TRANSPLANT RECIPIENTS; CYCLOOXYGENASE-2 INHIBITION; KETOROLAC TROMETHAMINE AB Many patients with rheumatic diseases have their management complicated by renal problems. Renal failure modifies the metabolism of many drugs, especially by retention. Questions often arise about the effects of renal failure on the handling of drugs commonly used in rheumatology. For which drugs must we be especially concerned about increased toxicity? Patients on chronic dialysis may also need a variety of drugs for rheumatic disease. How are our drugs dialyzed, and which of these can be safety used and how best to use them? Decisions about dosing of rheumatic drugs are often required for the patients with chronic renal insufficiency or on long-term dialysis, although many drugs have not been formally studied in these settings. Patients with renal insufficiency are excluded from most drug trials. Data for some of these drugs have to be extrapolated based on the information available about the pharmacokinetics of the drug. This review addresses dosing of commonly used drugs in rheumatology in patients with chronic renal insufficiency or failure. It is compiled from a MEDLINE search of papers dealing with renal handling of antirheumatic drugs and suggestions for dose adjustments for these drugs. Drugs reviewed include commonly used disease-modifying antirheumatic drugs (DMARDS), drugs used for treatment of gout, commonly used nonsteroidal antnflammatory drugs (NSAIDS) and the newer COX-2 inhibitors. C1 Arizona Arthritis Rheumatol Associates, Paradise Valley, AZ USA. Wall St Internal Med, Louisville, KY USA. Univ Penn, Sch Med, Div Rheumatol, Philadelphia, PA 19104 USA. Dept Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. RP Swarup, A (reprint author), 10599 N Tatum Blvd S,F 150, Paradise Valley, AZ 85253 USA. EM areena1@hotmail.com NR 131 TC 8 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-1608 J9 JCR-J CLIN RHEUMATOL JI JCR-J. Clin. Rheumatol. PD AUG PY 2004 VL 10 IS 4 BP 190 EP 204 DI 10.1097/01.rhu.0000135555.83088.a2 PG 15 WC Rheumatology SC Rheumatology GA 846DZ UT WOS:000223296600006 PM 17043508 ER PT J AU Cibis, GW Walton, DS AF Cibis, GW Walton, DS TI Congenital pupillary-iris-lens membrane with goniodysgenesis SO JOURNAL OF AAPOS LA English DT Article; Proceedings Paper CT 29th Annual Meeting of the American-Association-for-Pediatric-Ophthalmology-and-Strabismus CY MAR 23-27, 2003 CL WIAKOLO, HI SP Amer Assoc Pediatric Ophthalmol Strabismus AB Background. A unilateral congenital pupil-iris-lens membrane with goniodysgenesis syndrome, not benign tunica vasculosa lentis, was first described by Cibis et al. One of three cases developed angle closure. Robb described catastrophic vision loss from angle closure in one of his seven cases. Methods: We did a retrospective review of previously unreported cases of pupil-iris-lens membrane with goniodysgenesis seen in our practices. Results: We report the clinical spectrum of a further nine cases, three of which needed surgery for angle closure, two of which needed surgery for clearing the visual axis. Conclusion: Congenital pupil-iris-lens membrane with goniodysgenesis is a unilateral membrane clearly differentiated from benign persistent tunica vasculosa lentis tissue. The membrane represents ectopic iris on the lens with abnormal iris stroma and chamber angle from aberrant induction, migration, or regression of neural crest cells. The membrane can be progressive. Catastrophic vision loss from angle closure can occur and may be controlled with surgery. Surgery may be needed to open the visual axis even when glaucoma is not present and may prevent angle closure. C1 Univ Kansas, Med Ctr, Dept Ophthalmol, Kansas City, KS 66103 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. RP Cibis, GW (reprint author), 4621 JC Nichols Pkwy 421, Kansas City, MO 64112 USA. NR 4 TC 14 Z9 15 U1 1 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1091-8531 J9 J AAPOS JI J. AAPOS PD AUG PY 2004 VL 8 IS 4 BP 378 EP 383 DI 10.1016/j.jaapas.2004.04.010 PG 6 WC Ophthalmology; Pediatrics SC Ophthalmology; Pediatrics GA 846YM UT WOS:000223355600015 PM 15314601 ER PT J AU Chen, T Hosogi, Y Nishikawa, K Abbey, K Fleischmann, RD Walling, J Duncan, MJ AF Chen, T Hosogi, Y Nishikawa, K Abbey, K Fleischmann, RD Walling, J Duncan, MJ TI Comparative whole-genome analysis of virulent and avirulent strains of Porphyromonas gingivalis SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ALVEOLAR BONE LOSS; BACTEROIDES-GINGIVALIS; STREPTOCOCCUS-MUTANS; SEQUENCE; IDENTIFICATION; MODEL; PERIODONTITIS; MICROARRAY; BIOFILMS; MICE AB We used Porphyromonas gingivalis gene microarrays to compare the total gene contents of the virulent strain W83 and the avirulent type strain, ATCC 33277. Signal ratios and scatter plots indicated that the chromosomes were very similar, with approximately 93% of the predicted genes in common, while at least 7% of them showed very low or no signals in ATCC 33277. Verification of the array results by PCR indicated that several of the disparate genes were either absent from or variant in ATCC 33277. Divergent features included already reported insertion sequences and ragB, as well as additional hypothetical and functionally assigned genes. Several of the latter were organized in a putative operon in W83 and encoded enzymes involved in capsular polysaccharide synthesis. Another cluster was associated with two paralogous regions of the chromosome with a low G+C content, at 41%, compared to that of the whole genome, at 48%. These regions also contained conserved and species-specific hypothetical genes, transposons, insertion sequences, and integrases and were located adjacent to tRNA genes; thus, they had several characteristics of pathogenicity islands. While this global comparative analysis showed the close relationship between W83 and ATCC 33277, the clustering of genes that are present in W83 but divergent in or absent from ATCC 33277 is suggestive of chromosomal islands that may have been acquired by lateral gene transfer. C1 Forsyth Inst, Dept Mol Genet, Boston, MA 02115 USA. Inst Genom Res, Rockville, MD 20850 USA. RP Duncan, MJ (reprint author), Forsyth Inst, Dept Mol Genet, 140 Fenway, Boston, MA 02115 USA. EM mduncan@forsyth.org FU NIDCD NIH HHS [R01 DC012082]; NIDCR NIH HHS [K22 DE014742, K22 DE14742, R01 DE010510, R01 DE12082, R01DE10510] NR 34 TC 58 Z9 72 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD AUG PY 2004 VL 186 IS 16 BP 5473 EP 5479 DI 10.1128/JB.186.16.5473-5479.2004 PG 7 WC Microbiology SC Microbiology GA 844SC UT WOS:000223179000032 PM 15292149 ER PT J AU Lee, H Ryan, RT Kim, J Choi, B Arakeri, NV Teichman, JMH Welch, AJ AF Lee, H Ryan, RT Kim, J Choi, B Arakeri, NV Teichman, JMH Welch, AJ TI Dependence of calculus retropulsion dynamics on fiber size and radiant exposure during Ho : YAG lithotripsy SO JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; PULSED DYE-LASER; SOLID BOUNDARY; CAVITATION BUBBLES; BIOLOGICAL TISSUES; URINARY CALCULI; ABLATION; RADIATION; COLLAPSE AB During pulsed laser lithotripsy, the calculus is subject to a strong recoil momentum which moves the calculus away from laser delivery and prolongs the operation. This study was designed to quantify the recoil momentum during Ho:YAG laser lithotripsy. The correlation among crater shape, debris trajectory, laser-induced bubble and recoil momentum was investigated. Calculus phantoms made from plaster of Paris were ablated with free. running Ho:YAG lasers. The dynamics of recoil action of a calculus phantom was monitored by a high-speed video camera and the laser ablation craters were examined with Optical Coherent Tomography (OCT). Higher radiant exposure resulted in larger ablation volume (mass) which increased the recoil momentum. Smaller fibers produced narrow craters with a steep contoured geometry and decreased recoil momentum compared to larger fibers. In the presence of water recoil motion of the phantom deviated from that of phantom in air Under certain conditions, we observed the phantom rocking towards the fiber after the laser pulse. The shape of the crater is one of the major contributing factors to the diminished recoil momentum of smaller fibers. The re-entrance flow of water induced by the bubble collapse is considered to be the cause of the rocking of the phantom. C1 Harvard Univ, Sch Med, Wellman Labs Photomed, Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Texas, Dept Mech Engn, Austin, TX 78712 USA. Univ Texas, Hlth Sci Ctr, Div Urol, San Antonio, TX 78229 USA. Univ Texas, Dept Biomed Engn, Austin, TX 78712 USA. Univ Calif Irvine, Beckman Laser Inst & Med Clin, Irvine, CA 92612 USA. RP Lee, H (reprint author), Harvard Univ, Sch Med, Wellman Labs Photomed, Massachusetts Gen Hosp, BHX 630,50 Blossom St, Boston, MA 02114 USA. EM hlee14@partners.org; urobro@msn.com; jeehyun@mail.utexas.edu; bchoi@laser.bli.uci.edu; navanit_a@hotmail.com; teichman@uthscsa.edu; welch@mail.utexas.edu NR 32 TC 9 Z9 9 U1 0 U2 2 PU ASME-AMER SOC MECHANICAL ENG PI NEW YORK PA THREE PARK AVE, NEW YORK, NY 10016-5990 USA SN 0148-0731 J9 J BIOMECH ENG-T ASME JI J. Biomech. Eng.-Trans. ASME PD AUG PY 2004 VL 126 IS 4 BP 506 EP 515 DI 10.1115/1.1786297 PG 10 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 864YI UT WOS:000224668800014 PM 15543869 ER PT J AU Ring, D Prommersberger, K Jupiter, JB AF Ring, D Prommersberger, K Jupiter, JB TI Combined dorsal and volar plate fixation of complex fractures of the distal part of the radius SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID DISPLACED ARTICULAR FRACTURES; INTRAARTICULAR FRACTURES; EXTERNAL FIXATION; OPEN REDUCTION; INTERNAL-FIXATION; END AB Background: Fractures of the distal part of the radius that are associated with complex comminution of both the articular surface and the metaphysis (subgroup C3.2 according to the Comprehensive Classification of Fractures) are a challenge for surgeons using standard operative techniques. Methods: Twenty-five patients with subgroup-C3.2 fractures that had been treated with combined dorsal and volar plate fixation were evaluated at an average of twenty-six months after the injury. Subsequent procedures included implant removal in twenty-one patients and reconstruction of a ruptured tendon in two patients. Results: An average of 54degrees of extension, 51degrees of flexion, 79degrees of pronation, and 74degrees of supination were achieved. The grip strength in the involved limb was an average of 78% of that in the contralateral limb. The average radiographic measurements were 2degrees of dorsal angulation, 21degrees of ulnar inclination, 0.8 mm of positive ulnar variance, and 0.7 mm of articular incongruity. Seven patients had radiographic signs of arthrosis during the follow-up period. A good or excellent functional result was achieved for twenty-four patients (96%) according to the rating system of Gartland and Werley and for ten patients (40%) according to the more stringent modified system of Green and O'Brien. Conclusions: Combined dorsal and volar plate fixation of the distal part of the radius can achieve a stable, mobile wrist in patients with very complex fractures. The results are limited by the severity of the injury and may deteriorate with longer follow-up. A second operation for implant removal is common, and there is a small risk of tendon-related complications. Level of Evidence: Therapeutic study, Level IV (case series [no, or historical, control group]). See Instructions to Authors for a complete description of levels of evidence. C1 Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. Klin Handchirurg, D-97615 Bad Neustadt an der Saale, Germany. RP Ring, D (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, ACC 525,15 Parkman St, Boston, MA 02114 USA. EM dring@partners.org NR 25 TC 26 Z9 34 U1 0 U2 0 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD AUG PY 2004 VL 86A IS 8 BP 1646 EP 1652 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 843NA UT WOS:000223089400007 PM 15292411 ER PT J AU Jamali, AA Dungy, DS Mark, A Schule, S Harris, WH AF Jamali, AA Dungy, DS Mark, A Schule, S Harris, WH TI Isolated acetabular revision with use of the Harris-Galante cementless component - Study with intermediate-term follow-up SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID TOTAL HIP-ARTHROPLASTY; CLASSIFICATION AB Background: Isolated revision of an acetabular total hip component is associated with special problems related to the retention of the femoral component. We reviewed the intermediate-term results of a series of such operations with use of the Harris-Galante Porous acetabular component. Methods: We retrospectively studied the results of ninety-five isolated acetabular revisions, specifically focusing on sixty-three that had been followed for a minimum of sixty months (average, 130 months). Evaluation measures included the Harris hip score, radiographic analysis, complications, and prosthetic survival. Follow-up information was obtained with self-administered questionnaires, telephone contact, and/or clinical examination. The effects of a femoral component with a modular neck-head junction and of trochanteric osteotomy on the dislocation rate were evaluated. Results: Nine shells were rerevised: four because of recurrent dislocation, four because of aseptic loosening, and one because of dissociation of the liner. The survival rate with rerevision of the shell as the end point was 90.5% at 120 months. Pelvic osteolysis occurred in 4% of the cases. The dislocation rate for the sixty-three hips was 8%. When femoral component modularity was accounted for, the analysis of the dislocations revealed a significantly higher dislocation rate for the hips without a trochanteric osteotomy (p = 0.04). Eight arthroplasties were complicated by nerve palsies, seven of which resolved fully or nearly so. Conclusions: Isolated acetabular revision with use of the Harris-Galante Porous acetabular component was associated with a low rate of loosening, lysis, and rerevision of the shell at the time of intermediate-term follow-up. However, there was a high rate of complications, including trochanteric nonunion, dislocation, and nerve palsy. The performance of a trochanteric osteotomy was associated with a decreased rate of dislocation. Level of Evidence: Therapeutic study, Level IV (case series [no, or historical, control group]). See Instructions to Authors for a complete description of levels of evidence. C1 Massachusetts Gen Hosp, Dept Orthopaed Surg, Orthopaed Biomech & Biomat Lab, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Orthopaed Surg, Adult Reconstruct Unit, Boston, MA 02114 USA. RP Jamali, AA (reprint author), Univ Calif Davis, Med Ctr, Dept Orthopaed Surg, 4860 Y St,Suite 3800, Sacramento, CA 95817 USA. EM amir.jamali@ucdmc.ucdavis.edu; dsdungy@aol.com; artmarkmd@yahoo.com; orifmd@yahoo.com; wharris.obbl@partners.org NR 16 TC 17 Z9 17 U1 0 U2 0 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD AUG PY 2004 VL 86A IS 8 BP 1690 EP 1697 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 843NA UT WOS:000223089400012 PM 15292416 ER PT J AU Li, G Most, E Sultan, PG Schule, S Zayontz, S Park, SE Rubash, HE AF Li, G Most, E Sultan, PG Schule, S Zayontz, S Park, SE Rubash, HE TI Knee kinematics with a high-flexion posterior stabilized total knee prosthesis: An in vitro robotic experimental investigation SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID FOLLOW-UP; FLUOROSCOPIC ANALYSIS; CONDYLAR PROSTHESIS; DEEP FLEXION; ARTHROPLASTY; RANGE; MOTION; MOVEMENT; BEARING; REPLACEMENT AB Background: An analysis of contemporary total knee arthroplasty reveals that, on the average, patients rarely flex the knee beyond 120degrees. The biomechanical mechanisms that inhibit further flexion after total knee arthroplasty are unknown. The objective of the present study was to investigate the capability of a single design of a fixed-bearing, high-flexion posterior stabilized total knee arthroplasty system (LPS-Flex) to restore the range of flexion to that of the intact knee. Methods: Thirteen cadaveric human knees were tested, with use of a robotic testing system, before and after total knee arthroplasty with the LPS-Flex prosthesis. The passive path and the kinematics under an isolated quadriceps force of 400 N, under an isolated hamstring force of 200 N, and with these forces combined were determined. Posterior femoral translation of the lateral and medial femoral condyles and tibial rotation were recorded from 0degrees to 150degrees of flexion. Results: The medial and lateral condyles of the intact knee translated posteriorly from full extension to 1500, reaching a mean peak (and standard deviation) of 22.9 +/- 11.3 mm and 31.9 +/- 12.5 mm, respectively, under the combined muscle forces. Following total knee arthroplasty, the amount of posterior femoral translation was lower than that observed in the intact knee. At 1500, approximately 90% of the intact posterior femoral translation was recovered by the total knee replacement. Internal tibial rotation was observed for all knees throughout the range of motion. The camspine mechanism engaged at approximately 800 and disengaged at 135degrees. Despite the absence of cam-spine engagement, further posterior femoral translation occurred from 135degrees to 150degrees. Conclusions: The tibiofemoral articular geometry of the intact knee and the knee after total knee arthroplasty with use of the LPS-Flex design demonstrated similar kinematics at high flexion angles. The cam-spine mechanism enhanced posterior femoral translation only at the mid-range of flexion. The femoral component geometry of the LPS-Flex total knee prosthesis may improve posterior tibiofemoral articulation contact in high flexion angles. Clinical Relevance: Although sufficient posterior femoral translation and tibial rotation were restored following total knee arthroplasty with the LPS-Flex prosthesis, these conditions alone may not be sufficient to fully produce the amount of knee flexion that is observed in the intact knee. The clinical outcome after total knee arthroplasty may be affected by other factors, such as preoperative range of motion, flexion space balancing, posterior tibiofemoral articular contact stability, quadriceps contraction, and patient motivation. C1 Massachusetts Gen Hosp, Bioengn Lab, Dept Orthopaed Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Li, G (reprint author), Massachusetts Gen Hosp, Bioengn Lab, Dept Orthopaed Surg, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. EM glil@partners.org NR 53 TC 64 Z9 70 U1 0 U2 6 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD AUG PY 2004 VL 86A IS 8 BP 1721 EP 1729 PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 843NA UT WOS:000223089400017 PM 15292421 ER PT J AU Gopal, S Giannoudis, PV Murray, A Matthews, SJ Smith, RM AF Gopal, S Giannoudis, PV Murray, A Matthews, SJ Smith, RM TI The functional outcome of severe, open tibial fractures managed with early fixation and flap coverage SO JOURNAL OF BONE AND JOINT SURGERY-BRITISH VOLUME LA English DT Article ID HEALTH SURVEY QUESTIONNAIRE; EXTERNAL FIXATION; RECONSTRUCTION; AMPUTATION; LEG; SALVAGE; SF-36; EXTREMITIES; COMMUNITY; INFECTION AB We studied the outcome and functional status of 33 patients with 34 severe open tibial fractures (Gustilo grade IIIb and IIIc). The treatment regime consisted of radical debridement, immediate bony stabilisation and early soft-tissue cover using a muscle flap (free or rotational). The review included standardised assessments of health-related quality of life (SF-36 and Euroqol) and measurement of the following parameters: gait, the use of walking aids, limb-length discrepancy, knee and ankle joint function, muscle wasting and the cosmetic appearance of the limb. Personal comments and overall patient satisfaction were also recorded. The mean follow-up was 46 months (15 to 80). There were 30 Gustilo grade IIIb fractures and and four grade IIIc fractures. Of the 33 patients, 29 had primary internal fixation and four, external fixation; 11 (34%) later required further surgery to achieve union and two needed bone transport procedures to reconstruct large segmental defects. The mean time to union was 41 weeks (12 to 104). Two patients (6.1%) developed deep infection; both resolved with treatment. The mean SF-36 physical and mental scores were 49 and 62 respectively. The mean state of health score for the Euroqol was 68. Patients with isolated tibial fractures had a better outcome than those with other associated injuries on both scoring systems. Knee stiffness was noted in seven patients (21%) and ankle stiffness in 19 (56%); 12 patients (41%) returned to work. Our results compare favourably with previous outcome measurements published for both limb salvage and amputation. All patients were pleased to have retained their limbs. C1 Massachusetts Gen Hosp, Dept Traumat & Orthopaed, Boston, MA 02114 USA. St James Univ Hosp, Dept Trauma & Orthopaed, Leeds LS9 7TF, W Yorkshire, England. RP Smith, RM (reprint author), Massachusetts Gen Hosp, Dept Traumat & Orthopaed, WACC 5-525,55 Frith St, Boston, MA 02114 USA. NR 42 TC 50 Z9 52 U1 0 U2 2 PU BRITISH EDITORIAL SOC BONE JOINT SURGERY PI LONDON PA 22 BUCKINGHAM STREET, LONDON WC2N 6ET, ENGLAND SN 0301-620X J9 J BONE JOINT SURG BR JI J. Bone Joint Surg.-Br. Vol. PD AUG PY 2004 VL 86B IS 6 BP 861 EP 867 DI 10.1302/0301-620X.86B6.13400 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 848KR UT WOS:000223466900016 PM 15330028 ER PT J AU Ahmed, SH Pennington, WR Clark, LL Hardin, AE McClure, C Webb, CS Finklea, L Spinale, FG Zile, MR AF Ahmed, SH Pennington, WR Clark, LL Hardin, AE McClure, C Webb, CS Finklea, L Spinale, FG Zile, MR TI Hypertensive hypertrophy: Relation between left ventricular (LV) structure/function and matrix metalloproteinases (MMP) tissue inhibitors of metalloproteinases (TIMP) SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 8th Annual Scientific Meeting of the Heart-Failure-Society-of-American CY SEP 12-15, 2004 CL Toronto, CANADA SP Heart Failure Soc Amer C1 Med Univ S Carolina, Div Cardiol, Charleston, SC 29425 USA. Ralph H Johnson Dept Vet Affairs Med Ctr, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 4 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 AUG PY 2004 VL 10 IS 4 SU S MA 094 BP S44 EP S44 DI 10.1016/j.cardfail.2004.06.091 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 853VV UT WOS:000223857900094 ER PT J AU Ahmed, SH Baicu, CF Webb, CS Hapke, E Van Laer, AO Zile, MR AF Ahmed, SH Baicu, CF Webb, CS Hapke, E Van Laer, AO Zile, MR TI Pressure overload hypertrophy and aging: Effects on myocardial vs cellular viscoelastic properties SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 8th Annual Scientific Meeting of the Heart-Failure-Society-of-American CY SEP 12-15, 2004 CL Toronto, CANADA SP Heart Failure Soc Amer C1 Med Univ S Carolina, Dept Med, Div Cardiol, Charleston, SC 29425 USA. Med Univ S Carolina, Gazes Cardiac Res Inst, Charleston, SC 29425 USA. Ralph H Johnson Dept Vet Affairs Med Ctr, Charleston, SC USA. NR 0 TC 0 Z9 0 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 AUG PY 2004 VL 10 IS 4 SU S MA 027 BP S25 EP S25 DI 10.1016/j.cardfail.2004.06.024 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 853VV UT WOS:000223857900028 ER PT J AU Bhella, PS Doshi, HM Reuben, A O'Brien, TX AF Bhella, PS Doshi, HM Reuben, A O'Brien, TX TI Diastolic dysfunction in end-stage liver disease post-liver transplant SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 8th Annual Scientific Meeting of the Heart-Failure-Society-of-American CY SEP 12-15, 2004 CL Toronto, CANADA SP Heart Failure Soc Amer C1 Med Univ S Carolina, Charleston, SC 29425 USA. Ralph H Johnson VAMC, Off Res & Dev, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 AUG PY 2004 VL 10 IS 4 SU S MA 051 BP S32 EP S32 DI 10.1016/j.cardfail.2004.06.050 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 853VV UT WOS:000223857900051 ER PT J AU Huehnergarth, KV Mozaffarian, D Sullivan, MD Wilkinson, C Lawler, RL McDonald, GB Fishbein, DP Levy, WC AF Huehnergarth, KV Mozaffarian, D Sullivan, MD Wilkinson, C Lawler, RL McDonald, GB Fishbein, DP Levy, WC TI Relative lymphocyte count is an independent predictor of death/urgent transplant in heart failure SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 8th Annual Scientific Meeting of the Heart-Failure-Society-of-American CY SEP 12-15, 2004 CL Toronto, CANADA SP Heart Failure Soc Amer C1 Univ Washington, Seattle, WA 98195 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Vet Affairs Puget Sound Hlth Care Syst, Psychiat, Seattle, WA USA. Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. RI Mozaffarian, Dariush/B-2276-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 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 AUG PY 2004 VL 10 IS 4 SU S MA 119 BP S50 EP S50 DI 10.1016/j.cardfail.2004.06.116 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 853VV UT WOS:000223857900118 ER PT J AU Nagoshi, T Matsui, T Champion, HC Li, L Kass, DA Rosenzweig, A AF Nagoshi, T Matsui, T Champion, HC Li, L Kass, DA Rosenzweig, A TI Adenoviral expression of activated PI3-kinase rescues cardiac dysfunction and injury induced by ischemia-reperfusion in Akt transgenic mice SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 8th Annual Scientific Meeting of the Heart-Failure-Society-of-American CY SEP 12-15, 2004 CL Toronto, CANADA SP Heart Failure Soc Amer C1 Massachusetts Gen Hosp, Cardiovasc Res Ctr, Program Cardiovasc Gene Therapy, Charlestown, MA USA. Johns Hopkins Univ Hosp, Div Cardiol, Baltimore, MD 21287 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 AUG PY 2004 VL 10 IS 4 SU S MA 005 BP S18 EP S18 DI 10.1016/j.cardfail.2004.06.049 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 853VV UT WOS:000223857900006 ER PT J AU Teerlink, JR Massie, BM Cleland, JGF Tzivoni, D Rainisio, M Frey, A AF Teerlink, JR Massie, BM Cleland, JGF Tzivoni, D Rainisio, M Frey, A CA RITZ-1 Investigators TI The relationship between hypotension and renal dysfunction during Tezosentan treatment for acute decompensated heart failure: An analysis of the Randomized Interventions with Tezosentan (RITZ-1) trial SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 8th Annual Scientific Meeting of the Heart-Failure-Society-of-American CY SEP 12-15, 2004 CL Toronto, CANADA SP Heart Failure Soc Amer C1 UCSF, San Francisco VAMC, San Francisco, CA USA. Castle Hill Hosp, Kingston Upon Hull, Yorks, England. Shaare Zedek Med Ctr, Jerusalem, Israel. Actel Pharmaceut LTD, Allshwil, Switzerland. RI Teerlink, John/D-2986-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 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 AUG PY 2004 VL 10 IS 4 SU S MA 260 BP S89 EP S89 DI 10.1016/j.cardfail.2004.06.259 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 853VV UT WOS:000223857900259 ER PT J AU Yosefy, CA Magen, E Kiselevich, A Priluk, R London, D Volchek, L Viskoper, RJ AF Yosefy, CA Magen, E Kiselevich, A Priluk, R London, D Volchek, L Viskoper, RJ TI Rosiglitazone improves, while glibenclamide worsens blood pressure control in treated hypertensive diabetic and dyslipidemic subjects via modulation of insulin resistance and sympathetic activity SO JOURNAL OF CARDIOVASCULAR PHARMACOLOGY LA English DT Article DE hypertension; diabetes; rosiglitazone; glibenclamide; sympathetic activity ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; SMOOTH-MUSCLE-CELLS; PPAR-GAMMA; CARDIOVASCULAR-DISEASE; GLYCEMIC CONTROL; NERVE ACTIVITY; TROGLITAZONE; MELLITUS; STRESS; RAT AB Background: Type II diabetes is often associated with high blood pressure, elevated sympathetic activity, and high plasma insulin levels. Hypoglycemic agents may negatively interfere with blood pressure control, sympathetic activity, and plasma insulin level; therefore the choice of treatment in type II diabetes may be crucial. We aimed to compare the effects of two hypoglycemic drugs on blood glucose, blood pressure, sympathetic activity, and insulin levels in type II diabetic and hypertensive patients. Methods: Forty-eight (24M, 24F) type II diabetic, hypertensive, and hyperlipidemic subjects were enrolled and treated for 4 weeks with an ACE inhibitor (Cilazapril) and a statin (Simvastatin). They were then randomized into two groups to receive a thiazolidinedione (Rosiglitazone; ROS) or a sulfonylurea (Glibenclamide; GLB) for 8 weeks. Blood biochemistry, blood pressure, plasma insulin, endothelial function, and sympathetic skin activity were measured before and after treatment. Results: A significant drop in systolic and diastolic blood pressure by 6.1 +/- 1.4 mm Hg and 4.2 +/- 1.9 mm Hg respectively; a reduction in plasma insulin concentration by 4.3 +/- 1.9 mU/L and a decline in skin sympathetic activity were observed in the group receiving ROS. The GLB group showed an increase in systolic blood pressure by 3.1 +/- 2.5 mm Hg; no change in diastolic blood pressure, significant elevation in plasma insulin concentration by 2.3 +/- 1.4 mu/L, and augmentation of sympathetic activity. No significant changes in endothelial function were observed in either group. Conclusions: Rosiglitazone improved both plasma glucose and blood pressure levels, probably by attenuation of hyperinsulinemia and sympathetic activity, while Glibenclamide worsened blood pressure control possibly by elevation of insulin levels and activation of the sympathetic system. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Noninvas Cardiac Lab, Boston, MA 02114 USA. Ben Gurion Univ Negev, WHO Collaborat Ctr Prevent CVD, Ashqelon, Israel. Ben Gurion Univ Negev, Dept Neurol, Ashqelon, Israel. Ben Gurion Univ Negev, Dept Radiol, Ashqelon, Israel. RP Yosefy, CA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Noninvas Cardiac Lab, VBK 508, Boston, MA 02114 USA. EM cyosefy@partners.org RI Magen, Eli/N-7960-2014 OI Magen, Eli/0000-0002-7713-423X NR 37 TC 50 Z9 54 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0160-2446 J9 J CARDIOVASC PHARM JI J. Cardiovasc. Pharmacol. PD AUG PY 2004 VL 44 IS 2 BP 215 EP 222 DI 10.1097/00005344-200408000-00011 PG 8 WC Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy SC Cardiovascular System & Cardiology; Pharmacology & Pharmacy GA 841JW UT WOS:000222927100011 PM 15243303 ER PT J AU Jarade, EF Tabbara, KF AF Jarade, EF Tabbara, KF TI New formula for calculating intraocular lens power after laser in situ keratomileusis SO JOURNAL OF CATARACT AND REFRACTIVE SURGERY LA English DT Article ID PHOTOREFRACTIVE KERATECTOMY; CATARACT-SURGERY; RADIAL KERATOTOMY; COMPUTERIZED VIDEOKERATOGRAPHY; PENETRATING KERATOPLASTY; NONMECHANICAL TREPHINATION; CORNEAL TOPOGRAPHY; REFRACTIVE SURGERY; EYES; ACCURACY AB Purpose: To assess the validity and accuracy of a proposed formula for keratometry (K) readings after laser in situ keratomileusis (LASIK). Setting: The Eye Center and the Eye Foundation for Research, Riyadh, Saudi Arabia. Method. This studied comprised 34 eyes that had LASIK surgery. Refraction and an automated K-reading (auto-K) were performed preoperatively. Refraction, auto-K, and K-reading assessment by the clinical history method and the proposed formula were performed 4 to 12 weeks postoperatively. The proposed formula is K-postop = K-preop - [(N-c - 1) x (Ra-postop - Ra-preop)/(Ra-postop x Ra-preop)], where K-postop is the K-reading after LASIK, K-preop is the K-reading before LASIK, N-c is the index of refraction of the cornea (1.376), Ra-postop is the radius of curvature of the anterior corneal surface after LASIK, and Ra-preop is the radius of curvature of the anterior corneal surface before LASK Results: Twenty patients (10 men, 10 women) were included in the study. The mean age of the patients was 30.58 years +/- 17.68 (SD) (range 18 to 44 years). Preoperatively, the mean spherical equivalent (SE) was -4.99 +/- 2.82 diopters (D) (range -1.12 to -15.00 D), the mean R-a was 7.76 +/- 0.32 mm (range 7.33 to 8.50 mm), and the mean auto-K reading was 43.45 +/- 1.73 D (range 39.62 to 46.00 D). Postoperatively, the mean SE was +0.02 +/- 0.63 D (range -2.75 to +1.00 D), the mean Ra was 8.63 +/- 0.53 mm (range 7.80 to 9.92 mm), and the mean K-reading assessed by auto-K, clinical history method, and the proposed formula was 39.17 +/- 2.35 D (range 34.00 to 43.25 D), 38.79 +/- 2.52 D (range 33.1 to 42.78 D), and 38.69 +/- 2.51 D (range 33.1 to 43.0 D), respectively. The results obtained by the proposed formula were similar to those obtained by the clinical history method (P =.098). Auto-K readings significantly overestimated the K-values (P<.0001) when compared to the proposed formula and clinical history method. Conclusion: The proposed formula was simple, objective, not dependent on refraction, and as accurate as the clinical history method in determining K-readings after LASIK. (C) 2004 ASCRS and ESCRS. C1 Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Jarade, EF (reprint author), Massachusetts Eye & Ear Infirm, 20 Staniford St, Boston, MA 02114 USA. EM ejarade@yahoo.com NR 28 TC 23 Z9 24 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0886-3350 J9 J CATARACT REFR SURG JI J. Cataract. Refract. Surg. PD AUG PY 2004 VL 30 IS 8 BP 1711 EP 1715 DI 10.1016/j.jcrs.2003.012.056 PG 5 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 850XE UT WOS:000223646900021 PM 15313295 ER PT J AU Ollero, M Junaidi, O Zaman, MM Tzameli, I Ferrando, AA Andersson, C Blanco, PG Bialecki, E Freedman, SD AF Ollero, M Junaidi, O Zaman, MM Tzameli, I Ferrando, AA Andersson, C Blanco, PG Bialecki, E Freedman, SD TI Decreased expression of peroxisome proliferator activated receptor gamma in CFTR-/- mice SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID RETINOID-X-RECEPTOR; HUMAN BREAST-CANCER; CYSTIC-FIBROSIS; PPAR-GAMMA; INSULIN-RESISTANCE; GENE-EXPRESSION; TERMINAL DIFFERENTIATION; DIABETES-MELLITUS; FATTY-ACIDS; LIGAND AB Some of the pathological manifestations of cystic fibrosis are in accordance with an impaired expression and/or activity of PPARgamma. We hypothesized that PPARgamma expression is altered in tissues lacking the normal cystic fibrosis transmembrane regulator protein (CFTR). PPARgamma mRNA levels were measured in colonic mucosa, ileal mucosa, adipose tissue, lung, and liver from wild-type and cftr(-/-) mice by quantitative RT-PCR. PPARgamma expression was decreased twofold in CFTR-regulated tissues (colon, ileum, and lung) from cftr(-/-) mice compared to wild-type littermates. In contrast, no differences were found in fat and liver. immunohistochemical analysis of PPARgamma in ileum and colon revealed a predominantly nuclear localization in wild-type mucosal epithelial cells while tissues from cftr(-/-) mice showed a more diffuse, lower intensity labeling. A significant decrease in PPARgamma expression was confirmed in nuclear extracts of colon mucosa by Western blot analysis. In addition, binding of the PPARgamma/RXR heterodimer to an oligonucletotide containing a peroxisome proliferator responsive element (PPRE) was also decreased in colonic mucosa extracts from cftr(-/-) mice. Treatment of cftr(-/-) mice with the PPARgamma ligand rosiglitazone restored both the nuclear localization and binding to DNA, but did not increase RNA levels. We conclude that PPARgamma expression in cftr(-/-) mice is downregulated at the RNA and protein levels and its function diminished. These changes may be related to the loss of function of CFTR and may be relevant to the pathogenesis of metabolic abnormalities associated with cystic fibrosis in humans. (C) 2004 Wiley-Liss, Inc. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA. RP Freedman, SD (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, Dana 501,330 Brookline Ave, Boston, MA 02215 USA. EM sfreedma@bidmc.harvard.edu FU NIDDK NIH HHS [R01 DK52765] NR 54 TC 40 Z9 42 U1 0 U2 2 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 AUG PY 2004 VL 200 IS 2 BP 235 EP 244 DI 10.1002/jcp.20020 PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 835MB UT WOS:000222486400006 PM 15174093 ER PT J AU Hull, RL Westermark, GT Westermark, P Kahn, SE AF Hull, RL Westermark, GT Westermark, P Kahn, SE TI Islet amyloid: A critical entity in the pathogenesis of type 2 diabetes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Review ID GENE-RELATED PEPTIDE; IMPAIRED GLUCOSE-TOLERANCE; INSULIN-DEGRADING ENZYME; BETA-CELL FUNCTION; TRANSGENIC MOUSE MODEL; AMYLIN BINDING-SITES; POLYPEPTIDE FIBRIL FORMATION; HUMAN PANCREATIC-ISLETS; JAPANESE-AMERICAN MEN; PERFUSED RAT PANCREAS AB Islet amyloid deposition is a pathogenic feature of type 2 diabetes, and these deposits contain the unique amyloidogenic peptide islet amyloid polypeptide. Autopsy studies in humans have demonstrated that islet amyloid is associated with loss of beta-cell mass, but a direct role for amyloid in the pathogenesis of type 2 diabetes cannot be inferred from such studies. Animal studies in both spontaneous and transgenic models of islet amyloid formation have shown that amyloid forms in islets before fasting hyperglycemia and therefore does not arise merely as a result of the diabetic state. Furthermore, the extent of amyloid deposition is associated with both loss of beta-cell mass and impairment in insulin secretion and glucose metabolism, suggesting a causative role for islet amyloid in the islet lesion of type 2 diabetes. These animal studies have also shown that beta-cell dysfunction seems to be an important prerequisite for islet amyloid formation, with increased secretory demand from obesity and/or insulin resistance acting to further increase islet amyloid deposition. Recent in vitro studies suggest that the cytotoxic species responsible for islet amyloid-induced beta-cell death are formed during the very early stages of islet amyloid formation, when islet amyloid polypeptide aggregation commences. Interventions to prevent islet amyloid formation are emerging, with peptide and small molecule inhibitors being developed. These agents could thus lead to a preservation of beta-cell mass and amelioration of the islet lesion in type 2 diabetes. C1 Vet Affairs Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98108 USA. Linkoping Univ, Div Cell Biol, Linkoping, Sweden. Uppsala Univ, Dept Genet & Pathol, Rudbeck Lab, Uppsala, Sweden. Univ Washington, Seattle, WA 98108 USA. RP Kahn, SE (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, 1660 S Columbian Way, Seattle, WA 98108 USA. EM skahn@u.washington.edu OI Kahn, Steven/0000-0001-7307-9002; Hull, Rebecca/0000-0001-9690-4087 FU NIDDK NIH HHS [DK-02654, DK-17047, DK-50703] NR 225 TC 267 Z9 277 U1 1 U2 22 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 AUG PY 2004 VL 89 IS 8 BP 3629 EP 3643 DI 10.1210/jc.2004-0405 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 843IQ UT WOS:000223072400001 PM 15292279 ER PT J AU Swearingen, B Katznelson, L Miller, K Grinspoon, S Waltman, A Dorer, DJ Klibanski, A Biller, BMK AF Swearingen, B Katznelson, L Miller, K Grinspoon, S Waltman, A Dorer, DJ Klibanski, A Biller, BMK TI Diagnostic errors after inferior petrosal sinus sampling SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CORTICOTROPIN-RELEASING HORMONE; DEPENDENT CUSHINGS-SYNDROME; ECTOPIC ACTH SYNDROME; DIFFERENTIAL-DIAGNOSIS; ADRENOCORTICOTROPIN SYNDROME; DISEASE; PITUITARY; SECRETION; TUMOR; STIMULATION AB Although inferior petrosal sinus sampling (IPSS) is useful in the evaluation of Cushing's syndrome, false negative cases have been described, and many patients presumed to have ectopic tumors based upon negative IPSS remain without a final diagnosis. These patients are often managed as if they have as yet undiscovered ectopic tumors. To test this assumption, we conducted a retrospective review of our results to determine the ultimate diagnoses after IPSS. Between 1986 and 2002, 179 patients underwent 185 IPSS procedures as part of their evaluation for Cushing's syndrome. Confirmed diagnoses were available for 149 patients (83%): 139 patients had pituitary adenomas (94%), eight had bronchial carcinoids (5%), and two had adrenal tumors (1%). Threshold criteria for a pituitary source were defined as an inferior petrosal sinus to peripheral (IPS: P) basal ratio of 2: 1 or greater without CRH or an IPS: P ratio of 3: 1 or greater after CRH stimulation. There were nine patients in whom the IPS: P ratio failed to meet threshold criteria after successful sampling, but were nonetheless found to have pituitary tumors after transsphenoidal exploration (false negatives). Eight of these had received CRH and had a significant rise (>35%) in peripheral ACTH levels after CRH treatment, even though the IPS:P ratio did not reach the threshold. There were two patients in whom the IPS: P ratio reached threshold criteria, and ectopic tumors were demonstrated as the source of ACTH overproduction ( false positives). The sensitivity after CRH stimulation was 90% (95% confidence interval, 80.8-95.5%) with a specificity of 67% ( 95% confidence interval, 11.4-94.5%). The positive and negative predictive values were 99 and 20%, respectively. Our data show that patients with an IPS: P ratio suggestive of a nonpituitary source of ACTH overproduction may still have Cushing's disease. Analyzing the CRH-stimulated peripheral ACTH levels in addition to the standard IPS: P ratios may provide improved diagnostic accuracy. Transsphenoidal exploration should be considered in all cases of unsuccessful sampling and in those cases for which no ectopic source can be identified after further body imaging, even if the IPSS is negative, and especially if peripheral ACTH levels rise significantly with CRH stimulation. C1 Massachusetts Gen Hosp, Neuroendocrine Clin Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Neurosurg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Swearingen, B (reprint author), Massachusetts Gen Hosp, Neuroendocrine Clin Ctr, ACC 331,Fruit St, Boston, MA 02114 USA. EM bswearingen@partners.org NR 42 TC 76 Z9 89 U1 0 U2 1 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 AUG PY 2004 VL 89 IS 8 BP 3752 EP 3763 DI 10.1210/jc.2003-032249 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 843IQ UT WOS:000223072400023 PM 15292301 ER PT J AU Ince, BA Anderson, EJ Neer, RM AF Ince, BA Anderson, EJ Neer, RM TI Lowering dietary protein to US recommended dietary allowance levels reduces urinary calcium excretion and bone resorption in young women SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID POSTMENOPAUSAL WOMEN; ANIMAL PROTEIN; CHRONIC ACID; METABOLISM; HYPERCALCIURIA; BICARBONATE; PHOSPHORUS; TURNOVER; BALANCE; VALUES AB High-protein diets increase calciuria. No previous studies have examined the ad libitum U. S. diet's effect on calciuria or bone resorption. Thirty-nine healthy, premenopausal women consuming ad libitum diets [mean, 1.1 g/kg protein, 819 mg (20.5 mmol) Ca, 1152 mg (37 mmol) P, 129 mmol Na] were switched to isocaloric diets containing the U. S. recommended dietary allowance (RDA) of protein (0.8 g/kg) and similar amounts of calcium, phosphorus, and sodium. Bone resorption and related endpoints were assessed before and 1 wk after the switch. As dietary protein changed from ad libitum to RDA levels, mean urine nitrogen decreased 26% (2.4 g/d; P < 0.001) and mean blood urea nitrogen decreased 15% (1.9 mg/dl; P< 0.001). Mean urine pH increased from 6.3 to 6.8 ( P < 0.001), and net renal acid excretion (NRAE = urine ammonium plus titratable acids minus bicarbonate) decreased 68% (21.4 mEq/d; P < 0.001). Mean urinary calcium decreased 32% [42 mg (1 mmol)/d; P < 0.001], and bone resorption urine N-telopeptides) decreased 17% (74 mu mol bovine collagen equivalents/d; P < 0.001). Mean serum calcium, PTH, and 1,25 dihydroxy vitamin D remained unchanged. In this 2-wk study, decreasing dietary protein from ad libitum to RDA levels decreased NRAE, calciuria and estimates of bone resorption, suggesting that decreased U. S. protein consumption might reduce bone loss. Inasmuch as other dietary modifications, such as increasing vegetable and fruit intake, can result in sustained reductions in NRAE without reducing protein intake, the advisability of reducing protein intake for skeletal protection from acid attack requires further investigation. C1 Massachusetts Gen Hosp, Div Endocrine, Boston, MA 02114 USA. Massachusetts Gen Hosp, Mallinckrodt Gen Clin Res Ctr, Boston, MA 02114 USA. RP Ince, BA (reprint author), Massachusetts Gen Hosp, Div Endocrine, Bulfinch 327,55 Fruit St, Boston, MA 02114 USA. EM bince@partners.org FU NCRR NIH HHS [M01 RR01066]; PHS HHS [U01-A612531] NR 41 TC 22 Z9 23 U1 0 U2 4 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 AUG PY 2004 VL 89 IS 8 BP 3801 EP 3807 DI 10.1210/jc.2003-032016 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 843IQ UT WOS:000223072400030 PM 15292308 ER PT J AU Wang, C Swerdloff, R Kipnes, M Matsumoto, AM Dobs, AS Cunningham, G Katznelson, L Weber, TJ Friedman, TC Snyder, P Levine, HL AF Wang, C Swerdloff, R Kipnes, M Matsumoto, AM Dobs, AS Cunningham, G Katznelson, L Weber, TJ Friedman, TC Snyder, P Levine, HL TI New testosterone buccal system (striant) delivers physiological testosterone levels: Pharmacokinetics study in hypogonadal men SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ANDROGEN REPLACEMENT THERAPY; ELDERLY-MEN; TRANSDERMAL SYSTEM; SERUM TESTOSTERONE; BODY-COMPOSITION; METABOLISM; ESTRADIOL; YOUNG; GEL AB A new mucoadhesive testosterone buccal system (Striant), 30 mg testosterone ( T), was applied twice daily in 82 hypogonadal men for 3 months. Serum T, free T, and 5 alpha-dihydrotestosterone were measured during this period. T pharmacokinetics were determined from the data obtained during a 24-h sampling at wk 12. Physiological mean serum T concentrations were steady and consistently maintained. The mean percentage of time over a 24-h period that total serum T concentrations were above the lower limit of adult male range was 80.1%. During treatment, mean serum 5alpha-dihydrotestosterone, free T, and estradiol concentrations paralleled serum T. C1 Univ Calif Los Angeles, Harbor Med Ctr, Gen Clin Res Ctr, Torrance, CA 90509 USA. Res & Educ Inst, Torrance, CA 90509 USA. Diabet & Glandular Dis Res Associates, San Antonio, TX 78229 USA. Univ Washington, Ctr Geriatr Res Educ & Clin, Dept Med, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. Johns Hopkins Univ, Dept Med, Baltimore, MD 21287 USA. Baylor Univ, Sch Med, Dept Med, Houston, TX 77030 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27705 USA. Charles R Drew Univ Med, Dept Med, Div Endocrinol, Los Angeles, CA 90059 USA. Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. Columbia Labs Inc, Livingston, NJ 07039 USA. RP Wang, C (reprint author), Univ Calif Los Angeles, Harbor Med Ctr, Gen Clin Res Ctr, Box 16,1000 W Carson St, Torrance, CA 90509 USA. EM wang@gcrc.rei.edu FU NCRR NIH HHS [M01RR00425] NR 28 TC 52 Z9 55 U1 0 U2 4 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 AUG PY 2004 VL 89 IS 8 BP 3821 EP 3829 DI 10.1210/jc.2003-031866 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 843IQ UT WOS:000223072400034 PM 15292312 ER PT J AU Smith, MR Fallon, MA Lee, H Finkelstein, JS AF Smith, MR Fallon, MA Lee, H Finkelstein, JS TI Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: A randomized controlled trial SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ANDROGEN-DEPRIVATION THERAPY; VERTEBRAL FRACTURE RISK; MINERAL DENSITY; POSTMENOPAUSAL WOMEN; TURNOVER MARKERS; SEX STEROIDS; ESTROGEN; CARCINOMA; OSTEOPOROSIS; ORCHIECTOMY AB GnRH agonists decrease bone mineral density and increase fracture risk in men with prostate cancer. Raloxifene increases bone mineral density in postmenopausal women, but its efficacy in hypogonadal men is not known. In a 12-month open-label study, men with nonmetastatic prostate cancer (n = 48) who were receiving a GnRH agonist were assigned randomly to raloxifene (60 mg/d) or no raloxifene. Bone mineral densities of the posteroanterior lumbar spine and proximal femur were measured by dual energy x-ray absorptiometry. Mean (+/-SE) bone mineral density of the posteroanterior lumbar spine increased by 1.0 +/- 0.9% in men treated with raloxifene and decreased by 1.0 +/- 0.6% in men who did not receive raloxifene (P = 0.07). Bone mineral density of the total hip increased by 1.1 +/- 0.4% in men treated with raloxifene and decreased by 2.6 +/- 0.7% in men who did not receive raloxifene (P < 0.001). Similar between-group differences were observed in the femoral neck (P = 0.06) and trochanter (P < 0.001). In men receiving a GnRH agonist, raloxifene significantly increases bone mineral density of the hip and tends to increase bone mineral density of the spine. C1 Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. RP Smith, MR (reprint author), Massachusetts Gen Hosp, Div Hematol & Oncol, Cox 640,100 Blossom St, Boston, MA 02114 USA. EM smith.matthew@mgh.harvard.edu FU NCRR NIH HHS [M01-RR-01066]; NIDDK NIH HHS [K24 DK02759] NR 28 TC 144 Z9 147 U1 0 U2 1 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 AUG PY 2004 VL 89 IS 8 BP 3841 EP 3846 DI 10.1210/jc.2003-032058 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 843IQ UT WOS:000223072400037 PM 15292315 ER PT J AU Miller, KK Grieco, KA Mulder, J Grinspoon, S Mickley, D Yehezkel, R Herzog, DB Klibanski, A AF Miller, KK Grieco, KA Mulder, J Grinspoon, S Mickley, D Yehezkel, R Herzog, DB Klibanski, A TI Effect of risedronate on bone density in anorexia nervosa SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID POSTMENOPAUSAL WOMEN; CONTROLLED-TRIAL; OSTEOPOROSIS; FRACTURE; RISK; MASS AB Anorexia nervosa (AN), a psychiatric disease characterized by chronic starvation, is complicated by severe bone loss (1), for which there is no effective, available therapy. Although bone resorption is markedly increased in these patients, estrogen is an ineffective anti-resorptive therapy in the setting of undernutrition. We hypothesized bisphosphonate administration would result in a decrease in bone resorption and an increase in bone density in women with AN and bone loss, despite undernutrition. We therefore administered risedronate 5 mg daily for nine months to 10 women with AN, all of whom had osteopenia (mean AP spine T score: -2.7 +/- 2) and compared NTX and bone density with baseline values and with those from available control data prospectively followed for the same time period. Bone density increased significantly in patients who received risedronate compared with controls and compared with baseline, despite lack of significant weight gain, for an increase of AP spine bone density of 4.1 +/- 1.6% at six months and 4.9 +/- 1.0% at nine months. Bone resorption, as measured by NTX, decreased 23.8% at one month and 29.6% at three months, from the high-normal to mid-normal range of young women. Our data suggest that risedronate 5 mg daily administered to women with AN and osteopenia may increase in bone density at the AP spine despite low weight. This is the first study to demonstrate marked increases in bone density in women with AN. Because of the lack of data regarding the safety of such medications in women of reproductive age, bisphosphonates are not approved in the U.S. for premenopausal women other than those receiving glucocorticoids. Further studies are needed to establish the efficacy and safety of bisphosphonate therapy in this population. C1 Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Eating Disorders Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Wilkins Ctr Eating Disorders, Greenwich, CT 06831 USA. RP Miller, KK (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. EM kkmiller@partners.org FU NCRR NIH HHS [M01-RR-01066]; NIDDK NIH HHS [R01-DK-52625] NR 12 TC 45 Z9 46 U1 0 U2 1 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 AUG PY 2004 VL 89 IS 8 BP 3903 EP 3906 DI 10.1210/jc.2003-031885 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 843IQ UT WOS:000223072400047 PM 15292325 ER PT J AU Caballero, AE Delgado, A Aguilar-Salinas, CA Herrera, AN Castillo, JL Cabrera, T Gomez-Perez, FJ Rull, JA AF Caballero, AE Delgado, A Aguilar-Salinas, CA Herrera, AN Castillo, JL Cabrera, T Gomez-Perez, FJ Rull, JA TI The differential effects of metformin on markers of endothelial activation and inflammation in subjects with impaired glucose tolerance: A placebo-controlled, randomized clinical trial SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID C-REACTIVE PROTEIN; CARDIOVASCULAR RISK-FACTORS; VON-WILLEBRAND-FACTOR; INSULIN-RESISTANCE; DIABETES-MELLITUS; ADHESION MOLECULE-1; METABOLIC SYNDROME; OBESE-PATIENTS; HEART-DISEASE; TNF-ALPHA AB The effect of metformin ( 1000 mg twice a day) on markers of endothelial activation, inflammation, and coagulation was investigated in subjects with impaired glucose tolerance (IGT) in a 16-wk, randomized, placebo-controlled, double-blind study. Soluble intercellular adhesion molecule, soluble vascular cell adhesion molecule, C-reactive protein, TNFalpha, von Willebrand factor, and tissue plasminogen activator were measured at baseline and at the end of the trial. Subjects with IGT ( n = 55, 14 males and 41 females), aged 48.4 +/- 9.6 yr with a body mass index of 31.4 +/- 5.6 kg/m(2), were studied. All participants followed a 1-month stabilization period in their diet and physical activity. Afterward, 29 subjects were assigned to the treatment group and 26 to the control group. A significant reduction in weight, fasting plasma glucose, soluble intercellular adhesion molecule ( 306 +/- 75 vs. 268 +/- 61 ng/ml, P = 0.029), soluble vascular cell adhesion molecule ( 595 +/- 114 vs. 508 +/- 126 ng/ml, P = 0.006), and von Willebrand factor ( 124 +/- 34 vs. 94 +/- 34%, P = 0.001) was seen in the treatment group, whereas tissue plasminogen activator, TNFalpha, and C-reactive protein levels did not change. No change was seen in the control group. Thus, metformin improves the plasma levels of some markers of endothelial activation and coagulation in subjects with IGT, whereas it has no effect on markers of inflammation. C1 Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Endocrinol & Metab, Mexico City 14000, DF, Mexico. Harvard Univ, Sch Med, Joslin Diabet Ctr, Clin Res Ctr, Boston, MA 02215 USA. Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Radiol, Mexico City 14000, DF, Mexico. Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Med, Mexico City 14000, DF, Mexico. RP Aguilar-Salinas, CA (reprint author), Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Endocrinol & Metab, Vasco Quiroga 15, Mexico City 14000, DF, Mexico. EM caguilarsalinas@yahoo.com OI Castillo, Jose/0000-0002-6685-3001 NR 44 TC 73 Z9 77 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 AUG PY 2004 VL 89 IS 8 BP 3943 EP 3948 DI 10.1210/jc.2004-0019 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 843IQ UT WOS:000223072400053 PM 15292331 ER PT J AU Grinspoon, S Miller, KK Herzog, DB Grieco, KA Klibanski, A AF Grinspoon, S Miller, KK Herzog, DB Grieco, KA Klibanski, A TI Effects of estrogen and recombinant human insulin-like growth factor-I on ghrelin secretion in severe undernutrition SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GH-RELEASING HORMONE; IGF-BINDING PROTEINS; ANOREXIA-NERVOSA; ESTRADIOL SUPPLEMENTATION; POSTMENOPAUSAL WOMEN; PLASMA-LEVELS; FOOD-INTAKE; REDUCTION; SOMATOSTATIN; RESTRICTION AB Ghrelin is a nutritionally regulated gut peptide that increases with fasting and chronic undernutrition and decreases with food intake. Sex steroid levels change in chronic undernutrition and might signal changes in ghrelin. At the same time, chronic undernutrition is characterized by low IGF-I that might also influence ghrelin, either directly or through changes in the GH axis. Little is known regarding sex steroid regulation of ghrelin and the effects of IGF-I on ghrelin in severe undernutrition. We investigated the effects of sex steroids and IGF-I on ghrelin in 78 female subjects with anorexia nervosa simultaneously randomized to receive estrogen (Ovcon 35, 35 mug ethinyl estradiol, and 0.4 mg norethindrone) as well as recombinant human ( rh) IGF-I ( 30 mug/kg sc twice a day) in a two-by-two factorial model, in which the individual effects of estrogen ( E) and rhIGF-I on ghrelin could be determined. Subjects were 24.9 +/- 0.7 ( mean +/- SEM) yr of age and had low weight ( body mass index, 16.7 +/- 0.2 kg/m(2)). At baseline, ghrelin was inversely correlated with body mass index (r = - 0.39, P = 0.0005) and IGF-I ( r = - 0.30, P = 0.01). IGF-I increased significantly more in subjects receiving rhIGF-I alone ( Delta 23.0 +/- 5.8 nmol/liter) and rhIGF-I and E (Delta 34.9 +/- 6.3 nmol/liter) compared with subjects receiving E alone (Delta - 3.2 +/- 1.9 nmol/ liter) or control ( C; rhIGF-I placebo and no E) ( Delta 0.4 +/- 2.0 nmol/ liter) ( overall P < 0.0001 by multivariate analysis of variance, P < 0.0001 for rhIGF-I vs. C, P < 0.0001 for rhIGF-I and E vs. C). Ghrelin increased significantly more over 6 months in response to E alone ( Delta 150 +/- 86 pg/ml), rhIGF-I alone ( Delta 198 +/- 116 pg/ml), and the combination ( E and rhIGF-I) ( Delta 441 +/- 214 pg/ml) compared with C ( Delta - 39 +/- 48 pg/ml) ( overall P = 0.02 by multivariate analysis of variance, P = 0.01 for E vs. C, P = 0.04 for rhIGF-I vs. C, and P = 0.001 for rhIGF-I and E vs. C). Weight, caloric intake, and morning GH levels did not change significantly between the groups, but the change in ghrelin was inversely related to the change in GH among all subjects ( r = - 0.27, P = 0.03). Our data demonstrate that, in a model of severe undernutrition, rhIGF-I andEindividually increase ghrelin levels. The mechanisms of these effects are unknown and may relate to direct effects on ghrelin or changes in GH. Further studies are needed to determine the mechanisms by which rhIGF-I and E increase ghrelin in human physiology. C1 Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Eating Disorders Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Grinspoon, S (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. EM sgrinspoon@partners.org FU NCRR NIH HHS [M01-RR-01066]; NIDDK NIH HHS [DK 52625] NR 30 TC 34 Z9 35 U1 0 U2 2 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 AUG PY 2004 VL 89 IS 8 BP 3988 EP 3993 DI 10.1210/jc.2004-0287 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 843IQ UT WOS:000223072400060 PM 15292338 ER PT J AU Gaglio, PJ Rodriguez-Torres, M Herring, R Anand, B Box, T Rabinovitz, M Brown, RS AF Gaglio, PJ Rodriguez-Torres, M Herring, R Anand, B Box, T Rabinovitz, M Brown, RS CA Infergen Study Grp TI Racial differences in response rates to consensus interferon in HCV infected patients naive to previous therapy SO JOURNAL OF CLINICAL GASTROENTEROLOGY LA English DT Article DE hepatitis C; Hispanic; African American; consensus interferon ID CHRONIC HEPATITIS-C; PEGINTERFERON ALPHA-2A; INITIAL TREATMENT; VIRAL-HEPATITIS; PLUS RIBAVIRIN; TRIAL AB Background: Despite a rapid evolution in the treatment of Hepatitis C (HCV), response to therapy among different racial and ethnic groups is poorly characterized. Study: Three hundred and thirty HCV infected patients naive to previous therapy received induction therapy followed by every other day dosing with consensus interferon. Greater than 30% of treated patients were not white, allowing comparison of response among different races/ethnicities and genotypes. Results: An overall sustained virologic response (SVR) was achieved in 24% of white, 12% of Hispanic, and 4% of AA patients (P = 0.003 white vs. non-white). 15% of white and 13% of Hispanic Genotype I patients achieved an SVR; 2% of AA patients achieved an SVR (P = 0.001 AA vs. non AA). Surprisingly, an SVR of 50% and 40% was achieved by AA and White Genotype 2 patients, compared with 10% in Hispanic patients (P = 0.001). Conclusion: Significant differences in response rates to induction therapy followed by every other day dosing with consensus Interferon was observed when comparing white to non-white patients, particularly when comparing response rates by genotype. These observations reinforce the requirement that prospective studies that enroll a significant percentage of non-whites are needed to adequately characterize response rates to anti-HCV directed therapy. C1 Ponce Med Sch, Ponce, PR USA. Univ Tennessee, Sch Med, Nashville, TN USA. Baylor Univ, Coll Med, VA Med Ctr, Houston, TX 77030 USA. Mt W Gastroenterol, Salt Lake City, UT USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. RP Gaglio, PJ (reprint author), Columbia Univ Coll Phys & Surg, Ctr Liver Dis & Transplantat, 622 W 168th St PH-14, New York, NY 10032 USA. EM pg2011@columbia.edu NR 13 TC 16 Z9 16 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0192-0790 J9 J CLIN GASTROENTEROL JI J. Clin. Gastroenterol. PD AUG PY 2004 VL 38 IS 7 BP 599 EP 604 DI 10.1097/00004836-200408000-00012 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 840RA UT WOS:000222875800012 PM 15232365 ER PT J AU Ikeda, F Nishimura, R Matsubara, T Tanaka, S Inoue, J Reddy, SV Hata, K Yamashita, K Hiraga, T Watanabe, T Kukita, T Yoshioka, K Rao, A Yoneda, T AF Ikeda, F Nishimura, R Matsubara, T Tanaka, S Inoue, J Reddy, SV Hata, K Yamashita, K Hiraga, T Watanabe, T Kukita, T Yoshioka, K Rao, A Yoneda, T TI Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID LYMPH-NODE ORGANOGENESIS; KEY REGULATOR; KAPPA-B; OSTEOBLASTIC DIFFERENTIATION; DEFECTIVE INTERLEUKIN-1; INDUCED APOPTOSIS; KINASE; RECEPTOR; PROTEIN; LIGAND AB Receptor activator of NF-kappaB ligand (RANKL) plays an essential role in osteoclast formation and bone resorption. Although genetic and biochemical studies indicate that RANKL regulates osteoclast differentiation by activating receptor activator of NF-kappaB and associated signaling molecules, the molecular mechanisms of RANKL-regulated osteoclast differentiation have not yet been fully established. We investigated the role of the transcription factor c-Jun, which is activated by RANKL, in osteoclastogenesis using transgenic mice expressing dominant-negative c-Jun specifically in the osteoclast lineage. We found that the transgenic mice manifested severe osteopetrosis due to impaired osteoclastogenesis. Blockade of c-Jun signaling also markedly inhibited soluble RANKL-induced osteoclast differentiation in vitro. Overexpression of nuclear factor of activated T cells 1 (NFAT1) (NFATc2/NFATp) or NFAT2 (NFATc1/NFATc) promoted differentiation of osteoclast precursor cells into tartrate-resistant acid phosphatase-positive (TRAP-positive) multinucleated osteoclast-like cells even in the absence of RANKL. Overexpression of NFAT1 also markedly transactivated the TRAP gene promoter. These osteoclastogenic activities of NFAT were abrogated by overexpression of dominant-negative c-Jun. Importantly, osteoclast differentiation and induction of NFAT2 expression by NFAT1 overexpression or soluble RANKL treatment were profoundly diminished in spleen cells of the transgenic mice. Collectively, these results indicate that c-Jun signaling in cooperation with NFAT is crucial for RANKL-regulated osteoclast differentiation. C1 Osaka Univ, Grad Sch Dent, Dept Biochem, Suita, Osaka 5650871, Japan. Univ Tokyo, Fac Med, Dept Orthopaed Surg, Tokyo 113, Japan. Univ Tokyo, Inst Med Sci, Dept Canc Biol, Div Cell & Mol Biol, Tokyo 113, Japan. Univ Pittsburgh, Div Hematol & Oncol, Inst Canc, Pittsburgh, PA USA. Kyushu Univ, Fac Dent Sci, Sect Oral Cellular & Mol Biol, Fukuoka 812, Japan. Kanazawa Univ, Canc Res Inst, Div Cell Cycle Regulat, Kanazawa, Ishikawa 920, Japan. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Ctr Blood Res, Boston, MA 02115 USA. RP Nishimura, R (reprint author), Osaka Univ, Grad Sch Dent, Dept Biochem, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan. EM rikonisi@dent.osaka-u.ac.jp NR 41 TC 245 Z9 251 U1 1 U2 4 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 AUG PY 2004 VL 114 IS 4 BP 475 EP 484 DI 10.1172/JCI200419657 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 846AR UT WOS:000223287500007 PM 15314684 ER PT J AU Wu, JD Higgins, LM Steinle, A Cosman, D Haugk, K Plymate, SR AF Wu, JD Higgins, LM Steinle, A Cosman, D Haugk, K Plymate, SR TI Prevalent expression of the immunostimulatory MHC class I chain-related molecule is counteracted by shedding in prostate cancer SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID DELTA T-CELLS; TUMOR-ASSOCIATED IMMUNITY; HUMAN SEMINAL PLASMA; NKG2D RECEPTOR; RETINOIC-ACID; CUTTING EDGE; NK CELLS; RECOGNITION; LIGANDS; MICA AB The MHC class I chain-related molecules (MICs) have previously been shown to be induced on most epithelial tumor cells. Engagement of MIC by the activating immune receptor NKG2D triggers NK cells and augments antigen-specific CTL anti-tumor immunity. The MIC-NKG2D system was proposed to participate in epithelial tumor immune surveillance. Paradoxically, studies suggest that tumors may evade MIC-NKG2D-mediated immunity by MIC shedding-induced impairment of effector cell function. Here we demonstrate the first evidence to our knowledge of a significant correlation of MIC shedding and deficiency in NK cell function with the grade of disease in prostate cancer. MIC is widely expressed in prostate carcinoma. The presence of surface target MIC, however, is counteracted by shedding. A significant increase in serum levels of soluble MIC (sMIC) and deficiency in NK cell function was shown in patients with advanced cancer. Finally, the deficiency in NK cell function can be overcome by treatment with IL-2 or IL-15 in vitro. Our results suggest that (a) deficiency in MIC-NKG2D immune surveillance may contribute to prostate cancer progression, (b) sMIC may be a novel biomarker for prostate cancer, and (c) using cytokines to restore MIC-NKG2D-mediated immunity may have clinical significance for prostate cancer in cell-based adaptive immunotherapy. C1 Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Tubingen, Dept Immunol, Tubingen, Germany. Amgen Inc, Seattle, WA USA. Vet Affairs Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Tacoma, WA USA. RP Wu, JD (reprint author), Box 359755,325 9th Ave, Seattle, WA 98104 USA. EM wuj@u.washington.edu RI Steinle, Alexander/E-6131-2012 FU NCI NIH HHS [P01 CA085859, P01 CA 85859]; NIDDK NIH HHS [R01 DK 52683, R01 DK052683] NR 48 TC 188 Z9 207 U1 0 U2 7 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 AUG PY 2004 VL 114 IS 4 BP 560 EP 568 DI 10.1172/JCI200422206 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 846AR UT WOS:000223287500016 PM 15314693 ER PT J AU Ayanian, JZ Chrischilles, EA Wallace, RB Fletcher, RH Fouad, MN Kiefe, CI Harrington, DP Weeks, JC Kahn, KL Malin, JL Lipscomb, J Potosky, AL Provenzale, DT Sandler, RS van Ryn, M West, DW AF Ayanian, JZ Chrischilles, EA Wallace, RB Fletcher, RH Fouad, MN Kiefe, CI Harrington, DP Weeks, JC Kahn, KL Malin, JL Lipscomb, J Potosky, AL Provenzale, DT Sandler, RS van Ryn, M West, DW CA Canc Care Outcomes Res Surveillanc TI Understanding cancer treatment and outcomes: The Cancer Care Outcomes Research and Surveillance Consortium SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID QUALITY-OF-LIFE; COLORECTAL-CANCER; RECTAL-CANCER; LUNG-CANCER; ADJUVANT CHEMOTHERAPY; RACIAL-DIFFERENCES; RADIATION-THERAPY; PROCEDURE VOLUME; HOSPITAL VOLUME; COLON-CANCER C1 No Calif Canc Ctr, Union City, CA USA. Dept Vet Affairs Med Ctr, Minneapolis, MN USA. Univ N Carolina, Dept Med, Div Gastroenterol & Hepatol, Chapel Hill, NC USA. Dept Vet Affairs Med Ctr, Durham, NC USA. NCI, Div Canc Control & Populat Sci, Rockville, MD USA. Univ Calif Los Angeles, Dept Med, Div Gen Internal Med Hlth Serv Res & Hematol Onco, Los Angeles, CA 90024 USA. RAND Corp, Santa Monica, CA USA. Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Univ Alabama, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care, Dept Ambulatory Care & Prevent, Cambridge, MA 02138 USA. Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Div Gen Med, Boston, MA 02115 USA. RP Ayanian, JZ (reprint author), Brigham & Womens Hosp, Dept Med, Div Gen Med, 75 Francis St, Boston, MA 02115 USA. RI VAN RYN, MICHELLE/B-1664-2010 FU NCI NIH HHS [U01 CA93324, U01 CA93326, U01 CA93329, U01 CA93332, U01 CA93339, U01 CA93344, U01 CA93348] NR 39 TC 169 Z9 170 U1 1 U2 9 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 AUG 1 PY 2004 VL 22 IS 15 BP 2992 EP 2996 DI 10.1200/JCO.2004.06.020 PG 5 WC Oncology SC Oncology GA 843VN UT WOS:000223115000005 PM 15284250 ER PT J AU Adams, MJ Lipsitz, SR Colan, SD Tarbell, NJ Treves, ST Diller, L Greenbaum, N Mauch, P Lipshultz, SE AF Adams, MJ Lipsitz, SR Colan, SD Tarbell, NJ Treves, ST Diller, L Greenbaum, N Mauch, P Lipshultz, SE TI Cardiovascular status in long-term survivors of Hodgkin's disease treated with chest radiotherapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HEART-RATE-VARIABILITY; MEDIASTINAL IRRADIATION; DOPPLER-ECHOCARDIOGRAPHY; EXERCISE TOLERANCE; DIASTOLIC FUNCTION; CARDIAC-FUNCTION; FOLLOW-UP; RADIATION; CHILDREN; CHILDHOOD AB Purpose Cardiovascular status was assessed in 48 Hodgkin's disease (HD) survivors at a median of 14.3 years (range, 5.9 to 27.5 years) after diagnosis because they may be at increased risk for cardiovascular abnormalities. Patients and Methods Patients completed the Short-Form 36 quality-of-life instrument and were screened by echocardiography, exercise stress testing, and resting and 24-hour ECG. Results All patients received mediastinal irradiation (median, 40.0 Gy; range, 27.0 to 51.7 Gy) at a median age of 16.5 years (range, 6.4 to 25.0 years). Four patients received an anthracycline. Although every patient described their health as good or better, and none had symptomatic heart disease at screening, all but one had cardiac abnormalities on screening. Restrictive cardiomyopathy was suggested by reduced average left ventricular (LV) dimension (P < .001) and mass (P < .001), without increased LV wall thickness. Significant valvular defects were present in 42%; 75% had conduction defects. One survivor developed complete heart block shortly after the study visit. Autonomic dysfunction was suggested by a monotonous heart rate in 57%, persistent tachycardia in 31%, and blunted hemodynamic responses to exercise in 27%. Peak oxygen uptake (VO(2)max) during exercise, a predictor of mortality in heart failure, was significantly reduced (<20 mL/kg/m(2)) in 30% of survivors. VO(2)max was correlated with increasing fatigue, increasing shortness of breath (both, r = -0.35; P = .02), and decreasing physical component score on the SF-36 (r = 0.554; P = .00017). Conclusion A variety of unsuspected, clinically significant cardiovascular abnormalities are common in long-term survivors of HD who are treated at a young age with mediastinal irradiation. We recommend serial, comprehensive cardiac screening of HD survivors who fit this profile. (C) 2004 by American Society of Clinical Oncology. C1 Univ Miami, Sch Med, Dept Pediat, Miami, FL 33101 USA. Univ Rochester, Sch Med, Dept Community & Prevent Med, Rochester, NY 14627 USA. Univ Rochester, Sch Med & Dent, Dept Community & Prevent Med, Rochester, NY USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Brigham & Womens Hosp, Dept Radiol Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Cambridge, MA 02138 USA. Med Univ S Carolina, Dept Biostat, Charleston, SC USA. Miami Univ, Jackson Mem Med Ctr, Holtz Childrens Hosp, Miami, FL USA. Sylvester Comprehens Ctr, Miami, FL USA. RP Lipshultz, SE (reprint author), Univ Miami, Sch Med, Dept Pediat, POB 016820, Miami, FL 33101 USA. EM slipshultz@med.miami.edu OI Adams, Michael Jacob/0000-0002-3245-5793 FU NCI NIH HHS [CA68484, CA79060]; NCRR NIH HHS [RRO2172]; NHLBI NIH HHS [HL04161, HL07937, HL53392, HL59837, HL70930] NR 45 TC 246 Z9 259 U1 0 U2 4 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 AUG 1 PY 2004 VL 22 IS 15 BP 3139 EP 3148 DI 10.1200/JCO.2004.09.109 PG 10 WC Oncology SC Oncology GA 843VN UT WOS:000223115000024 PM 15284266 ER PT J AU Sekino, S Ramberg, P Uzel, NG Socransky, S Lindhe, J AF Sekino, S Ramberg, P Uzel, NG Socransky, S Lindhe, J TI The effect of a chlorhexidine regimen on de novo plaque formation SO JOURNAL OF CLINICAL PERIODONTOLOGY LA English DT Article DE checkerboard DNA-DNA hybridization technique; microorganisms; plaque formation ID DENTAL PLAQUE; GINGIVITIS; BACTERIA; MOUTHRINSES AB Objective: To evaluate the effect of a pretreatment regimen that combined meticulous mechanical tooth cleaning with the daily use of chlorhexidine (rinse, gargle and tongue application) on de novo plaque formation and on the recolonization of various microbiological species in plaque and saliva during a 4-day period of no oral hygiene. Material and Methods: Ten subjects aged 24-36 years with gingivitis were recruited. The study was designed as a double blind cross-over clinical trial including two phases. Each experimental phase comprised one preparatory period of 7 days and one plaque accumulation period of 4 days. During the preparatory period, the volunteers (i) performed meticulous mechanical tooth cleaning using toothbrush and dentifrice and (ii) were, in addition, given two sessions of professional tooth cleaning (PTC) The final PTC was delivered after bacterial sampling had been made on Day 0. In the Control group, no additional plaque control measures were included. In the Test group, the participants in addition to the mechanical measures (i) rinsed twice daily, for 60 s each time with a 0.2% chlorhexidine solution, (ii) gargled twice daily for 10 s with the chlorhexidine preparation, and finally (iii) brushed the dorsum of the tongue for 60 s, twice daily, with a 1.0% chlorhexidine gel. During the 4-day plaque accumulation period, the participants abstained from all mechanical and chemical plaque control measures. On Days 0, 1, 2 and 4 the quantity and quality of plaque formed was assessed by clinical means and by DNA probe techniques. The microbiota of the saliva was studied in samples obtained on Days 0 and 4. Results: It was demonstrated that chlorhexidine used as a mouthrinse combined with gargling and tongue application during the preparatory period significantly retarded the amount of plaque that formed on tooth surfaces during the following 4 days of no oral hygiene. Further, the number of microorganisms present in the biofilm representing Days 0, 1 and 2 of the "plaque accumulation period" was apparently affected by the use of the antiseptic. Among the microorganisms influenced by the chlorhexidine regimen, a substantial number belonged to the genus Actinomyces. It was also observed that the adjunctive use of chlorhexidine reduced the number of bacteria present in saliva at the end of the preparatory period (i.e. on Day 0). After 4 days of no oral hygiene, the microbiota of the newly formed plaque in the Test and Control groups had many features in common. Conclusion: Habitat is critical in controlling the bacterial composition of the dental biofilm. The microbiota will tend to go back to the one that is characteristic of a given subject, once chemical antimicrobial means are withdrawn. C1 Univ Gothenburg, Inst Odontol, Dept Periodontol, Sahlgrenska Acad,Fac Odontol, SE-40530 Gothenburg, Sweden. Forsyth Inst, Dept Periodontol, Boston, MA USA. RP Ramberg, P (reprint author), Univ Gothenburg, Inst Odontol, Dept Periodontol, Sahlgrenska Acad,Fac Odontol, Box 450, SE-40530 Gothenburg, Sweden. EM ramberg@odontologi.gu.se NR 20 TC 23 Z9 29 U1 1 U2 5 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0303-6979 J9 J CLIN PERIODONTOL JI J. Clin. Periodontol. PD AUG PY 2004 VL 31 IS 8 BP 609 EP 614 DI 10.1111/j.1600-051X.2004.00526.x PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 838KZ UT WOS:000222713500004 PM 15257736 ER PT J AU State, RC Frye, MA Altshuler, LL Strober, M DeAntonio, M Hwang, S Mintz, J AF State, RC Frye, MA Altshuler, LL Strober, M DeAntonio, M Hwang, S Mintz, J TI Chart review of the impact of attention-deficit/hyperactivity disorder comorbidity on response to lithium or divalproex sodium in adolescent mania SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 153rd Annual Meeting of the American-Psychiatric-Association CY MAY 13-18, 2000 CL CHICAGO, ILLINOIS SP Amer Psychiat Assoc ID DEFICIT HYPERACTIVITY DISORDER; BIPOLAR DISORDER; VALPROIC ACID; DOUBLE-BLIND; CHILDREN; CHILDHOOD; ONSET; SYMPTOMS; EXPERIENCE; EFFICACY AB Purpose: Although adolescent onset of bipolar disorder is common, the optimal treatment approach for mania in this age group remains understudied. Comorbid attention-deficit/hyperactivity disorder (ADHD) has been reported to predict lithium resistance in adolescents with bipolar disorder. Little is known about response to divalproex sodium in adolescents with bipolar disorder comorbid with ADHD. This study was conducted to evaluate comparative response rates to lithium and divalproex sodium in adolescent mania with and without this comorbidity. Method: Medical records were reviewed for 42 patients (ages 12-19 years) who were hospitalized for acute mania and discharged with a diagnosis of DSM-III-R or DSM-IV bipolar disorder on either lithium (N = 29) or divalproex sodium (N = 13) treatment. A clinician blinded to treatment status rated improvement on the basis of abstracted notes in each case utilizing the Clinical Global Impressions Scale modified for use in bipolar illness (CGI-BP). Response was defined as a discharge CGI-BP overall change score of I or 2 (much or very much improved). Data were collected from January 1992 through May 1999. Results: 36/42 (85.7%) patients presented with mixed mania, and 14/41 (34.1%)patients had a history of ADHD. The overall response rate was 80.9% (34/42). 92.6% (25/27) of patients without ADHD were responders versus 57.1% (8/14) of subjects with comorbid ADHD (p =.007). There were no significant differences in response rates for lithium versus divalproex sodium in subjects with and without ADHD. Conclusion: These retrospective data suggest overall equivalent response rates for lithium and divalproex sodium in predominantly mixed adolescent mania. However, a history of ADHD was associated with a significantly diminished acute response to both divalproex sodium and lithium as a primary treatment for the manic phase of bipolar disorder. C1 Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90095 USA. W Los Angeles Vet Affairs Med Ctr, Biostat Unit, Los Angeles, CA 90073 USA. Harbor UCLA Med Ctr, Dept Psychiat, Torrance, CA 90509 USA. Neuropsychiat Inst & Hosp, Dept Psychiat & Behav Sci, Los Angeles, CA USA. RP Altshuler, LL (reprint author), Univ Calif Los Angeles, Sch Med, 300 Med Plaza,1544,Box 957057, Los Angeles, CA 90095 USA. EM laltshuler@mednet.ucla.edu NR 34 TC 38 Z9 40 U1 3 U2 5 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2004 VL 65 IS 8 BP 1057 EP 1063 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 851FU UT WOS:000223671800005 PM 15323589 ER PT J AU Alpert, JE Franznick, DA Hollander, SB Fava, M AF Alpert, JE Franznick, DA Hollander, SB Fava, M TI Gepirone extended-release treatment of anxious depression: Evidence from a retrospective subgroup analysis in patients with major depressive disorder SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID GENERALIZED ANXIETY DISORDER; 5-HT1A AGONISTS; FOLLOW-UP; EFFICACY; FLUOXETINE; DIZZINESS; SYMPTOMS; PLACEBO; TOLERABILITY; OUTPATIENTS AB Objective: To evaluate the efficacy and tolerability of gepirone extended-release (ER) tablets in patients with major depressive disorder (MDD) and high ratings of anxiety (anxious depression). Method: This subgroup analysis was derived from an 8-week, double-blind, placebo-controlled study of gepirone ER in patients with MDD. Male and female patients 18 to 69 years of age who met DSM-IV criteria for MDD and had high ratings of anxiety (Hamilton Rating Scale for Depression [HAM-D-17] total score greater than or equal to20 and HAM-D-17 factor I [anxiety/somatization] score >6) were included in this subgroup analysis. Eligible patients with anxious depression were randomly assigned to receive either placebo or gepirone ER, 20 mg to 80 mg daily. Patient assessments were performed at weeks 1, 2, 3, 4, 6, and 8. Treatment efficacy was evaluated by mean HAM-D-17 total scores and mean changes from baseline in (1) HAM-D-17 total scores, (2) HAM-D-17 factor I (anxiety/somatization) scores, and (3) HAM-D-17 item 12 (anxiety, psychic) scores. All statistical tests were 2-sided and considered statistically significant if the p value was <.05. Between-group comparisons were analyzed using least-squares analysis of variance on the change from baseline at each visit with the last observation carried forward (LOCF). The Cochran-Mantel-Haenszel test adjusting for center was also performed on the percentage of patients in each treatment group at each visit (LOCF) who met the response criterion on the HAM-D-17 (greater than or equal to50% decrease from baseline) or remission criterion (HAM-D-17 total score less than or equal to7). Results: Gepirone ER-treated patients (N = 58) experienced a statistically significant (p <.05) reduction in mean HAM-D-17 total score at week 3, 6, and 8 compared with placebo-treated patients (N = 75). A statistically significant effect (p <.05) in favor of gepirone ER was observed in mean change from baseline in HAM-D-17 total scores and for HAM-D factor I (anxiety/somatization) scores from week 2 onward. A statistically significant (p less than or equal to01) effect in favor of gepirone ER was observed in HAM-D-17 item 12 (anxiety, psychic) scores throughout the 8-week trial. There were significantly more patients in the gepirone ER group compared with the placebo group who were HAM-D-17 responders (p <.05) at endpoint and who met the criteria for HAM-D-17 remission at week 3 (p <.05) and weeks 6 and 8 (p <.01). Overall, gepirone ER was well tolerated, with rates of weight gain and sexual dysfunction comparable to placebo. Adverse events were generally mild to moderate. The most commonly reported adverse events were dizziness and nausea. Conclusions: Gepirone ER is an effective and well-tolerated treatment for patients with anxious depression. C1 Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. Organon Pharmaceut USA Inc, Roseland, NJ USA. RP Alpert, JE (reprint author), Massachusetts Gen Hosp, Depress Clin & Res Program, 50 Staniford St,4th Floor, Boston, MA 02114 USA. EM jalpert@partners.org OI Alpert, Jonathan/0000-0002-4332-908X NR 38 TC 16 Z9 16 U1 0 U2 1 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2004 VL 65 IS 8 BP 1069 EP 1075 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 851FU UT WOS:000223671800007 PM 15323591 ER PT J AU Papakostas, GI Petersen, T Mischoulon, D Ryan, JL Nierenberg, AA Bottiglieri, T Rosenbaum, JE Alpert, JE Fava, M AF Papakostas, GI Petersen, T Mischoulon, D Ryan, JL Nierenberg, AA Bottiglieri, T Rosenbaum, JE Alpert, JE Fava, M TI Serum folate, vitamin B-12, and homocysteine in major depressive disorder, part I: Predictors of clinical response in fluoxetine-resistant depression SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID FOLIC-ACID; ANTIDEPRESSANT; DEFICIENCY; PLASMA; LEVEL AB Objective: In the present study, we assessed the relationship between serum folate, vitamin 13,2, and homocysteine levels and clinical response in patients with major depressive disorder (MDD) who had previously failed to respond to open treatment with fluoxetine 20 mg/day and were enrolled in a 4-week, double-blind trial of either (1) fluoxetine dose increase, (2) lithium augmentation of fluoxetine, or (3) desipramine augmentation of fluoxetine. Method: Fifty-five outpatients (mean +/-SD age = 41.7 +/- 10.6 years; 50.9% women) with MDD as assessed with the Structured Clinical Interview for DSM-III-R who were enrolled in the double-blind trial had serum folate, vitamin 13,2, and homocysteine measurements completed at baseline (prior to fluoxetine treatment initiation). Folate levels were classified as either low (less than or equal to2.5 ng/mL) or normal. Vitamin B-12 levels were classified as either low (less than or equal to200 pg/mL) or normal. Homocysteine levels were classified as either elevated (greater than or equal to13.2 mumol/L) or normal. With the use of a logistic regression, we then assessed the relationship between (1) low or normal folate levels, (2) normal or low 13,2 levels, and (3) elevated or normal homocysteine levels and clinical response to double-blind treatment. The study was conducted from November 1992 to January 1999. Results: Low serum folate levels (chi(2) = 3.626, p =.04), but not elevated homocysteine (p >.05) or low vitamin B,, levels (p >.05), were associated with poorer response to treatment. The response rates for patients with (N = 14) and without (N = 38) low folate levels were 7.1% versus 44.7%, respectively. Conclusion: Low serum folate levels were found to be associated with further treatment resistance among patients with fluoxetine-resistant MDD. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Boston, MA 02114 USA. Baylor Univ, Inst Metab Dis, Sch Med, Waco, TX 76798 USA. RP Papakostas, GI (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, 15 Parkman St,WACC 812, Boston, MA 02114 USA. EM .papakostas@partners.org RI Papakostas, George/I-6905-2013; OI Papakostas, George/0000-0002-2465-5103; Alpert, Jonathan/0000-0002-4332-908X FU NIMH NIH HHS [1R01-MH-48-483-05] NR 30 TC 70 Z9 72 U1 3 U2 7 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2004 VL 65 IS 8 BP 1090 EP 1095 PG 6 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 851FU UT WOS:000223671800010 PM 15323594 ER PT J AU Papakostas, GI Petersen, T Mischoulon, D Green, CH Nierenberg, AA Bottiglieri, T Rosenbaum, JE Alpert, JE Fava, M AF Papakostas, GI Petersen, T Mischoulon, D Green, CH Nierenberg, AA Bottiglieri, T Rosenbaum, JE Alpert, JE Fava, M TI Serum folate, vitamin B-12, and homocysteine in major depressive disorder, Part 2: Predictors of relapse during the continuation phase of pharmacotherapy SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID FLUOXETINE; LITHIUM AB Objective: In the present study, we assessed the relationship between serum folate, vitamin B-12, and homocysteine levels on the rate of relapse in outpatients with remitted major depressive disorder (MDD) during a 28-week continuation phase of treatment with fluoxetine. Method: Seventy-one outpatients (mean +/- SD age = 40.2 +/- 11.1 years; 56.3% women) with MDD (as assessed with the Structured Clinical Interview for DSM-III-R) who had remitted and who were enrolled in the continuation phase of treatment with fluoxetine had serum folate, vitamin B-12, and homocysteine measurements completed at baseline (prior to acute-phase treatment). Patients were followed for 28 weeks of continued treatment with fluoxetine 40 mg/day to monitor for depressive relapse. Folate levels were classified as either low (less than or equal to2.5 ng/mL) or normal. Vitamin B-12 levels were classified as either low (less than or equal to200 pg/mL) or normal. Homocysteine levels were classified as either elevated (greater than or equal to13.2 mumol/L) or normal. With the use of separate logistic regressions, we then assessed the relationship between folate, vitamin B-12, and homocysteine level status and relapse. The study was conducted from November 1992 to January 1999. Results: The presence of low serum folate levels (p =.004), but not low 13,2 (p >.05) or elevated homocysteine levels (p >.05), was associated with relapse during continuation treatment with fluoxetine. The relapse rates for patients with (N = 7) and without (N = 64) low folate levels were 42.9% versus 3.2%, respectively. Conclusion: Low serum folate levels were found to place patients with remitted MDD at risk for depressive relapse during the continuation phase of treatment with fluoxetine. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Boston, MA 02114 USA. Baylor Univ, Sch Med, Inst Metab Dis, Waco, TX 76798 USA. RP Papakostas, GI (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, 15 Parkman St,WACC 812, Boston, MA 02114 USA. EM gpapakostas@partners.org RI Papakostas, George/I-6905-2013; OI Papakostas, George/0000-0002-2465-5103; Alpert, Jonathan/0000-0002-4332-908X FU NIMH NIH HHS [1R01-MH-48-483-05] NR 7 TC 48 Z9 50 U1 1 U2 3 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2004 VL 65 IS 8 BP 1096 EP 1098 PG 3 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 851FU UT WOS:000223671800011 PM 15323595 ER PT J AU Anton, RF Pettinati, H Zweben, A Kranzler, HR Johnson, B Bohn, MJ McCaul, ME Anthenelli, R Salloum, I Galloway, G Garbutt, J Swift, R Gastfriend, D Kallio, A Karhuvaara, S AF Anton, RF Pettinati, H Zweben, A Kranzler, HR Johnson, B Bohn, MJ McCaul, ME Anthenelli, R Salloum, I Galloway, G Garbutt, J Swift, R Gastfriend, D Kallio, A Karhuvaara, S TI A multi-site dose ranging study of nalmefene in the treatment of alcohol dependence SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article ID PLACEBO-CONTROLLED TRIAL; COGNITIVE-BEHAVIORAL THERAPY; COMPULSIVE DRINKING SCALE; DOUBLE-BLIND; OPIOID ANTAGONISTS; ORAL NALMEFENE; PROJECT MATCH; NALTREXONE; ETHANOL; MULTICENTER AB The opiate antagonist nalmefene has been shown in 2 single-site studies to reduce alcohol consumption and relapse drinking in alcohol-dependent individuals. This safety and preliminary multisite efficacy study evaluated 3 doses of nalmefene (5, 20, or 40 mg) in a double-blind comparison to placebo over a 12-week treatment period in 270 recently abstinent outpatient alcohol-dependent individuals. Participants concomitantly received 4 sessions of a motivational enhancement therapy (with a medication compliance component) delivered from trained counselors. Although more subjects in the active medication groups terminated the study early secondary to adverse events, the rates did not differ significantly from that of placebo. The 20-mg/d group experienced more insomnia, dizziness, and confusion, while the 5-mg group also had more dizziness and the 40-mg group had more nausea than the placebo group. Most of these symptoms were mild and improved over time. Although all subjects had a reduction in heavy drinking days, craving, gamma-glutamyl transferase, and carbohydrate-deficient transferrin concentrations over the course of the study, there was no difference between the active medication and placebo groups on these measures. The time to first heavy drinking day was also not significantly different between the placebo and the active treatment groups. This relatively small multisite trial showed that nalmefene was reasonably well tolerated in recently abstinent alcoholics. However, possibly because of variation among the sites or the comparatively small sample size, there was no evidence of superior efficacy outcomes with nalmefene treatment. C1 Med Univ S Carolina, Dept Psychiat, Charleston, SC 29425 USA. Univ Penn, Treatment Res Ctr, Philadelphia, PA 19104 USA. Univ Wisconsin, Milwaukee, WI 53201 USA. Univ Connecticut, Ctr Hlth, Farmington, CT USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Dean Fdn Hlth Res & Educ, Middleton, WI USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Cincinnati Vet Affairs Med Ctr, Cincinnati, OH USA. Univ Pittsburgh, Med Ctr, Western Psychiat Inst & Clin, Pittsburgh, PA USA. Haight Ashbury Free Clin Inc, San Francisco, CA USA. Univ N Carolina, Chapel Hill, NC USA. VA Med Ctr, Ocean State Res Inst, Providence, RI USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. BioTie Therapies Corp, Espoo, Finland. RP Anton, RF (reprint author), Med Univ S Carolina, Dept Psychiat, 67 President St, Charleston, SC 29425 USA. EM antonr@musc.edu NR 42 TC 65 Z9 68 U1 6 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD AUG PY 2004 VL 24 IS 4 BP 421 EP 428 DI 10.1097/01.jcp.0000130555.63254.73 PG 8 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 838RO UT WOS:000222731000010 PM 15232334 ER PT J AU Murphy, M Carlson, JA Keough, MP Claffey, KP Signoretti, S Loda, M AF Murphy, M Carlson, JA Keough, MP Claffey, KP Signoretti, S Loda, M TI Hypoxia regulation of the cell cycle in malignant melanoma: putative role for the cyclin-dependent kinase inhibitor p27(Kip1) SO JOURNAL OF CUTANEOUS PATHOLOGY LA English DT Article ID DISEASE-FREE SURVIVAL; METASTATIC MELANOMA; TUMOR HYPOXIA; DOWN-REGULATION; P27 EXPRESSION; CANCER-CELLS; PROGRESSION; SUPPRESSOR; APOPTOSIS; CARCINOMA AB Background: Intratumor hypoxia has been shown to promote more aggressive and metastatic cancer phenotypes that are associated with treatment resistance and poor prognosis. Cellular proliferation and its control are known to be important components of tumor progression. Hypoxia induces cell-cycle arrest in cultured cell lines, possibly via up-regulation of the cyclin-dependent kinase inhibitor p27. The effect of hypoxia on cell-cycle regulation in excised human tumors has not been investigated. Methods: We performed immunohistochemistry for p27 and Ki-67 on 10 formalin-fixed paraffin-embedded metastatic melanomas, selected on the basis of histological evidence of zonal/geographic necrosis, adjacent to areas with viable perivascular tumor cells. Results: In the majority of cases, there was a significant increase in p27 staining in cells adjacent to necrotic areas compared to perivascular zones. An inverse staining pattern between Ki-67 and p27 was identified in these tumors. Tumors with no zonal increase in p27 staining demonstrated a diffuse pattern of staining for Ki-67 within tumor nests. Conclusions: While increased cellular proliferation is a characteristic of cancer, subsets of human melanomas may retain the ability to regulate their rate of proliferation in response to changes in the tumor microenvironment. The hypoxia-mediated cell-cycle arrest (decreased Ki-67) in these tumors may be mediated by p27 up-regulation. C1 Univ Connecticut, Ctr Hlth, Dept Dermatol, Div Dermatopathol, Farmington, CT 06030 USA. Albany Med Ctr, Dept Pathol, Albany, NY USA. Univ Connecticut, Ctr Hlth, Dept Physiol, Farmington, CT USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Murphy, M (reprint author), Univ Connecticut, Ctr Hlth, Dept Dermatol, Div Dermatopathol, MC-6230,Dowling S,Suite 300,263 Farmington Ave, Farmington, CT 06030 USA. EM drmichaelmurphy@netscape.net OI Carlson, John Andrew/0000-0002-6866-6314 NR 41 TC 14 Z9 14 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0303-6987 J9 J CUTAN PATHOL JI J. Cutan. Pathol. PD AUG PY 2004 VL 31 IS 7 BP 477 EP 482 DI 10.1111/j.0303-6987.2004.00205.x PG 6 WC Dermatology; Pathology SC Dermatology; Pathology GA 835LK UT WOS:000222484500003 PM 15239677 ER PT J AU Szyfelbein, K Kozakewicz, HPW Syed, NA Zembowicz, A AF Szyfelbein, K Kozakewicz, HPW Syed, NA Zembowicz, A TI Phakomatous choristoma of the eyelid: a report of a case SO JOURNAL OF CUTANEOUS PATHOLOGY LA English DT Article ID LIGHT; TUMOR AB Phakomatous choristoma is a rare congenital hamartoma of lens tissue. It presents in newborns or young infants as a subcutaneous mass in the medial lower eyelid. We present a case of phakomatous choristoma recently identified among old consultation files at Children's Hospital in Boston. Our case illustrates unique histological features of this entity which has to be included in differential diagnosis of skin lesions of the inferonasal eyelid. C1 Massachusetts Gen Hosp, Dermatopathol Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. Univ Iowa, Dept Ophtalmol & Pathol, Iowa City, IA USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Zembowicz, A (reprint author), Massachusetts Gen Hosp, Dermatopathol Unit, 820 Warren Bldg,55 Fruit St, Boston, MA 02114 USA. EM azembowicz@partners.org NR 9 TC 5 Z9 5 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0303-6987 J9 J CUTAN PATHOL JI J. Cutan. Pathol. PD AUG PY 2004 VL 31 IS 7 BP 506 EP 508 DI 10.1111/j.0303-6987.2004.00209.x PG 3 WC Dermatology; Pathology SC Dermatology; Pathology GA 835LK UT WOS:000222484500008 PM 15239682 ER PT J AU Challapalli, H Goldhaber, SZ Brown, DFM Nadel, ES AF Challapalli, H Goldhaber, SZ Brown, DFM Nadel, ES TI Shortness of breath in the postoperative patient SO JOURNAL OF EMERGENCY MEDICINE LA English DT Editorial Material ID ACUTE PULMONARY-EMBOLISM; BRAIN NATRIURETIC PEPTIDE; RISK STRATIFICATION; ALTEPLASE; HEPARIN C1 Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Div Emergency Med, Boston, MA USA. Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA USA. Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Nadel, ES (reprint author), Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. NR 9 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 0736-4679 J9 J EMERG MED JI J. Emerg. Med. PD AUG PY 2004 VL 27 IS 2 BP 171 EP 177 DI 10.1016/j.jemermed.2004.05.001 PG 7 WC Emergency Medicine SC Emergency Medicine GA 838NB UT WOS:000222719000013 PM 15261361 ER PT J AU Schneider, A Togel, S Barmada, MM Whitcomb, DC AF Schneider, A Togel, S Barmada, MM Whitcomb, DC TI Genetic analysis of the glutathione s-transferase genes MGST1, GSTM3, GSTT1, and GSTM1 in patients with hereditary pancreatitis SO JOURNAL OF GASTROENTEROLOGY LA English DT Article DE hereditary pancreatitis; chronic pancreatitis; oxidative stress ID IDIOPATHIC CHRONIC-PANCREATITIS; SERINE-PROTEASE INHIBITOR; SUPERGENE FAMILY; KAZAL TYPE-1; MUTATIONS; POLYMORPHISMS; RESISTANCE; DISEASE; CANCER; PSTI AB Background. Specific mutations in the cationic trypsinogen gene (PRSS1) are disease-causing in patients with hereditary pancreatitis, but the genetic background still remains mysterious in about 40% of patients with the disease. It has been suggested that oxidative stress contributes to pancreatic damage. The glutathione s-transferases (GSTs) represent major detoxification enzymes that protect cells from oxidative stress. Methods. In the present study we tested whether mutations in the MGST1 and GSTM3 genes or common deletions in the GSTT1 and GSTM1 genes are associated with hereditary pancreatitis. We analyzed the entire coding region of MGST1 and GSTM3 in 30 patients that were tested negative for PRSS1 mutations, and we studied 55 controls. For GSTT1 and GSTM1, we investigated 75 hereditary pancreatitis patients who had been tested negative for PRSS1 mutations, 135 hereditary pancreatitis patients with a PRSS1 mutation, and 183 controls. Patients were further subclassified with regard to age of onset of disease as a marker of severity. Results. No mutation was found in the MGST1 gene. In the GSTM3 gene, we detected a homozygous 670G > A polymorphism (V224I) with similar frequencies in patients and controls. We found no difference in the frequencies of the GSTT1 and GSTM1 null genotypes between patients and controls, and we detected no differences in age of onset in patients with or without GSTT1 and GSTM1 deletions. Conclusions. We conclude that genetic alterations in the MGST1, GSTM3, GSTT1, and GSTM1 genes do not play a dominant role in hereditary pancreatitis. C1 Univ Pittsburgh, Dept Med, Div Gastroenterol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA USA. Univ Pittsburgh, VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. Univ Pittsburgh, Ctr Genom Sci, Pittsburgh, PA USA. RP Whitcomb, DC (reprint author), Univ Pittsburgh, Dept Med, Div Gastroenterol, 571 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15213 USA. OI Barmada, M Michael/0000-0002-3604-6460 FU NIDDK NIH HHS [DK54709] NR 23 TC 11 Z9 12 U1 0 U2 0 PU SPRINGER TOKYO PI TOKYO PA 3-3-13, HONGO, BUNKYO-KU, TOKYO, 113-0033, JAPAN SN 0944-1174 J9 J GASTROENTEROL JI J. Gastroenterol. PD AUG PY 2004 VL 39 IS 8 BP 783 EP 787 DI 10.1007/s00535-004-1389-7 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 849RV UT WOS:000223559300011 PM 15338373 ER PT J AU Cox, LS Patten, CA Niaura, RS Decker, PA Rigotti, N Sachs, DPL Buist, AS Hurt, RD AF Cox, LS Patten, CA Niaura, RS Decker, PA Rigotti, N Sachs, DPL Buist, AS Hurt, RD TI Efficacy of bupropion for relapse prevention in smokers with and without a past history of major depression SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE smoking; relapse prevention; major depression; bupropion therapy ID SMOKING-CESSATION; ALCOHOLISM; DEPENDENCE; THERAPY AB BACKGROUND: This study evaluated the efficacy of bupropion for relapse prevention in smokers with and without a past history of major depressive disorder. Changes in depressive symptoms were also examined. DESIGN: Data were gathered prospectively from a randomized, double-blind relapse prevention trial of bupropion conducted at five study sites. A total of 784 smokers (54% female, 97% white) were enrolled. Using the Structured Clinical Interview for Depression, 17% of the subjects reported a past history of major depressive disorder at baseline. All subjects received open-label bupropion SR (300 mg/d) for 7 weeks. Subjects abstinent from smoking at the end of 7 weeks (N= 429) were randomized to bupropion SR (300 mg/d) or placebo for the remainder of the year and followed for 1 year off medication. The primary outcome measures were median time to relapse to smoking and the 7-day point-prevalence smoking abstinence rate. Self-reported abstinence from smoking was verified by expired air carbon monoxide. The Beck Depression Inventory was used to assess depressive symptoms at baseline and at weeks 8 and 12. RESULTS: Median time to relapse did not differ by past history of major depressive disorder. Bupropion was associated with higher point-prevalence smoking abstinence at the end of medication compared to placebo (P= .007), independent of a past history of major depressive disorder. Moreover, change in depressive symptoms during the double-blind phase did not differ for those with and without a past history of major depressive disorder. CONCLUSIONS: Extended use of bupropion for relapse prevention is effective for smokers with and without a history of major depression. C1 Mayo Clin & Mayo Fdn, Nicotine Dependence Ctr, Res Program, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Dept Psychiat & Psychol, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Div Community Internal Med, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Biostat Sect, Rochester, MN 55905 USA. Brown Univ, Miriam Hosp, Providence, RI USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Palo Alto Ctr Pulm Dis Prevent, Palo Alto, CA USA. Oregon Hlth & Sci Univ, Pulm & Crit Care Div, Portland, OR USA. RP Patten, CA (reprint author), Mayo Clin & Mayo Fdn, Nicotine Dependence Ctr, Res Program, 200 1st St SW, Rochester, MN 55905 USA. EM patten.christi@mayo.edu NR 21 TC 46 Z9 48 U1 2 U2 3 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD AUG PY 2004 VL 19 IS 8 BP 828 EP 834 DI 10.1111/j.1525-1497.2004.30423.x PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 834OW UT WOS:000222421400003 PM 15242467 ER PT J AU Shrank, WH Reed, VA Jernstedt, GC AF Shrank, WH Reed, VA Jernstedt, GC TI Fostering professionalism in medical education - A call for improved assessment and meaningful incentives SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE professionalism; incentives; medical education; evaluation ID STRUCTURED CLINICAL EXAMINATION; STANDARDIZED PATIENTS; HIDDEN CURRICULUM; STUDENTS; SKILLS; FEEDBACK; GENERALIZABILITY; PERSPECTIVES; RELIABILITY; ENVIRONMENT AB Increasing attention has been focused on developing professionalism in medical school graduates. Unfortunately, the culture of academic medical centers and the behaviors that faculty model are often incongruent with our image of professionalism. The need for improved role modeling, better assessment of student behavior, and focused faculty development is reviewed. We propose that the incentive structure be adjusted to reward professional behavior in both students and faculty. The third-year medicine clerkship provides an ideal opportunity for clinician-educators to play a leading role in evaluating, rewarding, and ultimately fostering professionalism in medical school graduates. C1 VA Greater Los Angeles Healthcare Syst, Div Gen Internal Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Hanover, NH 03756 USA. Ctr Educ Outcomes Dartmouth, Hanover, NH USA. RP Shrank, WH (reprint author), VA Greater Los Angeles Healthcare Syst, Div Gen Internal Med, 111G,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM shrankw@aol.com NR 67 TC 37 Z9 38 U1 11 U2 16 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD AUG PY 2004 VL 19 IS 8 BP 887 EP 892 DI 10.1111/j.1525-1497.2004.30635.x PG 6 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 834OW UT WOS:000222421400012 PM 15242476 ER PT J AU Haug, T Sigg, D Ciani, S Toro, L Stefani, E Olcese, R AF Haug, T Sigg, D Ciani, S Toro, L Stefani, E Olcese, R TI Regulation of K+ flow by a ring of negative charges in the outer pore of BKCa channels. Part I: Aspartate 292 modulates K+ conduction by external surface charge effect SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article DE MaxiK channel; conduction; permeation; surface charge; Markov model ID ACTIVATED POTASSIUM CHANNELS; ION CONDUCTION; SIGNATURE SEQUENCE; PERMEABILITY; SELECTIVITY; PERMEATION; MUTATIONS; SURVIVAL; KINETICS; RECEPTOR AB The pore region of the majority of K+ channels contains the highly conserved GYGD sequence, known as the K+ channel signature sequence, where the GYG is critical for K+ selectivity (Heginbotham, L., T. Abramson, and R. MacKinnon. 1992. Science. 258:1152-1155). Exchanging the aspartate residue with asparagine in this sequence abolishes ionic conductance of the Shaker K+ channel (D447N) (Hurst, R.S., L. Toro, and E. Stefani. 1996. FEBS Lett. 388:59-65). In contrast, we found that the corresponding mutation (D292N) in the pore forming a Subunit (hSlo) of the voltage- and Ca2+-activated K+ channel (BKCa, MaxiK) did not prevent conduction but reduced single channel conductance. We have investigated the role of outer pore negative charges in ion conduction (this paper) and channel gating (Haug, T, R. Olcese, T Ligia, and E. Stefani. 2004. J. Gen Physiol. 124: 185-197). In symmetrical 120 mM [K+], the D292N mutation reduced the outward single channel conductance by similar to40% and nearly abolished inward K+ flow (outward rectification). This rectification was partially relieved by increasing the external K+ concentration to 700 mM. Small inward currents were resolved by introducing an additional initiation (R207Q) that greatly increases the open probability of the channel. A four-state multi-ion pore model that incorporates the effects of surface charge was used to simulate the essential properties of channel conduction. The conduction properties of the mutant channel (D292N) could be predicted by a simple similar to8.5-fold reduction of the surface charge density without altering any other parameter. These results indicate that the, pore plays a key role in conduction and suggest that the pore structure is not affected aspartate residue in the BKCa by the mutation. We speculate that the negative charge strongly accumulates K+ in the outer vestibule close to the selectivity filter, thus increasing the rate of ion entry into the pore. C1 Univ Calif Los Angeles, David Geffen Sch Med, Dept Anesthesiol, Div Mol Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA 90095 USA. VA Greater Los Angeles Healthcare Syst, Dept Nucl Med, Los Angeles, CA 90073 USA. RP Olcese, R (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Anesthesiol, Div Mol Med, BH-570 CHS,Box 95711, Los Angeles, CA 90095 USA. EM rolcese@ucla.edu FU NHLBI NIH HHS [R01 HL054970, HL54970]; NIGMS NIH HHS [GM52203]; NINDS NIH HHS [NS43240, R01 NS043240] NR 42 TC 33 Z9 33 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD AUG PY 2004 VL 124 IS 2 BP 173 EP 184 DI 10.1085/jgp.200308949 PG 12 WC Physiology SC Physiology GA 844HT UT WOS:000223149600008 PM 15277578 ER PT J AU Berg, JT Ramanathan, S Gabrielli, MG Swenson, ER AF Berg, JT Ramanathan, S Gabrielli, MG Swenson, ER TI Carbonic anhydrase in mammalian vascular smooth muscle SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE carbonic anhydrase; smooth muscle; vasculature; acetazolamide; dorzolamide; immunocytochemistry; bovine ID HYPOXIC PULMONARY VASOCONSTRICTION; SKELETAL-MUSCLE; IMMUNOHISTOCHEMICAL LOCALIZATION; ACETAZOLAMIDE; INHIBITION; RABBIT; SULFONAMIDES; ISOENZYMES; CELLS; CA2+ AB Carbonic anhydrase (CA) is ubiquitously expressed and plays a pivotal role in acid-base balance, ion transport, and gas exchange. Limited observations by others, derived from functional, pharmacological, and histochemical studies, suggest that CA is present in vascular smooth muscle and is involved in vasoregulation. The present study, using measurements of bioactivity, inhibition characteristics, and immunohistochemical analysis, was undertaken to more fully evaluate CA in vascular smooth muscle. In isolated bovine aortic smooth muscle, which is devoid of erythrocytes, CA is present in low concentrations with a CO2 hydration activity (at 0C) of 3.5 +/- 2.7 U/g. The I-50 for acetazolamide inhibition is 0.07 +/- 0.01 muM. Results with dorzolamide and bromopyruvate, selective inhibitors of the CA II and I isozymes, respectively, show that roughly 75% of the CA activity is accounted for by CA I, with 20% due to CA II. These results accord qualitatively with immunocytochemical staining with specific CA I and II antibodies, showing that both isozymes are present and that their staining co-localizes with cells positive for smooth muscle alpha-actin. These data establish the activity, inhibition, and isozyme pattern of carbonic anhydrase expression in mammalian vascular smooth muscle. C1 Univ Washington, VA Puget Sound Hlth Care Syst, Pulm Sect, Dept Med, Seattle, WA 98108 USA. Univ Hawaii, John A Burns Sch Med, Dept Pharmacol, Honolulu, HI 96822 USA. Univ Camerino, Dept Comparat Morphol & Biochem, I-62032 Camerino, Italy. RP Swenson, ER (reprint author), Univ Washington, VA Puget Sound Hlth Care Syst, Pulm Sect, Dept Med, S-111 Pulm,1660 S Columbian Way, Seattle, WA 98108 USA. EM eswenson@u.washington.edu FU NHLBI NIH HHS [HL-24163] NR 36 TC 17 Z9 17 U1 0 U2 0 PU HISTOCHEMICAL SOC INC PI SEATTLE PA UNIV WASHINGTON, DEPT BIOSTRUCTURE, BOX 357420, SEATTLE, WA 98195 USA SN 0022-1554 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD AUG PY 2004 VL 52 IS 8 BP 1101 EP 1106 DI 10.1369/jhc.4a6266.2004 PG 6 WC Cell Biology SC Cell Biology GA 841JZ UT WOS:000222927400013 PM 15258186 ER PT J AU Dessain, SK Adekar, SP Stevens, JB Carpenter, KA Skorski, ML Barnoski, BL Goldsby, RA Weinberg, RA AF Dessain, SK Adekar, SP Stevens, JB Carpenter, KA Skorski, ML Barnoski, BL Goldsby, RA Weinberg, RA TI High efficiency creation of human monoclonal antibody-producing hybridomas SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE human monoclonal antibody; hybridoma; B-lymphocyte; interleukin-6; Streptococcus pneumoniae ID HUMAN-CHROMOSOME 22; NORMAL HUMAN-CELLS; CATALYTIC SUBUNIT; LIFE-SPAN; STREPTOCOCCUS-PNEUMONIAE; TELOMERASE ACTIVITY; TRANSGENIC MICE; EXPRESSION; POLYSACCHARIDE; HYBRIDIZATION AB The native human antibody repertoire holds unexplored potential for the development of novel monoclonal antibody therapeutics. Current techniques that fuse immortal cells and primary B-lymphocytes are sub-optimal for the routine production of hybridomas that secrete human monoclonal antibodies. We have found that a murine cell line that ectopically expresses murine interleukin-6 (mIL-6) and human telomerase (hTERT) efficiently forms stable human antibody-secreting heterohybridomas through cell fusion with primary human B-lymphocytes. The hybrid cells maintain secretion of human antibodies derived from the primary B-lymphocytes through multiple rounds of cloning. Using splenic B-lymphocytes from a patient immunized with a Streptococcus pneumoniae capsular polysaccharide vaccine, we have succeeded in creating hybridomas that secrete human monoclonal antibodies specific for S. pneumoniae antigens. Using peripheral blood lymphocytes, we have similarly cloned a human antibody that binds a viral antigen. These experiments establish that SP2/0-derived cell lines ectopically expressing mIL-6 and hTERT will enable the rapid cloning of native human monoclonal antibodies. (C) 2004 Elsevier B.V. All rights reserved. C1 Thomas Jefferson Univ, Cardeza Fdn Hematol Res, Philadelphia, PA 19107 USA. Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. Thomas Jefferson Univ, Div Genet & Prevent Med, Philadelphia, PA 19107 USA. Amherst Coll, Dept Biol, Amherst, MA 01002 USA. RP Dessain, SK (reprint author), Thomas Jefferson Univ, Cardeza Fdn Hematol Res, Curtis Bldg 812,1015 Walnut St, Philadelphia, PA 19107 USA. EM Scott.Dessain@jefferson.edu FU NCI NIH HHS [R01 CA78461]; NHLBI NIH HHS [K08 HL0463] NR 55 TC 27 Z9 27 U1 0 U2 5 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 AUG PY 2004 VL 291 IS 1-2 BP 109 EP 122 DI 10.1016/j.jim.2004.05.005 PG 14 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 855HO UT WOS:000223964200011 PM 15345310 ER PT J AU Schmidt-Supprian, M Tian, J Ji, HB Terhorst, C Bhan, AK Grant, EP Pasparakis, M Casola, S Coyle, AJ Rajewsky, K AF Schmidt-Supprian, M Tian, J Ji, HB Terhorst, C Bhan, AK Grant, EP Pasparakis, M Casola, S Coyle, AJ Rajewsky, K TI I kappa B kinase 2 deficiency in T cells leads to defects in priming, B cell help, germinal center reactions, and homeostatic expansion SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TOXOPLASMA-GONDII; DRUG DEVELOPMENT; ACTIVATION; REQUIREMENT; LYMPHOTOXIN; LYMPHOCYTES; RESPONSES; SURVIVAL; SYSTEM; ALPHA AB Signal transduction from proinflammatory stimuli leading to NF-kappaB-dependent gene expression is mediated by the IkappaB kinase 2 (IKK2/IKKbeta). Therefore, IKK2 has become an important drug target for treatment of inflammatory conditions. T cells, whose activation depends to a large extent on the activity of NF-kappaB transcription factors, play important roles in inflammation and autoimmunity. Ablation of IKK2 specifically in T cells in CD4cre/Ikk2(FL) mice allows their survival and activation by polyclonal stimuli in vitro, suggesting that IKK2 is dispensable for T cell activation. We report in this study that IKK2-deficient T cells expand efficiently in response to superantigen administration in vivo, but are completely deficient in recall responses, most likely due to inefficient priming. IKK2-deficient T cells provide suboptimal B cell help and fail to support germinal center reactions. Finally, IKK2 is essential for homeostatic expansion of naive T cells, reflected by the inability of IKK2-deficient T cells to induce colitis in lymphopenic hosts. C1 Harvard Univ, Sch Med, CBR Inst Biomed Res, Boston, MA 02115 USA. Millennium Pharmaceut Inc, Cambridge, MA 02139 USA. Beth Israel Deaconess Med Ctr, Div Immunol, Boston, MA 02215 USA. Massachusetts Gen Hosp, Immunopathol Unit, Boston, MA 02114 USA. European Mol Biol Lab, Mouse Biol Program, Monterotondo, Italy. RP Schmidt-Supprian, M (reprint author), Harvard Univ, Sch Med, CBR Inst Biomed Res, 200 Longwood Ave, Boston, MA 02115 USA. EM supprian@cbr.med.harvard.edu RI Schmidt-Supprian, Marc/F-5893-2011 OI Schmidt-Supprian, Marc/0000-0002-8543-6166 FU NIAID NIH HHS [AI057947] NR 32 TC 24 Z9 26 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 AUG 1 PY 2004 VL 173 IS 3 BP 1612 EP 1619 PG 8 WC Immunology SC Immunology GA 839TF UT WOS:000222807100016 PM 15265889 ER PT J AU Mycko, MP Waldner, H Anderson, DE Bourcier, KD Wucherpfennig, KW Kuchroo, VK Hafler, DA AF Mycko, MP Waldner, H Anderson, DE Bourcier, KD Wucherpfennig, KW Kuchroo, VK Hafler, DA TI Cross-reactive TCR responses to self antigens presented by different MHC class II molecules SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MYELIN BASIC-PROTEIN; T-CELL-RECEPTOR; PEPTIDE COMBINATORIAL LIBRARIES; MULTIPLE-SCLEROSIS PATIENTS; TRANSGENIC MICE; AUTOIMMUNE ENCEPHALOMYELITIS; SIGNAL-TRANSDUCTION; GENE REARRANGEMENTS; CRYSTAL-STRUCTURE; CLONAL EXPANSION AB Autoreactive T cells represent a natural repertoire of T cells in both diseased patients and healthy individuals. The mechanisms regulating the function of these autoreactive T cells are still unknown. Ob1A12 is a myelin basic protein (MBP)-reactive Th cell clone derived from a patient with relapsing-remitting multiple sclerosis. Mice transgenic for this human TCR and DRA and DRB1*1501 chains develop spontaneous experimental autoimmune encephalomyelitis. The reactivity of Ob1A12 is reported to be restricted to recognition of MBP peptide 85-99 in the context of DRB1*1501. DRA/DRB1*1501 and the patient's other restriction element, DRA/DRB1*0401, differ significantly in their amino acid sequences. In this study we describe an altered peptide ligand derived from MBP85-99 with a single amino acid substitution at position 88 (Val to Lys; 88V --> K), that could stimulate the Ob1A12.TCR in the context of both DRA/DRB1*1501 and DRA/DRB1*0401. Analysis of a panel of transfected T cell hybridomas expressing Ob1A12.TCR and CD4 indicated that Ob1AI2.TCR cross-reactivity in the context of DRA/DRB1*0401 is critically dependent on the presence of the CD4 coreceptor. Furthermore, we found that activation of Ob1A12.TCR with MBP altered peptide ligand 85-99 88V --> K presented by DRB1*1501 or DRB1*0401 resulted in significant differences in TCR phosphorylation. Our data indicate that injection of altered peptide ligand into patients heterozygous for MHC class II molecules may result in unexpected cross-reactivities, leading to activation of autoreactive T cells. C1 Harvard Univ, Sch Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02215 USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Hafler, DA (reprint author), Harvard Univ, Sch Med, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM dhafler@rics.bwh.harvard.edu RI Mycko, Marcin Przemyslaw/S-9386-2016 NR 51 TC 21 Z9 23 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2004 VL 173 IS 3 BP 1689 EP 1698 PG 10 WC Immunology SC Immunology GA 839TF UT WOS:000222807100025 PM 15265898 ER PT J AU Shams, H Klucar, P Ewer, SE Lalvani, A Moonan, PK Safi, H Wizel, B Ewer, K Nepom, GT Lewinsohn, DM Andersen, P Barnes, PF AF Shams, H Klucar, P Ewer, SE Lalvani, A Moonan, PK Safi, H Wizel, B Ewer, K Nepom, GT Lewinsohn, DM Andersen, P Barnes, PF TI Characterization of a Mycobacterium tuberculosis peptide that is recognized by human CD4(+) and CD8(+) T cells in the context of multiple HLA alleles SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GAMMA-INTERFERON PRODUCTION; SYNTHETIC PEPTIDES; ESAT-6 ANTIGEN; BEIJING GENOTYPE; RAPID DETECTION; INFECTED-CELLS; EPITOPES; RESPONSES; ENUMERATION; PROTEIN AB The secreted Mycobacterium tuberculosis 10-kDa culture filtrate protein (CFP)10 is a potent T cell Ag that is recognized by a high percentage of persons infected with M. tuberculosis. We determined the molecular basis for this widespread recognition by identifying and characterizing a 15-mer peptide, CFP10(71-85), that elicited IFN-gamma production and CTL activity by both CD4(+) and CD8(+) T cells from persons expressing multiple MHC class 11 and class I molecules, respectively. CFP1071-85 contained at least two epitopes, one of 10 aa (peptide T1) and another of 9 aa (peptide T6). T1 was recognized by CD4(+) cells in the context of DRB1*04, DR5*0101, and DQB1*03, and by CD8(+) cells of A2(+) donors. T6 elicited responses by CD4(+) cells in the context of DRB1*04 and DQB1*03, and by CD8(+) cells of B35(+) donors. Deleting a single amino acid from the amino or carboxy terminus of either peptide markedly reduced IFN-gamma production, suggesting that they are minimal epitopes for both CD4(+) and CD8(+) cells. As far as we are aware, these are the shortest microbial peptides that have been found to elicit responses by both T cell subpopulations. The capacity of CFP10(71-85) to Stimulate IFN-gamma production and CTL activity by CD4(+) and CD8(+) cells from persons expressing a spectrum of MHC molecules suggests that this peptide is an excellent candidate for inclusion in a subunit antituberculosis vaccine. C1 Univ Texas Hlth Ctr, Ctr Pulm & Infect Dis Control, Tyler, TX 75708 USA. Univ Texas Hlth Ctr, Dept Microbiol, Tyler, TX 75708 USA. Univ Texas Hlth Ctr, Dept Immunol, Tyler, TX 75708 USA. Univ Texas Hlth Ctr, Dept Med, Tyler, TX 75708 USA. Univ N Texas, Hlth Sci Ctr, Dept Internal Med, Ft Worth, TX 76107 USA. Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Med, Oxford OX3 9DU, England. Benaroya Res Inst, Seattle, WA 98101 USA. Oregon Hlth Sci Univ, Div Pulm & Crit Care Med, Portland Vet Affairs Med Ctr, Portland, OR 97207 USA. Statens Scruminst, Copenhagen, Denmark. RP Shams, H (reprint author), Univ Texas Hlth Ctr, Ctr Pulm & Infect Dis Control, 11937 US Highway 271, Tyler, TX 75708 USA. EM amir.shams@uthct.edu RI Moonan, Patrick/F-4307-2014; Ewer, Katie/B-4328-2011; Lewinsohn, David/I-4936-2013 OI Ewer, Katie/0000-0001-9827-9836; Moonan, Patrick/0000-0002-3550-2065; Lewinsohn, David/0000-0001-9906-9494 FU NIAID NIH HHS [AI44935] NR 49 TC 61 Z9 62 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 AUG 1 PY 2004 VL 173 IS 3 BP 1966 EP 1977 PG 12 WC Immunology SC Immunology GA 839TF UT WOS:000222807100058 PM 15265931 ER PT J AU SenGupta, D Norris, PJ Suscovich, TJ Hassan-Zahraee, M Moffett, HF Trocha, A Draenert, R Goulder, PJR Binder, RJ Levey, DL Walker, BD Srivastava, PK Brander, C AF SenGupta, D Norris, PJ Suscovich, TJ Hassan-Zahraee, M Moffett, HF Trocha, A Draenert, R Goulder, PJR Binder, RJ Levey, DL Walker, BD Srivastava, PK Brander, C TI Heat shock protein-mediated cross-presentation of exogenous HIV antigen on HLA class I and class II SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MHC CLASS-I; CYTOTOXIC T-LYMPHOCYTES; HEAT-SHOCK-PROTEIN-70 PEPTIDE COMPLEXES; DENDRITIC CELL MATURATION; GP96 INDUCES MATURATION; CD8-T-CELL MEMORY; IMMUNE-RESPONSES; CD4-T-CELL HELP; TUMOR AB Strong CD4(+) and CD8(+) T cell responses are considered important immune components for controlling HIV infection, and their priming may be central to an effective HIV vaccine. We describe in this study an approach by which multiple CD4(+) and CD8(+) T cell epitopes are processed and presented from an exogenously added HIV-1 Gag-p 4 peptide of 32 aa complexed to heat shock protein (HSP) gp96. CD8(+) T cell recognition of the HSP/peptide complex, but not the peptide alone, was inhibited by brefeldin A, suggesting an endoplasmic reticulum-dependent pathway. This is the first report to describe efficient processing and simultaneous presentation of overlapping class I- and class II-restricted epitopes from the same extracellularly added precursor peptide complexed to HSP. Given previous reports of the strong immunogenicity of HSP/peptide complexes, the present data suggest that HSP-complexed peptides containing multiple MHC class I- and class II-restricted epitopes represent potential vaccine candidates for HIV and other viral infections suitable to induce effective CTL memory by simultaneously providing CD4 T cell help. C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. Antigen Inc, Lexington, MA 02420 USA. RP Brander, C (reprint author), Massachusetts Gen Hosp, Ctr AIDS Res, 5214,149 13th St, Charlestown, MA 02129 USA. EM brander@helix.mgh.harvard.edu FU NCI NIH HHS [CA44786]; NIAID NIH HHS [AI01698-01, AI28568, K08 AI001698, K08 AI001698-04] NR 63 TC 59 Z9 67 U1 1 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 AUG 1 PY 2004 VL 173 IS 3 BP 1987 EP 1993 PG 7 WC Immunology SC Immunology GA 839TF UT WOS:000222807100060 PM 15265933 ER PT J AU Okamatsu, Y Kim, D Battaglino, R Sasaki, H Spate, U Stashenko, P AF Okamatsu, Y Kim, D Battaglino, R Sasaki, H Spate, U Stashenko, P TI MIP-1 gamma promotes receptor activator of NF-kappa B ligand-induced osteoclast formation and survival SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MACROPHAGE-INFLAMMATORY PROTEIN-1-ALPHA; COLONY-STIMULATING FACTOR; MOLECULAR-CLONING; CHEMOKINE FAMILY; PROTEIN 1-ALPHA; CC-CHEMOKINE; T-CELLS; DIFFERENTIATION; MEMBER; OSTEOPROTEGERIN AB Chemokines play an important role in immune and inflammatory responses by inducing migration and adhesion of leukocytes, and have also been reported to modulate osteoclast differentiation from hemopoietic precursor cells of the monocyte-macrophage lineage. In this study, we examined the effect of MIP-1gamma, a C-C chemokine family member, on receptor activator of NF-kappaB ligand (RANKL)-stimulated osteoclast differentiation, survival, and activation. RANKL induced osteoclasts to dramatically increase production of MIP-1gamma and to also express the MIP-1gamma receptor CCR1, but had only minor effects on the related C-C chemokines MIP-1alpha and RANTES. Neutralization of MIP-1gamma with specific Ab reduced RANKL-stimulated osteoclast differentiation by 60-70%. Mature osteoclasts underwent apoptosis within 24 h after removal of RANKL, as shown by increased caspase 3 activity and DNA fragmentation. Apoptosis was reduced by the addition of exogenous MIP-1gamma or RANKL, both of which increased NF-kappaB activation in osteoclasts. Neutralization studies showed that the prosurvival effect of RANKL was in part dependent on its ability to induce MIP-1gamma. Finally, osteoclast activation for bone resorption was stimulated by MIP-1gamma. Taken together, these results demonstrate that MIP-1gamma plays an important role in the differentiation and survival of osteoclasts, most likely via an autocrine pathway. C1 Forsyth Inst, Dept Cytokine BIol, Boston, MA 02115 USA. Showa Univ, Sch Dent, Dept Periodontol, Tokyo 142, Japan. RP Stashenko, P (reprint author), Forsyth Inst, Dept Cytokine BIol, 140 Fenway, Boston, MA 02115 USA. EM pstashenko@forsyth.org RI battaglino, ricardo/D-2892-2015 FU NIDCR NIH HHS [DE-07378] NR 29 TC 50 Z9 50 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 AUG 1 PY 2004 VL 173 IS 3 BP 2084 EP 2090 PG 7 WC Immunology SC Immunology GA 839TF UT WOS:000222807100071 PM 15265944 ER PT J AU Trial, J Rubio, JA Birdsall, HH Rodriguez-Barradas, M Rossen, RD AF Trial, J Rubio, JA Birdsall, HH Rodriguez-Barradas, M Rossen, RD TI Monocyte activation by circulating fibronectin fragments in HIV-1-infected patients SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS-INFECTION; CELL-BINDING DOMAIN; PERIPHERAL-BLOOD MONOCYTES; GELATIN-BOUND FIBRONECTIN; PLASMA FIBRONECTIN; TRANSENDOTHELIAL MIGRATION; ANTIRETROVIRAL THERAPY; STAPHYLOCOCCUS-AUREUS; SIGNAL-TRANSDUCTION; LEUKOCYTE ELASTASE AB To identify signals that can alter leukocyte function in patients receiving highly active antiretroviral therapy (HAART), we analyzed single blood samples from 74 HIV-1-infected patients and additional blood was collected at 90-day intervals from 51 HIV-1-infected patients over a 516 +/- 172 (mean +/- Sb) day interval. Despite the absence of circulating immune complexes and normalization of phagocytic function, compared with controls, the fraction of patients' monocytes expressing CD49e and CD62L was decreased and expression of CD11b and CD86 increased. Plasma from 63% of patients but none from normal controls contained 110-120 kDa fibronectin fragments (FNf). Presence of FNf did not reflect poor adherence to therapy. Addition of FNf to normal donor blood in vitro replicated changes in monocyte CD49e, CD62L, CD11b, and CD86 seen in vivo. FNf also induced monocytes to release a serine proteinase, nominally identified as proteinase-3, that hydrolyzed cell surface CD49e. alpha(1)-Antitrypsin blocked FNf-induced shedding of CD49e in a dose-dependent manner. Plasma with a normal frequency of CD49e(+) monocytes contained antiproteases that partially blocked FNf-induced monocyte CD49e shedding, whereas plasma from patients with a low frequency of CD49e(+) monocytes did not block this effect of FNf. Electrophoretic analyses of plasma from the latter group of patients suggested that a significant fraction of their alpha(1)-antitrypsin was tied up in high molecular mass complexes. These results suggest that monocyte behavior in HIV-1-infected patients may be influenced by FNf and the ratio of protease and antiproteases in the cells' microenvironment. C1 Michael E DeBakey Vet Affairs Med Ctr, Res Ctr AIDS & HIV Infect, Immunol Res Lab, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Baylor Coll Med, Dept Otorhinolaryngol, Houston, TX 77030 USA. Baylor Coll Med, Dept Immunol, Houston, TX 77030 USA. RP Rossen, RD (reprint author), Michael E DeBakey Vet Affairs Med Ctr, Res Ctr AIDS & HIV Infect, Immunol Res Lab, Bldg 109,Room 288,2002 Holcombe Blvd, Houston, TX 77030 USA. EM rrossen@bcm.tmc.edu FU NIAID NIH HHS [R01 AI046285]; NIMH NIH HHS [MH63035] NR 52 TC 14 Z9 14 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2004 VL 173 IS 3 BP 2190 EP 2198 PG 9 WC Immunology SC Immunology GA 839TF UT WOS:000222807100084 PM 15265957 ER PT J AU Tyler, KL AF Tyler, KL TI Oral transmission of kuru, Creutzfeldt- Jakob disease, and scrapie to nonhuman primates. Commentary SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID FOLLICULAR DENDRITIC CELLS; BOVINE SPONGIFORM ENCEPHALOPATHY; ENTERIC NERVOUS-SYSTEM; HUMAN PRION DISEASES; PROTEIN EXPRESSION; LAMININ RECEPTOR; B-CELLS; INFECTION; NEUROINVASION; HAMSTERS C1 Univ Colorado, Hlth Sci Ctr, Dept Neurol, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Microbiol, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Immunol, Denver, CO 80262 USA. Denver Vet Affairs Med Ctr, Neurol Serv, Denver, CO USA. RP Tyler, KL (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Neurol, 4200 E 9th Ave, Denver, CO 80262 USA. EM ken.tyler@uchsc.edu NR 42 TC 2 Z9 2 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 AUG 1 PY 2004 VL 190 IS 3 BP 653 EP 656 DI 10.1086/422260 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 836IQ UT WOS:000222549500035 PM 15243947 ER PT J AU Kunstfeld, R Hirakawa, S Hong, YK Schacht, V Lange-Asschenfeldt, B Velasco, P Wu, Y Hicklin, D Bohlen, P Detmar, M AF Kunstfeld, R Hirakawa, S Hong, YK Schacht, V Lange-Asschenfeldt, B Velasco, P Wu, Y Hicklin, D Bohlen, P Detmar, M TI VEGF-A plays a key role in the induction of chronic inflammation and the associated lymphangiogenic response SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 34th Annual Meeting of the European-Society-for-Dermatological-Research CY SEP 09-11, 2004 CL Vienna, AUSTRIA SP European Soc Dermatol Res, Serono, Galderma, Novartis, Chanel, LVMH C1 Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Imclone Syst Inc, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2004 VL 123 IS 2 MA 203 PG 1 WC Dermatology SC Dermatology GA 835LA UT WOS:000222483400231 ER PT J AU Schacht, V Dadras, SS Kremer, B Bruckner-Tuderman, L Detmar, M AF Schacht, V Dadras, SS Kremer, B Bruckner-Tuderman, L Detmar, M TI Differential expression of the lymphatic marker podoplanin in human squamous cell carcinomas and basal cell carcinomas SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 34th Annual Meeting of the European-Society-for-Dermatological-Research CY SEP 09-11, 2004 CL Vienna, AUSTRIA SP European Soc Dermatol Res, Serono, Galderma, Novartis, Chanel, LVMH C1 Univ Freiburg, Dept Dermatol, D-7800 Freiburg, Germany. Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. Massachusetts Gen Hosp, Dept Dermatol, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2004 VL 123 IS 2 MA 333 PG 1 WC Dermatology SC Dermatology GA 835LA UT WOS:000222483400361 ER PT J AU Clayton, AE Mikulec, AA Mikulec, KH Merchant, SN McKenna, MJ AF Clayton, AE Mikulec, AA Mikulec, KH Merchant, SN McKenna, MJ TI Association between osteoporosis and otosclerosis in women SO JOURNAL OF LARYNGOLOGY AND OTOLOGY LA English DT Article DE otoselerosis; osteoporosis; collagen type 1; genes ID COL1A1 NULL ALLELES; IMPERFECTA TYPE-I; OSTEOGENESIS-IMPERFECTA; GENETICS; HISTOPATHOLOGY; OTOSPONGIOSIS; COLLAGEN; LINKAGE; DISEASE AB Similarities between osteoporosis and otosclerosis have been noted, including a similar association with the COL1A1 gene. Herein, the authors explore the possible clinical relationship between these two common disorders of bone. In this retrospective study, the medical charts of 100 women aged 50 through 75 years who had under,gone stapedectomy for otosclerosis were reviewed and the prevalence of osteoporosis in these women was noted. Similarly, the prevalence of osteoporosis was determined in a control group of 100 women aged 50 to 75 years with presbycusis. Fifteen of 100 women with otosclerosis had a concomitant diagnosis of osteoporosis as compared with four of 100 women with presbycusis, yielding a significant clinical association (p = 0.007) between otosclerosis and osteoporosis. This study suggests an association between otosclerosis and osteoporosis, providing impetus and justification for future prospective clinical studies and related research. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otolaryngol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. Univ Wales Coll Med, Cardiff CF4 4XN, S Glam, Wales. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. RP McKenna, MJ (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. FU NIDCD NIH HHS [2 R01 DC03401-06A1] NR 32 TC 17 Z9 17 U1 0 U2 3 PU HEADLEY BROTHERS LTD PI ASHFORD PA INVICTA PRESS, ASHFORD TN24 8HH, KENT, ENGLAND SN 0022-2151 J9 J LARYNGOL OTOL JI J. Laryngol. Otol. PD AUG PY 2004 VL 118 IS 8 BP 617 EP 621 PG 5 WC Otorhinolaryngology SC Otorhinolaryngology GA 858OD UT WOS:000224200700006 PM 15453937 ER PT J AU Cho, G Segal, E Ackerman, JL AF Cho, G Segal, E Ackerman, JL TI Nuclear magnetic resonance-compatible furnace for high temperature MR imaging and spectroscopy in situ SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE NMR; nondestructive evaluation; ceramic; binder burnout; molten salt ID POLYMER BINDER BURNOUT; PRESSURE DISTRIBUTION; ADVANCED CERAMICS; INORGANIC OXIDES; NMR; GLASSES; CATALYSTS; METHANOL; REMOVAL; INSITU AB A high temperature magnetic resonance compatible furnace for real time in situ monitoring of materials, processes, and chemical reactions with magnetic resonance imaging and spectroscopy is described. Design issues are analyzed. Example applications are demonstrated with a time sequence of proton images of the binder burnout in a porous green ceramic cylinder containing polyethylene glycol binder at 200degreesC, and Li-7 images of the molten salt LiCl at 700degreesC. (C) 2004 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Dept Radiol, Biomat Lab, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Technion Israel Inst Technol, Dept Qual Assurance & Reliabil Techn, IL-32000 Haifa, Israel. RP Ackerman, JL (reprint author), Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Dept Radiol, Biomat Lab, Charlestown, MA 02129 USA. EM jerry@nmr.mgh.harvard.edu RI Ackerman, Jerome/E-2646-2015 OI Ackerman, Jerome/0000-0001-5176-7496 FU NIAMS NIH HHS [AR42258] NR 39 TC 3 Z9 3 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 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD AUG PY 2004 VL 169 IS 2 BP 328 EP 334 DI 10.1016/j.jmr.2004.05.012 PG 7 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 842BR UT WOS:000222978100018 PM 15261630 ER PT J AU Gow, DW Im, AM AF Gow, DW Im, AM TI A cross-linguistic examination of assimilation context effects SO JOURNAL OF MEMORY AND LANGUAGE LA English DT Article DE phonological variation; assimilation; spoken word recognition; connectionism; cross-linguistic comparison; speech perception ID SPOKEN WORD RECOGNITION; STOP-CONSONANT IDENTIFICATION; SPEECH-PERCEPTION; TRADING RELATIONS; LEXICAL AMBIGUITY; JAPANESE; REPRESENTATION; VOWELS; CUES; CONSEQUENCES AB Language-specific phonological processes routinely affect the pronunciation of words spoken in context, but do not appear to interfere with spoken word recognition. Five experiments are presented in which native and non-speakers of Hungarian and Korean monitored for segments in assimilated and non-assimilated control contexts related to language-specific assimilation phenomena in those languages. Native and non-speakers of Hungarian showed similar context effects related to Hungarian voicing assimilation in Experiments 1 and 2. In Experiments 3-5 native and non-speakers of Korean showed no context effects related to Korean labial-to-velar place assimilation. These results contrast with significant context effects related to Korean coronal place assimilation shown in Experiment 5. The results suggest that these context effects rely on perceptual mechanisms that interact with the acoustic characteristics of phonological modification rather than mechanisms driven by language-specific knowledge operating at an abstract phonological level. (C) 2004 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Neuropsychol Lab, Boston, MA 02114 USA. Salem State Coll, Salem, MA 01970 USA. RP Gow, DW (reprint author), Massachusetts Gen Hosp, Neuropsychol Lab, VBK 827, Boston, MA 02114 USA. EM gow@helix.mgh.harvard.edu NR 64 TC 40 Z9 41 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 0749-596X J9 J MEM LANG JI J. Mem. Lang. PD AUG PY 2004 VL 51 IS 2 BP 279 EP 296 DI 10.1016/j.jml.2004.05.004 PG 18 WC Linguistics; Psychology; Psychology, Experimental SC Linguistics; Psychology GA 841IP UT WOS:000222923800009 ER PT J AU Shen, X Li, QL Brent, GA Friedman, TC AF Shen, X Li, QL Brent, GA Friedman, TC TI Thyroid hormone regulation of prohormone convertase 1 (PC1): regional expression in rat brain and in vitro characterization of negative thyroid hormone response elements SO JOURNAL OF MOLECULAR ENDOCRINOLOGY LA English DT Article ID GENE-EXPRESSION; ANTERIOR-PITUITARY; MESSENGER-RNA; PROPROTEIN CONVERTASES; HALF-SITES; MICE; RECEPTOR; PROOPIOMELANOCORTIN; DISRUPTION; MECHANISM AB Most pro-neuropeptides are processed by the prohormone convertases, PC1 and PC2. We previously reported that changes in thyroid status altered anterior pituitary PC1 mRNA and this regulation was due to triiodothyronine (T-3)-dependent interaction of thyroid hormone receptor (TR) with negative thyroid hormone response elements (nTREs) contained in a large region of the human PC1 promoter. In this study, we demonstrated that hypothyroidism stimulated, while hyperthyroidism suppressed, PC1 mRNA levels in rat hypothalamus and cerebral cortex, but not in hippocampus. In situ hybridization was used to confirm real-time PCR changes and localize the regulation within the hypothalamus and cortex. Using a human PC1 (hPC1) promoter construct (with and without deletions in two regions that each contain a negative TRE) transiently transfected into GH3 cells, we found that T-3 negatively regulated hPC1 promoter activity, and this regulation required both of these two regions. Electrophoretic mobility shift assays (EMSAs) using purified thyroid hormone receptor alpha1 (TRalpha1) and retinoid X receptor beta (RXRbeta) proteins demonstrated that RXR and TRalpha both bound the PC1 promoter. Addition of TRalpha1/RXRbeta to the wild-type PC1 probe demonstrated binding as both homodimers and a heterodimer. EMSAs with oligonucleotides containing deletion mutations of the putative nTREs demonstrated that the proximal nTRE binds more strongly to TR and RXR than the distal nTRE, but that both regions exhibit specific binding. We conclude that there are multiple novel TRE-like sequences in the hPC1 promoter and that these regions act in a unique manner to facilitate the negative effect of thyroid hormone on PC1. C1 Univ Calif Los Angeles, Div Endocrinol, Charles R Drew Univ Med & Sci, Sch Med, Los Angeles, CA 90059 USA. W Los Angeles Vet Affairs Med Ctr, Dept Med, Div Endocrinol, Los Angeles, CA 90073 USA. Cedars Sinai Med Ctr, Dept Med, Div Endocrinol, Los Angeles, CA 90048 USA. RP Univ Calif Los Angeles, Div Endocrinol, Charles R Drew Univ Med & Sci, Sch Med, 1731 E 120th St, Los Angeles, CA 90059 USA. EM tefriedm@cdrewu.edu FU NCI NIH HHS [CA8936401]; NCRR NIH HHS [U54 RR14616-01, G21 RR03026-13] NR 44 TC 21 Z9 21 U1 0 U2 3 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0952-5041 J9 J MOL ENDOCRINOL JI J. Mol. Endocrinol. PD AUG PY 2004 VL 33 IS 1 BP 21 EP 33 DI 10.1677/jme.0.0330021 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 849PN UT WOS:000223552100003 PM 15291740 ER PT J AU Barker, FG Linskey, ME AF Barker, FG Linskey, ME TI History of the AANS/CNS Joint Section on Tumors and preface to the 20th anniversary Journal of Neuro-Oncology special issue SO JOURNAL OF NEURO-ONCOLOGY LA English DT Editorial Material DE brain tumors; congresses; craniotomy; historical article; mortality; subspecialization ID ACOUSTIC NEUROMA SURGERY; GLIOMA OUTCOMES PROJECT; BRAIN-TUMORS; NEUROLOGICAL SURGERY; PITUITARY SURGERY; TRANSSPHENOIDAL SURGERY; PEDIATRIC NEUROSURGERY; SUBSEQUENT PUBLICATION; SURGICAL-MANAGEMENT; NORTH-AMERICA AB The Joint Section on Tumors of the American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons (CNS) was formed in 1984, at the suggestion of Dr. Edward R. Laws, Jr. and with Dr. Mark Rosenblum as the first Section Chair. The Joint Section on Tumors is the first professional organization devoted to the study and treatment of brain tumors. Its initial goals were to 'assist in the education of neurosurgeons in neuro-oncology and to serve as a resource [to the AANS and CNS] and other national groups on the clinical treatment of and research into nervous system tumors'. During its 20-year history, the Section has facilitated both open and invited talks at the neurosurgical national meetings, conducted its own Satellite Symposia, and instituted multiple awards and grants. Members have conducted research surveys and national practice pattern studies, and have collected and disseminated information on clinical protocols, research funding opportunities, and fellowships in neurosurgical oncology. Guidelines for brain tumor treatment and for neuro-oncology fellowships for surgeons have been written by Section committees. Studies presented orally at Section meetings, 1999-2002, had a remarkably high rate of full publication compared to other meetings - 73% actuarial at 4 years after presentation. Finally, nationwide in-hospital mortality rates for craniotomy for malignant glioma have fallen from 8 to 2% during the Section's existence. These data suggest that the Section's goals of educating all surgeons in neurosurgical oncology are being successfully met. A bibliography of secondary sources on the history of brain tumor surgery is appended. C1 Harvard Univ, Sch Med, Neurosurg Serv, Massachusetts Gen Hosp, Boston, MA 02115 USA. Univ Calif Irvine, Irvine, CA USA. RP Barker, FG (reprint author), Harvard Univ, Sch Med, Neurosurg Serv, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM barker@helix.mgh.harvard.edu NR 231 TC 6 Z9 6 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD AUG-SEP PY 2004 VL 69 IS 1-3 BP 1 EP 18 DI 10.1023/B:NEON.0000041868.00906.0a PG 18 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 854PV UT WOS:000223916700001 PM 15527076 ER PT J AU Chiocca, EA Broaddus, WC Gillies, GT Visted, T Lamfers, MLM AF Chiocca, EA Broaddus, WC Gillies, GT Visted, T Lamfers, MLM TI Neurosurgical delivery of chemotherapeutics, targeted toxins, genetic and viral therapies in neuro-oncology SO JOURNAL OF NEURO-ONCOLOGY LA English DT Review DE brain delivery methods; convection-enhanced delivery; gene therapy; immunotoxins; oncolytic virus; toxins; viral therapy ID HUMAN-MALIGNANT GLIOMA; THYMIDINE-KINASE GENE; CONVECTION-ENHANCED DELIVERY; SELECTIVELY-REPLICATING ADENOVIRUS; POSITIVE-PRESSURE INFUSION; LONG-TERM SURVIVAL; PHASE-I TRIAL; BRAIN-TUMORS; GLIOBLASTOMA-MULTIFORME; RECURRENT GLIOBLASTOMA AB Local delivery of biologic agents, such as gene and viruses, has been tested preclinically with encouraging success, and in some instances clinical trials have also been performed. In addition, the positive pressure infusion of various therapeutic agents is undergoing human testing and approval has already been granted for routine clinical use of biodegradable implants that diffuse a chemotherapeutic agent into peritumoral regions. Safety in glioma patients has been shown, but anticancer efficacy needs additional refinements in the technologies employed. In this review, we will describe these modalities and provide a perspective on needed improvements that should render them more successful. C1 Virginia Commonwealth Univ, Dept Neurosurg, Med Coll Virginia Hosp, Richmond, VA 23298 USA. Harvard Univ, Sch Med, Mol Neurooncol Labs, Neurosurg Serv,Massachusetts Gen Hosp, Charlestown, MA USA. Univ Virginia, Dept Biomed Engn, Charlottesville, VA USA. RP Broaddus, WC (reprint author), Virginia Commonwealth Univ, Dept Neurosurg, Med Coll Virginia Hosp, POB 980631, Richmond, VA 23298 USA. EM wcbroadd@vcu.edu RI Lamfers, Martine/C-6246-2016; OI Lamfers, Martine/0000-0001-7745-9029 NR 105 TC 34 Z9 38 U1 0 U2 2 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD AUG-SEP PY 2004 VL 69 IS 1-3 BP 101 EP 117 DI 10.1023/B:NEON.0000041874.02554.b3 PG 17 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 854PV UT WOS:000223916700008 PM 15527083 ER PT J AU Paintlia, MK Paintlia, AS Barbosa, E Singh, I Singh, AK AF Paintlia, MK Paintlia, AS Barbosa, E Singh, I Singh, AK TI NAC prevents endotoxin induced loss of OPC in fetus and hypomyelination in postnatal rat brain SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 Med Univ S Carolina, Charleston, SC 29425 USA. Ralph H Johnson VA Med Ctr, Charleston, SC USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 5 EP 5 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900016 ER PT J AU Khan, M Jatana, M Giri, S Gilg, AG Singh, I Singh, AK AF Khan, M Jatana, M Giri, S Gilg, AG Singh, I Singh, AK TI Administration of N-acetylcysteine after focal cerebral ischemia protects brain in a rat model of experimental stroke SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. Ralph H Johnson VA Med Ctr, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 14 EP 14 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900047 ER PT J AU Lee, JK Won, JS Singh, AK Singh, I AF Lee, JK Won, JS Singh, AK Singh, I TI Adenosine kinase inhibitor attenuates the expression of iNOS in glial cells SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Pathol, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Lab Med, Charleston, SC 29425 USA. Ralph H Johnson VA Med Ctr, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 20 EP 20 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900073 ER PT J AU Won, JS Im, YB Singh, AK Singh, I AF Won, JS Im, YB Singh, AK Singh, I TI Dual role of cAMP in iNOS expression in glial cells and macrophages: differential regulation of P38 activation and iNOS stability SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Pathol, Charleston, SC 29425 USA. Ralph H Johnson VA Med Ctr, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 20 EP 20 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900072 ER PT J AU Kelleher, RJ Govindarajan, A Jung, HY Kang, H Tonegawa, S AF Kelleher, RJ Govindarajan, A Jung, HY Kang, H Tonegawa, S TI Translational control by MAPK signaling in long-term synaptic plasticity and memory SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 MIT, Picower Ctr Learning & Memory, Dept Biol, Cambridge, MA 02139 USA. MIT, Picower Ctr Learning & Memory, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Neurol Serv, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 5 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 30 EP 30 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900106 ER PT J AU Yao, JK Carroll, JJ Runyan, C Wengenack, TM Poduslo, JF AF Yao, JK Carroll, JJ Runyan, C Wengenack, TM Poduslo, JF TI Reduced membrane lipids in the cortex of AD transgenic model SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Mayo Clin, Coll Med, Rochester, MN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 42 EP 42 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900146 ER PT J AU Nath, N Giri, S Singh, AK Singh, I AF Nath, N Giri, S Singh, AK Singh, I TI Lovastatin induces bone marrow-derived dendritic cell maturation and production of pro-inflammatory cytokines SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 Med Univ S Carolina, Charleston, SC 29425 USA. Ralph H Johnson VA Med Ctr, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 46 EP 46 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900159 ER PT J AU Singh, I Stanislaus, RC Gilg, AG Singh, AK AF Singh, I Stanislaus, RC Gilg, AG Singh, AK TI N-acetyl-L-cysteine protects against the inflammatory disease process in experimental autoimmune encephalomyelitis SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 Med Univ S Carolina, Charleston, SC 29425 USA. Ralph H Johnson VA Med Ctr, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 48 EP 48 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900168 ER PT J AU Rowitch, D Ligon, K Sun, T Hafler, B Fancy, S Franklin, R Raine, C Brosnan, C Arnet, H Stiles, C AF Rowitch, D Ligon, K Sun, T Hafler, B Fancy, S Franklin, R Raine, C Brosnan, C Arnet, H Stiles, C TI Olig function in CNS development and disease SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 Harvard Univ, Sch Med, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Cambridge Ctr Brain Repair, Cambridge, England. Albert Einstein Coll Med, Bronx, NY 10467 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 52 EP 52 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900183 ER PT J AU Paintlia, AS Paintlia, MK Singh, AK Gilg, AG Barbosa, E Singh, I AF Paintlia, AS Paintlia, MK Singh, AK Gilg, AG Barbosa, E Singh, I TI Regulation of immune response genes associated with acute experimental autoimmune encephalomyelitis by lovastatin SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 Med Univ S Carolina, Charleston, SC 29425 USA. Ralph H Johnson VA Med Ctr, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 59 EP 59 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900210 ER PT J AU Giri, S Rattan, R Singh, AK Singh, I AF Giri, S Rattan, R Singh, AK Singh, I TI 15d PGJ2 inhibits inflammatory response in primary astrocytes via down regulating multiple steps in PI3K-Akt-NF-kappa B-P300 pathway SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 MUSC, Dept Pathol & Lab Med, Charleston, SC USA. MUSC, Dept Pediat, Charleston, SC USA. Ralph Johnson VA Med Ctr, Dept Pathol & Lab Med, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 61 EP 61 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900216 ER PT J AU Pannu, R Barbosa, E Singh, AK Singh, I AF Pannu, R Barbosa, E Singh, AK Singh, I TI Attenuation of acute inflammatory response by atorvastatin following spinal cord injury in rats SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Pathol, Charleston, SC 29425 USA. Ralph H Johnson VA Med Ctr, Charleston, SC USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 69 EP 69 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900244 ER PT J AU Haq, E Khan, A Giri, S Singh, I Singh, AK AF Haq, E Khan, A Giri, S Singh, I Singh, AK TI Peroxisomal participation in psychosine-mediated lipotoxicity: implications for Krabbe disease SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA. Ralph H Johnson VA Med Ctr, Charleston, SC USA. OI Haq, Ehtishamul/0000-0002-4195-0606 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 72 EP 72 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900254 ER PT J AU Lo, EH Jacobs, TP AF Lo, EH Jacobs, TP TI Stroke: inflammation in the neurovascular unit. Opportunities in the neurovascular unit SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 Massachusetts Gen Hosp, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 80 EP 80 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900281 ER PT J AU Green, PS Mendez, AJ Jacob, JS Crowley, JR Growdon, W Hyman, BT Heinecke, JW AF Green, PS Mendez, AJ Jacob, JS Crowley, JR Growdon, W Hyman, BT Heinecke, JW TI Neuronal expression of myeloperoxidase is increased in Alzheimer's disease SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE Alzheimer's disease; 3-chlorotyrosine; myeloperoxidase; oxidative stress; o,o '-dityrosine ID LOW-DENSITY-LIPOPROTEIN; GLYCATION END-PRODUCTS; OXIDATIVE DAMAGE; LIPID-PEROXIDATION; CATALYZED OXIDATION; NEUTROPHILS EMPLOY; HUMAN PHAGOCYTES; IN-VIVO; PROTEIN; SYSTEM AB Myeloperoxidase, a heme protein expressed by professional phagocytic cells, generates an array of oxidants which are proposed to contribute to tissue damage during inflammation. We now report that enzymatically active myeloperoxidase and its characteristic amino acid oxidation products are present in human brain. Further, expression of myeloperoxidase is increased in brain tissue showing Alzheimer's neuropathology. Consistent with expression in phagocytic cells, myeloperoxidase immunoreactivity was present in some activated microglia in Alzheimer brains. However, the majority of immunoreactive material in brain localized with amyloid plaques and, surprisingly, neurons including granule and pyramidal neurons of the hippocampus. Confirming neuronal localization of the enzyme, several neuronal cell lines as well as primary neuronal cultures expressed myeloperoxidase protein. Myeloperoxidase mRNA was also detected in neuronal cell lines. These results reveal the unexpected presence of myeloperoxidase in neurons. The increase in neuronal myeloperoxidase expression we observed in Alzheimer disease brains raises the possibility that the enzyme contributes to the oxidative stress implicated in the pathogenesis of the neurodegenerative disorder. C1 Univ Washington, Dept Med, Div Gerontol, Seattle, WA 98195 USA. Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. Univ Miami, Sch Med, Dept Med, Miami, FL USA. RP Green, PS (reprint author), Univ Washington, Dept Med, Div Gerontol, Box 356426, Seattle, WA 98195 USA. EM psgreen@u.washington.edu FU NIA NIH HHS [AG021191, AG05134, AG05681, AG08487]; NIDDK NIH HHS [DK02456] NR 66 TC 139 Z9 143 U1 3 U2 20 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 IS 3 BP 724 EP 733 DI 10.1111/j.1471-4159.2004.02527.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 838NQ UT WOS:000222720500023 PM 15255951 ER PT J AU Schule, B Kock, N Svetel, M Dragasevic, N Hedrich, K Aguiar, PD Liu, L Kabakci, K Garrels, J Meyer, EM Berisavac, I Schwinger, E Kramer, PL Ozelius, LJ Klein, C Kostic, V AF Schule, B Kock, N Svetel, M Dragasevic, N Hedrich, K Aguiar, PD Liu, L Kabakci, K Garrels, J Meyer, EM Berisavac, I Schwinger, E Kramer, PL Ozelius, LJ Klein, C Kostic, V TI Genetic heterogeneity in ten families with myoclonus-dystonia SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID EPSILON-SARCOGLYCAN GENE; MUTATIONS; PATIENT; LOCUS AB Background: Myoclonus-dystonia (M-D) is a movement disorder with autosomal dominant inheritance and reduced penetrance but may also occur sporadically. Recently, mutations in the epsilon-sarcoglycan gene (SGCE) were shown to cause M-D. Furthermore, single variants in the dopamine D2 receptor (DRD2) and DYT1 genes were found in combination with SGCE mutations in two M-D families, and another M-D locus was recently mapped to chromosome 18p11 in one family. Methods: The authors clinically and genetically characterised ten consecutive cases with myoclonus-dystonia; seven familial and three sporadic. Twenty nine M-D patients and 40 unaffected family members underwent a standardised clinical examination by a movement disorder specialist. Index cases were screened for mutations in the SGCE, DYT1, and DRD2 genes and for deletions of the SGCE gene. Suitable mutation negative families were tested for linkage to the SGCE region and to chromosome 18p11. Results: Two SGCE mutations were detected among the seven familial but no mutation in the sporadic cases. Haplotype analysis at the new M-D locus was compatible with linkage in two families and excluded in another family, suggesting at least one additional M-D gene. There were no obvious clinical differences between M-D families with and without detected mutations. Conclusion: M-D is genetically heterogeneous with SGCE mutations accounting for the disease in only part of the clinically typical cases. C1 Univ Lubeck, Dept Neurol, D-23538 Lubeck, Germany. Univ Lubeck, Dept Human Genet, D-23538 Lubeck, Germany. Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Univ Belgrade, Dept Neurol, Belgrade, Yugoslavia. Albert Einstein Coll Med, Dept Human Genet, Bronx, NY 10467 USA. Oregon Hlth Sci Univ, Dept Neurol, Portland, OR 97201 USA. RP Klein, C (reprint author), Univ Lubeck, Dept Neurol, Ratzeburger Allee 160, D-23538 Lubeck, Germany. EM klein_ch@neuro.mu-luebeck.de RI de Carvalho Aguiar, Patricia/B-2350-2013; de Carvalho Aguiar, Patricia/E-8520-2010 OI de Carvalho Aguiar, Patricia/0000-0003-2957-9573; de Carvalho Aguiar, Patricia/0000-0003-2957-9573 NR 13 TC 36 Z9 37 U1 0 U2 3 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 AUG PY 2004 VL 75 IS 8 BP 1181 EP 1185 DI 10.1136/jnnp.2003.027177 PG 5 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 838QJ UT WOS:000222727800024 PM 15258227 ER PT J AU Stiver, SI Tan, X Brown, LF Hedley-Whyte, ET Dvorak, HF AF Stiver, SI Tan, X Brown, LF Hedley-Whyte, ET Dvorak, HF TI VEGF-A angiogenesis induces a stable neovasculature in adult murine brain SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE adenovirus; angiogenesis; brain; cerebrovascular disorders; glioblastoma; vascular endothelial growth factor (VEGF) ID ENDOTHELIAL GROWTH-FACTOR; CENTRAL-NERVOUS-SYSTEM; VASCULAR-PERMEABILITY; RAT-BRAIN; IN-VIVO; GENE-TRANSFER; ARTERIOVENOUS-MALFORMATIONS; EMBRYONIC ANGIOGENESIS; BARRIER BREAKDOWN; FACTOR EXPRESSION AB Angiogenesis is a critical component of stroke, head injury, cerebral vascular malformation development, and brain tumor growth. An understanding of the mechanisms of adult cerebral angiogenesis is fundamental to therapeutic vessel modulation for these diseases. To study angiogenesis in the central nervous system, we injected an adenoviral vector engineered to express vascular endothelial growth factor (VEGF-A(164)) into adult murine striatum. Vector-infected astrocytes expressed VEGF-A(164) resulting in vascular permeability, hemorrhage, and the formation of greatly enlarged "mother" vessels. Subsequently, endothelial cells and pericytes lining mother vessels proliferated and assembled into glomeruloid bodies, complex cellular arrays interspersed by small vessel lumens. As VEGF-A(164) expression declined, glomeruloid bodies involuted through apoptotic processes to engender numerous small daughter vessels. Characterized by modestly enlarged lumens with prominent pericyte coverage, daughter vessels were distributed with a density greater than normal cerebral vessels. Daughter vessels remained stable and patent to 16 months and represented the final stage of VEGF-A-induced cerebral angiogenesis. Together, these findings provide a mechanistic understanding of angiogenesis in cerebral disease processes. Furthermore, the long-term stability of daughter vessels in the absence of exogenous VEGF-A(164) expression suggests that VEGF-A may enable therapeutic angiogenesis in brain. C1 Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Stiver, SI (reprint author), Beth Israel Deaconess Med Ctr, Dept Pathol, Room 289,99 Brookline Ave, Boston, MA 02215 USA. EM sstiver@bidmc.harvard.edu FU NHLBI NIH HHS [HL-64402]; NIA NIH HHS [AG-05134]; NINDS NIH HHS [NS-02236] NR 70 TC 27 Z9 34 U1 0 U2 2 PU AMER ASSN NEUROPATHOLOGISTS INC PI LAWRENCE PA 1041 NEW HAMPSHIRE ST, LAWRENCE, KS 66044 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD AUG PY 2004 VL 63 IS 8 BP 841 EP 855 PG 15 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 844VY UT WOS:000223190400006 PM 15330339 ER PT J AU Dawkins, R Sewell, WF AF Dawkins, R Sewell, WF TI Afferent synaptic transmission in a hair cell organ: Pharmacological and physiological analysis of the role of the extended refractory period SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID LATERAL-LINE ORGAN; AUDITORY-NERVE FIBERS; GENE-RELATED PEPTIDE; XENOPUS-LAEVIS; ENDOGENOUS CANNABINOIDS; GLUTAMATE RECEPTORS; POTASSIUM CHANNELS; ACOUSTIC STIMULI; GANGLION NEURONS; K+ CHANNELS AB One feature of neuronal discharge proposed to play a role in coding temporal information is the relative refractory period that follows each action potential. In neurons innervating hair cells, there is an extended refractory period that can last less than or equal to100 ms. We have taken a pharmacological approach to examine the extended refractory period in the Xenopus lateral line organ. We show that each action potential in the afferent fiber, whether generated spontaneously or through an antidromic electrical pulse, decreases the probability of subsequent afferent discharge for a period of less than or equal to100 ms. We show that the extended refractory period can be modulated with drugs that alter glutamatergic transmission between the hair cell and the afferent fiber. The extended refractory period can be enhanced by perfusion with agents that reduce synaptic activity. These agents include blockers of voltage-dependent transmitter release, such as cobalt, as well as glutamate receptor antagonists, such as CNQX and kynurenic acid. Conversely, perfusion with agents that increase synaptic activity through activation of the glutamate receptors, such as AMPA or kainate, reduces the magnitude of suppression during the extended refractory period. The extended refractory period is greatly reduced by iberiotoxin and tetraethylammonium (TEA), indicating it may be mediated in large part by a calcium-dependent potassium channel. The ability to modulate the extended refractory period with changes in synaptic input suggests a simple, dynamic mechanism by which strong input (i.e., large or frequent excitatory postsynaptic potentials) can be strengthened and weak inputs weakened. C1 Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. RP Sewell, WF (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM wfs@epl.meei.harvard.edu FU NIDCD NIH HHS [DC 00767, R01 DC000767-16A1] NR 47 TC 6 Z9 8 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD AUG PY 2004 VL 92 IS 2 BP 1105 EP 1115 DI 10.1152/jn.01107.2003 PG 11 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 841CZ UT WOS:000222908200039 PM 15056680 ER PT J AU Aron, AR Shohamy, D Clark, J Myers, C Gluck, MA Poldrack, RA AF Aron, AR Shohamy, D Clark, J Myers, C Gluck, MA Poldrack, RA TI Human midbrain sensitivity to cognitive feedback and uncertainty during classification learning SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID HUMAN BRAIN; DOPAMINE NEURONS; TEMPORAL PREDICTION; REWARD; STRIATUM; RESPONSES; FMRI; CORTEX; ERRORS; PROBABILITY AB Mesencephalic dopaminergic system (MDS) neurons may participate in learning by providing a prediction error signal to their targets, which include ventral striatal, orbital, and medial frontal regions, as well as by showing sensitivity to the degree of uncertainty associated with individual stimuli. We investigated the mechanisms of probabilistic classification learning in humans using functional magnetic resonance imaging to examine the effects of feedback and uncertainty. The design was optimized for separating neural responses to stimulus, delay, and negative and positive feedback components. Compared with fixation, stimulus and feedback activated brain regions consistent with the MDS, whereas the delay period did not. Midbrain activity was significantly different for negative versus positive feedback (consistent with coding of the "prediction error") and was reliably correlated with the degree of uncertainty as well as with activity in MDS target regions. Purely cognitive feedback apparently engages the same regions as rewarding stimuli, consistent with a broader characterization of this network. C1 Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90065 USA. Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90065 USA. Rutgers State Univ, Ctr Mol & Behav Neurosci, New Brunswick, NJ 08903 USA. Rutgers State Univ, Dept Psychol, New Brunswick, NJ 08903 USA. Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. RP Poldrack, RA (reprint author), Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90065 USA. EM poldrack@ucla.edu OI Myers, Catherine/0000-0002-2776-4823 NR 40 TC 176 Z9 175 U1 0 U2 12 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD AUG PY 2004 VL 92 IS 2 BP 1144 EP 1152 DI 10.1152/jn.01209.2003 PG 9 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 841CZ UT WOS:000222908200042 PM 15014103 ER PT J AU Hunt, SC Richardson, RD Engel, CC Atkins, DC McFall, M AF Hunt, SC Richardson, RD Engel, CC Atkins, DC McFall, M TI Gulf war veterans' illnesses: A pilot study of the relationship of illness beliefs to symptom severity and functional health status SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; CHRONIC FATIGUE SYNDROME; SELF-REPORTED SYMPTOMS; CAUSAL ATTRIBUTIONS; PHYSICAL SYMPTOMS; PRIMARY-CARE; UNEXPLAINED ILLNESS; PREVALENCE; THERAPY; SELECTION AB This investigation describes the illness beliefs of veterans regarding their Gulf War-related health concerns and investigates the relationship of these illness beliefs to physical and mental health functioning. Gulf War veterans (N = 583) presenting for evaluation at a Veteran's Affairs and Department of Defense facility completed se self-report measures of symptom-related beliefs, psychosocial distress, and functional status. Hierarchical multiple regression analyses were performed to determine the extent that symptom-related beliefs impacted symptom-reporting and functional status independent of demographic factors and psychiatric illness. Several beliefs predicted physical symptom reporting and functional impairment in physical health and mental health domains after controlling for demographic variables and psychiatric illness. Gulf War veterans' illness beliefs may impact clinical outcomes. Discussing illness beliefs and providing accurate information is an important component Of medical care for Gulf War veterans. C1 VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. Univ Washington, Dept Occupat & Environm Med, Seattle, WA 98195 USA. NW Network Mental Illness Res Educ & Clin Ctr, Seattle, WA USA. Uniformed Serv Univ Hlth Sci, Dept Psychiat, Bethesda, MD 20814 USA. Walter Reed Army Med Ctr, Deployment Hlth Clin Ctr, Washington, DC 20307 USA. Univ Washington, Dept Psychol, Seattle, WA 98195 USA. RP Hunt, SC (reprint author), VA Puget Sound Hlth Care Syst, 111PC,1660 S Columbian Way, Seattle, WA 98108 USA. EM stephen.hunt@med.va.gov OI Atkins, David/0000-0002-5781-9880 NR 66 TC 4 Z9 4 U1 3 U2 6 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 AUG PY 2004 VL 46 IS 8 BP 818 EP 827 DI 10.1097/01.jom.0000135529.88069.04 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 845WU UT WOS:000223276800010 PM 15300134 ER PT J AU Lento, J Glynn, S Shetty, V Asarnow, J Wang, JM Belin, T AF Lento, J Glynn, S Shetty, V Asarnow, J Wang, JM Belin, T TI Psychologic functioning and needs of indigent patients with facial injury: A prospective controlled study SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID OROFACIAL INJURY; TRAUMA PATIENTS; PSYCHOPATHOLOGY; DEPRESSION; DISORDER; SEQUELAE; ANXIETY; URBAN; LIFE; CAGE AB Purpose: This study sought to examine 1) temporal changes in psychologic functioning over 12 months and 2) baseline differences in mental health and social service needs between orofacial injury patients and sociodemographically comparable controls undergoing elective oral surgery. Materials and Methods: Prospective, case-control study of patients treated at a public hospital in Los Angeles, CA. A total of 336 subjects with mandible fractures and 119 subjects undergoing elective removal of their third molars participated in structured, repeated follow-up assessments (10 days, 6 months, and 12 months after their surgical procedures). Multiple imputation was used to manage incomplete data, and propensity score analysis was used to correct for covariate imbalances between the injury and the control cohort. A series of ANOVAs, chi(2) analyses, and odds ratios was conducted. Results: The injury patients continue to experience significant psychologic distress for tip to 12 months following the traumatic event. Orofacial injury patients also tend to report more lifetime and current mental health and social service needs than the sociodemographically similar elective-surgery cohort. Conclusion: The management of facial injuries in disadvantaged individuals should integrate case management that addresses psychosocial sequelae and service needs of patients. (C) 2004 American Association of Oral and Maxillofacial Surgeons. C1 Univ San Diego, Dept Psychol, San Diego, CA 92110 USA. VA Greater LA Hlth Care Syst, Los Angeles, CA USA. UCSD, SDSU, Joint Doctoral Program Clin Psychol, Los Angeles, CA USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Dent, Sect Oral & Maxillofacial Surg, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Inst Neuropsychiat, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA 90024 USA. RP Lento, J (reprint author), Univ San Diego, Dept Psychol, 5998 Alcala Pk, San Diego, CA 92110 USA. EM jlento@sandiego.edu FU NIDCR NIH HHS [P05 DE-10598] NR 31 TC 22 Z9 22 U1 2 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD AUG PY 2004 VL 62 IS 8 BP 925 EP 932 DI 10.1016/j.joms.2004.02.009 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 842RS UT WOS:000223022300004 PM 15278855 ER PT J AU Lin, AL Johnson, DA Stephan, KT Yeh, CK AF Lin, AL Johnson, DA Stephan, KT Yeh, CK TI Salivary secretory leukocyte protease inhibitor increases in HIV infection SO JOURNAL OF ORAL PATHOLOGY & MEDICINE LA English DT Article DE HAART; HIV; saliva; SLP1 ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL THERAPY; PROTEINASE-INHIBITOR; ANTILEUKOPROTEASE; TRANSMISSION; LOCALIZATION; DEFENSE; TYPE-1; AIDS; LEUKOPROTEASE AB BACKGROUND: Secretory leukocyte protease inhibitor (SLPI) is an antimicrobial protein found in saliva and having anti-HIV activity. The concentrations of SLPI in parotid and submandibular/sublingual (SMSL) saliva were determined in an HIV(+) population and compared with uninfected controls. The effect of highly active antiretroviral therapy (HAART) on the concentrations in saliva was determined. METHODS: Stimulated parotid and SMSL saliva was collected from 65 HIV(+) patients and 19 healthy controls. Flow rates, total protein and SLPI concentrations were determined as well as the effect of HAART on these measurements. RESULTS: Mean flow rates were reduced for parotid (64%) and SMSL (44%) saliva of HIV(+) patients. Flow rate reductions were unaffected by HAART. Total protein concentration in HIV(+) parotid saliva was increased 56%; patients on HAART had higher concentrations than control. For both groups, SLPI concentrations of SMSL saliva were twice that of parotid saliva. For HIV(+) patients SLPI concentrations of both saliva types were 70% greater than control; the increase in parotid saliva was greater for those taking HAART. For each saliva type, the secretory rate and specific SLPI protein concentration were not different between the groups. Patients with low CD4(+) counts had greater SLPI concentrations in parotid saliva than control. There was a negative correlation between CD4(+) counts and the SLPI concentration of parotid saliva. CONCLUSIONS: Salivary flow rate is decreased and the concentration of SLPI is increased in the presence of HIV infection. SLPI concentration in parotid and SMSL saliva is greater with HAART. C1 S Texas Vet Hlth Care Syst, Audie L Murphy Div, Geriatr Res Educ & Clin Ctr 182, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Dent Diagnost Sci, San Antonio, TX USA. Univ Texas, Hlth Sci Ctr, Dept Community Dent, San Antonio, TX USA. Wilford Hall USAF Med Ctr, Dept Infect Dis, HIV Unit, San Antonio, TX 78236 USA. RP Yeh, CK (reprint author), S Texas Vet Hlth Care Syst, Audie L Murphy Div, Geriatr Res Educ & Clin Ctr 182, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM yeh@uthscsa.edu FU NCRR NIH HHS [M01-RR-01346]; NIDCR NIH HHS [DE12188] NR 43 TC 22 Z9 23 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0904-2512 J9 J ORAL PATHOL MED JI J. Oral Pathol. Med. PD AUG PY 2004 VL 33 IS 7 BP 410 EP 416 DI 10.1111/j.1600-0714.2004.00218.x PG 7 WC Dentistry, Oral Surgery & Medicine; Pathology SC Dentistry, Oral Surgery & Medicine; Pathology GA 837ET UT WOS:000222611900006 PM 15250833 ER PT J AU Ring, D Gulotta, L Chin, K Jupiter, JB AF Ring, D Gulotta, L Chin, K Jupiter, JB TI Olecranon osteotomy for exposure of fractures and nonunions of the distal humerus SO JOURNAL OF ORTHOPAEDIC TRAUMA LA English DT Article DE olecranon; osteotomy; distal humerus; fracture; non-union ID ELBOW; COMPLICATIONS AB Although olecranon osteotomy provides excellent exposure of the distal humerus, enthusiasm for this approach has been limited by reports suggesting numerous complications. It has been suggested that specific techniques for creating and repairing an olecranon osteotomy may help limit complications. This paper describes a technique for olecranon osteotomy using an apex, distal, chevron-shaped osteotomy, Kirschner wires directed out the anterior ulnar cortex distal to the coronoid process and bent 180degrees and impacted into the olecranon proximally, and two 22- gauge, figure-of-eight, stainless steel tension wires. A single surgeon used this technique for exposure of a fracture (16 patients) or nonunion (29 patients) of the distal humerus in 45 consecutive patients. One patient returned to activity too soon, had loosening of the wire fixation, and required a second operation for plate fixation of the ulna. The remaining 44 osteotomies (98%) healed with good alignment within 6 months. There were no broken or migrated wires prior to healing. Twelve patients (27%) had removal of the wires used to repair the olecranon: in 6 patients, this was for symptoms related to the wires (13%); 1 for septic olecranon bursitis, and 5 at the time of another procedure (elbow capsular release in 4 patients and submuscular ulnar nerve transposition in 1). Olecranon osteotomy can be used for exposure of the distal humerus with a low rate of complications when specific techniques are used. C1 Massachusetts Gen Hosp, Dept Orthopaed Surg, Hand & Upper Extrem Serv, Boston, MA 02114 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Hand & Upper Extrem Serv, ACC 525,15 Parkman St, Boston, MA 02114 USA. EM dring@partners.org NR 12 TC 56 Z9 75 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-5339 J9 J ORTHOP TRAUMA JI J. Orthop. Trauma PD AUG PY 2004 VL 18 IS 7 BP 446 EP 449 DI 10.1097/00005131-200408000-00010 PG 4 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA 845YZ UT WOS:000223282800010 PM 15289692 ER PT J AU Chou, R Peterson, K Helfand, M AF Chou, R Peterson, K Helfand, M TI Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Review DE muscle relaxants; central; muscle spasticity; meta-analysis; musculoskeletal diseases ID LOW-BACK-PAIN; DOUBLE-BLIND CROSSOVER; CONTROLLED MULTICENTER TRIAL; MULTIPLE-SCLEROSIS PATIENTS; CHRONIC DAILY HEADACHE; TIZANIDINE DS 103-282; TENSION-TYPE HEADACHE; DANTROLENE SODIUM; PARAFON-FORTE; BACLOFEN WITHDRAWAL AB Skeletal muscle relaxants are a heterogeneous group of medications used to treat two different types of underlying conditions: spasticity from upper motor neuron syndromes and muscular pain or spasms from peripheral musculoskeletal conditions. Although widely used for these indications, there appear to be gaps in our understanding of the comparative efficacy and safety of different skeletal muscle relaxants. This systematic review summarizes and assesses the evidence for the comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions. Randomized trials (for comparative efficacy and adverse events) and observational studies (for adverse events only) that included oral medications classified as skeletal muscle relaxants by the FDA were sought using electronic databases, reference lists, and pharmaceutical company submissions. Searches were performed through January 2003. The validity of each included study was assessed using a data abstraction form and predefined criteria. An overall grade was allocated fir the body of evidence for each key question. A total of 101 randomized trials were included in this review. No randomized trial was rated good quality, and there was little evidence of rigorous adverse event assessment in included trials or observational studies. There is fair evidence that baclofen, tizanidine, and dantrolene are effective compared to placebo in patients with spasticity (primarily multiple sclerosis). There is fair evidence that baclofen and tizanidine are roughly equivalent for efficacy in patients with spasticity, but insufficient evidence to determine the efficacy of dantrolene compared to baclofen or tizanidine. There is fair evidence that although the overall rate of adverse effects between tizanidine and baclofen is similar, tizanidine is associated with more dry mouth and baclofen with more weakness. There is fair evidence that cyclobenzaprine, carisoprodol, orphenadrine, and tizanidine are effective compared to placebo in patients with muscaloskeletal conditions (primarily acute back or neck pain). Cyclobenzaprine has been evaluated in the most clinical trials and has consistently been found to be effective. There is very limited or inconsistent data regarding the effectiveness of metaxalonem methocarbamol, chlorzoxazone, baclofen, or dantrolene compared to placebo in patients with musculoskeletal conditions. There is insufficient evidence to determine the relative efficacy or safety of cyclobenzaprine, carisoprodol, orphenadrine, tizanidine, metaxalone, methocarbamol, and chlorzoxazone. Dantrolene, and to a lesser degree chlorzoxazone, have been associated. with rare serious hepatotoxicity. (C) 2004 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. C1 Oregon Hlth & Sci Univ, Dept Med, Portland, OR USA. Oregon Hlth & Sci Univ, Oregon Evidence Based Practice Ctr, Portland, OR USA. Portland Vet Affairs Med Ctr, Portland, OR USA. RP Chou, R (reprint author), 3181 SW Sam Jackson Pk Rd,Mail Code BICC, Portland, OR 97239 USA. NR 159 TC 98 Z9 103 U1 2 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD AUG PY 2004 VL 28 IS 2 BP 140 EP 175 DI 10.1016/j.jpainsymman.2004.05.002 PG 36 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 844US UT WOS:000223186700008 PM 15276195 ER PT J AU Levitsky, LL AF Levitsky, LL TI Symptomatic cerebral edema in diabetic ketoacidosis: The mechanism is clarified but still far from clear SO JOURNAL OF PEDIATRICS LA English DT Editorial Material ID ACIDOSIS C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Levitsky, LL (reprint author), Massachusetts Gen Hosp, Bartlett 410X,55 Fruit St, Boston, MA 02114 USA. EM LLevitsky@partners.org NR 13 TC 10 Z9 11 U1 0 U2 0 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 AUG PY 2004 VL 145 IS 2 BP 149 EP 150 DI 10.1016/j.jpeds.2004.05.030 PG 2 WC Pediatrics SC Pediatrics GA 847PA UT WOS:000223406200004 PM 15289757 ER PT J AU Tarazi, FI Zhang, KH Baldessarini, RJ AF Tarazi, FI Zhang, KH Baldessarini, RJ TI Dopamine D-4 receptors: Beyond schizophrenia SO JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION LA English DT Article; Proceedings Paper CT 6th World Congress of the International-Brain-Research-Organization CY JUL, 2003 CL Prague, CZECH REPUBLIC SP Int Brain Res Org DE antipsychotics; attention deficit hyperactivity disorder; dopamine D-4 receptors; schizophrenia; working memory ID DEFICIT HYPERACTIVITY DISORDER; ATTENTION DEFICIT/HYPERACTIVITY DISORDER; NEONATAL 6-HYDROXYDOPAMINE LESIONS; MESSENGER-RNA EXPRESSION; D-4 RECEPTOR; D4 RECEPTOR; DRD4 GENE; RAT-BRAIN; MOTOR HYPERACTIVITY; BEHAVIORAL-INHIBITION AB Dopamine D-4 receptors mediate a wide range of neuronal signal transduction cascades. Malfunctions of these mechanisms may contribute to the pathophysiology of neuropsychiatric disorders, and their modification underlies the actions of many psychotropic drugs. Postmortem neuropathological and genetic studies provide inconclusive associations between D-4 receptors and schizophrenia. Clinical trials of partially selective lead D-4 antagonists have proved them to be ineffective against psychotic symptoms in patients diagnosed with schizophrenia. However, associations are emerging between D-4 receptors and other neuropsychiatric disorders, including attention-deficit hyperactivity disorder as well as specific personality traits such as novelty seeking. Preclinical studies indicate that D-4 receptors play a pivotal role in the cellular mechanisms of hyperactivity, impulsivity, and working memory. Accordingly, D-4 receptors have broader implications for human illnesses than has been suggested by early focus on psychotic illness as a clinical target, and selective D-4 agents may yield clinically useful drugs for several neuropsychiatric disorders that require improved treatments. C1 Massachusetts Gen Hosp, McLean Div, Mailman Res Ctr, Belmont, MA USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. RP Tarazi, FI (reprint author), McLean Hosp, Lab Psychiat Neurosci, 115 Mill St, Belmont, MA 02478 USA. EM ftarazi@hms.harvard.edu FU NICHD NIH HHS [HD-043649]; NIMH NIH HHS [MH-068359, MH-068507] NR 97 TC 37 Z9 37 U1 1 U2 3 PU MARCEL DEKKER INC PI NEW YORK PA 270 MADISON AVE, NEW YORK, NY 10016 USA SN 1079-9893 J9 J RECEPT SIG TRANSD JI J. Recept. Signal Transduct. PD AUG PY 2004 VL 24 IS 3 BP 131 EP 147 DI 10.1081/LRST-200032076 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 860AC UT WOS:000224308500004 PM 15521359 ER PT J AU Thaker, HM Berlin, A Tycko, B Goldstein, DP Berkowitz, RS Castrillon, DH Genest, DR AF Thaker, HM Berlin, A Tycko, B Goldstein, DP Berkowitz, RS Castrillon, DH Genest, DR TI Immunohistochemistry for the imprinted gene product IPL/PHLDA2 for facilitating. the differential diagnosis of complete hydatidiform mole SO JOURNAL OF REPRODUCTIVE MEDICINE LA English DT Article; Proceedings Paper CT 12th World Congress on Gestational Trophoblastic Disease CY SEP 28-OCT 01, 2003 CL Boston, MA SP Int Soc Study Trophoblast Disease, Harvard Med Sch, Off Continuing Med Educ, New England Trophoblast Disease Ctr, Brigham & Women Hosp, Dept Obstetr & Gynecol DE hydatidiform mole; immunohistochemistry; IPL/PHLDA2 ID GESTATIONAL TROPHOBLASTIC DISEASE; FLOW-CYTOMETRY; CLINICOPATHOLOGICAL FEATURES; SPONTANEOUS-ABORTIONS; HYDROPIC ABORTIONS; COEXISTING FETUS; TWIN PREGNANCY; P57(KIP2); EXPRESSION; CLASSIFICATION AB OBJECTIVE: To determine if immunohistochemistry for PHLDA2 (also known as IPL and TSSC3), the product of a paternally imprinted, maternally expressed gene, can be used as a tool in the differential diagnosis of molar gestations. STUDY DESIGN: Twenty-five cases (15 complete moles, 5 partial moles and five hydropic abortions) were stained by immunohistochemistry for PHLDA2 and scored (without knowledge of the diagnosis)for positivity in the villous cytotrophoblast and then compared to adjacent sections stained by p57(KIP2) immunohistochemistry. RESULTS: All partial moles and hydropic abortions were positive for PHLDA2 and p57(KIP2). There was strong PHLDA2 staining of the cytoplasm in virtually all cells of the villous cytotrophoblast, while p57(KIP2) was localized to the nucleus in a subset of those cells. All complete moles were negative for both markers in the villous cytotrophoblast. CONCLUSION. Immunohistochemistry for PHLDA2 serves as a practical and reliable diagnostic marker for the discrimination of complete mole from partial mole and hydropic abortion. Since the immunohistochemical diagnosis of complete mole is based on a negative result, absence of staining, the use of both markers (PHLDA2 and p57(KIP2)) together could increase the level of confidence when making this prognostically important distinction. C1 Columbia Univ, Dept Pathol, Med Ctr, New York, NY 10032 USA. Columbia Univ, Med Ctr, Inst Canc Genet, New York, NY 10032 USA. Harvard Univ, Sch Med, Div Womens & Perinatal Pathol, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Div Gynecol Oncol, Dept Obstet & Gynecol,Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. New England Trophoblast Dis Ctr, Boston, MA USA. Trophoblast Tumor Registry, Boston, MA USA. Univ Texas, SW Med Ctr, Dept Pathol, Dallas, TX 75230 USA. RP Thaker, HM (reprint author), Columbia Univ, Dept Pathol, Med Ctr, P&S 14-451,630 W 168th St, New York, NY 10032 USA. EM ht89@columbia.edu NR 37 TC 20 Z9 23 U1 0 U2 1 PU SCI PRINTERS & PUBL INC PI ST LOUIS PA PO DRAWER 12425 8342 OLIVE BLVD, ST LOUIS, MO 63132 USA SN 0024-7758 J9 J REPROD MED JI J. Reprod. Med. PD AUG PY 2004 VL 49 IS 8 BP 630 EP 636 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 849UD UT WOS:000223565500007 PM 15457853 ER PT J AU Aghi, M Valery-Coumans, J Brisman, JL AF Aghi, M Valery-Coumans, J Brisman, JL TI Subarachnoid hematoma, hydrocephalus, and aseptic meningitis resulting from a high cervical myelogram SO JOURNAL OF SPINAL DISORDERS & TECHNIQUES LA English DT Article DE complication; hydrocephalus; myelography; subarachnoid hemorrhage ID PUNCTURE AB Despite its reduced use since the advent of magnetic resonance imaging, the high cervical myelogram remains a common diagnostic test in the evaluation of patients whose symptoms suggest cervical stenosis. We report a case of subarachnoid hematoma, hydrocephalus, and aseptic meningitis after a high cervical myelogram. A 52-year-old woman presented with headache, slurred speech, worsened neck pain and stiffness, and diffuse extremity weakness leading to gait instability beginning several hours after a cervical myelogram. Computed tomography (CT) scan revealed a C1-C2 hematoma below the dura, blood in the fourth and lateral ventricles, and hydrocephalus. An external ventricular drain was placed, and cerebrospinal fluid profile was consistent with aseptic meningitis. A suboccipital craniectomy and C1-C2 laminectomies were performed, followed by a C1-C2 durotomy, which revealed a large subarachnoid blood clot in the region of the cisterna magna extending down to the upper aspect of C2, which was evacuated by incising the arachnoid. In the midline at C1, an active source of intramedullary arterial bleeding on the dorsal surface of the spinal cord was coagulated. Spinal subarachnoid hematoma is a rare complication of high cervical myelogram. The extension of blood into the ventricular system with associated hydrocephalus has never been previously reported after myelography. Thus, severe persistent pain after cervical myelography should be evaluated by CT scans of the brain and cervical spine. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Aghi, M (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,White Bldg,Rm 502, Boston, MA 02114 USA. EM maghi@partners.org NR 11 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1536-0652 J9 J SPINAL DISORD TECH JI J. Spinal Disord. Tech. PD AUG PY 2004 VL 17 IS 4 BP 348 EP 351 DI 10.1097/01.bsd.0000095879.31937.50 PG 4 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 845PO UT WOS:000223257000019 PM 15280770 ER PT J AU Brothers, TE Cox, MH Robison, JG Elliott, BM Nietert, P AF Brothers, TE Cox, MH Robison, JG Elliott, BM Nietert, P TI Prospective decision analysis modeling indicates that clinical decisions in vascular surgery often fail to maximize patient expected utility SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE peripheral vascular disease; revascularization; angioplasty; amputation; quality of life; decision analysis ID QUALITY-OF-LIFE; LIMB SALVAGE; BYPASS; PREFERENCES; MANAGEMENT; OUTCOMES; ISCHEMIA AB Background. Applied prospectively to patients with peripheral arterial disease, individualized decision analysis has the potential to improve the surgeon's ability to optimize patient outcome. Methods. A prospective, randomized trial comparing Markov surgical decision analysis to standard decision-making was performed in 206 patients with symptomatic lower extremity arterial disease. Utility assessment and quality of life were determined from individual patients prior to treatment. Vascular surgeons provided estimates of probability of treatment outcome, intended and actual treatment plans, and assessment of comfort with the decision (PDPI). Treatment plans and PDPI evaluations were repeated after each surgeon was made aware of model predictions for half of the patients in a randomized manner. Results. Optimal treatments predicted by decision analysis differed significantly from the surgeon's initial plan and consisted of bypass for 30 versus 29%, respectively, angioplasty for 28 versus 11%, amputation for 31 versus 6%, and medical management for 34 versus 54% (agreement 50%, kappa 0.28). Surgeon awareness of the decision model results did not alter the verbalized final plan, but did trend toward less frequent use of bypass. Patients for whom the model agreed with the surgeon's initial plan were less likely to undergo bypass (13 versus 30%, P < 0.01). Greater surgeon comfort was present when the initial plan and model agreed (PDPI score 47.5 versus 45.6, P < 0.005). Conclusions. Individualized application of a decision model to patients with peripheral arterial disease suggests that arterial bypass is frequently recommended even when it may not maximize patient expected utility. (C) 2004 Elsevier Inc. All rights reserved. C1 Med Univ S Carolina, Charleston, SC 29425 USA. Ralph H Johnson Dept Vet Affairs Med Ctr, Charleston, SC 29425 USA. RP Brothers, TE (reprint author), 96 Jonathan Lucas St,POB 250614,Suite 424, Charleston, SC 29425 USA. EM brothete@musc.edu OI Nietert, Paul/0000-0002-3933-4986 NR 38 TC 21 Z9 21 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 0022-4804 J9 J SURG RES JI J. Surg. Res. PD AUG PY 2004 VL 120 IS 2 BP 278 EP 287 DI 10.1016/j.jss.2004.01.004 PG 10 WC Surgery SC Surgery GA 835RX UT WOS:000222504300016 PM 15234224 ER PT J AU Sink, KM Covinsky, KE Newcomer, R Yaffe, K AF Sink, KM Covinsky, KE Newcomer, R Yaffe, K TI Ethnic differences in the prevalence and pattern of dementia-related behaviors SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Geriatrics-Society CY MAY 14-18, 2003 CL BALTIMORE, MD SP American Geriatr Soc DE dementia; behavior; Alzheimer disease; ethnicity ID NURSING-HOME PLACEMENT; MILD COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; NEUROPSYCHIATRIC SYMPTOMS; CAREGIVER BURDEN; OLDER-PEOPLE; DEPRESSION; PATIENT; ELDERS; FRAIL AB OBJECTIVES: To determine the prevalence of dementia-related behaviors in a large, multiethnic sample of community-dwelling patients with moderate to severe dementia and to determine whether differences in patient or caregiver characteristics could explain any differences in prevalence of these behaviors between white and nonwhite patients. DESIGN: Cross-sectional study. SETTING: Community-based. PARTICIPANTS: A total of 5,776 Medicare patients (5,090 white, 469 black, 217 Latino; mean age 78.9) enrolled in the Medicare Alzheimer's Disease Demonstration and Evaluation study at eight sites across the United States between 1989 and 1991. MEASUREMENTS: Trained interviewers collected information on patient demographic characteristics, cognitive and functional status, and caregiver characteristics such as relationship to patient, functional status, depression, and burden. Ethnicity was obtained by self-report. Caregivers were asked if the patient typically demonstrated any of eight dementia-related behaviors. To determine the independent association between ethnicity and dementia-related behaviors, logistic regression models were developed for each of the behaviors, adjusting for patient and caregiver characteristics. RESULTS: Overall, 92% of patients had one or more dementia-related behaviors. Sixty-one percent of black and 57% of Latino patients were reported to have four or more behaviors, compared with 46% of white patients (P < .001). The prevalence of specific behaviors ranged from 24% for combativeness to 67% for wandering. After multivariate adjustment, black patients were significantly more likely than whites to be constantly talkative (odds ratio (OR) = 1.41, 95% confidence interval (CI) = 1.11-1.80), to have hallucinations (OR = 1.89, 95% CI = 1.49-2.40) and episodes of unreasonable anger (OR = 1.70, 95% CI = 1.34-2.15), to wander (OR = 1.40, 95% CI = 1.08-1.81), and to wake their caregiver (OR= 1.33, 95% CI = 1.04-1.69). Latinos had a significantly higher likelihood than whites of having hallucinations (OR = 1.49, 95% CI = 1.10-2.01), episodes of unreasonable anger (OR 1.59, 95% CI = 1.18-2.16), combativeness (OR = 1.59, 95% CI = 1.17-2.17), and wandering (OR 1.59, 95% CI = 1.21-2.26). For most behaviors, these adjusted ORs are similar in magnitude of effect and statistical significance to the unadjusted estimates. CONCLUSION: Black and Latino community-dwelling patients with moderate to severe dementia have a higher prevalence of dementia-related behaviors than whites. Therefore, as the aging minority population grows, it will be especially important to target caregiver education, in-home support, and resources to minority communities. C1 Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Social & Behav Sci, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94121 USA. San Francisco VA Med Ctr, San Francisco, CA USA. RP Sink, KM (reprint author), Univ Calif San Francisco, Div Geriatr, 4150 Clement St,Bldg 1,Rm 306, San Francisco, CA 94121 USA. EM ksink@itsa.ucsf.edu FU NIA NIH HHS [K23-AG00888, AG00888, R01AG19827, T32 AG000212-10] NR 33 TC 43 Z9 44 U1 0 U2 2 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2004 VL 52 IS 8 BP 1277 EP 1283 DI 10.1111/j.1532-5415.2004.52356.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 843ZQ UT WOS:000223127000007 PM 15271114 ER PT J AU Schnelle, JE Bates-Jensen, BM Chu, L Simmons, SE AF Schnelle, JE Bates-Jensen, BM Chu, L Simmons, SE TI Accuracy of nursing home medical record information about care-process delivery: Implications for staff management and improvement SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE quality improvement; staff management ID REFLECT DIFFERENCES; QUALITY INDICATORS; RESIDENTS; DOCUMENTATION; INCONTINENCE AB Arguments have been made that the culture of nursing homes (NHs) must change to improve the quality of care, and two initiatives have been designed to accomplish this goal. One initiative is to provide resident outcome information (quality indicators) to NH management and consumers via public reporting systems. This initiative is based on the assumptions that resident outcomes are related to care processes implemented by NH staff, the NH industry will respond to market forces, and there are management systems in place within NHs to change the behavior of direct care staff if outcomes are poor. A separate staffing initiative argues that NH care will not improve until there are resources available to increase the number of direct care staff and improve staff training. This initiative also assumes that systems are in place to manage staff resources. Unfortunately, these initiatives may have limited efficacy because information useful for managing the behavior of direct care providers is unavailable within NHs. Medical record documentation about daily care-process implementation may be so erroneous that even the best-intentioned efforts to improve the care received by residents will not be successful. A culture of inaccurate documentation is largely created by a discrepancy between care expectations placed on NHs by regulatory guidelines and inadequate reimbursement to fulfill these expectations. Nursing home staff have little incentive to implement the technologies necessary to audit and assure data quality if accurate documentation reveals that care consistent with regulatory guidelines is not or cannot be provided. A survey process that largely focuses on chart documentation to assess quality provides further incentive for care-process documentation as opposed to care-process delivery. This article reviews methods to improve the accuracy of NH medical record documentation and to create data systems useful for staff training and management. C1 Univ Calif Los Angeles, Dept Med, Los Angeles, CA USA. Jewish Home Aging, Borun Ctr Gerontol Res, Reseda, CA USA. Vet Adm Greater Los Angeles Healthcare Syst, Sepulveda, CA USA. RP Schnelle, JE (reprint author), 7150 Tampa Ave, Reseda, CA 91335 USA. EM jschnell@ucla.edu FU NIA NIH HHS [AG10415] NR 35 TC 47 Z9 47 U1 3 U2 11 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2004 VL 52 IS 8 BP 1378 EP 1383 DI 10.1111/j.1532-5415.2004.52372.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 843ZQ UT WOS:000223127000023 PM 15271130 ER PT J AU Rudski, LG Chow, CM Levine, RA AF Rudski, LG Chow, CM Levine, RA TI Prosthetic mitral regurgitation can be mimicked by Doppler color flow mapping: Avoiding misdiagnosis SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article ID TRANSESOPHAGEAL ECHOCARDIOGRAPHY; VALVE DYSFUNCTION; DIAGNOSIS; LIMITATIONS; ORIFICE AB Objectives: We sought to characterize a region of apparent systolic flow resembling mitral regurgitation (MR) in patients with mechanical disk mitral prostheses as artifact. Background Diagnosing MR in the presence of mechanical prostheses is challenging. Occasionally, important MR is suggested by a substantial region of systolic Doppler color flow in an acoustically shadowed region of the left atrium when, in fact, only trace MR exists. We hypothesized this pseudo-MR is caused by acoustic mirroring of the left ventricular outflow tract (LVOT) flow by sound reflected off the prosthesis, projecting flow into the left atrium because of longer transit time. Methods: We reviewed 19 patients with mechanical mitral valves and trace MR by transesophageal echocardiography who had transthoracic echocardiography studies within 1 week (group A), and prospectively studied 22 consecutive patients by transthoracic echocardiography with subtle transducer angulation variation to detect pseudo-MR and characterize it by pulsed Doppler (group B). Results: In group A, 12 of 19 patients had evidence of pseudo-MR on review of their transthoracic echocardiograms, absent by transesophageal echocardiography. In group B, this pseudo-MR signal was present in 13 of 22 patients, with velocity and timing by pulsed Doppler comparable with LVOT flow (onset at 125 +/- 27 milliseconds vs 135 +/- 11 milliseconds from QRS, P = not significant). The angle between the mitral plane and the LVOT, which determines whether this mirroring can occur, was smaller for patients with pseudo-MR. Conclusion: Artifactual pseudo-MR is often seen with mechanical mitral prostheses. Its behavior and sensitivity to geometric relationships are consistent with mirroring of LVOT flow. Practically, potential misdiagnosis can be readily avoided by pulsed Doppler sampling, sparing the patient further procedures. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, Boston, MA 02114 USA. McGill Univ, Dept Med, Div Cardiol, Sir Mortimer B Davis Jewish Gen Hosp, Montreal, PQ, Canada. RP Levine, RA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, VBK 508,32 Fruit St, Boston, MA 02114 USA. EM rlevine@partners.org FU NHLBI NIH HHS [HL 67434, HL 53702, HL 38176] NR 18 TC 2 Z9 2 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD AUG PY 2004 VL 17 IS 8 BP 829 EP 833 DI 10.1016/j.echo.2004.04.027 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 843UT UT WOS:000223112800005 PM 15282485 ER PT J AU Kline, JA Mitchell, AM Kabrhel, C Richman, PB Courtney, DM AF Kline, JA Mitchell, AM Kabrhel, C Richman, PB Courtney, DM TI Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE D-dimer; decision-making; decision rule; deep venous thrombosis; likelihood ratio; pulmonary embolism; venous thromboembolism ID DEEP-VEIN THROMBOSIS; VENOUS THROMBOEMBOLISM; D-DIMER; ANTICOAGULANT-THERAPY; METAANALYSIS; ANGIOGRAPHY; CT AB Overuse of the D-dimer to screen for possible pulmonary embolism (PE) can have negative consequences. This study derives and tests clinical criteria to justify not ordering a D-dimer. The test threshold was estimated at 1.8% using the method of Pauker and Kassirer. The PE rule-out criteria were derived from logistic regression analysis with stepwise backward elimination of 21 variables collected on 3148 emergency department patients evaluated for PE at 10 US hospitals. Eight variables were included in a block rule: Age <50 years, pulse <100 bpm, SaO(2)>94%, no unilateral leg swelling, no hemoptysis, no recent trauma or surgery, no prior PE or DVT, no hormone use. The rule was then prospectively tested in a low-risk group (1427 patients from two hospitals initially tested for PE with a D-dimer) and a very low-risk group (convenience sample of 382 patients with chief complaint of dyspnea, PE not suspected). The prevalence of PE was 8% (95% confidence interval: 7-9%) in the low-risk group and 2% (1-4%) in the very low-risk group on longitudinal follow-up. Application of the rule in the low-risk and very low-risk populations yielded sensitivities of 96% and 100% and specificities of 27% and 15%, respectively. The prevalence of PE in those who met the rule criteria was 1.4% (0.5-3.0%) and 0% (0-6.2%), respectively. The derived eight-factor block rule reduced the pretest probability below the test threshold for D-dimer in two validation populations, but the rule's utility was limited by low specificity. C1 Carolinas Med Ctr, Dept Emergency Med, Pulm Embolism Res Consortium, Charlotte, NC 28323 USA. Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. Mayo Clin Phoenix, Dept Emergency Med, Scottsdale, AZ USA. NW Mem Hosp, Div Emergency Med, Chicago, IL 60611 USA. RP Kline, JA (reprint author), Carolinas Med Ctr, Dept Emergency Med, Pulm Embolism Res Consortium, POB 32861, Charlotte, NC 28323 USA. EM Jklinc@carolina.rr.com NR 14 TC 121 Z9 123 U1 0 U2 2 PU BLACKWELL PUBL LTD PI OXFORD PA 108 COWLEY RD, OXFORD OX4 1JF, OXON, ENGLAND SN 1538-7933 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD AUG PY 2004 VL 2 IS 8 BP 1247 EP 1255 DI 10.1111/j.1538-7836.2004.00790.x PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 846AJ UT WOS:000223286700007 PM 15304025 ER PT J AU Jang, IK Lewis, BE Matthai, WH Kleiman, NS AF Jang, IK Lewis, BE Matthai, WH Kleiman, NS TI Argatroban anticoagulation in conjunction with glycoprotein IIb/IIIa inhibition in patients undergoing percutaneous coronary intervention: An open-label, nonrandomized pilot study SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE argatroban; direct thrombin inhibitor; glycoprotein IIb/IIIa inhibition; percutaneous coronary intervention ID HEPARIN-INDUCED THROMBOCYTOPENIA; TISSUE-PLASMINOGEN-ACTIVATOR; ACUTE MYOCARDIAL-INFARCTION; PLACEBO-CONTROLLED TRIAL; LOW-DOSE HEPARIN; THROMBIN INHIBITION; ARTERIAL THROMBOSIS; ANGIOPLASTY; BLOCKADE; RECEPTOR AB Background. Argatroban, a direct thrombin inhibitor, blocks clot-bound thrombin more effectively than does heparin. This multicenter, prospective pilot study evaluated the efficacy and safety of argatroban in combination with glycoprotein IIb/IIIa inhibition in patients undergoing percutaneous coronary intervention. Methods: Patients (N = 152) received argatroban as a 250- or 300-mug/kg bolus, followed by a 15-mug/kg/min infusion during percutaneous coronary intervention. An additional 150-mug/kg bolus was administered if activated clotting times 5-15 min after initiating argatroban were <275 s. Abciximab (N = 150) or double-bolus eptifibatide (N = 2) was administered simultaneously. Results: Median activated clotting times at the beginning and end of the procedure were approximately 300 s. The primary efficacy endpoint-a composite of death, myocardial infarction, or urgent revascularization at 30 days occurred in 4 (2.6%) patients (no death, 4 myocardial infarctions, and 2 revascularizations). Two (1.3%) patients had major bleeding by the Thrombolysis in Myocardial Infarction criteria (1 retroperitoneal, 1 groin hematoma). Conclusions: Argatroban in combination with glycoprotein IIb/IIIa inhibition appears to provide adequate anticoagulation and be well tolerated with an acceptable bleeding risk for patients undergoing percutaneous coronary intervention. Additional studies are warranted. Abbreviated Abstract. We describe a multicenter, prospective pilot study of the efficacy and safety of argatroban anticoagulation in conjunction with glycoprotein IIb/IIIa inhibition in 152 patients undergoing elective percutaneous coronary intervention. The primary efficacy composite endpoint of death, myocardial infarction or urgent revascularization at 30 days occurred in 2.6% of patients (no death, 4 myocardial infarctions, and 2 urgent revascularizations), and major bleeding occurred in 1.3% of patients. C1 Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Loyola Univ, Med Ctr, Chicago, IL 60611 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Baylor Coll Med, Houston, TX 77030 USA. Methodist DeBakey Heart Ctr, Houston, TX USA. RP Jang, IK (reprint author), Massachusetts Gen Hosp, Div Cardiol, Gray Bigelow 800,55 Fruit St, Boston, MA 02114 USA. EM ijang@partners.org NR 27 TC 43 Z9 45 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD AUG PY 2004 VL 18 IS 1 BP 31 EP 37 DI 10.1007/s11239-004-0171-2 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 886NL UT WOS:000226235500005 PM 15744551 ER PT J AU Marshburn, TH Legome, E Sargsyan, A Li, SMJ Noble, VA Dulchavsky, SA Sims, C Robinson, D AF Marshburn, TH Legome, E Sargsyan, A Li, SMJ Noble, VA Dulchavsky, SA Sims, C Robinson, D TI Goal-directed ultrasound in the detection of long-bone fractures SO JOURNAL OF TRAUMA-INJURY INFECTION AND CRITICAL CARE LA English DT Article; Proceedings Paper CT Annual Meeting of the Aerospace-Medical-Association CY MAY 04-09, 2002 CL Montreal, CANADA SP Aerospace Med Assoc DE ultrasound; fractures; humerus; femur ID SONOGRAPHIC DETECTION; DIAGNOSIS; ULTRASONOGRAPHY; ANKLE; INJURIES AB Background New portable ultrasound (US) systems are capable of detecting fractures in the remote setting. However, the accuracy of ultrasound by physicians with minimal ultrasound training is unknown. Methods: After one hour of standardized training, physicians with minimal US experience clinically evaluated patients presenting with pain and trauma to the upper arm or leg. The investigators then performed a long-bone US evaluation, recording their impression of fracture presence or absence. Results of the examination were compared with routine plain or computer aided radiography (CT). Results: 58 patients were examined. The sensitivity and specificity of US were 92.9% and 83.3%, and of the physical examination were 78.6% and 90.0%, respectively. US provided improved sensitivity with less specificity compared with physical examination in the detection of fractures in long bones. Conclusion: Ultrasound scans by minimally trained clinicians may be used to rule out a long-bone fracture in patients with a medium to low probability of fracture. C1 NASA, Lyndon B Johnson Space Ctr, Off Space Med, Houston, TX 77058 USA. NYU Med Ctr, Bellevue Hosp, New York, NY 10016 USA. Wyle Labs, Adv Project, Houston, TX USA. Mt Auburn Hosp, Dept Emergency, Cambridge, MA USA. Massachusetts Gen Hosp, Brigham & Womens Hosp Harvard Affiliated Emergenc, Dept Emergency Med, Boston, MA 02114 USA. Hermann Hosp, Dept Emergency Med, Houston, TX USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Detroit Receiving Hosp & Univ Hlth Ctr, Dept Surg, Detroit, MI USA. RP Marshburn, TH (reprint author), NASA, Lyndon B Johnson Space Ctr, Off Space Med, Mail Code SD2,2101 NASA Rd 1, Houston, TX 77058 USA. NR 23 TC 72 Z9 72 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5282 J9 J TRAUMA JI J. Trauma-Injury Infect. Crit. Care PD AUG PY 2004 VL 57 IS 2 BP 329 EP 332 DI 10.1097/01.TA.0000088005.35520.CB PG 4 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 859YG UT WOS:000224303700025 PM 15345981 ER PT J AU Samper, RE Taft, CT King, DW King, LA AF Samper, RE Taft, CT King, DW King, LA TI Posttraumatic stress disorder symptoms and parenting satisfaction among a national sample of male Vietnam veterans SO JOURNAL OF TRAUMATIC STRESS LA English DT Article DE posttraumatic stress disorder; parenting satisfaction; avoidance and emotional numbing ID COMBAT VETERANS; WAR VETERANS; CONFLICT; VALIDITY AB This study examined relationships between posttraumatic stress disorder ( PTSD) symptoms and parenting satisfaction. Total PTSD severity scores and avoidance and emotional numbing symptoms were significantly associated with parenting satisfaction. These associations remained significant even after controlling for partner violence, major depression, and alcohol abuse/dependence. Results suggest that higher levels of PTSD symptoms and avoidance and emotional numbing symptoms in particular may have a deleterious effect on parent-child relationship satisfaction. C1 VA Boston Healthcare Syst, Natl Ctr PTSD, Behav Sci Div, Boston, MA 02130 USA. VA Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA 02130 USA. Boston Univ, Boston, MA 02215 USA. RP Taft, CT (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, Behav Sci Div, 116B-2,150 S Huntington Ave, Boston, MA 02130 USA. EM casey.taft@med.va.gov FU NIMH NIH HHS [MH49169] NR 17 TC 79 Z9 81 U1 0 U2 5 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0894-9867 J9 J TRAUMA STRESS JI J. Trauma Stress PD AUG PY 2004 VL 17 IS 4 BP 311 EP 315 DI 10.1023/B:JOTS.0000038479.30903.ed PG 5 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 847NJ UT WOS:000223401900004 PM 15462538 ER PT J AU Rini, C Manne, S DuHamel, KN Austin, J Ostroff, J Boulad, F Parsons, SK Martini, R Williams, S Mee, L Sexson, S Redd, WH AF Rini, C Manne, S DuHamel, KN Austin, J Ostroff, J Boulad, F Parsons, SK Martini, R Williams, S Mee, L Sexson, S Redd, WH TI Changes in mothers' basic beliefs following a child's bone marrow transplantation: The role of prior trauma and negative life events SO JOURNAL OF TRAUMATIC STRESS LA English DT Article DE trauma; life events; severe stress; world assumptions; mothers; adaptation ID POSTTRAUMATIC-STRESS-DISORDER; ASSUMPTIVE WORLDS; PERCEIVED CONTROL; MENTAL-HEALTH; PARENTS; MODEL; DEPRESSION; ADJUSTMENT; SECONDARY; DISTRESS AB This longitudinal study examined the relation between life stress and basic beliefs about self-worth and the benevolence and meaningfulness of the world among mothers of children undergoing bone marrow transplantation (BMT). One hundred mothers completed study measures during the child's hospitalization for BMT and 1 year later. Prior trauma and recent negative events were associated with basic beliefs during hospitalization and also with changes in basic beliefs in the subsequent year, with distress mediating some of these relations. Findings also demonstrated relations between basic beliefs and physical and mental functioning. However, each basic belief exhibited different relations with study variables, suggesting the need to investigate them separately. C1 Mt Sinai Sch Med, Derald H Ruttenberg Canc Ctr, New York, NY 10029 USA. Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Northwestern Univ, Med Ctr, Childrens Mem Hosp, Chicago, IL 60611 USA. Stanford Univ, Med Ctr, Packard Childrens Hosp, Stanford, CA 94305 USA. Emory Univ, Med Ctr, Atlanta, GA 30322 USA. RP Rini, C (reprint author), Mt Sinai Sch Med, Derald H Ruttenberg Canc Ctr, 1 Gustave Levy Pl,Box 1130, New York, NY 10029 USA. EM christine.rini@mssm.edu FU NIMH NIH HHS [MH 57738] NR 40 TC 15 Z9 15 U1 1 U2 2 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0894-9867 J9 J TRAUMA STRESS JI J. Trauma Stress PD AUG PY 2004 VL 17 IS 4 BP 325 EP 333 DI 10.1023/B:JOTS.0000038481.17167.0d PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 847NJ UT WOS:000223401900006 PM 15462540 ER PT J AU Freedland, SJ Terris, MK Presti, JC Amling, CL Kane, CJ Trock, B Aronson, WJ AF Freedland, SJ Terris, MK Presti, JC Amling, CL Kane, CJ Trock, B Aronson, WJ CA Search Database Study Grp TI Obesity and biochemical outcome following radical prostatectomy for organ confined disease with negative surgical margins SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; prostatectomy; obesity; African Americans ID BODY-MASS INDEX; PATHOLOGICAL VARIABLES; SERUM TESTOSTERONE; US ADULTS; CANCER; MEN; FINASTERIDE; RACE; MORTALITY; DATABASE AB Purpose: We have previously shown that men with a body mass index (BMI) greater than 35 kg/m(2) had higher rates of positive surgical margins and significantly higher biochemical recurrence rates following radical prostatectomy (RP). To determine whether the higher prostate specific antigen (PSA) recurrence rates were due solely to the higher positive margin rate, we examined whether obesity was an independent predictor of biochemical failure among men with negative surgical margins. Materials and Methods: We examined data from 1,250 men treated with RP between 1988 and 2003 at 5 equal access medical centers, of whom 731 had pathologically organ confined disease and negative surgical margins. Multivariate Cox proportional hazards analysis was used to determine if BMI was a significant independent predictor of biochemical recurrence. Results: Mean BMI significantly increased over time (p = 0.010). Black men were significantly more likely to be obese than white or nonwhite-nonblack men. After controlling for all preoperative characteristics, body mass index was a significant predictor of biochemical failure with moderately and severely obese men (BMI 35 kg/m(2) or greater) having greater than a 4-fold increased risk of PSA failure (p = 0.035). After controlling for the higher pathological Gleason grades among obese men, body mass index remained a significant predictor of biochemical failure with moderately and severely obese men (BMI 35 kg/m(2) or greater) having nearly a 4-fold increased risk for PSA failure (p = 0.036). Conclusions: BMI 35 kg/m(2) or greater was associated with higher grade tumors and worse outcome following RP in a cohort of men with favorable pathological findings. Thus, surgical technique (margin status) cannot fully explain the worse outcomes among obese men, suggesting that obesity may be associated with a biologically more aggressive form of prostate cancer. C1 Johns Hopkins Sch Med, Dept Urol, Baltimore, MD 21287 USA. Med Coll Georgia, Urol Sect, Augusta, GA USA. Stanford Univ, Sch Med, Dept Urol, Palo Alto, CA USA. San Diego Naval Hosp, Dept Urol, San Diego, CA USA. Univ Calif San Francisco, Sch Med, Dept Urol, San Francisco, CA USA. Vet Adm Med Ctr, Dept Surg, Urol Sect, San Francisco, CA USA. Univ Calif Los Angeles, Sch Med, Dept Surg, Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Dept Urol, Los Angeles, CA USA. RP Freedland, SJ (reprint author), Johns Hopkins Sch Med, Dept Urol, 600 N Wolfe St, Baltimore, MD 21287 USA. EM sfreedl1@jhmi.edu OI Terris, Martha/0000-0002-3843-7270 FU NCI NIH HHS [P50 CA92131-01A1] NR 20 TC 62 Z9 68 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 AUG PY 2004 VL 172 IS 2 BP 520 EP 524 DI 10.1097/01.ju.0000135302.58378.ae PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 837MJ UT WOS:000222639300026 PM 15247719 ER PT J AU Zhou, W Lin, PH Bush, RL Nguyen, L Lumsden, AB AF Zhou, W Lin, PH Bush, RL Nguyen, L Lumsden, AB TI Acute arterial thrombosis associated with cocaine abuse SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID ACTIVATION; AUTOPSY; DISEASE AB Purpose: Cocaine-induced arterial thrombosis is uncommon, and most reported cases involved small-diameter vessels such as the cerebral and coronary arteries. This study was undertaken to review our experience with peripheral arterial thrombosis presumed caused by cocaine abuse. Methods: Hospital records were reviewed for all patients admitted over 10 years with acute arterial occlusion involving the peripheral arterial system. Patients with confirmation of cocaine use or of its derivative, crack cocaine, within 24 hours of hospital admission formed the basis of this study. Symptoms at presentation, management, and outcome in these patients were reviewed. Results: Three hundred eighty-two patients with acute peripheral arterial occlusion were identified during the study period. The presumptive diagnosis of cocaine-induced arterial occlusion was made in 5 patients (4 men, mean age 38 years). Cocaine use was achieved via intranasal inhalation in 2 patients (40%), whereas the 3 remaining patients smoked crack cocaine (60%). The mean time between cocaine use and onset of arterial thrombosis was 9.2 hours (range, 2-20 hours). Symptoms at presentation included acute limb ischemia without pedal Doppler signals (3 patients, 60%) and abdominal pain without femoral pulses (2 patients, 40%). Arterial occlusion was confirmed on angiograms in all patients, which revealed aortic thrombosis in 1 patient (20%), iliac thrombosis in 2 patients (40%), superficial femoral artery thrombosis in 1 patient (20%), and popliteal artery occlusion in 1 patient (20%). Surgical thrombectomy was successfully performed in 4 patients (80%), and 1 patient (20%) underwent successful thrombolytic therapy for femoropopliteal artery occlusion. There was no perioperative mortality. All 5 patients who were discharged were available for follow-up (mean, 36 months; range, 6-75 months). There was 1 late death from myocardial infarction. In 1 patient recurrent lower extremity arterial thrombosis developed after 28 months, which was successfully treated with thrombolytic therapy. Conclusions: Our study underscores cocaine abuse as a potential cause of acute arterial thrombosis. Cocaine-induced arterial thrombosis should be suspected in patients with recent history of cocaine abuse with acute limb ischemia without an identifiable source or overt cardiovascular risk factors. Prompt angiography with operative or endovascular intervention should be performed to avert arterial ischemic sequelae. C1 Baylor Coll Med, Dept Surg, Houston VAMC, Div Vasc Surg & Endovasc Therapy, Houston, TX 77030 USA. Methodist Hosp, Houston, TX 77030 USA. RP Lin, PH (reprint author), Baylor Coll Med, Dept Surg, Houston VAMC, Div Vasc Surg & Endovasc Therapy, 2002 Holcomb Blvd 112, Houston, TX 77030 USA. EM plin@bcm.tmc.edu NR 22 TC 18 Z9 19 U1 0 U2 0 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 AUG PY 2004 VL 40 IS 2 BP 291 EP 295 DI 10.1016/j.jvs.2004.04.026 PG 5 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 902WT UT WOS:000227388100017 PM 15297823 ER PT J AU Poulin, DL Kung, AL DeCaprio, JA AF Poulin, DL Kung, AL DeCaprio, JA TI p53 targets Simian virus 40 large T antigen for acetylation by CBP SO JOURNAL OF VIROLOGY LA English DT Article ID HISTONE ACETYLTRANSFERASE ACTIVITY; LARGE TUMOR-ANTIGEN; SIMIAN VIRUS-40; DNA-REPLICATION; MEDIATED TRANSFORMATION; P300/CBP COACTIVATORS; CARBOXYL-TERMINUS; ONCOPROTEIN E1A; HOST-RANGE; BINDING AB Simian virus 40 (SV40) large T antigen (T Ag) interacts with the tumor suppressor p53 and the transcriptional coactivators CBP and p300. Binding of these cellular proteins in a ternary complex has been implicated in T Ag-mediated transformation. It has been suggested that the ability of CBP/p300 to modulate p53 function underlies p53's regulation of cell proliferation and tumorigenesis. In this study, we provide further evidence that CBP activity may be mediated through its synergistic action with p53. We demonstrate that SV40 T Ag is acetylated in vivo in a p53-dependent manner and T Ag acetylation is largely mediated by CBP. The acetylation of T Ag is dependent on its interaction with p53 and on p53's interaction with CBP. We have mapped the site of acetylation on T Ag to the C-terminal lysine residue 697. This acetylation site is conserved between the T antigens of the human polyomaviruses JC and BK, which are also known to interact with p53. We show that both JC and BK T antigens are also acetylated at corresponding sites in vivo. While other proteins are known to be acetylated by CBP/p300, none are known to depend on p53 for acetylation. T Ag acetylation may provide a regulatory mechanism for T Ag binding to a cellular factor or play a role in another aspect of T Ag function. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP DeCaprio, JA (reprint author), Dana Farber Canc Inst, Mayer 457,44 Binney St, Boston, MA 02115 USA. EM james_decaprio@dfci.harvard.edu OI Kung, Andrew/0000-0002-9091-488X FU NCI NIH HHS [R01 CA063113, R01CA063113] NR 44 TC 44 Z9 54 U1 2 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2004 VL 78 IS 15 BP 8245 EP 8253 DI 10.1128/JVI.75.15.8254-8253.2004 PG 9 WC Virology SC Virology GA 839AL UT WOS:000222755600039 PM 15254196 ER PT J AU Murphy, SL Honczarenko, MJ Dugger, NV Hoffman, PM Gaulton, GN AF Murphy, SL Honczarenko, MJ Dugger, NV Hoffman, PM Gaulton, GN TI Disparate regions of envelope protein regulate syncytium formation versus spongiform encephalopathy in neurological disease induced by murine leukemia virus TR SO JOURNAL OF VIROLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; ENDOTHELIAL-CELL TROPISM; HUMAN-IMMUNODEFICIENCY-VIRUS; INTRACEREBRAL HEMORRHAGES; INDUCED NEURODEGENERATION; RETROVIRAL INFECTION; BINDING DOMAIN; CNS DISEASE; MICROGLIA; MUTANT AB The murine leukemia virus (MLV) TR1.3 provides an excellent model to study the wide range of retrovirus-induced central nervous system (CNS) pathology and disease. TR1.3 rapidly induces thrombotic events in brain microvessels and causes cell-specific syncytium formation of brain capillary endothelial cells (BCEC). A single amino acid substitution, W102G, in the MLV envelope protein (Env) regulates the pathogenic effects. The role of Env in determining this disease phenotype compared to the induction of spongiform encephalomyelitis with a longer latency, as seen in several other MLV and in human retroviruses, was determined by studying in vitro-attenuated TR1.3. Virus cloned from this selection, termed TRM, induced progressive neurological disease characterized by ataxia and paralysis and the appearance of spongiform neurodegeneration throughout the brain stem and spinal cord. This disease was associated with virus replication in both BCEC and highly ramified glial cells. TRM did not induce syncytium formation, either in vivo or in vitro. Sequence and mutational analyses demonstrated that TRM contained a reversion of Env G102W but that neurological disease mapped to the single amino acid substitution Env S159P. The results demonstrate that single nucleotide changes within disparate regions of Env control dramatically different CNS disease patterns. C1 Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Ctr Blood Res, Boston, MA 02115 USA. Univ Maryland, Res Serv, Vet Adm Maryland Hlth Care Syst, Baltimore, MD 21201 USA. Univ Maryland, Dept Neurol, Baltimore, MD 21201 USA. RP Gaulton, GN (reprint author), Univ Penn, Dept Pathol & Lab Med, 354 Biomed Res Bldg 2-3,421 Curie Blvd, Philadelphia, PA 19104 USA. EM Gaulton@mail.med.upenn.edu NR 56 TC 10 Z9 10 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 AUG PY 2004 VL 78 IS 15 BP 8392 EP 8399 DI 10.1128/jvi.78.15.8392-8399.2004 PG 8 WC Virology SC Virology GA 839AL UT WOS:000222755600054 PM 15254211 ER PT J AU Norris, PJ Moffett, HF Yang, OO Kaufmann, DE Clark, MJ Addo, MM Rosenberg, ES AF Norris, PJ Moffett, HF Yang, OO Kaufmann, DE Clark, MJ Addo, MM Rosenberg, ES TI Beyond help: Direct effector functions of human immunodeficiency virus type 1-specific CD4(+) T cells SO JOURNAL OF VIROLOGY LA English DT Article ID CELLULAR IMMUNE-RESPONSES; VIRAL LOAD; ANTIVIRAL FACTOR; HIV REPLICATION; LYMPHOCYTES-T; EX-VIVO; INFECTION; CD4+; VIREMIA; SUPPRESSION AB The immune correlates of protection in human immunodeficiency virus type 1 (HIV-1) infection remain poorly defined, particularly the contribution of CD4(+) T cells. Here we explore the effector functions of HIV-1-specific CD4(+) T cells. We demonstrate HIV-1 p24-specific CD4(+)-T-cell cytolytic activity in peripheral blood mononuclear cells directly ex vivo and after enrichment by antigen-specific stimulation. We further show that in a rare long-term nonprogressor, both an HIV-1-specific CD4(+)-T-cell clone and CD4(+) T cells directly ex vivo exert potent suppression of HIV-1 replication. Suppression of viral replication was dependent on cell-cell contact between the effector CD4(+) T cells and the target cells. While the antiviral effector activity of CD8(+) T cells has been well documented, these results strongly suggest that HIV-1-specific CD4(+) T cells are capable of directly contributing to antiviral immunity. C1 Blood Syst Res Inst, San Francisco, CA 94118 USA. Massachusetts Gen Hosp, Partners AIDS Res Ctr, Div Infect Dis, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. Univ Calif Los Angeles, Med Ctr,Geffen Sch Med, Dept Microbiol Immunol & Mol Genet, AIDS Inst,Div Infect Dis,Dept Med, Los Angeles, CA 90095 USA. RP Norris, PJ (reprint author), Blood Syst Res Inst, 270 Mason Ave, San Francisco, CA 94118 USA. EM pnorris@bloodsystems.org FU NIAID NIH HHS [AI-01698-01, AI-040873, K08 AI001698, K08 AI001698-04, R01 AI040873, R21 AI040873] NR 47 TC 64 Z9 68 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2004 VL 78 IS 16 BP 8844 EP 8851 DI 10.1128/JVI.78.16.8844-8851.2004 PG 8 WC Virology SC Virology GA 843AH UT WOS:000223046000043 PM 15280492 ER PT J AU Feeney, ME Tang, Y Roosevelt, KA Leslie, AJ McIntosh, K Karthas, N Walker, BD Goulder, PJR AF Feeney, ME Tang, Y Roosevelt, KA Leslie, AJ McIntosh, K Karthas, N Walker, BD Goulder, PJR TI Immune escape precedes breakthrough human immunodeficiency virus type 1 viremia and broadening of the cytotoxic T-lymphocyte response in an HLA-B27-positive long-term-nonprogressing child SO JOURNAL OF VIROLOGY LA English DT Article ID HIV-1; INFECTION; AIDS; HLA; MUTATIONS AB The emergence of cytotoxic T-lymphocyte (CTL) escape mutations in human immunodeficiency virus type 1 (HIV-1) proteins has been anecdotally associated with progression to AIDS, but it has been difficult to determine whether viral mutation is the cause or the result of increased viral replication. Here we describe a perinatally HIV-infected child who maintained a plasma viral load of <400 copies/ml for almost a decade until a nonbinding escape mutation emerged within the immunodominant CTL epitope. The child subsequently experienced a reemergence of HIV-1 viremia accompanied by a marked increase in the number of CTL epitopes targeted. This temporal pattern suggests that CD8 escape can play a causal role in the loss of immune control. C1 Partners AIDS Res Ctr, Boston, MA USA. Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Childrens Hosp, Boston, MA 02115 USA. Univ Oxford, Nuffield Dept Med, Dept Pediat, Oxford, England. Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Feeney, ME (reprint author), Partners AIDS Res Ctr, 5th Floor,149 13th St, Charlestown, MA 02129 USA. EM mfeeney@partners.org FU NIAID NIH HHS [K23 AI052078, AI52078, AI28568, R01 AI028568, R01 AI046995, R37 AI028568, AI46995] NR 13 TC 164 Z9 165 U1 1 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 AUG PY 2004 VL 78 IS 16 BP 8927 EP 8930 DI 10.1128/JVI.78.16.8927-8930.2004 PG 4 WC Virology SC Virology GA 843AH UT WOS:000223046000053 PM 15280502 ER PT J AU Friedenberg, WR Tallman, MS Brodsky, I Paietta, E Rowe, JM Lee, SJ Rowland, KM Schnetzer, GW Reed, JC AF Friedenberg, WR Tallman, MS Brodsky, I Paietta, E Rowe, JM Lee, SJ Rowland, KM Schnetzer, GW Reed, JC TI Modified VAD and PSC-833 in the treatment of resistant or relapsing chronic lymphocytic leukemia (E4996): a trial of the Eastern Cooperative Oncology Group SO LEUKEMIA RESEARCH LA English DT Article DE chronic lymphocytic leukemia; multidrug resistance; p-glycoprotein; PSC-833 ID ACUTE MYELOID-LEUKEMIA; MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; DRUG-RESISTANCE; IN-VITRO; MULTIPLE-MYELOMA; GENE-EXPRESSION; PHASE-II; CYCLOSPORINE; MODULATION AB Background & method: The role of multidrug resistance (MDR) was investigated in patients with relapsed chronic lymphocytic leukemia (CLL). PSC-833 was added to modified VAD (a 4-day infusion of vincristine, doxorubicin, with oral dexamethasone, every 3 weeks), in an attempt to improve the response rate (21%) in a prior study. Laboratory tests to determine MDR and apoptosis proteins were correlated with response. Results: Two of the seven MDR-positive cases and one of the four MDR-negative patients achieved a partial response (no significant difference). No significant correlation with response was found in any of the laboratory tests for apoptosis. Conclusion: VAD plus PSC-833 had the same (21%) partial response rate as a prior ECOG study without PSC-833. No correlation of response with MDR or apoptosis testing was found. Other drug resistance factors must play a significant role in determining the response of relapsed patients with CLL. (C) 2004 Published by Elsevier Ltd. C1 Guthrie Clin, Sayre, PA 18840 USA. Northwestern Univ, Sch Med, Feinberg Sch Med, Div Hematol Oncol, Chicago, IL 60611 USA. Drexel Univ, Coll Med, Philadelphia, PA 19102 USA. Our Lady Mercy Med Ctr, Bronx, NY 10466 USA. Rambam Med Ctr, IL-31096 Haifa, Israel. Technion Israel Inst Technol, IL-31096 Haifa, Israel. Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. Carle Clin Assoc, Champaign, IL 61820 USA. Burnham Inst, La Jolla, CA 92037 USA. RP Friedenberg, WR (reprint author), Guthrie Clin, 1 Guthrie Sq, Sayre, PA 18840 USA. EM wfriedenberg@clinic.guthrie.org; m-tallman@northwestern.edu; Ib32@drexel.edu; epaietta@email.msn.com; rowe@jimmy.harvard.edu; sjlee@jimmy.harvard.edu; kendrith.rowland@carle.com; gschnezer@aol.com; jreed@burnham.org FU NCI NIH HHS [CA66636, CA23318, CA13650, CA17145, CA21115] NR 39 TC 8 Z9 10 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD AUG PY 2004 VL 28 IS 8 BP 813 EP 819 DI 10.1016/j.leukres.2003.12.002 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 833YR UT WOS:000222378100006 PM 15203279 ER PT J AU Gragnoli, C Von Preussenthal, GM Habener, JF AF Gragnoli, C Von Preussenthal, GM Habener, JF TI Triple genetic variation in the HNF-4 alpha gene is associated with early-onset type 2 diabetes mellitus in a Philippino family SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID I ALPHA-GENE; INSULIN SECRETORY RESPONSES; YOUNG MODY1; MUTATIONS; GLUCOSE; METABOLISM; SEQUENCE; PROMOTER; DELETION; PEDIGREE AB Maturity-onset diabetes of the young-type 1 (MODY1) is a form of monogenic type 2 diabetes mellitus (T2DM) with long-term complications due to mutations in the HNF-4alpha gene. The HNF-4alpha gene is involved in hepatic differentiation and expression of genes regulating glucose transport, glycolysis, and lipid metabolism. The abnormal glucose-stimulated insulin secretion in MODY1 subjects may be due to reduced glucose transport and glycolysis. To date, 14 mutations in the HNF-4alpha gene have been identified as a cause of either MODY1 or late-onset type 2 diabetes. So far, no screening has been performed in subjects from the Philippines. We recruited a Philippino family with autosomal dominant early-onset type 2 diabetes and screened the proband for mutations in the genes for HNF-1alpha, GCK, HNF-4alpha, IPF-1, HNF-6, and NGN3. We identified a new missense mutation in exon 5 (V1991) of the HNF-4alpha gene and 2 new single-nucleotide substitutions in intron 4, IVS4-nt4 (G-->A) and IVS4-nt20 (C-->T), all cosegregating with diabetes in the 3 affected available siblings. These variations were not present in 100 normal healthy subjects. Bioinformatic analysis suggests that these variations in the whole, and overall the IVS4-nt4 variation located at splicing site, may affect the splicing potential of intron 4. We have biochemically and clinically characterized the Philippine-1 family. We suggest that the V1991 missense mutation located in the ligand binding/dimerization domain of HNF-4alpha contributes to type 2 diabetes in the Philippine-1 family. The intron variations may contribute susceptibility to diabetes. (C) 2004 Elsevier Inc. All rights reserved. C1 Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Lab Mol Endocrinol, Boston, MA 02115 USA. Univ Tor Vergata, Policlin Tor Vergata, Rome, Italy. RP Gragnoli, C (reprint author), Massachusetts Gen Hosp, Lab Mol Endocrinol, 55 Fruit St WEL 320, Boston, MA 02114 USA. FU NIDDK NIH HHS [DK-55365] NR 23 TC 10 Z9 10 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD AUG PY 2004 VL 53 IS 8 BP 959 EP 963 DI 10.1016/j.metabol.2004.03.003 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 846KL UT WOS:000223314300002 PM 15281001 ER PT J AU Jenkins, AJ Thorpe, SR Alderson, NL Hermayer, KL Lyons, TJ King, LP Chassereau, CN Klein, RL AF Jenkins, AJ Thorpe, SR Alderson, NL Hermayer, KL Lyons, TJ King, LP Chassereau, CN Klein, RL TI In vivo glycated low-density lipoprotein is not more susceptible to oxidation than nonglycated low-density lipoprotein in type 1 diabetes SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID LIPID-PEROXIDATION; DCCT/EDIC COHORT; CONTROLLED IDDM; LDL; PLASMA; COMPLICATIONS; GLYCOXIDATION; ASSOCIATIONS; CHOLESTEROL; CELLS AB It has been suggested that low-density lipoprotein (LDL) modified by glycation may be more susceptible to oxidation and thus, enhance its atherogenicity. Using affinity chromatography, LDL glycated in vivo (G-LDL) and relatively nonglycated. (N-LDL) subfractions can be isolated from the same individual. The extent of and susceptibility to oxidation of N-LDL compared with G-LDL was determined in 15 type 1 diabetic patients. Total LDL was isolated and separated by boronate affinity chromatography into relatively glycated (G-) and nonglycated (N-) subfractions. The extent of glycation, glycoxidation, and lipoxidation, lipid soluble antioxidant content, susceptibility to in vitro oxidation, and nuclear magnetic resonance (NMR)-determined particle size and subclass distribution were determined for each subfraction. Glycation, (fructose-lysine) was higher in G-LDL versus N-LDL, (0.28 +/- 0.08 v 0.13 +/- 0.04 mmol/mol lysine, P < .0001). However, levels of glycoxidation/ lipoxidation products and of antioxidants were similar or lower in G-LDL compared with N-LDL and were inversely correlated with fructose-lysine (FL) concentrations in G-LDL, but positively correlated in N-LDL. In vitro LDL (CuCl2) oxidation demonstrated a longer lag time for oxidation of G-LDL than N-LDL (50 +/- 0.16 v 37 +/- 0.15 min, P < .01), but there was no difference in the rate or extent of lipid oxidation, nor in any aspect of protein oxidation. Mean LDL particle size and subclass distribution did not differ between G-LDL and N-LDL. Thus, G-LDL from well-controlled type 1 diabetic patients is not more modified by oxidation, more susceptible to oxidation, or smaller than relatively N-LDL, suggesting alternative factors may contribute to the atherogenicity of LDL from type 1 diabetic patients. (C) 2004 Elsevier Inc. All rights reserved. C1 Med Univ S Carolina, Div Endocrinol Diabet & Med Genet, Charleston, SC 29403 USA. Univ Melbourne, St Vincents Hosp, Dept Med, Fitzroy, Vic 3065, Australia. Univ Oklahoma, Hlth Sci Fdn, Sect Endocrinol Diabet & Hypertens, Oklahoma City, OK USA. Univ S Carolina, Dept Chem & Biochem, Columbia, SC 29208 USA. Med Univ S Carolina, Dept Ophthalmol, Charleston, SC 29425 USA. Ralph H Johnson Dept Vet Affairs Med Ctr, Res Serv, Charleston, SC USA. RP Klein, RL (reprint author), Med Univ S Carolina, Div Endocrinol Diabet & Med Genet, Room 501,Strom Thurmond Gazes Biomed Res Bldg,114, Charleston, SC 29403 USA. RI Jenkins, Alicia/N-2482-2015 FU NIDDK NIH HHS [DK 19971] NR 37 TC 9 Z9 10 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD AUG PY 2004 VL 53 IS 8 BP 969 EP 976 DI 10.1016/j.metabol.2004.01.002 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 846KL UT WOS:000223314300004 PM 15281003 ER PT J AU Vetrini, F Auricchio, A Du, JY Angeletti, B Fisher, DE Ballabio, A Marigo, V AF Vetrini, F Auricchio, A Du, JY Angeletti, B Fisher, DE Ballabio, A Marigo, V TI The microphthalmia transcription factor (Mitf) controls expression of the ocular albinism type 1 gene: Link between melanin synthesis and melanosome biogenesis SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; OA1 GENE; REGULATES DIFFERENTIATION; WAARDENBURG SYNDROME; MOUSE HOMOLOG; IN-VIVO; TRANSDUCTION; MELANOCYTES; TYROSINASE; MUTATIONS AB Melanogenesis is the process that regulates skin and eye pigmentation. Albinism, a genetic disease causing pigmentation defects and visual disorders, is caused by mutations in genes controlling either melanin synthesis or melanosome biogenesis. Here we show that a common transcriptional control regulates both of these processes. We performed an analysis of the regulatory region of Oa1, the murine homolog of the gene that is mutated in the X-linked form of ocular albinism, as Oat's function affects melanosome biogenesis. We demonstrated that Oa1 is a target of Mitf and that this regulatory mechanism is conserved in the human gene. Tissue-specific control of Oa1 transcription lies within a region of 617 bp that contains the E-box bound by Mitf. Finally, we took advantage of a virus-based system to assess tissue specificity in vivo. To this end, a small fragment of the Oa1 promoter was cloned in front of a reporter gene in an adeno-associated virus. After we injected this virus into the subretinal space, we observed reporter gene expression specifically in the retinal pigment epithelium, confirming the cell-specific expression of the Oa1 promoter in the eye. The results obtained with this viral system are a preamble to the development of new gene delivery approaches for the treatment of retinal pigment epithelium defects. C1 Telethon Inst Genet & Med, I-80131 Naples, Italy. Univ Naples Federico II, Dept Pediat, Naples, Italy. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Marigo, V (reprint author), Telethon Inst Genet & Med, Via P Castellino 111, I-80131 Naples, Italy. EM marigo@tigem.it RI Marigo, Valeria/B-7947-2015; OI Marigo, Valeria/0000-0002-4428-2084; AURICCHIO, Alberto/0000-0002-0832-2472; BALLABIO, Andrea/0000-0003-1381-4604 FU NEI NIH HHS [1R01 EY 015136-01, R01 EY015136]; NIAMS NIH HHS [AR 43369, R01 AR043369]; Telethon [TGM03S01, TGM06S01] NR 37 TC 30 Z9 34 U1 2 U2 5 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 AUG PY 2004 VL 24 IS 15 BP 6550 EP 6559 DI 10.1128/mcb.24.15.6550-6559.2004 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 839DZ UT WOS:000222764800002 PM 15254223 ER PT J AU Chiang, YJ Hemann, MT Hathcock, KS Tessarollo, L Feigenbaum, L Hahn, WC Hodes, RJ AF Chiang, YJ Hemann, MT Hathcock, KS Tessarollo, L Feigenbaum, L Hahn, WC Hodes, RJ TI Expression of telomerase RNA template, but not telomerase reverse transcriptase, is limiting for telomere length maintenance in vivo SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CATALYTIC SUBUNIT; DYSKERATOSIS-CONGENITA; MOUSE TELOMERASE; MICE; CELLS; CANCER; MTERT; ELONGATION; SENESCENCE; COMPONENT AB Telomerase consists of two essential components, the telomerase RNA template (TR) and telomerase reverse transcriptase (TERT). The haplo-insufficiency of TR was recently shown to cause one form of human dyskeratosis congenita, an inherited disease marked by abnormal telomere shortening. Consistent with this finding, we recently reported that mice heterozygous for inactivation of mouse TR exhibit a similar haplo-insufficiency and are deficient in the ability to elongate telomeres in vivo. To further assess the genetic regulation of telomerase activity, we have compared the abilities of TR-deficient and TERT-deficient mice to maintain or elongate telomeres in interspecies crosses. Homozygous TERT knockout mice had no telomerase activity and failed to maintain telomere length. In contrast, TERT+/- heterozygotes had no detectable defect in telomere elongation compared to wild-type controls, whereas TR+/- heterozygotes were deficient in telomere elongation. Levels of TERT mRNA in heterozygous mice were one-third to one-half the levels expressed in wild-type mice, similar to the reductions in telomerase RNA observed in TR heterozygotes. These findings indicate that both TR and TERT are essential for telomere maintenance and elongation but that gene copy number and transcriptional regulation of TR, but not TERT, are limiting for telomerase activity under the in vivo conditions analyzed. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NIA, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. SAIC Frederick Inc, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. SAIC Frederick Inc, Transgen Med Model Lab, Frederick, MD 21702 USA. NCI, Frederick, MD 21702 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Chiang, YJ (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,4B36,9000 Rockville Pike, Bethesda, MD 20892 USA. EM chiangj@mail.nih.gov FU NCI NIH HHS [CA16519, K01 CA094223, K01 CA94223, P01 CA016519] NR 37 TC 72 Z9 77 U1 0 U2 1 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 AUG PY 2004 VL 24 IS 16 BP 7024 EP 7031 DI 10.1128/MCB.24.16.7024-7031.2004 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 843AF UT WOS:000223045600013 PM 15282303 ER PT J AU Massol, RH Larsen, JE Fujinaga, Y Lencer, WI Kirchhausen, T AF Massol, RH Larsen, JE Fujinaga, Y Lencer, WI Kirchhausen, T TI Cholera toxin toxicity does not require functional Arf6-and dynamin-dependent endocytic pathways SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID ESCHERICHIA-COLI ENTEROTOXINS; ADP-RIBOSYLATION FACTOR; INDUCED MORPHOLOGICAL-CHANGES; UNIQUE DITERPENE ACTIVATOR; HEAT-LABILE ENTEROTOXIN; ENDOPLASMIC-RETICULUM; ADENYLATE-CYCLASE; PLASMA-MEMBRANE; GOLGI-COMPLEX; ADRENAL-CELLS AB Cholera toxin (CT) and related AB(5) toxins bind to glycolipids at the plasma membrane and are then transported in a retrograde manner, first to the Golgi and then to the endoplasmic reticulum (ER). In the ER, the catalytic subunit of CT is translocated into the cytosol, resulting in toxicity. Using fluorescence microscopy, we found that CT is internalized by multiple endocytic pathways. Inhibition of the clathrin-, caveolin-, or Arf6-dependent pathways by overexpression of appropriate dominant mutants had no effect on retrograde traffic of CT to the Golgi and ER, and it did not affect CT toxicity. Unexpectedly, when we blocked all three endocytic pathways at once, although fluorescent CT in the Golgi and ER became undetectable, CT-induced toxicity was largely unaffected. These results are consistent with the existence of an additional retrograde pathway used by CT to reach the ER. C1 Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Ctr Blood Res Biomed Res, Boston, MA 02115 USA. Childrens Hosp, Dept Pediat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Harvard Digest Dis Ctr, Boston, MA 02115 USA. RP Kirchhausen, T (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. EM kirchhausen@crystal.harvard.edu FU NIAID NIH HHS [U54 AI057159, 1U54AI057159-01]; NIDDK NIH HHS [R37 DK048106, R01 DK048106, DK48106] NR 89 TC 65 Z9 69 U1 0 U2 2 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 AUG PY 2004 VL 15 IS 8 BP 3631 EP 3641 DI 10.1091/mbc.E04-04-0283 PG 11 WC Cell Biology SC Cell Biology GA 841SK UT WOS:000222951500012 PM 15146065 ER PT J AU Kurtz, A Lueth, M Kluwe, L Zhang, TG Foster, R Mautner, VF Hartmann, M Tan, DJ Martuza, RL Friedrich, RE Driever, PH Wong, LJC AF Kurtz, A Lueth, M Kluwe, L Zhang, TG Foster, R Mautner, VF Hartmann, M Tan, DJ Martuza, RL Friedrich, RE Driever, PH Wong, LJC TI Somatic mitochondrial DNA mutations in neurofibromatosis type 1-associated tumors SO MOLECULAR CANCER RESEARCH LA English DT Article ID NF1 GENE; HIGH-FREQUENCY; SCHWANN-CELLS; EXPRESSION; SEQUENCE; CANCER; NUCLEAR; GENOME; AMPLIFICATION; DELETIONS AB Neurofibromatosis type 1 is an autosomal dominantly inherited disease predisposing to a multitude of tumors, most characteristically benign plexiform neurofibromas and diffuse cutaneous neurofibromas. We investigated the presence and distribution of somatic mitochondrial DNA (mtDNA) mutations in neurofibromas and in nontumor tissue of neurofibromatosis type 1 patients. MtDNA alterations in the entire mitochondrial genome were analyzed by temporal temperature gradient gel electrophoresis followed by DNA sequencing. Somatic mtDNA mutations in tumors were found in 7 of 19 individuals with cutaneous neurofibromas and in 9 of 18 patients with plexiform neurofibromas. A total of 34 somatic mtDNA mutations were found. All mutations were located in the displacement loop region of the mitochondrial genome. Several plexiform neurofibromas from individual patients had multiple homoplasmic mtDNA mutations. In cutaneous neurofibromas, the same mtDNA mutations were always present in tumors from different locations of the same individual. An increase in the proportion of the mutant mtDNA was always found in the neurofibromas when compared with nontumor tissues. The somatic mtDNA mutations were present in the Schwann cells of the analyzed multiple cutaneous neurofibromas of the same individual. The observed dominance of a single mtDNA mutation in multiple cutaneous neurofibromas of individual patients indicates a common tumor cell ancestry and suggests a replicative advantage rather than random segregation for cells carrying these mutated mitochondria. C1 Georgetown Univ, Med Ctr, Inst Mol & Human Genet, Washington, DC 20007 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA USA. Univ Hamburg, Hosp Eppendorf, Hamburg, Germany. Humboldt Univ, Charite Med Ctr, Berlin, Germany. RP Wong, LJC (reprint author), Georgetown Univ, Med Ctr, Inst Mol & Human Genet, 3800 Reservoir Rd,M4000, Washington, DC 20007 USA. EM wonglj@georgetown.edu NR 48 TC 31 Z9 33 U1 0 U2 1 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 AUG PY 2004 VL 2 IS 8 BP 433 EP 441 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 849HK UT WOS:000223529100002 PM 15328370 ER PT J AU Klopper, JP Hays, WR Sharma, V Baumbusch, MA Hershman, JM Haugen, BR AF Klopper, JP Hays, WR Sharma, V Baumbusch, MA Hershman, JM Haugen, BR TI Retinoid X receptor-gamma and peroxisome proliferator-activated receptor-gamma expression predicts thyroid carcinoma cell response to retinoid and thiazolidinedione treatment SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID HUMAN PROSTATE-CANCER; REDIFFERENTIATION THERAPY; INDUCE APOPTOSIS; PPAR-GAMMA; ACID; LIGAND; GROWTH; LINES; DIFFERENTIATION; INFLAMMATION AB Poorly differentiated, metastatic thyroid cancer is difficult to treat. These tumors often do not concentrate radioactive iodine and may require chemotherapy, which is suboptimal and toxic. Nuclear hormone receptors peroxisome proliferator-activated receptor gamma (PPARgamma) and retinoid X receptor (RXR) are variably expressed in thyroid carcinoma cell lines. Expression of these receptors may predict thyroid cancer cell response to treatment with rexinoids and thiazolidinediones. We studied three thyroid carcinoma cell lines: BHP 5-16 (PPARgamma-/RXRgamma+), BHP 2-7 (PPARgamma+/-/RXRgamma-), and DRO-90 (RXRgamma+/PPARgamma+). BHP 5-16 (RXRgamma+) cells treated with rexinoid had decreased proliferation to 69 +/- 6% growth compared with vehicle. BHP 2-7 (PPARgamma+) cells treated with thiazolidinedione had no decrease in cellular proliferation. DRO-90 (RXRgamma+ and PPARgamma+) cells had 36 +/- 10%, 15 +/- 3%, and 13 +/- 4% growth when treated with rexinoid, thiazolidinedione, or a combination, respectively. We next investigated the role of apoptosis in the ligand-responsive BHP 5-16 and DRO-90 cells. BHP 5-16 cells underwent no significant apoptosis with rexinoid (1 mumol/L). DRO-90 cells, however, had 3.6 +/- 1.3% apoptotic cells with vehicle, 13 +/- 3.5% with rexinoid (1 mumol/L), 18 +/- 4% with thiazolidinedione (1 mumol/L), and 28 +/- 6% with combination treatment (1 mumol/L), suggesting that apoptosis plays a major role in this anaplastic cell line and that the effects of the two ligands are additive. We conclude that receptor expression is necessary for inhibition of thyroid carcinoma growth with ligand treatment but may not be sufficient for response. Additionally, expression of both RXRgamma and PPARgamma may be necessary for maximal growth inhibition by ligands and may be required for the increased apoptosis. C1 Univ Colorado, Ctr Hlth Sci, Ctr Canc, Dept Med,Div Endocrinol Metab & Diabet, Denver, CO 80262 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. W Los Angeles VAMC, Dept Med, Los Angeles, CA USA. RP Klopper, JP (reprint author), Univ Colorado, Ctr Hlth Sci, Ctr Canc, Dept Med,Div Endocrinol Metab & Diabet, Box B151,4200 E 9th Ave, Denver, CO 80262 USA. EM joshua.klopper@uchsc.edu FU NCI NIH HHS [R25CA49981]; NIDDK NIH HHS [DK54383] NR 33 TC 38 Z9 45 U1 0 U2 1 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 AUG PY 2004 VL 3 IS 8 BP 1011 EP 1020 PG 10 WC Oncology SC Oncology GA 845LR UT WOS:000223244700013 PM 15299084 ER PT J AU Malo, MS Zhang, WY Alkhoury, F Pushpakaran, P Abedrapo, MA Mozumder, M Fleming, E Siddique, A Henderson, JW Hodin, RA AF Malo, MS Zhang, WY Alkhoury, F Pushpakaran, P Abedrapo, MA Mozumder, M Fleming, E Siddique, A Henderson, JW Hodin, RA TI Thyroid hormone positively regulates the enterocyte differentiation marker intestinal alkaline phosphatase gene via an atypical response element SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID RETINOID-X-RECEPTOR; TRANSCRIPTIONAL REGULATION; POSTNATAL-DEVELOPMENT; GROWTH-HORMONE; NUCLEAR RECEPTORS; DIRECT REPEATS; BINDING-SITE; TR-ALPHA; RAT; BETA AB Thyroid hormone (T-3) is a critical regulator of intestinal epithelial development and homeostasis, but its mechanism of action within the gut is not well understood. We have examined the molecular mechanisms underlying the T-3 activation of the enterocyte differentiation marker intestinal alkaline phosphatase (IAP) gene. RT-PCR and Western blotting showed that thyroid hormone receptors TRalpha1 and TRbeta1 were expressed in human colorectal adenocarcinoma Caco-2 cells. Northern blotting detected expression of two IAP transcripts, which were increased approximately 3-fold in response to T-3. Transient transfection studies with luciferase reporter plasmids carrying various internal and 5' deletion mutations of the IAP promoter localized a putative thyroid hormone response element (TRE) to a region approximately 620 nucleotides upstream (-620) of the ATG start codon. EMSAs using TRalpha1-retinoid X receptor alpha (RXRalpha) on sequential 5' and 3' single nucleotide deletions defined the TRE between -632 and -612 (5'-TTGAACTCAgccTGAGGTTAC-3'). Compared with the consensus TRE, the IAP-TRE is novel in that it contains an everted repeat of two nonamers (not hexamers) separated by three nucleotides. Neither TRalpha1 nor RXRalpha binds to the IAP-TRE; however, TRbeta1 binds to this TRE with minimal affinity. In the presence of TR and RXRalpha, only the TR-RXRalpha heterodimer binds to the IAP-TRE. Mutagenesis of either nonamer abolishes the biological activity of IAP promoter. We have thus identified a novel response element that appears to mediate the T-3-induced activation of the enterocyte differentiation marker, intestinal alkaline phosphatase. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Hodin, RA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Gray Bigelow 504,55 Fruit St, Boston, MA 02114 USA. EM rhodin@partners.org RI pushpakaran, dr prem raj/D-3540-2009 OI pushpakaran, dr prem raj/0000-0002-2289-5277 FU NIDDK NIH HHS [DK47186, DK50623] NR 69 TC 23 Z9 27 U1 0 U2 3 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 AUG PY 2004 VL 18 IS 8 BP 1941 EP 1962 DI 10.1210/me.2003-0351 PG 22 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 841CT UT WOS:000222907600007 PM 15143152 ER PT J AU Jain, RK Stroh, M AF Jain, RK Stroh, M TI Zooming in and out with quantum dots SO NATURE BIOTECHNOLOGY LA English DT Editorial Material ID IN-VIVO C1 Massachusetts Gen Hosp, Dept Radiat Oncol, EL Steele Lab Tumor Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, EL Steele Lab Tumor Biol, 100 Blossom St, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu NR 12 TC 24 Z9 27 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD AUG PY 2004 VL 22 IS 8 BP 959 EP 960 DI 10.1038/nbt0804-959 PG 2 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 842YB UT WOS:000223039500016 PM 15286644 ER PT J AU Saito, RM Perreault, A Peach, B Satterlee, JS van den Heuvel, S AF Saito, RM Perreault, A Peach, B Satterlee, JS van den Heuvel, S TI The CDC-14 phosphatase controls developmental cell-cycle arrest in C-elegans SO NATURE CELL BIOLOGY LA English DT Article ID DEPENDENT KINASE INHIBITOR; HUMAN CDC14A PHOSPHATASE; CAENORHABDITIS-ELEGANS; SACCHAROMYCES-CEREVISIAE; CHROMOSOME SEGREGATION; MITOTIC EXIT; S PHASE; PROGRESSION; MITOSIS; COMPLEX AB Temporal control of cell division is critical for proper animal development. To identify mechanisms involved in developmental arrest of cell division, we screened for cell-cycle mutants that disrupt the reproducible pattern of somatic divisions in the nematode C. elegans. Here, we show that the cdc-14 phosphatase is required for the quiescent state of specific precursor cells. Whereas budding yeast Cdc14p is essential for mitotic exit, inactivation of C. elegans cdc-14 resulted in extra divisions in multiple lineages, with no apparent defects in mitosis or cell-fate determination. CDC-14 fused to the green fluorescent protein (GFP-CDC-14) localized dynamically and accumulated in the cytoplasm during G1 phase. Genetic interaction and transgene expression studies suggest that cdc-14 functions upstream of the cki-1 Cip/Kip inhibitor to promote accumulation of CKI-1 in the nucleus. Our data support a model in which CDC-14 promotes a hypophosphorylated and stable form of CKI-1 required for developmentally programmed cell-cycle arrest. C1 Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP van den Heuvel, S (reprint author), Massachusetts Gen Hosp, Ctr Canc, Bldg 149,13th St, Charlestown, MA 02129 USA. EM heuvel@helix.mgh.harvard.edu RI van den Heuvel, Sander/B-8892-2011 NR 30 TC 59 Z9 67 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 AUG PY 2004 VL 6 IS 8 BP 777 EP 783 DI 10.1038/ncb1154 PG 7 WC Cell Biology SC Cell Biology GA 842YA UT WOS:000223039400017 PM 15247923 ER PT J AU Suzuki, T Delgado-Escueta, AV Aguan, K Alonso, ME Shi, J Hara, Y Nishida, M Numata, T Medina, MT Takeuchi, T Morita, R Bai, DS Ganesh, S Sugimoto, Y Inazawa, J Bailey, JN Ochoa, A Jara-Prado, A Rasmussen, A Ramos-Peek, J Cordova, S Rubio-Donnadieu, F Inoue, Y Osawa, M Kaneko, S Oguni, H Mori, Y Yamakawa, K AF Suzuki, T Delgado-Escueta, AV Aguan, K Alonso, ME Shi, J Hara, Y Nishida, M Numata, T Medina, MT Takeuchi, T Morita, R Bai, DS Ganesh, S Sugimoto, Y Inazawa, J Bailey, JN Ochoa, A Jara-Prado, A Rasmussen, A Ramos-Peek, J Cordova, S Rubio-Donnadieu, F Inoue, Y Osawa, M Kaneko, S Oguni, H Mori, Y Yamakawa, K TI Mutations in EFHC1 cause juvenile myoclonic epilepsy SO NATURE GENETICS LA English DT Article ID IDIOPATHIC GENERALIZED EPILEPSY; CHILDHOOD ABSENCE EPILEPSY; E CALCIUM-CHANNEL; CA2+ CHANNEL; GENE; LINKAGE; CANDIDATE; SUBUNIT; LOCUS; HETEROGENEITY AB Juvenile myoclonic epilepsy (JME) is the most frequent cause of hereditary grand mal seizures(1,2). We previously mapped and narrowed a region associated with JME on chromosome 6p12-p11 (EJM1)(3-5). Here, we describe a new gene in this region, EFHC1, which encodes a protein with an EF-hand motif. Mutation analyses identified five missense mutations in EFHC1 that cosegregated with epilepsy or EEG polyspike wave in affected members of six unrelated families with JME and did not occur in 382 control individuals. Overexpression of EFHC1 in mouse hippocampal primary culture neurons induced apoptosis that was significantly lowered by the mutations. Apoptosis was specifically suppressed by SNX-482, an antagonist of R-type voltage-dependent Ca2+ channel (Ca(v)2.3). EFHC1 and Ca(v)2.3 immunomaterials overlapped in mouse brain, and EFHC1 coimmunoprecipitated with the Cav2.3 C terminus. In patch-clamp analysis, EFHC1 specifically increased R-type Ca2+ currents that were reversed by the mutations associated with JME. C1 RIKEN, Brain Sci Inst, Neurogenet Lab, Wako, Saitama 3510198, Japan. Tokyo Med & Dent Univ, Med Res Inst, Dept Mol Cytogenet, Tokyo, Japan. Univ Calif Los Angeles, David Geffen Sch Med, Comprehens Epilepsy Program, Epilepsy Genet Gen Labs, Los Angeles, CA 90024 USA. VA GLAHS W Los Angeles, W Los Angeles DVA Med Ctr, Los Angeles, CA 90073 USA. Natl Inst Neurol & Neurosurg, Mexico City, DF, Mexico. Grad Univ Adv Studies, Ctr Integrat Biosci, Okazaki, Aichi, Japan. Kyoto Univ, Grad Sch Engn, Kyoto, Japan. Natl Autonomous Univ, Tegucigalpa, Honduras. Univ Calif Los Angeles, David Geffen Sch Med, Inst Neuropsychiat, Los Angeles, CA USA. Shizuoka Med Inst Neurol Disorders, Natl Epilepsy Ctr, Shizuoka, Japan. Tokyo Womens Med Univ, Dept Pediat, Tokyo, Japan. Hirosaki Univ, Sch Med, Dept Neuropsychiat, Aomori, Japan. RP Delgado-Escueta, AV (reprint author), RIKEN, Brain Sci Inst, Neurogenet Lab, 2-1 Hirosawa, Wako, Saitama 3510198, Japan. EM escueta@ucla.edu; yamakawa@brain.riken.go.jp RI Ganesh, Subramniam/B-4131-2009; shi, jun/C-2389-2011; Yamakawa, Kazuhiro/N-5050-2015; OI Delgado-Escueta, Antonio V./0000-0002-1581-6999 NR 29 TC 206 Z9 218 U1 3 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD AUG PY 2004 VL 36 IS 8 BP 842 EP 849 DI 10.1038/ng1393 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 842AG UT WOS:000222974000016 PM 15258581 ER PT J AU Chang, S Multani, AS Cabrera, NG Naylor, ML Laud, P Lombard, D Pathak, S Guarente, L DePinho, RA AF Chang, S Multani, AS Cabrera, NG Naylor, ML Laud, P Lombard, D Pathak, S Guarente, L DePinho, RA TI Essential role of limiting telomeres in the pathogenesis of Werner syndrome SO NATURE GENETICS LA English DT Article ID SYNDROME GENE-PRODUCT; IONIZING-RADIATION; WRN; TOPOISOMERASE; DYSFUNCTION; SENSITIVITY; FIBROBLASTS; HELICASES; HOMOLOG; GENOME AB Mutational inactivation of the gene WRN causes Werner syndrome, an autosomal recessive disease characterized by premature aging, elevated genomic instability and increased cancer incidence(1,2). The capacity of enforced telomerase expression to rescue premature senescence of cultured cells from individuals with Werner syndrome(3) and the lack of a disease phenotype in Wrn-deficient mice with long telomeres(4) implicate telomere attrition in the pathogenesis of Werner syndrome. Here, we show that the varied and complex cellular phenotypes of Werner syndrome are precipitated by exhaustion of telomere reserves in mice. In late-generation mice null with respect to both Wrn and Terc ( encoding the telomerase RNA component), telomere dysfunction elicits a classical Werner-like premature aging syndrome typified by premature death, hair graying, alopecia, osteoporosis, type II diabetes and cataracts. This mouse model also showed accelerated replicative senescence and accumulation of DNA-damage foci in cultured cells, as well as increased chromosomal instability and cancer, particularly nonepithelial malignancies typical of Werner syndrome. These genetic data indicate that the delayed manifestation of the complex pleiotropic of Wrn deficiency relates to telomere shortening. C1 Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. RP Chang, S (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Box 11,1515 Holcombe Blvd, Houston, TX 77030 USA. EM schang@mdanderson.org; ron_depinho@dfci.harvard.edu FU NIA NIH HHS [K08 AG001019, K08 AG024873] NR 24 TC 273 Z9 286 U1 1 U2 22 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD AUG PY 2004 VL 36 IS 8 BP 877 EP 882 DI 10.1038/ng1389 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 842AG UT WOS:000222974000022 PM 15235603 ER PT J AU Nardone, J Lee, DU Ansel, KM Rao, A AF Nardone, J Lee, DU Ansel, KM Rao, A TI Bioinformatics for the 'bench biologist': how to find regulatory regions in genomic DNA SO NATURE IMMUNOLOGY LA English DT Editorial Material ID SPECIES SEQUENCE COMPARISONS; T-CELL DIFFERENTIATION; GENE-EXPRESSION; IL-4 GENE; TRANSCRIPTION FACTOR; MAST-CELLS; HYPERSENSITIVE SITES; COORDINATE REGULATOR; CHROMATIN-STRUCTURE; LINEAGE COMMITMENT AB The combination of bioinformatic and biological approaches constitutes a powerful method for identifying gene regulatory elements. High-quality genome sequences are available in public databases for several vertebrate species. Comparative cross-species sequence analysis of these genomes shows considerable conservation of noncoding sequences in DNA. Biological analyses show that an unexpectedly high number of the conserved sequences correspond to functional cis-regulatory regions that influence gene transcription. Because research biologists are often unfamiliar with the bioinformatic resources at their disposal, this commentary discusses how to integrate biological and bioinformatic methods in the discovery of gene regulatory regions and includes a tutorial on widely available comparative genomics programs. C1 Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. CBR, Inst Biomed Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Grad Program Immunol, Boston, MA 02115 USA. RP Nardone, J (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM arao@cbr.med.harvard.edu NR 76 TC 56 Z9 57 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD AUG PY 2004 VL 5 IS 8 BP 768 EP 774 DI 10.1038/ni0804-768 PG 7 WC Immunology SC Immunology GA 841TX UT WOS:000222955600004 PM 15282556 ER PT J AU von Boehmer, H AF von Boehmer, H TI Type 1 diabetes: focus on prevention SO NATURE MEDICINE LA English DT Editorial Material ID REGULATORY T-CELLS; PEPTIDE; ANTIGEN; INSULIN; FOXP3; MICE AB Two new approaches prevent disease in a model of type 1 diabetes. One approach blocks an activation receptor on disease-conferring T cells. The second deploys suppressor T cells renowned for their ability to inhibit the local immune response. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP von Boehmer, H (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 1 Jimmy Fund Way, Boston, MA 02115 USA. EM Harald_von_Boehmer@dfci.harvard.edu NR 16 TC 9 Z9 9 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 2004 VL 10 IS 8 BP 783 EP 784 DI 10.1038/nm0804-783 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 843DK UT WOS:000223055700018 PM 15286776 ER PT J AU Chen, L Hamrah, P Cursiefen, C Zhang, Q Pytowski, B Streilein, JW Dana, MR AF Chen, L Hamrah, P Cursiefen, C Zhang, Q Pytowski, B Streilein, JW Dana, MR TI Vascular endothelial growth factor receptor-3 mediates induction of corneal alloimmunity SO NATURE MEDICINE LA English DT Article ID LYMPHATIC-SYSTEM; DENDRITIC CELLS; LYMPHANGIOGENESIS; NODES AB There are no studies so far linking molecular regulation of lymphangiogenesis and induction of adaptive immunity. Here, we show that blockade of vascular endothelial growth factor receptor-3 (VEGFR-3) signaling significantly suppresses corneal antigen-presenting ( dendritic) cell trafficking to draining lymph nodes, induction of delayed-type hypersensitivity and rejection of corneal transplants. Regulating the function of VEGFR-3 may therefore be a mechanism for modulating adaptive immunity in the periphery. C1 Schepens Eye Res Inst, Immunol Lab, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. ImClone Syst, New York, NY USA. RP Dana, MR (reprint author), Schepens Eye Res Inst, Immunol Lab, 20 Staniford St, Boston, MA 02114 USA. EM dana@vision.eri.harvard.edu NR 13 TC 140 Z9 145 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 2004 VL 10 IS 8 BP 813 EP 815 DI 10.1038/nm1078 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 843DK UT WOS:000223055700034 PM 15235599 ER PT J AU Bar, M AF Bar, M TI Visual objects in context SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID MEDIAL TEMPORAL-LOBE; ASSOCIATIVE RECOGNITION MEMORY; INFEROTEMPORAL CORTEX; SCENE RECOGNITION; TIME-COURSE; CONSCIOUS IDENTIFICATION; HIPPOCAMPAL-FORMATION; REPETITION BLINDNESS; SELECTIVE ATTENTION; BOUNDARY EXTENSION AB We see the world in scenes, where visual objects occur in rich surroundings, often embedded in a typical context with other related objects. How does the human brain analyse and use these common associations? This article reviews the knowledge that is available, proposes specific mechanisms for the contextual facilitation of object recognition, and highlights important open questions. Although much has already been revealed about the cognitive and cortical mechanisms that subserve recognition of individual objects, surprisingly little is known about the neural underpinnings of contextual analysis and scene perception. Building on previous findings, we now have the means to address the question of how the brain integrates individual elements to construct the visual experience. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Ctr, Charlestown, MA 02129 USA. RP Bar, M (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Ctr, 149 13th St, Charlestown, MA 02129 USA. EM bar@nmr.mgh.harvard.edu NR 157 TC 590 Z9 597 U1 17 U2 82 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 AUG PY 2004 VL 5 IS 8 BP 617 EP 629 DI 10.1038/nrn1476 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 842AD UT WOS:000222973700013 PM 15263892 ER PT J AU Jara, A Chacon, C Ibaceta, M Valdivieso, A Felsenfeld, AJ AF Jara, A Chacon, C Ibaceta, M Valdivieso, A Felsenfeld, AJ TI Effect of ammonium chloride and dietary phosphorus in the azotaemic rat. I. Renal function and biochemical changes SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE ammonium chloride; calcium; dietary phosphorus; phosphorus; renal failure ID CHRONIC METABOLIC-ACIDOSIS; SEVELAMER HYDROCHLORIDE; PHOSPHATE-DEPLETION; FAILURE; CALCIUM; PROGRESSION; DISEASE; CALCIFICATION; SERUM AB Background. Both dietary phosphorus restriction and the ingestion of ammonium chloride (NH4Cl) given to rats on a high-phosphorus diet have been shown to preserve renal function in the azotaemic rat. Parathyroidectomy also has been reported to preserve renal function and, in addition, to prevent kidney hypertrophy in the remnant kidney model. Our goals were (i) to evaluate in azotaemic rats the effect of dietary phosphorus on renal function in a shorter time frame than previously studied and (ii) to determine whether NH4Cl administration (a) enhances the renoprotective effect of dietary phosphorus restriction and (b) improves renal function in the absence of parathyroid hormone (PTH). Methods. High (H; 1.2%), normal (N; 0.6%) and low (L; <0.05%) phosphorus diets (PD) were given for 30 days to 5/6 nephrectomized rats. In each dietary group, one-half of the rats were given NH4Cl in the drinking water. The six groups were HPD+NH4Cl, HPD, NPD + NH4Cl, NPD, LPD + NH4Cl and LPD. The effect of NH4Cl administration was also evaluated in 5/6 nephrectomized, parathyroidectomized (PTX) rats on NPD. Results. In each of the three dietary phosphorus groups, creatinine and urea clearances were greater (P<0.01) in rats receiving NH4Cl. Neither creatinine nor urea clearance was reduced by high dietary phosphorus. Urine calcium excretion was greatest in the LPD group and was increased (Pless than or equal to0.001) in all three groups by NH4Cl ingestion. An inverse correlation was present between plasma calcium and phosphorus in the parathyroid intact (r = -0.79, P<0.001) and PTX groups (r = -0.46, P = 0.02). In PTX rats, NH4Cl ingestion increased (P<0.01) creatinine and urea clearances and both an increasing plasma calcium concentration (r = 0.67, P<0.001) and urine calcium excretion (r = 0.73, P<0.001) increased urine phosphorus excretion. Conclusions. At 30 days of renal failure (i) NH4Cl ingestion increased creatinine and urea clearances, irrespective of dietary phosphorus; (ii) high urine calcium excretion, induced by dietary phosphorus restriction and NH4Cl ingestion, did not adversely affect renal function; (iii) high dietary phosphorus did not decrease renal function; (iv) the absence of PTH did not preserve renal function or prevent NH4Cl from improving renal function; and (v) both an increasing plasma calcium concentration and urine calcium excretion resulted in an increase in urine phosphorus excretion in PTX rats. C1 Pontificia Univ Catolica Chile, Dept Nephrol, Santiago, Chile. W Los Angeles Vet Affairs Med Ctr, Dept Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. RP Jara, A (reprint author), Pontificia Univ Catolica Chile, Dept Nephrol, Lira 85, Santiago, Chile. EM ajara@med.puc.cl NR 20 TC 9 Z9 9 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD AUG PY 2004 VL 19 IS 8 BP 1986 EP 1992 DI 10.1093/ndt/gfh311 PG 7 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 843VF UT WOS:000223114000007 PM 15173378 ER PT J AU Jara, A Chacon, C Ibaceta, M Valdivieso, A Felsenfeld, AJ AF Jara, A Chacon, C Ibaceta, M Valdivieso, A Felsenfeld, AJ TI Effect of ammonium chloride and dietary phosphorus in the azotaemic rat. Part II - kidney hypertrophy and calcium deposition SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE ammonium chloride; dietary phosphorus; kidney hypertrophy; nephrocalcinosis ID SEVELAMER HYDROCHLORIDE; RENAL HYPERTROPHY; HEMODIALYSIS-PATIENTS; PHOSPHATE; PROGRESSION; RESTRICTION; PREVENTION; FAILURE; PARATHYROIDECTOMY; NEPHROCALCINOSIS AB Background. Kidney hypertrophy is stimulated by both partial nephrectomy and NH4Cl administration. Also, parathyroidectomy (PTX) has been reported to prevent kidney hypertrophy induced by a high protein diet. Our goal was to determine in the azotaemic rat: (i) the combined effects of NH4Cl administration and dietary phosphorus on the development of kidney hypertrophy and calcium deposition in the kidney and (11) whether the absence of parathyroid hormone (PTH) affected the development of kidney hypertrophy and calcium deposition. Methods. High (HPD., 1.2%), normal (NPD, 0.6%) or low (LPD, <0.05%) phosphorus diets were given to 5/6 nephrectomized rats for 30 days. In each dietary group, one-half of the rats were given NH4Cl in the drinking water. The six groups of rats were: (i) HPD+NH4Cl; (ii) HPD; (iii) NPD+NH4Cl; (iv) NPD; (v) LPD + NH4Cl and (vi) LPD. In a separate study, PTX was performed to determine whether PTH affected renal hypertrophy in 5/6 nephrectomized rats given NH4Cl. Results. Both with and without NH4Cl (+/-NH4Cl), kidney weight was greatest (P<0.05) in the HPD groups. In each dietary phosphorus group, kidney weight was greater (P<0.05) in the NH4Cl group. In both the +/-NH4Cl groups, kidney calcium content was greatest (P<0.05) in the HPD group, but was less (P<0.05) in the NPD and HPD groups given NH4Cl. An inverse correlation was present between creatinine clearance and kidney, calcium content (r=-0.51, P<0.001). When factored for kidney weight, creatinine clearance was less (P<0.05) in the HPD group in both the +/-NH4Cl groups, but was greater in the HPD+NH4Cl than in the HPD group. In PTX rats, kidney weight was greater (P<0.05) and kidney calcium deposition was less (P<0.05) in rats given NH4Cl. Conclusions. In azotaemic rats studied for 30 days, NH4Cl administration induced kidney hypertrophy. A HPD also induced kidney hypertrophy. The effects on kidney calcium deposition were divergent for which NH4Cl administration decreased and a HPD increased calcium deposition. The inverse correlation between kidney calcium content and creatinine clearance suggests that kidney calcium deposition is harmful to renal function. When factored for kidney weight, the lower creatinine clearance in the high phosphorus group suggests that kidney hypertrophy does not completely compensate for the harmful effects of a HPD. This result also suggests that a longer study would probably result in more rapid deterioration in the high phosphorus group. In PTX rats, the absence of PTH did not prevent NH4Cl from inducing kidney hypertrophy and reducing kidney calcium deposition. In conclusion, NH4Cl and dietary phosphorus each independently affect kidney growth and calcium deposition in the growing rat with renal failure. C1 Pontificia Univ Catolica Chile, Dept Nephrol, Santiago, Chile. W Los Angeles Vet Affairs Med Ctr, Dept Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. RP Jara, A (reprint author), Pontificia Univ Catolica Chile, Dept Nephrol, Lira 85, Santiago, Chile. EM ajara@med.puc.cl NR 25 TC 11 Z9 12 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD AUG PY 2004 VL 19 IS 8 BP 1993 EP 1998 DI 10.1093/ndt/gfh301 PG 6 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 843VF UT WOS:000223114000008 PM 15161952 ER PT J AU Bartzokis, G Sultzer, D Lu, PH Neuchterlein, KH Mintz, J Cummings, JL AF Bartzokis, G Sultzer, D Lu, PH Neuchterlein, KH Mintz, J Cummings, JL TI Heterogeneous age-related breakdown of white matter structural integrity: implications for cortical "disconnection" in aging and Alzheimer's diesase SO NEUROBIOLOGY OF AGING LA English DT Article; Proceedings Paper CT 4th Annual Rural Policy Conference CY APR 28-29, 2003 CL Kansas City, MO SP Fed Reserve Bank Kansas City, Ctr Study Rural Amer DE aging; Alzheimer; myelin; oligodendrocyte; white matter; degeneration; MRI; relaxation; corpus callosum; amyloid; toxic; prevention ID T2 RELAXATION-TIME; MYELINATED NERVE-FIBERS; IN-VIVO EVALUATION; A-BETA PEPTIDES; MAGNETIC-RESONANCE; BRAIN IRON; CORPUS-CALLOSUM; RHESUS-MONKEY; DISEASE; MATURATION AB Human and non-human primate data suggest that the structural integrity of myelin sheaths deteriorates during normal aging, especially in the late-myelinating association regions and may result in "disconnection" of widely distributed neural networks. Magnetic resonance imaging (MRI) was used to assess the heterogeneity of this process and its impact on brain aging and Alzheimer's disease (AD) by evaluating early- and later-myelinating regions of the corpus callosum, the splenium (See) and genu (Gee), respectively. Calculated transverse relaxation rates (R-2), an indirect measure of white matter structural integrity for the Gee and See, were examined. The relationship between age and R2 differed in the two regions. A quadratic (inverted U) function with an accelerating rate of decline beginning at age 31 best represented the Gee pattern while the See decline was three-fold smaller, gradual, and linear. These data suggest that the severity of age-related myelin breakdown is regionally heterogeneous, consistent with the hypothesis that differences in myelin properties make later-myelinating regions more susceptible to this process. In AD this process is globally exacerbated, consistent with an extracellular deleterious process such as amyloid beta-peptide toxicity. Non-invasive measures such as R2 may be useful in primary prevention studies of AD. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Calif Los Angeles, Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Dept Neurol, Lab Neuroimaging,Div Brain Mapping, Los Angeles, CA 90095 USA. Greater Los Angeles VA Healthcare Syst, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. RP Bartzokis, G (reprint author), Univ Calif Los Angeles, Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. EM gbar@ucla.edu RI Bartzokis, George/K-2409-2013 FU NIA NIH HHS [AG 16570]; NIMH NIH HHS [MH-30911, MH-37705, MH-51928] NR 71 TC 217 Z9 221 U1 1 U2 9 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 AUG PY 2004 VL 25 IS 7 BP 843 EP 851 DI 10.1016/j.neurobiolaging.2003.09.005 PG 9 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 838JQ UT WOS:000222709900002 PM 15212838 ER PT J AU Ichikawa, T Terada, K AF Ichikawa, T Terada, K TI Molecular imaging of transgene expression in brain tumor SO NEUROLOGICAL SURGERY LA Japanese DT Review DE gene therapy; gene expression; monitoring; molecular imaging; brain tumor ID POSITRON-EMISSION-TOMOGRAPHY; REPORTER GENE-EXPRESSION; SODIUM-IODIDE SYMPORTER; TYPE-1 THYMIDINE KINASE; RECURRENT GLIOBLASTOMA-MULTIFORME; MAGNETIC-RESONANCE-SPECTROSCOPY; CONVECTION-ENHANCED DELIVERY; ADENOVIRUS-MEDIATED TRANSFER; TRANSFERRIN RECEPTOR GENE; IN-VIVO DETECTION C1 Okayama Univ, Grad Sch Med & Dent, Dept Neurol Surg, Okayama 7008530, Japan. Kagawa Univ, Dept Neurosurg, Kagawa, Japan. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Imaging Res, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Mol Neurooncol Lab, Boston, MA USA. RP Ichikawa, T (reprint author), Okayama Univ, Grad Sch Med & Dent, Dept Neurol Surg, 2-5-1 Shikata Cho, Okayama 7008530, Japan. NR 103 TC 0 Z9 0 U1 3 U2 3 PU IGAKU-SHOIN LTD PI TOKYO PA 5-24-3 HONGO BUNKYO-KU, TOKYO, 113 91, JAPAN SN 0301-2603 J9 NEUROL SURG TOKYO JI Neurol. Surg. PD AUG PY 2004 VL 32 IS 8 BP 805 EP 824 PG 20 WC Neurosciences; Surgery SC Neurosciences & Neurology; Surgery GA 871OW UT WOS:000225144100001 PM 15478648 ER PT J AU Rasmusson, AM Vasek, J Lipschitz, DS Vojvodal, D Mustone, ME Shi, QH Gudmundsen, G Morgan, CA Wolfe, J Charney, DS AF Rasmusson, AM Vasek, J Lipschitz, DS Vojvodal, D Mustone, ME Shi, QH Gudmundsen, G Morgan, CA Wolfe, J Charney, DS TI An increased capacity for adrenal DHEA release is associated with decreased avoidance and negative mood symptoms in women with PTSD SO NEUROPSYCHOPHARMACOLOGY LA English DT Review DE post-traumatic stress disorder; PTSD; cortisol; DHEA; premenopausal women; HPA axis ID POSTTRAUMATIC-STRESS-DISORDER; URINARY CORTISOL EXCRETION; DEHYDROEPIANDROSTERONE-SULFATE DHEAS; DEXAMETHASONE-SUPPRESSION TEST; SUSTAINED CHILDHOOD ABUSE; MAJOR DEPRESSION; MENSTRUAL-CYCLE; GLUCOCORTICOID-RECEPTOR; 21-HYDROXYLASE DEFICIENCY; ANTIGLUCOCORTICOID ACTION AB We recently found increased adrenal cortisol responses to adrenocorticotropic hormone (ACTH)(1-24) and increased pituitary ACTH and adrenal cortisol responses to corticotropin-releasing factor in premenopausal women with chronic post-traumatic stress disorder (PTSD) compared to healthy nontraumatized subjects. This pattern of hypothalamic-pituitary-adrenal axis (HPA) hyper-reactivity has been previously seen in healthy individuals treated with the antiglucocorticoid mifepristone. We therefore investigated whether endogenous plasma levels of antiglucocorticoids such as dehydroepiandrosteroine (DHEA) and progesterone were increased in premenopausal women with PTSD at baseline or in response to adrenal activation by ACTH(1-24). The study revealed that DHEA responses to 250 mug ACTH(1-24) were increased in 13 PTSD subjects compared to 13 healthy nontraumatized subjects, while DHEA levels were generally increased in the PTSD subjects compared to seven healthy traumatized subjects. Cortisol responses to ACTH(1-24) were also higher in the women with PTSD, while progesterone levels and responses were not different among the three groups. In addition, among the PTSD subjects, the peak change in DHEA in response to ACTH(1-24) was negatively correlated with the total Clinician Administered PTSD Scale score, while the peak DHEA to cortisol ratio was inversely associated with negative mood symptoms measured by the Profile of Mood States scale. This work suggests that an increased capacity for DHEA release in response to extreme adrenal activation may influence the pattern of HPA axis adaptation to extreme stress, as well as mitigate the severity of PTSD and negative mood symptoms in premenopausal women with PTSD. C1 Yale Univ, Dept Psychiat, Sch Med, Boston, MA USA. VA Boston Healthcare Syst, VA Natl Ctr PTSD, Clin Neurosci Div, West Haven, CT USA. Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. VA Boston Healthcare Syst, VA Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA USA. New York Med Coll, Sch Publ Hlth, Learning Ctr, Valhalla, NY 10595 USA. NIMH, Mood & Anxiety Disorders Branch, Bethesda, MD 20892 USA. RP Rasmusson, AM (reprint author), VA Connecticut Healthcare Syst, Psychiat Serv 116A, 950 Campbell Ave, West Haven, CT 06516 USA. EM ann.rasmusson@yale.edu FU NIDA NIH HHS [1K12DA14038-01]; NIMH NIH HHS [MH30929] NR 111 TC 79 Z9 83 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2004 VL 29 IS 8 BP 1546 EP 1557 DI 10.1038/sj.npp.1300432 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 841OW UT WOS:000222941200017 PM 15199367 ER PT J AU Szentirmai, O Carter, BS AF Szentirmai, O Carter, BS TI Genetic and cellular therapies for cerebral infarction SO NEUROSURGERY LA English DT Review DE cellular therapy; cerebral infarct; gene therapy; neuroregeneration; stem cells; stroke ID NEURAL STEM-CELLS; CENTRAL-NERVOUS-SYSTEM; ISCHEMIC BRAIN-INJURY; ADULT MAMMALIAN BRAIN; INTERLEUKIN-1 RECEPTOR ANTAGONIST; ENHANCES NEURONAL SURVIVAL; PROTECTS STRIATAL NEURONS; MARROW STROMAL CELLS; BONE-MARROW; RAT-BRAIN AB NEUROSURGEONS, WORKING AS surgical scientists, can have a prominent role in developing and implementing genetic and cellular therapies for cerebral ischemia. The rapid emergence of both genetic and cellular therapies for neural regeneration warrants a careful analysis before implementation of human studies to understand the pitfalls and promises of this strategy. In this article, we review the topic of genetic and cellular therapy for stroke to provide a foundation for practicing neurosurgeons and clinical scientists who may become involved in this type of work. In Part 1, we review preclinical approaches with gene transfer, such as 1) improved energy delivery, 2) reduction of intracellular calcium availability, 3) abrogation of effects of reactive oxygen species, 4) reduction of proinflammatory cytokine signaling, 5) inhibition of apoptosis mediators, and 6) restorative gene therapy, that are paving the way to develop new strategies to treat cerebral infarction. In Part 2, we discuss the results of studies that address the possibility of using cellular therapies for stroke in animal models and in human trials by reviewing 1) the basics of stem cell biology, 2) exogenous and 3) and endogenous cell sources for therapy, and 4) clinical considerations in cell therapy applications. These emerging technologies based on the advancements made in recent years in the fields of genetics, therapeutic cloning, neuroscience, stem cell biology, and gene therapy provide significant potential for new therapies for stroke. C1 Massachusetts Gen Hosp, Neurosurg Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Lab Genet & Cellular Engn, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Carter, BS (reprint author), Massachusetts Gen Hosp, Neurosurg Serv, VBK 730, Boston, MA 02114 USA. EM bcarter@partners.org NR 117 TC 13 Z9 25 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD AUG PY 2004 VL 55 IS 2 BP 283 EP 296 DI 10.1227/01.NEU.000012968185731.00 PG 14 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 844WJ UT WOS:000223191500004 PM 15271234 ER PT J AU Steinberg, GK Ogilvy, CS Shuer, LM Connolly, ES Solomon, RA Lam, A Kassell, NF Baker, CJ Giannotta, SL Cockroft, KM Bell-Stephens, TE Allgren, RL AF Steinberg, GK Ogilvy, CS Shuer, LM Connolly, ES Solomon, RA Lam, A Kassell, NF Baker, CJ Giannotta, SL Cockroft, KM Bell-Stephens, TE Allgren, RL TI Comparison of endovascular and surface cooling during unruptured cerebral aneurysm repair SO NEUROSURGERY LA English DT Article DE aneurysm repair; clinical trial; cooling; hypothermia; intravascular cooling device; rewarming ID MILD HYPOTHERMIA; CARDIAC-ARREST; INFARCT SIZE; FOCAL MODEL; SURGERY; NORMOTHERMIA; INDUCTION; ISCHEMIA; STROKE; TRIAL AB OBJECTIVE: To compare endovascular versus surface methods for the induction and reversal of hypothermia during neurosurgery in a multicenter, prospective, randomized study. METHODS: Patients undergoing elective open craniotomy for repair of an unruptured cerebral aneurysm (n = 153) were randomly assigned (2:1) to undergo whole-body hypothermia to 33degreesC, either with an endovascular cooling device placed in the inferior vena Cava via the femoral vein (n = 92) or with a surface convective air blanket (n 61). Active rewarming was accomplished using the same devices. RESULTS: Cooling rates in endovascular and surface blanket groups averaged 4.77 and 0.87degreesC/h, respectively (P < 0.001). When the first temporary arterial or aneurysm clip was placed, 99% of endovascular patients and 20% of surface blanket patients had reached the target of 33&DEG;C (P < 0.001). Obese patients were cooled efficiently with the endovascular approach (3.56degreesC/h). Rewarming rates averaged 1.88degreesC/h for endovascular patients and 0.69degreesC/h for surface blanket patients (P < 0.001). By the end of surgery, 89 and 53% of these patients, respectively, had rewarmed to at least 35&DEG;C (P < 0.001). On leaving the operating room, 14% of endovascular patients and 28% of surface blanket patients were still intubated (P = 0.035). The overall safety of the two procedures was comparable. No clinically significant catheter-related thrombotic, bleeding, or infectious complications were reported in the endovascular group. CONCLUSION: Endovascular cooling provided superior induction, maintenance, and reversal of hypothermia compared with the surface blanket, without an increase in complications. Endovascular cooling may have clinical benefit for patients undergoing cerebrovascular surgery, as well as patients with acute stroke, head injury, or acute myocardial infarction. C1 Stanford Univ, Dept Neurosurg, Sch Med, Med Ctr, Stanford, CA 94305 USA. Harvard Univ, Massachusetts Gen Hosp, Boston, MA USA. Columbia Presbyterian Med Ctr, New York, NY 10032 USA. Univ Washington, Harborview Med Ctr, Seattle, WA 98104 USA. Univ Virginia, Med Ctr, Charlottesville, VA USA. Florida Hosp, Orlando, FL USA. Univ So Calif, Univ Hosp, LAC USC Med Ctr, Los Angeles, CA USA. Penn State Univ, Milton S Hershey Med Ctr, Hershey, PA 17033 USA. Stanford Univ, Med Ctr, Stanford, CA 94305 USA. Innercool Therapies, San Diego, CA USA. RP Steinberg, GK (reprint author), Stanford Univ, Dept Neurosurg, Sch Med, Med Ctr, 300 Pasteur Dr R200, Stanford, CA 94305 USA. EM gsteinberg@stanford.edu NR 18 TC 43 Z9 49 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD AUG PY 2004 VL 55 IS 2 BP 307 EP 314 DI 10.1227/01.NEU.0000129683.99430.8C PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 844WJ UT WOS:000223191500008 PM 15271236 ER PT J AU Zapol, WM Jenney, R AF Zapol, WM Jenney, R TI Inhaled nitric oxide: update 2004 SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 3rd International Conference on the Biology, Chemistry and Therapeutic Applications of Nitric Oxide/4th Annual Meeting of the Nitric-Oxide-Society-of-Japan CY MAY 24-28, 2004 CL Nara, JAPAN SP Nitr Oxide Soc Japan C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NR 1 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 AUG PY 2004 VL 11 IS 1 BP 28 EP 29 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 856CX UT WOS:000224022300006 ER PT J AU Lowenstein, CJ Matsushita, K Morrella, C Yamakuchi, M Cambien, B Wagner, DD AF Lowenstein, CJ Matsushita, K Morrella, C Yamakuchi, M Cambien, B Wagner, DD TI Nitric oxide regulation of exocytosis SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 3rd International Conference on the Biology, Chemistry and Therapeutic Applications of Nitric Oxide/4th Annual Meeting of the Nitric-Oxide-Society-of-Japan CY MAY 24-28, 2004 CL Nara, JAPAN SP Nitr Oxide Soc Japan C1 Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. Harvard Univ, Sch Med, Ctr Blood Res, Cambridge, MA 02138 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 AUG PY 2004 VL 11 IS 1 BP 34 EP 34 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 856CX UT WOS:000224022300018 ER PT J AU Matsushita, K Morrell, CN Cambien, B Yamakuchi, M Cao, WS Wagner, DD Lowenstein, CJ AF Matsushita, K Morrell, CN Cambien, B Yamakuchi, M Cao, WS Wagner, DD Lowenstein, CJ TI Nitric oxide and hydrogen peroxide regulation of exocytosis by S-nitrosylation and oxidation of N-ethylmaleimide sensitive factor SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 3rd International Conference on the Biology, Chemistry and Therapeutic Applications of Nitric Oxide/4th Annual Meeting of the Nitric-Oxide-Society-of-Japan CY MAY 24-28, 2004 CL Nara, JAPAN SP Nitr Oxide Soc Japan C1 Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21218 USA. Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Ctr Blood Res, Cambridge, MA 02138 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 AUG PY 2004 VL 11 IS 1 BP 56 EP 56 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 856CX UT WOS:000224022300099 ER PT J AU Michel, T Erwin, P AF Michel, T Erwin, P TI Dynamic receptor modulation of eNOS S-nitrosylation in endothelial cells SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 3rd International Conference on the Biology, Chemistry and Therapeutic Applications of Nitric Oxide/4th Annual Meeting of the Nitric-Oxide-Society-of-Japan CY MAY 24-28, 2004 CL Nara, JAPAN SP Nitr Oxide Soc Japan C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 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 AUG PY 2004 VL 11 IS 1 BP 70 EP 70 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 856CX UT WOS:000224022300148 ER PT J AU Rao, GG Skinner, E Gehrig, PA Duska, LR Coleman, RL Schorge, JO AF Rao, GG Skinner, E Gehrig, PA Duska, LR Coleman, RL Schorge, JO TI Surgical staging of ovarian low malignant potential tumors SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the Society-of-Gynecologic-Oncology CY FEB 07-11, 2004 CL San Diego, CA SP Soc Gynecol Oncol ID GYNECOLOGIC-ONCOLOGY-GROUP; SEROUS BORDERLINE TUMORS; INVOLVEMENT; CARCINOMA; DIAGNOSIS; BEHAVIOR; FROZEN AB OBJECTIVE: Women diagnosed with ovarian tumors of low malignant potential have an excellent prognosis. Because few will receive adjuvant therapy, the benefit of surgical staging has recently been challenged. The purpose of this study was to compare the outcome of surgically staged patients with low malignant potential tumors with those who were not staged. METHODS: Between 1984 and 2003, all women with ovarian low malignant potential tumors were identified at 3 institutions. Data were extracted from. clinical records. RESULTS: One hundred eighty-three (74%) of 248 women were surgically staged. Forty of 183 staged patients had clinically obvious extraovarian disease. Forty (28%) of the remaining 143 women with disease apparently confined to the ovary were upstaged. Cytologic washings were positive in 28 cases, 10 had microscopic implants detected by peritoneal or omental biopsy, and 2 were upstaged to stage IIIC solely on the basis of nodal metastases. One hundred eighteen women underwent pelvic node dissection (median: 5 nodes), and 86 underwent para-aortic node dissection (median: 2 nodes). Overall, 9 (1%) metastases were detected in 832 submitted pelvic nodes. All 314 para-aortic nodes were negative. Intraoperative blood loss (P <.001) and length of hospital stay (P <.001) were increased in women without gross disease who were surgically staged. Eight (3%) of 248 patients received adjuvant platinum-based chemotherapy, but neither of the women upstaged to IRC based on the results of their nodal dissection were treated. Fifteen (6%) recurrences developed and 1 (0.4%) death occurred after a median follow-up'of 28 (range, 1-208) months. CONCLUSION: Routine pelvic and para-aortic lymph node dissection is not necessary in the majority of women with ovarian low malignant potential tumors. (C) 2004 by The American College of Obstetricians and Gynecologists. C1 Univ Texas, SW Med Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Dallas, TX 75235 USA. Univ N Carolina, Dept Obstet & Gynecol, Sch Med, Chapel Hill, NC 27515 USA. Massachusetts Gen Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02114 USA. RP Schorge, JO (reprint author), Univ Texas, SW Med Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, 5323 Harry Hines Blvd,J7-124, Dallas, TX 75235 USA. EM john.schorge@utsouthwestern.edu NR 27 TC 35 Z9 39 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 AUG PY 2004 VL 104 IS 2 BP 261 EP 266 DI 10.1097/01.AOG.0000133484.92629.88 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 875IX UT WOS:000225414800010 PM 15291997 ER PT J AU LaMontagne, AD Barbeau, E Youngstrom, RA Lewiton, M Stoddard, AM McLellan, D Wallace, LM Sorensen, G AF LaMontagne, AD Barbeau, E Youngstrom, RA Lewiton, M Stoddard, AM McLellan, D Wallace, LM Sorensen, G TI Assessing and intervening on OSH programmes: effectiveness evaluation of the Wellworks-2 intervention in 15 manufacturing worksites SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID PERFORMANCE-MEASUREMENT TOOL; HEALTH PROMOTION PROGRAMS; OCCUPATIONAL-HEALTH; MANAGEMENT-SYSTEM; MASSACHUSETTS HOSPITALS; MEDICAL SURVEILLANCE; SAFETY CLIMATE; UNITED-STATES; PUBLIC-HEALTH; INJURY AB Aims: ( 1) To develop a transparent and broadly applicable method for assessing occupational safety and health (OSH) programmes or management systems; ( 2) to assess OSH programmes in a sample of manufacturing worksites; and ( 3) to determine whether a management focused occupational health intervention results in greater improvement in OSH programmes compared to minimal intervention controls. Methods: OSH programmes were assessed using an adaptation of the US Occupational Safety & Health Administration's 1995 Program Evaluation Profile. Scores were generated from 91 binary indicator variables grouped under four "Essential Elements''. Essential Element scores were weighted to contribute to an overall programme score on a 100 point scale. Seventeen large manufacturing worksites were assessed at baseline; 15 sites completed the 16 month intervention and follow up assessments. Results: There was considerable variation in Essential Element scores across sites at baseline as judged by our instrument, particularly in "management commitment and employee participation'' and "workplace analysis''. Most sites scored highly on "hazard prevention and control'' and "training and education''. For overall OSH programme scores, most sites scored in the 60-80% range at baseline, with four sites scoring below 60%, suggesting weak programmes. Intervention sites showed greater improvements than controls in the four programme elements and in overall programme scores, with significantly greater improvements in "management commitment and employee participation''. Conclusions: The OSH programme assessment method used is broadly applicable to manufacturing work settings, and baseline profiles suggest needs for improvement in OSH programmes in most such worksites. Despite a small sample size, results showed that sustained management focused intervention can result in improvement in these OSH programme measures. C1 Univ Melbourne, Sch Populat Hlth, Ctr Study Hlth & Soc, Melbourne, Vic 3010, Australia. Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Dept Biostat & Epidemiol, Amherst, MA 01003 USA. RP LaMontagne, AD (reprint author), Univ Melbourne, Sch Populat Hlth, Ctr Study Hlth & Soc, 207 Bouverie St,Level 4, Melbourne, Vic 3010, Australia. EM alamonta@unimelb.edu.au FU NCI NIH HHS [5 R01 CA68087]; NIOSH CDC HHS [5 R01 OH04012] NR 46 TC 43 Z9 46 U1 1 U2 8 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD AUG PY 2004 VL 61 IS 8 BP 651 EP 660 DI 10.1136/oem.2003.011718 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 838HN UT WOS:000222704200006 PM 15258270 ER PT J AU Agostini, M Silva, SD Zecchina, KG Coletta, RD Jorge, J Loda, M Graner, E AF Agostini, M Silva, SD Zecchina, KG Coletta, RD Jorge, J Loda, M Graner, E TI Fatty acid synthase is required for the proliferation of human oral squamous carcinoma cells SO ORAL ONCOLOGY LA English DT Article DE oral squmous cell carcinoma; fatty acid synthase; cerulenin; c-erb-B2; EGFR; oral cancer ID PROSTATE-CANCER CELLS; IMMUNOHISTOCHEMICAL EXPRESSION; OVARIAN NEOPLASMS; GENE-EXPRESSION; PROGRESSION; PATHWAY; BINDING; OVEREXPRESSION; INHIBITION; MECHANISM AB Fatty acid synthase (FAS) is the enzyme responsible for the endogenous synthesis of saturated tong-chain fatty acids from the precursors acetyl-CoA and malonyl-CoA. A growing body of evidence indicates that FAS is over expressed in several human cancers, such as prostate, breast, bladder, liver, lung, melanoma and oral squamous cell carcinoma (SCC). In the present study we used human oral SCC cell Lines (SCC-4, -9, -15 and -25) as a model to investigate the role of FAS in the pathogenesis of oral cancer. RT-PCR and western blot experiments demonstrated that FAS is differentially expressed by the four oral SCC cell lines, with the highest production in SCC-9 followed by SCC-25. FAS expression in SCC-4 and -15 was similarly tower than the other cell lines. Proliferation curves and immunocytochemistry for PCNA and Ki-67 demonstrated that SCC-25 has the highest proliferative potential. In addition, the specific inhibitor of FAS activity cerulenin was able to significantly reduce the proliferation of oral SCC cells. Expression of androgen receptor was tow in SCC-4, -9 and -15 and undetectable in SCC-25, whereas EGFR and c-erb-B2 were expressed in high amounts by the four cell lines. Immunocytochemical reactions showed that SCC-25 expresses higher levels of EGF compared to the other three cell lines. Finally, oral SCC cells exposed to nanomolar concentrations of exogenous EGF presented a reduction in the FAS protein levels concomitant with a decrease in their proliferation rates. Taken together, our results indicate that FAS is expressed in an apparently androgen-independent fashion in oral SCC cells and it is necessary for their proliferation. (C) 2004 Elsevier Ltd. All rights reserved. C1 UNICAMP, Sch Dent, Dept Oral Diag, BR-13414018 Piracicaba, SP, Brazil. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Graner, E (reprint author), UNICAMP, Sch Dent, Dept Oral Diag, Av Limeira 901,CP 52, BR-13414018 Piracicaba, SP, Brazil. EM egraner@fop.unicamp.br RI Agostini, Michelle/I-1275-2012; Graner, Edgard/K-4411-2012; Coletta, Ricardo/B-4909-2015 OI Coletta, Ricardo/0000-0001-5285-3046 NR 46 TC 29 Z9 29 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1368-8375 J9 ORAL ONCOL JI Oral Oncol. PD AUG PY 2004 VL 40 IS 7 BP 728 EP 735 DI 10.1016/j.oraloncology.2004.01.011 PG 8 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 839UI UT WOS:000222810000011 PM 15172643 ER PT J AU Whitcomb, DC Ermentrout, GB AF Whitcomb, DC Ermentrout, GB TI A mathematical model of the pancreatic duct cell generating high bicarbonate concentrations in pancreatic juice SO PANCREAS LA English DT Article; Proceedings Paper CT 34th Meeting of the European-Pancreas-Club CY JUN 20, 2002 CL Heidelberg, GERMANY SP European Pancreas Club DE bicarbonate; chloride; pancreatitis; pancreas; secretin; sodium bicarbonate cotransporter (NBC); cystic fibrosis transmembrane conductance regulator (CFTR); antiporter; anion channel ID TRANSMEMBRANE CONDUCTANCE REGULATOR; GUINEA-PIG PANCREAS; DEPENDENT HCO3-TRANSPORT; CYSTIC-FIBROSIS; INTERLOBULAR DUCTS; EPITHELIAL-CELLS; SECRETION; COTRANSPORTER; EXPRESSION; SELECTIVITY AB Objective: To develop a simple, physiologically based mathematical model of pancreatic duct cell secretion using experimentally derived parameters that generates pancreatic fluid bicarbonate concentrations of > 140 mM after CFTR activation. Methods: A new mathematical model was developed simulating a duct cell within a proximal pancreatic duct and included a sodium-2-bicarbonate cotransporter (NBC) and sodium-potassium pump (NaK pump) on a chloride-impermeable basolateral membrane, CFTR on the luminal membrane with 0.2 to 1 bicarbonate to chloride permeability ratio. Chloride-bicarbonate antiporters (Cl-/HCO3- AP) were added or subtracted from the basolateral (AP(b)) and luminal (AP(l)) membranes. The model was integrated over time using XPPAUT. Results: This model predicts robust, NaK pump - dependent bicarbonate secretion with opening of the CFTR, generates and maintains pancreatic fluid secretion with bicarbonate concentrations > 140 mM, and returns to basal levels with CFTR closure. Limiting CFTR permeability to bicarbonate, as seen in some CFTR mutations, markedly inhibited pancreatic bicarbonate and fluid secretion. Conclusions: A simple CFTR-dependent duct cell model can explain active, high-volume, high-concentration bicarbonate secretion in pancreatic juice that reproduces the experimental findings. This model may also provide insight into why CFTR mutations that predominantly affect bicarbonate permeability predispose to pancreatic dysfunction in humans. C1 Univ Pittsburgh, UPMC Presbyterian, Dept Med, Pittsburgh, PA 15213 USA. Univ Pittsburgh, UPMC Presbyterian, Dept Cell Biol & Physiol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, UPMC Presbyterian, Dept Human Genet, Pittsburgh, PA 15213 USA. VA Pittsburgh Hlth Care Syst, Dept Math, Pittsburgh, PA USA. RP Whitcomb, DC (reprint author), Univ Pittsburgh, UPMC Presbyterian, Dept Med, Mezzanine Level,C Wing,200 Lothrop St, Pittsburgh, PA 15213 USA. EM whitcomb@pitt.edu NR 26 TC 31 Z9 32 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD AUG PY 2004 VL 29 IS 2 BP E30 EP E40 DI 10.1097/00006676-200408000-00016 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 861ZO UT WOS:000224458000016 PM 15257112 ER PT J AU Fleming, M Pinkus, J Alexander, S Tam, C Loda, M Sallan, S Nichols, K Carpentieri, D Pinkus, G Rollins, B AF Fleming, M Pinkus, J Alexander, S Tam, C Loda, M Sallan, S Nichols, K Carpentieri, D Pinkus, G Rollins, B TI Coincident expression of the chemokine receptors CCR6 and CCR7 by histiocytes in histiocytoses SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Med Oncol,Dept Med, Boston, MA USA. NR 0 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 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2004 VL 43 IS 2 BP 199 EP 199 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 835JM UT WOS:000222479000042 ER PT J AU Nathan, DG AF Nathan, DG TI Acceptance of the 2003 John Howland Award: A journey in clinical research SO PEDIATRIC RESEARCH LA English DT Editorial Material ID BONE-MARROW TRANSPLANTATION; COLONY-STIMULATING FACTOR; SEVERE APLASTIC-ANEMIA; SICKLE-CELL-ANEMIA; CHRONIC GRANULOMATOUS-DISEASE; FETAL-HEMOGLOBIN PRODUCTION; PYRUVATE KINASE DEFICIENCY; ACUTE LYMPHOBLASTIC-LEUKEMIA; DIAMOND-BLACKFAN ANEMIA; HEMATOPOIETIC GROWTH-FACTORS C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Nathan, DG (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM david_nathan@dfci.harvard.edu NR 118 TC 0 Z9 0 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 AUG PY 2004 VL 56 IS 2 BP 169 EP 176 DI 10.1203/01/PDR.0000132816.06344.EA PG 8 WC Pediatrics SC Pediatrics GA 840FI UT WOS:000222842200003 PM 15181196 ER EF