FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Oliveria, SA Lapuerta, P McCarthy, BD L'Italien, GJ Berlowitz, DR Asch, SM AF Oliveria, SA Lapuerta, P McCarthy, BD L'Italien, GJ Berlowitz, DR Asch, SM TI Physician-related barriers to the effective management of uncontrolled hypertension SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID BLOOD-PRESSURE CONTROL; INNER-CITY; CARE; HEALTH; POPULATION; PATIENT; TRIAL; RECOMMENDATIONS; PRACTITIONERS; MEDICATIONS AB Background: Primary care physicians may not be aggressive enough with the management of hypertension. The purpose of this study was to identify barriers to primary care physicians' willingness to increase the intensity of treatment among patients with uncontrolled hypertension. Methods: Descriptive survey study. We sampled patient visits in a large midwestern health system to identify patients with uncontrolled hypertension. The treating primary care physicians were asked to complete a survey about the patient visit with a copy of the office notes attached to the survey (patient visits, n=270; response rate, 86%). Results: Pharmacologic therapy was initiated or changed at only 38% of visits, despite documented hypertension for at least 6 months before the patients' most recent visit. The most frequently cited reason for no initiation or change in therapy was related to the primary care physicians being satisfied with the blood pressure (BP) value (satisfactory BP response, 30%; satisfactory diastolic BP response, 16%; only borderline hypertension, 10%). At 93% of these visits, systolic BP values were 140 mm Hg or higher, which is above the cut point recommended by Sixth Report of the joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines, and 35% were 150 mm. Hg or higher. On average, physicians reported that 150 mm Hg was the lowest systolic BP at which they would recommend pharmacologic treatment to patients, compared with 91 mm Hg for diastolic BP. Conclusions: Our findings suggest that an important reason why physicians do not treat hypertension more aggressively is that they are willing to accept an elevated systolic BP in their patients. This has an important impact on public health because of the positive association between systolic BP and cardiovascular disease. C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Cornell Univ & Med, Weill Med Coll, Ithaca, NY 14853 USA. Bristol Myers Squibb Co, Pharmaceut Res Inst, Princeton, NJ USA. Henry Ford Hlth Syst, Detroit, MI USA. Ctr Hlth Qual Outcomes & Econ Res, Bedford, England. Bedford VA Hosp, Bedford, England. Boston Univ, Sch Med, Boston, MA USA. Univ Calif Los Angeles, W Los Angeles Vet Adm Med Ctr, Los Angeles, CA USA. RAND, Santa Monica, CA USA. RP Oliveria, SA (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave Box 99, New York, NY 10021 USA. NR 56 TC 310 Z9 318 U1 0 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD FEB 25 PY 2002 VL 162 IS 4 BP 413 EP 420 DI 10.1001/archinte.162.4.413 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 521RF UT WOS:000173854800006 PM 11863473 ER PT J AU Narlikar, GJ Fan, HY Kingston, RE AF Narlikar, GJ Fan, HY Kingston, RE TI Cooperation between complexes that regulate chromatin structure and transcription SO CELL LA English DT Review ID YEAST SWI/SNF COMPLEX; SWI-SNF COMPLEX; HISTONE ACETYLATION; REMODELING COMPLEX; NUCLEOSOMAL DNA; SACCHAROMYCES-CEREVISIAE; ORDERED RECRUITMENT; GENE-EXPRESSION; IN-VIVO; BINDING AB Chromatin structure creates barriers for each step in eukaryotic transcription. Here we discuss how the activities of two major classes of chromatin-modifying complexes, ATIP-dependent remodeling complexes and HAT or HDAC complexes, might be coordinated to create a DNA template that is accessible to the general transcription apparatus. 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. NR 88 TC 1060 Z9 1095 U1 12 U2 93 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD FEB 22 PY 2002 VL 108 IS 4 BP 475 EP 487 DI 10.1016/S0092-8674(02)00654-2 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 524XW UT WOS:000174039000006 PM 11909519 ER PT J AU Hung, AY Sheng, M AF Hung, AY Sheng, M TI PDZ domains: Structural modules for protein complex assembly SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID NITRIC-OXIDE SYNTHASE; POSTSYNAPTIC DENSITY PROTEINS; EXCHANGER REGULATORY FACTOR; NMDA RECEPTOR SUBUNITS; TYROSINE-PHOSPHATASE; INTERACTING PROTEIN; PHOTORECEPTOR CELLS; SIGNALING PROTEINS; CRYSTAL-STRUCTURES; GUANYLATE KINASES C1 MIT, Howard Hughes Med Inst, Dept Brain Cognit Sci, RIKEN Ctr Learning & Memory Neurosci Res Ctr, Cambridge, MA 02139 USA. MIT, Howard Hughes Med Inst, Dept Biol, RIKEN Ctr Learning & Memory Neurosci Res Ctr, Cambridge, MA 02139 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Sheng, M (reprint author), MIT, Howard Hughes Med Inst, Dept Brain Cognit Sci, RIKEN Ctr Learning & Memory Neurosci Res Ctr, Cambridge, MA 02139 USA. NR 76 TC 480 Z9 500 U1 4 U2 32 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 FEB 22 PY 2002 VL 277 IS 8 BP 5699 EP 5702 DI 10.1074/jbc.R100065200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 524AF UT WOS:000173989200001 PM 11741967 ER PT J AU Gilbert, GE Kaufman, RJ Arena, AA Miao, HZ Pipe, SW AF Gilbert, GE Kaufman, RJ Arena, AA Miao, HZ Pipe, SW TI Four hydrophobic amino acids of the factor VIIIC2 domain are constituents of both the membrane-binding and von Willebrand factor-binding motifs SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID COAGULATION-FACTOR-V; PHOSPHATIDYL-L-SERINE; C-TYPE DOMAIN; PHOSPHOLIPID-VESICLES; VONWILLEBRAND-FACTOR; BLOOD-COAGULATION; MAMMALIAN-CELLS; MOLECULAR-BASIS; FACTORS-IXA; FACTOR-X AB Factor VIII binds to phospholipid membranes and to von Willebrand factor (vWf) via its second C domain, which has lectin homology. The crystal structure of the C2 domain has prompted a model in which membrane binding is mediated by two hydrophobic spikes, each composed of a pair of residues displayed on a beta-hairpin turn, and also by net positive charge and specific interactions with phospho-L-serine. To test this model, we prepared 16 factor VIII mutants in which single or multiple amino acids were changed to alanine. Mutants at Arg(2215), Arg(2220), Lys(2227), Lys(2249), Gln(2213), Asn(2217), and Phe(2196)/Thr(2197) had specific activities that were >70% of the wild type. Mutants at Arg(2209), Lys(2227), Trp(2313), and Arg(2320) were degraded within the cell. Hydrophobic spike mutants at Met(2199)/Phe(2200), Leu(2251)/Leu(2252), and Met(2199)/Phe(2200)/Leu(2251)/Leu(22520) (4-Ala) exhibited 43, 59, and 91% reduction in specific activity in the activated partial thromboplastin time assay. In a phospholipid-limiting factor Xa activation assay, these mutants had a 65, 85, and 96% reduction in specific activity. Equilibrium binding of fluorescent, sonicated phospholipid vesicles to mutants immobilized on Superose beads was measured by flow cytometry. The affinities for phospholipid were reduced similar to20-, 30-, and >35-fold for 2199/2200, 2251/2252, and 4-Ala, respectively. A dimeric form of mature vWf bound to immobilized factor VIII and the same mutants, but the affinities of the mutants were reduced similar to5-, 10-, and >20-fold, respectively. In a competition, solution phase enzyme-linked immunosorbent assay, plasma vWf bound factor VIII and the same mutants with the affinities for the mutants reduced >5-, >5-, and >50-fold, respectively. We conclude that the two hydrophobic spikes are constituents of both the phospholipid-binding and vWf-binding motifs. In plasma, vWf apparently binds the inherently sticky membrane-binding motif, preventing nonspecific interactions. C1 Brigham & Womens Hosp, Vet Affairs Boston Healthcare Syst, W Roxbury, MA 02132 USA. Harvard Univ, Sch Med, W Roxbury, MA 02132 USA. Univ Michigan, Med Ctr, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA. RP Gilbert, GE (reprint author), VA Boston Healthcare Syst, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. FU NHLBI NIH HHS [P01 HL42443, R01 HL52173] NR 47 TC 78 Z9 79 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 FEB 22 PY 2002 VL 277 IS 8 BP 6374 EP 6381 DI 10.1074/jbc.M104732200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 524AF UT WOS:000173989200090 PM 11698391 ER PT J AU McLaughlin, M Hale, R Ellston, D Gaudet, S Lue, RA Viel, A AF McLaughlin, M Hale, R Ellston, D Gaudet, S Lue, RA Viel, A TI The distribution and function of alternatively spliced insertions in hD1g SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR-SUPPRESSOR PROTEIN; HUMAN HOMOLOG; DISCS LARGE; INTRAMOLECULAR INTERACTION; TYROSINE KINASE; MEMBRANE; IDENTIFICATION; CHANNEL; BINDING; DOMAINS AB hDlg is the human homolog of the Drosophila Discs. large tumor suppressor. As a member of the MAGUK (membrane-associated guanylate kinase) family of scaffolding proteins, hDlg is composed of three PDZ (PSD-95, Dlg, and ZO-1) repeats, an SH3 (Src homology 3) motif, and a GUK (guanylate kinase-ne) domain. Additionally, hDlg contains two regions of alternative splicing. Here we identify a novel insertion, I1B, located N-terminal to the PDZ repeats. We further analyze the tissue-specific combinations of insertions and correlate those results with the distribution of protein isoforms. We also identify the functions of the two alternatively spliced regions. The N-terininal alternatively spliced region is capable of binding several SH3 domains and also moderates the level of protein oligomerization. Insertions in the second region are responsible for determining the localization of hDlg, with insertion I3 targeting the protein to the membrane regions of cell-cell contact and insertion 12 targeting the protein to the nucleus. C1 Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. RP Viel, A (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, 13th St,Bldg 149, Charlestown, MA 02129 USA. FU NIGMS NIH HHS [GM57314] NR 23 TC 58 Z9 59 U1 0 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 FEB 22 PY 2002 VL 277 IS 8 BP 6406 EP 6412 DI 10.1074/jbc.M108724200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 524AF UT WOS:000173989200094 PM 11723125 ER PT J AU Brummelkamp, TR Kortlever, RM Lingbeek, M Trettel, F MacDonald, ME van Lohuizen, M Bernards, R AF Brummelkamp, TR Kortlever, RM Lingbeek, M Trettel, F MacDonald, ME van Lohuizen, M Bernards, R TI TBX-3, the gene mutated in ulnar-mammary syndrome, is a negative regulator of p19(ARF) and inhibits senescence SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR-SUPPRESSOR P53; TRANSCRIPTION FACTOR; STABILIZES P53; ONCOGENIC RAS; G(1) CONTROL; INK4A LOCUS; CELL; IMMORTALIZATION; APOPTOSIS; MDM2 AB Prolonged culturing of rodent cells in vitro activates p19(ARF) (named p14(ARF) in man), resulting in a p53-dependent proliferation arrest known as senescence. The p19(ARF)-Mdm2-p53 pathway also serves to protect primary cells against oncogenic transformation. We have used a genetic screen in mouse neuronal cells, conditionally immortalized by a temperature-sensitive mutant of SV40 large T antigen, to identify genes that allow bypass of senescence. Using retroviral cDNA expression libraries, we have identified TBX-3 as a potent inhibitor of senescence. TBX-3 is a T-box gene, which is found mutated in the human developmental disorder Ulnar-Mammary Syndrome. We have shown that TBX-3 potently represses expression of both mouse p19(ARF) and human P14(ARF). We have also shown here that point mutants of TBX-3, which are found in UInar-Mammary Syndrome, have lost the ability to inhibit senescence and fail to repress mouse p19(ARF) and human p14(ARF) expression. These data suggest that the hypoproliferative features of this genetic disorder may be caused, at least in part, by deregulated expression of p14(ARF). C1 Netherlands Canc Inst, Div Mol Carcinogenesis, NL-1066 CX Amsterdam, Netherlands. Netherlands Canc Inst, Div Mol Genet, NL-1066 CX Amsterdam, Netherlands. Netherlands Canc Inst, Ctr Biomed Genet, NL-1066 CX Amsterdam, Netherlands. Massachusetts Gen Hosp, Mol Neurogenet Unit, Charlestown, MA 02129 USA. RP Bernards, R (reprint author), Netherlands Canc Inst, Div Mol Carcinogenesis, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. OI trettel, flavia/0000-0002-7983-2955; Bernards, Rene/0000-0001-8677-3423 FU NINDS NIH HHS [NS32765] NR 36 TC 110 Z9 117 U1 0 U2 1 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 FEB 22 PY 2002 VL 277 IS 8 BP 6567 EP 6572 DI 10.1074/jbc.M110492200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 524AF UT WOS:000173989200115 PM 11748239 ER PT J AU Luo, Y Leszyk, J Li, B Li, ZX Gergely, J Tao, T AF Luo, Y Leszyk, J Li, B Li, ZX Gergely, J Tao, T TI Troponin-I interacts with the Met47 region of skeletal muscle actin. Implications for the mechanism of thin filament regulation by calcium SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE striated muscle; troponin; actin; photocrosslinking; calcium regulation ID CONFORMATIONAL TRANSITION; MYOSIN SUBFRAGMENT-1; INHIBITORY REGION; BINDING-SITE; TROPOMYOSIN; CONTRACTION; MUTANTS; COMPLEX; MODEL; CA2+ AB Striated muscles are regulated by Ca2+ via the thin filament proteins troponin (Tn) and tropomyosin (Tm). In the absence of Ca2+, contraction is inhibited, whereas myosin-actin interaction and contraction can take place in its presence. Although it is well established that the interaction of troponin-I (TnI), the inhibitory subunit of Tn, with actin is required for the inhibition process and that there are two separate actin-binding regions in TnI that interact with actin, the molecular mechanism of this inhibition process is still not clear. Using TnI mutants with photocrosslinking probes attached to genetically engineered cysteine residues in each of the two actin-binding regions, we show that both regions are close to Met47 of actin in its outer domain. It has been proposed that the Ca2+-induced activation of contraction involves the movement of Tm from the outer to the inner domain of the actin filament. On the basis of our results presented here, we propose that the position of Tm at the outer domain of actin in the Ca2+-free state is stabilized by the presence of TnI over actin's outer domain via mutual interactions of all three components. In the presence of Ca2+, TnI's actin-binding regions dissociate from actin allowing Tm to move toward actin's inner domain. (C) 2002 Elsevier Science Ltd. C1 Boston Biomed Res Inst, Muscle Res Grp, Watertown, MA 02472 USA. Univ Massachusetts, Sch Med, Dept Biochem, Shrewsbury, MA 01545 USA. Massachusetts Gen Hosp, Neurol Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. Tufts Univ, Sch Med, Dept Biochem, Boston, MA 02111 USA. RP Luo, Y (reprint author), Boston Biomed Res Inst, Muscle Res Grp, Watertown, MA 02472 USA. FU NIAMS NIH HHS [AR21673] NR 32 TC 22 Z9 22 U1 1 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD FEB 22 PY 2002 VL 316 IS 3 BP 429 EP 434 DI 10.1006/jmbi.2001.5358 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 527YW UT WOS:000174216400003 PM 11866508 ER PT J AU Pascual, M Theruvath, T Kawai, T Tolkoff-Rubin, N Cosimi, AB AF Pascual, M Theruvath, T Kawai, T Tolkoff-Rubin, N Cosimi, AB TI Medical progress - Strategies to improve long-term outcomes after renal transplantation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID CHRONIC ALLOGRAFT NEPHROPATHY; DELAYED GRAFT FUNCTION; TRIAL COMPARING TACROLIMUS; DONOR BONE-MARROW; MYCOPHENOLATE-MOFETIL; ACUTE REJECTION; KIDNEY-TRANSPLANTATION; STEROID WITHDRAWAL; RANDOMIZED TRIAL; DOUBLE-BLIND C1 Massachusetts Gen Hosp, Renal Unit, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Transplantat Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Pascual, M (reprint author), Massachusetts Gen Hosp, Renal Unit, Dept Med, Box MZ 70, Boston, MA 02114 USA. FU NHLBI NIH HHS [P0I-HL 18646]; NIAID NIH HHS [R01 AI037692, R01 AI037692-09, R21 AI037692, R21 AI037692-06]; PHS HHS [R01 A 137692-05] NR 101 TC 533 Z9 586 U1 1 U2 10 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 FEB 21 PY 2002 VL 346 IS 8 BP 580 EP 590 DI 10.1056/NEJMra011295 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 522ZK UT WOS:000173926700007 PM 11856798 ER PT J AU Chauhan, D Auclair, D Robinson, EK Hideshima, T Li, GL Podar, K Gupta, D Richardson, P Schlossman, RL Krett, N Chen, LB Munshi, NC Anderson, KC AF Chauhan, D Auclair, D Robinson, EK Hideshima, T Li, GL Podar, K Gupta, D Richardson, P Schlossman, RL Krett, N Chen, LB Munshi, NC Anderson, KC TI Identification of genes regulated by Dexamethasone in multiple myeloma cells using oligonucleotide arrays SO ONCOGENE LA English DT Article DE multiple myeloma; dexamethasone; interleukin-6 ID NF-KAPPA-B; MARROW STROMAL CELLS; TRANSCRIPTION FACTORS; INDUCED APOPTOSIS; GROWTH-FACTORS; IN-VITRO; EXPRESSION; INTERLEUKIN-6; RECEPTOR; INDUCTION AB Our previous studies have characterized Dexamethasone (Dex)-induced apoptotic signaling pathways in multiple myeloma (MM) cells; however, related transcriptional events are not fully defined. In the present study, gene expression profiles of Dex-treated MM cells were determined using oligonucleotide arrays. Dex triggers early transient induction of many genes involved in cell defense/repair-machinery. This is followed by induction of genes known to mediate cell death and repression of growth/survival-related genes. The molecular and genetic alterations associated with Dex resistance in MM cells are also unknown. We compared the gene expression profiles of Dex-sensitive and Dex-resistant MM cells and identified a number of genes which may confer Dex-resistance. Finally, gene profiling of freshly isolated MM patient cells validates our in vitro MM cell line data, confirming an in vivo relevance of these studies. Collectively, these findings provide insights into the basic mechanisms of Dex activity against MM, as well as mechanisms of Dex-resistance in MM cells. These studies may therefore allow improved therapeutic uses of Dex, based upon targeting genes that regulate MM cell growth and survival. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol Jerome Lipper Multiple, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Northwestern Univ, Med Sch, Robert H Lurie Canc Ctr, Chicago, IL USA. RP Anderson, KC (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol Jerome Lipper Multiple, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA 78373] NR 67 TC 110 Z9 110 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 21 PY 2002 VL 21 IS 9 BP 1346 EP 1358 DI 10.1038/sj/onc/1205205 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 521VA UT WOS:000173861000005 PM 11857078 ER PT J AU Ortiz-Vega, S Khokhlatchev, A Nedwidek, M Zhang, XF Dammann, R Pfeifer, GP Avruch, J AF Ortiz-Vega, S Khokhlatchev, A Nedwidek, M Zhang, XF Dammann, R Pfeifer, GP Avruch, J TI The putative tumor suppressor RASSF1A homodimerizes and heterodimerizes with the Ras-GTP binding protein Nore1 SO ONCOGENE LA English DT Article DE Ras; Nore1; RASSF1; tumor suppressor; apoptosis ID IDENTIFICATION; EFFECTOR; M-RAS/R-RAS3; PATHWAY; DOMAINS; FAMILY AB Nore and RASSF1A are noncatalytic proteins that share 50% identity over their carboxyterminal 300 AA, a segment that encompasses a putative Ras-Rap association (RA) domain. RASSF1 is expressed as several splice variants, each of which contain an RA domain, however the 340 AA RASSF1A, but not the shorter RASSF1C variant, is a putative tumor suppressor. Nore binds to Ras and several Ras-like GTPases in a GTP dependent fashion however neither RASSF1 (A or C) or the C. elegans Nore/RASSF1 homolog, T24F1.3 exhibit any interaction with Ras or six other Ras-like GTPases in a yeast two-hybrid expression assay. A low recovery of RASSF1A (but not RASSF1C) in association with RasG12V is observed however on transient expression in COS cells. Nore and RASSF1A can each efficiently homodimerize and heterodimerize with each other through their nonhomologous aminoterminal segments. Recombinant RASSF1C exhibits a much weaker ability to homodimerize or heterodimerize; thus the binding of RASSF1C to Nore is very much less than the binding of RASSF1A to Nore. The association of RASSF1A with RasG12V in COS cells appears to reflect the hetero-dimerization of RASSF1A with Nore, inasmuch the recovery of RASSF1A with RasG12V is increased by concurrent expression of full length Nore, and abolished by expression of Nore deleted of its RA domain. The preferential ability of RASSF1A to heterodimerize with Nore and thereby associate with Ras-like GTPases may be relevant to its putative tumor suppressor function. C1 Massachusetts Gen Hosp, Dept Mol Biol, Diabet Res Lab, Boston, MA 02114 USA. Massachusetts Gen Hosp, Diabetes Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Med Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. RP Avruch, J (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Diabet Res Lab, 50 Blossom St, Boston, MA 02114 USA. FU NIDDK NIH HHS [T32DK07028] NR 38 TC 162 Z9 174 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 21 PY 2002 VL 21 IS 9 BP 1381 EP 1390 DI 10.1038/sj/onc/1205192 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 521VA UT WOS:000173861000008 PM 11857081 ER PT J AU Sattler, M Pride, YB Quinnan, LR Verma, S Malouf, NA Husson, H Salgia, R Lipkowitz, S Griffin, JD AF Sattler, M Pride, YB Quinnan, LR Verma, S Malouf, NA Husson, H Salgia, R Lipkowitz, S Griffin, JD TI Differential expression and signaling of CBL and CBL-B in BCR/ABL transformed cells SO ONCOGENE LA English DT Article DE CBL-B; BCR/ABL; gene expression; cell migration; signal transduction ID GROWTH-FACTOR RECEPTOR; ADAPTER PROTEINS CRKL; C-CBL; TYROSINE PHOSPHORYLATION; PHOSPHATIDYLINOSITOL 3-KINASE; PROTOONCOGENE PRODUCT; HEMATOPOIETIC-CELLS; NEGATIVE REGULATOR; ANTIGEN RECEPTOR; BINDING-PROTEIN AB CBL and the related CBL-B protein are two members of a family of RING finger type ubiquitin E3 ligases that are believed to function as negative regulators of signal transduction in hematopoietic and immune cells. In mice, expression of v-Cbl causes lymphomas, and targeted disruption of either the CBL gene or the CBL-B gene can result in a lymphoproliferative disorder or hypersensitivity of lymphocytes. CBL is one of the most prominent targets of the BCR/ABL tyrosine kinase oncogene. We compared the role of CBL and CBL-B in signal transduction of BCR/ABL using pairs of cell lines before and after expression of BCR/ABL. In contrast to CBL, BCR/ABL was found to rapidly downregulate the expression of CBL-B protein. The decrease in CBL-B protein induced by BCR/ABL was associated with down-regulation of CBL-B mRNA. Downregulation and tyrosine phosphorylation of CBL-B required BCR/ABL kinase activity. However, despite their known similarities in structure and function, we found CBL and CBL-B proteins to be involved in distinct signaling complexes. CBL was predominantly in a complex with phosphatidylinositol 3'-kinase and CRKL, while CBL-B was not associated with any significant phosphatidylinositol 3'-kinase activity. A major CBL-B associated protein was identified as mono-ubiquitinated Vav, a nucleotide exchange factor for Rac1. These results demonstrate that BCR/ABL signals differentially through CBL and CBL-B, with downregulation of the CBL-B protein potentially contributing to BCR/ABL-mediated transformation. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Natl Naval Med Res Inst, Med Branch, Genet Dept, NCI, Bethesda, MD 20889 USA. RP Sattler, M (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. EM martin_sattler@dfci.harvard.edu FU NCI NIH HHS [CA78348]; NIDDK NIH HHS [DK50654] NR 49 TC 22 Z9 23 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 21 PY 2002 VL 21 IS 9 BP 1423 EP 1433 DI 10.1038/sj/onc/1205202 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 521VA UT WOS:000173861000012 PM 11857085 ER PT J AU Jang, IK Bouma, BE Kang, DH Park, SJ Park, SW Seung, KB Choi, KB Shishkov, M Schlendorf, K Pomerantsev, E Houser, SL Aretz, HT Tearney, GJ AF Jang, IK Bouma, BE Kang, DH Park, SJ Park, SW Seung, KB Choi, KB Shishkov, M Schlendorf, K Pomerantsev, E Houser, SL Aretz, HT Tearney, GJ TI Visualization of coronary atherosclerotic plaques in patients using optical coherence tomography: Comparison with intravascular ultrasound SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID IN-VIVO; CATHETER; ARTERIES; SPECTROSCOPY; THROMBOSIS; RUPTURE AB OBJECTIVES The aim of this study was to evaluate the feasibility and the ability of intravascular optical coherence tomography (OCT) to visualize the components of coronary plaques in living patients. BACKGROUND Disruption of a vulnerable coronary plaque with subsequent thrombosis is currently recognized as the primary mechanism for acute myocardial infarction. Although such plaques are considered to have a thin fibrous cap overlying a lipid pool, imaging modalities in current clinical practice do not have sufficient resolution to identify thin (<65 μm) fibrous caps. Optical coherence tomography is a new imaging modality capable of obtaining cross-sectional images of coronary vessels at a resolution of approximately 10 μm. METHODS The OCT images and corresponding histology of 42 coronary plaques were compared to establish OCT criteria for different types of plaques. Atherosclerotic lesions with mild to moderate stenosis were identified on angiograms in 10 patients undergoing cardiac catheterization. Optical coherence tomography and intravascular ultrasound (IVUS) images of these sites were obtained in all patients without complication. RESULTS Comparison between OCT and histology demonstrated that lipid-rich plaques and fibrous plaques have distinct OCT characteristics. A total of 17 IVUS and OCT image pairs obtained from patients were compared. Axial resolution measured 13 &PLUSMN; 3 μm with OCT and 98 &PLUSMN; 19 μm with IVUS. All fibrous plaques, macrocalcifications and echolucent regions identified by IVUS were visualized in corresponding OCT images. Intimal hyperplasia and echolucent regions, which may correspond to lipid pools, were identified more frequently by OCT than by IVUS. CONCLUSIONS Intracoronary OCT appears to be feasible and safe. Optical coherence tomography identified most architectural features detected by IVUS and may provide additional detailed structural information. © 2002 by the American College of Cardiology. C1 Massachusetts Gen Hosp, Div Cardiol, 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. Kangnam St Marys Hosp, Dept Cardiol, Seoul, South Korea. Catholic Univ Korea, Seoul, South Korea. Asan Med Ctr, Dept Cardiol, Seoul, South Korea. Univ Ulsan, Coll Med, Seoul, South Korea. RP Jang, IK (reprint author), Massachusetts Gen Hosp, Div Cardiol, Bulfinch 105,55 Fruit St, Boston, MA 02114 USA. NR 23 TC 514 Z9 542 U1 2 U2 30 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 FEB 20 PY 2002 VL 39 IS 4 BP 604 EP 609 AR PII S0735-1097(01)01799-5 DI 10.1016/S0735-1097(01)01799-5 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 522PB UT WOS:000173904800008 PM 11849858 ER PT J AU Hunziker, PR Imsand, C Keller, D Hess, N Barbosa, V Nietlispach, F Liel-Cohen, N Weyman, AE Pfisterer, M Buser, P AF Hunziker, PR Imsand, C Keller, D Hess, N Barbosa, V Nietlispach, F Liel-Cohen, N Weyman, AE Pfisterer, M Buser, P TI Bedside quantification of atherosclerosis severity for cardiovascular risk stratification: A prospective cohort study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID NONINVASIVE DOPPLER ULTRASOUND; STAGE RENAL-DISEASE; AORTIC DISTENSIBILITY; ELASTIC PROPERTIES; MODEL; REPRODUCIBILITY; STIFFNESS; INVITRO AB OBJECTIVES We sought to assess the ability of a new noninvasive method to quantify atherosclerosis severity and to examine its power to predict cardiovascular events. BACKGROUND Drug prevention of cardiovascular events is effective but costly, leading to a debate about who should receive this treatment. Patient selection is often based on surrogate markers, but quantification of atherosclerosis severity is desirable. METHODS Atherosclerosis severity was quantified by determination of specific aortic wall elastance in transthoracic echocardiography, applying the biomechanics of pulse wave propagation. After validating the method in 52 patients by measuring aortic plaque burden in transesophageal echo directly, another 336 patients were prospectively studied by monitoring atherosclerotic events at one year and comparing the results with conventional risk stratification. RESULTS Specific aortic elastance was well correlated with plaque burden (p < 0.0001) and largely independent of confounding variables. Specific aortic elastance predicted the primary end point of "atherosclerotic death, myocardial infarction or stroke" at one year (p < 0.0002). Event rate at one year in the lowest specific elastance tertile was 1.8% (CI 0.0% to 4.3%), in the middle tertile 5.4% (CI 1.1% to 9.7%) and in the highest tertile 12.7% (CI 6.3% to 19%). Secondary end points supported these findings. Stepwise multivariate analysis identified specific aortic elastance, prior atherosclerotic events and left ventricular ejection fraction as independent risk predictors. Specific elastance was of incremental value to clinically identified variables. CONCLUSIONS Bedside measurement of specific aortic elastance allows assessment of atherosclerosis severity. It predicts the risk for future atherosclerotic events beyond conventional risk factors, promising better targeting of pharmacologic prevention and improved cost effectiveness. (C) 2002 by the American College of Cardiology. C1 Univ Hosp, Med Intens Care Unit, Basel, Switzerland. Univ Hosp, Div Cardiol, Basel, Switzerland. Massachusetts Gen Hosp, Dept Med, Cardiac Unit, Boston, MA USA. RP Hunziker, PR (reprint author), Univ Hosp, Med Intens Care Unit, Basel, Switzerland. NR 20 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 20 PY 2002 VL 39 IS 4 BP 702 EP 709 AR PII S0735-1097(01)01780-6 DI 10.1016/S0735-1097(01)01780-6 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 522PB UT WOS:000173904800022 PM 11849872 ER PT J AU Green, RJ Metlay, JP Propert, K Catalano, PJ Macdonald, JS Mayer, RJ Haller, DG AF Green, RJ Metlay, JP Propert, K Catalano, PJ Macdonald, JS Mayer, RJ Haller, DG TI Surveillance for second primary colorectal cancer after adjuvant chemotherapy: An analysis of intergroup 0089 SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID PREVENTION; POLYPECTOMY; GUIDELINES; COLON AB Background: The incidence of second primary colorectal cancer in patients with a history of colon cancer, compared with patients with a history of adenomatous polyps, is unknown. It is unclear whether guidelines for colonoscopy screening in patients with polyps are appropriate for patients with previous colon cancer. Objective: To determine the incidence of second primary colorectal cancer after treatment for localized colon cancer and to compare this incidence with that of first primary colorectal cancer in both the general population and high-risk patients. Design: Historical cohort study. Setting: An international, multi-institutional trial of adjuvant 5-fluorouracil-based chemotherapy for localized colon cancer. Patients: 3278 patients with resected stage II and stage III colon cancer. Measurements: Occurrence of endoscopic or radiologic colon surveillance and incidence of second primary colorectal cancer. Results: Forty-two cases of second primary invasive colon cancer were found over 15 345 person-years of follow-up, yielding an incidence rate of 274 per 100 000 person-years (95% Cl, 196 to 369 per 100 000 person-years) and a cumulative incidence of 1.5% (CI, 1.1% to 2.0%) at 5 years. This rate was compared with rates of first colon cancer in two reference groups: the general population and patients who had undergone frequent colonoscopy and polypectomy because of a history of adenomatous polyps; standardized incidence ratios were 1.6 (Cl, 1.2 to 2.2) and 6.8 (Cl, 2.7 to 22.0), respectively. Conclusion: The incidence of second primary colorectal cancer remains high despite intensive surveillance strategies. C1 Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. St Vincents Comprehens Canc Ctr, New York, NY USA. RP Haller, DG (reprint author), 16 Penn Tower,3400 Spruce St, Philadelphia, PA 19104 USA. FU NCI NIH HHS [T32 CA-09679, CA66636, CA23318, CA32102, P30-CA-16520-25, 5U10 CA-32291-19, CA15488, CA21115, CA31946] NR 17 TC 93 Z9 95 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD FEB 19 PY 2002 VL 136 IS 4 BP 261 EP 269 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 523FQ UT WOS:000173943700001 PM 11848723 ER PT J AU Li, L Messas, E Batista, EL Levine, RA Amar, S AF Li, L Messas, E Batista, EL Levine, RA Amar, S TI Porphyromonas gingivalis infection accelerates the progression of atherosclerosis in a heterozygous apolipoprotein E-deficient murine model SO CIRCULATION LA English DT Article DE atherosclerosis; infection; cardiovascular diseases; Porphyromonas gingivalis ID CORONARY HEART-DISEASE; CHLAMYDIA-PNEUMONIAE; PERIODONTAL-DISEASE; ENDOTHELIAL-CELLS; RISK-FACTORS; MICE; ARTERY; INFLAMMATION; PROTEIN; SERUM AB Background-Current epidemiological data suggest that dental infections affecting tooth-supporting tissues (periodontitis) can disseminate into the systemic circulation and thereby contribute to atherosclerosis progression. To test this hypothesis, we investigated the effect of repeated systemic inoculations with Porphyromonas gingivalis (Pg), a putative periodontal pathogen, on the progression of atherosclerosis in heterozygous apolipoprotein E-deficient (ApoE(+/-)) mice. Methods and Results-Ten-week-old, male ApoE(+/-) mice fed either a high-fat diet or regular chow were inoculated intravenously with live Pg (10(7) CFU) or vehicle once per week for 10, 14, or 24 consecutive weeks. Histomorphometry of plaque cross-sectional area in the proximal aortas, en face measurement of plaque area over the aortic trees, Pg 16S ribosomal DNA amplification with polymerase chain reaction, ELISA for systemic proinflammatory mediators, and immunolocalization of macrophages in the proximal aorta were,performed. Atherosclerotic lesions of the proximal aortas and aortic trees were more advanced in Pg-challenged animals than in vehicle control animals and occurred earlier (at 10 weeks) when no lesions were apparent in control animals. At 24 weeks after inoculation, proximal aortic lesion size quantified by histomorphometry was 9-fold greater in chow-fed mice inoculated with Pg than in noninoculated mice (P<0.001) and was 2-fold greater in Pg-inoculated versus noninoculated high-fat diet-fed mice (P<0.001); all atherosclerotic lesions were macrophage-rich. Pg ribosomal DNA was found in the aortas, livers, and hearts 24 weeks after inoculation. Conclusions-These results provide evidence that long-term systemic challenge with Porphyromonas gingivalis, an oral pathogen, can accelerate atherogenic plaque progression. C1 Boston Univ, Dept Periodontol & Oral Biol, Sch Dent Med, Boston, MA 02118 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Amar, S (reprint author), Boston Univ, Dept Periodontol & Oral Biol, Sch Dent Med, 100 E Newton St,G05, Boston, MA 02118 USA. OI Amar, Salomon/0000-0002-0017-5930; Batista Junior, Eraldo/0000-0003-0429-3560 FU NIDCR NIH HHS [DE 12482] NR 40 TC 265 Z9 284 U1 2 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 19 PY 2002 VL 105 IS 7 BP 861 EP 867 DI 10.1161/hc0702.104178 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 523UL UT WOS:000173974800017 PM 11854128 ER PT J AU Khokhlatchev, A Rabizadeh, S Xavier, R Nedwidek, M Chen, T Zhang, XF Seed, B Avruch, J AF Khokhlatchev, A Rabizadeh, S Xavier, R Nedwidek, M Chen, T Zhang, XF Seed, B Avruch, J TI Identification of a novel Ras-regulated proapoptotic pathway SO CURRENT BIOLOGY LA English DT Article ID APOPTOTIC CELL-DEATH; PROTEIN-KINASE; ONCOGENIC RAS; ACTIVATE RAF-1; GROWTH ARREST; TRANSFORMATION; P53; EFFECTOR; STIMULATION; CASPASE AB Background: The Ras-GTPase controls cell fate decisions through the binding of an array of effector molecules, such as Raf and PI 3-kinase, in a GTP-dependent manner. NORE1, a noncatalytic polypeptide, binds specifically to Ras-GTP and to several other Ras-like GTPases. NORE is homologous to the putative tumor suppressor RASSF1 and to the Caenorhabditis elegans polypeptide T24F1.3. Results: We find that all three NORE-related polypeptides bind selectively to the proapoptotic protein kinase MST1, a member of the Group 11 GC kinases. Endogenous NORE and MST1 occur in a constitutive complex in vivo that associates with endogenous Ras after serum stimulation. Targeting recombinant MST1 to the membrane, either through NORE or myristoylation, augments the apoptotic efficacy of MST1. Overexpression of constitutively active Ki-RasG12V promotes apoptosis in a variety of cell lines; Ha-RasG12V is a much less potent proapoptotic agent; however, a Ha-RasG12V effector loop mutant (E37G) that binds NORE, but not Raf or PI 3-kinase, exhibits proapoptotic efficacy approaching that of Ki-RasG12V. The apoptotic action of both Ki-RasG12V and Ha-RasG12V, E37G is suppressed by overexpression of the MST1 carboxy-terminal noncatalytic segment or by the NORE segment that binds MST1. Conclusions: MST1 is a phylogenetically conserved partner of the NORE/RASSF polypeptide family, and the NORE-MST1 complex is a novel Ras effector unit that mediates the apoptotic effect of Ki-RasG12V. C1 Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Med Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Biol Mol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Avruch, J (reprint author), Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. FU NIAID NIH HHS [AI 01472]; NIGMS NIH HHS [GM51281] NR 56 TC 268 Z9 286 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD FEB 19 PY 2002 VL 12 IS 4 BP 253 EP 265 AR PII S0960-9822(02)00683-8 DI 10.1016/S0960-9822(02)00683-8 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 523RL UT WOS:000173969100014 PM 11864565 ER PT J AU Shibata, T Takeshima, F Chen, F Alt, FW Snapper, SB AF Shibata, T Takeshima, F Chen, F Alt, FW Snapper, SB TI Cdc42 facilitates invasion but not the actin-based motility of Shigella SO CURRENT BIOLOGY LA English DT Article ID ALDRICH-SYNDROME PROTEIN; N-WASP; ARP2/3 COMPLEX; FLEXNERI; ICSA; ACTIVATION; CELLS; IDENTIFICATION; POLYMERIZATION; SUFFICIENT AB The enteric pathogen Shigella utilizes host-encoded proteins to invade the gastrointestinal tract. Efficient invasion of host cells requires the stimulation of Rho-family GTPases and cytoskeletal alterations by Shigella-encoded IpaC [1]. Following invasion and lysis of the phagosome, Shigella exploits the host's actin-based polymerization machinery to assemble an actin tail that serves as the propulsive force required for spreading within and between cells (2,3]. The Shigella surface protein IcsA stimulates actin-tail formation by recruiting host-encoded N-WASP to drive Arp2/3-mediated actin assembly [4-7]. N-WASP is absolutely required for Shigella motility, but not for Shigella invasion [4, 6]. Although Rho-family GTPases have been implicated in both the invasion and motility of Shigella, the role of Cdc42, an N-WASP activator, in this process has been controversial [8, 9]. In these studies, we have examined the role of Cdc42 in Shigella invasion and actin-based motility using Cdc42-deficient cells. We demonstrate that Cdc42 is required for efficient Shigella invasion but reveal a minor Cdc42-independent pathway that can permit Shigella invasion. However, the actin-based motility of Shigella, as well as vaccinia, proceeds unperturbed in the absence of Cdc42. These data further support the involvement of distinct host-encoded proteins in the steps regulating invasion and intercellular spread of Shigella. C1 Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Snapper, SB (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, 55 Blossom St, Boston, MA 02114 USA. NR 24 TC 30 Z9 32 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD FEB 19 PY 2002 VL 12 IS 4 BP 341 EP 345 AR PII S0960-9822(02)00689-9 DI 10.1016/S0960-9822(02)00689-9 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 523RL UT WOS:000173969100026 PM 11864577 ER PT J AU Almind, K Delahaye, L Hansen, T Van Obberghen, E Pedersen, O Kahn, CR AF Almind, K Delahaye, L Hansen, T Van Obberghen, E Pedersen, O Kahn, CR TI Characterization of the Met3261Ie variant of phosphatidylinositol 3-kinase p85 alpha SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RECEPTOR SUBSTRATE-1 PHOSPHORYLATION; REGULATORY SUBUNIT; INSULIN-RECEPTOR; SKELETAL-MUSCLE; PHOSPHOINOSITIDE 3-KINASE; BROWN ADIPOCYTES; GLUCOSE-UPTAKE; STIMULATION; POLYMORPHISM; EXPRESSION AB Phosphatidylinositol 3-kinase is a key step in the metabolic actions of insulin. Two amino acid substitutions have been identified in the gene for the regulatory subunit of human p85alpha, Met-326Ile, and Asn-330Asp, and the former has been associated with alterations in glucose/insulin homeostasis. When the four human p85alpha proteins were expressed in yeast, a 27% decrease occurred in the level of protein expression of p85alpha(Ile/Asp) (p = 0.03) and a 43% decrease in p85alpha(Ile/Asn) (P = 0.08) as compared with p85alpha(Met/Asp). Both p85alpha(Ile/Asp) and p85alpha(Ile/Asn) also exhibited increased binding to phospho-insulin receptor substrate-1 by 41% and 83%, respectively (P < 0.001), as compared with p85alpha(Met/Asp). The expression of p85alpha(Ile) was also slightly decreased and the binding to insulin receptor substrate-1 slightly increased in brown preadipocytes derived from p85alpha knockout mice. Both p85alpha(Met) and p85alpha(Ile) had similar effects on AKT activity and were able to reconstitute differentiation of the preadipocytes, although the triglyceride concentration in fully differentiated adipocytes and insulin-stimulated 2-deoxyglucose uptake were slightly lower than in adipocytes expressing p85alpha(Met). Thus, the Met-326Ile variant of p85alpha is functional for intracellular signaling and adipocyte differentiation but has small alterations in protein expression and activity that could play a role in modifying insulin action. C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. Fac Med Nice, INSERM, U145, F-06034 Nice, France. Steno Diabet Ctr, DK-2820 Gentofte, Denmark. Hagedorn Res Inst, DK-2820 Gentofte, Denmark. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. FU NIDDK NIH HHS [P30 DK036836, DK-36836, R01 DK055545] NR 23 TC 18 Z9 20 U1 0 U2 0 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 FEB 19 PY 2002 VL 99 IS 4 BP 2124 EP 2128 DI 10.1073/pnas.042688799 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 524UK UT WOS:000174031100068 PM 11842213 ER PT J AU Nicolau, C Greferath, R Balaban, TS Lazarte, JE Hopkins, RJ AF Nicolau, C Greferath, R Balaban, TS Lazarte, JE Hopkins, RJ TI A liposome-based therapeutic vaccine against beta-amyloid plaques on the pancreas of transgenic NORBA mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immune tolerance; anti-A beta-antibodles; lipid A; A beta-fiber solubilization ID ALZHEIMERS-DISEASE; PEPTIDE; IMMUNIZATION; MODEL; ACCUMULATION; PATHOLOGY; MOUSE AB Immune tolerance to beta-amyloid (Abeta) was broken in NORBA transgenic mice presenting Abeta plaques on their pancreases. Vaccination of Black C57, BALB/c, and NORBA mice with the synthetic Abeta(1-16) sequence modified by covalently attaching two palmitoyl residues at each end of the peptide, subsequently reconstituted in liposomes-Lipid A elicited titers of 1:5,000 of anti-Abeta(1-16) antibodies within 10 weeks after the first inoculation. On direct interaction, sera with antibody titers of 1:5,000 solubilized in vitro up to 80% of preformed Abeta(1-42) aggregates. Cryosections of pancreases of unvaccinated NORBA mice show, on staining with Thioflavin T, extensive areas of high-intensity fluorescence in the acinar cell fields. Quantitation of the average fluorescence intensity in each section indicated that: (i) whereas nonvaccinated NORBA mice develop plaques within 45-60 days after birth, vaccinated 8-week-old NORBA mice did not develop amyloid plaques on their pancreases over a period of 7 months; (ii) cryosections from pancreases of 9- and 15-month-old vaccinated NORBA mice showed less than 50% of the fluorescence shown by cryosections from unvaccinated animals of the same age. The results indicate that palmitoylated Abeta peptides, reconstituted in liposomes-lipid A, are highly immunogenic, eliciting "therapeutic" antibody titers within 3 months of the first inoculation and preventing amyloid plaque formation in young animals or significantly reducing existing plaques in older transgenic mice. Possible implications for the therapy of Alzheimer's disease are discussed. C1 Univ Strasbourg 1, Ecole Super Biotechnol Strasbourg, F-67091 Strasbourg, France. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02116 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02116 USA. RP Nicolau, C (reprint author), Univ Strasbourg 1, Ecole Super Biotechnol Strasbourg, F-67091 Strasbourg, France. NR 21 TC 35 Z9 38 U1 2 U2 6 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 FEB 19 PY 2002 VL 99 IS 4 BP 2332 EP 2337 DI 10.1073/pnas.022627199 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 524UK UT WOS:000174031100104 PM 11842183 ER PT J AU Bjorklund, LM Sanchez-Pernaute, R Chung, SM Andersson, T Chen, IYC McNaught, KS Brownell, AL Jenkins, BG Wahlestedt, C Kim, KS Isacson, O AF Bjorklund, LM Sanchez-Pernaute, R Chung, SM Andersson, T Chen, IYC McNaught, KS Brownell, AL Jenkins, BG Wahlestedt, C Kim, KS Isacson, O TI Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DIRECT NEURAL INDUCTION; PHARMACOLOGICAL MRI; NERVOUS-SYSTEM; IN-VIVO; VENTRAL MESENCEPHALON; SPEMANN ORGANIZER; HUMAN BLASTOCYSTS; PROGENITOR CELLS; XENOPUS ECTODERM; MOUSE NODE AB Although implantation of fetal dopamine (DA) neurons can reduce parkinsonism in patients, current methods are rudimentary, and a reliable donor cell source is lacking. We show that transplanting low doses of undifferentiated mouse embryonic stem (ES) cells into the rat striatum results in a proliferation of ES cells into fully differentiated DA neurons. ES cell-derived DA neurons caused gradual and sustained behavioral restoration of DA-mediated motor asymmetry. Behavioral recovery paralleled in vivo positron emission tomography and functional magnetic resonance imaging data demonstrating DA-mediated hemodynamic changes in the striatum and associated brain circuitry. These results demonstrate that transplanted ES cells can develop spontaneously into DA neurons. Such DA neurons can restore cerebral function and behavior in an animal model of Parkinson's disease. C1 Harvard Univ, McLean Hosp, Sch Med, Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02478 USA. Harvard Univ, McLean Hosp, Sch Med, Neuroregenerat Labs, Belmont, MA 02478 USA. Harvard Univ, McLean Hosp, Sch Med, Mol Neurobiol Lab, Belmont, MA 02478 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Program Neurosci, Sch Med, Boston, MA 02114 USA. Karolinska Inst, SE-17177 Stockholm, Sweden. RP Bjorklund, LM (reprint author), Harvard Univ, McLean Hosp, Sch Med, Udall Parkinsons Dis Res Ctr Excellence, 115 Mill St, Belmont, MA 02478 USA. RI Wahlestedt, Claes/A-7039-2009 FU NINDS NIH HHS [P50 NS039793, P50 NS39793] NR 63 TC 770 Z9 843 U1 1 U2 78 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 FEB 19 PY 2002 VL 99 IS 4 BP 2344 EP 2349 DI 10.1073/pnas.022438099 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 524UK UT WOS:000174031100106 PM 11782534 ER PT J AU Wu, SV Rozengurt, N Yang, M Young, SH Sinnett-Smith, J Rozengurt, E AF Wu, SV Rozengurt, N Yang, M Young, SH Sinnett-Smith, J Rozengurt, E TI Expression of bitter taste receptors of the T2R family in the gastrointestinal tract and enteroendocrine STC-1 cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE stomach; intestine; gustducin; transducin ID SIGNALING MECHANISMS; GUSTDUCIN; TRANSDUCTION; ACTIVATION; RESPONSES AB Although a role for the gastric and intestinal mucosa in molecular sensing has been known for decades, the initial molecular recognition events that sense the chemical composition of the luminal contents has remained elusive. Here we identified putative taste receptor gene transcripts in the gastrointestinal tract. Our results, using reverse transcriptase-PCR, demonstrate the presence of transcripts corresponding to multiple members of the T2R family of bitter taste receptors in the antral and fundic gastric mucosa as well as in. the lining of the duodenum. In addition, cDNA clones of T2R receptors were detected in a rat gastric endocrine cell cDNA library, suggesting that these receptors are expressed, at least partly, in enteroendocrine cells. Accordingly, expression of multiple T2R receptors also was found in STC-1 cells, an enteroendocrine cell line. The expression of alpha subunits of G proteins implicated in intracellular taste signal transduction, namely Galphagust, and Galphat-2, also was demonstrated in the gastrointestinal mucosa as well as in STC-1 cells, as revealed by reverse transcriptase-PCR and DNA sequencing, immunohistochemistry, and Western blotting. Furthermore, addition of compounds widely used in bitter taste signaling (e.g., denatonium, phenylthiocarbamide, 6-n-propil-2-thiouracil, and cycloheximide) to STC-1 cells promoted a rapid increase in intracellular Ca2+ concentration. These results demonstrate the expression of bitter taste receptors of the T2R family in the mouse and rat gastrointestinal tract. C1 Univ Calif Los Angeles, Div Digest Dis,Ctr Ulcer Res & Educ,Digest Dis Re, Unit Signal Transduct & Gastrointestinal Canc,Sch, Dept Med,Sch Med,Vet Adm Greater Los Angeles Hea, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Vet Adm Greater Los Angeles Healthcare Syst, Ctr Ulcer Res & Educ,Sch Med, Digest Dis Res Ctr,Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. RP Rozengurt, E (reprint author), Univ Calif Los Angeles, Div Digest Dis,Ctr Ulcer Res & Educ,Digest Dis Re, Unit Signal Transduct & Gastrointestinal Canc,Sch, Dept Med,Sch Med,Vet Adm Greater Los Angeles Hea, Los Angeles, CA 90095 USA. FU NIDDK NIH HHS [DK56930, DK17294, DK55003, R01 DK055003, R01 DK056930] NR 21 TC 258 Z9 286 U1 2 U2 11 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 FEB 19 PY 2002 VL 99 IS 4 BP 2392 EP 2397 DI 10.1073/pnas.04261769 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 524UK UT WOS:000174031100114 PM 11854532 ER PT J AU Lambolez, F Azogui, O Joret, AM Garcia, C von Boehmer, H Di Santo, J Ezine, S Rocha, B AF Lambolez, F Azogui, O Joret, AM Garcia, C von Boehmer, H Di Santo, J Ezine, S Rocha, B TI Characterization of T cell differentiation in the murine gut SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE T cells; precursors; differentiation; pre-TCR alpha; CD3-epsilon ID INTESTINAL INTRAEPITHELIAL LYMPHOCYTES; RECEPTOR-BETA LOCUS; ALPHA-BETA; LINEAGE COMMITMENT; ALLELIC EXCLUSION; GENE-EXPRESSION; CUTTING EDGE; IN-VIVO; GAMMA; MICE AB Gut intraepithelial CD8 T lymphocytes (T-IEL) are distinct from thymus-derived cells and are thought to derive locally from cryptopatch (CP) precursors. The intermediate stages of differentiation between CP and mature T-IEL were not identified, and the local differentiation process was not characterized. We identified and characterized six phenotypically distinct lineage-negative populations in the CP and the gut epithelium: (a) we determined the kinetics of their generation from bone marrow precursors; (b) we quantified CD3-E, recombination activating gene (Rag)-1, and pre-Talpha mRNAs expression at single cell level; (c) we characterized TCR-beta, -gamma, and -alpha locus rearrangements; and (d) we studied the impact of different mutations on the local differentiation. These data allowed us to establish a sequence of T cell precursor differentiation in the gut. We also observed that the ut differentiation varied from that of the thyrnus by a very low fi-equency of pre-Ta chain inRNA expression, a different kinetics of Rag-1 mRNA expression, and a much higher impact of CD3 epsilon/delta and pre-Ta deficiencies. Finally, only 3% of CP cells were clearly involved in T cell differentiation, suggesting that these structures may have additional physiological roles in the gut. C1 CHU Necker, Inst Necker, INSERM U345, F-75730 Paris 15, France. Inst Necker, INSERM E9925, F-75730 Paris, France. Inst Necker, INSERM U373, F-75730 Paris 15, France. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Inst Pasteur, F-75015 Paris, France. RP Rocha, B (reprint author), CHU Necker, Inst Necker, INSERM U345, 156 Rue Vaugirard, F-75730 Paris 15, France. RI Di Santo, James/M-4298-2014 OI Di Santo, James/0000-0002-7146-1862 NR 52 TC 72 Z9 72 U1 1 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 FEB 18 PY 2002 VL 195 IS 4 BP 437 EP 449 DI 10.1084/jem.20010798 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 560ZA UT WOS:000176110200006 PM 11854357 ER PT J AU Yu, XG Shang, H Addo, MM Eldridge, RL Phillips, MN Feeney, ME Strick, D Brander, C Goulder, PJR Rosenberg, ES Walker, BD Altfeld, M AF Yu, XG Shang, H Addo, MM Eldridge, RL Phillips, MN Feeney, ME Strick, D Brander, C Goulder, PJR Rosenberg, ES Walker, BD Altfeld, M CA HIV Study Collaboration TI Important contribution of p15 Gag-specific responses to the total Gag-specific CTL responses SO AIDS LA English DT Article DE HIV-1; cytotoxic T lymphocytes; CTL epitopes; HIV-1 Gag; p15 Gag; HLA-A*0201 ID CYTOTOXIC T-LYMPHOCYTE; IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-1 INFECTION; NUCLEOCAPSID PROTEIN; CELLS; INDIVIDUALS AB Objectives: HIV-1 p15 Gag and its protease cleavage products, NCp7 and p6, are believed to play a major role in viral infectivity and assembly during the early and late stages of the retroviral life cycle. However, the extent to which p15 Gag is targeted by the host immune system in natural infection as well as precise cytotoxic T lymphocyte (CTL) epitopes within this protein remains to be defined. Methods: In this study, 57 HIV-1 infected individuals and 10 HIV-1 negative controls were screened for CD8 and CD4 T-cell responses using overlapping peptides spanning the entire p15 Gag protein as well as the p] 7 Gag and p24 Gag proteins. Peptide-specific interferon-gamma production was measured by Elispot assay and flow-based intracellular cytokine quantification, and cytotoxic activity was confirmed after isolation of peptide-specific CD8 T-cell lines. Results: CD8 T lymphocytes specific to p15 Gag were found in 46% (26/57) of HIV-1 infected individuals studied and contributed on average 17% (range, 0-100%) to the total Gag-specific T-cell responses. Responses were clustered within three immunodominant regions of p15 Gag, mapping to important functional sites. These studies also include the description of the first three optimally defined CTL epitopes within p15 Gag. Conclusions: These results indicate that p] 5 Gag is frequently recognized by HIV-1 specific CD8 T cells in HIV-1 infection and will be important in the comprehensive assessments of CTL responses in infected persons, as well as the design and testing of future HIV-1 vaccines and immunotherapeutic interventions. (C) 2002 Lippincott Williams Wilkins. C1 Massachusetts Gen Hosp, Partner AIDS Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. First Affiliated Hosp China Med Univ, AIDS Res Ctr, Shenyang, Peoples R China. John Radcliffe Hosp, Nuffield Dept Med, Oxford OX3 9DU, England. RP Altfeld, M (reprint author), MGH E, CNY 5212,149 13th St, Charlestown, MA 02129 USA. FU NIAID NIH HHS [U01 AI 41535, R01 AI 44656, R01 AI 30914, R37 AI 28568, R01 AI 40873, U01 AI 41531] NR 34 TC 22 Z9 25 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD FEB 15 PY 2002 VL 16 IS 3 BP 321 EP 328 DI 10.1097/00002030-200202150-00002 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 523AV UT WOS:000173929900002 PM 11834942 ER PT J AU Omland, T de Lemos, JA Morrow, DA Antman, EN Cannon, CP Hall, C Braunwald, E AF Omland, T de Lemos, JA Morrow, DA Antman, EN Cannon, CP Hall, C Braunwald, E TI Prognostic value of N-terminal pro-atrial and pro-brain natriuretic peptide in patients with acute coronary syndromes SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; UNSTABLE ANGINA; PLASMA-LEVELS; TROPONIN-I; MORTALITY; THROMBOLYSIS; PREDICTOR; RISK AB From a cohort of 681 patients admitted with unstable angina and/or non-ST-segment acute myocardial infarction, baseline N-terminal pro-atrial and pro-brain natriuretic peptide (Nt-proANP and Nt-proBNP) levels were measured in 53 patients who died or experienced a new nonfatal acute myocardial infarction within 43 days of admission and in 53 age- and sex-matched control subjects. Plasma Nt-proANP and Nt-proBNP levels were both significantly related to death within 4-3 days, and for Nt-proBNP this relation remained significant after adjusting for conventional risk indicators. C1 Univ Oslo, Natl Hosp, Dept Cardiol, N-0027 Oslo 1, Norway. Univ Oslo, Natl Hosp, Internal Med Res Inst, N-0027 Oslo, Norway. Univ Texas, SW Med Ctr, Donald W Reynolds Cardiovasc Clin Res Unit, Dallas, TX USA. Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. RP Omland, T (reprint author), Univ Oslo, Natl Hosp, Dept Cardiol, N-0027 Oslo 1, Norway. NR 16 TC 109 Z9 124 U1 0 U2 1 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD FEB 15 PY 2002 VL 89 IS 4 BP 463 EP + DI 10.1016/S0002-9149(01)02271-8 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 521AQ UT WOS:000173816400021 PM 11835931 ER PT J AU Karim, MA Suzuki, K Fukai, K Oh, J Nagle, DL Moore, KJ Barbosa, E Falik-Borenstein, T Filipovich, A Ishida, Y Kivrikko, S Klein, C Kreuz, F Levin, A Miyajima, H Regueiro, J Russo, C Uyama, E Vierimaa, O Spritz, RA AF Karim, MA Suzuki, K Fukai, K Oh, J Nagle, DL Moore, KJ Barbosa, E Falik-Borenstein, T Filipovich, A Ishida, Y Kivrikko, S Klein, C Kreuz, F Levin, A Miyajima, H Regueiro, J Russo, C Uyama, E Vierimaa, O Spritz, RA TI Apparent genotype-phenotype correlation in childhood, adolescent, and adult Chediak-Higashi syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE Chediak-Higashi syndrome; CHS1 gene; LYST; beige ID SYNDROME GENE; IDENTIFICATION; MUTATIONS; BEIGE; MOUSE AB Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by severe immunologic defects, reduced pigmentation, bleeding tendency, and progressive neurological dysfunction. Most patients present in early childhood and die unless treated by bone marrow transplantation. About 10-15% of patients exhibit a much milder clinical phenotype and survive to adulthood, but develop progressive and often fatal neurological dysfunction. Very rare patients exhibit an intermediate adolescent CHS phenotype, presenting with severe infections in early childhood, but a milder course by adolescence, with no accelerated phase. Here, we describe the organization and genomic DNA sequence of the CHS1 gene and mutation analysis of 21 unrelated patients with the childhood, adolescent, and adult forms of CHS. In patients with severe childhood CHS, we found only functionally null mutant CHS1 alleles, whereas in patients with the adolescent and adult forms of CHS we also found missense mutant alleles that likely encode CHS I polypeptides with partial function. Together, these results suggest an allelic genotype-phenotype relationship among the various clinical forms of CHS. (C) 2002 Wiley-Liss, Inc. C1 Univ Colorado, Hlth Sci Ctr, Human Med Genet Program, Denver, CO 80262 USA. Osaka City Univ, Dept Dermatol, Osaka 558, Japan. Millennium Pharmaceut Inc, Cambridge, MA USA. Med Univ S Carolina, Div Pediat Neurol, Charleston, SC 29425 USA. Bnai Zion Med Ctr, Haifa, Israel. Childrens Hosp, Med Ctr, Div Hematol Oncol, Cincinnati, OH 45229 USA. Ehime Univ, Dept Pediat, Sch Med, Matsuyama, Ehime, Japan. Oulu Univ Hosp, Dept Clin Genet, Oulu, Finland. Dana Farber Canc Inst, Boston, MA 02115 USA. Tech Univ Dresden, Inst Klin Genet, D-8027 Dresden, Germany. Hosp Sick Children, Dept Ophthalmol, Toronto, ON M5G 1X8, Canada. Hamamatsu Med Sch, Hamamatsu, Shizuoka, Japan. Univ Complutense, Dept Immunol, E-28040 Madrid, Spain. Univ Calif San Francisco, San Francisco, CA 94143 USA. Kumamoto Univ, Sch Med, Dept Neurol, Kumamoto 860, Japan. RP Spritz, RA (reprint author), Univ Colorado, Hlth Sci Ctr, Human Med Genet Program, 4200 E 9th Ave,Campus Box B161, Denver, CO 80262 USA. FU NIAMS NIH HHS [AR39892] NR 19 TC 77 Z9 83 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD FEB 15 PY 2002 VL 108 IS 1 BP 16 EP 22 DI 10.1002/ajmg.10184 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 515PB UT WOS:000173503500004 PM 11857544 ER PT J AU Gripp, KW Scott, CI Nicholson, L McDonald-McGinn, DM Ozeran, JD Jones, MC Lin, AE Zackai, EH AF Gripp, KW Scott, CI Nicholson, L McDonald-McGinn, DM Ozeran, JD Jones, MC Lin, AE Zackai, EH TI Five additional Costello syndrome patients with rhabdomyosarcoma: Proposal for a tumor screening protocol SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE Costello syndrome; Chiari 1 malformation; childhood cancer; fetal tachycardia; rhabdomyosarcoma; solid tumors; tumor screening ID BECKWITH-WIEDEMANN-SYNDROME; BLADDER-CARCINOMA; NATURAL-HISTORY; CANCER; DELINEATION; PHENOTYPE; CHILDREN; RISK AB We report five new cases of rhabdomyosarcoma (RMS) in Costello syndrome. These cases, combined with those previously reported, increase the number of solid tumors to 17 (10 RMSs, 3 neuroblastomas, 2 bladder carcinomas, 1 vestibular schwannoma, 1 epithelioma), in at least 100 known Costello syndrome patients. Despite possible ascertainment bias, and the incomplete identification of all Costello syndrome patients, the tumor frequency could be as high as 17%. This is comparable to the 7-21% frequency of solid tumors in Beckwith-Wiedemann syndrome (BWS), and may justify tumor screening. Based on the recommendations for screening BWS patients, we propose a screening protocol consisting of ultrasound examination of the abdomen and pelvis every 3-6 months until age 8-10 years for RMS and abdominal neuroblastoma; urine catecholamine metabolite analysis every 6-12 months until age 5 years for neuroblastoma; and urinalysis for hematuria annually for bladder carcinoma after age 10 years. These recommendations may need to be modified, as new information becomes available. Potential criticism of the tumor screening protocol concerns the lack of evidence for improved outcome, and possible overestimation of the tumor risk. The ability of RMSs to occur at various sites complicates tumor screening, but 8 of the 10 RMSs in Costello syndrome patients originated from the abdomen, pelvis and urogenital area. Prior diagnosis of Costello syndrome is a prerequisite for the implementation of any screening protocol. The diagnosis of Costello syndrome should also be considered in individuals with RMS and physical findings suggestive of Costello syndrome. (C) 2002 Wiley-Liss, Inc. C1 AI duPont Hosp Children, Div Med Genet, Wilmington, DE 19899 USA. Childrens Hosp Philadelphia, Div Human Genet & Mol Biol, Philadelphia, PA 19104 USA. Univ Calif Los Angeles, Mattel Childrens Hosp, Div Pediat Hematol & Oncol, Los Angeles, CA USA. Univ Calif San Diego, Div Dysmorphol & Teratol, San Diego, CA 92103 USA. Massachusetts Gen Hosp, Genet & Teratol Unit, Boston, MA 02114 USA. RP Gripp, KW (reprint author), AI duPont Hosp Children, Div Med Genet, POB 269, Wilmington, DE 19899 USA. NR 27 TC 79 Z9 83 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD FEB 15 PY 2002 VL 108 IS 1 BP 80 EP 87 DI 10.1002/ajmg.10241 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 515PB UT WOS:000173503500016 PM 11857556 ER PT J AU Hynes, DM Stroupe, KT Greer, JW Reda, DJ Frankenfield, DL Kaufman, JS Henderson, WG Owen, WF Rocco, MV Wish, JB Kang, J Feussner, JR AF Hynes, DM Stroupe, KT Greer, JW Reda, DJ Frankenfield, DL Kaufman, JS Henderson, WG Owen, WF Rocco, MV Wish, JB Kang, J Feussner, JR TI Potential cost savings of erythropoietin administration in end-stage renal disease SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID RECOMBINANT-HUMAN-ERYTHROPOIETIN; PATIENTS RECEIVING HEMODIALYSIS; EPOETIN; PHARMACOKINETICS; POPULATION; THERAPY; TRENDS; PAIN AB BACKGROUND: In a Department of Veterans Affairs randomized controlled trial, a lower dose of recombinant human erythropoietin (epoetin) was shown to attain target hematocrit levels when administered subcutaneously compared with intravenously. Since epoetin is expensive, optimizing the therapeutic effect of epoetin using a strategy that includes subcutaneous administration could lead to substantial cost savings. METHODS: We used an economic cost projection model to estimate potential savings to the Medicare End-Stage Renal Disease Program that could occur during a transition from intravenous to subcutaneous administration of epoetin among hemodialysis patients. Data included clinical results from the Department of Veterans Affairs randomized controlled trial, the 1998 Centers for Medicare and Medicaid Services' End-Stage Renal Disease Core Indicators Survey, and the 1997-1998 Medicare claims files. In sensitivity analyses, we varied the expected dose reductions (10% to 50%) and the proportion of patients (25% to 100%) who switched to subcutaneous administration. RESULTS: Medicare cost savings were estimated at $47 to $142 million annually as 25% to 75% of hemodialysis patients who received epoetin intravenously switched to subcutaneous administration while reducing the dose by 32%. A minimal reduction (10%) in epoetin dose would result in Medicare cost savings of an estimated $15 to $44 million annually. CONCLUSION: Administering epoetin subcutaneously would provide substantial cost savings to Medicare. For the transition to occur, consensus among stakeholders is needed, especially among patients whose treatment satisfaction and health-related quality of life would be most affected. (C)2002 by Excerpta Medica, Inc. C1 Dept Vet Affairs, Cooperat Studies Program Coordinating Ctr, Hines, IL USA. Midwest Ctr Hlth Serv & Policy Res, Hines, IL USA. VA Informat Resource Ctr, Hines, IL USA. Loyola Univ, Dept Med, Maywood, IL 60153 USA. Northwestern Univ, Dept Med, Chicago, IL 60611 USA. Ctr Medicare, Off Strateg Planning, Baltimore, MD USA. Ctr Medicaid Serv, Off Strateg Planning, Baltimore, MD USA. Off Clin Stand & Qual, Baltimore, MD USA. VA Boston Healthcare Syst, Renal Sect, Boston, MA USA. Duke Univ, Med Ctr, Duke Inst Renal Outcomes Res & Hlth Policy, Durham, NC USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Univ Hosp Cleveland, Div Nephrol, Cleveland, OH 44106 USA. Dept Vet Affairs, Washington, DC USA. RP Hynes, DM (reprint author), Edward Hines Jr Vet Adm Hosp, VA Cooperat Studies Program Coordinating Ctr 151K, 5th & Roosevelt Rd,Bldg 1,Room B240, Hines, IL 60141 USA. NR 22 TC 37 Z9 38 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 FEB 15 PY 2002 VL 112 IS 3 BP 169 EP 175 AR PII S0002-9343(01)01103-2 DI 10.1016/S0002-9343(01)01103-2 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 534TD UT WOS:000174602100001 PM 11893342 ER PT J AU Alvarez, B Carbo, N Lopez-Soriano, J Drivdahl, RH Busquets, S Lopez-Soriano, FJ Argiles, JM Quinn, LS AF Alvarez, B Carbo, N Lopez-Soriano, J Drivdahl, RH Busquets, S Lopez-Soriano, FJ Argiles, JM Quinn, LS TI Effects of interleukin-15 (IL-15) on adipose tissue mass in rodent obesity models: evidence for direct IL-15 action on adipose tissue SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Article DE interleukin-15; white adipose tissue; Zucker rat; ob/ob mouse; obesity ID TUMOR-NECROSIS-FACTOR; LIPOPROTEIN-LIPASE; FACTOR-ALPHA; BETA-CHAIN; RECEPTOR; CLONING; MUSCLE; PROTEIN; CELLS AB Interleukin-15 (IL-15) is a proinflammatory cytokine with multifunctional effects outside the immune system. Previous studies have indicated that treatment of normal rats with IL-15 reduces white adipose tissue (WAT) mass, but it was unclear if these effects were direct or indirect. In the present study, the effects of IL-15 on WAT mass and lipid metabolism were studied in two genetic models of obesity: the leptin receptor-negative falfa Zucker rat and the leptin-deficient ob/ob mouse. Lean Zucker rats, lean (+/+), and obese mice (ob/ob) responded to IL-15 with reductions in WAT mass and lipoprotein lipase activity (LPL), with no decreases in food intake. In contrast, falfk Zucker rats did not respond to IL-15 administration by any of the above measures of fat mass or lipid metabolism. In addition, ribonuclease protection assays (RPAs) were used to demonstrate that all three subunits (gammac, beta and alpha) of the IL-15 receptor complex are expressed by rat and mouse WAT, suggesting that the effects of IL-15 on adipose tissue metabolism could be direct. Additionally, the fal fa rats expressed 84% lower levels of the gammac signaling receptor subunit than lean Zucker rats, suggesting this decrease may play a role in the lack of adipose tissue response to IL-15 in the falfa genotype and lending further support for a direct action of IL-15 on adipose tissue. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Barcelona, Fac Biol, Canc Res Grp, Dept Bioquim & Biol Mol, E-08071 Barcelona, Spain. VA Puget Sound Hlth Care Syst, Res Serv, Tacoma, WA USA. Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA USA. VA Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Tacoma, WA USA. Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. RP Argiles, JM (reprint author), Univ Barcelona, Fac Biol, Canc Res Grp, Dept Bioquim & Biol Mol, Diagonal 645, E-08071 Barcelona, Spain. EM argiles@porthos.bio.ub.es; quinnl@u.washington.edu NR 20 TC 54 Z9 56 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD FEB 15 PY 2002 VL 1570 IS 1 BP 33 EP 37 AR PII S0304-4165(02)00148-4 DI 10.1016/S0304-4165(02)00148-4 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 545LW UT WOS:000175219800005 PM 11960686 ER PT J AU Tai, YT Podar, K Gupta, D Lin, B Young, G Akiyama, M Anderson, KC AF Tai, YT Podar, K Gupta, D Lin, B Young, G Akiyama, M Anderson, KC TI CD40 activation induces p53-dependent vascular endothelial growth factor secretion in human multiple myeloma cells SO BLOOD LA English DT Article ID WILD-TYPE P53; FACTOR EXPRESSION; PLASMA-CELLS; FACTOR VEGF; IN-VIVO; B-CELLS; ANGIOGENESIS; GENE; INTERLEUKIN-6; CANCER AB It was previously demonstrated that p53 status in human multiple myeloma (MM) cells regulates distinct cell cycle responses to CD40 activation. In this study, the production of vascular endothelial growth factor (VEGF) and migration in MM cells triggered by CD40 activation was examined, and the influence of p53 status in regulating this process was determined. Two human MM cell lines that express wild-type p53 at permissive (28degreesC) and mutant p53 at restrictive (37degreesC) temperatures were used as a model system. CD40 activation induces a 4-fold (RPMI 8226) and a 6-fold (SV) increase in VEGF transcripts, respectively, under restrictive, but not permissive, temperatures. VEGF expression is significantly induced after CD40 activation in patient MM cells expressing mutant p53. Increased VEGF transcripts result in increased protein and secretion levels, as evidenced by immunoblotting and enzyme-linked immunosorbent assay. In a double-chamber transmigration assay, CD40 activation of MM cells induced a 3-fold (RPMI 8226) and a 5-fold (SV) increase in migration under restrictive, but not permissive, conditions. A 2- to 8-fold induction in migration of patient MM cells expressing mutant p53 was similarly observed. Transduction of MM cells with a luciferase reporter under the control of a human VEGF promoter further indicated that CD40-induced VEGF expression was mediated through a transcriptional control mechanism. Finally, adenovirus-mediated wildtype p53 overexpression down-regulated CD40-induced VEGF expression and transmigration in MM cells expressing mutant p53. These studies demonstrate that CD40 induces VEGF secretion and MM cell migration, suggesting a role for CD40 in regulating MM homing and angiogenesis. (C) 2002 by The American Society of Hematology. C1 Dana Farber Canc Inst, Dept Adult Oncol, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. Harvard Med Sch, Dept Med, Boston, MA 02115 USA. RP Anderson, KC (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Jerome Lipper Multiple Myeloma Ctr, M557,44 Binney St, Boston, MA 02115 USA. NR 43 TC 65 Z9 68 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 15 PY 2002 VL 99 IS 4 BP 1419 EP 1427 DI 10.1182/blood.V99.4.1419 PG 9 WC Hematology SC Hematology GA 520NH UT WOS:000173787600046 PM 11830495 ER PT J AU Tzachanis, D Berezovskaya, A Nadler, LM Boussiotis, VA AF Tzachanis, D Berezovskaya, A Nadler, LM Boussiotis, VA TI Blockade of B7/CD28 in mixed lymphocyte reaction cultures results in the generation of alternatively activated macrophages, which suppress T-cell responses SO BLOOD LA English DT Article ID COLONY-STIMULATING FACTOR; VERSUS-HOST DISEASE; BLOOD STEM-CELLS; LONG-TERM ACCEPTANCE; DENDRITIC CELLS; APOPTOTIC CELLS; INTERFERON-GAMMA; HUMAN MONOCYTES; ANTIGEN PRESENTATION; CYTOKINE PRODUCTION AB Blockade of B7/CD28 costimulation allows human haploidentical bone marrow transplantation without graft-versus-host disease. This study shows that blockade of B7/CD28 in anergizing mixed lymphocyte reaction (MLR) cultures of peripheral blood mononuclear cells results in the generation of alternatively activated macrophages (AAMPhi)). In contrast, priming MLR cultures result in generation of classically activated macrophages (CAMPhi). AAMPhi had enhanced expression of CD14, major histocompatibility complex class II, and CD23; produced alternative macrophage activation-associated CC-chemokine 1 (AMAC-1) chemokine; and displayed increased phagocytotic activity but decreased ability for antigen presentation. Suppression subtractive hybridization revealed that although AAMPhi had undergone terminal maturation and differentiation, they entered a distinct gene expression program as compared with CAMPhi and selectively expressed beta2-microglobulin, lysozyme, ferritin heavy and light chain, and the scavenger receptors macrophage Mannose receptor and sortilin. Anergic T cells isolated from cultures that led to the development of AAMPhi produced low amounts of interleukin-2 (IL-2), IL-4, and interferon-gamma, but high amounts of IL-10. Addition of anti-IL-10 neutralizing monoclonal antibody in anergizing cultures reversed the functional characteristics of AAMPhi, indicating that at least one mechanism involved in the generation of AAMPhi was mediated by IL-10. Importantly, when added in MLR cultures, AAMPhi suppressed T-cell responses. Therefore, besides direct inhibition of T-cell costimulation, blockade of B7/CD28 may facilitate induction of T-cell unresponsiveness by generating AAMPhi Because in healthy individuals, AAMPhi are found in the placenta and lung, where they protect from unwanted immune reactivity, the results suggest that AAMPhi may play a critical role in the induction of transplantation tolerance. (C) 2002 by The American Society of Hematology. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Div Med Oncol, Boston, MA 02115 USA. RP Boussiotis, VA (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Mayer 547,44 Binney St, Boston, MA 02115 USA. FU NHLBI NIH HHS [HL 54785]; NIAID NIH HHS [AI 41584, AI 43552] NR 68 TC 41 Z9 42 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 15 PY 2002 VL 99 IS 4 BP 1465 EP 1473 DI 10.1182/blood.V99.4.1465 PG 9 WC Hematology SC Hematology GA 520NH UT WOS:000173787600052 PM 11830501 ER PT J AU Haiman, CA Brown, M Hankinson, SE Spiegelman, D Colditz, GA Willett, WC Kantoff, PW Hunter, DJ AF Haiman, CA Brown, M Hankinson, SE Spiegelman, D Colditz, GA Willett, WC Kantoff, PW Hunter, DJ TI The androgen receptor CAG repeat polymorphism and risk of breast cancer in the Nurses' Health Study SO CANCER RESEARCH LA English DT Article ID VITAMIN-D-RECEPTOR; POSTMENOPAUSAL WOMEN; PROSTATE-CANCER; ADRENAL ANDROGENS; HORMONE LEVELS; GENE; LENGTH; TRANSACTIVATION; TESTOSTERONE; ASSOCIATION AB Shorter alleles of a polymorphic [CAG](n) repeat in exon 1 of the androgen receptor (AR) have been associated with increased risk of prostate cancer and decreased risk of breast cancer. We prospectively assessed the association between the [CAG](n) repeat polymorphism in the androgen receptor and breast cancer risk among Caucasian women in a case-control study nested within the Nurses' Health Study cohort (cases, n=727; controls, n=969). In addition, we assessed whether androgen receptor genotype influences endogenous steroid hormone levels in women and whether the associations between androgen receptor alleles and breast cancer risk differed according to established breast cancer risk factors. Women with one or more long AR [CAG](n) repeat alleles (greater than or equal to22 repeats) were not at increased risk of breast cancer [odds ratio (OR), 1.06; 95% confidence interval (CI), 0.83-1.35]. Significant associations were not observed between AR genotypes comprised of two short alleles ([CAG](n) less than or equal to20 versus both alleles greater than or equal to22: OR, 0.92; 95% CI, 0.62-1.36) or two long alleles ([CAG](n) greater than or equal to25 versus both alleles less than or equal to 22: OR, 1.42; 95% CI, 0.81-2.50) and breast cancer risk. We also observed no strong overall association between average repeat length and breast cancer risk (OR, 1.04 per CAG repeat; 95% CI, 0.99-1.10) or between average repeat length and plasma hormone levels. We also examined the cross-classification of AR genotype and first-degree family history of breast cancer. Compared with women with both alleles <22 and no family history, we observed a significant positive association limited to women with both a first-degree family history of breast cancer and longer alleles (one or two [CAG](n) alleles &GE;22; OR, 1.70; 95% CI, 1.20-2.40; P for interaction = 0.04). In summary, we observed no overall relation of AR genotype with breast cancer risk among mostly postmenopausal Caucasian women. However, these data suggest that longer AR [CAG](n) repeat alleles may increase breast cancer risk among women with a first-degree family history of breast cancer. C1 Univ So Calif, USC Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90089 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Harvard Ctr Canc Prevent, Boston, MA 02115 USA. Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Haiman, CA (reprint author), Univ So Calif, USC Norris Comprehens Canc Ctr, Dept Prevent Med, 1441 Eastlake Ave,Room 4411, Los Angeles, CA 90089 USA. RI Myles, Brown/B-6906-2008; Colditz, Graham/A-3963-2009; OI Colditz, Graham/0000-0002-7307-0291; Brown, Myles/0000-0002-8213-1658 FU NCEH CDC HHS [EH00002]; NCI NIH HHS [CA40356, CA49449, CA57374, CA65725, CA80111] NR 30 TC 81 Z9 85 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2002 VL 62 IS 4 BP 1045 EP 1049 PG 5 WC Oncology SC Oncology GA 523RP UT WOS:000173969400019 PM 11861380 ER PT J AU Revankar, SG Patterson, JE Sutton, DA Pullen, R Rinaldi, MG AF Revankar, SG Patterson, JE Sutton, DA Pullen, R Rinaldi, MG TI Disseminated phaeohyphomycosis: Review of an emerging mycosis SO CLINICAL INFECTIOUS DISEASES LA English DT Review ID IN-VITRO ACTIVITY; SCEDOSPORIUM-PROLIFICANS INFECTION; FATAL DISSEMINATED INFECTION; 1ST CASE-REPORT; EXOPHIALA-DERMATITIDIS; CURVULARIA-LUNATA; MYCELIOPHTHORA-THERMOPHILA; VORICONAZOLE UK-109,496; AUREOBASIDIUM-PULLULANS; SCYTALIDIUM-DIMIDIATUM AB Disseminated phaeohyphomycosis is an uncommon infection caused by dematiaceous fungi, although the number of case reports about this infection has been increasing in recent years. A total of 72 cases are reviewed. Scedosporium prolificans is by far the most common cause. The presence of melanin in their cell walls may be a virulence factor for these fungi. The primary risk factor is decreased host immunity, although cases in apparently immunocompetent patients have been reported. Eosinophilia was seen in 11% of cases. Endocarditis is mostly reported on bioprosthetic valves, particularly those of porcine origin. The outcome of antifungal therapy remains poor, with an overall mortality rate of 79%. Special precautions taken for immunocompromised patients may help prevent exposure to fungi during the patients' period of greatest risk. The development of newer antifungal agents and combination therapy may hold promise in improving the management of these devastating infections in the future. C1 Vet Adm Med Ctr, Div Infect Dis 111D, Dallas, TX 75216 USA. Univ Texas, SW Med Ctr, Dept Med, Dallas, TX USA. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78284 USA. Audie L Murphy Mem Vet Adm Med Ctr, San Antonio, TX 78284 USA. RP Revankar, SG (reprint author), Vet Adm Med Ctr, Div Infect Dis 111D, 4500 S Lancaster Rd, Dallas, TX 75216 USA. NR 92 TC 211 Z9 217 U1 3 U2 6 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 FEB 15 PY 2002 VL 34 IS 4 BP 467 EP 476 DI 10.1086/338636 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 514UD UT WOS:000173458700007 PM 11797173 ER PT J AU Li, W Nadelman, C Gratch, NS Li, WQ Chen, M Kasahara, N Woodley, DT AF Li, W Nadelman, C Gratch, NS Li, WQ Chen, M Kasahara, N Woodley, DT TI An important role for protein kinase C-delta in human keratinocyte migration on dermal collagen SO EXPERIMENTAL CELL RESEARCH LA English DT Article ID ATP BINDING MUTANT; TYROSINE PHOSPHORYLATION; PKC-DELTA; CELLS; GROWTH; EXPRESSION; ACTIVATION; ALPHA; OVEREXPRESSION; PROLIFERATION AB Migration of human keratinocytes plays a critical role in the re-epithelialization of human skin wounds, the process by which the wound bed is resurfaced and closed by keratinocytes as it forms a new epidermis. While the importance of ECM components and serum factors in the regulation of keratinocytes motility is well established, the intracellular signaling mechanisms remain fragmentary. In this study, we investigated the role of protein kinase Cdelta (PKCdelta) signaling in the promotion of human keratinocyte migration by a collagen matrix and bovine pituitary extract. We found that pharmacological inhibition of the PKCdelta pathway completely blocks migration. Using a lentivirus-based vector system, which offers more than 90% gene transduction efficiency to human keratinocytes, we show that the kinase-defective mutant of PKCdelta (K376R) dramatically inhibits human keratinocyte migration. Furthermore, PKCdelta is activated in migrating human keratinocytes. These observations indicate for the first time that the PKCdelta pathway plays an important role in the control of human keratinocyte migration. m (C) 2002 Elsevier Science (USA). C1 Univ So Calif, Keck Sch Med, Dept Med, Div Dermatol, Los Angeles, CA 90033 USA. Univ So Calif, Keck Sch Med, Norris Canc Ctr, Los Angeles, CA 90033 USA. Univ So Calif, Keck Sch Med, Inst Med Genet, Los Angeles, CA 90033 USA. Greater Los Angeles Vet Adm Hlth Syst, Los Angeles, CA USA. Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. RP Li, W (reprint author), Univ So Calif, Keck Sch Med, Dept Med, Div Dermatol, Los Angeles, CA 90033 USA. FU NCI NIH HHS [R01 CA65567-05]; NIAMS NIH HHS [R01 AR46538-01] NR 37 TC 15 Z9 16 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD FEB 15 PY 2002 VL 273 IS 2 BP 219 EP 228 DI 10.1006/excr.2001.5422 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 524JL UT WOS:000174009400011 PM 11822877 ER PT J AU Tsukamoto, H AF Tsukamoto, H TI Iron regulation of hepatic macrophage TNF alpha expression SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Review DE NF-kappa B; redox regulation; Kupffer cells; iron chelator; alcoholic liver disease; free radicals ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; INDUCED LIVER-INJURY; NITRIC-OXIDE; ACTIVATED MACROPHAGES; LIPID-PEROXIDATION; MOLECULAR MECHANISMS; FERRITIN SYNTHESIS; INTERFERON-GAMMA; CYTO-TOXICITY AB Sustained TNFalpha induction is central to the pathogenesis of chronic liver disease including alcoholic liver disease (ALD). However, molecular understanding of this abnormality at the cellular level remains elusive. Redox regulation of NF-kappaB is critical in the transcriptional control of TNFa expression. Evidence supports that increased iron storage in hepatic macrophages (HM) is causally associated with accentuated and sustained NF-kappaB activation in these cells in ALD. Treatment of cultured HM with a lipophilic iron chelator (deferiprone) abrogates LPS-induced NF-kappaB activation. HM from an animal model of ALD have increased nonheme iron content accompanied by increased generation of EPR-detected radicals, NF-kappaB activation, and TNFa induction, all of which are normalized by ex vivo treatment of the cells with deferiprone. A moderate increase in the nonheme iron content in HM by erythrophagocytosis, promotes subsequent LPS-stimulated NF-kappaB activation in a hemeoxygenase-dependent manner. Recent evidence also suggests a role of intracellular low molecular weight iron in the early signal transduction for LPS-mediated NF-kappaB activation. (C) 2002 Elsevier Science Inc. C1 Univ So Calif, Keck Sch Med, Res Ctr Liver Dis, Los Angeles, CA 90089 USA. Univ So Calif, UCLA Res Ctr Alcohol Liver & Pancreat Dis, Los Angeles, CA 90089 USA. Greater Los Angeles VA Hlth Care Syst, Los Angeles, CA USA. RP Tsukamoto, H (reprint author), Univ So Calif, Keck Sch Med, Res Ctr Liver Dis, 1333 San Pablo St,MMR-402, Los Angeles, CA 90089 USA. FU NIAAA NIH HHS [P50AA19999, R37AA06603]; NIDDK NIH HHS [P30DK48522] NR 51 TC 28 Z9 29 U1 1 U2 1 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 FEB 15 PY 2002 VL 32 IS 4 BP 309 EP 313 AR PII S0891-5849(01)00772-9 DI 10.1016/S0891-5849(01)00772-9 PG 5 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 522YU UT WOS:000173925200002 PM 11841920 ER PT J AU Turley, EA Noble, PW Bourguignon, LYW AF Turley, EA Noble, PW Bourguignon, LYW TI Signaling properties of hyaluronan receptors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID ENDOTHELIAL-CELL PROLIFERATION; TYROSINE KINASE-ACTIVITY; MEDIATED MOTILITY RHAMM; BINDING PROTEIN; EXTRACELLULAR-MATRIX; MOUSE MACROPHAGES; EPITHELIAL-CELLS; MULTIPLE-MYELOMA; CD44; ACID C1 Univ Western Ontario, London Reg Canc Ctr, London, ON N6A 4L6, Canada. Yale Univ, Sch Med, Pulm & Crit Care Sect, New Haven, CT 06520 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA. San Francisco Vet Affairs Med Ctr, San Francisco, CA 94121 USA. RP Turley, EA (reprint author), Univ Western Ontario, London Reg Canc Ctr, 790 Commissioners Rd E, London, ON N6A 4L6, Canada. NR 83 TC 606 Z9 627 U1 6 U2 58 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 FEB 15 PY 2002 VL 277 IS 7 BP 4589 EP 4592 DI 10.1074/jbc.R100038200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 523NX UT WOS:000173962900005 PM 11717317 ER PT J AU Singh, IS He, JR Calderwood, S Hasday, JD AF Singh, IS He, JR Calderwood, S Hasday, JD TI A high affinity HSF-1 binding site in the 5 '-untranslated region of the murine tumor necrosis factor-alpha gene is a transcriptional repressor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEAT-SHOCK FACTOR; FEBRILE-RANGE TEMPERATURE; FACTOR-I; PROTECTS MICE; EXPRESSION; ENDOTOXIN; ACTIVATION; CACHECTIN; TNF; INHIBITION AB Tumor necrosis factor-alpha (TNFalpha) is a pivotal early mediator of host defenses that is essential for survival in infections. We previously reported that exposing macrophages to febrile range temperatures (FRT) (38.5-40 degreesC) markedly attenuates TNFalpha expression by causing abrupt and premature cessation of transcription. We showed that this inhibitory effect of FRT is mediated by an alternatively activated repressor form of heat shock factor 1 (HSF-1) and that a fragment of the TNFalpha gene comprising a minimal 85-nucleotide (nt) proximal promoter and the 138-nt 5'-untranslated region (UTR) was sufficient for mediating this effect. In the present study we have used an electrophoretic mobility shift assay (EMSA) to identify a high affinity binding site for HSF-1 in the 5'-UTR of the TNFalpha gene and have used a chromosome immunoprecipitation assay to show that HSF-1 binds to this region of the endogenous TNFalpha gene. Mutational inactivation of this site blocks the inhibitory effect of overexpressed HSF-1 on activity of the minimal TNFalpha promoter (-85/+138) in Raw 264.7 murine macrophages, identifying this site as an HSF-1-dependent repressor. However, the same mutation fails to block repression of a full-length (-1080/+138) TNFalpha promoter construct by HSF-1 overexpression, and HSF-1 binds to upstream sequences in the regions -1080/-845, -533/-196, and -326/-39 nt in EMSA, suggesting that additional HSF-1-dependent repressor elements are present upstream of the minimal -85-nt promoter. Furthermore, although mutation of the HSF-1 binding site in the minimal TNFalpha promoter construct abrogates HSF-1-mediated repression, the same mutation fails to abrogate repression of this construct by high levels of HSF-1 overexpression or exposure to 39.5 degreesC. This suggests that HSF-1 might repress TNFalpha transcription through redundant mechanisms, some of which might not require high affinity binding of HSF-1. C1 Univ Maryland, Sch Med, Dept Med, Div Pulm & Crit Care Med, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Biochem, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Mol Biol, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. Univ Maryland, Biopolymer Cytokine Core Lab, Baltimore, MD 21201 USA. Baltimore VA Med Ctr, Res Serv, Baltimore, MD 21201 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Joint Ctr Radiat Therapy, Boston, MA 02115 USA. Baltimore VA Med Ctr, Med Serv, Baltimore, MD 21201 USA. RP Singh, IS (reprint author), Baltimore VA Med Ctr, Med Serv, Rm 3D127,10 N Greene St, Baltimore, MD 21201 USA. FU NIAID NIH HHS [AI42117] NR 31 TC 97 Z9 108 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 15 PY 2002 VL 277 IS 7 BP 4981 EP 4988 DI 10.1074/jbc.M108154200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 523NX UT WOS:000173962900058 PM 11734555 ER PT J AU Duggan, A Garcia-Anoveros, J Corey, DP AF Duggan, A Garcia-Anoveros, J Corey, DP TI The PDZ domain protein PICK1 and the sodium channel BNaC1 interact and localize at mechanosensory terminals of dorsal root ganglion neurons and dendrites of central neurons SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MAMMALIAN DEGENERIN MDEG; NMDA RECEPTOR SUBUNITS; YEAST 2-HYBRID SYSTEM; GATED CATION CHANNEL; SENSING ION CHANNELS; KINASE-C-ALPHA; NA+ CHANNEL; MOLECULAR-CLONING; CAENORHABDITIS-ELEGANS; GUANYLATE KINASES AB Members of the BNaC/ASIC family of ion channels have been implicated in mechanotransduction and nociception mediated by dorsal root ganglion (DRG) neurons. These ion channels are also expressed in the CNS. We identified the PDZ domain protein PICK1 as an interactor of BNaC1(ASIC2) in a yeast two-hybrid screen. We show by two-hybrid assays, glutathione S-transferase pull-down assays, and coimmunoprecipitations that the BNaC1(.)PICK1 interaction is specific, and that coexpression of both proteins leads to their clustering in intracellular compartments. The interaction between BNaC1 and PICK1 requires the PDZ domain of PICK1 and the last four amino acids of BNaC1. BNaC1 is similar to two other BNaC/ASIC family members, BNaC2 (ASIC1) and ASIC4, at its extreme C terminus, and we show that PICK1 also interacts with BNaC2. We found that PICK1, like BNaC1 and BNaC2, is expressed by DRG neurons and, like the BNaC1alpha isoform, is present at their peripheral mechanosensory endings. Both PICK1 and BNaC1alpha are also coexpressed by some pyramidal neurons of the cortex, by pyramidal neurons of the CA3 region of hippocampus, and by cerebellar Purkinje neurons, localizing to their dendrites and cell bodies. Therefore, PICK1 interacts with BNaC/ASIC channels and may regulate their subcellular distribution or function in both peripheral and central neurons. C1 Massachusetts Gen Hosp, Dept Neurobiol, Boston, MA 02114 USA. Howard Hughes Med Inst, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Corey, DP (reprint author), Massachusetts Gen Hosp, Dept Neurobiol, WEL414, Boston, MA 02114 USA. OI Corey, David/0000-0003-4497-6016 NR 67 TC 95 Z9 100 U1 1 U2 1 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 FEB 15 PY 2002 VL 277 IS 7 BP 5203 EP 5208 DI 10.1074/jbc.M104748200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 523NX UT WOS:000173962900085 PM 11739374 ER PT J AU Liang, WH Burnett, CB Rowland, JH Meropol, NJ Eggert, L Hwang, YT Silliman, RA Weeks, JC Mandelblatt, JS AF Liang, WH Burnett, CB Rowland, JH Meropol, NJ Eggert, L Hwang, YT Silliman, RA Weeks, JC Mandelblatt, JS TI Communication between physicians and older women with localized breast cancer: Implications for treatment and patient satisfaction SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RADIATION-THERAPY; CONSERVING SURGERY; DECISION-MAKING; AGE-DIFFERENCES; CARE; INFORMATION; MASTECTOMY; LUMPECTOMY; PREFERENCES; ATTITUDES AB Purpose: To identify factors associated with patient-physician communication and to examine the impact of communication on patients' perception of having a treatment choice, actual treatment received, and satisfaction with care among older breast cancer patients. Materials and Methods: Data were collected from 613 pairs of surgeons and their older (greater than or equal to 67 years) patients diagnosed with localized breast cancer. Measures of patients' self-reported communication included physician- and patient-initiated communication and the number of treatment options discussed. Logistic regression analyses were conducted to examine the relationships between communication and outcomes. Results: Patients who reported that their surgeons mentioned more treatment options were 2.21 times (95% confidence interval [CI], 1.62 to 3.01) more likely to report being given a treatment choice, and 1.33 times (95% CI, 1.02 to 1.73) more likely to get breast-conserving surgery with radiation than other types of treatment. Surgeons who were trained in surgical oncology, or who treated a high volume of breast cancer patients (greater than or equal to 75% of practice), were more likely to initiate communication with patients (odds ratio [OR] = 1.62; 95% CI, 1.02 to 2.56; and OR = 1.68; 95% CI, 1.01 to 2.76, respectively). A high degree of physician-initiated communication, in turn, was associated with patients' perception of having a treatment choice (OR = 2.46; 95% CI, 1.29 to 4.70), and satisfaction with breast cancer care (OR = 2.13; 95% CI, 1.17 to 3.85) in the 3 to 6 months after surgery. Conclusion: Greater patient-physician communication was associated with a sense of choice, actual treatment, and satisfaction with care. Technical information and caring components of communication impacted outcomes differently. Thus, the quality of cancer care for older breast cancer patients may be improved through interventions that improve communication within the physician-patient dyad. (C) 2002 by American Society of Clinical Oncology. C1 Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Med, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Sch Nursing, Washington, DC 20007 USA. NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. Fox Chase Canc Ctr, Div Med Sci, Philadelphia, PA 19111 USA. Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. Boston Univ, Med Ctr, Boston, MA USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Oncol, Boston, MA 02115 USA. RP Liang, WH (reprint author), Georgetown Univ, Med Ctr, Dept Oncol, 2233 Wisconsin Ave NW,Ste 440, Washington, DC 20007 USA. FU AHRQ HHS [HS08395] NR 44 TC 113 Z9 113 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 15 PY 2002 VL 20 IS 4 BP 1008 EP 1016 DI 10.1200/JCO.20.4.1008 PG 9 WC Oncology SC Oncology GA 522GZ UT WOS:000173889100021 PM 11844824 ER PT J AU Chakravarti, A Noll, E Black, PM Finkelstein, DF Finkelstein, DM Dyson, NJ Loeffler, JS AF Chakravarti, A Noll, E Black, PM Finkelstein, DF Finkelstein, DM Dyson, NJ Loeffler, JS TI Quantitatively determined survivin expression levels are of prognostic value in human gliomas SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ANTI-APOPTOSIS GENE; MALIGNANT GLIOMA; CANCER; OLIGODENDROGLIOMAS; NEUROBLASTOMA; RADIOTHERAPY; INHIBITION; PREDICTORS; CARCINOMAS; CELLS AB Purpose: Survivin is a novel antiapoptotic gene that has been recently cloned and characterized. Its expression has been found to be of prognostic significance in several tumor types. This is the first study on the prognostic significance of survivin expression in human gliomas. Materials and Methods: We used quantitative Western blot analysis with densitometry to determine survivin protein expression levels in 92 glioma cases for which frozen tissue was available for analysis. Survivin positivity and expression levels were correlated with histopothologic features of the tumors, apoptosis (as measured by cleaved, or activated, caspase 3 levels), and clinical outcome. Results: Survivin expression has clear prognostic value in human gliomas. Patients with detectable survivin expression had significantly shorter overall survival times (P < .0001) compared with those without detectable expression when all glioma patients were considered. Although glioblastoma multiforme (GBM) patients had significantly higher rates of survivin positivity and higher levels of survivin expression (P < .0001) than their non-GBM counterparts, the prognostic value of survivin expression seemed to be independent of histology alone. Survivin-positive GBM patients had significantly shorter overall survival times compared with survivin-negative GBM patients (P < .0001). Likewise, survivin-positive non-GBM patients had shorter survival times compared with survivin-negative non-GBM patients (P = .029). Furthermore, increasing levels of survivin expression significantly correlated with reduced survival times when all glioma patients were considered, and markedly so for GBM patients (P < .0001). Increasing survivin levels significantly correlated with reduced expression of cleaved caspase 3, indicating its association with antiapoptotic activity. Conclusion: Survivin positivity and protein expression levels, as determined quantitatively, are of significant prognostic value in human gliomas and seem to be associated with reduced apoptotic capacity of these tumors. (C) 2002 by American Society of Clinical Oncology. C1 Massachusetts Gen Hosp, Oncol Mol Lab, Ctr Canc, Dept Radiat Oncol, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Dept Biostat, Ctr Canc, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. RP Chakravarti, A (reprint author), Massachusetts Gen Hosp, Oncol Mol Lab, Ctr Canc, Dept Radiat Oncol, 13th St,Bldg 149,Room 7330, Charlestown, MA 02129 USA. FU NCI NIH HHS [KO8CA82163, R01CA64402] NR 27 TC 209 Z9 256 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 15 PY 2002 VL 20 IS 4 BP 1063 EP 1068 DI 10.1200/JCO.20.4.1063 PG 6 WC Oncology SC Oncology GA 522GZ UT WOS:000173889100028 PM 11844831 ER PT J AU Carter, AR Chen, CF Schwartz, PM Segal, RA AF Carter, AR Chen, CF Schwartz, PM Segal, RA TI Brain-derived neurotrophic factor modulates cerebellar plasticity and synaptic ultrastructure SO JOURNAL OF NEUROSCIENCE LA English DT Article DE neurotrophin; BDNF; Trk receptor; cerebellum; facilitation; ultrastructure; presynaptic plasticity ID LONG-TERM POTENTIATION; CULTURED HIPPOCAMPAL-NEURONS; PAIRED-PULSE FACILITATION; BDNF KNOCKOUT MICE; NEUROTRANSMITTER RELEASE; VESICLE CYCLE; ADULT HIPPOCAMPUS; GRANULE NEURONS; NERVOUS-SYSTEM; SYNAPSIN-I AB Neurotrophins are key regulators of neuronal survival and function. Here we show that TrkB, the receptor for brain-derived neurotrophic factor (BDNF), is located at parallel fiber to Purkinje cell (PF/PC) synapses of the cerebellum. To determine the effects of TrkB receptor activation on synapse formation and function, we examined the parallel fiber to Purkinje cell synapses of mice with a targeted deletion of the BDNF gene. Although Purkinje cell dendrites are abnormal in BDNF -/- mice, PF/PC synapses are still able to form. Immunohistochemical analysis of mutant animals revealed the formation of numerous PF/PC synapses with the appropriate apposition of presynaptic and postsynaptic proteins. These synapses are functional, and no differences were detected in the waveform of evoked EPSCs, the amplitude of spontaneous mini-EPSCs, or the response to prolonged 10 Hz stimulus trains. However, paired-pulse facilitation, a form of short-term plasticity, is significantly decreased in BDNF -/- mice. Detailed ultrastructural analysis of the presynaptic terminals demonstrated that this change in synaptic function is accompanied by an increase in the total number of synaptic vesicles in mutant mice and a decrease in the proportion of vesicles that are docked. These data suggest that BDNF regulates both the mechanisms that underlie short-term synaptic plasticity and the steady-state relationship between different vesicle pools within the terminal. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurobiol, Dept Pediat Oncol, Boston, MA 02115 USA. Childrens Hosp, Dept Neurol, Div Neurosci, Boston, MA 02115 USA. RP Segal, RA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Dana 620,44 Binney St, Boston, MA 02115 USA. FU NINDS NIH HHS [NS37757]; NLM NIH HHS [5F31LM00040-05] NR 66 TC 121 Z9 122 U1 1 U2 4 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 FEB 15 PY 2002 VL 22 IS 4 BP 1316 EP 1327 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 525HE UT WOS:000174062300016 PM 11850459 ER PT J AU Berven, S Zurakowski, D Mankin, HJ Gebhardt, MC Springfield, DS Hornicek, FJ AF Berven, S Zurakowski, D Mankin, HJ Gebhardt, MC Springfield, DS Hornicek, FJ TI Clinical outcome in chordoma - Utility of flow cytometry in DNA determination SO SPINE LA English DT Article ID DEDIFFERENTIATED CHORDOMA; RADIATION-THERAPY; SACRAL CHORDOMAS; OSTEO-SARCOMA; BONE-TUMORS; CHEMOTHERAPY; LEUKEMIA; SPINE; CHONDROSARCOMA; CYTOGENETICS AB Study Design. A retrospective review of 100 patients with chordoma of the lumbar spine and sacrum. Twenty-three patients had flow cytometry data available and a minimum follow-up period of 5 years. Objectives. To determine whether DNA content and cell cycle analysis were associated with patient outcome. Summary of Background Data, DNA flow cytometry has been shown to be predictive for biologic behavior of various tumors. Chordoma has been evaluated in very small numbers of patients using DNA flow cytometric analysis, and the utility of DNA patterns in predicting outcome has not been clearly demonstrated. Methods. Between January 1979 and December 1995, 100 patients underwent surgical resection for chordoma, and 23 had a minimum follow-up period of 5 years with flow cytometry data. DNA content and cell cycle analysis were determined by enzymatically staining cells with propidium iodide dye and passing them through a flow cytometer. DNA histograms were generated. Survivorship and freedom from local recurrence curves were constructed by the Kaplan-Meier method and compared by the log-rank test. Results. The mean follow-up period was 7.3 years. For this group of 23 patients, mortality was 61% (14 patients) and local recurrence was 78% (18 patients). Eleven patients had tumors with diploid DNA content, and 12 patients had tumors with aneuploid DNA content. Metastases occurred in 4 of the 11 patients with a diploid pattern and 6 of the 12 with an aneuploid pattern. Six of the 11 patients with the diploid pattern died, in comparison with 8 of 12 patients with the aneuploid pattern. The Kaplan-Meier estimated survivorship (95% confidence interval) was 78% (66-90%) at a follow-up period of 5 years and 36% at a follow-up period of 10 years (22-50%), and no significant differences were found between patients with diploid and aneuploid patterns. Conclusions. Patients in whom metastases did not develop had a more favorable clinical outcome, DNA pattern was not associated with local recurrence or survival. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg, Boston, MA 02115 USA. Childrens Hosp, Dept Orthopaed Surg, Boston, MA 02115 USA. Childrens Hosp, Dept Biostat, Boston, MA 02115 USA. RP Berven, S (reprint author), Univ Calif San Francisco, Dept Orthopaed Surg, 500 Parnassus Ave,MU320W, San Francisco, CA 94143 USA. NR 58 TC 20 Z9 26 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD FEB 15 PY 2002 VL 27 IS 4 BP 374 EP 379 DI 10.1097/00007632-200202150-00010 PG 6 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 524HE UT WOS:000174006500008 PM 11840103 ER PT J AU Allan, JS Wain, JC Schwarze, ML Houser, SL Benjamin, LG Madsen, JC Sachs, DH AF Allan, JS Wain, JC Schwarze, ML Houser, SL Benjamin, LG Madsen, JC Sachs, DH TI Modeling chronic lung allograft rejection in miniature swine SO TRANSPLANTATION LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; OBLITERATIVE AIRWAY DISEASE; LARGE-ANIMAL-MODEL; MONOCLONAL-ANTIBODIES; TRANSPLANT RECIPIENTS; HETEROTOPIC LUNG; T-CELLS; CLASS-I; BRONCHIOLITIS; EXPRESSION AB Background. The success of lung transplantation has been limited by the perplexing problem of chronic rejection. The development of a large-animal model for the systematic study of the mechanisms underlying chronic lung rejection has been problematic. We have developed a new preclinical model of chronic lung rejection using MHC-inbred miniature swine. Methods. Using standard operative techniques, four orthotopic left lung allografts were performed using MHC-matched, minor-antigen-mismatched donors. Recipient animals received a 12-day course of postoperative cyclosporine. Grafts were followed with open biopsies and high-resolution computed tomography. Cellular immune responses were monitored by mixed lymphocyte reaction, cytometric analysis of graft-infiltrating lymphocytes, and skin grafting. Results. All grafts survived 2:5 months and developed manifestations of chronic rejection, including obliterative bronchiolitis, interstitial fibrosis, and occlusive vasculopathy. A mononuclear infiltrate was also present in all grafts by the fourth posttransplant month. High-resolution computed tomography demonstrated several cardinal radiographic findings known to correlate with chronic rejection. Cytometric analysis of graft-infiltrating lymphocytes showed a predominance of CD8(+) cells. The development of alloreactivity in the host was confirmed by mixed lymphocyte reaction and skin grafting. Conclusions. We report a reproducible, whole-lung, large-animal model of chronic lung rejection. In this immunogenetically defined construct, we have observed a full spectrum of histopathologic lesions that reproduce with fidelity those lesions observed in human lung transplant recipients suffering from chronic rejection. We anticipate that this preclinical model will facilitate further study of the pathogenesis and therapy of chronic lung rejection. C1 Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Cardiac Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Allan, JS (reprint author), Massachusetts Gen Hosp, Div Thorac Surg, Blake 1570,55 Fruit jSt, Boston, MA 02114 USA. NR 26 TC 26 Z9 26 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD FEB 15 PY 2002 VL 73 IS 3 BP 447 EP 453 AR UNSP 0041-1337/02/7303-447/0 DI 10.1097/00007890-200202150-00020 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 526EA UT WOS:000174115400020 PM 11884943 ER PT J AU Parekh-Olmedo, H Krainc, D Kmiec, EB AF Parekh-Olmedo, H Krainc, D Kmiec, EB TI Targeted gene repair and its application to neurodegenerative disorders SO NEURON LA English DT Review ID CHIMERIC RNA/DNA OLIGONUCLEOTIDES; RNA-DNA OLIGONUCLEOTIDE; MAMMALIAN-CELLS; MUTATION; STRAND AB Synthetic DNA oligonucleotides can direct the exchange of single nucleotides within coding regions of mammalian genes by hybridizing to their complementary sequence in the chromosome and creating a recombination joint structure with a single mismatched base pair. Inherent DNA repair processes recognize the mismatch and resolve it using the DNA sequence of the oligonucleotide vector as the template. This gene surgery approach can be used to repair mutations or to disrupt tri-nucleotide repeats in dysfunctional genes responsible for neurological disorders. C1 Univ Delaware, Dept Biol Sci, Delaware Biotechnol Inst, Newark, DE 19716 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA. RP Kmiec, EB (reprint author), Univ Delaware, Dept Biol Sci, Delaware Biotechnol Inst, Newark, DE 19716 USA. NR 19 TC 9 Z9 9 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD FEB 14 PY 2002 VL 33 IS 4 BP 495 EP 498 DI 10.1016/S0896-6273(02)00594-9 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 522RQ UT WOS:000173911100004 PM 11856524 ER PT J AU Rigotti, NA AF Rigotti, NA TI Treatment of tobacco use and dependence. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SUSTAINED-RELEASE BUPROPION; SMOKING CESSATION; CONTROLLED TRIAL; NICOTINE REPLACEMENT; TRANSDERMAL NICOTINE; RANDOMIZED TRIAL; WEIGHT-GAIN; SMOKERS; THERAPY; PLACEBO C1 Massachusetts Gen Hosp, Dept Med, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Rigotti, NA (reprint author), Massachusetts Gen Hosp, Dept Med, Tobacco Res & Treatment Ctr, 50 Staniford St,9th Fl, Boston, MA 02114 USA. FU NHLBI NIH HHS [HL04440] NR 39 TC 187 Z9 192 U1 4 U2 9 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 FEB 14 PY 2002 VL 346 IS 7 BP 506 EP 512 DI 10.1056/NEJMcp012279 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 521AE UT WOS:000173815300008 PM 11844853 ER PT J AU Barnett, PG Chen, S Boden, WE Chow, B Every, NR Lavori, PW Hlatky, MA AF Barnett, PG Chen, S Boden, WE Chow, B Every, NR Lavori, PW Hlatky, MA TI Cost-effectiveness of a conservative, ischemia-guided management strategy after non-Q-wave myocardial infarction - Results of a randomized trial SO CIRCULATION LA English DT Article DE cost-benefit analysis; myocardial infarction; angiography; tests ID CORONARY ANGIOGRAPHY; UNSTABLE ANGINA; CARE COSTS; OUTCOMES; SURGERY; VA AB Background-Use of coronary angiography after myocardial infarction has been controversial, with some physicians advocating routine use and others advocating selective use only after documentation of residual myocardial ischemia. The effects of these strategies on economic outcomes have not been established. Methods and Results-We analyzed data from a randomized, controlled clinical trial conducted in 17 Department of Veterans Affairs hospitals that enrolled 876 clinically uncomplicated patients 24 to 72 hours after an acute non-Q-wave myocardial infarction. The routine invasive strategy included early coronary angiography with revascularization based on established guidelines. The conservative, ischemia-guided strategy included noninvasive testing with radionuclide ventriculography and exercise thallium scintigraphy, followed by coronary angiography in patients with objective evidence of myocardial ischemia. We measured the cost of hospitalization and outpatient visits and tests during follow-up and calculated the incremental cost-effectiveness ratio. The conservative, ischemia-guided strategy had lower costs than the routine invasive strategy, both during the initial hospitalization ($14 733 versus $19 256, P<0.001) and after a mean follow-up of 1.9 years ($39 707 versus $41 893, P=0.04). The hazard ratio for death was 0.72 (confidence limits, 0.51 to 1.01) in the conservative strategy. The conservative strategy had lower costs and better outcomes in 76% of 1000 bootstrap replications, and a cost-effectiveness ratio below $50 000 per year of life added in 96% of replications. Conclusions-A conservative, ischemia-guided strategy of selective coronary angiography and revascularization for patients who develop objective evidence of recurrent ischemia is more cost-effective than a strategy of routine coronary angiography after uncomplicated non-Q-wave myocardial infarction. C1 Stanford Univ, Sch Med, Stanford, CA 94305 USA. VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. Syracuse VA Med Ctr, Syracuse, NY USA. VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Hlatky, MA (reprint author), Stanford Univ, Sch Med, HRP Redwood Bldg,Room 150, Stanford, CA 94305 USA. NR 21 TC 30 Z9 32 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 12 PY 2002 VL 105 IS 6 BP 680 EP 684 DI 10.1161/hc0602.103584 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 522YM UT WOS:000173924600015 PM 11839621 ER PT J AU Quinn, J Moore, M Benson, DF Clark, CM Doody, R Jagust, W Knopman, D Kaye, JA AF Quinn, J Moore, M Benson, DF Clark, CM Doody, R Jagust, W Knopman, D Kaye, JA TI A Videotaped CIBIC for dementia patients - Validity and reliability in a simulated clinical trial SO NEUROLOGY LA English DT Article ID ALZHEIMERS-DISEASE; GLOBAL CHANGE; RATING-SCALE; DOUBLE-BLIND; DRUG TRIALS; TACRINE; MULTICENTER; IMPRESSION AB Background: The global impression of a clinician is an Food and Drug Administration-mandated primary outcome measure for clinical trials in dementia. Reliability and validity of these measures are not well established. Methods: A videotaped version of the Clinician's Interview Based Impression-of Change (CIBIC) was evaluated. Raters were informed that the videotaped interviews were taken at baseline and 6 to 12 months later, when in fact half of the interviews were shown in reverse order. Ratings on "true order" interviews were compared with ratings on "reverse order" interviews. In addition, ratings by neurologists experienced in dementia were compared with those of less experienced raters. Results: Inter-rater reliability of the neurologists was poor when measured by absolute agreement on a 7-point scale (kappa = 0.18). With a less stringent 3-point scale (better, worse, or unchanged), inter-rater reliability was significantly better for the true order videos (kappa = 0.51) than for the reversed order videos (kappa = 0.12). Validity also was reduced in the reverse order group: neurologists rated 90% of subjects correctly in the "true order" group and 63% correctly in the "reversed order" group. The inter-rater reliability of the neurologists was greater than the less experienced raters, but the validity of the neurologists' ratings was only marginally better. Conclusions: The reliability and validity of the videotape CIBIC are reasonable when patients follow the expected course of gradual decline, but are poor when patients appear to improve. These findings suggest that global assessments should be modified as outcome measures in clinical trials with patients with dementia. C1 Portland Vet Affairs Med Ctr, Dept Neurol, Portland, OR 97201 USA. Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. Univ Calif Davis, Dept Neurol, Davis, CA 95616 USA. Mayo Clin, Dept Neurol, Rochester, MN USA. RP Quinn, J (reprint author), Portland Vet Affairs Med Ctr, Dept Neurol, P3 R&D,3710 SW US Vet Hosp Rd, Portland, OR 97201 USA. OI Kaye, Jeffrey/0000-0002-9971-3478 FU NIA NIH HHS [AG 08017] NR 24 TC 30 Z9 30 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD FEB 12 PY 2002 VL 58 IS 3 BP 433 EP 437 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 520FT UT WOS:000173770900018 PM 11839844 ER PT J AU Mathis, CA Bacskai, BJ Kajdasz, ST McLellan, ME Frosch, MP Hyman, BT Holt, DP Wang, YM Huang, GF Debnath, ML Klunk, WE AF Mathis, CA Bacskai, BJ Kajdasz, ST McLellan, ME Frosch, MP Hyman, BT Holt, DP Wang, YM Huang, GF Debnath, ML Klunk, WE TI A lipophilic thioflavin-T derivative for positron emission tomography (PET) Imaging of amyloid in brain SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID ALZHEIMERS-DISEASE; TRANSGENIC MICE; IN-VIVO; PROTEIN; PLAQUES AB The synthesis of a new lipophilic thioflavin-T analogue (2-[4'-(methylamino)phenyl]benzothiazole, 6) with high affinity for amyloid is reported. Intravenous injection of [C-11]-labeled 6 in control mice resulted in high brain uptake. Amyloid deposits were imaged with multiphoton microscopy in the brains of living transgenic mice following the systemic injection of unlabeled 6. [C-11]6 is a promising amyloid imaging agent for Alzheimer's disease. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Univ Pittsburgh, Dept Radiol, PET Facil, Pittsburgh, PA 15213 USA. Massachusetts Gen Hosp, Alzheimers Res Unit, Charlestown, MA 02129 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. RP Mathis, CA (reprint author), Univ Pittsburgh, Dept Radiol, PET Facil, Pittsburgh, PA 15213 USA. RI Mathis, Chester/A-8607-2009; OI Klunk, William/0000-0001-5512-0251 FU NIA NIH HHS [AG08487, AG15379, AG18402] NR 25 TC 232 Z9 241 U1 0 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 11 PY 2002 VL 12 IS 3 BP 295 EP 298 AR PII S0960-894X(01)00734-X DI 10.1016/S0960-894X(01)00734-X PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 526TJ UT WOS:000174145500008 PM 11814781 ER PT J AU Ayoub, IA Maynard, KI AF Ayoub, IA Maynard, KI TI Therapeutic window for nicotinamide following transient focal cerebral ischemia SO NEUROREPORT LA English DT Article DE middle cerebral artery occlusion; neuroprotection; niacin; stroke; vitamin B3 ID INFARCT VOLUME; WISTAR RATS AB The therapeutic window with the neuroprotectant nicotinamide (NAm) was tested in a model of stroke. Either 2,4 or 6 h after the onset of transient (2 h) focal cerebral ischemia, Wistar rats received either saline or NAm (500 mg/kg). Sensory and motor behavioral scores and weight of the animals were obtained before surgery, and 2 h, 3 and 7 days after stroke onset. Cerebral infarct volumes were measured on day 7 after sacrifice. NAm given 4 or 6 h after stroke onset significantly (p < 0.05) reduced the cerebral infarction and improved the behavioral scores, respectively, compared to saline-injected animals. There was a non-significant improvement in weight gained by NAm-treated rats at 3 and 7 days following stroke compared to the saline-injected controls. NeuroReport 13:213-2.16 (C) 2002 Lippincott Williams & Wilkins. C1 Aventis Pharmaceut Inc, Bridgewater, NJ 08807 USA. Massachusetts Gen Hosp, Neurosurg Serv, Neurophysiol Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Maynard, KI (reprint author), Aventis Pharmaceut Inc, Route 202-206,L-103D, Bridgewater, NJ 08807 USA. NR 18 TC 30 Z9 30 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD FEB 11 PY 2002 VL 13 IS 2 BP 213 EP 216 DI 10.1097/00001756-200202110-00008 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 518XA UT WOS:000173692300008 PM 11893912 ER PT J AU Capasso, V Burke, D Stanley, D Abbott, W AF Capasso, V Burke, D Stanley, D Abbott, W TI Unit-based specialty vascular transitional home care program: An example of evidence-based nursing practice SO ONLINE JOURNAL OF KNOWLEDGE SYNTHESIS FOR NURSING LA English DT Article ID RANDOMIZED CLINICAL-TRIAL; EARLY HOSPITAL DISCHARGE; FOLLOW-UP; BIRTH; WOMEN C1 Nursing Business Ctr, Vasc Nursing & Home Care Program, Boston, MA 02114 USA. Nursing Business Ctr, Massachusetts Gen Hosp, Wound Care Ctr, Boston, MA 02114 USA. MGH Wound Care Ctr, Div Vasc Surg, Boston, MA USA. MGH Vasc Home Care Program, Boston, MA USA. RP Capasso, V (reprint author), Nursing Business Ctr, Vasc Nursing & Home Care Program, Bigelow 10,32 Fruit St, Boston, MA 02114 USA. NR 9 TC 0 Z9 0 U1 1 U2 1 PU SIGMA THETA TAU INT PI INDIANAPOLIS PA 550 W NORTH STREET, INDIANAPOLIS, IN 46202 USA SN 1072-7639 J9 ONLINE J KNOWL SYN N JI Online J. Knowl. Synth. Nurs. PD FEB 11 PY 2002 VL 9 IS 3C AR 3C PG 3 WC Nursing SC Nursing GA 561EQ UT WOS:000176127600001 PM 12089638 ER PT J AU Boas, DA Culver, JP Stott, JJ Dunn, AK AF Boas, DA Culver, JP Stott, JJ Dunn, AK TI Three dimensional Monte Carlo code for photon migration through complex heterogeneous media including the adult human head SO OPTICS EXPRESS LA English DT Article ID NEAR-INFRARED SPECTROSCOPY; TISSUE OPTICAL-PROPERTIES; HUMAN BRAIN; NONSCATTERING REGIONS; BOUNDARY-CONDITIONS; RADIATIVE-TRANSFER; LIGHT-PROPAGATION; STEADY-STATE; TOMOGRAPHY; TRANSPORT AB We describe a novel Monte Carlo code for photon migration through 3D media with spatially varying optical properties. The code is validated against analytic solutions of the photon diffusion equation for semi-infinite homogeneous media. The code is also cross-validated for photon migration through a slab with an absorbing heterogeneity. A demonstration of the utility of the code is provided by showing time-resolved photon migration through a human head. This code, known as 'tMCimg', is available on the web and can serve as a resource for solving the forward problem for complex 3D structural data obtained by MRI or CT. (C) 2002 Optical Society of America. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, NMR Ctr, Charlestown, MA 02129 USA. RP Boas, DA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, NMR Ctr, Charlestown, MA 02129 USA. EM dboas@nmr.mgh.harvard.edu; jculver@nmr.mgh.harvard.edu; jstott@nmr.mgh.harvard.edu; adunn@nmr.mgh.harvard.edu RI Dunn, Andrew/I-9527-2014 NR 42 TC 334 Z9 343 U1 1 U2 26 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 FEB 11 PY 2002 VL 10 IS 3 BP 159 EP 170 DI 10.1364/OE.10.000159 PG 12 WC Optics SC Optics GA 520WG UT WOS:000173805700003 PM 19424345 ER PT J AU Griffin, JD AF Griffin, JD TI Resistance to targeted therapy in leukaemia SO LANCET LA English DT Editorial Material C1 Dana Farber Canc Inst, Leukemia Program, Boston, MA 02115 USA. RP Griffin, JD (reprint author), Dana Farber Canc Inst, Leukemia Program, Boston, MA 02115 USA. NR 7 TC 15 Z9 15 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD FEB 9 PY 2002 VL 359 IS 9305 BP 458 EP 459 DI 10.1016/S0140-6736(02)07671-7 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 520ML UT WOS:000173785600004 PM 11853786 ER PT J AU Costigan, M Woolf, CJ AF Costigan, M Woolf, CJ TI No DREAM, no pain: Closing the spinal gate SO CELL LA English DT Review ID PRODYNORPHIN GENE AB Pain transmission in the spinal cord is regulated by a balance of facilitatory and inhibitory influences operating on the neural circuits of the somatosensory system. The transcriptional repressor DREAM acts constitutively to suppress prodynorphin expression in spinal cord neurons. Knocking out DREAM results in sufficient dynorphin expression to produce a strong reduction in generalized pain behavior, highlighting the role that intracellular molecules play in modulating pain gating in the spinal cord. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp E, Charlestown, MA 02129 USA. RP Woolf, CJ (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, Charlestown, MA 02129 USA. NR 14 TC 46 Z9 53 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD FEB 8 PY 2002 VL 108 IS 3 BP 297 EP 300 DI 10.1016/S0092-8674(02)00640-2 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 520VB UT WOS:000173801600001 PM 11853663 ER PT J AU Holt, JR Gillespie, SKH Provance, DW Shah, K Shokat, KM Corey, DP Mercer, JA Gillespie, PG AF Holt, JR Gillespie, SKH Provance, DW Shah, K Shokat, KM Corey, DP Mercer, JA Gillespie, PG TI A chemical-genetic strategy implicates myosin-1c in adaptation by hair cells SO CELL LA English DT Article ID MECHANOELECTRICAL TRANSDUCTION; BULLFROGS SACCULUS; I-BETA; BLOCK ADAPTATION; MOUSE UTRICLE; INNER-EAR; TIP LINKS; LOCALIZATION; KINASE; IDENTIFICATION AB Myosin-1c (also known as myosin-1beta) has been proposed to mediate the slow component of adaptation by hair cells, the sensory cells of the inner ear. To test this hypothesis, we mutated tyrosine-61 of myosin-1c to glycine, conferring susceptibility to inhibition by N-6-modified ADP analogs. We expressed the mutant myosin-1c in utricular hair cells of transgenic, mice, delivered an ADP analog through a whole-cell recording pipette, and found that the analog rapidly blocked adaptation to positive and negative deflections in transgenic cells but not in wild-type cells. The speed and specificity of inhibition suggests that myosin-1c participates in adaptation in hair cells. C1 Oregon Hlth & Sci Univ, Oregon Hearing Res Ctr, Portland, OR 97201 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. Univ Virginia, Sch Med, Dept Neurosci, Charlottesville, VA 22908 USA. McLaughlin Res Inst, Great Falls, MT 59405 USA. Genom Inst Novartis Res Fdn, San Diego, CA 92121 USA. Univ Calif San Francisco, Dept Mol & Cellular Pharmacol, San Francisco, CA 94143 USA. Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97201 USA. RP Gillespie, PG (reprint author), Oregon Hlth & Sci Univ, Oregon Hearing Res Ctr, Portland, OR 97201 USA. RI Provance Jr., David/D-5294-2013; OI Provance Jr., David/0000-0002-9824-0672; Corey, David/0000-0003-4497-6016; Barr-Gillespie, Peter/0000-0002-9787-5860 FU NCI NIH HHS [CA70331]; NIDCD NIH HHS [R01 DC003279-04, DC00304, DC02368, DC03279, R01 DC002368-06] NR 44 TC 210 Z9 220 U1 0 U2 10 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD FEB 8 PY 2002 VL 108 IS 3 BP 371 EP 381 DI 10.1016/S0092-8674(02)00629-3 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 520VB UT WOS:000173801600009 PM 11853671 ER PT J AU Muller, JG Isomatsu, Y Koushik, SV O'Quinn, M Xu, L Kappler, CS Hapke, E Zile, MR Conway, SJ Menick, DR AF Muller, JG Isomatsu, Y Koushik, SV O'Quinn, M Xu, L Kappler, CS Hapke, E Zile, MR Conway, SJ Menick, DR TI Cardiac-specific expression and hypertrophic upregulation of the feline Na+-Ca2+ exchanger gene H1-promoter in a transgenic mouse model SO CIRCULATION RESEARCH LA English DT Article DE Na+-Ca2+ exchanger; pressure-overload hypertrophy; transgenic mice ID SODIUM-CALCIUM EXCHANGER; HUMAN VENTRICULAR MYOCYTES; FAILING HUMAN HEART; NA-CA EXCHANGE; SARCOPLASMIC-RETICULUM; NA+/CA2+ EXCHANGER; HUMAN MYOCARDIUM; NCX1; CONTRACTION; RELAXATION AB The NCX1 gene contains three promoters (H1, K1, and Br1), and as a result of alternative promoter usage and alternative splicing, there are multiple tissue-specific variants of the Na+-Ca2+ exchanger. We have proposed that for NCX1, the H1 promoter regulates expression in the heart, the K1 promoter regulates expression in the kidney, and the Br1 promoter regulates expression in the brain as well as low-level ubiquitous expression. Here, using a transgenic mouse model, we test the role of the DNA region including -1831 to 67 by of intron 1, encompassing exon H1 of the feline NCX1 gene (NCX1H1). The NCX1H1 promoter was sufficient for driving the normal spatiotemporal pattern of NCX1 expression in cardiac development. The luciferase reporter gene was expressed in a heart-restricted pattern both in early embryos (embryonic days 8 to 14) and in later embryos (after embryonic day 14), when NCX1 is also expressed in other tissues. In the adult, no luciferase activity was detected in the kidney, liver, spleen, uterus, or skeletal muscle; minimal activity was detected in the brain; and very high levels of luciferase expression were detected in the heart. Transverse aortic constriction-operated mice showed significantly increased left ventricular mass after 7 days. In addition, there was a 2-fold upregulation of NCX1H1 promoter activity in the left ventricle in animals after 7 days of pressure overload compared with both control and sham-operated animals. This work demonstrates that the NCX1H1 promoter directs cardiac-specific expression of the exchanger in both the embryo and adult and is also sufficient for the upregulation of NCX1 in response to pressure overload. C1 Med Univ S Carolina, Gazes Cardiac Res Inst, Charleston, SC 29425 USA. Med Univ S Carolina, Div Cardiol, Charleston, SC 29425 USA. Ralph H Johnson Dept Vet Affairs, Charleston, SC USA. Med Coll Georgia, Inst Mol Med & Genet, Augusta, GA 30912 USA. RP Menick, DR (reprint author), Med Univ S Carolina, Gazes Cardiac Res Inst, 114 Doughty St,Room 203,POB 250773, Charleston, SC 29425 USA. FU NHLBI NIH HHS [HL-60104, HL-60714, HL-48788] NR 37 TC 24 Z9 25 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD FEB 8 PY 2002 VL 90 IS 2 BP 158 EP 164 DI 10.1161/hh0202.103231 PG 7 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 521CT UT WOS:000173821800010 PM 11834708 ER PT J AU Nghiem, P Park, PK Kim, YS Desai, BN Schreiber, SL AF Nghiem, P Park, PK Kim, YS Desai, BN Schreiber, SL TI ATR is not required for p53 activation but synergizes with p53 in the replication check-point SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-CYCLE CHECKPOINT; EARLY EMBRYONIC LETHALITY; DNA-DAMAGE CHECKPOINT; ATAXIA-TELANGIECTASIA; INDUCED PHOSPHORYLATION; IONIZING-RADIATION; MAMMALIAN-CELLS; KINASE; PROTEIN; GENE AB ATR (ataxia telangiectasia and Rad-3-related) is a protein kinase required for survival after DNA damage. A critical role for ATR has been hypothesized to be the regulation of p53 and other cell cycle checkpoints. ATR has been shown to phosphorylate p53 at Ser(15), and this damage-induced phosphorylation is diminished by expression of a catalytically inactive (ATR-kd) mutant. p53 function could not be examined directly in prior studies of ATR, however, because p53 was mutant or because cells expressed the SV40 large T antigen that blocks p53 function. To test the interactions of ATR and p53 directly we generated human U2OS cell lines inducible for either wild-type or kinase-dead ATR that also have an intact p53 pathway. Indeed, ATR-kd expression sensitized these cells to DNA damage and caused a transient decrease in damage-induced serine 15 phosphorylation of p53. However, we found that the effects of ATR-kd expression do not result in blocking the response of p53 to DNA damage. Specifically, prior ATR-kd expression had no effect on DNA damage-induced p53 protein up-regulation, p53-DNA binding, p21 mRNA up-regulation, or G(1) arrest. Instead of promoting survival via p53 regulation, we found that ATR protects cells by delaying the generation of mitotic phosphoproteins and inhibiting premature chromatin condensation after DNA damage or hydroxyurea. Although p53 inhibition (by E6 or MDM2 expression) had little effect on premature chromatin condensation, when combined with ATR-kd expression there was a marked loss of the replication checkpoint. We conclude that ATR and p53 can function independently but that loss of both leads to synergistic disruption of the replication checkpoint. C1 Harvard Univ, Howard Hughes Med Inst, Dept Chem & Biol Chem, Cambridge, MA 02138 USA. Dana Farber Canc Inst, Cutaneous Oncol Unit, Boston, MA 02115 USA. RP Schreiber, SL (reprint author), Harvard Univ, Howard Hughes Med Inst, Dept Chem & Biol Chem, 12 Oxford St, Cambridge, MA 02138 USA. RI Nghiem, Paul/A-9210-2011; OI Nghiem, Paul/0000-0003-2784-963X; Desai, Bimal/0000-0002-3928-5854 FU NIAMS NIH HHS [K08-AR0208703]; NIGMS NIH HHS [GM-52067] NR 40 TC 74 Z9 75 U1 0 U2 1 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 FEB 8 PY 2002 VL 277 IS 6 BP 4428 EP 4434 DI 10.1074/jbc.M106113200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 520ZP UT WOS:000173813900085 PM 11711532 ER PT J AU Thomson, CC Tager, AM Weller, PF AF Thomson, CC Tager, AM Weller, PF TI More than your average wheeze SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CHURG-STRAUSS-SYNDROME; HYPEREOSINOPHILIC SYNDROME; SYSTEMIC VASCULITIS C1 Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pulm & Crit Care Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Beth Israel Deaconess Med Ctr, Dept Med, Div Allergy & Inflammat, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Med, Div Infect Dis, Boston, MA 02215 USA. RP Thomson, CC (reprint author), Massachusetts Gen Hosp, Pulm & Crit Care Unit, Bulfinch 148,55 Fruit St, Boston, MA 02114 USA. NR 11 TC 7 Z9 7 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 FEB 7 PY 2002 VL 346 IS 6 BP 438 EP 442 DI 10.1056/NEJMcps012402 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 518UN UT WOS:000173686400009 PM 11832533 ER PT J AU Lowenstein, E Wanzer, SH AF Lowenstein, E Wanzer, SH TI Sounding board - The US Attorney General's intrusion into medical practice SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Lowenstein, E (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 7 TC 6 Z9 6 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 FEB 7 PY 2002 VL 346 IS 6 BP 447 EP 448 DI 10.1056/NEJM200202073460613 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 518UN UT WOS:000173686400011 PM 11832536 ER PT J AU Kimura, Y Senda, M Alpert, NM AF Kimura, Y Senda, M Alpert, NM TI Fast formation of statistically reliable FDG parametric images based on clustering and principal components SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID GLUCOSE; PET AB Formation of parametric images requires voxel-by-voxel estimation of fate constants, a process sensitive to noise and computationally demanding. A model-based clustering method for a two-parameter model (CAKS) was extended to the FDG three-parameter model. The concept was to average voxels with similar kinetic signatures to reduce noise. Voxel kinetics were categorized by the first two principal components of the tissue time-activity curves for all voxels. k(2) and k(3) were estimated cluster-by-cluster, and K-1 was estimated voxel-by-voxel within clusters. When CAKS was applied to simulated images with noise levels similar to brain FDG scans, estimation bias was well suppressed, and estimation errors were substantially smaller-1.3 times for K-i and 1.5 times for k(3)-than those of conventional voxel-based estimation. The statistical reliability of voxel-level estimation by CAKS was comparable with ROI analysis including 100 voxels. CAKS was applied to clinical cases with Alzheimer's disease (ALZ) and cortico basal degeneration (CBD). In ALZ, the affected regions had low K-i(K(1)k(3)/(k(2) + k(3))) and k(3). In CBD, K-i was low, but k(3) was preserved. These results were consistent with ROI-based kinetic analysis. Because CAKS decreased (lie number of invoked estimations, the calculation time was reduced substantially. In conclusion, CAKS has been extended to allow parametric imaging of a three-compartment model. The method is computationally efficient, with low bias and excellent noise properties. C1 Tokyo Metropolitan Inst Gerontol, Positron Med Ctr, Tokyo 1730022, Japan. 7F Chamber Commerce, Fdn Biomed Res & Innovat, Kobe, Hyogo 6508543, Japan. Massachusetts Gen Hosp, Div Nucl Med, Boston, MA 02114 USA. RP Alpert, NM (reprint author), Tokyo Metropolitan Inst Gerontol, Positron Med Ctr, 1-1 Itabashi, Tokyo 1730022, Japan. RI Kimura, Yuichi/B-3045-2008 NR 18 TC 48 Z9 48 U1 0 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD FEB 7 PY 2002 VL 47 IS 3 BP 455 EP 468 AR PII S0031-9155(02)25559-1 DI 10.1088/0031-9155/47/3/307 PG 14 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 526QW UT WOS:000174142000007 PM 11848122 ER PT J AU Clinton, JM Chansky, HA Odell, DD Zielinska-Kwiatkowska, A Hickstein, DD Yang, L AF Clinton, JM Chansky, HA Odell, DD Zielinska-Kwiatkowska, A Hickstein, DD Yang, L TI Characterization and expression of the human gene encoding two translocation liposarcoma protein-associated serine-arginine (TASR) proteins SO GENE LA English DT Article DE U12-type intron; retroposition; alternative splicing; RNA-binding protein ID SPLICE SITES; RNA; TRANSCRIPTION; SPECIFICITY; RETROPOSONS; SEQUENCES; INTERACTS; INTRONS; FAMILY AB Translocation liposarcoma protein (TLS)-associated serine-arginine (TASR)-1 and -2 are two newly identified serine-arginine splicing factors. Our recent studies suggest that disruption of TASR-mediated pre-mRNA splicing is involved in the pathogenesis of human leukemia and sarcomas. The mRNA transcripts for TASR-1 and -2 share an identical sequence at the 5' untranslated region (5' UTR) and in part of the coding region; however the other regions of the transcripts diverge from each other and it was not clear whether the differences resulted from alternative splicing or transcription from two distinct genes. Here we describe the assignment of both TASR cDNAs to the same 16 kb DNA segment located on chromosome 1. Despite the presence of at least three retroposed products of TASR-1 mRNA in the human genome, only the 16 kb structural TASR gene on chromosome 1 is actively transcribed. In addition, multiple polyadenylation sites and a rare U12-type intron were found within the TASR gene. Transcription initiation site of the TASR gene was determined by primer extension; analysis of the TASR promoter revealed that it lacks the TATA box but contains a GC-rich sequence. When cloned into a luciferase reporter and transfected into human cells, the TASR promoter construct generated luciferase activity that was at least 2000 fold greater than the promoterless plasmid. Northern blot analysis showed that at least five different TASR-1 and -2 transcripts are expressed in a broad range of human tissues. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Washington, Sch Med, Dept Orthoped & Sports Med, Seattle, WA 98108 USA. VA Puget Sound Hlth Care Syst, Med Res Serv, Seattle, WA 98108 USA. NCI, Dept Expt Transplantat & Immunol, Bethesda, MD 20892 USA. RP Yang, L (reprint author), Univ Washington, Sch Med, Dept Orthoped & Sports Med, 1660 S Columbian Way GMR 151, Seattle, WA 98108 USA. NR 21 TC 8 Z9 10 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD FEB 6 PY 2002 VL 284 IS 1-2 BP 141 EP 147 AR PII S0378-1119(02)00382-7 DI 10.1016/S0378-1119(02)00382-7 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 534QN UT WOS:000174598100014 PM 11891055 ER PT J AU Jayaraman, A Yarmush, ML Roth, CM AF Jayaraman, A Yarmush, ML Roth, CM TI Molecular bioengineering SO INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH LA English DT Review ID GREEN FLUORESCENT PROTEIN; T-CELL RECEPTOR; BISPECIFIC ANTIBODY FRAGMENTS; DIRECTED EVOLUTION; IN-VITRO; GENE DELIVERY; DRUG DISCOVERY; PHAGE-DISPLAY; BINDING-PROTEINS; ANTISENSE OLIGONUCLEOTIDES AB Molecular bioengineering is an emerging discipline that draws from advances in science and engineering to seek molecular-level solutions to complex problems in medicine and biotechnology. Based on tremendous advances in our understanding of biology and physiology, a number of promising molecular diagnostics, therapeutics, and biotechnological solutions are under development, but the properties of the molecules used in such techniques often require some modifications to satisfy the constraints of a particular application. In this review, we present an integrative view of how one might address problems in molecular bioengineering. We present the relevant properties of base constituent molecules (proteins, nucleic acids, small organics), describe some of the design principles that are determinants of effectiveness for various applications, review some of the tools of modern molecular biology that are being used to address these problems, and discuss some of the means being used to assess potential solutions accurately and rapidly. Taken together, these tools and approaches are likely to play a significant role in improving the development of biological molecules for applications in biotechnology and medicine. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med & Surg Sci Serv, Boston, MA 02114 USA. RP Yarmush, ML (reprint author), Shriners Hosp Children, 51 Blossom St, Boston, MA 02114 USA. OI Roth, Charles/0000-0002-4924-0721 NR 167 TC 5 Z9 5 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0888-5885 J9 IND ENG CHEM RES JI Ind. Eng. Chem. Res. PD FEB 6 PY 2002 VL 41 IS 3 BP 441 EP 455 DI 10.1021/ie0102549 PG 15 WC Engineering, Chemical SC Engineering GA 517XQ UT WOS:000173636100016 ER PT J AU Langer, CJ Manola, J Bernardo, P Kugler, JW Bonomi, P Cella, D Johnson, DH AF Langer, CJ Manola, J Bernardo, P Kugler, JW Bonomi, P Cella, D Johnson, DH TI Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: Implications of Eastern Cooperative Oncology Group 5592, a randomized trial SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID QUALITY-OF-LIFE; LONGITUDINAL DATA; CLINICAL-TRIALS; SURVIVAL; OLDER; AGE AB dBackground: Older patients, even if fit, are often considered incapable of tolerating platinum-based systemic therapy. We performed a retrospective analysis of Eastern Cooperative Oncology Group (ECOG) 5592, a phase III randomized trial of platinum-based chemotherapy regimens for non-small-cell lung cancer (NSCLC), and compared outcomes in enrollees 70 years of age and older with those in younger patients. Methods: ECOG carried out a randomized phase III trial of cisplatin plus either etoposide or paclitaxel in chemotherapy-naive NSCLC patients with stages IIIB, or IV disease. Toxic effects, response rates, and survival rates were compared between age groups. All P values were two-sided. Results: A total of 574 patients enrolled from August 1993 through December 1994 were evaluable. Eighty-six (15%) were 70 years old or older. Older patients had a higher incidence of cardiovascular (P =.009) and respiratory (P =.04) comorbidities and nonanalgesic medication use (P =.02). Leukopenia (P<.001) and neuropsychiatric toxicity (P =.002) were more common in elderly men than in younger men. Elderly women lost more weight than younger women (P =.006). Other toxic effects were similar in older and younger patients. The proportions with clinical partial or complete response (21.5% versus 23.3%; Fisher's exact test, P =.66), median time to progression (4.37 versus 4.30 months; log-rank test, P =.29), and survival distribution (log-rank test, P =.29; median survival, 9.05 versus 8.53 months; 1-year survival, 38% versus 29%; and 2-year survival, 14% versus 12%) were similar in patients younger than 70, ears and 70 years old or older. Baseline quality-of-life and treatmentoutcome indices were similar. Equivalent declines over time in functional well-being occurred in both groups. Conclusion: Response rate, toxicity, and survival in fit, elderly NSCLC patients receiving platinum-based treatment appear to be similar to those in younger patients, although patients 70 years old or older have more comorbidities and can expect more leukopenia and neuropsychiatric toxicity. Advanced age alone should not preclude appropriate NSCLC treatment. C1 Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Illinois Oncol Res Assoc, Peoria, IL USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. Northwestern Univ, Evanston, IL USA. Vanderbilt Univ, Nashville, TN USA. RP Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. EM CJ_Langer@fccc.edu RI Johnson, David/A-7437-2009 FU NCI NIH HHS [CA21115, CA23318, CA49957, CA66636] NR 35 TC 344 Z9 360 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD FEB 6 PY 2002 VL 94 IS 3 BP 173 EP 181 PG 9 WC Oncology SC Oncology GA 517KC UT WOS:000173608800008 PM 11830607 ER PT J AU Walsh, CR Larson, MG Evans, JC Djousse, L Ellison, RC Vasan, RS Levy, D AF Walsh, CR Larson, MG Evans, JC Djousse, L Ellison, RC Vasan, RS Levy, D TI Alcohol consumption and risk for congestive heart failure in the Framingham Heart Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID IDIOPATHIC DILATED CARDIOMYOPATHY; CIGARETTE-SMOKING; NATURAL-HISTORY; BLOOD-PRESSURE; MORTALITY; POPULATION; DISEASE; WOMEN; MEN; DYSFUNCTION AB Background: Although excessive alcohol consumption can promote cardiomyopathy, little is known about the association between alcohol consumption and risk for congestive heart failure in the community. Objective: To determine the relation between alcohol consumption and risk for congestive heart failure in the community. Design: Community-based, prospective observational study. Setting: Framingham, Massachusetts. Participants: Participants in the Framingham Heart Study who were free of congestive heart failure and coronary heart disease. Measurements: Self-reported alcohol consumption; sex-specific rates of congestive heart failure per 1000 person-years of follow-up by level of alcohol consumption. Results: In men, 99 cases of congestive heart failure occurred during 26 035 person-years of follow-up. In women, 120 cases of congestive heart failure occurred during 35 563 person-years of follow-up. After adjustment for multiple confounders, risk for congestive heart failure was lower among men at all levels of alcohol consumption compared with men who consumed less than 1 drink/wk. The hazard ratio for congestive heart failure was lowest among men who consumed 8 to 14 drinks/wk (0.41 [95% CI, 0.21 to 0.81]) compared with those who consumed less than 1 drink/wk. In women, the age-adjusted hazard ratio for congestive heart failure was lowest among those who consumed 3 to 7 drinks/wk (0.49 [CI, 0.25 to 0.96]) compared with those who consumed less than 1 drink/wk. However, after adjustment for multiple predictors of congestive heart failure, this association was no longer statistically significant. Conclusions: In the community, alcohol consumption is not associated with increased risk for congestive heart failure, even among heavy drinkers (greater than or equal to15 drinks/wk in men and greater than or equal to8 drinks/wk in women). To the contrary, when consumed in moderation, alcohol appears to protect against congestive heart failure. C1 NHLBI, Framingham Heart Study, NIH, Framingham, MA 01702 USA. Boston Univ, Sch Med, Massachusetts Gen Hosp, Beth Israel Deaconess Med Ctr, Boston, MA 02118 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, NIH, 5 Thurber St, Framingham, MA 01702 USA. RI Djousse, Luc/F-5033-2017; OI Djousse, Luc/0000-0002-9902-3047; Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [N01-HC-38038, 1K24 HL04334]; NIAMS NIH HHS [AR/AG 41398] NR 47 TC 109 Z9 112 U1 0 U2 12 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD FEB 5 PY 2002 VL 136 IS 3 BP 181 EP 191 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 517YD UT WOS:000173637400001 PM 11827493 ER PT J AU Fiore, LD Ezekowitz, MD Brophy, MT Lu, D Sacco, J Peduzzi, P AF Fiore, LD Ezekowitz, MD Brophy, MT Lu, D Sacco, J Peduzzi, P CA CHAMP Study Grp TI Department of Veterans Affairs Cooperative Studies Program clinical trial comparing combined warfarin and aspirin with aspirin alone in survivors of acute myocardial infarction - Primary results of the CHAMP study SO CIRCULATION LA English DT Article DE myocardial infarction; aspirin; anticoagulants; trials ID ORAL ANTICOAGULANT-THERAPY; CORONARY-ARTERY DISEASE; ANGINA AB Background-Both aspirin and warfarin when used alone are effective in the secondary prevention of vascular events and death after acute myocardial infarction. We tested the hypothesis that aspirin and warfarin therapy, when combined, would be more effective than aspirin monotherapy. Methods and Results-We conducted a randomized open-label study to compare the efficacy of warfarin (target international normalized ratio 1.5 to 2.5 IU) plus aspirin (81 mg daily) with the efficacy of aspirin monotherapy (162 mg daily) in reducing the total mortality in 5059 patients enrolled within 14 days of infarction and followed for a median of 2.7 years. Secondary end points included recurrent myocardial infarction, stroke, and major hemorrhage. Four hundred thirty-eight (17.3%) of 2537 patients assigned to the aspirin group and 444 (17.6%) of 2522 patients assigned to the combination group died (log-rank P=0.76). Recurrent myocardial infarction occurred in 333 patients (13.1%) taking aspirin and in 336 patients (13.3%) taking combination therapy (log-rank P=0.78). Stroke occurred in 89 patients (3.5%) taking aspirin and in 79 patients (3.1%) taking combination therapy (log-rank P=0.52). Major bleeding occurred more frequently in the combination therapy group than in the aspirin group (1.28 versus 0.72 events per 100 person years of follow-up, respectively; P<0.001). There were 14 individuals with intracranial bleeds in both the aspirin and combination therapy groups. Conclusions-In post-myocardial infarction patients, warfarin therapy (at a mean international normalized ratio of 1.8) combined with low-dose aspirin did not provide a clinical benefit beyond that achievable with aspirin monotherapy. C1 Dept Vet Affairs Cooperat Studies Program Coordin, West Haven, CT USA. Dept Vet Affairs Boston Hlth Care Syst, Med Serv, Boston, MA USA. Dept Vet Affairs New England Hlth Care Syst, Med Serv, New Haven, CT USA. Dept Vet Affairs Med Ctr, Med Serv, Washington, DC USA. Dept Vet Affairs Med Ctr, Albany, NY USA. RP Ezekowitz, MD (reprint author), VA Boston Healthcare Syst, MAVERIC 151 MAV, 150 S Huntington Ave, Boston, MA 02130 USA. NR 16 TC 149 Z9 158 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 5 PY 2002 VL 105 IS 5 BP 557 EP 563 DI 10.1161/hc0502.103329 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 519PV UT WOS:000173735400020 PM 11827919 ER PT J AU Kohli, RM Takagi, J Walsh, CT AF Kohli, RM Takagi, J Walsh, CT TI The thioesterase domain from a nonribosomal peptide synthetase as a cyclization catalyst for integrin binding peptides SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID POLYKETIDE SYNTHASE; VIBRIO-HARVEYI; ANTAGONISTS; RECOGNITION; LIBRARY; RGD; SPECIFICITY; ANTIBIOTICS; DESIGN AB Nonribosomal peptide synthetases responsible for the production of macrocyclic compounds often use their C-terminal thioesterase (TE) domain for enzymatic cyclization of a linear precursor. The excised TE domain from the nonribosomal peptide synthetase responsible for the production of the cyclic decapeptide tyrocidine A, TycC TE, retains autonomous ability to catalyze head-to-tail macrocyclization of a linear peptide thioester with the native sequence of tyrocidine A and can additionally cyclize peptide analogs that incorporate limited alterations in the peptide sequence. Here we show that TycC TE can catalyze macrocyclization of peptide substrates that are dramatically different from the native tyrocidine linear precursor. Several peptide thioesters that retain a limited number of elements of the native peptide sequence are shown to be substrates for TycC TE. These peptides were designed to integrate an Arg-Gly-Asp sequence that confers potential activity in the inhibition of ligand binding by integrin receptors. Although enzymatic hydrolysis of the peptide thioester substrates is preferred over cyclization, TycC TE can be used on a preparative scale to generate both linear and cyclic peptide products for functional characterization. The products are shown to be inhibitors of ligand binding by integrin receptors, with cyclization and N-alpha-methylation being important contributors to the nanomolar potency of the best inhibitors of fibrinogen binding to alphallbbeta3 integrin. This study provides evidence for TycC TE as a versatile macrocyclization catalyst and raises the prospect of using TE catalysis for the generation of diverse macrocyclic peptide libraries that can be probed for novel biological function. C1 Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Ctr Blood Res, Boston, MA 02115 USA. RP Walsh, CT (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. OI Kohli, Rahul/0000-0002-7689-5678 FU NHLBI NIH HHS [HL-48675, P01 HL048675]; NIGMS NIH HHS [F32 GM020011, GM-20011, R01 GM020011] NR 31 TC 43 Z9 46 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 FEB 5 PY 2002 VL 99 IS 3 BP 1247 EP 1252 DI 10.1073/pnas.251668398 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 519YF UT WOS:000173752500029 PM 11805307 ER PT J AU Lichtenthaler, SF Beher, D Grimm, HS Wang, R Shearman, MS Masters, CL Beyreuther, K AF Lichtenthaler, SF Beher, D Grimm, HS Wang, R Shearman, MS Masters, CL Beyreuther, K TI The intramembrane cleavage site of the amyloid precursor protein depends on the length of its transmembrane domain SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GAMMA-SECRETASE CLEAVAGE; BETA-PROTEIN; ALZHEIMERS-DISEASE; SPECIFICITY; METALLOPROTEASE; PROTEOLYSIS; MECHANISM; MUTATIONS; SEQUENCE; PEPTIDES AB Proteolytic processing of the amyloid precursor protein by beta-secretase generates C99, which subsequently is cleaved by gamma-secretase, yielding the amyloid beta peptide (Abeta). This gamma-cleavage occurs within the transmembrane domain (TMD) of C99 and is similar to the intramembrane cleavage of Notch. However, Notch and C99 differ in their site of intramembrane cleavage. The main gamma-cleavage of C99 occurs in the middle of the TMD, whereas the cleavage of Notch occurs close to the C-terminal end of the TMD, making it unclear whether both are cleaved by the same protease. To investigate whether gamma-cleavage always occurs in the middle of the TMD of C99 or may also occur at the end of the TMD, we generated C99-mutants with an altered length of the TMD and analyzed their gamma-cleavage in COS7 cells. The C terminus of Abeta and thus the site of gamma-cleavage were determined by using monoclonal antibodies and mass spectrometry. Compared with C99-wild type (wt), most mutants with an altered length of the TMD changed the cleavage site of gamma-secretase, whereas control mutants with mutations outside the TMD did not. Thus, the length of the whole TMD is a major determinant for the cleavage site of gamma-secretase. Moreover, the C99-mutants were not only cleaved at one site but at two sites within their TMD. One cleavage site was located around the middle of the TMD, regardless of its actual length. An additional cleavage occurred within the N-terminal half of their TMD and thus at the opposite side of the Notch cleavage site. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. Merck Sharp & Dohme Ltd, Neurosci Res Ctr, Res Labs, Dept Mol Biol, Harlow CM20 2QR, Essex, England. Univ Heidelberg, Ctr Mol Biol, D-69120 Heidelberg, Germany. CUNY Mt Sinai Sch Med, Dept Human Genet, New York, NY 10029 USA. Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia. RP Lichtenthaler, SF (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Bldg,50 Blossom St, Boston, MA 02114 USA. RI Wang, Rong/A-8721-2009; Lichtenthaler, Stefan/B-6587-2016 OI Lichtenthaler, Stefan/0000-0003-2211-2575 NR 37 TC 53 Z9 54 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 FEB 5 PY 2002 VL 99 IS 3 BP 1365 EP 1370 DI 10.1073/pnas.032395699 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 519YF UT WOS:000173752500050 PM 11805291 ER PT J AU You, MJ Castrillon, DH Bastian, BC O'Hagan, RC Bosenberg, MW Parsons, R Chin, L DePinho, RA AF You, MJ Castrillon, DH Bastian, BC O'Hagan, RC Bosenberg, MW Parsons, R Chin, L DePinho, RA TI Genetic analysis of Pten and Ink4a/Arf interactions in the suppression of tumorigenesis in mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TUMOR-SUPPRESSOR; IN-VIVO; EMBRYONIC LETHALITY; CHROMOSOMES 1P; NEOPLASIA; MUTATION; PATHWAY; LOSSES; PHEOCHROMOCYTOMAS; SUSCEPTIBILITY AB Dual inactivation of PTEN and INK4a/ARF tumor suppressor genes is a common feature observed in a broad spectrum of human cancer types. To validate functional collaboration between these genes in tumor suppression, we examined the biological consequences of Pten and/or Ink4a/Arf deficiency in cells and mice. Relative to single mutant controls, Ink4a/Arf-I-Pten+I- mouse embryonic fibroblast cultures exhibited faster rates of growth in reduced serum, grew to higher saturation densities, produced more colonies upon low density seeding, and showed increased susceptibility to transformation by oncogenic H-Ras. Ink4a/Arf deficiency reduced tumor-free survival and shortened the latency of neoplasias associated with Pten heterozygosity, specifically pheochromocytoma, prostatic intraepithelial neoplasia, and endometrial hyperplasia. Compound mutant mice also exhibited an expanded spectrum of tumor types including melanoma and squamous cell carcinoma. Functional synergy between Ink4a/Arf and Pten manifested most prominently in the development of pheochromocytoma, prompting an analysis of genes and loci implicated in this rare human neoplasm. The classical pheochromocytoma genes Ret, Vhl, and Nf-1 remained intact, a finding consistent with the intersection of these genes with pathways engaged by Pten and Ink4a/Arf. Notably, conventional and array-comparative genomic hybridization revealed frequent loss of distal mouse chromosome 4 in a region syntenic to human chromosome 1p that is implicated in human pheochromocytoma. This study provides genetic evidence of collaboration between Pten and Ink4a/Arf in constraining the growth and oncogenic transformation of cultured cells and in suppressing a wide spectrum of tumors in vivo. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Adult Oncol,Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Univ Calif San Francisco, Dept Dermatol & Pathol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Ctr Comprehens Canc, San Francisco, CA 94143 USA. Columbia Univ, Coll Phys & Surg, Inst Canc Genet, New York, NY 10031 USA. RP DePinho, RA (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Adult Oncol,Dana Farber Canc Inst, Boston, MA 02115 USA. FU NCI NIH HHS [R01 CA082783, R01 CA082783-03, R01 CA082783-01A2, R01 CA082783-02] NR 44 TC 99 Z9 100 U1 0 U2 0 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 FEB 5 PY 2002 VL 99 IS 3 BP 1455 EP 1460 DI 10.1073/pnas.022632099 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 519YF UT WOS:000173752500066 PM 11818530 ER PT J AU Nau, GJ Richmond, JFL Schlesinger, A Jennings, EG Lander, ES Young, RA AF Nau, GJ Richmond, JFL Schlesinger, A Jennings, EG Lander, ES Young, RA TI Human macrophage activation programs induced by bacterial pathogens SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TOLL-LIKE RECEPTOR-2; MYCOBACTERIUM-TUBERCULOSIS; MICE; INTERLEUKIN-12; INFECTION; IL-12; LIPOPOLYSACCHARIDE; RECOGNITION; DEFICIENCY; IMMUNITY AB Understanding the response of innate immune cells to pathogens may provide insights to host defenses and the tactics used by pathogens to circumvent these defenses. We used DNA microarrays to explore the responses of human macrophages to a variety of bacteria. Macrophages responded to a broad range of bacteria with a robust, shared pattern of gene expression. The shared response includes genes encoding receptors, signal transduction molecules, and transcription factors. This shared activation program transforms the macrophage into a cell primed to interact with its environment and to mount an immune response. Further study revealed that the activation program is induced by bacterial components that are Toll-like receptor agonists, including lipopolysaccharide, lipoteichoic acid, muramyl dipeptide, and heat shock proteins. Pathogen-specific responses were also apparent in the macrophage expression profiles. Analysis of Mycobacterium tuberculosis-specific responses revealed inhibition of interleukin-12 production, suggesting one means by which this organism survives host defenses. These results improve our understanding of macrophage defenses, provide insights into mechanisms of pathogenesis, and suggest targets for therapeutic intervention. C1 Whitehead Inst, Cambridge, MA 02142 USA. Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. RP Young, RA (reprint author), Whitehead Inst, 9 Cambridge Ctr, Cambridge, MA 02142 USA. RI Young, Richard/F-6495-2012; OI Young, Richard/0000-0001-8855-8647; Nau, Gerard/0000-0001-7921-8317 FU NIAID NIH HHS [AI-753230] NR 32 TC 474 Z9 497 U1 3 U2 15 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 FEB 5 PY 2002 VL 99 IS 3 BP 1503 EP 1508 DI 10.1073/pnas.022649799 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 519YF UT WOS:000173752500074 PM 11805289 ER PT J AU Murray, M AF Murray, M TI Determinants of cluster distribution in the molecular epidemiology of tuberculosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MULTIDRUG-RESISTANT TUBERCULOSIS; NEW-YORK-CITY; MYCOBACTERIUM-TUBERCULOSIS; TRANSMISSION DYNAMICS; EXOGENOUS REINFECTION; POPULATION-GENETICS; SOUTH-AFRICA; COMMUNITY; NETHERLANDS; EMERGENCE AB Recently developed molecular techniques have revolutionized the epidemiology of tuberculosis. Multiple studies have used these tools to examine the population structure of Mycobacterium tuberculosis isolates in different communities. The distributions of clusters of M. tuberculosis isolates in these settings may variously reflect social mixing patterns or the differential fitness of specific clones of the organism. We developed an individual-based microsimulation of tuberculosis transmission to explore social and demographic determinants of cluster distribution and to observe the effect of transmission dynamics on the empiric data from molecular epidemiologic studies. Our results demonstrate that multiple host-related factors contribute to wide variation in cluster distributions even when all strains of the organism are assumed to be equally transmissible. These host characteristics include interventions such as chemotherapy, vaccination and chemoprophylaxis, HIV prevalence, the age structure of the population, and the prevalence of latent tuberculosis infection. We consider the implications of these results for the interpretation of cluster studies of M. tuberculosis as well as the more general application of microsimulation models to infectious disease epidemiology. C1 Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. RP Murray, M (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 665 Huntington Ave, Boston, MA 02115 USA. FU NIAID NIH HHS [AI-01430-01] NR 54 TC 34 Z9 35 U1 0 U2 0 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 FEB 5 PY 2002 VL 99 IS 3 BP 1538 EP 1543 DI 10.1073/pnas.022618299 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 519YF UT WOS:000173752500080 PM 11818527 ER PT J AU Schellingerhout, D Chew, FS Mullins, ME Gonzalez, RG AF Schellingerhout, D Chew, FS Mullins, ME Gonzalez, RG TI Projected digital radiologic images for teaching: Balance of image quality with data size constraints SO ACADEMIC RADIOLOGY LA English DT Article DE education; images, processing; images, quality ID SCIENTIFIC PRESENTATIONS; RADIOGRAPHY; SYSTEM; CHEST AB Rationale and Objectives. The authors performed this study to determine, in the context of a teaching presentation with slides, the information content needed in a digitized radiologic image for it to be equivalent in quality to an analog image. Materials and Methods. Eleven sets of radiologic images were obtained from a teaching file collection and digitized. The images were scanned at high resolution and saved as image files. The information content of each image was then halved repeatedly with repeat sampling of the image. This procedure was repeated nine times to yield a total of 10 images with an information content that ranged from very low (32 kB) to high (12 MB). Each of these image files was made into a 35-mm. slide by using a digital slide maker. The original radiographs were subsequently made into slides by using conventional photographic methods. Care was taken to make the images identical in every respect except digitization and information content. The slides were shown to radiologists, who filled out questionnaires to rate image quality. Results. Digitized slides that contain an average of 416 kB of data (the equivalent of a 750 X 570-pixel matrix with 8-bit gray levels) were equivalent to analog images for 90% of viewers. At 830 kB (1,060 X 800-pixel matrix with 8-bit gray levels), 100% of viewers found no difference between digitized and analog images. Conclusion. Digital images become indistinguishable from analog images if a sufficient amount of information is retained in the digital image. There is a defined relationship between the perception of quality and the information content of a digital image. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02112 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Radiol, Winston Salem, NC USA. Harvard Univ, Sch Med, Boston, MA 02112 USA. RP Schellingerhout, D (reprint author), Massachusetts Gen Hosp, Dept Radiol, 32 Fruit St, Boston, MA 02112 USA. OI Chew, Felix/0000-0003-2711-2013 NR 15 TC 8 Z9 9 U1 0 U2 0 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 FEB PY 2002 VL 9 IS 2 BP 157 EP 162 DI 10.1016/S1076-6332(03)80165-4 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 531DX UT WOS:000174401700004 PM 11918368 ER PT J AU Gazelle, GS Dunnick, NR AF Gazelle, GS Dunnick, NR TI Subsidizing radiology research SO ACADEMIC RADIOLOGY LA English DT Article C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. RP Gazelle, GS (reprint author), Massachusetts Gen Hosp, Dept Radiol, Zero Emerson Pl,Suite 2H, Boston, MA 02114 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 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 FEB PY 2002 VL 9 IS 2 BP 195 EP 197 DI 10.1016/S1076-6332(03)80170-8 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 531DX UT WOS:000174401700009 PM 11918372 ER PT J AU Kuo, B Camilleri, M Burton, D Viramontes, B McKinzie, S Thomforde, G O'Connor, MK Brinkmann, BH AF Kuo, B Camilleri, M Burton, D Viramontes, B McKinzie, S Thomforde, G O'Connor, MK Brinkmann, BH TI Effects of 5-HT3 antagonism on postprandial gastric volume and symptoms in humans SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID RECEPTOR ANTAGONIST; FUNCTIONAL DYSPEPSIA; DISTENSION; PERCEPTION; ALOSETRON; ACCOMMODATION; MEAL; PHYSIOLOGY; BOWEL; ROLES AB Background: Alosetron reduces symptoms of dyspepsia, but the physiological basis for the symptomatic benefit is unclear. Aim: To assess 5-HT3 antagonism on postprandial gastric volume and symptoms after ingestion of maximum tolerable volume of a liquid meal. Methods: In 36 healthy volunteers, we assessed effects of placebo, 0.5 and 1 mg b.d. alosetron on fasting and postprandial gastric volumes (using single photon emission computed tomography) and symptoms based on 100 mm VAS, 30 min after maximum volume ingested. Results: The 5-HT3 antagonist reduced postprandial symptoms (aggregate score: P < 0.05), nausea (P < 0.001), and tended to reduce bloating (P = 0.08). Both 0.5 and 1 mg alosetron reduced nausea (P < 0.025); 1 mg alosetron reduced aggregate symptoms (P < 0.05) and bloating (P < 0.05). Effects on pain (P = 0.19) and fullness (P = 0.14) were not statistically significant. There were no significant effects of the 5-HT3 antagonist on volume of meal tolerated or on SPECT-measured fasting or postprandial gastric volumes. Conclusion: 5-HT3 antagonism reduces aggregate symptoms, nausea and bloating after a liquid meal without increase in gastric volumes, suggesting a role for 5-HT3 in afferent functions in healthy humans during the postprandial period. C1 Mayo Clin & Mayo Fdn, Enter Neurosci Program, Gastroenterol Res Unit, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Nucl Med Sect, Rochester, MN 55905 USA. Massachusetts Gen Hosp, Gastroenterol Unit, Boston, MA 02114 USA. RP Camilleri, M (reprint author), Mayo Clin & Mayo Fdn, Enter Neurosci Program, Gastroenterol Res Unit, Charlton 7-154,200 1st St SW, Rochester, MN 55905 USA. OI Brinkmann, Benjamin/0000-0002-2392-8608 FU NCRR NIH HHS [RR 00585]; NIDDK NIH HHS [T32 DK 07191-26, R01 DK 54681, K24 DK 02638] NR 37 TC 39 Z9 39 U1 0 U2 0 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 FEB PY 2002 VL 16 IS 2 BP 225 EP 233 DI 10.1046/j.1365-2036.2002.01144.x PG 9 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 521WP UT WOS:000173864600007 PM 11860405 ER PT J AU Antman, EM McCabe, CH Braunwald, E AF Antman, EM McCabe, CH Braunwald, E CA TIMI 8 Investigators TI Bivalirudin as a replacement for unfractionated heparin in unstable angina/non-ST-elevation myocardial infarction: Observations from the TIMI 8 trial SO AMERICAN HEART JOURNAL LA English DT Article ID THROMBIN INHIBITION; HIRULOG; ASPIRIN; DISEASE AB Background The Thrombolysis in Myocardial Infarction (TIMI) 8 trial was undertaken to compare the efficacy and safety of bivalirudin versus unfractionated heparin in a double-blind phase III trial of patients with unstable angina/non-ST-elevation myocardial infarction (MI). Methods All patients received aspirin and were randomized either to unfractionated heparin (bolus of 70 U/kg followed by an infusion of 15 U/kg/h) or bivalirudin (bolus of 0.1 mg/kg followed by an infusion of 0.25 mg/kg/h) for a minimum of 72 hours. The primary efficacy end point was a composite of all cause mortality or nonfatal recurrent MI. Results A total of 133 of the planned 5320 patients were enrolled, at which point the study was terminated by the sponsor because of a decision at the time to suspend further development of bivalirudin. Through 14 days, the incidence of death or nonfatal MI was 9.2% in the 65 patients in the unfractionated heparin group and was 2.9% in the 68 patients in the bivalirudin group, odds ratio (95% CI) 0.30 (0.06-1.53). Major hemorrhage occurred in 3 patients in the unfractionated heparin group (4.6%) but in none of the patients in the bivalirudin group (P = .11). Conclusions The trend toward a lower rate of death or nonfatal MI in the bivalirudin group is consistent with a therapeutic effect of the drug and is consistent with other trials of bivalirudin in patients with acute coronary syndromes. The potential for clinically meaningful antithrombotic activity without an increased risk of bleeding and availablility of an alternative anticoagulation strategy in patients who cannot tolerate unfractionated heparin are particularly attractive and underscore the need for further evaluation of bivalirudin. C1 Brigham & Womens Hosp, Dept Med, Cardiovasc Div, Boston, MA 02115 USA. Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. RP Antman, EM (reprint author), Brigham & Womens Hosp, Dept Med, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA. NR 22 TC 36 Z9 37 U1 0 U2 1 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 FEB PY 2002 VL 143 IS 2 BP 229 EP 234 DI 10.1067/mhj.2002.120405 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 522HR UT WOS:000173890800008 PM 11835024 ER PT J AU Bechard, L Duggan, C Holmes, C Lehmann, L Guinan, E AF Bechard, L Duggan, C Holmes, C Lehmann, L Guinan, E TI Resting energy expenditure changes during stem cell transplantation in children. SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Meeting Abstract C1 Childrens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 FEB PY 2002 VL 75 IS 2 SU S MA 232 BP 411S EP 411S PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 516FU UT WOS:000173542600230 ER PT J AU Creager, AJ Pitman, MB Geisinger, KR AF Creager, AJ Pitman, MB Geisinger, KR TI Cytologic features of clear cell sarcoma (malignant melanoma) of soft parts - A study of fine-needle aspirates and exfoliative specimens SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE cytology; cytopathology; fine-needle aspiration; malignant melanoma of soft parts; clear cell sarcoma; pleural fluid; ascites fluid; cytogenetic; immunohistochemistry; electron microscopy ID SYNOVIAL SARCOMA; EPITHELIOID SARCOMA; DIAGNOSIS; TISSUE; BIOPSY; APONEUROSES; TUMORS AB We describe the cytologic features of clear cell sarcoma of soft tissue (CCS) in 11 fine-needle aspiration biopsy (FNAB) specimens and 6 exfoliative specimens from 11 patients. In 3 patients, FNAB was the initial method of tumor evaluation. In 6 of 11 cases, immunostaining with S-100 or HMB-45 was evaluated. Electron microscopic evaluation was performed in 1 case. Both the FNAB and exfoliative specimens varied in overall cellularity, although reproducible cytologic features were identified. A significant diagnostic pitfall, namely the potential of CCS to form microacinar structures mimicking adenocarcinoma, is described with particular reference to CCS metastatic to regional lymph nodes. A rare case of the granular cell variant Of CCS is illustrated as well. Owing to the rarity of CCS, the diagnosis on cytologic smears is extremely difficult and is aided substantially by pertinent clinical data. The diagnosis can be made conclusively by FNAB in conjunction with immunocytochemical confirmation of HMB-45 or S-100 protein expression, cytogenetic demonstration of the t(12;22) translocation, or electron microscopic studies demonstrating melanosomes. C1 Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Wake Forest Univ, Baptist Med Ctr, Winston Salem, NC 27109 USA. RP Creager, AJ (reprint author), Duke Univ, Med Ctr, Dept Pathol, DUMC 3712, Durham, NC 27710 USA. NR 34 TC 16 Z9 16 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 FEB PY 2002 VL 117 IS 2 BP 217 EP 224 PG 8 WC Pathology SC Pathology GA 518HK UT WOS:000173661600007 PM 11863218 ER PT J AU Hussein, MR Wood, GS AF Hussein, MR Wood, GS TI Building bridges in cancer - Mismatch repair and microsatellite instability SO AMERICAN JOURNAL OF DERMATOPATHOLOGY LA English DT Review DE mismatch repair; microsatellite instability; high-frequency microsatellite instability; low-frequency microsatellite instability; microsatellite stable ID NONPOLYPOSIS COLORECTAL-CANCER; SPORADIC GASTRIC CARCINOMAS; SQUAMOUS-CELL CARCINOMA; HMLH1 PROMOTER; COLON-CANCER; DNA-REPAIR; P16 GENE; ENDOMETRIAL CARCINOMAS; ALTERED EXPRESSION; HYPERMETHYLATION AB Mismatch repair (MMR) defects and microsatellite instability (MSI) are two genetic alterations that have been documented in a wide variety of human cancers, including some that involve the skin. Available evidence indicates that these two features are sometimes directly related, although their connection seems to he indirect or nonexistent in other instances. The purposes, of this review are to summarize the variable relations between MMR and MSI as deduced from analysis of a diverse array of human neoplasms and to give brief insights as to the other molecular mechanisms potentially involved in the maintenance of genomic stability. C1 Univ Wisconsin, Dept Med Dermatol, Madison, WI 53705 USA. William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Wood, GS (reprint author), Univ Wisconsin, Dept Med Dermatol, Madison, WI 53705 USA. FU NIAMS NIH HHS [AR02136] NR 96 TC 13 Z9 15 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0193-1091 J9 AM J DERMATOPATH JI Am. J. Dermatopathol. PD FEB PY 2002 VL 24 IS 1 BP 76 EP 81 DI 10.1097/00000372-200202000-00016 PG 6 WC Dermatology SC Dermatology GA 517HY UT WOS:000173606100016 PM 11803288 ER PT J AU Rosenberg, PM Farrell, JJ Abraczinskas, DR Graeme-Cook, FM Dienstag, JL Chung, RT AF Rosenberg, PM Farrell, JJ Abraczinskas, DR Graeme-Cook, FM Dienstag, JL Chung, RT TI Rapidly progressive fibrosing cholestatic hepatitis-hepatitis C virus in HIV coinfection SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; LIVER-TRANSPLANTATION; NATURAL-HISTORY; INFECTION; PATIENT; HEMOPHILIACS; FAILURE; THERAPY AB Fibrosing cholestatic hepatitis (FCH) is a severe and progressive form of liver dysfunction seen in organ transplant recipients infected with hepatitis B virus or hepatitis C virus (HCV) and has been attributed to cytopathic liver injury. To date, no case of FCH due to HCV has been reported in HIV-positive individuals. We describe two cases of HCV-induced FCH in two patients coinfected with HIV, culminating in rapidly progressive liver failure and death. Histo,logical features and progression in both cases were not consistent with drug effect or obstruction. Late institution of interferon-based therapy was ultimately unsuccessful. The HCV RNA was not markedly elevated in these cases, suggesting that the cytopathic effect of HCV in these patients was not simply a consequence of viral load. FCH may in part explain the accelerated development of cirrhosis previously observed among coinfected patients. Clinicians should remain vigilant for FCH in the HIV/HCV population and consider antiviral treatment in this setting. (Am J Gastroenterol 2002;97:478-483. (C) 2002 by Am. Coll. of Gastroenterology). C1 Massachusetts Gen Hosp, Gastrointestinal Unit, Med Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA USA. RP Chung, RT (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Med Serv, 55 Fruit St, Boston, MA 02114 USA. NR 20 TC 35 Z9 35 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD FEB PY 2002 VL 97 IS 2 BP 478 EP 483 AR PII S0002-9270(01)04021-7 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 522DL UT WOS:000173880400039 PM 11866292 ER PT J AU Gao, HL Boustany, RMN Espinola, JA Cotman, SL Srinidhi, L Antonellis, KA Gillis, T Qin, XB Liu, SM Donahue, LR Bronson, RT Faust, JR Stout, D Haines, JL Lerner, TJ MacDonald, ME AF Gao, HL Boustany, RMN Espinola, JA Cotman, SL Srinidhi, L Antonellis, KA Gillis, T Qin, XB Liu, SM Donahue, LR Bronson, RT Faust, JR Stout, D Haines, JL Lerner, TJ MacDonald, ME TI Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID LYSOSOMAL STORAGE DISEASES; BATTEN-DISEASE; MODEL; GENE; CLN6; LOCALIZATION; PATHOGENESIS; DEGENERATION; THIOESTERASE; 15Q21-23 AB The CLN6 gene that causes variant late-infantile neuronal ceroid lipofuscinosis (vLINCL), a recessively inherited neurodegenerative disease that features blindness, seizures, and cognitive decline, maps to 15q21-23. We have used multiallele markers spanning this similar to4-Mb candidate interval to reveal a core haplotype, shared in Costa Rican families with vLINCL but not in a Venezuelan kindred, that highlighted a region likely to contain the CLN6 defect. Systematic comparison of genes from the minimal region uncovered a novel candidate, FLJ20561, that exhibited DNA sequence changes specific to the different disease chromosomes: a G T transversion in exon 3, introducing a stop codon on the Costa Rican haplotype, and a codon deletion in exon 5, eliminating a conserved tyrosine residue on the Venezuelan chromosome. Furthermore, sequencing of the murine homologue in the nclf mouse, which manifests recessive NCL-like disease, disclosed a third lesion-an extra base pair in exon 4, producing a frameshift truncation on the nclf chromosome. Thus, the novel similar to36-kD CLN6-gene product augments an intriguing set of unrelated membrane-spanning proteins, whose deficiency causes NCL in mouse and man. C1 Massachusetts Gen Hosp, Mol Neurogenet Unit, Charlestown, MA 02129 USA. Duke Univ, Med Ctr, Div Pediat Neurol, Durham, NC USA. Tufts Univ, Sch Med, Dept Physiol, Boston, MA 02111 USA. Jackson Lab, Bar Harbor, ME 04609 USA. Vanderbilt Univ, Med Ctr, Program Human Genet, Nashville, TN USA. RP MacDonald, ME (reprint author), Massachusetts Gen Hosp, Mol Neurogenet Unit, Bldg 149,13th St, Charlestown, MA 02129 USA. EM macdonam@helix.mgh.harvard.edu RI Haines, Jonathan/C-3374-2012 FU NINDS NIH HHS [NS30170, NS33648, R01 NS033648] NR 38 TC 122 Z9 126 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB PY 2002 VL 70 IS 2 BP 324 EP 335 DI 10.1086/338190 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 511FQ UT WOS:000173254300006 PM 11791207 ER PT J AU Ingelfinger, JR Woods, LL AF Ingelfinger, JR Woods, LL TI Perinatal programming, renal development, and adult renal function SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article; Proceedings Paper CT 1st Scientific Meeting of the International-Pediatric-Hypertension-Association CY MAY, 2001 CL SAN FRANCISCO, CALIFORNIA SP Int Pediatr Hypertension Assoc DE perinatal programming; fetal origins of adult disease; organogenesis; kidney; hypertension; renin-angiotensin system ID BLOOD-PRESSURE; CARDIOVASCULAR-DISEASE; NEPHRON DEFICIT; HYPERTENSION; RAT; EXPOSURE; GROWTH; GENE; RESTRICTION; PREGNANCY AB Substantial data indicate that maternal diet during gestation, as well as perinatal events, affect organogenesis and, furthermore, may affect organ function at maturity, thus determining whether an individual is prone or resistant to a variety of health problems such as hypertension, cardiovascular disease, or renal dysfunction. This concept is called perinatal programming, or the fetal origins of adult disease (FOAD), a concept that arose after the publication of epidemiologic observations by Barker and colleagues that birth weight among apparently normal individuals studied in midlife was inversely associated with the presence of cardiovascular disease and hypertension. We now review evidence from studies in experimental animal models that have used nutritional and phamacologic manipulation to extend epidemiologic observations. Am J Hypertens 2002; 15:46S-49S (C) 2002 American Journal of Hypertension, Ltd. C1 Massachusetts Gen Hosp, Div Pediat Nephrol, Boston, MA 02114 USA. Oregon Hlth Sci Univ, Div Nephrol, Portland, OR 97201 USA. RP Ingelfinger, JR (reprint author), Massachusetts Gen Hosp, Div Pediat Nephrol, ACC 709,15 Parkman St, Boston, MA 02114 USA. FU NHLBI NIH HHS [HL40210, HL48455]; NICHD NIH HHS [1P01 HD34430] NR 40 TC 30 Z9 31 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD FEB PY 2002 VL 15 IS 2 SU S BP 46S EP 49S AR PII S0895-7061(01)02302-0 DI 10.1016/S0895-7061(01)02302-0 PN 2 PG 4 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 523MW UT WOS:000173958900006 PM 11866229 ER PT J AU Walsh, CR Larson, MG Vasan, RS Levy, D AF Walsh, CR Larson, MG Vasan, RS Levy, D TI Serum potassium is not associated with blood pressure tracking in the Framingham Heart Study SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article; Proceedings Paper CT American-Heart-Association Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 02, 2001 CL SAN ANTONIO, TEXAS SP Amer Heart Assoc DE hypertension; potassium; prospective studies; blood pressure ID MODERATE SODIUM RESTRICTION; ESSENTIAL-HYPERTENSION; SUPPLEMENTATION; ALDOSTERONISM; HYPERKALEMIA; MAGNESIUM; LINKAGE; MEN AB Background: Abnormal potassium homeostasis accompanies many secondary forms of hypertension as well as uncommon inherited, monogenic forms of hypertension. We hypothesized that serum potassium may be associated with longitudinal tracking of blood pressure (BP) and development of hypertension. Methods: A total of 2358 participants (1292 women, 1066 men) in the Framingham Heart Study who were free of hypertension, were not taking drugs affecting potassium homeostasis, and had serum potassium measured in 1979 to 1983 were followed for longitudinal tracking of BP and development of hypertension at examination 4 years later. Progression of BP stage was defined as an increment of one or more BP category, as defined by the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI), between baseline and follow-up examinations. Results: At baseline, there were no differences in systolic or diastolic BP across serum potassium quartiles. Over 4 years of follow up, 37%, (457 women, 412 men) of subjects progressed by one or more JNC-VI BP category. In a logistic regression model adjusting for multiple confounders, serum potassium quartile was not associated with risk of BP progression. During follow-up, 14% (162 women, 175 men) of subjects progressed to hypertension. After adjustment for multiple confounders, there was no significant association between serum potassium quartile and risk for progression to hypertension, Conclusions: In our community-based study sample, serum potassium was not associated with current BP, longitudinal BP tracking, or progression to hypertension. Am J Hypertens 2002 15:130-136 (C) 2002 American Journal of Hypertension, Ltd. C1 NHLBI, Framingham Heart Study, NIH, Framingham, MA 01702 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div, Boston, MA USA. Boston Univ, Sch Med, Evans Dept Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med, Boston, MA 02215 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, NIH, 5 Thurber St, Framingham, MA 01702 USA. OI Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [1K24 HL04334] NR 31 TC 9 Z9 9 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD FEB PY 2002 VL 15 IS 2 BP 130 EP 136 AR PII S0895-7061(01)02293-2 DI 10.1016/S0895-7061(01)02293-2 PN 1 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 522JH UT WOS:000173892500006 PM 11863248 ER PT J AU Wang, XR Pan, LD Zhang, HX Sun, BX Dai, HL Christiani, DC AF Wang, XR Pan, LD Zhang, HX Sun, BX Dai, HL Christiani, DC TI Follow-up study of respiratory health of newly-hired female cotton textile workers SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE respiratory symptoms; pulmonary function; textile workers; cotton dust; endotoxin; occupational lung disease ID ACROSS-SHIFT DROP; LUNG-FUNCTION; ENDOTOXIN EXPOSURE; LANCASHIRE COTTON; PULMONARY-FUNCTION; MILL OPERATIVES; DUST EXPOSURE; DISEASE; SYMPTOMS; DECLINE AB Background Numerous studies have investigated adverse effects of exposure to cotton dust on respiratory health, but very limited longitudinal data are available with regard to the early pulmonary response to cotton dust. Moreover, the adverse effects of occupational exposure to cotton dust have been difficult to separate from the confounding effects of smoking. This setting provided a unique opportunity to evaluate early respiratory effects in newly hired and non-smoking female textile workers. Methods To identify early pulmonary responses to cotton dust exposure and associated gram-negative bacterial endotoxin, respiratory symptoms and pulmonary function in. 225 newly-hired textile workers were assessed at work initiation, and at three and twelve months later. Results All the workers were females and nonsmokers, with an average age of 18 years. Symptom incidence at three months was 3.6% for usual cough with phlegm, and 6.7% for usual dry cough. Lung function changes were detectable at one year: FEV1 declined by 70 ml and FVC by 124 ml over the year; and workers reporting respiratory symptoms at three months showed a significantly greater cross-shift drop in FEV1 (-2.3%) than those without the symptoms (-0.7%). Conclusions These results suggest that the occurrence of respiratory symptoms represents the earliest response to cotton dust exposure, followed by lung function. changes. Early respiratory symptoms may be a risk factor for subsequent loss of pulmonary function in cotton textile workers. Am. J. Ind. Med. 41:111-118, 2002. (C) 2002 Wiley-Liss, Inc. C1 Harvard Univ, Sch Publ Hlth, Occupat Hlth Program, Dept Environm Hlth, Boston, MA 02115 USA. Shanghai Text Bur, Hosp 1, Shanghai, Peoples R China. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Pulm & Crit Care Unit, Boston, MA USA. RP Christiani, DC (reprint author), Harvard Univ, Sch Publ Hlth, Occupat Hlth Program, Dept Environm Hlth, 665 Huntington Ave, Boston, MA 02115 USA. RI Lin, Sihao/A-8412-2012 FU NIEHS NIH HHS [ES00002]; PHS HHS [R010H02421] NR 25 TC 27 Z9 27 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD FEB PY 2002 VL 41 IS 2 BP 111 EP 118 DI 10.1002/ajim.10042 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 513WN UT WOS:000173403700005 PM 11813216 ER PT J AU Sorensen, AG AF Sorensen, AG TI Apparently, diffusion coefficient value and stroke treatment remains mysterious SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Sorensen, AG (reprint author), Massachusetts Gen Hosp, Dept Radiol, 32 Fruit St, Boston, MA 02114 USA. NR 2 TC 2 Z9 2 U1 0 U2 0 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 FEB PY 2002 VL 23 IS 2 BP 177 EP 178 PG 2 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 532JX UT WOS:000174472300001 PM 11847037 ER PT J AU Tzika, AA Zarifi, MK Goumnerova, L Astrakas, LG Zurakowski, D Young-Poussaint, T Anthony, DC Scott, RM Black, PM AF Tzika, AA Zarifi, MK Goumnerova, L Astrakas, LG Zurakowski, D Young-Poussaint, T Anthony, DC Scott, RM Black, PM TI Neuroimaging in pediatric brain tumors: Gd-DTPA-enhanced, hemodynamic, and diffusion MR Imaging compared with MR spectroscopic Imaging SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID MAGNETIC-RESONANCE SPECTROSCOPY; BLOOD-VOLUME MAPS; IN-VIVO; RADIATION-THERAPY; CHOLINE LEVEL; GLIOBLASTOMA-MULTIFORME; METABOLIC HETEROGENEITY; PROTON SPECTROSCOPY; NMR-SPECTROSCOPY; CEREBRAL GLIOMAS AB BACKGROUND AND PURPOSE: Gadolinium-enhanced MR images assist in defining tumor borders; however, the relation between tumor cell extent and contrast-enhanced regions is unclear. Our aim was to improve conventional neuroimaging of pediatric brain tumors with hemodynamic, diffusion, and spectroscopic MR imaging. METHODS: We performed conventional MR and MR spectroscopic imaging in 31 children with neuroglial brain tumors. Hemodynamic MR imaging was performed in 16 patients with a first-pass intravenous bolus of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA); apparent diffusion coefficients (ADCs) were measured in 12 patients. To account for multiple measurements in a patient, we used a nested analysis of variance. RESULTS: At MR spectroscopy, choline (Cho) -containing compounds (indicating tumor) and lipid levels (indicating necrosis) did not correlate with percent Gd-DTPA enhancement on MR images. Percent enhancement was positively correlated with relative cerebral blood volumes (rCBVs) (P =.05) and negatively correlated with ADCs (P <.001). Stepwise multiple linear regression revealed that rCBV (P =.008), ADC (P =.022), and lipid (P <.001) levels were significant independent predictors of percent enhancement. Tumor spectral patterns were detected in tumor regions and outside enhancing tumor beds in patients with clinical progression; these were confirmed at neuropathologic analysis. CONCLUSION. MR spectroscopic imaging improves the assessment of pediatric brain tumors by adding biochemical information regarding tumor involvement and by depicting residual or recurrent tumor outside the Gd-DTPA-enhanced tumor bed. rCBV and ADC mapping complemented MR spectroscopic imaging. We recommend the use of MR spectroscopic imaging in addition to conventional MR imaging in assessing pediatric brain tumors. C1 Harvard Univ, Childrens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. Harvard Univ, Childrens Hosp, Sch Med, Dept Neurosurg, Boston, MA 02115 USA. Harvard Univ, Childrens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Childrens Hosp, Sch Med, Dept Biostat, Boston, MA 02115 USA. RP Tzika, AA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, NMR Surg Lab, 51 Blossom St,Room 261, Boston, MA 02114 USA. RI Astrakas, Loukas/F-5918-2011; OI Anthony, Douglas/0000-0002-3815-2240 NR 60 TC 54 Z9 58 U1 0 U2 0 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 FEB PY 2002 VL 23 IS 2 BP 322 EP 333 PG 12 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 532JX UT WOS:000174472300028 PM 11847064 ER PT J AU Oberley, TD AF Oberley, TD TI Oxidative damage and cancer SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Editorial Material ID MANGANESE SUPEROXIDE-DISMUTASE; RENAL-CELL CARCINOMA; ANTIOXIDANT ENZYMES; FERRIC NITRILOTRIACETATE; 4-HYDROXY-2-NONENAL-MODIFIED PROTEINS; IMMUNOGOLD ANALYSIS; BREAST-CANCER; RATS; KIDNEY; LOCALIZATION C1 Univ Wisconsin, Sch Med, Dept Pathol & Lab Med, Madison, WI USA. Vet Adm Hosp, Madison, WI USA. RP Oberley, TD (reprint author), William S Middleton Mem Vet Adm Med Ctr, Dept Pathol & Lab Med, 2500 Overlook Terrace,Room A-35, Madison, WI 53705 USA. NR 44 TC 114 Z9 125 U1 1 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 FEB PY 2002 VL 160 IS 2 BP 403 EP 408 DI 10.1016/S0002-9440(10)64857-2 PG 6 WC Pathology SC Pathology GA 519NZ UT WOS:000173733500002 PM 11839558 ER PT J AU Joussen, AM Poulaki, V Qin, WY Kirchhof, B Mitsiades, N Wiegand, SJ Rudge, J Yancopoulos, GD Adamis, AP AF Joussen, AM Poulaki, V Qin, WY Kirchhof, B Mitsiades, N Wiegand, SJ Rudge, J Yancopoulos, GD Adamis, AP TI Retinal vascular endothelial growth factor induces intercellular adhesion molecule-1 and endothelial nitric oxide synthase expression and initiates early diabetic retinal leukocyte adhesion in vivo SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID COLONY-STIMULATING FACTOR; PERMEABILITY FACTOR; ICAM-1 EXPRESSION; CELLS; RETINOPATHY; VEGF; NEOVASCULARIZATION; ANGIOGENESIS; LEUKOSTASIS; MIGRATION AB Leukocyte adhesion to the diabetic retinal vasculature results in early blood-retinal barrier breakdown, capillary nonperfusion, and endothelial cell injury and death. Previous work has shown that intercellular adhesion molecule-1 (ICAM-1) and CD18 are required for these processes. However the relevant in vivo stimuli for ICAM-1 and CD18 expression in diabetes remain unknown. The current study investigated the causal role of endogenous vascular endothelial growth factor (VEGF) and nitric oxide in initiating these events. Diabetes was induced in Long-Evans rats with streptozotocin, resulting in a two- to threefold increase in retinal leukocyte adhesion. Confirmed diabetic animals were treated with a highly specific VEGF-neutralizing Flt-Fc construct (VEGF TrapA(40)). Retinal ICAM-1 mRNA levels in VEGF TrapA(40)-treated diabetic animals were reduced by 83.5% compared to diabetic controls (n = 5, P < 0.0001). VEGF TrapA40 also potently suppressed diabetic leukocyte adhesion in retinal arterioles (47%, n = 11, P < 0.0001), venules (36%, n = 11, P < 0.0005), and capillaries (36%, n = 11, P < 0.001). The expression of endothelial nitric oxide synthase (eNOS), a downstream mediator of VEGF activity, was increased in diabetic retina, and was potently suppressed with VEGF TrapA(40) treatment (n = 8 P < 0.005). Further, VEGF TrapA(40) reduced the diabetes-related nitric oxide increases in the retinae of diabetic animals. The inhibition of eNOS with N-ω-nitro-L-arginine methyl ester also potently reduced retinal leukocyte adhesion. Although neutrophil CD11a, CD11b, and CD18 levels were increased in 1-week diabetic animals, VEGF TrapA(40) did not alter the expression of these integrin adhesion molecules. Taken together, these data demonstrate that VEGF induces retinal ICAM-1 and eNOS expression and initiates early diabetic retinal leukocyte adhesion in vivo. The inhibition of VEGF bioactivity may prove useful in the treatment of the early diabetic retinopathy. C1 Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Childrens Hosp, Surg Res Lab, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA. Univ Cologne, Dept Vitreoretinal Surg, Ctr Opthalmol, Cologne, Germany. Univ Cologne, Zentrum Mol Med, Cologne, Germany. RP Adamis, AP (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. FU NEI NIH HHS [EY 12611, R01 EY 11627] NR 27 TC 216 Z9 236 U1 1 U2 7 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 FEB PY 2002 VL 160 IS 2 BP 501 EP 509 DI 10.1016/S0002-9440(10)64869-9 PG 9 WC Pathology SC Pathology GA 519NZ UT WOS:000173733500014 PM 11839570 ER PT J AU Sugita, H Kaneki, M Tokunaga, E Sugita, M Koike, C Yasuhara, S Tompkins, RG Martyn, JAJ AF Sugita, H Kaneki, M Tokunaga, E Sugita, M Koike, C Yasuhara, S Tompkins, RG Martyn, JAJ TI Inducible nitric oxide synthase plays a role in LPS-induced hyperglycemia and insulin resistance SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE endotoxin; hepatic glucose output; euglycemic hyperinsulinemic clamp; aminoguanidine; glycogen phosphorylase; phosphoenolpyruvate carboxykinase ID LIVER-GLYCOGEN PHOSPHORYLASE; TUMOR-NECROSIS-FACTOR; TISSUE GLUCOSE-UPTAKE; SKELETAL-MUSCLE; IN-VIVO; BACTERIAL TRANSLOCATION; MYOCARDIAL DYSFUNCTION; ENDOTOXIN CHALLENGE; BLOOD-FLOW; RATS AB The molecular mechanisms underlying endotoxin-induced insulin resistance remain unclear. Endotoxin or lipopolysaccharide (LPS) injection is a potent stimulator of inducible nitric oxide synthase (iNOS). This study in rats, using the specific iNOS inhibitor aminoguanidine, investigated the role of iNOS in endotoxin-induced hyperglycemia and insulin resistance. LPS injection led to hyperglycemia, insulin resistance, and increased iNOS protein expression and activity. Aminoguanidine prevented LPS-induced hyperglycemia without affecting insulin levels or iNOS expression. Aminoguanidine attenuated the LPS-induced insulin resistance, reflected by the requirement for a higher glucose infusion rate to maintain euglycemia during a hyperinsulinemic clamp study. Aminoguanidine completely blocked the LPS-elevated hepatic glucose output and also inhibited LPS-induced increases in hepatic glycogen phosphorylase activities and phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression, key enzymes for glycogenolysis and gluconeogenesis, respectively. Thus, these data demonstrate an important role for iNOS in LPS-induced insulin resistance, evidenced by the attenuation of LPS-induced hyperglycemia and reversal of increased hepatic glucose output by aminoguanidine. The protective effect of aminoguanidine on insulin resistance is probably by attenuation of hepatic glucose output via its inhibition of key enzymes for glycogenolysis and gluconeogenesis, including glycogen phosphorylase and PEPCK. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Anesthesia Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Surg Serv, Boston, MA 02114 USA. Shriners Hosp Children, Boston, MA 02114 USA. Univ Texas, SW Med Ctr, Ctr Dev Biol, Dallas, TX 75390 USA. RP Kaneki, M (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 55 Fruit St, Boston, MA 02114 USA. FU NIGMS NIH HHS [GM-61411, R01 GM-31569, GM-55082] NR 59 TC 68 Z9 68 U1 0 U2 1 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 FEB PY 2002 VL 282 IS 2 BP E386 EP E394 PG 9 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 514UZ UT WOS:000173460600018 PM 11788371 ER PT J AU Yu, YM Ryan, CM Fei, ZW Lu, XM Castillo, L Schultz, JT Tompkins, RG Young, VR AF Yu, YM Ryan, CM Fei, ZW Lu, XM Castillo, L Schultz, JT Tompkins, RG Young, VR TI Plasma L-5-oxoproline kinetics and whole blood glutathione synthesis rates in severely burned adult humans SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE flux; glycine; de novo synthesis; clearance; urinary excretion ID CRITICALLY-ILL PATIENTS; NECROSIS-FACTOR-ALPHA; RECEIVING PARENTERAL-NUTRITION; AMINO-ACID SYNTHESIS; LOW PROTEIN-DIET; METABOLIC RESPONSE; URINARY-EXCRETION; NITROGEN KINETICS; LEUCINE KINETICS; ACUTE-PHASE AB Compromised glutathione homeostasis is associated with increased morbidity in various disease states. We evaluated the kinetics of L-5-oxoproline, an intermediate in the gamma-glutamyl cycle of glutathione production, in fourteen severely burned adults by use of a primed, constant intravenous infusion of L-5-[1-C-13] oxoproline. In nine of these patients, whole blood glutathione synthesis and plasma kinetics of glycine and leucine were also measured with [N-15] glycine and L-[H-2(3)] leucine tracers. Patients were studied under a "basal" condition that provided a low dose of glucose and total parenteral nutrition. For comparison with control subjects, whole blood glutathione synthesis was estimated in six healthy adults. Burn patients in a basal condition showed significantly higher rates of plasma oxoproline clearance and urinary D- and L-oxoproline excretion compared with fasting healthy control subjects. Whole blood glutathione concentration and absolute synthesis rate in the basal state were lower than for control subjects. Total parenteral feeding without cysteine but with generous methionine did not affect oxoproline kinetics or whole blood glutathione synthesis. The estimated rate of glycine de novo synthesis was also lower in burn patients, suggesting a possible change in glycine availability for glutathione synthesis. The roles of precursor amino acid availability, as well as alterations in metabolic capacity, in modulating whole blood glutathione production in burns now require investigation. C1 Shriners Burns Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Trauma Serv, Boston, MA 02114 USA. MIT, Clin Res Ctr, Cambridge, MA 02142 USA. MIT, Human Nutr Lab, Cambridge, MA 02142 USA. RP Young, VR (reprint author), Shriners Burns Hosp, 51 Blossom St, Boston, MA 02114 USA. FU NCRR NIH HHS [RR-88]; NIDDK NIH HHS [DK-15856, P-30-DK-40561]; NIGMS NIH HHS [GM-02700] NR 57 TC 26 Z9 28 U1 0 U2 3 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 FEB PY 2002 VL 282 IS 2 BP E247 EP E258 PG 12 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 514UZ UT WOS:000173460600002 PM 11788355 ER PT J AU Schultz, D Su, XF Wei, CC Bishop, SP Powell, P Hankes, GH Dillon, AR Rynders, P Spinale, FG Walcott, G Ideker, R Dell'Italia, LJ AF Schultz, D Su, XF Wei, CC Bishop, SP Powell, P Hankes, GH Dillon, AR Rynders, P Spinale, FG Walcott, G Ideker, R Dell'Italia, LJ TI Downregulation of ANG II receptor is associated with compensated pressure-overload hypertrophy in the young dog SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE angiotensin II; hypertrophy; angiotensin II receptors; arrhythmias ID RENIN-ANGIOTENSIN SYSTEM; LEFT-VENTRICULAR HYPERTROPHY; NITRIC-OXIDE SYNTHASE; INDUCED HEART-FAILURE; MYOCARDIAL-INFARCTION; MOLECULAR-CLONING; CONVERTING ENZYME; CARDIAC FIBROSIS; GENE-EXPRESSION; DOWN-REGULATION AB We studied the gradual onset of pressure overload (PO) induced by a mildly constricting aortic band in 8-wk-old puppies (n = 8) that increased to 98 +/- 11 mmHg at 9 mo. Left ventricular (LV) weight/body weight was increased in PO versus sham-operated littermate controls [8.11 +/- 0.60 (SE) vs. 4.46 +/- 0.38 g/kg, P < 0.001]. LV end-diastolic diameter, diastolic pressure, and fractional shortening did not differ in PO versus control dogs. There were no inducible arrhythmias in response to an aggressive electrophysiological stimulation protocol in PO dogs. Furthermore, isolated cardiomyocyte function did not differ between control and PO dogs. LV angiotensin II (ANG II) levels were increased (68 +/- 12 vs. 20 +/- 5 pg/g, P < 0.01) as steady-state ANG II type 1 (AT(1)) receptor mRNA was decreased 40% and endothelial nitric oxide synthase mRNA levels were increased 2.5-fold in PO versus control dogs (P < 0.05). Total ANG II receptor binding sites of freshly prepared cardiac membranes demonstrated no difference in the dissociation constant, but there was a 60% decrease in maximum binding (B-max) in PO versus control dogs (P < 0.01). LV ANG II levels correlated negatively with AT(1) receptor mRNA levels (r = -0.75, P < 0.01) and total AT(1) receptor B-max (r = -0.77, P < 0.02). These results suggest that LV ANG II negatively regulates AT(1) receptor expression and that this is an adaptive response to chronic PO before the onset of myocardial failure in the young dog. C1 Univ Alabama, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA. Univ Alabama, Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA. Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. Auburn Univ, Coll Vet Med, Auburn, AL 36849 USA. Emory Univ, Atlanta, GA 30322 USA. Med Univ S Carolina, Charleston, SC 29425 USA. RP Dell'Italia, LJ (reprint author), Univ Alabama, Dept Med, Div Cardiol, MCLM 834, 1530 3rd Ave S, Birmingham, AL 35295 USA. NR 43 TC 8 Z9 9 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD FEB PY 2002 VL 282 IS 2 BP H749 EP H756 PG 8 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 514BR UT WOS:000173416900043 PM 11788426 ER PT J AU Ricono, JM Arar, M Choudhury, GG Abboud, HE AF Ricono, JM Arar, M Choudhury, GG Abboud, HE TI Effect of platelet-derived growth factor isoforms in rat metanephric mesenchymal cells SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE kidney; development; mesangial cell; signal transduction ID FACTOR RECEPTOR-BETA; SIGNAL-TRANSDUCTION; MESANGIAL CELLS; DNA-SYNTHESIS; KINASE; CHEMOTAXIS; PROTEIN; MIGRATION; KIDNEY; ALPHA AB Platelet-derived growth factor (PDGF) B-chain or PDGF beta-receptor-deficient mice lack mesangial cells. To explore potential mechanisms for failure of PDGF A-chain to rescue mesangial cell phenotype, we investigated the biological effects and signaling pathways of PDGF AA and PDGF BB in metanephric mesenchymal (MM) cells isolated from rat kidney. PDGF AA caused modest cell migration but had no effect on DNA synthesis, unlike PDGF BB, which potently stimulated migration and DNA synthesis. PDGF AA and PDGF BB significantly increased the activities of phosphatidylinositol 3-kinase (PI 3-K) and mitogen-activated protein kinase (MAPK). PDGF BB was more potent than PDGF AA in activating PI 3-K or MAPK in these cells. Pretreatment of MM cells with the MAPK kinase (MEK) inhibitor PD-098059 abrogated PDGF BB-induced DNA synthesis, whereas the PI 3-K inhibitor wortmannin had a very modest inhibitory effect on DNA synthesis (approximately Delta20%). On the other hand, wortmannin completely blocked PDGF AA- and PDGF BB-induced migration, whereas PD-098059 had a modest inhibitory effect on cell migration. These data demonstrate that activation of MAPK is necessary for the mitogenic effect of PDGF BB, whereas PI 3-K is required for the chemotactic effect of PDGF AA and PDGF BB. Although PDGF AA stimulates PI 3-K and MAPK activity, it is not mitogenic and only modestly chemotactic. Collectively, the data may have implications related to the failure of PDGF AA to rescue mesangial cell phenotype in PDGF B-chain or PDGF-beta-receptor deficiency. C1 Univ Texas, Hlth Sci Ctr, Div Nephrol, Dept Med, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Pediat, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Inst Biotechnol, Dept Mol Med, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, Ctr Geriatr Res Educ & Clin, San Antonio, TX 78229 USA. RP Abboud, HE (reprint author), Univ Texas, Hlth Sci Ctr, Div Nephrol, Dept Med, MC 7882,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM abboud@uthscsa.edu FU NIDDK NIH HHS [DK-55815, DK-33665] NR 25 TC 12 Z9 12 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD FEB PY 2002 VL 282 IS 2 BP F211 EP F219 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 512XD UT WOS:000173348100004 PM 11788434 ER PT J AU Edgerton, EA Duan, NH Seidel, JS Asch, S AF Edgerton, EA Duan, NH Seidel, JS Asch, S TI Predictors of seat-belt use among school-aged children in two low-income Hispanic communities SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article DE child; Hispanic Americans; motor vehicles; seat belts ID INJURY SEVERITY AB Objectives: To examine the prevalence of seat belt use among school-aged children in low-income Hispanic communities. Methods: We conducted unobtrusive observations of school-aged children (aged 5 to 12 years) traveling to and from nine elementary schools in two communities. We documented vehicle type, and belted status and seating position of children, driver, and other passengers. Results are presented as percentages with 95% confidence intervals (CIs). Results: We observed 3651 children, of which restraint use could be determined for 2741. Overall, 29% of children were using seat belts. By seating location, 58% were in the front seat with 40% belted, and 42% were in the back seat with 14% belted. Children were most likely to be restrained when traveling in the front seat (40.0%, CI=37.6-42.5); traveling with a belted driver (42.4%, CI=40.0-44.8); or traveling without additional passengers (40.3%, CI=37.0-43.7). Conclusions. Seat belt use among children from this Study population was below the national average and was alarmingly low among children in the back scat. While traveling, being belted in the back seat provides the most protection in a collision. Prevention efforts need to be based on an understanding of the barriers to restraint use for children traveling in the back seat. C1 Univ Calif Los Angeles, Harbor Med Ctr, Div Gen & Emergency Pediat, Torrance, CA 90509 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Los Angeles, CA 90024 USA. RAND Corp, Santa Monica, CA USA. Vet Adm Greater Los Angeles, Res Serv, Los Angeles, CA USA. RP Edgerton, EA (reprint author), Childrens Natl Med Ctr, MPII,111 Michigan Ave NW, Washington, DC 20010 USA. NR 26 TC 7 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD FEB PY 2002 VL 22 IS 2 BP 113 EP 116 AR PII S0749-3797(01)00411-1 DI 10.1016/S0749-3797(01)00412-3 PG 4 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 529VR UT WOS:000174322100007 PM 11818181 ER PT J AU Mataix-Cols, D Rauch, SL Baer, L Eisen, JL Shera, DM Goodman, WK Rasmussen, SA Jenike, MA AF Mataix-Cols, D Rauch, SL Baer, L Eisen, JL Shera, DM Goodman, WK Rasmussen, SA Jenike, MA TI Symptom stability in adult obsessive-compulsive disorder: Data from a naturalistic two-year follow-up study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID FACTOR-ANALYZED SYMPTOM; PERSONALITY; ADOLESCENTS; DIMENSIONS; SUBTYPES; CHILDREN; SCALE AB Objective: Little is known about the longitudinal course of symptoms in adult patients with obsessive-compulsive disorder (OCD), although some evidence exists regarding symptom stability in children and adolescents. This study systematically investigated the temporal stability of individual symptoms and symptom dimensions of OCD in adult patients who were followed prospectively for 2 years. Method: One hundred seventeen adult outpatients with OCD from three U.S. sites were administered the Yale-Brown Obsessive Compulsive Scale symptom checklist four times over a period of 2 years. Eighty-one (69%), 83 (71%), and 67 (57%) patients were available 6 months, 1 year, and 2 years after initial screening, respectively. Different analytic methods assessed the stability of OCD symptoms within and between previously identified symptom dimensions. Results: For the most part, patients maintained their symptoms throughout follow-up, although some symptoms were more stable than others. For the symptoms that changed, changes occurred within rather than between symptom dimensions; qualitative shifts from one dimension to another were rare. The strongest predictor of the presence of a particular symptom was having had that symptom in the past. Although most patients had received pharmacological and behavioral treatment during the follow-up period, changes within symptom dimensions could not be explained by overall clinical improvement over time. Conclusions: Symptoms of adult patients with OCD might be more stable across time than previously thought, with some symptoms waxing and waning within symptom dimensions and rarely involving shifts between dimensions. Longer follow-up studies involving larger samples are needed to better understand the fluctuations of OCD symptoms across time. C1 Univ London Imperial Coll Sci Technol & Med, Sch Med, Dept Psychiat, Div Neurosci & Psychol Med,Stress Self Help Clin, London W14 9NS, England. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. Brown Univ, Sch Med, Dept Psychiat & Human Behav, Butler Hosp, Providence, RI 02912 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. RP Mataix-Cols, D (reprint author), Univ London Imperial Coll Sci Technol & Med, Sch Med, Dept Psychiat, Div Neurosci & Psychol Med,Stress Self Help Clin, 303 N End Rd, London W14 9NS, England. RI Mataix-Cols, David/G-3843-2010 OI Mataix-Cols, David/0000-0002-4545-0924 NR 22 TC 153 Z9 155 U1 2 U2 10 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD FEB PY 2002 VL 159 IS 2 BP 263 EP 268 DI 10.1176/appi.ajp.159.2.263 PG 6 WC Psychiatry SC Psychiatry GA 519LJ UT WOS:000173727500014 PM 11823269 ER PT J AU Dougherty, DD Baer, L Cosgrove, GR Cassem, EH Price, BH Nierenberg, AA Jenike, MA Rauch, SL AF Dougherty, DD Baer, L Cosgrove, GR Cassem, EH Price, BH Nierenberg, AA Jenike, MA Rauch, SL TI Prospective long-term follow-up of 44 patients who received cingulotomy for treatment-refractory obsessive-compulsive disorder SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID TRIAL AB Objective: Long-term outcome associated with cingulotomy for obsessive-compulsive disorder (OCD) was prospectively assessed. Findings are reported for 18 patients previously described in 1995 and for 26 new patients. Method: An open preoperative and follow-up assessment was conducted at multiple time points for 44 patients undergoing one or more cingulotomies for treatment-refractory OCD. The patients were assessed by using the Structured Clinical interview for DSM-III-R preoperatively and with the Yale-Brown Obsessive Compulsive Scale, the Beck Depression inventory, and the Sickness Impact Profile both preoperatively and at all follow-up assessments. The patients completed clinical global improvement scales at all follow-up assessments. Results: At mean follow-up of 32 months after one or more cingulotomies, 14 patients (32%) met criteria for treatment response and six others (14%) were partial responders. Thus, 20 patients (45%) were at least partial responders at long-term follow-up after one or more cingulotomies. Few adverse effects were reported. Conclusions: Thirty-two percent to 45% of patients previously unresponsive to medication and behavioral treatments for OCD were at least partly improved after cingulotomy. Cingulotomy remains a viable treatment option for patients with severe treatment-refractory OCD. C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurosurg, Boston, MA 02115 USA. RP Rauch, SL (reprint author), Massachusetts Gen Hosp East, Psychiat Neurosci Program, Dept Psychiat, CNY-9130,Bldg 149,13th St, Charlestown, MA 02129 USA. NR 27 TC 149 Z9 154 U1 2 U2 3 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD FEB PY 2002 VL 159 IS 2 BP 269 EP 275 DI 10.1176/appi.ajp.159.2.269 PG 7 WC Psychiatry SC Psychiatry GA 519LJ UT WOS:000173727500015 PM 11823270 ER PT J AU Oliva, E Amin, MB Jimenez, R Young, RH AF Oliva, E Amin, MB Jimenez, R Young, RH TI Clear cell carcinoma of the urinary bladder - A report and comparison of four tumors of mullerian origin and nine of probable urothelial origin with discussion of histogenesis and diagnostic problems SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE urinary bladder; clear cell carcinoma; mullerian epithelium; transitional epithelium; immunochemistry; histogenesis ID NEPHROGENIC ADENOMA; CLINICOPATHOLOGICAL ANALYSIS; PRIMARY ADENOCARCINOMA; TRACT; FEATURES; URETHRA; ENDOMETRIOSIS; EXPRESSION; METAPLASIA; CA-125 AB Carcinomas of the bladder that resemble clear cell carcinoma of mullerian type are rare. Whether such neoplasms 1) arise from mullerian elements in the bladder and are histogenetically identical to the female genital tract cancer, 2) are a peculiar variant of vesical adenocarcinoma of nonmullerian derivation, or 3) represent a peculiar morphologic expression of transitional cell (urothelial) carcinoma with gland differentiation is often uncertain. We reviewed the clinical, conventional pathologic, and immunohistochemical features of 13 neoplasms with exclusive, or predominant, morphologic features of clear cell carcinoma. The 11 female and two male patients were 22-83 (mean 57) years of age. The clinical and gross features had no unique aspects. On microscopic examination the most common pattern, present in all cases, was tubulocystic, with a papillary pattern, present in six tumors and a predominant solid growth in one. Cells with abundant clear cytoplasm were conspicuous in nine tumors and hobnail cells were seen in eight. Four tumors showed focally recognizable patterns of transitional cell (urothelial) carcinoma in the available material. In five other tumors pseudostratified epithelium reminiscent of transitional epithelium was present focally. Endometriosis was present in two cases. In two other cases benign cysts focally lined by ciliated epithelium and surrounded by elastosis were interpreted as most likely mullerian. Immunohistochemistry was performed in 10 cases. All tumors stained for CA 125 (usually strong, ranging from focal to diffuse) and nine tumors stained for CK7 (usually strong and diffuse). CK20 was focally and weakly positive in four tumors and extensively positive in another. The same immunohistochemical panel was performed on 10 typical transitional cell carcinomas, 4 transitional cell carcinomas With,land differentiation, not otherwise specified, and 5 pure ad enocarcinomas of the bladder (one of urachal origin). Minimal CA 125 positivity was seen in two transitional cell carcinomas. CA 125 staining was seen in the areas of gland differentiation in three of four transitional cell carcinomas and three of five pure adenocarcinomas but was focal in most cases. All transitional cell carcinomas and transitional cell carcinomas with gland differentiation showed extensive CK7 positivity. In contrast, only one of four positive pure adenocarcinomas showed >5% CK7-positive cells. Although all groups showed CK20 positivity, the percentage of CK20 positive cells was higher in pure adenocarcinomas. Prostate specific antigen was negative in all tumors. The cytokeratin immunoprofile of clear cell carcinomas of the bladder is closer to transitional cell carcinomas and transitional cell carcinomas with gland differentiation than pure adenocarcinomas arguing against an unusual form of adenocarcinoma. Our finding of CA 125 expression in bladder tumors of apparent urothelial origin contrasts with some studies that have regarded CA 125 expression as evidence for a mullerian origin. The frequency of gland differentiation in transitional cell carcinomas and the rarity of vesical endometriosis could be taken to suggest that these tumors are mostly of urothelial derivation, but the strong female preponderance in our series argues for a mullerian origin in at least some cases, and this is almost certain in the four cases with benign mullerian components. In the absence of endometriosis or conventional foci of transitional cell carcinoma, it may be impossible to determine whether a tumor with the morphology of clear cell carcinoma is of mullerian or transitional (urothelial) cell lineage, and at this time immunochemistry does not solve this problem. C1 Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Emory Univ Hosp, Dept Pathol, Atlanta, GA 30322 USA. RP Oliva, E (reprint author), Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Fruit St, Boston, MA 02114 USA. NR 37 TC 76 Z9 78 U1 0 U2 2 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 FEB PY 2002 VL 26 IS 2 BP 190 EP 197 DI 10.1097/00000478-200202000-00005 PG 8 WC Pathology; Surgery SC Pathology; Surgery GA 519NW UT WOS:000173733200005 PM 11812940 ER PT J AU Martins, D Tareen, N Norris, KC AF Martins, D Tareen, N Norris, KC TI The epidemiology of end-stage renal disease among African Americans SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article DE epidemiology; renal disease; end-stage renal disease (ESRD); African Americans; hypertension; diabetes ID NUTRITION EXAMINATION SURVEY; HIV-ASSOCIATED NEPHROPATHY; 3RD NATIONAL-HEALTH; BLOOD-PRESSURE CONTROL; HYPERTENSIVE NEPHROSCLEROSIS; DIABETES-MELLITUS; RACIAL-DIFFERENCES; RISK; METAANALYSIS; PROGRESSION AB Although disparities in outcomes among African Americans compared with whites with respect to cardiovascular disease, cancer, diabetes, infant mortality, and other health standards have been well-described, these disparities are most dramatic with respect to kidney diseases. End-stage renal disease (ESRD) occurs almost 4 times more commonly in African Americans than in their white counterparts. These disparate rates of kidney disease may be caused by the complex interplay of genetic, environmental, cultural, and socioeconomic factors. African Americans are particularly vulnerable to the deleterious renal effects of hypertension and may require more aggressive blood pressure control than whites to accrue benefit with respect to preservation of renal function. Diabetes, the leading cause of ESRD in the United States, is another important factor in the excess renal morbidity and mortality of African Americans because of its prevalence in this population. Other renal diseases, especially those associated with HIV/AIDS, are also much more likely to affect African Americans than other American population subgroups. A more thorough understanding of the epidemiology of renal diseases in African Americans and the cultural, social, and biological differences that underlie racial disparities in prevalence of renal disease will be essential to the design of effective public health strategies for prevention and treatment of this burdensome problem. C1 Charles R Drew Univ Med & Sci, Dept Internal Med, Los Angeles, CA 90059 USA. Univ Calif Los Angeles, Sch Med, Dept Internal Med, Los Angeles, CA 90024 USA. W Los Angeles Vet Adm Med Ctr, Los Angeles, CA USA. RP Norris, KC (reprint author), Charles R Drew Univ Med & Sci, Dept Internal Med, 12021 S Wilmington, Los Angeles, CA 90059 USA. FU NCRR NIH HHS [G12-RR03026, P20-RR11145] NR 43 TC 57 Z9 59 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-9629 EI 1538-2990 J9 AM J MED SCI JI Am. J. Med. Sci. PD FEB PY 2002 VL 323 IS 2 BP 65 EP 71 DI 10.1097/00000441-200202000-00002 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 520ND UT WOS:000173787200002 PM 11863081 ER PT J AU Eltzschig, HK Goetz, AE Schroeder, TH Ehlers, R Felbinger, TW AF Eltzschig, HK Goetz, AE Schroeder, TH Ehlers, R Felbinger, TW TI Transesophageal echocardiography: Perioperative evaluation of valvular function SO ANAESTHESIST LA German DT Article DE perioperative Transesophageal echocardiography; TEE; aortic valve; mitral valve; pulmonic valve; tricuspid valve ID LEFT-VENTRICULAR FUNCTION; WAVE DOPPLER ULTRASOUND; MITRAL-VALVE PROLAPSE; SURFACE-AREA METHOD; PRESSURE HALF-TIME; AORTIC REGURGITATION; QUANTITATIVE ASSESSMENT; HEART-DISEASE; SEVERITY; STENOSIS AB Since its introduction into the operating room, transesophageal echocardiography (TEE) has proven to be an invaluable diagnostic tool for perioperative patient management. TEE allows direct visualization of structural and functional cardiac abnormalities. Therefore, it has become the most important imaging technique to evaluate valvular function. Pressure gradients across a stenotic valve can be calculated by measuring the blood flow velocity within the valve. Additionally, the area of the valve can be estimated by using the continuity equation. The severity of regurgitant blood flow across an incompetent valve can be assessed using color flow, continuous or pulsed-wave Doppler. Surgical patients experience significant changes in blood pressure, intrathoracic pressures and volume status in the perioperative period. Therefore, the interaction between these parameters and valvular function is the focus of recent clinical studies and might in future contribute to the perioperative as well as anesthesiological management of patients with valvular dysfunction. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. Univ Tubingen, Abt Anaesthesiol & Intensivmed, Tubingen, Germany. Univ Munich, Klinikum Grosshadern, Anasthesiol Klin, D-8000 Munich, Germany. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc, Boston, MA 02115 USA. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. RP Eltzschig, HK (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Anesthesiol Perioperat & Pain Med, 75 Francis St, Boston, MA 02115 USA. NR 68 TC 12 Z9 12 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0003-2417 J9 ANAESTHESIST JI Anaesthesist PD FEB PY 2002 VL 51 IS 2 BP 81 EP 102 PG 22 WC Anesthesiology SC Anesthesiology GA 530JK UT WOS:000174354400002 PM 11963310 ER PT J AU McKenna, MJ Kristiansen, AG Tropitzsch, AS AF McKenna, MJ Kristiansen, AG Tropitzsch, AS TI Similar COL1A1 expression in fibroblasts from some patients with clinical otosclerosis and those with type I osteogenesis imperfecta SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE COL1A1; genetics; mutation; osteogenesis imperfecta; otosclerosis ID NULL ALLELES; COLLAGEN; LESIONS; GENE; PCR AB Because of the clinical and histopathologic similarities between otosclerosis and type I osteogenesis imperfecta, we examined COL1A1 messenger RNA (mRNA) expression in cultured fibroblasts from patients with clinical otosclerosis to determine whether abnormalities of expression of COL1A1 were present, as has been reported in type I osteogenesis imperfecta. Type I osteogenesis imperfecta has been found to result from mutations in the COL1A1 gene that result in null expression of the mutant allele. Patients with clinical otosclerosis were genotyped for the presence of an expressed 4 base-pair insertion polymorphism in the 3' region of the COL1A1 gene. Skin biopsies were performed, and cultured fibroblast cell lines were established from patients who were heterozygous for the polymorphism. Allelic expression was examined by reverse transcription-polymerase chain reaction and silver-stained polyacrylamide gel electrophoresis. Two of 9 patients with clinical otosclerosis demonstrated null or reduced expression of one COL1A1 allele. The differential expression of the two COL1A1 alleles in all subjects was also examined by a semiquantitative method using an ABI Prism 7700 Sequence Detection System (Taqman). We did this examination to determine whether milder abnormalities in COL1A1 expression might account for the development of otosclerosis in the 7 clinical cases that did not reveal evidence of null expression by the gel technique. Of the same 2 cases of otosclerosis that demonstrated evidence of null expression by gel electrophoresis, both were found to have significant differences in COL1A1 mRNA expression by the Taqman analysis. The remaining 7 cases revealed equal expression of the two COL1A1 alleles similar to that seen in controls. These results suggest that mutations in COL1A1 that are similar to those that occur in type I osteogenesis imperfecta may account for a small percentage of cases of otosclerosis, and that the majority of cases of clinical otosclerosis are related to other genetic abnormalities that have yet to be identified. C1 Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP McKenna, MJ (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. FU NIDCD NIH HHS [5 R01 DC03401] NR 21 TC 23 Z9 23 U1 0 U2 1 PU ANNALS PUBL CO PI ST LOUIS PA 4507 LACLEDE AVE, ST LOUIS, MO 63108 USA SN 0003-4894 J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD FEB PY 2002 VL 111 IS 2 BP 184 EP 189 PG 6 WC Otorhinolaryngology SC Otorhinolaryngology GA 521AV UT WOS:000173816800014 PM 11860074 ER PT J AU Sims, CA Berger, DL AF Sims, CA Berger, DL TI Airway risk in hospitalized trauma patients with cervical injuries requiring halo fixation SO ANNALS OF SURGERY LA English DT Article ID EARLY TRACHEOSTOMY; SPINE INJURIES; BLUNT TRAUMA; MANAGEMENT; INTUBATION; EMERGENCY AB Objective To identify the incidence and outcomes of emergent and semiemergent intubations in hospitalized trauma patients with cervical fractures and/or dislocations treated with halo fixation. Summary Background Data Intubating a trauma patient in halo fixation can be extremely difficult, with the potential for dire consequences. Methods The authors retrospectively reviewed the medical records of trauma patients with cervical injuries requiring halo fixation admitted to a level 1 trauma center between January 1992 and January 1997. The in-hospital need for emergent or semiemergent intubation was assessed and correlated with a variety of patient characteristics, including outcome. Results Of the 105 patients identified, 14 (13%) required an emergent or semiemergent intubation. Injury Severity Score, cardiac history, and intubation on arrival were significant indicators of the need for an in-hospital emergent or semiemergent intubation or reintubation. A total of seven deaths were reported, six of which were associated with an emergent or semiemergent in-hospital intubation. Although age did not appear significant in predicting the need for an emergent intubation, it was significant in predicting arrest-related deaths. A total of 17 tracheostomies were performed. Eight were considered "initial" in that they were performed before an emergent intubation, and nine were performed after an emergent intubation. Patients in the initial tracheostomy group did not differ in terms of the variables investigated from those who required an emergent intubation. None of the patients who underwent initial tracheostomy, however, had an airway emergency or died. Conclusions A significant number of trauma patients treated with halo fixation ultimately require an in-hospital emergent or semiemergent intubation. Given the difficulty and potential lethality associated with these intubations, heightened vigilance regarding the airway is warranted. The authors recommend that early tracheostomy be considered in patients with a history of cardiac disease, especially when a high Injury Severity Score is present. Older patients (older than 60 years) are more at risk for arrest-related death and may also benefit from early tracheostomy. C1 Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Berger, DL (reprint author), Massachusetts Gen Hosp, Dept Surg, 15 Parkman St ACC 465, Boston, MA 02114 USA. NR 15 TC 9 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD FEB PY 2002 VL 235 IS 2 BP 280 EP 284 DI 10.1097/00000658-200202000-00017 PG 5 WC Surgery SC Surgery GA 518WM UT WOS:000173690900017 PM 11807369 ER PT J AU Akins, CW AF Akins, CW TI Operative and 5-year outcomes of combined carotid and coronary revascularization: Review of a large contemporary experience - Invited commentary SO ANNALS OF THORACIC SURGERY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Cardiac Surg Unit, Boston, MA 02114 USA. RP Akins, CW (reprint author), Massachusetts Gen Hosp, Cardiac Surg Unit, 55 Fruit St, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD FEB PY 2002 VL 73 IS 2 BP 497 EP 498 DI 10.1016/S0003-4975(01)03554-8 PG 2 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 517RW UT WOS:000173624500030 ER PT J AU Bitondo, JM Daggett, WM Torchiana, DF Akins, CW Hilgenberg, AD Vlahakes, GJ Madsen, JC MacGillivray, TE Agnihotri, AK AF Bitondo, JM Daggett, WM Torchiana, DF Akins, CW Hilgenberg, AD Vlahakes, GJ Madsen, JC MacGillivray, TE Agnihotri, AK TI Endoscopic versus open saphenous vein harvest: A comparison of postoperative wound complications SO ANNALS OF THORACIC SURGERY LA English DT Article AB Background. Wound complications associated with long incisions used to harvest the greater saphenous vein are well documented. Recent reports suggest that techniques of endoscopic vein harvest may result in decreased wound complications. A prospective, nonrandomized study was developed to compare outcomes of open versus endoscopic vein harvest procedures. Methods. There were 106 patients in the open vein harvest group, and 154 patients in the endoscopic vein harvest group. Patient characteristics and demographics were similar in both groups. Wound complications identified were dehiscence, drainage for greater than 2 weeks postoperatively, cellulitis, hematoma, and seroma/ lymphocele. Results. Wound complications were significantly less in the endoscopic vein harvest group (9 of 133, 6.8%) versus. the open vein harvest group (26 of 92, 28.3%), p less than 0.001. By multivariable analysis with logistic regression, the open vein harvest technique was the only risk factor for postoperative leg wound complication (relative risk 4.0). Conclusions. Endoscopic vein harvest offered improved patient outcomes in terms of wound healing compared with the open vein harvest technique. (C) 2002 by The Society of Thoracic Surgeons. C1 Massachusetts Gen Hosp, Div Cardiac Surg, Boston, MA 02114 USA. RP Torchiana, DF (reprint author), Massachusetts Gen Hosp, Div Cardiac Surg, Bulfinch 119,55 Fruit St, Boston, MA 02114 USA. NR 16 TC 37 Z9 40 U1 2 U2 3 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 FEB PY 2002 VL 73 IS 2 BP 523 EP 528 DI 10.1016/S0003-4975(01)03334-3 PG 6 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 517RW UT WOS:000173624500035 PM 11845868 ER PT J AU Goldstein, JM Seidman, LJ O'Brien, LM Horton, NJ Kennedy, DN Makris, N Caviness, VS Faraone, SV Tsuang, MT AF Goldstein, JM Seidman, LJ O'Brien, LM Horton, NJ Kennedy, DN Makris, N Caviness, VS Faraone, SV Tsuang, MT TI Impact of normal sexual dimorphisms on sex differences in structural brain abnormalities in schizophrenia assessed by magnetic resonance Imaging SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 7th International Congress on Schizophrenia Research CY APR 17-21, 1999 CL SANTA FE, NEW MEXICO ID PLANUM TEMPORALE ASYMMETRY; GRAY-MATTER; CEREBROSPINAL-FLUID; GENDER DIFFERENCES; VOLUME REDUCTION; CEREBRAL-CORTEX; WHITE-MATTER; TOPOGRAPHIC PARCELLATION; EPISODE SCHIZOPHRENIA; MORPHOMETRIC ANALYSIS AB Background: Previous studies suggest that the impact of early insults predisposing to schizophrenia may have differential consequences by sex. We hypothesized that brain regions found to be structurally different in normal men and women (sexual dimorphisms) and abnormal in schizophrenia would show significant sex differences in brain abnormalities, particularly in the cortex, in schizophrenia. Methods: Forty outpatients diagnosed as having schizophrenia by DSM-III-R were systematically sampled to be comparable within sex with 48 normal comparison subjects on the basis of age, ethnicity, parental socioeconomic status, and handedness. A comprehensive assessment of the entire brain was based on T1-weighted 3-dimensional images acquired from a 1.5-T magnet. Multivariate general linear models for correlated data were used to test for sex-specific effects regarding 22 hypothesized C, cortical, subcortical, and cerebrospinal fluid brain volumes, adjusted for age and total cerebrum size. Sex X group interactions were also tested on asymmetries of the planum temporale. Heschl's gyrus, and superior temporal gyrus, additionally controlled for handedness. Results: Normal patterns of sexual diniorphLsn-is were disrupted in schizophrenia. Sex-specific effects were primarily evident in the cortex, particularly in the frontomedial cortex, basal forebrain, cingulate and paracingulate gyri, posterior supramarginal gurus, and planum temporale. Normal asymmetry of the planum was also disrupted differentially in men and women with schizophrenia. There were no significant differential sex effects in subcortical gray matter regions or cerebrospinal fluid. Conclusion: Factors that produce normal sexual dimorphisms may be associated with modulating insults producing schizophrenia, particularly in the cortex. C1 Harvard Univ, Inst Psychiat Epidemiol & Genet, Massachusetts Mental Hlth Ctr, Sch Med,Dept Psychiat, Boston, MA 02115 USA. Vet Affairs Boston Healthcare Syst, Brockton, MA USA. Harvard Univ, Inst Psychiat Epidemiol & Genet, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Boston Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Boston, MA 02215 USA. Boston Univ, Sch Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Ctr Morphometr Anal, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol Serv,Ctr Morphometr Anal, Boston, MA 02115 USA. RP Goldstein, JM (reprint author), Harvard Univ, Inst Psychiat Epidemiol & Genet, Massachusetts Mental Hlth Ctr, Sch Med,Dept Psychiat, 74 Fenwood Rd, Boston, MA 02115 USA. RI Horton, Nicholas/A-2493-2008; Kennedy, David/H-3627-2012; OI Horton, Nicholas/0000-0003-3332-4311; Faraone, Stephen/0000-0002-9217-3982 FU NIMH NIH HHS [MH 43518, MH 46318, R01 MH56956] NR 86 TC 158 Z9 160 U1 3 U2 8 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 FEB PY 2002 VL 59 IS 2 BP 154 EP 164 DI 10.1001/archpsyc.59.2.154 PG 11 WC Psychiatry SC Psychiatry GA 519YX UT WOS:000173754000008 PM 11825137 ER PT J AU Spencer, TJ AF Spencer, TJ TI Attention-deficit/hyperactivity disorder SO ARCHIVES OF NEUROLOGY LA English DT Article ID HYPERACTIVE BOYS; FOLLOW-UP; CHILDREN AB Attention-deficit/hyperactivity disorder (ADHD) is an early-onset clinically heterogeneous disorder of inattention, hyperactivity, and impulsivity. The nosology has changed during the past century from minimal brain damage to hyperkinetic reaction of childhood and now to ADH. These names reflect shifting causative theories, from an early emphasis on subtle "minimal" brain injuries to motor hyperactivity and eventually to the primacy of cognitive and attentional symptoms. Indeed, neuropsychological deficits reported in patients with ADHD implicate executive dysfunctions and working memory deficits that are similar to those in patients with acquired frontal lobe damage. In addition, neuroimaging studies' implicate frontal-subcortical pathways in patients with ADHD. While there is undoubtedly a complex interplay between genetic and environmental interactions, estimates of heritability from twin studies are high (approximately 80%).(1) Moreover, recently there has been a growing appreciation of the magnitude of impairment experienced by adults with continuing ADHD after childhood onset. C1 Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Spencer, TJ (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Room WACC-725,15 Parkman St, Boston, MA 02114 USA. FU NIMH NIH HHS [R29MH57511] NR 18 TC 12 Z9 12 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 FEB PY 2002 VL 59 IS 2 BP 314 EP 316 DI 10.1001/archneur.59.2.314 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 520UN UT WOS:000173799900021 PM 11843707 ER PT J AU Novis, DA Renner, S Friedberg, R Walsh, MK Saladino, AJ AF Novis, DA Renner, S Friedberg, R Walsh, MK Saladino, AJ TI Quality indicators of blood utilization - Three college of American Pathologists Q-Probes studies of 12 288 404 red blood cell units in 1639 hospitals SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID ORDER SCHEDULE; INSTITUTIONS AB Objectives To determine the normative rates of blood unit crossmatched to transfused (C:T) ratios, red blood cell (RBC) unit wastage, and RBC unit expiration that exist in hospital communities throughout the United States, and to examine hospital blood bank practices associated with more desirable (lower) rates. Design In 3 separate studies, participants in the College of American Pathologists Q-Probes laboratory quality improvement program collected data retrospectively on the number of transfusion crossmatches performed in their institutions and the number of RBC-containing units that were transfused into patients, the number of units that expired (outdated) prior to being utilized, and the number that were wasted due to mishandling. Participants also completed questionnaires describing their hospitals' and blood banks' laboratory and transfusion practices. Setting and Participants One thousand six hundred thirty-nine public and private institutions, well more than 80% of which were known to be located in the United States. Main Outcome Measures Quality indicators of blood utilization (namely, the C:T ratio, the rate of RBC unit expiration, and the rate of RBC unit wastage). Results Participants submitted data on 12 288 404 RBC unit transfusions. The C:T ratios were 1.5 or less in the top-performing 10% of participating institutions (90th percentile and above), 1.8 to 1.9 in the midrange of participating institutions (50th percentile), and 2.4 or greater in the bottom-performing 10% of participating institutions (10th percentile and below). Red blood cell unit expiration rates were 0.1% or less at the 90th percentile and above, 0.3% to 0.9% at the 50th percentile, and 3.5% or greater at the 10th percentile and below. Red blood cell unit wastage rates were 0.1% or less at the 90th percentile and above, 0.1% to 0.4% at the 50th percentile, and 0.7% or greater at the 10th percentile and below. Depending on which quality indicator was examined, lower values (ie, better performances) were found in institutions that had fewer than 200 hospital beds, no teaching programs, no on-site full-time medical directors of transfusion services, did not utilize maximum surgical blood order schedules, set C:T threshold goals of 2.0 or less, monitored categories of health care workers responsible for RBC wastage, monitored requests for RBC components by transfusion indication, did not accept short-dated units from blood distribution centers, and if they did accept short-dated units, were allowed to return those units to the distribution centers. Conclusions Hospital blood bank personnel can achieve C:T ratios below 2.0, RBC unit expiration rates below 1.0%, and RBC unit wastage rates below 0.5%. Lower C:T ratios and/or RBC unit expiration rates were associated with blood bank personnel setting C:T thresholds of 2.0 or less, monitoring requests for blood components by transfusion indication criteria, monitoring categories of health care workers responsible for blood wastage, not accepting short-dated units from blood distribution centers, and if short-dated units were accepted, being allowed to return those units to the blood distribution center. These practices were not associated with lower blood wastage rates. C1 Wentworth Douglass Hosp, Dept Pathol, Dover, NH 03820 USA. Vet Adm Greater Los Angeles Healthcare Syst, Dept Pathol, Los Angeles, CA USA. Univ Alabama, Birmingham Vet Adm Med Ctr, Birmingham, AL USA. Coll Amer Pathologists, Northfield, IL USA. Dept Vet Affairs Med Ctr, Ft Howard, MD USA. RP Novis, DA (reprint author), Wentworth Douglass Hosp, Dept Pathol, Dover, NH 03820 USA. NR 15 TC 32 Z9 32 U1 0 U2 1 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 FEB PY 2002 VL 126 IS 2 BP 150 EP 156 PG 7 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 520NA UT WOS:000173786900005 PM 11825109 ER PT J AU Cooper, RA Thorman, T Cooper, R Dvorznak, MJ Fitzgerald, SG Ammer, W Song-Feng, G Boninger, ML AF Cooper, RA Thorman, T Cooper, R Dvorznak, MJ Fitzgerald, SG Ammer, W Song-Feng, G Boninger, ML TI Driving characteristics of electric-powered wheelchair users: How far, fast, and often do people drive? SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE community action; rehabilitation; wheelchairs ID DISABLED-CHILDREN AB Objectives: To determine the driving characteristics of electric-powered wheelchair users during unrestricted community activities and to compare the activity levels among an active group and a group of regular users. Design: Multisite engineering evaluation of electric-powered wheelchair driving activity during unrestricted community mobility. Setting: Data were collected in the communities of Pittsburgh, PA, and the National Veterans Wheelchair Games (NVWG) in San Antonio, TX. Participants: Seventeen people participated, all of whom used electric-powered wheelchairs as their primary means of mobility. Intervention: Each subject was asked standarized questions about self and wheelchair use. Data logger and sensor installed on wheelchair. Data downloaded from logger. Main Outcome Measures: Speed, distance traveled, and the time that each subject's personal wheelchair was being driven were recorded for 24hr/d over approximately 5 days for each subject by using a custom-built data logger. Results: The NVWG group traveled faster than the Pittsburgh group, but this difference was only statistically significant on the first day. The NVWG group was more likely to travel longer than the Pittsburgh group with significant differences seen in day 4 (P = .03) and day 5 (P = .05). Total distance traveled during the 5-day period and average distance traveled per day were also significantly different between the groups (P = .02 for both 5-day distance and daily distance), with the NVWG group traveling longer (17.164 +/- 8708m) when compared with the Pittsburgh group (8335 +/- 7074m) over the 5-day period. Both distance traveled and speed increased during afternoon and evening hours. The maximum distance traveled by any Subject for each hour across the 2 groups was used to create the theoretic maximum distance day, which resulted in 7970m of driving. Conclusion: Drivers of electric-powered wheelchairs are most active during the afternoon and evening hours. Over the 5-day period of this study, there was little Variation in the speed or distance driven per day. The Subjects participating in the NVWG were more active than their Counterparts during a typical week at home. The maximum theoretic distance that a wheelchair user in our group would travel is less than 8km. The range of current electric-powered wheelchairs appears adequate. if not generous. for the subjects in our study. C1 VA Pittsburgh Healthcare Syst, VA Rehabil Res & Dev Ctr, Human Engn Res Labs 151R1, Pittsburgh, PA 15206 USA. Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA USA. Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. RP Cooper, RA (reprint author), VA Pittsburgh Healthcare Syst, VA Rehabil Res & Dev Ctr, Human Engn Res Labs 151R1, 7180 Highland Dr, Pittsburgh, PA 15206 USA. OI Boninger, Michael/0000-0001-6966-919X NR 14 TC 51 Z9 51 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 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD FEB PY 2002 VL 83 IS 2 BP 250 EP 255 DI 10.1053/apmr.2002.28020 PG 6 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 519DP UT WOS:000173709900018 PM 11833031 ER PT J AU Stein, CM Olson, JM Gray-McGuire, C Bruner, GR Harley, JB Moser, KL AF Stein, CM Olson, JM Gray-McGuire, C Bruner, GR Harley, JB Moser, KL TI Increased prevalence of renal disease in systemic lupus erythematosus families with affected male relatives SO ARTHRITIS AND RHEUMATISM LA English DT Article ID SIB-PAIR FAMILIES; CLINICAL MANIFESTATIONS; SUSCEPTIBILITY GENES; LABORATORY FEATURES; COMPLEMENT; SUBSETS; LINKAGE; GENDER; MICE; RACE AB Objective. To distinguish familial differences from sex-related differences in the clinical manifestations of systemic lupus erythematosus (SLE). Methods. A total of 372 affected individuals from 160 multiplex SLE pedigrees were analyzed. Twenty-five of these pedigrees contained at least 1 affected male relative. Comparisons of the presence of each of the 11 1982 American College of Rheumatology criteria for SLE were made between female family members with affected male relatives and those without affected male relatives, using Fisher's exact tests. Results. The presence of renal disease was significantly increased in female family members with an affected male relative when compared with those with no affected male relative (68% and 43%, respectively; P = 0.002). This trend remained after stratifying by race and was most pronounced in European Americans. A familial basis for differences in hematologic and immunologic manifestations was also suggested, while arthritis and dermatologic features appeared to be most influenced by sex. Conclusion. Our results demonstrate that the increased prevalence of renal disease previously reported in men with SLE is, in large part, a familial rather than sex-based difference, at least in multiplex SLE families. Distinguishing familial from sex-related differences may facilitate efforts to understand the genetic and hormonal factors that underlie this complex autoimmune disease. C1 Univ Minnesota, Dept Med, Rheumat & Autoimmune Dis Div, Minneapolis, MN 55455 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. US Dept Vet Affairs, Med Ctr, Oklahoma City, OK USA. RP Moser, KL (reprint author), Univ Minnesota, Dept Med, Rheumat & Autoimmune Dis Div, 6-122 BSBE Bldg,312 Church St SE, Minneapolis, MN 55455 USA. OI Stein, Catherine/0000-0002-9763-5023 FU NCRR NIH HHS [RR-03655]; NHGRI NIH HHS [HG-01577]; NHLBI NIH HHS [HL-07567]; NIAID NIH HHS [AI-24717, AI-31584]; NIAMS NIH HHS [AR-42460, AR-45231] NR 52 TC 19 Z9 19 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD FEB PY 2002 VL 46 IS 2 BP 428 EP 435 DI 10.1002/art.10105 PG 8 WC Rheumatology SC Rheumatology GA 520MN UT WOS:000173785800017 PM 11840445 ER PT J AU Orces, CH del Rincon, I Abel, MP Escalante, A AF Orces, CH del Rincon, I Abel, MP Escalante, A TI The number of deformed joints as a surrogate measure of damage in rheumatoid arthritis SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article DE rheumatoid arthritis; joint damage; joint deformity; joint counts ID PRELIMINARY CORE SET; CLINICAL-TRIALS; DISABILITY; COUNTS; HLA-DRB1; ALLELES; DISEASE; MOTION; SCALE; SCORE AB Objective, To evaluate the reliability and validity of the number of deformed joints (NDJ) as a surrogate measure of joint damage in rheumatoid arthritis (RA). Methods. We tested interrater reliability and validity in determining the NDJ as a surrogate for joint damage in consecutive patients with RA. We rated each of 48 joints as normal or abnormal in terms of alignment and range of motion, and expressed the results as the total number of deformed joints. We compared the NDJ with the severity of damage on a plain radiograph of the hands, scored using Sharp's technique, as the gold standard measure of joint damage. We also compared the correlation between the NDJ and radiographic joint damage, on the one hand, and disease duration, performance-based measures of physical function, and the self-reported level of disability. Results. The interrater reliability of the NDJ was excellent, with an intraclass correlation among four examiners of 0.94. To assess validity of the NDJ, we studied 273 RA patients from 5 clinical settings. Their average NDJ was 14 (range 0-43), and their average Sharp's score for joint space narrowing and erosions combined was 106 (range 4-309). The NDJ and the total Sharp's score were highly correlated (r = 0.83). Both measures were correlated to a similar degree with disease duration (r = 0.51 for each measure), grip strength (r = -0.49 for NDJ, and r = -0.51 for Sharp's score), walking velocity (r = -0.44 for NDJ, and r = -0.45 for Sharp's score), the timed button test (r = -0.62 for NDJ, and r = -0.57 for Sharp's score), and the Modified Health Assessment Questionnaire (r = 0.38 for NDJ, and r = 0.38 for Sharp's score). Both the Sharp's score and the NDJ worsened significantly in 38 patients for whom 1-2 year followup data were available. Conclusion. The NDJ is reliable and is strongly associated with the standard measure of joint damage in RA. Because it is easily performed in a clinical setting, it could be used as an economical surrogate of joint damage in studies of the long-term outcome of RA. C1 Univ Texas, Hlth Sci Ctr, San Antonio, TX 78229 USA. S Texas Vet Adm Hlth Syst, San Antonio, TX USA. Wilford Hall USAF Med Ctr, San Antonio, TX 78236 USA. RP Escalante, A (reprint author), Univ Texas, Hlth Sci Ctr, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. FU NCRR NIH HHS [M01-RR-01346]; NHLBI NIH HHS [K23-HL-004481]; NIAMS NIH HHS [K24-AR-47530]; NICHD NIH HHS [R01-HD-37151] NR 29 TC 41 Z9 42 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD FEB PY 2002 VL 47 IS 1 BP 67 EP 72 DI 10.1002/art1.10160 PG 6 WC Rheumatology SC Rheumatology GA 520VU UT WOS:000173803700011 PM 11932880 ER PT J AU Zamora, A Matejuk, A Silverman, M Vandenbark, AA Offner, H AF Zamora, A Matejuk, A Silverman, M Vandenbark, AA Offner, H TI Inhibitory effects of incomplete Freund's aduvant on experimental autoimmune encephalomyelitis SO AUTOIMMUNITY LA English DT Article DE IFA; EAE; gamma INF; IL10; MBP Ac1-11 ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; BV8S2 TRANSGENIC MICE; GUINEA-PIG; T-CELLS; ADJUVANT; PROTEIN; SUPPRESSION; PROTECTION; INDUCTION; ANTIGEN AB Freund's incomplete adjuvant (IFA), an aqueous/oil emulsion that is widely used in combination with antigenic proteins and peptides to induce tolerance, is considered to be immunologically inert. However, sporadic reports indicate that IFA may itself have inhibitory proper-ties on induction of adjuvant induced arthritis and spontaneous diabetes. In the current study, the effects of IFA/saline were evaluated on the induction of experimental autoimmune encephalomyelitis (EAE) in three different strains of mice, IFA/saline given i.p. in two doses of > 100 mul 10 days apart were found to inhibit EAE induction to varying degrees in all three strains of mice in a dose dependent fashion. The IFA/saline injections inhibited both mitogen and antigen-induced T cell proliferation, induced elevated secretion of IFN-gamma and IL-10 by neuroantigen specific T cells, and reduced expression of cytokines. chemokines, and chemokine receptors of CNS-infiltrating mononuclear cells. These data demonstrate for the first time a direct inhibitory effect of IFA/saline on EAE. and re-emphasize the need to Properly control experiments using IFA to induce antigen-specific tolerance. C1 Portland VA Med Ctr, Neuroimmunol Res R&D 31, Portland, OR 97201 USA. RP Offner, H (reprint author), Portland VA Med Ctr, Neuroimmunol Res R&D 31, 3710 SW US Vet Hosp Rd, Portland, OR 97201 USA. FU NIAID NIH HHS [AI42376]; NINDS NIH HHS [NS23444, NS23221] NR 15 TC 8 Z9 8 U1 1 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK,, ABINGDON OX14 4RN, OXON, ENGLAND SN 0891-6934 J9 AUTOIMMUNITY JI Autoimmunity PD FEB PY 2002 VL 35 IS 1 BP 21 EP 28 DI 10.1080/08916930290005873 PG 8 WC Immunology SC Immunology GA 525DR UT WOS:000174053900003 PM 11908703 ER PT J AU Lyamin, OI Mukhametov, LM Siegel, JM Nazarenko, EA Polyakova, IG Shpak, OV AF Lyamin, OI Mukhametov, LM Siegel, JM Nazarenko, EA Polyakova, IG Shpak, OV TI Unihemispheric slow wave sleep and the state of the eyes in a white whale SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE unihemispheric sleep; slow wave sleep; unilateral eye closure; eye state; Beluga; white whale; Cetaceans ID DOLPHINS AB We recorded electroencephalogram (EEG) and simultaneously documented the state of both eyelids during sleep and wakefulness in a sub-adult male white whale over a 4-day-period. We showed that the white whale was the fifth species of Cetaceans, which exhibits unihemispheric slow wave sleep. We found that the eye contralateral to the sleeping hemisphere in this whale was usually closed (right eye, 52% of the total sleep time in the contralateral hemisphere; left eye, 40%) or in an intermediate state (31 and 46%, respectively) while the ipsilateral eye was typically open (89 and 80%). Episodes of bilateral eye closure in this whale occupied less than 2% of the observation time and were usually recorded during waking (49% of the bilateral eye closure time) or low amplitude sleep (48%) and rarely in high amplitude sleep (3%). In spite of the evident overall relationship between the sleeping hemisphere and eye state, EEG and eye position in this whale could be independent over short time periods (less than 1 min). Therefore, eye state alone may not accurately reflect sleep state in Cetaceans. Our data support the idea that unihemispheric sleep allows Cetaceans to monitor the environment. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Severtsov Inst Ecol & Evolut, Moscow 117071, Russia. Univ Calif Los Angeles, Sch Med, Dept Psychiat, North Hills, CA 91343 USA. RP Lyamin, OI (reprint author), VA Greater Los Angeles Healthcare Syst, Ctr Sleep Res 151A3, 16111 Plummer St, North Hills, CA 91343 USA. FU NINDS NIH HHS [NS32819] NR 17 TC 43 Z9 44 U1 3 U2 19 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 FEB 1 PY 2002 VL 129 IS 1-2 BP 125 EP 129 AR PII S0166-4328(01)00346-1 DI 10.1016/S0166-4328(01)00346-1 PG 5 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 521KL UT WOS:000173839100014 PM 11809503 ER PT J AU Furst, BA Champion, KM Pierre, JM Wirshing, DA Wirshing, WC AF Furst, BA Champion, KM Pierre, JM Wirshing, DA Wirshing, WC TI Possible association of QTc interval prolongation with co-administration of quetiapine and lovastatin SO BIOLOGICAL PSYCHIATRY LA English DT Article DE quetiapine; lovastatin; QTc prolongation; schizophrenia; dyslipidemia; weight ID REDUCTASE INHIBITORS; PHARMACOKINETICS AB Background: QTc interval prolongation can occur as a result of treatment with both conventional and novel antipsychotic medications and is of clinical concern because of its association with the potentially fatal ventricular arrhythmia, torsade de pointes. Methods: One case is described in which a patient with schizophrenia, who was being treated for dyslipidemia, developed a prolonged QTc interval while taking quetiapine and lovastatin. Results: QTc returned to baseline when the lovastatin dose was reduced. Conclusions: QTc prolongation associated with antipsychotic medication occurs in a dose-dependent manner. We therefore hypothesize that the addition of lovastatin caused an increase in plasma quetiapine levels through competitive inhibition of the cytochrome P-450 (CYP) isoenzyme 3A4. Our case highlights the potential for a drug interaction between quetiapine and lovastatin leading to QTc prolongation during the management of dysipidemia inpatients with schizophrenia. Biol Psychiatry 2002,51: 264-265 (C) 2002 Society of Biological Psychiatry. C1 VA Greater Los Angles Healthcare Syst, Dept Psychiat, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. RP Wirshing, DA (reprint author), VA Greater Los Angles Healthcare Syst, Dept Psychiat, 11301 Wilshire Blvd,Bldg 210,Room 15 B151H, Los Angeles, CA 90073 USA. NR 11 TC 24 Z9 25 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 1 PY 2002 VL 51 IS 3 BP 264 EP 265 DI 10.1016/S0006-3223(01)01333-6 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 520YH UT WOS:000173811000009 PM 11839370 ER PT J AU Townson, DH O'Connor, CL Pru, JK AF Townson, DH O'Connor, CL Pru, JK TI Expression of monocyte chemoattractant protein-1 and distribution of immune cell populations in the bovine corpus luteum throughout the estrous cycle SO BIOLOGY OF REPRODUCTION LA English DT Article DE corpus luteum; corpus luteum function; cytokines; immunology; ovary; progesterone ID NECROSIS-FACTOR-ALPHA; ENDOTHELIAL-CELLS; CORPORA-LUTEA; LEUKOCYTE SUBPOPULATIONS; PROGESTERONE SECRETION; FINE-STRUCTURE; GUINEA-PIG; RAT; MACROPHAGES; LUTEOLYSIS AB This study characterizes the expression of monocyte chemoattractant protein-1 (MCP-1) and the relative distribution of immune cell populations in the bovine corpus luteum throughout the estrous cycle. Immunodetectable MCP-1 was evident in corpora lutea of cows at Days 6, 12, and 18 postovulation (Day 0 = ovulation, n = 4 cows/stage). Day 6 corpora lutea contained minimal MCP-1 that was confined primarily to blood vessels. In contrast, relatively intense staining for MCP-1 was observed in corpora lutea from Days 12 and 18 postovulation. MCP-1 was again most evident in the cells of the vasculature, but it was also observed surrounding individual luteal cells, particularly by Day 18. An increase in immunohistochemical expression of MCP-1 on Days 12 and 18 postovulation corresponded with increases in MCP-1 mRNA and protein in corpora lutea as determined by Northern blot analysis and ELISA. Monocytes and macrophages were the most abundant immune cells detected in the bovine corpus luteum, followed by CD8(+) and CD4(+) T lymphocytes. In all instances, Day 6 corpora lutea contained fewer immune cells than corpora lutea from Days 12 and 18. In conclusion, increased expression of MCP-1 was accompanied by the accumulation of immune cells in the corpora lutea of cows during the latter half of the estrous cycle (Days 12-18 postovulation). These results support the hypothesis that MCP-1 promotes immune cell recruitment into the corpus luteum to facilitate luteal regression. These results also raise a provocative issue, however, concerning the recruitment of immune cells several days in advance of the onset of luteal regression. C1 Univ New Hampshire, Dept Anim & Nutr Sci, Durham, NH 03824 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. RP Townson, DH (reprint author), Univ New Hampshire, Dept Anim & Nutr Sci, Kendall Hall,128 Main St, Durham, NH 03824 USA. NR 44 TC 53 Z9 55 U1 0 U2 2 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD FEB PY 2002 VL 66 IS 2 BP 361 EP 366 DI 10.1095/biolreprod66.2.361 PG 6 WC Reproductive Biology SC Reproductive Biology GA 515EF UT WOS:000173481900013 PM 11804949 ER PT J AU Muratoglu, OK O'Connor, DO Bragdon, CR Delaney, J Jasty, M Harris, WH Merrill, E Venugopalan, P AF Muratoglu, OK O'Connor, DO Bragdon, CR Delaney, J Jasty, M Harris, WH Merrill, E Venugopalan, P TI Gradient crosslinking of UHMWPE using irradiation in molten state for total joint arthroplasty SO BIOMATERIALS LA English DT Article DE irradiation; UHMWPE; total hip; wear; gradient crosslinking ID MOLECULAR-WEIGHT POLYETHYLENE; CROSS-LINKING; WEAR; REPLACEMENTS; MODEL AB Increased crosslink density increases the wear resistance of ultra-high molecular weight polyethylene (UHMWPE) acetabular components used in total hip reconstructions, However, increasing crosslink density can reduce the mechanical properties of UHMWPE, Other researchers have tried to limit the crosslinking to a superficial layer on the articulating surfaces to retain the properties of the virgin polymer. We present here a method of producing a gradient of crosslink density across the acetabular component. Acetabular liners with 26 min inner diameter were machined from the UHMWPE. The liners were then irradiated at 140 degreesC in the molten state of the polymer using a 2 MeV electron beam with limited penetration of the effects of radiation into polyethylene. The liners were then machined to an inner diameter of 32 min to remove the radiation induced oxidized surface layer. The limited penetration of the e-beam resulted in a gradient of crosslink density with a crosslink density of 0.15 +/-0.01 mol/dm(3) near the articulating Surfaces and 0.12 +/-0.01 mol/dm(3) near the backside. The concentration of the trans-vinylene unsaturations decreased gradually, as a function of depth from the articulating Surfaces to the backside of the liners. The wear resistance of the melt-irradiated liners was contrasted with those of conventional liners using the Boston hip simulator. The gravimetric wear rate was 21 +/-5 mg/million cycles with the conventional liners. while the melt-irradiated acetabular liners did not show any weight loss. (C) 2001 Published by Elsevier Science Ltd. C1 Massachusetts Gen Hosp, Orthopaed Biomech & Biomat Lab, Boston, MA 02114 USA. MIT, Dept Chem Engn, Cambridge, MA 02139 USA. Natl Chem Lab, Dept Chem Engn, Pune 41008, Maharashtra, India. RP Muratoglu, OK (reprint author), Massachusetts Gen Hosp, Orthopaed Biomech & Biomat Lab, Jackson 1206,55 Fruit St, Boston, MA 02114 USA. NR 30 TC 38 Z9 38 U1 0 U2 10 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 FEB PY 2002 VL 23 IS 3 BP 717 EP 724 DI 10.1016/S0142-9612(01)00176-4 PG 8 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 500RF UT WOS:000172640000011 PM 11771692 ER PT J AU Wang, H Jiang, XH Yang, F Chapman, GB Durante, W Sibinga, NES Schafer, AI AF Wang, H Jiang, XH Yang, F Chapman, GB Durante, W Sibinga, NES Schafer, AI TI Cyclin A transcriptional suppression is the major mechanism mediating homocysteine-induced endothelial cell growth inhibition SO BLOOD LA English DT Article ID SMOOTH-MUSCLE CELLS; CHRONIC-RENAL-FAILURE; MAP KINASE CASCADE; BRAIN-TUMOR CELLS; VASCULAR-DISEASE; DOWN-REGULATION; RISK FACTOR; S-ADENOSYLHOMOCYSTEINE; A GENE; CORONARY ATHEROSCLEROSIS AB Previously, it was reported that homocysteine (Hcy) specifically inhibits the growth of endothelial cells (ECs), suppresses Ras/mitogen-activated protein (MAP) signaling, and arrests cell growth at the G(1)/S transition of the cell cycle. The present study investigated the molecular mechanisms underlying this cell-cycle effect. Results showed that clinically relevant concentrations (50 muM) of Hcy significantly inhibited the expression of cyclin A messenger RNA (mRNA) in ECs in a dose- and time-dependent manner. G(1)/S-associated molecules that might account for this block were not changed, because Hcy did not affect mRNA and protein expression of cyclin D1 and cyclin E. Cyclin D1- and E-associated kinase activities were unchanged. In contrast, cyclin A-associated kinase activity and CDK2 kinase activity were markedly suppressed. Nuclear run-on assay demonstrated that Hcy decreased the transcription rate of the cyclin A gene but had no effect on the half-life of cyclin A mRNA. In transient transfection experiments, Hcy significantly inhibited cyclin A promoter activity in endothelial cells, but not in vascular smooth muscle cells. Finally, adenovirus-transduced cyclin A expression restored EC growth inhibition and overcame the S phase block imposed by Hcy. Taken together, these findings indicate that cyclin A is a critical functional target of Hcy-mediated EC growth inhibition. (C) 2002 by The American Society of Hematology. C1 Baylor Coll Med, VA Med Ctr, Houston, TX 77030 USA. Rice Univ, Baylor Coll Med, Dept Bioengn, Dept Med, Houston, TX 77251 USA. Rice Univ, Baylor Coll Med, Dept Bioengn, Dept Pharmacol, Houston, TX 77251 USA. Albert Einstein Coll Med, New York, NY USA. RP Wang, H (reprint author), Baylor Coll Med, VA Med Ctr, 2002 Holcombe Ave 109-129, Houston, TX 77030 USA. FU NHLBI NIH HHS [HL-62467, HL-59976] NR 69 TC 40 Z9 43 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 1 PY 2002 VL 99 IS 3 BP 939 EP 945 PG 7 WC Hematology SC Hematology GA 515ZQ UT WOS:000173527000030 PM 11806997 ER PT J AU Oh, WK George, DJ Kantoff, PW AF Oh, WK George, DJ Kantoff, PW TI Rapid rise of serum prostate specific antigen levels after discontinuation of the herbal therapy PC-SPES in patients with advanced prostate carcinoma - Report of four cases SO CANCER LA English DT Article DE prostate carcinoma; herbal therapy; PC-SPES; prostate specific antigen ID CANCER; SUPPLEMENT AB BACKGROUND. PC-SPES is an herbal supplement whose mechanisms of action are poorly understood, but may be estrogenic. The objective of the current report is to describe the effects of discontinuing PC-SPES treatment in four patients with androgen-independent prostate carcinoma. METHODS. Patient charts were retrospectively reviewed. A MEDLINE search was performed to investigate whether these effects of PC-SPES had been reported. RESULTS. Four men whose metastatic prostate carcinoma progressed despite androgen ablation and subsequent PC-SPES treatment are described. All four patients developed a rapid increase in serum prostate specific antigen (PSA) within one month of stopping PC-SPES, ranging from 345% to 880%. Two patients increased their PSA levels to 1300% and 1400% after 7 weeks. Compared to the rate of rise of PSA levels prior to and during PC-SPES therapy, the rise after stopping this treatment was much higher than expected. Clinical symptoms remained relatively stable despite the serologic changes. CONCLUSIONS. Discontinuing PC-SPES therapy can be associated with a rapid rise in PSA. To the authors' knowledge, this effect has not been reported previously. This effect should be considered in the design of clinical trials as well as in the standard management of androgen-independent prostate carcinoma patients. Cancer 2002;94:686-9. (C) 2002 American Cancer Society. C1 Dana Farber Canc Inst, Dept Adult Oncol, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Oh, WK (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Lank Ctr Genitourinary Oncol, 44 Binney St, Boston, MA 02115 USA. RI Oh, William/B-9163-2012 OI Oh, William/0000-0001-5113-8147 NR 10 TC 4 Z9 5 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD FEB 1 PY 2002 VL 94 IS 3 BP 686 EP 689 DI 10.1002/cncr.10269 PG 4 WC Oncology SC Oncology GA 517QB UT WOS:000173620400013 PM 11857300 ER PT J AU Codington, JF Haavik, S Nikrui, N Kuter, I Vassileva, C Zhang, H Matson, S Chen, XM Wu, ZB AF Codington, JF Haavik, S Nikrui, N Kuter, I Vassileva, C Zhang, H Matson, S Chen, XM Wu, ZB TI Immunologic quantitation of the carcinoma specific human carcinoma antigen in clinical samples SO CANCER LA English DT Article DE epiglycanin; human carcinoma antigen; carcinoma; anti-idiotypic antibody; anti-anti-idiotypic antibody; immunoassay ID MUCIN-TYPE GLYCOPROTEIN; TA3 TUMOR; CELL-LINE; EPIGLYCANIN; MOUSE; RADIOIMMUNOASSAY; ANTIBODY; CANCER AB BACKGROUND. Based on the cross-reactivity of the human carcinoma antigen, HCA, with epiglycanin, a mouse mammary carcinoma cell surface glycoprotein, HCA has been detected in the tissue and blood of patients with every type of epithelium-derived cancer tested. METHODS. Competitive binding assays utilized the following antiepiglycanin antibodies: a polyclonal rabbit antiserum (immunoglobulin [Ig] G and IgM) in a radioimmunoassay,; mouse monoclonal antibodies (Ab-1, IgM) on immunoplates; anti-idiotypic (Ab-2) and anti-anti-idiotypic (Ab-3) monoclonal antibodies (both IgG) from spleen cells of C57BL mice immunized, respectively, with Ab-1 and Ab-2, and utilized on immunoplates. IgG and IgM antibodies were evaluated for their ability to detect HCA and to distinguish between the blood of patients with, or without, carcinomas. RESULTS. Assays with the rabbit antiserum distinguished plasmas of metastatic breast carcinoma patients from those of patients with benign breast disease with a sensitivity of approximately 93% (specificity 90%). Antiepiglycanin IgM monoclonal antibodies (i.e., AE3) showed high specificity and sensitivity (> 90%) with sera from advanced carcinoma patients when compared with normal sera. The IgG anti-anti-idiotypic (Ab-3) monoclonal antibodies (i.e., AF2), which bind the same epitope as Ab-1, appear to possess less nonspecific binding capacity, however, than the Ab-1 (IgM) antibodies. Anti-Ab-1 (i.e., C8F2) anti-idiotypic monoclonal antibodies, which bear an idiotope equivalent to the epitope present in epiglycanin and the HCA, demonstrated greater consistency as a standard calibrator and for coating wells than epiglycanin. CONCLUSIONS. The concentration of the HCA in the body fluids of patients with carcinomas may be accurately determined by competitive binding assays. It is suggested that the use of anti-idiotypic antibodies (IgG), rather than epiglycanin/ HCA, and Ab-3 anti-anti-idiotypic antibodies (IgG), rather than Ab-1 (IgM), will improve the consistency, as well as the sensitivity and specificity, of the assay. Cancer 2002;94:803-13. (C) 2002 American Cancer Society. C1 Boston Biomed Res Inst, Boston, MA USA. Massachusetts Gen Hosp, Lab Carbohydrates Res, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Codington, JF (reprint author), Boston Biomed Res Inst, 64 Grove St, Watertown, MA 02472 USA. FU NCI NIH HHS [CA-08418] NR 25 TC 7 Z9 7 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD FEB 1 PY 2002 VL 94 IS 3 BP 803 EP 813 DI 10.1002/cncr.10124 PG 11 WC Oncology SC Oncology GA 517QB UT WOS:000173620400029 PM 11857316 ER PT J AU Ferrando, AA Neuberg, DS Staunton, J Loh, ML Huard, C Raimondi, SC Behm, FG Pui, CH Downing, JR Gilliland, DG Lander, ES Golub, TR Look, AT AF Ferrando, AA Neuberg, DS Staunton, J Loh, ML Huard, C Raimondi, SC Behm, FG Pui, CH Downing, JR Gilliland, DG Lander, ES Golub, TR Look, AT TI Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia SO CANCER CELL LA English DT Article ID INTERNAL TANDEM DUPLICATION; ACUTE MYELOID-LEUKEMIA; LOOP-HELIX PROTEIN; EARLY THYMOCYTE DEVELOPMENT; PEDIATRIC-ONCOLOGY-GROUP; SWI-SNF COMPLEX; CHROMOSOMAL TRANSLOCATION; TRANSGENIC MICE; HOMEOBOX GENE; DEVELOPMENTAL REGULATION AB Human T cell leukemias can arise from oncogenes activated by specific chromosomal translocations involving the T cell receptor genes. Here we show that five different T cell oncogenes (HOX11, TAL1, LYL1, LMO1, and LMO2) are often aberrantly expressed in the absence of chromosomal abnormalities. Using oligonucleotide microarrays, we identified several gene expression signatures that were indicative of leukemic arrest at specific stages of normal thymocyte development: LYL1(+) signature (pro-T), HOX11(+) (early cortical thymocyte), and TAL1(+) (late cortical thymocyte). Hierarchical clustering analysis of gene expression signatures grouped samples according to their shared oncogenic pathways and identified HOX11L2 activation as a novel event in T cell leukemogenesis. These findings have clinical importance, since HOX11 activation is significantly associated with a favorable prognosis, while expression of TAL1, LYL1, or, surprisingly, HOX11L2 confers a much worse response to treatment. Our results illustrate the power of gene expression profiles to elucidate transformation pathways relevant to human leukemia. C1 Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. MIT, Whitehead Inst, Ctr Genome Res, Cambridge, MA 02142 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. St Jude Childrens Res Hosp, Dept Hematol Oncol, Memphis, TN 38105 USA. RP Look, AT (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM thomas_look@dfci.harvard.edu RI Ferrando, Adolfo /Q-7026-2016 FU NCI NIH HHS [CA 21765, CA 68484] NR 91 TC 607 Z9 626 U1 5 U2 32 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD FEB PY 2002 VL 1 IS 1 BP 75 EP 87 DI 10.1016/S1535-6108(02)00018-1 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 599QZ UT WOS:000178347800012 PM 12086890 ER PT J AU Haiman, CA Hankinson, SE Spiegelman, D Brown, M Hunter, DJ AF Haiman, CA Hankinson, SE Spiegelman, D Brown, M Hunter, DJ TI No association between a single nucleotide polymorphism in CYP19 and breast cancer risk SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID AROMATASE C1 Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Hunter, DJ (reprint author), Channing Labs, 181 Longwood Ave, Boston, MA 02115 USA. RI Myles, Brown/B-6906-2008; OI Brown, Myles/0000-0002-8213-1658 FU NCI NIH HHS [CA57374, CA40356, CA49449, CA65725] NR 4 TC 32 Z9 34 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2002 VL 11 IS 2 BP 215 EP 216 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 528FE UT WOS:000174233100010 PM 11867511 ER PT J AU Fonseca, R Harrington, D Oken, MM Dewald, GW Bailey, RJ Van Wier, SA Henderson, KJ Blood, EA Rajkumar, SV Kay, NE Van Ness, B Greipp, PR AF Fonseca, R Harrington, D Oken, MM Dewald, GW Bailey, RJ Van Wier, SA Henderson, KJ Blood, EA Rajkumar, SV Kay, NE Van Ness, B Greipp, PR TI Biological and prognostic significance of interphase fluorescence in situ hybridization detection of chromosome 13 abnormalities (Delta 13) in multiple myeloma: An Eastern Cooperative Oncology Group study SO CANCER RESEARCH LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; DEXAMETHASONE-INDUCED APOPTOSIS; STEM-CELL TRANSPLANTATION; BONE-MARROW ANGIOGENESIS; CYTOGENETIC ABNORMALITIES; PLASMABLASTIC MORPHOLOGY; INTERFERON-ALPHA; CLINICAL-TRIAL; PLASMA-CELLS; TRANSLOCATIONS AB Chromosome 13 abnormalities (Delta13) have been associated with an unfavorable prognosis in patients with multiple myeloma (MM). The significance of this has been unresolved because of diverse methods of detection and heterogeneous groups of patients. We conducted a study of Delta13 in patients entered into the Eastern Cooperative Oncology Group trial E9486/E9487. Patients with newly diagnosed MM (median follow-up of survivors >100 months) were studied for Delta13, using bone marrow samples obtained at study enrollment. We used interphase fluorescence in situ hybridization with the probes LSI13 (Rb)D13S319 with simultaneous immunofluorescence detection of bone marrow plasma cells (PCs). We detected Delta13 in 176 of 325 (54%) evaluable patients. Patients with Delta13 were more likely to have a serum monoclonal protein at a concentration less than or equal to1 g/dl (22 versus 13%; P = 0.04), light-chain-only MM (19.3 versus 10.8%; P = 0.04), lambda light chain (42 versus 28%; P = 0.027), stage III (56 versus 42%; P = 0.014), and be female (60 versus 50%; P = 0.087). The PC labeling index and Delta13 correlated (P = 0.03). Patients with Delta13 were less likely to respond to treatment (74 versus 63%; P = 0.041) and bad a significantly shorter median overall survival (34.9 versus 51 months; P = 0.021). The association of Delta13 and survival remained an independent prognostic variable in a regression model. Among patients with Delta13, those receiving IFN had a worse overall survival that those not receiving the medication (P = 0.03). The presence of Delta13 is an important and independent adverse prognostic factor in newly diagnosed MM and is associated with specific biological features. C1 Mayo Clin, Dept Hematol & Internal Med, Dept Lab Med & Pathol, Rochester, MN 55905 USA. Dana Farber Canc Inst, Eastern Cooperat Oncol Grp, Ctr Stat, Boston, MA 02115 USA. Virginia Piper Canc Inst, Minneapolis, MN 55407 USA. Univ Minnesota, Minneapolis, MN 55455 USA. RP Fonseca, R (reprint author), Div Hematol & Internal Med, Stabile 6-22, Rochester, MN 55905 USA. OI Fonseca, Rafael/0000-0002-5938-3769 FU NCI NIH HHS [P01 CA 62242, R01 CA 83724-01, CA-21115-25C] NR 47 TC 138 Z9 147 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2002 VL 62 IS 3 BP 715 EP 720 PG 6 WC Oncology SC Oncology GA 519TB UT WOS:000173740600018 PM 11830525 ER PT J AU Keith, RL Miller, YE Hoshikawa, Y Moore, MD Gesell, TL Gao, BF Malkinson, AM Golpon, HA Nemenoff, RA Geraci, MW AF Keith, RL Miller, YE Hoshikawa, Y Moore, MD Gesell, TL Gao, BF Malkinson, AM Golpon, HA Nemenoff, RA Geraci, MW TI Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer SO CANCER RESEARCH LA English DT Article ID CONTINUOUS INTRAVENOUS EPOPROSTENOL; BUTYLATED HYDROXYTOLUENE; BETA-CAROTENE; CARDIOVASCULAR-DISEASE; COLORECTAL-CANCER; TRANSGENIC MICE; ORGAN-CULTURE; ASPIRIN USE; VITAMIN-A; A/J MICE AB Inhibition of cyclooxygenase (COX) activity decreases eicosanoid production and prevents lung cancer in animal models. Prostaglandin (PG) I-2 (PGI(2) prostacyclin) is a PGH(2) metabolite with anti-inflammatory, antiproliferative, and antimetastatic properties. The instability of PGI(2) has limited its evaluation in animal models of cancer. We hypothesized that pulmonary overexpression of prostacyclin synthase may prevent the development of murine lung tumors. Transgenic mice with selective pulmonary prostacyclin synthase overexpression were exposed to two distinct carcinogenesis protocols: an initiation/promotion model and a simple carcinogen model. The transgenic mice exhibited significantly reduced lung tumor multiplicity (tumor number) in proportion to transgene expression, a dose-response effect. Moreover, the highest expressing mice demonstrated reduced tumor incidence. To investigate the mechanism for protection, we evaluated PG levels and inflammatory responses. At the time of sacrifice following one carcinogenesis model, the transgenics exhibited only an increase in 6-keto-PGF(1alpha), not a decrease in PGE(2). Thus, elevated PGI(2) levels and not decreased PGE(2) levels appear to be necessary for the chemopreventive effects. When exposed to a single dose of butylated hydroxytoluene, transgenic mice exhibited a survival advantage; however, reduction in alveolar inflammatory response was not observed. These studies demonstrate that manipulation of PG metabolism downstream from COX produces even more profound lung cancer reduction than COX inhibition alone and could be the basis for new approaches to understanding the pathogenesis and prevention of lung cancer. C1 Univ Colorado, Hlth Sci Ctr, Div Pulm Sci & Crit Care Med, Dept Med, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Pharmaceut Sci, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Pharmacol, Denver, CO 80262 USA. Denver VA Med Ctr, Dept Med, Div Pulm Sci & Crit Care Med, Denver, CO 80220 USA. RP Geraci, MW (reprint author), Univ Colorado, Hlth Sci Ctr, Div Pulm Sci & Crit Care Med, Dept Med, 4200 E 9th Ave,Campos Box C-272, Denver, CO 80262 USA. FU NCI NIH HHS [CA 33497, P50 CA 58187]; NHLBI NIH HHS [HL-03001, HL-43180]; NIDDK NIH HHS [DK-39902] NR 43 TC 81 Z9 81 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2002 VL 62 IS 3 BP 734 EP 740 PG 7 WC Oncology SC Oncology GA 519TB UT WOS:000173740600020 PM 11830527 ER PT J AU Reimer, CL Agata, N Tammam, JG Bamberg, M Dickerson, WM Kamphaus, GD Rook, SL Milhollen, M Fram, R Kalluri, R Kufe, D Kharbanda, S AF Reimer, CL Agata, N Tammam, JG Bamberg, M Dickerson, WM Kamphaus, GD Rook, SL Milhollen, M Fram, R Kalluri, R Kufe, D Kharbanda, S TI Antineoplastic effects of chemotherapeutic agents are potentiated by NM-3, an inhibitor of angiogenesis SO CANCER RESEARCH LA English DT Article ID DISTINCT ANTITUMOR PROPERTIES; CYTOTOXIC CANCER THERAPIES; TUMOR-GROWTH; ANTIANGIOGENIC AGENTS; ANGIOSTATIN; EFFICACY AB Antiangiogenic therapy, although effective in shrinking tumors, has not yet been established as a standalone treatment for cancer. This therapeutic limitation can be overcome by combining angiogenesis inhibitors with chemotherapeutic agents. NM-3, a small molecule isocoumarin, is a recently discovered angiogenesis inhibitor. Here we demonstrate that NM-3 inhibits the proliferation of human umbilical vein endothelial cells in vitro, at concentrations 10-fold less than those required to inhibit normal fibroblasts or tumor cells (HT29, MKN28, and MCF-7). NM-3 alone inhibits endothelial sprouting and tube formation in vitro. The results also show that synergistic antiproliferative activity is observed when human umbilical vein endothelial cells are treated with NM-3 in combination with 5-fluorouracil. The effects of treatment with NM-3 and various chemotherapeutic agents were also evaluated in tumor xenografts. The results demonstrate that combined treatment with NM-3 and chemotherapeutic agents significantly reduced mean tumor volume compared with either treatment alone, with no effects on body weight changes. Taken together, these findings demonstrate that NM-3 is a well-tolerated angiogenesis inhibitor that significantly increases the efficacy of existing antineoplastic agents. C1 Ilex Oncol Inc, Boston, MA 02215 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Program Matrix Biol, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Ctr Canc, Dept Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Kharbanda, S (reprint author), Ilex Oncol Inc, 20 Overland St, Boston, MA 02215 USA. RI Kalluri, Raghu/E-2677-2015 OI Kalluri, Raghu/0000-0002-2190-547X NR 33 TC 40 Z9 44 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2002 VL 62 IS 3 BP 789 EP 795 PG 7 WC Oncology SC Oncology GA 519TB UT WOS:000173740600027 PM 11830534 ER PT J AU Teshima, T Liu, C Lowler, KP Dranoff, G Ferrara, JLM AF Teshima, T Liu, C Lowler, KP Dranoff, G Ferrara, JLM TI Donor leukocyte infusion from immunized donors increases tumor vaccine efficacy after allogeneic bone marrow transplantation SO CANCER RESEARCH LA English DT Article ID VERSUS-HOST DISEASE; COLONY-STIMULATING FACTOR; TOTAL-BODY IRRADIATION; T-CELLS; PROSTATE-CANCER; GENE-TRANSFER; ANTITUMOR IMMUNITY; IN-VIVO; LYMPHOCYTES; LEUKEMIA AB Donor T cells play a critical role in mediating both harmful graft-versus-host disease (GVHD) and beneficial graft-versus-tumor effect after allogeneic bone marrow transplantation (BMT). We have recently demonstrated a novel treatment strategy to stimulate specific antitumor activity with preservation of tolerance to host antigens after T cell-depleted allogeneic BMT by vaccination of recipients with irradiated B16 melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor. In this marine system, donor leukocyte infusion from a donor immunized with the recipient-derived B16 vaccines enhanced clinical activity of tumor vaccines without exacerbating GVHD. CD4(+) T cells are essential for this enhancement. lit vitro analysis of splenocytes from donor leukocyte infusion donor mice demonstrated that immunization of donors with the recipient-derived B16 vaccines elicited potent T-cell proliferation and cytokine responses specific to B16 antigens. These results demonstrate that immunization of donors with recipient-derived tumor vaccines preferentially induces tumor-specific T-cell responses and that vaccination of both donors and recipients can generate potent antitumor immunity without exacerbating GVHD. This strategy has important implications to prevent recurrence of malignancies after BMT. C1 Univ Michigan, Ctr Canc, BMT Program, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Ctr Canc, Dept Pediat, Ann Arbor, MI 48109 USA. Univ Florida, Dept Pathol Immunol & Lab Med, Gainesville, FL 32610 USA. Harvard Univ, Sch Med, Dept Adult Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ferrara, JLM (reprint author), Univ Michigan, Ctr Canc, BMT Program, Dept Internal Med, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. RI teshima, takanori/G-1671-2012 FU NCI NIH HHS [CA 39542] NR 47 TC 26 Z9 27 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2002 VL 62 IS 3 BP 796 EP 800 PG 5 WC Oncology SC Oncology GA 519TB UT WOS:000173740600028 PM 11830535 ER PT J AU Pru, JK Tilly, JL AF Pru, JK Tilly, JL TI Genomic plasticity in cell death susceptibility SO CELL DEATH AND DIFFERENTIATION LA English DT Editorial Material ID CHROMOSOMAL BREAKPOINT; APOPTOSIS; BCL-2; MITOCHONDRIA; FAMILY C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Obstet & Gynecol Vincent Ctr Reprod Biol, Boston, MA 02114 USA. RP Tilly, JL (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Obstet & Gynecol Vincent Ctr Reprod Biol, Boston, MA 02114 USA. NR 29 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD FEB PY 2002 VL 9 IS 2 BP 96 EP 98 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 517PY UT WOS:000173620100002 PM 11840158 ER PT J AU Levine, SM Sako, EY AF Levine, SM Sako, EY TI Waiting to make the weight for lung transplantation SO CHEST LA English DT Editorial Material ID BODY-MASS INDEX; PREOPERATIVE OBESITY; SURVIVAL; MORTALITY C1 Univ Texas, Hlth Sci Ctr, Lung Transplant Program, San Antonio, TX USA. S Texas Vet Hlth Care Syst, Audie L Murphy Mem Vet Hosp Div, San Antonio, TX USA. RP Levine, SM (reprint author), S Texas Vet Hlth Care Syst, Audie L Murphy Div, Pulm Sect, 111E,7400 Merton Minter Blvd, San Antonio, TX 78229 USA. NR 16 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 FEB PY 2002 VL 121 IS 2 BP 317 EP 320 DI 10.1378/chest.121.2.317 PG 4 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 521JJ UT WOS:000173836600003 PM 11834634 ER PT J AU Sorenson, SM Moradzadeh, E Bakhda, R AF Sorenson, SM Moradzadeh, E Bakhda, R TI Repeated infections in a 68-year-old man SO CHEST LA English DT Article C1 Univ Calif Los Angeles, Sch Med, Dept Radiol, Los Angeles, CA 90095 USA. W Los Angeles Vet Adm Med Ctr, Los Angeles, CA USA. RP Sorenson, SM (reprint author), Univ Calif Los Angeles, Sch Med, Dept Radiol, 10833 Le Conte Ave, Los Angeles, CA 90095 USA. NR 6 TC 3 Z9 4 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 FEB PY 2002 VL 121 IS 2 BP 644 EP 646 DI 10.1378/chest.121.2.644 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 521JJ UT WOS:000173836600052 PM 11834683 ER PT J AU Basile, JN AF Basile, JN TI Halting the progression of heart failure: Finding the optimal combination therapy SO CLEVELAND CLINIC JOURNAL OF MEDICINE LA English DT Article ID HYPERTENSION; CAPTOPRIL; MORTALITY; LOSARTAN; ELITE AB Finding the optimal combination of drugs in the correct dosages, which requires careful monitoring over time, is key to slowing the disease process and prolonging life. For most patients, treating heart failure involves correcting underlying left ventricular dysfunction, thereby slowing the remodeling process. C1 Med Univ S Carolina, Ralph H Johnson VA Med Ctr, Charleston, SC 29403 USA. RP Basile, JN (reprint author), Med Univ S Carolina, Ralph H Johnson VA Med Ctr, 109 Bee St, Charleston, SC 29403 USA. NR 18 TC 0 Z9 0 U1 0 U2 0 PU CLEVELAND CLINIC PI CLEVELAND PA 9500 EUCLID AVE, CLEVELAND, OH 44106 USA SN 0891-1150 J9 CLEV CLIN J MED JI Clevel. Clin. J. Med. PD FEB PY 2002 VL 69 IS 2 BP 104 EP + PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 523ER UT WOS:000173941500001 PM 11990640 ER PT J AU Gregor, SM Perell, KL Rushatakankovit, S Miyamoto, E Muffoletto, R Gregor, RJ AF Gregor, SM Perell, KL Rushatakankovit, S Miyamoto, E Muffoletto, R Gregor, RJ TI Lower extremity general muscle moment patterns in healthy individuals during recumbent cycling SO CLINICAL BIOMECHANICS LA English DT Article DE recumbent; cycling; biomechanics; general muscle moment; rehabilitation; lower extremity ID PARADOX AB Objective. The purpose of this study was to compare lower extremity generalized muscle moments across two workloads during recumbent bicycling in younger and older healthy adults. Design. The study design was a comparative investigation of cycling patterns. Background. Biomechanical data regarding muscle activation, kinematic, and kinetic patterns have been presented for upright cycling, but only a few studies have evaluated biomechanical patterns during the alternative configuration of recumbent cycling, Methods. Twenty-four healthy adults, classified by age into two different groups, tinder 35 and over 50 years of age, rode a recumbent bicycle at a constant cadence (60-65 rpm) and at two different resistances (0.5 and 1.0 kg m) while kinematic and kinetic data were recorded. General muscle moments were calculated using joint kinematic and kinetic data via inverse dynamic equations. Results. The ankle general muscle moment remained plantar flexor throughout the pedaling cycle; the knee general muscle moment remained flexor throughout the cycle, except during the power phase of the higher workload where an extensor general muscle moment was observed; and the hip general muscle moment was extensor with a transient flexor general muscle moment period during the recovery phase. Increased workload led to increases in ankle plantar flexor and knee extensor general muscle moment magnitudes, but no changes at the hip. Age had no effect on general muscle moment magnitudes or patterns. Conclusions. Configurational differences between the upright and recumbent bicycle do not affect patterns, but the total output requirements do affect the magnitudes of the general muscle moments. C1 VA Greater Los Angeles Healthcare Syst, W Los Angeles Healthcare Ctr, PM&R Gait Lab 117G, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Mt St Marys Coll, Los Angeles, CA USA. Georgia Inst Technol, Atlanta, GA 30332 USA. RP Perell, KL (reprint author), VA Greater Los Angeles Healthcare Syst, W Los Angeles Healthcare Ctr, PM&R Gait Lab 117G, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 11 TC 23 Z9 23 U1 1 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0268-0033 J9 CLIN BIOMECH JI Clin. Biomech. PD FEB PY 2002 VL 17 IS 2 BP 123 EP 129 AR PII S0268-0033(01)00112-7 DI 10.1016/S0268-0033(01)00112-7 PG 7 WC Engineering, Biomedical; Orthopedics; Sport Sciences SC Engineering; Orthopedics; Sport Sciences GA 527PD UT WOS:000174193700006 PM 11832262 ER PT J AU Cavacini, LA Duval, M Eder, JP Posner, MR AF Cavacini, LA Duval, M Eder, JP Posner, MR TI Evidence of determinant spreading in the antibody responses to prostate cell surface antigens in patients immunized with prostate-specific antigen SO CLINICAL CANCER RESEARCH LA English DT Article ID RECOMBINANT VACCINIA VIRUS; DENDRITIC CELLS; TUMOR-CELLS; MULTIPLE-SCLEROSIS; CANCER-THERAPY; T-CELLS; PHASE-I; IMMUNOTHERAPY; TRIAL; VACCINATION AB Purpose: Prostate cancer consistently remains a difficult clinical problem. The development of novel therapy strategies for effective control and treatment of prostate cancer is essential. The prostate represents a unique site for immunotherapy, in part because prostate-specific immunity would most probably be without significant long-term sequellae. Antibodies and cell-mediated immunity, induced by either active or passive immunization, represent potential means to specifically target prostate tumor cells. Experimental Design: The serum IgG response to cell surface antigens expressed on LNCAP [prostate-specific antigen (PSA)-positivel and PC-3 (PSA-negative) were analyzed in individuals with advanced disease receiving vaccinia- or fowlpox-expressed PSA (v-PSA or f-PSA, respectively) by flow cytometry. Results: Sera from all seven patients in a Phase I study of v-PSA, collected prior to the third immunization, reacted with both prostate tumor cell lines. The majority of individuals (n = 12) in a Phase II trial of v-PSA and f-PSA developed sustainable antibody responses to cell surface antigens on the prostate tumor cell lines. The magnitude and kinetics of these responses were dependent on the immunization schedule. Of importance, the baseline serum of only one of nine patients tested had reactivity with nonprostate tumor cell lines. Sera from three normal males also lacked reactivity with prostate tumor cells. Conclusions: PSA vaccine constructs are immunogenic and induce antibody responses to a multitude of surface antigens on prostate tumor cell lines by epitope or determinant spreading after stimulation of the immune system by PSA immunization. C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Cavacini, LA (reprint author), Beth Israel Deaconess Med Ctr, 21-27 Burlington Ave,Room 556,POB 15709, Boston, MA 02215 USA. FU NCI NIH HHS [5U01 CA 62490] NR 34 TC 23 Z9 26 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB PY 2002 VL 8 IS 2 BP 368 EP 373 PG 6 WC Oncology SC Oncology GA 522QN UT WOS:000173908600007 PM 11839651 ER PT J AU Bramwell, VHC Morris, D Ernst, DS Hings, I Blackstein, M Venner, PM Ette, EI Harding, MW Waxman, A Demetri, GD AF Bramwell, VHC Morris, D Ernst, DS Hings, I Blackstein, M Venner, PM Ette, EI Harding, MW Waxman, A Demetri, GD TI Safety and efficacy of the multidrug-resistance inhibitor biricodar (VX-710) with concurrent doxorubicin in patients with anthracycline-resistant advanced soft tissue sarcoma SO CLINICAL CANCER RESEARCH LA English DT Article ID PHASE-II TRIAL; HIGH-DOSE IFOSFAMIDE; GASTROINTESTINAL STROMAL TUMORS; MDR1 GENE-EXPRESSION; LIPOSOMAL DOXORUBICIN; P-GLYCOPROTEIN; FIRST-LINE; EUROPEAN-ORGANIZATION; CLINICAL RELEVANCE; PROGNOSTIC FACTORS AB Purpose: Incel (biricodar, VX-710) restores drug sensitivity to P-glycoprotein and multidrug resistance-associated protein-1-expressing cells. This Phase I/II study, evaluated the safety/tolerability, pharmacokinetics, and efficacy of VX-710 plus doxorubicin in patients with inoperable, locally advanced or metastatic, anthracycline-resistant/refractory, soft tissue sarcoma. Experimental Design: In Phase I, i.v. bolus doxorubicin at 60, 75, or 67.5 mg/m(2) was administered 8 h after initiation of a 72-h continuous i.v. (CIV) infusion of VX-710 (120 mg/m(2)/h) to cohorts of patients to establish a maximum tolerated dose. For efficacy evaluations in Phase 11, eligible patients had inoperable, locally advanced or metastatic, anthracycline-resistant/refractory soft tissue sarcoma; :5225 mg/m(2) cumulative prior doxorubicin; and adequate hematological, liver, and kidney function. Cycles were repeated every 3 weeks. Results: Fourteen patients were enrolled in Phase I. Myelosuppression was the dose-limiting toxicity with 75 and then 67.5 mg/m(2) doxorubicin, and the maximum tolerated dose was established at 60 mg/m(2) with VX-710, 120 mg/ m(2)/h, 72-h CIV. VX-710 had no apparent effect on doxorubicin pharmacokinetics. Twenty-nine patients enrolled in Phase II were treated with VX-710, 120 mg/m(2)/h 72-h CIV, and 60 mg/m(2) doxorubicin. Among 26 evaluable patients, minimal activity was noted among 11 patients with gastrointestinal stromal tumors (GISTs); however, in 15 patients with anthracycline-resistant sarcomas of other histologies, 2 achieved :partial responses and 7 patients had disease stabilization with an overall median progression-free interval of 3.4 months. Conclusion: Anthracycline resistance in GISTs appears to be independent of P-glycoprotein or multidrug resistance-associated protein-1 resistance mechanisms. However, the combination of VX-710 and doxorubicin resulted in objective responses or disease stabilization in patients with strictly defined anthracycline-refractory non-GIST sarcomas, which warrants further evaluation. C1 London Reg Canc Ctr, Dept Med Oncol, London, ON N6A 4L6, Canada. Tom Baker Canc Clin, Calgary, AB T2N 4N2, Canada. Montreal Gen Hosp, Montreal, PQ H3G 1A4, Canada. Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. Vertex Pharmaceut Inc, Cambridge, MA 02139 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Bramwell, VHC (reprint author), London Reg Canc Ctr, Dept Med Oncol, 790 Commissioners Rd E, London, ON N6A 4L6, Canada. NR 96 TC 35 Z9 35 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB PY 2002 VL 8 IS 2 BP 383 EP 393 PG 11 WC Oncology SC Oncology GA 522QN UT WOS:000173908600009 PM 11839653 ER PT J AU Maulik, G Kijima, T Ma, PC Ghosh, SK Lin, J Shapiro, GI Schaefer, E Tibaldi, E Johnson, BE Salgia, R AF Maulik, G Kijima, T Ma, PC Ghosh, SK Lin, J Shapiro, GI Schaefer, E Tibaldi, E Johnson, BE Salgia, R TI Modulation of the c-Met/hepatocyte growth factor pathway in small cell lung cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID FACTOR SCATTER FACTOR; TYROSINE KINASE INHIBITOR; MET PROTOONCOGENE; PHOSPHATIDYLINOSITOL 3-KINASE; HEMATOPOIETIC-CELLS; PROTEIN PAXILLIN; RECEPTOR; ADHESION; EXPRESSION; MOTILITY AB The c-Met receptor tyrosine kinase and its ligand HGF (hepatocyte growth factor) have been shown to be involved in angiogenesis, cellular motility, growth, invasion, and differentiation. The role of c-Met/HGF axis in small cell lung cancer (SCLC) has not been reported previously. We have determined the expression of p170(c-Met) precursor and p140(c-Met) beta-chain in seven SCLC cell lines by immunoblotting. We used the SCLC cell line H69, which expressed an abundant amount of c-Met to study the function and downstream effects of c-Met activation. Stimulation of H69 cells with HGF (40 ng/ml, 6-h stimulation) significantly altered cell motility of the SCLC cells with increased formation of filopodia and membrane ruffling, characterized as membrane blebbing, as well as increased migration of the cellular clusters were seen. We have further studied the signal transduction pathways of HGF/c-Met in the H69 cell line. The stimulation of H69 with HGF (40 ng/ml, >24 h, maximal at 1 h) increased the amount of reactive oxygen species formed by 34%. HGF stimulation (40 ng/ml, 7.5-min stimulation) of H69 cells showed increased tyrosine phosphorylated bands identified at M-r 68,000, 120,000-140,000, and 200,000. Some of these tyrosine-phosphorylated bands were identified as the focal adhesion proteins paxillin, FAK, PYK2, and the c-Met receptor itself. Phospho-specific antibodies show that tyrosines at amino acid (a.a.) 31 of paxillin, and autophosphorylation sites at a.a. 397 of p125FAK, and a.a. 402 of PYK2 are phosphorylated in response to HGF/c-Met signaling. We also demonstrate that the Hsp90 inhibitor geldanamycin, which also affects c-Met, reduced the growth and viability of four of four SCLC cell lines by 25% to 85%, over a 72-h time period. Geldanamycin caused apoptosis of SCLC cells, as well as led to increased levels of Hsp70 but not Hsp90. These results demonstrate that c-Met/HGF pathway is functional in SCLC, and it would be useful to target this pathway toward novel therapy. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Immunobiol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Biosource Int, Hopkinton, MA 01748 USA. Indian Inst Technol, Dept Biotechnol, Kharagpur 721302, W Bengal, India. RP Salgia, R (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Dana 1234B,44 Binney St, Boston, MA 02115 USA. FU PHS HHS [75348-04] NR 35 TC 173 Z9 179 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB PY 2002 VL 8 IS 2 BP 620 EP 627 PG 8 WC Oncology SC Oncology GA 522QN UT WOS:000173908600041 PM 11839685 ER PT J AU Anderson, F Game, BA Atchley, D Xu, MF Lopes-Virella, MF Huang, Y AF Anderson, F Game, BA Atchley, D Xu, MF Lopes-Virella, MF Huang, Y TI IFN-gamma pretreatment augments immune complex-induced matrix metalloproteinase-1 expression in U937 histiocytes SO CLINICAL IMMUNOLOGY LA English DT Article DE IFN-gamma; LDL; metalloproteinase; immune complex ID COLLAGEN GENE-EXPRESSION; ACUTE CORONARY SYNDROMES; ATHEROSCLEROTIC PLAQUES; INTERFERON-GAMMA; OXIDIZED LDL; MURINE MACROPHAGES; LYMPHOCYTES-T; ACTIVATION; CELLS; LOCALIZATION AB We reported recently that immune complexes (ICs) induced matrix metalloproteinase-1 (AMP-1) expression in U937 histiocytes. The present study was undertaken to determine the effect of pretreatment of U937 cells with interferon-gamma (IFN-gamma) on IC-induced MMP-1 expression. Our flow cytometry studies showed that IFN-gamma upregulated the surface expression of FcgammaRI, but not FcgammaRII. Results also showed that pretreatment of the cells with IFN-gamma augmented LDL-containing IC (LDL-10-induced NRKP-1 secretion in a dose- and time-dependent manner. Furthermore, Northern blot analysis revealed that IFN-gamma pretreatment led to a marked increase in MMP-1 mRNA. Finally, we demonstrated that PD98059 was able to block LDL-IC-induced MMP-1 secretion, regardless of whether the cells were pretreated with IFN-gamma or not, suggesting that IFN-gamma pretreatment did not alter the essential role of the ERR signaling pathway in LDL-IC-induced MMP-1 expression. In conclusion, the present study has demonstrated that IFN-gamma pretreatment augments LDL-IC-induced AMP-1 expression in U937 cells, thus elucidating an immune mechanism potentially involved in plaque destabilization. (C) 2002 Elsevier Science (USA). C1 Med Univ S Carolina, Dept Med, Ralph H Johnson Vet Adm Med Ctr, Charleston, SC 29403 USA. Med Univ S Carolina, Dept Med, Div Endocrinol Diabet & Med Genet, Charleston, SC 29403 USA. RP Huang, Y (reprint author), Med Univ S Carolina, Dept Med, Ralph H Johnson Vet Adm Med Ctr, 114 Doughty St, Charleston, SC 29403 USA. NR 35 TC 7 Z9 7 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD FEB PY 2002 VL 102 IS 2 BP 200 EP 207 DI 10.1006/clim.2001.5161 PG 8 WC Immunology SC Immunology GA 527PB UT WOS:000174193500012 PM 11846463 ER PT J AU Siegle, GJ Ingram, RE Matt, GE AF Siegle, GJ Ingram, RE Matt, GE TI Affective interference: An explanation for negative attention biases in dysphoria? SO COGNITIVE THERAPY AND RESEARCH LA English DT Article DE depression; information processing; attention; rumination ID AFFECTIVE WORDS; DEPRESSED MOOD; MEMORY; INFORMATION; ANXIETY; TASK; STIMULI; TIME AB Research suggests that individuals with features of depression pay excessive attention to negative information. Yet, it is unclear what aspects of negative information are attended to by these individuals. Different answers to this question suggest different roles for attention in the onset and maintenance of depressive states. This study investigated aspects of emotional information to which college students with and without features of depression attend. Research participants completed an affective lexical decision task and an affective valence identification task. Dysphoric individuals were slow to identify the emotional valence of positive information and nonemotional aspects of negative information (the lexicality of negative words), but were not slow to identify the emotional valence of negative words. An "affective-interference" hypothesis is advanced to explain these results. Dysphoric individuals are proposed to attend to the emotional content of negative information at the expense of attending to other aspects of the information. Results are related to theories of ruminative coping with depression. C1 Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. VA Pittsburgh Healtcare Syst, Pittsburgh, PA 15213 USA. San Diego State Univ, San Diego, CA USA. RP Siegle, GJ (reprint author), Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, 2811 O Hara St, Pittsburgh, PA 15213 USA. NR 43 TC 49 Z9 51 U1 2 U2 17 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0147-5916 J9 COGNITIVE THER RES JI Cogn. Ther. Res. PD FEB PY 2002 VL 26 IS 1 BP 73 EP 87 AR UNSP 0147-5916/02/0200-0073/0 DI 10.1023/A:1013893705009 PG 15 WC Psychology, Clinical SC Psychology GA 522KX UT WOS:000173896100005 ER PT J AU Buckley, TC Blanchard, EB Hickling, EJ AF Buckley, TC Blanchard, EB Hickling, EJ TI Automatic and strategic processing of threat stimuli: A comparison between PTSD, panic disorder, and nonanxiety controls SO COGNITIVE THERAPY AND RESEARCH LA English DT Article DE PTSD; panic-disorder; information-processing; stroop ID POSTTRAUMATIC-STRESS-DISORDER; EMOTIONAL INFORMATION; ANXIETY DISORDERS; RAPE VICTIMS; STROOP TASK; DEPRESSION; AWARENESS; CUES; BIAS AB This study evaluated 2 hypotheses derived from the theoretical work of A. T Beck and D. A. Clark (1997). Two anxiety disorder groups, posttraumatic stress disorder (PTSD) and panic disorder (PD), and a nonanxiety control group participated in a modified-Stroop study. The study evaluated whether the diagnostic groups could be differentiated on the basis of responses to stimulus valence and content at different stages of information processing (IP). We found no support for the hypothesis that the diagnostic groups would be sensitive to stimulus valence at automatic stages of IP Consistent with the second of our 2 hypotheses, the PD group showed delayed vocal responses when processing disorder-specific threat stimuli at strategic stages of IP The PTSD group showed a generalized valence effect at strategic stages of IP, evincing delayed vocal responses to all stimuli with negative valence. The clinical implications of these findings are discussed, as are directions for future research. C1 Boston VA Med Ctr, Boston, MA USA. Boston Univ, Sch Med, Boston, MA USA. SUNY Albany, Ctr Stress & Anxiety Disorders, New York, NY USA. RP Buckley, TC (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, 150 S Huntington Ave 116B-2, Boston, MA 02131 USA. NR 48 TC 28 Z9 28 U1 2 U2 7 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0147-5916 J9 COGNITIVE THER RES JI Cogn. Ther. Res. PD FEB PY 2002 VL 26 IS 1 BP 97 EP 115 AR UNSP 0147-5916/02/0200-0097/0 DI 10.1023/A:1013897805918 PG 19 WC Psychology, Clinical SC Psychology GA 522KX UT WOS:000173896100007 ER PT J AU Miller, E AF Miller, E TI What's in a condom? HIV and sexual politics in Japan SO CULTURE MEDICINE AND PSYCHIATRY LA English DT Article DE AIDS history; HIV; Japan; sexual politics ID INNER-CITY WOMEN; AIDS; POVERTY AB Utilizing a range of ethnographic data from an AIDS hotline, a women's shelter, a night club, AIDS campaigns, news articles, and interviews with health bureaucrats, this paper explores the history of AIDS in Japan and the ways in which official practices reproduce systems of domination. This paper examines the official categories of "foreign woman'' and "prostitution'' as discursive strategies of containment, and argues that nationalist discourses and representations of sexuality are closely linked in maintaining relations of power. C1 Massachusetts Gen Hosp, John D Stoeckle Ctr Primary Care, Boston, MA 02114 USA. RP Miller, E (reprint author), Massachusetts Gen Hosp, John D Stoeckle Ctr Primary Care, 50 Staniford St,9th Floor, Boston, MA 02114 USA. RI Miller, Elizabeth/E-7939-2012 NR 31 TC 9 Z9 9 U1 0 U2 5 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0165-005X J9 CULT MED PSYCHIAT JI Cult. Med. Psychiatr. PD FEB PY 2002 VL 26 IS 1 BP 1 EP 32 DI 10.1023/A:1015239429419 PG 32 WC Anthropology; Psychiatry; Social Sciences, Biomedical SC Anthropology; Psychiatry; Biomedical Social Sciences GA 543FM UT WOS:000175090800001 PM 12088095 ER PT J AU Tuveson, DA Jacks, T AF Tuveson, DA Jacks, T TI Technologically advanced cancer modeling in mice SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Review ID MUTANT MICE; TELOMERE DYSFUNCTION; MLH1 DEFICIENCY; GENE; CELLS; MOUSE; MUTATION; CARCINOGENESIS; TUMORIGENESIS; ACTIVATION AB Multiple approaches now exist for the generation of genetically engineered murine cancer models. These new models utilize latent, conditional and inducible alleles to better mimic the in vivo setting in which sporadic human cancers occur. The murine tumor models are beginning to reveal mysteries of tumorigenesis, such as the role of the tumor microenvironment and the dependence of tumors on continuous oncogenic stimulation. C1 MIT, Dept Biol, Cambridge, MA 02139 USA. Ctr Canc, Cambridge, MA 02139 USA. Howard Hughes Med Inst, Cambridge, MA 02139 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Tuveson, DA (reprint author), MIT, Dept Biol, 40 Ames St, Cambridge, MA 02139 USA. NR 53 TC 52 Z9 55 U1 0 U2 6 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD FEB PY 2002 VL 12 IS 1 BP 105 EP 110 DI 10.1016/S0959-437X(01)00272-6 PG 6 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 513BF UT WOS:000173357500016 PM 11790563 ER PT J AU Luster, AD AF Luster, AD TI The role of chemokines in linking innate and adaptive immunity SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID TOLL-LIKE RECEPTORS; NAIVE T-CELLS; DENDRITIC CELLS; EXPRESSION; TRAFFICKING; INFECTION; LIGAND AB It is becoming clear that chemokine function is necessary to translate an innate-immune response into an acquired response. Dendritic cells activated by innate stimuli and loaded with foreign antigen travel to regional lymph nodes to activate the acquired-immune system. Subsequently, the activated acquired-immune cells move into tissue, where the innate immune system sets-off the danger signal. The chemokine system has emerged as an essential regulator of this dendritic cell and lymphocyte trafficking, which is necessary to turn an innate immune response into an adaptive response. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Charlestown, MA 02129 USA. RP Luster, AD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bldg 149,13th St, Charlestown, MA 02129 USA. NR 30 TC 331 Z9 342 U1 0 U2 20 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 FEB PY 2002 VL 14 IS 1 BP 129 EP 135 DI 10.1016/S0952-7915(01)00308-9 PG 7 WC Immunology SC Immunology GA 510DR UT WOS:000173193900017 PM 11790543 ER PT J AU Aballay, A Ausubel, FM AF Aballay, A Ausubel, FM TI Caenorhabditis elegans as a host for the study of host-pathogen interactions SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID PSEUDOMONAS-AERUGINOSA; SALMONELLA-TYPHIMURIUM; MOLECULAR MECHANISMS; MODEL; MUTANTS; IMMUNITY; CELLS AB Recently, pathogenicity models that involve the killing of the genetically tractable nematode Caenorhabditis elegans by human pathogens have been developed. From the perspective of the pathogen, the advantage of these models is that thousands of mutagenized bacteria clones can be individually screened for avirulent mutants on separate petri plates seeded with C. elegans. The advantages of using C. elegans to study host responses to pathogen attack are the extensive genetic and genomic resources available and the relative ease of identifying C. elegans mutants that exhibit altered susceptibility to pathogen attack. The use of Caenorhabditis elegans as the host for a variety of human pathogens is discussed. C1 Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Aballay, A (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. NR 28 TC 96 Z9 97 U1 1 U2 11 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD FEB PY 2002 VL 5 IS 1 BP 97 EP 101 DI 10.1016/S1369-5274(02)00293-X PG 5 WC Microbiology SC Microbiology GA 520PV UT WOS:000173791000015 PM 11834377 ER PT J AU Maulik, G Shrikhande, A Kijima, T Ma, PC Morrison, PT Salgia, R AF Maulik, G Shrikhande, A Kijima, T Ma, PC Morrison, PT Salgia, R TI Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Review DE c-Met; hepatocyte growth factor/scatter factor; signal transduction; cell motility and migration; metastasis; inhibitors ID FACTOR SCATTER FACTOR; TYROSINE KINASE RECEPTOR; PAPILLARY RENAL CARCINOMAS; FOCAL ADHESION KINASE; CELL LUNG CARCINOMAS; ADAPTER PROTEIN CRKL; HUMAN HEPATOCELLULAR-CARCINOMA; FACTOR HGF; IN-VITRO; SOMATIC MUTATIONS AB Receptor tyrosine kinases have become important therapeutic targets for anti-neoplastic molecularly targeted therapies. c-Met is a receptor tyrosine kinase shown to be over-expressed and mutated in a variety of malignancies. Stimulation of c-Met via its ligand hepatocyte growth factor also known as scatter factor (HGF/SF), leads to a plethora of biological and biochemical effects in the cell. There has been considerable knowledge gained on the role of c-Met-HGF/SF axis in normal and malignant cells. This review summarizes the structure of c-Met and HGF/SF and their family members. Since there are known mutations of c-Met in solid tumors, particularly in papillary renal cell carcinoma, we have summarized the various mutations and over-expression of c-Met known thus far. Stimulation of c-Met can lead to scattering, angiogenesis, proliferation, enhanced cell motility, invasion, and eventual metastasis. The biological functions altered by c-Met are quite unique and described in detail. Along with biological functions, various signal transduction pathways, including the cytoskeleton are altered with the activation of c-Met-HGF/SF loop. We have recently shown the phosphorylation of focal adhesion proteins, such as paxillin and p125FAK in response to c-Met stimulation in lung cancer cells, and this is detailed here. Finally, c-Met when mutated or over-expressed in malignant cells serves as an important therapeutic target and the most recent data in terms of inhibition of c-Met and downstream signal transduction pathways is summarized. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Lowe Ctr Thorac Oncol, Dept Med, Div Adult Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Mol Biol Core Facil, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Tufts Univ New England Med Ctr, Dept Hematol & Oncol, Boston, MA 02111 USA. RP Salgia, R (reprint author), Lowe Ctr Thorac Oncol, Dept Med, Div Adult Oncol, Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA75348-05] NR 126 TC 270 Z9 299 U1 1 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD FEB PY 2002 VL 13 IS 1 BP 41 EP 59 DI 10.1016/S1359-6101(01)00029-6 PG 19 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 521CW UT WOS:000173822100007 PM 11750879 ER PT J AU Barbara, PD Roberts, DJ AF Barbara, PD Roberts, DJ TI Tail gut endoderm and gut/genitourinary/tail development: a new tissue-specific role for Hoxa13 SO DEVELOPMENT LA English DT Article DE Hoxa13; tail; endoderm; gut; HFG; chick ID CHICK LIMB BUDS; POSTERIOR REGION; GENE-EXPRESSION; VERTEBRATE LIMB; CELL-DEATH; EMBRYO; HOXD-13; MORPHOGENESIS; HOXA-13; HINDGUT AB Hoxa13 is expressed early in the caudal mesoderm and endoderm of the developing hindgut. The tissue-specific roles of Hoxa13 function have not been described. Hand-foot-genital syndrome, a rare dominantly inherited human malformation syndrome characterized by distal extremity and genitourinary anomalies, is caused by mutations in the HOXA13 gene. We show evidence that one specific HOXA13 mutation likely acts as a dominant negative in vivo. When chick HFGa13 is overexpressed in the chick caudal endoderm early in development, caudal structural malformations occur. The phenotype is specific to HFGa13 expression in the posterior endoderm, and includes taillessness and severe gut/genitourinary (GGU) malformations. Finally, we show that chick HFGa13 negatively regulates expression of Hoxd13 and antagonizes functions of both endogenous Hoxa13 and Hoxd13 proteins. We suggest a fundamental role for epithelial specific expression of Hoxa 13 in the epithelial-mesenchymal interaction necessary for tail growth and posterior GGU patterning. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pediat Surg, Boston, MA 02114 USA. RP Roberts, DJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. NR 62 TC 53 Z9 53 U1 0 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD FEB PY 2002 VL 129 IS 3 BP 551 EP 561 PG 11 WC Developmental Biology SC Developmental Biology GA 530LW UT WOS:000174360000001 ER PT J AU Huang, NN Mootz, DE Walhout, AJM Vidal, M Hunter, CP AF Huang, NN Mootz, DE Walhout, AJM Vidal, M Hunter, CP TI MEX-3 interacting proteins link cell polarity to asymmetric gene expression in Caenorhabditis elegans SO DEVELOPMENT LA English DT Article DE Caenorhabditis elegans; pattern formation; polarity; RNA-binding protein; translational control ID C-ELEGANS; GERMLINE SPECIFICATION; TRANSLATIONAL CONTROL; PATTERN-FORMATION; KH DOMAIN; EMBRYOS; RNA; ENCODES; KINASE; PAR-3 AB The KH domain protein MEX-3 is central to the temporal and spatial control of PAL-1 expression in the C. elegans early embryo. PAL-1 is a Caudal-like homeodomain protein that is required to specify the fate of posterior blastomeres. While pal-1 mRNA is present throughout the oocyte and early, embryo, PAL-1 protein is expressed only in posterior blastomeres, starting at the four-cell stage. To better understand how PAL-1 expression is regulated temporally and spatially, we have identified MEX-3 interacting proteins (MIPs) and characterized in detail two that are required for the patterning of PAL-1 expression. RNA interference of MEX-6, a CCCH zinc-finger protein, or SPN-4, an RNA recognition motif protein, causes PAL-1 to be expressed in all four blastomeres starting at the four-cell stage. Genetic analysis of the interactions between these mip genes and the par genes, which provide polarity information in the early embryo, defines convergent genetic pathways that regulate MEX-3 stability and activity to control the spatial pattern of PAL-1 expression. These experiments suggest that par-1 and par-4 affect distinct processes. par-1 is required for many aspects of embryonic polarity, including the restriction of MEX-3 and MEX-6 activity to the anterior blastomeres. We find that PAL-1 is not expressed in par-1 mutants, because MEX-3 and MEX6 remain active in the posterior blastomeres. The role of par-4 is less well understood. Our analysis suggests that par-4 is required to inactivate MEX-3 at the four-cell stage. Thus, PAL-1 is not expressed in par-4 mutants because MEX-3 remains active in all blastomeres. We propose that MEX-6 and SPN-4 act with MEX-3 to translate the temporal and spatial information provided by the early acting par genes into the asymmetric expression of the cell fate determinant PAL-1. C1 Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Hunter, CP (reprint author), Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. OI Walhout, Marian/0000-0001-5587-3608 FU NHGRI NIH HHS [R01 HG 01715-A1]; NIGMS NIH HHS [GM 61677, R01 GM061677-05, R01 GM061677] NR 37 TC 41 Z9 50 U1 0 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD FEB PY 2002 VL 129 IS 3 BP 747 EP 759 PG 13 WC Developmental Biology SC Developmental Biology GA 530LW UT WOS:000174360000018 PM 11830574 ER PT J AU Childs, S Chen, JN Garrity, DM Fishman, MC AF Childs, S Chen, JN Garrity, DM Fishman, MC TI Patterning of angiogenesis in the zebrafish embryo SO DEVELOPMENT LA English DT Article DE zebrafish; angiogenesis; vascular pattern ID ENDOTHELIAL GROWTH-FACTOR; RECEPTOR TYROSINE KINASES; CARDIOVASCULAR DEVELOPMENT; SPROUTING ANGIOGENESIS; VASCULAR-PERMEABILITY; VEGF; VASCULOGENESIS; EXPRESSION; GENE; ANGIOPOIETIN-1 AB Little is known about how vascular patterns are generated in the embryo. The vasculature of the zebrafish trunk has an extremely regular pattern. One intersegmental vessel (ISV) sprouts from the aorta, runs between each pair of somites, and connects to the dorsal longitudinal anastomotic vessel (DLAV). We now define the cellular origins, migratory paths and cell fates that generate these metameric vessels of the trunk. Additionally, by a genetic screen we define one gene, out of bounds (obd), that constrains this angiogenic growth to a specific path. We have performed lineage analysis, using laser activation of a caged dye and mosaic construction to determine the origin of cells that constitute the ISV. Individual angioblasts destined for the ISVs arise from the lateral posterior mesoderm (LPM), and migrate to the dorsal aorta, from where they migrate between somites to their final position in the ISVs and dorsal longitudinal anastomotic vessel (DLAV). Cells of each ISV leave the aorta only between the ventral regions of two adjacent somites, and migrate dorsally to assume one of three ISV cell fates. Most dorsal is a T-shaped cell, based in the DLAV and branching ventrally; the second constitutes a connecting cell; and the third an inverted T-shaped cell, based in the aorta and branching dorsally. The ISV remains between somites during its ventral course, but changes to run mid-somite dorsally. This suggests that the pattern of ISV growth ventrally and dorsally is guided by different cues. We have also performed an ENU mutagenesis screen of 750 mutagenized genomes and identified one mutation, obd that disrupts this pattern. In obd mutant embryos, ISVs sprout precociously at abnormal sites and migrate anomalously in the vicinity of ventral somite. The dorsal extent of the ISV is less perturbed. Precocious sprouting can be inhibited in a VEGF morphant, but the anomalous site of origin of obd ISVs remains. In mosaic embryos, obd somite causes adjacent wild-type endothelial cells to assume the anomalous ISV pattern of obd embryos. Thus, the launching position of the new sprout and its initial trajectory are directed by inhibitory signals from ventral somites. Zebrafish ISVs are a tractable system for defining the origins and fates of vessels, and for dissecting elements that govern patterns of vessel growth. C1 Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Med Sch, Charlestown, MA 02129 USA. RP Fishman, MC (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. OI Chen, Jau-Nian/0000-0001-8807-3607 FU NHLBI NIH HHS [HL63206, HL49579]; NIDDK NIH HHS [DK55383] NR 46 TC 184 Z9 196 U1 2 U2 20 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD FEB PY 2002 VL 129 IS 4 BP 973 EP 982 PG 10 WC Developmental Biology SC Developmental Biology GA 528YV UT WOS:000174274000015 PM 11861480 ER PT J AU White, K AF White, K TI Signaling survival: How axons rescue their glia SO DEVELOPMENTAL CELL LA English DT Editorial Material ID NERVOUS-SYSTEM MIDLINE; PROGRAMMED CELL-DEATH; DROSOPHILA EMBRYOS; DIFFERENTIATION; GENES AB The trophic theory of cell survival hypothesizes that cell number is regulated by survival signals generated by other cells. Work published in this issue of Developmental Cell confirms that neurons can provide trophic support for glia in Drosophila, and fills in important molecular details of this interaction. C1 Massachusetts Gen Hosp, Harvard Med Sch, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. RP White, K (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, Cutaneous Biol Res Ctr, Bldg 149,13th St, Charlestown, MA 02129 USA. RI White, Kristin/D-7936-2013 NR 9 TC 2 Z9 2 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD FEB PY 2002 VL 2 IS 2 BP 128 EP 130 DI 10.1016/S1534-5807(02)00123-5 PG 3 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 546XQ UT WOS:000175302000003 PM 11832236 ER PT J AU Laybutt, DR Kaneto, H Hasenkamp, W Grey, S Jonas, JC Sgroi, DC Groff, A Ferran, C Bonner-Weir, S Sharma, A Weir, GC AF Laybutt, DR Kaneto, H Hasenkamp, W Grey, S Jonas, JC Sgroi, DC Groff, A Ferran, C Bonner-Weir, S Sharma, A Weir, GC TI Increased expression of antioxidant and antiapoptotic genes in islets that may contribute to beta-cell survival during chronic hyperglycemia SO DIABETES LA English DT Article ID NF-KAPPA-B; DEPENDENT DIABETES-MELLITUS; CYTOKINE-INDUCED APOPTOSIS; INDUCED INSULIN-SECRETION; PANCREATIC-ISLETS; OXIDATIVE STRESS; HEME OXYGENASE; NITRIC-OXIDE; TRANSCRIPTION FACTORS; ENDOTHELIAL-CELLS AB Hypertrophy is one mechanism of pancreatic beta-cell. growth and is seen as an important compensatory response to insulin resistance. We hypothesized that the induction of protective genes contributes to the survival of enlarged (hypertrophied) beta-cells. Here, we evaluated changes in stress gene expression that accompany beta-cell hypertrophy in islets from hyperglycemic rats 4 weeks after partial pancreatectomy (Px). A variety of protective genes were upregulated, with markedly increased expression of the antioxidant genes heme oxygenase-1 and glutathione peroxidase and the antiapoptotic gene A20. Cu/Zn-superoxide dismutase (SOD) and Mn-SOD were modestly induced, and Bcl-2 was modestly reduced; however, several other stress genes (catalase, heat shock protein 70, and p53) were unaltered. The increases in mRNA levels corresponded to the degree of hyperglycemia and were reversed in Px rats by 2-week treatment with phlorizin (treatment that normalized hyperglycemia), strongly suggesting the specificity of hyperglycemia in eliciting the response. Hyperglycemia in Px rats also led to activation of nuclear factor-kappaB in islets. The profound change in beta-cell phenotype of hyperglycemic Px rats resulted in a reduced sensitivity to the beta-cell toxin streptozotocin. Sensitivity to the toxin was restored, along with the beta-cell phenotype, in islets from phlorizin-treated Px rats. Furthermore, beta-cells of Px rats were not vulnerable to apoptosis when further challenged in vivo with dexamethasone, which increases insulin resistance. In conclusion, beta-cell adaptation to chronic hyperglycemia and, hence, increased insulin demand is accompanied by the induction of protective stress genes that may contribute to the survival of hypertrophied beta-cells. C1 Beth Israel Deaconess Med Ctr, Immunobiol Res Ctr, Boston, MA 02215 USA. Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA 02114 USA. RP Weir, GC (reprint author), Joslin Diabet Ctr, Islet Transplantat & Cell Biol, Sect Islet Transplantat & Cell Biol, 1 Joslin Pl, Boston, MA 02215 USA. RI Grey, Shane/B-3020-2008; Jonas, Jean-Christophe/C-6766-2011 OI Grey, Shane/0000-0003-2160-1625; Jonas, Jean-Christophe/0000-0001-9882-5438 FU NIDDK NIH HHS [DK35449, DK36836] NR 64 TC 134 Z9 145 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2002 VL 51 IS 2 BP 413 EP 423 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 516HU UT WOS:000173548500019 PM 11812749 ER PT J AU Howlett, KF Sakamoto, K Hirshman, MF Aschenbach, WG Dow, M White, MF Goodyear, LJ AF Howlett, KF Sakamoto, K Hirshman, MF Aschenbach, WG Dow, M White, MF Goodyear, LJ TI Insulin signaling after exercise in insulin receptor substrate-2-deficient mice SO DIABETES LA English DT Article ID HUMAN SKELETAL-MUSCLE; GLUCOSE-TRANSPORT; PHOSPHOTYROSINE PROTEIN; 3-KINASE ACTIVITY; SUBSTRATE FAMILY; SENSITIVITY; CONTRACTION; RAT; DISRUPTION; ACTIVATION AB The period immediately after exercise is characterized by enhanced insulin action in skeletal muscle, and on the molecular level, by a marked increase in insulin-stimulated, phosphotyrosine-associated phosphatidylinositol (PI) 3-kinase activity. Because the increase in PI 3-kinase activity cannot be explained by increased insulin receptor substrate (IRS)-1 signaling, the present study examined whether this effect is mediated by enhanced IRS-2 signaling. In wild-type (WT) mice, insulin increased IRS-2 tyrosine phosphorylation (similar to2.5-fold) and IRS-2-associated PI 3-kinase activity (similar to3-fold). Treadmill exercise, per se, had no effect on IRS-2 signaling, but in the period immediately after exercise, there was a further increase in insulin-stimulated IRS-2 tyrosine phosphorylation (similar to3.5-fold) and IRS-2-associated PI 3-kinase activity (similar to5-fold). In IRS-2-deficient (IRS-2(-/-)) mice, the increase in insulin-stimulated, phosphotyrosine-associated PI 3-kinase activity was attenuated as compared with WT mice. However, in IRS2(-/-) mice, the insulin-stimulated, phosphotyrosine-associated PI 3-kinase response after exercise was slightly higher than the insulin-stimulated response alone. In conclusion, IRS-2 tyrosine phosphorylation and associated PI 3-kinase activity are markedly enhanced by insulin in the immediate period after exercise. IRS-2 signaling can partially account for the increase in insulin-stimulated phosphotyrosine-associated PI 3-kinase activity after exercise. C1 Joslin Diabet Ctr, Div Res, Metab Sect, Boston, MA 02215 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Goodyear, LJ (reprint author), Joslin Diabet Ctr, Div Res, Metab Sect, 1 Joslin Pl, Boston, MA 02215 USA. OI Howlett, Kirsten/0000-0002-8571-4867 FU NIAMS NIH HHS [AR-42238, AR45670]; NIDDK NIH HHS [DK43808, DK59769] NR 28 TC 35 Z9 38 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2002 VL 51 IS 2 BP 479 EP 483 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 516HU UT WOS:000173548500028 PM 11812758 ER PT J AU Roper, MG Qian, WJ Zhang, BB Kulkarni, RN Kahn, CR Kennedy, RT AF Roper, MG Qian, WJ Zhang, BB Kulkarni, RN Kahn, CR Kennedy, RT TI Effect of the insulin mimetic L-783,281 on intracellular [Ca2+] and insulin secretion from pancreatic beta-cells SO DIABETES LA English DT Article; Proceedings Paper CT 2nd Servier-IGIS Symposium CY MAR 22-24, 2001 CL ST JEAN CAP FERRAT, FRANCE ID TYROSINE PHOSPHORYLATION; RECEPTOR SUBSTRATE-1; DISRUPTION; ISLETS; IRS-1; MICE; GENE; HOMEOSTASIS; EXOCYTOSIS; EXPRESSION AB L-783,281, an antidiabetic fungal metabolite than has previously been shown to activate insulin signaling in CHO cells, was tested for its effect on intracellular Ca2+ ([Ca2+](i)) and insulin secretion in single mouse pancreatic beta-cells. Application of 10 mumol/l L-783,281 for 40 s to isolated beta-cells in the presence of 3 mmol/l glucose increased [Ca2+](i) to 178 +/- 10% of basal levels (n = 18) as measured by fluo-4 fluorescence. L-767,827, an inactive structural analog of the insulin mimetic, had no effect on beta-cell [Ca2+](i). The L-783,281-evoked [Ca2+](i) increase was reduced by 82 +/- 4% (n = 6, P < 0.001) in cells incubated with 1 mumol/l of the SERCA (sarco/ endoplasmic reticulum calcium ATPase) pump inhibitor thapsigargin and reduced by 33 +/- 6% (n = 6, P < 0.05) in cells incubated with 20 mumol/l of the L-type Ca2+-channel blocker nifedipine. L-783,281-stimulated [Ca2+](i) increases were reduced to 31 +/- 3% (n = 9, P <: 0.05) and 48 +/- 10% (n = 6, P < 0.05) of control values by the phosphatidylinositol 3-kinase (PI3-K) inhibitors LY294002 (25 mumol/l) and wortmannin (100 nmol/l), respectively. In beta-cells from IRS-1(-/-) mice, 10 mumol/l L-783,281 had no significant effect on [Ca2+](i) (n = 5). L-783,281 also resulted in insulin secretion at single beta-cells. Application of 10 mumol/l L-783,281 for 40 s resulted in 12.2 2.1 (n = 14) exocytotic events as measured by amperometry, whereas the inactive structural analog had no stimulatory effect on secretion. Virtually no secretion was evoked by L-783,281 in IRS-1(-/-) beta-cells. LY294002 (25 mumol/l) significantly reduced the effect of the insulin mimetic on beta-cell exocytosis. It is concluded that L-783,281 evokes [Ca2+](i) increases and exocytosis in beta-cells via an IRS-1/PI3-K-dependent pathway and that the [Ca2+](i) increase involves release of Ca2+ from intracellular stores. C1 Univ Florida, Dept Chem, Gainesville, FL 32611 USA. Merck Res Labs, Dept Mol Endocrinol, Rahway, NJ USA. Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Kennedy, RT (reprint author), Univ Florida, Dept Chem, Gainesville, FL 32611 USA. RI Roper, Michael/D-2386-2010; Qian, Weijun/C-6167-2011; Kennedy, Robert/G-9095-2016 OI Kennedy, Robert/0000-0003-2447-7471 FU NIDDK NIH HHS [DK 31036, DK 46960, DK 02885-01] NR 39 TC 26 Z9 28 U1 1 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2002 VL 51 SU 1 BP S43 EP S49 DI 10.2337/diabetes.51.2007.S43 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 517FF UT WOS:000173599900009 PM 11815457 ER PT J AU de Vos, P Hamel, AF Tatarkiewicz, K AF de Vos, P Hamel, AF Tatarkiewicz, K TI Considerations for successful transplantation of encapsulated pancreatic islets SO DIABETOLOGIA LA English DT Review DE transplantation; encapsulated pancreatic islets ID ALGINATE-POLYLYSINE MICROCAPSULES; ARTIFICIAL ENDOCRINE PANCREAS; STREPTOZOTOCIN-DIABETIC RATS; MAMMALIAN-CELL ENCAPSULATION; PROLONGS XENOGRAFT SURVIVAL; ENDOTHELIAL GROWTH-FACTOR; MOLECULAR-WEIGHT CUTOFF; PORCINE ISLETS; IN-VITRO; BIOARTIFICIAL PANCREAS AB Encapsulation of pancreatic islets allows for transplantion in the absence of immunosuppression. The technology is based on the principle that transplanted tissue is protected for the host immune system by an artificial membrane. Encapsulation offers a solution to the shortage of donors in clinical islet transplantation because it allows animal islets or insulin-producing cells engineered from stem cells to be used. During the past two decades three major approaches to encapsulation have been studied. These include intravascular macrocapsules, which are anastomosed to the vascular system as AV shunt; extravascular macrocapsules, which are mostly diffusion chambers transplanted at different sites; and extravascular microcapsules transplanted in the peritoneal cavity. The advantages and pitfalls of these three approaches are discussed and compared in the light of their applicability to clinical islet transplantation. All systems have been shown to be successful in preclinical studies but not all approaches meet the technical or physiological requirements for application in human beings. The extravascular approach has advantages over the intravascular because since it is associated with less complications such as thrombosis and infection. Microcapsules, due to their spatial characteristics, have a better diffusion capacity than macrocapsules. Recent progress in biocompatibility of microcapsules has brought this technology close to clinical application. Critical issues such as limitations in the functional performance and survival are being discussed. The latest results show that both issues can be solved by the transplantation of microencapsulated islets close to blood vessels in prevascularized solid supports. C1 Univ Groningen, Dept Pathol & Lab Med, Sect Med Biol, NL-9700 RB Groningen, Netherlands. Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. RP de Vos, P (reprint author), Univ Groningen, Dept Pathol & Lab Med, Sect Med Biol, Hanzepl 1, NL-9700 RB Groningen, Netherlands. RI de Vos, Paul/A-3170-2013 NR 131 TC 154 Z9 154 U1 3 U2 31 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD FEB PY 2002 VL 45 IS 2 BP 159 EP 173 DI 10.1007/s00125-001-0729-x PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 536LJ UT WOS:000174701300003 PM 11935147 ER PT J AU Schlozman, SC AF Schlozman, SC TI The shrink in the classroom - Quit obsessing! SO EDUCATIONAL LEADERSHIP LA English DT Editorial Material C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cambridge, MA 02138 USA. Harvard Univ, Grad Sch Educ, Cambridge, MA 02138 USA. RP Schlozman, SC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cambridge, MA 02138 USA. NR 2 TC 1 Z9 1 U1 0 U2 0 PU ASSOC SUPERVISION CURRICULUM DEVELOPMENT PI ALEXANDRIA PA 1703 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0013-1784 J9 EDUC LEADERSHIP JI Educ. Leadership PD FEB PY 2002 VL 59 IS 5 BP 95 EP 97 PG 3 WC Education & Educational Research SC Education & Educational Research GA 519RQ UT WOS:000173739600017 ER PT J AU Ohh, M Kim, WY Moslehi, JJ Chen, YZ Chau, V Read, MA Kaelin, WG AF Ohh, M Kim, WY Moslehi, JJ Chen, YZ Chau, V Read, MA Kaelin, WG TI An intact NEDD8 pathway is required for Cullin-dependent ubiquitylation in mammalian cells SO EMBO REPORTS LA English DT Article ID TUMOR-SUPPRESSOR PROTEIN; UBIQUITIN-LIGASE; GENE-PRODUCT; CONJUGATION; COMPLEX; BINDING; FAMILY; SYSTEM; YEAST; SCF AB Skpl-Cdc53/Cul1-F-box (SCF) complexes constitute a class of E3 ubiquitin ligases. Recently, a multiprotein complex containing pVHL, elongin C and Cul2 (VEC) was shown to structurally and functionally resemble SCF complexes. Cdc53 and the Cullins can become covalently linked to the ubiquitin-like molecule Rub1/NEDD8. Inhibition of neddylation inhibits SCF function in vitro and in yeast and plants. Here we show that ongoing neddylation is likewise required for VEC function in vitro and for the degradation of SCF and VEC targets in mammalian cells. Thus, neddylation regulates the activity of two specific subclasses of mammalian ubiquitin ligases. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat, Belmont, MA 02478 USA. Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. Millenium Pharmaceut, Cambridge, MA 02139 USA. Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Kaelin, WG (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. NR 41 TC 122 Z9 125 U1 1 U2 4 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 FEB PY 2002 VL 3 IS 2 BP 177 EP 182 DI 10.1093/embo-reports/kvf028 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 526XX UT WOS:000174156100017 PM 11818338 ER PT J AU Matikainen, TM Moriyaia, T Morita, Y Perez, GI Korsmeyer, SJ Sherr, DH Tilly, JL AF Matikainen, TM Moriyaia, T Morita, Y Perez, GI Korsmeyer, SJ Sherr, DH Tilly, JL TI Ligand activation of the aromatic hydrocarbon receptor transcription factor drives bax-dependent apoptosis in developing fetal ovarian germ cells SO ENDOCRINOLOGY LA English DT Article ID MOUSE; BCL-2; OOGENESIS; MICE; REQUIREMENT; DEFICIENCY; SURVIVAL; EXPOSURE; SMOKING; FAMILY AB We recently reported that a targeted disruption of the gene encoding the aromatic hydrocarbon receptor (AHR) in mice reduces fetal oocyte apoptosis, leading to a 2-fold increase in the number of primordial follicles endowed at birth. although the identity of the natural ligand(s) for the AHR remains to be unequivocally established, these findings indicate that the level of AHR function is an important physiological determinant of how many oocytes will succumb to apoptosis during development of the fetal ovaries. Furthermore, the AHR is a well established receptor for polycyclic aromatic hydrocarbons (PAHs), a class of ubiquitous environmental chemicals known to cause the death of female germ cells in fetal life. Given the possibility that the AHR serves as a key mediator of fetal oocyte death under both physiological and pathological situations, this study was conducted to more fully examine the impact of PAH-AHR interaction on fetal ovarian germ cells. In addition, experiments were designed to begin identification of the mechanism(s) by which ligand activation of the AHR induces prenatal oocyte depletion after transplacental exposure of fetuses to PAHs in vivo. Embryonic d 13.5 murine fetal ovaries cultured in the presence of PAHs exhibited a high level of germ cell loss via apoptosis that was prevented by the selective AHR antagonist, alpha-napthoflavone (ANF). Immunohistochemical analysis revealed an accumulation of Bax protein in germ cells of fetal ovaries exposed to PAHs before the onset of apoptosis, whereas cotreatment with ANF inhibited the induction of Bax expression. The functional importance of increased Bax expression to the cytotoxic response was confirmed by findings that fetal ovarian germ cell loss caused by in utero exposure of wild-type female fetuses to PAHs was not observed in Bax,deficient female fetuses exposed in parallel. We conclude that a central role exists for the AHR in transducing the actions of PAHs in fetal ovarian germ cells, and that the proapoptotic Bcl-2 family member, Bax, is a required mediator PAH-induced oocyte loss in female fetuses exposed to PAHs in utero. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Obstet & Gynecol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. Boston Univ, Sch Med, Dept Environm Hlth, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02118 USA. RP Tilly, JL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Obstet & Gynecol, Vincent Ctr Reprod Biol, VBK137C-GYN,55 Fruit St, Boston, MA 02114 USA. FU NIEHS NIH HHS [R01-ES-08430] NR 30 TC 93 Z9 100 U1 0 U2 3 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2002 VL 143 IS 2 BP 615 EP 620 DI 10.1210/en.143.2.615 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 514KA UT WOS:000173437000033 PM 11796517 ER PT J AU Liu, BY Wu, PW Bringhurst, FR Wang, JT AF Liu, BY Wu, PW Bringhurst, FR Wang, JT TI Estrogen inhibition of PTH-stimulated osteoclast formation and attachment in vitro: Involvement of both PKA and PKC SO ENDOCRINOLOGY LA English DT Article ID PARATHYROID-HORMONE PTH; GROWTH-FACTOR-BETA; BONE-RESORPTION; CELL-FORMATION; POSTMENOPAUSAL OSTEOPOROSIS; DIFFERENTIATION FACTOR; MURINE OSTEOCLASTS; OSTEOSARCOMA CELLS; RAT OSTEOCLASTS; RECEPTOR AB Estrogens modulate the catabolic effects of PTH on bone in vivo and in vitro. PTH-stimulated cAMP accumulation in osteoblasts is thought to be linked to increased osteoclastic activity, but the precise mechanism is still unknown. In cocultures of clonal marrow stromal cells (MS1) and normal mouse spleen cells, both 1,25-dihydroxyvitamin D-3 and rat PTH (rPTH)-(1-34) can induce the formation of tartrate-resistant acid phosphatase- and calcitonin receptor-positive multinucleated osteoclast-like cells, which can attach to dentine slices and produce resorption pits. In this system, osteoclastogenesis stimulated by PTH, but not by 1,25-dihydroxyvitamin D-3, was suppressed by 17beta-E2 (10(-10)-10(-8) m), whereas 17alpha-E2 (10(-8) m) had no effect. Exposure to 10(-8) m 17beta-E2, but not 17alpha-E2, also significantly decreased the PTH-induced attachment of osteoclast-like cells to dentine slices. 17beta-E2 inhibited osteoclast-like cell formation induced by 8-bromo-cAMP (10(-4) m), 12-O-tetradecanoylphorbol 13-acetate (10-(8) m), or rat PTH-(1-34) (10(-7) M) in combination with either rp-adenosine-3',5'-cyclic monophosphorothioate (10-(4) M) or 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (10(-5) m). 17beta-E2 suppressed the partial stimulation of tartrate-resistant acid phosphatase-positive multinucleated. osteoclastlike cell formation induced by [Arg(2)]human (h) PTH-(1-34) (10(-7) m) or hPTH-(3-34) (10(-7) m), but not that caused by 10(-7)m hPTH-(53-84). We conclude that estrogens suppress PTH-stimulated osteoclast-like cell formation by blocking both the cAMP-dependent PKA pathway and the PLC-coupled calcium/PKC pathway. In addition to inhibiting formation of osteoclasts and promoting their apoptosis, estrogen may regulate bone resorption by blocking attachment of osteoclasts to bone. C1 Natl Taiwan Univ Hosp, Dept Dent, Taipei 10016, Taiwan. Natl Taiwan Univ, Coll Med, Sch Dent, Taipei 10016, Taiwan. Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Liu, BY (reprint author), Natl Taiwan Univ Hosp, Dept Dent, 1 Chang Te St, Taipei 10016, Taiwan. EM byliu@ha.mc.ntu.edu.tw FU NIDDK NIH HHS [DK-11794] NR 50 TC 18 Z9 18 U1 0 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2002 VL 143 IS 2 BP 627 EP 635 DI 10.1210/en.143.2.627 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 514KA UT WOS:000173437000035 PM 11796519 ER PT J AU Eisenberg, JNS Wade, TJ Charles, S Vu, M Hubbard, A Wright, CC Levy, D Jensen, P Colford, JM AF Eisenberg, JNS Wade, TJ Charles, S Vu, M Hubbard, A Wright, CC Levy, D Jensen, P Colford, JM TI Risk factors in HIV-associated diarrhoeal disease: the role of drinking water, medication and immune status SO EPIDEMIOLOGY AND INFECTION LA English DT Article ID CRYPTOSPORIDIUM INFECTION; OUTBREAK; AIDS; CONSUMPTION AB In a cross-sectional survey of 226 HIV-infected men, we examined the occurrence of diarrhoea and its relationship to drinking water consumption patterns, risk behaviours, immune status and medication use. Diarrhoea was reported by 47% of the respondents. Neither drinking boiled nor filtered water was significantly associated with diarrhoea (OR = 0.5 [0.2 1.6], 1.2 [0.6, 2.5] respectively), whereas those that drank bottled water were at risk for diarrhoea (OR = 3.0 [1.1, 7.8]). Overall, 47% always or often used at least one water treatment. Of the 37% who were very concerned about drinking water, 62% had diarrhoea, 70% always or often used at least one water treatment. An increase in CD4 count was protective only for those with a low risk of diarrhoea associated with medication (OR = 0.6 [0.5, 0.9]). A 30% attributable risk to diarrhoea was estimated for those with high medication risk compared to those with low medication risk. The significant association between concern with drinking water and diarrhoea as well as between concern with drinking water and water treatment suggests awareness that drinking water is a potential transmission pathway for diarrhoeal disease. At the same time we found that a significant portion of diarrhoea was associated with other sources not related to drinking water such as medication usage. C1 Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. Univ Calif Berkeley, Ctr Occupational & Environm Hlth, Berkeley, CA 94720 USA. San Francisco Vet Adm Med Ctr, San Francisco, CA 94121 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. RP Eisenberg, JNS (reprint author), Univ Calif Berkeley, Sch Publ Hlth, 140 Warren Hall MC 7360, Berkeley, CA 94720 USA. FU ODCDC CDC HHS [UR2/CCU916252-02] NR 19 TC 11 Z9 13 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 0950-2688 J9 EPIDEMIOL INFECT JI Epidemiol. Infect. PD FEB PY 2002 VL 128 IS 1 BP 73 EP 81 DI 10.1017/S0950268801006252 PG 9 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 540CG UT WOS:000174910400010 PM 11895094 ER PT J AU Licht, EA Jacobsen, RH Fujikawa, DG AF Licht, EA Jacobsen, RH Fujikawa, DG TI Chronically impaired frontal lobe function from subclinical Epileptiform discharges SO EPILEPSY & BEHAVIOR LA English DT Article DE cognitive deficits; subclinical epileptiform discharges; frontal lobe deficits; subclinical seizures ID EEG DISCHARGES; INTELLIGENCE; EPILEPSY; SEIZURES AB Subclinical epileptiform discharges (SEDs) are a common occurrence on electroencephalograms (EEGs). Their potential for acutely disrupting cognitive functions has been well documented, but detailed studies of cognitive performance by patients with chronic exposure to disruptive SEDs have been lacking and scant data have been available to guide treatment decisions or to assist in predicting recovery. We identified a patient with frequent frontotemporally (FT) predominant SEDs and monitored cognitive performance over time with periodic neuropsychological testing and EEGs. Over a 16-year period, Full Scale 10 rose 23 points and Verbal IQ rose 30 as SEDs were suppressed. Severity of impairment, reflected by the marked increase in cognitive performance overtime, was not predicted by his appearance and performance on routine tests of cognitive functions in the clinic. Quantitating total SED duration per EEG provided an objective marker to track severity over time. The cumulative effects of chronic exposure to disruptive SEDs may create a sustained "cognitive burden" or encephalopathic state that persists even in the absence of ongoing discharges. (C) 2002 Elsevier Science (USA). C1 VA Greater Los Angeles Healthcare Syst, Sepulveda Ambulatory Care Ctr, Dept Neurol, Sepulveda, CA 91343 USA. VA Greater Los Angeles Healthcare Syst, Nursing Home Care Unit, Dept Neurol, Sepulveda, CA 91343 USA. VA Greater Los Angeles Healthcare Syst, Nursing Home Care Unit, Dept Mental Hlth, Sepulveda, CA 91343 USA. VA Greater Los Angeles Healthcare Syst, Sepulveda Ambulatory Care Ctr, Dept Mental Hlth, Sepulveda, CA 91343 USA. Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Dept Neurol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Brain Res Inst, Los Angeles, CA 90024 USA. RP Fujikawa, DG (reprint author), Dept Vet Affairs, Greater Los Angeles Healthcare Syst, Sepulveda Ambulatory Care Ctr, Neurol Dept 127, 16111 Plummer St, Sepulveda, CA 91343 USA. NR 10 TC 11 Z9 11 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 1525-5050 J9 EPILEPSY BEHAV JI Epilepsy Behav. PD FEB PY 2002 VL 3 IS 1 BP 96 EP 100 DI 10.1006/ebeh.2001.0312 PG 5 WC Behavioral Sciences; Clinical Neurology; Psychiatry SC Behavioral Sciences; Neurosciences & Neurology; Psychiatry GA 553ML UT WOS:000175679500015 ER PT J AU Chasan, B Geisse, NA Pedatella, K Wooster, DG Teintze, M Carattino, MD Goldmann, WH Cantiello, HF AF Chasan, B Geisse, NA Pedatella, K Wooster, DG Teintze, M Carattino, MD Goldmann, WH Cantiello, HF TI Evidence for direct interaction between actin and the cystic fibrosis transmembrane conductance regulator SO EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS LA English DT Article DE cytoskeleton; ion channel reconstitution; electrophysiology; cystic fibrosis; atomic force microscopy ID ATOMIC-FORCE MICROSCOPE; CHLORIDE CHANNEL; MEMBRANE-PROTEIN; BINDING; CELLS; RESOLUTION AB Previous studies have demonstrated that actin filament organization controls the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel function. The precise molecular nature of the interaction between actin and CFTR, however, remains largely unknown. In this report, interactions between actin and purified human epithelial CFTR were directly assessed by reconstitution of the channel protein in a lipid bilayer system and by atomic force microscopy (AFM). CFTR-containing liposomes in solution were deposited on freshly cleaved mica and imaging was performed in tapping-mode AFM. CFTR function was also determined in identical preparations. Images of single CFTR molecules were obtained, and addition of monomeric actin below its critical concentration showed the formation of actin filaments associated with CFTR. The data indicate a direct interaction between actin and CFTR exists, which may explain the regulatory role of the cytoskeleton in ion channel function. This was confirmed by functional studies of CFTR single-channel currents, which were regulated by addition of various conformations of actin. The present study indicates that CFTR may directly bind actin and that this interaction helps affect the functional properties of this channel protein. C1 Massachusetts Gen Hosp East, Renal Unit, Charlestown, MA 02129 USA. Boston Univ, Dept Phys, Boston, MA 02215 USA. Montana State Univ, Dept Chem & Biochem, Bozeman, MT 59717 USA. Fac Farm & Bioquim, Catedra Quim Gen & Inorgan, Lab Canales Ion, Buenos Aires, DF, Argentina. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Cantiello, HF (reprint author), Massachusetts Gen Hosp East, Renal Unit, 149 13th St, Charlestown, MA 02129 USA. RI Goldmann, Wolfgang/H-5572-2013 NR 26 TC 47 Z9 47 U1 0 U2 7 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0175-7571 J9 EUR BIOPHYS J BIOPHY JI Eur. Biophys. J. Biophys. Lett. PD FEB PY 2002 VL 30 IS 8 BP 617 EP 624 DI 10.1007/s00249-001-0188-9 PG 8 WC Biophysics SC Biophysics GA 530NA UT WOS:000174362700006 PM 11908853 ER PT J AU Greenwald, RJ Oosterwegel, MA van der Woude, D Kubal, A Mandelbrot, DA Boussiotis, VA Sharpe, AH AF Greenwald, RJ Oosterwegel, MA van der Woude, D Kubal, A Mandelbrot, DA Boussiotis, VA Sharpe, AH TI CTLA-4 regulates cell cycle progression during a primary immune response SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE CTLA-4; p27(kip1); cell cycle; T lymphocyte; costimulation ID T-LYMPHOCYTES; MICE LACKING; CD28 COSTIMULATION; ACTIVATION PATHWAY; P27(KIP1); PD-1; EXPRESSION; RAS; RECEPTOR; ANTIGEN AB Engagement of CTLA-4 is critical for inhibiting T cell immune responses. Recent studies have shown that CTLA-4 plays a key role in regulating peripheral T cell tolerance. It has been suggested that one mechanism by which CTLA-4 performs this function is by regulating cell cycle progression. Here, we investigate in depth the role of CTLA-4 in regulating cell cycle progression in naive T cells by comparing the immune responses in the absence or presence of CTLA-4. In the absence of CLTA-4, T cells exhibit marked increases in T cell proliferation, IL-2 mRNA and protein secretion, and cells cycling in the S and G2-M phase. Analyses of cyclins, cyclin-dependent kinases, and cell cycle inhibitors involved in the transition from the G1 to S phase reveal that cell cycle progression is prolonged in the absence of CTLA-4. This is due to the early exit from the G1 phase, entry into the S phase, and prolonged S phase period. Re-expression of the cell cycle inhibitor p27(klp1) is delayed in the absence of CTLA-4. These studies demonstrate that the B7: CTLA-4 pathway exerts its major effects on T cell immune responses via regulation of the cell cycle. C1 Brigham & Womens Hosp, Dept Pathol, Div Immunol Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Univ Utrecht, Med Ctr, Dept Immunol, NL-3584 CH Utrecht, Netherlands. Univ Massachusetts, Med Hlth Sci Ctr, Div Renal, Dept Med, Worcester, MA 01605 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Sharpe, AH (reprint author), Brigham & Womens Hosp, Dept Pathol, Div Immunol Res, Boston, MA 02115 USA. RI van der Woude, Diane/N-3874-2015 FU NIAID NIH HHS [AI 46548, AI 40614, AI 43552, F32 AI 10415] NR 39 TC 86 Z9 90 U1 0 U2 6 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 FEB PY 2002 VL 32 IS 2 BP 366 EP 373 DI 10.1002/1521-4141(200202)32:2<366::AID-IMMU366>3.0.CO;2-5 PG 8 WC Immunology SC Immunology GA 524DE UT WOS:000173996100009 PM 11807776 ER PT J AU Lin, YH Andersen, KK AF Lin, YH Andersen, KK TI On the tautomerism of 2,4-disubstituted thiazolones SO EUROPEAN JOURNAL OF ORGANIC CHEMISTRY LA English DT Article DE heterocycles; thiazolones; synthesis; tautomerism ID NUCLEOPHILES AB Four series of thiazolones - 2-phenyl-, 2-ethyl, 2-ethoxy, and 2-(ethylthio)thiazol-5-ones - have been synthesized. The tautomeric behavior of these thiazolones is discussed, and the keto form II, i.e. 2-ethylthiazol-5(2H)one has been characterized by IR, H-1 and C-13 NMR spectroscopic methods for the first time. C1 Univ New Hampshire, Dept Chem, Durham, NH 03824 USA. RP Lin, YH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Charlestown, MA 02129 USA. NR 20 TC 5 Z9 5 U1 1 U2 1 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1434-193X J9 EUR J ORG CHEM JI Eur. J. Org. Chem. PD FEB PY 2002 IS 3 BP 557 EP 563 PG 7 WC Chemistry, Organic SC Chemistry GA 518XY UT WOS:000173694500021 ER PT J AU Wunderbaldinger, P Bremer, C Schellenberger, E Cejna, M Turetschek, K Kainberger, F AF Wunderbaldinger, P Bremer, C Schellenberger, E Cejna, M Turetschek, K Kainberger, F TI Imaging features of iliopsoas bursitis SO EUROPEAN RADIOLOGY LA English DT Article DE iliopsoas; bursitis; hip; US; CT; MRI ID CT APPEARANCE; BURSA; MR; ENLARGEMENT; ARTHRITIS; DISEASE; CYSTS; HIPS AB The aim of this study was firstly to describe the spectrum of imaging findings seen in iliopsoas bursitis, and secondly to compare cross-sectional imaging techniques in the demonstration of the extent, size and appearance of the iliopsoas bursitis as referenced by surgery. Imaging studies of 18 patients (13 women, 5 men: mean age 53 years) with surgically proven iliopsoas bursitis were reviewed. All patients received conventional radiographs of the pelvis and hip, US and MR imaging of the hip. The CT was performed in 5 of the 18 patients. Ultrasound, CT and MR all demonstrated enlarged iliopsoas bursae. The bursal wall was thin and well defined in 83% and thickened in 17% of all cases. The two cases with septations on US were not seen by CT and MRI. A communication between the bursa and the hip joint was seen, and surgically verified, in all 18 patients by MR imaging, whereas US and CT failed to demonstrate it in 44 and 40% of the cases, respectively. Hip joint effusion was seen and verified by surgery in 16 patients by MRI, whereas CT (4 of 5) and US (n = 12) underestimated the number. The overall size of the bursa corresponded best between MRI and surgery, whereas CT and US tended to underestimate the size. Contrast enhancement of the bursal wall was seen in all cases. The imaging characteristics of iliopsoas bursitis are a well-defined, thin-walled cystic mass with a communication to the hip joint and peripheral contrast enhancement. The most accurate way to assess iliopsoas bursitis is with MR imaging; thus, it should be used for accurate therapy planning and follow-up studies. In order to initially prove an iliopsoas bursitis, US is the most cost-effective, easy-to-perform and fast alternative. C1 Univ Vienna, Dept Radiol, Vienna, Austria. Univ Munster, Dept Radiol, Munster, Germany. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. Univ Halle Wittenberg, Dept Radiol, Witten, Germany. RP Wunderbaldinger, P (reprint author), Univ Vienna, Dept Radiol, Waehringer Guertel 18, Vienna, Austria. NR 21 TC 42 Z9 49 U1 2 U2 4 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0938-7994 J9 EUR RADIOL JI Eur. Radiol. PD FEB PY 2002 VL 12 IS 2 BP 409 EP 415 DI 10.1007/s003300101041 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 526JR UT WOS:000174127700023 PM 11870443 ER PT J AU Sakamoto, H Zhao, LH Jain, F Kradin, R AF Sakamoto, H Zhao, LH Jain, F Kradin, R TI IL-12p40(-/-) mice treated with intratracheal bleomycin exhibit decreased pulmonary inflammation and increased fibrosis SO EXPERIMENTAL AND MOLECULAR PATHOLOGY LA English DT Article ID INDUCED LUNG INJURY; DENDRITIC CELLS; INDUCIBLE PROTEIN-10; IFN-GAMMA; T-CELLS; IN-VIVO; INTERFERON-GAMMA; MURINE LUNG; IL-12; EXPRESSION AB Pulmonary lymphohistiocytic inflammation and fibrosis characterize bleomycin (BLM) lung injury. IL-12, a p70 cytokine produced primarily by macrophages and dendritic cells, promotes T-helper-1-mediated inflammation. IL-12 production by blood monocytes and bronchoalveolar large mononuclear cells (BAMC) was investigated at Days 1-14 following intratracheal administration of BLM. In the lung, BAMC showed a large peak of IL-12 expression at Day 5 that returned rapidly toward baseline. IL-12p40(-/-) mice treated with BLM intratracheally showed less pulmonary mononuclear cell inflammation at Day 7 than wild-type controls. whereas pulmonary fibrosis and hydroxyproline content were increased in IL-12p40(-/-) mice at Day 14. The expression of IP-10, RANTES, and eotaxin were decreased in IL-12p40(-/-) mice and lung IL-6 expression was increased, all compared to controls. We conclude that IL-12 promotes the lymphohistiocytic response to BLM and may inhibit the late development of pulmonary fibrosis. (C) 2002 Elsevier Science. C1 Massachusetts Gen Hosp, Immunopathol Unit, Boston, MA 02114 USA. RP Kradin, R (reprint author), Massachusetts Gen Hosp, Immunopathol Unit, Warren 5, Boston, MA 02114 USA. FU NIAID NIH HHS [R01 AI39054] NR 33 TC 26 Z9 30 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 0014-4800 J9 EXP MOL PATHOL JI Exp. Mol. Pathol. PD FEB PY 2002 VL 72 IS 1 BP 1 EP 9 DI 10.1006/exmp.2001.2409 PG 9 WC Pathology SC Pathology GA 517CE UT WOS:000173592900001 PM 11784117 ER PT J AU Sugawara, M Sugawara, Y Wen, K Giulivi, C AF Sugawara, M Sugawara, Y Wen, K Giulivi, C TI Generation of oxygen free radicals in thyroid cells and inhibition of thyroid peroxidase SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Article DE thyroid peroxidase; superoxide; hydrogen peroxide; quinones; thyroid cells ID HYDROGEN-PEROXIDE; NADPH OXIDASE; SUPEROXIDE-DISMUTASE; IRREVERSIBLE INACTIVATION; PLASMA-MEMBRANE; HUMAN-TISSUES; PORCINE; MECHANISM; FOLLICLES; H2O2 AB We examined whether superoxide (O-2(-)) IS produced as a precursor of hydrogen peroxide (H2O2) in cultured thyroid cells using the cytochrome c method and the electron paramagnetic resonance (EPR) method. No O-2(-) or its related radicals was detected in thyroid cells under the physiological condition. The presence of quinone, 2,3-dimethoxy-1-naphthoquinone (DMNQ), or 2-methyl-1,4-naphthoquinone (menadione), in the medium produced O-2(-) and hydroxyl radicals (OH.); the amount of H2O2 generation was also increased. Incubation of follicles with DMNQ or menadione inhibited iodine organification (a step of thyroid hormone formation) and its catalytic enzyme, thyroid peroxidase (TPO). This inhibition should be caused by reactive oxygen species because the two quinones, particularly DMNQ, exert their effect through the generation of reactive oxygen species. It is speculated that the site-specific inactivation of TPO might have occurred at the heme-linked histidine residue of the TPO molecule, a critical amino acid for enzyme activity because OH. (vicious free radicals) can be formed at the iron-linked amino acid. TPO mRNA level and electrophoretic mobility of TPO were not inhibited by quinones. Our study suggests that thyroid H2O2 IS produced by divalent reduction of oxygen without O-2(-) generation. If thyroid cells happen to be exposed to significant amount of reactive oxygen species, TPO and subsequent thyroid hormone formation are inhibited. C1 W Los Angeles Vet Affairs, Div Endocrinol & Metab, Med Ctr 111M, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90073 USA. Univ So Calif, Sch Pharm, Dept Mol Pharmacol & Toxicol, Los Angeles, CA 90033 USA. RP Sugawara, M (reprint author), W Los Angeles Vet Affairs, Div Endocrinol & Metab, Med Ctr 111M, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. RI Giulivi, Cecilia/C-4015-2012 OI Giulivi, Cecilia/0000-0003-1033-7435 NR 30 TC 29 Z9 33 U1 0 U2 1 PU SOC EXPERIMENTAL BIOLOGY MEDICINE PI MAYWOOD PA 195 WEST SPRING VALLEY AVE, MAYWOOD, NJ 07607-1727 USA SN 1535-3702 J9 EXP BIOL MED JI Exp. Biol. Med. PD FEB PY 2002 VL 227 IS 2 BP 141 EP 146 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 514JV UT WOS:000173436500009 PM 11815678 ER PT J AU Ledoux, WR Hillstrom, HJ AF Ledoux, WR Hillstrom, HJ TI The distributed plantar vertical force of neutrally aligned and pes planus feet SO GAIT & POSTURE LA English DT Article DE ground reaction force; gait; flat foot; pes planus ID HALLUX-VALGUS; FOOT; RELIABILITY AB The distributed vertical ground reaction forces were determined for a normative population and contrasted with data from subjects with flat feet. Nineteen asymptomatic subjects, 11 with a neutrally aligned foot type (normal arch) and 8 with a pes planus foot type (low arch), were studied as they walked barefoot across a pressure plate. The pressure plate data were converted to force values at seven locations (subhallucal, five submetatarsal and subcalcaneal) on the plantar aspect of the foot. The distributed loading pattern of the plantar soft tissue throughout the stance phase of gait was determined. Pes planus feet had significantly more force at the subhallucal area with no difference seen under the other areas. These data are indicative of aberrant first ray mechanics in pes planus feet. Published by Elsevier Science B.V. C1 Univ Washington, VA Puget Sound Hlth Care Syst, Dept Orthopaed & Sports Med, RR&D Ctr Excellence Limb Loss Prevent & Prosthet, Seattle, WA 98108 USA. Temple Univ, Sch Podiat Med, Gait Study Ctr, Philadelphia, PA 19107 USA. RP Ledoux, WR (reprint author), Univ Washington, VA Puget Sound Hlth Care Syst, Dept Orthopaed & Sports Med, RR&D Ctr Excellence Limb Loss Prevent & Prosthet, 1660 S Columbian Way,MS 151, Seattle, WA 98108 USA. RI Ledoux, William/K-6815-2015 OI Ledoux, William/0000-0003-4982-7714 NR 26 TC 64 Z9 71 U1 4 U2 7 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0966-6362 J9 GAIT POSTURE JI Gait Posture PD FEB PY 2002 VL 15 IS 1 BP 1 EP 9 AR PII S0966-6362(01)00165-5 DI 10.1016/S0966-6362(01)00165-5 PG 9 WC Neurosciences; Orthopedics; Sport Sciences SC Neurosciences & Neurology; Orthopedics; Sport Sciences GA 571JV UT WOS:000176715000001 PM 11809575 ER PT J AU Marten, K Bremer, C Khazaie, K Sameni, M Sloane, B Tung, CH Weissleder, R AF Marten, K Bremer, C Khazaie, K Sameni, M Sloane, B Tung, CH Weissleder, R TI Detection of dysplastic intestinal adenomas using enzyme-sensing molecular beacons in mice SO GASTROENTEROLOGY LA English DT Article ID COLORECTAL-CANCER; CATHEPSIN-B; COLON-CANCER; BETA-CATENIN; MULTISTAGE TUMORIGENESIS; MIN MICE; APC GENE; FLUORESCENCE; EXPRESSION; TUMORS AB Background & Aims: Proteases play key roles in the pathogenesis of tumor growth and invasion. This study assesses the expression of cathepsin B in dysplastic adenomatous polyps. Methods: Aged ApC(Min/+) mice served as an experimental model for familial adenomatous polyposis. The 4 experimental groups consisted of (a) animals injected with a novel activatable, cathepsin B sensing near infrared fluorescence (NIRF) imaging probe; (b) animals injected with a nonspecific NIRF; (c) uninjected control animals; and (d) non-ApC(Min/+) mice injected with the cathepsin B probe. Lesions were analyzed by immunohistochemistry, Western blotting, reverse transcription-polymerase chain reaction, and optical imaging. Results: Cathepsin B was consistently overexpressed in adenomatous polyps. When mice were injected intravenously with the cathepsin reporter probe, intestinal adenomas became highly fluorescent indicative of high cathepsin B enzyme activity. Even microscopic adenomas were readily detectable by fluorescence, but not light, imaging. The smallest lesion detectable measured 50 mum in diameter. Adenomas in the indocyanine green and/or noninjected group were only barely detectable above the background. Conclusions: The current experimental study shows that cathepsin B is up-regulated in a mouse model of adenomatous polyposis. Cathepsin B activity can be used as a biomarker to readily identify such lesions, particularly when contrasted against normal adjacent mucosa. This detection technology can be adapted to endoscopy or tomographic optical imaging methods for screening of suspicious lesions and potentially for molecular profiling in vivo. C1 Massachusetts Gen Hosp, Ctr Mol Imaging Res, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Wayne State Univ, Sch Med, Dept Pharmacol, Detroit, MI 48201 USA. RP Weissleder, R (reprint author), Massachusetts Gen Hosp, Ctr Mol Imaging Res, Bldg 149,13th St,5403, Charlestown, MA 02129 USA. RI Sloane, Bonnie/A-1050-2009; OI Tung, Ching-Hsuan/0000-0001-6648-6195 FU NCI NIH HHS [N0I-CO97065, P50 CA86355, R33 CA88365] NR 47 TC 146 Z9 150 U1 1 U2 10 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 FEB PY 2002 VL 122 IS 2 BP 406 EP 414 DI 10.1053/gast.2002.30990 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 517QK UT WOS:000173621200021 PM 11832455 ER PT J AU Clerc, P Leung-Theung-Long, S Wang, TC Dockray, GJ Bouisson, M Delisle, MB Vaysse, N Pradayrol, L Fourmy, D Dufresne, M AF Clerc, P Leung-Theung-Long, S Wang, TC Dockray, GJ Bouisson, M Delisle, MB Vaysse, N Pradayrol, L Fourmy, D Dufresne, M TI Expression of CCK2 receptors in the murine pancreas: Proliferation, transdifferentiation of acinar cells, and neoplasia SO GASTROENTEROLOGY LA English DT Article ID TRANSFORMING-GROWTH-FACTOR; CHOLECYSTOKININ-B/GASTRIN RECEPTOR; TRANSGENIC MICE; FACTOR-ALPHA; S6 KINASE; DIFFERENTIAL EXPRESSION; EXOCRINE PANCREAS; GASTRIN RECEPTORS; B RECEPTORS; A RECEPTOR AB Background & Aims: To explore the pancreatic function of CCK2/gastrin receptor, we created ElasCCK2 transgenic mice expressing the human receptor in pancreatic exocrine cells. In previous studies, the transgenic CCK2/gastrin receptor was demonstrated to mediate enzyme release and protein synthesis. We now report results of phenotypic and long-term studies. Methods: Pancreas was characterized using morphometry and immunohistochemistry. ElasCCK2 mice were crossed with INS-GAS mice expressing gastrin in pancreatic 13 cells to achieve continuous stimulation of the CCK2/gastrin receptor. Results: The pancreatic weight of ElasCCK2 mice was increased by 40% and correlated with an increase in the area of exocrine tissue. Alterations in pancreatic histology were apparent from postnatal day 50. Crossing the ElasCCK2 mice with INS-GAS mice resulted in development of morphologic changes in younger animals. Malignant transformation occurred in 3 of 20 homozygous ElasCCK2 mice. Although tumors had different phenotypes, they all developed through an acinar-ductal carcinoma sequence. Conclusions: Our data show that transgenic expression of a G protein-coupled receptor can lead to cancer. This study also supports a key role of the CCK2/gastrin receptor in the development of pre-and neoplastic lesions of the pancreas. ElasCCK2 mice provide a model for carcinogenesis by transformation and dedifferentiation of acinar cells. C1 CHU Rangueil, Inst Louis Bugnard, INSERM U531, F-31403 Toulouse, France. CHU Rangueil, Anatompathol Unit, F-31403 Toulouse, France. Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Univ Liverpool, Physiol Lab, Liverpool L69 3BX, Merseyside, England. RP Dufresne, M (reprint author), CHU Rangueil, Inst Louis Bugnard, INSERM U531, Bat L3, F-31403 Toulouse, France. RI Dufresne, Marlene/M-6332-2014 OI Dufresne, Marlene/0000-0002-8654-963X NR 48 TC 58 Z9 63 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 FEB PY 2002 VL 122 IS 2 BP 428 EP 437 DI 10.1053/gast.2002.30984 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 517QK UT WOS:000173621200023 PM 11832457 ER PT J AU Wang, ZC Yunis, EJ De Los Santos, MJ Xiao, L Anderson, DJ Hill, JA AF Wang, ZC Yunis, EJ De Los Santos, MJ Xiao, L Anderson, DJ Hill, JA TI T helper 1-type immunity to trophoblast antigens in women with a history of recurrent pregnancy loss is associated with polymorphism of the IL1B promoter region SO GENES AND IMMUNITY LA English DT Article DE IL1B; polymorphism; Th1 immunity; recurrent pregnancy loss ID SPONTANEOUS-ABORTION; IFN-GAMMA; RECEPTOR ANTAGONIST; IN-VITRO; INTERLEUKIN-1; IL-1-BETA; CELLS; CYTOKINES; CYCLE; GENE AB Recurrent pregnancy loss (RPL) is a common disorder during early gestation. Recent evidence suggests that T helper 1 (Th1)-type immunity is associated with unsuccessful pregnancy especially in women with RPL of otherwise unknown etiology, while Th2-type immunity is associated with pregnancy success. Interleukin (IL)-1 may influence Th1/Th2 immune responsiveness and has been implicated in the establishment of successful pregnancy. In the present study, we investigated polymorphism of the IL-1beta gene (IL1B) in women with a history of RPL. Significant increases in the frequencies of IL 1 B promoter region variants IL1-511C and IL1B-31T were found in women with a history of RPL. Increased frequencies of these two variants and their homozygotes were found only in cases having evidence of Th1 immunity to trophoblast as determined by IFN-gamma production of peripheral blood mononuclear cells (PBMCs) stimulated with a trophoblast cell-line extract. Significantly higher IFN-gamma production by PBMCs in response to trophoblast correlated with variant IL1B-511C and its homozygocity in women with RPL. These results suggest that variants -511C and -31T in the IL 1 B promoter region confer risk for RPL associated with Th1 immunity to trophoblast antigens. C1 Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Fearing Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Ctr Reprod Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Hill, JA (reprint author), Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Fearing Lab, 75 Francis St, Boston, MA 02115 USA. FU NHLBI NIH HHS [HL29583] NR 35 TC 50 Z9 54 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD FEB PY 2002 VL 3 IS 1 BP 38 EP 42 DI 10.1038/sj/gene/6363812 PG 5 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 524TA UT WOS:000174027900009 PM 11857060 ER PT J AU Saleque, S Cameron, S Orkin, SH AF Saleque, S Cameron, S Orkin, SH TI The zinc-finger proto-oncogene Gfi-1b is essential for development of the erythroid and megakaryocytic lineages SO GENES & DEVELOPMENT LA English DT Article DE transcription factor; hematopoiesis; development; oncogene ID TRANSCRIPTION FACTOR GATA-1; CHROMOSOMAL TRANSLOCATIONS; CELL-DIFFERENTIATION; GENE-EXPRESSION; STEM-CELLS; MICE; DROSOPHILA; LEUKEMIA; DNA; HEMATOPOIESIS AB Gfi-1 and Gfi-1b are novel proto-oncogenes identified by retroviral insertional mutagenesis. By gene targeting, we establish that Gfi-1b is required for the development of two related blood lineages, erythroid and megakaryocytic, in mice. Gfi-1b(-/-) embryonic stem cells fail to contribute to red cells of adult chimeras. Gfi-1b(-/-) embryos exhibit delayed maturation of primitive erythrocytes and subsequently die with failure to produce definitive enucleated erythrocytes. The fetal liver of mutant mice contains erythroid and megakaryocytic precursors arrested in their development. Myelopoiesis is normal. Therefore, Gfi-1b is an essential transcriptional regulator of erythroid and megakaryocyte development. C1 Harvard Univ, Childrens Hosp, Sch Med, Dana Farber Canc Inst,Dept Pediat Oncol, Boston, MA 02115 USA. Howard Hughes Med Inst, Boston, MA 02115 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. Howard Hughes Med Inst, Cambridge, MA 02139 USA. RP Orkin, SH (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Dana Farber Canc Inst,Dept Pediat Oncol, Boston, MA 02115 USA. NR 34 TC 140 Z9 142 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD FEB 1 PY 2002 VL 16 IS 3 BP 301 EP 306 DI 10.1101/gad.959102 PG 6 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 517RN UT WOS:000173623800004 PM 11825872 ER PT J AU Yu, WH Woessner, JF McNeish, JD Stamenkovic, I AF Yu, WH Woessner, JF McNeish, JD Stamenkovic, I TI CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling SO GENES & DEVELOPMENT LA English DT Article DE CD44; MMP-7; HB-EGF; ErbB4; complex; remodeling ID MATRIX-METALLOPROTEINASE MATRILYSIN; EXTRACELLULAR-MATRIX; RAT UTERUS; CELL-MIGRATION; EGF; RECEPTOR; SURFACE; MICE; HYALURONATE; EXPRESSION AB CD44 is a facultative proteoglycan implicated in cell adhesion and trafficking, as well as in tumor survival and progression. We demonstrate here that CD44 heparan sulfate proteoglycan (CD44HSPG) recruits proteolytically active matrix metalloproteinase 7 (matrilysin, MMP-7) and heparin-binding epidermal growth factor precursor (pro-HB-EGF) to form a complex on the surface of tumor cell lines, postpartum uterine and lactating mammary gland epithelium, and uterine smooth muscle. The HB-EGF precursor within this complex is processed by MMP-7, and the resulting mature HB-EGF engages and activates its receptor, ErbB4, leading to, among other events, cell survival. In CD44(-/-) mice, postpartum uterine involution is accelerated and maintenance of lactation is impaired. In both uterine and mammary epithelia of these mice, MMP-7 localization is altered and pro-HB-EGF processing as well as ErbB4 activation are decreased. Our observations provide a mechanism for the assembly and function of a cell surface complex composed of CD44HSPG, MMP 7, HB-EGF, and ErbB4 that may play an important role in the regulation of physiological tissue remodeling. C1 Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA 02129 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02129 USA. Univ Miami, Sch Med, Dept Biochem & Mol Biol, Miami, FL 33101 USA. Pfizer Inc, Cent Res, Groton, CT 06340 USA. RP Stamenkovic, I (reprint author), Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA 02129 USA. OI Yu, Wei-Hsuan/0000-0002-1782-3738 FU NCI NIH HHS [CA55735]; NIGMS NIH HHS [GM48614] NR 55 TC 324 Z9 328 U1 1 U2 8 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD FEB 1 PY 2002 VL 16 IS 3 BP 307 EP 323 DI 10.1101/gad.925702 PG 17 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 517RN UT WOS:000173623800005 PM 11825873 ER PT J AU Valentini, SR Casolari, JM Oliveira, CC Silver, PA McBride, AE AF Valentini, SR Casolari, JM Oliveira, CC Silver, PA McBride, AE TI Genetic interactions of yeast eukaryotic translation initiation factor 5A (eIF5A) reveal connections to poly(A)-binding protein and protein kinase C signaling SO GENETICS LA English DT Article ID HYPUSINE-CONTAINING PROTEIN; MESSENGER-RNA STABILIZATION; POLY(A) BINDING-PROTEIN; SACCHAROMYCES-CEREVISIAE; DEOXYHYPUSINE SYNTHASE; CELL-CYCLE; IN-VITRO; SUBCELLULAR-DISTRIBUTION; DEPENDENT TRANSLATION; ANGSTROM RESOLUTION AB The highly conserved eukaryotic translation initiation factor eIF5A has been proposed to have various roles in the cell, from translation to mRNA decay to nuclear protein export. To further our understanding of this essential protein, three temperature-sensitive alleles of the yeast TIF51A gene have been characterized. Two mutant eIF5A proteins contain mutations in a proline residue at the junction between the two eIF5A domains and the third, strongest allele encodes a protein with a single mutation in each domain, both of which are required for the growth defect. The stronger tif51A alleles cause defects in degradation of short-lived mRNAs, supporting a role for this protein in mRNA decay. A multicopy suppressor screen revealed six genes, the overexpression of which allows growth of a tif51A-1 strain at high temperature; these genes include PAB1, PKC1, and PKC1 regulators WSC1, WSC2, and WSC3. Further results suggest that eIF5A may also be involved in ribosomal synthesis and the WSC/PKC1 signaling pathway for cell wall integrity or related processes. C1 Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Sao Paulo State Univ, Sch Pharm, Dept Biol Sci, BR-14801902 Araraquara, SP, Brazil. Univ Sao Paulo, Inst Chem, Dept Biochem, BR-05508900 Sao Paulo, Brazil. RP Silver, PA (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St,SM922, Boston, MA 02115 USA. RI Valentini, Sandro/C-4353-2012; Oliveira, Carla/F-2323-2011 NR 79 TC 71 Z9 80 U1 0 U2 5 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD FEB PY 2002 VL 160 IS 2 BP 393 EP 405 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 525WT UT WOS:000174097600006 PM 11861547 ER PT J AU Gunter-Hunt, G Mahoney, JE Sieger, CE AF Gunter-Hunt, G Mahoney, JE Sieger, CE TI A comparison of state advance directive documents SO GERONTOLOGIST LA English DT Article DE end-of-life treatment decisions; advance decision making; medical ethics ID SELF-DETERMINATION ACT; SUPPORT INTERVENTION; NURSING-HOME; PREFERENCES; CARE; LIFE; END; DECISIONS; SURROGATE AB Purpose: Advance directive (AD) documents are based on state-specific statutes and vary in terms of content. These differences can create confusion and inconsistencies resulting in a possible failure to honor the health care wishes of people who execute health care documents for one state and receive health care in another state. The purpose of this study was to compare similarities and differences in the content of state AD documents. Design and Methods: AD documents for 50 states and the District of Columbia posted on the Partnership for Caring website were reviewed. States and regions of the country were compared for type or types of documents used and issues included in AD documents. Results: Three states had statutory living will documents only; however, these states did allow for appointment of a health care agent for limited end-of-life decisions. Three states had statutory durable power of attorney for health care documents only, 32 had both statutory living will and durable power of attorney for health care documents, and 13 had statutory forms which combine both types of directive in one document (advance health care directives). Of 8 identified key issues, those addressed by at least 90% of states were designation of a proxy, personal instructions for care, general life-sustaining measures, and terminal illness. When document types were compared, advance health care directive documents included more of the key issues than did living will or durable power of attorney for health care documents (p < .001). Implications: This variability suggests a need for national dialogue to standardize some provisions of AD documents. C1 William S Middleton Mem Vet Adm Med Ctr, Res Educ & Clin Ctr, Madison, WI 53705 USA. Univ Wisconsin, Sch Med, Dept Med, Madison, WI USA. Partnership Caring Inc, New York, NY USA. RP Gunter-Hunt, G (reprint author), William S Middleton Mem Vet Adm Med Ctr, Res Educ & Clin Ctr, 2500 Overlook Terrace, Madison, WI 53705 USA. NR 22 TC 15 Z9 15 U1 1 U2 4 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 FEB PY 2002 VL 42 IS 1 BP 51 EP 60 PG 10 WC Gerontology SC Geriatrics & Gerontology GA 520TQ UT WOS:000173797800006 PM 11815699 ER PT J AU Pfutzer, R Myers, E Applebaum-Shapiro, S Finch, R Ellis, I Neoptolemos, J Kant, JA Whitcomb, DC AF Pfutzer, R Myers, E Applebaum-Shapiro, S Finch, R Ellis, I Neoptolemos, J Kant, JA Whitcomb, DC TI Novel cationic trypsinogen (PRSS1) N29T and R122C mutations cause autosomal dominant hereditary pancreatitis SO GUT LA English DT Article; Proceedings Paper CT Digestive Disease Week/102nd Annual Meeting of the American-Gastroenterological-Association CY MAY 20-23, 2001 CL ATLANTA, GEORGIA SP Amer Gastroenterol Assoc ID GENE AB Hereditary pancreatitis (HP) is usually caused by mutations In the cationic trypsinogen (PRSS1) gene, especially R122H or N291. We sequenced the PRSS1 gene in the proband of families without these common mutations. Novel R122C and N29T mutations were detected in independent families that segregated with the disease in an autosomal dominant fashion. The R122C mutation eliminates the arginine autolysis site as with R122H mutations. The N29T mutation may also enhance intrapancreatic trypsin activity as has been demonstrated in vitro. Identification of these new mutations requires special attention as commonly used detection methods may fail. C1 Univ Pittsburgh, Dept Med, Pittsburgh, PA 15101 USA. Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. Univ Pittsburgh, Dept Physiol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Cell Biol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Ctr Genom Sci, Pittsburgh, PA USA. VA Pittsburgh Hlt Care Syst, Div Gastroenterol, Pittsburgh, PA USA. Univ Liverpool, Dept Surg, Liverpool L69 3BX, Merseyside, England. Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA. RP Whitcomb, DC (reprint author), Univ Pittsburgh, Dept Med, 571 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15101 USA. RI Neoptolemos, John/G-4488-2010 FU NIAAA NIH HHS [AA10855]; NIDDK NIH HHS [R01 DK054709] NR 6 TC 59 Z9 60 U1 1 U2 2 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD FEB PY 2002 VL 50 IS 2 BP 271 EP 272 DI 10.1136/gut.50.2.271 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 514BQ UT WOS:000173416800025 PM 11788572 ER PT J AU Lea, JS Sheets, EE Duska, LR Miller, DS Schorge, JO AF Lea, JS Sheets, EE Duska, LR Miller, DS Schorge, JO TI Early-stage cervical adenocarcinoma treated by surgical intent: The role of para-aortic lymph node dissection SO GYNECOLOGIC ONCOLOGY LA English DT Article ID GYNECOLOGIC-ONCOLOGY-GROUP; UTERINE CERVIX; PARAAORTIC METASTASES; RADICAL HYSTERECTOMY; PROGNOSTIC FACTORS; STAGES IB; CARCINOMA; CANCER; IIA; RADIATION AB Objective. Previous reports suggest that cervical adenocarcinomas have a unique pattern of spread and are more apt to metastasize to para-aortic lymph nodes. The purpose of this study was to further define the node of para-aortic lymph node dissection in early-stage cervical adenocarcinoma treated by surgical intent. Methods. Institutional review board approval was obtained to perform a computerized search of the data of all women diagnosed with cervical adenocarcinoma between 1982 and 2000. Hospital charts were retrospectively reviewed. Follow-up was obtained from the tumor registry, medical records, and correspondence with health care providers. Results. Three hundred (87%) of 345 early-stage (FIGO IA(1)-IIA) cervical adenocarcinoma patients were primarily treated by surgical intent. Two hundred seventy-six underwent pelvic and para-aortic node dissection (n = 69) or pelvic node dissection only (n = 207); 24 had no lymph node dissection. The median number of lymph nodes removed was 13 pelvic (range, 1-58) and 3 paraaortic (range, 1-17). Three (4%) of 69 patients had para-aortic nodal metastases. Each had either grossly evident para-aortic adenopathy (n = 2) or an adnexal metastasis. Thirty-six of 40 women developing recurrent disease had at least some component of pelvic recurrence; 4 had only extrapelvic disease. Three patients undergoing para-aortic node dissection developed an isolated extrapelvic recurrence despite originally negative para-aortic nodes (n = 2) or treatment by extended-field radiation for para-aortic metastases. One woman undergoing only pelvic node dissection had an isolated extrapelvic recurrence despite originally negative nodes. Conclusions. Early-stage cervical adenocarcinoma primarily treated by surgical intent has a very low risk of para-aortic metastases. These were detected only when there was gross evidence of nodal or adnexal disease. (C) 2002 Elsevier Science. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Texas SW, Div Gynecol Oncol, Dallas, TX 75390 USA. RP Schorge, JO (reprint author), 5323 Harry Hines Blvd,J7124, Dallas, TX 75390 USA. RI Miller, David/H-4604-2011 OI Miller, David/0000-0002-8215-5887 NR 24 TC 9 Z9 10 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 FEB PY 2002 VL 84 IS 2 BP 285 EP 288 DI 10.1006/gyno.2001.6524 PG 4 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 520UE UT WOS:000173799100016 PM 11812088 ER PT J AU McKay, PL Katarincic, JA AF McKay, PL Katarincic, JA TI Fractures of the proximal ulna olecranon and coronoid fractures SO HAND CLINICS LA English DT Article ID NON-UNION; FIXATION; ELBOW AB Fractures of the proximal ulna are relatively common, with olecranon fractures occurring considerably more frequently than coronoid fractures. The severity of the fracture, concomitant elbow trauma, and ligamentous instability influence surgical decision-making and outcome. A carefully thought out operative plan and early motion are key to optimizing surgical result in these sometimes deceptive injuries. This article reviews the history, mechanism, classification, treatment, rehabilitation, and outcome for olecranon and coronoid fractures. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed, Boston, MA 02129 USA. Natl Naval Med Res Inst, Div Hand Surg, Dept Orthopaed, Bethesda, MD USA. RP Katarincic, JA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed, Boston, MA 02129 USA. EM jkatarincic@partners.org NR 48 TC 8 Z9 9 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 0749-0712 J9 HAND CLIN JI Hand Clin. PD FEB PY 2002 VL 18 IS 1 BP 43 EP + AR PII S0749-0712(02)00013-6 DI 10.1016/S0749-0712(02)00013-6 PG 12 WC Orthopedics SC Orthopedics GA 573LD UT WOS:000176830400004 PM 12143417 ER PT J AU Ring, D Jupiter, JB AF Ring, D Jupiter, JB TI Fracture-dislocation of the elbow SO HAND CLINICS LA English DT Article ID RADIAL HEAD; JOINT AB Fracture-dislocations of the elbow occur in common patterns that provide some indication of what structures have been injured, the prognosis, and potential complications. Treatment focuses on restoration of osseous/articular contributions to elbow stability Large fractures of the coronoid are usually associated with olecranon fracture-dislocations and must be realigned and secured. Small coronoid fractures are associated with terrible triad injuries and should also be strongly considered for fixation. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hand & Upper Extrem Serv,Dept Orthopaed Surg, Boston, MA 02114 USA. RP Ring, D (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hand & Upper Extrem Serv,Dept Orthopaed Surg, ACC 525,15 Parkman St, Boston, MA 02114 USA. NR 44 TC 17 Z9 19 U1 1 U2 5 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0749-0712 J9 HAND CLIN JI Hand Clin. PD FEB PY 2002 VL 18 IS 1 BP 55 EP + AR PII S0749-0712(02)00004-5 DI 10.1016/S0749-0712(02)00004-5 PG 10 WC Orthopedics SC Orthopedics GA 573LD UT WOS:000176830400005 PM 12143418 ER PT J AU Thiers, FA Burgess, BJ Nadol, JB AF Thiers, FA Burgess, BJ Nadol, JB TI Axodendritic and dendrodendritic synapses within outer spiral bundles in a human SO HEARING RESEARCH LA English DT Article DE axodendritic; dendrodendritic; type II spiral ganglion cell; outer spiral bundle; neural network; mitochondria-associated adherens complex ID HAIR-CELLS; ELECTRON-MICROSCOPY; EFFERENT SYNAPSES; OLFACTORY-BULB; GANGLION-CELLS; HUMAN ORGAN; INNERVATION; AFFERENT; CORTI; COCHLEA AB Axodendritic and dendrodendritic synapses have been described at the level of the outer spiral bundle (OSB) (Nadol, J.B., Jr., 1983. Laryngoscope 93, 780-791; Bodian, D., 1978. Proc. Natl. Acad. Sci. USA 75, 4582-4586). The objectives of this study were to quantify these synaptic interactions and to describe their ultrastructural morphology in a young human subject. The temporal bone of an 8-month old infant was processed for transmission electron microscopy and semiserial section reconstructions of the three OSBs were performed. The nerve fibers ((NFs)) forming the OSBs were found to segregate into two morphological groups: (1) vesicle-rich and neurofilament-poor (VR/NP); (2) vesicle-poor and neurofilament-rich (VP/NR). Synapses between VR/NP and VP/NR NFs and synapses between two VP/NR NFs were quantified. Presumed axodendritic synapses (i.e. between VR/NP and VP/NR NFs) were numerous and their numbers decreased from the first towards the third row. Presumed dendrodendritic synapses (i.e. between two VP/NR NFs) were also frequent but their numbers did not vary significantly among different rows. The presence of axodendritic synapses may provide the morphological basis for modulation of the function of the type 11 spiral ganglion cells (type II's) by the olivocochlear efferent system. Similarly, numerous presumed dendrodendritic synapses may provide a morphological substrate for interaction between dendrites of type H's. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. Harvard Mit Div Hlth Sci & Technol, Speech & Hearing Sci Program, Cambridge, MA 02139 USA. RP Nadol, JB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. FU NIDCD NIH HHS [R01-DC00152-20] NR 29 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD FEB PY 2002 VL 164 IS 1-2 BP 97 EP 104 AR PII S0378-5955(01)00414-2 DI 10.1016/S0378-5955(01)00414-2 PG 8 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 544TV UT WOS:000175178100011 PM 11950529 ER PT J AU Ryan, DP Willett, CG AF Ryan, DP Willett, CG TI Management of locally advanced adenocarcinoma of the pancreas SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article ID COOPERATIVE-ONCOLOGY-GROUP; PHASE-I TRIAL; CONCURRENT RADIATION; INTRAOPERATIVE IRRADIATION; COMPUTED-TOMOGRAPHY; WEEKLY GEMCITABINE; EXTERNAL-BEAM; CANCER; CARCINOMA; THERAPY AB In 2002, approximately 30,300 people were expected to develop pancreatic adenocarcinoma in the United States, and almost all were expected to die from the disease. Surgical resection still offers the only chance of cure, but at diagnosis, only 15% to 20% of patients have resectable disease. Most patients have either focally advanced or metastatic disease. For patients with locally advanced, unresectable tumors, median survival is 8 to 12 months, and 5-year survival is rare. This article focuses on the management of patients with locally advanced disease. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Canc Ctr, Boston, MA 02114 USA. RP Ryan, DP (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Canc Ctr, Cox 640,100 Blossom St, Boston, MA 02114 USA. NR 39 TC 9 Z9 9 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 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD FEB PY 2002 VL 16 IS 1 BP 95 EP + AR PII S0889-8588(01)00009-0 DI 10.1016/S0889-8588(01)00009-0 PG 11 WC Oncology; Hematology SC Oncology; Hematology GA 558WV UT WOS:000175991100007 PM 12063831 ER PT J AU Gong, WS Merfeld, DM AF Gong, WS Merfeld, DM TI System design and performance of a unilateral horizontal semicircular canal prosthesis SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE adaptation; electrical stimulation; guinea pig; neural prosthesis; semicircular canal; vestibular ID GALVANIC VESTIBULAR STIMULATION; VESTIBULOOCULAR REFLEX; SQUIRREL MONKEY; ELECTRICAL-STIMULATION; OCULAR REFLEX; GUINEA-PIG; NEURONS; PHYSIOLOGY; ORIENTATIONS; ADAPTATION AB We have reported preliminary results regarding a prototype semicircular canal prosthesis and concluded that it can provide rotational cues to the nervous system. This paper presents the system design of the prosthesis, and also reports the prosthesis system performance and effectiveness. The prosthesis delivers electrical pulses to the nerve branch innervating the horizontal semicircular canal on one side via implanted electrodes. To allow us to encode both directions of angular velocity, the baseline stimulation pulse frequency was set at 150 Hz, which is somewhat higher than; the average firing rate of afferents innervating the semicircular canals in normal guinea pigs (similar to60 Hz). A sensor measures angular velocity to modulate (increase or decrease) the pulse rate. The prosthetic system was provided to a guinea pig whose horizontal canals were surgically plugged. The animal responded to the baseline stimulation initially and adapted to the baseline stimulation in roughly one day. After this baseline adaptation the animal responded to yaw rotation, showing that the function of the canals was partially restored. The experiments also show that the nervous system adapts to the artificial rotational cue provided via electrical stimulation. C1 Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, Jenks Vestibular Physiol Lab, Boston, MA 02114 USA. RP Merfeld, DM (reprint author), Harvard Univ, Sch Med, Dept Otol & Laryngol, 243 Charles St,Room 421, Boston, MA 02114 USA. FU NIDCD NIH HHS [DC03066] NR 28 TC 62 Z9 64 U1 0 U2 5 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD FEB PY 2002 VL 49 IS 2 BP 175 EP 181 DI 10.1109/10.979358 PG 7 WC Engineering, Biomedical SC Engineering GA 515EM UT WOS:000173482500011 PM 12066886 ER PT J AU Ji, H Ohmura, K Mahmood, U Lee, DM Hofhuis, FMA Boackle, SA Takahashi, K Holers, VM Walport, M Gerard, C Ezekowitz, A Carroll, MC Brenner, M Weissleder, R Verbeek, JS Duchatelle, V Degott, C Benoist, C Mathis, D AF Ji, H Ohmura, K Mahmood, U Lee, DM Hofhuis, FMA Boackle, SA Takahashi, K Holers, VM Walport, M Gerard, C Ezekowitz, A Carroll, MC Brenner, M Weissleder, R Verbeek, JS Duchatelle, V Degott, C Benoist, C Mathis, D TI Arthritis critically dependent on innate immune system players SO IMMUNITY LA English DT Article ID COLLAGEN-INDUCED ARTHRITIS; ALTERNATIVE COMPLEMENT PATHWAY; FC-GAMMA-RII; B-CELL RESPONSE; RHEUMATOID-ARTHRITIS; T-CELL; AUTOIMMUNE-DISEASE; ARTHUS REACTION; DEFICIENT MICE; IN-VIVO AB Disease in these animals is focused specifically on the joints but stems from autoreactivity to a ubiquitously expressed antigen, glucose-6-phosphate isomerase (GPI). T and B cells are both required for disease initiation, but anti-GPI immunoglobulins; (Igs), alone, can induce arthritis in lymphocyte-deficient recipients. Here, we show that the arthritogenic Igs act through both Fc receptors (in particular, FcgammaRIII) and the complement network (C5a). Surprisingly, the alternative pathway of complement activation is critical, while classical pathway components are entirely dispensable. We suggest that autoimmune disease, even one that is organ specific, can occur when mobilization of an adaptive immune response results in runaway activation of the innate response. C1 Brigham & Womens Hosp, Joslin Diabet Ctr, Sect Immunol & Immunogenet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. Brigham & Womens Hosp, Dept Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. ULP, INSERM, CNRS, Inst Genet & Biol Mol & Cellulaire, F-67404 Strasbourg, France. Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. Leiden Univ, Med Ctr, Dept Human & Clin Genet, NL-2300 RA Leiden, Netherlands. Univ Colorado, Hlth Sci Ctr, Dept Rheumatol, Denver, CO 80262 USA. Massachusetts Gen Hosp, Div Pediat, Boston, MA 02115 USA. Univ London Imperial Coll Sci Technol & Med, Sch Med, Hammersmith Hosp, Div Med, London W12 0NN, England. Childrens Hosp, Div Pulm, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Hop Beaujon, Serv Anat & Cytol Pathol, F-92118 Clichy, France. RP Benoist, C (reprint author), Brigham & Womens Hosp, Joslin Diabet Ctr, Sect Immunol & Immunogenet, 75 Francis St, Boston, MA 02115 USA. OI Walport, Mark/0000-0001-7220-5273 FU NCI NIH HHS [P50 CA86355]; NIAMS NIH HHS [1R01 AR/AI46580-01]; NIDDK NIH HHS [5 P30 DK36836-15] NR 56 TC 453 Z9 462 U1 3 U2 14 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD FEB PY 2002 VL 16 IS 2 BP 157 EP 168 DI 10.1016/S1074-7613(02)00275-3 PG 12 WC Immunology SC Immunology GA 524YC UT WOS:000174039600001 PM 11869678 ER PT J AU Ueno, T Hara, K Willis, MS Malin, MA Hopken, UE Gray, DHD Matsushima, K Lipp, M Springer, TA Boyd, RL Yoshie, O Takahama, Y AF Ueno, T Hara, K Willis, MS Malin, MA Hopken, UE Gray, DHD Matsushima, K Lipp, M Springer, TA Boyd, RL Yoshie, O Takahama, Y TI Role for CCR7 Ligands in the emigration of newly generated T lymphocytes from the neonatal thymus SO IMMUNITY LA English DT Article ID LYMPHOID-TISSUE CHEMOKINE; HIGH ENDOTHELIAL VENULES; EPITHELIAL-CELLS; STROMAL CELLS; MOUSE THYMUS; EBI1-LIGAND CHEMOKINE; CHEMOTACTIC AGENT-4; MOLECULAR-CLONING; FUNCTIONAL LIGAND; DENDRITIC CELLS AB Most T lymphocytes are generated within the thymus. It is unclear, however, how newly generated T cells relocate out of the thymus to the circulation. The present study shows that a CC chemokine CCL19 attracts mature T cells out of the fetal thymus organ culture. Another CC chemokine CCL21, which shares CCR7 with CCL19 but has a unique C-terminal extension containing positively charged amino acids, failed to show involvement in thymic emigration. Neonatal appearance of circulating T cells was defective in CCL19-neutralized mice as well as in CCR7-deficient mice but not in CCL21-neutralized mice. In the thymus, CCL19 is predominantly localized in the medulla including endothelial venules. These results indicate a CCL19- and CCR7-dependent pathway of thymic emigration, which represents a major pathway of neonatal T cell export. C1 Univ Tokushima, Inst Genome Res, Div Expt Immunol, Tokushima 7708503, Japan. RIKEN, Res Ctr Allergy & Immunol, Lab Immune Syst Dev, Tokushima 7708503, Japan. Kinki Univ, Sch Med, Dept Microbiol, Osaka 5890014, Japan. Univ Tokyo, Sch Med, Dept Mol Prevent Med, Tokyo 1130033, Japan. Max Delbruck Ctr Mol Med, Dept Mol Tumorgenet & Immunogenet, Berlin, Germany. Monash Univ, Sch Med, Dept Pathol & Immunol, Prahran, Vic 3181, Australia. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. RP Takahama, Y (reprint author), Univ Tokushima, Inst Genome Res, Div Expt Immunol, Tokushima 7708503, Japan. RI Takahama, Yousuke/A-5863-2010; Lipp, Martin/G-2235-2010; Gray, Daniel/A-3293-2013 OI Gray, Daniel/0000-0002-8457-8242 NR 51 TC 140 Z9 146 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD FEB PY 2002 VL 16 IS 2 BP 205 EP 218 DI 10.1016/S1074-7613(02)00267-4 PG 14 WC Immunology SC Immunology GA 524YC UT WOS:000174039600005 PM 11869682 ER PT J AU Mizoguchi, A Mizoguchi, E Takedatsu, H Blumberg, RS Bhan, AK AF Mizoguchi, A Mizoguchi, E Takedatsu, H Blumberg, RS Bhan, AK TI Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation SO IMMUNITY LA English DT Article ID KILLER T-CELLS; ALPHA MUTANT MICE; RECEPTOR-DERIVED SIGNALS; BOWEL-DISEASE; CYTOKINE PRODUCTION; EPITHELIAL-CELLS; DEFICIENT MICE; AUTOIMMUNE-DISEASE; MURINE MODEL; IN-VIVO AB B cells possess a variety of immune functions that are involved in normal and abnormal immune responses, including autoimmune disorders. Through murine models of intestinal inflammation, we here demonstrate a B cell subset that is induced in gut-associated lymphoid tissues and is characterized by CD1d upregulation. This B cell subset appears under a chronic inflammatory environment, produces IL-10, and suppresses progression of intestinal inflammation by downregulating inflammatory cascades associated with IL-1 upregulation and STAT3 activation rather than by altering polarized T helper responses. This study indicates that B cells, by producing cytokines such as IL-10, can act as regulatory cells in immunologically mediated inflammatory reactions. C1 Massachusetts Gen Hosp, Dept Pathol, Immunopathol Unit, Boston, MA 02114 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, Div Gastroenterol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Ctr Stusy Inflammatory Bowel Dis, Boston, MA 02114 USA. RP Mizoguchi, A (reprint author), Massachusetts Gen Hosp, Dept Pathol, Immunopathol Unit, Boston, MA 02114 USA. FU NIDDK NIH HHS [DK34584, DK43351, DK44319, DK47677, DK51362, DK53056] NR 58 TC 464 Z9 490 U1 1 U2 16 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD FEB PY 2002 VL 16 IS 2 BP 219 EP 230 DI 10.1016/S1074-7613(02)00274-1 PG 12 WC Immunology SC Immunology GA 524YC UT WOS:000174039600006 PM 11869683 ER PT J AU Mauceri, HJ Seetharam, S Beckett, MA Lee, JY Gupta, VK Gately, S Stack, MS Brown, CK Swedberg, K Kufe, DW Weichselbaum, RR AF Mauceri, HJ Seetharam, S Beckett, MA Lee, JY Gupta, VK Gately, S Stack, MS Brown, CK Swedberg, K Kufe, DW Weichselbaum, RR TI Tumor production of angiostatin is enhanced after exposure to TNF-alpha SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE adenoviral gene therapy; angiostatin; plasminogen activator; MMPs ID NECROSIS-FACTOR-ALPHA; LEWIS-LUNG-CARCINOMA; IONIZING-RADIATION; ANGIOGENESIS INHIBITOR; MATRIX-METALLOPROTEINASE; ENDOTHELIAL-CELLS; HUMAN-MELANOMA; PLASMINOGEN; EXPRESSION; GENE AB Infection of tumors with an adenoviral vector expressing a chimeric gene composed of the CArG elements of the Egr-1 promoter and a cDNA encoding TNF-alpha (Ad.Egr-TNF) has previously been shown to result in the production of high intratumoral levels of TNF-alpha and thereby tumor regression. The antitumor effects of TNF-alpha were ascribed to vascular thrombosis. We and others, have reported that inhibition of tumor vessel thrombosis using anticoagulation therapy does not abrogate the antitumor effects after TNF-alpha treatment. To investigate the potential antiangiogenic effects of TNF-alpha, we studied the generation of angiostatin after intratumoral injection of Ad.Egr-TNF. We report an increase in plasma angiostatin levels both during and after treatment with Ad.Egr-TNF that parallel tumor regression. We also report that TNF-alpha enhances angiostatin production by inducing the activity of plasminogen activator and the release of MMP-9 by tumor cells. These studies support a model in which the antiangiogenic effects of TNF-alpha on the tumor microvasculature are mediated by generation of angiostatin. (C) 2002 Wiley-Liss. Inc. C1 Univ Chicago, Dept Radiat & Cellular Oncol, Duchossois Ctr Adv Med, Chicago, IL 60637 USA. Univ Chicago, Dept Surg, Chicago, IL 60637 USA. Northwestern Univ, Sch Med, Div Hematol Oncol, Chicago, IL USA. Northwestern Univ, Sch Med, Dept Obstet & Gynecol, Chicago, IL USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Weichselbaum, RR (reprint author), Univ Chicago, Dept Radiat & Cellular Oncol, Duchossois Ctr Adv Med, 5758 S Maryland Ave,MC 9006, Chicago, IL 60637 USA. FU NIDCR NIH HHS [P50DE/CA11921] NR 40 TC 22 Z9 25 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 1 PY 2002 VL 97 IS 4 BP 410 EP 415 DI 10.1002/ijc.1629 PG 6 WC Oncology SC Oncology GA 508FV UT WOS:000173078800002 PM 11802200 ER PT J AU Taniguchi, T D'Andrea, AD AF Taniguchi, T D'Andrea, AD TI Molecular pathogenesis of Fanconi anemia SO INTERNATIONAL JOURNAL OF HEMATOLOGY LA English DT Article DE Fanconi anemia; checkpoint; DNA repair; ubiquitin; BRCA1 ID DNA-DAMAGE RESPONSE; ATM-DEPENDENT PHOSPHORYLATION; DOUBLE-STRAND BREAKS; GROUP-C PROTEIN; ATAXIA-TELANGIECTASIA; NUCLEAR-COMPLEX; CHROMOSOMAL INSTABILITY; TARGETED DISRUPTION; GAMMA-INTERFERON; MEIOTIC CELLS AB Fanconi anemia (FA) is a rare autosomal recessive chromosomal breakage disorder characterized by the childhood onset of aplastic anemia, developmental defects, cancer susceptibility, and cellular hypersensitivity to DNA-cross-linking agents. FA patients can be divided into at least 8 complementation groups (FA-A, FA-B, FA-C, FA-D1. FA-D2, FA-E, FA-F, and FA-G). FA proteins encoded by 6 cloned FA genes (FANCA, FANCC, FANCD2, FANCE, FANCF, and FANCG) cooperate in a common pathway, culminating in the monoubiquitination of FANCD2 protein and colocalization of FANCD2 and BRCA1 proteins in nuclear foci. These BRCA1 foci have been implicated in the process of homologous recombination-mediated DNA repair. In this review, we will summarize the current progress in the field of FA research and highlight some of the potential functions of the FA pathway in DNA-damage response. Int J HematoL 2002,75:123-128. (C)2002 The Japanese Society of Hematology. C1 Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP D'Andrea, AD (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. FU NHLBI NIH HHS [P01 HL54785, R01 HL52725]; NIDDK NIH HHS [R01 DK43889] NR 82 TC 26 Z9 26 U1 0 U2 4 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 0925-5710 J9 INT J HEMATOL JI Int. J. Hematol. PD FEB PY 2002 VL 75 IS 2 BP 123 EP 128 DI 10.1007/BF02982016 PG 6 WC Hematology SC Hematology GA 534FC UT WOS:000174573000002 PM 11939257 ER PT J AU Kaban, LB AF Kaban, LB TI Biomedical technology revolution: opportunities and challenges for oral and maxillofacial surgeons SO INTERNATIONAL JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Review DE biomedical technology; 3D-imaging; molecular biology; endoscopy; distraction osteogenesis ID GIANT-CELL LESIONS; DISTRACTION OSTEOGENESIS; INTERFERON; INFANCY; CANCER; HEMANGIOMAS; SIMULATION; DIAGNOSIS; DYSPLASIA; OSTEOTOMY C1 Massachusetts Gen Hosp, Oral & Maxillofacial Surg Serv, Harvard Sch Dent Med, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. RP Kaban, LB (reprint author), Massachusetts Gen Hosp, Oral & Maxillofacial Surg Serv, Harvard Sch Dent Med, Dept Oral & Maxillofacial Surg, Fruit St, Boston, MA 02114 USA. NR 73 TC 15 Z9 15 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 0901-5027 J9 INT J ORAL MAX SURG JI Int. J. Oral Maxillofac. Surg. PD FEB PY 2002 VL 31 IS 1 BP 1 EP 12 DI 10.1054/ijom.2001.0187 PG 12 WC Dentistry, Oral Surgery & Medicine; Surgery SC Dentistry, Oral Surgery & Medicine; Surgery GA 528XL UT WOS:000174270100001 PM 11936389 ER PT J AU Smalley, SR Gunderson, L Tepper, J Martenson, JA Minsky, B Willett, C Rich, T AF Smalley, SR Gunderson, L Tepper, J Martenson, JA Minsky, B Willett, C Rich, T TI Gastric surgical adjuvant radiotherapy consensus report: Rationale and treatment implementation SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE gastric surgical adjuvant radiotherapy; radiation treatment planning; supportive care; patterns of failure; phase III trials ID RANDOMIZED TRIAL; RADIATION-THERAPY; STOMACH-CANCER; ADENOCARCINOMA; CHEMOTHERAPY; CARCINOMA; RESECTION; DOXORUBICIN; DISSECTION; 5-FU AB Purpose: Radiation therapy has recently emerged as a pivotal modality in the management of completely resected, high-risk gastric cancer. The recently published results of the Intergroup 0116 Gastric Surgical Adjuvant Trial randomized high-risk (T3,4 and/or node positive), completely resected gastric or gastroesophageal adenocarcinomas to receive either observation alone or radiochemotherapy after complete resection. Radiochemotherapy produced significant improvements in relapse-free (p < 0.0001) and overall survival (p = 0.01). Radiation oncologists must now clearly comprehend the principles governing the rationale supporting this therapy to apply it to those afflicted with this disease. This paper represents a consensus report reviewing data supporting radiotherapy, important clinical and anatomic issues related to radiotherapy, and details of the practical application of radiation therapy to commonly occurring clinical presentations. Supportive therapy during and after radiochemotherapy is also discussed. (C) 2002 Elsevier Science Inc. C1 Radiat Oncol Ctr Olathe, Olathe, KS 66061 USA. Mayo Clin, Dept Radiat Oncol, Rochester, MN USA. Univ N Carolina, Dept Radiat Oncol, Chapel Hill, NC USA. Mem Sloan Kettering Canc Ctr, New York, NY USA. Massachusetts Gen Hosp, Cox Canc Ctr, Dept Radiat Oncol, Boston, MA USA. Univ Virginia, Hlth Sci Ctr, Dept Radiat Oncol, Charlottesville, VA USA. RP Smalley, SR (reprint author), Radiat Oncol Ctr Olathe, 20375 W 151st St, Olathe, KS 66061 USA. NR 53 TC 93 Z9 107 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD FEB 1 PY 2002 VL 52 IS 2 BP 283 EP 293 DI 10.1016/S0360-3016(01)02646-3 PG 11 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 512TR UT WOS:000173340100001 PM 11872272 ER PT J AU Galper, S Gelman, R Recht, A Silver, B Kohli, A Wong, JS Van Buren, T Baldini, EH Harris, JR AF Galper, S Gelman, R Recht, A Silver, B Kohli, A Wong, JS Van Buren, T Baldini, EH Harris, JR TI Second nonbreast malignancies after conservative surgery and radiation therapy for early-stage breast cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article; Proceedings Paper CT 42nd Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) CY OCT 21-26, 2000 CL BOSTON, MASSACHUSETTS SP Amer Soc Therapeut Radiol & Oncol DE breast cancer; second malignancy; radiation therapy ID LUNG-CANCER; PROPHYLACTIC MASTECTOMY; HODGKINS-DISEASE; DECISION-ANALYSIS; 3-FIELD TECHNIQUE; 2ND MALIGNANCIES; LIFE EXPECTANCY; BRCA2 MUTATIONS; RISK; WOMEN AB Purpose: Breast cancer patients treated with conservative surgery and radiation therapy are at risk of developing second nonbreast malignancies (SNBMs). The purpose of this study was to determine the incidence of all SNBMs and SNBMs by specific location among long-term survivors and to compare the risk of these events to the age-specific incidence of malignances as first cancers in the Surveillance Epidemiology and End-Results Program (SEER) population. Methods and Materials: We analyzed the likelihood of SNBM development for 1884 patients with clinical Stage I or II breast cancer treated with gross excision and greater than or equal to60 Gy (median 63) to the breast between 1970 and 1987. Fifty-seven percent received supraclavicular/axillary radiation (median dose 45 Gy, range 20-60) and 28% received systemic therapy. The median age at diagnosis was 52 years. The median clinical tumor size was 2 cm. Patients were considered at risk of an SNBM until the development of the first of distant metastases or contralateral breast cancer or death or, if alive and disease-free, until the last follow-up visit. The expected numbers of cancers were obtained from the SEER database, using the age-specific incidence for white women within 5-year age groups and 5-year calendar intervals. The median time at risk for an SNBM was 10.9 years (range 0.2-27.9). Results: By 8 years of follow-up, 432 patients (23%) had developed distant metastases, 295 patients (16%) a local/regional recurrence, and 159 (8%) a contralateral primary. Of the 1884 patients in our cohort, 147 (8%) developed an SNBM compared with the 127.7 expected from SEER. This corresponds to an absolute excess of 1% of the study population and a relative increase of 15% greater than that expected from SEER (p = 0.05). Within the first 5 years, the observed and expected rates of SNBMs were identical (47 vs. 46.9). After 5 years, 24% more SNBMS were observed than expected (100 vs. 80.8,p = 0.02). Among patients <50 years old at breast cancer diagnosis, 43% more observed SNBMs occurred than expected (40 vs. 28, p = 0.02). For patients greater than or equal to50 years, 7% more SNBMs were observed than expected (107 vs. 99.7, p = 0.25). Lung SNBMs were observed in 33 women, 52% more than the 21.67 predicted by SEER (p = 0.01). Most of the lung SNBMs occurred >5 years after treatment (n = 23) and in women who were >50 years at the time of their breast cancer diagnosis (n = 27). The observed incidence of ovarian cancer was significantly greater than expected among patients <50 years (7 vs. 1.96,p = 0.004) but was not different than expected for patients greater than or equal to50 years (5 vs. 5.3, p = 0.61). Among the 7 sarcomas, 3 developed in the radiation field. Conclusions: SNBMs occur in a substantial minority (8%) of patients treated with conservative surgery and radiotherapy. However, the absolute excess risk compared with the general population is very small (1%). This excess risk is only evident after 5 years. In particular, a slightly increased incidence of lung SNBMs and a somewhat larger increase in ovarian cancer among younger patients was found. Our data suggest that preventive strategies to reduce the incidence of certain cancers (e.g., smoking cessation and prophylactic oophorectomy) and/or continued monitoring for SNBMs to increase the likelihood of early detection and treatment may be prudent in this population. (C) 2002 Elsevier Science Inc. C1 Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Boston, MA USA. Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA USA. Harvard Univ, Sch Med, Joint Ctr Radiat Therapy, Boston, MA USA. RP Galper, S (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, 44 Binney St, Boston, MA 02115 USA. NR 20 TC 58 Z9 60 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD FEB 1 PY 2002 VL 52 IS 2 BP 406 EP 414 DI 10.1016/S0360-3016(01)02661-X PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 512TR UT WOS:000173340100015 PM 11872286 ER PT J AU Bernstein, PS Leppert, M Singh, N Dean, M Lewis, RA Lupski, JR Allikmets, R Seddon, JM AF Bernstein, PS Leppert, M Singh, N Dean, M Lewis, RA Lupski, JR Allikmets, R Seddon, JM TI Genotype-phenotype analysis of ABCR variants in macular degeneration probands and siblings SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID DISEASE GENE ABCR; CASSETTE TRANSPORTER GENE; CONE-ROD DYSTROPHY; STARGARDT-DISEASE; RETINITIS-PIGMENTOSA; MOLECULAR-GENETICS; RETINAL DISEASE; MUTATIONS; AUTOFLUORESCENCE; PROTEIN AB PURPOSE. Single-copy variants of the autosomal recessive Stargardt disease (STGD1) gene ABCR (ABCA4) have been shown to confer enhanced susceptibility to age-related macular degeneration (AMD), To investigate the role of ABCR alleles in AMD further, genotype-phenotype analysis was performed on siblings of patients with AMD who had known ABCR variants. This genetically related population provides a cohort of subjects with similar age and ethnic background for genotype-phenotype comparison to the original probands. METHODS. All available siblings of 26 probands carrying probable disease-associated ABCR variants were examined clinically. Blood samples were collected from these siblings for genotype analysis to search for the ABCR variant alleles corresponding to the isofamilial proband. RESULTS. Nineteen of 33 siblings from 15 families carried the respective proband's variant ABCR allele. Some families exhibited concordance of ABCR alleles with macular degeneration phenotype, but others did not. Exudative AMD was uncommon among both probands and siblings. CONCLUSIONS. Although population Studies have indicated that some ABCR variant alleles may enhance susceptibility to AMD, investigation of the extent of ABCR involvement by kindred analysis is complicated by a plethora of environmental and other hereditary factors not investigated in the current study that may also play important roles. C1 Univ Utah, Sch Med, Dept Ophthalmol & Visual Sci, Moran Eye Ctr, Salt Lake City, UT 84132 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. Columbia Univ, Dept Pathol, New York, NY USA. Columbia Univ, Dept Ophthalmol, New York, NY USA. Baylor Coll Med, Huffington Ctr Aging, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. Baylor Coll Med, Dept Ophthalmol, Houston, TX 77030 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Genomic Divers, Frederick, MD USA. Univ Utah, Dept Human Genet, Salt Lake City, UT USA. RP Bernstein, PS (reprint author), Univ Utah, Sch Med, Dept Ophthalmol & Visual Sci, Moran Eye Ctr, 50 N Med Dr, Salt Lake City, UT 84132 USA. RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU NCI NIH HHS [5P30CA42014]; NCRR NIH HHS [M01-RR00064]; NEI NIH HHS [EY11309, EY11600] NR 48 TC 29 Z9 35 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD FEB PY 2002 VL 43 IS 2 BP 466 EP 473 PG 8 WC Ophthalmology SC Ophthalmology GA 518PK UT WOS:000173676900024 PM 11818392 ER PT J AU Rauniyar, RK Suzuma, K King, AL Aiello, LP King, GL AF Rauniyar, RK Suzuma, K King, AL Aiello, LP King, GL TI Differential effects of bactericidal/permeability-increasing protein (BPI) analogues on retinal neovascularization and retinal pericyte growth SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID VASCULAR-PERMEABILITY FACTOR; HUMAN POLYMORPHONUCLEAR LEUKOCYTES; ENDOTHELIAL-CELLS; PSEUDOMONAS-AERUGINOSA; DIABETIC-RETINOPATHY; TERMINAL FRAGMENT; TUMOR-GROWTH; ANGIOGENESIS; INHIBITOR; RECEPTORS AB PURPOSE. Bactericidal/permeability-increasing protein (BPI), an antibacterial and lipopolysaccharide-neutralizing protein, also has an antiangiogenic effect. To evaluate the therapeutic role of BPI in ischemic retinopathies, the antiangiogenic activity of a human recombinant 21-kDa modified N-terminal fragment of BPI (rBPI(21)), which has the biological properties of the holo-protein, and a peptidomimetic (XMP.Z) derived from BPI were examined. METHODS. The effects of rBPI(21) and XMP.Z on VEGF-induced growth of bovine retinal microvascular endothelial cells (BRECs) and on serum-induced growth of bovine retinal pericytes (BRPs) and retinal pigment epithelial cells (BRPECs) were evaluated by determining total DNA content. The neonatal mouse model of retinopathy of prematurity (ROP) was used to study the effect of XMP.Z in vivo. Intraperitoneal injections of the peptidomimetic (10 mg/kg) were administered every 24 hours for 5 days (postnatal [P]12-P17) during induction of neovascularization. Retinal neovascularization was evaluated using flatmounts of fluorescein-dextran-perfused retinas and quantitated by counting retinal cell nuclei anterior to the internal limiting membrane. RESULTS. VEGF (25 ng/mL increased the total DNA per well of BRECs by 120% +/- 50% (P < 0.001), which was inhibited by addition of rBPI(21) or XMP.Z, with decreases of 77% +/- 15%(P < 0.05) and 107% +/- 19% (P < 0.01) at maximum effective doses of 75 and 15 mug/mL rBPI(21) and XMP.Z, respectively. In contrast, rBPI(21) at 75 mug/mL enhanced the total DNA per well of BRP 53% +/- 14% (P < 0.001) in the presence of 5% fetal bovine serum (FBS), whereas XMP.Z enhanced BRP growth by 27% +/- 7% (P < 0.001) at 5 mug/mL. In the presence of 10% FBS, rBPI(21) and XMP.Z increased BRP growth by 91% +/- 35% (P < 0.001) and 43% +/- 18% (P < 0.01), respectively. In the oxygen-induced ROP neonatal mouse model, retinal neovascularization was decreased by 40% +/- 16% (n = 5, P < 0.01) when animals were treated with XMP.Z. CONCLUSIONS. Two BPI-derived compounds, rBPI(21) and XMP.Z, significantly suppressed VEGF-induced BREC growth in vitro, while conversely enhancing the growth of BRPs. even above that induced by 20% FBS. When tested in animals, XMP.Z also suppressed ischemia-induced retinal neovascularization in mice. These data suggest that BPI-derived compounds may have unique therapeutic potential for proliferative retinal diseases such as diabetic retinopathy, if physiological levels can be achieved in clinical settings. C1 Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP King, GL (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. FU NEI NIH HHS [EY5110] NR 46 TC 6 Z9 7 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD FEB PY 2002 VL 43 IS 2 BP 503 EP 509 PG 7 WC Ophthalmology SC Ophthalmology GA 518PK UT WOS:000173676900029 PM 11818397 ER PT J AU Volberding, PA AF Volberding, PA TI Navigating emerging challenges to long-term HIV therapy SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Editorial Material C1 San Francisco Vet Affairs Med Ctr, Med Serv, San Francisco, CA 94121 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Volberding, PA (reprint author), San Francisco Vet Affairs Med Ctr, Med Serv, 4150 Clement St,VAMC 111, San Francisco, CA 94121 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD FEB 1 PY 2002 VL 29 SU 1 BP S1 EP S1 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 523MU UT WOS:000173958500001 ER PT J AU Ostacher, MJ Nierenberg, AA AF Ostacher, MJ Nierenberg, AA TI Who responds to antidepressants? SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Meeting Abstract C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bipolar Programs, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD FEB PY 2002 VL 68 IS 1 BP 86 EP 86 PG 1 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 538KM UT WOS:000174815200022 ER PT J AU Booij, L Van der Does, V Benkelfat, C Bremner, JD Cowen, PJ Fava, M Gillin, C Leyton, M Moore, P Smith, KA Van der Kloot, WA AF Booij, L Van der Does, V Benkelfat, C Bremner, JD Cowen, PJ Fava, M Gillin, C Leyton, M Moore, P Smith, KA Van der Kloot, WA TI Predictors of mood response to acute tryptophan depletion: A reanalysis SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Meeting Abstract C1 Leiden Univ, Dept Psychol, Leiden, Netherlands. Leiden Univ, Dept Psychiat, Leiden, Netherlands. McGill Univ, Dept Psychiat, Montreal, PQ, Canada. Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. Univ Oxford, Dept Psychiat, Oxford, England. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. VA San Diego Healthcare Syst, San Diego, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD FEB PY 2002 VL 68 IS 1 BP 103 EP 103 PG 1 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 538KM UT WOS:000174815200067 ER PT J AU Kirkpatrick, WR Perea, S Coco, BJ Patterson, TF AF Kirkpatrick, WR Perea, S Coco, BJ Patterson, TF TI Efficacy of ravuconazole (BMS-207147) in a guinea pig model of disseminated aspergillosis SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article; Proceedings Paper CT 101st General Meeting of the American-Society-for-Microbiology CY MAY, 2001 CL ORLANDO, FLORIDA SP Ameri Soc Microbiol ID EXPERIMENTAL INVASIVE ASPERGILLOSIS; IN-VITRO; AMPHOTERICIN-B; ORAL TRIAZOLE; ITRACONAZOLE; VORICONAZOLE; FUMIGATUS; ER-30346; SPECTRUM AB Ravuconazole (BMS-207147, ER-30346), an oral triazole, was evaluated in an immunosuppressed temporarily neutropenic guinea pig model of invasive aspergillosis. In this model, guinea pigs were immunosuppressed with triamcinolone 20 mg/kg sc od beginning 4 days before challenge and made neutropenic with cyclophosphamide 300 mg/kg ip 1 day before challenge. Treatments of ravuconazole 5, 10 and 25 mg/kg po od were compared with itraconazole 2.5 and 5.0 mg/kg po bd and amphotericin B 1.25 mg/kg ip od. Treatment began 24 h after lethal intravenous challenge with Aspergillus fumigatus and continued for 5 days. Mortality occurred in eight of eight untreated control animals versus none of eight treated with ravuconazole 5 or 10 mg/kg/day or itraconazole 10 mg/kg/day. Mortality occurred in one of eight animals treated with ravuconazole 25 mg/kg/day, one of eight with amphotericin B and two of eight treated with itraconazole 5 mg/kg/day. Compared with controls, each of the antifungals examined significantly reduced the tissue burden in liver and brain, although only the highest doses of the azole drugs and amphotericin B significantly reduced tissue burden in the kidney. All three doses of ravuconazole improved survival and also reduced the tissue burden of Aspergillus. In this model of invasive aspergillosis, ravuconazole showed significant activity and may be a useful compound in human disease. C1 Univ Texas, Hlth Sci Ctr, Dept Med, Div Infect Dis, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, Audie Murphy Div, San Antonio, TX 78284 USA. RP Kirkpatrick, WR (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med, Div Infect Dis, 7703 Floyd Curl Dr,Mail Code 7881, San Antonio, TX 78229 USA. NR 19 TC 28 Z9 29 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-7453 J9 J ANTIMICROB CHEMOTH JI J. Antimicrob. Chemother. PD FEB PY 2002 VL 49 IS 2 BP 353 EP 357 DI 10.1093/jac/49.2.353 PG 5 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 523NE UT WOS:000173960000019 PM 11815579 ER PT J AU Choi, JY Sifri, CD Goumnerov, BC Rahme, LG Ausubel, FM Calderwood, SB AF Choi, JY Sifri, CD Goumnerov, BC Rahme, LG Ausubel, FM Calderwood, SB TI Identification of virulence genes in a pathogenic strain of Pseudomonas aeruginosa by representational difference analysis SO JOURNAL OF BACTERIOLOGY LA English DT Article ID YERSINIA-PESTIS; CAENORHABDITIS-ELEGANS; NEISSERIA-GONORRHOEAE; ESCHERICHIA-COLI; TRANSCRIPTIONAL ACTIVATOR; MOLECULAR MECHANISMS; PILIATION CONTROL; PILIN GENES; EXOTOXIN-A; SEQUENCE AB Pseudomonas aeruginosa is an opportunistic pathogen that may cause severe infections in humans and, other vertebrates. In addition, a human clinical isolate of P. aeruginosa, strain PA14, also causes disease in a variety of nonvertebrate hosts, including plants, Caenorhabditis elegans, and the greater wax moth, Galleria mellonella. This has led to the development of a multihost pathogenesis system in which plants, nematodes, and insects have been used as adjuncts to animal models for the identification of P. aeruginosa virulence factors. Another approach to identifying virulence genes in bacteria is to take advantage of the natural differences in pathogenicity between isolates of the same species and to use a subtractive hybridization technique to recover relevant genomic differences. The sequenced strain of P. aeruginosa, strain PAO1, has substantial differences in virulence from strain PA14 in several of the multihost models of pathogenicity, and we have utilized the technique of representational difference analysis (RDA) to directly identify genomic differences between P. aeruginosa strains PA14 and PAO1. We have found that the pilC, pilA, and uvrD genes in strain PA14 differ substantially from their counterparts in strain PAO1. In addition, we have recovered a gene homologous to the ybtQ gene from Yersinia, which is specifically present in strain PA14 but absent in strain PAO1. Mutation of the ybtQ homolog in P. aeruginosa strain PA14 significantly attenuates the virulence of this strain in both G. mellonella and a burned mouse model of sepsis to levels comparable to those seen with PAO1. This suggests that the increased virulence of P. aeruginosa strain PA14 compared to PAO1 may relate to specific genomic differences identifiable by RDA. C1 Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02114 USA. Shriners Burn Inst, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Calderwood, SB (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 55 Fruit St, Boston, MA 02114 USA. EM scalderwood@partners.org NR 62 TC 60 Z9 61 U1 2 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD FEB PY 2002 VL 184 IS 4 BP 952 EP 961 DI 10.1128/jb.184.4.952-961.2002 PG 10 WC Microbiology SC Microbiology GA 518VJ UT WOS:000173688300011 PM 11807055 ER PT J AU Tzivion, G Avruch, J AF Tzivion, G Avruch, J TI 14-3-3 proteins: Active cofactors in cellular regulation by serine/threonine phosphorylation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID INSULIN-RECEPTOR SUBSTRATE-1; DEATH AGONIST BAD; IN-VIVO; NUCLEAR-LOCALIZATION; KINASE-ACTIVITY; TRYPTOPHAN-HYDROXYLASE; SERINE PHOSPHORYLATION; SIGNAL-TRANSDUCTION; AMPHIPATHIC GROOVE; MOLECULAR-CLONING C1 Massachusetts Gen Hosp, Dept Biol Mol, Diabet Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. Texas A&M Univ, Hlth Sci Ctr, Div Mol Cardiol, Inst Cardiovasc Res, Temple, TX 76504 USA. RP Avruch, J (reprint author), Massachusetts Gen Hosp, Dept Biol Mol, Diabet Res Lab, 50 Blossom St,Wellman 8, Boston, MA 02114 USA. RI Tzivion, Guri/D-8954-2011 NR 93 TC 349 Z9 361 U1 5 U2 20 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 FEB 1 PY 2002 VL 277 IS 5 BP 3061 EP 3064 DI 10.1074/jbc.R100059200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 518VF UT WOS:000173688000001 PM 11709560 ER PT J AU Kaneto, H Suzuma, K Sharma, A Bonner-Weir, S King, GL Weir, GC AF Kaneto, H Suzuma, K Sharma, A Bonner-Weir, S King, GL Weir, GC TI Involvement of protein kinase CB2 in c-myc induction by high glucose in pancreatic beta-cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID JUN ACTIVATION DOMAIN; DIABETIC RATS; INSULIN-SECRETION; OXIDATIVE STRESS; GENE-EXPRESSION; TRANSCRIPTION; ISOFORM; MODEL; IDENTIFICATION; COMPLICATIONS AB The expression of the basic helix-loop-helix transcription factor c-Myc is induced in pancreatic islets of several different diabetic model animals and is possibly involved in suppression of the insulin gene transcription. In this study, we found that activity of protein kinase C is increased by high glucose, preceding the induction of c-myc expression and that PKC beta2 specifically regulates c-myc expression in pancreatic beta-cells. Since PKC alpha, beta2, delta, epsilon, and zeta were expressed in rat pancreatic islets, we prepared each wild type (WT) and dominant negative type (DN) PKC isoform (alpha, beta2, delta, epsilon, and zeta)-expressing adenovirus to examine the effect of each KC isoform on c-myc expression. In isolated rat pancreatic islets, adenovirus-mediated overexpression of WT PKC beta2, but not other PKC isoforms, markedly increased c-myc expression. Moreover, c-myc induction by high glucose was suppressed by adenovirus-mediated overexpression of DN PKC beta2 but not by other DN PKC isoforms. Finally, adenovirus-mediated overexpression of WT PKC beta2, but not of other PKC isoforms, leads to suppression of the insulin gene transcription in pancreatic islets. These results suggest that at least some of the reduction of insulin gene transcription found in the diabetic state is mediated by PKC beta2 regulation of c-myc expression. C1 Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. Joslin Diabet Ctr, Sect Vasc Cell Biol, Boston, MA 02215 USA. RP Kaneto, H (reprint author), Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, 1 Joslin Pl, Boston, MA 02215 USA. FU NEI NIH HHS [EY-5110]; NIDDK NIH HHS [DK-35449] NR 42 TC 45 Z9 46 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 FEB 1 PY 2002 VL 277 IS 5 BP 3680 EP 3685 DI 10.1074/jbc.M109647200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 518VF UT WOS:000173688000082 PM 11714718 ER PT J AU Kurtz, SM Muratoglu, OK Gsell, R Greer, K Shen, FW Cooper, C Buchanan, FJ Spiegelberg, S Yau, SS Edidin, AA AF Kurtz, SM Muratoglu, OK Gsell, R Greer, K Shen, FW Cooper, C Buchanan, FJ Spiegelberg, S Yau, SS Edidin, AA TI Interlaboratory validation of oxidation-index measurement methods for UHMWPE after long-term shelf aging SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH LA English DT Article DE ultra-high molecular weight polyethylene; UHMWPE; oxidation; degradation; Fourier-transform infrared spectroscopy; FTIR; repeatability; reproducibility precision; accuracy; bias; experimental uncertainty ID MOLECULAR-WEIGHT POLYETHYLENE; INFRARED SPECTROMETRY; GAMMA-STERILIZATION; PERFORMANCE; DEGRADATION; IMPLANTS AB An international oxidation index standard would greatly benefit the orthopedic community by providing a universal scale for reporting oxidation data of ultra-high molecular weight polyethylene (UHMWPE). We investigated whether severe oxidation associated with long-term shelf aging affects the repeatability and reproducibility of area-based oxidation index measurement techniques based on normalization with the use of 1370- or 2022-cm(-1) infrared (111) absorption reference peaks. Because an oxidation index is expected to be independent of sample thickness, subsurface oxidation was examined with the use of both 100- and 200-mum-thick sections from tibial components (compression-molded GUR 1120, gamma irradiated in air) that were shelf aged for up to 11.5 years. Eight institutions in the United States and Europe participated in the present study, which was administered in accordance with ASTM E691. On average, the 100-mum-thick samples were associated with significantly greater interlaboratory relative standard uncertainty (40.3%) when compared with the 200-mum samples (21.8%,p = 0.002). In contrast, the intralaboratory relative standard uncertainty was not significantly affected by the sample thickness (p = 0.21). The oxidation index method did not significantly influence either the interlaboratory or intralaboratory relative standard uncertainty (p = 0.32 or 0.75, respectively). Our interlaboratory data suggest that with the suitable choice of specimen thickness (e.g., 200 mum) and either of the two optimal oxidation index methods, interlaboratory reproducibility of the most heavily oxidized regions in long-term shelf-aged components can be quantified with a relative standard uncertainty of 21% or less. Therefore, both the 1370-cm(-1) and the 2022-cm(-1) reference peaks appear equally suitable for use in defining a standard method for calculating an oxidation index for UHMWPE. (C) 2001 John Wiley Sons, Inc. C1 Exponent Inc, Philadelphia, PA 19103 USA. Drexel Univ, Philadelphia, PA 19104 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Zimmer Inc, Warsaw, IN USA. DePuy Orthoped, Warsaw, IN USA. Orthoped Hosp, Los Angeles, CA 90007 USA. Perplas Med Ltd, Bacup, England. Queens Univ Belfast, Belfast, Antrim, North Ireland. Cambridge Polymer Grp, Somerville, MA USA. Stryker Howmed Osteon, Mahwah, NJ USA. RP Kurtz, SM (reprint author), Exponent Inc, 2300 Chestnut St,Suite 150, Philadelphia, PA 19103 USA. OI Knowles, Jonathan Campbell/0000-0003-3917-3446 NR 33 TC 15 Z9 15 U1 0 U2 7 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9304 J9 J BIOMED MATER RES JI J. Biomed. Mater. Res. PD FEB PY 2002 VL 63 IS 1 BP 15 EP 23 DI 10.1002/jbm.10039 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 517BF UT WOS:000173590700003 PM 11787024 ER PT J AU Herndon, JH Pollick, KJ AF Herndon, JH Pollick, KJ TI Continuing concerns, new challenges, and next steps in physician-patient communication SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID MEDICAL PROFESSIONALISM; MANAGED CARE C1 Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Herndon, JH (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Gray 624,55 Fruit St, Boston, MA 02114 USA. NR 21 TC 6 Z9 6 U1 0 U2 2 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 FEB PY 2002 VL 84A IS 2 BP 309 EP 315 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 521RX UT WOS:000173856300019 PM 11861738 ER PT J AU Yamaguchi, DT Huang, J Ma, DF Wang, PKC AF Yamaguchi, DT Huang, J Ma, DF Wang, PKC TI Inhibition of gap junction intercellular communication by extremely low-frequency electromagnetic fields in osteoblast-like models is dependent on cell differentiation SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID COMBINED MAGNETIC-FIELDS; DOUBLE-BLIND TRIAL; BONE-CELLS; PARATHYROID-HORMONE; BIOLOGICAL-SYSTEMS; CALCIUM; CULTURE; MC3T3-E1; INVITRO; PERMEABILITY AB Electromagnetic fields have been used to augment the healing of fractures because of its ability to increase new bone formation. The mechanism of flow electromagnetic fields can promote new bone formation is unknown, although the interaction of electromagnetic fields with components of the plasma membrane of cells has been hypothesized to occur in bone cells. Gap junctions occur among bone forming cells, the osteoblasts, and have been hypothesized to play a role in new bone formation. Thus it was investigated whether extremely low-frequency (ELF) magnetic fields alter gap junction intercellular communication in the preosteoblastic model, MC3T3-E1, and the well-differentiated osteoblastic model, ROS 17/2.8. ELF magnetic field exposure systems were designed to be used for all inverted microscope stage and for a tissue culture incubator. Using these systems, it was found that magnetic fields over a frequency range from 30 to 120 Hz and field intensities LIP to 12.5 G dose dependently decreased gap junction intercellular communication in MC3T3-E1 cells during their proliferative phase of development. The total amount of connexin 43 protein and the distribution of connexin 43 gap junction protein between cytoplasmic and plasma membrane pools were unaltered by treatment with ELF magnetic fields. Cytosolic calcium ([Ca2+](i)) which can inhibit gap junction communication, was not altered by magnetic field exposure. Identical exposure conditions did not affect gap junction communication in the ROS 17/2.8 cell line and when MC3T3-E1 cells were more differentiated. Thus ELF magnetic fields may affect only less differentiated or preosteoblasts and not fully differentiated osteoblasts. Consequently, electromagnetic fields may aid in the repair of bone by effects exerted only on osteoprogenitor or pre-osteoblasts. J. Cell. Physiol. 190: 180-188, 2002. (C) 2002 Wiley-Liss, Inc. C1 VAMC, Res Serv, Los Angeles, CA USA. VAMC, Geriatr Res Educ & Clin Ctr, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Univ Calif Los Angeles, Dept Elect Engn, Los Angeles, CA USA. RP Yamaguchi, DT (reprint author), VA Greater Los Angeles Healthcare Syst, Res Serv 151, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 43 TC 23 Z9 32 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD FEB PY 2002 VL 190 IS 2 BP 180 EP 188 DI 10.1002/JCP.10047 PG 9 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 508NP UT WOS:000173095600004 PM 11807822 ER PT J AU Hartman, ML Crowe, BJ Biller, BMK Ho, KKY Clemmons, DR Chipman, JJ AF Hartman, ML Crowe, BJ Biller, BMK Ho, KKY Clemmons, DR Chipman, JJ CA HypoCCS Advisory Board US HypoCCS Study Grp TI Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency? SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article; Proceedings Paper CT 82nd Annual Meeting of the Endocrine-Society CY JUN 21-24, 2000 CL TORONTO, CANADA SP Endocrine Soc ID GROWTH-HORMONE DEFICIENCY; CLINICAL RESEARCH-CENTER; INSULIN TOLERANCE-TEST; IGF-BINDING PROTEIN-3; FACTOR-I; POSTMENOPAUSAL WOMEN; NORMAL MEN; SECRETION; POPULATION; CHILDREN AB Adult GH deficiency (GHD) is currently diagnosed in patients with either a history of childhood-onset GHD or acquired hypothalamic-pituitary disease by GH stimulation testing. However, GH stimulation tests are invasive, time consuming, and associated with side effects. Based on preliminary analyses of patients enrolled in the U.S. Hypopituitary Control and Complications Study (HypoCCS), we proposed the presence of adult GHD could be predicted with 95% accuracy by the presence of three or more pituitary hormone deficiencies (PHDs) or a serum IGF-I concentration less than 84 mug/liter (11 nmol/ liter). To validate the diagnostic utility of these criteria, we studied results obtained in 817 adult patients (mean [SDI age: 46.4 [15.7] yr, body mass index: 30.1 [7.2] kg/m(2)) enrolled in HypoCCS who had serum GH concentrations from stimulation tests (11 different tests used, excluding clonidine) and serum IGF-I (competitive binding RIA) measured at the central laboratory (Esoterix Endocrinology, Calabasas Hills, CA). When patients were stratified into subgroups on the basis of the presence of zero, one, two, three, and four additional PHDs, median (25th, 75th percentile) peak GH levels (micrograms per liter) were 3.5 (0.85, 7.1), 0.73 (0.18, 4.2), 0.29 (0.05, 1.4), 0.06 (0.025,0.295), and 0.025 (0.025, 0.07), respectively. The mean log (peak GH) concentration was significantly different among the subgroups (P < 0.05). The proportion of patients in each group with severe GHD diagnosed by stimulation testing (peak GH < 2.5 mug/liter) was 41%, 67%, 83%, 96%, and 99% for patients with zero, one, two, three, and four PHDs, respectively. The positive predictive values (PPVs) for GHD of three PHDs, four PHDs, and serum IGF-I less than 84 mug/liter were 96%, 99%, and 96%, respectively. The PPV of these three diagnostic criteria was also 95% or more after excluding the data originally used to identify these potential predictors. Taken together, the presence of either three or four additional PHDs or IGF-I less than 84 mug/liter (55% of the patients met at least one of these criteria) reliably predicted GHD with a high PPV (95%), high specificity (89%), and moderate sensitivity (69%). We concluded that patients with an appropriate clinical history and either the presence of three or four additional PHDs or serum IGF-I less than 84 mug/liter (measured in the Esoterix assay) do not require GH stimulation testing for the diagnosis of adult GHD. In clinical practice, we suggest that other causes of low serum IGF-I should be excluded before applying these diagnostic criteria. C1 Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. St Vincents Hosp Sydney, Garvan Inst Med Res, Sydney, NSW 2064, Australia. Univ N Carolina, Chapel Hill, NC 27599 USA. RP Hartman, ML (reprint author), Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Drop Code 5015, Indianapolis, IN 46285 USA. EM hartman@lilly.com RI Ho, Ken/E-5832-2011 NR 31 TC 185 Z9 190 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 FEB PY 2002 VL 87 IS 2 BP 477 EP 485 DI 10.1210/jc.87.2.477 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 530HD UT WOS:000174351500010 PM 11836272 ER PT J AU Smith, MR Finkelstein, JS McGovern, FJ Zietman, AL Fallon, MA Schoenfeld, DA Kantoff, PW AF Smith, MR Finkelstein, JS McGovern, FJ Zietman, AL Fallon, MA Schoenfeld, DA Kantoff, PW TI Changes in body composition during androgen deprivation therapy for prostate cancer SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID BONE-MINERAL DENSITY; HIV-INFECTED MEN; HORMONE AGONISTS; TESTOSTERONE REPLACEMENT; ACQUIRED HYPOGONADISM; ABDOMINAL OBESITY; YOUNG MEN; CARCINOMA; MASS; OSTEOPOROSIS AB The aim of this study was to determine the effects of initial treatment with a GnRH agonist on body composition in asymptomatic men with nonmetastatic prostate cancer. Forty men with locally advanced, node-positive or biochemically recurrent prostate cancer, no radiographic evidence of metastases, and no prior androgen deprivation therapy were treated with leuprolide 3-month depot 22.5 mg im every 12 wk for 48 wk. The main outcome measures were percentage changes in weight, percentage fat body mass, percentage lean body mass, fat distribution, and muscle size after 48 wk. Thirty-two subjects were evaluable. Serum T concentrations decreased by 96.3% plus or minus 0.4% (P < 0.001). Weight increased by 2.4% plus or minus 0.8% (P = 0.005). Percentage fat body mass increased by 9.4% plus or minus 1.7% (P < 0.001), and percentage lean body mass decreased by 2.7% plus or minus 0.5% (P < 0.001). Cross-sectional areas of the abdomen and abdominal se fat increased by 3.9% plus or minus 1.2% (P = 0.003) and 11.1% plus or minus 3.4% (P = 0.003), respectively. In contrast, the cross-sectional area of intraabdominal fat did not change significantly (P = 0.94). Cross-sectional paraspinal muscle area decreased by 3.2% plus or minus 1.3% (P = 0.02). GnRH agonists increase weight and percentage fat body mass and decrease percentage lean body mass and muscle size in men with nonmetastatic prostate cancer. Increased fatness resulted primarily from accumulation of se rather than intraabdominal adipose tissue. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Smith, MR (reprint author), Massachusetts Gen Hosp, Cox 640,100 Blossom St, Boston, MA 02114 USA. EM smith.matthew@mgh.harvard.edu FU NCRR NIH HHS [RR-1066]; NIDDK NIH HHS [K24-DK02759] NR 41 TC 336 Z9 342 U1 2 U2 5 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 FEB PY 2002 VL 87 IS 2 BP 599 EP 603 DI 10.1210/jc.87.2.599 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 530HD UT WOS:000174351500026 PM 11836291 ER PT J AU Canellos, GP AF Canellos, GP TI New treatments for advanced Hodgkin's disease: An uphill fight beginning close to the top SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID INVOLVED-FIELD RADIOTHERAPY; 6 CYCLES; CHEMOTHERAPY; REGIMEN; ABVD; LYMPHOMA; MOPP; CONSOLIDATION; CANCER; TRIAL C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Canellos, GP (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 19 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2002 VL 20 IS 3 BP 607 EP 609 PG 3 WC Oncology SC Oncology GA 518LG UT WOS:000173669400001 PM 11821436 ER PT J AU Brooks, J Bani, JC Fletcher, CDM Demeteri, CD AF Brooks, J Bani, JC Fletcher, CDM Demeteri, CD TI Challenges in oncology - Case 4. Response of metastatic gastrointestinal stromal tumor including CNS involvement to imatinib mesylate (STI-571) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article C1 Ochsner Clin Fdn, Baton Rouge, LA USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Brooks, J (reprint author), Ochsner Clin Fdn, Baton Rouge, LA USA. NR 5 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2002 VL 20 IS 3 BP 870 EP 872 PG 3 WC Oncology SC Oncology GA 518LG UT WOS:000173669400040 ER PT J AU Greist, JH Marks, IM Baer, L Kobak, KA Wenzel, KW Hirsch, MJ Mantle, JM Clary, CM AF Greist, JH Marks, IM Baer, L Kobak, KA Wenzel, KW Hirsch, MJ Mantle, JM Clary, CM TI Behavior therapy for obsessive-compulsive disorder guided by a computer or by a clinician compared with relaxation as a control SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID CONDUCTED TELEPHONE INTERVIEW; HOME SELF-ASSESSMENT; PHARMACOLOGICAL TREATMENTS; UK-US; METAANALYSIS; EXPOSURE; CLOMIPRAMINE; SCALE; EPIDEMIOLOGY; RITUALS AB Background: The demand for effective behavior therapy for obsessive-compulsive disorder (OCD) by exposure and ritual prevention exceeds its supply by trained therapists. A computer-guided behavior therapy self-help system (BT STEPS) was created that patients access by telephone from home via interactive voice response technology. This study compared the value of computer-guided behavior therapy value with that of clinician-guided behavior therapy and systematic relaxation as a control treatment. Method: After screening by a clinician. 218 patients with DSM-IV OCD at 8 North American sites were randomly assigned to 10 weeks of behavior therapy treatment guided by (1) a computer accessed by telephone and a user workbook (N = 74) or (2) a behavior therapist (N = 69) or (3) systematic relaxation guided by an audio-tape and manual (N = 75). Results: By week 10, in an intent-to-treat analysis, mean change in score on the Yale-Brown Obsessive Compulsive Scale was significantly greater in clinician-guided behavior therapy (8.0) than in computer-guided (5.6), and changes in scores with both clinician-guided and computer-guided behavior therapy were significantly greater than with relaxation (1.7), which was ineffective. Similarly, the percentage of responders on the Clinical Global Impressions scale was significantly (p < .05) greater with clinician-guided (60%) than computer-guided behavior therapy (38%), and both were significantly greater than with relaxation (14%,). Clinician-guided was superior to computer-guided behavior therapy overall, but not when patients completed at least I self-exposure session (N = 36 [65%]). At endpoint, patients were more satisfied with either behavior therapy group than with relaxation. Patients assigned to computer-guided behavior therapy improved more the longer they spent telephoning the computer (mostly outside usual office hours) and doing self-exposure. They improved slightly further by week 26 follow-up, unlike the other 2 groups. Conclusion: For OCD. computer-guided behavior therapy was effective. although clinician-guided behavior therapy was even more effective. Systematic relaxation was ineffective. Computer-guided behavior therapy can be a helpful first step in treating patients with OCD when clinician-guided behavior therapy is unavailable. C1 Healthcare Technol Syst, Madison, WI 53717 USA. Univ Wisconsin, Madison, WI USA. Maudsley Hosp & Inst Psychiat, Inst Psychiat, London SE5 8AZ, England. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. Pfizer Inc, New York, NY USA. RP Greist, JH (reprint author), Healthcare Technol Syst, 7617 Mineral Point Rd,Suite 300, Madison, WI 53717 USA. NR 37 TC 159 Z9 162 U1 2 U2 17 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 FEB PY 2002 VL 63 IS 2 BP 138 EP 145 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 525BZ UT WOS:000174048500009 PM 11874215 ER PT J AU Taylor, F Raskind, MA AF Taylor, F Raskind, MA TI The alpha 1-adrenergic antagonist prazosin improves sleep and nightmares in civilian trauma posttraumatic stress disorder SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article ID LOCUS-COERULEUS; MODULATION; PTSD; ACTIVATION; MECHANISM; NEURONS AB Heightened noradrenergic reactivity may be a contributing factor in the pathophysiology of post-traumatic stress disorder (PTSD). Prazosin is an alpha(1)-adrenoceptor antagonist commonly used as an antihypertensive agent. Because (alpha(1)-adrenergic activity has been associated with fear and startle responses, a drug that blocks central alpha(1)-adrenergic activity may be useful in the treatment of PTSD symptoms. An outpatient who had been exposed to civilian trauma and had subsequent chronic refractory PTSD was thus prescribed prazosin. The marked reduction in PTSD symptoms, particularly sleep and nightmares, prompted the following open-label feasibility trial. Five outpatients with non-combat-related PTSD were consecutively identified and received prazosin in a 6-week open-label trial. In each case, the prazosin doses were slowly increased until optimal benefit was achieved. Change was assessed with the Clinician-Administered PTSD Scale for DSM-IV, One Week Symptom Version (CAPS-SX), the Clinical Global Impression of Change Scale (CGIC), and the Clinical Impression of Change-Nightmares (CIC-Nightmares) score. All five patients experienced moderate to marked improvement on the CGIC. The CAPS-SX PTSD nightmare and sleep PTSD categories showed at least a four-point reduction of those symptoms. All patients reported at least moderate improvement on the CIC-Nightmare score. Optimal doses of prazosin ranged from 1 to 4 mg/day. The drug was reasonably tolerated, and there were no drug discontinuations. These preliminary findings provide a rationale for blind placebo-controlled efficacy trials of the alpha(1)-antagonist prazosin for PTSD. C1 Rainier Associates, Tacoma, WA 98467 USA. Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. VA Puget Sound Hlth Care Syst, NW Network VA Mental Illness Res Educ & Clin Ctr, Seattle, WA USA. RP Taylor, F (reprint author), Rainier Associates, 5909 Orchard W, Tacoma, WA 98467 USA. NR 16 TC 88 Z9 89 U1 1 U2 6 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 FEB PY 2002 VL 22 IS 1 BP 82 EP 85 DI 10.1097/00004714-200202000-00013 PG 4 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 514TM UT WOS:000173457200013 PM 11799347 ER PT J AU Todd, R Wong, DTW AF Todd, R Wong, DTW TI DNA hybridization arrays for gene expression analysis of human oral cancer SO JOURNAL OF DENTAL RESEARCH LA English DT Review DE microarray; gene expression; oral cancer ID LASER CAPTURE MICRODISSECTION; SQUAMOUS-CELL CARCINOMA; SELF-ORGANIZING MAPS; MICROARRAY ANALYSIS; DISCOVERY; PROFILES; HEAD; NECK; PREDICTION; DIFFERENTIATION AB DNA hybridization arrays permit global gene expression profiling to be done in a single experiment. The evolution and challenges of DNA hybridization arrays are reflected in the variety of experimental platforms, probe composition, hybridization/signal detection methods, and bioinformatic interpretation. In tumor biology, DNA hybridization arrays are being used for gene/gene pathway discovery, diagnosis, and therapeutic design. Similar applications are advancing our understanding of oral cancer cell biology. C1 Harvard Sch Dent Med, Lab Oral & Maxillofacial Surg, Boston, MA 02115 USA. Harvard Sch Dent Med, Dept Oral Med & Diagnost Sci, Div Oral Pathol, Lab Mol Pathol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Todd, R (reprint author), Harvard Sch Dent Med, Lab Oral & Maxillofacial Surg, 188 Longwood Ave, Boston, MA 02115 USA. FU NIDCR NIH HHS [P01 DE12467, R29 DE11983, K02 DE00456, P30 DE11814] NR 40 TC 12 Z9 12 U1 1 U2 2 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD FEB PY 2002 VL 81 IS 2 BP 89 EP 97 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559JP UT WOS:000176023300002 PM 11829015 ER PT J AU Mick, E Biederman, J Prince, J Fischer, MJ Faraone, SV AF Mick, E Biederman, J Prince, J Fischer, MJ Faraone, SV TI Impact of low birth weight on attention-deficit hyperactivity disorder SO JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS LA English DT Article DE attention-deficit disorder with hyperactivity; low birth weight infant; risk factors ID MATERNAL SMOKING; LEARNING-DISABILITIES; PSYCHIATRIC SEQUELAE; SCHOOL AGE; CHILDREN; PREGNANCY; SELECTION; RISK; PSYCHOPATHOLOGY; ADOLESCENTS AB The objective of the study was to evaluate an association between low birth weight (LBW) and attention-deficit hyperactivity disorder (ADHD) attending to potential family-genetic and environmental confounders. We examined 252 ADHD cases (boys and girls) and 231 non-ADHD controls and their parents. All subjects were extensively assessed with structured diagnostic interviews, cognitive assessments, and structured interviews of prenatal, infancy, and delivery complications. ADHD cases were three times more likely to have been born LBW than were non-ADHD controls, after attending to potential confounders such as prenatal exposure to alcohol and cigarettes, parental ADHD, social class, and comorbid disruptive behavior disorders in parents and offspring. If this association was causal, 13.8% of all ADHD cases could be attributed to LBW. These results converge with prior studies documenting similar associations and indicate that LBW is an independent risk factor for ADHD. Children with LBW, however, make up a relatively small proportion of children with ADHD. C1 Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Pediat Psychopharmacol Res, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. Univ Massachusetts, Ctr Hlth, Boston, MA 02125 USA. Harvard Univ, Massachusetts Gen Hosp,Pediat Psychopharmacol Unit, Sch Med,Inst Psychiat Epidemiol & Genet, Dept Psychiat,W Roxbury Vet Affairs Med Ctr, Boston, MA 02114 USA. RP Mick, E (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Pediat Psychopharmacol Res, 15 Parkman St WACC 725, Boston, MA 02114 USA. OI Mick, Eric/0000-0001-8505-8145; Faraone, Stephen/0000-0002-9217-3982 FU NICHD NIH HHS [R01 SHD36317]; NIMH NIH HHS [R01 MH41314] NR 47 TC 148 Z9 151 U1 5 U2 20 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-206X J9 J DEV BEHAV PEDIATR JI J. Dev. Behav. Pediatr. PD FEB PY 2002 VL 23 IS 1 BP 16 EP 22 PG 7 WC Behavioral Sciences; Psychology, Developmental; Pediatrics SC Behavioral Sciences; Psychology; Pediatrics GA 525YR UT WOS:000174102100003 PM 11889347 ER PT J AU Wilens, TE Biederman, J Brown, S Monuteaux, M Prince, J Spencer, TJ AF Wilens, TE Biederman, J Brown, S Monuteaux, M Prince, J Spencer, TJ TI Patterns of psychopathology and dysfunction in clinically referred preschoolers SO JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS LA English DT Article DE preschoolers; psychopathology; disruptive disorders; mood disorders; anxiety disorders ID DEFICIT HYPERACTIVITY DISORDER; SCHOOL-AGE-CHILDREN; SEMISTRUCTURED INTERVIEW; PSYCHIATRIC-DISORDERS; ONSET MANIA; DRUG-USE; ADOLESCENTS; FAMILY; COMORBIDITY; ADJUSTMENT AB Despite the growing interest in the use of psychotropic medications in preschoolers, little is known about the clinical presentation of young children referred for psychiatric services. We describe the clinical characteristics, psychiatric disorders, and functioning of preschoolers referred for pediatric psychiatry evaluation. Structured psychiatric interviews assessing lifetime psychopathology by DSM-III-R criteria were completed on clinically referred youth. Family, social, and overall functioning were assessed at intake. From the pool of 1658 consecutive referrals, we identified 200 children less than or equal to (less than or equal to) 6 years of age (12%). The most common psychopathology identified was attention deficit hyperactivity disorder (ADHD) (86%), followed by other disruptive behavioral (61%), mood (43%), and anxiety disorders (28%). Cooccurring psychiatric disorders were common with preschoolers manifesting a mean of two major psychiatric disorders per child, Despite their young age, the onset of psychopathology preceded evaluation by a mean (+/-SD) of 2.2 +/- 1.3 years. Preschoolers referred for psychiatric services had high rates of psychopathology with prominent comorbidity and associated dysfunction. These preschoolers are likely to require aggressive interventions including psychopharmacology. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Clin Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. RP Wilens, TE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Clin Res Program Pediat Psychopharmacol, ACC 725,15 Parkman St, Boston, MA 02114 USA. NR 60 TC 41 Z9 41 U1 3 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-206X J9 J DEV BEHAV PEDIATR JI J. Dev. Behav. Pediatr. PD FEB PY 2002 VL 23 IS 1 SU S BP S31 EP S36 PG 6 WC Behavioral Sciences; Psychology, Developmental; Pediatrics SC Behavioral Sciences; Psychology; Pediatrics GA 527FU UT WOS:000174176700006 PM 11875288 ER PT J AU Leptak, CL Nadel, ES Brown, DFM AF Leptak, CL Nadel, ES Brown, DFM TI A snake bite associated with trauma SO JOURNAL OF EMERGENCY MEDICINE LA English DT Article C1 Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Div Emergency Med, 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 FEB PY 2002 VL 22 IS 2 BP 199 EP 201 AR PII S0736-4679(02)00472-3 DI 10.1016/S0736-4679(01)00472-3 PG 3 WC Emergency Medicine SC Emergency Medicine GA 525HA UT WOS:000174061800015 PM 11858928 ER PT J AU Zhang, SL Chen, X Hsieh, TJ Leclerc, M Henley, N Allidina, A Halle, JP Brunette, MG Filep, JG Tang, SS Ingelfinger, JR Chan, JSD AF Zhang, SL Chen, X Hsieh, TJ Leclerc, M Henley, N Allidina, A Halle, JP Brunette, MG Filep, JG Tang, SS Ingelfinger, JR Chan, JSD TI Hyperglycemia induces insulin resistance on angiotensinogen gene expression in diabetic rat kidney proximal tubular cells SO JOURNAL OF ENDOCRINOLOGY LA English DT Article ID RENIN MESSENGER-RNA; CELLULAR HYPERTROPHY; GROWTH-FACTOR; MELLITUS; GLUCOSE; SYSTEM; KINASE; BLOCKS; BETA; TRANSCRIPTION AB Clinical and animal studies have shown that treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor antagonists slows the progression of nephropathy in diabetes, indicating that Ang II plays an important role in its development. We have reported previously that insulin inhibits the stimulatory effect of high glucose levels on angiotensinogen (ANG) gene expression in rat immortalized renal proximal tubular cells (IRPTCs) via the mitogen-activated protein kinase (p44/42 MAPK) signal transduction pathway. We hypothesize that the suppressive action of insulin on ANG gene expression might be attenuated in renal proximal tubular cells (RPTCs) of rats with established diabetes. Two groups of male adult Wistar rats were studied: controls and streptozotocin (STZ)-induced diabetic rats at 2, 4, 8 and 12 weeks post-STZ administration. Kidney proximal tubules were isolated and cultured in either normal glucose (i.e. 5 mM) or high glucose (i.e. 25 mM) medium to determine the inhibitory effect of insulin on ANG gene expression. Immunoreactive rat ANG (IR-rANG) in culture media and cellular ANG mRNA were measured by a specific radioimmunoassay and reverse transcription-polymerase chain reaction assay respectively. Activation of the p44/42 MAPK signal transduction pathway in rat RPTCs was evaluated by p44/42 MAPK phosphorylation employing a PhosphoPlus p44/42 MAPK antibody kit. Insulin (10(-7)M) inhibited the stimulatory effect of high glucose levels on IR-rANG secretion and ANG gene expression and increased p44/42 MAPK phosphorylation in normal rat RPTCs. In contrast, it failed to affect these parameters in diabetic rat RPTCs. In conclusion, our studies demonstrate that hyperglycaemia induces insulin resistance on ANG gene expression in diabetic rat RPTCs by altering the MAPK signal transduction pathway. C1 CHUM, Hotel Dieu, Ctr Rech, Montreal, PQ H2W 1T8, Canada. Hop Maison Neuve Rosemont, Res Ctr, Montreal, PQ H1T 2M4, Canada. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Nephrol Unit, Boston, MA 02114 USA. RP Chan, JSD (reprint author), CHUM, Hotel Dieu, Ctr Rech, Pavillon Masson,3850 St Urbain St, Montreal, PQ H2W 1T8, Canada. NR 44 TC 24 Z9 27 U1 0 U2 1 PU SOC ENDOCRINOLOGY PI BRISTOL PA 17/18 THE COURTYARD, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4NQ, ENGLAND SN 0022-0795 J9 J ENDOCRINOL JI J. Endocrinol. PD FEB PY 2002 VL 172 IS 2 BP 333 EP 344 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 524QW UT WOS:000174025200012 ER PT J AU Gow, DW AF Gow, DW TI Does English coronal place assimilation create lexical ambiguity? SO JOURNAL OF EXPERIMENTAL PSYCHOLOGY-HUMAN PERCEPTION AND PERFORMANCE LA English DT Article ID SPOKEN-WORD-RECOGNITION; SPEECH-PERCEPTION; PHONOLOGICAL VARIATION; CONNECTIONIST MODEL; ACCESS; REPRESENTATION; INFERENCE; FORM; DISTINCTION; CONTEXT AB The purpose of this study was to determine how potential lexical ambiguity produced by place assimilation is resolved. Four cross-modal form priming experiments using primes in sentential contexts were performed. In the first 2, prime items had underlyingly coronal offsets (e.g., right) with assimilated noncoronal place, The primes were judged to be perceptually ambiguous (between right and ripe) in Experiment I and noncoronal (ripe) in Experiment 2 in off-line testing. In Experiment 3, primes were replaced with corresponding underlyingly noncoronal items (ripe). In all 3 experiments, participants showed selective priming for the underlying form of the prime. A 4th form priming experiment using the gated tokens of priming stimuli used in Experiment 2 examined the role of postlexical context on this process. In this experiment, participants showed priming for both underlying and surface forms of the prime. C1 Massachusetts Gen Hosp, Neuropsychol Lab, Boston, MA 02114 USA. Salem State Coll, Dept Psychol, Salem, MA 01970 USA. RP Gow, DW (reprint author), Massachusetts Gen Hosp, Neuropsychol Lab, VBK 821,55 Fruit St, Boston, MA 02114 USA. NR 58 TC 81 Z9 81 U1 0 U2 2 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0096-1523 J9 J EXP PSYCHOL HUMAN JI J. Exp. Psychol.-Hum. Percept. Perform. PD FEB PY 2002 VL 28 IS 1 BP 163 EP 179 DI 10.1037//0096-1523.28.1.163 PG 17 WC Psychology; Psychology, Experimental SC Psychology GA 519XM UT WOS:000173750800010 ER PT J AU Metlay, JP Shea, JA Crossette, LB Asch, DA AF Metlay, JP Shea, JA Crossette, LB Asch, DA TI Tensions in antibiotic prescribing - Pitting social concerns against the interests of individual patients SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 24th Annual Meeting of the Society-of-General-Internal-Medicine CY MAY 02-05, 2001 CL SAN DIEGO, CALIFORNIA SP Soc Gen Internal Med DE antibiotics; drug utilization; physician's practice patterns; drug resistance, microbial; pneumonia ID COMMUNITY-ACQUIRED PNEUMONIA; ANTIMICROBIAL RESISTANCE; STREPTOCOCCUS-PNEUMONIAE; LIFE-SUPPORT; MAIL SURVEYS; GUIDELINES; MANAGEMENT; FLUOROQUINOLONES; EPIDEMIOLOGY; WITHDRAW AB BACKGROUND: To reduce the prevalence of antibiotic-resistant bacteria in the community, physicians must optimize their use of antibiotics. However, optimal use from the perspective of the community (reserving newer agents for future use) is not always consistent with optimal use from the perspective of the individual patient (prescribing newer, broader agents). OBJECTIVES: To identify preferred patterns of antibiotic prescribing for patients with community-acquired pneumonia (CAP), measure explicit attitudes toward antibiotics and antibiotic resistance, and determine the relationship between these prescribing patterns and attitudes. DESIGN. Cross-sectional anonymous mail survey. PARTICIPANTS: National random sample of 400 generalist physicians (general internal medicine and family practice) and 429 Infectious diseases specialists. MEASUREMENTS: Rank ordering of antibiotic preferences for a hypothetical outpatient with CAP and reasons for antibiotic selection. Endorsement of attitudes regarding antibiotic prescribing decisions and resistance. RESULTS: Both generalists and infectious diseases specialists were more likely to prefer newer, broader drugs for the treatment of CAP compared to older agents still recommended by national guidelines. Physicians rated the issue of contributing to antibiotic resistance lowest among 7 determinants of their choices. CONCLUSIONS: Despite national guidelines and increasing public awareness, the public health concern of contributing to the problem of antibiotic resistance does not exert a strong impact on physician prescribing decisions for CAP. Future efforts to optimize antibiotic prescribing decisions will need to consider options for increasing the impact of public health issues on the patient-oriented decisions of individual physicians. C1 Univ Penn, Sch Med, Dept Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Penn, Ctr Educ & Res Therapeut, Philadelphia, PA 19104 USA. Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. Vet Affairs Med Ctr, Philadelphia, PA USA. RP Metlay, JP (reprint author), Univ Penn, Sch Med, Dept Med, Div Gen Internal Med, 712 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. NR 28 TC 63 Z9 64 U1 1 U2 2 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 FEB PY 2002 VL 17 IS 2 BP 87 EP 94 DI 10.1046/j.1525-1497.2002.10711.x PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 543UG UT WOS:000175119100001 PM 11841523 ER PT J AU Calvert, PD Govardovskii, VI Arshavsky, VY Makino, CL AF Calvert, PD Govardovskii, VI Arshavsky, VY Makino, CL TI Two temporal phases of light adaptation in retinal rods SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article DE photoreceptors; phototransduction; adaptation; calcium; cGMP ID PHOTORECEPTOR GUANYLYL CYCLASE; CGMP BINDING-SITES; OUTER SEGMENTS; CYTOPLASMIC CALCIUM; SALAMANDER RODS; CYCLIC-GMP; GAMMA-SUBUNIT; PHOTOTRANSDUCTION CASCADE; AMPHIBIAN PHOTORECEPTORS; SENSITIVITY REGULATION AB Vertebrate rod photoreceptors adjust their sensitivity as they adapt during exposure to steady light. Light adaptation prevents the rod from saturating and significantly extends its dynamic range. We examined the time course of the onset of light adaptation in bullfrog rods and compared it with the projected onset of feedback reactions thought to underlie light adaptation on the molecular level. We found that adaptation developed in two distinct temporal phases: (I) a fast phase that operated within seconds after the onset of illumination, which is consistent with most previous reports of a 1-2-s time constant for the onset of adaptation; and (2) a slow phase that engaged over tens of seconds of continuous illumination. The fast phase desensitized the rods as much as 80-fold, and was observed at every light intensity tested. The slow phase was observed only at. light intensities that suppressed more than half of the dark current. It provided an additional sensitivity loss of tip to 40-fold before the rod saturated. Thus, rods achieved a total degree of adaptation of similar to3,000-fold. Although the fast. adaptation is likely to originate from the well characterized Ca2+-dependent feedback mechanisms regulating the activities of several phototransduction cascade components, the molecular mechanism underlying slow adaptation is unclear. We tested the hypothesis that the slow adaptation phase is mediated by cGMP dissociation from noncatalytic binding sites on the cGMP phosphodiesterase, which has been shown to reduce the lifetime of activated phosphodiesterase in vitro. Although cGMP dissociated from the noncatalytic binding sites in intact rods with kinetics approximating that for the slow adaptation phase, this hypothesis was ruled out because the intensity of light required for cGMP dissociation far exceeded that required to evoke the slow phase. Other possible mechanisms are discussed. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. Russian Acad Sci, Inst Evolut Physiol & Biochem, St Petersburg 194223, Russia. RP Calvert, PD (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. FU NEI NIH HHS [EY12944, EY10336, P30 EY012196, F32 EY006857, EY06857, R01 EY012944, R01 EY010336, P30 EY12196] NR 76 TC 34 Z9 36 U1 0 U2 3 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 FEB PY 2002 VL 119 IS 2 BP 129 EP 145 DI 10.1085/jgp.119.2.129 PG 17 WC Physiology SC Physiology GA 561LL UT WOS:000176142100002 PM 11815664 ER PT J AU Kilbourne, AM Herndon, B Andersen, RM Wenzel, SL Gelberg, L AF Kilbourne, AM Herndon, B Andersen, RM Wenzel, SL Gelberg, L TI Psychiatric symptoms, health services, and HIV risk factors among homeless women SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article DE homeless; HIV; mental disorders; health services ID MENTALLY-ILL; MEDICAL-CARE; LOS-ANGELES; ANAL SEX; BEHAVIORS; PREDICTORS; ACCESS; ADULTS; MEN; PERCEPTIONS AB The authors determined whether psychiatric symptoms and lack of health and/or social services contacts were associated with HIV risk behaviors among a probability sample of homeless women. Women were interviewed regarding socioeconomic indicators, psychiatric symptoms, health and/or social services contacts, and past-year HIV risk behaviors. Overall, 8 percent of the women injected drugs, 64 percent engaged in unprotected sex, and 22 percent traded sex. Multiple logistic regression results revealed that substance abuse was positively associated with injection drug use and trading sex. Homeless women with case managers were less likely to inject drugs. Although barriers to obtaining drug treatment were associated with trading sex, women attending self-help meetings for substance abuse were also more likely to trade sex. Homeless women who are substance abusers are vulnerable to HIV risk behaviors. Risk reduction interventions for homeless women should be implemented through substance abuse and intensive case management programs. C1 Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA. Univ Calif Los Angeles, Sch Publ Hlth, Hlth Serv, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Dept Family Med, Los Angeles, CA 90024 USA. RP Kilbourne, AM (reprint author), Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. FU AHRQ HHS [R01 HS08323]; NIMH NIH HHS [MH-19127] NR 38 TC 30 Z9 31 U1 3 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-2089 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD FEB PY 2002 VL 13 IS 1 BP 49 EP 65 DI 10.1177/10492080222148610 PG 17 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 514BC UT WOS:000173415400005 PM 11836913 ER PT J AU Stanchina, ML Tantisira, KG Aquino, SL Wain, JC Ginns, LC AF Stanchina, ML Tantisira, KG Aquino, SL Wain, JC Ginns, LC TI Association of lung perfusion disparity and mortality in patients with cystic fibrosis awaiting lung transplantation SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article ID DISEASE; CANDIDATES; DIAGNOSIS; PROGNOSIS; SURVIVAL; HEART; ADULT AB Background: The risk of death for patients with end-stage cystic fibrosis awaiting lung transplantation remains high and most patients succumb to respiratory failure. This study was conducted to evaluate the usefulness of ventilation-perfusion scintillation scans, obtained during the pre-transplant period, to identify patterns that predict prognosis while on the waiting list. These patterns were compared with other pulmonary physiologic markers of ventilation and perfusion obtained from pulmonary function and cardiopulmonary exercise tests. Methods: From November 1990 to January 1999, 46 patients with cystic fibrosis were listed for bilateral lung transplantation. Fourteen (30.4%) died while waiting for a transplant (Group 1), whereas 32 were transplanted successfully or remain alive and waiting (Group 2). Mean arterial blood gas values, Brasfield radiograph scores, cardiopulmonary exercise data and the degree of scintillation scan abnormalities between lungs were compared for each group. Results: Mean survival for Group 1 was 10.2 +/- 1.7 months, and for Group 2 was 23.5 +/- 3.0 months (p < 0.001). The right upper lung zone was the most severely affected segment. The Cox proportional hazards model revealed an increased perfusion disparity and resting hypercapnia as the main predictors of death while on the transplant list. The Kaplan-Meier analysis indicated greater survival for the groups with <30% disparity between lungs on the pre-transplant scintillation scans. Conclusions: The results suggest that severe, unilateral perfusion abnormalities seen on scintillation scans in patients with cystic fibrosis are associated with an increased risk of dying while on the lung transplant waiting list and may be helpful in identifying patients who should be considered for early or living-donor transplantation. C1 Massachusetts Gen Hosp, Pulm & Crit Care Unit, Div Thorac Radiol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Lung Transplant Program, Boston, MA 02115 USA. RP Ginns, LC (reprint author), Massachusetts Gen Hosp, Pulm & Crit Care Unit, Div Thorac Radiol, Bigelow Bldg,Room 806, Boston, MA 02114 USA. NR 29 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 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD FEB PY 2002 VL 21 IS 2 BP 217 EP 225 DI 10.1016/S1053-2498(01)00376-X PG 9 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 518JK UT WOS:000173664100004 PM 11834350 ER PT J AU Mikkola, HKA Orkin, SH AF Mikkola, HKA Orkin, SH TI The search for the hemangioblast SO JOURNAL OF HEMATOTHERAPY & STEM CELL RESEARCH LA English DT Review ID EMBRYONIC STEM-CELLS; FETAL LIVER HEMATOPOIESIS; MURINE YOLK-SAC; DEFINITIVE HEMATOPOIESIS; MOUSE EMBRYO; IN-VITRO; ENDOTHELIAL-CELLS; COMMON PRECURSOR; ADULT-MOUSE; SCL GENE C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Howard Hughes Med Inst, Childrens Hosp, Boston, MA 02115 USA. RP Orkin, SH (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. NR 60 TC 24 Z9 28 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1525-8165 J9 J HEMATOTH STEM CELL JI J. Hematother. Stem Cell Res. PD FEB PY 2002 VL 11 IS 1 BP 9 EP 17 DI 10.1089/152581602753448504 PG 9 WC Hematology; Medicine, Research & Experimental; Transplantation SC Hematology; Research & Experimental Medicine; Transplantation GA 523NA UT WOS:000173959500005 PM 11847000 ER PT J AU Kubis, N Besnard, S Silvestre, JS Feletou, M Huang, PL Levy, BI Tedgui, A AF Kubis, N Besnard, S Silvestre, JS Feletou, M Huang, PL Levy, BI Tedgui, A TI Decreased arteriolar density in endothelial nitric oxide synthase knockout mice is due to hypertension, not to the constitutive defect in endothelial nitric oxide synthase enzyme SO JOURNAL OF HYPERTENSION LA English DT Article DE angiogenesis; hypertension; nitric oxide ID CARDIAC-HYPERTROPHY; RATS; MICROVASCULATURE; ANGIOGENESIS; RAREFACTION; INHIBITOR; ISCHEMIA; MUSCLE; GENE AB Background Hypertension in endothelial nitric oxide synthase knockout (eNOS(-/-)) mice is believed to be partly due to altered vasodilatation. However, nitric oxide (NO) is also known to play an important part in angiogenesis. Objective To investigate whether capillary and arteriolar density were impaired in eNOS(-/-) mice, as this could account for increased vascular resistance and hypertension. Methods Using immunohistochemistry with mouse monoclonal smooth muscle a-actin antibody to detect arterioles and rabbit polyclonal fibronectin antibody to detect capillaries, we quantified arteriolar and capillary density in the left ventricle and in the gracills muscle from eNOS(-/-) mice compared with those in C57BL6J littermates (n = 6-8) in 8- and in 12-week-old mice. In a second set of experiments, we treated 8-week-old normotensive eNOS(-/-) mice with the anti hypertensive vasodilator, hydralazine, for 1 month. Results Eight-week-old eNOS(-/-) mice were normotensive and presented similar arteriolar and capillary densities in cardiac and skeletal mucles compared with those in eNOS(+/+) mice. Twelve-week-old eNOS(-/-) mice were hypertensive (mean arterial pressure 118 +/- 21 mmHg compared with 64 +/- 2 mmHg; P < 0.05). Capillary densities were similar in eNOS(-/-) mice and eNOS(+/+) mice in the heart (4154 123 and 4051 2471 mm 2, respectively) and in skeletal muscle (961 40 and 1025 +/- 41/mm(2), respectively). Arteriolar densities were 1510 lower in skeletal muscle and in the heart in eNOS(-/-) mice than in the eNOS(+/+) control group (P < 0.05). Hydralazine prevented hypertension and arteriolar rarefaction in eNOS(-/-) mice, whereas capillary density was unaffected by treatment with the vasodilator. Conclusion In young non-hypertensive eNOS(-/-) mice, the lack of eNOS did not affect microvascular densities in either of the muscles studied. In adult hypertensive eNOS(-/-) mice, we observed a lower arteriolar density, but a similar capillary density compared with controls. Hydralazine prevented hypertension and arteriolar rarefaction in adult mice, suggesting a non-NO-dependent pathway. Capillary density was not affected by hydralazine. J hlypertens 20:273-280 (C) 2002 Lippincott Williams Wilkins. C1 Hop Lariboisiere, INSERM, U541, F-75010 Paris, France. SERVIER, Dept Diabetol, Suresnes, France. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Levy, BI (reprint author), Hop Lariboisiere, INSERM, U541, 2 Rue Ambroise Pare, F-75010 Paris, France. NR 23 TC 34 Z9 34 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD FEB PY 2002 VL 20 IS 2 BP 273 EP 280 DI 10.1097/00004872-200202000-00017 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 520LW UT WOS:000173784200017 PM 11821712 ER PT J AU Einav, S Pozdnyakova, OO Ma, MH Carroll, MC AF Einav, S Pozdnyakova, OO Ma, MH Carroll, MC TI Complement C4 is protective for lupus disease independent of C3 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTIBODY-SECRETING CELLS; IGG AUTOANTIBODIES; AUTOIMMUNE-DISEASE; IMMUNE-COMPLEXES; C1Q DEFICIENCY; SELF-TOLERANCE; RENAL-DISEASE; ERYTHEMATOSUS; MICE; DNA AB The role of complement C3 in mediating systemic lupus erythematosus; (SLE) was examined using a double-knockout C3(null)C4(null) Fas (CD95)-deficient mouse model. Results from this study reveal significant lymphadenopathy, splenomegaly, elevated titers of anti-nuclear Abs and anti-dsDNA Abs, an increased number of anti-dsDNA-producing cells in ELISPOT assay, as well as severe glomerulonephritis in the double-deficient mice. Based on these clinical, serological, and histological parameters, we find that autoimmune disease in the double-knockout group is similar in severity to that in C4(null) lpr mice, but not to that in C3(null) lpr mice. The development of severe SLE in the absence of both classical and alternative complement pathways suggests that it is the absence of C4, and not the presence of C3, that is critical in SLE pathogenesis. Thus, complement C4 provides an important protective role against the development of SLE. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Carroll, MC (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, 200 Longwood Ave, Boston, MA 02115 USA. FU NICHD NIH HHS [R01 HD 38749] NR 38 TC 49 Z9 50 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2002 VL 168 IS 3 BP 1036 EP 1041 PG 6 WC Immunology SC Immunology GA 514FY UT WOS:000173429300010 PM 11801636 ER PT J AU Sasada, T Yang, HL Reinherz, EL AF Sasada, T Yang, HL Reinherz, EL TI CD2 facilitates differentiation of CD4 Th cells without affecting Th1/Th2 polarization SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTIGEN RECOGNITION; CYTOKINE PRODUCTION; OX40 LIGAND; ALPHA-BETA; B-CELLS; IN-VIVO; RECEPTOR; ACTIVATION; LFA-3; MICE AB The role of CD2 in murine CD4 helper T cell differentiation and polarization was examined using TCR-Cyt-5CC7-I transgenic recombination activating gene-2(-/-) H-2(a) mice on CD2(+/+) or CD2(-/-) backgrounds. In the absence of CD2, thymic development was abnormal as judged by reduction in the steady state number of total, double-positive, and CD4 single-positive (SP) thymocytes, as well as a defect in their restorative dynamics after peptide-induced negative selection in vivo. In addition, in CD2(-/-) animals, lymph node CD4 SP T cells manifest a 10- to 100-fold attenuated activation response to cytochrome c (CytC) agonist peptides as judged by induction of CD25 and CD69 cell surface expression or [H-3]TdR incorporation; differences in the magnitude of responsiveness and requisite molar peptide concentrations were even greater for altered peptide ligands. Although the presence or absence of CD2 did not impact the final Th1 or Th2 polarization outcome, CD2 expression reduced the CytC peptide concentration threshold necessary to facilitate both Th1 and Th2 differentiation. In vivo administration of CytC peptide to CD2(-/-) animals yielded an impaired CD4 SP T cell effector/memory phenotype compared with similarly treated CD2(+/+) mice. Analysis of TCR-Cyt-5CC7-I human CD2 double-transgenic mice similarly failed to reveal a preferential Th1 vs Th2 polarization. Collectively, these results indicate that CD2 is important for the efficient development of CD4 SP thymocytes and TCR-dependent activation of mature CD4 lymph node T cells, but does not direct a particular helper T cell subset polarity. C1 Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Reinherz, EL (reprint author), Dana Farber Canc Inst, Immunobiol Lab, 44 Binney St, Boston, MA 02115 USA. FU NIAID NIH HHS [AI 21226] NR 69 TC 11 Z9 12 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2002 VL 168 IS 3 BP 1113 EP 1122 PG 10 WC Immunology SC Immunology GA 514FY UT WOS:000173429300019 PM 11801645 ER PT J AU Li, R Haruta, I Rieu, P Sugimori, T Xiong, JP Arnaout, MA AF Li, R Haruta, I Rieu, P Sugimori, T Xiong, JP Arnaout, MA TI Characterization of a conformationally sensitive murine monoclonal antibody directed to the metal ion-dependent adhesion site face of integrin CD11b SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FUNCTION-ASSOCIATED ANTIGEN-1; I-DOMAIN; A-DOMAIN; CRYSTAL-STRUCTURE; DIVALENT-CATION; CR3 CD11B/CD18; LIGAND-BINDING; RECEPTOR; LFA-1; ACTIVATION AB Integrin binding to physiologic ligands requires divalent cations and an inside-out-driven switch of the integrin to a high-affinity state. Divalent cations at the metal ion-dependent adhesion site (MIDAS) face of the alpha subunit-derived A domain provide a direct bridge between ligands and the integrin, and it has been proposed that activation dependency is caused by reorientation of the surrounding residues relative to the metal ion, forming an optimal binding interface. To gain more insight into the functional significance of the protein movements on the MIDAS face, we raised and characterized a murine mAb 107 directed against the MIDAS face of the A domain from integrin CD11b. We find that mAb 107 behaves as a ligand mimic. It binds in a divalent-cation-dependent manner to solvent-exposed residues on the MIDAS face of CD11b,blocks interaction of 11bA or the holoreceptor with ligands, and inhibits spreading and phagocytosis by human neutrophils. However, in contrast to physiologic ligands, mAb 107 preferentially binds to the inactive low-affinity form of the integrin, suggesting that its antagonistic effects are exerted in part by stabilizing the receptor in the low-affinity state. These data support a functional relevance of the protein movements on the MIDAS face and suggest that stabilizing the A domain in the low-affinity state may have therapeutic benefit. C1 Massachusetts Gen Hosp, Renal Unit, Struct Biol Program, Leukocyte Biol & Inflammat Program, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Arnaout, MA (reprint author), Massachusetts Gen Hosp, Renal Unit, Struct Biol Program, Leukocyte Biol & Inflammat Program, 149 13th St,8th Floor, Charlestown, MA 02129 USA. FU NIDDK NIH HHS [DK 43351] NR 40 TC 23 Z9 23 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2002 VL 168 IS 3 BP 1219 EP 1225 PG 7 WC Immunology SC Immunology GA 514FY UT WOS:000173429300032 PM 11801658 ER PT J AU Cretin, N Bracy, J Hanson, K Iacomini, J AF Cretin, N Bracy, J Hanson, K Iacomini, J TI The role of T cell help in the production of antibodies specific for Gal alpha 1-3Gal SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RETROVIRAL GENE-THERAPY; NATURAL ANTIBODIES; HUMORAL IMMUNITY; HUMAN SERUM; MICE; EPITOPES; MOUSE; CD40; XENOTRANSPLANTATION; TRANSPLANTATION AB The majority of xenoreactive natural Abs in humans recognize the carbohydrate Ag present on pig tissue, Galalphal-3Galbeta14GlcNAc-R (alphaGal), synthesized by the enzyme UDP galactose: beta-D-galactosyl-1,4-N-aCetyl-D-glucosaminide alpha(1-3)galactosyltransferase or alphaGT. Using alphaGT knockout mice (GTO mice), which like humans produce serum Abs that bind aGal, we examined the role of T cells in production of Abs specific for alphaGal. GTO mice were crossed with TCR-beta knockout mice (TCR-beta(0)) to generate double-knockout mice (GT(0)/TCR-beta(0)). While GT(0)/TCR-beta(+) mice exhibited an age-dependent increase in the serum titer of natural Abs specific for alphaGal, a similar increase was not observed in GT(0)/TCR-beta(0) mice, and the titer of alphaGal-specific Abs in double knockouts was significantly lower than in age-matched GT(0)/TCR-beta(+) mice. Immunization with pig cells resulted in a significant increase in the serum titer of aGal-specific Abs in GTO/TCR-beta(+) mice, but had no effect on the level of alphaGal-specific serum Abs in GT(0)/TCR-beta(0) mice. Treatment of GT(0)/TCR-beta(+) mice with anti-CD40L Abs before immunization with pig cells prevented sensitization to alphaGal. Our data suggest that the majority of alphaGal-specific Abs are T cell dependent and that production of alphaGal-specific Abs after sensitization can be prevented by blocking costimulatory pathways. C1 Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Iacomini, J (reprint author), Massachusetts Gen Hosp, Transplantat Biol Res Ctr, MGH E,Bldg 149,13th St, Boston, MA 02129 USA. FU NIAID NIH HHS [T32 AI 07529, R01 AI 44268] NR 32 TC 33 Z9 34 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 FEB 1 PY 2002 VL 168 IS 3 BP 1479 EP 1483 PG 5 WC Immunology SC Immunology GA 514FY UT WOS:000173429300066 PM 11801692 ER PT J AU Lofgren, J Ramet, M Renko, M Marttila, R Hallman, M AF Lofgren, J Ramet, M Renko, M Marttila, R Hallman, M TI Association between surfactant protein A gene locus and severe respiratory syncytial virus infection in infants SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Annual Meeting of the Pediatric-Academic-Societies CY APR 30-MAY 13, 2001 CL BALTIMORE, MARYLAND SP Pediatr Academ Soci ID SP-A GENE; PULMONARY SURFACTANT; DISTRESS SYNDROME; YOUNG-CHILDREN; MARKER ALLELES; DISEASE; RISK; BRONCHIOLITIS; POPULATION; AGE AB Respiratory syncytial virus (RSV) causes seasonal epidemics of bronchiolitis among susceptible infants. Surfactant protein A (SP-A), a lung C-type lectin involved in innate host defense, opsonizes RSV and enhances phagocytosis. The candidate gene approach was used to investigate association of SP-A polymorphism with susceptibility to severe RSV infection. Genotype analysis was done for 86 infants with severe RSV infection and 95 matched control subjects. A significant difference in the frequency of SP-A2 was observed. The SP-A2 allele 1A(3) was overrepresented in RSV-infected infants, compared with control subjects (5% vs. 0.5%; P = .006), whereas allele 1A was underrepresented (1% vs. 6%; P = .011). The allele pool in which lysine was amino acid 223 was overrepresented in infants with severe RSV infection (28% vs. 18%; P = .023), whereas the allele pool in which proline was amino acid 99 was underrepresented (5% vs. 16%; P = .001). These results indicate that a genetic association exists between SP-A gene locus and severe RSV infection. C1 Univ Oulu, Dept Pediat, FIN-90014 Oulu, Finland. Univ Oulu, Bioctr Oulu, FIN-90014 Oulu, Finland. Seinajoki Cent Hosp, Seinajoki, Finland. Massachusetts Gen Hosp, Lab Dev Immunol, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Hallman, M (reprint author), Univ Oulu, Dept Pediat, FIN-90014 Oulu, Finland. RI Renko, Marjo/F-7811-2014 OI Renko, Marjo/0000-0003-0507-4773 NR 44 TC 105 Z9 105 U1 0 U2 0 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 FEB 1 PY 2002 VL 185 IS 3 BP 283 EP 289 DI 10.1086/338473 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 514UF UT WOS:000173458900002 PM 11807709 ER PT J AU Baxter, RM Brissette, JL AF Baxter, RM Brissette, JL TI Role of the nude gene in epithelial terminal differentiation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE Foxn1; Hfh11; keratinocyte; mitogen-activated protein kinase; Whn ID TRANSCRIPTION FACTOR; EPIDERMAL-CELLS; CALCIUM REGULATION; IN-VITRO; PROTEIN; MOUSE; EXPRESSION; ACTIVATION; KINASE; INVOLUCRIN AB Loss-of-function mutations in Whn (Hfh11, Foxn1), a winged-helix/forkhead transcription factor, cause the nude phenotype, which is characterized by the abnormal morphogenesis of the epidermis, hair follicles, and thymus. To delineate the biochemical pathway of Whn, we investigated its upstream regulation and downstream effects using primary keratinocytes from wild-type and transgenic mice. The transgenic animals express whn from the involucrin promoter, which is active in keratinocytes undergoing terminal differentiation. In wild-type cultures, as in the epidermis, Whn was induced during the early stages of terminal differentiation and declined during later stages. In transgenic keratinocytes, whit overexpression altered the terminal differentiation program, stimulating an early differentiation marker (keratin 1) and suppressing later markers (profilaggrin, loricrin, and involucrin). These results suggest a role for Whn in the stepwise or temporal regulation of differentiation, as Whn can ensure that the differentiation program is carried out in proper sequence. Before the start of differentiation, Whn levels were suppressed by the p42/p44 mitogen-activated protein kinase cascade, and this signaling pathway was rapidly inactivated as differentiation began. Thus, as keratinocytes commit to terminal differentiation, mitogen-activated protein kinase signaling decreases, which permits the induction of Whn; Whn then activates early features of the differentiation program. C1 Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. RP Brissette, JL (reprint author), MGH E, Cutaneous Biol Res Ctr, 13th St, Charlestown, MA 02129 USA. FU NIAMS NIH HHS [R01 AR45284] NR 43 TC 38 Z9 40 U1 1 U2 3 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 FEB PY 2002 VL 118 IS 2 BP 303 EP 309 DI 10.1046/j.0022-202x.2001.01662.x PG 7 WC Dermatology SC Dermatology GA 527ZE UT WOS:000174217400014 PM 11841548 ER PT J AU Zaki, MH Wysocka, M Everetts, SE Wang, KS French, LE Ritz, J Rook, AH AF Zaki, MH Wysocka, M Everetts, SE Wang, KS French, LE Ritz, J Rook, AH TI Synergistic enhancement of cell-mediated immunity by interleukin-12 plus interleukin-2: Basis for therapy of cutaneous T cell lymphoma SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE CTCL T cell; IL-2; IL-12; IL-12 receptors ID NATURAL-KILLER-CELLS; SEZARY-SYNDROME; MYCOSIS-FUNGOIDES; CYTOKINE PRODUCTION; GAMMA INDUCTION; RECEPTOR; RESPONSES; IMMUNOPATHOGENESIS AB Cutaneous T cell lymphoma is a clonally derived, skin-invasive malignancy of CD4(+) T lymphocytes with the phenotype of mature helper T cells. Previous work has demonstrated that the Sezary form, or typically leukemic form of cutaneous T cell lymphoma, is characterized by prominent immunologic defects, including depressed cell-mediated immunity associated with marked defects in the production of interleukin-12 and other type 1 helper T cell cytokines. Recent clinical trials with recombinant human interleukin-12 for cutaneous T cell lymphoma have demonstrated that it is a potent therapeutic agent, which induces cytotoxic T cell responses. Nevertheless, a high rate of refractoriness to recombinant human interleukin-12 occurred in these studies that may be related to the downmodulation of interleukin-12 receptor expression by chronic interleukin-12 use. In an effort to enhance the overall response rate and to overcome the refractoriness to recombinant human interleukin-12 therapy, we studied the immunologic effects hi vitro of adding interleukin-2 to interleukin-12 as a model to achieve these goals. We examined the stimulation of interferon-gamma production, natural killer cell activity and interleukin-12 receptor expression by T cells of cutaneous T cell lymphoma. patients. The addition of interleukin-12 to cutaneous T cell lymphoma patient peripheral blood cells resulted in the production of interferon-gamma (mean = 7914 pg per ml +/- 2161, n = 15) as did interleukin-2 alone (mean 7222 pg per ml +/- 2228, n = 15). Importantly, the addition of interleukin-2 to the interleukin-12 synergistically enhanced the levels of interferon-gamma produced (mean = 16 792 pg per ml +/- 2492 n = 15) (p <0.01). Similarly, addition of interleukin-2 to interleukin-12 synergistically enhanced both the natural killer cell activity of 15 cutaneous T cell lymphoma patients as well as T cell surface interleukin-12 receptor expression in comparison with the effects of interleukin-12 or interleukin-2 alone. Thus, interleukin-2 plus interleukin-12 unequivocally produces the synergistic enhancement of multiple parameters of cell-mediated immunity as well as upmodulating interleukin-12 receptor expression; this indicates that protocols combining these two potent immune enhancing cytokines may have added therapeutic benefit for cutaneous T cell lymphoma. C1 Univ Penn, Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. Dana Farber Canc Inst, Ctr Hematol Oncol, Boston, MA 02115 USA. Univ Hosp Geneva, Dept Dermatol, Geneva, Switzerland. RP Wysocka, M (reprint author), Univ Penn, Sch Med, Dept Dermatol, 245 CRB,415 Curie Blvd, Philadelphia, PA 19104 USA. RI Ritz, Jerome/C-7929-2009 OI Ritz, Jerome/0000-0001-5526-4669 FU NCI NIH HHS [CA 10815] NR 29 TC 12 Z9 14 U1 0 U2 2 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 FEB PY 2002 VL 118 IS 2 BP 366 EP 371 DI 10.1046/j.1523-1747.2002.01646.x PG 6 WC Dermatology SC Dermatology GA 527ZE UT WOS:000174217400024 PM 11841558 ER PT J AU Hasirci, V Litman, AE Trantolo, DJ Gresser, JD Wise, DL Margolis, HC AF Hasirci, V Litman, AE Trantolo, DJ Gresser, JD Wise, DL Margolis, HC TI PLGA bone plates reinforced with crosslinked PPF SO JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE LA English DT Article ID ETHYLENE GLYCOL) HYDROGELS; SCANNING FORCE MICROSCOPY; IN-VIVO DEGRADATION; SURFACE; VITRO; BIOCOMPATIBILITY; POLYETHYLENE; POLYMERS; FIXATION; SCREWS AB In this study a matrix of poly(propylene fumarate) (PPF) was crosslinked with N-vinylpyrrolidone (NVP), 2-hydroxyethylmethacrylate (HEMA), or a mixture of NVP and ethyleneglycol dimethacrylate (EGDMA) in the presence of poly(lactide-co-glycolide) (PLGA) to reinforce and preserve the form of PLGA bone plates. The degree of crosslinkage varied depending on the crosslinker as shown by the rapid and almost complete leaching of NVP upon incubation in phosphate buffered saline at 37degrees C in 900 h and retention of 92% of HEMA. With the reinforced bone plates extracted for 72 h at room temperature methylene chloride, the extracted PLGA from NVP/PPF, NVP-EGDMA/PPF, and HEMA/PPF were 75.42% (w/w), 59.52% (w/w), and 30.86% (w/w), respectively. The flexural modulus and compressive strength of the crosslinked PPF reinforced bone plates were higher than that of the unreinforced bone plate. Atomic force microscopy showed that NVP/PPF reinforced PLGA bone plates eroded substantially (a mean surface roughness of 19.319 nm) whereas NVP-EGDMA-PPF reinforced bone plate showed a distinct crystalline organization (and a higher roughness, 43.525 nm). In conclusion, we propose the consideration of NVP-EGDMA/PPF reinforced PLGA as a biodegradable orthopedic implant material that has a lower likelihood of warping or failing catastrophically than the currently available materials. (C) 2002 Kluwer Academic Publishers.rid C1 Middle E Tech Univ, Dept Biol Sci, Biotechnol Res Unit, TR-06531 Ankara, Turkey. Northeastern Univ, Dept Chem Engn, Snell Engn Ctr 342, Boston, MA 02115 USA. Forsyth Inst, Dept Biomineralizat, Boston, MA 02115 USA. Cambridge Sci Inc, Cambridge, MA 02138 USA. RP Hasirci, V (reprint author), Middle E Tech Univ, Dept Biol Sci, Biotechnol Res Unit, TR-06531 Ankara, Turkey. NR 36 TC 2 Z9 3 U1 0 U2 2 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-4530 J9 J MATER SCI-MATER M JI J. Mater. Sci.-Mater. Med. PD FEB PY 2002 VL 13 IS 2 BP 159 EP 167 DI 10.1023/A:1013877928988 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 527ZV UT WOS:000174219100004 PM 15348638 ER PT J AU Nash, JD Burgess, DS Talbert, RL AF Nash, JD Burgess, DS Talbert, RL TI Effect of fluvastatin and pravastatin, HMG-CoA reductase inhibitors, on fluconazole activity against Candida albicans SO JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Article ID AMPHOTERICIN-B; ITRACONAZOLE; PHARMACODYNAMICS; PHARMACOKINETICS; INFECTIONS AB Synergy between fluvastatin, at clinically unachievable concentrations, and fluconazole against Candida albicans has been reported. The purpose of the present study was to evaluate the in-vitro activity of fluconazole alone and in combination with clinically achievable concentrations of pravastatin and fluvastatin against C albicans. In-vitro susceptibility and synergy testing were performed against clinical isolates of C albicans with fluconazole, pravastatin and fluvastatin. Both checkerboard method and time-kill studies were performed. MICs for fluconazole ranged from 0.5 (susceptible) to >256 mg/L (resistant) at 24 h. All isolates had MICs >2 mg/L for both statins. No synergy or antagonism was observed with fluconazole in combination with either agent against any isolate of C. albicans by the checkerboard assay or time-kill studies. Clinically achievable concentrations of pravastatin and fluvastatin did not affect the invitro activity of fluconazole against C. albicans. C1 Univ Texas, Coll Pharm, Austin, TX 78712 USA. Univ Texas, Hlth Sci Ctr, Dept Pharmacol, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78284 USA. S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Burgess, DS (reprint author), Univ Texas, Coll Pharm, Austin, TX 78712 USA. NR 12 TC 23 Z9 24 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-2615 J9 J MED MICROBIOL JI J. Med. Microbiol. PD FEB PY 2002 VL 51 IS 2 BP 105 EP 109 PG 5 WC Microbiology SC Microbiology GA 520LU UT WOS:000173784000003 PM 11863260 ER PT J AU Rasmussen, RA Hofmann-Lehmann, R Montefiori, DC Li, PL Liska, V Vlasak, J Baba, TW Schmitz, JE Kuroda, MJ Robinson, HL McClure, HM Lu, S Hu, SL Rizvi, TA Ruprecht, RM AF Rasmussen, RA Hofmann-Lehmann, R Montefiori, DC Li, PL Liska, V Vlasak, J Baba, TW Schmitz, JE Kuroda, MJ Robinson, HL McClure, HM Lu, S Hu, SL Rizvi, TA Ruprecht, RM TI DNA prime/protein boost vaccine strategy in neonatal macaques against simian human immunodeficiency virus SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article DE cytolytic T lymphocytes; gp160; neutralizing antibodies ID CYTOTOXIC T-LYMPHOCYTES; ENHANCING ANTIBODY-RESPONSES; CELLULAR IMMUNE-RESPONSES; INFECTED RHESUS-MONKEYS; NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; NONHUMAN-PRIMATES; TYPE-1 INFECTION; NITRIC-OXIDE; PLASMID DNA AB Newborn macaques were vaccinated against a chimeric simian human immunodeficiency (SHIV) virus, SHIV-vpu(+), by DNA priming and boosting with homologous HIV-1 gp160. Following SHIV-vpu(+) challenge, containment of infection was observed in 4 of 15 animals given DNA priming/protein boost vaccination and in three of four animals given gp160 boosts only. Rechallenge with homologous virus of six animals that contained the first challenge virus resulted in rapid viral clearance or low viral loads. Upon additional rechallenge with heterologous, pathogenic SHIV89.6P, four of these six animals maintained normal CD4(+) T-cell counts with no or limited SHIV89.6P infection. Our data suggest that humoral and cellular immune mechanisms may have contributed to the containment of SHIV89.6P; however, viral interference with SHIV-vpu+ could also have played a role. Our results indicate that immunogenicity and efficacy of candidate AIDS vaccines are not affected when vaccination is initiated during infancy as compared with later in life. C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. Tufts Univ, Sch Med, Dept Pediat, Div Newborn Med, Boston, MA 02111 USA. Beth Israel Deaconess Med Ctr, Dept Med, Div Viral Pathogenesis, Boston, MA 02215 USA. Emory Univ, Yerkes Reg Primate Res Ctr, Div Microbiol & Immunol, Atlanta, GA 30322 USA. Emory Univ, Yerkes Reg Primate Res Ctr, Div Res Resources, Atlanta, GA 30322 USA. Univ Massachusetts, Med Ctr, Div Infect Dis, Worcester, MA USA. Univ Washington, Washington Reg Primate Res Ctr, Seattle, WA 98195 USA. Univ Texas, MD Anderson Canc Ctr, Dept Vet Sci, Bastrop, TX USA. RP Ruprecht, RM (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St, Boston, MA 02115 USA. RI Hu, Shiu-Lok/A-3196-2008; Hofmann-Lehmann, Regina/C-6528-2009 OI Hu, Shiu-Lok/0000-0003-4336-7964; FU NCRR NIH HHS [P51 RR000165, RR00165]; NIAID NIH HHS [P01 AI48240, AI40337, K08-AI01327, P01 AI048240, R21 AI6177]; PHS HHS [A126503] NR 62 TC 25 Z9 26 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD FEB PY 2002 VL 31 IS 1 BP 40 EP 60 DI 10.1034/j.1600-0684.2002.1o019.x PG 21 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 531DL UT WOS:000174400700005 PM 12076047 ER PT J AU Levin, M AF Levin, M TI Isolation and community: A review of the role of gap-junctional communication in embryonic patterning SO JOURNAL OF MEMBRANE BIOLOGY LA English DT Review DE gap junction; embryo; development; morphogenesis; connexin ID LEFT-RIGHT ASYMMETRY; NEURAL CREST CELLS; VACUOLAR H+-ATPASE; EARLY AMPHIBIAN EMBRYO; EARLY XENOPUS EMBRYO; IMPLANTATION MOUSE EMBRYO; PAPILLOMAVIRUS TYPE-4 E8; MICE LACKING CONNEXIN43; INTERCELLULAR COMMUNICATION; MEMBRANE CHANNELS AB Gap junctions are specialized channels formed between the membranes of two adjacent cells. They permit the direct passage of small molecules from the cytosol of one cell to that of its neighbor, and thus form a system of cell-cell communication that exists alongside familiar secretion/receptor signaling. Gap junction states can be regulated at many levels by factors such as membrane voltage, pH, phosphorylation state, and biochemical signals. Because of the rich potential for regulation of junctional conductance, and directional and molecular gating (specificity), gap junctional communication (GJC) plays a crucial role in many aspects of normal tissue physiology, as well as in tumor progression. However, arguably the most exciting role for GJC is in the regulation of information flow that takes place during embryonic development. This review summarizes the current knowledge of how GJC controls various aspects of embryonic morphogenesis in both vertebrate and invertebrate systems. Modern molecular embryology approaches have complemented biophysical and ultrastructural data, and we are beginning to unravel the patterning roles of GJC in embryonic events such as the patterning of the embryonic left-right axis, as well as the morphogenesis of the heart and limb. Proteins from the Connexin (Cx) gene family, as well as innexins and ductin, are now beginning to be understood as the basis for GJC underlying important embryonic patterning events. C1 Forsyth Inst, Cytokine Biol Dept, Boston, MA USA. RP Levin, M (reprint author), Forsyth Inst, Cytokine Biol Dept, 140 Fenway, Boston, MA USA. EM mlevin@forsyth.org NR 188 TC 44 Z9 49 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0022-2631 EI 1432-1424 J9 J MEMBRANE BIOL JI J. Membr. Biol. PD FEB 1 PY 2002 VL 185 IS 3 BP 177 EP 192 DI 10.1007/s00232-001-0129-7 PG 16 WC Biochemistry & Molecular Biology; Cell Biology; Physiology SC Biochemistry & Molecular Biology; Cell Biology; Physiology GA 520PQ UT WOS:000173790600001 PM 11891576 ER PT J AU Plumbley, JA Fan, HX Eagan, PA Ehsan, A Schnitzer, B Gulley, ML AF Plumbley, JA Fan, HX Eagan, PA Ehsan, A Schnitzer, B Gulley, ML TI Lymphoid tissues from patients with infectious mononucleosis lack monoclonal B and T cells SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID EPSTEIN-BARR-VIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; NON-HODGKINS-LYMPHOMAS; LYMPHOPROLIFERATIVE DISORDERS; HEMOPHAGOCYTIC SYNDROME; MOLECULAR PATHOLOGY; GENE REARRANGEMENTS; CLONAL EXPANSIONS; LOW-GRADE; DISEASE AB In typical cases of infectious mononucleosis (IM), lymphoid tissue is rarely submitted for pathological examination. When lymphoid tissues from IM cases are examined, the histological appearance of IM may be difficult to distinguish from malignant lymphoma. The purpose of this study was to address the utility of clinical molecular assays for T and B cell clonality in distinguishing IM from lymphoid malignancy. DNA was recovered from paraffin-embedded archival lymphoid tissues of 18 cases of IM and 13 control cases representing other reactive lymphoid hyperplasias. T cell receptor gamma (TCR-gamma) and immunoglobulin heavy chain (IgH) gene rearrangements were assayed using our standard clinical polymerase chain reaction procedures targeting each of the four functional variable (V) families and the three joining 0) families of the TCR-gamma gene, and framework III of the IgH gene, respectively. In 17 of 18 cases of IM, no monoclonal T or B cell populations were detectable. One case, the only spleen specimen in the study, had an oligoclonal pattern of TCR-gamma rearrangements. The control cases representing other reactive hyperplasias also lacked monoclonality. The assays used were sensitive to clonal populations as small as 5% of cells. In this case series, no monoclonal lymphoid populations were identified in any case of IM. This finding suggests that molecular studies are useful in distinguishing IM from lymphoidneoplasms. C1 Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Keesler Hosp, Med Def Grp 81, Keesler AFB, MS USA. Audie L Murphy Mem Vet Adm Med Ctr, San Antonio, TX 78284 USA. Univ Michigan, Med Ctr, Ann Arbor, MI USA. RP Gulley, ML (reprint author), Univ N Carolina, Dept Pathol, 101 Manning Dr,Brinkhouse Bullitt Bldg, Chapel Hill, NC 27599 USA. NR 28 TC 10 Z9 12 U1 0 U2 0 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD FEB PY 2002 VL 4 IS 1 BP 37 EP 43 DI 10.1016/S1525-1578(10)60678-2 PG 7 WC Pathology SC Pathology GA 561LC UT WOS:000176141300004 PM 11826186 ER PT J AU Yeung, A Howarth, S Chan, R Sonawalla, S Nierenberg, AA Fava, M AF Yeung, A Howarth, S Chan, R Sonawalla, S Nierenberg, AA Fava, M TI Use of the Chinese version of the beck depression inventory for screening depression in primary care SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article ID LOS-ANGELES; SOMATIZATION; NEURASTHENIA; PREVALENCE; AMERICANS; CULTURE; AREA AB Many Asian-Americans are unfamiliar with depression and its treatment. When depressed, they generally seek treatment from their primary care physicians and complain about their physical symptoms, resulting in under-recognition and under-treatment of depression. This study evaluates the effectiveness of the Chinese version of the Beck Depression Inventory (CBDI) for screening depression among Chinese-Americans in primary care. A total of 503 Chinese-Americans in the primary care clinic of a community health center were administered the CBDI for depression screening. Patients who screened positive (CBDI greater than or equal to 16) were interviewed by a psychiatrist using the Structured Clinical Interview for DSM-III-R, patient version (SCID-I/P) for confirmation of the diagnosis. Patients who screened negative (CBDI < 16) were randomly selected to be interviewed using the depression module of the SCID-I/P. The results of the SCID-I/P interview were used as the standard for evaluating the sensitivity and specificity of the CBDI. A total of 815 Chinese-Americans in a primary care clinic were approached, and 503 completed the CBDI. Seventy-six (1596) screened positive (CBDI greater than or equal to 16), and the prevalence of major depression was 19.6% by using extrapolated results from SCID-I/P interviews. When administered by a native-speaking research assistant, the CBDI has good sensitivity (.79), specificity (.91), positive predictive value (.79), and negative predictive value (.91). Despite the commonly believed tendency to focus on physical symptoms rather than depressed mood, Chinese-Americans are able to report symptoms of depression in response to a questionnaire. The CBDI, when administered by research assistants, has good sensitivity and specificity in recognizing major depression in this population. Lack of interest among Chinese-American patients in using the CBDI as a self-rating instrument has limited its use for depression screening in primary care settings. C1 Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. S Cove Community Hlth Ctr, Boston, MA USA. RP Yeung, A (reprint author), Massachusetts Gen Hosp, Depress Clin & Res Program, 50 Staniford St,Suite 401, Boston, MA 02114 USA. FU NIMH NIH HHS [5T32MH19126-10] NR 24 TC 37 Z9 39 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3018 J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD FEB PY 2002 VL 190 IS 2 BP 94 EP 99 DI 10.1097/00005053-200202000-00005 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 527MN UT WOS:000174190000005 PM 11889362 ER PT J AU Merfeld, DM Zupan, LH AF Merfeld, DM Zupan, LH TI Neural processing of gravitoinertial cues in humans. III. Modeling tilt and translation responses SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID INNERVATING SEMICIRCULAR CANALS; EYE-MOVEMENT RESPONSES; VERTICAL AXIS ROTATION; GRAVITO-INERTIAL CUES; VESTIBULOOCULAR REFLEX; SQUIRREL-MONKEY; LINEAR ACCELERATION; ECCENTRIC ROTATION; OCULOGRAVIC ILLUSION; VIEWING DISTANCE AB All linear accelerometers measure gravitoinertial force, which is the sum of gravitational force (tilt) and inertial force due to linear acceleration (translation). Neural strategies must exist to elicit tilt and translation responses from this ambiguous cue. To investigate these neural processes, we developed a model of human responses and simulated a number of motion paradigms used to investigate this tilt/translation ambiguity. In this model, the separation of GIF into neural estimates of gravity and linear acceleration is accomplished via an internal model made up of three principal components: 1) the influence of rotational cues (e. g., semicircular canals) on the neural representation of gravity, 2) the resolution of gravitoinertial force into neural representations of gravity and linear acceleration, and 3) the neural representation of the dynamics of the semicircular canals. By combining these simple hypotheses within the internal model framework, the model mimics human responses to a number of different paradigms, ranging from simple paradigms, like roll tilt, to complex paradigms, like postrotational tilt and centrifugation. It is important to note that the exact same mechanisms can explain responses induced by simple movements as well as by more complex paradigms; no additional elements or hypotheses are needed to match the data obtained during more complex paradigms. Therefore these modeled response characteristics are consistent with available data and with the hypothesis that the nervous system uses internal models to estimate tilt and translation in the presence of ambiguous sensory cues. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otol & Laryngol,Jenks Vestibular Physiol Lab, Boston, MA 02114 USA. RP Merfeld, DM (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otol & Laryngol,Jenks Vestibular Physiol Lab, Suite 421,243 Charles St, Boston, MA 02114 USA. EM dan_merfeld@meei.harvard.edu FU NIDCD NIH HHS [DC 03066, DC 04158] NR 86 TC 89 Z9 90 U1 1 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD FEB PY 2002 VL 87 IS 2 BP 819 EP 833 DI 10.1152/jn.00485.2001 PG 15 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 537AV UT WOS:000174735100017 PM 11826049 ER PT J AU Litovsky, RY Delgutte, B AF Litovsky, RY Delgutte, B TI Neural correlates of the precedence effect in the inferior colliculus: Effect of localization cues SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID AUDITORY-NERVE FIBERS; IPSILATERALLY EVOKED INHIBITION; BINAURAL RESPONSE PROPERTIES; INTERAURAL TIME DIFFERENCES; LATERAL LEMNISCUS; DORSAL NUCLEUS; SOUND LOCALIZATION; SIMULATED ECHOES; RECEPTIVE-FIELDS; EXTERNAL-EAR AB The precedence effect (PE) is an auditory phenomenon involved in suppressing the perception of echoes in reverberant environments, and is thought to facilitate accurate localization of sound sources. We investigated physiological correlates of the PE in the inferior colliculus (IC) of anesthetized cats, with a focus on directional mechanisms for this phenomenon. We used a virtual space (VS) technique, where two clicks (a "lead" and a "lag") separated by a brief time delay were each filtered through head-related transfer functions (HRTFs). For nearly all neurons, the response to the lag was suppressed for short delays and recovered at long delays. In general, both the time course and the directional patterns of suppression resembled those reported in free-field studies in many respects, suggesting that our VS simulation contained the essential cues for studying PE phenomena. The relationship between the directionality of the response to the lead and that of its suppressive effect on the lag varied a great deal among IC neurons. For a majority of units, both excitation produced by the lead and suppression of the lag response were highly directional, and the two were similar to one another. For these neurons, the long-lasting inhibitory inputs thought to be responsible for suppression seem to have similar spatial tuning as the inputs that determine the excitatory response to the lead. Further, the behavior of these neurons is consistent with psychophysical observations that the PE is strongest when the lead and the lag originate from neighboring spatial locations. For other neurons, either there was no obvious relationship between the directionality of the excitatory lead response and the directionality of suppression, or the suppression was highly directional whereas the excitation was not, or vice versa. For these neurons, the excitation and the suppression produced by the lead seem to depend on different mechanisms. Manipulation of the directional cues (such as interaural time and level differences) contained in the lead revealed further dissociations between excitation and suppression. Specifically, for about one-third of the neurons, suppression depended on different directional cues than did the response to the lead, even though the directionality of suppression was similar to that of the lead response when all cues were present. This finding suggests that the inhibitory inputs causing suppression may originate in part from subcollicular auditory nuclei processing different directional cues than the inputs that determine the excitatory response to the lead. Neurons showing such dissociations may play an important role in the PE when the lead and the lag originate from very different directions. C1 Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02143 USA. Boston Univ, Hearing Res Ctr, Boston, MA 02215 USA. MIT, Elect Res Labs, Boston, MA 02114 USA. RP Litovsky, RY (reprint author), Univ Wisconsin, Waisman Ctr, Rm 525,1500 Highland Ave, Madison, WI 53705 USA. FU NIDCD NIH HHS [DC 00119, P01 DC000119-25] NR 87 TC 30 Z9 32 U1 1 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD FEB PY 2002 VL 87 IS 2 BP 976 EP 994 DI 10.1152/jn.00568.2001 PG 19 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 537AV UT WOS:000174735100030 PM 11826062 ER PT J AU Fredduzzi, S Moratalla, R Monopoli, A Cuellar, B Xu, K Ongini, E Impagnatiello, F Schwarzschild, MA Chen, JF AF Fredduzzi, S Moratalla, R Monopoli, A Cuellar, B Xu, K Ongini, E Impagnatiello, F Schwarzschild, MA Chen, JF TI Persistent behavioral sensitization to chronic L-DOPA requires A(2A) adenosine receptors SO JOURNAL OF NEUROSCIENCE LA English DT Article DE A(2A) adenosine receptor; L-DOPA; behavioral sensitization; Parkinson's disease; dyskinesia; dynorphin ID 6-HYDROXYDOPAMINE LESIONED RATS; LEVODOPA-INDUCED DYSKINESIAS; PRODYNORPHIN MESSENGER-RNA; MPTP-TREATED MONKEYS; PARKINSONS-DISEASE; GENE-EXPRESSION; MICE LACKING; DARPP-32 PHOSPHORYLATION; MOTOR COMPLICATIONS; MEDIATED MODULATION AB To investigate the role of A(2A) adenosine receptors in adaptive responses to chronic intermittent dopamine receptor stimulation, we compared the behavioral sensitization elicited by repeated L-DOPA treatment in hemiparkinsonian wild-type (WT) and A(2A) adenosine receptor knock-out (A(2A) KO) mice. Although the unilateral nigrostriatal lesion produced by intrastriatal injection of 6-hydroxydopamine was indistinguishable between WT and A(2A) KO mice, they developed strikingly different patterns of behavioral sensitization after daily treatment with low doses of L-DOPA for 3 weeks. WT mice initially displayed modest contralateral rotational responses and then developed progressively greater responses that reached a maximum within 1 week and persisted for the duration of the treatment. In contrast, any rotational behavioral sensitization in A(2A) KO mice was transient and completely reversed within 2 weeks. Similarly, the time to reach the peak rotation was progressively shortened in WT mice but remained unchanged in A(2A) KO mice. Furthermore, daily L-DOPA treatment produced gradually sensitized grooming in WT mice but failed to induce any sensitized grooming in A(2A) KO mice. Finally, repeated L-DOPA treatment reversed the 6-OHDA-induced reduction of striatal dynorphin mRNA in WT but not A(2A) KO mice, raising the possibility that the A(2A) receptor may contribute to L-DOPA-induced behavioral sensitization by facilitating adaptations within the dynorphin-expressing striatonigral pathway. Together these results demonstrate that the A(2A) receptor plays a critical role in the development and particularly the persistence of behavioral sensitization to repeated L-DOPA treatment. Furthermore, they raise the possibility that the maladaptive dyskinetic responses to chronic L-DOPA treatment in Parkinson's disease may be attenuated by A(2A) receptor inactivation. C1 Massachusetts Gen Hosp, Mol Neurobiol Lab, Boston, MA 02129 USA. Schering Plough Corp, Res Inst, I-20132 Milan, Italy. Inst Cajal, Madrid 20082, Spain. RP Schwarzschild, MA (reprint author), Massachusetts Gen Hosp, Ctr Aging Genet & Neurodegenerat, Room 2900,114 16th St, Charlestown, MA 02129 USA. RI Moratalla, Rosario/H-9280-2015 OI Moratalla, Rosario/0000-0002-7623-8010 FU NIDA NIH HHS [DA07496]; NINDS NIH HHS [NS37403] NR 73 TC 95 Z9 95 U1 0 U2 1 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 FEB 1 PY 2002 VL 22 IS 3 BP 1054 EP 1062 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 518HB UT WOS:000173660800054 PM 11826134 ER PT J AU Troulis, MJ AF Troulis, MJ TI Do position and soft tissue affect distraction vector? An in vitro investigation - Discussion SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Troulis, MJ (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 7 TC 0 Z9 0 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 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD FEB PY 2002 VL 60 IS 2 BP 155 EP 156 DI 10.1053/joms.2002.29809 PG 2 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 519QD UT WOS:000173736200005 ER PT J AU Yang, J Lam, EWN Hammad, HM Oberley, TD Oberley, LW AF Yang, J Lam, EWN Hammad, HM Oberley, TD Oberley, LW TI Antioxidant enzyme levels in oral squamous cell carcinoma and normal human oral epithelium SO JOURNAL OF ORAL PATHOLOGY & MEDICINE LA English DT Article DE antioxidant enzymes; immunohistochemistry; oral squamous cell carcinoma ID MANGANESE SUPEROXIDE-DISMUTASE; GLUTATHIONE-S-TRANSFERASE; SYRIAN-HAMSTER TISSUES; IMMUNOHISTOCHEMICAL LOCALIZATION; KIDNEY DEVELOPMENT; GENE-TRANSFER; GLIOMA-CELLS; OVEREXPRESSION; IMMUNOLOCALIZATION; CARCINOGENESIS AB Background. The antioxidant enzymes (manganese- and copper-zinc-containing superoxide dismutases, catalast and glutathione peroxidase) limit cell injury induced by reactive oxygen species. The purpose of the study was to determine whether human oral squamous cell carcinomas have altered antioxidant enzyme levels. This study is the first to undertake this task in human oral mucosa and squamous cell carcinoma. Methods: Semiquantitative immunohistochemistry was used to examine 26 archived oral squamous cell carcinoma biopsies. Fourteen well-differentiated and 12 poorly differentiated tumors were examined, as were 12 specimens of oral mucosa. All sections were reviewed by two oral and maxillofacial pathologists, and image analysis of the immunostained sections was performed using NIH Image. Antioxidant enzyme staining intensities were compared in the different groups by Duncan's multiple range test. Results: In general, mucosal basal cells displayed lower antioxidant enzyme levels than spinous cells, and primary tumor cells displayed lower antioxidant enzyme staining intensities than did their normal cell counterparts. Moreover, poorly differentiated tumor cells showed lower antioxidant enzyme staining intensities than well-differentiated tumor cells. Manganese-containing superoxide dismutase staining intensities were, however, higher in well-differentiated oral squamous cell carcinomas than their normal cells of origin. Conclusions: Detection of antioxidant enzymes may be a useful future marker in the molecular diagnosis of the oral cancer. Moreover, it may be possible to not only monitor the effectiveness of chemopreventitive and therapeutic strategies in oral cancer using these enzymes, but to monitor tumor recurrence. C1 Temple Univ, Sch Dent, Dept Oral Med, Philadelphia, PA 19104 USA. Univ Alberta, Dept Dent, Edmonton, AB, Canada. Jordan Univ Sci & Technol, Fac Dent, Irbid, Jordan. William S Middleton Mem Vet Adm Med Ctr, Pathol Serv, Madison, WI USA. Univ Iowa, Coll Med, Dept Radiat Oncol, Free Rad & Radiat Biol Grad Program, Iowa City, IA USA. RP Yang, J (reprint author), Temple Univ, Sch Dent, Dept Oral Med, 3223 N Broad St, Philadelphia, PA 19104 USA. EM jyang@dental.temple.edu FU NIDCR NIH HHS [P50 DE 10758] NR 23 TC 58 Z9 60 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0904-2512 J9 J ORAL PATHOL MED JI J. Oral Pathol. Med. PD FEB PY 2002 VL 31 IS 2 BP 71 EP 77 DI 10.1034/j.1600-0714.2002.310202.x PG 7 WC Dentistry, Oral Surgery & Medicine; Pathology SC Dentistry, Oral Surgery & Medicine; Pathology GA 529LV UT WOS:000174301700002 PM 11896826 ER PT J AU Borodic, GE Acquadro, MA AF Borodic, GE Acquadro, MA TI The use of botulinum toxin for the treatment of chronic facial pain SO JOURNAL OF PAIN LA English DT Article DE botulinum type A; BOTOX (Allergan Inc Irvine, CA); DYSPORT (Ipsen Inc, Milford, MA); NEUROBLOK (Elan Pharmaceuticals, Dublin; Ireland); temporal mandibular joint disease; trigeminal neuralgia; surgical pain ID TRIGEMINAL NEURALGIA; SPASMODIC TORTICOLLIS; A TOXIN; MECHANISMS; BLEPHAROSPASM; INJECTIONS; MIGRAINE AB An open label pilot study was conducted to evaluate efficacy of botulinum toxin injections for the treatment of patients with chronic facial pain seeking tertiary care at a pain clinic. Diagnoses included temporomandibular joint syndrome, postsurgical pain syndromes, essential headache, and idiopathic trigeminal neuralgia.: Thirty-three (75%) of 44 patients favorably responded, including 8 of 11 patients with trigeminal neuralgia. The duration of beneficial effect ranged from 2 to 4 months, and all responding patients desired further injections. Complications were mild and included temporary facial asymmetry and weakness secondary to neuromuscular effects of botulinum toxin. Doses ranged from 25 to 75 LD 50 units with Hall strain-derived botulinum toxin type A. A small degree of facial edema during pain or erythema seemed to have predictive value when categorically evaluated against response. (C) 2002 by the American Pain Society. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Borodic, GE (reprint author), 100 Charles River Plaza,3rd Floor, Boston, MA 02114 USA. NR 27 TC 46 Z9 48 U1 0 U2 3 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD FEB PY 2002 VL 3 IS 1 BP 21 EP 27 DI 10.1054/jpai.2002.27142 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 524ZQ UT WOS:000174043100005 PM 14622850 ER PT J AU Kohler, H Donarski, S Stocks, B Parret, T Edwards, C Schroten, H AF Kohler, H Donarski, S Stocks, B Parret, T Edwards, C Schroten, H TI Antibacterial characteristics in the feces of breast-fed and formula-fed infants during the first year of life SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Article DE breast-feeding; feces; Iga; sialic acid; bacterial adhesion; transepithelial electrical resistance ID ENTEROPATHOGENIC ESCHERICHIA-COLI; HUMAN-MILK; EPITHELIAL MONOLAYERS; NEONATAL SEPSIS; S-FIMBRIAE; INFECTION; ADHESION; CELLS; OLIGOSACCHARIDES; GLYCOPROTEINS AB Background: Human milk is known to protect infants front a number of infectious diseases. Much less is known about the bioactivity of milk-derived factors in the intestine. In this study, potentially protective characteristics in the feces of breast-fed and formula-fed infants were compared. Methods: The feces of 26 breast-fed and IS formula-fed infants were collected during the first year of life. In each sample, the concentrations of total protein, immunoglobulin A, and sialic acid were measured. In addition, the effect of the fecal samples was measured on the adhesion of enteropathogenic Escherichia coli (EPEC) to Caco-2 cells and on transepithelial electrical resistance (TER) during an infection. Results: In the first month, sialic acid and immunoglobulin A were found in the feces of breast-fed infants in substantially higher concentrations than in the feces of formula fed infants (sialic acid, 1197 +/- 370 mug/ mL versus 31 +/- 19 mug/ mL; immunoglobulin A. 0.11 +/- 7 mg/mL versus 0.3 +/- 1 mg/mL) and thereafter decreased to similar levels in half a year. Adhesion of EPEC to Caco-2 cells was inhibited between 65% and 85% by stools from both groups, The decrease of TER during EPEC infection was unaffected by fecal samples of any origin or age. Conclusion: Potentially protective factors are present in higher concentrations in the stools of breast-fed infants than in stools of formula-fed infants. Interestingly, feces from breast-fed and formula-fed infants inhibited bacterial adhesion to a similar level. but neither was able to preserve epithelial barrier function. C1 Massachusetts Gen Hosp, Combined Program Pediat Gastroenterol & Nutr, Charlestown, MA 02129 USA. Univ Dusseldorf, Childrens Hosp, D-4000 Dusseldorf, Germany. Univ Glasgow, Yorkhill Natl Hlth Serv Trust, Dept Human Nutr, Glasgow, Lanark, Scotland. Harvard Univ, Sch Med, Boston, MA USA. RP Kohler, H (reprint author), Massachusetts Gen Hosp, Combined Program Pediat Gastroenterol & Nutr, 114 16th St 114-3503, Charlestown, MA 02129 USA. EM hkohler@helix.mgh.harvard.edu NR 35 TC 12 Z9 12 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-2116 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD FEB PY 2002 VL 34 IS 2 BP 188 EP 193 DI 10.1097/00005176-200202000-00015 PG 6 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA 520LX UT WOS:000173784300015 PM 11840038 ER PT J AU Strack, S Kinder, BN AF Strack, S Kinder, BN TI Special series: Personality autobiographies - Introduction SO JOURNAL OF PERSONALITY ASSESSMENT LA English DT Editorial Material C1 US Dept Vet Affairs, Psychol Serv 116B, Ctr Ambulatory Care, Los Angeles, CA 90012 USA. Univ S Florida, Dept Psychol, Tampa, FL 33620 USA. RP Strack, S (reprint author), US Dept Vet Affairs, Psychol Serv 116B, Ctr Ambulatory Care, 351 E Temple St, Los Angeles, CA 90012 USA. NR 9 TC 2 Z9 2 U1 0 U2 0 PU LAWRENCE ERLBAUM ASSOC INC PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430-2262 USA SN 0022-3891 J9 J PERS ASSESS JI J. Pers. Assess. PD FEB PY 2002 VL 78 IS 1 BP 1 EP 3 DI 10.1207/S15327752JPA7801_01 PG 3 WC Psychology, Clinical; Psychology, Social SC Psychology GA 531TM UT WOS:000174433400001 PM 11936203 ER PT J AU Schlesinger, N Detry, MA Holland, BK Baker, DG Beutler, AM Rull, M Hoffman, BI Schumacher, HR AF Schlesinger, N Detry, MA Holland, BK Baker, DG Beutler, AM Rull, M Hoffman, BI Schumacher, HR TI Local ice therapy during bouts of acute gouty arthritis SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE gout; cold; inflammation; treatment ID COLD; HEAT; TEMPERATURE; URATE AB Objective. To evaluate the effect of local application of ice on duration and severity of acute gouty arthritis. Methods. Nineteen patients with acute gout were enrolled and randomized into 2 groups. Group A (n = 10) received topical ice therapy, oral prednisone 30 mg PO tapered to 0 over 6 days and colchicine 0.6 mg/day. Group B was the control group (n = 9), given the same regimen but without the ice therapy. The patients were followed for one week. Results. The mean reduction in pain for those patients treated with ice therapy was 7.75 cm (on 10 cm visual analog scale) with standard deviation 2.58 compared with 4.42 cm (+/- SD 2.96) for the control group. Using a Wilcoxon rank-sum test there was a significant difference (p = 0.021) in pain reduction between the ice therapy and control groups. Joint circumference and synovial fluid volume also tended to be more effectively reduced after one week of therapy in the ice group compared with controls, but these did not achieve statistical significance. Conclusion. The group treated with ice had a significantly greater reduction in pain compared with the control group. Although the clinical improvement was impressive, due to the small sample size we could not show statistically significant improvement in all the variables that tended to suggest that effect was more than simply analgesic. Cold applications may be a useful adjunct to treatment of acute gouty arthritis. C1 Vet Affairs Med Ctr, Arthrit Immunol Ctr, Philadelphia, PA USA. Univ Penn, Sch Med, Div Rheumatol, Philadelphia, PA 19104 USA. Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Prevent Med, Newark, NJ 07103 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Med, Rheumatol Sect, Newark, NJ 07103 USA. Allegheny Univ Hosp, Div Rheumatol, Dept Med, Philadelphia, PA USA. RP Schlesinger, N (reprint author), 68 Hart Dr, W Orange, NJ 07052 USA. NR 10 TC 53 Z9 57 U1 0 U2 3 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD FEB PY 2002 VL 29 IS 2 BP 331 EP 334 PG 4 WC Rheumatology SC Rheumatology GA 517PC UT WOS:000173618300022 PM 11838852 ER PT J AU BenDebba, M Torgerson, WS Boyd, RJ Dawson, EG Hardy, RW Robertson, JT Sypert, GW Watts, C Long, DLM AF BenDebba, M Torgerson, WS Boyd, RJ Dawson, EG Hardy, RW Robertson, JT Sypert, GW Watts, C Long, DLM TI Persistent low back pain and sciatica in the United States: Treatment outcomes SO JOURNAL OF SPINAL DISORDERS & TECHNIQUES LA English DT Article DE low back pain; patient outcomes; functional disability; health care use; physical symptoms; psychologic distress; pain severity AB Patients with persistent low back pain (LBP) appear to be different in several important ways from patients who have traditionally been classified as patients with acute or chronic LBP, and data on the effectiveness of the treatments prescribed for them are lacking. The aim of the current study was to evaluate the short- and long-term effectiveness of the treatments currently prescribed for these patients. The data reported in this article were gathered as part of a multicenter, prospective, cross-sectional study of patients who were treated for persistent LBP by neurologic and orthopedic surgeons who are recognized specialists in spinal disorders. At enrollment, patients completed a baseline evaluation, and their physicians recorded relevant clinical and treatment data on standardized study forms. At 3, 6, 13, and 24 months after treatment, patients completed follow-up evaluations. Patients were divided into five treatment groups, and effectiveness was evaluated separately for each group using five patient-reported measures of outcome: gain severity, functional disability, psychologic distress, physical symptoms, and health care use. The data revealed that at the 2-year follow-up, the typical patient of the no-treatment group had improved slightly in terms of pain severity and health care use, but had experienced little or no improvement in functional disability, physical symptoms, and psychologic distress. The average patient in the conservative care group reported small improvements in pain severity, functional disability, physical symptoms, and health care use, with no change in psychologic distress. These small improvements occurred within the first 3 months after enrollment, with essentially no change thereafter. The average patient in the immediate; surgical care group showed substantial improvement on all of the outcome measures. The observed improvements were evident shortly after treatment and were maintained for the duration of the study. Patients in the delayed surgical care group had outcomes that were less dramatic than those observed in the immediate surgery care group, but greater than those observed in the conservative care group. The patients who were treated surgically by physicians outside the study, outside surgical care group, did not improve over time. Patients with persistent LBP who received no treatment showed no spontaneous recovery. Conservative pare treatments prescribed by surgeons who specialize in spinal disorders, did not appear to be any more effective than no treatment. The outcome of surgery for persistent LBP varied from dramatic for one subgroup of surgical patients, to poor for another subgroup of patients. Patients who were selected immediately for surgical treatment improved substantially. Those treated surgically later by study physicians or by physicians not associated with the study fared less well. C1 Johns Hopkins Sch Med, Dept Neurosurg, Baltimore, MD 21287 USA. Massachusetts Gen Hosp, Ctr Ambulatory Care, Boston, MA 02114 USA. Univ Calif Los Angeles, Sch Med, Div Orthoped Surg, Los Angeles, CA USA. Case Western Reserve Univ, Dept Neurosurg, Cleveland, OH 44106 USA. Univ Tennessee, Dept Neurosurg, Memphis, TN 38163 USA. Univ Florida, Dept Neurosurg, Gainesville, FL USA. Univ Missouri, Dept Neurosurg, Columbia, MO USA. RP BenDebba, M (reprint author), Johns Hopkins Sch Med, Dept Neurosurg, 9-100 Meyer Bldg,600 N Wolfe St, Baltimore, MD 21287 USA. FU NINDS NIH HHS [NS 21718] NR 20 TC 14 Z9 14 U1 0 U2 2 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 FEB PY 2002 VL 15 IS 1 BP 2 EP 15 PG 14 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 537WE UT WOS:000174782000002 PM 11891445 ER PT J AU Nurcombe, B Drell, MJ Leonard, HL McDermott, JF AF Nurcombe, B Drell, MJ Leonard, HL McDermott, JF TI Clinical problem solving: The case of Matthew, Part II SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article C1 Univ Queensland, Royal Brisbane Hosp, Mental Hlth Ctr, Herston, Qld, Australia. LSU, Hlth Sci Ctr, New Orleans, LA USA. Brown Univ, Sch Med, Providence, RI 02912 USA. Univ Hawaii, Sch Med, Honolulu, HI 96822 USA. RP Nurcombe, B (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Bulfinch 351, Boston, MA 02114 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 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD FEB PY 2002 VL 41 IS 2 BP 215 EP 222 DI 10.1097/00004583-200202000-00016 PG 8 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 514PZ UT WOS:000173451400016 PM 11837412 ER PT J AU Robinson-Bostom, L Pomerantz, D Wilkel, C Mader, R Lerner, L Dufresne, R Flotte, T AF Robinson-Bostom, L Pomerantz, D Wilkel, C Mader, R Lerner, L Dufresne, R Flotte, T TI Localized argyria with pseudo-ochronosis SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID OCCUPATIONAL ARGYRIA; HYPERPIGMENTATION; MICROANALYSIS AB Background: Localized argyria is uncommon and presents clinically as asymptomatic slate gray macules or blue macules resembling blue nevi. Its histopathologic features are usually similar to those of generalized argyria in which silver granules are found most commonly around the eccrine glands, in the walls of blood vessels, and along elastic fibers. Ochre swollen homogenized collagen bundles resembling ochronosis have not been previously described. Objective: The purpose of this study is to report a series of 5 patients with localized argyria with the histologic feature of "pseudo-ochronosis." In one patient, biopsy was performed on 2 distinct lesions. Methods: All patients underwent skin biopsies for light microscopy and darkfield microscopy, In two patients, the biopsy specimens were analyzed with a mass spectrophotometer; scanning electron microscopy and energy-dispersive x-ray analysis were performed. In one patient, the biopsy specimen was decolorized with 1% potassium ferricyanide in 20% sodium thiosulfate. Results: All 5 patients presented with the typical clinical and histologic features of localized argyria. Ochre swollen and homogenized collagen bundles were seen in all cases. in addition, light microscopy in 4 cases revealed an ellipsoid black globule within a zone of collagen degeneration, Conclusion: The histologic features of localized argyria include swollen and homogenized collagen bundles resembling ochronosis, "pseudo-ochronosis," which may he more common than previously recognized. C1 Brown Univ, Rhode Isl Hosp, Sch Med, Dept Dermatol, Providence, RI 02903 USA. Brown Univ, Rhode Isl Hosp, Sch Med, Dept Pathol, Providence, RI 02903 USA. Boston Univ, Sch Med, Roger Williams Gen Hosp, Dept Dermatol, Providence, RI USA. Boston Univ, Sch Med, Roger Williams Gen Hosp, Dept Pathol, Providence, RI USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dermatol Associates Kingsport, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. RP Robinson-Bostom, L (reprint author), Brown Univ, Rhode Isl Hosp, Sch Med, Dept Dermatol, APC 10,593 Eddy St, Providence, RI 02903 USA. NR 12 TC 19 Z9 19 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD FEB PY 2002 VL 46 IS 2 BP 222 EP 227 DI 10.1067/mjd.2002.116227 PG 6 WC Dermatology SC Dermatology GA 519ED UT WOS:000173711200008 PM 11807434 ER PT J AU Nghiem, P Pearson, G Langley, RG AF Nghiem, P Pearson, G Langley, RG TI Tacrolimus and pimecrolimus: From clever prokaryotes to inhibiting calcineurin and treating atopic dermatitis SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID PYODERMA-GANGRENOSUM; TOPICAL TACROLIMUS; CYCLOSPORINE-A; IMMUNOPHILIN LIGANDS; BINDING-PROTEIN; FK506; FK-506; TRANSCRIPTION; CYCLOPHILIN; OINTMENT AB Tacrolimus ointment, a topical inhibitor of the phosphatase calcineurin, has recently been approved in the United States for use in the treatment of atopic dermatitis. It is the first topical immune suppressant that is not one of the hydrocortisone derivatives, important allies in dermatology for nearly 50 years. Although tacrolimus is less able to penetrate thick skin than glucocorticoids, it does not cause dermal atrophy, an important advantage over the hydrocortisone class. Pimecrolimus (ASM 981), a newer calcineurin inhibitor closely related to tacrolimus, is also being developed for atopic dermatitis therapy. Pimecrolimus has an altered skin penetration profile but the same mechanism of action as tacrolimus. In this review we chronicle the discovery of the calcineurin inhibitors, their presumed evolutionary role as a bacterial "smart bomb" against fungi, molecular and cellular mechanisms of action in the immune system, systemic and topical side effects, efficacy in atopic dermatitis, and future applications within the specialty of dermatology. Particular attention is given to the issues of systemic absorption of tacrolimus, the conditions in which absorption can become a concern, efficacy relative to glucocorticoids, and the choice of 0.03% or 0.1% tacrolimus ointment for use in adults and children. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Cutaneous Oncol Unit, Boston, MA 02115 USA. Univ Missouri, Div Dermatol, Columbia, MO 65211 USA. Dalhousie Univ, Dept Med, Div Dermatol, Halifax, NS, Canada. RP Nghiem, P (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Cutaneous Oncol Unit, 44 Binney St, Boston, MA 02115 USA. RI Nghiem, Paul/A-9210-2011 OI Nghiem, Paul/0000-0003-2784-963X NR 60 TC 127 Z9 141 U1 0 U2 3 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD FEB PY 2002 VL 46 IS 2 BP 228 EP 241 DI 10.1067/mjd.2002.120942 PG 14 WC Dermatology SC Dermatology GA 519ED UT WOS:000173711200009 PM 11807435 ER PT J AU Tannous, ZS Mihm, MC Flotte, TJ Gonzalez, S AF Tannous, ZS Mihm, MC Flotte, TJ Gonzalez, S TI In vivo examination of lentigo maligna and malignant melanoma in situ, lentigo maligna type by near-infrared reflectance confocal microscopy: Comparison of in vivo confocal ages with histologic sections SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID SCANNING LASER MICROSCOPY; IN-VIVO; HUMAN SKIN; CONTRAST AB In vivo confocal microscopy can noninvasively image thin en face sections within living intact human tissue with high resolution and contrast. This evolving technique may provide clinicians with tools to help detect lentigo maligna lesion progression in vivo and may be important in defining tumor margins, thus providing a more definitive surgical eradication of lentigo maligna and malignant melanoma in situ, lentigo maligna type. We present a case of malignant melanoma in situ, lentigo maligna type, and we describe the images seen with confocal microscopy in correlation with routine histopathology. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatol,Wellman Labs Photomed, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dermatopathol Unit,Pathol Dept, Boston, MA 02114 USA. RP Gonzalez, S (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatol,Wellman Labs Photomed, Barlett Hall 814,55 Blossom St, Boston, MA 02114 USA. NR 12 TC 67 Z9 70 U1 1 U2 3 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD FEB PY 2002 VL 46 IS 2 BP 260 EP 263 DI 10.1067/mjd.2002.118345 PG 4 WC Dermatology SC Dermatology GA 519ED UT WOS:000173711200014 PM 11807439 ER PT J AU Bloomstone, J Chow, CM Isselbacher, E VanCott, E Isaacson, KB AF Bloomstone, J Chow, CM Isselbacher, E VanCott, E Isaacson, KB TI A pilot study examining the frequency and quantity of gas embolization during operative hysteroscopy using a monopolar resectoscope SO JOURNAL OF THE AMERICAN ASSOCIATION OF GYNECOLOGIC LAPAROSCOPISTS LA English DT Article; Proceedings Paper CT 30th Annual Meeting of the American-Association-of-Gyecologic-Laparoscopists CY NOV 16-19, 2001 CL SAN FRANCISCO, CALIFORNIA SP Amer Assoc Gyecol Laparoscopists ID AIR-EMBOLISM; MICROBUBBLES; AGGREGATION; NITROGEN; DEATH AB Study Objective. To assess baseline frequency of gas embolization during standard monopolar resectoscopic surgery. Design. Prospective, nonrandomized, observational study (Canadian Task Force classification 11-2). Setting. Tertiary care medical center. Patients. Eleven women and three controls. Intervention. Operative hysteroscopy. Measurements and Main Results. Echocardiography and serum studies were performed to detect bubble formation in the inferior vena cava, hepatic veins, and right heart. Cas bubbles were present in the hepatic veins or right heart in 10 patients and no controls. No patients had changes in coagulation profile and only one had clinical changes during surgery. Conclusion. Cas bubbles can been detected by echocardiography in most patients undergoing resectoscopic surgery in the uterus. Clinical significance may relate to anatomic variations as well as to gas bubble content and volume. C1 Massachusetts Gen Hosp, Dept Anesthesia, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Cardiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Special Clotting, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. RP Isaacson, KB (reprint author), Massachusetts Gen Hosp, Dept Gynecol, VBK 206,55 Fruit St, Boston, MA 02114 USA. NR 13 TC 9 Z9 13 U1 0 U2 0 PU JOURNAL AMER ASSOC GYNECOLOGIC LAPAROSCOPISTS PI SANTA FE SPRINGS PA 13021 EAST FLORENCE AVE, SANTA FE SPRINGS, CA 90670-4505 USA SN 1074-3804 J9 J AM ASSOC GYN LAP JI J. Am. Assoc. Gynecol. Laparoscopists PD FEB PY 2002 VL 9 IS 1 BP 9 EP 14 DI 10.1016/S1074-3804(05)60098-9 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 551RF UT WOS:000175574500004 PM 11821600 ER PT J AU Marrie, TJ Fine, MJ Kapoor, WN Coley, CM Singer, DE Obrosky, DS AF Marrie, TJ Fine, MJ Kapoor, WN Coley, CM Singer, DE Obrosky, DS TI Community-acquired pneumonia and do not resuscitate orders SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE pneumonia; do not resuscitate; nursing home ID CARDIOPULMONARY-RESUSCITATION; OUTCOMES; PHYSICIANS; EPIDEMIOLOGY; MULTICENTER; PREFERENCES; DECISIONS; IMPACT; CARE AB OBJECTIVES: From a cohort of patients with community-acquired pneumonia (CAP) who required admission to hospital; to describe the subset of patients having a do not resuscitate (DNR) order and to compare them with those who did not have such an order. DESIGN: Retrospective subset analysis of data from the pneumonia patient outcomes research team study. SETTING: Three hospitals in the United States and one in Canada. PARTICIPANTS: Hospitalized patients aged 18 and older with CAP. MEASUREMENTS: Sociodemographic features, severity of illness, antibiotic therapy, length of stay, mortality, admission to special care units, and mortality attributable to pneumonia. RESULTS: The 199 (14.9%) of 1,339 inpatients with CAP who had a DNR order written within 24 hours of admission and an additional 96 (7.2%) patients who had such an order written later were compared with the 1,044 who never had a DNR order. The 199 patients with an initial DNR and 96 later DNR were older (median age 81 and 78 vs 65 years, respectively; P <.001), more likely to be white (92.5% and 90.6% vs 84.8%; P = .007), and more likely to have came from a nursing home or chronic care facility (53.8% and 31.3% vs 4.5%; P <.001). The two DNR groups received more antibiotics for a longer time than the never DNR patients. The DNR patients had longer lengths of stay than the never DNR patients (medians 9 and 12 vs 7 days). There were 89 in-hospital deaths among the 1,339 patients, but only 11 of these were among patients who did not have a DNR order during the first 30 days (sensitivity, specificity, and positive and negative predictive values of a DNR order for in-hospital mortality were 87.6%; 82.6%, 26.4%, and 98.9%, respectively). The 90-day mortality rates were 43.2% for the initial DNR group, 61.5% in the later DNR group, and 4.7% for the never DNR group (P <.001). Pneumonia-attributable mortality accounted for most of the in-hospital deaths but did not differ by DNR status. Only 31.7% of the initial DNR patients and 24.0% of the later DNR patients were discharged home, versus 82.6% of the other patients (P <.001). In a multivariate analysis, the following were predictive of initial DNR: age; nursing home care, active cancer, dementia, neuromuscular disorders, altered mental status, low systolic blood pressure, tachypnea, abnormal hematocrit, abnormal blood urea nitrogen, and absence of alcohol or intravenous drug abuse. In similar analyses of DNR at any time, additional predictors included aspiration, low white blood count, chronic pulmonary disease, cerebrovascular disease, and congestive heart failure. CONCLUSION: Most in-hospital pneumonia deaths occur in patients who have a DNR order. DNR orders written within 24 hours of admission primarily reflect comorbid status, whereas DNR orders written later during hospitalization reflect the futility of care plus comorbidity. C1 Dalhousie Univ, Dept Med, Halifax, NS, Canada. Dalhousie Univ, Dept Microbiol, Halifax, NS, Canada. Queen Elizabeth II Hlth Sci Ctr, Halifax, NS, Canada. Univ Pittsburgh, Div Gen Internal Med, Pittsburgh, PA USA. Univ Pittsburgh, Ctr Res Hlth Care, Pittsburgh, PA USA. Massachusetts Gen Hosp, Dept Med, Gen Internal Med Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Marrie, TJ (reprint author), Walter C Mackenzie Hlth Sci Ctr, 2F1-30,8440-112 St, Edmonton, AB T6G 2B7, Canada. NR 23 TC 26 Z9 26 U1 0 U2 1 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 FEB PY 2002 VL 50 IS 2 BP 290 EP 299 DI 10.1046/j.1532-5415.2002.50061.x PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 520EL UT WOS:000173767600011 PM 12028211 ER PT J AU Small, GW McDonnell, DD Brooks, RL Papadopoulos, G AF Small, GW McDonnell, DD Brooks, RL Papadopoulos, G TI The impact of symptom severity on the cost of Alzheimer's disease SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE Alzheimer's disease; cost of illness; caregivers; disease progression ID PLACEBO-CONTROLLED TRIAL; MANAGED CARE; DOUBLE-BLIND; DONEPEZIL; CAREGIVERS; DEMENTIA; AD; GALANTAMINE; PATTERNS; PROGRAM AB OBJECTIVES: To examine the economic impact of Alzheimer's disease (AD) as the disease progresses on patients' medical costs and caregivers' productivity. DESIGN: A 12-page, self-administered mail survey, fielded in November 1999. SETTING: Households with AD caregivers, selected from a nationwide (U.S.) consumer database. PARTICIPANTS: One thousand seven hundred fifteen caregivers of noninstitutionalized AD patients. MEASUREMENTS: Disease progression was measured using a scale of symptom frequency and measures of instrumental and physical functioning. Cost components included hospital days, physician visits, and emergency room visits. Lost productivity was assessed using hours per week that caregivers provided care and the number of days that they missed from work because of caregiving. RESULTS: The direct costs of caring for AD patients for 6 months totaled $3,129, whereas the indirect costs were $26,080. Patients with more-frequent symptoms used all healthcare resources, including the hospital, emergency room, and physicians, more often than those with less-frequent symptoms. Those with lower levels of physical and instrumental functioning also used the hospital and physicians more often than those with higher levels of physical and instrumental functioning. Caregivers of these more severely impaired patients spent more hours providing care and reported missing more work than those caring for higher-functioning patients. These relationships remained after controlling for potentially confounding factors. CONCLUSIONS: This large study of patients at all stages of AD shows that the direct and indirect costs of AD are considerably lower for patients with fewer symptoms. Longitudinal studies will determine the impact on the overall cost of care of interventions that reduce symptoms and maintain patients at earlier stages of the disease. C1 Univ Calif Los Angeles, Inst Neuropsychiat, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Ctr Aging, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Alzheimers Dis Ctr, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Consumer Hlth Sci, Princeton, NJ USA. Janssen Pharmaceut Prod LP, Titusville, NJ USA. RP Small, GW (reprint author), Univ Calif Los Angeles, Inst Neuropsychiat, 88-201,760 Westwood Plaza, Los Angeles, CA 90024 USA. OI McDonnell, Diana/0000-0003-3044-3147 NR 32 TC 65 Z9 65 U1 4 U2 8 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 FEB PY 2002 VL 50 IS 2 BP 321 EP 327 DI 10.1046/j.1532-5415.2002.50065.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 520EL UT WOS:000173767600015 PM 12028215 ER PT J AU Zhang, SL To, C Chen, X Filep, JG Tang, SS Ingelfinger, JR Chan, JSD AF Zhang, SL To, C Chen, X Filep, JG Tang, SS Ingelfinger, JR Chan, JSD TI Essential role(s) of the intrarenal renin-angiotensin system in transforming growth factor-beta 1 gene expression and induction of hypertrophy of rat kidney proximal tubular cells in high glucose SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; CELLULAR HYPERTROPHY; DIABETIC NEPHROPATHY; MESSENGER-RNA; FACTOR-BETA; COLLAGEN; STIMULATE; RECEPTOR; ISOPROTERENOL; TRANSCRIPTION AB These studies investigated the question of whether the intrarenal renin-angiotensin system (RAS) is essential for transforming growth factor-beta1 (TGF-beta1) gene expression and induction of hypertrophy of renal proximal tubular cells in high glucose in vitro. Antisense and sense angiotensinogen (ANG) cDNAs were stably transfected into rat immortalized renal proximal tubular cells (IRPTC). ANG secretion from rat IRPTC was quantified by a specific RIA for rat ANG. Cellular ANG, TGF-beta1, and collagen alpha1 (type IV) mRNA levels were determined by Northern blot analysis or by reverse transcriptase-PCR assay. Hypertrophy of IRPTC was analyzed by Western blotting of cellular p27(Kip1) protein, flow cytometry, and cellular protein assay. The results showed that stable transfer of antisense ANG cDNA into IRPTC suppressed the basal TGF-beta1 and collagen alpha1 (type IV) mRNA expression and blocked the stimulatory effect of high glucose (i.e., 25 mM) on TGF-beta1 and collagen alpha1 (type IV) mRNA expression and induction of IRPTC hypertrophy. In contrast, stable transfer of sense ANG cDNA into IRPTC had no significant effect on these parameters. These data demonstrate that local intrarenal RAS activation is essential for TGF-beta1 gene expression and induction of hypertrophy of renal proximal tubular cells in high glucose. C1 Univ Montreal, Ctr Hosp Univ Montreal, Hotel Dieu, Ctr Rech, Montreal, PQ H2W 1T8, Canada. Hop Maison Neuve Rosemont, Montreal, PQ H1T 2M4, Canada. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Nephrol Unit, Boston, MA USA. RP Chan, JSD (reprint author), Univ Montreal, Ctr Hosp Univ Montreal, Hotel Dieu, Ctr Rech, Pavillon Masson,3850 St Urbain St, Montreal, PQ H2W 1T8, Canada. FU NHLBI NIH HHS [HL-48455]; NIDDK NIH HHS [DK-50836] NR 43 TC 40 Z9 46 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD FEB PY 2002 VL 13 IS 2 BP 302 EP 312 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 514NT UT WOS:000173448500002 PM 11805157 ER PT J AU Kathiresan, S Shiomura, J Jang, IK AF Kathiresan, S Shiomura, J Jang, IK TI Argatroban SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE argatroban; anticoagulation; direct thrombin inhibitor ID HEPARIN-INDUCED THROMBOCYTOPENIA; INTERNATIONAL NORMALIZED RATIO; THROMBIN INHIBITOR ARGATROBAN; PLASMINOGEN-ACTIVATOR; CORONARY SYNDROMES; UNSTABLE ANGINA; SMALL-MOLECULE; ANTICOAGULANT; INFUSION; WARFARIN AB Antithrombotic and antiplatelet therapies are the cornerstones of management of cardiovascular disorders today. Due to the safety and efficacy limitations of the classic antithrombotic, unfractionated heparin, considerable effort has been directed at developing novel anticoagulants. Direct thrombin inhibitors as a class of drugs offer inhibition of clot-bound as well as fluid-phase thrombin and a more predictable anticoagulant response. Specifically, argatroban, a synthetic small molecule direct thrombin inhibitor, selectively inhibits the catalytic site of thrombin in a reversible manner. Overall, argatroban's short half-life, ease of monitoring with an activated partial thromboplastin time, and safety in renal failure patients make this drug the preferable mode therapy for prevention of thrombosis in heparin-induced thrombocytopenia. The role of adjunctive argatroban therapy in acute coronary syndromes and during percutaneous coronary intervention is currently being studied. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02114 USA. Mitsubishi Pharma Corp, Tokyo, Japan. RP Jang, IK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Bulfinch 105,55 Fruit St, Boston, MA 02114 USA. NR 35 TC 30 Z9 32 U1 1 U2 2 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 FEB PY 2002 VL 13 IS 1 BP 41 EP 47 DI 10.1023/A:1015368126304 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 549AD UT WOS:000175421600007 PM 11994559 ER PT J AU Prout, GR AF Prout, GR TI Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors - Comment SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Prout, GR (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 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 FEB PY 2002 VL 167 IS 2 BP 893 EP 894 PN 2 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 510MX UT WOS:000173212800032 ER PT J AU Yang, OO Nguyen, PT Kalams, SA Dorfman, T Gottlinger, HG Stewart, S Chen, ISY Threlkeld, S Walker, BD AF Yang, OO Nguyen, PT Kalams, SA Dorfman, T Gottlinger, HG Stewart, S Chen, ISY Threlkeld, S Walker, BD TI Nef-mediated resistance of human immunodeficiency virus type 1 to antiviral cytotoxic T lymphocytes SO JOURNAL OF VIROLOGY LA English DT Article ID BLOOD-BANK COHORT; HISTOCOMPATIBILITY COMPLEX PROTEINS; LONG-TERM NONPROGRESSORS; HIV-1 NEF; DOWN-REGULATION; CELL-CYCLE; VIRAL REPLICATION; FINE SPECIFICITY; CD4 LYMPHOCYTES; INFECTED CELLS AB Although Nef has been proposed to effect the escape of human immunodeficiency virus type 1 (HIV-1) from cytotoxic T lymphocytes (CTL) through downmodulation of major histocompatibility complex class I molecules, little direct data have been presented previously to support this hypothesis. By comparing nef-competent and nef-deleted HIV-1 strains in an in vitro coculture system, we demonstrate that the presence of this viral accessory gene leads to impairment of the ability of HIV-1-specific CTL clones to suppress viral replication. Furthermore, inhibition by genetically modified CTL that do not require major histocompatibility complex class I-presented antigen (expressing the CD4 T-cell receptor [TCR] zeta-chain hybrid receptor) is similar for both nef-competent and -deleted strains, indicating that Nef does not impair the effector functions of CTL but acts at the level of TCR triggering. In contrast, we note that another accessory gene, vpr, does not induce resistance of HIV-1 to suppression by CTL clones. We conclude that Nef (and not Vpr) contributes to functional HIV-1 immune evasion and that this effect is mediated by diminished antigen presentation to CTL. C1 Univ Calif Los Angeles, Ctr Med, Div Infect Dis, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Ctr Med, AIDS Inst, Los Angeles, CA 90095 USA. Massachusetts Gen Hosp E, Partners AIDS Res Ctr, Charlestown, MA 02129 USA. Massachusetts Gen Hosp E, Infect Dis Unit, Charlestown, MA 02129 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Yang, OO (reprint author), Univ Calif Los Angeles, Ctr Med, Div Infect Dis, 37-121 CHS,10833 LeConte Ave, Los Angeles, CA 90095 USA. FU NIAID NIH HHS [R01 AI043203, AI43203] NR 68 TC 89 Z9 91 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2002 VL 76 IS 4 BP 1626 EP 1631 DI 10.1128/JVI.76.4.1626-1631.2002 PG 6 WC Virology SC Virology GA 514TT UT WOS:000173457700010 PM 11799157 ER PT J AU Ahmed, A Allman, RM DeLong, JF AF Ahmed, A Allman, RM DeLong, JF TI Inappropriate use of digoxin in older hospitalized heart failure patients SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID PAROXYSMAL ATRIAL-FIBRILLATION; CONVERTING ENZYME-INHIBITORS; SINUS RHYTHM; VENTRICULAR RATE; GENERAL-PRACTICE; ELDERLY PATIENTS; DIGITALIS; MANAGEMENT; TRIAL; PRESCRIPTION AB Background. Older adults are more likely to suffer from the adverse effects of digoxin. Studies have described the inappropriate use of digoxin in various populations, The objective of this study was to determine the correlates of inappropriate digoxin use in older heart failure patients. Methods. We studied older hospitalized heart failure patients with documented left ventricular (LV) function evaluation and electrocardiography. Digoxin use was considered inappropriate if patients had preserved LV systolic function (ejection fraction greater than or equal to40%) or if they had no atrial fibrillation (AF). We compared baseline patient characteristics by indication for digoxin and tested statistical significance using Pearson's chi-square analysis and Student's t tests. using logistic regression, we determined the correlates of inappropriate use and initiation of digoxin. Results. Subjects (N = 603) had a mean age of 79 (+/-7) years; 59% were women, and 18% were African American. A total of 376 patients (62%) were discharged on dioxin, and 223 (37%) had no indication for its use. Half of the patients without an indication for digoxin received the drug. Of 132 patients without an indication and not already on digoxin, 38 (29%) were initiated on it. After adjustment for various patient and care characteristics, prior digoxin use (adjusted odds ratio [OR] 11.47, 95% confidence internal [CI] 5.72-23.02) and pulse greater than or equal to100/min (adjusted OR 2.33, 95% CI 1.10-4.94) were associated with inappropriate digoxin use. Pulse greater than or equal to100/min was also associated with inappropriate initiation of the drug (adjusted OR 2.95. 95% CI 1.28-6.78). Conclusions. Inappropriate use of dioxin was common and was associated with prior use. Tachycardia was associated with inappropriate use and initiation. Electrocardiography and echocardiography should be performed in all older heart failure patients. Digoxin therapy should not be initiated or continued in patients without any evidence of LV systolic dysfunction or chronic AF. C1 Univ Alabama, Sch Med, Dept Med, Div Gerontol & Geriatr Med, Birmingham, AL 35200 USA. Univ Alabama, Sch Publ Hlth, Dept Epidemiol & Int Hlth, Birmingham, AL 35294 USA. Univ Alabama, Ctr Aging, Birmingham, AL USA. Birmingham VA Med Ctr, Sect Geriatr, Birmingham, AL USA. Birmingham VA Med Ctr, Birmingham Atlanta Geratr Res Educ & Clin Ctr, Birmingham, AL USA. Alabama Qual Assurance Fdn, Birmingham, AL USA. RP Ahmed, A (reprint author), Univ Alabama, Sch Med, Dept Med, Div Gerontol & Geriatr Med, Birmingham, AL 35200 USA. RI Ahmed, Ali/A-2934-2008 OI Ahmed, Ali/0000-0002-6832-6424 NR 52 TC 10 Z9 10 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD FEB PY 2002 VL 57 IS 2 BP M138 EP M143 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 523ZP UT WOS:000173987700014 PM 11818435 ER PT J AU Matsumoto, AM AF Matsumoto, AM TI Andropause: Clinical implications of the decline in serum testosterone levels with aging in men SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Review ID BONE-MINERAL DENSITY; BENIGN PROSTATIC HYPERPLASIA; FOLLICLE-STIMULATING-HORMONE; ANDROGEN RECEPTOR GENE; CORONARY-ARTERY DISEASE; AGE-RELATED-CHANGES; PITUITARY-GONADAL FUNCTION; HEALTHY OLDER MEN; LEAN BODY-MASS; IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM C1 Univ Washington, Sch Med, Populat Ctr Res Reprod,Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. VA Puget Sound Hlth Care Syst, Clin Res Unit, Ctr Geriatr Res Educ & Clin, Seattle, WA 98108 USA. RP Matsumoto, AM (reprint author), VA Puget Sound Hlth Care Syst, Clin Res Unit, Ctr Geriatr Res Educ & Clin, 1660 S Columbia Way,S-182-GRECC, Seattle, WA 98108 USA. FU NICHD NIH HHS [HD12629] NR 475 TC 237 Z9 243 U1 3 U2 10 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD FEB PY 2002 VL 57 IS 2 BP M76 EP M99 PG 24 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 523ZP UT WOS:000173987700006 PM 11818427 ER PT J AU Perkel, JM Simon, MC Rao, A AF Perkel, JM Simon, MC Rao, A TI Identification of a c-myb attenuator-binding factor SO LEUKEMIA RESEARCH LA English DT Article DE c-myb; transcription elongation; attenuation; pausing; B-cell ID NF-KAPPA-B; ERYTHROLEUKEMIA CELL-DIFFERENTIATION; TRANSCRIPTION ELONGATION; NUCLEAR FACTOR; MESSENGER-RNA; GENE-EXPRESSION; PROTEIN; INTRON; DELTA-EF1; MECHANISM AB Expression of the c-myb proto-oncogene is developmentally regulated at the level of transcription elongation. In pre-B cells, complete c-myb transcripts are produced, whereas transcripts are attenuated near or within a 300-base pair (bp) interval of the first c-myb intron in mature cells. Hypothesizing that transcription attenuation results from a protein complex that physically impedes the progress of RNA polymerase II through the intron. we used electrophoretic mobility shift assays (EMSA) to search for DNA-binding activities that correlated with downregulation of c-myb transcription. We identified a stage-specific, DNA binding activity, termed ABF, present in mature B cells but not in pre-B cells. ABF binds to a 15-bp DNA element located within a 300-bp BstEII-XhaI fragment. DMSO-treatment of murine erythroleukemia cells results in rapid downregulation of c-myb transcription and upregulation of ABF DNA binding activity. Thus, ABF binding activity correlates with downregulation of c-myb transcription in two systems. Preliminary biochemical characterization of ABF from mature B cells demonstrates that its primary DNA-binding component is a 64-kDa-protein. We hypothesize that this factor may represent a member of the transcriptional attenuation complex. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. Univ Penn, Howard Hughes Med Inst, Philadelphia, PA 19104 USA. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Simon, MC (reprint author), Univ Penn, Abramson Family Canc Res Inst, Room 456,BRB 11-111,421 Curie Blvd, Philadelphia, PA 19104 USA. FU NCI NIH HHS [CA42471]; NHLBI NIH HHS [HL52094]; NIGMS NIH HHS [GM19556-01A1] NR 29 TC 3 Z9 3 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 FEB PY 2002 VL 26 IS 2 BP 179 EP 190 DI 10.1016/S0145-2126(01)00101-1 PG 12 WC Oncology; Hematology SC Oncology; Hematology GA 520HC UT WOS:000173774400007 PM 11755468 ER PT J AU Ryu, JS Choi, NC Fischman, AJ Lynch, TJ Mathisen, DJ AF Ryu, JS Choi, NC Fischman, AJ Lynch, TJ Mathisen, DJ TI FDG-PET in staging and restaging non-small cell lung cancer after neoadjuvant chemoradiotherapy: correlation with histopathology SO LUNG CANCER LA English DT Article DE FDG-PET; non-small cell lung cancer; chemoradiotherapy; restaging ID POSITRON-EMISSION-TOMOGRAPHY; ONCOLOGY-GROUP; PHASE-II; RADIOTHERAPY; CHEMOTHERAPY; CARCINOMA; SURGERY; RADIATION; TUMOR; CT AB This study was performed to investigate the utility of FDG-PET for: (1) initial staging, and (2) restaging of the primary and mediastinal nodal lesions 2 weeks after the completion of preoperative chemoradiotherapy in patients with stage III non-small cell lung cancer (NSCLC). Twenty-six patients with histologically confirmed stage III NSCLC were accrued to this study from April 1993 to July 1998. They included 21 with stage IIIA (N2) NSCLC who were enrolled into an institutional phase 11 study, and 5 patients with a highly selected subset of stage IIIB disease characterized by the presence of microscopic metastatic disease in contralateral mediastinal lymph nodes who were also treated with preoperative chemoradiotherapy; N3 lesions (n = 3) and minimal T4 lesions. Demographic characteristics included median age 62 years (a range from 47 to 73) and gender ratio of male 15 to female 11. Histologic types of tumor consisted of squamous cell carcinoma 6, adenocarcinoma 11, large cell carcinoma 5, and non-small cell carcinoma 4. All patients had FDG-PET imaging of the chest before the initiation and 2 weeks after completion of preoperative therapy. The FDG-PET images were evaluated qualitatively for uptake at the primary tumor sites and mediastinal lymph nodes. Standard uptake values (SUVs) were also calculated for the primary tumors and all PET findings were correlated with surgical histopathologic data. Preoperative chemoradiotherapy resulted in complete pathologic response in 8 of 26 primary lesions. By qualitative analysis, 96% of these tumors showed level 3 or 4 uptake before preoperative chemoradiotherapy. After chemoradiotherapy, 57% (15/26) of patients showed at least a one level decrease in uptake, and the sensitivity and specificity of FDG-PET for differentiating residual tumor from pathologic complete response were 67% (12/18) and 63% (518). Mean SUV was 14.87+/-7.11 at baseline and decreased to 5.72+/-3.35 after chemoradiotherapy (n = 21, P < 0.00001). When a value of 3.0 was used as the SUV cut-off, sensitivity and specificity were 88 and 67%, respectively. The mean values of visual intensity were 3.87+/-0.35 and 3.8+/-0.51 for patients who achieved pathologic complete response (n = 8) and for those who showed residual cancer after the preoperative therapy (n 18), respectively. The mean SUVs were 16.97+/-8.52 and 14.03+/-6.61 for patients who achieved pathologic complete response (n 6) and for those who showed residual cancer (n = 15) after the preoperative therapy, respectively. Therefore, the degree of FDG uptake before preoperative chemoradiotherapy did not provide predictive value for subsequent tumor response. For mediastinal initial staging, the sensitivity and specificity of FDG-PET were 75 and 90.5%. The sensitivity and specificity of FDG-PET for mediastinal restaging were 58.0 and 93.0%. These results indicate that FDG-PET is useful for monitoring the therapeutic effect of neoadjuvant chemoradiotherapy in patients with stage III NSCLC. For the primary lesions, SUV based analysis has high sensitivity but limited specificity for detecting residual tumor. In contrast, for restaging of mediastinal lymph nodes, FDG-PET is highly specific, but has limited sensitivity. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Fischman, AJ (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med, 32 Fruit St, Boston, MA 02114 USA. NR 26 TC 137 Z9 148 U1 0 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0169-5002 J9 LUNG CANCER-J IASLC JI Lung Cancer PD FEB PY 2002 VL 35 IS 2 BP 179 EP 187 AR PII S0169-5002(01)00332-4 DI 10.1016/S0169-5002(01)00332-4 PG 9 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 525JH UT WOS:000174065400011 PM 11804691 ER PT J AU Wunderbaldinger, P Josephson, L Bremer, C Moore, A Weissleder, R AF Wunderbaldinger, P Josephson, L Bremer, C Moore, A Weissleder, R TI Detection of lymph node metastases by contrast-enhanced MRI in an experimental model SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE lymphatic system; MRI; contrast media; iron oxide; metastases ID SUPERPARAMAGNETIC IRON-OXIDE; LUNG-CARCINOMA; LYMPHOGRAPHY; CELLS; PARTICLES; MELANOMA; COMBIDEX; CANCER; AGENT; PET AB Lymph node size, the accumulation of a nodal lymphotrophic contrast agent (LCDIO), and MRI were compared as methods for detecting nodal metastases in an experimental murine model. Lymph node metastases (B16-F1 melanoma expressing green fluorescent protein (GFP) and C57BL/6 mice) were generated to obtain a wide spectrum of nodes, including normal nodes and nodes bearing micrometastases, small metastases, or large metastases. Nodal uptake of LCDIO was measured using (111)Indium-labeled LCDIO and was found to be lower in micrometastastic nodes (4.20 +/- 1.4%ID/gm) than in normal nodes (8.60 +/- 0.22% ID dose/gram, P < 0.005). Nodal tumor burden was quantified from the amount of GFP present in nodes measured using the Western blot method, and was found to correlate with the decrease of LCDIO uptake. By MRI, nodes bearing small and large metastases contained regions of high signal intensity (SI) that corresponded to the visual pattern of tumor in nodes. Micrometastatic nodes were distinguishable from normal nodes based on a diffuse pattern of inhomogeneous SI. The signal-to-background ratio (SBR) of normal nodes (0.0112 +/- 0.0061) was different from micrometastatic nodes (0.179 +/- 0.080, P < 0.00046) and nodes bearing small metastases (0.723 +/- 0.269, P < 0.00013), with high degrees of significance. Magn Reson Med 47:292-297, 2002. (C) 2002 Wiley-Liss, Inc. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. RP Josephson, L (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Imaging Res, Room 5403,Bldg 149,13th St, Charlestown, MA 02129 USA. NR 28 TC 52 Z9 53 U1 0 U2 6 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD FEB PY 2002 VL 47 IS 2 BP 292 EP 297 DI 10.1002/mrm.10068 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 516WA UT WOS:000173578700010 PM 11810672 ER PT J AU Pinto, BM Maruyama, NC Clark, MM Cruess, DG Park, E Roberts, M AF Pinto, BM Maruyama, NC Clark, MM Cruess, DG Park, E Roberts, M TI Motivation to modify lifestyle risk behaviors in women treated for breast cancer SO MAYO CLINIC PROCEEDINGS LA English DT Article ID SELF-EFFICACY; PHYSICAL-ACTIVITY; DECISIONAL BALANCE; WEIGHT MANAGEMENT; PLANNED BEHAVIOR; EXERCISE; READINESS; OBESITY; PROGRAM; HEALTH AB Objective: To determine motivators of health behaviors (relevant to risk for chronic disease and cancer recurrence) after a cancer diagnosis. Patients and Methods: Eighty-six women who had been treated for breast cancer (mean age, 54.8 years; median time since diagnosis, 23.5 months) participated in this cross-sectional study (1997-1998). Respondents completed a questionnaire assessing overweight or obesity status, dietary fat intake, energy expenditure, motivational readiness for exercise and weight loss, and variables associated with readiness for exercise adoption and weight loss. Results: Forty-six women (54%) were overweight or obese, and 47 women (55%) reported dietary fat intake of 30% or higher. Sixty-one women (72%) were in action! maintenance stages for exercise adoption. A majority believed that diet and exercise can change the course of cancer. Overweight and obese women in the sample were more likely to be in early stages of motivational readiness for weight loss, and they reported significantly lower exercise self-efficacy and lower eating self-efficacy than their nonoverweight peers. However, they endorsed more benefits associated with weight loss than the nonoverweight subgroup. Thirty-three women (39%) reported both a low-fat diet and exercising at recommended levels. Conclusions: Only a minority of respondents reported consuming a diet low in fat and exercising at recommended levels, which suggests a need to improve both diet and exercise behaviors among women treated for breast cancer. Overweight and obese women reported low self-efficacy for exercise and eating, suggesting that interventions should focus on increasing self-efficacy for behavior change. C1 Miriam Hosp, Ctr Behav & Prevent Med, Providence, RI 02903 USA. Brown Univ, Sch Med, Providence, RI 02912 USA. Beth Israel Med Ctr, Dept Consultat Liaison Psychiat & Behav Med, New York, NY 10003 USA. Mayo Clin & Mayo Fdn, Dept Psychiat & Psychol, Rochester, MN 55905 USA. Univ Penn, Dept Psychol, Philadelphia, PA 19104 USA. Massachusetts Gen Hosp, Dept Psychiat & Med, Boston, MA USA. RP Pinto, BM (reprint author), Miriam Hosp, Ctr Behav & Prevent Med, Coro Bldg,Suite 500,1 Hoppin St, Providence, RI 02903 USA. NR 46 TC 56 Z9 57 U1 0 U2 6 PU MAYO CLINIC PROCEEDINGS PI ROCHESTER PA 660 SIEBENS BLDG MAYO CLINIC, ROCHESTER, MN 55905 USA SN 0025-6196 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD FEB PY 2002 VL 77 IS 2 BP 122 EP 129 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 518LK UT WOS:000173669700004 PM 11838645 ER PT J AU Heanue, TA Davis, RJ Rowitch, DH Kispert, A McMahon, AP Mardon, G Tabin, CJ AF Heanue, TA Davis, RJ Rowitch, DH Kispert, A McMahon, AP Mardon, G Tabin, CJ TI Dach1, a vertebrate homologue of Drosophila dachshund, is expressed in the developing eye and ear of both chick and mouse and is regulated independently of Pax and Eya genes SO MECHANISMS OF DEVELOPMENT LA English DT Article DE Dach1; dachshund; eye; ear; Pax6; Pax2; Eya1 ID DEVELOPING EXCRETORY SYSTEM; DEVELOPING NEURAL PLATE; ECTOPIC EYES; MURINE HOMOLOG; MULTIPLE STEPS; THYROID-GLAND; EYELESS GENE; ABSENT; SKI; COMPLEX AB We have cloned a chick homologue of Drosophila dachshund (dac), termed Dach1. Dach1 is the orthologue of mouse and human Dac1 Dach (hereafter referred to as Dach1). We show that chick Dach1 is expressed in a variety of sites during embryonic development, including the eye and ear. Previous work has demonstrated the existence of a functional network and genetic regulatory hierarchy in Drosophila in which eyeless (ey, the Pax6 orthologue), eyes absent (eya), and dac operate together to regulate Drosophila eye development, and that ey regulates the expression of eya and dac. We find that in the developing eye of both chick and mouse, expression domains of Dach1 overlap with those of Pax6, a gene required for normal eye development. Similarly, in the developing ear of both mouse and chick, Dach1 expression overlaps with the expression of another Pax gene, Pax2. In the mouse, Dach1 expression in the developing ear also overlaps with the expression of Eya1 (an cya homologue). Both Pax2 and Eya1 are required for normal ear development. Our expression studies suggest that the Drosophila Pax-eya-dac regulatory network may be evolutionarily conserved such that Pax genes, Eya1, and Dach1 may function together in vertebrates to regulate neural development. To address the further possibility that a regulatory hierarchy exists between Pax, Eya, and Dach genes, we have examined the expression of mouse Dach1 in Pax6, Pax2 and Eya1 mutant backgrounds. Our results indicate that Pax6, Pax2, and Eya1 do not regulate Dach1 expression through a simple linear hierarchy. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Hannover Med Sch, Inst Mol Biol, D-30625 Hannover, Germany. Harvard Univ, Dept Cellular & Mol Biol, Cambridge, MA 02138 USA. RP Tabin, CJ (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. NR 61 TC 40 Z9 41 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD FEB PY 2002 VL 111 IS 1-2 BP 75 EP 87 DI 10.1016/S0925-4773(01)00611-6 PG 13 WC Developmental Biology SC Developmental Biology GA 519PA UT WOS:000173733600007 PM 11804780 ER PT J AU Petersen, LA AF Petersen, LA TI Racial differences in trust - Reaping what we have sown? SO MEDICAL CARE LA English DT Editorial Material ID AFRICAN-AMERICAN CHURCHES; MANAGED CARE; MEDICAL-RESEARCH; HEALTH-CARE; PHYSICIANS; INTERVENTION; ATTITUDES; VIEWS; WHITE; RACE C1 Houston Vet Affairs Med Ctr, Hlth Serv Res & Dev 152, Houston Ctr Qual Care & Utilizat Studies, Hlt Serv Res & Dev Ctr Excellence, Houston, TX 77030 USA. Baylor Coll Med, Sect Hlth Serv Res, Houston, TX 77030 USA. RP Petersen, LA (reprint author), Houston Vet Affairs Med Ctr, Hlth Serv Res & Dev 152, Houston Ctr Qual Care & Utilizat Studies, Hlt Serv Res & Dev Ctr Excellence, 2002 Holcombe Blvd, Houston, TX 77030 USA. NR 31 TC 31 Z9 31 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD FEB PY 2002 VL 40 IS 2 BP 81 EP 84 DI 10.1097/00005650-200202000-00002 PG 4 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 517DB UT WOS:000173594900002 PM 11802080 ER PT J AU Reker, DM Rosen, AK Hoenig, H Berlowitz, DR Laughlin, J Anderson, L Marshall, CR Rittman, M AF Reker, DM Rosen, AK Hoenig, H Berlowitz, DR Laughlin, J Anderson, L Marshall, CR Rittman, M TI The hazards of stroke case selection using administrative data SO MEDICAL CARE LA English DT Article DE stroke; risk adjustment; mortality ID ICD-9-CM; MORTALITY AB BACKGROUND. Administrative data and ICD-9-CM diagnostic codes are frequently used in research efforts to evaluate risk adjusted patient outcomes, particularly mortality. Varying ICD-9-CM sampling algorithms have been used to identify stroke patients. OBJECTIVES. This study evaluates the effects of different sampling strategies (one high sensitivity and one high specificity) on modeling stroke mortality as a performance indicator. RESEARCH DESIGN. Risk adjustment models were developed for two stroke cohorts identified using differing ICD-9-CM algorithms. Standard mortality ratios were calculated in a validation sample as network performance measures and compared across the two stroke samples. SUBJECTS. VHA inpatients with stroke during years 1997 (model development) and 1998 (model validation) were selected from the Patient Treatment File based on cerebrovascular diagnostic codes. MEASURES. Patient mortality within 30 days of admission. RESULTS. The model development and validation for each stroke sampling method produced consistent results: c-statistics 0.74 to 0.75, R-2 0.07 to 0.09, concordance 73% to 74%. However, ranking differences in network performance varied by 5 or more positions for 7 of the 22 patient networks. CONCLUSIONS. These findings highlight a potential problem when using administrative data to assess stroke mortality. In the absence of an agreed upon definition of stroke patients, results of provider profiling will vary depending on the ICD-9 algorithm used. C1 Vet Adm Med Ctr, Kansas City, MO 64128 USA. Univ Kansas, Med Ctr, Ctr Aging, Kansas City, KS 66103 USA. Bedford VA Med Ctr, Bedford, MA USA. Duke Univ, Med Ctr, Durham VA Med Ctr, Durham, NC USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Denver VA Med Ctr, Denver, CO USA. Memphis VA Med Ctr, Memphis, TN USA. Bay Pines VA Med Ctr, Bay Pines, FL USA. Gainesville VA Med Ctr, Gainesville, FL USA. RP Reker, DM (reprint author), Vet Adm Med Ctr, Res 151,4801 Linwood Blvd, Kansas City, MO 64128 USA. FU NIA NIH HHS [P60AG 14635-02, P60AG-11268] NR 12 TC 36 Z9 36 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD FEB PY 2002 VL 40 IS 2 BP 96 EP 104 DI 10.1097/00005650-200202000-00004 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 517DB UT WOS:000173594900004 PM 11802082 ER PT J AU Parchman, ML Pugh, JA Noel, PH Larme, AC AF Parchman, ML Pugh, JA Noel, PH Larme, AC TI Continuity of care, self-management behaviors, and glucose control in patients with type 2 diabetes SO MEDICAL CARE LA English DT Article DE continuity of patient care; diabetes mellitus; self care ID PROVIDER CONTINUITY; REGULAR EXERCISE; ATTITUDES; BARRIERS; IMPACT; TRIAL; SITE AB BACKGROUND. The influence of continuity of care on outcomes of care for patients with type 2 diabetes is poorly understood. OBJECTIVE. To examine the relationships between continuity, glucose control, and advancement through stages of change for self-management behaviors. DESIGN. Prospective cohort study. SETTING. Five community health centers on the Texas-Mexico border. SUBJECTS. A random sample of 256 adults, :18 years of age and older with an established diagnosis of type 2 diabetes. MEASURES. Stage of change for diet and exercise were assessed during two patient interviews, averaging 18.9 months apart. Phlebotomy was performed at each interview to measure glycosolated hemoglobin (HbA,c). Medical records were abstracted for ambulatory care utilization. A continuity score was calculated based on the number of visits and number of providers seen. RESULTS. Patients who advanced one or more stages of change for diet had higher levels of continuity. As continuity improved, the change in HbA,c was smaller. (r = -0.25; P <0.001) This relationship remained significant after controlling for number of visits, months since diagnosis, number of days in the study, duration of diabetes, and advancement in stage of change for diet. Advancement through stage of change for diet explained a significant amount of the variance in the relationship between continuity and HbA(1C) (t test = -11.33; P <0.01). CONCLUSIONS. Continuity of care with a primary care provider is associated with better glucose control among patients with type 2 diabetes. This relationship appears to be mediated by changes in patient behavior regarding diet. C1 Univ Texas, Hlth Sci Ctr, Dept Family & Community Med, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, S Texas Vet Hlth Care Syst,VERDICT, Audie L Murphy Div,VA Hlth Serv Res Ctr Excellenc, San Antonio, TX 78229 USA. RP Parchman, ML (reprint author), Univ Texas, Hlth Sci Ctr, Dept Family & Community Med, 7703 Floyd Curl Dr,MSC 7795, San Antonio, TX 78229 USA. OI Pugh, Jacqueline/0000-0003-4933-141X; Parchman, Michael/0000-0001-7129-2889 FU PHS HHS [H507397] NR 32 TC 86 Z9 90 U1 3 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD FEB PY 2002 VL 40 IS 2 BP 137 EP 144 DI 10.1097/00005650-200202000-00008 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 517DB UT WOS:000173594900008 PM 11802086 ER PT J AU Meininger, G Hadigan, C Laposata, M Brown, J Rabe, J Louca, J Aliabadi, N Grinspoon, S AF Meininger, G Hadigan, C Laposata, M Brown, J Rabe, J Louca, J Aliabadi, N Grinspoon, S TI Elevated concentrations of free fatty acids are associated with increased insulin response to standard glucose challenge in human immunodeficiency virus-infected subjects with fat redistribution SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID DEPENDENT DIABETES-MELLITUS; PERIPHERAL LIPODYSTROPHY; FASTING HYPERINSULINEMIA; BODY-COMPOSITION; RESISTANCE; HYPERLIPIDEMIA; LIPOLYSIS; OBESITY; PATHOGENESIS; INHIBITION AB Fat redistribution, defined by both increased abdominal visceral fat and/or decreased abdominal, extremity, and facial subcutaneous fat, is increasingly recognized among human immunodeficiency virus (HIV)-infected patients treated with combination antiretroviral therapy. Fat redistribution in this population is associated with insulin resistance and dyslipidemia and is often referred to as the HIV lipodystrophy syndrome (LIPO). Fatty acids are known to modulate insulin resistance in other disease states, but a comprehensive evaluation of fatty acids has not been undertaken among HIV-infected patients with fat redistribution. In this study, we investigated fatty acid concentrations in 64 HIV-infected individuals (45 men and 19 women) with evidence of fat redistribution (LIPO) in comparison to 30 HIV-infected individuals (20 men and 10 women) without evidence of fat redistribution (NONLIPO) and 32 HIV-negative healthy control subjects (C) (21 males and 11 females) of similar age and body mass index (BMI). Glucose, insulin, and free fatty acid (FFA) levels were measured in response to a 75-g oral glucose tolerance test (OGTT) in the LIPO, NONLIPO, and C subjects. In addition, fasting lipids were obtained, and body composition was determined by anthropometric measurements and dual-energy x-ray absorptiometry (DXA). Fasting FFA concentrations were significantly increased in the LIPO group as compared with NONLIPO and C subjects (0.74 +/- 0.03 v 0.60 +/- 0.04 [mean +/- SEM] mmol/L, P =.002, LIPO v NONLIPO; 0.74 +/- 0.03 v 0.59 +/-0.03 mmol/L, P =.001, LIPO v C). In contrast, fasting FFA concentrations were not increased in the NONLIPO group (0.60 +/- 0.04 v 0.59 +/- 0.03, P =.909, NONLIPO v C). Similarly, fasting triglycerides and 120-minute OGTT FFA were significantly increased in the LIPO group as compared with the NONLIPO and C group. FFA decreased in HIV-infected LIPO, NONLIPO, and C subjects in response to OGTT, but the 120-minute FFA concentrations remained significantly elevated in LIPO patients compared with NONLIPO and C subjects. In a multivariate regression model of LIPO patients, fasting FFA (P =.027) was a strong independent predictor of insulin area under the curve (AUC), controlling for age, BMI, gender, and body composition (r(2) for model =.31). No differences were observed in FFA concentrations in the LIPO group in an analysis based on current protease inhibitor (PI) use. These data suggest that FFA concentrations are increased in HIV-infected patients with fat redistribution. Increased fasting concentrations of fatty acids are associated with abnormal insulin responses to standard glucose challenge in HIV-infected patients with fat redistribution. Further studies are necessary to determine the mechanism of increased fatty acid concentrations and the role played by increased FFA in mediating insulin resistance in this population. Copyright (C) 2002 by W.B. Saunders Company. C1 Massachusetts Gen Hosp, Dept Pathol, Neuroendocrine Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Combined Program Pediat Gastroenterol & Nutr, Boston, MA 02114 USA. Childrens Hosp, Boston, MA 02115 USA. RP Grinspoon, S (reprint author), Massachusetts Gen Hosp, Dept Pathol, Neuroendocrine Unit, Bulfinch 457B, Boston, MA 02114 USA. FU NCRR NIH HHS [MO1-RR01066]; NIDDK NIH HHS [K23-DK02844, R01-DK59535] NR 33 TC 57 Z9 57 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 FEB PY 2002 VL 51 IS 2 BP 260 EP 266 DI 10.1053/meta.2002.29999 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 519RG UT WOS:000173738800022 PM 11833059 ER PT J AU Brodsky, AS Silver, PA AF Brodsky, AS Silver, PA TI Identifying proteins that affect mRNA localization in living cells SO METHODS LA English DT Article ID ASH1 MESSENGER-RNA; STRUCTURAL ELEMENTS; NUCLEAR EXPORT; BUDDING YEAST; IN-VIVO; REGION AB Messenger RNA transport has emerged as a significant mechanism for regulating gene expression. Many of the protein factors affecting RNA transport remain unknown. The emergence of green fluorescent protein (GFP) fluorescence microscopy allows imaging in living cells and an increased understanding of in vivo molecular transport. GFP imaging is now applied to RNA transport by engineering RNA hairpins into the RNA of interest and observing fluorescence from GFP fused to an RNA-binding protein that recognizes the hairpins. In yeast, different genetic backgrounds can be tested to identify various proteins that affect RNA transport and localization. The technology also allows the swapping of different regions of the RNA to determine the cis requirements for transport. GFP RNA imaging opens many possibilities to examine RNA transport in real time in a variety of different organisms. (C) 2002 Elsevier Science (USA). All rights reserved. C1 Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Silver, PA (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. NR 16 TC 21 Z9 22 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD FEB PY 2002 VL 26 IS 2 BP 151 EP 155 AR PII S1046-2023(02)00017-8 DI 10.1016/S1046-2023(02)00017-8 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 558MP UT WOS:000175971400007 PM 12054891 ER PT J AU Chadee, DN Yuasa, T Kyriakis, JM AF Chadee, DN Yuasa, T Kyriakis, JM TI Direct activation of mitogen-activated protein kinase kinase kinase MEKK1 by the Ste20p homologue GCK and the adapter protein TRAF2 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID GERMINAL CENTER KINASE; T-CELL ACTIVATION; N-TERMINAL KINASE; SIGNAL-TRANSDUCTION; KAPPA-B; JNK; PATHWAY; DOMAIN; APOPTOSIS; PHOSPHORYLATION AB Mitogen-activated protein kinase (MAPK) pathways coordinate critical cellular responses to mitogens, stresses, and developmental cues. The coupling of MAPK kinase kinase (MAP3K) --> MAPK kinase (MEK) --> MAPK core pathways to cell surface receptors remains poorly understood. Recombinant forms of MAP3K MEK kinase I (MEKK1) interact in vivo and in vitro with the STE20 protein homologue germinal center kinase (GCK), and both GCK and MEKK1 associate in vivo with the adapter protein tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2). These interactions may couple TNF receptors to the SAPK/JNK family of MAPKs; however, a molecular mechanism by which these proteins might collaborate to recruit the SAPKs/JNKs has remained elusive. Here we show that endogenous GCK and MEKK1 associate in vivo. In addition, we have developed an in vitro assay system with which we demonstrate that purified, active GCK and TRAF2 activate MEKK1. The RING domain of TRAF2 is necessary for optimal in vitro activation of MEKK1, but the kinase domain of GCK is not. Autophosphorylation within the MEKK1 kinase domain activation loop is required for activation, Forced oligomerization also activates MEKK1, and GCK elicits enhanced oligomerization of coexpressed MEKK1 in vivo. These results represent the first activation of MEKK1 in vitro using purified proteins and suggest a mechanism for MEKK1 activation involving induced oligomerization and consequent auto phosphorylation mediated by upstream proteins. C1 Massachusetts Gen Hosp, Med Serv, Diabet Res Lab, Charlestown, MA USA. Harvard Univ, Sch Med, Dept Med, Charlestown, MA USA. Univ Tokyo, Grad Sch Arts & Sci, Dept Life Sci, Tokyo 1130033, Japan. RP Kyriakis, JM (reprint author), Massachusetts Gen Hosp East, Diabet Res Lab, 149 13th St, Charlestown, MA 02129 USA. RI Yuasa, Takashi/B-2595-2010 FU NIGMS NIH HHS [GM46577, R01 GM046577] NR 49 TC 61 Z9 66 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 FEB PY 2002 VL 22 IS 3 BP 737 EP 749 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 511FE UT WOS:000173253300004 PM 11784851 ER PT J AU Ueki, K Fruman, DA Brachmann, SM Tseng, YH Cantley, LC Kahn, CR AF Ueki, K Fruman, DA Brachmann, SM Tseng, YH Cantley, LC Kahn, CR TI Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID INSULIN-RECEPTOR SUBSTRATE-1; FORKHEAD TRANSCRIPTION FACTOR; INDUCED GLUCOSE-TRANSPORT; PROTEIN-KINASE-B; PHOSPHATIDYLINOSITOL 3-KINASE; CAENORHABDITIS-ELEGANS; NEGATIVE REGULATION; P85-ALPHA SUBUNIT; MICE LACKING; PC12 CELLS AB Class Ia phosphoinositide (PI) 3-kinase is a central component in growth factor signaling and is comprised of a p110 catalytic subunit and a regulatory subunit, the most common family of which is derived from the p85alpha gene (Pik3r1). Optimal signaling through the PI 3-kinase pathway depends on a critical molecular balance between the regulatory and catalytic subunits. In wild-type cells, the p85 subunit is more abundant than p110, leading to competition between the p85 monomer and the p85-p110 dimer and ineffective signaling. Heterozygous disruption of Pik3r1 results in increased Akt activity and decreased apoptosis by insulin-like growth factor 1 (IGF-1) through up-regulated phosphatidylinositol (3,4,5)-triphosphate production. Complete depletion of p85alpha, on the other hand, results in significantly increased apoptosis due to reduced PI 3-kinase-dependent signaling. Thus, a reduction in p85alpha represents a novel therapeutic target for enhancing IGF-1/insulin signaling, prolongation of cell survival, and protection against apoptosis. C1 Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02215 USA. Free Univ Berlin, Inst Biochem, D-1000 Berlin, Germany. RP Kahn, CR (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. RI Cantley, Lewis/D-1800-2014 OI Cantley, Lewis/0000-0002-1298-7653 FU NIDDK NIH HHS [DK33201, DK38434, DK55545, R01 DK033201, R01 DK055545]; NIGMS NIH HHS [GM41890, R01 GM041890, R37 GM041890] NR 56 TC 174 Z9 182 U1 0 U2 7 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 FEB PY 2002 VL 22 IS 3 BP 965 EP 977 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 511FE UT WOS:000173253300024 PM 11784871 ER PT J AU Li, XY Bu, X Lu, BF Avraham, H Flavell, RA Lim, B AF Li, XY Bu, X Lu, BF Avraham, H Flavell, RA Lim, B TI The hematopoiesis-specific GTP-binding protein RhoH is GTPase deficient and modulates activities of other Rho GTPases by an inhibitory function SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID GDP-DISSOCIATION INHIBITOR; NF-KAPPA-B; CELL-CYCLE PROGRESSION; ACTIN STRESS FIBERS; EPSTEIN-BARR-VIRUS; C-JUN; ACTIVATING-PROTEIN; SIGNALING PATHWAY; CRYSTAL-STRUCTURE; CDC42 GTPASES AB The Rho subfamily of small GTP-binding proteins mediates many fundamental cellular functions. The commonly studied members (Rho, Rac, and CDC42) regulate actin reorganization, affecting diverse cellular responses, including adhesion, cytokinesis, and motility. Another major function of the Rho GTPases is their role in regulating transcriptional factors and nuclear signaling. RhoH is encoded by a hematopoiesis-specific Rho-related gene recently identified in a fusion transcript with bc16 in lymphoma cell lines. Significantly, translocations and a high frequency of RhoH mutation have been detected in primary lymphoma cells. We show here that RhoH functions differently from other Rho GTPases. RhoH exerts no significant effect on actin reorganization. However, RhoH is a potent inhibitor of the activation of NFkappaB and p38 by other Rho GTPases. This property, together with the differential expression of RhoH in the Th1 subset of T cells, suggests a role for RhoH in the functional differentiation of T cells. RhoH has different amino acids in two highly conserved residues critical for GTPase activity. Consequently, RhoH is GTPase deficient, remaining in a GTP-bound activated state without cycling. Reduction of RhoH levels in T cells augments the response to Rac activation. Furthermore, RhoH is dramatically down regulated after phorbol myristate acetate treatment and in Th1 cells after activation by anti-CD3. Hence, a mechanism for regulation of RhoH function is likely to exist at the transcriptional level. The inhibitory function of RhoH supports a model in which Rho GTPases with opposing functions may compete to modulate the final outcome of a particular GTPase-activated pathway. C1 Harvard Univ, Sch Med,Harvard Inst Med, Beth Deaconess Med Ctr, Canc Biol Program,Div Hematol & Oncol, Boston, MA 02115 USA. Yale Univ, Sch Med, Immunobiol Sect, New Haven, CT 06520 USA. Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06520 USA. RP Lim, B (reprint author), Harvard Univ, Sch Med,Harvard Inst Med, Beth Deaconess Med Ctr, Canc Biol Program,Div Hematol & Oncol, HIM 955 77 Ave Louis Pasteur, Boston, MA 02115 USA. FU NIDDK NIH HHS [R01DK-47535, R01DK-54417] NR 66 TC 85 Z9 90 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 FEB PY 2002 VL 22 IS 4 BP 1158 EP 1171 DI 10.1128/MCB.22.4.1158-1171.2002 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 514JL UT WOS:000173435600017 PM 11809807 ER PT J AU Kim, TJ Cariappa, A Iacomini, J Tang, M Shih, S Bernards, A Jacks, T Pillai, S AF Kim, TJ Cariappa, A Iacomini, J Tang, M Shih, S Bernards, A Jacks, T Pillai, S TI Defective proliferative responses in B lymphocytes and thymocytes that lack neurofibromin SO MOLECULAR IMMUNOLOGY LA English DT Article DE B lymphocytes; signal transduction; cellular activation ID DROSOPHILA NF1; GENE; ACTIVATION; CELLS; GAP; HAPLOINSUFFICIENCY; SELECTION; PROTEINS; RECEPTOR; ENCODES AB Nf1(-/-) fetal liver cells were used to reconstitute B and T cells in Rag-1(-/-) mice. Lymphocyte development was largely unimpaired in the absence of neurofibromin. However antigen-receptor induced proliferation was defective in neurofibromin deficient peripheral B cells and CD4(+) single positive thymocytes. In contrast to its role as a negative regulator of proliferation in many other cell types, neurofibromin may be a positive regulator of lymphocyte proliferation. Peripheral B cells exhibited circumscribed defects in anti-IgM induced protein tyrosine phosphorylation, which may contribute to the unexpected proliferative defect seen in these cells. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Charlestown, MA 02129 USA. MIT, Canc Res Ctr, Cambridge, MA 02139 USA. MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA. RP Pillai, S (reprint author), Massachusetts Gen Hosp, Ctr Canc, Bldg 149,13th St,Charlestown Navy Yard, Boston, MA 02129 USA. RI Kim, Tae Jin/D-6544-2011 OI Kim, Tae Jin/0000-0001-9802-0568 FU NCI NIH HHS [CA 69618]; NIAID NIH HHS [AI 33507] NR 26 TC 6 Z9 6 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD FEB PY 2002 VL 38 IS 9 BP 701 EP 708 AR PII S0161-5890(01)00101-8 DI 10.1016/S0161-5890(01)00101-8 PG 8 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 528WD UT WOS:000174266500006 PM 11858825 ER PT J AU Weber, G Shendure, J Tanenbaum, DM Church, GM Meyerson, M AF Weber, G Shendure, J Tanenbaum, DM Church, GM Meyerson, M TI Identification of foreign gene sequences by transcript filtering against the human genome SO NATURE GENETICS LA English DT Article ID DNA-SEQUENCES; PATHOGENS; SEARCH; TAGS AB We have developed a computational subtraction approach to detect microbial causes for putative infectious diseases by filtering a set of human tissue-derived sequences against the human genome. We demonstrate the potential of this method by identifying sequences from known pathogens in established expressed-sequence tag libraries. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Hosp, Decis Syst Grp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Meyerson, M (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. EM matthew_meyerson@dfci.harvard.edu RI Meyerson, Matthew/E-7123-2012; OI Weber, Griffin/0000-0002-2597-881X NR 14 TC 47 Z9 47 U1 0 U2 4 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 FEB PY 2002 VL 30 IS 2 BP 141 EP 142 DI 10.1038/ng818 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 519CY UT WOS:000173708700009 PM 11788827 ER PT J AU Xu, XL Meiler, SE Zhong, TP Mohideen, M Crossley, DA Burggren, WW Fishman, MC AF Xu, XL Meiler, SE Zhong, TP Mohideen, M Crossley, DA Burggren, WW Fishman, MC TI Cardiomyopathy in zebrafish due to mutation in an alternatively spliced exon of titin SO NATURE GENETICS LA English DT Article ID DILATED CARDIOMYOPATHY; CARDIAC-MUSCLE; DANIO-RERIO; GENE; DISRUPTION; EXPRESSION; EMBRYOS; SYSTEM AB The zebrafish embryo is transparent and can tolerate absence of blood flow because its oxygen is delivered by diffusion rather than by the cardiovascular system(1). It is therefore possible to attribute cardiac failure directly to particular genes by ruling out the possibility that it is due to a secondary effect of hypoxia. We focus here on pickwick(m171) (pik(m171)), a recessive lethal mutation discovered in a large-scale genetic screen(2). There are three other alleles in the pik complementation group with this phenotype (pik(m242), pik(m740), pik(m186); ref. 3) and one allele (pik(mVO62H)) with additional skeletal paralysis(4). The pik heart develops normally but is poorly contractile from the first beat. Aside from the edema that inevitably accompanies cardiac dysfunction, development is normal during the first three days. We show by positional cloning that the 'causative' mutation is in an alternatively-spliced exon of the gene (ttn) encoding Titin. Titin is the biggest known protein and spans the half-sarcomere from Z-disc to M-line in heart and skeletal muscles. It has been proposed to provide a scaffold for the assembly of thick and thin filaments(6) and to provide elastic recoil engendered by stretch during diastole(7). We found that nascent myofibrils form in pik mutants, but normal sarcomeres are absent. Mutant cells transplanted to wildtype hearts remain thin and bulge outwards as individual cell aneurysms without affecting nearby wildtype cardiomyocytes, indicating that the contractile deficiency is cell-autonomous. Absence of Titin function thus results in blockage of sarcomere assembly and causes a functional disorder resembling human dilated cardiomyopathies, one form of which is described in another paper in this issue(8). C1 Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. Univ Calif Irvine, Dept Biol Sci, Irvine, CA 92697 USA. Univ N Texas, Dept Biol Sci, Denton, TX 76203 USA. RP Fishman, MC (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. RI Burggren, Warren/A-1561-2016 OI Burggren, Warren/0000-0001-8023-420X NR 29 TC 168 Z9 174 U1 3 U2 16 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD FEB PY 2002 VL 30 IS 2 BP 205 EP 209 DI 10.1038/ng816 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 519CY UT WOS:000173708700023 PM 11788825 ER PT J AU Bolay, H Reuter, U Dunn, AK Huang, ZH Boas, DA Moskowitz, MA AF Bolay, H Reuter, U Dunn, AK Huang, ZH Boas, DA Moskowitz, MA TI Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model SO NATURE MEDICINE LA English DT Article ID GENE-RELATED PEPTIDE; CEREBRAL BLOOD-FLOW; VASCULAR HEAD PAIN; SPREADING DEPRESSION; SUBSTANCE-P; DURA-MATER; POSSIBLE PATHWAY; RAT; STIMULATION; NEURONS AB Although the trigeminal nerve innervates the meninges and participates in the genesis of migraine headaches, triggering mechanisms remain controversial and poorly understood. Here we establish a link between migraine aura and headache by demonstrating that cortical spreading depression, implicated in migraine visual aura, activates trigeminovascular afferents and evokes a series of cortical meningeal and brainstem events consistent with the development of headache. Cortical spreading depression caused long-lasting blood-flow enhancement selectively within the middle meningeal artery dependent upon trigeminal and parasympathetic activation, and plasma protein leakage within the dura mater in part by a neurokinin-1-receptor mechanism. Our findings provide a neural mechanism by which extracerebral cephalic blood flow couples to brain events; this mechanism explains vasodilation during headache and links intense neurometabolic brain activity with the transmission of headache pain by the trigeminal nerve. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Stroke & Neurovasc Regulat Lab, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,NMR Ctr, Boston, MA USA. RP Moskowitz, MA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Stroke & Neurovasc Regulat Lab, Boston, MA 02114 USA. RI Moskowitz, Michael/D-9916-2011; Dunn, Andrew/I-9527-2014 FU NINDS NIH HHS [K25 NS41291, 1R29NS38842, 2P01 NS10828] NR 45 TC 593 Z9 615 U1 7 U2 45 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD FEB PY 2002 VL 8 IS 2 BP 136 EP 142 DI 10.1038/nm0202-136 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 517FN UT WOS:000173600600022 PM 11821897 ER PT J AU Tong, JY Hannan, F Zhu, YH Bernards, A Zhong, Y AF Tong, JY Hannan, F Zhu, YH Bernards, A Zhong, Y TI Neurofibromin regulates G protein-stimulated adenylyl cyclase activity SO NATURE NEUROSCIENCE LA English DT Article ID DROSOPHILA NF1; TYPE-1; GENE; MODEL C1 Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. SUNY Stony Brook, Dept Neurobiol & Behav, Stony Brook, NY 11790 USA. Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. RP Zhong, Y (reprint author), Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA. OI Zhong, Yi/0000-0001-7810-9899 FU NINDS NIH HHS [NS34779] NR 14 TC 123 Z9 130 U1 1 U2 3 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD FEB PY 2002 VL 5 IS 2 BP 95 EP 96 DI 10.1038/792 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 516NB UT WOS:000173558400007 PM 11788835 ER PT J AU Sharpe, AH Freeman, GJ AF Sharpe, AH Freeman, GJ TI The B7-CD28 superfamily SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID T-CELL ACTIVATION; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MAJOR HISTOCOMPATIBILITY COMPLEX; MAMMARY EPITHELIAL-CELLS; ANTIGEN-PRESENTING CELLS; FAT GLOBULE-MEMBRANE; INDUCIBLE COSTIMULATOR; CO-STIMULATION; MOLECULE ICOS; CTLA-4-MEDIATED INHIBITION AB The B7-1/B7-2-CD28/CTLA-4 pathway is crucial in regulating T-cell activation and tolerance. New B7 and CD28 molecules have recently been discovered and new pathways have been delineated that seem to be important for regulating the responses of previously activated T cells. Several B7 homologues are expressed on cells other than professional antigen-presenting cells, indicating new mechanisms for regulating T-cell responses in peripheral tissues. Some B7 homologues have unknown receptors, indicating that other immunoregulatory pathways remain to be described. Here, we summarize our current understanding of the new members of the B7 and CD28 families, and discuss their therapeutic potential. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol,Immunol Res Div, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Sharpe, AH (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol,Immunol Res Div, 221 Longwood Ave, Boston, MA 02115 USA. NR 118 TC 962 Z9 1047 U1 5 U2 28 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 FEB PY 2002 VL 2 IS 2 BP 116 EP 126 DI 10.1038/nri727 PG 11 WC Immunology SC Immunology GA 635KQ UT WOS:000180398400025 PM 11910893 ER PT J AU Stroud, JC Lopez-Rodriguez, C Rao, A Chen, L AF Stroud, JC Lopez-Rodriguez, C Rao, A Chen, L TI Structure of a TonEBP-DNA complex reveals DNA encircled by a transcription factor SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID NF-KAPPA-B; TONICITY-RESPONSIVE ENHANCER; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURE; BINDING PROTEIN; GENE; HOMODIMER; IDENTIFICATION; FAMILY; REGION AB Tonicity-responsive enhancer binding protein (TonEBP), also known as NFAT5, is a unique member of the NFAT family of transcription factors that regulates gene expression induced by osmotic stress in mammalian cells. Unlike monomeric members of the NFAT family, TonEBP exists as a homodimer and binds asymmetric TonE DNA sites; furthermore, the affinity of TonEBP for DNA is much lower than that of other NFAT proteins. How TonEBP recognizes the TonE site and regulates the activation of hypertonicity response genes has not been clear. Here we show that TonEBP adopts a NF-kappaB-like structure upon binding to DNA, providing a direct structural link between the NFAT and NF-kappaB family of transcription factors. We also show that TonEBP completely encircles its DNA target and present biochemical evidence that the DNA encirclement may lead to increased kinetic stability of the TonEBP-DNA complex. Thus, the list of proteins that bind DNA by encirclement is now expanded to include sequence-specific transcription factors. C1 Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Chen, L (reprint author), Univ Colorado, Dept Chem & Biochem, Campus Box 215, Boulder, CO 80309 USA. RI Chen, Lin/A-3392-2008; Stroud, James/B-3230-2012; Lopez-Rodriguez, C/G-4482-2014 OI Stroud, James/0000-0003-0850-4812; Lopez-Rodriguez, C/0000-0002-2311-2406 FU NIAID NIH HHS [R21 AI049905] NR 30 TC 70 Z9 72 U1 0 U2 2 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1072-8368 J9 NAT STRUCT BIOL JI Nat. Struct. Biol. PD FEB PY 2002 VL 9 IS 2 BP 90 EP 94 DI 10.1038/nsb749 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 516PH UT WOS:000173562000009 PM 11780147 ER PT J AU Brown, EN Barbieri, R Ventura, V Kass, RE Frank, LM AF Brown, EN Barbieri, R Ventura, V Kass, RE Frank, LM TI The time-rescaling theorem and its application to neural spike train data analysis SO NEURAL COMPUTATION LA English DT Article ID POINT-PROCESSES; NEURONAL-ACTIVITY; CELLS; HIPPOCAMPUS; MODELS; RAT; MAP AB Measuring agreement between a statistical model and a spike train data series, that is, evaluating goodness of fit, is crucial for establishing the model's validity prior to using it to make inferences about a particular neural system. Assessing goodness-of-fit is a challenging problem for point process neural spike train models, especially for histogram-based models such as perstimulus time histograms (PSTH) and rate functions estimated by spike train smoothing. The time-rescaling theorem is a well-known result in probability theory, which states that any point process with an integrable conditional intensity function maybe transformed into a Poisson process with unit rate. We describe how the theorem may be used to develop goodness-of-fit tests for both parametric and histogram-based point process models of neural spike trains. We apply these tests in two examples: a comparison of PSTH, inhomogeneous Poisson, and inhomogeneous Markov interval models of neural spike trains from the supplementary eye field of a macque monkey and a comparison of temporal and spatial smoothers, inhomogeneous Poisson, inhomogeneous gamma, and inhomogeneous inverse gaussian models of rat hippocampal place cell spiking activity. To help make the logic behind the time-rescaling theorem more accessible to researchers in neuroscience, we present a proof using only elementary probability theory arguments. We also show how the theorem may be used to simulate a general point process model of a spike train. Our paradigm makes it possible to compare parametric and histogram-based neural spike train models directly. These results suggest that the time-rescaling theorem can be a valuable toot for neural spike train data analysis. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neurosci Stat Res Lab, Boston, MA 02114 USA. MIT, Harvard Med Sch, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. Carnegie Mellon Univ, Dept Stat, Ctr Neural Basis Cognit, Pittsburgh, PA 15213 USA. RP Brown, EN (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neurosci Stat Res Lab, Boston, MA 02114 USA. OI Barbieri, Riccardo/0000-0001-9381-3833; Frank, Loren/0000-0002-1752-5677 FU NCI NIH HHS [CA54652]; NIMH NIH HHS [MH59733, MH61637] NR 35 TC 236 Z9 237 U1 0 U2 11 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0899-7667 J9 NEURAL COMPUT JI Neural Comput. PD FEB PY 2002 VL 14 IS 2 BP 325 EP 346 DI 10.1162/08997660252741149 PG 22 WC Computer Science, Artificial Intelligence SC Computer Science GA 512JN UT WOS:000173321400003 PM 11802915 ER PT J AU Bates, B Hirt, L Thomas, SS Akbarian, S Le, D Amin-Hanjani, S Whalen, M Jaenisch, R Moskowitz, MA AF Bates, B Hirt, L Thomas, SS Akbarian, S Le, D Amin-Hanjani, S Whalen, M Jaenisch, R Moskowitz, MA TI Neurotrophin-3 promotes cell death induced in cerebral ischemia, oxygen-glucose deprivation, and oxidative stress: Possible involvement of oxygen free radicals SO NEUROBIOLOGY OF DISEASE LA English DT Article ID NERVE GROWTH-FACTOR; NITRIC-OXIDE SYNTHASE; SUPEROXIDE-DISMUTASE DEFICIENCY; TRANSIENT FOREBRAIN ISCHEMIA; STRIATAL CHOLINERGIC NEURONS; AFFINITY NGF RECEPTOR; REDUCES INFARCT SIZE; MESSENGER-RNA; HIPPOCAMPAL-NEURONS; RAT-BRAIN AB To explore the role of neurotrophin-3 (NT-3) during cerebral ischemia, NT-3-deficient brains were subjected to transient focal ischemia. Conditional mutant brains produced undetectable amounts of NT-3 mRNA, whereas the expression of the neurotrophin, BDNF, the NT-3 receptor, TrkC, and the nonselective, low-affinity neurotrophin receptor p75NTR, were comparable to wild-type. Baseline absolute blood flow, vascular and neuroanatomical features, as well as physiological measurements were also indistinguishable from wild-type. Interestingly, the absence of NT-3 led to a significantly decreased infarct volume 23 h after middle cerebral artery occlusion. Consistent with this, the addition of NT-3 to primary cortical cell cultures exacerbated neuronal death caused by oxygen-glucose deprivation. Coincubation with the oxygen free radical chelator, trolox, diminished potentiation of neuronal death. NT-3 also enhanced neuronal cell death and the production of reactive oxygen species caused by oxidative damage inducing agents. We conclude that endogenous NT-3 enhanced neuronal injury during acute stroke, possible by increasing oxygen-radical mediated cell death. (C) 2002 Elsevier Science (USA). C1 Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. Harvard Univ, Sch Med, Stroke & Neurovasc Regulat Lab, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. MIT, Dept Biol, Cambridge, MA USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Genet Inst Inc, 35 Cambridge Pk Dr, Cambridge, MA 02140 USA. EM bbates@genetics.com RI Moskowitz, Michael/D-9916-2011; Hirt, Lorenz/G-3553-2010 OI Hirt, Lorenz/0000-0002-2921-5000 FU NCI NIH HHS [5-R350CA44339]; NINDS NIH HHS [5-P50NS10828] NR 75 TC 23 Z9 27 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD FEB PY 2002 VL 9 IS 1 BP 24 EP 37 DI 10.1006/nbdi.2001.0458 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 523UZ UT WOS:000173976800003 PM 11848682 ER PT J AU Romero, JM Schaefer, PW Grant, PE Becerra, L Gonzalez, RG AF Romero, JM Schaefer, PW Grant, PE Becerra, L Gonzalez, RG TI Diffusion MR imaging of acute ischemic stroke SO NEUROIMAGING CLINICS OF NORTH AMERICA LA English DT Article ID CEREBRAL BLOOD-FLOW; HIGH-RESOLUTION MEASUREMENT; CREUTZFELDT-JAKOB-DISEASE; EXPERIMENTAL BRAIN-TUMORS; TRACER BOLUS PASSAGES; MAGNETIC-RESONANCE; WEIGHTED MR; TIME-COURSE; RAT-BRAIN; MULTIPLE-SCLEROSIS AB Diffusion-weighted MR imaging has demonstrated advantages over conventional MR techniques. It has much higher sensitivity for acute ischemic stroke and can differentiate acute stroke from other pathologies. Diffusion-weighted MR in combination with perfusion MR yields unique information about the evolution of stroke. C1 Massachusetts Gen Hosp, Neuroradiol Div, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Gonzalez, RG (reprint author), Massachusetts Gen Hosp, Neuroradiol Div, GRB 285,75 Fruit St, Boston, MA 02114 USA. NR 76 TC 18 Z9 22 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 1052-5149 J9 NEUROIMAG CLIN N AM JI Neuroimaging Clin. N. Am. PD FEB PY 2002 VL 12 IS 1 BP 35 EP + DI 10.1016/S1052-5149(03)00069-8 PG 20 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 540LC UT WOS:000174929600004 PM 11998252 ER PT J AU Corbitt, J Hagerty, T Fernandez, E Morgan, WW Strong, R AF Corbitt, J Hagerty, T Fernandez, E Morgan, WW Strong, R TI Transcriptional and post-transcriptional regulation of tyrosine hydroxylase messenger RNA in PC12 cells during persistent stimulation by VIP and PACAP38: differential regulation by protein kinase A and protein kinase C-dependent pathways SO NEUROPEPTIDES LA English DT Article ID CYCLASE-ACTIVATING POLYPEPTIDE; SUPERIOR CERVICAL-GANGLION; ADRENAL CHROMAFFIN CELLS; GENE-EXPRESSION; SHORT-TERM; COLD STRESS; LONG-TERM; NERVOUS-SYSTEM; PC-12 CELLS; I RECEPTORS AB VIP and PACAP38 are closely related peptides that are released in the adrenal gland and sympathetic ganglia and regulate catecholamine synthesis and release. We used PC12 cells as a model system to examine receptor and second messenger pathways by which each peptide stimulates transcriptional and post-transcriptional mechanisms that regulate the level of the mRNA for tyrosine hydroxylase (TH), the rate-limiting enzymatic step in catecholamine synthesis. Concentration-response studies revealed that PACAP38 had both greater efficacy and potency than VIP. The specific PAC1 receptor antagonist PACAP[6-38] blocked the effects of each peptide on TH mRNA content while the PACAP/VIP type II receptor antagonist (N-AC-Tyr(1)-D-Phe(2))-GRF-(1-29)-NH2 was without effect. At equipotent concentrations, each peptide stimulated a transient increase in TH gene transcription lasting less than 3 h. Continuous VIP treatment stimulated a transient increase in TH mRNA lasting less than 24 h. In contrast, continuous exposure to PACAP38 stimulated a stable increase in TH mRNA that persisted for 2 days in the absence of elevated transcription, pointing to different post-transcriptional effects of the two peptides. PACAP38 alone had no effect on the magnitude of TH gene transcription or TH mRNA in A126-1B2 PKA-deficient PC12 cells. However, when combined with dexamethasone, PACAP38 produced a synergistic increase in TH mRNA in the absence of PACAP38-stimulated TH gene transcription. In contrast, VIP had no effect on either TH mRNA content or TH gene transcription in this model. PACAP38, but not VIP, stimulated PKC activity. Calphostin C antagonized the effect of PACAP38 on the persistent post-transcriptional elevation in TH mRNA. Thus, the results support the conclusion that VIP and PACAP38 each stimulate PAC1 receptors to increase TH gene transcription through a PKA-controlled pathway, but their divergent post-transcriptional effects result at least partly from differing abilities to stimulate PKC. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Audie L Murphy Mem Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Pharmacol, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78284 USA. RP Strong, R (reprint author), Audie L Murphy Mem Vet Adm Med Ctr, Geriat Res Educ & Clin Ctr 182, 7400 Merton Minter Blvd, San Antonio, TX 78284 USA. FU NIDDK NIH HHS [DK 52543] NR 58 TC 23 Z9 23 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 0143-4179 J9 NEUROPEPTIDES JI Neuropeptides PD FEB PY 2002 VL 36 IS 1 BP 34 EP 45 DI 10.1054/npep.2002.0885 PG 12 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 580NR UT WOS:000177241100005 PM 12147212 ER PT J AU Kumar, A Mintz, J Bilker, W Gottlieb, G AF Kumar, A Mintz, J Bilker, W Gottlieb, G TI Autonomous neurobiological pathways to late-life major depressive disorder: Clinical and pathophysiological implications SO NEUROPSYCHOPHARMACOLOGY LA English DT Article; Proceedings Paper CT 30th Annual Meeting of the Society-for-Neuroscience CY NOV 04-09, 2000 CL NEW ORLEANS, LOUISIANA SP Soc Neurosci DE late-life depression; major depression; magnetic resonance imaging; high-intensity lesions; atrophy; path analysis ID CEREBROVASCULAR RISK-FACTORS; DEFINED VASCULAR DEPRESSION; MEDICAL COMORBIDITY; GERIATRIC DEPRESSION; WHITE-MATTER; CARDIOVASCULAR HEALTH; DISEASE; MRI; LESIONS; ATROPHY AB The objective of our study was to elucidate distinct paths to depression in a model that incorporates age, measures of medical comorbidity, neuroanatomical compromise, and cognitive status hi a sample of patients with late-life major depressive disorder (MDD) and nondepressed controls. Our study was cross-sectional in nature and utilized magnetic resonance imaging (MRI) estimates of brain and high-intensity lesion volumes together with clinical indices of cerebrovascular and nonvascular medical comorbidity. Neuroanatomic and clinical measures were incorporated into a structural covariance model in order to test pathways to MDD. Our data indicate that there are two paths to MDD; one path is represented by vascular and nonvascular medical comorbidity that contribute to high-intensity lesions that lead to depression. Smaller brain volumes represent a distinct path to the mood disorder. Age influences depression by increasing atrophy and overall medical comorbidity but has no direct impact on MDD. These findings demonstrate that there are distinct biological substrates to the neuroanatomical changes captured on MRI. These observations further suggest that neurobiological mechanisms acting hi parallel may compromise brain structure/function, thereby predisposing individuals to clinical brain disorders such as depression. (C) 2002 American College of Neuropsychopharmacology. Published by Elsevier Science Inc. C1 Univ Calif Los Angeles, Sch Med, Inst Neuropsychiat, Los Angeles, CA 90024 USA. Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Kumar, A (reprint author), Univ Calif Los Angeles, Sch Med, Inst Neuropsychiat, 37-384 B,760 Westwood Plaza, Los Angeles, CA 90024 USA. FU NIMH NIH HHS [MH 52129, MH 55115, MH61567] NR 64 TC 34 Z9 34 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2002 VL 26 IS 2 BP 229 EP 236 DI 10.1016/S0893-133X(01)00331-1 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 514FD UT WOS:000173427200010 PM 11790518 ER PT J AU Michel, SS Ekong, A Baltatzis, S Foster, CS AF Michel, SS Ekong, A Baltatzis, S Foster, CS TI Multifocal choroiditis and panuveitis - Immunomodulatory therapy SO OPHTHALMOLOGY LA English DT Article ID PROGRESSIVE SUBRETINAL FIBROSIS; CHORIORETINITIS; UVEITIS AB Purpose: To report our analysis of the efficacy of immunomodulatory therapy on the course of 19 patients with multifocal choroiditis and panuveitis (MCP). Design: Retrospective, noncomparative, interventional case series. Participants. Nineteen patients with multifocal choroiditis with panuveitis evaluated on the Ocular Immunology and Uveitis Service of the Massachusetts Eye and Ear Infirmary from 1978 to 2000. Methods. Fifteen patients were treated with systemic immunomodulatory therapy; 4 patients (who refused therapy) were treated with systemic steroids. All patients were analyzed for control of inflammation, visual acuity outcome, and tolerance of immunomodulatory therapy. Main Outcome Measures: Control of inflammation and visual acuity. Results: Nineteen patients with bilateral MCP with a mean follow-up of 72.7 months were studied. Fifteen were treated with immunomodulatory agents, whereas 4 patients received only systemic steroids; these 4 developed serious systemic steroid-related complications, and 12 others had cataract and/or glaucoma related to chronic topical, regional, or systemic steroid use before immunomodulatory therapy. Two patients who refused immunomodulatory therapy lost considerable vision in three of their four eyes. Of the 15 patients treated with immunomodulatory drugs, 7 patients lost considerable vision in one eye on steroid therapy but maintained good vision in the other eye once immunomodulatory therapy was instituted. No patient lost vision in any eye once he or she was treated with immunomodulatory treatment. Conclusions: Immunomodulatory therapy controls inflammation and preserves vision in patients with multifocal choroiditis and panuveitis. (C) 2002 by the American Academy of Ophthalmology. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Immunol & Uveitis Serv, Boston, MA 02114 USA. Univ Athens, Dept Ophthalmol, Athens, Greece. RP Foster, CS (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Immunol & Uveitis Serv, 243 Charles St, Boston, MA 02114 USA. NR 19 TC 28 Z9 34 U1 0 U2 1 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 FEB PY 2002 VL 109 IS 2 BP 378 EP 383 DI 10.1016/S0161-6420(01)00901-0 PG 6 WC Ophthalmology SC Ophthalmology GA 515KZ UT WOS:000173495900046 PM 11825826 ER PT J AU Zhao, HZ Webb, RH Ortel, B AF Zhao, HZ Webb, RH Ortel, B TI A new approach for noninvasive skin blood imaging in microcirculation SO OPTICS AND LASER TECHNOLOGY LA English DT Article DE noninvasive diagnosis; linear polarizer; mini-mirror ID POSITRON EMISSION TOMOGRAPHY; IN-VIVO; FLOW; MONITOR; OPTICS; SYSTEM AB A new noninvasive method is proposed for optically imaging blood under skin. A mini-mirror is used to guide the light incident onto the skin surface, while blocking specularly reflected light from the tissue. Moreover, by using two linear polarizers at right angles, the specular reflection can be reduced further, while also blocking the rough surface scattered light. A circular polarizer may be used to obtain the same effect. As a result, the blood flow beneath the surface of skin can be visualized clearly. The effect of the mini-mirror is also analyzed theoretically and experimentally. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Labs Photomed,Dept Dermatol, Boston, MA 02114 USA. RP Zhao, HZ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Labs Photomed,Dept Dermatol, BAR 713,40 Blossom St, Boston, MA 02114 USA. NR 21 TC 3 Z9 4 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0030-3992 J9 OPT LASER TECHNOL JI Opt. Laser Technol. PD FEB PY 2002 VL 34 IS 1 BP 51 EP 54 DI 10.1016/S0030-3992(01)00093-7 PG 4 WC Optics; Physics, Applied SC Optics; Physics GA 520RL UT WOS:000173794800008 ER PT J AU Yang, EY Tanner, ACR Milgrom, P Mokeem, SA Riedy, CA Spadafora, AT Page, RC Bruss, J AF Yang, EY Tanner, ACR Milgrom, P Mokeem, SA Riedy, CA Spadafora, AT Page, RC Bruss, J TI Periodontal pathogen detection in gingiva/tooth and tongue flora samples from 18-to 48-month old children and periodontal status of their mothers SO ORAL MICROBIOLOGY AND IMMUNOLOGY LA English DT Article DE child; mother; periodontal pathogens; periodontitis; preschool ID NEGATIVE ANAEROBIC-BACTERIA; PORPHYROMONAS-GINGIVALIS; YOUNG-CHILDREN; ACTINOBACILLUS-ACTINOMYCETEMCOMITANS; MUTANS STREPTOCOCCI; PRIMARY DENTITION; COLONIZATION; MICROBIOTA; FAMILIES; HYBRIDIZATION AB Few studies have detected periodontal pathogens in young children, and when detected the prevalence has been relatively low. In this epidemiological study, we determined the prevalence of periodontal pathogen colonization in young children and examined the relationship between periodontitis in mothers and detection of periodontal pathogens in their children aged 18-48 months. Children were selected and enrolled randomly into the study; tongue and gingival/tooth plaque samples were harvested and analyzed by DNA probe checkerboard assay for Porphyromonas gingivalis and Bacteroides forsythus. Clinical measurements included a gingival bleeding score in the children and a periodontal screening and recording (PSR) score in the mothers. Mothers having one or more periodontal sites with probing depths >5.5 mm were classified as having periodontitis. In this population, 71% (66/93) of the 18- to 48-month-old children were infected with at least one periodontal pathogen. Detection rates for children were 68.8% for P gingivalis and 29.0% for A forsythus. About 13.8% (11/80) of children had gingival bleeding in response to a toothpick inserted interproximally. Children in whom B. forsythus was detected were about 6 times more likely to have gingival bleeding than other children. There was no relationship between bleeding and detection of P. gingivalis. 17.0% (16/94) of the mothers had periodontitis. When all mother-child pairs were considered, the periodontal status of the mother was found not to be a determinant for detection of periodontal pathogens in the floral samples from the children, However, the odds ratio that a daughter of a mother with periodontitis would be colonized was 5.2 for B. forsythus. A much higher proportion of children in this population were colonized by P. gingivalis and/or B. forsythus than has been previously reported for other populations. A modest level of association between manifestations of periodontitis in mothers and detection of B. forsythus in their daughters was observed. C1 Univ Washington, Sch Dent, Dept Dent Publ Hlth Sci, Seattle, WA 98195 USA. Forsyth Inst, Boston, MA USA. Univ Washington, Reg Clin Dent Res Ctr, Seattle, WA 98195 USA. Dept Publ Hlth Sci, Saipan, CM USA. RP Page, RC (reprint author), Univ Washington, Sch Dent, Dept Dent Publ Hlth Sci, Box 357480, Seattle, WA 98195 USA. OI Milgrom, Peter/0000-0003-0784-9181 FU NIDCR NIH HHS [P01 DE 08555, DE 09513, P30 DE 09743, T32 DE 07150] NR 26 TC 24 Z9 26 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0902-0055 J9 ORAL MICROBIOL IMMUN JI Oral Microbiol. Immunol. PD FEB PY 2002 VL 17 IS 1 BP 55 EP 59 DI 10.1046/j.0902-0055.2001.00092.x PG 5 WC Dentistry, Oral Surgery & Medicine; Immunology; Microbiology SC Dentistry, Oral Surgery & Medicine; Immunology; Microbiology GA 517YK UT WOS:000173638100009 PM 11860557 ER PT J AU Mela, T Galvin, JM McGovern, BA AF Mela, T Galvin, JM McGovern, BA TI Magnesium deficiency during lactation as a precipitant of ventricular tachyarrhythmias SO PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY LA English DT Article DE hypomagnesemia; ventricular fibrillation; lactation; magnesium-losing kidney ID ACUTE MYOCARDIAL-INFARCTION; INTRAVENOUS MAGNESIUM; TACHYCARDIA; SULFATE AB A young ICD recipient with a history of syncope and idiopathic polymorphic ventricular tachycardia/ventricular fibrillation presented after an ICD discharge. She had delivered her first child 8 days prior to the event and she had been lactating. Numerous short runs of polymorphic ventricular tachycardia/ventricular fibrillation resolved with aggressive replacement of magnesium and elimination of breast-feeding. C1 Massachusetts Gen Hosp, Div Cardiol, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. RP Mela, T (reprint author), Massachusetts Gen Hosp, Div Cardiol, Cardiac Arrhythmia Serv, 75 Fruit St, Boston, MA 02114 USA. NR 8 TC 2 Z9 2 U1 1 U2 1 PU FUTURA PUBL CO PI ARMONK PA 135 BEDFORD RD, PO BOX 418, ARMONK, NY 10504-0418 USA SN 0147-8389 J9 PACE JI PACE-Pacing Clin. Electrophysiol. PD FEB PY 2002 VL 25 IS 2 BP 231 EP 233 DI 10.1046/j.1460-9592.2002.00231.x PG 3 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA 531EU UT WOS:000174403700019 PM 11915995 ER PT J AU Marler, JJ Rubin, JB Trede, NS Connors, S Grier, H Upton, J Mulliken, JB Folkman, J AF Marler, JJ Rubin, JB Trede, NS Connors, S Grier, H Upton, J Mulliken, JB Folkman, J TI Successful antiangiogenic therapy of giant cell angioblastoma with interferon alfa 2b: Report of 2 cases SO PEDIATRICS LA English DT Article DE interferon alfa 2b; giant cell angioblastoma; angiogenesis; basic fibroblast growth factor ID FIBROBLAST GROWTH-FACTOR; LIFE-THREATENING HEMANGIOMAS; KAPOSIFORM HEMANGIOENDOTHELIOMA; ANGIOGENESIS; INFANCY; INHIBITION; CHILDHOOD; ALPHA-2A; TUMOR; EXPRESSION AB We describe 2 cases of angioblastoma, a rare, destructive pediatric tumor, treated with interferon alfa 2b (IFNalpha2b). The first patient is a 10-month-old male who presented with an ulcerated palatal neoplasm that could not be completely resected. The second is a male neonate with a congenital tumor of the right hand that invaded the hypothenar eminence, destroying the fourth and fifth metacarpals. Biopsy in both patients was interpreted as giant cell angioblastoma. Angioblastoma is rare; there is only 1 reported case that necessitated amputation of an upper extremity, also initially recommended for our patient. Because there is little experience with chemotherapy, permission was granted to employ an antiangiogenic regimen of IFNalpha2b. The angiogenic protein, basic fibroblast growth factor (bFGF), was abnormally elevated in both patients. Both patients received IFNalpha2b. In the first child, it was used after incomplete resection, because biopsy-proven tumor was present at the margin and in the nasopharynx. Biopsies 15 months after initiation of IFN2alphab were negative for tumor. Therapy was stopped after 3 1/2 years. Eighteen months later, the patient remains disease-free. In the second child, IFNalpha2b was started after debridement of the ulcerated tumor. Over 11 months, the tumor completely regressed and there was bony regeneration of the metacarpals. The fifth digit was amputated because of damage to the metacarpophalangeal joint by the tumor. IFNalpha2b therapy was discontinued after 1 year of treatment, and the child remains disease-free 2 years and 8 months later. In conclusion, this report demonstrates that: 1) a bFGF-overexpressing low-grade tumor can respond to IFNalpha2b in a manner similar to life-threatening infantile hemangiomas, 2) urinary bFGF levels can help guide IFNalpha dosage in such patients, and 3) although bFGF-mediated tumor angiogenesis is inhibited by IFNalpha, physiologic angiogenesis seems to be unaffected. C1 Childrens Hosp, Dept Surg, Boston, MA 02115 USA. Childrens Hosp, Div Plast Surg, Boston, MA 02115 USA. Dana Farber Canc Inst, Jimmy Fund Clin, Boston, MA 02115 USA. RP Folkman, J (reprint author), Childrens Hosp, Dept Surg, Hunnewell 103,300 Longwood Ave, Boston, MA 02115 USA. NR 41 TC 50 Z9 55 U1 0 U2 2 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2002 VL 109 IS 2 AR e37 DI 10.1542/peds.109.2.e37 PG 5 WC Pediatrics SC Pediatrics GA 517FV UT WOS:000173601200019 PM 11826247 ER PT J AU Yang, H AF Yang, H TI Central and peripheral regulation of gastric acid secretion by peptide YY SO PEPTIDES LA English DT Review ID DORSAL VAGAL COMPLEX; ENTEROCHROMAFFIN-LIKE CELLS; THYROTROPIN-RELEASING-HORMONE; NUCLEUS-TRACTUS-SOLITARIUS; NEUROPEPTIDE-Y; PANCREATIC-POLYPEPTIDE; RAT-BRAIN; RAPHE PALLIDUS; TRH ANALOG; GASTROINTESTINAL-TRACT AB Peptide YY (PYY) released postprandially from the ileum and colon displays a potent inhibition of cephalic and gastric phases of gastric acid secretion through both central and peripheral mechanisms. To modulate vagal regulation of gastric functions, circulating PYY enters the brain through the area postrema and the nucleus of the solitary tract. where it exerts a stimulatory action through PYY-preferring Y1-like receptors, and an inhibitory action through Y2 receptors. In the gastric mucosa, PYY binds to Y1 receptors in the enterochromaffin-like cells to inhibit gastrin-stimulated histamine release and calcium signaling via a pertussis toxin-sensitive pathway. (C) 2002 Elsevier Science Inc. All rights reserved. C1 VA Greater Los Angeles Healthcare Syst, CURE Digest Dis Res Ctr, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Med, Div Digest Dis, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Inst Brain Res, Los Angeles, CA 90073 USA. RP Yang, H (reprint author), VA Greater Los Angeles Healthcare Syst, CURE Digest Dis Res Ctr, Bldg 115,Rm 203,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 105 TC 29 Z9 29 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD FEB PY 2002 VL 23 IS 2 BP 349 EP 358 AR PII S0196-9781(01)00611-8 DI 10.1016/S0196-9781(01)00611-8 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 522QD UT WOS:000173907700011 PM 11825649 ER PT J AU Krebs, DE Goldvasser, D Lockert, JD Portney, LG Gill-Body, KM AF Krebs, DE Goldvasser, D Lockert, JD Portney, LG Gill-Body, KM TI Is base of support greater in unsteady gait? SO PHYSICAL THERAPY LA English DT Article DE gait; interfoot distance; kinematics; stability; vestibular dysfunction ID REHABILITATION; WALKING; AGE AB Background and Purpose. We investigated dynamic interfoot distance (IFD) throughout the gait cycle in people with unsteady gait caused by vestibulopathy and in people without known neuromuscular pathology. We expected that the subjects with unsteady gait would use a greater IFD than subjects without neuromuscular pathology and that this IFD would be correlated with other measures of locomotor stability. Subjects and Methods. Simultaneous whole-body (11-segment) dynamic kinematic data were collected from 22 subjects with vestibulopathy and 22 subjects without known neuromuscular pathology who were matched for age, height, weight, and body mass index. Two trials each of the participants' gait at preferred speed and paced gait at 120 steps/min were analyzed with a repeated-measures design with multiple dependent variables. Quantitative data were analyzed descriptively and with inferential statistics. Results. Interfoot distance at preferred gait speed did not differentiate unsteady subjects with vestibulopathy from the comparison subjects. Paced gait IFD total range and IFD in single-limb support differed between groups, but IFD at heel-strike did not. However, IFD at heel-strike, the traditional measure of "base-of-support width," was correlated with measurements of whole-body center-of-gravity stability (r=.32-.55). Discussion and Conclusion. Gait at preferred speed permitted the unsteady subjects and the comparison subjects to select similar IFD values, but at the cost of slower gait in the unsteady subjects. When required to walk at a "normal" pace of 120 steps/min subjects with vestibulopathy increased their IFD. These data suggest that wide-based gait alone cannot differentiate between subjects with and without balance impairments. Base of support and other whole-body kinematic variables are mechanical compensations of vestibulopathic instability. Further studies are needed to determine whether development of active control of these whole-body control variables can occur after vestibular rehabilitation. C1 Massachusetts Gen Hosp, Inst Hlth Profess, Boston, MA 02114 USA. Massachusetts Gen Hosp, Biomot Lab, Boston, MA 02114 USA. RP Krebs, DE (reprint author), Massachusetts Gen Hosp, Inst Hlth Profess, 101 Merrimac St, Boston, MA 02114 USA. FU NIA NIH HHS [R01AG11255]; PHS HHS [H133G30041] NR 37 TC 28 Z9 29 U1 0 U2 3 PU AMER PHYSICAL THERAPY ASSOC PI ALEXANDRIA PA 1111 N FAIRFAX ST, ALEXANDRIA, VA 22314 USA SN 0031-9023 J9 PHYS THER JI Phys. Ther. PD FEB PY 2002 VL 82 IS 2 BP 138 EP 147 PG 10 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA 518CU UT WOS:000173649700003 PM 11856065 ER PT J AU Yaremchuk, MJ AF Yaremchuk, MJ TI Curve analysis of the aging orbital aperture - Discussion SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Editorial Material C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Plast Surg, Boston, MA 02114 USA. RP Yaremchuk, MJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Plast Surg, WACC-453, Boston, MA 02114 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0032-1052 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD FEB PY 2002 VL 109 IS 2 BP 758 EP 760 DI 10.1097/00006534-200202000-00053 PG 3 WC Surgery SC Surgery GA 518PX UT WOS:000173678000053 ER PT J AU Rivas-Vazquez, RA Blais, MA AF Rivas-Vazquez, RA Blais, MA TI Pharmacologic treatment of personality disorders SO PROFESSIONAL PSYCHOLOGY-RESEARCH AND PRACTICE LA English DT Article ID SELF-MUTILATION; BORDERLINE; NALTREXONE; CLOZAPINE C1 Neurol Ctr S Florida, Miami, FL 33176 USA. Miami Res Associates, Miami, FL USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Rivas-Vazquez, RA (reprint author), Neurol Ctr S Florida, Baptist Med Arts Bldg,8940 N Kendall Dr,802-E, Miami, FL 33176 USA. NR 29 TC 2 Z9 2 U1 3 U2 3 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7028 J9 PROF PSYCHOL-RES PR JI Prof. Psychol.-Res. Pract. PD FEB PY 2002 VL 33 IS 1 BP 104 EP 107 DI 10.1037//0735-7028.33.1.104 PG 4 WC Psychology, Multidisciplinary SC Psychology GA 514QJ UT WOS:000173452300015 ER PT J AU Davids, E Zhang, KH Tarazi, FI Baldessarini, RJ AF Davids, E Zhang, KH Tarazi, FI Baldessarini, RJ TI Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning SO PSYCHOPHARMACOLOGY LA English DT Article DE attention deficit-hyperactivity disorder (ADHD) enantiomers; hyperactivity; 6-hydroxydopamine; methylphenidate; neonatally lesioned rat; potency ID DL-THREO-METHYLPHENIDATE; DOPAMINE TRANSPORTERS; ENANTIOSELECTIVE PHARMACOKINETICS; ATTENTION; DISORDER; BRAIN; CHILDREN; DEFICITS; PHARMACODYNAMICS; PHARMACOLOGY AB Rationale: The psychostimulant dl-threo-methylphenidate is commonly used to treat attention deficit-hyperactivity disorder (ADHD). Consistent with its effects in ADHD patients, racemic methylphenidate antagonizes behavioral hyperactivity in several animal models of ADHD, including juvenile rats with neonatal 6-hydroxydopamine (6-OHDA) lesions of forebrain dopamine projections. The enantiomers of methylphenidate differ markedly in stimulant potency but have not been compared in the 6-OHDA lesion model. Objective: Locomotor-inhibiting effects of methylphenidate enantiomers were compared in 6-OHDA-lesioned rats to test the hypothesis that d-methylphenidate is more potent than dl- and l-methylphenidate. Methods: Selective dopamine lesions were made using 6-OHDA (100 mug, intracisternal, IC) on postnatal day (PD) 5 after desipramine (25 mg/kg, SC) pretreatment to protect noradrenergic neurons. Effects of d-, l- and dl-threo-methylphenidate on locomotor activity of lesioned and sham control rats were quantified at PD 23-27. Results: Lesioning yielded robust motor hyperactivity at PD 23-27. Both d- and dl-methylphenidate stimulated locomotor activity in intact rats, and inhibited activity in lesioned rats. l-Methylphenidate did not affect locomotor activity in either lesioned rats or controls. d-Methylphenidate (ED50 = 1.66 mg/kg) was 3.3 times more potent than dl-methylphenidate (ED50 = 5.45 mg/kg) in reducing locomotor hyperactivity in lesioned rats. In addition, pretreatment of lesioned rats with l-methylphenidate significantly reduced the motor inhibiting effects of d-methylphenidate. Conclusions: The more active enantiomer, as predicted, was d-methylphenidate, but the l-enantiomer interfered with its effects, suggesting that clinical potency of d-methylphenidate may be more than twice that of the racemate. C1 Harvard Univ, Sch Med, Dept Psychiat, Belmont, MA 02478 USA. Harvard Univ, Sch Med, Neurosci Program, Belmont, MA 02478 USA. Massachusetts Gen Hosp, McLean Div, Mailman Res Ctr, Belmont, MA 02478 USA. McLean Hosp, Mailman Res Ctr, Belmont, MA 02478 USA. RP Baldessarini, RJ (reprint author), Harvard Univ, Sch Med, Dept Psychiat, Belmont, MA 02478 USA. FU NIMH NIH HHS [MH-34006, MH-47370] NR 47 TC 55 Z9 57 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD FEB PY 2002 VL 160 IS 1 BP 92 EP 98 DI 10.1007/s00213-001-0962-5 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 535UK UT WOS:000174664600011 PM 11862378 ER PT J AU Aravagiri, M Marder, SR AF Aravagiri, M Marder, SR TI Brain, plasma and tissue pharmacokinetics of risperidone and 9-hydroxyrisperidone after separate oral administration to rats SO PSYCHOPHARMACOLOGY LA English DT Article DE risperidone; 9-hydroxyrisperidone; pharmacokinetics; rat; oral dose; plasma; brain; tissue; LC-MS-MS ID RECEPTOR OCCUPANCY; METABOLISM; EXCRETION; 5-HT2; D-2 AB Rationale: Following an oral dose of risperidone (RSP), concentrations of its major metabolite 9-hydroxyrisperidone (9-OHRSP) were high in plasma and tissues but disproportionately lower in the brain compared to RSP, indicating that 9-OHRSP may have different pharmacokinetic properties. Objectives: To investigate non-compartmental pharmacokinetics of RSP and 9-OHRSP in plasma, brain and other tissues after separate administration of a single oral dose of 6 mg/kg RSP and 9-OHRSP to rats. Methods: Plasma, brain, liver, lung, kidney and spleen tissues were collected at pre-dose and at 0.5, 1, 2, 5, 6, 12, 24, 36 and 48 h post-dose, homogenized in saline and assayed for RSP and 9-OHRSP using a sensitive and specific liquid chromatography tandem mass spectrometry method. Results: The concentrationtime curve of RSP and 9-OHRSP showed that they were readily absorbed and followed a multiphase elimination pattern. The terminal elimination half-life (t(1/2)) of RSP after the RSP dose was longest in the liver (17.6 h) and shortest in the spleen (1.2 h). The t(1/2) of 9-OHRSP after the RSP dose was shorter in plasma (3.4 h) and other tissues (similar to8-11 h) than that for RSP but it was longer in the spleen. However, the t(1/2) of 9-OHRSP after the 9-OHRSP dose was shorter in most tissues as compared to the t(1/2) of 9-OHRSP after the RSP dose. The area under the concentration-time curve (AUC) of RSP and 9-OHRSP was 6-67 times higher in the plasma and tissues than in the brain. AUCs of 9-OHRSP in tissues after the RSP close were 2-5 times higher than those for RSP, except in the brain, where AUCs of RSP and 9-OHRSP were similar. Conclusion: Pharmacokinetics of 9-OHRSP in many tissues were different after RSP and 9-OHRSP doses. The reason for disproportionate brain levels of 9-OHRSP is not clear. The overall exposure to active drug in the brain as represented by AUC was similar after the RSP and 9-OHRSP doses and the 9-OHRSP is probably an equal contributor to the pharmacological actions of RSP. C1 Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Psychopharmacol Unit, Los Angeles, CA 90073 USA. RP Aravagiri, M (reprint author), Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Psychopharmacol Unit, Bldg 210,15,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 22 TC 33 Z9 35 U1 0 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD FEB PY 2002 VL 159 IS 4 BP 424 EP 431 DI 10.1007/s00213-001-0933-x PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 528KC UT WOS:000174242100010 PM 11823895 ER PT J AU O'Malley, ME Weir, MM Hahn, PF Misdraji, J Wood, BJ Mueller, PR AF O'Malley, ME Weir, MM Hahn, PF Misdraji, J Wood, BJ Mueller, PR TI US-guided fine-needle aspiration biopsy of thyroid nodules: Adequacy of cytologic material and procedure time with and without immediate cytologic analysis SO RADIOLOGY LA English DT Article DE thyroid, biopsy; thyroid, neoplasms ID MANAGEMENT; INCIDENTALOMAS; DIAGNOSIS; DISEASE; LUNG AB PURPOSE: To compare the adequacy of aspirated material and procedure time when performing ultrasonography-guided fine-needle aspiration biopsy of thyroid nodules with and without immediate cytologic analysis of the aspirated sample. MATERIALS AND METHODS: One hundred twenty-one thyroid nodules were sampled for biopsy in 109 patients. In group A, results of 50 biopsies in which immediate cytologic analysis was performed were retrospectively reviewed for cytologic adequacy. In group B, 50 biopsies were performed without immediate cytologic analysis, and the procedure time was recorded. In group C, 21 biopsies were performed with immediate cytologic analysis, and the procedure time was recorded. Cytologic adequacy rates were compared by using the proportional odds model, and procedure times were compared by using linear regression to adjust for differences in the character of the nodules. RESULTS: For groups A and C (immediate cytologic analysis performed), the adequacy categories included the following results: 39 (55%) satisfactory, 15 (21%) limited, and 17 (24%) unsatisfactory. For group B (immediate cytologic analysis not performed), the adequacy categories included the following results: 25 (50%) satisfactory, 15 (30%) limited, and 10 (20%) unsatisfactory (Wald test, P = .815). The average procedure time was 12.5 minutes for group B and 44.4 minutes for group C (P < .001). CONCLUSION: There was no significant difference in cytologic adequacy whether immediate cytologic analysis of aspirated material was performed or not. The procedure time was significantly shorter when immediate cytologic analysis was not performed. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP O'Malley, ME (reprint author), Toronto Gen Hosp, Joint Dept Med Imaging, ES 1-401A 200 Elizabeth St, Toronto, ON M5G 2C4, Canada. NR 20 TC 68 Z9 69 U1 0 U2 0 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 FEB PY 2002 VL 222 IS 2 BP 383 EP 387 DI 10.1148/radiol.2222010201 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 515NQ UT WOS:000173502500014 PM 11818603 ER PT J AU Hung, PW Paik, DS Napel, S Yee, J Jeffrey, RB Steinauer-Gebauer, A Min, J Jathavedam, A Beaulieu, CF AF Hung, PW Paik, DS Napel, S Yee, J Jeffrey, RB Steinauer-Gebauer, A Min, J Jathavedam, A Beaulieu, CF TI Quantification of distention in CT colonography: Development and validation of three computer algorithms SO RADIOLOGY LA English DT Article DE colon, CT; computers, diagnostic aid; computed tomography (CT), computer programs; computed tomography (CT), image processing; phantoms ID VIRTUAL COLONOSCOPY; COLORECTAL POLYPS; DISPLAY MODES; HELICAL CT; GLUCAGON; COLON AB Three bowel distention-measuring algorithms for use at computed tomographic (CT) colonography were developed, validated in phantoms, and applied to a human CT colonographic data set. The three algorithms are the cross-sectional area method, the moving spheres method, and the segmental volume method. Each algorithm effectively quantified distention, but accuracy varied between methods. Clinical feasibility was demonstrated. Depending on the desired spatial resolution and accuracy, each algorithm can quantitatively depict colonic diameter in CT colonography. C1 Stanford Univ, Med Ctr, Dept Radiol, Stanford, CA 94305 USA. Mayo Clin & Mayo Grad Sch Med, Rochester, MN USA. Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. San Francisco Vet Adm Med Ctr, San Francisco, CA USA. NYU, Sch Med, Dept Radiol, New York, NY USA. RP Beaulieu, CF (reprint author), Stanford Univ, Med Ctr, Dept Radiol, MC 5105,300 Pasteur Dr, Stanford, CA 94305 USA. FU NCI NIH HHS [R01 CA72023] NR 27 TC 9 Z9 9 U1 0 U2 3 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 FEB PY 2002 VL 222 IS 2 BP 543 EP 554 DI 10.1148/radiol.2222010600 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 515NQ UT WOS:000173502500035 PM 11818626 ER PT J AU Fiorenza, D Viglio, S Lupi, A Baccheschi, J Tinelli, C Trisolini, R Iadarola, P Luisetti, M Snider, GL AF Fiorenza, D Viglio, S Lupi, A Baccheschi, J Tinelli, C Trisolini, R Iadarola, P Luisetti, M Snider, GL TI Urinary desmosine excretion in acute exacerbations of COPD: a preliminary report SO RESPIRATORY MEDICINE LA English DT Article DE elastin; high performance capillary electrophoresis; micellar electrokinetic chromatography ID OBSTRUCTIVE PULMONARY-DISEASE; ALPHA(1)-ANTITRYPSIN DEFICIENCY; ELASTIN; ISODESMOSINE; DEGRADATION; THERAPY AB Desmosine (DES) is an elastin-derived, cross-link amino acid, which is not metabolized: hence, its urinary levels reflect elastin breakdown. We hypothesized that elastin degradation should increase as a result of increased lung inflammation during an acute exacerbation of COPD and should decrease after recovery, To test this hypothesis we measured DES in three urine samples from nine COPD subjects during the first 5 days of an acute exacerbation and at 2 months after recovery. We also measured forced expiratory volume in I sec (FEV1) to monitor the effects of the exacerbation on ventilatory function. The mean (SD) FEV1 was 45 (15)% predicted during the exacerbation and 57.8 (16)% predicted 2 months later (P=0.00001). The mean (SD) DES excretion was 25.3 (9) mug g(-1) creatinine at day 1;23.5 (9) at day 3 and 24 (9) at day 5 of the exacerbation. The mean ( D) urinary DES excretion 60 days after discharge was 20.9 (7) mug g(-1) creatinine (P=0.049) in comparison with the mean of the three acute-phase values. The size of the increase in desmosine excretion during exacerbation is small, 3.2 mug g(-1) creatinine or 16% of the recovery desmosine value. We conclude that there is a small but statistically significant increase in lung elastin breakdown in the body during an acute exacerbation of COPD. (C) 2001 Elsevier Science Ltd. C1 Univ Pavia, IRCCS, Policlin San Matteo, Clin Malattie Apparato Resp,Lab Biochim & Genet, I-27100 Pavia, Italy. Univ Pavia, IRCCS, Policlin San Matteo, Dipartimento Biochim, I-27100 Pavia, Italy. Univ Pavia, IRCCS, Policlin San Matteo, Serv Biometria & Epidemiol Clin, I-27100 Pavia, Italy. Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. VA Boston Healthcare Syst, Dept Med, Boston, MA USA. RP Luisetti, M (reprint author), Univ Pavia, IRCCS, Policlin San Matteo, Clin Malattie Apparato Resp,Lab Biochim & Genet, Via Taramelli 5, I-27100 Pavia, Italy. OI Tinelli, Carmine/0000-0002-8749-1978 NR 18 TC 19 Z9 19 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0954-6111 J9 RESP MED JI Respir. Med. PD FEB PY 2002 VL 96 IS 2 BP 110 EP 114 DI 10.1053/rmed.2001.1224 PG 5 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA 521ZM UT WOS:000173871300006 PM 11860167 ER PT J AU Haimovici, R Ciulla, TA Miller, JW Hasan, T Flotte, TJ Kenney, AG Schomacker, KT Gragoudas, ES AF Haimovici, R Ciulla, TA Miller, JW Hasan, T Flotte, TJ Kenney, AG Schomacker, KT Gragoudas, ES TI Localization of rose bengal, aluminum phthalocyanine tetrasulfonate, and chlorin e(6) in the rabbit eye SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE angiography; rose bengal; aluminum phthalocyanine tetrasulfonate; chlorin e(6); choroid; eye; photodynamic therapy; photosensitizer; rabbit; retina ID VERTEPORFIN PHOTODYNAMIC THERAPY; SINGLET OXYGEN PRODUCTION; PHOTOCHEMICAL INITIATION; HYDROPHILIC SENSITIZER; CHOROIDAL MELANOMAS; VASCULAR OCCLUSION; RETINAL-DETACHMENT; CILIARY BODY; PHOTOSENSITIZERS; ANGIOGRAPHY AB Purpose: The localization and site of action of photosensitizers in the eye may be important for photodynamic therapy for fundus disorders but remain poorly understood for most agents. We investigated the intraocular localization of xanthene, phthalocyanine, and chlorin photosensitizers by using fluorescence microscopy and digital fundus fluorescence angiography. Methods: Rose bengal (40 mg/kg), aluminum phthalocyanine tetrasulfonate (CASPc) (5 mg/kg), or chlorin e, (2 mg/kg) was intravenously administered to albino rabbits. The eyes were enucleated and examined by means of fluorescence microscopy 5, 20, 60, and 120 minutes and 24 hours after dye injection. In vivo digital funclus fluorescence angiography with use of rose bengal (2-4 mg/kg), CASPc (2 mg/kg), and chlorin e, (2 mg/kg) was performed. Results: For all agents studied pathologically, there was moderate fluorescence from the choroid and retinal pigment epithelium 5 minutes after dye injection. Mild fluorescence detected from the photoreceptor outer segments at 5 minutes was increased at 20 minutes. Angiographic studies with use of rose bengal, CASPc, and chlorin e, revealed differences in the pattern and rate of photosensitizer accumulation. Conclusions: Rose bengal, CASPc, and chlorin e, accumulate rapidly in the choroid and retinal pigment epithelium and less rapidly in the outer retina. Differences in ocular localization of these photosensitizers were demonstrated. The significance of these findings for potential photodynamic therapy with these agents requires further investigation. C1 Harvard Univ, Sch Med, Retina Serv Dept Ophthalmol, Laser Res Lab Massachusetts Eye & Ear Infirm, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Massachesetts Gen Hosp, Wellman Labs Photomed Dept Dermatol, Cambridge, MA 02138 USA. Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Haimovici, R (reprint author), Gundersen Eye Ctr, DOB 10 720 Harrison Ave, Boston, MA 02118 USA. NR 49 TC 10 Z9 13 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0275-004X J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD FEB PY 2002 VL 22 IS 1 BP 65 EP 74 DI 10.1097/00006982-200202000-00012 PG 10 WC Ophthalmology SC Ophthalmology GA 529BF UT WOS:000174279600012 PM 11884881 ER PT J AU Goldblum, JR Lauwers, GY AF Goldblum, JR Lauwers, GY TI Dysplasia arising in Barrett's esophagus: Diagnostic pitfalls and natural history SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article DE Barrett's esophagus; intestinal metaplasia; dysplasia; natural history; biomarker ID HIGH-GRADE DYSPLASIA; P53 PROTEIN ACCUMULATION; FLOW-CYTOMETRY; RISK-FACTORS; FOLLOW-UP; ADENOCARCINOMA; SURVEILLANCE; PROGRESSION; CARCINOMA; CANCER AB Barrett's esophagus is a complication of chronic gastroesophageal reflux disease and is defined as a change in the esophageal epithelium of any length that can be recognized at endoscopy and is confirmed to have intestinal metaplasia by biopsy. Esophageal ulcerations and stricture are rarely seen, and the major complications of this disease are epithelial dysplasia and esophageal adenocarcinoma. Dysplasia is felt to represent the best currently available marker of increased cancer risk in these patients. However, there are many pitfalls in the histologic recognition of dysplasia, a particularly difficult problem in the face of active inflammation in patients with ongoing reflux disease. The recognition and grading of dysplasia is subject to significant interobserver variability, particularly at the lower end of the histologic spectrum (negative v indefinite for dysplasia v low-grade dysplasia). High-grade dysplasia and to a lesser degree low-grade dysplasia are markers of increased cancer risk, although their natural history are difficult to determine. Up to 40% of patients with a preoperative diagnosis of high-grade dysplasia have an adenocarcinoma in their esophagectomy specimen. Despite this observation, there is still debate as to whether esophagectomy or close endoscopic surveillance with biopsy is the most appropriate and cost-effective way to manage these patients. The search for more objective surrogate biomarkers that recognize patients who are truly at risk of progressing along the dysplasia-carcinoma sequence is underway. However, no biomarker has yet proven to be superior to the histologic recognition of dysplasia in identifying these high-risk patients. Copyright 2002, Elsevier Science (USA). All rights reserved. C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Goldblum, JR (reprint author), Cleveland Clin Fdn, 9500 Euclid Ave L25, Cleveland, OH 44195 USA. NR 38 TC 33 Z9 36 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 0740-2570 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD FEB PY 2002 VL 19 IS 1 BP 12 EP 19 DI 10.1053/sdia.2002.31767 PG 8 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 535TN UT WOS:000174662600003 PM 11936261 ER PT J AU Misdraji, J Lauwers, GY AF Misdraji, J Lauwers, GY TI Gastric epithelial dysplasia SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Review DE stomach; dysplasia; adenoma ID FAMILIAL ADENOMATOUS POLYPOSIS; FUNDIC GLAND POLYPS; HELICOBACTER-PYLORI INFECTION; UPPER GASTROINTESTINAL POLYPS; COLI GARDNERS-SYNDROME; FOLLOW-UP; HYPERPLASTIC POLYPS; NATURAL-HISTORY; MALIGNANT TRANSFORMATION; CLINICAL-SIGNIFICANCE AB Gastric dysplasia is considered to be the penultimate stage of the gastric carcinogenesis sequence. Its clinical importance has been underscored since its association with gastric adenocarcinoma was established. High-grade dysplasia and to a lesser degree low-grade dysplasia are markers of increased cancer risk, although their natural histories are difficult to determine. There are many pitfalls in the diagnosis of gastric dysplasia. Its recognition and grading are subject to interobserver variability, particularly at the lower end of the histologic spectrum (negative v indefinite for dysplasia v low-grade dysplasia) when inflammation is present. Also, diagnostic criteria and grading schemes have evolved differently worldwide resulting in disagreement between pathologists. Against this background, the authors review contemporary issues related to gastric dysplasia, its definition, classification, grading, and natural history. We also discuss new classifications of gastric epithelial dysplasia designed to develop equivalence between grading schemes worldwide. Copyright 2002, Elsevier Science (USA). All rights reserved. C1 Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Misdraji, J (reprint author), Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Warren 2,55 Fruit St, Boston, MA 02114 USA. NR 101 TC 30 Z9 37 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 0740-2570 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD FEB PY 2002 VL 19 IS 1 BP 20 EP 30 DI 10.1053/sdia.2002.31546 PG 11 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 535TN UT WOS:000174662600004 PM 11936263 ER PT J AU Tambouret, R Pitman, MB Wang, HH AF Tambouret, R Pitman, MB Wang, HH TI Cytologic diagnosis of dysplasia in the alimentary tract SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article DE cytology; brushing; balloon sampling; glandular dysplasia; squamous dysplasia; carcinoma; reactive atypia; gastrointestinal tract; alimentary tract; esophagus; stomach; large intestine; anus ID UPPER GASTROINTESTINAL-TRACT; ANAL INTRAEPITHELIAL NEOPLASIA; HUMAN PAPILLOMAVIRUS DNA; HIGH-GRADE DYSPLASIA; BARRETTS-ESOPHAGUS; ULCERATIVE-COLITIS; BRUSH CYTOLOGY; ENDOSCOPIC CYTOLOGY; FOLLOW-UP; GASTROESOPHAGEAL MALIGNANCY AB Diagnosis of dysplasia in the gastrointestinal tract has important clinical implications for management decisions. Although dysplasia is generally recognized by histology, cytologic specimens have been shown to increase the sensitivity of tissue diagnosis. The advantage of cytology is the ability to sample a much larger mucosal area. The relatively low specificity caused by the overlap in cytologic features of reactive atypia, dysplasia, and carcinoma is a disadvantage. This article reviews the cytology of squamous and glandular dysplasia in the alimentary tract as well as the studies that have evaluated the clinical utility of cytologic sampling of the gastrointestinal tract in the evaluation of dysplasia. Copyright 2002, Elsevier Science (USA). All rights reserved. C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. RP Tambouret, R (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 88 TC 1 Z9 1 U1 0 U2 4 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0740-2570 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD FEB PY 2002 VL 19 IS 1 BP 38 EP 47 DI 10.1053/sdia.2002.31545 PG 10 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 535TN UT WOS:000174662600006 PM 11936265 ER PT J AU Zukerberg, L AF Zukerberg, L TI The molecular basis of dysplasia SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article DE oncogene; cell cycle; apoptosis; tumor suppressor gene ID COLORECTAL-CANCER; ESOPHAGUS; ADENOCARCINOMAS; TUMORIGENESIS; MUTATIONS; RAS; APC AB Detailed descriptions of the molecular pathways involved in dysplasia and carcinoma would fill many bound volumes. This article illustrates the molecular concepts involved in the pathogenesis of dysplasia and carcinoma, with examples that are most relevant to the gastrointestinal tract. At this time, there are at least 4 circuits that must be altered for a cell to become dysplastic: 1) requirement of a continuous or autonomous growth stimulus, 2) development of resistance to growth inhibitory signals, 3) avoidance of apoptosis, and 4) ability to transcend the limits imposed by the generational clock. Although it is likely that 1 or 2 additional circuits must also be altered for the development of carcinoma, they are not defined at this time. Copyright 2002, Elsevier Science (USA). All rights reserved. C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Zukerberg, L (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 2, Boston, MA 02114 USA. NR 26 TC 4 Z9 4 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 0740-2570 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD FEB PY 2002 VL 19 IS 1 BP 48 EP 53 DI 10.1053/sdia.2002.31955 PG 6 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 535TN UT WOS:000174662600007 PM 11936266 ER PT J AU Wilson, WH Gutierrez, M O'Connor, P Frankel, S Jaffe, E Chabner, BA Grossbard, ML AF Wilson, WH Gutierrez, M O'Connor, P Frankel, S Jaffe, E Chabner, BA Grossbard, ML TI The role of rituximab and chemotherapy in aggressive B-cell lymphoma: A preliminary report of dose-adjusted EPOCH-R SO SEMINARS IN ONCOLOGY LA English DT Review ID NON-HODGKINS-LYMPHOMA; MULTIDRUG-RESISTANCE; HEMATOLOGICAL MALIGNANCIES; MONOCLONAL-ANTIBODY; DRUG-RESISTANCE; P-GLYCOPROTEIN; GLUTATHIONE; ACTIVATION; APOPTOSIS; CYCLE C1 NCI, Ctr Canc Res, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Dept Oncol, Boston, MA 02114 USA. Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. St Lukes Roosevelt Hosp, Dept Oncol, New York, NY USA. RP Wilson, WH (reprint author), NCI, Ctr Canc Res, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 37 TC 46 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 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD FEB PY 2002 VL 29 IS 1 SU 2 BP 41 EP 47 DI 10.1053/sonc.2002.30151 PG 7 WC Oncology SC Oncology GA 523MT UT WOS:000173958400007 PM 11842388 ER PT J AU Zellos, LS Sugarbaker, DJ AF Zellos, LS Sugarbaker, DJ TI Multimodality treatment of diffuse malignant pleural mesothelioma SO SEMINARS IN ONCOLOGY LA English DT Review ID 188 CONSECUTIVE PATIENTS; EXTRAPLEURAL PNEUMONECTOMY; TRIMODALITY THERAPY; RANDOMIZED TRIAL; PHASE-II; EXPERIENCE; DIAGNOSIS; EFFUSIONS; RADIOTHERAPY; CHEMOTHERAPY C1 Brigham & Womens Hosp, Div Thorac Surg, Dept Surg, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Surg Serv, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Sugarbaker, DJ (reprint author), Brigham & Womens Hosp, Div Thorac Surg, Dept Surg, 75 Francis St, Boston, MA 02115 USA. NR 42 TC 51 Z9 52 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 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD FEB PY 2002 VL 29 IS 1 BP 41 EP 50 DI 10.1053/sonc.2002.30230 PG 10 WC Oncology SC Oncology GA 522FM UT WOS:000173885200006 PM 11836668 ER PT J AU Iwasko, N Steinbach, LS Disler, D Pathria, M Hottya, GA Kattapuram, S Varma, DGK Kumar, R AF Iwasko, N Steinbach, LS Disler, D Pathria, M Hottya, GA Kattapuram, S Varma, DGK Kumar, R TI Imaging findings in Mazabraud's syndrome: seven new cases SO SKELETAL RADIOLOGY LA English DT Article DE Mazabraud's syndrome; MRI; fibrous dysplasia; myxoma ID INTRAMUSCULAR MYXOMA; FIBROUS DYSPLASIA; BONE; TUMORS AB Objective: To present seven new cases of Mazabraud's syndrome with particular observations on the magnetic resonance imaging findings and a review of the literature. Design and patients: A multi- institutional retrospective review was performed on seven patients with confirmed Mazabraud's syndrome. The patient group was composed of six women and one man, ranging in age from 39 to 65 years, with a mean age of 53 years. Results: Fibrous dysplasia was more often polyostotic (n=6) and right-sided (n=4). Fibrous dysplasia involved the femur in five cases. The soft tissue myxomas were intramuscular in origin. The most commonly affected location was the thigh (n=4). On computed tomography, myxomas were well- circumscribed, low-attenuation masses. On magnetic resonance images, the lesions were significantly low in signal intensity on T1-weighted images and high in signal intensity on T2-weighted images relative to adjacent skeletal muscle. Enhancement of the myxomas was heterogeneous with irregular, peripheral rim enhancement, and a variable degree of central enhancement depending on the abundance of solid myxoid tissue and bridging fibrous septa. Conclusions: knowledge of mazabraud's syndrome and the imaging appearance of intramuscular myxoma is important in order to avoid unnecessary biopsies of the osseous and soft tissue lesions. The unique features of this disorder allow discrimination from soft tissue malignancies such as sarcoma. C1 Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. Radiol Associates Indianapolis, Dept Radiol, Indianapolis, IN USA. Commonwealth Radiol, Richmond, VA USA. Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Steinbach, LS (reprint author), Univ Calif San Francisco, Dept Radiol, 505 Parnassus,Rm M392, San Francisco, CA 94143 USA. NR 25 TC 27 Z9 30 U1 1 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0364-2348 J9 SKELETAL RADIOL JI Skeletal Radiol. PD FEB PY 2002 VL 31 IS 2 BP 81 EP 87 DI 10.1007/s00256-001-0453-0 PG 7 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA 528GR UT WOS:000174236500002 PM 11828328 ER PT J AU Graham, JS Schomacker, KT Glatter, RD Briscoe, CM Braue, EH Squibb, KS AF Graham, JS Schomacker, KT Glatter, RD Briscoe, CM Braue, EH Squibb, KS TI Bioengineering methods employed in the study of wound healing of sulphur mustard burns SO SKIN RESEARCH AND TECHNOLOGY LA English DT Article DE sulphur mustard; wound healing; transepidermal water loss; reflectance colourimetry; laser Doppler perfusion imaging ID LASER DOPPLER FLOWMETRY; HAIRLESS GUINEA-PIGS; SULFUR MUSTARD; SKIN INJURY; MODEL; TOXICITY; DEPTH; EAR AB Background/purpose: Sulphur mustard (SM) is a potent incapacitating chemical warfare agent that remains a threat to war fighters and civilians worldwide. SM lesions may require weeks or months to heal, depending upon their severity. This study was undertaken to find a treatment regimen that promotes speedier healing of deep cutaneous SM burns in a weanling pig model. The principal objective of the study was to compare four treatment regimens and establish which achieved the shortest healing time. Methods: Twelve Yorkshire Cross weanling pigs were exposed to SM liquid for 2h, generating six large deep dermal/full thickness burns on the ventrum of each animal. Three additional animals served as sham-exposed controls. Surgical intervention occurred at 48 h postexposure. Treatments included: (i) full-thickness debridement of the burns with a computer controlled, raster scanned continuous wave CO2 laser followed by autologous split-thickness skin grafting; (ii) full-thickness sharp surgical tangential excision followed by skin grafting, the 'Gold Standard' used in human deep dermal/full-thickness thermal burns management; (iii) partial-thickness laser ablation with no grafting; and (iv) partial-thickness sharp surgical excision with no grafting. Several non-invasive bioengineering methods were used to monitor the progress of wound healing throughout a 36-day healing period: reflectance colourimetry, evaporimetry, laser Doppler perfusion imaging and ballistometry. Results: Bioengineering methods indicated that laser debridement followed by autologous split-thickness skin grafting was as efficacious in improving the wound healing of deep SM burns in weanling swine as the 'Gold Standard.' Regardless of the method of debridement, barrier function, skin colour and mechanical properties returned to near-normal levels within 15 days of treatment in the grafted sites. Regardless of surgical approach, blood flux levels remained approximately 50-60% of normal tissue throughout the 36-day postsurgical observation period. Mid-dermal debridement by sharp surgical tangential excision or laser ablation without the use of skin grafts did not produce as good a result as those attained through the use of grafts, but was better than no surgical treatment of the wounds. Conclusion: Bioengineering methods were useful in evaluating multiple characteristics during wound healing: (i) reflectance colourimetry for skin colour, (ii) evaporimetry to measure transepidermal water loss as an indicator of barrier function, (iii) laser Doppler perfusion imaging to assess cutaneous blood flow, and (iv) ballistometry to measure the mechanical properties of skin hardness and elasticity. Perhaps the most useful method was evaporimetry, as a restored barrier function was the best indicator of healed wounds. The use of reflectance colourimetry and ballistometry will continue in future wound healing studies for their contributions in judging cosmetic and functional outcomes. While useful, laser Doppler perfusion imaging was found to be rather time consuming. This methodology will be limited in the future to burn depth estimation prior to treatment, and for evaluation of pharmaceuticals specifically designed to improve or sustain blood flow into damaged areas. C1 USA, Med Res Inst Chem Def, Div Comparat Med, Comparat Pathol Branch, Aberdeen Proving Ground, MD 21010 USA. Massachusetts Gen Hosp, Wellman Labs Photomed, Boston, MA 02114 USA. USA, Med Res Inst Chem Def, Drug Assessment Div, Adv Assessment Branch, Aberdeen Proving Ground, MD 21010 USA. Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. RP Graham, JS (reprint author), USA, Med Res Inst Chem Def, Div Comparat Med, Comparat Pathol Branch, 3100 Ricketts Point Rd, Aberdeen Proving Ground, MD 21010 USA. NR 51 TC 23 Z9 24 U1 0 U2 5 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0909-752X J9 SKIN RES TECHNOL JI Skin Res. Technol. PD FEB PY 2002 VL 8 IS 1 BP 57 EP 69 DI 10.1046/j.0909-752x.2001.10314.x PG 13 WC Dermatology SC Dermatology GA 528GM UT WOS:000174236100009 PM 12005121 ER PT J AU Takeuchi, T Fukuda, K Sasaki, Y Inugami, M Murphy, TI AF Takeuchi, T Fukuda, K Sasaki, Y Inugami, M Murphy, TI TI Factors related to the occurrence of isolated sleep paralysis elicited during a multi-phasic sleep-wake schedule SO SLEEP LA English DT Article DE sleep; sleep paralysis; normal; SOREMP; REM; sleep disruption; performance; sleep wake cycle; fatigue; sleepiness ID REM-SLEEP; CIRCADIAN-RHYTHM; BODY-TEMPERATURE; BLACK SUBJECTS; PREVALENCE; ONSET; INTERRUPTION; STRESS; OCCURS; CYCLE AB Study Objectives: To further investigate mechanisms of isolated sleep paralysis (ISP) in normal individuals, we experimentally elicited ISPs by facilitating sleep onset REM periods (SOREMP), a prerequisite of ISPs, and examined behavioral and psychological measurements relating to ISP appearances. Design: The multi-phasic sleep/wake schedule (MPS) began at approximately midnight and ended when net sleep reached 7.5 hours. Participants were awakened after every 5 min of REM sleep to obtain a maximum number of SOREMPs. Upon each awakening, mentation reports and subjective measurements were collected. Performance tests were then assigned. Setting: Sleep lab, Tokyo Metropolitan Institute for Neurosciences, Japan. Participants: Thirteen healthy Japanese students (10 males) with high self-reported frequencies of ISPs but no other narcolepsy-related symptoms. Interventions: NA Measurements and results: From 184 sleep interruptions, 8 ISP episodes were obtained. In within participant comparisons between episodes with and without ISPs, the vigilance task (VT) reaction times were elevated before SOREMPs with ISPs. In between analyses (ISP vs non-ISP), the ISP group showed poorer performance, more complaints of physical, mental, and neurotic symptoms, increased subjective fatigue and increased stage 1 throughout the entire schedule. VT hit rates remained constant in the non-ISP group, but dropped in the later part of schedule in the ISP group. Subjective sleepiness dropped over time in the non-ISP group while it slightly increased in the ISP group. Conclusions: ISP is likely to appear as a phenotype of REM dissociation during SOREMP when participants with low tolerance for disrupted sleep-wake rhythms are placed in this type of schedule. C1 Hop Sacre Coeur, Ctr Etud Sommeil, Montreal, PQ H4J 1C5, Canada. Fukushima Univ, Fukushima, Japan. Massachusetts Gen Hosp, Dept Radiol, NMR Ctr, Boston, MA 02114 USA. Tokyo Metropolitan Inst Neurosci, Tokyo, Japan. Univ Waterloo, Waterloo, ON N2L 3G1, Canada. RP Takeuchi, T (reprint author), Hop Sacre Coeur, Ctr Etud Sommeil, 5400 Gouin Boul Ouest, Montreal, PQ H4J 1C5, Canada. NR 54 TC 14 Z9 16 U1 2 U2 6 PU AMER ACAD SLEEP MEDICINE PI ROCHESTER PA 6301 BANDEL RD, STE 101, ROCHESTER, MN 55901 USA SN 0161-8105 J9 SLEEP JI Sleep PD FEB 1 PY 2002 VL 25 IS 1 BP 89 EP 96 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 514AZ UT WOS:000173415100014 PM 11833865 ER PT J AU Howard, VJ Sides, EG Newman, GC Cohen, SN Howard, G Malinow, MR Toole, JF AF Howard, VJ Sides, EG Newman, GC Cohen, SN Howard, G Malinow, MR Toole, JF CA Stability Plasma Homocysteine Acut TI Changes in plasma homocyst(e)ine in the acute phase after stroke SO STROKE LA English DT Article DE homocyst(e)ine; stroke, acute; stroke, ischemic ID ACUTE MYOCARDIAL-INFARCTION; TOTAL HOMOCYSTEINE LEVELS; CARDIOVASCULAR-DISEASE; ISCHEMIC STROKE; RISK FACTOR; FOLIC-ACID AB Background and Purpose-Elevated plasma homocyst(e)ine [H(e)] concentration has been associated with an increased risk of stroke. Although the literature suggests that H(e) increases from the acute to the convalescent phase after a stroke, it is not known whether H(e) changes within the acute period. Methods-A prospective, multicenter study was conducted to examine changes in H(e) during the 2 weeks after an incident stroke. Blood samples were collected at days 1, 3, 5, 7, and between 10 and 14 days after the stroke. Results-Seventy-six participants (51 men) were enrolled from 9 sites from February 1997 through June 1998. Mean age was 65.6 years, and subjects had at least two H(e) measurements. The estimated mean H(e) level at baseline was 11.3+/-0.5 mumol/L, which increased consistently to a mean of 12.0+/-0.05, 12.4+/-0.5, 13.3+/-0.5, and 13.7+/-0.7 mumol/L at days 3, 5, 7, and 10 to 14, respectively. The magnitude of the change in H(e) was not affected by age, sex, smoking status, alcohol use, history of hypertension or diabetes, or Rankin Scale Score. Conclusions-These data suggest that the clinical interpretation of H(e) after stroke and the eligibility for clinical trials assessing treatment for elevated H(e) levels require an adjustment in time since stroke to properly interpret the observed H(e) levels. C1 Univ Alabama, Dept Epidemiol & Int Hlth, Birmingham, AL 35294 USA. Univ Alabama, Dept Biostat, Birmingham, AL 35294 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Neurol, Ctr Stroke Res, Winston Salem, NC 27103 USA. SUNY Stony Brook, Dept Neurol, Stony Brook, NY 11794 USA. Cedars Sinai Med Ctr, Div Neurol, Los Angeles, CA 90048 USA. W Los Angeles Vet Affairs Healthcare Ctr, Dept Neurol, Los Angeles, CA USA. Oregon Reg Primate Res Ctr, Beaverton, OR 97006 USA. RP Howard, VJ (reprint author), Univ Alabama, Dept Epidemiol & Int Hlth, 1530 3rd Ave S,RPHB 210F, Birmingham, AL 35294 USA. FU NINDS NIH HHS [R01 NS34447] NR 32 TC 62 Z9 66 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2002 VL 33 IS 2 BP 473 EP 478 DI 10.1161/hs0202.103069 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 518AX UT WOS:000173644900010 PM 11823655 ER PT J AU Sweeney, T Rayan, S Warren, H Rattner, D AF Sweeney, T Rayan, S Warren, H Rattner, D TI Intestinal anastomoses detected with a photopolymerized hydrogel SO SURGERY LA English DT Article ID FIBRIN GLUE; ADHESION PREVENTION; SUTURELESS; SEALANT; RAT; EFFICACY; BARRIERS AB Background. This study examines the efficacy of a novel, absorbable Photopolymerized hydrogel sealant, Focalseal (Focal Inc, Lexington, Mass), in protecting high-risk suture deficient intestinal anastomoses (HRA) compared with conventional sutured anastomoses (CSA). Methods. Twenty-four New Zealand white rabbits were either randomized to small bowel HRA constructed with 4 interrupted 510 polyglyconate sutures and treated with Focalseal or small bowel CSA constructed with 8 to 10 interrupted 510 polyglyconate sutures. Four rabbits from each group were killed at postoperative days 3, 7, and 21. Anastomoses were assessed for evidence of dehiscence, adhesion formation, stenosis, and bursting pressure; they were also examined histologically for collagen content estimation and blood vessel formation. Results. Mean operative time was 35 minutes (SD 5)for CSA and 35 minutes (SD 5) for HRA. There was I Postoperative death in the HRA group. A postmortem examination revealed no evidence of anastomotic leak. The remaining 23 animals were assessed as planned. There was no evidence of anastomotic dehiscence in any animal. There was no significant difference in adhesion formation (P = .09), stenosis (P = .6), or bursting pressure (P = .2) between HRA and CSA groups. Collagen (P 007) and blood vessel (P =. 002) formation were significantly increased in HRA. Conclusions. I-IRA treated with Focalseal heat well and have similar strength to CSA, This technique may prove valuable in procedures such as laparoscopic bowel resection. C1 Massachusetts Gen Hosp, Div Gen & Gastrointestinal Surg, Dept Surg, Harvard Ctr Minimally Invas Surg, Boston, MA 02114 USA. RP Rattner, D (reprint author), Massachusetts Gen Hosp, Div Gen & Gastrointestinal Surg, Dept Surg, Harvard Ctr Minimally Invas Surg, 15 Parkman St,Wang ACC 337, Boston, MA 02114 USA. NR 18 TC 7 Z9 7 U1 1 U2 1 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 FEB PY 2002 VL 131 IS 2 BP 185 EP 189 DI 10.1067/msy.2002.119492 PG 5 WC Surgery SC Surgery GA 525AJ UT WOS:000174044800012 PM 11854697 ER PT J AU Omoto, T Tanabe, H LaRia, PJ Guererro, J Vlahakes, GJ AF Omoto, T Tanabe, H LaRia, PJ Guererro, J Vlahakes, GJ TI Right ventricular performance during left ventricular unloading conditions: The contribution of the right ventricular free wall SO THORACIC AND CARDIOVASCULAR SURGEON LA English DT Article DE ventricular assist device; right ventricle; right ventricular failure ID CANINE RIGHT VENTRICLE; SYSTOLIC PRESSURE-VOLUME; ASSIST DEVICE; HEART; SUPPORT; PRELOAD; WORK; DOGS AB Aim: Right ventricular (RV) dysfunction is a significant complication following implantation of left ventricular assist device (LVAD). However, RV performance after LVAD implantation remains unclear. We have studied the effects of preload and afterload on RV performance under left ventricular (LV) unloading. Methods: Six adult mongrel dogs were subjected to cardiopulmonary bypass. RV preload and afterload were independently regulated. Dynamic pressure-length analysis of RV free walls was performed using micromanometer catheter and sonomicrometric dimension transducers. Global RV systolic function was evaluated by the relationship between stroke volume vs. end-diastolic length (EDL) or end-diastolic pressure (EDP). We also examined the afterload dependency of RV performance at constant stroke volume. Results: Stroke volume vs. EDP and stroke volume vs. EDL demonstrated a linear relationship (r(2)=0.849+/-0.147 and 0.776+/-0.121, respectively). At constant stroke volume, RV systolic peak pressure vs. EDL or EDP were shown to have a linear relationship (r(2)=0.906+/-0.050 vs. 0.909+/-0.047, respectively). Conclusion: The Frank-Starling relationship for RV performance was shown in this animal model. Without interventricular interaction, RV preload is dependent on RV afterload. C1 Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Omoto, T (reprint author), Heart Ctr N Rhine Westphalia, Dept Cardiovasc Thorac Surg, Georgstr 11, D-32545 Bad Oeynhausen, Germany. NR 24 TC 7 Z9 7 U1 0 U2 2 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0171-6425 J9 THORAC CARDIOV SURG JI Thorac. Cardiovasc. Surg. PD FEB PY 2002 VL 50 IS 1 BP 16 EP 20 DI 10.1055/s-2002-20158 PG 5 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 527BG UT WOS:000174164900004 PM 11847598 ER PT J AU Xu, JM Kogai, T Brent, GA Hershman, JM AF Xu, JM Kogai, T Brent, GA Hershman, JM TI A GC box in the human sodium iodide symporter gene promoter is essential for full activity SO THYROID LA English DT Article ID THYROID TRANSCRIPTION FACTOR; HUMAN NA+/I SYMPORTER; CANCER CELL-LINE; SODIUM/IODIDE-SYMPORTER; MESSENGER-RNA; FACTOR-I; EXPRESSION; THERAPY; CLONING; TUMORS AB We previously reported that the human sodium iodide symporter (hNIS) 5-flanking region between -603 and -415 is essential for full expression. In this study, we further localized sequences within this region required for the basal expression of the hNIS promoter and identified a functional GC box. Activity of the hNIS promoter was assessed by transient transfection of luciferase reporter gene constructs with progressive 5' deletions into the human papillary thyroid cancer cell line BHP 2-7. Deletion from -603 to -535 enhanced promoter activity, further deletion to -469 decreased promoter activity, and deletion to -415 nearly abolished promoter activity. The DNA sequence within this critical 55 bp region from -469 to -415 contains a GC box. Introduction of mutations into the GC box of the deletion constructs -603, -535 and -469 decreased promoter activity in both thyroid cells (BHP 2-7 and rat thyroid cell FRTL-5) and nonthyroid cells (human prostate cancer cell LNCaP-2 and human breast cancer cell MCF-7). The magnitude of reduction for the - 603 mutation construct was significantly greater than that for the -469 mutation construct in thyroid cells compared to nonthyroid cells. In vitro transcription using nuclear extracts isolated from HeLa cells was reduced from DNA templates with the GC box mutation and nearly abolished from templates with 5' deletion to -415. Identification of proteins interacting with the GC box was performed by gel retardation assays with or without Sp1 specific antibodies. Sp1 and an "Sp1-like" protein bound to the wild-type GC box sequence but not to the GC box mutant. In summary, the GC box is a positive regulatory element in the hNIS basal promoter. C1 VA Greater Los Angeles Healthcare Syst, Div Endocrinol & Metab, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. RP Hershman, JM (reprint author), VA Greater Los Angeles Healthcare Syst, Div Endocrinol 111D, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. RI Ain, Kenneth/A-5179-2012 OI Ain, Kenneth/0000-0002-2668-934X NR 31 TC 8 Z9 8 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1050-7256 J9 THYROID JI Thyroid PD FEB PY 2002 VL 12 IS 2 BP 107 EP 114 DI 10.1089/105072502753522338 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 530GU UT WOS:000174350600004 PM 11916279 ER PT J AU Fukata, S Miyauchi, A Kuma, K Sugawara, M AF Fukata, S Miyauchi, A Kuma, K Sugawara, M TI Acute suppurative thyroiditis caused by an infected piriform sinus fistula with thyrotoxicosis SO THYROID LA English DT Article; Proceedings Paper CT 71st Annual Meeting of the American-Thyroid-Association CY SEP 16-20, 1998 CL PORTLAND, OREGON SP Amer Thyroid Assoc ID BODY AB We report herein an unusual case of thyrotoxicosis caused by acute suppurative thyroiditis (AST) infected through a piriform sinus fistula (PSF). A 28-year-old man presented with pain over the thyroid gland and elevated serum thyroid hormone levels, a picture similar to subacute thyroiditis. A fine-needle aspiration biopsy from the left lobe showed neutrophil. infiltration, and culture from the aspirate grew anaerobic peptostreptococcus. A neck computed tomography (CT) scan showed an abscess in the thyroid gland, and barium swallow revealed the presence of PSF. Appropriate antibiotic treatment ameliorated his symptoms of infection, followed by normalization of thyroid function. Three months later, he underwent fistulectomy and partial left lobectomy. The end of the PSF track was found in the left thyroid lobe. Thus infection of the thyroid gland through the infected PSF was likely the cause of supprative thyroiditis. The unusual clinical features of AST in this patient include the presence of severe thyrotoxicosis, relatively late onset (28-years-old) of infection despite the presence of congenital PSF, and the lack of acute inflammatory signs on the overlying skin of the thyroid gland. It is important to recognize this type of AST, since fistulectomy is required to prevent recurrent AST. C1 Kuma Hosp, Chuo Ku, Kobe, Hyogo 6500011, Japan. Univ Calif Los Angeles, Sch Med, W Los Angeles Vet Affairs Med Ctr, Dept Endocrinol & Metab, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Dept Internal Med, Los Angeles, CA USA. RP Fukata, S (reprint author), Kuma Hosp, Chuo Ku, 8-2-35 Shimoyamate Dori, Kobe, Hyogo 6500011, Japan. NR 13 TC 15 Z9 20 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1050-7256 J9 THYROID JI Thyroid PD FEB PY 2002 VL 12 IS 2 BP 175 EP 178 DI 10.1089/105072502753522428 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 530GU UT WOS:000174350600013 PM 11916288 ER PT J AU Kamil, SH Aminuddin, BS Bonassar, LJ Silva, CAA Weng, Y Woda, M Vacanti, CA Eavey, RD Vacanti, MP AF Kamil, SH Aminuddin, BS Bonassar, LJ Silva, CAA Weng, Y Woda, M Vacanti, CA Eavey, RD Vacanti, MP TI Tissue-engineered human auricular cartilage demonstrates euploidy by flow cytometry SO TISSUE ENGINEERING LA English DT Article ID NUCLEAR-DNA CONTENT; GROWTH-FACTORS; TUMORS; CHONDROSARCOMA; PROLIFERATION AB Transforming growth factor-beta (TGF-beta) and basic fibroblast growth factor (bFGF) are known to stimulate the rate of chondrocyte proliferation. The theoretical risk of malignant transformation associated with growth factor stimulation of chondrocytes should be addressed; aneuploidy has been found to occur in human cartilaginous tumors. In this study, chondrocytes were obtained from six human auricles and cultured in vitro for 6 weeks in the presence or absence of TGF-beta and bFGF. Cells were analyzed for DNA at 3-, 4-, 5-, and 6-week intervals by flow cytometry (FACScan), which demonstrated no evidence of aneuploidy. A persistent increase in S-phase was noted in cells cultured only with TGF-beta. Cells were implanted in athymic mice, and after 8 weeks of implantation, the cartilage constructs formed were examined histologically. The tissue-engineered cartilage cultured originally in bFGF most resembled normal, native cartilage. Specimens cultured in TGF-beta produced suboptimal cartilage morphology. Flow cytometry shows no evidence of aneuploidy, with chondrocytes maintaining their normal diploid state. Further studies incorporating additional methods of analysis need to be done. C1 Univ Massachusetts, Sch Med, Dept Anesthesiol, Lab Tissue Engn, Worcester, MA 01655 USA. Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. Univ Massachusetts, Sch Med, Core Flow Cytometry Lab, Worcester, MA USA. Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01605 USA. RP Vacanti, MP (reprint author), Univ Massachusetts, Sch Med, Dept Anesthesiol, Lab Tissue Engn, Worcester, MA 01655 USA. RI Bonassar, Lawrence/C-2103-2016 OI Bonassar, Lawrence/0000-0003-1094-6433 NR 19 TC 21 Z9 24 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1076-3279 J9 TISSUE ENG JI Tissue Eng. PD FEB PY 2002 VL 8 IS 1 BP 85 EP 92 DI 10.1089/107632702753503081 PG 8 WC Cell & Tissue Engineering SC Cell Biology GA 526YG UT WOS:000174157000009 PM 11886657 ER PT J AU Purmal, A Valeri, CR Dzik, W Pivacek, L Ragno, G Lazo, A Chapman, J AF Purmal, A Valeri, CR Dzik, W Pivacek, L Ragno, G Lazo, A Chapman, J TI Process for the preparation of pathogen-inactivated RBC concentrates by using PEN110 chemistry: preclinical studies SO TRANSFUSION LA English DT Article ID TRANSFUSION AB BACKGROUND: A pathogen-inactivation process for RBC concentrates is being developed by using PEN 110 chemistry (INACTINE, V.I. Technologies). The objective of this study was to characterize the quality of RBCs prepared by using the PEN 110 process and to measure the virucidal effect achieved against two viruses. STUDY DESIGN AND METHODS: Virology and RBC studies were conducted with standard RBC units treated with 0.1-percent (vol/vol) PEN110 at 22degreesC for 6 hours. The quality of PEN 110-treated human RBCs was assessed with biochemical and phenotypic variables. The in vivo viability of PEN110-treated RBCs in baboons was studied with the double-label Cr-51/125l method. RESULTS: Decreases in infectious titer by inactivation of greater than a 5 log 50-percent tissue culture infectious doses per mL of bovine viral diarrhea virus (an enveloped RNA virus) and porcine parvovirus (a nonenveloped DNA virus) was observed. RBC hemolysis was less than 1 percent after 42 days of storage, and no changes in RBC antigens were observed. The in vivo viability of PEN110-treated baboon RBCs was unchanged from control. CONCLUSION: The preparation of RBCs by using the PEN110 process achieved a significant viral reduction of two diverse viruses without causing adverse effects to the RBCs. The process appears to be a promising approach, thus justifying further study. C1 VI Technol Inc, Watertown, MA 02472 USA. Boston Univ, Sch Med, Naval Blood Res Lab, Boston, MA 02118 USA. Massachusetts Gen Hosp, Blood Transfus Serv, Boston, MA 02114 USA. RP Purmal, A (reprint author), VI Technol Inc, 134 Coolidge Ave, Watertown, MA 02472 USA. FU NHLBI NIH HHS [HL 63552] NR 17 TC 42 Z9 45 U1 0 U2 2 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD FEB PY 2002 VL 42 IS 2 BP 139 EP 145 DI 10.1046/j.1537-2995.2002.00020.x PG 7 WC Hematology SC Hematology GA 531ZJ UT WOS:000174446900003 PM 11896326 ER PT J AU Oh, WK Small, EJ AF Oh, WK Small, EJ TI PC-SPES and prostate cancer SO UROLOGIC CLINICS OF NORTH AMERICA LA English DT Article ID CHINESE HERBAL PREPARATION; ETHANOLIC EXTRACTS; CELLS; SUPPLEMENT; APOPTOSIS; INDUCTION; AGENT AB PC-SPES (Botanic Lab, Brea, CA) is a combination of eight herbal therapies with activity against prostate cancer, both in vitro and in vivo. Studies in human prostate cancer cell lines demonstrate significant dose-dependent decreases in cellular viability after exposure to extracts of PC-SPES. Clinical studies suggest that PC-SPES can reduce specific antigen levels in both androgen-dependent and androgen-independent prostate cancer patients. Toxicity is mild, thought there is an approximately 5% risk of thromboembolic events with treatment. Although PC-SPES has apparent estrogenic activity, controversy exists over the exact mechanism of its effects. C1 Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Univ Calif San Francisco, UCSF Comprehens Canc Ctr, San Francisco, CA 94115 USA. RP Oh, WK (reprint author), Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. RI Oh, William/B-9163-2012 OI Oh, William/0000-0001-5113-8147 NR 18 TC 3 Z9 3 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 0094-0143 J9 UROL CLIN N AM JI Urol. Clin. N. Am. PD FEB PY 2002 VL 29 IS 1 BP 59 EP + AR PII S0094-0143(02)00017-4 DI 10.1016/S0094-0143(02)00017-4 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 568JG UT WOS:000176538200007 PM 12109356 ER PT J AU Welch, G Weinger, K Barry, MJ AF Welch, G Weinger, K Barry, MJ TI Quality-of-life impact of lower urinary tract symptom severity: Results from the health professionals follow-up study SO UROLOGY LA English DT Article ID BENIGN PROSTATIC HYPERPLASIA; NATURAL-HISTORY; MEN; HYPERTROPHY; COMMUNITY; STATES AB Objectives. To estimate the magnitude of the quality-of-life impact of lower urinary tract symptom (LUTS) severity using a large (n = 8406) sample of U.S. men participating in the Health Professionals Follow-up Study. Methods. Multiple regression modeling was used to estimate the relative quality-of-life burden of different levels of LUTS severity (defined using the American Urological Association Symptom Index as none-mild symptoms, 0 to 7; low moderate, 8 to 14; high moderate, 15 to 19; and severe, 20 to 35) and to compare these with age-matched U.S. male norms. A standardized and validated measure of both LUTS severity (the American Urological Association Symptom Index) and a widely used, standardized, multidimensional measure of quality of life (Short Form 36) were used. In addition, the relative impact of severe LUTS on the quality of life was compared with that experienced for other chronic illness conditions (diabetes, angina, hypertension, gout). Results. The results showed that high-moderate LUTS was associated with small to moderate deficits in anxious and depressed mood and poorer role functioning related to emotional problems arising from illness. Severe LUTS was associated with additional quality-of-life deficits related to vitality and the ability to work and carry out daily tasks as a result of illness. Comparisons of the severe LUTS patient group with four other chronic illness groups showed vitality/energy, in particular, but also role functioning and depressed and anxious feelings, to be poorer in the severe LUTS group. Conclusions. Men with high-moderate and severe LUTS identified in a large U.S. cohort have a poorer health status in several important quality-of-life dimensions. The detection and effective treatment of LUTS may substantially improve the health status for these men in these dimensions. UROLOGY 59: 245-250, 2002. (C) 2002, Elsevier Science Inc. C1 Joslin Diabet Ctr, Behav & Mental Hlth Res Div, Boston, MA 02215 USA. Massachusetts Gen Hosp, Med Practices Evaluat Ctr, Boston, MA USA. RP Welch, G (reprint author), Joslin Diabet Ctr, Behav & Mental Hlth Res Div, 1 Joslin Pl, Boston, MA 02215 USA. FU AHRQ HHS [HS 08397] NR 24 TC 104 Z9 107 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD FEB PY 2002 VL 59 IS 2 BP 245 EP 250 DI 10.1016/S0090-4295(01)01506-0 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 520QQ UT WOS:000173792900017 PM 11834396 ER PT J AU Jones, HA Metz, JM Devine, P Hahn, SM Whittington, R AF Jones, HA Metz, JM Devine, P Hahn, SM Whittington, R TI Rates of unconventional medical therapy use in patients with prostate cancer: Standard history versus directed questions SO UROLOGY LA English DT Article ID COMPLEMENTARY THERAPIES; CONTROLLED TRIAL; UNITED-STATES; PC-SPES; CARCINOMA; PATTERNS; SUPPLEMENTATION; PREVALENCE; LYCOPENE AB Objectives. The use of unconventional medical therapies (UMTs) in the general population has increased dramatically in the past decade. Studies have estimated that 9% to 64% of patients with cancer use UMTs, and many do not disclose this information to their physicians. This study was designed to evaluate the rates of UMT use by patients with prostate cancer revealed by standard versus directed questioning and to identify demographic markers that may predict use. Methods. A prospective study of 287 consecutive patients with cancer presenting to the Department of Radiation Oncology was performed. The prostate cancer population was 29% (84 of 287) of the total cancer patient population. Each patient underwent the standard history interview, including questions regarding prescription and over-the-counter medication. At the completion of the standard history interview, patients were then asked a set of directed questions regarding the use of UMTs. Results. Of the 84 patients with prostate cancer, 31 (37%) used unconventional therapies. The standard history revealed that 6 (19%) of 31 used UMTs, and directed questioning revealed an additional 25 patients (81%) used UMTs in the study population (P < 0.001). Of those using UMTs, 65% used megavitamins, 49% used herbal remedies, 13% used meditation or guided imagery, and 20% used nonherbal natural supplements. Conclusions. UMT use is prevalent among patients with prostate cancer. Some of these treatments may have a potential biologic impact on tumor behavior, therapeutic endpoints, and measured prostate-specific antigen values. The use of directed questioning during the patient evaluation significantly increases the physician's ability to identify patients with prostate cancer using UMTs. UROLOGY 59: 272-276, 2002. (C) 2002, Elsevier Science Inc. C1 Vet Affairs Med Ctr, Dept Radiat Oncol, Philadelphia, PA USA. Univ Penn, Sch Med, Dept Radiat Oncol, Philadelphia, PA 19104 USA. RP Jones, HA (reprint author), Hosp Univ Penn, Dept Radiat Oncol, 2 Donner,3400 Spruce St, Philadelphia, PA 19104 USA. NR 21 TC 24 Z9 24 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD FEB PY 2002 VL 59 IS 2 BP 272 EP 276 DI 10.1016/S0090-4295(01)01491-1 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 520QQ UT WOS:000173792900022 PM 11834401 ER PT J AU Carlsson, B Singh, BN Temciuc, M Nilsson, S Li, YL Mellin, C Malm, J AF Carlsson, B Singh, BN Temciuc, M Nilsson, S Li, YL Mellin, C Malm, J TI Synthesis and preliminary characterization of a novel antiarrhythmic compound (KB130015) with an improved toxicity profile compared with amiodarone SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID FUNCTIONAL FULL LENGTH; HIGH-LEVEL EXPRESSION; CEREBRAL-CORTEX; CARDIAC MUSCLE; CELLS; RECEPTOR; BINDING; GENE; AGENTS; DRUGS AB Recent developments in antiarrhythmic therapy have indicated that the best approach to pharmacologically controlling supraventricular arrhythmias and life-threatening ventricular tachyarrhythmias is by prolonging cardiac repolarization rather than by blocking conduction. In this context, amiodarone has emerged as the most potent compound, but its universal use has been limited by its toxicity profile. There are data to suggest that an important component of amiodarones antiarrhythmic action might be mediated via inhibition of thyroid hormone action in the heart. Therefore, a new series of carboxymethoxybenzoyl and benzyl derivatives of benzofuran has been prepared and evaluated as thyroid hormone receptor antagonists. Within this series, 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran KB130015 (7) was found to reveal the most promising in vitro data. It inhibits the binding of I-125-T-3 to the human thyroid hormone receptors (hThR) alpha(1) and beta(1). T-3-Antagonism was confirmed in reporter cell assays employing CHOKl cells (Chinese hamster ovary cells) stably transfected with hThRalpha(1) or hThRbeta(1) and an alkaline phosphatase reporter gene downstream a thyroid response element. The derived IC50 values were 2.2 muM for hThRalpha(1) and 4.1 muM for hThRbeta(1). Compound 7 was selected for further characterization of chronic effects on ventricular papillary muscle by transmembrane electrophysiology after daily intraperitoneal injection of the ligand (40 mg/kg body weight) in guinea pigs. Compound 7 was found to prolong the action potential duration at 90% (APD(90)) repolarization time (219 +/- 22 ms, control: 186 +/- 9 ms, p < 0.01) without exhibiting any reverse-rate dependency of action in a manner similar to that of amiodarone. In general, preliminary tolerance experiments with 7 demonstrated an improved safety profile compared to that of amiodarone. In summary, 7 appears to be less toxic than amiodarone while maintaining its electrophysiologic properties consistent with antiarrhythmic activity. Its potential antiarrhythmic actions warrant further investigations. C1 Karolinska Inst, Novum, Karo Bio AB, S-14157 Huddinge, Sweden. W Los Angeles Vet Affairs Med Ctr, Cardiol Sect 111E, Los Angeles, CA 90073 USA. Ideon, Synthelec AB, S-22370 Lund, Sweden. RP Malm, J (reprint author), Karolinska Inst, Novum, Karo Bio AB, S-14157 Huddinge, Sweden. NR 34 TC 91 Z9 93 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JAN 31 PY 2002 VL 45 IS 3 BP 623 EP 630 DI 10.1021/jm001126+ PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 517MZ UT WOS:000173615600008 PM 11806713 ER PT J AU Monney, L Sabatos, CA Gaglia, JL Ryu, A Waldner, H Chernova, T Manning, S Greenfield, EA Coyle, AJ Sobel, RA Freeman, GJ Kuchroo, VK AF Monney, L Sabatos, CA Gaglia, JL Ryu, A Waldner, H Chernova, T Manning, S Greenfield, EA Coyle, AJ Sobel, RA Freeman, GJ Kuchroo, VK TI Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease SO NATURE LA English DT Article ID CHEMOKINE RECEPTOR EXPRESSION; CENTRAL-NERVOUS-SYSTEM; CD4(+) T-CELLS; CUTTING EDGE; LYMPHOCYTES; TH1; ENCEPHALOMYELITIS; THERAPY; ANTIGEN; SUBSETS AB Activation of naive CD4(+) T-helper cells results in the development of at least two distinct effector populations, Th1 and Th2 cells(1-3). Th1 cells produce cytokines (interferon (IFN)-gamma, interleukin (IL)-2, tumour-necrosis factor (TNF)-alpha and lymphotoxin) that are commonly associated with cell-mediated immune responses against intracellular pathogens, delayed-type hypersensitivity reactions 4, and induction of organ-specific autoimmune diseases(5). Th2 cells produce cytokines (IL-4, IL-10 and IL-13) that are crucial for control of extracellular helminthic infections and promote atopic and allergic diseases(4). Although much is known about the functions of these two subsets of T-helper cells, there are few known surface molecules that distinguish between them(6). We report here the identification and characterization of a transmembrane protein, Tim-3, which contains an immunoglobulin and a mucin-like domain and is expressed on differentiated Th1 cells. In vivo administration of antibody to Tim-3 enhances the clinical and pathological severity of experimental autoimmune encephalomyelitis (EAE), a Th1-dependent autoimmune disease, and increases the number and activation level of macrophages. Tim-3 may have an important role in the induction of autoimmune diseases by regulating macrophage activation and/or function. C1 Brigham & Womens Hosp, Dept Neurol, Ctr Neurol Dis, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Millennium Pharmaceut, Cambridge, MA 02139 USA. Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 95305 USA. VA Hlth Care Syst, Palo Alto, CA USA. RP Kuchroo, VK (reprint author), Brigham & Womens Hosp, Dept Neurol, Ctr Neurol Dis, 75 Francis St, Boston, MA 02115 USA. NR 24 TC 565 Z9 651 U1 4 U2 27 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 31 PY 2002 VL 415 IS 6871 BP 536 EP 541 DI 10.1038/415536a PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 516PQ UT WOS:000173564300049 PM 11823861 ER PT J AU Fischl, B Salat, DH Busa, E Albert, M Dieterich, M Haselgrove, C van der Kouwe, A Killiany, R Kennedy, D Klaveness, S Montillo, A Makris, N Rosen, B Dale, AM AF Fischl, B Salat, DH Busa, E Albert, M Dieterich, M Haselgrove, C van der Kouwe, A Killiany, R Kennedy, D Klaveness, S Montillo, A Makris, N Rosen, B Dale, AM TI Whole brain segmentation: Automated labeling of neuroanatomical structures in the human brain SO NEURON LA English DT Article ID EARLY ALZHEIMERS-DISEASE; HUMAN CEREBRAL-CORTEX; OBSESSIVE-COMPULSIVE DISORDER; HIPPOCAMPAL VOLUME REDUCTIONS; MAGNETIC-RESONANCE IMAGES; DEFORMABLE SURFACE MODEL; MEDIAL TEMPORAL ATROPHY; AGE-RELATED-CHANGES; MR-IMAGES; IN-VIVO AB We present a technique for automatically assigning a neuroanatomical label to each voxel in an MRI volume based on probabilistic information automatically estimated from a manually labeled training set. In contrast to existing segmentation procedures that only label a small number of tissue classes, the current method assigns one of 37 labels to each voxel, including left and right caudate, putamen, pallidum, thalamus, lateral ventricles, hippocampus, and amygdala. The classification technique employs a registration procedure that is robust to anatomical variability, including the ventricular enlargement typically associated with neurological diseases and aging. The technique is shown to be comparable in accuracy to manual labeling, and of sufficient sensitivity to robustly detect changes in the volume of noncortical structures that presage the onset of probable Alzheimer's disease. C1 Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Charlestown, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. Massachusetts Gen Hosp, Ctr Neurosci, Ctr Morphometr Anal, Charlestown, MA 02129 USA. Univ Penn, Dept Comp Sci, Philadelphia, PA 19104 USA. RP Dale, AM (reprint author), Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Rm 2328,Bldg 149,13th St, Charlestown, MA 02129 USA. RI Dale, Anders/A-5180-2010; Kennedy, David/H-3627-2012 FU NCRR NIH HHS [P41-RR14075, R01-RR13609]; NINDS NIH HHS [R01-NS34189, R01-NS39581] NR 99 TC 2575 Z9 2593 U1 27 U2 137 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JAN 31 PY 2002 VL 33 IS 3 BP 341 EP 355 DI 10.1016/S0896-6273(02)00569-X PG 15 WC Neurosciences SC Neurosciences & Neurology GA 518AG UT WOS:000173643200006 PM 11832223 ER PT J AU Bazari, H Mauiyyedi, S O'Malley, M McDougal, WS Colvin, RB Niles, JL AF Bazari, H Mauiyyedi, S O'Malley, M McDougal, WS Colvin, RB Niles, JL TI A 75-year-old man with acute renal failure five months after cystoprostatectomy and urethrectomy for carcinoma - Glomerulonephritis mediated by anti glomerular-basement-membrane antibodies. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS; ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES; GOODPASTURES-SYNDROME; CIPROFLOXACIN; VASCULITIS; DISEASE; INSUFFICIENCY; SECONDARY; KIDNEYS; LUNG C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Bazari, H (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 39 TC 3 Z9 3 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 JAN 31 PY 2002 VL 346 IS 5 BP 353 EP 360 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 516GJ UT WOS:000173545300009 PM 11821513 ER PT J AU Bonventre, JV AF Bonventre, JV TI Daily hemodialysis - Will treatment each day improve the outcome in patients with acute renal failure? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID HEMOFILTRATION C1 Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Bonventre, JV (reprint author), Massachusetts Gen Hosp, Charlestown, MA 02129 USA. NR 7 TC 15 Z9 15 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 JAN 31 PY 2002 VL 346 IS 5 BP 362 EP 364 DI 10.1056/NEJM200201313460512 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 516GJ UT WOS:000173545300011 PM 11821514 ER PT J AU Petersen, T Papakostas, GI Bottonari, K Iacoviello, B Alpert, JE Fava, M Nierenberg, AA AF Petersen, T Papakostas, GI Bottonari, K Iacoviello, B Alpert, JE Fava, M Nierenberg, AA TI NEO-FFI factor scores as predictors of clinical response to fluoxetine in depressed outpatients SO PSYCHIATRY RESEARCH LA English DT Article DE depression; neuroticism; NEO-FFI; response to treatment; personality ID CHRONIC-FATIGUE-SYNDROME; MAJOR DEPRESSION; 5-FACTOR MODEL; PERSONALITY-DISORDER; PSYCHOLOGICAL DISTRESS; FOLLOW-UP; UNIPOLAR; BIPOLAR; NEUROTICISM; DIMENSIONS AB Research in unipolar depression suggests that neuroticism is associated with poor long-term outcome and greater chronicity. The objective of this study was to determine whether baseline neuroticism scores predict response to treatment with fluoxetine in depressed outpatients. Seventy-six depressed outpatients participating in a clinical trial of fluoxetine (fixed/flexible dosing) completed the NEO-FFI (five factor inventory short form) at baseline. Clinical response was defined as a 50% or greater decrease in the 17-item Hamilton Depression Rating Scale (HAM-D-17) total score (final visit - baseline). Logistic regression evaluated NEO-FFI factor scores as predictors of treatment outcome within an intent-to-treat model. Scores on the neuroticism scale were not found to significantly predict treatment response as measured by the HAM-D-17. Strengths of this study include a standardized treatment protocol and use of structured interview instruments, while limitations include a modest sample size, lack of continuation data, state/trait effects, and lack of generalizability to other antidepressant treatments. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Dept Psychiat, Depress Clin & Res Program, Boston, MA 02114 USA. RP Petersen, T (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Depress Clin & Res Program, 15 Parkman St,WAC 812, Boston, MA 02114 USA. RI Papakostas, George/I-6905-2013; OI Papakostas, George/0000-0002-2465-5103; Alpert, Jonathan/0000-0002-4332-908X NR 57 TC 24 Z9 24 U1 0 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD JAN 31 PY 2002 VL 109 IS 1 BP 9 EP 16 AR PII S0165-1781(01)00359-6 DI 10.1016/S0165-1781(01)00359-6 PG 8 WC Psychiatry SC Psychiatry GA 525TN UT WOS:000174087200002 PM 11850046 ER PT J AU Kalechstein, AD Newton, TF Leavengood, AH AF Kalechstein, AD Newton, TF Leavengood, AH TI Apathy syndrome in cocaine dependence SO PSYCHIATRY RESEARCH LA English DT Article DE abstinence; depression; Neuropsychiatric Inventory Apathy Subscale; Beck Depression Inventory ID HIV-1 INFECTION; DEPRESSION; ABSTINENCE; WITHDRAWAL; SYMPTOMS; ADDICTS; SLEEP; MOOD AB The cocaine abstinence syndrome has been associated with a range of symptoms, including apathy and depression. Although initial studies reported high prevalence rates of 'apathy/amotivation' and depression, validated rating scales of apathy were not then available. Using a validated measure of apathy, we hypothesized that newly abstinent cocaine-dependent subjects would report increased apathy compared with non-cocaine-using control subjects. Furthermore, because apathy and depression are dissociable in other neuropsychiatric syndromes, we examined whether they were dissociable in recently abstinent cocaine-dependent subjects. Following 4 days of monitored abstinence, cocaine-dependent subjects (n = 11) and non-drug-using control subjects (n = 19) were administered standardized tests of apathy and depression. Cocaine-dependent subjects had elevated scores on the apathy rating scale compared with the control group, but the groups did not differ in ratings of depression. These data suggest that apathy is present during the initial phases of abstinence for a subset of cocaine-dependent individuals. This group may benefit from targeted pharmacological intervention. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Calif Los Angeles, Sch Med, Inst Neuropsychiat, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. W Los Angeles Vet Adm Med Ctr, Psychiat Serv, Los Angeles, CA 90073 USA. RP Kalechstein, AD (reprint author), Univ Calif Los Angeles, Sch Med, Inst Neuropsychiat, Dept Psychiat & Biobehav Sci, 760 Westwood Plaza,A7-372, Los Angeles, CA 90024 USA. OI newton, thomas/0000-0002-3198-5901 FU NIDA NIH HHS [DA00388, DA50038, DA98095, DA07272] NR 18 TC 14 Z9 14 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD JAN 31 PY 2002 VL 109 IS 1 BP 97 EP 100 AR PII S0165-1781(01)00354-7 DI 10.1016/S0165-1781(01)00354-7 PG 4 WC Psychiatry SC Psychiatry GA 525TN UT WOS:000174087200012 PM 11850056 ER PT J AU Wu, SL Mikhailov, A Kallo-Hosein, H Hara, K Yonezawa, K Avruch, J AF Wu, SL Mikhailov, A Kallo-Hosein, H Hara, K Yonezawa, K Avruch, J TI Characterization of ubiquilin 1, an mTOR-interacting protein SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE mTOR; rapamycin; ubiquilin 1; p70 S6 kinase ID 66-KDA PROTEIN; S6 KINASE; RAPAMYCIN; YEAST; PHOSPHORYLATION; 3-KINASE; INSULIN; IDENTIFICATION; INVOLVEMENT; ADIPOCYTES AB The mTOR protein kinase is known to control cell cycle progression and cell growth through regulation of translation, transcription, membrane traffic and protein degradation. Known interactions of mTOR do not account for the multiple functions of this protein. Using a non-catalytic segment of mTOR (1-670) as bait in a yeast two-hybrid screen for interacting proteins, ubiquilin 1 (NM013438) was identified. Ubiquilin 1 is a member of a phylogenetically conserved gene family of unknown function, characterized by an N-terminal ubiquitin-like (Ubq) domain, a C-terminal ubiquitin associated (Uba) domain and a central region containing numerous NPXphi motifs (X, any; phi hydrophobic amino acid). GST-ubiquilin 1 binds specifically to FLAG-mTOR (residues 1-670) in mammalian cells; residues 570-670 of mTOR and 226-323 of ubiquilin 1 are required for this interaction. Both mTOR and ubiquilin immunoreactivity appear as fine speckles throughout the cytoplasm; significant colocalization with cytoskeletal elements, early endosomes or proteasomes is not observed. As assessed by cell fractionation, mTOR is predominantly associated with low density membranes, along with 10% of ubiquilin 1. Ubiquilin 1 is a rapamycin-insensitive phosphoprotein. Overexpression of ubiquilin 1 does not alter the kinase activity of cotransfected mTOR or the phosphorylation of the mTOR target, p70 S6 kinase, in the presence or absence of rapamycin. Our data suggest that we have identified a novel mTOR interactor, ubiquilin 1. The biological significance of this, presumably membrane based, interaction, requires further study. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Massachusetts Gen Hosp, Dept Biol Mol, Brighton, MA 02135 USA. Harvard Univ, Sch Med, Dept Med, Brighton, MA 02135 USA. Kobe Univ, Biosignal Res Ctr, Nada Ku, Kobe, Hyogo 6578501, Japan. RP Avruch, J (reprint author), Massachusetts Gen Hosp, Dept Biol Mol, 50 Blossom St, Brighton, MA 02135 USA. NR 24 TC 40 Z9 43 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD JAN 30 PY 2002 VL 1542 IS 1-3 BP 41 EP 56 AR PII S0167-4889(01)00164-1 DI 10.1016/S0167-4889(01)00164-1 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 525AA UT WOS:000174044000005 PM 11853878 ER PT J AU Alvarez, B Quinn, LS Busquets, S Quiles, MT Lopez-Soriano, FJ Argiles, JM AF Alvarez, B Quinn, LS Busquets, S Quiles, MT Lopez-Soriano, FJ Argiles, JM TI Tumor necrosis factor-alpha exerts interleukin-6-dependent and -independent effects on cultured skeletal muscle cells SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE tumor necrosis factor alpha; skeletal muscle; interleukin-6; cytokine ID CANCER CACHEXIA; EXPRESSION; PROTEIN; MYOGENESIS; CYTOKINES; UBIQUITIN; TNF AB In vivo studies have shown that cancer-associated skeletal muscle wasting (cachexia) is mediated by two cytokines, tumor necrosis factor-alpha (TNF) and interleukin-6 (IL-6). It has been unclear from these studies whether TNF exerts direct effects on skeletal muscle and/or whether these effects are mediated via IL-6. Previous studies from our laboratory have shown that TNF induces IL-6 mRNA expression in cultured skeletal muscle cells. To further investigate the relationship between TNF and IL-6. the effects of TNF and IL-6 on protein and DNA dynamics in murine C2C12 skeletal myotube cultures were determined. At 1000 U/ml. TNF induced 30% increases in protein and DNA content. The effects of TNF on protein accumulation were inhibited by aphidicolin, an inhibitor of DNA synthesis. IL-6 mimicked the effects of TNF on C2C12 cultures. inducing a 32% increase in protein accumulation and a 71% increase in the rate of protein synthesis. IL-6 also decreased expression of mRNA for several proteolytic system components, including ubiquitin 2.4 kb (51%) and 1.2 kb (63%). cathepsin B (39%) and m-calpain (47%), indicating that IL-6 acts on both protein synthesis and degradation. Incubation of murine C2C12 myotube cultures with TNF (1000 U/ml) in the presence of a polyclonal mouse anti-IL-6 antibody resulted in an abolishment of the effects of TNF on protein synthesis. but did not inhibit TNF-induced stimulation of DNA synthesis. These findings indicate that the effects of TNF on muscle protein synthesis are mediated by IL-6, but that TNF exerts IL-6-independent effects on proliferation of marine skeletal myoblasts. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Barcelona, Fac Biol, Canc Res Grp, Dept Bioquim & Biol Mol, Barcelona 08028, Spain. VA Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Amer Lake Div, Tacoma, WA 98493 USA. Hosp Gen Valle Hebron, Barcelona, Spain. RP Argiles, JM (reprint author), Univ Barcelona, Fac Biol, Canc Res Grp, Dept Bioquim & Biol Mol, Diagonal 645, Barcelona 08028, Spain. NR 21 TC 44 Z9 45 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD JAN 30 PY 2002 VL 1542 IS 1-3 BP 66 EP 72 AR PII S0167-4889(01)00167-7 DI 10.1016/S0167-4889(01)00167-7 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 525AA UT WOS:000174044000007 PM 11853880 ER PT J AU Kodama, T Doukas, AG Hamblin, MR AF Kodama, T Doukas, AG Hamblin, MR TI Shock wave-mediated molecular delivery into cells SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE shock tube; membrane permeabilization; FITC-dextran; digitonin; flow cytometry; fluorescence ID DIGITONIN-PERMEABILIZED CELLS; GENE-TRANSFER; ANTISENSE OLIGONUCLEOTIDES; PLASMA-MEMBRANE; LEUKEMIA-CELLS; NUCLEAR IMPORT; IN-VITRO; ELECTROPORATION; DNA; ELECTROPERMEABILIZATION AB A single shock wave generated by a shock tube is able to effectively deliver macromolecules such as fluorescein isothiocyanate-dextran into the cytoplasm of living cells without causing cytotoxicity. We report on the effect of varying the molecular weight of the dextran and the number of shock waves on the efficiency of delivery into a cancer cell line. The fraction of cells permeabilized and the total fluorescence delivered were measured by flow cytometry, and the cellular viability by a tetrazolium assay on adherent cells and these values were compared to cell permeabilization using digitonin. Shock waves can deliver molecules of up to 2 000 000 molecular weight into the cytoplasm of cells without toxicity and may have applications in gene therapy. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Massachusetts Gen Hosp, Wellman Labs Photomed, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02114 USA. RP Kodama, T (reprint author), Massachusetts Gen Hosp, Wellman Labs Photomed, BAR314B,55 Fruit St, Boston, MA 02114 USA. OI kodama, tetsuya/0000-0003-4727-9558; Hamblin, Michael/0000-0001-6431-4605 NR 30 TC 40 Z9 40 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD JAN 30 PY 2002 VL 1542 IS 1-3 BP 186 EP 194 AR PII S0167-4889(01)00177-X DI 10.1016/S0167-4889(01)00177-X PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 525AA UT WOS:000174044000018 PM 11853891 ER PT J AU Betensky, RA Lindsey, JC Ryan, LM Wand, MP AF Betensky, RA Lindsey, JC Ryan, LM Wand, MP TI A local likelihood proportional hazards model for interval censored data SO STATISTICS IN MEDICINE LA English DT Article DE local likelihood methods; interval censored data; proportional hazards; regression model ID FAILURE TIME DATA; REGRESSION-MODELS; TRUNCATED DATA; SPLINES; AIDS; INFERENCE AB We discuss the use of local likelihood methods to fit proportional hazards regression models to right and interval censored data. The assumed model allows for an arbitrary, smoothed baseline hazard on which a vector of covariates operates in a proportional manner, and thus produces an interpretable baseline hazard function along with estimates of global covariate effects. For estimation, we extend the modified EM algorithm suggested by Betensky, Lindsey, Ryan and Wand. We illustrate the method with data on times to deterioration of breast cosmeses and HIV-1 infection rates among haemophiliacs. Copyright (C) 2002 John Wiley Sons, Ltd. C1 Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Betensky, RA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, 655 Huntington Ave, Boston, MA 02115 USA. RI Ryan, Louise/A-4562-2009; Wand, Matt /F-9413-2012 OI Ryan, Louise/0000-0001-5957-2490; Wand, Matt /0000-0003-2555-896X FU NCI NIH HHS [CA48061, CA75791]; NIAID NIH HHS [1U01 41 AI 41110] NR 34 TC 37 Z9 37 U1 0 U2 3 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD JAN 30 PY 2002 VL 21 IS 2 BP 263 EP 275 DI 10.1002/sim.993 PG 13 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 510PV UT WOS:000173217200008 PM 11782064 ER PT J AU Niimura, H Patton, KK McKenna, WJ Soults, J Maron, BJ Seidman, JG Seidman, CE AF Niimura, H Patton, KK McKenna, WJ Soults, J Maron, BJ Seidman, JG Seidman, CE TI Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly SO CIRCULATION LA English DT Article DE cardiomyopathy; genes; aging; hypertrophy ID PROGNOSTIC IMPLICATIONS; SUBAORTIC STENOSIS; HYPERTENSION; FEATURES; HISTORY; AGE AB Background-Hypertrophic cardiomyopathy, a familial myocardial condition caused by sarcomere protein mutations, is usually recognized by early adulthood. Hypertrophic cardiomyopathy of the elderly has similar clinical features but, notably, a later age of onset and noncontributory family history. Causes of elderly-onset hypertrophic cardiomyopathy are unknown. Methods and Results-Eighteen women and 13 men diagnosed with late-onset hypertrophic cardiomyopathy were studied. Initial symptoms occurred at 59.3 (+/-12.3) years, and diagnosis was made at 62.8 (+/-10.8) years. None had family histories of cardiomyopathy. Echocardiography demonstrated maximal left ventricular wall thickness of 19.9+/-3.8 mm systolic anterior motion of the mitral valve (58%), and, in 11 individuals, left ventricular outflow tract gradients (average, 63+/-42.8 mm). Sarcomere protein gene analyses revealed 8 sequence variants in cardiac myosin binding protein-C (1 nonsense, 1 splice acceptor site, and 3 missense), cardiac troponin I (2 missense), and alpha-cardiac myosin heavy chain (1 missense). Seven variants were not found in over 170 normal chromosomes; 1 variant (cardiac myosin binding protein-C Arg326Gln) also occurred in a healthy adult. Conclusions-Hypertrophic cardiomyopathy of the elderly can be a genetic disorder caused by dominant sarcomere protein mutations. The distribution of mutations in elderly-onset disease is strikingly different (P<0.00001) from that of familial, early onset hypertrophic cardiomyopathy. Whereas defects in beta-cardiac myosin heavy chain, cardiac troponin T, and alpha-tropomyosin account for >45% of familial hypertrophic cardiomyopathy, none were found here. Rather, mutations in cardiac myosin binding protein-C, troponin I, and alpha-cardiac myosin heavy chain caused elderly-onset hypertrophic cardiomyopathy. 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, Massachusetts Gen Hosp, Sch Med, Cardiac Unit, Boston, MA USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Kagoshima Univ, Dept Internal Med 1, Kagoshima 890, Japan. Univ London St Georges Hosp, Sch Med, London SW17 0RE, England. Minneapolis Heart Inst Fdn, Minneapolis, MN USA. Brigham & Womens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. RP Seidman, CE (reprint author), Harvard Univ, Sch Med, Dept Genet, 200 Longwood Ave, Boston, MA 02115 USA. RI Patton, Kristen/A-5626-2008; Niimura, Hideshi/H-1814-2012; McKenna, William/C-3243-2008; OI McKenna, William/0000-0001-7994-2460; Patton, Kristen K./0000-0002-9034-6966 NR 31 TC 187 Z9 209 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 29 PY 2002 VL 105 IS 4 BP 446 EP 451 DI 10.1161/hc0402.102990 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 517FM UT WOS:000173600500021 PM 11815426 ER PT J AU Baron, C Pastural, M Lang, P Bentabet, R el Kassar, N Seror, T Dahmane, D Desvaux, D Chopin, D Fruchaud, G Remy, P Grimbert, P Lepage, E Bierling, P AF Baron, C Pastural, M Lang, P Bentabet, R el Kassar, N Seror, T Dahmane, D Desvaux, D Chopin, D Fruchaud, G Remy, P Grimbert, P Lepage, E Bierling, P TI Long-term kidney graft survival across a positive historic but negative current sensitized cross-match SO TRANSPLANTATION LA English DT Article ID RENAL-TRANSPLANTATION; ANTIBODIES; DONOR; SPECIFICITY; RECIPIENT; SERA; RELEVANCE; REJECTION; ASSAY AB Background. The sensitive cross-match (XM) techniques that have been introduced for clinical transplantation can detect anti-donor immune reactivity despite a negative standard National Institute of Health (NIH) cross-match. One of them uses antikappa human light chain globulins (AHG). But there is some discussion about the clinical consequences of a positive AHG-XM in the historical sera that became negative in the sera collected just before the transplantation (pretransplant sera). This study was intended to assess the risk of kidney graft failure associated with a positive historic but negative pretransplant AHG-XM in allosensitized patients having a negative historic NIH-XM. Methods. This retrospective study includes 90 consecutive renal transplants in immunized patients performed at one center between 1985 and 1991. All of the patients had negative historical and pretransplant standard NIH lymphocytotoxic cross-matches and received the same immunosuppressive regimen. The AHG-XMs were done retrospectively using peak historic and sera collected on the day of the transplantation. Results. The AHG cross-match (AHG-XM) was positive in 17 patients, although the standard NIH crossmatch was negative. Fourteen of them had a positive historical but negative pretransplant AHG-XM. The actuarial graft survival in this group of 14 patients was 100% at 1 year and 78% at 9 years compared with 90 and 67%, respectively, in patients with negative historical AHG-XM. In addition, the number of rejection episodes per patient as well as renal function at 1, 2, and 5 years were similar in the two groups. IgG anti-donor HT,A class I accounted for the XM positivity in 12 of the 14 patients; most rapidly lost all antibody reactivity by NTH technique in an average time of 8 months before the transplantation. In conclusion, this study suggests that transplant patients having a negative historic NIH-XM but a positive historic AHG-XM may not be at high risk of graft failure especially if there is a well-documented sera history showing a marked decrease in PRA level before transplantation and a negative pretransplant AHG-XM. C1 Hop Henri Mondor, Dept Nephrol, AP HP, F-94010 Creteil, France. Hop Henri Mondor, Ctr Transfus Sud Est Francilien, F-94010 Creteil, France. Hop Henri Mondor, Dept Histopathol, F-94010 Creteil, France. Hop Henri Mondor, Dept Urol, F-94010 Creteil, France. Hop Henri Mondor, Dept Biostat, F-94010 Creteil, France. Univ Paris 12, JE 2199, F-94010 Creteil, France. Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. RP Baron, C (reprint author), Hop Henri Mondor, Serv Nephrol, 51 Ave Marechal de Lattre de Tassigny, F-94000 Creteil, France. NR 27 TC 7 Z9 9 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JAN 27 PY 2002 VL 73 IS 2 BP 232 EP 236 DI 10.1097/00007890-200201270-00014 PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 519TD UT WOS:000173740800014 PM 11821736 ER PT J AU Alvarez, B Busquets, S Lopez-Soriano, FJ Argiles, JM AF Alvarez, B Busquets, S Lopez-Soriano, FJ Argiles, JM TI TNF-alpha modulates cytokine and cytokine receptors in C2C12 myotubes SO CANCER LETTERS LA English DT Article DE tumour necrosis factor-alpha; skeletal muscle; cachexia; cytokines ID TUMOR-NECROSIS-FACTOR; SKELETAL-MUSCLE; CANCER CACHEXIA; PROTEIN-TURNOVER; INTERLEUKIN-6; EXPRESSION; RATS; INVOLVEMENT; SEPSIS; INDUCE AB Incubation of C2C12 differentiated myotubes in the presence of 1000 units/ml (100 ng/ml) of recombinant murine tumor necrosis factor-alpha (TNF-alpha) for up 6 h caused an important increase in mRNA content of the cytokine (10-fold at 6 h). The levels of expression of the two cytokine receptors were not changed by the cytokine at short-time intervals, but 48 h of treatment resulted in a decreased expression of TNFR1 (33%). Interestingly, the presence of the cytokine resulted in significant increases in mRNA content for the catabolic pro-inflammatory cytokines IL-6 (17-fold) and IFN-gamma (8-fold). Similarly, TNF-alpha also caused a moderate increased expression of different anti-inflammatory cytokines such as IL-9 (104%), IL-10 (24%) and IL-15 (47%). The results suggest that other cytokines may be involved in mediating TNF-a action in skeletal muscle and that anti-inflammatory cytokines may be released as a counter-regulatory mechanism. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Barcelona, Fac Biol, Dept Bioquim & Biol Mol, Canc Res Grp, E-08028 Barcelona, Spain. VA Puget Sound Hlth Care Syst, Amer Lake Div, Geriatr Res Educ & Clin Ctr, Tacoma, WA 98493 USA. RP Argiles, JM (reprint author), Univ Barcelona, Fac Biol, Dept Bioquim & Biol Mol, Canc Res Grp, Diagonal 645, E-08028 Barcelona, Spain. NR 20 TC 23 Z9 23 U1 0 U2 6 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD JAN 25 PY 2002 VL 175 IS 2 BP 181 EP 185 DI 10.1016/S0304-3835(01)00717-0 PG 5 WC Oncology SC Oncology GA 511DX UT WOS:000173250300009 PM 11741746 ER PT J AU Saunders, PR Maillot, C Million, M Tache, Y AF Saunders, PR Maillot, C Million, M Tache, Y TI Peripheral corticotropin-releasing factor induces diarrhea in rats: role of CRF1 receptor in fecal watery excretion SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE CRF (corticotropin-releasing factor); diarrhea; CRF1 receptor; CP-154,526; colon; fecal output ID IRRITABLE-BOWEL-SYNDROME; SMALL-INTESTINE; GUINEA-PIG; HORMONE; ANTAGONIST; STRESS; MOTILITY; CELLS AB Systemic injection of corticotropin-releasing factor (CRF) stimulates colonic secretory and motor functions, and CRF receptors play a role in stress-related alterations of colonic functions. Stress has also been reported to induce diarrhea and we investigated if peripheral injection of CRF can mimic this response in conscious rats. Intravenous (i.v.) injection of CRF (3, 10 or 30 mug/kg) caused diarrhea in 13%, 63% and 75% of rats, respectively, and dose dependently increased the fecal fluid content by 5.1-, 8.6- and 10.8-fold, while the dried solid weight was increased by 5.2-, 4.9- and 5.8-fold, respectively, compared to the i.v. saline group. CRF actions were rapid in onset and blocked by the CRF1 receptor, antagonist CP-154,526 (butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]ethylamine). These results demonstrate that peripheral CRF induces watery diarrhea, primarily through the activation of CRF1 receptor suggesting a possible role for these pathways in colonic responses to stress. (C) 2002 Published by Elsevier Science B.V. C1 Vet Affairs Greater Los Angeles Healthcare Syst, CURE, Digest Dis Res Ctr, Dept Med,Digest Dis Div, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Inst Brain Res, Los Angeles, CA 90073 USA. RP Saunders, PR (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, CURE, Digest Dis Res Ctr, Dept Med,Digest Dis Div, Bldg 115,Rm 117,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. FU NIDDK NIH HHS [DK-41301, DK-57238-01A1S1, DK-57238] NR 26 TC 60 Z9 61 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD JAN 25 PY 2002 VL 435 IS 2-3 BP 231 EP 235 DI 10.1016/S0014-2999(01)01574-6 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 520QU UT WOS:000173793200015 PM 11821031 ER PT J AU Falk, K Lau, JM Santambrogio, L Esteban, VM Puentes, F Rotzschke, O Strominger, JL AF Falk, K Lau, JM Santambrogio, L Esteban, VM Puentes, F Rotzschke, O Strominger, JL TI Ligand exchange of major histocompatibility complex class II proteins is triggered by H-bond donor groups of small molecules SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMATURE DENDRITIC CELLS; MYELIN BASIC-PROTEIN; HLA-DR MOLECULES; IN-VIVO; ANTIGEN PRESENTATION; ENCEPHALITOGENIC DETERMINANT; INFLUENZA HEMAGGLUTININ; PROTEOLIPID PROTEIN; CRYSTAL-STRUCTURE; PEPTIDE EXCHANGE AB Hydrogen bonds (H-bonds) are crucial for the stability of the peptide-major histocompatibility complex (MHC) complex. In particular, the H-bonds formed between the peptide ligand and the MHC class 11 binding site appear to have a great influence on the half-life of the complex. Here we show that functional groups with the capacity to disrupt hydrogen bonds (e.g. -OH) can efficiently catalyze ligand exchange reactions on HLA-DR molecules. In conjunction with simple carrier molecules (such as propyl or benzyl residues), they trigger the release of low affinity ligands, which permits the rapid binding of peptides with higher affinity. Similar to HLA-DM, these compounds are able to influence the MHC class 11 ligand repertoire. In contrast to HLA-DM, however, these simple small molecules are still active at neutral pH. Under physiological conditions, they increase the number of "peptide-receptive" MHC class 11 molecules and facilitate exogenous peptide loading of dendritic cells. The drastic acceleration of the ligand exchange on these antigen presenting cells suggests that, in general, availability of H-bond donors in the extracellular milieu controls the rate of MHC class II ligand exchange reactions on the cell surface. These molecules may therefore be extremely useful for the loading of antigens onto dendritic cells for therapeutic purposes. C1 Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany. Dana Farber Canc Inst, Dept Canc Immunol AIDS, Boston, MA 02115 USA. RP Strominger, JL (reprint author), Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. RI Marin-Esteban, Viviana/A-8856-2014 FU NCI NIH HHS [5R35-CA47554]; NIAID NIH HHS [N01-AI-45198]; PHS HHS [R01-48832] NR 45 TC 35 Z9 37 U1 1 U2 9 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 JAN 25 PY 2002 VL 277 IS 4 BP 2709 EP 2715 DI 10.1074/jbc.M109098200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 514CY UT WOS:000173421500045 PM 11602608 ER PT J AU Seykora, JT Mei, L Dotto, GP Stein, PL AF Seykora, JT Mei, L Dotto, GP Stein, PL TI Srcasm: a novel Src activating and signaling molecule SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; PROTEIN-TYROSINE KINASE; LONG-TERM POTENTIATION; C-SRC; PHOSPHATIDYLINOSITOL 3-KINASE; KERATINOCYTE DIFFERENTIATION; BINDING-SPECIFICITY; REVERSE 2-HYBRID; FACTOR RECEPTOR; FAMILY KINASES AB The Src family tyrosine kinase, Fyn, can facilitate regulation of cell proliferation and differentiation. Mice with mutations in the fyn gene have defects in the brain, immune system, and epidermal differentiation. To identify molecules that may interact with Fyn in the epidermis, we performed a yeast two-hybrid interaction screen of a murine keratinocyte library. A novel adaptor-like molecule was isolated and termed Srcasm for Src activating and signaling molecule. Murine Srcasm is a 52.7-kDa protein that contains a VHS membrane association domain and a number of tyrosine motifs suggesting that it may be a substrate for Src family kinases and serve as an adaptor protein. Northern blot analysis of murine tissues demonstrates that Srcasm expression is highest in brain and kidney. In situ hybridization analysis reveals that srcasm mRNA is expressed in regions of the epidermis and hair follicle where keratinocyte differentiation occurs. In the brain, srcasm mRNA distribution correlates with that of fyn, with both being highly expressed in the hippocampal and cerebellar Purkinje neurons. Fyn can phosphorylate Srcasm, and association of these molecules relies on cooperative binding between the SH2 and SH3 domains of Fyn and corresponding canonical binding sites in Srcasm. Srcasm is capable of interacting with Grb2 and the regulatory subunit of phosphoinositide 3-kinase, p85, in a phosphorylation-dependent manner. The evidence suggests that Srcasm may help promote Src family kinase signaling in cells. C1 Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Stein, PL (reprint author), Rm 217,Clin Res Bldg,415 Curie Blvd, Philadelphia, PA 19104 USA. FU NIAMS NIH HHS [K08 AR047597, ARO7465] NR 70 TC 36 Z9 47 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 JAN 25 PY 2002 VL 277 IS 4 BP 2812 EP 2822 DI 10.1074/jbc.M106813200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 514CY UT WOS:000173421500059 PM 11711534 ER PT J AU Counter, SA Buchanan, LH Ortega, F Laurell, G AF Counter, SA Buchanan, LH Ortega, F Laurell, G TI Elevated blood mercury and neuro-otological observations in children of the Ecuadorian gold mines SO JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A LA English DT Article ID NERVOUS-SYSTEM; FETAL METHYLMERCURY; ELEMENTAL MERCURY; CLINICAL-FEATURES; INORGANIC MERCURY; MINAMATA DISEASE; AMAZON BASIN; MINING AREA; EXPOSURE; VAPOR AB The prevalence of mercury (Hg) intoxication seas investigated in 114 Andean Saraguro and non-Saraguro (Mestizo) children living in remote gold-mining settlements in Nambija and Portovelo, Ecuador. Venous blood samples showed a mean total blood mercury (B-Hg) level of 18.2 mug/L (SE) 15.5; range 2-89.) for 77 Saraguro and non-Saraguro children in the Nambija settlement, which was significantly higher than that of children in the Portovelo and reference groups. Comparison of groups showed mean B-Hg levels of 26.4 mug/L (range 4-89 mug/L) for 32 indigenous/Saraguro children; 12.3 mug/L (range 2-33 mug/L) for 45 non-Saraguro children; 4.9 mug/L (range 1-10 mug/L) for 37 children in Portovelo; and 2.4 mug/L (range 1-6 mug/L) for a reference group of 15 children. Fisher's post hoc analysis revealed significant differences among groups, except between the Portovelo and the reference groups. Neuro-otological symptoms and abnormalities were observed in Saraguro, non-Saraguro, and Portovelo children, Samples of soil collected at sites near the local school were found to contain Hg levels ranging from 0.1 to 38 ppm, cadmium (Cd) levels from 0.07 to 0.82 ppm and arsenic (As) levels from < 1 to 3.9 ppm. In conclusion, the children of Nambija, particularly the Saraguro "Amer-Indians," exhibited elevated B-Hg levels from exposure to Hg used in the gold-mining process, and are at risk for neurological impairment. The children of Portovelo who reported neuro-otological symptoms but had low B-Hg levels (<10 mug/L) may be affected by exposure to sodium cyanide, which is used extensively in the local gold-mining operations. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Biol Labs, Cambridge, MA 02138 USA. Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden. Harvard Univ Hlth Serv, Shriver Ctr, LEND Program, Dept Audiol, Waltham, MA USA. Univ San Francisco, Dept Dev & Community Hlth, Quito, Ecuador. Karolinska Inst Hosp, Dept Physiol & Pharmacol, Stockholm, Sweden. Karolinska Inst Hosp, Dept Otolaryngol, Stockholm, Sweden. RP Counter, SA (reprint author), Harvard Univ, Biol Labs, Cambridge, MA 02138 USA. NR 51 TC 53 Z9 59 U1 0 U2 12 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1528-7394 J9 J TOXICOL ENV HEAL A JI J. TOXICOL. ENV. HEALTH PT A PD JAN 25 PY 2002 VL 65 IS 2 BP 149 EP 163 DI 10.1080/152873902753396785 PG 15 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 514NF UT WOS:000173447000002 PM 11820503 ER PT J AU Pomeroy, SL Tamayo, P Gaasenbeek, M Sturla, LM Angelo, M McLaughlin, ME Kim, JYH Goumnerova, LC Black, PM Lau, C Allen, JC Zagzag, D Olson, JM Curran, T Wetmore, C Biegel, JA Poggio, T Mukherjee, S Rifkin, R Califano, A Stolovitzky, G Louis, DN Mesirov, JP Lander, ES Golub, TR AF Pomeroy, SL Tamayo, P Gaasenbeek, M Sturla, LM Angelo, M McLaughlin, ME Kim, JYH Goumnerova, LC Black, PM Lau, C Allen, JC Zagzag, D Olson, JM Curran, T Wetmore, C Biegel, JA Poggio, T Mukherjee, S Rifkin, R Califano, A Stolovitzky, G Louis, DN Mesirov, JP Lander, ES Golub, TR TI Prediction of central nervous system embryonal tumour outcome based on gene expression SO NATURE LA English DT Article ID HUMAN HOMOLOG; CEREBELLAR MEDULLOBLASTOMA; SONIC HEDGEHOG; RECEPTOR TRKC; CELL LINEAGE; GERM-LINE; MUTATIONS; CANCER; PATTERNS AB Embryonal tumours of the central nervous system (CNS) represent a heterogeneous group of tumours about which little is known biologically, and whose diagnosis, on the basis of morphologic appearance alone, is controversial. Medulloblastomas, for example, are the most common malignant brain tumour of childhood, but their pathogenesis is unknown, their relationship to other embryonal CNS tumours is debated(1,2), and patients' response to therapy is difficult to predict(3). We approached these problems by developing a classification system based on DNA microarray gene expression data derived from 99 patient samples. Here we demonstrate that medulloblastomas are molecularly distinct from other brain tumours including primitive neuroectodermal tumours (PNETs), atypical teratoid/rhabdoid tumours (AT/RTs) and malignant gliomas. Previously unrecognized evidence supporting the derivation of medulloblastomas from cerebellar granule cells through activation of the Sonic Hedgehog (SHH) pathway was also revealed. We show further that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumours at diagnosis. C1 Harvard Univ, Sch Med, Dept Neurol, Div Neurosci, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurosurg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Childrens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol & Neurosurg Serv, Boston, MA 02115 USA. MIT, Whitehead Inst MIT Ctr Genome Res, Cambridge, MA 02139 USA. MIT, McGovern Inst, Ctr Biol & Computat Learning, AI Lab, Cambridge, MA 02139 USA. Baylor Coll Med, Div Pediat Oncol, Houston, TX 77030 USA. Beth Israel Deaconess Med Ctr, New York, NY 10128 USA. NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA. Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Pediat,Div Human Genet, Philadelphia, PA 19104 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. IBM Corp, Thomas J Watson Res Ctr, Yorktown Hts, NY 10598 USA. RP Pomeroy, SL (reprint author), Harvard Univ, Sch Med, Dept Neurol, Div Neurosci, Boston, MA 02115 USA. EM scott.pomeroy@tch.harvard.edu; golub@genome.wi.mit.edu RI Califano, Andrea/F-7239-2012; Curran, Tom/C-1164-2008; Curran, Tom/D-7515-2011; OI Curran, Tom/0000-0003-1444-7551; Mukherjee, Sayan/0000-0002-6715-3920 NR 30 TC 1354 Z9 1393 U1 7 U2 52 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 24 PY 2002 VL 415 IS 6870 BP 436 EP 442 DI 10.1038/415436a PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 514HR UT WOS:000173433600052 PM 11807556 ER PT J AU Walsh, TJ Pappas, P Winston, DJ Lazarus, HM Petersen, F Raffalli, J Yanovich, S Stiff, P Greenberg, R Donowitz, G Lee, J AF Walsh, TJ Pappas, P Winston, DJ Lazarus, HM Petersen, F Raffalli, J Yanovich, S Stiff, P Greenberg, R Donowitz, G Lee, J CA Natl Inst Allergy Infect Dis Mycos TI Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID IN-VITRO ACTIVITY; INVASIVE ASPERGILLOSIS; PROGNOSTIC FACTORS; RANDOMIZED TRIAL; PROLONGED FEVER; CANCER-PATIENTS; RISK-FACTORS; AGENTS; FLUCONAZOLE; FUNGI AB Background: Patients with neutropenia and persistent fever are often treated empirically with amphotericin B or liposomal amphotericin B to prevent invasive fungal infections. Antifungal triazoles offer a potentially safer and effective alternative. Methods: In a randomized, international, multicenter trial, we compared voriconazole, a new second-generation triazole, with liposomal amphotericin B for empirical antifungal therapy. Results: A total of 837 patients (415 assigned to voriconazole and 422 to liposomal amphotericin B) were evaluated for success of treatment. The overall success rates were 26.0 percent with voriconazole and 30.6 percent with liposomal amphotericin B (95 percent confidence interval for the difference, -10.6 to 1.6 percentage points); these rates were independent of the administration of antifungal prophylaxis or the use of colony-stimulating factors. There were fewer documented breakthrough fungal infections in patients treated with voriconazole than in those treated with liposomal amphotericin B (8 [1.9 percent] vs. 21 [5.0 percent], P=0.02). The voriconazole group had fewer cases of severe infusion-related reactions (P<0.01) and of nephrotoxicity (P<0.001). The incidence of hepatotoxicity was similar in the two groups. Patients receiving voriconazole had more episodes of transient visual changes than those receiving liposomal amphotericin B (22 percent vs. 1 percent, P<0.001) and more hallucinations (4.3 percent vs. 0.5 percent, P<0.001). Parenteral voriconazole was changed to the oral formulation in 22 percent of the voriconazole group, with a reduction in the mean duration of hospitalization by one day in all patients (P=0.17) but by two days in patients at high risk (P=0.03). Conclusions: Voriconazole is a suitable alternative to amphotericin B preparations for empirical antifungal therapy in patients with neutropenia and persistent fever. (N Engl J Med 2002;346:225-34.) Copyright (C) 2002 Massachusetts Medical Society. C1 NCI, Immunocompromised Host Sect, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. Univ Utah, Salt Lake City, UT USA. New York Med Coll, New York, NY USA. Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. Loyola Univ, Med Ctr, Chicago, IL 60611 USA. Univ Kentucky, Lexington, KY USA. Univ Virginia, Charlottesville, VA USA. NIAID, Mycoses Study Grp, Birmingham, AL USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Med & Dent New Jersey, Cooper Hosp, Camden, NJ 08103 USA. Univ Florida, Gainesville, FL USA. Mayo Clin, Rochester, MN USA. Med Ctr Delaware, Newark, DE USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Maisonneuve Rosemont Hosp, Montreal, PQ, Canada. Duke Univ, Durham, NC USA. Univ Ottawa, Ottawa, ON, Canada. Osped ASL Pescara, Pescara, Italy. Univ Arkansas, Little Rock, AR 72204 USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Bldg 10,Rm 13N240, Bethesda, MD 20892 USA. FU NIAID NIH HHS [N01-AI-65296] NR 37 TC 589 Z9 635 U1 1 U2 15 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 JAN 24 PY 2002 VL 346 IS 4 BP 225 EP 234 DI 10.1056/NEJM200201243460403 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 513UR UT WOS:000173398900002 PM 11807146 ER PT J AU Seth, P Krop, I Porter, D Polyak, K AF Seth, P Krop, I Porter, D Polyak, K TI Novel estrogen and tamoxifen induced genes identified by SAGE (Serial Analysis of Gene Expression) SO ONCOGENE LA English DT Article DE estrogen; tamoxifen; SAGE (Serial Analysis of Gene Expression); breast cancer ID SURGICAL-ADJUVANT-BREAST; FACTOR-RESPONSIVE GENE; CANCER CELL-LINE; MESSENGER-RNAS; IN-VITRO; GROWTH; SM-20; DIFFERENTIATION; ANTIESTROGENS; RECEPTORS AB The breast cancer promoting effects of estrogen and the chemopreventive effects of tamoxifen are thought to be mediated by the estrogen receptor, a ligand-dependent transcription factor. Therefore, comprehensive analysis of gene expression profiles following estrogen or tamoxifen treatment may help us better understand the role estrogen plays in tumorigenesis. We utilized SAGE (Serial Analysis of Gene Expression) technology to identify genes regulated by estrogen and tamoxifen in the ZR75-1 estrogen dependent breast cancer cell line. In this manner we have identified several genes that were regulated by estrogen or tamoxifen. Here we report the identification and initial characterization of EIT-6 (Estrogen Induced Tag-6), a novel nuclear protein and a new member of the evolutionarily conserved SM-20 family of growth regulatory immediate-early genes. EIT-6 appears to be a direct transcriptional target of the estrogen receptor and constitutive expression of EIT-6 promotes colony growth in human breast cancer cells. These data indicate that EIT-6 may play a role in estrogen induced cell growth. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Polyak, K (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St D740C, Boston, MA 02115 USA. NR 41 TC 79 Z9 84 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 24 PY 2002 VL 21 IS 5 BP 836 EP 843 DI 10.1038/sj.onc.1205113 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 514FB UT WOS:000173427000014 PM 11850811 ER PT J AU Campbell, EG Clarridge, BR Gokhale, NN Birenbaum, L Hilgartner, S Holtzman, NA Blumenthal, D AF Campbell, EG Clarridge, BR Gokhale, NN Birenbaum, L Hilgartner, S Holtzman, NA Blumenthal, D TI Data withholding in academic genetics - Evidence from a national survey SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID LIFE-SCIENCE; INDUSTRY; FACULTY AB Context The free and open sharing of information, data, and materials regarding published research is vital to the replication of published results, the efficient advancement of science, and the education of students. Yet in daily practice, the ideal of free sharing is often breached. Objective To understand the nature, extent, and consequences of data withholding in academic genetics. Design, Setting, and Participants Mailed survey (March-July 2000) of geneticists and other life scientists In the 100 US universities that received the most funding from the National Institutes of Health in 1998. Of a potential 3000 respondents, 2893 were eligible and 1849 responded, yielding an overall response rate of 64%. We analyzed a subsample of 1240 self-identified geneticists and made a limited number of comparisons with 600 self-identified nongeneticists. Main Outcome Measures Percentage of faculty who made requests for data that were denied; percentage of respondents who denied requests; influences on and consequences of withholding data; and changes over time in perceived willingness to share data. Results Forty-seven percent of geneticists who asked other faculty for additional information, data, or materials regarding published research reported that at least I of their requests had been denied In the preceding 3 years. Ten percent of all post-publication requests for additional information were denied. Because they were denied access to data, 28% of geneticists reported that they had been unable to confirm published research. Twelve percent said that in the previous 3 years, they had denied another academician's request for data concerning published results, Among geneticists who said they had Intentionally withheld data regarding their published work, 80% reported that it required too much effort to produce the materials or information; 64%, that they were protecting the ability of a graduate student, post-doctoral fellow, or junior faculty member to publish; and 53%, that they were protecting their own ability to publish. Thirty-five percent of geneticists said that sharing had decreased during the last decade; 14%, that sharing had increased. Geneticists were as likely as other life scientists to deny others' requests (odds ratio [OR], 1.39; 95% confidence interval [CI], 0.81-2.40) and to have their own requests denied (OR, 0.97; 95% CI, 0.69-1.40). However, other life scientists were less likely to report that withholding had a negative impact on their own research as well as their field of research. Conclusions Data withholding occurs in academic genetics and it affects essential scientific activities such as the ability to confirm published results. Lack of resources and issues of scientific priority may play an important role in scientists' decisions to withhold data, materials, and information from other academic geneticists. C1 Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Univ Massachusetts, Survey Res Ctr, Boston, MA 02125 USA. Johns Hopkins Univ, Dept Hlth Policy & Management, Baltimore, MD 21218 USA. Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Univ, Inst Med Genet, Baltimore, MD USA. Cornell Univ, Dept Sci & Technol Studies, Ithaca, NY USA. RP Campbell, EG (reprint author), Inst Hlth Policy, 50 Staniford St,9th Floor, Boston, MA 02114 USA. FU NHGRI NIH HHS [1R01HG01789-01] NR 18 TC 222 Z9 225 U1 2 U2 23 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 JAN 23 PY 2002 VL 287 IS 4 BP 473 EP 480 DI 10.1001/jama.287.4.473 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 513VX UT WOS:000173401900024 PM 11798369 ER PT J AU Lyamin, OI Mukhametov, LM Chetyrbok, IS Vassiliev, AV AF Lyamin, OI Mukhametov, LM Chetyrbok, IS Vassiliev, AV TI Sleep and wakefulness in the southern sea lion SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE slow wave sleep; paradoxical sleep; interhemispheric EEG asymmetry; southern sea lion; otariidae; pinnipeds ID OTARIA-FLAVESCENS; PAGOPHILUS-GROENLANDICA; ELEPHANT SEALS; BEHAVIOR; PATTERNS; DOLPHINS; BYRONIA; PUPS; EEG AB We recorded an electroencephalogram from the two hemispheres, a neck musculature electromyogram, an electrooculogram, and respiratory acts during sleep and wakefulness on land in three 1-year-old sea lion females for 3 or 4 consecutive days. On average active wakefulness (AW) occupied 20.4 +/- 2.0% of the 24-h period; quiet wakefulness (QW) 54.9 +/- 2.5%; slow wave sleep (SWS) 15.0 +/- 2.5% and paradoxical sleep (PS) 9.7 +/- 2.0%. Between 30 and 50% (average 39.1 +/- 3.4%) of total sleep time was spent in PS. From 8 to 31 episodes of PS were recorded per day (average 17 +/- 6 per day), with the longest episode lasting 20 m in (average 5.6 +/- 0.5 min). Episodes of interhemispheric EEG asymmetry accounted for 5.5 +/- 1.3% of total SWS time. Respiratory pauses in these animals varied in QW between 4 and 36 s (average 15.7 +/- 0.4 s), in SWS between 11 and 37 s (20.9 +/- 0.6 s) and in PS between 2 and 69 s (15.0 +/- 1.5 s). AW, QW, SWS and PS were approximately equally distributed between light (07:00-19:00) and dark time (19:00-07:00). The low amount of SWS with interhemispheric EEG asymmetry, the high proportion of PS in total sleep time and the nearly even distribution of sleep and wakefulness over the 24-h period could be both species-specific features and/or ontogenetic characteristics of the animals studied. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Russian Acad Sci, Severtsov Inst Ecol & Evolut, Moscow 117071, Russia. RP Lyamin, OI (reprint author), VA Greater Los Angeles Healthcare Syst, Ctr Sleep Res 151A3, 16111 Plummer St, North Hills, CA 91343 USA. NR 42 TC 13 Z9 13 U1 2 U2 5 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 JAN 22 PY 2002 VL 128 IS 2 BP 129 EP 138 AR PII S0166-4328(01)00317-5 DI 10.1016/S0166-4328(01)00317-5 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 522NJ UT WOS:000173903200003 PM 11796158 ER PT J AU Angeja, BG Gunda, M Murphy, SA Sobel, BE Rundle, AC Syed, M Asfour, A Borzak, S Gourlay, SG Barron, HV Gibbons, RJ Gibson, CM AF Angeja, BG Gunda, M Murphy, SA Sobel, BE Rundle, AC Syed, M Asfour, A Borzak, S Gourlay, SG Barron, HV Gibbons, RJ Gibson, CM CA LIMIT AMI Study Gpr TI TIMI myocardial perfusion grade and ST segment resolution: Association with infarct size as assessed by single photon emission computed tomography imaging SO CIRCULATION LA English DT Article DE myocardial infarction; microcirculation; electrocardiography; angiography; thrombolysis ID THROMBOLYTIC THERAPY; ANGIOPLASTY; TRIAL AB Background-The TIMI myocardial perfusion grade (TMPG) and ST-segment resolution both reflect perfusion and are associated with mortality after thrombolysis for acute myocardial infarction. We hypothesized that these measures would also be associated with infarct size by single photon emission computed tomography (SPECT). Methods and Results-In the LIMIT AMI trial (Limitation of Myocardial Injury following Thrombolysis in Acute Myocardial Infarction) of lytic monotherapy versus lytic plus rhuMAb CD18, early 90-minute TMPG (n=221) and ST segment resolution (n=242) were compared with subsequent SPECT Technetium-99 m Sestamibi, measuring the percentage of the left ventricle with no Sestamibi uptake. Infarct sizes were larger with TMPG 0 or 1 (a closed or stained myocardium) than with TMPG 2 or 3 (open myocardium, median 13%, versus 7%, P=0.004). Infarcts were also larger in patients with no ST segment resolution (median 15%) or incomplete resolution (11%) than in those with complete resolution (6%, overall P=0.0001). The difference in infarct size by TMPG persisted when stratified by category of ST resolution. Conclusions-There may be a pathophysiological link between early restoration of tissue-level perfusion and reduced subsequent infarct size that may partially explain why these early angiographic and electrocardiographic measures are associated with long-term survival. C1 Harvard Univ, Clin Res Inst, Core Cardiovasc Serv, TIMI Data Coordinating Ctr, Boston, MA 02215 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Henry Ford Hosp, Dept Med, Detroit, MI 48202 USA. Univ Vermont, Dept Med, Burlington, VT USA. Genentech Inc, San Francisco, CA 94080 USA. Florida Cardiol Grp, Atlantis, FL USA. Mayo Clin, Rochester, MN USA. RP Gibson, CM (reprint author), Harvard Univ, Clin Res Inst, Core Cardiovasc Serv, TIMI Data Coordinating Ctr, 900 Commonwealth Ave,2nd Floor, Boston, MA 02215 USA. NR 13 TC 105 Z9 111 U1 1 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 JAN 22 PY 2002 VL 105 IS 3 BP 282 EP 285 DI 10.1161/hc0302.103588 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 514XJ UT WOS:000173466100007 PM 11804979 ER PT J AU Chou, E Suzuma, I Way, KJ Opland, D Clermont, AC Naruse, K Suzuma, K Bowling, NL Vlahos, CJ Aiello, LP King, GL AF Chou, E Suzuma, I Way, KJ Opland, D Clermont, AC Naruse, K Suzuma, K Bowling, NL Vlahos, CJ Aiello, LP King, GL TI Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic states - A possible explanation for impaired collateral formation in cardiac tissue SO CIRCULATION LA English DT Article DE growth substances; diabetes mellitus; myocardium; collateral circulation; insulin ID PROTEIN-KINASE-C; MESSENGER-RNA EXPRESSION; RISK-FACTORS; ANGIOGENESIS; RETINOPATHY; CELLS; VEGF; PERMEABILITY; ACTIVATION; INHIBITOR AB Background-Inadequate angiogenic response to ischemia in the myocardium of diabetic patients could result in poor collateral formation. Yet, excessive neovascularization in the retina causes proliferative diabetic retinopathy. Since vascular endothelial growth factor (VEGF) is the major angiogenic factor expressed in response to hypoxia, we have characterized expression of VEGF and its receptors in retina, renal glomeruli, aorta, and myocardium in insulin-resistant and diabetic states. Methods and Results-The expression of mRNA and protein for VEGF and its receptors, VEGF-R1 and VEGF-R2, in the myocardium was decreased significantly by 40% to 70% in both diabetic and insulin-resistant nondiabetic rats. Twofold reductions in VEGF and VEGF-R2 were observed in ventricles from diabetic patients compared with nondiabetic donors. In contrast, expression of VEGF and its receptors were increased 2-fold in retina and glomeruli from diabetic or insulin-resistant rats. Insulin treatment of diabetic rats normalized changes in both cardiac and microvascular tissues. Insulin increased VEGF mRNA expression in cultured rat neonatal cardiac myocytes. Conclusions-The results documented for the first time that differential regulation of VEGF and its receptors exist between microvascular and cardiac tissues, which can be regulated by insulin. These results provide a potential explanation for concomitant capillary leakage and neovascularization in the retina and inadequate collateral formation in the myocardium of insulin-resistant and diabetic patients. C1 Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02115 USA. Lilly Res Labs, Indianapolis, IN USA. RP King, GL (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. FU NEI NIH HHS [R01-EY5110]; NIDDK NIH HHS [DK-597201, DK-59725-01] NR 31 TC 206 Z9 226 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 22 PY 2002 VL 105 IS 3 BP 373 EP 379 DI 10.1161/hc0302.102143 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 514XJ UT WOS:000173466100023 PM 11804995 ER PT J AU Froy, O Chang, DC Reppert, SM AF Froy, O Chang, DC Reppert, SM TI Redox potential: Differential roles in dCRY and mCRY1 functions SO CURRENT BIOLOGY LA English DT Article ID MAMMALIAN CIRCADIAN CLOCK; DNA PHOTOLYASE; ELECTRON-TRANSFER; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; CRYPTOCHROME; DROSOPHILA; CRY; PHOTORECEPTOR; TIMELESS AB Cryptochromes (CRYs) are flavoproteins important for the molecular clocks of animals [1]. The Drosophila cryptochrome (dCRY) is a circadian photoreceptor [2-5], whereas mouse cryptochromes (mCRY1 and mCRY2) are essential negative elements of circadian clock transcriptional feedback loops [6-9]. It has been proposed that reduction/oxidation (redox) reactions are important for dCRY light responsiveness [10] and mCRY1 transcriptional inhibition [11-13]. We therefore evaluated the role of redox in light-dependent activation of dCRY and in mCRY1 transcriptional inhibition in Drosophila Schneider 2 cells. Using site-directed mutagenesis, three of the four conserved flavin binding residues in dCRY were found to be essential for light responses, whereas three of the four corresponding residues in mCRY1 did not abolish transcriptional responses. Two tryptophan residues in dCRY are critical for its function and are likely involved in an intramolecular redox reaction. The corresponding tryptophan residues do not play a redox-mediated role in mCRY1 function. The data provide a multistep redox model for the light-dependent activities of dCRY and suggest that such a model does not apply to mCRY1 transcriptional responses. C1 Massachusetts Gen Hosp, Mass Gen Hosp Children, Lab Dev Chronobiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Reppert, SM (reprint author), Univ Massachusetts, Sch Med, Dept Neurobiol, 55 Lake Ave N, Worcester, MA 01655 USA. RI Froy, Oren/C-3550-2009 FU NIGMS NIH HHS [GM55820] NR 27 TC 70 Z9 70 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JAN 22 PY 2002 VL 12 IS 2 BP 147 EP 152 DI 10.1016/S0960-9822(01)00656-X PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 515FV UT WOS:000173485500025 PM 11818067 ER PT J AU Suzuma, K Takahara, N Suzuma, I Isshiki, K Ueki, K Leitges, M Aiello, LP King, GL AF Suzuma, K Takahara, N Suzuma, I Isshiki, K Ueki, K Leitges, M Aiello, LP King, GL TI Characterization of protein kinase C beta isoform's action on retinoblastoma protein phosphorylation, vascular endothelial growth factor-induced endothelial cell proliferation, and retinal neovascularization SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IN-VIVO; E2F BINDING; ANGIOGENESIS; INHIBITION; RECEPTORS; MICE; RETINOPATHY; ACTIVATION; INSULIN; INVIVO AB Retinal neovascularization is a major cause of blindness and requires the activities of several signaling pathways and multiple cytokines. Activation of protein kinase C (PKC) enhances the angiogenic process and is involved in the signaling of vascular endothelial growth factor (VEGF). We have demonstrated a dramatic increase in the angiogenic response to oxygen-induced retinal ischemia in transgenic mice overexpressing PKCbeta2 isoform and a significant decrease in retinal neovascularization in PKCbeta isoform null mice. The mitogenic action of VEGF, a potent hypoxia-induced angiogenic factor, was increased by 2-fold in retinal endothelial cells by the overexpression of PKCbeta1 or beta2 isoforms and inhibited significantly by the overexpression of a dominant-negative PKCbeta2 isoform but not by the expression of PKC alpha, delta, and isoforms. Association of PKCbeta2 isoform with retinoblastoma protein was discovered in retinal endothelial cells, and PKCbeta2 isoform increased retinoblastoma phosphorylation under basal and VEGF-stimulated conditions. The potential functional consequences of PKCbeta-induced retinoblastoma phosphorylation could include enhanced E2 promoter binding factor transcriptional activity and increased VEGF-induced endothelial cell proliferation. C1 Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Max Planck Expt Endokrinol, D-30625 Hannover, Germany. RP King, GL (reprint author), Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. FU NEI NIH HHS [R01 EY5110, EY10827] NR 32 TC 113 Z9 121 U1 0 U2 0 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 JAN 22 PY 2002 VL 99 IS 2 BP 721 EP 726 DI 10.1073/pnas.022644499 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 514PK UT WOS:000173450100035 PM 11805327 ER PT J AU Cui, Y Wong, WH Bornberg-Bauer, E Chan, HS AF Cui, Y Wong, WH Bornberg-Bauer, E Chan, HS TI Recombinatoric exploration of novel folded structures: A heteropolymer-based model of protein evolutionary landscapes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE crossovers; neutral nets; sequence space; thermodynamic stability; lattice protein models ID STATISTICAL-MECHANICS; DIRECTED EVOLUTION; ENERGY LANDSCAPE; SEQUENCE SPACE; FOLDING UNITS; GENE-TRANSFER; IN-VITRO; STABILITY; FUNNELS; MUTATIONS AB The role of recombination in evolution is compared with that of point mutations (substitutions) in the context of a simple, polymer physics-based model mapping between sequence (genotype) and conformational (phenotype) spaces. Crossovers and point mutations of lattice chains with a hydrophobic polar code are investigated. Sequences encoding for a single ground-state conformation are considered viable and used as model proteins. Point mutations lead to diffusive walks on the evolutionary landscape, whereas crossovers can "tunnel" through barriers of diminished fitness. The degree to which crossovers allow for more efficient sequence and structural exploration depends on the relative rates of point mutations versus that of crossovers and the dispersion in fitness that characterizes the ruggedness of the evolutionary landscape. The probability that a crossover between a pair of viable sequences results in viable sequences is an order of magnitude higher than random, implying that a sequence's overall propensity to encode uniquely is embodied partially in local signals. Consistent with this observation, certain hydrophobicity patterns are significantly more favored than others among fragments (i.e., subsequences) of sequences that encode uniquely, and examples reminiscent of autonomous folding units in real proteins are found. The number of structures explored by both crossovers and point mutations is always substantially larger than that via point mutations alone, but the corresponding numbers of sequences explored can be comparable when the evolutionary landscape is rugged. Efficient structural exploration requires intermediate nonextreme ratios between point-mutation and crossover rates. C1 Univ Toronto, Dept Biochem, Fac Med, Toronto, ON M5S 1A8, Canada. Univ Toronto, Dept Med Genet & Microbiol, Fac Med, Toronto, ON M5S 1A8, Canada. Univ Manchester, Sch Biol Sci, Bioinformat Grp, Manchester M13 9PT, Lancs, England. Harvard Univ, Fac Arts & Sci, Dept Stat, Cambridge, MA 02138 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Chan, HS (reprint author), Univ Toronto, Dept Biochem, Fac Med, Med Sci Bldg,5th Floor,1 Kings Coll Circle, Toronto, ON M5S 1A8, Canada. RI Bornberg-Bauer, Erich/A-1563-2013 OI Bornberg-Bauer, Erich/0000-0002-1826-3576 NR 53 TC 66 Z9 69 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 JAN 22 PY 2002 VL 99 IS 2 BP 809 EP 814 DI 10.1073/pnas.022240299 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 514PK UT WOS:000173450100050 PM 11805332 ER PT J AU Zhang, Y Schlossman, SF Edwards, RA Ou, CN Gu, J Wu, MX AF Zhang, Y Schlossman, SF Edwards, RA Ou, CN Gu, J Wu, MX TI Impaired apoptosis, extended duration of immune responses, and a lupus-like autoimmune disease in IEX-1-transgenic mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE antiapoptosis; autoimmunity; NF-kappa B; T cells ID NF-KAPPA-B; INDUCED CELL-DEATH; BLOOD T-CELLS; LYMPHOPROLIFERATIVE SYNDROME; GENE; SURVIVAL; EXPRESSION; TOLERANCE; INDUCTION; CONSEQUENCE AB Susceptibility of activated T cells to apoptosis must be tightly regulated to ensure sufficient T cell progeny for an effective response, while allowing a rapid depletion of them at the end of the immune response. We show here that a previously isolated, NF-kappaB/rel target gene IEX-1 (Immediate Early response gene X-1) is highly expressed in T cells at early stages of activation, but declines with a prolonged period of activation time, coincident with an increased susceptibility of T cells to apoptosis during the late phases of an immune response. Transgenic expression of IEX-1 specifically in lymphocytes impaired apoptosis in activated T cells, extended a duration of an effector-phase of a specific immune response, and increased the accumulation of effector/memory-like T cells and the susceptibility to a lupus-like autoimmune disease. Our study demonstrated an antiapoptotic effect of IEX-1 on T cell apoptosis triggered by ligation of Fas and T cell receptor (TCR)/CD3 complex. The ability of extending life expectancy of T effectors, in line with a decrease in its expression following prolonged T cell activation, suggests a key role for IEX-1 in regulating T cell homeostasis during immune responses. C1 Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Wu, MX (reprint author), Baylor Coll Med, Dept Pathol, 6621 Fannin St,MC 1-2261, Houston, TX 77030 USA. FU NIAID NIH HHS [AI45003] NR 48 TC 75 Z9 77 U1 0 U2 0 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 JAN 22 PY 2002 VL 99 IS 2 BP 878 EP 883 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 514PK UT WOS:000173450100062 PM 11782530 ER PT J AU Pekkonen, E Hirvonen, J Ahveninen, J Kahkonen, S Kaakkola, S Huttunen, J Jaaskelainen, IP AF Pekkonen, E Hirvonen, J Ahveninen, J Kahkonen, S Kaakkola, S Huttunen, J Jaaskelainen, IP TI Memory-based comparison process not attenuated by haloperidol: a combined MEG and EEG study SO NEUROREPORT LA English DT Article DE haloperidol; dopamine D2 receptors; electroencephalography (EEG); event-related potentials (ERP); magnetoencephalography (MEG); Parkinson's disease; schizophrenia ID MISMATCH NEGATIVITY; SCHIZOPHRENIA; POTENTIALS; GENERATION; RECEPTORS AB Auditory PSO and NI00 responses reflect preattentive processing, whereas subsequent mismatch negativity (MMN) response indexes memory-based comparison process. Divergent ERP responses have been found in schizophrenia and in Parkinson's disease (PD), which have abnormalities in cerebral dopamine activity. We used simultaneously magnetoencephalography and electroencephalography to investigate, whether a single dose of haloperidol, a dopamine D2-receptor antagonist, modulates preattentive auditory processing using a randomized, double-blind, placebo-controlled crossover design. Our results showed that haloperidol did not alter MMN to frequency and duration changes, whereas the magnetic MMN to frequency change was significantly accelerated. The amplitude and latency changes of the electric and magnetic PSO and N100 were insignificant, Our results indicate that memory-based sound comparison and preceding cortical processing underlying stimulus detection are not attenuated by haloperidol, whereas haloperidol appears to accelerate preattentive sound comparison. NeuroReport 13:177-181 (C) 2002 Lippincott Williams Wilkins. C1 Univ Helsinki, Cent Hosp, BioMag Lab, Med Engn Ctr, FIN-00029 HUS, Finland. Univ Helsinki, Cent Hosp, Dept Neurol, FIN-00029 HUS, Finland. Univ Helsinki, Cent Hosp, Dept Clin Neurophysiol, FIN-00029 HUS, Finland. Univ Helsinki, Dept Psychol, Cognit Brain Res Unit, HUS, Finland. HUCH, Jorvi Hosp, Dept Psychiat, Helsinki, Finland. Harvard Univ, Massachusetts Gen Hosp, Sch Med, NMR Ctr, Cambridge, MA 02138 USA. RP Pekkonen, E (reprint author), Univ Helsinki, Cent Hosp, BioMag Lab, Med Engn Ctr, POB 340, FIN-00029 HUS, Finland. RI Jaaskelainen, Iiro/C-7392-2012 OI Jaaskelainen, Iiro/0000-0001-6001-6950 NR 22 TC 36 Z9 37 U1 2 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JAN 21 PY 2002 VL 13 IS 1 BP 177 EP 181 DI 10.1097/00001756-200201210-00040 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 514NY UT WOS:000173449000041 PM 11924884 ER PT J AU Vonderheide, RH AF Vonderheide, RH TI Telomerase as a universal tumor-associated antigen for cancer immunotherapy SO ONCOGENE LA English DT Article DE telomerase; hTERT; tumor-associated antigen; immunotherapy ID PULSED DENDRITIC CELLS; CATALYTIC SUBUNIT; MELANOMA PATIENTS; T-CELLS; REVERSE-TRANSCRIPTASE; IMMORTAL CELLS; LIFE-SPAN; EXPRESSION; LYMPHOCYTES; VACCINATION AB Although the search for pharmacologic inhibitors of telomerase activity represents a promising approach for telomerase-based anti-cancer therapy, the immunological properties of the telomerase reverse transcriptase hTERT suggest that the enzyme is also an attractive target for novel immunotherapies against cancer. Data from both human and murine systems demonstrate that cytotoxic T-lymphocytes (CTL) can recognize peptides derived from TERT and kill TERT-positive tumor cells of multiple histologies. Given the vast overexpression of hTERT in human tumors and its low-level expression in rare normal tissues, clinical trials have begun that test the credentials of hTERT as a broadly applicable target for immunotherapy of cancer. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Vonderheide, RH (reprint author), Univ Penn, Sch Med, Abramson Family Canc Res Inst, 421 Curie Blvd, Philadelphia, PA 19104 USA. NR 47 TC 107 Z9 125 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 21 PY 2002 VL 21 IS 4 BP 674 EP 679 DI 10.1038/sj.onc.1205074 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 513QU UT WOS:000173390500022 PM 11850795 ER PT J AU Dirienzo, AG Van der Horst, C Finkelstein, DM Frame, P Bozzette, SA Tashima, KT AF Dirienzo, AG Van der Horst, C Finkelstein, DM Frame, P Bozzette, SA Tashima, KT TI Efficacy of trimethoprim-sulfamethoxazole for the prevention of bacterial, infections in a randomized prophylaxis trial of patients with advanced HIV infection SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID PNEUMOCYSTIS-CARINII-PNEUMONIA; IMMUNODEFICIENCY-VIRUS INFECTION; AEROSOLIZED PENTAMIDINE; ANTIRETROVIRAL THERAPY; REGRESSION-MODELS; SULFONAMIDES; FAILURE; DAPSONE AB We compared the occurrences of several types of infections in HIV-infected patients participating in a randomized clinical trial of three treatment strategies given for the primary prevention of Pneumocystis carinii pneumonia (PCP) and toxoplasmosis. In a phase III open label trial, 842 patients with HIV infection and fewer than 200 CD4(+) celIS/mm(3) received zidovudine, (standard dose) plus,one of three randomly assigned prophylactic agents: trimethoprim-sulfamethoxazole (TMP-SMZ), or dapsone (DAP), or aerosolized pentamidine (AP). Patients developing intolerance to treatment were crossed over to another predefined prophylactic therapy. Patients were monitored for infections every other week for 8 weeks and then monthly until the study was completed. Primary statistical models were proportional hazards models adapted to recurrent end points. In an intent-to-treat analysis, compared with AP and DAP, TMP-SMZ significantly reduced the risk of any bacterial infection (combining all distinct types) (p = 0.02 and p = 0.01, respectively). When considering distinct types separately, compared with AP, TMP-SMZ significantly reduced the risk of infectious diarrhea (p = 0.04); compared with DAP, AP and TMP-SMZ significantly reduced the risk of sinusitis/otitis media (p = 0.03 and p = 0.04, respectively); compared with AP and DAP, TMP-SMZ significantly reduced the risk of a second occurrence of pneumonia (p = 0.04 and 0.02, respectively). For any bacterial infection, infection rates per 100 patient-years of follow-up were 31,39, and 38 for TMP-SMZ, DAP, and AP, respectively. In patients with advanced HIV infection not taking highly active antiretroviral therapy, the treatment strategy that initiates prophylaxis with TMP-SMZ is superior to those initiating with AP or DAP for preventing any bacterial infection, with most of the advantage manifested through infectious diarrhea, sinusitis/otitis media, and pneumonia. C1 Harvard Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02215 USA. Univ N Carolina, Chapel Hill, NC USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Cincinnati, Cincinnati, OH USA. Univ Calif San Diego, San Diego, CA 92103 USA. Brown Univ, Providence, RI 02912 USA. RP Dirienzo, AG (reprint author), Harvard Univ, Dept Biostat, Sch Publ Hlth, 655 Huntington Ave, Boston, MA 02215 USA. EM dirienzo@sdac.harvard.edu FU NIAID NIH HHS [AI07358]; PHS HHS [P30-A142853] NR 20 TC 29 Z9 31 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JAN 20 PY 2002 VL 18 IS 2 BP 89 EP 94 DI 10.1089/08892220252779629 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 516ZR UT WOS:000173587100001 PM 11839141 ER PT J AU Lin, JD Puigserver, P Donovan, J Tarr, P Spiegelman, BM AF Lin, JD Puigserver, P Donovan, J Tarr, P Spiegelman, BM TI Peroxisome proliferator-activated receptor gamma coactivator 1 beta (PGC-1 beta), a novel PGC-1-related transcription coactivator associated with host cell factor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEAR-LOCALIZATION; HCF; PROTEIN; VP16; EXPRESSION; ALPHA AB Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) plays a critical role in regulating multiple aspects of energy metabolism, including adaptive thermogenesis, mitochondrial biogenesis, and fatty acid beta-oxidation. Recently, this coactivator of nuclear receptors/transcription factors has been shown to control hepatic gluconeogenesis, an important component of the pathogenesis of both type-1 and type-2 diabetes. We described here the cloning of a novel bona fide homologue of PGC-1, PGC-1beta (PGC-1 was renamed as PGC-1alpha), first identified through searches of new data base entries. Despite the fact that PGC-1alpha and -1beta share similar tissue distributions with highest levels of expression in brown fat and heart, their mRNAs are differentially regulated in the brown adipose tissue upon cold exposure and during brown fat cell differentiation. Like PGC-1alpha, PGC-1beta mRNA levels are increased significantly in the liver during fasting, suggesting a possible role for this factor in the regulation of hepatic gluconeogenesis and/or fatty acid oxidation. Consistent with this, PGC-1beta was shown to physically interact and potently coactivate hepatic nuclear factor 4 and peroxisome proliferator-activated receptor a, nuclear receptors that are essential for hepatic adaptation to fasting. Finally, using sequence comparisons between PGC-1alpha and -1beta we have identified a conserved amino acid motif that serves as a docking site for host cell factor, a cellular protein implicated in cell cycle regulation and viral infection. HCF is shown to bind to both PGC-1alpha and -1beta and augment their transcriptional activity. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Spiegelman, BM (reprint author), Dana Farber Canc Inst, Smith Bldg,Rm 958,1 Jimmy Fund Way, Boston, MA 02115 USA. FU NIDDK NIH HHS [R37DK31405] NR 21 TC 318 Z9 334 U1 1 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 JAN 18 PY 2002 VL 277 IS 3 BP 1645 EP 1648 DI 10.1074/jbc.C100631200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 514CW UT WOS:000173421300005 PM 11733490 ER PT J AU Greene, MF AF Greene, MF TI Perspective - Outcomes of very low birth weight in young adults SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Greene, MF (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 12 Z9 12 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 JAN 17 PY 2002 VL 346 IS 3 BP 146 EP 148 DI 10.1056/NEJM200201173460302 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 511NZ UT WOS:000173273600001 PM 11796847 ER PT J AU Chang, A Tourtellotte, WW Rudick, R Trapp, BD AF Chang, A Tourtellotte, WW Rudick, R Trapp, BD TI Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RAT OPTIC-NERVE; GLIAL PROGENITOR-CELL; PDGF ALPHA-RECEPTOR; ADULT HUMAN CNS; NG2 PROTEOGLYCAN; PRECURSOR CELLS; SPINAL-CORD; REMYELINATION; SURVIVAL; BRAIN AB Background: Multiple sclerosis is an inflammatory disease of the central nervous system that destroys myelin, oligodendrocytes, and axons. Since most of the lesions of multiple sclerosis are not remyelinated, enhancement of remyelination is a possible therapeutic strategy that could perhaps be achieved with the transplantation of oligodendrocyte-producing cells into the lesions. We investigated the frequency distribution and configuration of oligodendrocytes in chronic lesions of multiple sclerosis to determine whether these factors limit remyelination. Methods: Forty-eight chronic lesions obtained at autopsy from 10 patients with multiple sclerosis were examined immunocytochemically for oligodendrocytes and oligodendrocyte progenitor cells. Using confocal microscopy, we examined the three-dimensional relations between axons and the processes of premyelinating oligodendrocytes. Results: Thirty-four of the 48 chronic lesions of multiple sclerosis contained oligodendrocytes with multiple extended processes that associated with demyelinated axons but failed to myelinate them. These axons were dystrophic and contained multiple swellings. In some regions, the densities of premyelinating oligodendrocytes (25 per square millimeter of tissue) were similar to those in the developing rodent brain (23 per square millimeter). In the patients with disease of long duration (more than 20 years), there were fewer lesions with premyelinating oligodendrocytes (P<0.001). Conclusions: Premyelinating oligodendrocytes are present in chronic lesions of multiple sclerosis, so remyelination is not limited by an absence of oligodendrocyte progenitors or their failure to generate oligodendrocytes. Our findings suggest that in the chronic lesions of multiple sclerosis, the axons are not receptive for remyelination. Understanding the cellular interactions between premyelinating oligodendrocytes, axons, and the microenvironment of lesions of multiple sclerosis may lead to effective strategies for enhancing remyelination. (N Engl J Med 2002;346:165-73.) Copyright (C) 2002 Massachusetts Medical Society. C1 Cleveland Clin Fdn, Lerner Res Inst, Dept Neurosci, NC30, Cleveland, OH 44195 USA. Cleveland Clin Fdn, Mellen Ctr Multiple Sclerosis, Cleveland, OH 44195 USA. W Los Angeles Vet Affairs Med Ctr, Dept Neurol, Los Angeles, CA 90073 USA. RP Trapp, BD (reprint author), Cleveland Clin Fdn, Lerner Res Inst, Dept Neurosci, NC30, 9500 Euclid Ave, Cleveland, OH 44195 USA. FU NINDS NIH HHS [P01 NS38667, R01 NS35058] NR 38 TC 505 Z9 520 U1 2 U2 21 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 JAN 17 PY 2002 VL 346 IS 3 BP 165 EP 173 DI 10.1056/NEJMoa010994 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 511NZ UT WOS:000173273600004 PM 11796850 ER PT J AU D'Amico, DJ Dryja, T AF D'Amico, DJ Dryja, T TI A 58-year-old woman with unilateral loss of vision and postmenopausal bleeding - Bilateral, diffuse uveal melanocytic proliferation. Widely metastatic endometrial carcinoma, mixed epithelioid type, with endometrioid, mucinous and undifferentiated patterns. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID CANCER-ASSOCIATED RETINOPATHY; CELL-CARCINOMA; MELANOMA; TUMORS; HYPERPLASIA; BLINDNESS; LESIONS; PROTEIN C1 Massachusetts Eye & Ear Infirm, Diabet Retinopathy Unit, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP D'Amico, DJ (reprint author), Massachusetts Eye & Ear Infirm, Diabet Retinopathy Unit, Boston, MA 02114 USA. NR 41 TC 0 Z9 1 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 JAN 17 PY 2002 VL 346 IS 3 BP 189 EP 195 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 511NZ UT WOS:000173273600008 PM 11796854 ER PT J AU Weeks, JC Nelson, H Gelber, S Sargent, D Schroeder, G AF Weeks, JC Nelson, H Gelber, S Sargent, D Schroeder, G CA COST Study Grp TI Short-term quality-of-life outcomes following laparoscopic-assisted colectomy vs open colectomy for colon cancer - A randomized trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID COLORECTAL-CANCER; SURGERY; CHOLECYSTECTOMY AB Context Laparoscopic-assisted colectomy (LAC) has emerged as the preferred minimally invasive surgical strategy for diseases of the colon. The safety and efficacy of LAC for colon cancer are unknown, and the nature and magnitude of any quality-of-life (QOL) benefit resulting from LAC for colon cancer is also unknown. Objective To compare short-term QOL outcomes after LAC vs open colectomy for colon cancer. Design, Setting, and Participants Multicenter, randomized controlled trial (Clinical Outcomes of Surgical Therapy [COST]). Between September 1994 and February 1999, 37 of 48 centers provided data for the QOL component of the trial for 449 consecutive patients with clinically resectable colon cancer. Main Outcome Measures Scores on the Symptoms Distress Scale (SIDS), Quality of Life Index, and a single-item global rating scale at 2 days, 2 weeks, and 2 months postoperative; duration of postoperative in-hospital analgesic use; and length of stay. Results Of 449 patients, 428 provided QOL data. In an intention-to-treat analysis comparing SDS pain intensity, SDS summary, QOL Index summary, and global rating scale scores at each time point, the only statistically significant difference observed between groups was the global rating scale score for 2 weeks postsurgery. The mean (median) global rating scale scores for 2 weeks postsurgery were 76.9 (80) for LAC vs 74.4 (75) for open colectomy (P=.009). While in the hospital, patients assigned to LAC required fewer days of both parenteral analgesics compared with patients assigned to open colectomy (mean [median], 3.2 [3] vs 4.0 [4] days; P<.001) and oral analgesics (mean [median], 1.9 [1] vs 2.2 [2] days; P=.03). Conclusion Only minimal short-term QOL benefits were found with LAC for colon cancer compared with standard open colectomy. Until ongoing trials establish that LAC is as effective as open colectomy in preventing recurrence and death from colon cancer, this procedure should not be offered to patients with colon cancer. C1 Mayo Clin, Dept Surg, Rochester, MN 55905 USA. Mayo Clin, Dept Biostat, Rochester, MN USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Nelson, H (reprint author), Mayo Clin, Dept Surg, 200 1st St SW, Rochester, MN 55905 USA. OI Sargent, Daniel/0000-0002-2684-4741 FU NCI NIH HHS [CA21115, CA12027, CA21661, CA25244, CA31946, CA32102, U01 CA65157] NR 34 TC 429 Z9 448 U1 1 U2 10 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 JAN 16 PY 2002 VL 287 IS 3 BP 321 EP 328 DI 10.1001/jama.287.3.321 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 511YQ UT WOS:000173294700026 PM 11790211 ER PT J AU Lowe, HC Oesterle, SN Khachigian, LM AF Lowe, HC Oesterle, SN Khachigian, LM TI Coronary in-stent restenosis: Current status and future strategies SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review ID INTRACORONARY GAMMA-RADIATION; SERIAL INTRAVASCULAR ULTRASOUND; MUSCLE-CELL-PROLIFERATION; PROLONGED ANTIPLATELET THERAPY; CUTTING BALLOON ANGIOPLASTY; PALMAZ-SCHATZ STENTS; LOCAL-DRUG DELIVERY; GENE-THERAPY; ARTERY-DISEASE; NEOINTIMAL HYPERPLASIA AB In-stent restenosis (ISR) is a novel pathobiologic process, histologically distinct from restenosis after balloon angioplasty and comprised largely of neointima formation. As percutaneous coronary intervention increasingly involves the use of stents, ISR is also becoming correspondingly more frequent. In this review, we examine the available studies of the histology and pathogenesis of ISR, with particular reference to porcine and other animal models. An overview of mechanical treatments is then provided, which includes PTCA, directional coronary atherectomy and high speed rotational atherectomy. Radiation-based therapies are discussed, including a summary of current problems associated with this modality of treatment. Finally, novel strategies for the prevention of ISR are addressed, including novel developments in stents and stent coatings, conventional drugs, nucleic acid-based drugs and gene transfer. Until recently, limited pharmacologic and mechanical treatment options have been available for both treatment and prevention of ISR. However, recent advances in gene modification and gene transfer therapies and, more particularly, in local stent-based drug delivery systems make it conceivable that the incidence of ISR will now be seriously challenged. (C) 2002 by the American College of Cardiology. C1 Univ New S Wales, Ctr Thrombosis & Vasc Res, Sch Pathol, Sydney, NSW 2052, Australia. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Khachigian, LM (reprint author), Univ New S Wales, Ctr Thrombosis & Vasc Res, Sch Pathol, Sydney, NSW 2052, Australia. EM L.Khachigian@unsw.edu.au NR 163 TC 244 Z9 276 U1 1 U2 28 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JAN 16 PY 2002 VL 39 IS 2 BP 183 EP 193 DI 10.1016/S0735-1097(01)01742-9 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 511EZ UT WOS:000173252800001 PM 11788206 ER PT J AU Morrison, DA Sethi, G Sacks, J Henderson, W Grover, F Sedlis, S Esposito, R Ramanathan, KB Weiman, D Talley, J Saucedo, J Antakli, T Paramesh, V Pett, S Vernon, S Birjiniuk, V Welt, F Krucoff, M Wolfe, W Lucke, JC Mediratta, S Booth, D Barbiere, C Lewis, D AF Morrison, DA Sethi, G Sacks, J Henderson, W Grover, F Sedlis, S Esposito, R Ramanathan, KB Weiman, D Talley, J Saucedo, J Antakli, T Paramesh, V Pett, S Vernon, S Birjiniuk, V Welt, F Krucoff, M Wolfe, W Lucke, JC Mediratta, S Booth, D Barbiere, C Lewis, D CA Investigators Dept Vet Affairs Coo AWESOME TI Percutaneous coronary coronary bypass graft intervention versus surgery for patients with medically refractory myocardial ischemia and risk factors for adverse outcomes with bypass - The VA AWESOME Multicenter Registry: Comparison with the randomized clinical trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID REVASCULARIZATION INVESTIGATION BARI; ANGIOPLASTY; DISEASE; METAANALYSIS AB OBJECTIVES This study was designed to compare the three-year survival after percutaneous coronary intervention (PCI) or coronary artery, by-pass graft surgery (CABG) in physician-directed and patient-choice registries with the Angina With Extremely Serious Operative Mortality Evaluation (AWESOME) randomized trial results. BACKGROUND The AWESOME multicenter randomized trial and registry compared the long-term survival after PCI and CABG for the treatment of patients with medically refractory myocardial ischemia and at least one additional risk factor for adverse outcome with CABG. The randomized trial demonstrated comparable three-year survival. METHODS Over a five-year period (1995 to 2000), 2,431 patients with medically, refractory myocardial ischemia and at least one of five risk factors (prior heart surgery, myocardial infarction within seven days, left ventricular ejection fraction <0.35, age >70 years, intra-aortic balloon required to stabilize) were identified. By physician consensus, 1,650 patients formed a physician-directed registry assigned to CABG (692), PCI (651) or further medical therapy (307), and 781 were angiographically eligible for random allocation; 454 of these patients constitute the randomized trial, and the remaining 327 constitute a patient choice registry. Survival for CABG and PCI was compared using Kaplan-Meier curves and log-rank tests. RESULTS The CABG and PCI 36-month survival rates for randomized patients were 79% and 80%, respectively. The CABG and PCI 36-month survival rates were both 76% for the physician-directed subgroup; comparable survival rates for the patient-choice subgroup were 80% and 89%, respectively. None of the global log-rank tests for survival demonstrated significant differences. CONCLUSIONS Both registries support the randomized trial conclusion: PCI is an alternative to CABG for some medically refractory high-risk patients. (C) 2002 by the American College of Cardiology. C1 Vet Adm Med Ctr, Cardiac Catheterizat Lab, Tucson, AZ 85723 USA. Edward Hines Jr Vet Adm Hosp, CSPCC, Hines, IL 60141 USA. Denver VA Med Ctr, Denver, CO USA. New York VA Med Ctr, New York, NY USA. Memphis VA Med Ctr, Memphis, TN USA. Little Rock VA Med Ctr, Little Rock, AR USA. Albuquerque VA Med Ctr, Albuquerque, NM USA. W Roxbury VA Med Ctr, W Roxbury, MA USA. Durham VA Med Ctr, Durham, NC USA. Asheville VA Med Ctr, Asheville, NC USA. Lexington VA Med Ctr, Lexington, KY USA. Kansas City VA Med Ctr, Kansas City, KS USA. RP Morrison, DA (reprint author), Vet Adm Med Ctr, Cardiac Catheterizat Lab, 111C,3601 S 6th Ave, Tucson, AZ 85723 USA. NR 22 TC 36 Z9 37 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 JAN 16 PY 2002 VL 39 IS 2 BP 266 EP 273 DI 10.1016/S0735-1097(01)01720-X PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 511EZ UT WOS:000173252800013 PM 11788218 ER PT J AU Zareparsi, S Camicioli, R Sexton, G Bird, T Swanson, P Kaye, J Nutt, J Payami, H AF Zareparsi, S Camicioli, R Sexton, G Bird, T Swanson, P Kaye, J Nutt, J Payami, H TI Age at onset of Parkinson disease and apolipoprotein E genotypes SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE Parkinson disease; apolipoprotein E genotypes; onset age of Parkinson disease ID ALZHEIMERS-DISEASE; EPSILON-4 ALLELE; E POLYMORPHISM; E GENE; DEMENTIA; FREQUENCY; METAANALYSIS; ASSOCIATION; RELATIVES; RISK AB Several lines of evidence suggest that the variable age at onset of Parkinson disease (PD) is likely influenced by genes. The apolipoprotein E (APOE) gene is associated with onset of Alzheimer disease, and possibly other neurodegenerative disorders. APOE has been investigated in relation to onset of PD, but results have been inconsistent. The aim of the present study was to determine if APOE genotypes are associated with onset age of PD, using a patient population large enough to assure sufficient power. We studied 521 unrelated Caucasian patients with idiopathic PD from movement disorder clinics in Oregon and Washington. Genotyping and statistical analyses were carried out using standard methods. Age at onset, of PD was significantly earlier in patients with the epsilon3epsilon4/epsilon4epsilon4 genotype than in patients with the epsilon3epsilon3 genotype (56.1 +/- 10.9 vs. 59.6 +/- 11.0, P = 0.003). The significantly earlier onset of PD was not influenced by the possible effects of recruitment site, family history and gender. The effect of the epsilon2epsilon3 genotype on onset of PD differed between the two recruitment sites. There was a trend for earlier onset of PD in epsilon2epsilon3 patients than in epsilon3epsilon3 patients only in the Oregon sample. In conclusion, APOE is associated with age at onset of PD. (C) 2001 Wiley-Liss, Inc. C1 Oregon Hlth Sci Univ, Dept Neurol, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. Univ Washington, Dept Neurol, Seattle, WA 98195 USA. Vet Affaire Puget Sound Hlth Care Syst, Seattle, WA USA. Portland Vet Affairs Med Ctr, Portland, OR USA. RP Zareparsi, S (reprint author), Oregon Hlth Sci Univ, Dept Neurol, 3181 SW Sam Jackson Pk Rd,CR-131, Portland, OR 97201 USA. OI Kaye, Jeffrey/0000-0002-9971-3478; Camicioli, Richard/0000-0003-2977-8660 FU NCRR NIH HHS [5M01 RR00334]; NIA NIH HHS [AG08017]; NINDS NIH HHS [NS36960] NR 37 TC 43 Z9 44 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD JAN 15 PY 2002 VL 107 IS 2 BP 156 EP 161 DI 10.1002/ajmg.10111 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 508NZ UT WOS:000173096500013 PM 11807891 ER PT J AU Barry, MJ AF Barry, MJ TI Health decision aids to facilitate shared decision making in office practice SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID BENIGN PROSTATIC HYPERPLASIA; CONTROLLED TRIAL; CURRENT CONTROVERSY; BREAST-CANCER; PATIENT PARTICIPATION; INFORMED CONSENT; RANDOMIZED TRIAL; INFORMATION; CARE; WOMEN AB For medical decisions with more than one reasonable option, patient participation in decision making is often necessary to optimally match management decisions with patient preferences. Health decision aids are designed to facilitate shared decision making by helping patients and their physicians choose among: reasonable clinical options. Although these aids vary in content, common denominators are the presentation of more than one reasonable strategy for a clinical management question and a description of the possible outcomes of the various options. Although the number of published randomized trials assessing the impact of health decision aids on the quality of medical decisions is limited (but growing), various types of decision aids do generally appear to inform patients about their treatment options better than "usual care" can. Little evidence is available to determine whether one type of decision aid is optimal, but more complicated programs seem to have larger effects. The cost-effectiveness of decision aids has not been studied, although it is enticing to think that the pattern of more conservative decisions by users of some decision aids could reduce medical care costs in a manner that is dictated by patient preferences. C1 Massachusetts Gen Hosp, Gen Med Unit, Boston, MA 02114 USA. RP Barry, MJ (reprint author), Massachusetts Gen Hosp, Gen Med Unit, 50 Staniford St,9th Floor, Boston, MA 02114 USA. NR 53 TC 145 Z9 149 U1 0 U2 4 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 15 PY 2002 VL 136 IS 2 BP 127 EP 135 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 512PZ UT WOS:000173333900005 PM 11790064 ER PT J AU Berg, AO Allan, JD Frame, PS Homer, CJ Johnson, MS Klein, JD Lieu, TA Mulrow, CD Orleans, CT Peipert, JF Pender, NJ Siu, AL Teutsch, SM Westhoff, C Woolf, SH AF Berg, AO Allan, JD Frame, PS Homer, CJ Johnson, MS Klein, JD Lieu, TA Mulrow, CD Orleans, CT Peipert, JF Pender, NJ Siu, AL Teutsch, SM Westhoff, C Woolf, SH CA US Preventive Serv Task Force TI Aspirin for the primary prevention of cardiovascular events: Recommendation and rationale SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID LOW-DOSE ASPIRIN; RANDOMIZED TRIAL; DISEASE; RISK AB This statement summarizes the recommendation of the third U.S. Preventive Services Task Force (USPSTF) for aspirin for the primary prevention of cardiovascular events, as well as the supporting scientific evidence. The complete information on which this statement is based, including evidence tables and references, can be found in a companion article in this issue. Copies of this document, the summary of the evidence, and the systematic evidence review can be obtained through the USPSTF Web site (www.ahrq.gov/clinic/uspstfix.htm) and in print: through the Agency for Healthcare Research and Quality Publications Clearinghouse (800-358-9295). C1 Univ Washington, Seattle, WA 98195 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX 78284 USA. TriCty Family Med, Cohocton, NY USA. Univ Rochester, Sch Med, Rochester, NY 14627 USA. Natl Initiat Childrens Healthcare Qual, Boston, MA USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Newark, NJ 07103 USA. Harvard Univ, Pilgrim Hlth Care, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Audie L Murphy Mem Vet Adm Med Ctr, San Antonio, TX 78284 USA. Robert Wood Johnson Fdn, Princeton, NJ 08540 USA. Women & Infants Hosp Rhode Isl, Providence, RI 02908 USA. Univ Michigan, Ann Arbor, MI 48109 USA. CUNY Mt Sinai Sch Med, New York, NY 10029 USA. Mt Sinai Med Ctr, New York, NY 10029 USA. Merck & Co Inc, W Point, PA USA. Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. Virginia Commonwealth Univ, Med Coll Virginia, Fairfax, VA USA. RP Berg, AO (reprint author), Univ Washington, Seattle, WA 98195 USA. NR 16 TC 206 Z9 212 U1 0 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 15 PY 2002 VL 136 IS 2 BP 157 EP 160 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 512PZ UT WOS:000173333900010 ER PT J AU Gines, S Marino, M Mallol, J Canela, EI Morimoto, C Callebaut, C Hovanessian, A Casado, V Lluis, C Franco, R AF Gines, S Marino, M Mallol, J Canela, EI Morimoto, C Callebaut, C Hovanessian, A Casado, V Lluis, C Franco, R TI Regulation of epithelial and lymphocyte cell adhesion by adenosine deaminase-CD26 interaction SO BIOCHEMICAL JOURNAL LA English DT Article DE Caco-2 cells; cell-to-cell interaction; integrins; T lymphocytes ID DIPEPTIDYL PEPTIDASE-IV; MONOCLONAL-ANTIBODY; T-CELLS; ACTIVATION ANTIGEN; CD26; SURFACE; RECEPTORS; LIGAND; INTEGRINS; MOLECULE AB The extra-enzymic function of cell-surface adenosine deaminase (ADA), an enzyme mainly localized in the cytosol but also found on the cell surface of monocytes, B cells and T cells, has lately been the subject of numerous studies. Cell-surface ADA is able to transduce co-stimulatory signals in T cells via its interaction with CD26, an integral membrane protein that acts as ADA-binding protein. The aim of the present study was to explore whether ADA-CD26 interaction plays a role in the adhesion of lymphocyte cells to human epithelial cells. To meet this aim, different lymphocyte cell lines (Jurkat and CEM T) expressing endogenous, or overexpressing human, CD26 protein were tested in adhesion assays to monolayers of colon adenocarcinoma human epithelial cells, Caco-2, which express high levels of cell-surface ADA. Interestingly, the adhesion of Jurkat and CEM T cells to a monolayer of Caco-2 cells was greatly dependent on CD26. An increase by 50% in the cell-to-cell adhesion was found in cells containing higher levels of CD26. Incubation with an anti-CD26 antibody raised against the ADA-binding site or with exogenous ADA resulted in a significant reduction (50-70%) of T-cell adhesion to monolayers of epithelial cells. The role of ADA-CD26 interaction in the lymphocyte-epithelial cell adhesion appears to be mediated by CD26 molecules that are not interacting with endogenous ADA (ADA-free CD26), since SKW6.4 (B cells) that express more cell-surface ADA showed lower adhesion than T cells. Adhesion stimulated by CD26 and ADA is mediated by T cell lymphocyte function-associated antigen. A role for ADA-CD26 interaction in cell-to-cell adhesion was confirmed further in integrin activation assays. FACS analysis revealed a higher expression of activated integrins on T cell lines in the presence of increasing amounts of exogenous ADA. Taken together, these results suggest that the ADA-CD26 interaction on the cell surface has a role in lymphocyte-epithelial cell adhesion. C1 Univ Barcelona, Dept Biochem & Mol Biol, E-08028 Barcelona, Spain. Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Tumor Biol, Boston, MA 02115 USA. Natl Inst Infect Dis, AIDS Res Ctr, Tokyo 1620052, Japan. Inst Pasteur, Dept Cellular Immunol, F-75724 Paris 15, France. RP Gines, S (reprint author), Massachusetts Gen Hosp E, Neurogenet Unit, Bldg 149,13th St, Charlestown, MA 02129 USA. RI Franco, Rafael/C-3694-2015; Casado, Vicent/K-1660-2014; Canela, Enric I./M-8726-2013; OI Franco, Rafael/0000-0003-2549-4919; Canela, Enric I./0000-0003-4992-7440; Gines Padros, Silvia/0000-0002-9479-8185; Casado, Vicent/0000-0002-1764-3825 NR 40 TC 30 Z9 33 U1 0 U2 0 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD JAN 15 PY 2002 VL 361 BP 203 EP 209 DI 10.1042/0264-6021:3610203 PN 2 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 523XJ UT WOS:000173982600003 PM 11772392 ER PT J AU Mauritz, R Peters, GJ Priest, DG Assaraf, YG Drori, S Kathmann, I Noordhuis, P Bunni, MA Rosowsky, A Schornagel, JH Pinedo, HM Jansen, G AF Mauritz, R Peters, GJ Priest, DG Assaraf, YG Drori, S Kathmann, I Noordhuis, P Bunni, MA Rosowsky, A Schornagel, JH Pinedo, HM Jansen, G TI Multiple mechanisms of resistance to methotrexate and novel antifolates in human CCRF-CEM leukemia cells and their implications for folate homeostasis SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE folate homeostasis; reduced folate carrier; thymidylate synthase; polyglutamylation; folylpolyglutamate synthetase; antifolate resistance ID THYMIDYLATE SYNTHASE INHIBITOR; FOLYLPOLYGLUTAMATE SYNTHETASE-ACTIVITY; SITE-DIRECTED MUTAGENESIS; DENOVO PURINE SYNTHESIS; CHILDHOOD LEUKEMIA; HUMAN-BREAST; FOLIC-ACID; MOLECULAR CHARACTERIZATION; MULTITARGETED ANTIFOLATE; DIHYDROFOLATE-REDUCTASE AB We determined the mechanisms of resistance of human CCRF-CEM leukemia cells to methotrexate (MTX) vs. those to six novel antifolates: the polyglutamatable thymidylate synthase (TS) inhibitors ZD1694, multitargeted antifolate, pemetrexed, ALIMTA (MTA) and GW1843U89, the non-polyglutamatable inhibitors of TS, ZD9331, and dihydrofolate reductase, PT523, as well as DDATHF, a polyglutamatable glycinamide ribonucleotide transformylase inhibitor. CEM cells were made resistant to these drugs by clinically relevant intermittent 24 hr exposures to 5-10 muM of MTX, ZD1694, GW1843U89, NITA and DDATHF, by intermittent 72 hr exposures to 5 PM of ZD9331 and by continuous exposure to stepwise increasing concentrations of ZD9331, GW1843U89 and PT523. Development of resistance required only 3 cycles of intermittent drug exposure to ZD1694 and NITA, but 5 cycles for MTX, DDATHF and GW1843U89 and 8 cycles for ZD9331. The predominant mechanism of resistance to ZD1694, NITA, MTX and DDATHF was impaired polyglutamylation due to similar to10-fold decreased folylpolyglutamate synthetase activity. Resistance to intermittent exposures to GW1843U89 and ZD9331 was associated with a 2-fold decreased transport via the reduced folate carrier (RFC). The CEM cell lines resistant to intermittent exposures to MTX, ZD1694, MTA, DDATHF, GW1843U89 and ZD9331 displayed a depletion (up to 4-fold) of total intracellular reduced folate pools. Resistance to continuous exposure to ZD9331 was caused by a 14-fold increase in TS activity. CEM/GW70, selected by continuous exposure to GW1843U89 was 50-fold resistant to GW1843U89, whereas continuous exposure to PT523 generated CEM/PT523 cells that were highly resistant (1550-fold) to PT523. Both CEM/GW70 and CEM/PT523 displayed cross-resistance to several antifolates that depend on the RFC for cellular uptake, including MTX (95- and 530-fold). CEM/GW70 cells were characterized by a 12-fold decreased transport of [H-3]MTX Interestingly, however, CENVGW70 cells displayed an enhanced transport of foHc acid, consistent with the expression of a structurally altered RFC resulting in a 2.6-fold increase of intracellular folate pools. CEM/PT523 cells displayed a markedly impaired (100-fold) transport of [H-3]MTX along with 12-fold decreased total folate pools. In conclusion, multifunctional mechanisms of resistance in CEM cells have a differential impact on cellular folate homeostasis: decreased polyglutamylation and transport defects lead to folate depletion, whereas a structurally altered RFC protein can provoke expanded intracellular folate pools. (C) 2002 Published by Elsevier Science Inc. C1 VU Med Ctr, Dept Med Oncol, Amsterdam, Netherlands. Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Netherlands Canc Inst, Dept Internal Med, Amsterdam, Netherlands. VU Med Ctr, Dept Reumatol, Amsterdam, Netherlands. RP Peters, GJ (reprint author), VU Med Ctr, Dept Med Oncol, Amsterdam, Netherlands. NR 76 TC 37 Z9 39 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD JAN 15 PY 2002 VL 63 IS 2 BP 105 EP 115 AR PII S0006-2952(01)00824-3 DI 10.1016/S0006-2952(01)00824-3 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 533XU UT WOS:000174556200003 PM 11841783 ER PT J AU Pitman, RK Sanders, KM Zusman, RM Healy, AR Cheema, F Lasko, NB Cahill, L Orr, SP AF Pitman, RK Sanders, KM Zusman, RM Healy, AR Cheema, F Lasko, NB Cahill, L Orr, SP TI Pilot study of secondary prevention of posttraumatic stress disorder with propranolol SO BIOLOGICAL PSYCHIATRY LA English DT Article DE stress disorders; posttraumatic; propranolol; prevention ID MEMORY CONSOLIDATION; SYSTEMS AB Background: Preclinical considerations suggest that treatment with a beta-adrenergic blocker following an acute psychologically traumatic event may reduce subsequent posttraumatic stress disorder (PTSD) symptoms. This pilot study addressed this hypothesis. Methods: Patients were randomized to begin, within 6 hours of the event, a 10-day course of double-blind propranolol (n = 18) versus placebo (n = 23) 40 mg four times daily. Results: The mean (SD) 1-month Clinician-Administered PTSD Scale (CAPS) score of 11 propranolol completers was 27.6 (15.7), with one outlier 5.2 SDs above the others' mean, and of 20 placebo completers, 35.5 (21.5), t = 1.1, df = 29, p = .15. Two propranolol patients' scores fell above, and nine below, the placebo group's median, p =. 03 (sign test). Zero of eight propranolol, but six of 14 placebo, patients were physiologic responders during script-driven imagery of the traumatic event when tested 3 months afterward, p = .04 (all p values one-tailed). Conclusions: These pilot results suggest that acute, post-trauma propranolol may have a preventive effect on subsequent PTSD. Biol Psychiatry 2002;51:189-142 (C) 2002 Society, of Biological Psychiatry. C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Vet Adm Med Ctr, Res Serv, Manchester, NH USA. Univ Calif Irvine, Ctr Neurobiol Learning & Memory, Irvine, CA USA. RP Pitman, RK (reprint author), Massachusetts Gen Hosp E, PTSD Res Lab, Bldg 149,13th St, Charlestown, MA 02129 USA. FU NIMH NIH HHS [MH58671] NR 11 TC 475 Z9 488 U1 7 U2 45 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 15 PY 2002 VL 51 IS 2 BP 189 EP 192 DI 10.1016/S0006-3223(01)01279-3 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 516RQ UT WOS:000173570900008 PM 11822998 ER PT J AU Lange-Asschenfeldt, B Weninger, W Velasco, P Kyriakides, TR von Andrian, UH Bornstein, P Detmar, M AF Lange-Asschenfeldt, B Weninger, W Velasco, P Kyriakides, TR von Andrian, UH Bornstein, P Detmar, M TI Increased and prolonged inflammation and angiogenesis in delayed-type hypersensitivity reactions elicited in the skin of thrombospondin-2-deficient mice SO BLOOD LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; TUMOR-GROWTH; ENDOGENOUS INHIBITOR; TRANSGENIC MICE; FACTOR VPF/VEGF; CELLS; OVEREXPRESSION; TISSUE; MOUSE; EXPRESSION AB Anglogenesis and enhanced microvascular permeability are hallmarks of a large number of inflammatory diseases. Although up-regulation of proangiogenic factors such as vascular endothelial growth factor and interleukin-8 have been previously reported in inflamed tissue, the biologic role of endogenous inhibitors of angiogenesis in inflammation has remained unclear. To investigate the biologic role of the potent angiogenesis inhibitor thrombospondin-2 (TSP-2) in the control of cutaneous inflammation, delayed-type hypersensitivity reactions were elicited in the ear skin of wild-type and TSP-2-deficient mice by topical sensitization and challenge with oxazolone. Cutaneous TSP-2 expression was up-regulated in the inflamed skin of wild-type mice, predominantly in dermal fibroblasts and microvessels. Lack of TSP-2 resulted in a significantly enhanced inflammatory response with increased angiogenesis, edema formation, and inflammatory infiltration. Ear swelling and inflammation persisted for more than 2 weeks in TSP-2-deficient mice, as compared with 1 week in wild-type mice. Although baseline vascular permeability was unchanged, significantly enhanced microvascular leakage was found In the inflamed skin of TSP-2-deficient mice. Moreover, the fraction of rolling leukocytes was significantly Increased In the untreated skin of TSP-2-deficient mice. These results reveal an important role of TSP-2 in limiting the extent and the duration of edema formation, angiogenesis, and inflammatory cell Infiltration during acute and chronic inflammation. (Blood. 2002;99:538-545) (C) 2002 by The American Society of Hematology. C1 Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA USA. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Univ Washington, Dept Biochem, Seattle, WA 98195 USA. RP Detmar, M (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Bldg 149,13th St, Charlestown, MA 02129 USA. RI von Andrian, Ulrich/A-5775-2008 FU NCI NIH HHS [CA69184, CA86410]; NHLBI NIH HHS [HL62524, HL18645, HL54936]; NIAMS NIH HHS [AR42689, AR45418] NR 53 TC 55 Z9 57 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 15 PY 2002 VL 99 IS 2 BP 538 EP 545 DI 10.1182/blood.V99.2.538 PG 8 WC Hematology SC Hematology GA 510PF UT WOS:000173215900020 PM 11781236 ER PT J AU An, JB Lichtenstein, AK Brent, G Rettig, MB AF An, JB Lichtenstein, AK Brent, G Rettig, MB TI The Kaposi sarcoma-associated herpesvirus (KSHV) induces cellular interleukin 6 expression: role of the KSHV latency-associated nuclear antigen and the AP1 response element SO BLOOD LA English DT Article ID MULTICENTRIC CASTLEMANS-DISEASE; HUMAN-IMMUNODEFICIENCY-VIRUS; EFFUSION LYMPHOMA-CELLS; BLOOD MONONUCLEAR-CELLS; DNA-SEQUENCES; PERIPHERAL-BLOOD; GENE-EXPRESSION; ENDOTHELIAL-CELLS; GROWTH-FACTOR; HUMAN-HERPESVIRUS-8 AB Cellular interleukin 6 (IL-6) is an important growth factor for Kaposi sarcoma-associated herpesvirus (KSHV)-associated neoplasms, which include human immunodeficiency virus (HIV)-related and -unrelated cases of Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). Increased IL-6 levels are found in tissues affected with these diseases, and KSHV exists in a latent state in the majority of virally infected cells. In addition, acute infection with KSHV up-regulates IL-6 expression in endothelial cells. Thus, the hypothesis was considered that a latent KSHV gene product up-regulates IL-6 expression. To evaluate this hypothesis, the KSHV latency-associated nuclear antigen (LANA) was expressed in human embryonal kidney 293 cells and a bone marrow stromal cell line. LANA up-regulates IL-6 expression by inducing transcription from the IL-6 promoter, and the AP1 response element within the IL-6 promoter is necessary for and mediates IL-6 up-regulation by LANA. Thus, LANA may play a key pathophysiologic role in KSHV-associated neoplasms by functioning to up-regulate expression of IL-6. (Blood. 2002;99:649-654) (C) 2002 by The American Society of Hematology. C1 VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. RP Rettig, MB (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Med, 11301 Wilshire Blvd,Bldg 304,Rm E1-108, Los Angeles, CA 90073 USA. NR 37 TC 72 Z9 74 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 15 PY 2002 VL 99 IS 2 BP 649 EP 654 DI 10.1182/blood.V99.2.649 PG 6 WC Hematology SC Hematology GA 510PF UT WOS:000173215900034 PM 11781250 ER PT J AU Mow, BMF Chandra, J Svingen, PA Hallgren, CG Weisberg, E Kottke, TJ Narayanan, VL Litzow, MR Griffin, JD Sausville, EA Tefferi, A Kaufmann, SH AF Mow, BMF Chandra, J Svingen, PA Hallgren, CG Weisberg, E Kottke, TJ Narayanan, VL Litzow, MR Griffin, JD Sausville, EA Tefferi, A Kaufmann, SH TI Effects of the Bcr/abl kinase inhibitors STI571 and adaphostin (NSC 680410) on chronic myelogenous leukemia cells in vitro SO BLOOD LA English DT Article ID ABL TYROSINE KINASE; CHRONIC MYELOID-LEUKEMIA; DNA-BINDING ACTIVITY; BCR-ABL; SIGNAL-TRANSDUCTION; POSITIVE CELLS; IN-VITRO; C-KIT; APOPTOSIS; RESISTANCE AB The adenosine triphosphate binding-site-directed agent STI571 and the tyrphostin adaphostin are undergoing evaluation as bcr/abl kinase inhibitors. The current study compared the effects of these agents on the survival of K562 cells, bcr/abl-transduced FDC-P1 cells, and myeloid progenitors from patients with chronic myelogenous leukemia (CML) compared with healthy donors. Treatment of K562 cells with 10 muM adaphostin resulted in decreased p210(bcr/abl) polypeptide levels in the first 6 hours, followed by caspase activation and accumulation of apoptotic cells in less than 12 hours. By 24 hours, 90% of the cells were apoptotic and unable to form colonies. In contrast, 20 muM STI571 caused rapid inhibition of bcr/abl autophosphorylation without p210(bcr/abl) degradation. Although this was followed by the inhibition of Stat5 phosphorylation and the down-regulation of BCI-x(L) and Mcl-1, only 7%+/-3% and 25%+/-9% of cells were apoptotic at 16 and 24 hours, respectively. Instead, the cytotoxic effects of STI571 became more pronounced with prolonged exposure, with IC90 values greater than 20 muM and 1.0+/-0.6 muM after 24 and 48 hours, respectively. Consistent with these results, 24-hour adaphostin exposure inhibited CML granulocyte colony-forming units (CFU-G) (median IC50,12 muM) but not normal CFU-G (median IC50, greater than 20 muM), whereas 24-hour STI571 treatment had no effect on CML or normal CFU-G. Additional experiments revealed that STI571-resistant K562 cells remained sensitive to adaphostin. Moreover, the combination of STI571 + adaphostin Induced more cytotoxicity In K562 cells and In CML CFU-G than either agent alone did. Collectively, these results Identify adaphostin as a mechanistically distinct CML-selective agent that retains activity In STI571-resistant cell lines. (Blood. 2002;99:664-671) (C) 2002 by The American Society of Hematology. C1 Mayo Clin, Dept Oncol, Div Oncol Res, Rochester, MN 55901 USA. Mayo Clin, Dept Internal Med, Div Hematol, Rochester, MN 55901 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. NCI, Dev Therapeut Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Kaufmann, SH (reprint author), Mayo Clin, Dept Oncol, Div Oncol Res, Guggenheim 1301,200 1st St SW, Rochester, MN 55901 USA. FU NCI NIH HHS [R01 CA85972, R01 CA69008, T32 CA09441] NR 57 TC 95 Z9 98 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 15 PY 2002 VL 99 IS 2 BP 664 EP 671 DI 10.1182/blood.V99.2.664 PG 8 WC Hematology SC Hematology GA 510PF UT WOS:000173215900036 PM 11781252 ER PT J AU Shannon, KM Lubratovich, ML Finkelstein, DM Smith, BL Powell, SN Seiden, MV AF Shannon, KM Lubratovich, ML Finkelstein, DM Smith, BL Powell, SN Seiden, MV TI Model-based predictions of BRCA1/2 mutation status in breast carcinoma patients treated at an academic medical center SO CANCER LA English DT Article DE BRCA1; BRCA2; genetic testing; breast carcinoma; predictive models ID POPULATION-BASED SAMPLE; OVARIAN-CANCER; FAMILY HISTORY; SEQUENCE-ANALYSIS; WOMEN; RISK; FREQUENCY; CARRIERS AB BACKGROUND. Women with an existing breast carcinoma diagnosis who are found to carry a BRCA1/2 mutation have a substantial risk of developing both a contralateral breast carcinoma and ovarian carcinoma. In a newly diagnosed breast carcinoma patient, this genetic information may influence the management of her disease. To assess the volume of patients who may need genetic services at the time of diagnosis, the authors determined the proportion of women with newly diagnosed breast carcinoma at the study institution who would be eligible for genetic testing. METHODS. Fifty consecutive women with new breast carcinoma who were attending a multidisciplinary clinic were interviewed, Detailed, three-generation pedigrees were collected for each patient by a genetic counselor. Three commonly used probability models were used to calculate each woman's predicted risk of harboring a germline BRCA1/2 mutation. RESULTS. Eleven of 50 patients (22% [95% confidence interval, 12-36%]) were calculated to have a greater than or equal to 10% probability of carrying a BRCA1/2 mutation by at least one mathematic model and should have been offered genetic counseling that included the discussion of genetic testing. There were considerable discrepancies between probability calculations among the three mathematic models. One of the 11 patients who was eligible for genetic testing pursued genetic counseling within 12 months of diagnosis, CONCLUSIONS. At a large academic medical center, a substantial proportion of unselected women attending a multidisciplinary clinic were found to have a 10% risk of carrying a BRCA1/2 mutation, The actual number of patients eligible to receive BRCA1/2 genetic testing outweighs the number of patients seen for genetic counseling at the study institution. Finally, limited correlation was found between current predictive models. (C) 2002 American Cancer Society. C1 Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Seiden, MV (reprint author), Massachusetts Gen Hosp, Div Hematol Oncol, 100 Blossom St,COX 640, Boston, MA 02114 USA. NR 27 TC 19 Z9 19 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JAN 15 PY 2002 VL 94 IS 2 BP 305 EP 313 DI 10.1002/cncr.10223 PG 9 WC Oncology SC Oncology GA 512CP UT WOS:000173303800004 PM 11900216 ER PT J AU Kerrigan, SAJ Turnnir, RT Clement, PB Young, RH Churg, A AF Kerrigan, SAJ Turnnir, RT Clement, PB Young, RH Churg, A TI Diffuse malignant epithelial mesotheliomas of the peritoneum in women - A clinicopathologic study of 25 patients SO CANCER LA English DT Article DE peritoneum; female; mesothelioma; epithelial mesotheliomas ID TUMORS AB BACKGROUND. The behavior of diffuse peritoneal mesotheliomas in women and the possible relation between tumor morphology and outcome are uncertain. Reported survival has ranged from < 1 month to > 14 years, and a previous study found that tumor morphology could not be used reliably for predicting outcome. The authors examined the behavior of diffuse epithelial peritoneal mesotheliomas in women and the possible relation between pathologic feature and outcome. METHODS. Twenty-Five female patients with diffuse peritoneal epithelial malignant mesotheliomas were divided into two groups: those who survived for < 4 years (60%) and those who survived for > 4 years (40%), Both group were compared in terms of age, presentation, treatment, survival, tumor architecture, mitotic rate, necrosis, nuclear grade, and immunohistochemical profile. RESULTS. Patients in the two groups were similar in terms of age at diagnosis (median ages, 50.7 years and 49.9 years), presentation, initial tumor burden, and treatment. In both groups, the most common initial clinical presenting features were ascites and abdominal pain. The tumors typically took the form of multiple nodules measuring < 1.5 cm in greatest dimension, slightly less than 50% of patients in both groups received some Form of chemotherapy or radiation therapy after undergoing tumor-reductive surgery or biopsy, Overall survival ranged from 1 month to 15 years. The median survival was 12 months in the group of women who survived for < 4 years and 7 years in the group of women who survived fur > 4 years. Overall, 10 of 25 patients Survived for greater than or equal to 5 years. One patient was alive with disease 15 years after diagnosis. Although there was a suggestion that the tumors in patients with short survival more often had solid architecture and high-grade nuclei, these findings were not significant statistically. The frequency of necrosis and the mitotic activity were the same in both groups. CONCLUSIONS. The spectrum of diffuse epithelial peritoneal mesotheliomas in women includes tumors that are highly aggressive and behave much like pleural mesotheliomas, although a sizeable number of tumors, unlike the pleural tumors, are relatively indolent. However, because there do not appear to be morphologic features that reliably identify favorable tumors versus unfavorable tumors, aggressive therapy for all women with diffuse peritoneal mesotheliomas may be warranted. (C) 2002 American Cancer Society. C1 Univ British Columbia, Dept Pathol, Vancouver, BC V6T 2B5, Canada. Vancouver Hosp & Hlth Sci Ctr, Dept Pathol, Vancouver, BC V5Z 1M9, Canada. Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Churg, A (reprint author), Univ British Columbia, Dept Pathol, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada. NR 20 TC 54 Z9 56 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 JAN 15 PY 2002 VL 94 IS 2 BP 378 EP 385 DI 10.1002/cncr.10209 PG 8 WC Oncology SC Oncology GA 512CP UT WOS:000173303800012 PM 11905410 ER PT J AU Wood, BJ Ramkaransingh, JR Fojo, T Walther, MM Libutti, SK AF Wood, BJ Ramkaransingh, JR Fojo, T Walther, MM Libutti, SK TI Percutaneous tumor ablation with radiofrequency SO CANCER LA English DT Article DE radiofrequency thermal ablation; minimally invasive therapy; hyperthermia; tumor ablation ID RENAL-CELL CARCINOMA; TISSUE ABLATION; HEPATOCELLULAR-CARCINOMA; LIVER METASTASES; HEPATIC MALIGNANCIES; COAGULATION NECROSIS; COLORECTAL-CANCER; BLOOD-FLOW; EX-VIVO; IN-VIVO AB BACKGROUND. Radiofrequency thermal ablation (RFA) is a new minimally invasive treatment for localized cancer. Minimally invasive surgical options require less resources, time, recovery, and cost, and often offer reduced morbidity and mortality, compared with more invasive methods. To be useful, image-guided, minimally invasive, local treatments will have to meet those expectations without sacrificing efficacy. METHODS. Image-guided, local cancer treatment relies on the assumption that local disease control may improve survival. Recent developments in ablative techniques are being applied to patients with inoperable, small, or solitary liver tumors, recurrent metachronous hereditary renal cell carcinoma, and neoplasms in the bone, lung, breast, and adrenal gland. RESULTS. Recent refinements in ablation technology enable large tumor volumes to be treated with image-guided needle placement, either percutaneously, laparoscopically, or with open surgery. Local disease control potentially could result in improved survival, or enhanced operability. CONCLUSIONS. Consensus indications in oncology are ill-defined, despite widespread proliferation of the technology. A brief review is presented of the current status of image-guided tumor ablation therapy. More rigorous scientific review, long-term follow-up, and randomized prospective trials are needed to help define the role of RFA in oncology. Cancer 2002;94:443-51. Published 2002 by the American Cancer Society.* C1 NIH, Ctr Clin, Dept Diagnost Radiol, Special Procedures Div, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Dept Radiol, Div Abdominal & Intervent Radiol, Boston, MA 02114 USA. Georgetown Univ, Med Ctr, Dept Radiol, Div Vasc & Intervent Radiol, Washington, DC 20007 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Wood, BJ (reprint author), NIH, Ctr Clin, Dept Diagnost Radiol, Special Procedures Div, Bldg 10,Room 1C-660,9000 Rockville Pike, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CL999999] NR 62 TC 105 Z9 113 U1 0 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JAN 15 PY 2002 VL 94 IS 2 BP 443 EP 451 DI 10.1002/cncr.10234 PG 9 WC Oncology SC Oncology GA 512CP UT WOS:000173303800021 PM 11900230 ER PT J AU Jena, N Deng, M Sicinska, E Sicinski, P Daley, GQ AF Jena, N Deng, M Sicinska, E Sicinski, P Daley, GQ TI Critical role for cyclin D2 in BCR/ABL-induced proliferation of hematopoietic cells SO CANCER RESEARCH LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; BCR-ABL ONCOGENE; TRANSFORMATION; APOPTOSIS; PROTEIN; INHIBITION; MICE; GENE; TRANSITION AB Chronic myeloid leukemia is caused by the tyrosine kinase oncoprotein BCR/ABL. Using oligonucleotide arrays to assay mRNAs at different phases of the cell cycle in BCR/ABL-transformed cells, we found that cyclin D2 mRNA was constitutively expressed at high levels throughout the cell cycle, a pattern confirmed by immunoblotting of protein lysates. Bone marrow cells from cyclin D2-deficient strains of mice failed to proliferate in response to infection with a retrovirus carrying BCR/ABL and failed to generate transformed lymphoid cell lines in vitro. These results establish that BCR/ABL promotes cell cycle progression by altering expression of cyclin D2 and that cyclin D2 induction plays a critical role in proliferation of hematopoietic cells by BCR/ABL. C1 Whitehead Inst, Cambridge Ctr 9, Cambridge, MA 02142 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, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. RP Daley, GQ (reprint author), Whitehead Inst, Cambridge Ctr 9, Cambridge, MA 02142 USA. FU NCI NIH HHS [CA86991, CA76418] NR 36 TC 45 Z9 46 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2002 VL 62 IS 2 BP 535 EP 541 PG 7 WC Oncology SC Oncology GA 515HE UT WOS:000173488700034 PM 11809706 ER PT J AU Yuan, C Zhang, SX Polissar, NL Echelard, D Ortiz, G Davis, JW Ellington, E Ferguson, MS Hatsukami, TS AF Yuan, C Zhang, SX Polissar, NL Echelard, D Ortiz, G Davis, JW Ellington, E Ferguson, MS Hatsukami, TS TI Identification of fibrous cap rupture with magnetic resonance imaging is highly associated with recent transient ischemic attack or stroke SO CIRCULATION LA English DT Article DE magnetic resonance imaging; atherosclerosis; carotid arteries; stroke ID ATHEROSCLEROTIC PLAQUE RUPTURE; IN-VIVO; NMR; THROMBOSIS; DISRUPTION; MICROSCOPY; CARTILAGE; STENOSIS; CONTRAST; GRADIENT AB Background-High-resolution MRI has been shown to be capable of distinguishing intact, thick fibrous caps from thin and ruptured caps in human carotid atherosclerosis in vivo. The aim of this study was to determine whether MRI identification of fibrous cap thinning or rupture is associated with a history of recent transient ischemic attack (TIA) or stroke. Methods and Results-Fifty-three consecutive patients (mean age, 71 years; 49 male) scheduled for carotid endarterectomy were recruited after obtaining informed consent. Twenty-eight subjects had a recent history of TIA or stroke on the side appropriate to the index carotid lesion, and 25 were asymptomatic. Preoperative carotid MRI was performed in a 1.5-T GE Signa scanner that generated T-1-, PD-, and T-2-weighted and three-dimensional time-of-flight images. Using previously reported MRI criteria, the fibrous cap was categorized as intact-thick, intact-thin, or ruptured for each carotid plaque by blinded review. There was a strong and statistically significant trend showing a higher percentage of symptomatic patients for ruptured caps (70%) compared with thick caps (9%) (P=0.001 Mann-Whitney test for cap status versus symptoms). Compared with patients with thick fibrous caps, patients with ruptured caps were 23 times more likely to have had a recent TIA or stroke (95% CI=3, 210). Conclusions-MRI identification of a ruptured fibrous cap is highly associated with a recent history of TIA or stroke. Ongoing prospective studies will determine the predictive value fibrous cap characteristics, as visualized by MRI, for risk of subsequent ischemic events. C1 Univ Washington, Dept Radiol, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Mt Whisper Light Stat Consulting, Seattle, WA USA. VA Puget Sound Hlth Care Syst, Surg & Perioperat Care, Seattle, WA USA. RP Yuan, C (reprint author), Univ Washington, Dept Radiol, Box 357115,1959 NE Pacific Ave, Seattle, WA 98195 USA. FU NHLBI NIH HHS [R01 HL56874, R01 HL60213] NR 31 TC 252 Z9 287 U1 1 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 15 PY 2002 VL 105 IS 2 BP 181 EP 185 DI 10.1161/hc0202.102121 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 512NR UT WOS:000173330900025 PM 11790698 ER PT J AU Chappell, JD Prota, AE Dermody, TS Stehle, T AF Chappell, JD Prota, AE Dermody, TS Stehle, T TI Crystal structure of reovirus attachment protein sigma 1 reveals evolutionary relationship to adenovirus fiber SO EMBO JOURNAL LA English DT Article DE adenovirus; evolution; reovirus; sigma 1; virus-receptor interactions ID CENTRAL-NERVOUS-SYSTEM; ANGSTROM RESOLUTION; INDUCED APOPTOSIS; MEMBRANE-FUSION; TYPE-3; HEMAGGLUTININ; BINDING; IDENTIFICATION; PARTICLES; SEQUENCE AB Reovirus attaches to cellular receptors with the sigma1 protein, a fiber-like molecule protruding from the 12 vertices of the icosahedral virion. The crystal structure of a receptor-binding fragment of sigma1 reveals an elongated trimer with two domains: a compact head with a new beta-barrel fold and a fibrous tail containing a triple beta-spiral. Numerous structural and functional similarities between reovirus sigma1 and the adenovirus fiber suggest an evolutionary link in the receptor-binding strategies of these two viruses. A prominent loop in the sigma1 head contains a cluster of residues that are conserved among reovirus serotypes and are likely to form a binding site for junction adhesion molecule, an integral tight junction protein that serves as a reovirus receptor. The fibrous tail is mainly responsible for sigma1 trimer formation, and it contains a highly flexible region that allows for significant movement between the base of the tail and the head. The architecture of the trimer interface and the observed flexibility indicate that sigma1 is a metastable structure poised to undergo conformational changes upon viral attachment and cell entry. C1 Vanderbilt Univ, Dept Pediat, Sch Med, Nashville, TN 37232 USA. Vanderbilt Univ, Dept Microbiol & Immunol, Sch Med, Nashville, TN 37232 USA. Vanderbilt Univ, Elizabeth B Lamb Ctr Pediat Res, Sch Med, Nashville, TN 37232 USA. Massachusetts Gen Hosp, Lab Dev Immunol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Renal Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Dermody, TS (reprint author), Vanderbilt Univ, Dept Pediat, Sch Med, Nashville, TN 37232 USA. FU NCI NIH HHS [CA68485, P30 CA068485]; NIAID NIH HHS [AI38296, AI45716, R01 AI038296, R01 AI045716, R37 AI038296]; NIDDK NIH HHS [DK20593, P30 DK020593, P60 DK020593] NR 54 TC 132 Z9 137 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD JAN 15 PY 2002 VL 21 IS 1-2 BP 1 EP 11 DI 10.1093/emboj/21.1.1 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 513UN UT WOS:000173398000001 PM 11782420 ER PT J AU Goorin, AM Harris, MB Bernstein, M Ferguson, W Devidas, M Siegal, GP Gebhardt, MC Schwartz, CL Link, M Grier, HE AF Goorin, AM Harris, MB Bernstein, M Ferguson, W Devidas, M Siegal, GP Gebhardt, MC Schwartz, CL Link, M Grier, HE TI Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: A Pediatric Oncology Group trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MALIGNANT SOLID TUMORS; OSTEOGENIC-SARCOMA; PREOPERATIVE CHEMOTHERAPY; CHILDHOOD OSTEOSARCOMA; ADJUVANT CHEMOTHERAPY; CIS-DICHLORODIAMMINEPLATINUM(II); COMBINATION; CHILDREN; METHOTREXATE; DOXORUBICIN AB Purpose: The objectives of this trial were to estimate the response rate, progression-free survival, and overall survival of patients who received therapy with etoposide and high-dose ifosfamide, and to define the toxicity of this combination when provided with standard chemotherapy in patients with newly diagnosed metastatic osteosarcoma. Patients and Methods: Eligible patients received infusions of 100 mg/m(2) per day of etoposide and 3.5 g/m(2) per day of ifosfamide for 5 days. Therapy with granulocyte colony-stimulating factor was begun on day 6. This was repeated 3 weeks after therapy was begun. Response was determined at week 6 by both standard World Health Organization response criteria and by pathologic determination of tumor necrosis of the primary tumor. Results: Forty-three patients were registered; 39 were assessable for response and 41 for toxicity and survival. Twenty-eight (68%) of 41 had metastatic sites only in the lung; 12 (29%) had metastatic sites in other bones with or without lung involvement. Four patients (10%) experienced complete response, and 19 patients (49%) experienced partial response, for an overall response rate of 59% +/- 8%. The projected 2-year progression-free survival (PFS) for the 28 patients with metastases to lungs was 39% +/- 11%. The projected 2-year PFS for the 12 patients with metastases to other bones (with or without pulmonary metastases) was 58% +/- 17%. Two patients died as a result of therapy toxicity. Eighty-three percent of patients had grade 4 neutropenia, and 29% had grade 4 thrombocytopenia. Ten patients (24%) had sepsis. Fanconi's syndrome was observed in five patients. Conclusion: The combination of etoposide and high-dose ifosfamide is effective induction chemotherapy for patients with metastatic osteasarcoma, despite significant associated myelosuppression sometimes complicated by infection and renal toxicity. (C) 2002 by American Society of Clinical Oncology. C1 Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Tomorrows Childrens Inst, Hackensack, NJ USA. Univ Med & Dent New Jersey, Hackensack, NJ USA. Ste Justine Hosp, Montreal, PQ, Canada. Univ Montreal, Montreal, PQ, Canada. Rhode Isl Hosp, Brown Med Sch, Div Pediat Hematol Oncol, Providence, RI USA. Univ Florida, Dept Stat, Gainesville, FL USA. Pediat Oncol Grp, Stat Off, Gainesville, FL USA. Univ Alabama, Div Anat Pathol, Birmingham, AL USA. Johns Hopkins Oncol Ctr, Baltimore, MD USA. Stanford Univ, Sch Med, Div Hematol Oncol & Bone Marrow Transplantat, Stanford, CA 94305 USA. RP Goorin, AM (reprint author), Childrens Oncol Grp, POB 60012, Arcadia, CA 91066 USA. RI Siegal, Gene/A-8653-2009 FU NCI NIH HHS [CA15989, CA35906, CA28476, CA41573, CA30969, CA29139] NR 46 TC 99 Z9 109 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 15 PY 2002 VL 20 IS 2 BP 426 EP 433 DI 10.1200/JCO.20.2.426 PG 8 WC Oncology SC Oncology GA 513WR UT WOS:000173404000011 PM 11786570 ER PT J AU Goessling, W McKee, PH Mayer, RJ AF Goessling, W McKee, PH Mayer, RJ TI Merkel cell carcinoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID SENTINEL LYMPH-NODE; CUTANEOUS NEUROENDOCRINE CARCINOMA; FINE-NEEDLE ASPIRATION; TUMOR-NECROSIS-FACTOR; SOMATOSTATIN RECEPTOR SCINTIGRAPHY; COMPARATIVE GENOMIC HYBRIDIZATION; POSTOPERATIVE RADIATION-THERAPY; POSITRON-EMISSION-TOMOGRAPHY; CHRONIC LYMPHOCYTIC-LEUKEMIA; MOHS MICROGRAPHIC SURGERY C1 Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Mayer, RJ (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. NR 175 TC 179 Z9 183 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 15 PY 2002 VL 20 IS 2 BP 588 EP 598 DI 10.1200/JCO.20.2.588 PG 11 WC Oncology SC Oncology GA 513WR UT WOS:000173404000031 PM 11786590 ER PT J AU Abe, M Cheng, J Qi, J Glaser, RM Thall, AD Sykes, M Yang, YG AF Abe, M Cheng, J Qi, J Glaser, RM Thall, AD Sykes, M Yang, YG TI Elimination of porcine hemopoietic cells by macrophages in mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; IMMUNE-DEFICIENT MICE; NATURAL-KILLER-CELLS; BONE-MARROW GRAFTS; FC-MU-RECEPTOR; T-CELLS; MONOCLONAL-ANTIBODIES; IMMUNODEFICIENT MICE; XENOGRAFT REJECTION; GENETIC-RESISTANCE AB The difficulty in achieving donor hemopoietic engraftment across highly disparate xenogeneic species barriers poses a major obstacle to exploring xenograft tolerance induction by mixed chimerism. In this study, we observed that macrophages mediate strong rejection of porcine hemopoietic cells in mice. Depletion of macrophages with medronate-encapsulated liposomes (M-liposomes) markedly improved porcine chimerism, and early chimerism in particular, in sublethally irradiated immunodeficient and lethally irradiated immunocompetent mice. Although porcine chimerism in the peripheral blood and spleen of M-liposome-treated nice rapidly declined after macrophages had recovered and became indistinguishable from controls by wk 5 post-transplant, the levels of chimerism in the marrow of these mice remained higher than those in control recipients at 8 wks after transplant. These results suggest that macrophages that developed in the presence of porcine chimerism were not adapted to the porcine donor and that marrow-resident macrophages did not phagocytose porcine cells. Moreover, M-liposome treatment had no effect on the survival of porcine PBMC injected into the recipient peritoneal cavity, but was essential for the migration and relocation of these cells into other tissues/organs, such as spleen, bone marrow, and peripheral blood. Together, our results suggest that murine reticuloendothelial macrophages, but not those in the bone marrow and peritoneal cavity, play a significant role in the clearance of porcine hemopoietic cells in vivo. Because injection of M-liposomes i.v. mainly depletes splenic macrophages and liver Kupffer cells, the spleen and/or liver are likely the primary sites of porcine cell clearance in vivo. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med,Transplantat Biol Res Ctr, Bone Marrow Transplantat Sect,Surg Serv, Boston, MA 02129 USA. BioTransplant Inc, Boston, MA 02129 USA. RP Yang, YG (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Transplantat Biol Res Ctr, Bone Marrow Transplantat Sect,Surg Serv, MGH East,Bldg 149-5102,13th St, Boston, MA 02129 USA. RI Glaser, Ronald/E-3124-2011 NR 62 TC 34 Z9 34 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 JAN 15 PY 2002 VL 168 IS 2 BP 621 EP 628 PG 8 WC Immunology SC Immunology GA 510DP UT WOS:000173193700012 PM 11777954 ER PT J AU Neuzil, KM Zhu, YW Griffin, MR Edwards, KM Thompson, JM Tollefson, SJ Wright, PF AF Neuzil, KM Zhu, YW Griffin, MR Edwards, KM Thompson, JM Tollefson, SJ Wright, PF TI Burden of interpandemic influenza in children younger than 5 years: A 25-year prospective study SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; OTITIS-MEDIA; PANDEMIC INFLUENZA; HEALTHY INFANTS; DAY-CARE; A-VIRUS; INFECTION; VACCINE; EPIDEMIOLOGY; DISEASE AB Many respiratory viruses cause morbidity in young children, but a licensed vaccine and effective oral therapy are available only for influenzavirus. To determine the incidence of laboratory-confirmed influenza illness, we prospectively followed up 1665 healthy children aged, 5 years who were enrolled in the Vanderbilt Vaccine Clinic at some point from 1974 through 1999. Viral cultures were obtained when the children presented with clinical illness. The isolation of influenzavirus was associated with an estimated 95 health care visits for children with symptoms of influenza, 46 episodes of acute otitis media, and 8 episodes of lower respiratory tract disease per 1000 children yearly. Rates of acute otitis media and lower respiratory tract disease were highest among children aged, <2 years. Hospitalizations associated with culture-positive influenza occurred at an annual rate of 3-4 per 1000 children aged, <2 years. Influenza is associated with substantial morbidity in otherwise healthy children aged, <5 years. C1 Univ Washington, Sch Med, Dept Med, Div Infect Dis, Seattle, WA 98195 USA. VA Puget Sound Hlth Care Syst, Seattle, WA USA. Vanderbilt Univ, Sch Med, Dept Prevent Med, Nashville, TN 37212 USA. Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. Vanderbilt Univ, Sch Med, Dept Pediat, Div Infect Dis, Nashville, TN 37212 USA. RP Neuzil, KM (reprint author), Med Serv 111, 1660 S Columbian Way, Seattle, WA 98108 USA. FU NIAID NIH HHS [N01-AI-05050, N01-AI-64298]; ODCDC CDC HHS [UR6/CCU417579] NR 38 TC 302 Z9 327 U1 1 U2 9 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 JAN 15 PY 2002 VL 185 IS 2 BP 147 EP 152 DI 10.1086/338363 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 508LX UT WOS:000173091300002 PM 11807687 ER PT J AU Cao, HY Agrawal, D Kushner, N Touzjian, N Essex, M Lu, YC AF Cao, HY Agrawal, D Kushner, N Touzjian, N Essex, M Lu, YC TI Delivery of exogenous protein antigens to major histocompatibility complex class I pathway in cytosol SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID TOXIN-MEDIATED DELIVERY; CYTOTOXIC T-LYMPHOCYTES; ANTHRAX LETHAL FACTOR; PROTECTIVE ANTIGEN; MHC MOLECULES; PARTICULATE ANTIGENS; PROCESSING PATHWAY; CELLS; TRANSPORTER; VIRUS AB A fragment of anthrax lethal factor possesses the interesting function of delivering recombinant protein antigens through the classical major histocompatibility complex (MHC) class I pathway. This region of the lethal factor lacks the domain associated with anthrax cytotoxicity and functions independently of its binary partner, protective antigen. Experiments that used inhibitors at different steps of the MHC class I pathway supported this hypothesis. Application of this discovery to current T cell assays allows for the measurement of cytotoxic T lymphocyte function without resorting to live vectors and provides a useful new tool to design and test T cell-dependent vaccines. C1 Calif Dept Hlth Serv, Viral & Rickettsial Dis Lab, Richmond, CA 94804 USA. Massachusetts Gen Hosp, AIDS Res Ctr, Charlestown, MA USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Cao, HY (reprint author), Calif Dept Hlth Serv, Viral & Rickettsial Dis Lab, 850 Marina Bay Pkwy, Richmond, CA 94804 USA. FU NIAID NIH HHS [AI47539] NR 41 TC 18 Z9 21 U1 0 U2 0 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 JAN 15 PY 2002 VL 185 IS 2 BP 244 EP 251 DI 10.1086/338448 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 508LX UT WOS:000173091300014 PM 11807699 ER PT J AU Ji, RR Befort, K Brenner, GJ Woolf, CJ AF Ji, RR Befort, K Brenner, GJ Woolf, CJ TI ERK MAP kinase activation in superficial spinal cord neurons induces prodynorphin and NK-1 upregulation and contributes to persistent inflammatory pain hypersensitivity SO JOURNAL OF NEUROSCIENCE LA English DT Article DE ERK; MAP kinase; prodynorphin; neurokinin-1; spinal cord; inflammatory pain ID SUBSTANCE-P RECEPTOR; DORSAL HORN NEURONS; FORMALIN-INDUCED NOCICEPTION; NERVE-INJURED RATS; NEUROKININ-1 RECEPTOR; SENSORY NEURONS; MESSENGER-RNA; PERIPHERAL INFLAMMATION; NEUROPATHIC PAIN; GENE-EXPRESSION AB Activation of ERK (extracellular signal-regulated kinase) MAP (mitogen-activated protein) kinase in dorsal horn neurons of the spinal cord by peripheral noxious stimulation contributes to short-term pain hypersensitivity. We investigated ERK activation by peripheral inflammation and its involvement in regulating gene expression in the spinal cord and in contributing to inflammatory pain hypersensitivity. Injection of complete Freund's adjuvant (CFA) into a hindpaw produced a persistent inflammation and a sustained ERK activation in neurons in the superficial layers (laminae l-llo) of the dorsal horn. CFA also induced an upregulation of prodynorphin and neurokinin-1 (NK-1) in dorsal horn neurons, which was suppressed by intrathecal delivery of the MEK (MAP kinase kinase) inhibitor U0126. CFA-induced phospho-ERK primarily colocalized with prodynorphin and NK-1 in superficial dorsal horn neurons. Although intrathecal injection of U0126 did not affect basal pain sensitivity, it did attenuate both the establishment and maintenance of persistent inflammatory heat and mechanical hypersensitivity. Activation of the ERK pathway in a subset of nociceptive spinal neurons contributes, therefore, to persistent pain hypersensitivity, possibly via transcriptional regulation of genes, such as prodynorphin and NK-1. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Ji, RR (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care,Neural Plast Res Grp, 149 13th St,Room 4309, Charlestown, MA 02129 USA. OI Ji, Ru-Rong/0000-0002-9355-3688 FU NINDS NIH HHS [R01 NS040698, NS40698, R01 NS38253] NR 63 TC 311 Z9 339 U1 2 U2 10 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 JAN 15 PY 2002 VL 22 IS 2 BP 478 EP 485 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 510JK UT WOS:000173204800019 PM 11784793 ER PT J AU Alam, MN Gong, H Alam, T Jaganath, R McGinty, D Szymusiak, R AF Alam, MN Gong, H Alam, T Jaganath, R McGinty, D Szymusiak, R TI Sleep-waking discharge patterns of neurons recorded in the rat perifornical lateral hypothalamic area SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID MELANIN-CONCENTRATING HORMONE; LOCUS-COERULEUS NEURONS; DORSAL RAPHE NEURONS; EYE-MOVEMENT SLEEP; OREXIN-A; FEEDING-BEHAVIOR; NEUROPEPTIDE-Y; BRAIN; NARCOLEPSY; AROUSAL AB The perifornical lateral hypothalamic area (PF-LHA) has been implicated in the control of several waking behaviours, including feeding, motor activity and arousal. Several cell types are located in the PF-LHA, including projection neurons that contain the hypocretin peptides (also known as orexins). Recent findings suggest that hypocretin neurons are involved in sleep-wake regulation. Loss of hypocretin neurons in the human disorder narcolepsy is associated with excessive somnolence, cataplexy and increased propensity for rapid eye movement (REM) sleep. However, the relationship of PF-LHA neuronal activity to different arousal states is unknown. We recorded neuronal activity in the PF-LHA of rats during natural sleep and waking. Neuronal discharge rates were calculated during active waking (waking accompanied by movement), quiet waking, non-REM sleep and REM sleep. Fifty-six of 106 neurons (53 %) were classified as wake/REM-related. These neurons exhibited peak discharge rates during waking and REM sleep and reduced discharge rates during non-REM sleep. Wake-related neurons (38 %) exhibited reduced discharge rates during both non-REM and REM sleep when compared to that during waking. Wake-related neurons exhibited significantly higher discharge rates during active waking than during quiet waking. The discharge of wake-related neurons was positively correlated with muscle activity across all sleep-waking states. Recording sites were located within the hypocretin-immunoreactive neuronal field of the PF-LHA, Although the neurotransmitter phenotype of recorded cells was not determined, the prevalence of neurons with wake-related discharge patterns is consistent with the hypothesis that the PF-LHA participates in the regulation of arousal, muscle activity and sleep-waking states. C1 VA Greater Los Angeles Healthcare Syst, Res Serv, North Hills, CA 91343 USA. Univ Calif Los Angeles, Sch Med, Dept Psychol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Dept Neurobiol, Los Angeles, CA 90024 USA. RP Szymusiak, R (reprint author), VA Greater Los Angeles Healthcare Syst, Res Serv, 151A3,16111 Plummer St, North Hills, CA 91343 USA. FU NHLBI NIH HHS [HL60296, P50 HL060296]; NIMH NIH HHS [MH61354, MH47480, R01 MH047480] NR 45 TC 113 Z9 116 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD JAN 15 PY 2002 VL 538 IS 2 BP 619 EP 631 DI 10.1013/jphysiol.2001.12888 PG 13 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 522DW UT WOS:000173881300022 PM 11790824 ER PT J AU Arita, S Nagai, T Ochiai, M Sakamoto, Y Shevlin, LA Smith, CV Mullen, Y AF Arita, S Nagai, T Ochiai, M Sakamoto, Y Shevlin, LA Smith, CV Mullen, Y TI Prevention of primary nonfunction of canine islet autografts by treatment with pravastatin SO TRANSPLANTATION LA English DT Article ID LIVER-TRANSPLANTATION; MEVALONATE PATHWAY; REJECTION; ALLOGRAFTS; SURVIVAL; RAT; 15-DEOXYSPERGUALIN; ISOGRAFTS; MICE AB Background. Nonspecific inflammation is the primary cause of early islet graft loss. We have shown in mice that pravastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, prevents primary nonfunction of islet isografts by reducing inflammatory reactions at the graft site. This study was designed to test the effectiveness of this agent in a large animal model, dogs, by transplanting autologous islets. Methods. After total pancreatectomy, islets were isolated by using a two-step digestion method, followed by discontinuous gradient centrifugation on EuroFicoll. A known number of freshly isolated islets were immediately transplanted back into the same dog via the portal vein. Results. First, we determined the minimal islet number required to reverse diabetes by transplanting 3,000-10,000 IEQ/kg with no additional treatment. The number was found to be 4,000 IEQ/kg, and islets less than 4,000 IEQ/kg consistently failed. To test the effect of pravastatin, 3,000 IEQ/kg were transplanted into dogs that either received no further treatment or were treated daily with 20 mg/kg of pravastatin from days -2 to 14. Without pravastatin, this number of islets lowered blood glucose only transiently, and all four of these dogs became hyperglycemic within 1 week. In contrast, four of the five dogs treated with pravastatin became normoglycemic (<150 mg/dL) and maintained this level during the observation period of 12 weeks (P<0.05). Postprandial plasma glucose and insulin levels returned to normal, and K values of intravenous glucose tolerance tests were significantly higher in pravastatin-treated dogs than in controls (P<0.04 at week 2 and P<0.01 at week 4). Conclusion. Peritransplant pravastatin treatment reduced the number of autologous islets required to reverse diabetes in totally pancreatectomized dogs. These results suggest that pravastatin may also facilitate better islet graft survival and function in clinical transplantation. C1 Univ Calif Los Angeles, Sch Med, Islet Transplant Program, Dept Surg, Los Angeles, CA 90073 USA. W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. RP Mullen, Y (reprint author), City Hope Natl Med Ctr, 1500 E Duarte Rd, Duarte, CA 91010 USA. NR 29 TC 26 Z9 26 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JAN 15 PY 2002 VL 73 IS 1 BP 7 EP 12 DI 10.1097/00007890-200201150-00003 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 515FJ UT WOS:000173484500003 PM 11792971 ER PT J AU Buhler, L Awwad, M Treter, S Chang, Q Basker, M Alwayn, IPJ Teranishi, K Ericsson, T Moran, K Harper, D Kurilla-Mahon, B Huang, CA Sackstein, R Sykes, M White-Scharf, ME Sachs, DH Down, JD Cooper, DKC AF Buhler, L Awwad, M Treter, S Chang, Q Basker, M Alwayn, IPJ Teranishi, K Ericsson, T Moran, K Harper, D Kurilla-Mahon, B Huang, CA Sackstein, R Sykes, M White-Scharf, ME Sachs, DH Down, JD Cooper, DKC TI Pig hematopoietic cell chimerism in baboons conditioned with a nonmyeloablative regimen and CD154 blockade SO TRANSPLANTATION LA English DT Article ID BONE-MARROW ENGRAFTMENT; NONLETHAL PREPARATIVE REGIMEN; RENAL-ALLOGRAFT TOLERANCE; MIXED CHIMERISM; ANTI-GAL-ALPHA-1-3GAL ANTIBODY; IMMUNODEFICIENT MICE; CYNOMOLGUS MONKEYS; FREQUENCY-ANALYSIS; MINIATURE SWINE; GROWTH-FACTORS AB Background In an attempt to induce mixed hematopoietic chimerism and transplantation tolerance in the pig-to-primate model, we have infused high-dose porcine peripheral blood progenitor cells (PBPC) into baboons pretreated with a nonmyeloablative regimen and anti-CD154 monoclonal antibody (mAb). Methods. Group 1 baboons (n=2) received a nonmyeloablative regimen including whole body irradiation, pharmacological immunosuppression, porcine hematopoietic growth factors, and immunoadsorption of anti-Galalpha1,3Gal (Gal) antibody before infusion of high doses of PBPC (2.7-4.6x10(10) cells/kg). In group 2 (n=5), cyclosporine was replaced by anti-CD154 mAb. Group 3 (n=3) received the group 1 regimen plus anti-CD154 mAb. Results. In group 1, pig chimerism was detected in the blood by flow cytometry TACS) for 5 days (with a maximum of 14%), and continuously up to 13 days by polymerase chain reaction (PCR). In group 2, pig chimerism was detectable for 5 days by FACS (maximum 33%) and continuously up to 28 days by PCR In group 3, initial pig chimerism was detectable for 5 days by FACS (maximum 73%). Two of three baboons showed reappearance of pig cells on days 11 and 16, respectively. In one, in which no anti-Gal IgG could be detected for 30 days, pig cells were documented in the blood by FACS on days 16-22 (maximum 6% on day 19) and pig colony-forming cells were present in the blood on days 19-33, which we interpreted as evidence of engraftment. Microchimerism was continuous by PCR up to 33 days. Conclusions. These results suggest that there is no absolute barrier to pig hematopoietic cell engraftment in primates, and that this may be facilitated if the return of anti-Gal IgG can be prevented. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. BioTransplant Inc, Charlestown, MA 02129 USA. RP Cooper, DKC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, MGH East,Bldg 149-9019,13th St, Boston, MA 02129 USA. FU NIAID NIH HHS [5P01 AI39755, 1PO1 AI45897] NR 45 TC 32 Z9 33 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JAN 15 PY 2002 VL 73 IS 1 BP 12 EP 22 PG 11 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 515FJ UT WOS:000173484500004 PM 11792972 ER PT J AU Teranishi, K Gollackner, B Buhler, L Knosalla, C Correa, L Down, JD White-Scharf, ME Sachs, DH Awwad, M Cooper, DKC AF Teranishi, K Gollackner, B Buhler, L Knosalla, C Correa, L Down, JD White-Scharf, ME Sachs, DH Awwad, M Cooper, DKC TI Depletion of anti-gal antibodies in baboons by intravenous therapy with bovine serum albumin conjugated to gal oligosaccharides SO TRANSPLANTATION LA English DT Article ID HEMATOPOIETIC-CELL TRANSPLANTATION; BONE-MARROW TRANSPLANTATION; NATURAL ANTIBODIES; IMMUNE-COMPLEXES; ANTI-GAL-ALPHA-1-3GAL ANTIBODY; IMMUNOAFFINITY COLUMN; HYPERACUTE REJECTION; TOLERANCE INDUCTION; NONHUMAN-PRIMATES; IN-VITRO AB Background. Anti-Gala 1-3Gal (Gal) antibodies (Ab) play a key role in the rejection of pig cells or organs transplanted into primates. A course of extracorporeal immunoadsorption (ELA) of anti-Gal Ab using an immunoaffinity column of a Gal type 6 oligosaccharide depletes Ab successfully, but Ab returns during the next few days. Although therapy with an anti-CD154 monoclonal antibody (mAb) prevents an induced Ab response to Gal or non-Gal epitopes, T cell-independent natural anti-Gal IgM and IgG return to baseline (pretransplant) levels. We have investigated the capacity of continuous i.v. infusion of bovine serum albumin conjugated to Gal type 6 oligosaccharide (BSA-Gal) to deplete or maintain depletion of circulating anti-Gal Ab. Methods. Porcine peripheral blood mobilized progenitor cells (PBPC) obtained by leukapheresis from MHC-inbred miniature swine (n=6) were transplanted into baboons. Group 1 baboons (n=4) underwent whole body (300 cGy) and thymic (700 cGy) irradiation, T cell depletion with antithymocyte globulin, complement depletion with cobra venom factor, short courses of anti-CD154 mAb therapy (20 mg/kg i.v. on alternate days), cyclosporine (CyA) (in two baboons only), mycophenolate mofetil, and porcine hematopoietic growth factors. Anti-Gal Ab depletion by EIA was carried out before transplantation of high doses (2-4 x 10(10) cells/kg) of PBPC. Group 2 baboons (n=3) received the group 1 regimen (including CyA) plus a continuous i.v. infusion of BSA-Gal. To prevent sensitization to BSA, anti-CD154 mAb therapy was continued until BSA-Gal administration was discontinued. Results. In group 1, Gal-reactive Ab returned to pre-PBPC transplant levels within 15-21 days, but no induced Ab to Gal or non-Gal determinants developed while anti-CD154 mAb therapy was being administered. In group 2, anti-Gal Ab was either not measurable or minimally measurable while BSA-Gal was being administered. After discontinuation of BSA-Gal, Ab did not return to pre-PBPC transplant level for more than 40-60 days, and no sensitization developed even when all therapy was discontinued. In one baboon, however, Ab to Gal type 2, but not type 6, returned during BSA-Gal therapy. Conclusions. Prevention of the induced humoral response to Gal and non-Gal epitopes by anti-CD154 mAb therapy has been reported previously by our group, but our studies are the first to demonstrate a therapy that resulted in an absence of natural anti-Gal Ab for a prolonged period. The combination of BSA-Gal and T cell costimulatory blockade may facilitate survival of pig cells and organs transplanted into primates. The return in one baboon of Ab reactive with the Gal type 2 oligosaccharide, but not type 6, indicates some polymorphism of anti-Gal Ab and suggests that, to be effective in all cases, the infusion of a combination of type 6 and type 2 BSA-Gal may be required. C1 Harvard Univ, Transplantat Biol Res Ctr, Sch Med, Massachusetts Gen Hosp, Boston, MA 02129 USA. Boston & Biotransplant Inc, Charlestown, MA USA. RP Cooper, DKC (reprint author), Harvard Univ, Transplantat Biol Res Ctr, Sch Med, Massachusetts Gen Hosp, MGH E,Bldg 149-9019,13th St, Boston, MA 02129 USA. NR 46 TC 29 Z9 31 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JAN 15 PY 2002 VL 73 IS 1 BP 129 EP 139 DI 10.1097/00007890-200201150-00024 PG 11 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 515FJ UT WOS:000173484500024 PM 11792992 ER PT J AU Yamada, A Sayegh, MH AF Yamada, A Sayegh, MH TI The CD154-CD40 costimulatory pathway in transplantation SO TRANSPLANTATION LA English DT Article; Proceedings Paper CT 1st Beaune Seminar in Transplant Research CY JUN 07-08, 2001 CL BEAUNE, FRANCE ID T-CELL APOPTOSIS; LONG-TERM SURVIVAL; INTRAHEPATIC ISLET ALLOGRAFTS; DONOR-SPECIFIC TRANSFUSION; CD40 LIGAND; ANTI-CD154 ANTIBODY; HEMATOPOIETIC CHIMERISM; HUMANIZED ANTI-CD154; MONOCLONAL-ANTIBODY; SKIN ALLOGRAFTS AB The CD154-CD40 pathway is one of the critical costimulatory pathways that are required for full activation of T cells during alloimmune responses. Blockade of this pathway with anti-CD154 antibodies has been reported to prolong allograft survival in experimental transplantation models and to induce tolerance in some instances. However, anti-CD154 monotherapy cannot induce tolerance in "stringent" models such as skin and islet transplantation and is not sufficient to prevent chronic graft vasculopathy in vascularized organ transplantation. Therefore, combined therapies of anti-CD154 antibodies plus donor-specific transfusion, bone marrow infusion, or B7 blockade by CTLA4-Ig have been tried, and synergistic effects for tolerance induction have been reported. Furthermore, the efficacy of CD154 blockade in primate models has been confirmed for islet and kidney transplantation. The mechanisms of CD154 blockade in vivo include CTLA4-dependent anergy or regulation, T-cell apoptosis, and induction of regulatory cells. Finally, anti-CD154 antibody therapy has been reported to result in unexpected thromboembolic complications in both primates and humans, although the etiology of these conditions remains unclear. In addition, not all antibodies cause this side effect. Clinical trials with humanized anti-CD154 monoclonal antibodies are underway in severe autoimmune diseases, but its development in transplantatin is unclear at this time. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Lab Immunogenet & Transplantat, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Unit, Boston, MA 02115 USA. Harvard Univ, Childrens Hosp, Sch Med, Div Nephrol, Boston, MA 02115 USA. RP Sayegh, MH (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Lab Immunogenet & Transplantat, 75 Francis St, Boston, MA 02115 USA. NR 50 TC 47 Z9 53 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JAN 15 PY 2002 VL 73 IS 1 SU S BP S36 EP S39 DI 10.1097/00007890-200201151-00012 PG 4 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 516NT UT WOS:000173559800012 PM 11810060 ER PT J AU Intes, X Ntziachristos, V Chance, B AF Intes, X Ntziachristos, V Chance, B TI Analytical model for dual-interfering sources diffuse optical tomography SO OPTICS EXPRESS LA English DT Article ID PHOTON-DENSITY WAVES; BREAST-CANCER; SINGLE-SOURCE; TURBID MEDIA; LOCALIZATION; APPROXIMATION; HETEROGENEITY; SPECTROSCOPY; REFLECTANCE; SENSITIVITY AB An analytical model to perform tomographic reconstructions for absorptive inclusions in highly scattering media using dual interfering sources was derived. A perturbation approach within the first order Rytov expansion was used to solve the heterogeneous diffusion equation. Analytical weight functions necessary to solve the inverse problem were obtained. The reconstructions performance was assessed using simulated data of breast-like media after contrast agent enhancement. We further investigated the reconstruction quality as a function of object depth location, modulation frequency and source separation. The ability of the algorithm to resolve multi-objects was also demonstrated. (C) 2002 Optical Society of America. C1 Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. Univ Penn, Dept Phys & Astron, Philadelphia, PA 19104 USA. Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Intes, X (reprint author), Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. EM intes@mail.med.upenn.edu NR 36 TC 15 Z9 15 U1 0 U2 3 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 JAN 14 PY 2002 VL 10 IS 1 BP 2 EP 14 DI 10.1364/OE.10.000002 PG 13 WC Optics SC Optics GA 511GE UT WOS:000173255600002 PM 19424324 ER PT J AU Beckman, JA Goldfine, AB Gordon, MB Garrett, LA Creager, MA AF Beckman, JA Goldfine, AB Gordon, MB Garrett, LA Creager, MA TI Inhibition of protein kinase C beta prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans SO CIRCULATION RESEARCH LA English DT Article DE protein kinase C; nitric oxide; hyperglycemia; endothelium; diabetes ID NITRIC-OXIDE SYNTHASE; HIGH GLUCOSE-CONCENTRATIONS; SMOOTH-MUSCLE CELLS; DIABETES-MELLITUS; MEDIATED VASODILATION; VASCULAR REACTIVITY; IN-VIVO; ACTIVATION; INSULIN; EXPRESSION AB The bioavailability of nitric oxide is decreased in animal models and humans with diabetes mellitus. Hyperglycemia, in particular, attenuates endothelium-dependent vasodilation in healthy subjects. In vitro and in vivo animal studies implicate activation of protein kinase Cbeta as an important mechanism whereby hyperglycemia decreases endothelium-derived nitric oxide. Accordingly, this study tested the hypothesis that inhibition of protein kinase Cbeta would prevent impairment of endothelium-dependent vasodilation in healthy humans exposed to hyperglycemia. This study was a randomized, double-blind, placebo-controlled, crossover trial. Healthy subjects were treated with an orally active, selective, protein kinase Cbeta inhibitor, LY333531, or matching placebo once a day for 7 days before vascular function testing. Forearm blood flow was measured using venous-occlusion, strain-gauge plethysmography. Endothelium-dependent vasodilation was measured via incremental brachial artery administration of methacholine chloride (0.3 to 10 mug/min) during euglycemia and after 6 hours of hyperglycemic clamp. The forearm blood flow dose-response curve to methacholine was significantly attenuated by hyperglycemia after placebo treatment (P=0.009 by ANOVA, euglycemia versus hyperglycemia) but not after treatment with LY333531. Inhibition of protein kinase Cbeta prevents the reduction in endothelium-dependent vasodilation induced by acute hyperglycemia in healthy humans in vivo. These findings suggest that hyperglycemia impairs endothelial function, in part, via protein kinase Cbeta activation. C1 Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Cellular & Mol Physiol, Boston, MA 02115 USA. RP Creager, MA (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. OI Beckman, Joshua/0000-0001-8332-8439 FU NHLBI NIH HHS [HL-48743, HL-56607, K23 HL-04169] NR 48 TC 191 Z9 198 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JAN 11 PY 2002 VL 90 IS 1 BP 107 EP 111 DI 10.1161/hh0102.102359 PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 513PJ UT WOS:000173386700020 PM 11786526 ER PT J AU Kang, HY Schneider, H Rudd, CE AF Kang, HY Schneider, H Rudd, CE TI Phosphatidylinositol 3-kinase p85 adaptor function in T-cells. Co-stimulation and regulation of cytokine transcription independent of associated p110. SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-B; PHOSPHOINOSITIDE 3-KINASE; DISTINCT ROLES; PI 3-KINASE; CD28; ACTIVATION; BINDING; WORTMANNIN; PATHWAYS; MEMBRANE AB Phosphatidylinositol 3-kinase (PI3K) is a key regulator of a variety of cellular functions from cytoskeletal organization, vesicular trafficking, and cell proliferation to apoptosis. The enzyme complex is comprised of an 85-kDa adaptor (p85) coupled to a 110-kDa catalytic subunit (p110). While the function of PI3K has been largely attributed to the generation of D-3 lipids, an unanswered question has been whether p85 with a number of motifs (SH2, SH3, Bell homology (1311) region) can generate independent intracellular signals. In this study, we demonstrate that p85 lacking p110 (Deltap85) can activate NFAT transcription in T-cell hybridomas and normal splenocytes. This up-regulatory effect was unaffected by inhibition of PI 3-kinase, and cooperated specifically with Rac1, but not related family members. Stimulation correlated with Rac1 binding and was lost with the deletion of the BH domain. Lastly, the CD28-Deltap85 chimera also cooperated with TcR/CD3 to provide co-signals that enhanced IL-2 transcription. Our findings identify for the first time p85 as an adaptor that operates independently of the classic PI 3-kinase catalytic pathway and further shows that this pathway can provide co-signals in the regulation of T-cell function. C1 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 Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Sch Med, Dept Haematol, London W12 0NN, England. RP Rudd, CE (reprint author), Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. NR 65 TC 30 Z9 31 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 JAN 11 PY 2002 VL 277 IS 2 BP 912 EP 921 DI 10.1074/jbc.M107648200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 509TY UT WOS:000173166800008 PM 11679587 ER PT J AU Suzuma, I Suzuma, K Ueki, K Hata, Y Feener, EP King, GL Aiello, LP AF Suzuma, I Suzuma, K Ueki, K Hata, Y Feener, EP King, GL Aiello, LP TI Stretch-induced retinal vascular endothelial growth factor expression is mediated by phosphatidylinositol 3-kinase and protein kinase C (PKC)-zeta but not by stretch-induced ERK1/2, Akt, Ras, or classical/novel PKC pathways SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID SMOOTH-MUSCLE CELLS; DIABETIC-RETINOPATHY; SIGNAL-TRANSDUCTION; PERMEABILITY FACTOR; GLUCOSE-TRANSPORT; RISK-FACTORS; MECHANICAL-STRESS; MAP KINASE; RECOMBINANT ADENOVIRUSES; MACULAR DEGENERATION AB Stretch-induced expression of vascular endothelial growth factor (VEGF) is thought to be important in mediating the exacerbation of diabetic retinopathy by systemic hypertension. However, the mechanisms underlying stretch-induced VEGF expression are not fully understood. We present novel findings demonstrating that stretch-induced VEGF expression in retinal capillary pericytes is mediated by phosphatidylinositol (PI) 3-kinase and protein kinase C (PKC)-zeta but is not mediated by ERK1/2, classical/novel isoforms of PKC, Akt, or Ras despite their activation by stretch. Cardiac profile cyclic stretch at 60 cpm increased VEGF mRNA expression in a time- and magnitude-dependent manner without altering mRNA stability. Stretch increased ERK1/2 phosphorylation, PI 3-kinase activity, Akt phosphorylation, and PKC-zeta activity. Signaling pathways were explored using inhibitors of PKC, MEK1/2, and PI 3-kinase; adenovirus-mediated overexpression of ERK, PKC-alpha, PKC-delta, PKC-zeta, and Akt; and dominant negative (DN) mutants of ERK, PKC-zeta, Ras, PI 3-kinase and Akt. Although stretch activated ERK1/2 through a Ras- and PKC classical/novel isoform-dependent pathway, these pathways were not responsible for stretch-induced VEGF expression. Overexpression of DN ERK and Ras had no effect on VEGF expression in these cells. In contrast, DN PI 3-kinase as well as pharmacologic inhibitors of PI 3-kinase blocked stretch-induced VEGF expression. Although stretch-induced PI 3-kinase activation increased both Akt phosphorylation and activity of PKC-zeta, VEGF expression was dependent on PKC-zeta but not Akt. In addition, PKC-zeta did not mediate stretch-induced ERK1/2 activation. These results suggest that stretch-induced expression of VEGF involves a novel mechanism dependent upon PI 3-kinase-mediated activation of PKC-zeta that is independent of stretch-induced activation of ERK1/2, classical/novel PKC isoforms, Ras, or Akt. This mechanism may play a role in the well documented association of concomitant hypertension with clinical exacerbation of neovascularization and vascular permeability. C1 Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA. Kyushu Univ, Fac Med, Dept Ophthalmol, Fukuoka 6068507, Japan. Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02215 USA. RP Aiello, LP (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. FU NEI NIH HHS [EY-5110, EY-10827]; NIDDK NIH HHS [P30 DK036836, DK-48358]; PHS HHS [36836] NR 96 TC 61 Z9 63 U1 0 U2 1 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 JAN 11 PY 2002 VL 277 IS 2 BP 1047 EP 1057 DI 10.1074/jbc.M105336200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 509TY UT WOS:000173166800024 PM 11694503 ER PT J AU Aguirre, V Werner, ED Giraud, J Lee, YH Shoelson, SE White, MF AF Aguirre, V Werner, ED Giraud, J Lee, YH Shoelson, SE White, MF TI Phosphorylation of Ser(307) in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED PROTEIN-KINASE; PHOSPHOTYROSINE-DEPENDENT INTERACTION; STIMULATED TYROSINE PHOSPHORYLATION; GROWTH-FACTOR-I; PLECKSTRIN HOMOLOGY; SERINE/THREONINE PHOSPHORYLATION; PHOSPHATIDYLINOSITOL 3-KINASE; YMXM MOTIFS; NPEY MOTIF; IRS-1 AB Serine phosphorylation of insulin receptor substrate-1 (IRS-1) inhibits insulin signal transduction in a variety of cell backgrounds, which might contribute to peripheral insulin resistance. However, because of the large number of potential phosphorylation sites, the mechanism of inhibition has been difficult to determine. One serine residue located near the phosphotyrosine-binding (PTB) domain in IRS-1 (Ser(307) in rat IRS-1 or Ser(312) in human IRS-1) is phosphorylated via several mechanisms, including insulin-stimulated kinases or stress-activated kinases like JNK1. During a yeast trihybrid assay, phosphorylation of Ser(307) by JNK1 disrupted the interaction between the catalytic domain of the insulin receptor and the PTB domain of IRS-1. In 32D myeloid progenitor cells, phosphorylation of Ser(307) inhibited insulin stimulation of the phosphatidylinositol 3-kinase and MAPK cascades. These results suggest that inhibition of PTB domain function in IRS-1 by phosphorylation of Ser(307) (Ser(312) in human IRS-1) might be a general mechanism to regulate insulin signaling. C1 Harvard Univ, Howard Hughes Med Inst, Joslin Diabet Ctr, Sch Med, Boston, MA 02215 USA. RP White, MF (reprint author), Harvard Univ, Howard Hughes Med Inst, Joslin Diabet Ctr, Sch Med, 1 Joslin Pl, Boston, MA 02215 USA. NR 54 TC 551 Z9 580 U1 1 U2 23 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 JAN 11 PY 2002 VL 277 IS 2 BP 1531 EP 1537 DI 10.1074/jbc.M101521200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 509TY UT WOS:000173166800086 PM 11606564 ER PT J AU Chao, W Huynh, KD Spencer, RJ Davidow, LS Lee, JT AF Chao, W Huynh, KD Spencer, RJ Davidow, LS Lee, JT TI CTCF, a candidate trans-acting factor for X-inactivation choice SO SCIENCE LA English DT Article ID ENHANCER-BLOCKING ACTIVITY; XIST EXPRESSION; CHROMOSOME; GENE; METHYLATION; MOUSE; TSIX; INSULATOR; REGION; PARENT AB In mammals, X-inactivation silences one of two female X chromosomes. Silencing depends on the noncoding gene, Xist ((i) under bar nactive (X) under bar-(s) under bar pecific (t) under bar ranscript), and is blocked by the antisense gene, Tsix. Deleting the choice/imprinting center in Tsix affects X-chromosome selection. Here, we identify the insulator and transcription factor, CTCF, as a candidate trans-acting factor for X-chromosome selection. The choice/imprinting center contains tandem CTCF binding sites that function in an enhancer-blocking assay. In vitro binding is reduced by CpG methylation and abolished by including non-CpG methylation. We postulate that Tsix and CTCF together establish a regulatable epigenetic switch for X-inactivation. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USA. RP Lee, JT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Genet, Howard Hughes Med Inst,Dept Mol Biol, Boston, MA 02114 USA. OI Chao, Wendy/0000-0002-9418-8723 NR 27 TC 194 Z9 209 U1 0 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JAN 11 PY 2002 VL 295 IS 5553 BP 345 EP 347 DI 10.1126/science.1065982 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 511RD UT WOS:000173278600055 PM 11743158 ER PT J AU Schiller, JH Harrington, D Belani, CP Langer, C Sandler, A Krook, J Zhu, JM Johnson, DH AF Schiller, JH Harrington, D Belani, CP Langer, C Sandler, A Krook, J Zhu, JM Johnson, DH CA Eastern Cooperative Oncology Grp TI Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID COOPERATIVE-ONCOLOGY-GROUP; QUALITY-OF-LIFE; RANDOMIZED TRIAL; CISPLATIN; SURVIVAL; COMBINATION; PACLITAXEL; ETOPOSIDE AB Background We conducted a randomized study to determine whether any of three chemotherapy regimens was superior to cisplatin and paclitaxel in patients with advanced non-small-cell lung cancer. Methods A total of 1207 patients with advanced non-small-cell lung cancer were randomly assigned to a reference regimen of cisplatin and paclitaxel or to one of three experimental regimens: cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel. Results The response rate for all 1155 eligible patients was 19 percent, with a median survival of 7.9 months (95 percent confidence interval, 7.3 to 8.5), a 1-year survival rate of 33 percent (95 percent confidence interval, 30 to 36 percent), and a 2-year survival rate of 11 percent (95 percent confidence interval, 8 to 12 percent). The response rate and survival did not differ significantly between patients assigned to receive cisplatin and paclitaxel and those assigned to receive any of the three experimental regimens. Treatment with cisplatin and gemcitabine was associated with a significantly longer time to the progression of disease than was treatment with cisplatin and paclitaxel but was more likely to cause grade 3, 4, or 5 renal toxicity (in 9 percent of patients, vs. 3 percent of those treated with cisplatin plus paclitaxel). Patients with a performance status of 2 had a significantly lower rate of survival than did those with a performance status of 0 or 1. Conclusions None of four chemotherapy regimens offered a significant advantage over the others in the treatment of advanced non-small-cell lung cancer. (N Engl J Med 2002;346:92-8.) Copyright (C) 2002 Massachusetts Medical Society. C1 Univ Wisconsin Hosp & Clin, Madison, WI 53792 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Indiana Univ, Indianapolis, IN 46204 USA. Duluth Clin, Duluth, MN USA. Vanderbilt Univ, Nashville, TN USA. RP Schiller, JH (reprint author), Univ Wisconsin Hosp & Clin, Madison, WI 53792 USA. RI Johnson, David/A-7437-2009 FU NCI NIH HHS [CA-23318] NR 21 TC 3044 Z9 3312 U1 44 U2 207 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 JAN 10 PY 2002 VL 346 IS 2 BP 92 EP 98 DI 10.1056/NEJMoa011954 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 509EM UT WOS:000173133400004 PM 11784875 ER PT J AU Yehuda, R AF Yehuda, R TI Current concepts - Post-traumatic stress disorder SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID HOLOCAUST SURVIVORS; DEPRESSED-PATIENTS; VIETNAM VETERANS; COMBAT VETERANS; PLASMA-CORTISOL; PTSD; NOREPINEPHRINE; SUPPRESSION; EXPOSURE; SYMPTOMS C1 Bronx Vet Affairs Med Ctr, Bronx, NY 10468 USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. Mt Sinai Sch Med, Div Traumat Stress Studies, New York, NY USA. RP Yehuda, R (reprint author), Bronx Vet Affairs Med Ctr, 130 Kingsbridge Rd, Bronx, NY 10468 USA. NR 55 TC 573 Z9 596 U1 16 U2 94 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 JAN 10 PY 2002 VL 346 IS 2 BP 108 EP 114 DI 10.1056/NEJMra012941 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 509EM UT WOS:000173133400007 PM 11784878 ER PT J AU Juppner, H AF Juppner, H TI The genetic basis of progressive osseous heteroplasia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID ALPHA-SUBUNIT; PROTEIN C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Juppner, H (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 16 TC 11 Z9 12 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 JAN 10 PY 2002 VL 346 IS 2 BP 128 EP 130 DI 10.1056/NEJM200201103460212 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 509EM UT WOS:000173133400011 PM 11784882 ER PT J AU Silverman, JM Smith, CJ Schmeidler, J Hollander, E Lawlor, BA Fitzgerald, M Buxbaum, JD Delaney, K Galvin, P AF Silverman, JM Smith, CJ Schmeidler, J Hollander, E Lawlor, BA Fitzgerald, M Buxbaum, JD Delaney, K Galvin, P CA Autism Genetic Res Excange Consort TI Symptom domains in autism and related conditions: Evidence for familiality SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE autism spectrum; heterogeneity; genetics; affected sibling pairs; multiplex siblingships; broader affected phenotype; asperger disorder ID PERVASIVE DEVELOPMENTAL DISORDERS; FAMILY HISTORY; INDIVIDUALS; PHENOTYPE; TWIN; PARENTS AB Heterogeneity in autism impairs efforts to localize and identify the genes underlying this disorder. As autism comprises severe but variable deficits and traits in three symptom domains (social interaction, communication, and repetitive behaviors) and shows variability in the presence and emergence of useful phrase speech, different genetic factors may be associated with each. The affected cases (n = 457) in multiply affected siblingships (n = 212), including a proband with autism and one or more siblings with either autism or marked deficits in autism symptom domains, were assessed using the Autism Diagnostic Interview, Revised. Symptom domain scores and language features were examined to determine their similarity within siblingships. The variance within siblingships was reduced for the repetitive behavior domain and for delays in and the presence of useful phrase speech. These features and the nonverbal communication subdomain provided evidence of familiality when we considered only the diagnosis of autism to define multiply affected siblingships (cases: n = 289; siblingships: n = 136). In addition, the same familial features identified also appeared familial for those with autism-related conditions. Finally, the level of severity of almost all of the familial features varied within multiplex siblingships independently. The features identified as familial replicate the combined set suggested in earlier, smaller studies. Furthermore, the familiality of these features extend to related conditions of milder severity than autism and appear to be independent. Making distinctions among families by the severity of these features may be useful for identifying more genetically homogeneous subgroups in studies targeted at genes for specific autism-related symptom domains. (C) 2001 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. St Jamess & St Patricks Hosp, Dept Psychiat Elderly, Dublin, Ireland. Univ Dublin Trinity Coll, Dept Psychiat, Dublin 2, Ireland. RP Silverman, JM (reprint author), Mt Sinai Sch Med, Dept Psychiat, Box 1230,1 Gustave L Levy Pl, New York, NY 10029 USA. OI Buxbaum, Joseph/0000-0001-8898-8313 NR 25 TC 85 Z9 87 U1 3 U2 13 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD JAN 8 PY 2002 VL 114 IS 1 SI SI BP 64 EP 73 DI 10.1002/ajmg.10048 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 509EP UT WOS:000173133600011 PM 11840508 ER PT J AU Maher, NE Golbe, LI Lazzarini, AM Mark, MH Currie, LJ Wooten, GF Saint-Hilaire, M Wilk, JB Volcjak, J Maher, JE Feldman, RG Guttman, M Lew, M Schuman, S Suchowersky, O Lafontaine, AL Labelle, N Vieregge, P Pramstaller, PP Klein, C Hubble, J Reider, C Growdon, J Watts, R Montgomery, E Baker, K Singer, C Stacy, M Myers, RH AF Maher, NE Golbe, LI Lazzarini, AM Mark, MH Currie, LJ Wooten, GF Saint-Hilaire, M Wilk, JB Volcjak, J Maher, JE Feldman, RG Guttman, M Lew, M Schuman, S Suchowersky, O Lafontaine, AL Labelle, N Vieregge, P Pramstaller, PP Klein, C Hubble, J Reider, C Growdon, J Watts, R Montgomery, E Baker, K Singer, C Stacy, M Myers, RH TI Epidemiologic study of 203 sibling pairs with Parkinson's disease - The GenePD study SO NEUROLOGY LA English DT Article ID RECESSIVE JUVENILE PARKINSONISM; RISK-FACTORS; ENVIRONMENTAL-FACTORS; DIETARY FACTORS; YOUNG-ONSET; ANTIOXIDANTS; MUTATIONS; ETIOLOGY; ASSOCIATION; ALZHEIMERS AB Objective: To examine patterns of familial aggregation and factors influencing onset age in a sample of siblings with PD. Methods: Sibling pairs (n = 203) with PD were collected as part of the GenePD study. Standardized family history, medical history, and risk factor data were collected and analyzed. Results: The mean age at onset was 61.4 years and did not differ according to sex, exposure to coffee, alcohol, or pesticides. Head trauma was associated with younger onset (P = 0.03) and multivitamin use with later onset (p = 0.007). Age at onset correlation between sibling pairs was significant (r = 0.56, P = 0.001) and was larger than the correlation in year of onset (r = 0.29). The mean difference in onset age between siblings was 8.7 years (range, 0 to 30 years). Female sex was associated with increased frequency of relatives with PD. The frequency of affected parents (7.0%) and siblings (5.1%) was increased when compared with frequency in spouses (2.0%). Conclusions: The greater similarity for age at onset than for year of onset in sibling pairs with PD, together with increased risk for biological relatives over spouses of cases, supports a genetic component for PD. Risk to siblings in this series is increased over that seen in random series of PD cases; however, patients in this sample have similar ages at onset and sex distribution as seen for PD generally. These analyses suggest that factors influencing penetrance are critical to the understanding of this disease. C1 Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. Univ Med & Dent, New Jersey Robert Wood Johnson Med Sch, New Brunswick, NJ USA. Univ Virginia Hlth Syst, Dept Neurol, Charlottesville, VA USA. Univ Toronto, Dept Med, Div Neurol, Toronto, ON, Canada. Univ So Calif, Dept Neurol, Los Angeles, CA USA. Univ Calgary, Dept Clin Neurosci, Calgary, AB T2N 1N4, Canada. Univ Calgary, Dept Med Genet, Calgary, AB T2N 1N4, Canada. Med Univ Lubeck, Dept Neurol, Lubeck, Germany. Ohio State Univ, Dept Neurol, Columbus, OH 43210 USA. Gen Reg Hosp, Dept Neurol, Bolzano, Italy. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. Emory Univ, Dept Neurol, Atlanta, GA USA. Cleveland Clin Fdn, Dept Neurol, Cleveland, OH USA. Univ Miami, Coral Gables, FL 33124 USA. Barrow Clin, Dept Neurol, Phoenix, AZ USA. RP Myers, RH (reprint author), Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. RI Pramstaller, Peter/C-2357-2008 FU NCRR NIH HHS [1 P41 RR03655]; NINDS NIH HHS [R0-1 NS36711-04] NR 54 TC 39 Z9 41 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 8 PY 2002 VL 58 IS 1 BP 79 EP 84 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 509CR UT WOS:000173127800016 PM 11781409 ER PT J AU Singhal, AB Caviness, VS Begleiter, AF Mark, EJ Rordorf, G Koroshetz, WJ AF Singhal, AB Caviness, VS Begleiter, AF Mark, EJ Rordorf, G Koroshetz, WJ TI Cerebral vasoconstriction and stroke after use of serotonergic drugs SO NEUROLOGY LA English DT Article ID THUNDERCLAP HEADACHE; ASSOCIATION; INFARCTION AB Serotonin (5-hydroxytryptamine) is a potent vasoconstrictor amine. The authors report three patients who developed thunderclap headache, reversible cerebral arterial vasoconstriction, and ischemic strokes (i.e., the Call-Fleming syndrome). The only cause for vasoconstriction was recent exposure to serotonergic drugs in all patients, and to pseudoephedrine in one patient. These cases, and the literature, suggest that the use of serotonin-enhancing drugs can precipitate a cerebrovascular syndrome due to reversible, multifocal arterial narrowing. C1 Massachusetts Gen Hosp, Stroke Serv, Dept Neurol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Stroke Serv, Dept Pathol, Boston, MA 02114 USA. RP Singhal, AB (reprint author), Massachusetts Gen Hosp, Stroke Serv, Dept Neurol, VBK-802,55 Fruit St, Boston, MA 02114 USA. NR 10 TC 109 Z9 111 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 8 PY 2002 VL 58 IS 1 BP 130 EP 133 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 509CR UT WOS:000173127800026 PM 11781419 ER PT J AU Kiaris, H Schally, AV Busto, R Halmos, G Artavanis-Tsakonas, S Varga, JL AF Kiaris, H Schally, AV Busto, R Halmos, G Artavanis-Tsakonas, S Varga, JL TI Expression of a splice variant of the receptor for GHRH in 3T3 fibroblasts activates cell proliferation responses to GHRH analogs SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HORMONE-RELEASING HORMONE; IN-VIVO PROLIFERATION; LUNG-CARCINOMA; GROWTH-FACTOR; NUDE-MICE; ANTAGONISTS; CANCERS; INHIBITION; RH; TUMORS AB The stimulatory effects of growth hormone-releasing hormone (GHRH) and the antiproliferative action of GHRH antagonists have been demonstrated in various cancers, but the receptors that mediate these responses are not clearly identified. Recently, we reported that human cancer cell lines express splice variants (SVs) of the receptors for GHRH. SV1 exhibits the greatest similarity to the pituitary GHRH receptor and is most likely to be functional. To ascertain whether SV1 mediates mitogenic effects on nonpituitary tissues, we expressed SV1 in 3T3 mouse fibroblasts and studied the properties of the transfected cells. Radioligand binding assays with I-125-labeled GHRH antagonist JV-1-42 detected high affinity (K-d = 0.58 +/- 0.17 nM) binding sites for GHRH with a maximal binding capacity (B-max) of 103 +/- 17.4 fmol/mg of membrane protein in 3T3 cells transfected with pcDNA3-SV1, whereas the control cells transfected with the empty vector did not show any GHRH binding. Cell proliferation studies showed that cells expressing SV1 are much more sensitive to GHRH analogs than the pcDNA3 controls. Thus, the expression of SV1 augments the stimulatory responses to GHRH(1-29)NH2 or GHRH agonist JI-38 and inhibitory responses to GHRH antagonist JV-1-38 as compared with pcDNA3 controls. The stimulation of SV1-expressing cells by GHRIH or JI-38 is followed by an increase in cAMP production, but no GH release occurs. Vasoactive intestinal peptide had no effect, and its antagonist JV-1-53 did not inhibit the proliferation of SV1-expressing cells stimulated by GHRH. Our results suggest that SV1 could mediate responses of nonpituitary cells and various tumors to GHRH and GHRIH antagonists. The presence of SV1 in several human cancer cell lines provides a rationale for antitumor therapy based on the blockade of this receptor by specific GHRH antagonists. C1 Tulane Univ, Sch Med, Inst Endocrine Polypeptide & Canc, Vet Affairs Med Ctr, New Orleans, LA 70112 USA. Tulane Univ, Sch Med, Dept Med, Sect Expt Med, New Orleans, LA 70112 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Schally, AV (reprint author), Tulane Univ, Sch Med, Inst Endocrine Polypeptide & Canc, Vet Affairs Med Ctr, 1430 Tulane Ave, New Orleans, LA 70112 USA. OI Kiaris, Hippokratis/0000-0002-8999-8289; Schally, Andrew/0000-0003-1273-6747 FU NINDS NIH HHS [NS2608412] NR 33 TC 55 Z9 55 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 JAN 8 PY 2002 VL 99 IS 1 BP 196 EP 200 DI 10.1073/pnas.012590999 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 510XV UT WOS:000173233300038 PM 11773624 ER PT J AU Miyoshi, K Shillingford, JM Le Provost, F Gounari, F Bronson, R von Boehmer, H Taketo, MM Cardiff, RD Hennighausen, L Khazaie, K AF Miyoshi, K Shillingford, JM Le Provost, F Gounari, F Bronson, R von Boehmer, H Taketo, MM Cardiff, RD Hennighausen, L Khazaie, K TI Activation of beta-catenin signaling in differentiated mammary secretory cells induces transdifferentiation into epidermis and squamous metaplasias SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mammary gland; cell identity; Wnt-signaling; Cre; differentiation ID TRANSGENIC MICE; GENE; PROTEIN; GLAND AB Mammary anlagen are formed in the embryo as a derivative of the epidermis, a process that is controlled by Lef-1 and therefore possibly by beta-catenin. To investigate the role of beta-catenin signaling in mammary alveolar epithelium, we have stabilized endogenous beta-catenin in differentiating alveolar epithelium through the deletion of exon 3 (amino acids 5-80) of the beta-catenin gene. This task was accomplished in mice carrying a floxed beta-catenin gene and a Cre transgene under control of the mammary-specific whey acidic protein (WAP) gene promoter or the mouse mammary tumor virus-long terminal repeat (MMTV-LTR). Stabilized beta-catenin was obtained during the first pregnancy, and its presence resulted in the dedifferentiation of alveolar epithelium followed by a transdifferentiation into epidermal and pilar structures. Extensive squamous metaplasia, but no adenocarcinomas, developed upon beta-catenin activation during pregnancy and persisted throughout involution. These data demonstrate that the activation of beta-catenin signaling induces a program that results in loss of mammary epithelial cell differentiation and induction of epidermal structures. C1 NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. INRA, Lab Genet Biochim 7 Cytogenet, F-78352 Jouy En Josas, France. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Kyoto Univ, Grad Sch Med, Dept Pharmacol, Sakyo Ku, Kyoto 6068501, Japan. Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA. RP Khazaie, K (reprint author), NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. NR 20 TC 96 Z9 100 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 8 PY 2002 VL 99 IS 1 BP 219 EP 224 DI 10.1073/pnas.012414099 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 510XV UT WOS:000173233300042 PM 11773619 ER PT J AU Segev, DL Hoshiya, Y Hoshiya, M Tran, TT Carey, JL Stephen, AE MacLaughlin, DT Donahoe, PK Maheswaran, S AF Segev, DL Hoshiya, Y Hoshiya, M Tran, TT Carey, JL Stephen, AE MacLaughlin, DT Donahoe, PK Maheswaran, S TI Mullerian-inhibiting substance regulates NF-kappa B signaling in the prostate in vitro and in vivo SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CANCER CELL-GROWTH; TGF-BETA RECEPTOR; II RECEPTOR; TRANSFORMING GROWTH-FACTOR-BETA-1; SEXUAL DEVELOPMENT; LNCAP CELLS; APOPTOSIS; HORMONE; TRANSDUCTION; TGF-BETA-1 AB Mullerian-inhibiting substance (MIS) is a member of the transforming growth factor beta superfamily, a class of molecules that regulates growth, differentiation, and apoptosis in many cells. MIS type 11 receptor in the Mullerian duct is temporally and spatially regulated during development and becomes restricted to the most caudal ends that fuse to form the prostatic utricle. In this article, we have demonstrated MIS type 11 receptor expression in the normal prostate, human prostate cancer cell lines, and tissue derived from patients with prostate adenocarcinomas. MIS induced NF-kappaB DNA binding activity and selectively up-regulated the immediate early gene IEX-1S in both androgen-dependent and independent human prostate cancer cells in vitro. Dominant negative IkappaBalpha expression ablated both MIS-induced increase of IEX-1S mRNA and inhibition of growth, indicating that activation of NF-kappaB signaling was required for these processes. Androgen also induced NF-kappaB DNA binding activity in prostate cancer cells but without induction of IEX-1S mRNA, suggesting that MIS-mediated increase in IEX-1S was independent of androgen-mediated signaling. Administration of MIS to male mice induced IEX-1S mRNA in the prostate in vivo, suggesting that MIS may function as an endogenous hormonal regulator of NF-kappaB signaling and growth in the prostate gland. C1 Massachusetts Gen Hosp, Dept Pediat Surg, Pediat Surg Res Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Maheswaran, S (reprint author), Massachusetts Gen Hosp, Dept Pediat Surg, Pediat Surg Res Lab, WRN 1024, Boston, MA 02114 USA. FU NCI NIH HHS [T32 CA071345, T32 CA-71345-04, F32 CA077945, F32 CA77945-01A1, CA08910-01A1, R01 CA017393, CA17393, R01 CA089138]; NICHD NIH HHS [R01 HD032112, HD32112] NR 43 TC 44 Z9 47 U1 0 U2 0 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 JAN 8 PY 2002 VL 99 IS 1 BP 239 EP 244 DI 10.1073/pnas.221599298 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 510XV UT WOS:000173233300045 PM 11773638 ER PT J AU Sharon, D Blackshaw, S Cepko, CL Dryja, TP AF Sharon, D Blackshaw, S Cepko, CL Dryja, TP TI Profile of the genes expressed in the human peripheral retina, macula, and retinal pigment epithelium determined through serial analysis of gene expression (SAGE) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ADULT HUMAN RETINA; CELLS; TOPOGRAPHY; DEFICIENCY; LIBRARY; CANCER AB We used the serial analysis of gene expression (SAGE) technique to catalogue and measure the relative levels of expression of the genes expressed in the human peripheral retina, macula, and retinal pigment epithelium (RPE) from one or both of two humans, aged 88 and 44 years. The cone photoreceptor contribution to all transcription in the retina was found to be similar in the macula versus the retinal periphery, whereas the rod contribution was greater in the periphery versus the macula. Genes encoding structural proteins for axons were found to be expressed at higher levels in the macula versus the retinal periphery, probably reflecting the large proportion of ganglion cells in the central retina. In comparison with the younger eye, the peripheral retina of the older eye had a substantially higher proportion of mRNAs from genes encoding proteins involved in iron metabolism or protection against oxidative damage and a substantially lower proportion of mRNAs from genes encoding proteins involved in rod phototransduction. These differences may reflect the difference in age between the two donors or merely interindividual variation. The RPE library had numerous previously unencountered tags, suggesting that this cell type has a large, idiosyncratic repertoire of expressed genes. Comparison of these libraries with 100 reported nonocular SAGE libraries revealed 89 retina-specific or enriched genes expressed at substantial levels, of which 14 are known to cause a retinal disease and 53 are RPE-specific genes. We expect that these libraries will serve as a resource for understanding the relative expression levels of genes in the retina and the RPE and for identifying additional disease genes. C1 Massachusetts Eye & Ear Infirm, Ocular Mol Genet Inst, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02114 USA. RP Dryja, TP (reprint author), Massachusetts Eye & Ear Infirm, Ocular Mol Genet Inst, 243 Charles St, Boston, MA 02114 USA. RI Sharon, Dror/P-4539-2015 OI Sharon, Dror/0000-0002-1789-5811 FU NEI NIH HHS [EY 09676, R01 EY008683, R01 EY009676, EY08683] NR 25 TC 106 Z9 111 U1 3 U2 6 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 JAN 8 PY 2002 VL 99 IS 1 BP 315 EP 320 DI 10.1073/pnas.012582799 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 510XV UT WOS:000173233300058 PM 11756676 ER PT J AU Ueki, K Yballe, CM Brachmann, SM Vicent, D Watt, JM Kahn, CR Cantley, LC AF Ueki, K Yballe, CM Brachmann, SM Vicent, D Watt, JM Kahn, CR Cantley, LC TI Increased insulin sensitivity in mice lacking p85 beta subunit of phosphoinositide 3-kinase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PROTEIN-KINASE-B; INDUCED GLUCOSE-TRANSPORT; GROWTH-FACTOR-I; PHOSPHATIDYLINOSITOL 3-KINASE; REGULATORY SUBUNIT; GLYCOGEN-SYNTHASE; 3T3-L1 ADIPOCYTES; P85-ALPHA GENE; ACTIVATION; RECEPTOR AB On the basis of ex vivo studies using insulin-responsive cells, activation of a Class IA phosphoinositide 3-kinase (PI3K) seems to be required for a wide variety of cellular responses downstream of insulin. The Class IA PI3K enzymes are heterodimers of catalytic and regulatory subunits. In mammals, insulin-responsive tissues express both the p85alpha and p85beta isoforms of the regulatory subunit. Surprisingly, recent studies have revealed that disruption of the p85alpha gene in the mouse (p85alpha(-/-) mice) results in hypoglycemia with decreased plasma insulin, and the p85alpha(+/-) mice exhibit significantly increased insulin sensitivity. These results suggest either that p85a negatively regulates insulin signaling, or that p85beta, which mediates the major fraction of Class IA PI3K signaling in the absence of p85a, is more efficient than p85a in mediating insulin responses. To address this question, we have generated mice in which the p85beta gene is deleted (p85beta(-/-) mice). As with the p85alpha(-/-) mice, the p85beta(-/-) mice showed hypoinsulinemia, hypoglycemia, and improved insulin sensitivity. At the molecular level, PI3K activity associated with phosphotyrosine complexes was preserved despite a 20-30% reduction in the total protein level of the regulatory subunits. Moreover, insulin-induced activation of AKT was significantly up-regulated in muscle from the p85beta(-/-) mice. In addition, insulin-dependent tyrosine phosphorylation of insulin receptor substrate-2 was enhanced in the p85beta(-/-) mice a phenotype not observed in the p85alpha(-/-) mice. These results indicate that in addition to their roles in recruiting the catalytic subunit of PI3K to the insulin receptor substrate proteins, both p85a and p85beta play negative roles in insulin signaling. C1 Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02215 USA. Free Univ Berlin, Inst Biochem, D-14195 Berlin, Germany. RP Cantley, LC (reprint author), Harvard Univ, Inst Med, Div Signal Transduct, 10th Floor,330 Brookline Ave, Boston, MA 02215 USA. EM cantley@helix.mgh.harvard.edu RI Cantley, Lewis/D-1800-2014; Vicent, David/O-2255-2014 OI Cantley, Lewis/0000-0002-1298-7653; Vicent, David/0000-0002-6663-0350 FU NIDDK NIH HHS [R01 DK055545, DK33201, DK34834, DK55545, R01 DK033201]; NIGMS NIH HHS [GM41890, R01 GM041890, R37 GM041890] NR 39 TC 148 Z9 150 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 8 PY 2002 VL 99 IS 1 BP 419 EP 424 DI 10.1073/pnas.012581799 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 510XV UT WOS:000173233300075 PM 11752399 ER PT J AU Sperling, R Greve, D Dale, A Killiany, R Holmes, J Rosas, HD Cocchiarella, A Firth, P Rosen, B Lake, S Lang, N Routledge, C Albert, M AF Sperling, R Greve, D Dale, A Killiany, R Holmes, J Rosas, HD Cocchiarella, A Firth, P Rosen, B Lake, S Lang, N Routledge, C Albert, M TI Functional MRI detection of pharmacologically induced memory impairment SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RANDOM-EFFECTS MODELS; ALZHEIMERS-DISEASE; SCOPOLAMINE; FMRI; HIPPOCAMPUS; LORAZEPAM; RETRIEVAL; DIAZEPAM; REPRODUCIBILITY; RATS AB To examine alterations in brain activation associated with pharmacologically induced memory impairment, we used functional MRI (fMRI) to study the effects of lorazepam and scopolamine on a face-name associative encoding paradigm. Ten healthy young subjects were scanned on four occasions, 2 weeks apart; they were administered i.v. saline during two placebo-scanning sessions and then alternately administered i.v. lorazepam (1 mg) or scopolamine (0.4 mg) in a double-blind, randomized, cross-over design. Both the extent and magnitude of activation within anatomic regions of interest (ROIs) were examined to determine the reproducibility of activation in the placebo sessions and the regional specificity of the pharmacologic effects. Activation within all ROIs was consistent across the two placebo scans during the encoding of novel face-name pairs (compared with visual fixation). With the administration of either lorazepam or scopolamine, significant decreases were observed in both the extent and magnitude of activation within the hippocampal, fusiform, and inferior prefrontal ROIs, but no significant alterations in activation in the striate cortex were found. Both medications impaired performance on postscan memory measures, and significant correlations between memory performance and extent of activation were found in hippocampal and fusiform ROIs. These findings suggest that pharmacologic effects can be detected with fMRI by using a reproducible experimental paradigm and that medications that impair memory also diminish activation in specific brain regions thought to subserve complex memory processes. C1 Massachusetts Gen Hosp, Boston, MA 02129 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. McLean Hosp, Belmont, MA 02478 USA. Glaxo Smith Kline, Harlow CM19 5AW, Essex, England. RP Sperling, R (reprint author), Memory Disorders Unit, 221 Longwood Ave, Boston, MA 02115 USA. RI Dale, Anders/A-5180-2010 FU NIA NIH HHS [P01 AG004953, P01-AG04953]; NINDS NIH HHS [K23-NS02189, K23 NS002189] NR 32 TC 135 Z9 138 U1 1 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 JAN 8 PY 2002 VL 99 IS 1 BP 455 EP 460 DI 10.1073/pnas.012467899 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 510XV UT WOS:000173233300081 PM 11756667 ER PT J AU Bush, G Vogt, BA Holmes, J Dale, AM Greve, D Jenike, MA Rosen, BR AF Bush, G Vogt, BA Holmes, J Dale, AM Greve, D Jenike, MA Rosen, BR TI Dorsal anterior cingulate cortex: A role in reward-based decision making SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article; Proceedings Paper CT 7th Annual Meeting of the Organization for Human Brain Mapping CY JUN 10-14, 2001 CL BRIGHTON, ENGLAND ID POSITRON EMISSION TOMOGRAPHY; CEREBRAL BLOOD-FLOW; EVENT-RELATED FMRI; HUMAN-BRAIN; RESPONSE SELECTION; COUNTING STROOP; FRONTAL-CORTEX; MOTOR AREAS; MEDIAL WALL; ATTENTION AB Dorsal anterior cingulate cortex (dACC) is a brain region that subserves cognition and motor control, but the mechanisms of these functions remain unknown. Human neuroimaging and monkey electrophysiology studies have provided valuable insights, but it has been difficult to link the two literatures. Based on monkey single-unit recordings, we hypothesized that human dACC is comprised of a mixture of functionally distinct cells that variously anticipate and detect targets, indicate novelty, influence motor responses, encode reward values, and signal errors. As an initial test of this conceptualization, the current event-related functional MRI study used a reward-based decision-making task to isolate responses from a subpopulation of dACC cells sensitive to reward reduction. As predicted, seven of eight subjects showed significant (p < 10(-4)) dACC activation when contrasting reduced reward (REDrew) trials to fixation (FIX). Confirmatory group analyses then corroborated the predicted ordinal relationships of functional MRI activation expected during each trial type (REDrew > SWITCH > CONrew greater than or equal to FIX). The data support a role for dACC in reward-based decision making, and by linking the human and monkey literatures, provide initial support for the existence of heterogeneity within dACC. These findings should be of interest to those studying reward, cognition, emotion, motivation, and motor control.(parallel to) C1 Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, MIT,Sch Med, Athinoula A Martinos Ctr Funct & Struct Biomed Im, Charlestown, MA 02129 USA. MIT, Cambridge, MA 02139 USA. Cingulum Neurosci Inst, Syracuse, NY 13210 USA. RP Bush, G (reprint author), Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RI Dale, Anders/A-5180-2010; Vogt, Brent/C-4038-2015 OI Vogt, Brent/0000-0003-1228-4410 FU NIMH NIH HHS [K01-MH01611] NR 42 TC 537 Z9 543 U1 8 U2 43 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 JAN 8 PY 2002 VL 99 IS 1 BP 523 EP 528 DI 10.1073/pnas.012470999 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 510XV UT WOS:000173233300093 PM 11756669 ER PT J AU Calautti, E Grossi, M Mammucari, C Aoyama, Y Pirro, M Ono, Y Li, J Dotto, GP AF Calautti, E Grossi, M Mammucari, C Aoyama, Y Pirro, M Ono, Y Li, J Dotto, GP TI Fyn tyrosine kinase is a downstream mediator of Rho/PRK2 function in keratinocyte cell-cell adhesion SO JOURNAL OF CELL BIOLOGY LA English DT Article DE E-cadherin; beta- and gamma-catenin; p120(ctn); PKN/PRK2; adherens junctions ID EPIDERMAL GROWTH-FACTOR; SMALL G-PROTEINS; BETA-CATENIN; ACTIN CYTOSKELETON; P120 CATENIN; RHO-GTPASES; SRC KINASE; PHOSPHORYLATION; FAMILY; DIFFERENTIATION AB The Rho GTPase and Fyn tyrosine kinase have been implicated previously in positive control of keratinocyte cell-cell adhesion. Here, we show that Rho and Fyn operate along the same signaling pathway. Endogenous Rho activity increases in differentiating keratinocytes and is required for both Fyn kinase activation and increased tyrosine phosphorylation of beta- and gamma-catenin, which is associated with the establishment of keratinocyte cell-cell adhesion. Conversely, expression of constitutive active Rho is sufficient to promote cell-cell adhesion through a tyrosine kinase- and Fyn-dependent mechanism, trigger Fyn kinase activation, and induce tyrosine phosphorylation of beta- and gamma-catenin and p120(ctn). The positive effects of activated Rho on cell-cell adhesion are not induced by an activated Rho mutant with defective binding to the serine/threonine PRK2/PKN kinases. Endogenous PRK2 kinase activity increases with keratinocyte differentiation, and, like activated Rho, increased PRK2 activity promotes keratinocyte cell-cell adhesion and induces tyrosine phosphorylation of beta- and gamma-catenin and Fyn kinase activation, Thus, these findings reveal a novel role of Fyn as a downstream mediator of Rho in control of keratinocyte cell-cell adhesion and implicate the PRK2 kinase, a direct Rho effector, as a link between Rho and Fyn activation. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. RP Dotto, GP (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Bldg 149 13th St, Charlestown, MA 02129 USA. OI CALAUTTI, Vincenzo/0000-0002-4439-9709 FU NCI NIH HHS [P01 CA016038, CA16038, R01 CA073796, CA73796]; NIAMS NIH HHS [AR39190, R01 AR039190] NR 44 TC 120 Z9 125 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD JAN 7 PY 2002 VL 156 IS 1 BP 137 EP 148 DI 10.1083/jcb.200105140 PG 12 WC Cell Biology SC Cell Biology GA 511GM UT WOS:000173256300014 PM 11777936 ER PT J AU Rio, C Dikkes, P Liberman, MC Corfas, G AF Rio, C Dikkes, P Liberman, MC Corfas, G TI Glial fibrillary acidic protein expression and promoter activity in the inner ear of developing and adult mice SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE transgenic; supporting cells; cochlea; vestibular; Schwann cell; spiral ganglion ID HAIR-CELL REGENERATION; SUPPORTING CELLS; NEUROTROPHIC FACTOR; TRANSGENIC MICE; GUINEA-PIG; BRAIN; ASTROCYTES; COCHLEA; RAT AB The intermediate filament glial fibrillary acidic protein (GFAP) is a classic marker for several types of glial cells, including astrocytes and nonmyelinating Schwann cells. The pattern of expression of GFAP in the postnatal murine inner ear, from postnatal day 3 (P3) to P38, was studied by anti-GFAP immunostaining in wild-type mice as well as in two lines of transgenic mice expressing either beta -galactosidase (LacZ) or green fluorescent protein (GFP) under the control of the GFAP promoter. Analysis of protein and promoter activity shows that several classes of supporting cells in the sensory epithelia, as well as Schwann cells and satellite cells express GFAP. Early after birth, all cochlear supporting cells express GFAP, in a gradient decreasing in intensity from base to apex. After P15, GFAP expression in the organ of Corti is mostly restricted to supporting cells of the inner hair cell area (i.e., inner border and inner phalangeal cells) and outer hair cell area (i.e., Deiters' cells). A small population of limbic cells also showed expression in a base-to-apex gradient. In the vestibular organs, high expression was detected in supporting cells in extrastriolar regions of the utricular macula and in the canal ampullae, with weaker staining in the saccular macula. These results suggest that supporting cells of the inner ear have important similarities to glial cells and may play roles similar to those of astrocytes or Schwann cells in supporting the normal development and maintenance of neurons and sensory cells of the inner ear. J. Comp. Neurol. 442:156-162, 2002. (C) 2002 Wiley-Liss, Inc. C1 Childrens Hosp, Div Neurosci, Boston, MA 02115 USA. Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. RP Corfas, G (reprint author), Childrens Hosp, Div Neurosci, 300 Longwood Ave, Boston, MA 02115 USA. FU NICHD NIH HHS [P30-HD 18655]; NIDCD NIH HHS [R01 DC0188]; NINDS NIH HHS [R01 NS35884] NR 23 TC 67 Z9 70 U1 1 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD JAN 7 PY 2002 VL 442 IS 2 BP 156 EP 162 DI 10.1002/cne.10085 PG 7 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 500UC UT WOS:000172644300005 PM 11754168 ER PT J AU Intes, X Ntziachristos, V Culver, JP Yodh, A Chance, B AF Intes, X Ntziachristos, V Culver, JP Yodh, A Chance, B TI Projection access order in algebraic reconstruction technique for diffuse optical tomography SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID COMPUTED-TOMOGRAPHY; BREAST-CANCER; ART; SPECTROSCOPY; SCHEME AB Algebraic reconstruction technique (ART) is one of the popular image reconstruction techniques used in diffuse optical tomography (DOT). We investigate in this note the influence of the order in which data are accessed in ART. Simulations mimicking breast tissues in transmission geometry with contrast agent tumour enhancement were used to evaluate the image quality of the diverse projection access investigated. We show that by selecting proper projection access order, the convergence speed can be significantly improved when ART is used to perform DOT. Moreover, low-contrast detection is improved. C1 Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. Univ Penn, Dept Phys & Astron, Philadelphia, PA 19104 USA. Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, NMR Ctr, Charlestown, MA 02129 USA. RP Intes, X (reprint author), Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. EM intes@mail.med.upenn.edu FU NCI NIH HHS [CA 87046, R01-CA 60182-05] NR 26 TC 64 Z9 64 U1 1 U2 9 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JAN 7 PY 2002 VL 47 IS 1 BP N1 EP N10 DI 10.1088/0031-9155/47/1/401 PG 10 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 516YE UT WOS:000173583700013 PM 11814231 ER PT J AU Lorenzo, HK Teixeira, J Pahlavan, N Laurich, VM Donahoe, PK MacLaughlin, DT AF Lorenzo, HK Teixeira, J Pahlavan, N Laurich, VM Donahoe, PK MacLaughlin, DT TI New approaches for high-yield purification of Mullerian inhibiting substance improve its bioactivity SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE protein purification; Mullerian inhibiting substance; transforming growth factor beta ID TERMINAL DOMAIN; OOCYTE MEIOSIS; IN-VIVO; CELLS; HORMONE; EXPRESSION; LINES; GENE AB We have established a new method to purify Mullerian inhibiting substance (MIS) with higher purity and recovery over existing procedures. Recombinant human MIS was expressed in Chinese hamster ovary cells and secreted into chemically defined serum-free media. The secreted products were concentrated by either precipitation with ammonium sulfate or lectin-affinity chromatography, each of which was followed by anion-exchange chromatography. Further separation of the active carboxy-terminal domain of MIS was achieved after cleavage by plasmin followed by lectin-affinity chromatography. This method may be applicable to other members of the transforming growth factor (3 family with which MIS shares sequence homology. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02114 USA. RP MacLaughlin, DT (reprint author), Massachusetts Gen Hosp, Pediat Surg Res Labs, Warren 10,55 Fruit St, Boston, MA 02114 USA. FU NCI NIH HHS [R01CA17393]; NICHD NIH HHS [U54HD28138] NR 29 TC 26 Z9 28 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD JAN 5 PY 2002 VL 766 IS 1 BP 89 EP 98 DI 10.1016/S0378-4347(01)00436-4 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 508NC UT WOS:000173094500010 PM 11820299 ER PT J AU Du, JY Fisher, DE AF Du, JY Fisher, DE TI Identification of aim-1 as the underwhite mouse mutant and its transcriptional regulation by MITF SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MICROPHTHALMIA GENE-PRODUCT; WAARDENBURG SYNDROME; REPETITIVE ELEMENTS; TIETZ-SYNDROME; EXPRESSION; ACTIVATION; MUTATION; ALBINISM; MELANOMA; REPEATS AB Animal pigmentation mutants have provided rich models for the identification of genes modulating pathways from melanocyte development to melanoma. One mouse model is the underwhite locus, alleles of which manifest altered pigmentation of both eye and fur, sometimes in an age-dependent fashion. Here we show that the mouse homolog of a recently identified gene whose mutation produces Japanese gold-colored fish, medaka b, maps to the mouse underwhite locus. We identify distinct mutations of this gene, known as Aim-1, in three underwhite mouse alleles and find that structure/function differences correlate with recessive versus dominant inheritance. The human ortholog of AIM-1 was originally identified as a melanocyte-restricted antigen that is recognized by autologous T cells from a patient with melanoma. We also provide evidence that AIM-1 is transcriptionally modulated by MITF, a melanocyte-specific transcription factor essential to pigmentation and a clinical diagnostic marker in human melanoma. Although AIM-1 appears to reside downstream of MITF, chromatin immunoprecipitations do not reveal binding of MITF to a 5'-flanking region containing histone 3 acetylation, indicating that MITF either acts indirectly on AIM-1 or it binds to a remote regulatory sequence. Nevertheless, MITF links AIM-1 expression and the underwhite phenotype to a transcriptional network central to pigmentation in mammals. C1 Harvard Univ, Childrens Hosp, Sch Med, Div Pediat Hematol Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. FU NIAMS NIH HHS [AR43369] NR 28 TC 57 Z9 59 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 JAN 4 PY 2002 VL 277 IS 1 BP 402 EP 406 DI 10.1074/jbc.M110229200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 508KU UT WOS:000173087900054 PM 11700328 ER PT J AU Phan, J Pesaran, T Davis, RC Reue, K AF Phan, J Pesaran, T Davis, RC Reue, K TI The Diet1 locus confers protection against hypercholesterolemia through enhanced bile acid metabolism SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEAR RECEPTOR LXR; CHOLESTEROL 7-ALPHA-HYDROXYLASE EXPRESSION; DENSITY-LIPOPROTEIN CHOLESTEROL; BILIARY LIPID SECRETION; TRANSGENIC MICE; BIOSYNTHESIS; GENE; TRANSPORT; LIVER; HOMEOSTASIS AB The C57BL,/6ByJ (B6By) mouse strain is resistant to diet-induced hypercholesterolemia and atherosclerosis, despite its near genetic identity with the atherosclerosis-susceptible C57BL/6J (B6J) strain. We previously identified a genetic locus, Diet1, which is responsible for the resistant phenotype in B6By mice. To investigate the function of Diet1, we compared mRNA expression profiles in the liver of B6By and B6J mice fed an atherogenic diet using a DNA microarray. These studies revealed elevated expression levels in B6By liver for key bile acid synthesis proteins, including cholesterol 7alpha-hydroxylase and sterol-27-hydroxylase, and the oxysterol nuclear receptor liver X receptor alpha. Expression levels for several other genes involved in bile acid metabolism were subsequently found to differ between B6By and B6J mice, including the bile acid receptor farnesoid X receptor, oxysterol 7alpha-hydroxylase, sterol-12alpha-hydroxylase, and hepatic bile acid transporters on both sinusoidal and canalicular membranes. The overall expression profile of the B6By strain suggests a higher rate of bile acid synthesis and transport in these mice. Consistent with this interpretation, fecal bile acid excretion is increased 2-fold in B6By mice, and bile acid levels in blood and urine are elevated 3- and 18-fold, respectively. Genetic analysis of serum bile acid levels revealed co-segregation with Diet1, indicating that this locus is likely responsible for both increased bile acid excretion and resistance to hypercholesterolemia in B6By mice. C1 Univ Calif Los Angeles, Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90073 USA. RP Reue, K (reprint author), Univ Calif Los Angeles, Vet Affairs Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd,Bldg 113,Rm 312, Los Angeles, CA 90073 USA. FU NHLBI NIH HHS [HL28481, HL58627] NR 53 TC 16 Z9 17 U1 0 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 JAN 4 PY 2002 VL 277 IS 1 BP 469 EP 477 DI 10.1074/jbc.M107107200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 508KU UT WOS:000173087900063 PM 11682476 ER PT J AU Boulton, SJ Gartner, A Reboul, J Vaglio, P Dyson, N Hill, DE Vidal, M AF Boulton, SJ Gartner, A Reboul, J Vaglio, P Dyson, N Hill, DE Vidal, M TI Combined functional genomic maps of the C-elegans DNA damage response SO SCIENCE LA English DT Article ID CAENORHABDITIS-ELEGANS; PROTEIN; CHECKPOINT; REPAIR; YEAST; INTERFERENCE; PATHWAY; LENGTH; RNA AB Many human cancers originate from defects in the DNA damage response (DDR). Although much is known about this process, it is likely that additional DDR genes remain to be discovered. To identify such genes, we used a strategy that combines protein-protein interaction mapping and large-scale phenotypic analysis in Caenorhabditis elegans. Together, these approaches identified 12 worm DDR orthologs and 11 novel DDR genes. One of these is the putative ortholog of hBCL3, a gene frequently altered in chronic lymphocytic leukemia. Thus, the combination of functional genomic mapping approaches in model organisms may facilitate the identification and characterization of genes involved in cancer and, perhaps, other human diseases. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA 02129 USA. Max Planck Inst Biochem, D-82152 Martinsried, Germany. RP Vidal, M (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM marc_vidal@dfci.harvard.edu RI Hill, David/B-6617-2011; Reboul, Jerome/P-9103-2016; OI Reboul, Jerome/0000-0002-5513-4546; Gartner, Anton/0000-0003-4639-9902 FU NCI NIH HHS [7 R33 CA81658-02, P01CA80111-02]; NHGRI NIH HHS [5R01HG01715-02] NR 28 TC 205 Z9 210 U1 3 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JAN 4 PY 2002 VL 295 IS 5552 BP 127 EP 131 DI 10.1126/science.1065986 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 509HV UT WOS:000173143100049 PM 11778048 ER PT J AU Maeshima, Y Sudhakar, A Lively, JC Ueki, K Kharbanda, S Kahn, CR Sonenberg, N Hynes, RO Kalluri, R AF Maeshima, Y Sudhakar, A Lively, JC Ueki, K Kharbanda, S Kahn, CR Sonenberg, N Hynes, RO Kalluri, R TI Tumstatin, an endothelial cell-specific inhibitor of protein synthesis SO SCIENCE LA English DT Article ID DISTINCT ANTITUMOR PROPERTIES; CAP-DEPENDENT INITIATION; PHOSPHORYLATION; RAPAMYCIN; KINASE; TRANSLATION; ANGIOGENESIS; ENDOSTATIN; TARGET; MICE AB Tumstatin is a 28-kilodalton fragment of type IV collagen that displays both anti-angiogenic and proapoptotic activity. Here we show that tumstatin functions as an endothelial cell-specific inhibitor of protein synthesis. Through a requisite interaction with alphaV beta3 integrin, tumstatin inhibits activation of focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3-kinase), protein kinase B (PKB/Akt), and mammalian target of rapamycin (mTOR), and it prevents the dissociation of eukaryotic initiation factor 4E protein (eIF4E) from 4E-binding protein 1. These results establish a rote for integrins in mediating ceti-specific inhibition of cap-dependent protein synthesis and suggest a potential mechanism for tumstatin's selective effects on endothelial cells. C1 Beth Israel Deaconess Med Ctr, Dept Med, Program Matrix Biol, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Ctr Canc, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. MIT, Ctr Canc Res, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02139 USA. Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Canc Pharmacol, Boston, MA 02215 USA. McGill Univ, Dept Biochem, Montreal, PQ H3G 1V6, Canada. McGill Univ, McGill Canc Ctr, Montreal, PQ H3G 1V6, Canada. RP Kalluri, R (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Program Matrix Biol, Boston, MA 02215 USA. RI Kalluri, Raghu/E-2677-2015 OI Kalluri, Raghu/0000-0002-2190-547X FU NHLBI NIH HHS [P01-HL66105]; NIDDK NIH HHS [DK-51711, DK-55001] NR 26 TC 319 Z9 364 U1 1 U2 10 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 JAN 4 PY 2002 VL 295 IS 5552 BP 140 EP 143 DI 10.1126/science.1065298 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 509HV UT WOS:000173143100053 PM 11778052 ER PT J AU Rosowsky, A Forsch, RA Queener, SF AF Rosowsky, A Forsch, RA Queener, SF TI Inhibition of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductases by 2,4-diamino-5-[2-methoxy-5-[omega-carboxyalkyloxy)benzyl]pyrimidines: Marked improvement in potency relative to trimethoprim and species selectivity relative to piritrexim SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID IN-VITRO; PHASE-II; OPPORTUNISTIC INFECTIONS; DAPSONE-PYRIMETHAMINE; PRIMARY PROPHYLAXIS; ORAL PIRITREXIM; AIDS PATIENTS; PNEUMONIA; ANALOGS; SULFAMETHOXAZOLE AB A series of previously undescribed 2,4-diamino-5-[2-methoxy-5-alkoxybenzyl]pyrimidines (3a-e) and 2,4-diamino-5-[2-methoxy-5-(omega-carboxyalkyloxy)benzyl]pyrimidines (3f-k) with up to eight CH2 groups in the alkoxy or omega-carboxyalkyloxy side chain were synthesized and tested for the ability to inhibit partially purified dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), Mycobacterium avium (Ma), and rat liver in comparison with two standard inhibitors, trimethoprim (1) and piritrexim (2). The latter drug is known to be extremely potent but shows a marked preference for binding to mammalian DHFR, whereas the former is very selective for the parasite enzymes but is a much weaker inhibitor. The underlying strategy for the synthesis of compounds 3a-k was that a hybrid structure embodying some features of both I and 2 might possess a more favorable combination of potency and selectivity than either parent drug. The choice of analogues 3f-k was based on the idea that the acidic omega-carboxyl group might interact preferentially with a basic center in the active site of DHFR from any of the parasite species relative to the active site of mammalian DHFR. In addition, the omega-carboxyl group was expected to improve water solubility relative to 1 or 2. In standardized spectrophotometric assays with dihydrofolate as the substrate and NADPH as the cofactor, 2,4-diamino-5-[(2-methoxy-4-carboxybutyloxy)benzyl]pyrimidine (3g) inhibited Pc DHFR with an IC50 of 0.049 muM and rat DHFR with IC50 of 3.9 muM. Its potency against Pc DHFR was 140-fold greater than that of I and close to that of 2, and its selectivity index, defined as the ratio IC50(rat liver)/IC50(P. carinii), was 8-fold higher than that of 1 and > 10(4)-fold higher than that of 2. Although it was less potent and less selective against Tg than Pc DHFR, it was very potent as well as highly selective against Ma DHFR, with an IC50 of 0.0058 muM and an IC50(rat liver)/IC50(M. avium) ratio of >600. Because of this favorable combination of potency and selectivity relative to 1 and 2, compound 3g may be viewed as a promising lead in the search for new antifolates with potential clinical activity against P. carinii and other opportunistic pathogens in patients with AIDS. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Indiana Univ, Sch Med, Dept Pharmacol & Toxicol, Indianapolis, IN 46202 USA. RP Rosowsky, A (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. FU NIAID NIH HHS [R01-AI29904] NR 55 TC 37 Z9 39 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JAN 3 PY 2002 VL 45 IS 1 BP 233 EP 241 DI 10.1021/jm010407u PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 508KZ UT WOS:000173088800020 PM 11754594 ER PT J AU Grabowski, EF AF Grabowski, EF TI The hemolytic-uremic syndrome - Toxin, thrombin, and thrombosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID VON-WILLEBRAND-FACTOR; FACTOR-CLEAVING PROTEASE; THROMBOCYTOPENIC PURPURA; ACTIVATION; PLASMA; FIBRINOLYSIS; COAGULATION; VIII C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Grabowski, EF (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 16 TC 7 Z9 10 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 JAN 3 PY 2002 VL 346 IS 1 BP 58 EP 61 DI 10.1056/NEJM200201033460113 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 507NB UT WOS:000173033600012 PM 11778006 ER PT J AU Yang, L Xia, L Wu, DY Wang, HB Chansky, HA Schubach, WH Hickstein, DD Zhang, Y AF Yang, L Xia, L Wu, DY Wang, HB Chansky, HA Schubach, WH Hickstein, DD Zhang, Y TI Molecular cloning of ESET, a novel histone H3-specific methyltransferase that interacts with ERG transcription factor SO ONCOGENE LA English DT Article DE histone methyltransferase; ESET; ERG ID HUMAN MYELOID-LEUKEMIA; EWINGS-SARCOMA; CHROMOSOMAL TRANSLOCATION; EWS-ERG; GENE; PROTEINS; DOMAIN; FAMILY; RNA; METHYLATION AB The ets-related gene erg encodes a transcription factor that is implicated in the control of cell growth and differentiation. To identify interacting partners of ERG, we screened a yeast two-hybrid cDNA library constructed from mouse hematopoietic cells using the N-terminal region of ERG as a bait. We isolated a 4.6 kb full-length mouse cDNA encoding a 1307-amino acid protein migrating as a 180 kD band, which was termed ESET (ERG-associated protein with SET domain). ESET is 92% identical to the human protein SETDB1 (SET domain, bifurcated 1). The interaction between ESET and ERG was supported by in vitro pull-down using glutathione S-transferase (GST) fusion protein, by transfection and co-immunoprecipitation experiments, and by association of endogenous SETDB1 with ERG. Since ESET possesses evolutionarily conserved SET, preSET, and postSET domains implicated in histone methylation, we tested the ability of ESET to methylate core histones. The results of these studies demonstrated that ESET is a histone H3-specific methyltransferase, and that mutations within ESET abolished its methyltransferase activity. Together, these findings raise the possibility that transcription factor ERG may participate in transcriptional regulation through ESET-mediated histone methylation. C1 Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. NCI, Dept Expt Transplantat & Immunol, Bethesda, MD 20892 USA. Univ Washington, Dept Med Oncol, Seattle, WA 98108 USA. Univ Washington, Dept Orthoped, Seattle, WA 98108 USA. Univ Washington, VA Puget Sound Hlth Care Syst, Med Res Serv, Seattle, WA 98108 USA. RP Zhang, Y (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. FU NIGMS NIH HHS [GM63067-01] NR 30 TC 145 Z9 151 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 3 PY 2002 VL 21 IS 1 BP 148 EP 152 DI 10.1038/sj.onc.1204998 PG 5 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 505AD UT WOS:000172887800015 PM 11791185 ER PT J AU Zhou, X Potoka, DA Boyle, P Nadler, EP McGinnis, K Ford, HR AF Zhou, X Potoka, DA Boyle, P Nadler, EP McGinnis, K Ford, HR TI Aminoguanidine renders inducible nitric oxide synthase knockout mice more susceptible to Salmonella typhimurium infection SO FEMS MICROBIOLOGY LETTERS LA English DT Article DE aminoguinidine; iNOS knockout mouse; Salmonella typhimurium ID NADPH PHAGOCYTE OXIDASE; IN-VIVO; PERITONEAL-MACROPHAGES; ANTIMICROBIAL ACTIONS; MECHANISM; IMMUNOSUPPRESSION AB Aminoguanidine (AG), a nitric oxide synthase (NOS) inhibitor, has been widely used to study the role of inducible NOS (iNOS) in host defense against infections caused by various pathogens including Salmonella typhimurium. iNOS has been reported to play an important role in host defense against S. typhimurium infection both in vitro and in vivo. In this report we show those AG treatment lead to weight loss in both wild-type and NOS knockout mice, and rendered them more susceptible to Salmonella infection. These results suggest that AG may have side effects other than the inhibition or iNOS, and that data obtained from studies using AG should be interpreted with caution. (C) 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Microbiological Societies. C1 Childrens Hosp Pittsburgh, Dept Surg, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. VA Pittsburgh Healthcare Syst, Ctr Hlth Serv Res, Pittsburgh, PA USA. RP Zhou, X (reprint author), Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. FU NIAID NIH HHS [R01-AI-14032] NR 16 TC 9 Z9 9 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1097 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD JAN 2 PY 2002 VL 206 IS 1 BP 93 EP 97 DI 10.1111/j.1574-6968.2002.tb10992.x PG 5 WC Microbiology SC Microbiology GA 511UU UT WOS:000173284600015 PM 11786263 ER PT S AU Badawi, RD Adam, LE Zimmerman, RE AF Badawi, RD Adam, LE Zimmerman, RE BE Seibert, JA TI A simulation-based assessment of the revised NEMA NU-2 70-cm long test phantom for PET SO 2001 IEEE NUCLEAR SCIENCE SYMPOSIUM, CONFERENCE RECORDS, VOLS 1-4 SE IEEE NUCLEAR SCIENCE SYMPOSIUM - CONFERENCE RECORD LA English DT Proceedings Paper CT IEEE Nuclear Science Symposium CY NOV 04-10, 2001 CL SAN DIEGO, CA SP IEEE, Nucl Plasma Sci Soc AB A 70cm long polyethylene cylinder of radius 10 cm containing an off-center line source has been suggested for the characterization of PET tomograph whole-body performance in terms of scatter fraction, sensitivity to randoms and count-rate capability. In this work we perform a series of Monte Carlo simulations of a full-ring BGO system operating in 3D mode and a full-ring sodium iodide system operating in 3D mode to determine how closely scatter fraction and NEC results from the 70 cm cylinder follow those found in anthropomorphic activity and attenuation distributions. We rind that the 70 cm cylinder measurements correctly rank-order the tomographs in terms of scatter fraction and NEC performance, but do not always accurately predict the actual scatter fractions or the peak NEC values encountered in the anthropomorphic models. Peak NEC for the phantom occurs at around double the activity concentrations which give rise to peak NEC in the anthropomorphic objects. C1 Dana Farber Canc Inst, Div Nucl Med, Boston, MA 02115 USA. RP Badawi, RD (reprint author), Dana Farber Canc Inst, Div Nucl Med, 44 Binney St, Boston, MA 02115 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1082-3654 BN 0-7803-7324-3 J9 IEEE NUCL SCI CONF R PY 2002 BP 1466 EP 1470 PG 5 WC Engineering, Electrical & Electronic; Nuclear Science & Technology; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Nuclear Science & Technology; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BV30L UT WOS:000178495800320 ER PT S AU Correia, JA Burnham, CA Kaufman, D Fischman, AJ AF Correia, JA Burnham, CA Kaufman, D Fischman, AJ BE Seibert, JA TI Design studies for a volumetric high resolution small animal PET. SO 2001 IEEE NUCLEAR SCIENCE SYMPOSIUM, CONFERENCE RECORDS, VOLS 1-4 SE IEEE NUCLEAR SCIENCE SYMPOSIUM - CONFERENCE RECORD LA English DT Proceedings Paper CT IEEE Nuclear Science Symposium CY NOV 04-10, 2001 CL SAN DIEGO, CA SP IEEE, Nucl Plasma Sci Soc AB We have developed two LSO block detectors for single-plane small animal PET instruments which have spatial resolution of approximately 1 mm. They have served mainly as demonstration prototypes but have also been used for numerous rat and mouse imaging studies. By extending the axial length of the detector element from these systems and adding a second ring of photomultiplier tubes, a high-resolution 2-dimensional block using analog position sensing in both the radial and axial dimensions has been implemented. It consists of ten 1.2 mm. wide x 7 mm deep x 20 mm high LSO crystals that are discrete in the radial direction and continuous in the axial direction. An instrument based on this design results in a substantial increase in sensitivity. Experiments with this detector element have demonstrated 1.2-mm radial resolution and approximately 1.6-mm axial coincidence resolution over the central 15 mm of the 20 mm high block element. A preliminary design for an instrument based on the 2-dimensional block has been evaluated by simulation studies. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Correia, JA (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 3 TC 1 Z9 1 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1082-3654 BN 0-7803-7324-3 J9 IEEE NUCL SCI CONF R PY 2002 BP 1550 EP 1554 PG 5 WC Engineering, Electrical & Electronic; Nuclear Science & Technology; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Nuclear Science & Technology; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BV30L UT WOS:000178495800338 ER PT B AU Tuch, DS AF Tuch, DS GP IEEE IEEE TI Mapping cortical connectivity with diffusion MRI SO 2002 IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING, PROCEEDINGS LA English DT Proceedings Paper CT IEEE International Symposium on Biomedical Imaging CY JUL 07-10, 2002 CL WASHINGTON, D.C. SP IEEE Signal Processing Sco, Engn Med & Biol Soc ID AXONAL PROJECTIONS; BRAIN; TRACKING AB Functional brain imaging methods have contributed enormously to our knowledge of the anatomic location of particular brain functions. However, there remains a significant gap in our understanding of how these regions communicate as part of a distributed network. This shortcoming is due in large part to the scarcity of information on the connectivity of the human brain compared to, for example, our knowledge of such anatomy in lower primates. Recently, investigators have undertaken to infer neuroanatomic connectivity from magnetic resonance diffusion imaging, an MRI method which measures the molecular mobility of the endogenous water in tissue. The method is based on the observation that in fibrous tissues such as skeletal muscle and white matter, the diffusion is greater along the direction of the fibers relative to, for example, the perpendicular direction. The direction of greatest diffusion provides an indication of the local white matter fiber direction within each voxel. The connectivity inference problem is then, simple stated, how to infer large-scale neuroanatomic connectivity from such fiber direction maps. Here, we present a physically-motivated, statistical framework for the connectivity inference problem. The particular benefits of the formulation include encapsulation of the unresolved aspects of the problem, and a statistical construction suitable for hypothesis testing of anatomical connectivity differences between groups of subjects. C1 Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Tuch, DS (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St,Room 2301, Charlestown, MA 02129 USA. NR 14 TC 0 Z9 0 U1 0 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 0-7803-7584-X PY 2002 BP 392 EP 394 PG 3 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BV15G UT WOS:000178000400098 ER PT B AU Meyer, JS Chowdhury, MH Quach, M AF Meyer, JS Chowdhury, MH Quach, M BE Korczyn, AD TI Treatment of vascular dementia with daily 325 mg oral aspirin SO 2ND INTERNATIONAL CONGRESS ON VASCULAR DEMENTIA LA English DT Proceedings Paper CT 2nd International Congress on Vascular Dementia CY JAN 24-27, 2002 CL SALZBURG, AUSTRIA C1 Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. Baylor Coll Med, Cerebrovasc Res Lab, Houston, TX USA. Vet Adm Hosp, Houston, TX USA. RP Meyer, JS (reprint author), Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. NR 3 TC 0 Z9 0 U1 1 U2 1 PU MEDIMOND S R L PI 40128 BOLOGNA PA VIA MASERATI 5, 40128 BOLOGNA, 00000, ITALY BN 88-323-1404-5 PY 2002 BP 215 EP 219 PG 5 WC Clinical Neurology; Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA BU06Q UT WOS:000174897200035 ER PT B AU Li, YS Meyer, JS Haque, A Chowdhury, MH Xu, G Quach, M AF Li, YS Meyer, JS Haque, A Chowdhury, MH Xu, G Quach, M BE Korczyn, AD TI Feasibility of vascular dementia treatment with cholinesterase inhibitors SO 2ND INTERNATIONAL CONGRESS ON VASCULAR DEMENTIA LA English DT Proceedings Paper CT 2nd International Congress on Vascular Dementia CY JAN 24-27, 2002 CL SALZBURG, AUSTRIA C1 Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. Baylor Coll Med, Cerebrovasc Res Lab, Houston, TX USA. Vet Adm Hosp, Houston, TX USA. RP Li, YS (reprint author), Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU MEDIMOND S R L PI 40128 BOLOGNA PA VIA MASERATI 5, 40128 BOLOGNA, 00000, ITALY BN 88-323-1404-5 PY 2002 BP 221 EP 225 PG 5 WC Clinical Neurology; Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA BU06Q UT WOS:000174897200036 ER PT B AU Bauer, KA Eriksson, BI Lassen, MR Turpie, AGG AF Bauer, KA Eriksson, BI Lassen, MR Turpie, AGG GP MONDUZZI EDITORE MONDUZZI EDITORE TI Consistency of fondaparinux superiority over enoxaparin in prevention of venous thromboembolism in orthopaedic surgery according to different composite efficacy endpoints SO 7TH ANNUAL MEETING OF THE EUROPEAN HAEMATOLOGY ASSOCIATION LA English DT Proceedings Paper CT 7th Annual Meeting of the European-Haematology-Association CY JUN 06-09, 2002 CL FLORENCE, ITALY SP European Haematol Assoc AB For thromboprophylaxis trials, the most reliable efficacy endpoint is still a matter of debate. In the fondaparinux (ArixtraO) phase III program versus enoxaparin in major orthopaedic surgery, a composite primary efficacy endpoint was predefined with regulatory bodies: venous thromboembolism (VTE) up to day 11, defined as deep vein thrombosis (DVT) detected by mandatory bilateral venography, or documented symptomatic DVT or pulmonary embolism (PE). Using the phase III fondaparinux database, we showed that the superior efficacy of fondaparinux over enoxaparin was maintained when other composite efficacy endpoints recently suggested for superiority studies by the ACCP Consensus (any proximal DVT+ fatal PE + symptomatic proven DVT or PE) and the CPMP (any proximal DVT + symptomatic proven PE + death from any causes) were considered. C1 VA Boston Healthcare Syst, Dept Med, Boston, MA USA. RP Bauer, KA (reprint author), VA Boston Healthcare Syst, Dept Med, Boston, MA USA. NR 5 TC 1 Z9 1 U1 0 U2 0 PU MEDIMOND S R L PI 40128 BOLOGNA PA VIA MASERATI 5, 40128 BOLOGNA, 00000, ITALY BN 88-323-2606-X PY 2002 BP 289 EP 292 PG 4 WC Hematology SC Hematology GA BV85J UT WOS:000180230800061 ER PT J AU Haidet, P O'Malley, KJ Richards, B AF Haidet, P O'Malley, KJ Richards, B TI An initial experience with "team learning" in medical education SO ACADEMIC MEDICINE LA English DT Article AB Team learning is an approach to large-group teaching that combines the strengths of small-group interactive learning with teacher-driven content delivery. Team learning has been used successfully in professional disciplines other than medicine. The authors describe a field test of team learning in the setting of an internal medicine residency noontime lecture in the spring of 2000 at Baylor College of Medicine. They surveyed residents on their attitudes toward the usefulness of the lecture content before and after the session and surveyed them on their engagement in learning. Residents reported their engagement as high and demonstrated favorable changes in their attitudes about the Usefulness of the lecture content to their daily medical practice. The authors describe their adaptation of the team-learning approach and conclude that team learning may be a useful new pedagogic tool in medical education. C1 Houston VAMC, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Baylor Coll Med, Off Curriculum, Houston, TX 77030 USA. RP Haidet, P (reprint author), Houston VAMC, 2002 Holcombe Blvd 152, Houston, TX 77030 USA. NR 9 TC 64 Z9 65 U1 2 U2 5 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD JAN PY 2002 VL 77 IS 1 BP 40 EP 44 DI 10.1097/00001888-200201000-00009 PG 5 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 512AY UT WOS:000173300000009 PM 11788321 ER PT J AU Augustinack, JC Schneider, A Mandelkow, EM Hyman, BT AF Augustinack, JC Schneider, A Mandelkow, EM Hyman, BT TI Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease SO ACTA NEUROPATHOLOGICA LA English DT Article DE epitope; intraneuronal; extraneuronal; pretangle; neurofibrillary tangle ID PAIRED HELICAL FILAMENTS; DEPENDENT PROTEIN-KINASE; GLYCOGEN-SYNTHASE KINASE-3-BETA; MICROTUBULE-ASSOCIATED PROTEINS; ADULT ONSET DEMENTIA; MONOCLONAL-ANTIBODY; NEUROFIBRILLARY TANGLES; ARGYROPHILIC GRAINS; REPEAT DOMAIN; CAG REPEAT AB Microtubule associated protein tau is abnormally phosphorylated in Alzheimer's disease (AD) and aggregates as paired helical filaments (PHFs) in neurofibrillary tangles (NFTs). We show here that the pattern of tau phosphorylation correlates with the loss of neuronal integrity. Studies using 11 phosphorylation dependent tau antibodies and a panel of AD cases of varying severity were evaluated in terms of three stages of neurofibrillary tangle development: (1) pre-neurofibrillary tangle, (2) intra-, and (3) extra-neuronal neurofibrillary tangles. The pretangle state, in which neurons display nonfibrillar, punctate regions in the cytoplasm, sound dendrites, somas, and nuclei, was observed especially with phosphotau antibodies TG3 (pT231), pS262, and pT153. Intraneuronal neurofibrillary tangles are homogenously stained with fibrillar tau structures, which were most prominently stained with pT175/181, 12E8 (pS262/pS356), pS422, pS46, pS214 antibodies. Extracellular NFTs, which contain substantial filamentous tau, are most prominently stained with AT8 (pS199/pS202/pT205), AT100 (pT212/pS214), and PHF-1 (pS396/pS404) antibodies, which also stain intracellular NFT. The sequence of early tau phosphorylation suggests that there are events prior to filament formation that are specific to particular phosphorylated tau epitopes, leading to conformational changes and cytopathological alterations. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Alzheimers Unit, Charlestown, MA 02129 USA. Max Planck Unit Struct Mol Biol, D-22607 Hamburg, Germany. RP Hyman, BT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Alzheimers Res Unit, 114 16th St,Rm 2009, Charlestown, MA 02129 USA. RI Schneider, Anja/F-5293-2010 NR 59 TC 427 Z9 441 U1 2 U2 27 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0001-6322 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD JAN PY 2002 VL 103 IS 1 BP 26 EP 35 PG 10 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 510AY UT WOS:000173187600004 PM 11837744 ER PT J AU Ferlito, A Silver, CE Zeitels, SM Rinaldo, A AF Ferlito, A Silver, CE Zeitels, SM Rinaldo, A TI Evolution of laryngeal cancer surgery SO ACTA OTO-LARYNGOLOGICA LA English DT Review ID SUPRACRICOID PARTIAL LARYNGECTOMY; EARLY SUPRAGLOTTIC CANCER; WHOLE-ORGAN SECTIONS; EARLY GLOTTIC CANCER; LASER-SURGERY; HORIZONTAL GLOTTECTOMY; ENDOSCOPIC TECHNIQUE; CLINICAL EXPERIENCE; FOLLOW-UP; CARCINOMA C1 Univ Udine, Policlin Univ, Dept Otolaryngol Head & Neck Surg, IT-33100 Udine, Italy. Montefiore Med Ctr, Albert Einstein Coll Med, Dept Surg, Bronx, NY 10467 USA. Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Boston, MA USA. RP Ferlito, A (reprint author), Univ Udine, Policlin Univ, Dept Otolaryngol Head & Neck Surg, Piazzale S Maria della Misericordia, IT-33100 Udine, Italy. NR 128 TC 5 Z9 5 U1 0 U2 0 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0001-6489 J9 ACTA OTO-LARYNGOL JI Acta Oto-Laryngol. PY 2002 VL 122 IS 6 BP 665 EP 672 DI 10.1080/000164802320396376 PG 8 WC Otorhinolaryngology SC Otorhinolaryngology GA 596GA UT WOS:000178155000014 PM 12403132 ER PT J AU Cradock, JA Young, AS Forquer, SL AF Cradock, JA Young, AS Forquer, SL TI Evaluating client and family preferences regarding outcomes in severe mental illness SO ADMINISTRATION AND POLICY IN MENTAL HEALTH LA English DT Article ID PERSPECTIVES; SCHIZOPHRENIA C1 W Los Angeles VA Healthcare Ctr, Dept Vet Affairs, VISN 22, Mental Illness Res Educ & Clin Ctr, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90024 USA. Comprehens NeuroSci Inc, Educ Serv, Colorado Springs, CO USA. Colorado Hlth Networks, Colorado Springs, CO USA. RP Young, AS (reprint author), W Los Angeles VA Healthcare Ctr, Dept Vet Affairs, VISN 22, Mental Illness Res Educ & Clin Ctr, Bldg 210A,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. RI Young, Alexander/A-1523-2009 OI Young, Alexander/0000-0002-9367-9213 FU NIMH NIH HHS [P50 MH-54623] NR 9 TC 4 Z9 4 U1 1 U2 1 PU KLUWER ACADEMIC-HUMAN SCIENCES PRESS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 0894-587X J9 ADM POLICY MENT HLTH JI Adm. Policy. Ment. Health PD JAN PY 2002 VL 29 IS 3 BP 257 EP 261 DI 10.1023/A:1015195626742 PG 5 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 553QM UT WOS:000175687000006 PM 12033670 ER PT S AU Birbes, H El Bawab, S Obeid, LM Hannun, YA AF Birbes, H El Bawab, S Obeid, LM Hannun, YA BE Weber, G TI Mitochondria and ceramide: intertwined roles in regulation of apoptosis SO ADVANCES IN ENZYME REGULATION, VOL 42, PROCEEDINGS SE ADVANCES IN ENZYME REGULATION LA English DT Article; Proceedings Paper CT 42nd International Symposium on Regulation of Enzyme Acitvity and Synthesis in Normal and Neoplastic Tissues CY SEP 24-25, 2001 CL INDIANA UNIV SCH MED, INDIANAPOLIS, INDIANA SP Banyu Pharmaceut Co, Eli Lilly & Co, Elsevier Sci Ltd, Roche Diagnost Corp HO INDIANA UNIV SCH MED ID PROTEIN-KINASE-C; SPHINGOMYELIN-DERIVED LIPIDS; PROGRAMMED CELL-DEATH; AIRWAY SMOOTH-MUSCLE; CYTOCHROME-C; SPHINGOSINE 1-PHOSPHATE; MOLECULAR-CLONING; DNA-DAMAGE; SACCHAROMYCES-CEREVISIAE; ENDOPLASMIC-RETICULUM C1 Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. Med Univ S Carolina, Ralph H Johnson Vet Adm, Charleston, SC 29425 USA. RP Hannun, YA (reprint author), Med Univ S Carolina, Dept Biochem & Mol Biol, 171 Ashley Ave, Charleston, SC 29425 USA. OI obeid, lina/0000-0002-0734-0847 FU NIA NIH HHS [AG16583]; NIDDK NIH HHS [DK59340]; NIGMS NIH HHS [GM43825] NR 109 TC 106 Z9 109 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0065-2571 BN 0-080-44123-8 J9 ADV ENZYME REGUL PY 2002 VL 42 BP 113 EP 129 AR PII S0065-2571(01)00026-7 DI 10.1016/S0065-2571(01)00026-7 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BV57M UT WOS:000179396600008 PM 12123710 ER PT B AU Russell, DC Kosolcharoen, P AF Russell, DC Kosolcharoen, P BE Kimchi, A TI Assessment of cardiac resynchronization therapy by quantitative gated blood pool spect imaging SO ADVANCES IN HEART FAILURE LA English DT Proceedings Paper CT 8th World Congress on Heart Failure - Mechanisms and Management CY JUL 13-16, 2002 CL WASHINGTON, D.C. ID HEART-FAILURE AB Mechanical remodelling of the left ventricle has been demonstrated following cardiac, resynchronization therapy with biventricular pacing in patients with cardiomyopathy primarily by serial echocardiography. Quantitative gated blood pool SPECT imaging provides an alternate technique for accurate serial three-dimensional display of right and left ventricular morphology and wall motion and calculation of right and left ventricular volumes and ejection fractions. Three-dimensional cine loop and quantitative polar motion displays clearly show improved ventricular synchronicity after bi-ventricular pacing in a representative patient with, ischemic cardiomyopathy. Quantitative gated blood pool SPECT imaging provides an accurate non-invasive means of assessment of acute and long term effects of cardiac resynchronization therapy on right and left ventricular function without the window constraints of echocardiocardiography. C1 William S Middleton Mem Vet Adm Med Ctr, Pathol & Lab Med Serv, Madison, WI 53705 USA. RP Russell, DC (reprint author), William S Middleton Mem Vet Adm Med Ctr, Pathol & Lab Med Serv, Madison, WI 53705 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU MEDIMOND S R L PI 40128 BOLOGNA PA VIA MASERATI 5, 40128 BOLOGNA, 00000, ITALY BN 88-323-2713-9 PY 2002 BP 429 EP 433 PG 5 WC Cardiac & Cardiovascular Systems; Surgery; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Surgery GA BX05Y UT WOS:000184146900071 ER PT J AU Brander, C Riviere, Y AF Brander, C Riviere, Y TI Early and late cytotoxic T lymphocyte responses in HIV infection SO AIDS LA English DT Article DE CTL; HIV; specificity; escape; acute infection ID HUMAN-IMMUNODEFICIENCY-VIRUS; CELLULAR IMMUNE-RESPONSES; RAPID DISEASE PROGRESSION; VIRAL LOAD; 1-INFECTED PATIENT; DENDRITIC CELLS; CD8(+); ESCAPE; CTL; CHILDREN C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. Inst Pasteur, URA 1930, Lab Immunopathol Virale, CNRS, F-75015 Paris, France. RP Brander, C (reprint author), Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA USA. NR 62 TC 10 Z9 10 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PY 2002 VL 16 SU 4 BP S97 EP S103 DI 10.1097/00002030-200216004-00014 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 656DT UT WOS:000181594100014 PM 12699006 ER PT J AU Taylor, AN Tio, DL Heng, NS Yirmiya, R AF Taylor, AN Tio, DL Heng, NS Yirmiya, R TI Alcohol consumption attenuates febrile responses to lipopolysaccharide and interieukin-1 beta in male rats SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE alcohol consumption; lipopolysaccharide; interleukin-1 beta; fever; acute-phase response ID TUMOR-NECROSIS-FACTOR; SICKNESS BEHAVIOR; FEVER; INTERLEUKIN-1-BETA; BRAIN; IMMUNE; ETHANOL; CORTICOSTERONE; CONSEQUENCES; ACTIVATION AB Background: Chronic and acute alcohol use exert profound modulatory effects on the immune system which manifest as impaired host defense against infections. An important feature of this response is the interaction between the immune and the central nervous systems. This study investigated the effects of 14 days of alcohol exposure on cytokine-mediated neuroimmune interactions that affect the febrile component of the host-defense response. Methods: Adult male rats were fed a liquid diet containing ethanol (EtOH, 5% w/v) for 14 days. Pair-fed and normal chow- and water-fed rats served as controls. Continuous biotelemetric recordings of body temperature and locomotor activity commencing after 14 days of EtOH feeding were used to determine the effects of chronic EtOH on the circadian pattern of temperature and activity, on the febrile response to intraperitoneal (ip) administration of lipopolysaccharide (LPS) and interleukin (IL)-1beta, and on fever induced by IL-1beta administered intracerebroventricularly. We also examined the effects of EtOH consumption on LPS-induced hypothalamic production of the pyrogenic cytokines IL-1beta and tumor necrosis factor-alpha (TNFalpha) and on the blood levels of IL-1beta, TNFalpha, IL-6. adrenocorticotropin, and corticosterone at 2. 4, and 6 hr after ip LPS. Results: Fourteen days of EtOH consumption blunted the circadian increases in temperature and activity that normally occur in the dark phase of the light/dark cycle without affecting light-phase temperature or activity. EtOH consumption attenuated fever induced by LPS or IL-1beta administered ip during the light phase and significantly reduced hypothalamic production of IL-1beta. LPS-induced increases in hypothalamic TNFalpha and blood cytokines, adrenocorticotropin, and corticosterone were unaffected. Central administration of IL-1beta produced a normal febrile response in chronic-EtOH rats. Conclusions: The attenuated LPS- and IL-1beta-induced febrile responses in EtOH-consuming rats and he corresponding deficit in hypothalamic production of IL-1beta suggest that alcohol may impair IL-1beta-mediated neuroimmune communication. C1 Univ Calif Los Angeles, Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Brain Res Inst, Los Angeles, CA 90095 USA. Vet Affairs Greater Los Angeles Healthcare Syst, W Los Angeles Healthcare ctr, Los Angeles, CA USA. Hebrew Univ Jerusalem, Dept Psychol, IL-91905 Jerusalem, Israel. RP Taylor, AN (reprint author), Univ Calif Los Angeles, Sch Med, Dept Neurobiol, 10833 Le Conte Ave, Los Angeles, CA 90095 USA. RI Yirmiya, Raz/D-1090-2014 FU NIAAA NIH HHS [AA09850] NR 50 TC 15 Z9 15 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 JAN PY 2002 VL 26 IS 1 BP 44 EP 52 PG 9 WC Substance Abuse SC Substance Abuse GA 513FZ UT WOS:000173368400006 PM 11821653 ER PT S AU Shin, Y Cho, HS Rebeck, GW Greenberg, SM AF Shin, Y Cho, HS Rebeck, GW Greenberg, SM BE DeLaTorre, JC Kalaria, R Nakajima, K Nagata, K TI Vascular changes in Iowa-type hereditary cerebral amyloid angiopathy SO ALZHEIMER'S DISEASE: VASCULAR ETIOLOGY AND PATHOLOGY SE Annals of the New York Academy of Sciences LA English DT Article; Proceedings Paper CT 3rd World Congress on Vascular Factors in Alzheimers Disease CY APR 07-10, 2002 CL KYOTO, JAPAN SP Banyu Pharmaceut, Commemorat Assoc Japan World Exposit, Esisai Pharmaceut Co Ltd, Janssen-Kyowa Co, Japan Arteriosclerosis Prevent Fund DE cerebral amyloid angiopathy (CAA); Alzheimer's disease (AD); vascular; beta-amyloid peptide (A beta) ID TRANSGENIC MOUSE MODEL; ALZHEIMERS-DISEASE; COGNITIVE FUNCTION; PRECURSOR PROTEIN; BETA-PROTEIN; DUTCH TYPE; DEMENTIA; INFARCTION; BRAIN; DEGENERATION AB Vascular dysfunction due to cerebral amyloid angiopathy (CAA) may contribute to cognitive impairment. The Iowa D694N amyloid precursor protein mutation, a recently identified cause of hereditary CAA with dementia, offers an opportunity to explore the anatomic basis of CAA-related vascular dysfunction. Examination by immunolabeling and confocal microscopy demonstrated extensive loss of smooth muscle cells in affected segments as well as a perivascular inflammatory reaction of astrocytes and microglia. On 3-D reconstruction, vessels appeared tortuous with twiglike projections that may represent areas of vascular degeneration. The observed changes in the Iowa brain suggest pathophysiologic mechanisms for vascular dysfunction in CAA and possible approaches to treatment of CAA-related cognitive impairment. C1 Massachusetts Gen Hosp, Neurol Clin Trials Unit, Dept Neurol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Alzheimers Res Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Greenberg, SM (reprint author), Massachusetts Gen Hosp, Neurol Clin Trials Unit, Dept Neurol, Wang ACC 836, Boston, MA 02114 USA. EM greenberg@helix.mgh.harvard.edu NR 24 TC 14 Z9 14 U1 0 U2 4 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-441-2 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2002 VL 977 BP 245 EP 251 PG 7 WC Genetics & Heredity; Multidisciplinary Sciences; Clinical Neurology; Neuroimaging; Pathology SC Genetics & Heredity; Science & Technology - Other Topics; Neurosciences & Neurology; Pathology GA BV68J UT WOS:000179767000030 PM 12480757 ER PT J AU Kuhlthau, KA Beal, AC Ferris, TG Perrin, JM AF Kuhlthau, KA Beal, AC Ferris, TG Perrin, JM TI Comparing a diagnosis list with a survey method to identify children with chronic conditions in an urban health center SO AMBULATORY PEDIATRICS LA English DT Article DE children; chronic conditions; definition; diagnoses ID SUPPLEMENTAL SECURITY INCOME; CARE NEEDS; DEFINITION; QUESTIONNAIRE; EXPENDITURES; DISABILITY AB Objective.-To compare a diagnosis list to the Questionnaire for Identifying Children with Chronic Conditions (QuICCC) to assess their relative usefulness as Measures for identifying children with chronic conditions. Methods.-Comparison of health encounter data and survey data for a cohort of 304 children aged 0-18 years at an urban health center affiliated with a teaching hospital. We used 2 strategies to identify children with a chronic condition: 1) identification by the existence of an encounter with an International Classification of Diseases, Ninth Revision code indicating a chronic condition and 2) identification by the QuICCC, We compared the characteristics of children identified by the diagnosis list with those of children identified by the QuICCC. Results.-This Population had high rates of chronic conditions, with 4417( identified by the diagnosis list aid 36% identified by the QuICCC. These 2 methods jointly identified 66% of children, yet only half (53%) of the children who had a diagnosis of a chronic condition in the encounter data were identified by the QuICCC. Asthma, anorexia, developmental delay, and adjustment reaction were among the common chronic conditions for children identified by the diagnosis list approach only. Conclusions.-We found only moderate concordance among the children identified a having chronic conditions by a diagnosis list and by the QuICCC in this high-risk urban population. These different results indicate that encounter data and survey approaches do not serve as simple substitutes for identifying children with chronic conditions for clinical or monitoring purposes. C1 MassGen Hosp Children, Ctr Child & Adolescent Hlth Policy, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Inst Hlth Policy, Div Gen Med, Boston, MA 02114 USA. RP Kuhlthau, KA (reprint author), MassGen Hosp Children, Ctr Child & Adolescent Hlth Policy, 50 Staniford St,Suite 901, Boston, MA 02114 USA. NR 16 TC 27 Z9 27 U1 1 U2 2 PU AMBULATORY PEDIATRIC ASSOC PI MCLEAN PA 6728 OLD MCLEAN VILLAGE DR, MCLEAN, VA 22101-3906 USA SN 1530-1567 J9 AMBUL PEDIATR JI Ambul. Pediatr. PD JAN-FEB PY 2002 VL 2 IS 1 BP 58 EP 62 DI 10.1367/1539-4409(2002)002<0058:CADLWA>2.0.CO;2 PG 5 WC Pediatrics SC Pediatrics GA 549VL UT WOS:000175467400013 PM 11888439 ER PT J AU Gariti, P Alterman, A Mulvaney, F Mechanic, K Dhopesh, V Yu, E Chychula, N Sacks, D AF Gariti, P Alterman, A Mulvaney, F Mechanic, K Dhopesh, V Yu, E Chychula, N Sacks, D TI Nicotine intervention during detoxification and treatment for other substance use. SO AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE LA English DT Article DE smoking cessation; substance abuse; inpatient detoxification ID DEPENDENCE AB This preliminary study evaluated the efficacy of a brief smoking cessation intervention (30 controls, 34 intervention groups) on a smoke-free inpatient unit for substance use detoxification. Controls received usual care, including the transdermal nicotine patch and referral to an outpatient smoking program. The intervention group additionally received a structured motivational enhancement program. Biochemically confirmed smoking cessation rate and abstinence/reduction of alcohol or other drug use were the main outcome measures taken 6 months after treatment initiation. The smoking cessation intervention did not result in greater participation in formal outpatient smoking cessation treatment and was not associated with either enhanced smoking cessation (6 vs. 0%) or greater smoking reduction at follow-up. Both groups significantly reduced the number of cigarettes smoked per day (cpd) from about 24 at baseline to 10 cpd. The groups did not differ on abstinence from nonnicotine addictive substances. Smoking cessation treatment in substance users undergoing detoxification resulted in little or no smoking cessation advantage. C1 Univ Penn, Treatment Res Ctr, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. RP Gariti, P (reprint author), Univ Penn, Treatment Res Ctr, Sch Med, Dept Psychiat, 3900 Chestnut St, Philadelphia, PA 19104 USA. NR 8 TC 6 Z9 6 U1 0 U2 1 PU MARCEL DEKKER INC PI NEW YORK PA 270 MADISON AVE, NEW YORK, NY 10016 USA SN 0095-2990 J9 AM J DRUG ALCOHOL AB JI Am. J. Drug Alcohol Abuse PY 2002 VL 28 IS 4 BP 673 EP 681 DI 10.1081/ADA-120015875 PG 9 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 623NX UT WOS:000179710700006 ER PT J AU Weintraub, JM Willett, WC Rosner, B Colditz, GA Seddon, JM Hankinson, SE AF Weintraub, JM Willett, WC Rosner, B Colditz, GA Seddon, JM Hankinson, SE TI Smoking cessation and risk of cataract extraction among US women and men SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cataract; smoking; smoking cessation ID AGE-RELATED CATARACT; CIGARETTE-SMOKING; LENS OPACITIES; LOGISTIC-REGRESSION; NUCLEAR; FRAMINGHAM; CANCER; INDIA AB Although the observational evidence linking cigarette smoking with risk of senile cataract is well-established, it is unclear whether any benefit is obtained from quitting smoking. Therefore, in this study, the authors examined the association between time since quitting smoking and incidence of cataract extraction in women and men enrolled in the Nurses' Health Study and the Health Professionals Follow-up Study, respectively. There were 4,281 incident physician-confirmed cases of cataract and 1,038,493 accumulated person-years of follow-up. Compared with current smokers, former smokers who had quit smoking 25 or more years previously had a 20% lower risk of cataract extraction after adjustment for age, average number of cigarettes smoked per day, and other potential risk factors (relative risk (RR) = 0.80, 95% confidence interval (Cl): 0.71, 0.91). However, risk among past smokers did not decrease to the level seen among never smokers (for never smokers, RR = 0.64, 95% Cl: 0.52, 0.79). The observed relation was similar when data were examined by cataract subtype (>25 years since quitting vs. current smoking: primarily nuclear cataract, RR = 0.82, 95% Cl: 0.68, 0.97; primarily posterior subcapsular cataract, RR = 0.90, 95% Cl: 0.71, 1.13). These findings suggest that any healing from damage due to cigarette smoking occurs at a very modest pace, and they emphasize the importance of never starting to smoke or quitting early in life. C1 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 Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02115 USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Weintraub, JM (reprint author), Channing Labs, 3rd Floor,181 Longwood Ave, Boston, MA 02115 USA. RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NCI NIH HHS [CA40356]; NEI NIH HHS [EY09611, EY12269]; NIEHS NIH HHS [T32 ES07069] NR 34 TC 25 Z9 25 U1 1 U2 2 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 JAN 1 PY 2002 VL 155 IS 1 BP 72 EP 79 DI 10.1093/aje/155.1.72 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 509GC UT WOS:000173137100011 PM 11772787 ER PT J AU Daskalakis, C Laird, NM Murphy, JM AF Daskalakis, C Laird, NM Murphy, JM TI Regression analysis of multiple-source longitudinal outcomes: A "Stirling County" depression study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE data interpretation; statistical; depression; epidemiologic methods; longitudinal studies; multivariate analysis ID NATIONAL-COMORBIDITY-SURVEY; PSYCHIATRIC-DISORDERS; MAJOR DEPRESSION; PREVALENCE; EPIDEMIOLOGY; RESPONSES; LIFETIME; SEX AB Epidemiologic studies of psychiatric disorders have increasingly relied on multiple sources of information to improve the validity of diagnoses and repeated assessments over time to provide a longitudinal perspective. In this paper, the authors present a general multivariate logistic regression method for the simultaneous analysis of discrete outcomes that exhibit such features. This approach permits risk factor and agreement analyses within a unified framework and appropriately uses data from subjects who may be missing some outcomes. The authors use this approach to analyze data from a "Stirling County" study of depression. During a 3- to 4-year period in the early 1990s, 631 subjects were assessed in two separate interviews, on each occasion with two diagnostic schedules (the DePression and AnXiety schedule (DPAX) and the Diagnostic Interview Schedule (DIS)). The female:male ratio of depression was found to be different for the DPAX and the DIS (0.8 and 1.6, respectively). Education was inversely associated with depression, while the effects of time, the subject's age, and the interviewers sex were essentially null. With respect to the outcomes' association, agreement between the DPAX and the DIS was low. In addition, stability of the DPAX over time was significantly higher than that of the DIS. No covariates were found to affect significantly the association between outcomes. C1 Thomas Jefferson Univ, Div Clin Pharmacol, Biostat Sect, Philadelphia, PA 19107 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Daskalakis, C (reprint author), Thomas Jefferson Univ, Div Clin Pharmacol, Biostat Sect, 125 S 9th St 402, Philadelphia, PA 19107 USA. FU NIMH NIH HHS [R01 MH39756, R01 MH54693] NR 28 TC 7 Z9 7 U1 0 U2 0 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 JAN 1 PY 2002 VL 155 IS 1 BP 88 EP 94 DI 10.1093/aje/155.1.88 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 509GC UT WOS:000173137100013 PM 11772789 ER PT J AU Montgomery, E Bronner, MP Greenson, JK Haber, MM Hart, J Lamps, LW Lauwers, GY Lazenby, AJ Lewin, DN Robert, ME Washington, K Goldblum, JR AF Montgomery, E Bronner, MP Greenson, JK Haber, MM Hart, J Lamps, LW Lauwers, GY Lazenby, AJ Lewin, DN Robert, ME Washington, K Goldblum, JR TI Are ulcers a marker for invasive carcinoma in Barrett's esophagus? Data from a diagnostic variability study with clinical follow-up SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article; Proceedings Paper CT 6th World Congress of the International Organization for Statisical Studies on Diseases of the Esophagus CY SEP, 2000 CL PARIS, FRANCE ID HIGH-GRADE DYSPLASIA; ENDOSCOPIC BIOPSY PROTOCOL; ADENOCARCINOMA; CANCER; RISK AB OBJECTIVES: We correlated follow-up information from 138 patients with Barrett's esophagus and varying degrees of dysplasia with the presence of ulcers. METHODS: A group of pathologist participants were asked to contribute patients' initial biopsy slides showing Barrett's esophagus (BE) without dysplasia and with epithelial changes indefinite for dysplasia, low grade dysplasia (LGD), high grade dysplasia (HGD), and adenocarcinoma. From the initial 250 cases used for a diagnostic reproducibility study, follow-up information was available for 138 patients. RESULTS: There were 44 cases submitted as BE, 22 as BE with epithelial changes indefinite for dysplasia, 26 as BE with LGD, 33 as BE with HGD, and 13 as BE with adenocarcinoma. Ulcers were present in 35/138 cases (25%), including 3/44 cases of BE without dysplasia (7%), 2/22 cases of BE with epithelial changes indefinite for dysplasia (9%), 0/26 cases of BE with LGD (0%), 10/33 cases of BE with HGD (30%), and 7/13 cases of BE with adenocarcinoma (54%). On follow-up, there were no invasive carcinomas detected among the BE without dysplasia group (median follow-up = 38.5 months). Adenocarcinomas were detected in 4/22 cases (18%) submitted as BE with epithelial changes indefinite for dysplasia at 19, 55, 60, and 62 months and in 4/26 cases (15%) of BE with LGD at 9, 9, 11, and 60 months. None of these carcinomas occurred in cases in which an ulcer was present in the initial biopsy specimen. Among the 33 HGD cases, 20 (60%) were found to have adenocarcinoma on subsequent resection specimens. The presence of an ulcer with HGD increased the likelihood of finding carcinoma in the resection specimen, as 8/10 biopsies (80%) of HGD patients with ulcers had carcinoma, compared to 12/23 biopsies (52%) of HGD patients without ulcers. All of the cases interpreted as adenocarcinomas on biopsy were found either to have invasive carcinoma on esophageal resection or to have metastases that were demonstrated in unresectable patients. CONCLUSION: If an ulcer accompanies HGD in a biopsy specimen from a patient with BE, it is likely that invasive carcinoma is also present at that time. (Am J Gastroenterol 2002;97: 27-31. (C) 2002 by Am. Coll. of Gastroenterology). C1 Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21205 USA. Univ Washington, Dept Pathol, Seattle, WA 98195 USA. Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. MCP Hahnemann Univ, Dept Pathol, Philadelphia, PA USA. Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. Univ Arkansas, Dept Pathol, Fayetteville, AR 72701 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. Med Univ S Carolina, Dept Pathol, Charleston, SC 29425 USA. Yale Univ, Dept Pathol, New Haven, CT USA. Vanderbilt Univ, Dept Pathol, Nashville, TN USA. Cleveland Clin Fdn, Dept Pathol, Cleveland, OH 44195 USA. RP Montgomery, E (reprint author), Johns Hopkins Univ, Dept Pathol, Ross 632,720 Rutland Ave, Baltimore, MD 21205 USA. NR 16 TC 30 Z9 32 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD JAN PY 2002 VL 97 IS 1 BP 27 EP 31 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 512CW UT WOS:000173304400006 PM 11808966 ER PT J AU Sorensen, G Emmons, K Stoddard, AM Linnan, L Avrunin, J AF Sorensen, G Emmons, K Stoddard, AM Linnan, L Avrunin, J TI Do social influences contribute to occupational differences in quitting smoking and attitudes toward quitting? SO AMERICAN JOURNAL OF HEALTH PROMOTION LA English DT Article DE worksites; social influences; social norms; smoking ID CIGARETTE-SMOKING; UNITED-STATES; CESSATION; WORKSITE AB Purpose. To examine occupational differences in social influences supporting quitting smoking and their relationships to intentions and self-efficacy to quit smoking and to quitting. Design. Data were collected as part of a large worksite cancer prevention intervention trial. Setting. Forty-four worksites, Subjects. Subjects included 2626 smokers from a total baseline survey sample of 11,456 employers (response rate = 63%). Measures. Differences by job category in social support for quitting, Pressure to quit smoking rewards for quitting, and nonacceptability of smoking were measured using mixed model analysis of variance and the Cochran-Mantel-Haenszel test, Their association to self-efficacy, intention to quit, and quitting smoking was assessed using mixed model analysis of variance and linear logistic regression modeling. Results. Compared with other workers, blue-collar workers reported less pressure to quit (p =.0001), social support for quitting (p =. 0001), and nonacceptability of smoking among their coworkers (p <.001). Intention to quit was associated with higher levels of social pressure to quit smoking (p =.0001) and social support for quitting (p =.002). Self-efficacy was associated with social pressure to quit (p =.0001), social support for quitting (p =. 004), and perceiving greater rewards for quitting (p =. 0001). Conclusions. Although these results are limited somewhat by response and attrition rates, these, results suggest that differing social environments may contribute to the differences by occupational category in smoking prevalence and smoking cessation. C1 Dana Farber Canc Inst, Ctr Community Based Res, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Sch Publ Hlth, Dept Hlth & Social Behav, Boston, MA USA. Univ Massachusetts, Sch Publ Hlth & Human Sci, Amherst, MA 01003 USA. Brown Univ, Miriam Hosp, Providence, RI USA. RP Sorensen, G (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [P0I CA50087, UO1 CA51686] NR 23 TC 62 Z9 62 U1 1 U2 4 PU AMER J HEALTH PROMOTION INC PI KEEGO HARBOR PA 1660 CASS LAKE RD, STE 104, KEEGO HARBOR, MI 48320 USA SN 0890-1171 J9 AM J HEALTH PROMOT JI Am. J. Health Promot. PD JAN-FEB PY 2002 VL 16 IS 3 BP 135 EP 141 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 513FR UT WOS:000173367700002 PM 11802258 ER PT J AU Street, VA Goldy, JD Golden, AS Tempel, BL Bird, TD Chance, PF AF Street, VA Goldy, JD Golden, AS Tempel, BL Bird, TD Chance, PF TI Mapping of Charcot-Marie-Tooth disease type 1C to chromosome 16p identifies a novel locus for demyelinating neuropathies SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID HEREDITARY MOTOR; GENE; DUPLICATION; MUTATIONS; PMP-22; PROTEIN-2; LINKAGE; FAMILY AB Charcot-Marie-Tooth (CMT) neuropathy represents a genetically heterogeneous group of diseases affecting the peripheral nervous system. We report genetic mapping of the disease to chromosome 16p13.1-p12.3, in two families with autosomal dominant CMT type 1C (CMT1C). Affected individuals in these families manifest characteristic CMT symptoms, including high-arched feet, distal muscle weakness and atrophy, depressed deep-tendon reflexes, sensory impairment, slow nerve conduction velocities, and nerve demyelination. A maximal combined LOD score of 14.25 was obtained with marker D16S500. The combined haplotype analysis in these two families localizes the CMT1C gene within a 9-cM interval flanked by markers D16S519 and D16S764. The disease-linked haplotypes in these two pedigrees are not conserved, suggesting that the gene mutation underlying the disease in each family arose independently. The epithelial membrane protein 2 gene (EMP2), which maps to chromosome 16p13.2, was evaluated as a candidate gene for CMT1C. C1 Univ Washington, Dept Pediat, Div Genet & Dev, Seattle, WA 98195 USA. Univ Washington, Dept Neurol, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Washington, VM Bloedel Hearing Res Ctr, Dept Otolaryngol Head & Neck Surg, Seattle, WA 98195 USA. Univ Washington, Undergrad Neurobiol Res Program, Seattle, WA 98195 USA. VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Chance, PF (reprint author), Univ Washington, Dept Pediat, Div Genet & Dev, Box 356320, Seattle, WA 98195 USA. FU NIA NIH HHS [T32 AG000057, AG00057]; NICHD NIH HHS [P30 HD002274, HD02274]; NIDCD NIH HHS [R01 DC002739, DC02739]; NINDS NIH HHS [R01 NS038181, NS38181] NR 36 TC 22 Z9 28 U1 1 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JAN PY 2002 VL 70 IS 1 BP 244 EP 250 DI 10.1086/337943 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 499LD UT WOS:000172571900022 PM 11713717 ER PT J AU Hand, CK Khoris, J Salachas, F Gros-Louis, F Lopes, AAS Mayeux-Portas, V Brown, RH Meininger, V Camu, W Rouleau, GA AF Hand, CK Khoris, J Salachas, F Gros-Louis, F Lopes, AAS Mayeux-Portas, V Brown, RH Meininger, V Camu, W Rouleau, GA TI A novel locus for familial amyotrophic lateral sclerosis, on chromosome 18q SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MANGANESE SUPEROXIDE-DISMUTASE; SPINAL MUSCULAR-ATROPHY; MOTOR-NEURON DISEASE; TRANSGENIC MICE; MUTANT MICE; LINKAGE; GENE; MUTATIONS; DEMENTIA; PARKINSONISM AB Amyotrophic lateral sclerosis (ALS) is an adult-onset degenerative disorder characterized by the death of motor neurons in the cortex, brain stem, and spinal cord. Despite intensive research the basic pathophysiology of ALS remains unclear. Although most cases are sporadic, similar to 10% of ALS cases are familial (FALS). Mutations in the Cu/Zn superoxide dismutase (SOD1) gene cause similar to 20% of FALS. The gene(s) responsible for the remaining 80% of FALS remain to be found. Using a large European kindred without SOD1 mutation and with classic autosomal dominant adult-onset ALS, we have identified a novel locus by performing a genome scan and linkage analysis. The maximum LOD score is 4.5 at recombination fraction 0.0, for polymorphism D18S39. Haplotype analysis has identified a 7.5-cM, 8-Mb region of chromosome 18q21, flanked by markers D18S846 and D18S1109, as a novel FALS locus. C1 McGill Univ, Ctr Res Neurosci, Montreal, PQ H3A 2T5, Canada. Montreal Gen Hosp, Res Inst, Montreal, PQ H3G 1A4, Canada. Hop Gui De Chauliac, Dept Neurol, Montpellier, France. Hop Gui De Chauliac, Inst Biol, INSERM,V336, UNCD Mol Unit, Montpellier, France. Hop La Pitie Salpetriere, Div Mazarin, Serv Neurol, Paris, France. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Rouleau, GA (reprint author), Montreal Gen Hosp L7 224, 1650 Cedar Ave, Montreal, PQ H3G 1A4, Canada. NR 35 TC 80 Z9 84 U1 1 U2 6 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JAN PY 2002 VL 70 IS 1 BP 251 EP 256 DI 10.1086/337945 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 499LD UT WOS:000172571900023 PM 11706389 ER PT J AU Lindner, A Bankson, DD Stehman-Breen, C Mahuren, JD Coburn, SP AF Lindner, A Bankson, DD Stehman-Breen, C Mahuren, JD Coburn, SP TI Vitamin B-6 metabolism and homocysteine in end-stage renal disease and chronic renal insufficiency SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article; Proceedings Paper CT 32nd Annual Meeting of the American-Society-of-Nephrology CY NOV 01-08, 1999 CL MIAMI, FLORIDA SP Amer Soc Nephrol DE pyridoxic acid (PA); pyridoxin; homocysteine (tHcy); kidney; uremia ID PLASMA HOMOCYSTEINE; FOLIC-ACID; DIALYSIS PATIENTS; CARDIOVASCULAR-DISEASE; PYRIDOXAL 5'-PHOSPHATE; HEMODIALYSIS-PATIENTS; ALKALINE-PHOSPHATASE; RISK FACTOR; HYPERHOMOCYSTEINEMIA; FAILURE AB Homocysteine (tHcy) is a risk factor for atherosclerosis inpatients with end-stage renal disease and chronic renal insufficiency (CRI). Vitamin B-6 deficiency may result in high tHcy levels, especially after a methionine load (PML). Therefore, we evaluated vitamin B-6 metabolism and tHcy (fasting and PML) levels in patients with CRI and those on hemodialysis (HD) therapy before and during high-dose sequential vitamin B-6 and folic acid supplementation in mate patients (27 patients, HD, 17 patients, CRI) and 19 age-matched healthy controls. Vitamin B-6 doses were 100 mg/d in patients with CRI and 200 mg/d in HD patients, plus folic acid (5 mg/d), for more than 3 months in each period. We analyzed vitamin B-6 metabolites by high-performance liquid chromatography In plasma and red blood cells (RBCs) and fasting tHcy in all cases and PML in subgroups of 11 HD patients and 14 patients with CRI. We found vitamin 136 deficiency and high tHcy (fasting and PML) levels in all patients. Plasma and RBC levels of pyridoxal and pyridoxal phosphate were abnormally low, whereas levels of pyridoxic acid (PA), an end product of vitamin B-6 metabolism, were extremely high in both groups. Fasting and PML tHcy levels were partially resistant to vitamin B-6 supplements, with different response patterns In HD patients and those with CRI. Thus, the PML defect was more responsive to folic acid in HD patients, whereas vitamin B-6 partially reduced PML tHcy levels in patients with CRI. Resistance of tHcy to vitamin B6 treatment in patients with CRI and HD patients Is not caused by poor absorption or low tissue stores. Rather, nonvitamin factors or potentially toxic PA levels may be implicated in abnormal vitamin B-6 and/or tHcy metabolism during renal insufficiency. (C) 2002 by the National Kidney Foundation, Inc. C1 Univ Washington, Vet Affairs Puget Sound Hlth Care Syst, Dept Med Nephrol, Seattle, WA 98195 USA. Univ Washington, Vet Affairs Puget Sound Hlth Care Syst, Dept Lab Med, Seattle, WA 98195 USA. Ft Wayne State Dev Ctr, Dept Biochem, Ft Wayne, IN USA. RP Lindner, A (reprint author), VA Puget Sound Hlth Care Syst, Renal Dialysis Unit, 1660 S Columbian Way, Seattle, WA 98108 USA. FU NIDDK NIH HHS [DK 35816] NR 40 TC 22 Z9 23 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 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JAN PY 2002 VL 39 IS 1 BP 134 EP 145 DI 10.1053/ajkd.2002.29904 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 509HU UT WOS:000173141700018 PM 11774112 ER PT J AU Sasaki, H Roberts, J Lykins, D Fujii, Y Auclair, D Chen, LB AF Sasaki, H Roberts, J Lykins, D Fujii, Y Auclair, D Chen, LB TI Novel chemiluminescence assay for serum periostin levels in women with preeclampsia and in normotensive pregnant women SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE periostin; preeclampsia; cell adhesion; transforming growth factor-beta 1; alternative splicing ID CELL-ADHESION MOLECULE-1; GROWTH-FACTOR-BETA; NECROSIS-FACTOR-ALPHA; SEQUENCE-ANALYSIS; LAMININ LEVELS; FASCICLIN-I; S-LAMININ; EXPRESSION; PROTEIN; ACTIVATION AB OBJECTIVE: We recently developed a novel sandwich chemiluminescence assay to determine serum concentrations of periostin. Periostin has high amino acid homology with transforming growth factor-beta-induced protein betaigh3, a molecule induced by transforming growth factor-beta(1), which promotes the adhesion and spreading of fibroblasts. It is also homologous with the insect cell adhesion molecule fasciclin 1. We determined serum periostin concentrations in women with preeclampsia and in normotensive pregnant women. STUDY DESIGN: The study groups included 30 women with preeclampsia and 30 normotensive pregnant women at Magee-Womens Hospital. Blood samples collected from these women were assayed for periostin by use of newly developed monoclonal and polyclonal antibodies. We studied periostin messenger ribonucleic acid (mRNA) expression in human tissues by using reverse transcriptase-polymerase chain reaction and in situ hybridization. RESULTS: Serum periostin concentrations were elevated in patients with preeclampsia (mean +/- SD, 311.8 +/- 56.3 ng/mL) compared with normotensive pregnant women (218.8 +/- 37.3 ng/mL), No correlation was found between serum concentrations of perostin and concentrations of TGF-beta(1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and interleukin-6. Reverse transcriptase-polymerase chain reaction analysis demonstrated human periostin expression in lung, kidney, and placenta but not in the heart, liver, brain, or skeletal muscle. For periostin complementary deoxyribonucleic acid cloned from placenta, there was a splicing deletion within the C-terminal domain. In situ hybridization data showed that the periostin gene was expressed in the stroma cells of placenta. CONCLUSION: Our study suggests that human periostin may play a role in the pathogenesis of preeclampsia. Although its function remains unclear, the expression of periostin as an adhesion molecule could suggest novel mechanisms in preeclampsia. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Univ Pittsburgh, Magee Womens Res Inst, Pittsburgh, PA USA. Univ Pittsburgh, Dept Obstet & Gynecol & Reprod Sci, Pittsburgh, PA USA. Nagoya City Univ, Sch Med, Dept Surg 2, Nagoya, Aichi 467, Japan. RP Chen, LB (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. NR 38 TC 14 Z9 14 U1 1 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2002 VL 186 IS 1 BP 103 EP 108 DI 10.1067/mob.2002.118157 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 515PU UT WOS:000173505200019 PM 11810094 ER PT J AU Coraci, IS Husemann, J Berman, JW Hulette, C Dufour, JH Campanella, GK Luster, AD Silverstein, SC El Khoury, JB AF Coraci, IS Husemann, J Berman, JW Hulette, C Dufour, JH Campanella, GK Luster, AD Silverstein, SC El Khoury, JB TI CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID TRANSGENIC MICE; HUMAN-MONOCYTES; BASEMENT-MEMBRANE; CELLS; PROTEIN; MACROPHAGES; ACTIVATION; THROMBOSPONDIN-1; CYTOADHERENCE; ERYTHROCYTES AB A pathological hallmark of Alzheimer's disease is the senile plaque, composed of beta-amyloid fibrils, microglia, astrocytes, and dystrophic neurites. We reported previously that class A scavenger receptors mediate adhesion of microglia and macrophages to beta-amyloid fibrils and oxidized low-density lipoprotein (oxLDL)coated surfaces. We also showed that CD36, a class B scavenger receptor and an oxLDL receptor, promotes H2O2 secretion by macrophages adherent to oxLDL-coated surfaces. Whether CD36 is expressed on microglia, and whether it plays a role in secretion of H2O2 by microglia interacting with fibrillar beta-amyloid is not known. Using fluorescence-activated cell sorting analysis and immunohistochemistry, we found that CD36 is expressed on human fetal microglia, and N9-immortalized mouse microglia. We also found that CD36 Is expressed on microglia and on vascular endothelial cells in the brains of Alzheimer's disease patients. Bowes human melanoma cells, which normally do not express CD36, gained the ability to specifically bind to surfaces coated with fibrillar beta-amyloid when transfected with a cDNA encoding human CD36, suggesting that CD36 is a receptor for fibrillar beta-amyloid. Furthermore, two different monoclonal antibodies to CD36 Inhibited H2O2, production by N9 microglia and human macrophages adherent to fibrillar beta-amyloid by similar to50%. Our data identify a role for CD36 in fibrillar beta-amyloid-induced H2O2 production by microglia, and imply that CD36 can mediate binding to fibrillar beta-amyloid. We propose that similar to their role in the interaction of macrophages with oxLDL, class A scavenger receptors and CD36 play complimentary roles in the interactions of microglia with fibrillar beta-amyloid. C1 Columbia Univ Coll Phys & Surg, Dept Physiol & Cellular Biophys, New York, NY 10032 USA. Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10467 USA. Bryan Alzheimer Dis Res Ctr, Durham, NC USA. Duke Univ, Med Ctr, Udall Parkinson Ctr Excellence, Durham, NC USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Infect Dis Div, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. RP El Khoury, JB (reprint author), Massachusetts Gen Hosp E, Ctr Immunol & Inflammatory Dis, Room 8301,CNY Bldg 149,13th St, Charlestown, MA 02129 USA. FU NHLBI NIH HHS [F32 HL010196]; NIA NIH HHS [P50 AG005138, P01 AG002219, P01-AG02219, P50-AG05138]; NIAID NIH HHS [R37 AI020516, R37-AI 20516]; NINDS NIH HHS [K08 NS041330, NS041330] NR 53 TC 215 Z9 224 U1 1 U2 14 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 JAN PY 2002 VL 160 IS 1 BP 101 EP 112 DI 10.1016/S0002-9440(10)64354-4 PG 12 WC Pathology SC Pathology GA 510XC UT WOS:000173231700014 PM 11786404 ER PT J AU Cario, E Brown, D McKee, M Lynch-Devaney, K Gerken, G Podolsky, DK AF Cario, E Brown, D McKee, M Lynch-Devaney, K Gerken, G Podolsky, DK TI Commensal-associated molecular patterns induce selective toll-like receptor-trafficking from apical membrane to cytoplasmic compartments in polarized intestinal epithelium SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID CELL WALL COMPONENTS; INNATE IMMUNE-SYSTEM; BACTERIAL LIPOPOLYSACCHARIDE; CUTTING EDGE; BARRIER FUNCTION; ENDOTOXIN; RECOGNITION; LOCALIZATION; MACROPHAGES; ESCHERICHIA AB Commensal-associated molecular patterns, the major products of nonpathogenic bacteria, are present at high concentrations at the apical surface of the intestinal epithelium. However, the nature of the interaction of commensal-associated molecular patterns with the lumenal surface of the epithelium has not been defined. We have recently demonstrated that intestinal epithelial cells constitutively express several Toll-like receptors (TLRs) in vitro and in vivo that seem to be the key receptors responsible for immune cell activation in response to various bacterial products. In this study we characterize the subcellular distribution of two major TLRs, TLR2 and TLR4, and their ligand-specific dynamic regulation in the model human intestinal epithelial cell fine T84. Immunocytochemical studies indicate that TLR2 and TLR4 are constitutively expressed at the apical pole of differentiated T84 cells. After stimulation with lipopolysaccharide or peptidoglycan, TLRs selectively traffic to cytoplasmic compartments near the basolateral membrane. Thus, we demonstrate that TLRs are positioned at the apical pole where they are poised to monitor the sensitive balance of the lumenal microbial array. The results of this dynamic epithelial surveillance can then be conveyed to the underlying cell populations of the lamina propria via these innate immune pattern recognition receptors. C1 Harvard Univ, Gastrointestinal Unit GRJ 719, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Membrane Biol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Renal Unit, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Study Inflammatory Bowel Dis, Boston, MA USA. Univ Essen Gesamthsch, Div Gastroenterol & Hepatol, Essen, Germany. RP Podolsky, DK (reprint author), Harvard Univ, Gastrointestinal Unit GRJ 719, Massachusetts Gen Hosp, Sch Med, 55 Fruit St, Boston, MA 02114 USA. FU NIDDK NIH HHS [DK 41557, DK 38452, DK 43351, P01 DK038452, P30 DK043351, R01 DK041557, R37 DK041557] NR 37 TC 209 Z9 222 U1 1 U2 8 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 JAN PY 2002 VL 160 IS 1 BP 165 EP 173 DI 10.1016/S0002-9440(10)64360-X PG 9 WC Pathology SC Pathology GA 510XC UT WOS:000173231700020 PM 11786410 ER PT J AU Senger, DR Perruzzi, CA Streit, M Koteliansky, VE de Fougerolles, AR Detmar, M AF Senger, DR Perruzzi, CA Streit, M Koteliansky, VE de Fougerolles, AR Detmar, M TI The alpha(1)beta(1) and alpha(2)beta(1) Integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID PERMEABILITY FACTOR; BLOOD-VESSELS; ALPHA(V) INTEGRINS; FACTOR ACTIVATION; TUBE FORMATION; MAP KINASE; TRANSDUCTION; ADHESION; MECHANISM; SURVIVAL AB Angiogenesis is a complex process, involving functional cooperativity between cytokines and endothelial cell (EC) surface integrins. in this study, we investigated the mechanisms through which the alpha(1)beta(1) and alpha(2)beta(1) integrins support angiogenesis driven by vascular endothelial growth factor (VEGF). Dermal microvascular EC attachment through either alpha(1)beta(1) or alpha(2)beta(1) supported robust VEGF activation of the Erk1/Erk2 (p44/42) mitogen-activated protein kinase signal transduction pathway that drives EC proliferation. Haptotactic EC migration toward collagen I was dependent on alpha(1)beta(1) and alpha(2)beta(1) as was VEGF-stimulated chemotaxis of ECs in a uniform collagen matrix. Consistent with the functions of alpha(1)beta(1) and alpha(2)beta(1) in supporting signal transduction and EC migration, antibody antagonism of either Integrin resulted in potent Inhibition of VEGF-driven angiogenesis in mouse skin. Moreover, combined antagonism of alpha(1)beta(1), and alpha(2)beta(1) substantially reduced tumor growth and angiogenesis of human squamous cell carcinoma xenografts. Collectively, these studies identify critical collaborative functions for the alpha(1)beta(1) and alpha(2)beta(1) integrins in supporting VEGF signal transduction, EC migration, and tumor angiogenesis. C1 Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. 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. Biogen Inc, Cambridge, MA 02142 USA. RP Senger, DR (reprint author), Beth Israel Deaconess Med Ctr, Dept Pathol, 99 Brookline Ave, Boston, MA 02215 USA. FU NCI NIH HHS [CA86410, CA77357, R01 CA077357, R01 CA086410, R01 CA069184, CA69184] NR 48 TC 186 Z9 194 U1 0 U2 10 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 JAN PY 2002 VL 160 IS 1 BP 195 EP 204 DI 10.1016/S0002-9440(10)64363-5 PG 10 WC Pathology SC Pathology GA 510XC UT WOS:000173231700023 PM 11786413 ER PT J AU Million, M Maillot, C Saunders, P Rivier, J Vale, W Tache, Y AF Million, M Maillot, C Saunders, P Rivier, J Vale, W Tache, Y TI Human urocortin II, a new CRF-related peptide, displays selective CRF2-mediated action on gastric transit in rats SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE partial restraint; gastric emptying; distal colonic transit; CP-154,526; astressin(2)-B ID CORTICOTROPIN-RELEASING FACTOR; FACTOR RECEPTORS; BINDING-PROTEIN; NERVOUS-SYSTEM; GUINEA-PIG; ANTAGONIST; HORMONE; STRESS; ANTISAUVAGINE-30; RESPONSES AB Human urocortin (hUcn) II is a new member of the corticotropin-releasing factor (CRF) family that selectively binds to the CRF2 receptor. We investigated the CRF receptors involved in mediating the effects of hUcn II and human/rat CRF (h/rCRF) on gut transit. Gastric emptying, 4 h after a solid meal, and distal colonic transit (bead expulsion time) were monitored simultaneously in conscious rats. CRF antagonists were given subcutaneously 30 min before intravenous injection of peptides or partial restraint (for 90 min). hUcn II (3 or 10 mug/kg iv) inhibited gastric emptying (by 45% and 55%, respectively) and did not influence distal colonic transit. The CRF2 peptide antagonist astressin(2)-B blocked hUcn II action. h/rCRF, rat Ucn, and restraint delayed gastric emptying while accelerating distal colonic transit. The gastric response to intravenous h/rCRF and restraint was blocked by the CRF2 antagonist but not by the CRF1 antagonist CP-154,526, whereas the colonic response was blocked only by CP-154,526. None of the CRF antagonists influenced postprandial gut transit. These data show that intravenous h/rCRF and restraint stress-induced delayed gastric emptying involve CRF2 whereas stimulation of distal colonic transit involves CRF1. The distinct profile of hUcn II, only on gastric transit, is linked to its CRF2 selectivity. C1 Univ Calif Los Angeles, CURE, Dept Med, Div Digest Dis, Los Angeles, CA 90073 USA. Vet Affairs Greater Los Angeles Healthcare Syst, CURE, Digest Dis Res Ctr, Los Angeles, CA 90073 USA. Salk Inst Biol Studies, Clayton Fdn Labs Peptide Biol, San Diego, CA 92186 USA. RP Million, M (reprint author), Univ Calif Los Angeles, CURE, Dept Med, Div Digest Dis, Bldg 115,Rm 203,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. FU NIDDK NIH HHS [DK-26741, DK-41301, DK-57238] NR 40 TC 56 Z9 57 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 JAN PY 2002 VL 282 IS 1 BP G34 EP G40 PG 7 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 505PN UT WOS:000172922700005 PM 11751155 ER PT J AU Frazier, JA Doyle, R Chiu, SF Coyle, JT AF Frazier, JA Doyle, R Chiu, SF Coyle, JT TI Treating a child with Asperger's disorder and comorbid bipolar disorder SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID PERVASIVE DEVELOPMENTAL DISORDERS; FAMILY HISTORY; RISPERIDONE TREATMENT; AUTISTIC-CHILDREN; INFANTILE-AUTISM; SYMPTOMS; TWIN; ADOLESCENTS; INDIVIDUALS; PREVALENCE C1 Harvard Univ, Sch Med, Consolidated Dept Psychiat, Boston, MA USA. Massachusetts Gen Hosp, McLean Div, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Coyle, JT (reprint author), McLean Hosp, 115 Mill St, Belmont, MA 02478 USA. FU NIMH NIH HHS [MH-01573] NR 46 TC 32 Z9 32 U1 4 U2 11 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JAN PY 2002 VL 159 IS 1 BP 13 EP 21 DI 10.1176/appi.ajp.159.1.13 PG 9 WC Psychiatry SC Psychiatry GA 508FZ UT WOS:000173079200005 PM 11772683 ER PT J AU Biederman, J Mick, E Faraone, SV Braaten, E Doyle, A Spencer, T Wilens, TE Frazier, E Johnson, MA AF Biederman, J Mick, E Faraone, SV Braaten, E Doyle, A Spencer, T Wilens, TE Frazier, E Johnson, MA TI Influence of gender on attention deficit hyperactivity disorder in children referred to a psychiatric clinic SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID DSM-III-R; DEFICIT/HYPERACTIVITY DISORDER; LEARNING-DISABILITIES; ADHD; COMORBIDITY; ADOLESCENTS; FAMILY; INTERVIEW; PATTERNS; SAMPLE AB Objective: The substantial discrepancy in the male-to-female ratio between clinic-referred (10 to 1) and community (3 to 1) samples of children with attention deficit hyperactivity disorder (ADHD) suggests that gender differences may be operant in the phenotypic expression of ADHD. In this study the authors systematically examined the impact of gender on the clinical features of ADHD in a group of children referred to a clinic. Method: The study included 140 boys and 140 girls with ADHD and 120 boys and 122 girls without ADHD as comparison subjects. All subjects were systematically assessed with structured diagnostic interviews and neuropsychological batteries for subtypes of ADHD as well as emotional, school, intellectual, interpersonal, and family functioning. Results: Girls with ADHD were more likely than boys to have the predominantly inattentive type of ADHD, less likely to have a learning disability, and less likely to manifest problems in school or in their spare time. in addition, girls with ADHD were at less risk for comorbid major depression, conduct disorder, and oppositional defiant disorder than boys with ADHD. A statistically significant gender-by-ADHD interaction was identified for comorbid substance use disorders as well. Conclusions: The lower likelihood for girls to manifest psychiatric, cognitive, and functional impairment than boys could result in gender-based referral bias unfavorable to girls with ADHD. C1 Harvard Univ, Pediat Psychopharmacol Unit, Massachusetts Gen Hosp, Sch Med,Child Psychiat Serv, Boston, MA 02114 USA. RP Biederman, J (reprint author), Harvard Univ, Pediat Psychopharmacol Unit, Massachusetts Gen Hosp, Sch Med,Child Psychiat Serv, WACC 725,15 Parkman St, Boston, MA 02114 USA. OI Mick, Eric/0000-0001-8505-8145; Faraone, Stephen/0000-0002-9217-3982 FU NICHD NIH HHS [HD-36317]; NIMH NIH HHS [MH-50657] NR 31 TC 336 Z9 341 U1 7 U2 39 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JAN PY 2002 VL 159 IS 1 BP 36 EP 42 DI 10.1176/appi.ajp.159.1.36 PG 7 WC Psychiatry SC Psychiatry GA 508FZ UT WOS:000173079200009 PM 11772687 ER PT J AU Keel, PK Dorer, DJ Eddy, KT Delinsky, SS Franko, DL Blais, MA Keller, MB Herzog, DB AF Keel, PK Dorer, DJ Eddy, KT Delinsky, SS Franko, DL Blais, MA Keller, MB Herzog, DB TI Predictors of treatment utilization among women with anorexia and bulimia nervosa SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article AB Objective: The authors sought predictors of treatment utilization among women with eating disorders. Method: Women diagnosed with either anorexia or bulimia nervosa (N=246) completed prospective evaluations of eating disorder status, comorbid disorders, global assessment of functioning, and treatment utilization. Results: Women with anorexia nervosa received significantly more inpatient treatment than did women with bulimia nervosa. Predictors of treatment utilization included lower global assessment of functioning scores and presence of personality disorders. Conclusions: Women with more severe pathology have higher treatment utilization rates. This pattern may explain the seeming lack of treatment efficacy for eating disorders outside of randomized controlled studies. C1 Harvard Univ, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. RP Keel, PK (reprint author), Harvard Univ, 1570 William James Hall,33 Kirkland St, Cambridge, MA 02138 USA. FU NIMH NIH HHS [MH-38333] NR 7 TC 44 Z9 44 U1 0 U2 1 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JAN PY 2002 VL 159 IS 1 BP 140 EP 142 DI 10.1176/appi.ajp.159.1.140 PG 3 WC Psychiatry SC Psychiatry GA 508FZ UT WOS:000173079200027 PM 11772705 ER PT J AU Schwartz, RS Olds, J AF Schwartz, RS Olds, J TI A phenomenology of closeness and its application to sexual boundary violations: A framework for therapists in training SO AMERICAN JOURNAL OF PSYCHOTHERAPY LA English DT Article ID MISCONDUCT; PSYCHOTHERAPY; BOARD AB Sexual boundary violations remain a persistent problem in psychiatry despite increased attention, disciplinary activity, and educational efforts. Currently, therapists in training are often overwhelmed by a sense of danger in every direction, including the risk of false accusation. The authors present a framework for understanding experiences of closeness that can help overcome a trainee's paralyzing bewilderment and attendant longing to retreat from the practice of psychotherapy. Eight characteristics of ordinary psychotherapeutic engagement effectively maximize the intensity of interpersonal closeness between patient and psychotherapist while simultaneously reducing the experience of closeness outside the treatment setting for both patient and clinician. An important consequence is that drifts toward sexual boundary violations can arise from the everyday dynamics of closeness, even in the absence of individual pathology or intent. The implications for the practice of psychotherapy and personal lives of psychotherapists are explored. C1 Harvard Univ, Sch Med, Cambridge, MA 02138 USA. McLean Hosp, Ambulatory Serv, Boston, MA USA. Boston Psychoanalyt Soc & Inst Inc, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Schwartz, RS (reprint author), 30 Hillside Ave, Cambridge, MA 02140 USA. NR 33 TC 2 Z9 2 U1 1 U2 3 PU ASSN ADVAN PSYCHOTHERAPY PI BRONX PA BELFER EDUC CENTER, ROOM 402 ALBERT EINSTEIN COLL MED 1300 MORRIS PARK AVE, BRONX, NY 10461-1602 USA SN 0002-9564 J9 AM J PSYCHOTHER JI Am. J. Psychother. PY 2002 VL 56 IS 4 BP 480 EP 493 PG 14 WC Psychology, Clinical; Psychiatry; Psychology; Psychology, Psychoanalysis SC Psychology; Psychiatry GA 634GE UT WOS:000180331000002 PM 12520885 ER PT J AU Linnan, LA Emmons, KM Abrams, DB AF Linnan, LA Emmons, KM Abrams, DB TI Beauty and the beast: Results of the Rhode Island smokefree shop initiative SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article AB Licensed hairdressing facilities are prevalent in communities nationwide and represent a unique and promising channel for delivering public health interventions. The Rhode Island Smokefree Shop Initiative tested the feasibility of using these facilities to deliver smoking policy interventions statewide. A statewide survey of hairdressing facilities was followed by interventions targeted to the readiness level (high/low) of respondents to adopt smoke-free policies. C1 Miriam Hosp, Ctr Behav & Prevent Med, Providence, RI 02906 USA. Brown Univ, Sch Med, Ctr Behav & Prevent Med, Providence, RI 02912 USA. Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. RP Linnan, LA (reprint author), Univ N Carolina, Sch Publ Hlth, 310A Rosenau Hall,CB 7440, Chapel Hill, NC 27599 USA. NR 8 TC 10 Z9 10 U1 0 U2 0 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 JAN PY 2002 VL 92 IS 1 BP 27 EP 28 DI 10.2105/AJPH.92.1.27 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 504VB UT WOS:000172875600010 PM 11772752 ER PT J AU Malhotra, A Pillar, G Fogel, RB Edwards, JK Ayas, N Akahoshi, T Hess, D White, DP AF Malhotra, A Pillar, G Fogel, RB Edwards, JK Ayas, N Akahoshi, T Hess, D White, DP TI Pharyngeal pressure and flow effects on genioglossus activation in normal subjects SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE upper airway; apnea; breath; negative pressure; genioglossus ID UPPER AIRWAY ANESTHESIA; OBSTRUCTIVE SLEEP-APNEA; NEGATIVE-PRESSURE; ELECTROMYOGRAM RESPONSES; NREM SLEEP; REFLEX; HUMANS; CO2; MUSCLES AB Pharyngeal dilator muscles are clearly important in the pathogenesis of obstructive sleep apnea syndrome. Substantial data support the role of local mechanisms in mediating pharyngeal dilator muscle activation in normal humans during wakefulness. Using a recently reported iron lung ventilation model, we sought to determine the stimuli modulating genioglossus activity, dissociating the influences of pharyngeal negative pressure, from inspiratory airflow, resistance, and CO2, To achieve this aim, we used two gas densities at several levels of end-tidal CO2 and a number of intrapharyngeal negative pressures. The correlations between genioglossus electromyography (GGEMG) and epiglottic pressure across a breath remained robust under all conditions (R values range from 0.71 +/- 0.07 to 0.83 +/- 0.05). In addition, there was no significant change in the slope of this relationship despite variable gas density or CO2 levels. Although flow also showed strong correlations with genioglossus activity, there was a significant change in the slope of the GGEMG/flow relationship with altered gas density. For the group averages across conditions (between breath analysis), the correlation with GGEMG was robust for negative pressure (R-2 = 0.98) and less strong for other variables such as flow and resistance. These data suggest that independent of central pattern generator activity, intrapharyngeal negative pressure itself modulates genioglossus activity both within breaths and between breaths. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Sleep Med Div, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Pulm & Crit Care Div, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Malhotra, A (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Sleep Med Div, RF 486,221 Longwood Bldg, Boston, MA 02115 USA. FU NCRR NIH HHS [M01 RR02635]; NHLBI NIH HHS [R01 HL48531, T32 HL07633, 1 P50 HL60292] NR 28 TC 66 Z9 66 U1 0 U2 3 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 JAN 1 PY 2002 VL 165 IS 1 BP 71 EP 77 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 509VY UT WOS:000173171500014 PM 11779733 ER PT J AU Lauwers, GY Terris, B Balis, UJ Batts, KP Regimbeau, JM Chang, YC Graeme-Cook, F Yamabe, H Ikai, I Cleary, KR Fujita, S Flejou, JF Zukerberg, LR Nagorney, DM Belghiti, J Yamaoka, Y Vauthey, JN AF Lauwers, GY Terris, B Balis, UJ Batts, KP Regimbeau, JM Chang, YC Graeme-Cook, F Yamabe, H Ikai, I Cleary, KR Fujita, S Flejou, JF Zukerberg, LR Nagorney, DM Belghiti, J Yamaoka, Y Vauthey, JN TI Prognostic histologic indicators of curatively resected hepatocellular carcinomas - A multi-institutional analysis of 425 patients with definition of a histologic prognostic index SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE hepatocellular carcinoma; histology; liver; nuclear grade; prognosis; survival; staging; vascular invasion ID NORTH-AMERICAN PATIENTS; HEPATIC RESECTION; SURGICAL-TREATMENT; SURVIVAL; RECURRENCE; LIVER; TRANSPLANTATION; INVASIVENESS; MALIGNANCY; PROPOSAL AB Despite growing information on the clinical behavior of hepatocellular carcinoma, the histologic features associated with survival are not well characterized. Clinical and pathologic data on 425 patients who underwent complete resection for hepatocellular carcinoma were reviewed. Six microscopic features, namely, microvascular invasion, nuclear pleomorphism, mitosis, tumor architecture, growth interface, and tumor necrosis, were examined. Independent predictors of survival were identified and combined into a simple prognostic index. By univariate analysis. microvascular invasion, seen in 51.3% of patients (p <0.001), nuclear grade 3. present in 42% of the cases (p <0.001), and mitosis (p <0.008) were significant predictors of poor survival. Hepatocellular carcinoma with a compact growth pattern had a better prognosis as compared with macrotrabecular (p = 0.014) and acinar (p = 0.051) patterns, By multiple regression analysis, only microvascular invasion (p <0.001) and nuclear grade 3 (p = 0.008) were independent predictors of poor survival. The predictive values of microvascular invasion and nuclear grade allowed the construction of a hepatocellular prognostic index (HPI) whereby HPI = (microvascular invasion status x 0.459) + (nuclear grade x 0.287), with microvascular invasion either absent (0) or present (1) and nuclear grade scored as 1, 2, or 3. Using a cut-off of 0,746 (corresponding to at least nuclear grade 2 with microvascular invasion), two groups could be segregated: fair prognosis (HPI less than or equal to0.746), with a 50% survival of 5.06 years, and poor prognosis (HPI >0.746) with a 50% survival of 2.71 years (p <0.001). HPI was more discriminating than Edmondson grade, with Edmondson II hepatocellular carcinomas dispersed in both fair and poor prognosis groups. Microvascular invasion and nuclear grade 3 emerge as strong prognostic indicators, and their combination provides adequate prognostic stratification. Practically, hepatocellular carcinoma can be stratified in two groups with regard to prognosis: 1) fair prognosis group (nuclear grade 1 with or without microvascular invasion and nuclear grade 2 without microvascular invasion), and 2) poor prognosis (nuclear grade 2 with microvascular invasion and nuclear grade 3 with or without microvascular invasion). The combination of these histologic parameters provides adequate prognostic stratification. C1 Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Labs, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Hop Beaujon, Dept Pathol Anat, Paris, France. Mayo Clin & Mayo Fdn, Dept Pathobiol, Rochester, MN 55905 USA. Hop Beaujon, Dept Surg, Paris, France. Massachusetts Gen Hosp, Clin Res Program, Boston, MA 02114 USA. Kyoto Univ, Grad Sch Med, Dept Pathol, Kyoto 6110011, Japan. Kyoto Univ, Grad Sch Med, Dept Surg, Kyoto 6110011, Japan. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. Mayo Clin & Mayo Fdn, Dept Surg, Rochester, MN 55905 USA. Univ Texas, MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. RP Lauwers, GY (reprint author), Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Labs, Warren 256,55 Fruit St, Boston, MA 02114 USA. NR 43 TC 85 Z9 87 U1 0 U2 3 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 JAN PY 2002 VL 26 IS 1 BP 25 EP 34 DI 10.1097/00000478-200201000-00003 PG 10 WC Pathology; Surgery SC Pathology; Surgery GA 508PL UT WOS:000173097600003 PM 11756766 ER PT J AU Nielsen, GP Fletcher, CDM Smith, MA Rybak, L Rosenberg, AE AF Nielsen, GP Fletcher, CDM Smith, MA Rybak, L Rosenberg, AE TI Soft tissue Aneurysmal bone cyst - A clinicopathologic study of five cases SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE soft tissue; aneurysmal bone cyst; cytogenetics ID OSSIFYING FIBROMYXOID TUMOR; GIANT-CELL TUMORS; PARTS; OSTEOSARCOMA; LESIONS AB We describe five primary soft tissue tumors that had histologic features identical to intraosseous aneurysmal bone cyst. The tumors occurred in three females and two males, who ranged in age from 8 to 37 years (median 28 years). They arose in the deep soft tissue of the upper extremities, thigh, and groin region and typically presented as a rapidly growing mass; no involvement of the adjacent bones was identified. The tumors ranged in size from 2.5 to 9 cm (median 4 cm). Grossly, they were surrounded by a thin rim of bone and on sectioning had hemorrhagic cystic spaces delineated by fibrous septa. Histologically, the cystic spaces were filled with blood and the fibrous septa were composed of fibroblasts, osteoclast-type giant cells, and woven bone, Cytogenetic analysis of one tumor showed 46.XY.t(17:17)(p13:q12), a result similar to that which has been reported for intraosseous aneurysmal bone cyst. The differential diagnosis includes a variety of bone-forming and giant cell-containing tumors, the most important being extraskeletal osteosarcoma. Follow-up showed that four patients are free of disease 16 months to 10 years after surgery one tumor regrew after incomplete initial excision, but the patient has been free of disease 16 months after a second operation. Soft tissue aneurysmal bone cyst is an uncommon benign tumor that can be treated by simple excision. and it should be distinguished from a variety of other reactive and neoplastic processes. C1 Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. St Thomas Hosp, Dept Orthoped Surg, London SE1 7EH, England. RP Nielsen, GP (reprint author), Massachusetts Gen Hosp, Dept Pathol, 32 Fruit St, Boston, MA 02114 USA. NR 19 TC 31 Z9 31 U1 0 U2 0 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 JAN PY 2002 VL 26 IS 1 BP 64 EP 69 DI 10.1097/00000478-200201000-00007 PG 6 WC Pathology; Surgery SC Pathology; Surgery GA 508PL UT WOS:000173097600007 PM 11756770 ER PT J AU Lee, RE Young, RH Castleman, B AF Lee, RE Young, RH Castleman, B TI James Homer Wright - A biography of the enigmatic creator of the Wright stain on the occasion of its centennial SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Biographical-Item DE James Homer Wright; Wright stain; multiple myeloma; actinomycosis; platelets; megakaryocytes; neuroblastoma; Homer Wright pseudorosettes; syphilis; history of pathology AB James Homer Wright (1869-1928), the eldest son of a Pittsburgh glass merchant, was educated in Baltimore and practiced pathology in Boston from 1893 until his death in 1928. In 1896, when not quite 27 years old, he assumed directorship of the newly founded Pathology Laboratory at the Massachusetts General Hospital, a post he held for the next 30 years. He is remembered eponymously by the blood cell stain that bears his name and the Homer Wright pseudorosettes of neuroblastoma, but he made many additional contributions to pathology. These include the following: determination of the cellular lineage of multiple myeloma, identification of the megakaryocyte as the cell of origin of blood platelets, recognition of the cell of origin of the neuroblastoma, demonstration of spirochetes in syphilitic aneurysms of the aorta. and clarification of misconceptions about actinomycosis. Additionally, Wright coauthored, with Dr. Frank B. Mallory, the book Pathological Technique, which was a staple of laboratories for >40 years and exemplifies Wright's wide-ranging interests in, and contributions to, practical aspects of pathology including staining, culture and frozen section techniques. photography, and development of the rotary microtome. He received Honorary Doctor of Science Degrees from Harvard University, the University of Maryland (his alma mater), and the University of Missouri. He was the recipient of the Gross prize in 1905 for his publication on actinomycosis and the Boylston Medical Prize in 1908 for his discovery of the origin of platelets, and he was inducted into the American Academy of Arts and Sciences in 1915. Although shy and somewhat austere in the workplace, a different side was shown by his anonymously sending flowers to a young Norwegian opera singer whom he subsequently married. The pathology laboratories of the Massachusetts General Hospital were named the "James Homer Wright Pathology Laboratories" in 1956. Today James Homer Wright is remembered and honored 100 years after his description of the stain that, along with the pseudorosettes of neuroblastoma, carry his name into eternity and ensure his great contributions will never be forgotten. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Homer Wright PatholLabs, Boston, MA 02114 USA. Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15260 USA. RP Young, RH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Homer Wright PatholLabs, Warren 2, Boston, MA 02114 USA. NR 1 TC 7 Z9 8 U1 0 U2 0 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 JAN PY 2002 VL 26 IS 1 BP 88 EP 96 DI 10.1097/00000478-200201000-00011 PG 9 WC Pathology; Surgery SC Pathology; Surgery GA 508PL UT WOS:000173097600011 PM 11756774 ER PT J AU Tkaczuk, J Yu, CL Baksh, S Milford, EL Carpenter, CB Burakoff, SJ McKay, DB AF Tkaczuk, J Yu, CL Baksh, S Milford, EL Carpenter, CB Burakoff, SJ McKay, DB TI Effect of anti-IL-2R alpha antibody on IL-2-induced Jak/STAT signaling SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE daclizumab; IL-2; intracellular signaling; Jak; monoclonal antibody ID INTERLEUKIN-2 RECEPTOR; RENAL-TRANSPLANTATION; MONOCLONAL-ANTIBODY; HUMANIZED ANTIBODY; BINDING; IMMUNOTHERAPY; PROLIFERATION; ACTIVATION; DACLIZUMAB; REJECTION AB Acute allograft rejection is driven by production of cytokines such as interleukin-2 (IL-2) that activate and expand alloreactive T cells by ligating high-affinity IL-2 receptors composed of three subunit chains: alpha, beta, gamma. The a chain, expressed only on activated T cells, has become an important therapeutic target. Monoclonal antibodies (mAbs) that bind IL-2Ralpha chains significantly decrease transplant rejection. We examined the ability of the humanized anti-IL-2Ralpha antibody daclizumab to block high-affinity IL-2Rs and interrupt T-lymphocyte signaling. Our evaluation focused on a pathway critical for T-cell proliferation, the Jak/STAT pathway. Daclizumab markedly inhibited phosphorylation of the Jak1, Jak3 and STAT5a/b components of the IL-2R-dependent pathway. Suppression by daclizumab was associated with internalization of IL-2Ralpha but not IL-2Rbetagamma chains. High IL2 doses overcame daclizumab-induced blockade of Jak/ STAT phosphorylation despite absent cell surface high-affinity IL-2Rs. Under these circumstances, IL-2-mediated Jak/STAT pathway activation might be generated through residual intermediate affinity IL-2Rbetagamma receptors, and this was demonstrated by complete blockade of signaling when anti-IL-2Rbeta monoclonal, antibody was added. Humanized antibodies are an important part of strategies to induce alloantigen tolerance. Understanding the molecular events associated with beneficial clinical effect is critical to design of future immunosuppressive strategies. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Renal Div, Boston, MA 02115 USA. RP McKay, DB (reprint author), Scripps Res Inst, Dept Immunol, IMM-1, La Jolla, CA 92037 USA. RI Yu, Chao-Lan/D-1834-2011 OI Yu, Chao-Lan/0000-0002-9381-6011 FU NCI NIH HHS [R01CA70758]; NIDDK NIH HHS [DK02472]; NINR NIH HHS [NRSA-F32CA79154] NR 21 TC 21 Z9 24 U1 1 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 JAN PY 2002 VL 2 IS 1 BP 31 EP 40 DI 10.1034/j.1600-6143.2002.020107.x PG 10 WC Surgery; Transplantation SC Surgery; Transplantation GA 534AA UT WOS:000174561400006 PM 12095053 ER PT B AU Murphy, SN Chueh, HC AF Murphy, SN Chueh, HC BE Kohane, IS TI A security architecture for query tools used to access large biomedical databases SO AMIA 2002 SYMPOSIUM, PROCEEDINGS: BIOMEDICAL INFORMATICS: ONE DISCIPLINE LA English DT Proceedings Paper CT Annual Symposium of the American-Medical-Informatics-Association CY NOV 09, 2002 CL San Antonio, TX SP Amer Med Informat Assoc AB Disseminating information from large biomedical databases can be crucial for research. Often this data will be patient-specific, and therefore require that the privacy of the patient be protected. In response to this requirement, HIPAA released regulations for the dissemination of patient data. In many cases, the regulations are so restrictive as to render data useless for many purposes. We propose in this paper a model for obfuscation of data when served to a client application, that will make it extremely unlikely that an individual will be identified. At Partners Healthcare Inc, with over 1.4 million patients and 400 research clinician users, we implemented this model. Based on the results, we believe that a web-client could be made generally available using the proposed data obfuscation scheme that could allow general usage of large biomedical databases of patient information without risk to patient privacy. C1 Massachusetts Gen Hosp, Comp Sci Lab, Boston, MA 02114 USA. RP Murphy, SN (reprint author), Massachusetts Gen Hosp, Comp Sci Lab, Boston, MA 02114 USA. NR 8 TC 4 Z9 4 U1 0 U2 0 PU HANLEY & BELFUS INC MED PUBLISHERS PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA BN 1-56053-600-4 PY 2002 BP 552 EP 556 PG 5 WC Computer Science, Information Systems; Medical Informatics SC Computer Science; Medical Informatics GA BY60A UT WOS:000189418100112 ER PT B AU Arnold, M DeJong, W AF Arnold, M DeJong, W BE Kohane, IS TI Developing and testing a theory-guided website to promote early melanoma detection among young adults SO AMIA 2002 SYMPOSIUM, PROCEEDINGS: BIOMEDICAL INFORMATICS: ONE DISCIPLINE LA English DT Proceedings Paper CT Annual Symposium of the American-Medical-Informatics-Association CY NOV 09, 2002 CL San Antonio, TX SP Amer Med Informat Assoc C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Arnold, M (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU HANLEY & BELFUS INC MED PUBLISHERS PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA BN 1-56053-600-4 PY 2002 BP 963 EP 963 PG 1 WC Computer Science, Information Systems; Medical Informatics SC Computer Science; Medical Informatics GA BY60A UT WOS:000189418100197 ER PT B AU Dubey, AK Meigs, JB Cagliero, E Chueh, HC AF Dubey, AK Meigs, JB Cagliero, E Chueh, HC BE Kohane, IS TI Implementation, usage, and impact of automated guidelines in the DMA - A web-based diabetes disease management system SO AMIA 2002 SYMPOSIUM, PROCEEDINGS: BIOMEDICAL INFORMATICS: ONE DISCIPLINE LA English DT Proceedings Paper CT Annual Symposium of the American-Medical-Informatics-Association CY NOV 09, 2002 CL San Antonio, TX SP Amer Med Informat Assoc C1 Massachusetts Gen Hosp, Lab Comp Sci, Boston, MA 02114 USA. RP Dubey, AK (reprint author), Massachusetts Gen Hosp, Lab Comp Sci, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HANLEY & BELFUS INC MED PUBLISHERS PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA BN 1-56053-600-4 PY 2002 BP 1011 EP 1011 PG 1 WC Computer Science, Information Systems; Medical Informatics SC Computer Science; Medical Informatics GA BY60A UT WOS:000189418100245 ER PT B AU Lasko, TA Feldman, MJ Barnett, GO AF Lasko, TA Feldman, MJ Barnett, GO BE Kohane, IS TI DXplain evoking strength - Clinician interpretation and consistency SO AMIA 2002 SYMPOSIUM, PROCEEDINGS: BIOMEDICAL INFORMATICS: ONE DISCIPLINE LA English DT Proceedings Paper CT Annual Symposium of the American-Medical-Informatics-Association CY NOV 09, 2002 CL San Antonio, TX SP Amer Med Informat Assoc AB The clinician interpretation of the Evoking Strength score in DXplain is being investigated with the purpose of allowing consistency and quality checking. Our experience is that not all of our physician developers agree on the meaning of this score, and various possibilities, calculated from other data in the DXplain knowledge base, have been correlated against the assigned ES scores. Preliminary results indicate that the most common interpretation was that of the relative frequency of the finding in the disease compared to the frequency of the finding in the general population. This is consistent with the algorithmic use of the ES scores in the program. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Comp Sci Lab, Boston, MA 02114 USA. RP Lasko, TA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Comp Sci Lab, Boston, MA 02114 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU HANLEY & BELFUS INC MED PUBLISHERS PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA BN 1-56053-600-4 PY 2002 BP 1073 EP 1073 PG 1 WC Computer Science, Information Systems; Medical Informatics SC Computer Science; Medical Informatics GA BY60A UT WOS:000189418100307 ER PT B AU Mah, V Ball, SS AF Mah, V Ball, SS BE Kohane, IS TI Senex II: Ordering of molecular mechanisms in cancer SO AMIA 2002 SYMPOSIUM, PROCEEDINGS: BIOMEDICAL INFORMATICS: ONE DISCIPLINE LA English DT Proceedings Paper CT Annual Symposium of the American-Medical-Informatics-Association CY NOV 09, 2002 CL San Antonio, TX SP Amer Med Informat Assoc C1 Univ Calif Los Angeles, Multictr Program Geriatr & Gerontol, VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. RP Mah, V (reprint author), Univ Calif Los Angeles, Multictr Program Geriatr & Gerontol, VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU HANLEY & BELFUS INC MED PUBLISHERS PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA BN 1-56053-600-4 PY 2002 BP 1095 EP 1095 PG 1 WC Computer Science, Information Systems; Medical Informatics SC Computer Science; Medical Informatics GA BY60A UT WOS:000189418100329 ER PT J AU Kang, HW Weissleder, R Bogdanov, A AF Kang, HW Weissleder, R Bogdanov, A TI Targeting of MPEG-protected polyamino acid carrier to human E-selectin in vitro SO AMINO ACIDS LA English DT Article; Proceedings Paper CT 7th International Congress on Amino Acids and proteins CY AUG 06-10, 2001 CL VIENNA, AUSTRIA DE E-selectin; endothelium; IL-1 beta; graft copolymer; indocyanine; antibody; optical imaging ID PROLIFERATING ENDOTHELIAL-CELLS; IN-VIVO; ADHESION MOLECULE; NEOVASCULATURE; EXPRESSION; DELIVERY; AGENT AB Targeted diagnostic agents are expected to have a significant impact in molecular imaging of cell-surface associated markers of proliferation, inflammation and angiogenesis. In this communication, we describe a new class of targeted polyamino acid-based protected graft copolymers (PGC) of poly-(L-lysine) and methyl poly-(ethylene glycol) (PGC) covalently conjugated with a monoclonal antibody fragment, F(ab')(2). We utilized targeted PGC conjugates as carriers of near-infrared indocyanine fluorophores (Cy5.5) for optical imaging of endothelial cell populations expressing IL-1beta inducible proinflanunatory marker E-selectin. We compared two conjugation chemistries, involving either introduction of sulfhydryl group to F(ab')(2), or via direct attachment of the antibody fragment directly to the chemically activated PGC. Both PGC-based targeted agents demonstrated high binding specificity (20-30 fold over non-specific uptake) and were utilized for imaging E-selectin expression on human endothelial cells, activated with IL-1beta. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med,Ctr Mol Imaging Res, Dept Radiol, Charlestown, MA 02129 USA. RP Bogdanov, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Ctr Mol Imaging Res, Dept Radiol, Bldg 149,13th St, Charlestown, MA 02129 USA. FU NCI NIH HHS [1P50CA86355-01, 5R01CA74424-01] NR 24 TC 15 Z9 17 U1 0 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0939-4451 J9 AMINO ACIDS JI Amino Acids PY 2002 VL 23 IS 1-3 BP 301 EP 308 DI 10.1007/s00726-001-0142-2 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 600VJ UT WOS:000178412200042 PM 12373551 ER PT J AU Rooke, GA Reves, JG Rosow, C AF Rooke, GA Reves, JG Rosow, C TI Anesthesiology and geriatric medicine - Mutual needs and opportunities SO ANESTHESIOLOGY LA English DT Editorial Material ID AGE C1 Univ Washington, Seattle, WA 98195 USA. Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. Amer Soc Anesthesiol, Comm Geriatr Anesthesia, Seattle, WA USA. Soc Adv Geriatr Anesthesia, Seattle, WA USA. Med Univ S Carolina, Charleston, SC 29425 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA USA. RP Rooke, GA (reprint author), Univ Washington, Seattle, WA 98195 USA. RI Rooke, Alec/F-8909-2013 NR 10 TC 12 Z9 12 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD JAN PY 2002 VL 96 IS 1 BP 2 EP 4 DI 10.1097/00000542-200201000-00006 PG 3 WC Anesthesiology SC Anesthesiology GA 508JY UT WOS:000173086000002 PM 11752993 ER PT J AU Takeuchi, M Williams, P Hess, D Kacmarek, RM AF Takeuchi, M Williams, P Hess, D Kacmarek, RM TI Continuous positive airway pressure in new-generation mechanical ventilators - A lung model study SO ANESTHESIOLOGY LA English DT Article ID ACUTE RESPIRATORY-FAILURE; INSPIRATORY WORK; ENDOTRACHEAL-TUBES; INTUBATED PATIENTS; FLOW SYSTEMS; T-PIECE; SUPPORT; CPAP; RESISTANCE; TRIGGER AB Background: A number of new microprocessor-controlled mechanical ventilators have become available over die last few years. However, the ability of these ventilators to provide continuous positive airway pressure without imposing or performing work has never been evaluated. Methods: In a spontaneously, breathing lung model, the authors evaluated the Bear 1000, Drager Evita 4, Hamilton Galileo, Nellcor-Puritan-Bennett 740 and 840, Siemens Servo 300A, and Bird Products Third AN'S at 10 cm H2O continuous positive airway pressure. Lung model compliance was 50 ml/cm H2O with a resistance of 8.2 cm H2O.l(-1).s(-1), and inspiratory time was set at 1.0 s with peak inspiratory flows of 40, 60, and 80 l/min. In ventilators with both Pressure and flow triggering, the response of each was evaluated. Results: With all ventilators, peak inspiratory flow, lung model tidal volume, and range of pressure change (below baseline to above baseline) increased as peak flow increased. Inspiratory trigger delay time, inspiratory cycle delay time, expiratory pressure time product, and total area of pressure change were not affected by peak flow, whereas pressure change to trigger inspiration, inspiratory pressure time product, and trigger pressure time product were affected by peak flow on some ventilators. There were significant differences among ventilators on all variables evaluated, but there was little difference between pressure and flow triggering in most variables on individual ventilators except for pressure to trigger. Pressure to trigger was 3.74+/-1.89 cm H2O (mean+/-SD) in flow triggering and 4.48+/-1.67 cm H2O in pressure triggering (P<0.01) across all ventilators. Conclusions: Most ventilators evaluated only imposed a small effort to trigger, but most also provided low-level pressure support and imposed an expiratory workload. Pressure triggering during continuous positive airway pressure does require a slightly greater pressure than flow triggering. C1 Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Anesthesia, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Kacmarek, RM (reprint author), Massachusetts Gen Hosp, Dept Resp Care, Ellison 401, Boston, MA 02114 USA. NR 35 TC 15 Z9 17 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD JAN PY 2002 VL 96 IS 1 BP 162 EP 172 DI 10.1097/00000542-200201000-00030 PG 11 WC Anesthesiology SC Anesthesiology GA 508JY UT WOS:000173086000026 PM 11753017 ER PT J AU Pham, W Weissleder, R Tung, CH AF Pham, W Weissleder, R Tung, CH TI An azulene dimer as a near-infrared quencher SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE azulenes; fluorescence; molecular imaging; proteases; sensors ID LIVING CELLS; FLUORESCENT-PROBES; ENERGY-TRANSFER; VIVO; REPORTER; TUMORS; DESIGN 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. OI Tung, Ching-Hsuan/0000-0001-6648-6195 FU NCI NIH HHS [P50 CA86355, R33 CA88365, T32 CA 79443] NR 31 TC 56 Z9 59 U1 2 U2 13 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1433-7851 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PY 2002 VL 41 IS 19 BP 3659 EP 3662 DI 10.1002/1521-3773(20021004)41:19<3659::AID-ANIE3659>3.0.CO;2-Q PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 604GZ UT WOS:000178609900029 PM 12370922 ER PT J AU Ely, EW Wheeler, AP Thompson, BT Ancukiewicz, M Steinberg, KP Bernard, GR AF Ely, EW Wheeler, AP Thompson, BT Ancukiewicz, M Steinberg, KP Bernard, GR CA Acute Respiratory Distress Syndrom TI Recovery rate and prognosis in older persons who develop acute lung injury and the acute respiratory distress syndrome SO ANNALS OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT International Conference of the American-Lung-Association and the American-Thoracic-Society CY MAY 08, 2000 CL TORONTO, CANADA SP American Lung Assoc, American Thoracic Soc ID CRITICALLY ILL PATIENTS; ELDERLY MEDICAL PATIENTS; MECHANICAL VENTILATION; INTENSIVE-CARE; HOSPITALIZED ADULTS; SERIOUSLY ILL; INFORMANT QUESTIONNAIRE; COGNITIVE DECLINE; PREDICTIVE MODEL; AGE AB Background: The incidence of acute respiratory failure requiring mechanical ventilation increases 10-fold from the ages of 55 to 85 years, yet the rate of recovery and outcomes in older persons who develop acute lung injury are poorly defined. Objective: To examine age as an independent risk factor in recovery and intensive care unit discharge after acute lung injury. Design: Prospective cohort study. Setting: 10 U.S. university-based medical centers. Patients: 902 mechanically ventilated patients enrolled in randomized, controlled trials for the treatment of acute lung injury. Ail patients were managed according to a standardized protocol for ventilator management and weaning. Measurements: Frequency and time to achieve well-defined recovery landmarks, duration of ventilation and intensive care unit stay, and survival. Results: Median duration of mechanical ventilation was 19 days (interquartile range, 7 to >28 days) for patients 70 years of age or older (n = 173) compared with 10 days (interquartile range, 5 to 26 days) for patients younger than 70 years of age (n = 729) (P < 0.001). The duration of intensive care unit stay was 21 days for the older group (interquartile range, 11 to >28 days) and 16 days for the younger group (8 to >28 days) (P = 0.004). Survival rates decreased across increasing decades of age (P < 0.001): Patients younger than 70 years of age had a greater 28-day survival rate than patients 70 years of age or older (74.6% vs. 50.3%; P < 0.001). The proportion of survivors achieving physiologic recovery landmarks did not differ between the older and younger age groups, and the median time to pass a 2-hour spontaneous breathing trial was similar between both the older and younger patients (4 days vs. 5 days; P > 0.2). After passing a spontaneous breathing trial, however, older patients required 1 more day than younger patients to achieve unassisted breathing (P = 0.002) and 3 more days to leave the intensive care unit (P = 0.005). In a multivariable Cox proportional hazards analysis, age of 70 years or older was a strong predictor of in-hospital death (hazard ratio, 2.5 [95% Cl, 2.0 to 3.2]; P < 0.001). Conclusions: Although the survival rate among patients 70 years of age or older was high, these patients were twice as likely to die of acute lung injury compared with their younger counterparts, even after adjustment for covariates. Older survivors recovered from respiratory failure and achieved spontaneous breathing at the same rate as younger patients but had greater difficulty achieving liberation from the ventilator and being discharged from the intensive care unit. C1 Vanderbilt Univ, Med Ctr, Div Allergy Pulm & Crit Care Med, Sch Med, Nashville, TN 37232 USA. Vet Affairs Tennessee Valley Healthcare Res & Edu, Nashville, TN USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Washington, Harborview Med Ctr, Sch Med, Seattle, WA 98104 USA. RP Ely, EW (reprint author), Vanderbilt Univ, Med Ctr, Div Allergy Pulm & Crit Care Med, Sch Med, 6th Floor,6109 Med Ctr E, Nashville, TN 37232 USA. FU NHLBI NIH HHS [N01-HR 46054-46064]; NIA NIH HHS [AG01023-01A1] NR 85 TC 113 Z9 119 U1 8 U2 9 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 1 PY 2002 VL 136 IS 1 BP 25 EP 36 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 510BF UT WOS:000173188300003 PM 11777361 ER PT J AU Ingelsson, M Hyman, BT AF Ingelsson, M Hyman, BT TI Disordered proteins in dementia SO ANNALS OF MEDICINE LA English DT Review DE dementia; mutation; protein dysregulation ID AMYLOID PRECURSOR PROTEIN; CREUTZFELDT-JAKOB-DISEASE; PROGRESSIVE SUPRANUCLEAR PALSY; FAMILIAL ALZHEIMERS-DISEASE; INHERITED PRION DISEASE; TAU-GENE MUTATION; STRAUSSLER-SCHEINKER-DISEASE; APOLIPOPROTEIN-E EPSILON-4; PAIRED HELICAL FILAMENTS; FRONTOTEMPORAL DEMENTIA AB Aggregates of dysfunctional proteins and peptides in or between brain neurons are key neuropathological features of dementia and are believed to directly cause or substantially contribute to the development of these diseases. Fundamental parts of the mechanisms underlying the dysregulation of proteins in Alzheimer's disease, frontotemporal dementia, prion diseases and other dementing disorders are now well characterized, mainly due to the discovery of genes causing dominantly inherited disease forms (Table 1). As of today, no efficient pharmacotherapies are available, but new insights into the underlying molecular mechanisms are providing strategies to prevent or even cure these devastating disorders. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Hyman, BT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, 114 16th St, Charlestown, MA 02129 USA. NR 150 TC 12 Z9 12 U1 0 U2 3 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1M 8AE, ENGLAND SN 0785-3890 J9 ANN MED JI Ann. Med. PY 2002 VL 34 IS 4 BP 259 EP 271 DI 10.1080/078538902320322529 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 595YH UT WOS:000178135500004 PM 12371710 ER PT J AU Ding, HF Fisher, DE AF Ding, HF Fisher, DE TI Induction of apoptosis in cancer: new therapeutic opportunities SO ANNALS OF MEDICINE LA English DT Review DE apoptosis; cancer therapy; oncogene; tumorigenesis; tumor suppressor gene ID NF-KAPPA-B; CELL-CYCLE ARREST; WILD-TYPE P53; TUMOR-SUPPRESSOR GENE; MYC-INDUCED APOPTOSIS; S-PHASE ENTRY; RADIATION-INDUCED APOPTOSIS; MYELOGENOUS LEUKEMIA-CELLS; DOMAIN-CONTAINING PROTEIN; FLICE-INHIBITORY PROTEIN AB Autonomous cell proliferation is one of the hallmarks of cancer cells, driven by activated growth-promoting oncogenes. However, deregulated activation of these oncogenes also triggers apoptosis via multiple pathways. Among them, the ARF-p53 pathway appears to play a major role in mediating oncogene-induced apoptosis. Consequently, suppression of apoptosis by inactivation of p53 and other tumor suppressors is central to tumor development. These findings have broad implications in understanding cancer genetics and therapy. They help define the roles for oncogenes and tumor suppressor genes in tumorigenesis. Furthermore, the notion that cancer cells often carry specific defects in apoptotic pathways but are inherently sensitive to apoptosis as a result of deregulated proliferation, offers numerous opportunities for manipulating apoptosis in directions of clinical application. C1 Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Childrens Hosp, Boston, MA 02115 USA. Med Coll Ohio, Dept Biochem & Mol Biol, Toledo, OH 43699 USA. RP Fisher, DE (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Dana 630F,44 Binney St, Boston, MA 02115 USA. NR 295 TC 34 Z9 37 U1 0 U2 3 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1M 8AE, ENGLAND SN 0785-3890 J9 ANN MED JI Ann. Med. PY 2002 VL 34 IS 6 BP 451 EP 469 DI 10.1080/078538902321012405 PG 19 WC Medicine, General & Internal SC General & Internal Medicine GA 630LV UT WOS:000180109100006 PM 12523501 ER PT J AU Ho, MF Gallardo, E McKenna-Yasek, D De Luna, N Illa, I Brown, RH AF Ho, MF Gallardo, E McKenna-Yasek, D De Luna, N Illa, I Brown, RH TI A novel, blood-based diagnostic assay for limb girdle muscular dystrophy 2B and Miyoshi myopathy SO ANNALS OF NEUROLOGY LA English DT Article ID DYSFERLIN; GENE; PROTEIN AB Limb girdle muscular dystrophy 213 and Miyoshi myopathy were recently found to be allelic disorders arising from defects in the dysferlin gene. We have developed a new diagnostic assay for limb girdle muscular dystrophy 2B and Miyoshi myopathy, which screens for dysferlin expression in blood using a commercially available monoclonal antibody. Unlike current methods that require muscle biopsy for immunodiagnosis, the new method is simple and entails a significantly less invasive procedure for tissue sampling. Moreover, it overcomes some of the problems associated with the handling and storage of muscle specimens. In our analysis of 12 patients with limb girdle muscular dystrophy 213 or Miyoshi myopathy, the findings obtained using the new assay are fully consistent with the results from muscle immunodiagnosis. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Day Lab Neuromuscular Res, Charlestown, MA 02129 USA. Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Neuromuscular Dis Sect, Dept Neurol, E-08193 Barcelona, Spain. RP Brown, RH (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Day Lab Neuromuscular Res, Bldg 114,16th St,Rm 3125, Charlestown, MA 02129 USA. OI de Luna Salva, Noemi/0000-0002-4342-794X; Gallardo, Eduard/0000-0002-3942-3436 NR 15 TC 63 Z9 65 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JAN PY 2002 VL 51 IS 1 BP 129 EP 133 DI 10.1002/ana.10080 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 508JK UT WOS:000173084800019 PM 11782994 ER PT J AU Kleinman, RE Hall, S Green, H Korzec-Ramirez, D Patton, K Pagano, ME Murphy, JM AF Kleinman, RE Hall, S Green, H Korzec-Ramirez, D Patton, K Pagano, ME Murphy, JM TI Diet, breakfast, and academic performance in children SO ANNALS OF NUTRITION AND METABOLISM LA English DT Article; Proceedings Paper CT 17th International Congress of Nutrition CY OCT 27-31, 2001 CL VIENNA, AUSTRIA DE school breakfast; low-income children; psychosocial functioning; nutrition; dietary intake ID PEDIATRIC SYMPTOM CHECKLIST; SCHOOL BREAKFAST; INCOME; HEALTH; HUNGER AB Objective: To determine whether nutrient intake and academic and psychosocial functioning improve after the start of a universal-free school breakfast program (USBP). Methods: Information was gathered from 97 inner city students prior to the start of a USBP and again after the program had been in place for 6 months. Students who had total energy intakes of <50% of the recommended daily allowance (RDA) and/or 2 or more micronutrients of <50% of RDA were considered to be at nutritional risk. Results: Prior to the USBP, 33% of all study children were classified as being at nutritional risk. Children who were at nutritional risk had significantly poorer attendance, punctuality, and grades at school, more behavior problems, and were less likely to eat breakfast at school than children who were not at nutritional risk. Six months after the start of the free school breakfast programs, students who decreased their nutritional risk showed significantly greater: improvements in attendance and school breakfast participation, decreases in hunger, and improvements in math grades and behavior than children who did not decrease their nutritional risk. Conclusion: Participation in a school breakfast program enhanced daily nutrient intake and improvements in nutrient intake were associated with significant improvements in student academic performance and psychosocial functioning and decreases in hunger. Copyright (C) 2002 S. Karger AG, Basel. C1 Massachusetts Gen Hosp, Child Psychiat Serv, Dept Psychiat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Pediat Gastroenterol & Nutr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Project Bread Walk Hunger, Boston, MA USA. Boston Publ Sch Syst, Dept Food & Nutr Serv, Boston, MA USA. Brown Univ, Dept Psychiat & Human Behav, Providence, RI 02912 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA USA. RP Murphy, JM (reprint author), Massachusetts Gen Hosp, Child Psychiat Serv, Dept Psychiat, 15 Parkman St,WAC 725, Boston, MA 02114 USA. FU NIAAA NIH HHS [L30 AA014994, L30 AA014994-03] NR 20 TC 71 Z9 76 U1 2 U2 34 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0250-6807 J9 ANN NUTR METAB JI Ann. Nutr. Metab. PY 2002 VL 46 SU 1 BP 24 EP 30 DI 10.1159/000066399 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 624PX UT WOS:000179769600005 PM 12428078 ER PT J AU Barry, MJ AF Barry, MJ TI Fecal occult blood testing for colorectal cancer: a perspective SO ANNALS OF ONCOLOGY LA English DT Editorial Material DE colorectal cancer; colorectal neoplasia; fecal occult blood testing; guaiac; mass screening ID SCREENING COLONOSCOPY; COST-EFFECTIVENESS; MORTALITY; SIGMOIDOSCOPY AB Colorectal cancer is an important health problem in western countries. Early detection of colorectal cancer reduces mortality, The best evidence for the effectiveness of screening for colorectal cancer is with annual or biennial fecal occult blood testing. While the benefit of fecal occult blood testing is small in absolute terms, the incremental cost-effectiveness of this screening strategy appears acceptable. Combining fecal occult blood testing with periodic flexible sigmoidoscopy or replacing it altogether with infrequent colonoscopy are theoretically attractive screening strategies, but the incremental costs and effectiveness of these more intensive screening strategies have not been well defined. Whether and how to implement population-based screening for colorectal cancer depends largely on available resources. C1 Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. RP Barry, MJ (reprint author), 50 Staniford St,9th Floor, Boston, MA 02114 USA. NR 30 TC 7 Z9 7 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD JAN PY 2002 VL 13 IS 1 BP 61 EP 64 DI 10.1093/annonc/mdf075 PG 4 WC Oncology SC Oncology GA 525GQ UT WOS:000174060900022 PM 11863113 ER PT J AU Goldhirsch, A Colleoni, M Gelber, RD AF Goldhirsch, A Colleoni, M Gelber, RD TI Endocrine therapy of breast cancer SO ANNALS OF ONCOLOGY LA English DT Article; Proceedings Paper CT 27th European-Society-for-Medical-Oncology Congress CY OCT 18-22, 2002 CL NICE, FRANCE SP European Soc Med Oncol ID FIRST-LINE THERAPY; SURGICAL ADJUVANT BREAST; GROWTH-FACTOR-BETA; RANDOMIZED TRIAL; PHASE-III; MEDROXYPROGESTERONE ACETATE; POSTMENOPAUSAL WOMEN; AROMATASE INHIBITOR; ONCOLOGY-GROUP; TAMOXIFEN C1 European Inst Oncol, Dept Med, Milan, Italy. Osped Civ, Oncol Inst So Switzerland, Lugano, Switzerland. European Inst Oncol, Div Med Oncol, Milan, Italy. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Goldhirsch, A (reprint author), European Inst Oncol, Dept Med, Milan, Italy. NR 80 TC 11 Z9 13 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PY 2002 VL 13 SU 4 BP 61 EP 68 DI 10.1093/annonc/mdf640 PG 8 WC Oncology SC Oncology GA 612XG UT WOS:000179100300010 PM 12401668 ER PT J AU Yahalom, J Mauch, P AF Yahalom, J Mauch, P TI The involved field is back: issues in delineating the radiation field in Hodgkin's disease SO ANNALS OF ONCOLOGY LA English DT Article; Proceedings Paper CT 5th International Symposium on Hodgkins Lymphoma CY SEP 22-25, 2001 CL COLOGNE, GERMANY DE Hodgkin's disease; involved field; radiation ID CHEMOTHERAPY; RADIOTHERAPY; IRRADIATION AB During the last century, the role of radiation therapy in the treatment of Hodgkin's disease (HD) has changed drastically. From a palliative treatment reserved for bulky lymph nodes of an incurable disease at the beginning of the century, to an exciting primary treatment used alone to cure most stages in the 1960s and 1970s, to the present more limited role as consolidation treatment after chemotherapy. Interestingly, the radiation field size has always influenced the evolution of treatment principles of HD. Over several decades, large or extended field radiotherapy has become synonymous with the successful treatment of HD. But the critical transformation from a single-modality to a combined-modality therapy, together with improvement in imaging and radiation planning techniques, mandates a reassessment of the delineation of appropriate radiation fields in HD. In this manuscript we review the comeback of the involved field, address design questions and offer field borders for common disease sites. C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Cornell Univ, Weill Med Coll, New York, NY USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Yahalom, J (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. NR 22 TC 75 Z9 78 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PY 2002 VL 13 SU 1 BP 79 EP 83 DI 10.1093/annonc/mdf616 PG 5 WC Oncology SC Oncology GA 556MA UT WOS:000175852500014 PM 12078908 ER PT J AU Josting, A Engert, A Diehl, V Canellos, GP AF Josting, A Engert, A Diehl, V Canellos, GP TI Prognostic factors and treatment outcome in patients with primary progressive and relapsed Hodgkin's disease SO ANNALS OF ONCOLOGY LA English DT Article; Proceedings Paper CT 5th International Symposium on Hodgkins Lymphoma CY SEP 22-25, 2001 CL COLOGNE, GERMANY ID CLINICAL STAGE-I; COMBINATION CHEMOTHERAPY; CELL TRANSPLANTATION; SALVAGE CHEMOTHERAPY; 1ST RELAPSE; MOPP; RADIOTHERAPY; MALIGNANCIES; STRATEGIES; INDUCTION C1 Univ Hosp Cologne, Dept Internal Med 1, D-50924 Cologne, Germany. German Hodgkin Lymphoma Study Grp, Cologne, Germany. Dana Faber Canc Inst, Dept Adult Oncol, Boston, MA USA. RP Josting, A (reprint author), Univ Hosp Cologne, Dept Internal Med 1, Joseph Stelmann Str 9, D-50924 Cologne, Germany. NR 27 TC 12 Z9 16 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PY 2002 VL 13 SU 1 BP 112 EP 116 DI 10.1093/annonc/mdf624 PG 5 WC Oncology SC Oncology GA 556MA UT WOS:000175852500022 PM 12078891 ER PT J AU Canellos, GP AF Canellos, GP TI Primary treatment of Hodgkin's disease SO ANNALS OF ONCOLOGY LA English DT Article; Proceedings Paper CT 27th European-Society-for-Medical-Oncology Congress CY OCT 18-22, 2002 CL NICE, FRANCE SP European Soc Med Oncol ID CLINICAL STAGE-I; PROGNOSTIC FACTORS; COMBINATION CHEMOTHERAPY; INITIAL TREATMENT; EUROPEAN ORGANIZATION; RANDOMIZED TRIALS; MVPP CHEMOTHERAPY; LATE RELAPSE; FOLLOW-UP; RADIOTHERAPY C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Canellos, GP (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. NR 47 TC 6 Z9 6 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PY 2002 VL 13 SU 4 BP 153 EP 158 DI 10.1093/annonc/mdf653 PG 6 WC Oncology SC Oncology GA 612XG UT WOS:000179100300023 PM 12401682 ER PT J AU Hartnick, CJ Liu, JH Cotton, RT Rudolph, C AF Hartnick, CJ Liu, JH Cotton, RT Rudolph, C TI Subglottic stenosis complicated by allergic esophagitis - Case report SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE allergic esophagitis; subglottic stenosis ID GASTROESOPHAGEAL REFLUX DISEASE; EOSINOPHILIC ESOPHAGITIS; LARYNGOTRACHEAL RECONSTRUCTION; CHILDREN; CORTICOSTEROIDS; MANIFESTATIONS; ACID AB Allergic esophagitis is a known entity that had been described in patients with dysphagia. It has not been previously described in association with subglottic stenosis. We report the case of a 2-year-old girl with symptoms suggestive of allergic esophagitis who suffered from subglottic stenosis that recurred despite surgical measures. Her esophageal pH monitoring results were normal, and she did not respond to antireflux medications. She did respond dramatically to corticosteroid therapy with improvement of both her esophageal and laryngeal symptoms. Allergic esophagitis as a clinical entity is discussed. C1 Childrens Hosp, Med Ctr, Dept Pediat Otolaryngol, Cincinnati, OH 45229 USA. Childrens Hosp, Med Ctr, Dept Pediat Gastroenterol, Cincinnati, OH 45229 USA. RP Hartnick, CJ (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. NR 21 TC 16 Z9 16 U1 0 U2 0 PU ANNALS PUBL CO PI ST LOUIS PA 4507 LACLEDE AVE, ST LOUIS, MO 63108 USA SN 0003-4894 J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD JAN PY 2002 VL 111 IS 1 BP 57 EP 60 PG 4 WC Otorhinolaryngology SC Otorhinolaryngology GA 512AW UT WOS:000173299800009 PM 11800370 ER PT J AU Erdag, G Morgan, JR AF Erdag, G Morgan, JR TI Interleukin-1 alpha and interleukin-6 enhance the antibacterial properties of cultured composite keratinocyte grafts SO ANNALS OF SURGERY LA English DT Article ID HUMAN EPIDERMAL-KERATINOCYTES; TOPICAL ANTIMICROBIAL AGENTS; HUMAN SKIN; INNATE IMMUNITY; PEPTIDE ANTIBIOTICS; BURN WOUNDS; CYTOTOXICITY; EPITHELIUM; DIFFERENTIATION; INFLAMMATION AB Objective To determine whether the antibacterial properties of cultured composite keratinocyte grafts can be enhanced by cytokines that stimulate the innate immune response. Summary Background Data Use of composite grafts of cultured keratinocytes has been limited because of their susceptibility to burn wound microorganisms as a result of their lack of a vasculature and immune cells when transplanted. Moreover, use of topical antimicrobial agents is limited with these composite grafts because of cytotoxic effects, Keratinocytes, like all epithelial cells in the body, maintain a natural defense mechanism called the innate immune system. Some components of this system can be induced by cytokines. Methods The innate immune response of cultured composite keratinocyte grafts treated with various cytokines was assessed indirectly by measuring the levels of mRNA encoding antimicrobial peptides (human beta defensin-1 and -2, LL-37, and anti leukoprotease) and antimicrobial proteins (lysozyme, bactericidal/permeability-inducing protein, and phospholipase A2) by reverse transcription-polymerase chain reaction and directly by measuring the ability of keratinocytes to inhibit the growth of added bacteria (Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus). Results Treatment with interluekin-1 alpha increased mRNA levels of antimicrobial peptides in keratinocytes on plastic dishes and in composite grafts. Interleukin-6 increased mRNA levels of antimicrobial proteins in composite grafts only. When added to composite grafts, both cytokines increased antibacterial activity against E coli, P. aeruginosa, and S. aureus. Moreover, interieukin-1 alpha and interleukin-6 did not impair the formation of a differentiated epidermis in vitro or after transplantation of the composite grafts. Conclusions Treatment with interleukin-I alpha or interleukin-6 of cultured composite keratinocyte grafts stimulates the innate immune response of keratinocytes, enhances the antibacterial properties of these grafts, and may better prepare them to combat infections in contaminated burn wounds. C1 Harvard Univ, Sch Med, Shriners Hosp Children, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Engn Med & Surg Serv, Boston, MA 02114 USA. RP Morgan, JR (reprint author), Harvard Univ, Sch Med, Shriners Hosp Children, 51 Blossom St, Boston, MA 02114 USA. EM jmorgan@sbi.org OI Morgan, Jeffrey/0000-0002-7546-3443 FU NICHD NIH HHS [HD-28528] NR 39 TC 55 Z9 57 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD JAN PY 2002 VL 235 IS 1 BP 113 EP 124 DI 10.1097/00000658-200201000-00015 PG 12 WC Surgery SC Surgery GA 508KB UT WOS:000173086300015 PM 11753050 ER PT J AU Pierie, JPEN Muzikansky, A Gaz, RD Faquin, WC Ott, MJ AF Pierie, JPEN Muzikansky, A Gaz, RD Faquin, WC Ott, MJ TI The effect of surgery and radiotherapy on outcome of anaplastic thyroid carcinoma SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 54th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 15-18, 2001 CL WASHINGTON, D.C. SP Soc Surg Oncol DE anaplastic thyroid cancer; surgery; radiotherapy; debulking ID RADIATION-THERAPY; GLAND; SURVIVAL AB Background: Anaplastic thyroid carcinoma (ATC) is an aggressive rare tumor. We analyzed our experience for prognosis and the effect of surgery and radiotherapy on patients with ATC. Methods: We conducted a retrospective review of all patients (n = 67) with ATC treated at a tertiary care center from 1969 to 1999. Survivor median follow-up was 51 months. Tumor and patient characteristics and therapy were assessed for effect on survival by multivariate analysis. Results: Patients presented with a neck mass (99%), change of voice (51%), dysphagia (33%), and dyspnea (28%). Surgery was performed in 44 of 67 patients, with 12 complete resections. The 6-month and 1- and 3-year survival rates were 92%, 92%, and 83% after complete resection; 53%, 35%, and 0% after debulking; and 22%, 4%, and 0% after no resection, respectively (P < .0001). A radiation dose of >45 Gy improved survival as compared with a lower dose (P = .02). Multivariate analysis showed that age less than or equal to70 years, absence of dyspnea or dysphagia at presentation, a tumor size :55 cm, and any surgical resection improved survival (P < .05). Conclusions: Candidates for surgery with curative intent for ATC are patients :570 years, tumors less than or equal to5 cm, and no distant disease. Radiotherapy >45 Gy improves outcome. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg Oncol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Canc Stat Ctr, Boston, MA USA. Med Ctr Leeuwarden, Dept Surg, Leeuwarden, Netherlands. RP Ott, MJ (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Surg Oncol, 626 Cox Bldg,100 Blossom St, Boston, MA 02114 USA. NR 20 TC 89 Z9 95 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JAN-FEB PY 2002 VL 9 IS 1 BP 57 EP 64 DI 10.1245/aso.2002.9.1.57 PG 8 WC Oncology; Surgery SC Oncology; Surgery GA 516QJ UT WOS:000173568000010 PM 11833496 ER PT J AU Ellison, B Liu, R Adams, J Elliot, P Baldwin, A Cusack, J AF Ellison, B Liu, R Adams, J Elliot, P Baldwin, A Cusack, J TI Selective inhibition of I Kappa B kinase 2 (IKK2) overcomes NF-kB mediated chemotherapy resistance in human colon cancer SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. Millenium Pharmaceut, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Surg Oncol, Boston, MA 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 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JAN PY 2002 VL 9 IS 1 SU S MA 51 BP S23 EP S23 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 516ZM UT WOS:000173586700052 ER PT J AU Esnaola, NF Lauwers, GY Nagorney, DM Ikai, I Yamaoka, Y Regimbeau, JM Belghiti, J Curley, SA Ellis, LM Vauthey, JN AF Esnaola, NF Lauwers, GY Nagorney, DM Ikai, I Yamaoka, Y Regimbeau, JM Belghiti, J Curley, SA Ellis, LM Vauthey, JN TI Clinicopathologic characteristics and predictors of outcome after resection of hepatocellular carcinoma in patients without hepatic fibrosis or cirrhosis SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Kyoto Univ, Grad Sch Med, Kyoto, Japan. Hop Beaujon, Paris, France. Mayo Clin, Rochester, MN USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JAN PY 2002 VL 9 IS 1 SU S MA P120 BP S76 EP S76 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 516ZM UT WOS:000173586700215 ER PT J AU Euhus, DM Aragaki, C Hughes, KS Haley, RW Lowry, WS Cann, J Elliott, T Tomlinson, G AF Euhus, DM Aragaki, C Hughes, KS Haley, RW Lowry, WS Cann, J Elliott, T Tomlinson, G TI Ethnic differences in breast cancer incidence and mortality in Bermuda SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Texas, SW Med Ctr, Dallas, TX USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. King Edward VII Mem Hosp, Hamilton, Bermuda. RI Haley, Robert/P-9026-2014 OI Haley, Robert/0000-0001-8849-9579 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 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JAN PY 2002 VL 9 IS 1 SU S MA P43 BP S53 EP S53 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 516ZM UT WOS:000173586700139 ER PT J AU Joseph, NE Sigurdson, ER Hanlon, AL Wang, H Mayer, RJ MacDonald, JS Catalano, PJ Haller, DG AF Joseph, NE Sigurdson, ER Hanlon, AL Wang, H Mayer, RJ MacDonald, JS Catalano, PJ Haller, DG TI Accuracy of determining nodal negativity in colorectal cancer based on the number of nodes retrieved on resection SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract C1 Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. CALBG, Boston, MA USA. SWOG, Philadelphia, PA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. ECOG, Philadelphia, PA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JAN PY 2002 VL 9 IS 1 SU S MA 18 BP S13 EP S13 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 516ZM UT WOS:000173586700019 ER PT J AU Park, JO Gupta, VK Brown, CK Lopez, CA Mauceri, HJ Cromie, WJ Manan, A Kufe, DW Hellman, S Posner, MC Weichselbaum, RR AF Park, JO Gupta, VK Brown, CK Lopez, CA Mauceri, HJ Cromie, WJ Manan, A Kufe, DW Hellman, S Posner, MC Weichselbaum, RR TI Early growth response-1 promoter induction by cisplatin enhances tumor necrosis factor mediated adenoviral gene therapy of solid tumors SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Chicago, Chicago, IL 60637 USA. Dana Farber Canc Inst, Boston, MA 02115 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 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JAN PY 2002 VL 9 IS 1 SU S MA 15 BP S12 EP S12 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 516ZM UT WOS:000173586700016 ER PT J AU Patten, LC Berger, DH Cleary, KR Curley, SA Hunt, KK Fagan, SP Lucci, A Feig, BW AF Patten, LC Berger, DH Cleary, KR Curley, SA Hunt, KK Fagan, SP Lucci, A Feig, BW TI A prospective evaluation of radiocolloid and immunohistochemical staining in colon cancer lymphatic mapping SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Baylor Coll Med, Houston, TX 77030 USA. Houston VA Med Ctr, Houston, TX USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JAN PY 2002 VL 9 IS 1 SU S MA P107 BP S72 EP S72 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 516ZM UT WOS:000173586700202 ER PT J AU Clouse, WD Hagino, RT Chiou, A DeCaprio, J Kashyap, VS AF Clouse, WD Hagino, RT Chiou, A DeCaprio, J Kashyap, VS TI Extracranial cerebrovascular revascularization for chronic ocular ischemia SO ANNALS OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT 26th Annual Meeting of the Peripheral-Vascular-Surgery-Society CY JUN 09, 2001 CL BALTIMORE, MARYLAND SP Peripheral Vasc Surg Soc ID CAROTID-ARTERY DISEASE; ENDARTERECTOMY; FLOW AB We investigated the demographics, presentation, and outcome of patients undergoing cerebrovascular reconstruction for chronic ocular ischemia (COI) at a single institution through a review of 17 patients over a 9-year period. A total of 558 extracranial cerebrovascular reconstructions were performed during the period of study. Seventeen patients (3%) suffered symptoms of COI. There were 19 symptomatic eyes and 15 asymptomatic eyes. Two patients suffered bilateral symptoms. Eighteen (95%) symptomatic eyes experienced rapidly degenerating global visual acuity, and one suffered bright-light amaurosis. Concomitant ocular pathology was present in 10 (59%) patients, consisting of glaucoma (n = 4), cataracts (n = 4), diabetic retinopathy (n = 3), and macular degeneration (n = 1). Symptomatic eyes were found to have significantly worse ipsilateral internal carotid artery (p = 0.004), external carotid artery (p = 0.002), aortic arch branch disease (p = 0,04), and vertebral artery disease (p = 0.04). All 17 reconstructions treated ipsilateral disease. Twelve patients (70.6%) had significant bilateral disease at the time of operation. Three patients underwent staged contralateral reconstruction. Following revascularization, subjective visual improvement or stabilization occurred in 16 patients (94%). A single patient worsened after developing acute narrow angle glaucoma in the perioperative period. Worse cerebrovascular disease is present ipsilateral to symptomatic eyes. When revascularization is performed, arrest of progression or improvement of symptoms occurs in most patients. C1 Wilford Hall USAF Med Ctr, Vasc Surg Sect, Dept Surg, Lackland AFB, TX 78236 USA. RP Clouse, WD (reprint author), Massachusetts Gen Hosp, Div Vasc Surg, 15 Parkman St,WAC 458, Boston, MA 02114 USA. NR 19 TC 6 Z9 6 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0890-5096 J9 ANN VASC SURG JI Ann. Vasc. Surg. PD JAN PY 2002 VL 16 IS 1 BP 1 EP 5 DI 10.1007/s10016-001-0137-1 PG 5 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 529PK UT WOS:000174307700001 PM 11904796 ER PT J AU Yarmush, ML Jayaraman, A AF Yarmush, ML Jayaraman, A TI Advances in proteomic technologies SO ANNUAL REVIEW OF BIOMEDICAL ENGINEERING LA English DT Review DE two-dimensional gel electrophoresis; mass spectrometry; protein maps; protein-protein interactions ID PROTEIN-PROTEIN INTERACTIONS; 2-DIMENSIONAL ELECTROPHORESIS IMAGES; LASER DESORPTION/IONIZATION-TIME; 3RD-GENERATION SOFTWARE PACKAGE; IMMOBILIZED PH GRADIENTS; MASS-SPECTROMETRY DATA; SACCHAROMYCES-CEREVISIAE; ELECTROSPRAY-IONIZATION; GEL-ELECTROPHORESIS; SEQUENCE DATABASES AB Proteomics is a rapidly emerging set of key technologies that are being used to identify proteins and map their interactions in a cellular context. With the sequencing of the human genome, the scope of proteomics has shifted from protein identification. and characterization to include protein structure, function and protein-protein interactions. Technologies used in proteomic research include two-dimensional gel electrophoresis, mass spectrometry, yeast two-hybrids screens, and computational prediction programs. While some of these technologies have been in use for a long time, they are currently being applied to study physiology and cellular processes in high-throughput formats. It is the high-throughput approach that defines and characterizes modem proteomics, In this review, we discuss the current status of these experimental and computational technologies relevant to the three major aspects of proteomics-characterization of proteomes, identification of proteins, and determination of protein function. We also briefly discuss the development of new proteomic technologies that are based on recent advances in analytical and biochemical techniques, engineering, microfabrication, and computational prowess. The integration of these advances with established technologies is invaluable for the drive toward a comprehensive understanding of protein structure and function in the cellular milieu. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med Surg Serv, Boston, MA 02114 USA. Shriners Burns Inst, Boston, MA 02114 USA. RP Yarmush, ML (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med Surg Serv, Boston, MA 02114 USA. NR 104 TC 70 Z9 74 U1 2 U2 9 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 1523-9829 J9 ANNU REV BIOMED ENG JI Annu. Rev. Biomed. Eng. PY 2002 VL 4 BP 349 EP 373 DI 10.1146/annurev.bioeng.4.020702.153443 PG 25 WC Engineering, Biomedical SC Engineering GA 590MZ UT WOS:000177827800015 PM 12117762 ER PT J AU Shimaoka, M Takagi, J Springer, TA AF Shimaoka, M Takagi, J Springer, TA TI Conformational regulation of integrin structure and function SO ANNUAL REVIEW OF BIOPHYSICS AND BIOMOLECULAR STRUCTURE LA English DT Review DE I domain; conformational change; affinity regulation; divalent cations; signal transmission ID FUNCTION-ASSOCIATED ANTIGEN-1; BETA-PROPELLER DOMAIN; INTERCELLULAR-ADHESION MOLECULE-1; P-ARYLTHIO CINNAMIDES; CYSTEINE-RICH REPEATS; C-TERMINAL REGION; CD11B A-DOMAIN; I-DOMAIN; CRYSTAL-STRUCTURE; LIGAND-BINDING AB Integrins are a structurally elaborate family of heterodimers that mediate divalent cation-dependent cell adhesion in a wide range of biological contexts. The inserted (1) domain binds ligand in the subset of integrins in which it is present. Its structure has been determined in two alternative conformations, termed open and closed. In striking similarity to signaling G proteins, rearrangement of a Mg2+-binding site is linked to large conformational movements in distant backbone regions. Mutations have been used to stabilize either the closed or open structures. These show that the snapshots of the open conformation seen only in the presence of a ligand or a ligand mimetic represent a high-affinity, ligand-binding conformation, whereas those of the closed conformation correspond to a low-affinity conformation. The C-terminal a-helix. moves 10 A down the side of the domain in the open conformation. Locking in the conformation of the preceding loop is sufficient to increase affinity for ligand 9000-fold. This C-terminal "bell-rope" provides a mechanism for linkage to conformational. movements in other domains. The transition from the closed to open conformation has been implicated in fast (<1 s) regulation of integrin affinity in response to activation signals from inside the cell. Recent integrin structures and functional studies reveal interactions between beta-propeller, I, and I-like domains in the headpiece, and a critical role for integrin EGF domains in the stalk region. These studies suggest that the headpiece of the integrin faces down toward the membrane in the inactive conformation and extends upward in a "switchblade"-like opening motion upon activation. These long-range structural rearrangements of the entire integrin molecule involving multiple interdomain contacts appear closely linked to conformational changes in the I domain, which result in increased affinity and competence for ligand binding. C1 Harvard Univ, Sch Med, Ctr Blood Res, Dept Pathol & Anesthesia, Boston, MA 02115 USA. RP Shimaoka, M (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, Dept Pathol & Anesthesia, 200 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [CA 31798 8, CA 31799]; NHLBI NIH HHS [HL 48675] NR 104 TC 351 Z9 363 U1 1 U2 21 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 1056-8700 J9 ANNU REV BIOPH BIOM JI Annu. Rev. Biophys. Biomolec. Struct. PY 2002 VL 31 BP 485 EP 516 DI 10.1146/annurev.biophys.31.101101.140922 PG 40 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 568MG UT WOS:000176545500019 PM 11988479 ER PT J AU Pasquinelli, AE Ruvkun, G AF Pasquinelli, AE Ruvkun, G TI Control of developmental timing by microRNAs and their targets SO ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY LA English DT Review DE stRNAs; miRNAs; let-7; lin-4; C. elegans ID NEMATODE CAENORHABDITIS-ELEGANS; TEMPORAL PATTERN-FORMATION; HETEROCHRONIC GENE LIN-14; EPIDERMAL-CELL IDENTITY; DOUBLE-STRANDED-RNA; C-ELEGANS; REGULATORY RNA; PROTEIN-SYNTHESIS; RING FINGER; ZINC-FINGER AB In Caenorhabditis elegans the timing of many developmental events is regulated by heterochronic genes. Such genes orchestrate the timing of cell divisions and fates appropriate for the developmental stage of an organism. Analyses of heterochronic mutations in the nematode C. elegans have revealed a genetic pathway that controls the timing of post-embryonic cell divisions and fates. Two of the genes in this pathway encode small regulatory RNAs. The 22 nucleotide (nt) RNAs downregulate the expression of protein-coding mRNAs of target heterochronic genes. Analogous variations in the timing of appearance of particular features have been noted among closely related species, suggesting that such explicit control of developmental timing may not be exclusive to C. elegans. In fact, some of the genes that globally pattern the temporal progression of C. elegans development, including one of the tiny RNA genes, are conserved and temporally regulated across much of animal phylogeny, suggesting that the molecular mechanisms of temporal control are ancient and universal. A very large family of tiny RNA genes called microRNAs, which are similar in structure to the heterochronic regulatory RNAs, have been detected in diverse animal species and are likely to be present in most metazoans. Functions of the newly discovered microRNAs are not yet known. Other examples of temporal programs during growth include the exquisitely choreographed temporal sequences of developmental fates in neurogenesis in Drosophila and the sequential programs of epidermal coloration in insect wing patterning. An interesting possibility is that microRNAs mediate transitions on a variety of time scales to pattern the activities of particular target protein-coding genes and in turn generate sets of cells over a period of time. Plasticity in these microRNA genes or their targets may lead to changes in relative developmental timing between related species, or heterochronic change. Instead of inventing new gene functions, even subtle changes in temporal expression of pre-existing control genes can result in speciation by altering the time at which they function. C1 Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Pasquinelli, AE (reprint author), Harvard Univ, Sch Med, Dept Genet, Wellman 8,50 Blossom St, Boston, MA 02114 USA. NR 91 TC 209 Z9 241 U1 3 U2 33 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 1081-0706 J9 ANNU REV CELL DEV BI JI Annu. Rev. Cell Dev. Biol. PY 2002 VL 18 BP 495 EP 513 DI 10.1146/annurev.cellbio.18.012502.105832 PG 23 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 618HV UT WOS:000179413400018 PM 12142272 ER PT J AU Shin, JT Fishman, MC AF Shin, JT Fishman, MC TI From zebrafish to human: Modular medical models SO ANNUAL REVIEW OF GENOMICS AND HUMAN GENETICS LA English DT Review DE developmental biology; genetic screen; chemical screen; integrative physiology; pathophysiology ID RECESSIVE RETINITIS-PIGMENTOSA; MUTATIONS AFFECTING DEVELOPMENT; RADIATION HYBRID MAP; DANIO-RERIO; NEURAL-CREST; POSITIONAL CLONING; GENETIC-ANALYSIS; CIRCADIAN CLOCK; SONIC HEDGEHOG; HEREDITARY HEMOCHROMATOSIS AB Genetic screens in Drosophila melanogaster, Caenorhabditis elegans, and Danio rerio clarified the logic of metazoan development by revealing critical unitary steps and pathways to embryogenesis. Can genetic screens similarly organize medicine? We here examine human diseases that resemble mutations in Danio rerio, the zebrafish, the one vertebrate species for which large-scale genetic screens have been performed and extensively analyzed. Zebrafish mutations faithfully phenocopy many human disorders. Each mutation, once cloned, provides candidate genes and pathways for evaluation in the human. The collection of mutations in their entirety potentially provides a medical taxonomy, one based in developmental biology and genetics. C1 Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Div Cardiol, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Shin, JT (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. EM jshin1@partners.org; mcfishman@partners.org FU NHLBI NIH HHS [5T32HL07208, 2R01HL49579, 5R01HL63206] NR 181 TC 159 Z9 172 U1 1 U2 22 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 1527-8204 EI 1545-293X J9 ANNU REV GENOM HUM G JI Annu. Rev. Genomics Hum. Genet. PY 2002 VL 3 BP 311 EP 340 DI 10.1146/annurev.genom.3.031402.131506 PG 34 WC Genetics & Heredity SC Genetics & Heredity GA 605LF UT WOS:000178678800013 PM 12142362 ER PT J AU Sklar, P AF Sklar, P TI Linkage analysis in psychiatric disorders: The emerging picture SO ANNUAL REVIEW OF GENOMICS AND HUMAN GENETICS LA English DT Review DE schizophrenia; bipolar disorder; genomics; candidate gene; linkage disequilibrium; complex genetic disease ID BIPOLAR AFFECTIVE-DISORDER; SCHIZOPHRENIA SUSCEPTIBILITY GENES; GENOME-WIDE SEARCH; GENETICS INITIATIVE PEDIGREES; CHROMOSOME-18 DNA MARKERS; MANIC-DEPRESSIVE ILLNESS; CARDIO-FACIAL SYNDROME; COSTA-RICAN PEDIGREES; OLD-ORDER AMISH; DSM-III-R AB Gene finding in genetically complex diseases has been difficult as a result of many factors that have diagnostic and methodologic considerations. For bipolar disorder and schizophrenia, numerous family, twin, and adoption studies have identified a strong genetic component to these behavioral psychiatric disorders. Despite difficulties that include diagnostic differences between sample populations and the lack of statistical significance in many individual studies, several promising patterns have emerged, suggesting that true susceptibility loci for schizophrenia and bipolar disorder may have been identified. In this review, the genetic epidemiology of these disorders is covered as well as linkage findings on chromosomes 4, 12, 13, 18, 2 1, and 22 in bipolar disorder and on chromosomes 1, 6, 8, 10, 13, 15, and 22 in schizophrenia. The sequencing of the human genome and identification of numerous single nucleotide polymorphisms (SNP) should substantially enhance the ability of investigators to identify disease-causing genes in these areas of the genome. C1 Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Cambridge, MA 02139 USA. Whitehead Inst, Ctr Genome Res, Cambridge, MA 02139 USA. RP Sklar, P (reprint author), Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Cambridge, MA 02139 USA. EM sklar@psych.mgh.harvard.edu NR 183 TC 60 Z9 64 U1 6 U2 11 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 1527-8204 EI 1545-293X J9 ANNU REV GENOM HUM G JI Annu. Rev. Genomics Hum. Genet. PY 2002 VL 3 BP 371 EP 413 DI 10.1146/annurev.genom.3.022502.103141 PG 43 WC Genetics & Heredity SC Genetics & Heredity GA 605LF UT WOS:000178678800015 PM 12142356 ER PT J AU Mann, DL Deswal, A Bozkurt, B Torre-Amione, G AF Mann, DL Deswal, A Bozkurt, B Torre-Amione, G TI New therapeutics for chronic heart failure SO ANNUAL REVIEW OF MEDICINE LA English DT Review DE left ventricular remodeling; renin angiotensin system; cyokines; adrenergic nervous system ID PARTIAL LEFT VENTRICULECTOMY; DILATED CARDIOMYOPATHY; RANDOMIZED TRIAL; ANGIOTENSIN-II; ENDOTHELIN; SURVIVAL; DISEASE; INHIBITOR; MORTALITY; MORBIDITY AB Traditionally, clinicians have viewed heart failure either as a problem of excessive salt and water retention caused by abnormalities of renal blood flow, or as a hemodynamic problem associated with a reduced cardiac output and excessive peripheral vasoconstriction. Recently, clinicians have begun to adopt a neurohormonal model in which heart failure progresses because of the toxic effects of endogenous biological systems that become activated in heart failure. We review the rationale for existing heart failure therapies and discuss the reasoning behind the development of some emerging therapies. C1 Baylor Coll Med, Dept Med, Winters Ctr Heart Failure Res, Houston, TX 77030 USA. Houston Vet Adm Med Ctr, Houston, TX 77030 USA. Methodist Hosp, Houston, TX 77030 USA. RP Mann, DL (reprint author), Baylor Coll Med, Dept Med, Winters Ctr Heart Failure Res, 6565 Fannin St, Houston, TX 77030 USA. OI Mann, Douglas /0000-0002-2516-0145 FU NHLBI NIH HHS [P50 HL-O6H, R01 HL58081-01, R01 HL61543-01, HL-42250-10/10] NR 38 TC 29 Z9 31 U1 0 U2 1 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4219 J9 ANNU REV MED JI Annu. Rev. Med. PY 2002 VL 53 BP 59 EP 74 DI 10.1146/annurev.med.53.082901.104004 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA 531KL UT WOS:000174414500008 PM 11818463 ER PT J AU Wilens, TE Biederman, J Spencer, TJ AF Wilens, TE Biederman, J Spencer, TJ TI Attention deficit/hyperactivity disorder across the lifespan SO ANNUAL REVIEW OF MEDICINE LA English DT Review DE ADHD; ADD; comorbidity; stimulants; antidepressants ID DEFICIT-HYPERACTIVITY DISORDER; SUBSTANCE USE DISORDERS; DOPAMINE TRANSPORTER; FOLLOW-UP; PSYCHIATRIC COMORBIDITY; BIPOLAR DISORDER; CORPUS-CALLOSUM; CHILDHOOD-ONSET; DOUBLE-BLIND; CHILDREN AB Attention deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder presenting for treatment in youth. ADHD is often chronic with prominent symptoms and impairment spanning into adulthood. ADHD is often associated with co-occurring anxiety, mood, and disruptive disorders, as well as substance abuse. The diagnosis of ADHD by careful review of symptoms and impairment is both reliable and valid. Recent genetic, imaging, neurochemistry, and neuropsychological data support the biological underpinning of the disorder. All aspects of an individual's life must be considered in the diagnosis and treatment of ADHD. Pharmacotherapy, including stimulants, antidepressants, and antihypertensives, plays a fundamental role in the management of ADHD across the lifespan. C1 Massachusetts Gen Hosp, Clin Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Wilens, TE (reprint author), Massachusetts Gen Hosp, Clin Res Program Pediat Psychopharmacol, 15 Parkman St, Boston, MA 02114 USA. NR 99 TC 262 Z9 265 U1 7 U2 29 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4219 J9 ANNU REV MED JI Annu. Rev. Med. PY 2002 VL 53 BP 113 EP 131 DI 10.1146/annurev.med.53.082901.103945 PG 19 WC Medicine, General & Internal SC General & Internal Medicine GA 531KL UT WOS:000174414500011 PM 11818466 ER PT J AU Cooper, DKC Gollackner, B Sachs, DH AF Cooper, DKC Gollackner, B Sachs, DH TI Will the pig solve the transplantation backlog? SO ANNUAL REVIEW OF MEDICINE LA English DT Review DE antibodies; complement; primate; rejection; xenotransplantation ID HEMATOPOIETIC-CELL TRANSPLANTATION; HUMAN NATURAL ANTIBODIES; ORGAN XENOTRANSPLANTATION; ENDOGENOUS RETROVIRUS; IN-VIVO; TOLERANCE; BABOONS; REJECTION; TRANSMISSION; COAGULATION AB The increasing shortage of human cadaveric organs for purposes of transplantation has become the critical limiting factor in the number of transplants performed each year. Some of this deficit is being met by the use of organs or partial organs from living donors, but this source is insufficient. Xenotransplantation-the transplantation of organs between species, namely from the pig to human-could provide a solution if immunologic and other associated problems could be solved. When a pig organ is transplanted into a primate, hyperacute rejection, induced by anti-pig antibody and mediated by complement and the coagulation system, develops rapidly. This immediate problem can now be overcome, but the return or persistence of anti-pig antibody leads to a delayed form of humoral rejection, acute humoral xenograft rejection, which leads to destruction of the organ within days or weeks. We review the various approaches being investigated to overcome this barrier. Whether they will also prevent subsequent acute cellular rejection remains unknown. Brief mention is made of the potential physiologic incompatibilities between pig and human organs, as well as the microbiologic safety aspects of xenotransplantation. Finally, the question of patient and societal acceptance of xenotransplantation is discussed. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. RP Cooper, DKC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. FU NIAID NIH HHS [1PO1AI45897] NR 46 TC 161 Z9 164 U1 5 U2 20 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4219 J9 ANNU REV MED JI Annu. Rev. Med. PY 2002 VL 53 BP 133 EP 147 DI 10.1146/annurev.med.53.082901.103900 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA 531KL UT WOS:000174414500012 PM 11818467 ER PT J AU Gandhi, RT Walker, BD AF Gandhi, RT Walker, BD TI Immunologic control of HIV-1 SO ANNUAL REVIEW OF MEDICINE LA English DT Review DE human immunodeficiency virus-1 (HIV-1); acquired immunodeficiency syndrome (A-EDS); immunology; virology; immunotherapy ID HUMAN-IMMUNODEFICIENCY-VIRUS; CYTOTOXIC T-LYMPHOCYTES; ACTIVE ANTIRETROVIRAL THERAPY; SUSTAINED VIRAL SUPPRESSION; CELLULAR IMMUNE-RESPONSES; LONG-TERM SURVIVOR; HEPATITIS-B VIRUS; DENDRITIC CELLS; CHORIOMENINGITIS VIRUS; TYPE-1 INFECTION AB By destroying CD4+ T cells, human immunodeficiency virus-1 (HIV-1) infection results in immunodeficiency and the inability of the immune system to contain the virus in most individuals. Although treatment of HIV-1 infection with potent antiretroviral medications has resulted in enormous clinical benefit, there is a growing recognition of the limitations of this therapy. As a result, novel approaches to treating HIV-1 infection are being considered. One such strategy is immunotherapy, which seeks to boost immune responses against HIV-1 and control the virus. This approach is based on studies of other viruses in which a coordinated immune response contains the chronic infection. Recent studies show that CD4+ helper responses, CD8+ T cell activity, and antibodies may contribute to control of the virus without antiretroviral therapy in some HIV-positive individuals. Based on this understanding of the immunologic correlates of control of HIV-1, exciting new immunotherapeutic strategies for HIV-1 infection are being designed and tested. C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. Harvard Univ, Sch Med, Div Aids, Boston, MA 02114 USA. RP Gandhi, RT (reprint author), Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. NR 111 TC 104 Z9 108 U1 1 U2 4 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4219 J9 ANNU REV MED JI Annu. Rev. Med. PY 2002 VL 53 BP 149 EP 172 DI 10.1146/annurev.med.53.082901.104011 PG 24 WC Medicine, General & Internal SC General & Internal Medicine GA 531KL UT WOS:000174414500013 PM 11818468 ER PT J AU Richardson, P Hideshima, T Anderson, K AF Richardson, P Hideshima, T Anderson, K TI Thalidomide: Emerging role in cancer medicine SO ANNUAL REVIEW OF MEDICINE LA English DT Review DE immunomodulation; antiangiogenesis; myeloma ID VERSUS-HOST DISEASE; HUMAN-IMMUNODEFICIENCY-VIRUS; BONE-MARROW ANGIOGENESIS; MULTIPLE-MYELOMA CELLS; NECROSIS-FACTOR-ALPHA; SINGLE-DOSE PHARMACOKINETICS; ERYTHEMA-NODOSUM LEPROSUM; HEALTHY MALE-VOLUNTEERS; PERIPHERAL-BLOOD; PHASE-II AB Thalidomide-removed from widespread clinical use by 1962 because of severe teratogenicity-has antiangiogenic and immunomodulatory effects, including the inhibition of tumor necrosis alpha factor. It has now returned to practice as an effective oral agent in the management of various disease states including erythema nodosum leprosum, for which it was approved by the U.S. Food and Drug Administration in 1998, and more recently certain malignancies, including multiple myeloma. Although thalidomide's mechanism of action remains incompletely understood, considerable insight has been generated by extensive preclinical studies in multiple myeloma. Moreover, clinical trials have confirmed benefit in relapsed disease, and the role of thalidomide in treating newly diagnosed patients is currently under study. Its use in other tumors is under evaluation, with promise in renal cell carcinoma, prostate cancer, glioma, and Kaposi's sarcoma. Activity has also been demonstrated in chronic graft-versus-host disease and in symptom relief as part of palliative care. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst,Dept Adult Oncol, Jerome Lipper Myeloma Ctr,Div Hematol Oncol, Boston, MA 02115 USA. RP Richardson, P (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst,Dept Adult Oncol, Jerome Lipper Myeloma Ctr,Div Hematol Oncol, 44 Binney St, Boston, MA 02115 USA. NR 112 TC 99 Z9 106 U1 0 U2 4 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4219 J9 ANNU REV MED JI Annu. Rev. Med. PY 2002 VL 53 BP 629 EP 657 DI 10.1146/annurev.med.53.082901.104043 PG 29 WC Medicine, General & Internal SC General & Internal Medicine GA 531KL UT WOS:000174414500038 PM 11818493 ER PT J AU Derose, SF Schuster, MA Fielding, JE Asch, SM AF Derose, SF Schuster, MA Fielding, JE Asch, SM TI Public health quality measurement: Concepts and challenges SO ANNUAL REVIEW OF PUBLIC HEALTH LA English DT Review DE outcome and process assessment (health care); public health administration/indicator; quality/quality assurance; health care/public health practice ID COMMUNITY PREVENTIVE SERVICES; SO-STRANGE BEDFELLOWS; LOCAL HEALTH; ORGANIZATIONAL PRACTICES; CONSUMER REPORTS; MANAGED CARE; IMPROVEMENT; PERFORMANCE; DEPARTMENTS; DIFFERENCE AB Public health agencies increasingly are recognizing the need to formally and quantitatively assess and improve the quality of their programs, information, and policies. Measuring quality can help organizations monitor their progress toward public health goals and become more accountable to both the populations they serve and policy makers. Yet quality assessment is a complex task that involves precise determination and specification of useful measures. We discuss a well-established conceptual framework for organizing quality assessment in the context of planning and delivery of programs and services by local health departments, and consider the strengths and limitations of this approach for guiding quality improvement. We review several past and present quality measurement-related initiatives designed for public health department use, and discuss current and future challenges in this evolving area of public health practice. C1 So Calif Kaiser Permanente, Pasadena, CA 91101 USA. Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Hlth Serv, Los Angeles, CA 90095 USA. RAND Corp, Santa Monica, CA 90407 USA. Univ Calif Los Angeles, Dept Med, Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. RP Derose, SF (reprint author), So Calif Kaiser Permanente, Pasadena, CA 91101 USA. FU ODCDC CDC HHS [U48/CCU915773] NR 87 TC 31 Z9 32 U1 2 U2 9 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0163-7525 J9 ANNU REV PUBL HEALTH JI Annu. Rev. Public Health PY 2002 VL 23 BP 1 EP 21 DI 10.1146/annurev.publhealth.23.092601.095644 PG 21 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 553QK UT WOS:000175686800002 PM 11910052 ER PT J AU Lawrence, LE Frosco, M Ryan, B Chaniewski, S Yang, H Hooper, DC Barrett, JF AF Lawrence, LE Frosco, M Ryan, B Chaniewski, S Yang, H Hooper, DC Barrett, JF TI Bactericidal activities of BMS-284756, a novel des-F(6)-quinolone, against Staphylococcus aureus strains with topoisomerase mutations SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID DNA GYRASE; STREPTOCOCCUS-PNEUMONIAE; IN-VITRO; RESISTANCE; QUINOLONE; IV; FLUOROQUINOLONES; LEVOFLOXACIN; LOCUS; OFLOXACIN AB The antistaphylococcal activities of BMS-284756 (T-3811ME), levofloxacin, moxifloxacin, and ciprofloxacin were compared against wild-type and grlA and grlA/gyrA mutant strains of Staphylococcus aureus. BMS-284756 was the most active quinolone tested, with MICs and minimal bactericidal concentrations against S. aureus wild-type strain MT5, grlA mutant MT5224c4, and grlA/gyrA mutant EN8 of 0.03 and 0.06, 0.125 and 0.125, and 4 and 4 mug/ml, respectively. In the time-kill studies, BMS-284756 and levofloxacin exhibited rapid killing against all strains. Ciprofloxacin, however, was not bactericidal for the double mutant, EN8. BMS-284756 and levofloxacin were bactericidal (3 log(10) decrease in CFU/ml) against the MT5 and MT5224c4 strains at two and four times the MIC within 2 to 4 h. Against EN8, BMS-284756 was bactericidal within 4 h at two and four times the MIC, and levofloxacin achieved similar results within 4 to 6 h. Both the wild-type strain MT5 and grlA mutant MT5224c4 should be considered susceptible to both BMS-284756 and levofloxacin, and both quinolones are predicted to have clinical efficacy. The in vivo efficacy of BMS-284756, levofloxacin, and moxifloxacin against S. aureus strain ISP794 and its single mutant 2C6(1)-1 directly reflected the in vitro activity: increased MICs correlated with decreased in vivo efficacy. The 50% protective doses of BMS-284756 against wild-type and mutant strains were 2.2 and 1.6 mg/kg of body weight/day, respectively, compared to the levofloxacin values of 16 and 71 mg/kg/day and moxifloxacin values of 4.7 and 61.6 mg/kg/day. BMS-284756 was more potent than levofloxacin and equipotent with moxifloxacin against ISP794 both in vitro and in vivo, while BMS-284756 was more potent than levofloxacin and moxifloxacin against 2C6(1)-1. C1 Bristol Myers Squibb Co, Pharmaceut Res Inst, Dept Microbiol, Wallingford, CT 06492 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Lawrence, LE (reprint author), Bristol Myers Squibb Co, Pharmaceut Res Inst, Dept Microbiol, 5 Res Pkwy, Wallingford, CT 06492 USA. NR 24 TC 11 Z9 11 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JAN PY 2002 VL 46 IS 1 BP 191 EP 195 DI 10.1128/AAC.46.1.191-195.2002 PG 5 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 504QP UT WOS:000172867600030 PM 11751133 ER PT J AU Kuritzkes, DR Bassett, RL Young, RK Barrett, H Koel, JL Hazelwood, JD Johnson, VA AF Kuritzkes, DR Bassett, RL Young, RK Barrett, H Koel, JL Hazelwood, JD Johnson, VA CA ACTG 306 370 Protocol Teams TI Rate of emergence of thymidine analogue resistance mutations in HIV-1 reverse transcriptase selected by stavudine or zidovudine-based regimens in treatment-naive patients SO ANTIVIRAL THERAPY LA English DT Meeting Abstract C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Colorado Hlth Sci Ctr, Denver, CO USA. Birmingham VA Med Ctr, Birmingham, AL USA. Univ Alabama, Sch Med, Birmingham, AL 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. PY 2002 VL 7 SU 1 MA 36 BP S41 EP S41 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 583HM UT WOS:000177401300037 ER PT J AU Carlson, JA Mu, XC Slominski, A Weismann, K Crowson, AN Malfetano, J Prieto, VG Mihm, MC AF Carlson, JA Mu, XC Slominski, A Weismann, K Crowson, AN Malfetano, J Prieto, VG Mihm, MC TI Melanocytic proliferations associated with lichen sclerosus SO ARCHIVES OF DERMATOLOGY LA English DT Review ID SQUAMOUS-CELL CARCINOMA; EXTRACELLULAR-MATRIX PROTEINS; MALIGNANT-MELANOMA; CHILDHOOD MELANOMA; VULVAR MELANOMA; ET-ATROPHICUS; DYSPLASTIC NEVI; LESIONS; CHILDREN; SKIN AB Objectives: To describe the clinicopathologic features of melanocytic proliferations associated with lichen sclerosus (LS) and to compare these findings with those in controls. Design: Cohort study. Setting: Academic and private practice dermatology and dermatopathology services. Patients: Cases of melanocytic proliferations associated with LS and consecutive controls with persistent (recurrent) melanocytic nevi, persistent malignant melanomas, and compound melanocytic nevi. Main Outcome Measures: Diagnostic criteria and disease recurrence. Results: Eleven patients, all female, with a mean age of 40 years (range, 8-83 years), presented with pigmented lesions clinically suspected to be malignant melanoma or atypical melanocytic nevi affecting the vulva (7 patients), perineum (3 patients), or chest (1 patient). Lichen sclerosus was first identified in the biopsy specimen and subsequently confirmed clinically. In 10 cases, melanocytic nevus was superimposed on LS (overlying or entrapped by sclerosis), whereas LS was found at the periphery of vulvar malignant melanoma. After complete excision, no recurrences have been reported for the melanocytic nevi in LS (mean follow-up, 29 months; range, 4-60 months). Compared with control lesions, the LS melanocytic nevi most closely resembled persistent melanocytic nevi and could be distinguished from persistent malignant melanoma histologically. Melanocytes, nevoid or malignant, proliferating contiguously with fibrotic or sclerotic collagen, contained abundant melanin, diffusely expressed HMB-45, and had a higher Ki-67 labeling index than ordinary melanocytic nevi. However, persistent malignant melanoma exhibited mitotic figures significantly higher Ki-67 labeling index, and deep dermal HMB-45 expression compared with LS melanocytic nevi and persistent melanocytic nevi. Conclusions: Melanocytic nevi occurring in LS have features in common with persistent melanocytic nevi and can mimic malignant melanoma. An "activated" melanocytic phenotype is seen in LS melanocytic nevi, implicating a stromal-induced change. C1 Albany Med Coll, Dept Pathol, Div Dermatol, Albany, NY 12208 USA. Albany Med Coll, Dept Pathol, Div Dermatopathol, Albany, NY 12208 USA. Univ Tennessee, Dept Pathol, Memphis, TN USA. Bispebjerg Hosp, Dept Dermatovenerol, DK-2400 Copenhagen, Denmark. Reg Med Labs, Tulsa, OK USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Carlson, JA (reprint author), Albany Med Coll, Dept Pathol, Div Dermatol, Campus Box MC-81, Albany, NY 12208 USA. OI Carlson, John Andrew/0000-0002-6866-6314 NR 106 TC 52 Z9 52 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD JAN PY 2002 VL 138 IS 1 BP 77 EP 87 DI 10.1001/archderm.138.1.77 PG 11 WC Dermatology SC Dermatology GA 512BB UT WOS:000173300300009 PM 11790170 ER PT J AU Tohen, M Chengappa, KNR Suppes, T Zarate, CA Calabrese, JR Bowden, CL Sachs, GS Kupfer, DJ Baker, RW Risser, RC Keeter, EL Feldman, PD Tollefson, GD Breier, A AF Tohen, M Chengappa, KNR Suppes, T Zarate, CA Calabrese, JR Bowden, CL Sachs, GS Kupfer, DJ Baker, RW Risser, RC Keeter, EL Feldman, PD Tollefson, GD Breier, A TI Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy SO ARCHIVES OF GENERAL 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 WEIGHT-GAIN; RATING-SCALE; DISORDERS; PLACEBO AB Background: A 6-week double-blind, randomized, placebo-controlled trial was conducted to determine the efficacy of combined therapy with olanzapine and either valproate or lithium compared with valproate or lithium alone in treating acute manic or mixed bipolar episodes. Methods: The primary objective was to evaluate the efficacy of olanzapine (5-20 mg/d) vs placebo when added to ongoing mood-stabilizer therapy as measured by reductions in Young Mania Rating Scale (YMRS) scores. Patients with bipolar disorder (n = 344), manic or mixed episode, who were inadequately responsive to more than 2 weeks of lithium or valproate therapy, were randomized to receive cotherapy (olanzapine + mood-stabilizer) or monotherapy (placebo + mood-stabilizer). Results: Olanzapine cotherapy improved patients' YMRS total scores significantly more than monotherapy (-13.11 vs -9.10; P=.003). Clinical response rates ( greater than or equal to50% improvement on YMRS) were significantly higher with cotherapy (67.7% vs 44.7%; P<.001). Olanzapine cotherapy improved 21-item Hamilton Depression Rating Scale (HAMD-21) total scores significantly more than monotherapy (4.98 vs 0.89 points; P<.001). In patients with mixed-episodes with moderate to severe depressive symptoms (DSM-IV mixed episode; HAMD-21 score of greater than or equal to20 at baseline), olanzapine cotherapy improved HAMD-21 scores by 10.31 points compared with 1.57 for monotherapy (P<.001). Extrapyramidal symptoms (Simpson-Angus Scale, Barnes Akathisia Scale, Abnormal Involuntary Movement Scale) were not significantly changed from baseline to end point in either treatment group. Treatment-emergent symptoms that were significantly higher for the olanzapine cotherapy group included somnolence, dry mouth, weight gain, increased appetite, tremor, and slurred speech. Conclusion: Compared with the use of valproate or lithium alone, the addition of olanzapine provided superior efficacy in the treatment of manic and mixed bipolar episodes. C1 Harvard Univ, Sch Med, McLean Hosp, Dept Psychiat, Belmont, MA 02178 USA. Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. Univ Pittsburgh, Med Ctr, Western Psychiat Inst & Clin, Pittsburgh, PA USA. SW Texas State Univ, Med Ctr, Dept Psychiat, Dallas, TX USA. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Case Western Reserve Univ, Dept Psychiat, Cleveland, OH 44106 USA. Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02138 USA. Univ Texas, Hlth Sci Ctr, Dept Psychiat, San Antonio, TX 78284 USA. RP Tohen, M (reprint author), Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. NR 23 TC 296 Z9 303 U1 4 U2 12 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 JAN PY 2002 VL 59 IS 1 BP 62 EP 69 DI 10.1001/archpsyc.59.1.62 PG 8 WC Psychiatry SC Psychiatry GA 508XV UT WOS:000173115800013 PM 11779284 ER PT J AU Pompeu, F Growdon, JH AF Pompeu, F Growdon, JH TI Diagnosing dementia with Lewy bodies SO ARCHIVES OF NEUROLOGY LA English DT Editorial Material ID PARKINSONS-DISEASE; ALPHA-SYNUCLEIN; BODY DISEASE C1 Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Pompeu, F (reprint author), Massachusetts Gen Hosp, Dept Neurol, WACC 830, Boston, MA 02114 USA. EM growdon@helix.mgh.harvard.edu NR 12 TC 8 Z9 8 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD JAN PY 2002 VL 59 IS 1 BP 29 EP 30 DI 10.1001/archneur.59.1.29 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 512BH UT WOS:000173300900002 PM 11790227 ER PT J AU de la Maza, MS Foster, CS Jabbur, NS Baltatzis, S AF de la Maza, MS Foster, CS Jabbur, NS Baltatzis, S TI Ocular characteristics and disease associations in scleritis-associated peripheral keratopathy SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID FLUORESCEIN ANGIOGRAPHY; SCLEROKERATITIS; SURGERY; CORNEAL AB Objectives: To evaluate ocular characteristics and systemic disease associations in patients with scleritis-associated peripheral keratopathy and its different patterns, and to assess any ocular or systemic prognostic significance of the presence of the types of peripheral keratopathy in patients with scleritis. Design: Review of 125 patients with scleritis alone and 47 patients with scleritis-associated peripheral keratopathy; review of patients with scleritis and the different patterns of peripheral keratopathy: peripheral corneal thinning, stromal keratitis, and peripheral ulcerative keratitis (PUK); review of ocular and systemic outcomes comparisons between patients with scleritis with and without peripheral keratopathy. Results: Patients with peripheral keratopathy had more necrotizing scleritis (57%, P<.001), decrease in vision (81%, P<.001), anterior uveitis (62%, P<.002), impending corneal perforation (62%, P<.001), and potentially lethal specific-disease association (87%, P<.001) than did patients with scleritis alone. Patients with PUK had the worst ocular and systemic outcomes. Of the 24 patients with PUK, 16 (67%) had necrotizing scleritis (P=.02), virtually all had a potentially lethal systemic disease (P=.02), and all had impending corneal perforation (P<.001). Conclusion: The detection of peripheral keratopathy, and especially PUK, in a patient with scleritis indicates a poor ocular and systemic prognosis. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Immumol & Uveitis Serv, Boston, MA 02114 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Hilles Immunol Lab, Boston, MA 02114 USA. Univ Athens, Dept Ophthalmol, Athens, Greece. RP Foster, CS (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Immumol & Uveitis Serv, 243 Charles St, Boston, MA 02114 USA. NR 10 TC 25 Z9 26 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 JAN PY 2002 VL 120 IS 1 BP 15 EP 19 PG 5 WC Ophthalmology SC Ophthalmology GA 510BH UT WOS:000173188500001 PM 11786052 ER PT J AU Chung, JH Spiegel, JH Varvares, MA AF Chung, JH Spiegel, JH Varvares, MA TI Pathology quiz case 1 - Metastatic BCC and lymphoma SO ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Article ID BASAL-CELL CARCINOMA; HEAD; NECK C1 Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. RP Chung, JH (reprint author), Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. NR 10 TC 1 Z9 1 U1 0 U2 0 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 JAN PY 2002 VL 128 IS 1 BP 75 EP + PG 3 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 510MM UT WOS:000173211900014 PM 11784260 ER PT J AU Sege, RD Kharasch, S Perron, C Supran, S O'Malley, P Li, WJ Stone, D AF Sege, RD Kharasch, S Perron, C Supran, S O'Malley, P Li, WJ Stone, D TI Pediatric violence-related injuries in Boston - Results of a city-wide emergency department surveillance program SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID PREVALENCE; PREVENTION; EXPOSURE; YOUTH AB Context: Violence-related injuries among children are common, but age-based incidence data are not easily available. Objectives: To describe injuries due to violence in a population-based case series of children and to estimate injury incidence. Design: Prospective surveillance of children residing in Boston, Mass, who received pediatric emergency department treatment for violence-related injury during a 4-year period beginning April 15, 1995. Setting: Pediatric emergency departments in Boston. Patients: Children aged 3 through 18 years who came to a hospital emergency department between April 1995 and April 1999. Violence-related injuries were defined as those resulting from a situation of conflict involving 2 or more persons with intent to harm, as assessed by health care personnel caring for the patients. Self-inflicted injuries and injuries caused by child abuse (including any injury resulting from a conflict with a parent or guardian) were excluded. Homicides of Boston children aged 3 through 18 years who were killed during the study period were included based on police data. Main Outcome Measure: Population-based violence-related injury rates. Results: There were 2035 injury-related visits caused by violence, which reflects a rate of 52.7 (95% confidence interval, 50.5-54.9) per 10000 person-years. Most injuries were relatively minor; 6.4% of visits resulted in admission. The youth violence-related injury rate in Boston declined at an average rate of 12% annually during the period studied. Conclusion: Pediatric emergency department monitoring of violence-related injury in Boston suggests that childhood injuries due to violence declined during the late 1990s. C1 Tufts Univ New England Med Ctr, Div Crit Care Res, Boston, MA 02111 USA. Childrens Natl Med Ctr, Floating Hosp, Pediat & Adolescent Hlth Res Ctr, Boston, MA USA. Boston Med Ctr, Dept Pediat, Boston, MA USA. Childrens Hosp, Dept Emergency Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Sege, RD (reprint author), Tufts Univ New England Med Ctr, Div Crit Care Res, Box 351, Boston, MA 02111 USA. RI Li, Wenjun/F-5634-2015; OI Li, Wenjun/0000-0001-5335-7386; Sege, Robert/0000-0003-1260-4787 NR 20 TC 15 Z9 16 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD JAN PY 2002 VL 156 IS 1 BP 73 EP 76 PG 4 WC Pediatrics SC Pediatrics GA 508GD UT WOS:000173079600014 PM 11772194 ER PT J AU Morton, SC Shekelle, PG Adams, JL Bennett, C Dobkin, BH Montgomerie, J Vickrey, BG AF Morton, SC Shekelle, PG Adams, JL Bennett, C Dobkin, BH Montgomerie, J Vickrey, BG TI Antimicrobial prophylaxis for urinary tract infection in persons with spinal cord dysfunction SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE bacteriuria; bladder, neurogenic; meta-analysis; myelopathy; rehabilitation; spinal cord injuries; urinary tract infections ID CATHETER-ASSOCIATED BACTERIURIA; INTERMITTENT CATHETERIZATION; TRIMETHOPRIM-SULFAMETHOXAZOLE; NEUROGENIC BLADDER; CONTROLLED TRIALS; CLINICAL-TRIALS; INJURY PATIENTS; DOUBLE-BLIND; CIPROFLOXACIN; EFFICACY AB Objective: To assess the benefits and harms Of antimicrobial prophylaxis to prevent urinary tract infections (UTIs) in persons with neurogenic bladders caused by spinal cord dysfunction. Data Sources: A broad search strategy with no language restriction was conducted of MEDLINE (1966-January 1998), EMBASE (1974-January 1998), and CINAHL (1982-July 1998) using the general search terms urinary tract, urinary tract infections, bacteriuria, paraplegia, quadriplegia, spinal cord injuries, multiple sclerosis, neurogenic bladder, and neuropathic bladder. Additional articles were identified by experts and by reviewing reference lists of articles obtained from searches. Study Selection: Criteria included human studies of adults and adolescents who had neurogenic bladder due to spinal cord dysfunction; the studies had to address antimicrobial prophylaxis of UTI and include bacteriuria or UTI as an outcome. We excluded any study that was clearly not a controlled trial or that only included children under the age of 13 years. Two reviewers independently abstracted data, and disagreements were resolved by consensus. Data Extraction: Two reviewers independently abstracted data, and disagreements were resolved by consensus. Studies were graded by 1 project investigator according to quality criteria developed by Jadad and Schulz. Data Synthesis: The sizes of the effect of antimicrobial prophylaxis on weekly infection rates from 15 trials that met the inclusion criteria were pooled by using a random effects model. Antimicrobial prophylaxis did not significantly decrease symptomatic infections. Prophylaxis was associated with a reduction in asymptomatic bacteriuria among acute patients (<90d after spinal cord injury; P <.05); 1 patient would require 3.7 weeks of treatment on average to prevent 1 symptomatic infection. For nonacute patients, the reduction approached statistical significance (P =.06) Prophylaxis resulted in an approximately twofold increase in antimicrobial-resistant bacteria. Conclusions: The regular use of antimicrobial prophylaxis for most patients who have neurogenic bladder caused by spinal cord dysfunction is not supported. A clinically important effect, however, has not been excluded. Future research should focus on randomized trials in those patients who have recurrent UTIs that limit their daily functioning and well-being. C1 So Calif Evidence Based Practice Ctr, Santa Monica, CA USA. W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Urol, Los Angeles, CA 90024 USA. Univ So Calif, Rancho Los Amigos Med Ctr, Dept Med, Downey, CA 90242 USA. RP Morton, SC (reprint author), RAND Corp, POB 2138,1700 Main St, Santa Monica, CA 90407 USA. NR 48 TC 63 Z9 66 U1 1 U2 6 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD JAN PY 2002 VL 83 IS 1 BP 129 EP 138 DI 10.1053/apmr.2002.26605 PG 10 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 509JU UT WOS:000173145300020 PM 11782843 ER PT J AU Sniger, W Garshick, E AF Sniger, W Garshick, E TI Alendronate increases bone density in chronic spinal cord injury: A case report SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE absortiometry, dual-energy x-ray; alendronate; case report; osteoporosis; rehabilitation; spinal cord injuries ID MINERAL DENSITY; OSTEOPOROSIS; FRACTURES; INTERVENTION; METABOLISM; HIP AB Over the first 6 to 16 months after spinal cord injury (SCI), up to a third of bone mass may be lost because of demineralization, resulting in an increased risk for fractures. Studies in postmenopausal women have shown the efficacy of oral alendronate, an aminobisphosphonate, in increasing bone mass. However, the efficacy of alendronate in reversing bone density loss has not been shown in patients with chronic SCI. This article reports on the efficacy of alendronate in increasing bone mass in a patient with neurologically incomplete American Spinal Injury Association class D SCI and Brown-Sequard's syndrome. Bone mass change over 2 years while taking alendronate is compared for a weak extremity (majority of muscles grade 2/5) and strong extremity (majority of muscles grade 4/5) and spine. There was a greater increase in bone mineral density in the weaker lower extremity compared with the stronger one; the spine had the greatest increase overall. C1 VA Boston Healthcare Syst, Spinal Cord Injury Med Serv, W Roxbury, MA USA. VA Boston Healthcare Syst, Med Serv, Pulm & Crit Care Med Scect, W Roxbury, MA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Sniger, W (reprint author), 360 Pleasant St, Raynham, MA 02767 USA. NR 20 TC 20 Z9 21 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 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD JAN PY 2002 VL 83 IS 1 BP 139 EP 140 DI 10.1053/apmr.2002.26828 PG 2 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 509JU UT WOS:000173145300021 PM 11782844 ER PT J AU Khuri, SF Daley, J Henderson, WG AF Khuri, SF Daley, J Henderson, WG TI The comparative assessment and improvement of quality of surgical care in the Department of Veterans Affairs SO ARCHIVES OF SURGERY LA English DT Article ID RISK ADJUSTMENT; LAPAROSCOPIC CHOLECYSTECTOMY; PROGRAM; MORBIDITY; MORTALITY; OUTCOMES; SURGERY; VOLUME; CANCER AB Prompted by the need to assess comparatively the quality of surgical care in 133 Veterans Affairs (VA) hospitals, the Department of Veterans Affairs conducted the National VA Surgical Risk Study between October 1, 1991, and December 31, 1993, in 44 VA medical centers. The study developed and validated models for risk adjustment of 30-day morbidity and 30-day mortality after major surgery in 8 noncardiac surgical specialties. Similar models were developed for cardiac surgery by the VA's Continuous Improvement in Cardiac Surgery Program. Based on the results of the National VA Surgical Risk Study and the Continuous Improvement in Cardiac Surgery Program, the VA established in 1994 a VA National Surgical Quality Improvement Program (NSQIP), in which all the medical centers performing major surgery participated. An NSQIP nurse at each center oversees the prospective collection of data and their electronic transmission for analysis at 1 of 2 data coordinating centers. Feedback to the providers and managers is aimed at achieving continuous quality improvement. It consists of (1) comparative, site-specific, and outcome-based annual reports; (2) periodic assessment of performance; (3) self-assessment tools; (4) structured site visits; and (5) dissemination of best practices. The NSQIP also provides an infrastructure to enable the VA investigators to query the database and produce scientific presentations and publications. Since the inception of the NSQIP data collection process, the 30-day postoperative mortality after major surgery in the VA has decreased by 27%, and the 30-day morbidity by 45%. The future of the NSQIP lies in expanding it to the private sector and in enhancing its capabilities by incorporating additional measures of outcome, structure, process, and cost. C1 Vet Affairs Boston Healthcare Syst, W Roxbury, MA 02132 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Inst Hlth Policy, Partners Healthcare Syst, Sch Med,Massachusetts Gen Hosp, Boston, MA 02114 USA. Hines Vet Affairs Cooperat Studies Program Coordi, Hines, IL USA. RP Khuri, SF (reprint author), Vet Affairs Boston Healthcare Syst, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. NR 41 TC 265 Z9 265 U1 1 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0004-0010 J9 ARCH SURG-CHICAGO JI Arch. Surg. PD JAN PY 2002 VL 137 IS 1 BP 20 EP 27 DI 10.1001/archsurg.137.1.20 PG 8 WC Surgery SC Surgery GA 512BA UT WOS:000173300200003 PM 11772210 ER PT J AU Grover, FL Cleveland, JC Shroyer, LW AF Grover, FL Cleveland, JC Shroyer, LW TI Quality improvement in cardiac care SO ARCHIVES OF SURGERY LA English DT Article ID STS NATIONAL DATABASE; ARTERY BYPASS-SURGERY; NEW-YORK-STATE; OPERATIVE MORTALITY; ANGIOGRAPHIC PREDICTORS; RISK ASSESSMENT; GRAFT-SURGERY; CORONARY; SOCIETY; OUTCOMES AB Quality improvement in cardiac care has made considerable progress over the past 30 years. During that period, there has been the development of multi-institutional databases to monitor outcomes following cardiothoracic surgery. These databases initially began using only volume and unadjusted operative (30-day) mortality as outcome criteria. There has been a progressive increase in their sophistication, with the building of risk models based on preoperative variables, which accurately predict the risk of adverse outcomes. Other outcomes have been added including risk-adjusted mortality and morbidity; efficiency outcomes such as length of stay, quality of life, functional health status, neuropsychological outcomes; and long-term outcomes. C1 Univ Colorado, Hlth Sci Ctr, Div Cardiothorac Surg, Denver, CO 80202 USA. Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80202 USA. Denver Vet Affairs Med Ctr, Denver, CO USA. RP Grover, FL (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Surg, Campus Box 305,4200 E 9th Ave,Room 5622, Denver, CO 80262 USA. RI Shroyer, Annie Laurie/B-8836-2016 OI Shroyer, Annie Laurie/0000-0001-6461-0623 NR 28 TC 10 Z9 10 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0004-0010 J9 ARCH SURG-CHICAGO JI Arch. Surg. PD JAN PY 2002 VL 137 IS 1 BP 28 EP 36 DI 10.1001/archsurg.137.1.28 PG 9 WC Surgery SC Surgery GA 512BA UT WOS:000173300200004 PM 11772211 ER PT J AU Reginato, AM Olsen, BR AF Reginato, AM Olsen, BR TI The role of structural genes in the pathogenesis of osteoarthritic disorders SO ARTHRITIS RESEARCH LA English DT Review DE cartilage; chromosomes; genetics; linkage; osteoarthritis ID MULTIPLE EPIPHYSEAL DYSPLASIA; OLIGOMERIC MATRIX PROTEIN; VITAMIN-D-RECEPTOR; ALPHA-1(II) COLLAGEN CHAINS; II PROCOLLAGEN COL2A1; SPONDYLOEPIPHYSEAL DYSPLASIA; TRANSGENIC MICE; AUTOSOMAL-DOMINANT; STICKLER-SYNDROME; RADIOGRAPHIC OSTEOARTHRITIS AB Osteoarthritis (OA), one of the most common age-related chronic disorders of articular cartilage, joints, and bone tissue, represents a major public health problem. Genetic studies have identified multiple gene variations associated with an increased risk of OA. These findings suggest that there is a large genetic component to OA and that the disorder belongs in the multigenetic, multifactorial class of genetic diseases. Studies of chondrodysplasias and associated hereditary OA have provided a better understanding of the role of structural genes in the maintenance and repair of articular cartilage, in the regulation of chondrocyte proliferation and gene expression, and in the pathogenesis of OA. C1 Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Olsen, BR (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, 240 Longwood Ave, Boston, MA 02115 USA. FU NIAMS NIH HHS [R37 AR036819, R01 AR036819, AR36819, AR36820, R01 AR036820] NR 94 TC 50 Z9 52 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1465-9913 J9 ARTHRITIS RES JI Arthritis Res. PY 2002 VL 4 IS 6 BP 337 EP 345 DI 10.1186/ar595 PG 9 WC Rheumatology SC Rheumatology GA 604BU UT WOS:000178596400005 PM 12453309 ER PT J AU He, CJ Charoenkul, V Kahn, T Langhoff, E Uribarri, J Sedlacek, M AF He, CJ Charoenkul, V Kahn, T Langhoff, E Uribarri, J Sedlacek, M TI Impact of the surgeon on the prevalence of arteriovenous fistulas SO ASAIO JOURNAL LA English DT Article ID VASCULAR ACCESS; HEMODIALYSIS AB Decreased use of native arteriovenous fistulas and an increased reliance on synthetic grafts as permanent dialysis access have accompanied the growth of the dialysis population in the United States, but not at our institution. Possible reasons for this difference were studied in a cross-sectional analysis in August of 2000. There were 51 chronic dialysis patients, all of whom had their access placed by the same surgeon; 75% of them were dialyzed through an arteriovenous fistula, which compares well with the 23% prevalence at the national level. Among our patients, 57% were diabetic, 98% had a history of hypertension, 35% had amputations or arterial bypass surgery, 37% had coronary artery disease, 12% had suffered a stroke, 35% were active smokers, and 22% had a history of intravenous drug use. The high prevalence of arteriovenous fistulas, despite so many comorbid conditions, suggests that the presence of a skilled and experienced surgeon may be more predictive of better dialysis access than other factors. C1 Bronx Vet Affairs Med Ctr, Div Nephrol, New York, NY USA. Bronx Vet Affairs Med Ctr, Dept Surg, New York, NY USA. Mt Sinai Sch Med, Div Nephrol, New York, NY USA. RP Sedlacek, M (reprint author), Mt Sinai Med Ctr, 1 Gustave L Levy Pl, New York, NY 10029 USA. NR 8 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1058-2916 J9 ASAIO J JI Asaio J. PD JAN-FEB PY 2002 VL 48 IS 1 BP 39 EP 40 DI 10.1097/00002480-200201000-00009 PG 2 WC Engineering, Biomedical; Transplantation SC Engineering; Transplantation GA 510MH UT WOS:000173211500009 PM 11814096 ER PT J AU Fu, YC Luo, NL Lopes-Virella, MF AF Fu, YC Luo, NL Lopes-Virella, MF TI Upregulation of interleukin-8 expression by prostaglandin D2 metabolite 15-deoxy-delta12, 14 prostaglandin J2 (15d-PGJ2) in human THP-1 macrophages SO ATHEROSCLEROSIS LA English DT Article DE interleukin-8; 15-deoxy-delta12,14 prostaglandin J2; THP-1 macrophage; atherosclerosis ID SMOOTH-MUSCLE CELLS; NF-KAPPA-B; ACTIVATED RECEPTOR-GAMMA; LOW-DENSITY-LIPOPROTEIN; PPAR-GAMMA; 15-DEOXY-DELTA(12,14)-PROSTAGLANDIN J(2); SIGNALING PATHWAY; GENE-EXPRESSION; MESSENGER-RNA; OXIDIZED LDL AB Interleukin-8 (IL-8) is one of cytokines detected at sites of inflammation and in macrophage-foam cells of atherosclerotic lesions. The expression of IL-8 gene can be induced in cholesterol loaded THP-1 macrophages by oxidized low density lipoprotein. We report for the first time that the expression of human IL-8 gene in THP-1 macrophages is upregulated in a time- and concentration-dependent manner by prostaglandin D2 metabolite 15-deoxy-delta12, 14 prostaglandin J2 (15d-PGJ2), which is a natural ligand for activation of peroxisome proliferator-activated receptor-gamma transcription factor. Studies to identify the signal transduction pathways involved showed that IL-8 upregulation-mediated by 15d-PGJ2 was markedly inhibited when the THP-1 macrophages were incubated with a highly selective and cell-permeable inhibitor of the mitogen-activated protein kinase (MAPK) signaling pathway, 2'-amino-3'-methoxyflavone (PD98059). This inhibition was concentration-dependent., suggesting that 15d-PGJ2 regulates the expression of IL-8 gene in THP-1 macrophages through a MAPK signaling pathway. In contrast, THP-1 macrophages when treated with pyrrolidine dithiocarbamate, an anti-oxidant and the selective inhibitor for nuclear factor kappaB, showed an enhanced 15d-PGJ2-mediated upregulation of IL-8 gene expression. The data presented in this report may contribute to unravel some of the mechanisms behind the inflammatory component of atherosclerosis. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Med Univ S Carolina, Dept Med, Div Endocrinol Diabet & Med Genet, Strom Thurmond Biomed Ctr, Charleston, SC 29403 USA. Ralph H Johnson Vet Adm Med Ctr, Charleston, SC 29403 USA. RP Fu, YC (reprint author), Med Univ S Carolina, Dept Med, Div Endocrinol Diabet & Med Genet, Strom Thurmond Biomed Ctr, Room 520,114 Doughty St, Charleston, SC 29403 USA. NR 38 TC 38 Z9 38 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD JAN PY 2002 VL 160 IS 1 BP 11 EP 20 DI 10.1016/S0021-9150(01)00541-X PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 517AG UT WOS:000173588500002 PM 11755918 ER PT B AU Lipinski, B Lipinska, I AF Lipinski, B Lipinska, I BE Kostner, GM Kostner, KM TI Free radical-induced modification of human fibrinogen: Implications for atherosclerosis SO ATHEROSCLEROSIS: RISK FACTORS, DIAGNOSIS, AND TREATMENT LA English DT Proceedings Paper CT 73rd Annual Congress of the European-Atherosclerosis-Society CY JUL 07-10, 2002 CL SALZBURG, AUSTRIA SP European Atherosclerosis Soc ID MACROMOLECULAR PROTEIN COMPLEX; DIABETES-MELLITUS; OXIDATIVE STRESS; HUMAN PLASMA C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Lipinski, B (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. NR 14 TC 1 Z9 1 U1 0 U2 2 PU MEDIMOND S R L PI 40128 BOLOGNA PA VIA MASERATI 5, 40128 BOLOGNA, 00000, ITALY BN 88-323-2707-4 PY 2002 BP 149 EP 152 PG 4 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Nutrition & Dietetics; Peripheral Vascular Disease SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Nutrition & Dietetics; Cardiovascular System & Cardiology GA BV31J UT WOS:000178569900030 ER PT J AU Baldini, RL Lau, GW Rahme, LG AF Baldini, RL Lau, GW Rahme, LG TI Use of plant and insect hosts to model bacterial pathogenesis SO BACTERIAL PATHOGENESIS, PT C SE METHODS IN ENZYMOLOGY LA English DT Review ID VIRULENCE FACTORS; IMMUNE-RESPONSE; CAENORHABDITIS-ELEGANS; DROSOPHILA; INFECTION; ANIMALS C1 Harvard Univ, Sch Med, Dept Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Cincinnati, Coll Med, Div Pulm & Crit Care Med, Cincinnati, OH 45267 USA. RP Baldini, RL (reprint author), Harvard Univ, Sch Med, Dept Surg, Boston, MA 02114 USA. RI Baldini, Regina/C-4035-2012 OI Baldini, Regina/0000-0003-4349-6352 NR 22 TC 6 Z9 6 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2002 VL 358 BP 3 EP 13 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BV73G UT WOS:000179914700001 PM 12474375 ER PT J AU Lewandrowski, KU Bondre, SP Wise, DL Trantolo, DJ AF Lewandrowski, KU Bondre, SP Wise, DL Trantolo, DJ TI Healing of osteochondral osteotomies after fixation with a hydroxyapatite-buffered polylactide. A histomorphometric and radiographic study in rabbits SO BIO-MEDICAL MATERIALS AND ENGINEERING LA English DT Article DE bioresorbable screw; hydroxyapatite; osteotomy healing; implant osteointegration ID FOREIGN-BODY REACTIONS; POLY-L-LACTIDE; POLY(L-LACTIDE) BONE PLATES; CONTINUOUS PASSIVE MOTION; FULL-THICKNESS DEFECTS; FRACTURE FIXATION; BIODEGRADABLE IMPLANTS; MECHANICAL-PROPERTIES; ARTICULAR-CARTILAGE; INTERNAL-FIXATION AB The tissue response of subchondral bone to a biodegradable fixation device manufactured in the shape of a screw and made of polylactide with a hydroxyapatite buffer were implanted through the articular surface of the intercondylar portion of the distal rabbit femur. One screw was implanted per animal. The screws had a core diameter of 3.2 mm and an outer diameter of 4.5 mm. At insertion, the implants were cut flush with the articular surface. After follow-up times of 8 and 16 weeks, the specimens were examined radiographically and histomorphometrically. The intact contralateral femur served as a control for comparison. Only minimal signs of degradation of the polymer could be seen in the histologic specimens. These implant degradation sites were commonly areas of new bone formation adjacent to the screw implant. A brim of repair tissue was formed at the entrance and exit of the implant channel. The width of the repair tissue from the tissue-implant boundary towards the center of the entrance hole varied greatly between the specimens, from 80 to 750 mum. In most specimens this bridging tissue consisted of newly formed bone and undifferentiated mesenchymal tissue. Degenerative chondrocyte clustering occurred in the pre-existing cartilage within a 400 mum wide zone from the tissue-implant interface into the recipient tissues. Some new-bone formation was seen to envelop the implant in all specimens, but the fractional osteoid formation surface of the trabeculae was only significantly higher in the screw-implanted 16-week specimens, when compared to the non-operated contralateral controls. Although the bony osteotomy was invariably healed in all specimens with good implant integration, the quality and quantity of the reparative tissue of the articular cartilage near the screw hole was variable. This study showed that large polylactide implants, which are buffered with hydroxyapatite show benign tissue responses and good implant osteointegration when implanted in bone. They may be suitable for fixation of small bone fractures. However, insertion through intra-articular surfaces may require further improvement of the implant material to avoid the degenerative repair processes seen in this study. C1 Cambridge Sci Inc, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Orthopaed Res Labs, Boston, MA 02114 USA. RP Trantolo, DJ (reprint author), Cambridge Sci Inc, 180 Fawcett St St, Cambridge, MA 02138 USA. NR 52 TC 3 Z9 6 U1 1 U2 4 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 0959-2989 J9 BIO-MED MATER ENG JI Bio-Med. Mater. Eng. PY 2002 VL 12 IS 3 BP 259 EP 270 PG 12 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 607KJ UT WOS:000178790500005 PM 12446941 ER PT J AU Lewandrowski, KU Bondre, SP Shea, M Untch, CA Hayes, WC Hile, DD Wise, DL Trantolo, DJ AF Lewandrowski, KU Bondre, SP Shea, M Untch, CA Hayes, WC Hile, DD Wise, DL Trantolo, DJ TI Composite resorbable polymer/hydroxylapatite composite screws for fixation of osteochondral osteotomies - A morphologic and biomechanical study in sheep SO BIO-MEDICAL MATERIALS AND ENGINEERING LA English DT Article DE bioresorbable screw; hydroxyapatite; osteotomy healing; implant osteointegration ID FOREIGN-BODY REACTIONS; POLY-L-LACTIDE; POLY(L-LACTIDE) BONE PLATES; CONTINUOUS PASSIVE MOTION; FULL-THICKNESS DEFECTS; FRACTURE FIXATION; BIODEGRADABLE IMPLANTS; MECHANICAL-PROPERTIES; ARTICULAR-CARTILAGE; INTERNAL-FIXATION AB The aim of this study was to evaluate biomechanically the healing of an osteochondral fragment created in the distal sheep femur in response to fixation with a resorbable composite screw made of polylactide and hydroxylapatite. Pure poly(L-lactide) screws were used for comparison. At follow-up times of 4 or 8 weeks, specimens were examined with standard radiography, biomechanics, and histology. The intact contralateral femur served as a control. Only minimal signs of polymer degradation were seen in the histologic specimens. At 8 weeks, most osteotomies had healed completely and there was no difference in compressive strength and elastic modulus of cylindrical cores between the two types of biodegradable implants used. The width of the repair tissue at the tissue-implant interface was 250 50 pm representing a clear transition zone of newly formed trabecular bone separating the implant from the surrounding plexiform bone. We conclude that relatively large polylactide implants, blended with hydroxyapatite, are capable of fixing an osteochondral fragment in an animal model. Biomechanical data assessing the quality of the bone formed at the osteotomy sites were found to be equivalent when compared to the control poly(L-lactide) implants of similar design and size. In addition, hydroxylapatite composite implants showed benign tissue responses and-good implant osteointegration. Results suggest that hydroxylapatite composite screw implants can be used for similar indications, as pure poly(L-lactide) implants in current clinical use. C1 Cambridge Sci Inc, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Orthopaed Res Labs, Boston, MA 02114 USA. Oregon Hlth & Sci Univ, Dept Orthopaed & Rehabil, Portland, OR 97201 USA. RP Trantolo, DJ (reprint author), Cambridge Sci Inc, 180 Fawcett St, Cambridge, MA 02138 USA. NR 46 TC 9 Z9 10 U1 1 U2 4 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 0959-2989 J9 BIO-MED MATER ENG JI Bio-Med. Mater. Eng. PY 2002 VL 12 IS 4 BP 423 EP 438 PG 16 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 642PC UT WOS:000180811900010 PM 12652036 ER PT J AU Cesati, RR Tamagnan, G Baldwin, RM Zoghbi, SS Innis, RB Kula, NS Baldessarini, RJ Katzenellenbogen, JA AF Cesati, RR Tamagnan, G Baldwin, RM Zoghbi, SS Innis, RB Kula, NS Baldessarini, RJ Katzenellenbogen, JA TI Synthesis of cyclopentadienyltricarbonyl rhenium phenyltropanes by double ligand transfer: Organometallic ligands for the dopamine transporter SO BIOCONJUGATE CHEMISTRY LA English DT Article ID CROSS-COUPLING REACTION; SUBSTITUTED CYCLOPENTADIENYL; 3-COMPONENT SYNTHESIS; BRAIN UPTAKE; TROPANE CONJUGATE; ARYLBORONIC ACIDS; BIARYL KETONES; IMAGING AGENT; RAT-BRAIN; COMPLEXES AB Cyclopentadienyltricarbonyl rhenium (CpRe(CO)(3)) systems can be prepared from ferrocenes and perrhenate by a double ligand transfer (DLT) reaction that gives reasonable yields and shows excellent functional group tolerance. We used this reaction for the direct preparation of CpRe(CO)(3)-phenyltropane conjugates. Such agents, when labeled with technetium-99m, might function as imaging agents for the dopamine transporter (DAT) system that would be useful for assessing the onset and severity of Parkinson's disease. Of the CpRe(CO)(3)-tropane conjugates prepared by the DLT reaction (as well as other analogues prepared by related methods), those substituted at the N-8 position seem most promising; their affinity for the DAT in all cases was high, and their ferrocene precursors for the DLT reaction can be prepared in a convenient manner. By contrast, the 3beta-conjugates were poor DAT binders. The modular nature of these systems offers considerable flexibility that could be used to improve the binding characteristics of these compounds further. C1 Univ Illinois, Dept Chem, Urbana, IL 61801 USA. Yale Univ, Sch Med, VA Connecticut HCS, West Haven, CT 06516 USA. RadioTracer Inc, New Haven, CT 06521 USA. Massachusetts Gen Hosp, Mailman Res Ctr, McLean Div, Belmont, MA 02478 USA. RP Katzenellenbogen, JA (reprint author), Univ Illinois, Dept Chem, 600 S Mathews Ave, Urbana, IL 61801 USA. EM gilles.tamagnan@yale.edu; jkatzene@uiuc.edu FU NCI NIH HHS [5 T32 CA09067]; NCRR NIH HHS [RR 01575, 1 S10 RR104444-01]; NIGMS NIH HHS [GM 27029] NR 60 TC 16 Z9 18 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD JAN-FEB PY 2002 VL 13 IS 1 BP 29 EP 39 DI 10.1021/bc010011x PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 513JG UT WOS:000173374300005 PM 11792176 ER PT J AU Hogemann, D Ntziachristos, V Josephson, L Weissleder, R AF Hogemann, D Ntziachristos, V Josephson, L Weissleder, R TI High throughput magnetic resonance imaging for evaluating targeted nanoparticle probes SO BIOCONJUGATE CHEMISTRY LA English DT Article AB The ability to image specific molecular targets in vivo would have significant impact in allowing earlier disease detection and in tailoring molecular therapies. One of the rate-limiting steps in the development of novel compounds as reporter probes has been the lack of cell-based, biologically relevant, high throughput screening methods. Here we describe the development and validation of magnetic resonance imaging (MRI) as a technique to rapidly screen compounds that are potential MR reporter agents for their interaction with specific cellular targets. We show that MR imaging can (1) evaluate thousands of samples simultaneously and rapidly, (2) provide exceedingly accurate measurements, and (3) provide receptor binding/internalization data as validated by radioactive assays. The technique allows the screening of libraries of peptide-nanoparticle conjugates against target cells and the identification of conjugates that may be subsequently used as reporter agents in vivo. The technology should greatly accelerate the development of target-specific or cell-specific MR contrast agents. C1 Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. RP Weissleder, R (reprint author), Massachusetts Gen Hosp, Ctr Mol Imaging Res, Bldg 149,13th St, Charlestown, MA 02129 USA. FU NCI NIH HHS [R01 CA 85240, P50 CA86355, R01 CA86782] NR 8 TC 97 Z9 104 U1 1 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD JAN-FEB PY 2002 VL 13 IS 1 BP 116 EP 121 DI 10.1021/bc015549h PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 513JG UT WOS:000173374300015 PM 11792186 ER PT J AU Kang, HW Josephson, L Petrovsky, A Weissleder, R Bogdanov, A AF Kang, HW Josephson, L Petrovsky, A Weissleder, R Bogdanov, A TI Magnetic resonance imaging of inducible E-selectin expression in human endothelial cell culture SO BIOCONJUGATE CHEMISTRY LA English DT Article ID MOLECULE E-SELECTIN; LEUKOCYTE ADHESION; IN-VIVO; ACTIVATION; NEOVASCULATURE; ARTHRITIS; PEPTIDE; CANCER AB Covalent conjugates of the cross-linked iron oxide nanoparticles (CLIO) and high-affinity (K-d(app) = 8.5 nM) anti-human E-selectin (CD62E) F(ab')(2) fragments were prepared and tested in vitro to establish feasibility of endothelial proinflammatory marker magnetic resonance (MR) imaging. The conjugates were obtained by using thiol-disulfide exchange reaction between 3-(2-pyridyl)propionyl-CLIO and S-acetylthioacetate-modified F(ab')(2) fragments. The purified CLIO-F(ab')(2) conjugates (average hydrodynamic diameter 40.6 nm) were used in experiments with the live human endothelial umbilical vein cells (HUVEC). Cells treated with IL-1beta expressed E-selectin and showed a 100-200 times higher binding of CLIO particles (83-104 ng iron/million cells) than control cells. The binding resulted in a high superparamagnetism of HUVEC with the transverse water proton relaxation time (T2) decrease to 30-40 ins in cell precipitates. Cells did not bind/internalize CLIO-F(ab')(2) conjugates prepared using a control fragment or nonconjugated iron oxide particles before or after treatment with IL-1beta. MR imaging of cells showed a highly specific T2-weighted signal darkening associated with cells treated with IL-1beta and incubated with anti-E selectin. Demonstration of MR imaging of E-selectin expression justifies further development of MR-targeted agents for monitoring tumor vascular endothelial proliferation, angiogenesis, and atherosclerosis. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Ctr Mol Imaging Res, Charlestown, MA 02129 USA. RP Bogdanov, A (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Ctr Mol Imaging Res, Bldg 149,13th St, Charlestown, MA 02129 USA. FU NCI NIH HHS [1P50CA86355-01, 5R01 CA74424-01] NR 32 TC 163 Z9 169 U1 1 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD JAN-FEB PY 2002 VL 13 IS 1 BP 122 EP 127 DI 10.1021/bc0155521 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 513JG UT WOS:000173374300016 PM 11792187 ER PT J AU Ollendick, TH Hirshfeld-Becker, DR AF Ollendick, TH Hirshfeld-Becker, DR TI The developmental psychopathology of social anxiety disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE developmental psychopathology; social anxiety disorder; etiology; maintenance; course of disorder ID MACARTHUR LONGITUDINAL TWIN; DIRECT-INTERVIEW FAMILY; BEHAVIORAL-INHIBITION; PANIC DISORDER; PSYCHIATRIC-DISORDERS; UNINHIBITED BEHAVIOR; CHILDHOOD SHYNESS; PARENTAL ANXIETY; PUBLIC SPEAKING; UNITED-STATES AB The role of developmental theory and developmental psychopathology in understanding the development, maintenance, and course of social anxiety disorder (SAD) is explored in this article. Following a brief examination of the phenomenology of SAD in Youth, we provide an overview of the tenets of developmental psychology and developmental psychopathology, including the principles of equifinality (i.e., the same outcome can result from diverse developmental pathways) and multifinality (i.e., the same risk factor can lead to or result in different outcomes). We review various pathways for the acquisition and maintenance of SAD (e.g., genetic and temperamental influences, parental factors, conditioning or learning experiences, peer influences, and cognitive styles) and conclude, consistent with a developmental psychopathology perspective, that multiple pathways to SAD exist and that the various precursors to SAD do not invariably lead to SAD, We suggest that specificity in outcome is afforded by the combination, timing, and circumstances surrounding these various risk factors. Finally, we propose studies to test the viability of the developmental psychopathology model in understanding SAD. (C) 2002 Society, of Biological Psychiatry. C1 Virginia Polytech Inst & State Univ, Dept Psychol, Ctr Child Study, Blacksburg, VA 24061 USA. Massachusetts Gen Hosp, Pediat Psychopharmacol Program, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Ollendick, TH (reprint author), Virginia Polytech Inst & State Univ, Dept Psychol, Ctr Child Study, Blacksburg, VA 24061 USA. NR 141 TC 117 Z9 123 U1 7 U2 48 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 1 PY 2002 VL 51 IS 1 BP 44 EP 58 DI 10.1016/S0006-3223(01)01305-1 PG 15 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 512NG UT WOS:000173330000006 PM 11801230 ER EF