FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Eskey, CJ Robson, CD Weber, AL AF Eskey, CJ Robson, CD Weber, AL TI Imaging of benign and malignant soft tissue tumors of the neck SO RADIOLOGIC CLINICS OF NORTH AMERICA LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; AGGRESSIVE FIBROMATOSIS; FIBROUS HISTIOCYTOMA; CT FINDINGS; PARAPHARYNGEAL SPACE; SYNOVIAL SARCOMA; CHILDHOOD RHABDOMYOSARCOMA; NODULAR FASCIITIS; MR; HEAD AB Soft tissue tumors of the neck are a heterogeneous group of neoplasms arising from adipose, muscular, and fibrous tissue. With the exception of lymphomas, they account for only a small fraction of neck masses. Nevertheless, accurate diagnosis is important since the behavior of these neoplasms differs markedly from each other and from other head and neck masses. Noninvasive imaging, usually with CT and MR imaging, plays an important role in diagnostic evaluation and treatment planning for these tumors. In some cases, imaging features may be suggestive of a single entity. In most cases, imaging is needed to assess the location and extent of the tumor prior to biopsy or excision. This article discusses imaging techniques used for such assessment, the imaging features that help to separate these neoplasms from other head and neck tumors, and the behavior and imaging features of each of the more common benign and malignant soft tissue tumors that occur in the neck. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Childrens Hosp, Dept Radiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. Massachusetts Eye & Ear Infirm, Dept Radiol, Boston, MA 02114 USA. RP Eskey, CJ (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. OI Robson, Caroline/0000-0001-5592-249X NR 54 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 0033-8389 J9 RADIOL CLIN N AM JI Radiol. Clin. N. Am. PD SEP PY 2000 VL 38 IS 5 BP 1091 EP + DI 10.1016/S0033-8389(05)70223-2 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 363MY UT WOS:000089840300012 PM 11054971 ER PT J AU Weber, AL Randolph, G Aksoy, FG AF Weber, AL Randolph, G Aksoy, FG TI The thyroid and parathyroid glands - CT and MR imaging and correlation with pathology and clinical findings SO RADIOLOGIC CLINICS OF NORTH AMERICA LA English DT Review ID NEEDLE ASPIRATION BIOPSY; PAPILLARY CARCINOMA; COMPUTED-TOMOGRAPHY; LYMPHOPROLIFERATIVE DISORDERS; PRIMARY HYPERPARATHYROIDISM; PREOPERATIVE LOCALIZATION; RESECTIONAL MANAGEMENT; ANAPLASTIC CARCINOMA; AMYLOID GOITER; CANCER AB This article describes the CT and MR imaging findings of inflammatory diseases, nodules, and benign and malignant tumors of the thyroid gland, supplemented by clinical and pathological findings. Parathyroid disorders with imaging findings and their respective value are briefly discussed. C1 Massachusetts Eye & Ear Infirm, Dept Radiol, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Univ Missouri, Sch Med, Dept Radiol, Kansas City, MO 64108 USA. Ankara Training & Res Hosp, Dept Radiol, Ankara, Turkey. RP Weber, AL (reprint author), Massachusetts Eye & Ear Infirm, Dept Radiol, 243 Charles St, Boston, MA 02114 USA. NR 137 TC 89 Z9 110 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 0033-8389 J9 RADIOL CLIN N AM JI Radiol. Clin. N. Am. PD SEP PY 2000 VL 38 IS 5 BP 1105 EP + DI 10.1016/S0033-8389(05)70224-4 PG 27 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 363MY UT WOS:000089840300013 PM 11054972 ER PT J AU Fulling, PD Peterfreund, RA AF Fulling, PD Peterfreund, RA TI Alkalinization and precipitation characteristics of 0.2% ropivacaine SO REGIONAL ANESTHESIA AND PAIN MEDICINE LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Society-of-Anesthesiologists CY OCT 17-21, 1998 CL ORLANDO, FLORIDA SP Amer Soc Anesthesiol DE ropivacaine; local anesthetics; alkalinization; pH adjustment ID EPIDURAL ANALGESIA; PH-ADJUSTMENT; BUPIVACAINE; ANESTHESIA; PAIN AB Background and Objectives: Alkalinization of local anesthetics has been used to increase the speed of onset of nerve blocks. However. alkalinization of local anesthetic solutions may cause precipitation, thereby decreasing bioavailability and anesthetic activity. Alkalinization of ropivacaine has not been described. This laboratory study assessed the alkalinization and precipitation characteristics of ropivacaine. Methods: Aliquots (2 mL) of commercially available ropivacaine (Na ropin, 0.2%; Astra Pharmaceutical, Westborough, MA) were alkalinized with increasing amounts (0.01, 0.02, 0.04 mL) of sodium bicarbonate (8.4%) and immediately monitored for pH change and onset of visible precipitation at room temperature. We then alkalinized ropivacaine with sodium bicarbonate and measured the amount of precipitate that accumulated after various incubation times. Results: The pH of ropivacaine increases with the addition of small amounts of bicarbonate. The calculated percentage of nonionized ropivacaine increased from 0.3% to greater than 30% with alkalinization from pH of 5.51 to 7.63. Drug loss to precipitation increased with higher doses of bicarbonate, reaching 25% to 30% of the total ropivacaine. Even with a low dose of bicarbonate (0.1 mL bicarbonate/20 mL ropivacaine), precipitation increased with time of incubation. reaching a plateau at 20 minutes. Conclusions: A laboratory evaluation that establishes the alkalinization characteristics of ropivacaine is a prerequisite for designing a clinical study of alkalinized ropivacaine. In our experiment, low doses of bicarbonate produced significant increases in the proportion of nonionized ropivacaine with only modest precipitation. There would be a low likelihood of substantial drug precipitation if the mixture was administered within 5 to 10 minutes after alkalinization. These results indicate that alkalinized ropivacaine should not be used for infusions and that ropivacaine should not be alkalinized until just before use. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care,Clin 314D, Boston, MA 02114 USA. RP Peterfreund, RA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care,Clin 314D, 55 Fruit St, Boston, MA 02114 USA. NR 15 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 1098-7339 J9 REGION ANESTH PAIN M JI Region. Anesth. Pain Med. PD SEP-OCT PY 2000 VL 25 IS 5 BP 518 EP 521 DI 10.1053/rapm.2000.8931 PG 4 WC Anesthesiology SC Anesthesiology GA 356DH UT WOS:000089428700014 PM 11009239 ER PT J AU Poon, CS Kazemi, H AF Poon, CS Kazemi, H TI Special Issue: Modeling and Control of Breathing - Preface SO RESPIRATION PHYSIOLOGY LA English DT Editorial Material C1 Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Med Serv,Pulm & Crit Care Unit, Boston, MA 02114 USA. RP Poon, CS (reprint author), Harvard Univ, MIT, Div Hlth Sci & Technol, Bldg E25-501, Cambridge, MA 02139 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0034-5687 J9 RESP PHYSIOL JI Respir. Physiol. PD SEP PY 2000 VL 122 IS 2-3 BP 81 EP 81 DI 10.1016/S0034-5687(00)00151-1 PG 1 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 350TE UT WOS:000089116600001 ER PT J AU Burton, MD Kazemi, H AF Burton, MD Kazemi, H TI Neurotransmitters in central respiratory control SO RESPIRATION PHYSIOLOGY LA English DT Article DE chemosensitivity central; control of breathing central respiratory drive; hypoxia central; mediators, ACh, GABA, glutamate, taurine; neurotransmission, fast-acting ID CENTRAL HYPOVENTILATION SYNDROME; HYPOXIC VENTILATORY RESPONSE; INFANT-DEATH-SYNDROME; NUCLEUS-TRACTUS-SOLITARII; GAMMA-AMINOBUTYRIC-ACID; METHYL-D-ASPARTATE; BRAIN-STEM; C-FOS; RET PROTOONCOGENE; CARDIOVASCULAR FUNCTION AB A diverse group of processes are involved in central control of ventilation. Both fast acting neurotransmitters and slower acting neuromodulators are involved in the central respiratory drive. This review deals with fast acting neurotransmitters that are essential centrally in the ventilatory response to H(+)/CO(2), and to acute hypoxia. Data are reviewed to show that the central response to H(+)/CO(2) is primarily at sites in the medulla, the most prominent being the ventral medullary surface (VMS), and that acetylcholine is the key neurotransmitter in this process. Genetic abnormalities in the cholinergic system lead to states of hypoventilation in man and that knock out mice for genes responsible for neural cost development have none or diminished CO(2) ventilatory response. In the acute ventilatory response to hypoxia the afferent impulses from the carotid body reach the nucleus tractus solitarius (NTS) releasing glutamate which stimulates ventilation. Glutamate release also occurs in the VMS, Hypoxia is also associated with release of GABA in the mid-brain and a biphasic change in concentration of another inhibitory amino acid, taurine. Collectively changes in these amino acids can account for the ventilatory output in response to acute hypoxia. Future studies should provide more data on molecular and genetic basis of central respiratory drive and the role of neurotransmitter in this essential function. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Med Serv,Pulm & Crit Care Unit, Boston, MA 02114 USA. RP Kazemi, H (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Med Serv,Pulm & Crit Care Unit, Bulfinch 148, Boston, MA 02114 USA. EM hkazemi@partners.org FU NHLBI NIH HHS [HL-29620] NR 76 TC 67 Z9 75 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0034-5687 J9 RESP PHYSIOL JI Respir. Physiol. PD SEP PY 2000 VL 122 IS 2-3 BP 111 EP 121 DI 10.1016/S0034-5687(00)00153-5 PG 11 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 350TE UT WOS:000089116600003 PM 10967338 ER PT J AU Xavier, RJ Podolsky, DK AF Xavier, RJ Podolsky, DK TI Microbiology - How to get along - Friendly microbes in a hostile world SO SCIENCE LA English DT Editorial Material ID PROTEIN C1 Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Xavier, RJ (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, 55 Fruit St,GRJ-719, Boston, MA 02114 USA. NR 9 TC 39 Z9 44 U1 0 U2 5 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 SEP 1 PY 2000 VL 289 IS 5484 BP 1483 EP 1484 DI 10.1126/science.289.5484.1483 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 349XW UT WOS:000089071700028 PM 10991734 ER PT J AU Rosen, T AF Rosen, T TI Hazardous hedgehogs SO SOUTHERN MEDICAL JOURNAL LA English DT Article AB The African pygmy hedgehog has recently become a fashionable exotic pet in the United States, particularly in the South. As illustrated by the three cases reported, this mammalian insectivore can be a carrier of fungi that cause human dermatomycoses. The African pygmy hedgehog has also been associated with contact urticaria and human salmonellosis. C1 Baylor Coll Med, VA Med Ctr, Dept Dermatol, Houston, TX 77030 USA. RP Rosen, T (reprint author), 6560 Fannin,Suite 802, Houston, TX 77030 USA. OI Rosen, Ted/0000-0002-5946-5529 NR 26 TC 12 Z9 14 U1 0 U2 2 PU SOUTHERN MEDICAL ASSN PI BIRMINGHAM PA 35 LAKESHORE DR PO BOX 190088, BIRMINGHAM, AL 35219 USA SN 0038-4348 J9 SOUTHERN MED J JI South.Med.J. PD SEP PY 2000 VL 93 IS 9 BP 936 EP 938 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 353LC UT WOS:000089274800023 PM 11005362 ER PT J AU Finklestein, SP AF Finklestein, SP TI Intravenous brain-derived neurotrophic factor reduces infarct size and counterregulates Bax and Bcl-2 expression after temporary focal cerebral ischemia - Editorial comment SO STROKE LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Finklestein, SP (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD SEP PY 2000 VL 31 IS 9 BP 2217 EP 2217 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 351YT UT WOS:000089188300030 ER PT J AU Bauer, KA Humphries, S Smillie, B Li, L Cooper, JA Barzegar, S Rosenberg, RD Miller, GJ AF Bauer, KA Humphries, S Smillie, B Li, L Cooper, JA Barzegar, S Rosenberg, RD Miller, GJ TI Prothrombin activation is increased among asymptomatic carriers of the prothrombin G20210A and factor V Arg506Gln mutations SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE prothrombin G20210A; factor V-Arg506Gln; coagulation activation markers; prothrombin activation fragment F1+2 ID PROTEIN-C RESISTANCE; HORIZONTAL POLYACRYLAMIDE GELS; THROMBIN-ANTITHROMBIN COMPLEX; CARDIOVASCULAR RISK-FACTORS; COAGULATION-FACTOR-V; MYOCARDIAL-INFARCTION; VENOUS THROMBOSIS; ARG(506)->GLN MUTATION; BLOOD-COAGULATION; APC-RESISTANCE AB The risk of venous thrombosis is increased in individuals who carry specific genetic abnormalities in blood coagulation proteins. Among Caucasians, the prothrombin G20210A and factor V Arg506Gln (FV R506Q) mutations are the most prevalent defects identified to date. We evaluated their influence on markers of coagulation activation among participants in the Second Northwick Park Heart Study, which recruited healthy men (aged 50-61 years) from nine general medical practices in England and Wales. They were free of clinical vascular disease and malignancy at the lime of recruitment. Genotypes for the two mutations were analyzed using microplate array diagonal gel electrophoresis, and coagulation markers (factor XIIa; activation peptides of factor IX, factor X, and prothrombin; fibrinopeptide A) were measured by immunoassay. Factor VII coagulant activity and factor VIIa levels were determined by a functional clotting assay. Among 1548 men genotyped for both mutations, 28 (1.8%) and 52 (3.4%) were heterozygous for prothrombin G20210A and FV R506Q, respectively. The only coagulation marker that was significantly associated with the two mutations was prothrombin activation fragment F1+2 [mean +/- SD, 0.88 +/- 0.32 nmol/L in men with prothrombin G20210A (p = 0.002) and 0.89 +/- 0.30 in men with FV R506Q (p = 0.0001) versus 0.72 +/- 0.24 among non-carriers for either mutation]. This data provides conclusive evidence that heterozygosity for the prothrombin G20210A as well as the FV R506Q mutations in the general population leads to an increased rate of prothrombin activation in vivo. C1 Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston VA Healthcare Syst, Boston, MA USA. MIT, Dept Biol, Cambridge, MA USA. UCL, Sch Med, Div Cardiovasc Genet, London W1N 8AA, England. St Bartholomews & Royal London Med Coll, MRC, Epidemiol & Med Care Unit, London, England. RP Bauer, KA (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, 330 Brookline Ave, Boston, MA 02215 USA. EM bauer.kenneth@med.va.gov NR 41 TC 18 Z9 18 U1 0 U2 0 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD SEP PY 2000 VL 84 IS 3 BP 396 EP 400 PG 5 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 357AD UT WOS:000089475600007 PM 11019961 ER PT J AU Alper, CA Awdeh, Z AF Alper, CA Awdeh, Z TI Incomplete penetrance of MHC susceptibility genes: prospective analysis of polygenic MHC-determined traits SO TISSUE ANTIGENS LA English DT Article DE major histocompatibility complex; incomplete penetrance; autoimmunity; polygenic disease ID MAJOR HISTOCOMPATIBILITY COMPLEX; HEPATITIS-B VACCINE; DIABETES-MELLITUS; PEMPHIGUS-VULGARIS; HAPLOTYPES; PREDICTION; RELATIVES; TWINS AB We propose an approach to understanding incomplete penetrance of disease susceptibility genes as a method of studying the underlying mechanisms of polygenic diseases. Incomplete penetrance is the failure of genetically susceptible individuals to exhibit a trait. We define as baseline penetrance that which occurs in genetically identical (monozygotic) twins of an index subject with a major histocompatibility complex (MHC)-associated disease or trait. We consider two mechanisms for incomplete baseline penetrance: an extrinsic (environmental) trigger and an intrinsic stochastic, gene-associated process. The latter can be detected fur dominant expression because susceptibility genes in homozygotes (with their two intrinsic triggers) will be up to twice as frequently penetrant as those in heterozygotes, The extent of MHC and non-MHC gene contribution determines differences between baseline penetrance and apparent penetrance in MHC-identical sib pairs, sib pairs in general and MHC-identical unrelated individuals. Inheritance patterns in families do not reveal modes of inheritance of incompletely penetrant polygenic MHC-determined traits. A method is proposed to study such traits prospectively in persons presumed to be homozygous, heterozygous or non-carrying for susceptibility genes by determining trait expression in homozygotes, heterozygotes or non-carriers of trait-associated conserved extended MHC haplotypes. The method provides direct estimates of apparent penetrance rates, modes of genetic determination, and, if the trait is dominant, the origin of penetrance. When applied to dominant MHC susceptibility gene-determined immunoglobulin deficiencies in two populations, the ratios of affected haplotype homozygotes to heterozygotes near 2.0 were consistent with an intrinsic mechanism for baseline penetrance acting on the MHC susceptibility genes. C1 Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Alper, CA (reprint author), Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. FU NHLBI NIH HHS [HL-29583]; NIAID NIH HHS [AI-14157] NR 27 TC 7 Z9 7 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD SEP PY 2000 VL 56 IS 3 BP 199 EP 206 DI 10.1034/j.1399-0039.2000.560301.x PG 8 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 357WF UT WOS:000089523200001 PM 11034555 ER PT J AU Alper, CA Marcus-Bagley, D Awdeh, Z Kruskall, MS Eisenbarth, GS Brink, SJ Katz, AJ Stein, R Bing, DH Bing, DH Yunis, EJ Schur, PH AF Alper, CA Marcus-Bagley, D Awdeh, Z Kruskall, MS Eisenbarth, GS Brink, SJ Katz, AJ Stein, R Bing, DH Bing, DH Yunis, EJ Schur, PH TI Prospective analysis suggests susceptibility genes for deficiencies of IgA and several other immunoglobulins on the [HLA-B8, SCO1, DR3] conserved extended haplotype SO TISSUE ANTIGENS LA English DT Article DE major histocompatibility complex; immunodeficiency; immunoglobulins; IgA deficiency; IgG subclass deficiency; extended haplotype ID MAJOR HISTOCOMPATIBILITY COMPLEX; COMMON VARIABLE IMMUNODEFICIENCY; CHAIN CONSTANT REGION; CLASS-III GENES; A DEFICIENCY; MOLECULAR ANALYSIS; ASSOCIATION; DONORS; SERUM; ANTIBODIES AB The extended major histocompatibility complex (MMC) haplotype [HLA-B8, SC01, DR3] is increased in frequency among patients with immunoglobulin (Ig)A deficiency and common variable immunodeficiency. Because the genomic region from HLA-B to HLA-DR/DQ is virtually the same on ail instances of the haplotype in the general population, we reasoned that all independent instances of [HLA-B8, SC01, DR3] carry MHC susceptibility genes for these disorders. To define immunoglobulin deficiencies determined by genes on this haplotype and their mode of expression and penetrance, serum immunoglobulin class and IgG subclass concentrations were determined prospectively in homozygotes and heterozygotes of this haplotype and in Caucasian controls. Prevalence of individual immunoglobulin deficiencies in persons with [HLA-B8, SC01, DR3] ranged from 13% to 37%, significantly higher than rates in non-carriers or general controls. We found significantly increased frequencies of IgA and IgG4 deficiency only homozygotes (13.3% and 30%, respectively) compared with heterozygotes (1.7% and 3.4%) or non-carriers (1.6% each), suggesting recessive expression. In contrast, IgD and IgG3 deficiencies were significantly more common in both homozygotes (36.7% and 30%) and heterozygotes (20.3% and 17.5%) compared with controls (4.9% and 3.4%), suggesting dominant inheritance. These results indicate multiple distinct susceptibility genes, some recessive and others dominant, fur deficiency of IgA, IgD, IgG3 or IgG4 (but not for IgE, IgG1, IgG2 or IgM) on [HLA-B8, SC01, DR3]. These observations may also help to explain the observed associations of [HLA-B8, SC01, DR3] with both IgA deficiency and common variable immunodeficiency and the common occurrence of IgG subclass deficiencies in some patients with IgA deficiency. C1 Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Alper, CA (reprint author), Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. FU NHLBI NIH HHS [HL-29583]; NIAID NIH HHS [AI-14157] NR 54 TC 27 Z9 28 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD SEP PY 2000 VL 56 IS 3 BP 207 EP 216 DI 10.1034/j.1399-0039.2000.560302.x PG 10 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 357WF UT WOS:000089523200002 PM 11034556 ER PT J AU Chen, JN Fishman, MC AF Chen, JN Fishman, MC TI Genetics of heart development SO TRENDS IN GENETICS LA English DT Review ID DROSOPHILA FGF-RECEPTOR; HOLT-ORAM SYNDROME; TRANSCRIPTION FACTOR; CARDIOVASCULAR DEVELOPMENT; VENTRAL MORPHOGENESIS; ENDODERM FORMATION; ENDOTHELIAL-CELLS; VERTEBRATE HEART; TUBE FORMATION; NF-ATC AB The genes that drive heart-cell differentiation in vertebrates and Drosophila are similar, even though the Drosophila 'heart' is a simple tube and the vertebrate heart is a multichambered physiologically complex organ. Mutational analysis in mice and, as particular focus of this review, in zebrafish, reveals the additional genes brought into play to fashion these evolutionarily 'new' organotypic components. C1 Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Chen, JN (reprint author), Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. OI Chen, Jau-Nian/0000-0001-8807-3607 FU NHLBI NIH HHS [HL49579, HL63206]; NIDDK NIH HHS [DK55383] NR 68 TC 55 Z9 56 U1 1 U2 5 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD SEP PY 2000 VL 16 IS 9 BP 383 EP 388 DI 10.1016/S0168-9525(00)02075-8 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 355GA UT WOS:000089376900004 PM 10973066 ER PT J AU Cha, JHJ AF Cha, JHJ TI Transcriptional dysregulation in Huntington's disease SO TRENDS IN NEUROSCIENCES LA English DT Review ID NEURONAL INTRANUCLEAR INCLUSIONS; BULBAR MUSCULAR-ATROPHY; UBIQUITIN-PROTEASOME PATHWAY; NF-KAPPA-B; MUTANT HUNTINGTIN; TRINUCLEOTIDE REPEATS; ANDROGEN RECEPTOR; GENE-EXPRESSION; TRANSGENIC MICE; GLUTAMINE REPEATS AB Although the gene responsible for Huntington's disease was discovered in 1993, the pathogenic mechanisms by which mutant huntingtin causes neuronal dysfunction and death remain unclear. However, increasing evidence suggests that mutant huntingtin disrupts the normal transcriptional program of susceptible neurons. Thus, transcriptional dysregulation might be an important pathogenic mechanism in Huntington's disease. C1 Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Cha, JHJ (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. FU NINDS NIH HHS [NS 38106, NS 01916] NR 104 TC 282 Z9 287 U1 1 U2 10 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD SEP PY 2000 VL 23 IS 9 BP 387 EP 392 DI 10.1016/S0166-2236(00)01609-X PG 6 WC Neurosciences SC Neurosciences & Neurology GA 350AD UT WOS:000089077100001 PM 10941183 ER PT J AU Benacerraf, BR Spiro, R Mitchell, AG AF Benacerraf, BR Spiro, R Mitchell, AG TI Using three-dimensional ultrasound to detect craniosynostosis in a fetus with Pfeiffer syndrome SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Article DE syndromes; 3D sonography; craniosynostosis; acrocephaly ID IDENTICAL MUTATIONS; DIAGNOSIS; TYPE-2; FACE AB A case of fetal Pfeiffer's syndrome is presented, showing the contribution of three dimensional (3D) sonography in the diagnosis of craniosynostosis - a major feature of this syndrome. C1 Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet & Gynecol & Radiol, Boston, MA 02115 USA. Fdn Blood Res, Scarborough, ME 04074 USA. RP Benacerraf, BR (reprint author), Diagnost Ultrasound Associates PC, 333 Longwood Ave,Suite 400, Boston, MA 02115 USA. NR 14 TC 30 Z9 32 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD SEP PY 2000 VL 16 IS 4 BP 391 EP 394 DI 10.1046/j.1469-0705.2000.00178.x PG 4 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 401DX UT WOS:000166913000018 PM 11169319 ER PT J AU Keyser, KT MacNeil, MA Dmitrieva, N Wang, F Masland, RH Lindstrom, JM AF Keyser, KT MacNeil, MA Dmitrieva, N Wang, F Masland, RH Lindstrom, JM TI Amacrine, ganglion, and displaced amacrine cells in the rabbit retina express nicotinic acetylcholine receptors SO VISUAL NEUROSCIENCE LA English DT Article DE acetylcholine; bungarotoxin; nicotinic acetylcholine receptors; receptors; neurotransmitters ID BUNGAROTOXIN BINDING-SITES; ALPHA-BUNGAROTOXIN; SYNAPTIC TRANSMISSION; GABA(A) RECEPTORS; MAMMALIAN RETINA; CILIARY GANGLION; OPTIC LOBE; NEURONS; CHICK; LOCALIZATION AB Acetylcholine (ACh) in the vertebrate retina affects the response properties of many ganglion cells, including those that display directional selectivity. Three beta and eight alpha subunits of neuronal nicotinic acetylcholine receptors (nAChRs) have been purified and antibodies have been raised against many of them. Here we describe biochemical and immunocytochemical studies of nAChRs in the rabbit retina. Radioimmunoassay and Western blot analysis demonstrated that many of the nAChRs recognized by a monoclonal antibody (mAb210) contain beta2 subunits, some of which are in combination with alpha3 and possibly other subunits. MAb210-immunoreactive cells in the inner nuclear layer (INL) were 7-14 mum in diameter and were restricted to the innermost one or two tiers of cells, although occasional cells were found in the middle of the INL. At least 60% of the cells in the ganglion cell layer (GCL) in the visual streak displayed mAb210 immunoreactivity; these neurons ranged from 7-18 mum in diameter. The dendrites of cells in both the INL and GCL could sometimes be followed until they entered one of two dense, poorly defined, bands of processes in the inner plexiform layer (IPL) that overlap the arbors of the cholinergic starburst cells. Parvalbumin and serotonin-positive neurons did not exhibit nAChR immunoreactivity. Although the level of receptor expression appeared to be low mAb210 immunoreactivity was observed in some of the ChAT-positive (starburst) amacrine cells. C1 Univ Alabama, Vis Sci Res Ctr, Birmingham, AL 35294 USA. Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. Univ Penn, Inst Neurol Sci, Philadelphia, PA 19104 USA. RP Keyser, KT (reprint author), Univ Alabama, Vis Sci Res Ctr, Worrell Bldg,924 S 18th St, Birmingham, AL 35294 USA. FU NEI NIH HHS [P30 EY03039, EY07845]; NINDS NIH HHS [NS11323] NR 69 TC 42 Z9 44 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0952-5238 J9 VISUAL NEUROSCI JI Visual Neurosci. PD SEP-OCT PY 2000 VL 17 IS 5 BP 743 EP 752 DI 10.1017/S095252380017508X PG 10 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 383QR UT WOS:000165894300008 PM 11153654 ER PT J AU Carlson, KJ AF Carlson, KJ TI Multidisciplinary women's health care and quality of care SO WOMENS HEALTH ISSUES LA English DT Article AB Multidisciplinary women's health centers have appeared in academic and community settings throughout the United States as a response to the historical fragmentation of women's health care. This paper addresses the influence of this model for comprehensive primary care on quality of care for women. Attributes of care that may differ between multidisciplinary centers and traditional sites for women's health care and quality measurements sensitive to these differences are considered. The paper reviews the literature on characteristics of patients who attend women's health centers and studies evaluating quality of care in these centers as compared to traditional settings. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Carlson, KJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 14 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1049-3867 J9 WOMEN HEALTH ISS JI Womens Health Iss. PD SEP-OCT PY 2000 VL 10 IS 5 BP 219 EP 225 DI 10.1016/S1049-3867(00)00052-9 PG 7 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA 357TY UT WOS:000089518000001 PM 10980439 ER PT J AU Salazar, M Varela, A Ramirez, LA Uribe, O Vasquez, G Egea, E Yunis, EJ Iglesias-Gamarra, A AF Salazar, M Varela, A Ramirez, LA Uribe, O Vasquez, G Egea, E Yunis, EJ Iglesias-Gamarra, A TI Association of HLA-DRB1*1602 and DRB1*1001 with Takayasu arteritis in Colombian mestizos as markers of Amerindian ancestry SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article; Proceedings Paper CT International Conference on Takayasu Arteritis and Buerger Disease CY OCT 28-30, 1999 CL KISARAZU, JAPAN DE HLA antigens; Takayasu arteritis; Amerindian ancestry ID PCR-SSOP; SSP AB We performed HLA Class I and Class II typing in 16 patients (15 women, one man) with a confirmed diagnosis of Takayasu arteritis. We did not find any of the previously described associations with HLA-B52, and/or HLA-DRB1*1301 alleles. However, in our patients, HLA-DRB1*1602 and HLA-DRB1*1001 were significantly increased. The association of Takayasu arteritis with Amerindian and Asian HLA-DRB1 alleles (DRB1*1602 and DRB1*1001) in the Colombian mestizo patients reported here, and with HLA-B*3906 previously reported in Mexicans, suggest the possibility that some HLA and disease associations are markers for ethnicity of a population carrying a disease gene which is present in an admired population with the disease. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 Corp CorpoGen, Bogota, Colombia. Fdn Santafe Bogota, Dept Pathol, Bogota, Colombia. Univ Antioquia, Medellin, Colombia. Univ Norte, Div Immunol, Barranquilla, Colombia. Dana Farber Canc Inst, Div Immunopathol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Hosp San Juan Dios, Dept Rheumatol, Bogota, Colombia. Univ Nacl Colombia, Bogota, Colombia. RP Salazar, M (reprint author), Corp CorpoGen, Bogota, Colombia. EM gmarcela@openway.com.co RI Iglesias Gamarra, Antonio/D-7920-2015 OI Iglesias Gamarra, Antonio/0000-0002-6734-5471 NR 20 TC 23 Z9 27 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD AUG 31 PY 2000 VL 75 SU 1 BP S113 EP S116 DI 10.1016/S0167-5273(00)00181-9 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 358BR UT WOS:000089537800019 PM 10980348 ER PT J AU Kim, DD Park, SJ Oettinger, MA AF Kim, DD Park, SJ Oettinger, MA TI V(D)J recombination: Site-specific cleavage and repair SO MOLECULES AND CELLS LA English DT Review ID SEVERE COMBINED IMMUNODEFICIENCY; STRAND BREAK REPAIR; DNA-LIGASE-IV; RAG2 PROTEINS; IN-VITRO; STRUCTURE REQUIREMENTS; SIGNAL SEQUENCES; 2 STEPS; COMPLEX; GENE AB V(D)J recombination is a site-specific gene rearrangement process that contributes to the diversity of antigen receptor repertoires, Two lymphoid-specific proteins, RAG1 and RAG2, initiate this process at two recombination signal sequences. Due to the recent development of an in vitro assay for V(D)J cleavage, the mechanism of cleavage has been elucidated clearly. The RAG complex recognizes a recombination signal sequence, makes a nick at the border between signal and coding sequence, and carries out a transesterification reaction, resulting in the production of a hairpin structure at the coding sequence and DNA double-strand breaks at the signal ends. RAG1 possesses the active site of the V(D)J recombinase although RAG2 is essential for signal binding and cleavage. After DNA cleavage by the RAG complex, the broken DNA ends are rejoined by the coordinated action of DNA double-strand break repair proteins as well as the RAG complex. The junctional variability resulting from imprecise joining of the coding sequences contributes additional diversity to the antigen receptors. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Biol Mol, Boston, MA 02114 USA. Univ Ulsan, Immunomodulat Res Ctr, Ulsan 680749, South Korea. Univ Ulsan, Dept Immunol & Biomed, Ulsan 680749, South Korea. RP Oettinger, MA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Biol Mol, Boston, MA 02114 USA. NR 66 TC 20 Z9 20 U1 0 U2 1 PU SPRINGER-VERLAG SINGAPORE PTE LTD PI SINGAPORE PA #04-01 CENCON I, 1 TANNERY RD, SINGAPORE 347719, SINGAPORE SN 1016-8478 J9 MOL CELLS JI Mol. Cells PD AUG 31 PY 2000 VL 10 IS 4 BP 367 EP 374 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 347PZ UT WOS:000088939500001 PM 10987131 ER PT J AU Verselis, SJ Rheinwald, JG Fraumeni, JF Li, FP AF Verselis, SJ Rheinwald, JG Fraumeni, JF Li, FP TI Novel p53 splice site mutations in three families with Li-Fraumeni syndrome SO ONCOGENE LA English DT Article DE p53; germline mutation; Li-Fraumeni syndrome; alternate splicing ID CANCER-PRONE FAMILY; CELL-LINES; GENE; TP53; DATABASE; PATIENT; POLYMORPHISM; DEFICIENCY; PROTEIN; TUMORS AB Germline mutations in the p53 tumor suppressor gene predispose to a variety of cancers in families with Li-Fraumeni syndrome. Most germline p53 mutations observed to date cause amino acid substitutions in the protein's central sequence-specific DNA binding domain. Outside this conserved core region, however, we found novel alterations in sequences that regulate precursor mRNA splicing in three Li-Fraumeni syndrome families. Two splice site mutations affected the consensus sequence at the splice donor sites of introns 1 and 9, and produced unstable variant transcripts in normal cells. A third mutation at the splice acceptor site of intron 9 generated splicing at a cryptic acceptor site in intron 9, These splice site alterations emphasize the need to examine both noncoding and untranslated regions of the p53 gene for germline mutations in Li-Fraumeni syndrome families. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Skin Dis Res Ctr, Boston, MA 02115 USA. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Li, FP (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. NR 33 TC 19 Z9 21 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 31 PY 2000 VL 19 IS 37 BP 4230 EP 4235 DI 10.1038/sj.onc.1203758 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 349FL UT WOS:000089032900005 PM 10980596 ER PT J AU Hatsukami, TS Ross, R Polissar, NL Yuan, C AF Hatsukami, TS Ross, R Polissar, NL Yuan, C TI Visualization of fibrous cap thickness and rupture in human atherosclerotic carotid plaque in vivo with high-resolution magnetic resonance imaging SO CIRCULATION LA English DT Article DE atherosclerosis; magnetic resonance imaging; imaging ID OPTICAL COHERENCE TOMOGRAPHY; CORONARY-ARTERY DISEASE; ACUTE MYOCARDIAL-INFARCTION; INTRAVASCULAR ULTRASOUND; IN-VIVO; CONVENTIONAL ANGIOGRAPHY; STENOSIS; PROGRESSION; MORPHOLOGY; THROMBOSIS AB Background-The results of studies of advanced lesions of atherosclerosis suggest that the thickness of the fibrous cap that overlies the necrotic core distinguishes the stable lesion from one that is at high risk for rupture and thromboembolic events. We have developed a high-resolution MRI technique that can identify the fine structure of the lesion, including the fibrous cap, in vivo. The aim of the present study was to determine the agreement between in vivo MRI and lesion architecture as seen on histology and gross tissue examination to identify fibrous cap thickness and rupture. Methods and Results-Twenty-two subjects who were scheduled for carotid endarterectomy underwent MRI with a 3-dimensional multiple overlapping thin slab angiography protocol. The appearance of the fibrous cap was categorized as (1) an intact, thick, (2) an intact, thin, or (3) a ruptured fibrous cap on MRI, gross, and histological sections. Thirty-six sites were available for comparison between MRI and histology. There was a high level of agreement between MRI and histological findings: 89% agreement, kappa (95% CI) = 0.83 (0.67 to 1.0), weighted kappa = 0.87. Spearman's correlation coefficient was 0.88 (significant to the 0.01 level). Conclusions-These findings indicate that high-resolution MRI with a 3-dimensional multiple overlapping thin slab angiography protocol is capable of distinguishing intact, thick fibrous caps from intact thin and disrupted caps in atherosclerotic human carotid arteries in vivo. This noninvasive technique has the potential to permit studies that examine the relationship between fibrous cap changes and clinical outcome and to permit trials that evaluate therapy intended to "stabilize" the fibrous cap. C1 VA Puget Sound Hlth Care Syst, Surg Serv 112, Seattle, WA 98108 USA. Mt Whisper Light Stat Consulting, Seattle, WA USA. Univ Washington, Dept Pathol, Seattle, WA 98195 USA. Univ Washington, Dept Radiol, Seattle, WA 98195 USA. RP Hatsukami, TS (reprint author), VA Puget Sound Hlth Care Syst, Surg Serv 112, 1660 S Columbian Way, Seattle, WA 98108 USA. FU NHLBI NIH HHS [R01-HL-60213, R29-HL-56874] NR 41 TC 374 Z9 397 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 AUG 29 PY 2000 VL 102 IS 9 BP 959 EP 964 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 348GK UT WOS:000088977000014 PM 10961958 ER PT J AU Buck, T Mucci, RA Guerrero, JL Holmvang, G Handschumacher, MD Levine, RA AF Buck, T Mucci, RA Guerrero, JL Holmvang, G Handschumacher, MD Levine, RA TI The power-velocity integral at the vena contracts - A new method for direct quantification of regurgitant volume flow SO CIRCULATION LA English DT Article DE echocardiography; regurgitation; mitral valve; blood flow ID WEIGHTED MEAN VELOCITY; WAVE DOPPLER SPECTRA; MITRAL REGURGITATION; AORTIC REGURGITATION; SIGNAL INTENSITY; CANINE MODEL; ORIFICE AREA; BLOOD-FLOW; SEVERITY; ECHOCARDIOGRAPHY AB Background-Non invasive quantification of regurgitation is limited because Doppler measures velocity, not flow. Because backscattered Doppler power is proportional to sonified blood volume, power times velocity should be proportional to flow rate. Early studies, however, suggested that this held only for laminar flow, not for regurgitant jets, in which turbulence and fluid entrainment augment scatter. We therefore hypothesized that this Doppler power principle can be applied at the proximal vena contracta, where flow is laminar before entrainment, so that the power-times-velocity integral should vary linearly with flow rate and its time integral with stroke volume (SV). Methods and Results-This was tested in vitro with steady and pulsatile flow through 0.07- to 0.8-cm(2) orifices and in 36 hemodynamic stages in vivo, replacing the left atrium with a rigid chamber and column for direct visual recording of mitral regurgitant SV (MRSV). In 12 patients, MRSV was compared with MRI mitral inflow minus aortic outflow and in 11 patients with 3D echo left ventricular ejection volume-Doppler aortic forward SV. Vena contracta power in the narrow high-velocity spectrum from a broad measuring beam was calibrated against that from a narrow reference beam of known area. Calculated and actual flow rates and SV correlated well in vitro (r-=0.99, 0.99; error= - 1.6+/-2.5 mL/s, -2.4+/-2.9 mL), in vivo (MRSV: r=0.98, error=0.04+/-0.87 mL), and in patients (MRSV: r=0.98, error= -2.8+/-4.5 mL). Conclusions-The power-velocity integral at the vena contracta provides an accurate direct measurement of regurgitant flow, overcoming the limitations of existing Doppler techniques. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Surg Unit, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac MRI Unit, Boston, MA 02114 USA. RP Levine, RA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, VBK 508, Boston, MA 02114 USA. RI Guerrero, Jorge/I-3666-2015 OI Guerrero, Jorge/0000-0003-4315-7318 FU NHLBI NIH HHS [HL-57302, HL-38176] NR 43 TC 23 Z9 24 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 29 PY 2000 VL 102 IS 9 BP 1053 EP 1061 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 348GK UT WOS:000088977000028 PM 10961972 ER PT J AU Loveland, BE Cooper, DKC Sandrin, MS AF Loveland, BE Cooper, DKC Sandrin, MS TI Are pigs transgenic for human complement regulatory proteins necessary for xenotransplantation? SO TRANSPLANTATION LA English DT Editorial Material ID MEMBRANE C1 Austin Res Inst, Heidelberg, Vic 3084, Australia. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. RP Loveland, BE (reprint author), Austin Res Inst, Studley Rd, Heidelberg, Vic 3084, Australia. NR 5 TC 1 Z9 1 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 AUG 27 PY 2000 VL 70 IS 4 BP 567 EP 568 DI 10.1097/00007890-200008270-00004 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 348LK UT WOS:000088986100004 PM 10972209 ER PT J AU Chow, SY Moul, J Tobias, CA Himes, BT Liu, Y Obrocka, M Hodge, L Tessler, A Fischer, I AF Chow, SY Moul, J Tobias, CA Himes, BT Liu, Y Obrocka, M Hodge, L Tessler, A Fischer, I TI Characterization and intraspinal grafting of EGF/bFGF-dependent neurospheres derived from embryonic rat spinal cord SO BRAIN RESEARCH LA English DT Article DE precursor; progenitor; stein cell; transplantation; BDNF; retinoic acid ID CENTRAL-NERVOUS-SYSTEM; NEURAL STEM-CELLS; FIBROBLAST GROWTH-FACTOR; PROGENITOR CELLS; NEURONAL PRECURSORS; SUBEPENDYMAL CELLS; IN-VIVO; DIFFERENTIATION; CNS; INJURY AB Recent advances in the isolation and characterization of neural precursor cells suggest that they have properties that would make them useful transplants for the treatment of central nervous system disorders. We demonstrate here that spinal cord cells isolated from embryonic day 13 Sprague-Dawley and Fischer 344 rats possess characteristics of precursor cells. They proliferate as undifferentiated neurospheres in the presence of EGF and bFGF and can be maintained in vitro or frozen, expanded and induced to differentiate into both neurons and glia. Exposure of these cells to serum in the absence of EGF and bFGF promotes differentiation into astrocytes; treatment with retinoic acid promotes differentiation into neurons. Spinal cord cells labeled with a nuclear dye or a recombinant adenovirus vector carrying the lacZ gene survive grafting into the injured spinal cord of immunosuppressed Sprague-Dawley rats and non-immunosuppressed Fischer 334 rats for up to 4 months following transplantation. Ln the presence of exogenously supplied BDNF, the grafted cells differentiate into both neurons and glia. These spinal cord cell grafts are permissive for growth by several populations of host axons, especially when combined with exogenous BDNF administration, as demonstrated by penetration into the graft of axons immunopositive for 5-HT and CGRP. Thus, precursor cells isolated from the embryonic spinal cord of rats, expanded in culture and genetically modified, are a promising type of transplant for repair of the injured spinal cord. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Med Coll Penn & Hahnemann Univ, Dept Neurobiol & Anat, Philadelphia, PA 19129 USA. Dept Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. RP Chow, SY (reprint author), Med Coll Penn & Hahnemann Univ, Dept Neurobiol & Anat, 3300 Henry Ave, Philadelphia, PA 19129 USA. RI Fischer, Itzhak/D-1080-2012 OI Fischer, Itzhak/0000-0003-3187-8740 FU NICHD NIH HHS [HD07467]; NINDS NIH HHS [NS24707, NS10090] NR 69 TC 111 Z9 127 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD AUG 25 PY 2000 VL 874 IS 2 BP 87 EP 106 DI 10.1016/S0006-8993(00)02443-4 PG 20 WC Neurosciences SC Neurosciences & Neurology GA 350NK UT WOS:000089107800001 PM 10960593 ER PT J AU Yang, SX Linette, GP Longerich, S Roberts, BL Haluska, FG AF Yang, SX Linette, GP Longerich, S Roberts, BL Haluska, FG TI HLA-A2.1/K-b transgenic murine dendritic cells transduced with an adenovirus encoding human gp100 process the same A2.1-restricted peptide epitopes as human antigen-presenting cells and elicit A2.1-restricted peptide-specific CTL SO CELLULAR IMMUNOLOGY LA English DT Article DE adenovirus vector; dendritic cells; gene therapy; transgenic mice; tumor immunity ID MHC CLASS-I; ANTITUMOR IMMUNITY; METASTATIC MELANOMA; TUMOR-ANTIGENS; HUMAN TAP; T-CELLS; IMMUNIZATION; RESPONSES; VIRUS; RECOGNITION AB HLA-A2.1/K-b transgenic mice (A2.1/K-b mice) were used to investigate the processing of human gp100 melanoma antigen by murine antigen presenting cells (APC). Bone marrow-derived dendritic cells (DC) from A2.1/Kb mice were transduced with adenovirus encoding human gp100 (Ad2/hugp100v2). The Ad2/ hugp100v2-transduced DC express human gp100, as documented by immunoperoxidase staining. Flow cytometric analysis demonstrates that Ad vector transduction does not downregulate expression of several markers, including MHC class I. We show that Ad2/ hugp100v2-transduced DC are recognized by peptide-specific, A2.1-restricted CTL, suggesting correct processing and presentation of the hugp100 antigen by murine DC. To assess-dominance among the various A2.1-restricted epitopes encoded by hugp100, A2.1/Kb transgenic mice were immunized with Ad2/hugp100v2-transduced DC. Resulting effector cytotoxic T lymphocytes (CTL) were assayed for peptide specificity using a panel of six synthetic peptides known to encode A2.1-restricted epitopes of human gp100 (denoted G154, G177, G209, G280, G457, G476). CTL obtained from Ad2/hugp100v2-transduced DC immunized A2.1/Kb mouse lysed target cells presenting five of the six epitopes, supporting the observation that murine cells correctly process the hugp100 antigen. The immunogenicity of individual gp100 epitopes correlates with their binding affinity to A2.1. CTL generated from A2.1/Kb mice immunized with Ad2/hugp100v2-transduced DC also specifically recognize A2.1(+)/gp100(+) human melanoma cells. These data suggest that murine APC process and present the same set of HLA-restricted peptides, similar to human APC. HLA transgenic mice serve as a useful model system to study class I-restricted epitopes of human tumor-associated antigens. (C) 2000 Academic Press. C1 Genzyme Corp, Framingham, MA 01701 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Hematol Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. RP Yang, SX (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Hematol Oncol, Boston, MA 02114 USA. NR 42 TC 8 Z9 8 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0008-8749 J9 CELL IMMUNOL JI Cell. Immunol. PD AUG 25 PY 2000 VL 204 IS 1 BP 29 EP 37 DI 10.1006/cimm.2000.1695 PG 9 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 362XH UT WOS:000089803200004 PM 11006015 ER PT J AU Zhuang, SG Demirs, JT Kochevar, IE AF Zhuang, SG Demirs, JT Kochevar, IE TI p38 mitogen-activated protein kinase mediates bid cleavage, mitochondrial dysfunction, and caspase-3 activation during apoptosis induced by singlet oxygen but not by hydrogen peroxide SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYTOCHROME-C RELEASE; OXIDATIVE STRESS; HL-60 CELLS; SUBSTRATE-SPECIFICITY; SIGNAL-TRANSDUCTION; CELLULAR STRESSES; ENDOTHELIAL-CELLS; DEATH RECEPTORS; PATHWAY; FAS AB p38 mitogen-activated protein kinase is activated and involved in cleavage of caspase-3 during apoptosis induced by a number of stimuli. However, the signaling events triggered by p38 that result in caspase-3 activation are still unknown. In human leukemia cells, two reactive oxygen species, singlet oxygen and hydrogen peroxide (H2O2), selectively stimulated the phosphorylation of p38, Preincubation of cells with SB203580, a specific inhibitor of p38, dose dependently inhibited DNA fragmentation induced by singlet oxygen but not by H2O2. Protection from apoptosis by SB203580 correlated with inhibition of caspase-3, and several events that are associated with caspase-3 activation, including Bid cleavage, decrease in mitochondrial transmembrane potential and release of cytochrome c from mitochondria, whereas caspase-8 cleavage was not affected by this inhibitor. In contrast, blockade of caspase-8 with Ile-Glu-Thr-Asp-fluoromethyl ketone is sufficient to prevent formation of DNA fragments and to inhibit all the above signaling events, with exception of p38 phosphorylation, in both singlet oxygen- and H2O2-treated cells. These data suggest that caspase-3 activation is regulated through redundant signaling pathways that involve p38 and caspase-8 acting upstream of Bid during singlet oxygen-induced apoptosis, whereas the activation of caspase-3 by H2O2 is only governed by a caspase-8-mediated apoptotic pathway. C1 Harvard Univ, Wellman Labs Photomed, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kochevar, IE (reprint author), Harvard Univ, Wellman Labs Photomed, Sch Med, Massachusetts Gen Hosp, WEL-224,55 Fruit St, Boston, MA 02114 USA. FU NIGMS NIH HHS [GM 30955] NR 56 TC 184 Z9 191 U1 2 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 25 PY 2000 VL 275 IS 34 BP 25939 EP 25948 DI 10.1074/jbc.M001185200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 348RF UT WOS:000088999700010 PM 10837470 ER PT J AU Wang, LX Barachina, MD Martinez, V Wei, JY Tache, Y AF Wang, LX Barachina, MD Martinez, V Wei, JY Tache, Y TI Synergistic interaction between CCK and leptin to regulate food intake SO REGULATORY PEPTIDES LA English DT Article DE cholecystokinin; feeding behavior; vagus; satiety; body weight; gastric emptying; nucleus tractus solitarius; paraventricular nucleus of the hypothalamus ID CORTICOTROPIN-RELEASING HORMONE; C-FOS EXPRESSION; BODY-WEIGHT REGULATION; CENTRAL-NERVOUS-SYSTEM; OBESE GENE; PARAVENTRICULAR NUCLEUS; PANCREATIC GLUCAGON; ENERGY-BALANCE; OB PROTEIN; BRAIN-STEM AB Leptin administered (either intracerebroventricularly, icv, or intraperitoneally, ip) acts in synergy with CCK to suppress food intake and body weight in lean mice or rats. The potentiating effect induced by the co-injection of ip CCK and leptin to inhibit food consumption in mice is mediated by the CCK-A receptor and capsaicin sensitive afferents. In vitro, studies: in rats showed that a subset of gastric vagal afferent fibers responded to leptin injected directly into the gastric artery only after a prior intra-arterial CCK injection. Moreover, the tonic activity of gastric-related neurons in the nucleus tractus solitarius (NTS) increased when leptin was delivered into the gastric chamber of an in vitro stomach-brainstem preparation. CCK co-injected with leptin potentiated Fos expression selectively in the area postrema, NTS and paraventricular nucleus of the hypothalamus (PVN), which points to the PVN as part of the afferent and efferent limbs of the circuitry involved in the synergistic interaction between leptin and CCK. The dampening of CCK or leptin inhibitory action on ingestive behavior when either factor is not present or their receptors are non functional supports the notion that such leptin-CCK interaction may have a physiological relevance. These observations provide a mean through which leptin and CCK integrate short- and mid-term meal-related input signals into long-term control of energy balance. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Calif Los Angeles, Digest Dis Res Ctr, CURE, Los Angeles, CA 90073 USA. VA Greater Los Angeles Healthcare Syst, Dept Med, Div Digest Dis, Los Angeles, CA 90073 USA. VA Greater Los Angeles Healthcare Syst, Brain Res Inst, Los Angeles, CA 90073 USA. Univ Valencia, Sch Med, Dept Pharmacol, Valencia, Spain. CEU San Pablo, Sch Vet, Dept Physiol, Valencia 46113, Spain. RP Wang, LX (reprint author), Univ Calif Los Angeles, Digest Dis Res Ctr, CURE, Bldg 115,Room 203,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. RI Martinez, Vicente/N-1189-2014 FU NIDDK NIH HHS [DK-41301, DK-30110, DK 48476] NR 78 TC 83 Z9 85 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD AUG 25 PY 2000 VL 92 IS 1-3 SI SI BP 79 EP 85 DI 10.1016/S0167-0115(00)00153-1 PG 7 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 368CR UT WOS:000090100500012 PM 11024569 ER PT J AU Kroll, TG Sarraf, P Pecciarini, L Chen, CJ Mueller, E Spiegelman, BM Fletcher, JA AF Kroll, TG Sarraf, P Pecciarini, L Chen, CJ Mueller, E Spiegelman, BM Fletcher, JA TI PAX8-PPAR gamma 1 fusion in oncogene human thyroid carcinoma SO SCIENCE LA English DT Article ID ACTIVATED RECEPTOR-GAMMA; ACUTE PROMYELOCYTIC LEUKEMIA; HUMAN BREAST-CANCER; PPAR-GAMMA; TRANSACTIVATION PROPERTIES; ALVEOLAR RHABDOMYOSARCOMA; TERMINAL DIFFERENTIATION; TRANSCRIPTION FACTORS; COLON-CANCER; IN-VITRO AB Chromosomal translocations that encode fusion oncoproteins have been observed consistently in leukemias/lymphomas and sarcomas but not in carcinomas, the most common human cancers. Here, we report that t(2;3)(q13;p25), a translocation identified in a subset of human thyroid follicular carcinomas, results in fusion of the DNA binding domains of the thyroid transcription factor PAX8 to domains A to F of the peroxisome proliferator-activated receptor (PPAR) gamma 1. PAX8-PPAR gamma 1 mRNA and protein were detected in 5 of 8 thyroid follicular carcinomas but not in 20 follicular adenomas, 10 papillary carcinomas, or 10 multinodular hyperplasias. PAX8-PPAR gamma 1 inhibited thiazolidinedione-induced transactivation by PPAR gamma 1 in a dominant negative manner. The experiments demonstrate an oncogenic role for PPAR gamma and suggest that PAX8-PPAR gamma 1 may be useful in the diagnosis and treatment of thyroid carcinoma. C1 Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. Childrens Hosp, Dept Pediat Oncol, Boston, MA 02115 USA. RP Kroll, TG (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. FU NCI NIH HHS [CA75425] NR 49 TC 536 Z9 569 U1 3 U2 17 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 25 PY 2000 VL 289 IS 5483 BP 1357 EP 1360 DI 10.1126/science.289.5483.1357 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 347RF UT WOS:000088942400041 PM 10958784 ER PT J AU MacLean, CH Louie, R Leake, B McCaffrey, DF Paulus, HE Brook, RH Shekelle, PG AF MacLean, CH Louie, R Leake, B McCaffrey, DF Paulus, HE Brook, RH Shekelle, PG TI Quality of care for patients with rheumatoid arthritis SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; ASSOCIATION TASK-FORCE; PRACTICE GUIDELINES; UNITED-STATES; PHYSICIAN MASTERFILE; DEATH; SENSITIVITY; MANAGEMENT; MAMMOGRAPHY; IMPROVEMENT AB Context Patients with rheumatoid arthritis are at risk for substantial morbidity because of their arthritis and premature mortality due to comorbid diseases. However, little is known about the quality of the health care that these patients receive. Objective To assess the quality of the health care that rheumatoid arthritis patients receive for their arthritis, comorbid diseases, and health care maintenance and to determine the effect of patterns of specialty care on quality. Design, Setting, and Participants Historical cohort study of 1355 adult rheumatoid arthritis patients en rolled in the fee-for-service or discounted fee-for-service plans of a nationwide US insurance company, Patients were identified and followed up through administrative data between 1991 and 1995. Main Outcome Measures Quality scores for arthritis, comorbid disease, and health care maintenance were developed from performance on explicit process measures that related to each of these domains and described the percentage of indicated health care processes performed within each domain during each person-year of the study. Results During 4598 person-years of follow-up, quality scores were 62% (95% confidence interval [CI], 61%-64%) for arthritis care, 52% (95% CI, 49%-55%) for comorbid disease care, and 42% (95% CI, 40%-43%) for health care maintenance. Across domains, care patterns including relevant specialists yielded performance scores 30% to 187% higher than those that did not (P<.001) and 45% to 67% of person-years were associated with patterns of care that did not include a relevant specialist. Presence of primary care without specialty care yielded health care maintenance scores that were 43% higher than those for patterns that included neither primary nor relevant specialty care (P<.001). Conclusions In this population, health care quality appears to be suboptimal for arthritis, comorbid disease, and health care maintenance. Patterns of care that included relevant specialists were associated with substantially higher quality across all domains. Patterns that included generalists were associated with substantially higher quality health care maintenance than patterns that included neither a generalist nor a relevant specialist. The optimal roles of primary care physicians and specialists in the care of patients with complex conditions should be reassessed. C1 Univ Calif Los Angeles, Div Rheumatol, Dept Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Nursing, Los Angeles, CA 90095 USA. RAND Corp, Hlth Program, Santa Monica, CA USA. Greater Los Angeles VA Hlth Care Syst, Los Angeles, CA USA. Vet Affairs Hlth Serv Res & Dev Serv, Los Angeles, CA USA. RP MacLean, CH (reprint author), Univ Calif Los Angeles, Div Rheumatol, Dept Med, 1000 Vet Ave,Room 32-59, Los Angeles, CA 90095 USA. FU NIAMS NIH HHS [P60-AR36834] NR 60 TC 130 Z9 130 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 23 PY 2000 VL 284 IS 8 BP 984 EP 992 DI 10.1001/jama.284.8.984 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 344PX UT WOS:000088769000025 PM 10944644 ER PT J AU Tamagnan, G Baldwin, RM Kula, NS Baldessarini, RJ Innis, RB AF Tamagnan, G Baldwin, RM Kula, NS Baldessarini, RJ Innis, RB TI Synthesis and monoamine transporter affinity of 2 beta-carbomethoxy-3 beta-(2 ''-, 3 ''- or 4 ''-substituted) biphenyltropanes SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID ACID METHYL-ESTERS; DOPAMINE TRANSPORTER; BINDING AFFINITIES; REUPTAKE SITES; PRIMATE BRAIN; SPECT; CIT AB A series of 11 novel 3 beta-substituted biphenyltropanes was synthesized and evaluated by selective radioligand binding assays for affinity to monoamine transporters. Both 5-HTT potency and selectivity for 5-HTT over DAT was greatest with electron withdrawing group at the 3"-position. (C) 2000 Elsevier Science Ltd. All fights reserved. C1 Yale Univ, Sch Med, VA Connecticut HCS 116A2, W Haven, CT 06516 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, McLean Div,Mailman Res Ctr,Dept Psychiat, Belmont, MA 02478 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, McLean Div,Mailman Res Ctr,Neurosci Program, Belmont, MA 02478 USA. RP Tamagnan, G (reprint author), Yale Univ, Sch Med, VA Connecticut HCS 116A2, 950 Campbell Ave, W Haven, CT 06516 USA. FU NIMH NIH HHS [MH-34006, MH-47370] NR 17 TC 15 Z9 15 U1 0 U2 0 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 AUG 21 PY 2000 VL 10 IS 16 BP 1783 EP 1785 DI 10.1016/S0960-894X(00)00317-6 PG 3 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 345WF UT WOS:000088837600002 PM 10969967 ER PT J AU Tsytsykova, AV Goldfeld, AE AF Tsytsykova, AV Goldfeld, AE TI Nuclear factor of activated T cells transcription factor NFATp controls superantigen-induced lethal shock SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE tumor necrosis factor alpha; staphylococcal enterotoxin B; lipopolysaccharide; transcription; toxic shock ID TUMOR-NECROSIS-FACTOR; FACTOR-ALPHA GENE; STAPHYLOCOCCAL ENTEROTOXIN-B; NF-AT; SEPTIC SHOCK; FAMILY; MICE; LIPOPOLYSACCHARIDE; IDENTIFICATION; CALCINEURIN AB Turner necrosis factor alpha (TNF-alpha) is the key mediator of superantigen-induced T cell lethal shock. Here, we show that nuclear factor of activated T cells transcription factor, NFATp, controls susceptibility to superantigen-induced lethal shock in mice through its activation of TNF-alpha gene transcription. In NFATp-deficient mice, T cell stimulation leads to delayed induction and attenuation of TNF-alpha mRNA levels, decreased TNF-alpha serum levels, and resistance to superantigen-induced lethal shock. By contrast, after lipopolysaccharide (LPS) challenge, serum levels of TNF-alpha and susceptibility to shock are unaffected. These results demonstrate that NFATp is an essential activator of immediate early TNF-alpha gene expression in T cells and they present in vivo evidence of the inducer- and cell type-specific regulation of TNF-alpha gene expression. Furthermore, they suggest NFATp as a potential selective target in the treatment of superantigen-induced lethal shock. C1 Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Goldfeld, AE (reprint author), Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. FU NIGMS NIH HHS [GM-56492, R01 GM056492] NR 29 TC 33 Z9 33 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 21 PY 2000 VL 192 IS 4 BP 581 EP 586 DI 10.1084/jem.192.4.581 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 349WB UT WOS:000089067600014 PM 10952728 ER PT J AU Spielberg, F Critchlow, C Vittinghoff, E Coletti, AS Sheppard, H Mayer, KH Metzger, D Judson, FN Buchbinder, S Chesney, M Gross, M AF Spielberg, F Critchlow, C Vittinghoff, E Coletti, AS Sheppard, H Mayer, KH Metzger, D Judson, FN Buchbinder, S Chesney, M Gross, M CA HIV Early Detection Study Gp TI Home collection for frequent HIV testing: acceptability of oral fluids, dried blood spots and telephone results SO AIDS LA English DT Article DE dried blood spots; early HIV detection; HIV diagnostic tests; home specimen collection; oral fluids; telephone counseling ID LONGITUDINAL DATA-ANALYSIS; ANTIRETROVIRAL THERAPY; INFECTION; AIDS; TIME AB Objective: To assess the feasibility and acceptability of bimonthly home oral fluid (OF) and dried blood spot (DBS) collection for HIV testing among high-risk individuals. Design: A total of 241 participants [including men who have sex with men (MSM), injecting drug users (IDU), and women at heterosexual risk] were recruited from a randomly selected subset of study participants enrolled at four sites in the HIV Network for Prevention Trials (HIVNET) cohort, and assigned at random to bimonthly home collection of OF or DBS specimens over a 6 month interval. Participants could select telephone calls or clinic visits to receive HIV test results. Methods: Bimonthly specimens were tracked for adherence to the schedule, were evaluated for adequacy for testing, and tested using antibody assays and polymerase chain reaction (PCR) for DBS. The acceptability of bimonthly home OF and DBS collection and telephone counseling was assessed in an end-of-study questionnaire. Results: The laboratory received 96 and 90% of expected OF and DBS specimens, respectively; 99% of each specimen type was adequate for testing. Almost all (95%) participants chose results disclosure by telephone. The majority of participants (85%) reported that bimonthly testing did not make them worry more about HIV, and almost all (98%) judged that with bimonthly testing their risk behavior remained the same (77%) or became less risky (21%). C1 Univ Washington, Harborview Med Ctr, Ctr AIDS & STD, Dept Family Med, Seattle, WA 98104 USA. Fred Hutchinson Canc Res Ctr, HIVNET Stat Ctr, Seattle, WA 98104 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. ABT Associates Inc, Cambridge, MA 02138 USA. ABT Associates Inc, Bethesda, MD USA. Calif Dept Hlth Serv, Berkeley, CA 94704 USA. Brown Univ, Mem Hosp Rhode Isl, Sch Med, Pawtucket, RI 02860 USA. Philadelphia VA Med Ctr, Philadelphia, PA USA. Denver Dept Publ Hlth, Denver, CO USA. San Francisco Dept Publ Hlth, AIDS Off, San Francisco, CA USA. Univ Calif San Francisco, Ctr AIDS Prevent Studies, San Francisco, CA 94143 USA. RP Spielberg, F (reprint author), Univ Washington, Harborview Med Ctr, Ctr AIDS & STD, Dept Family Med, 325 9th Ave,3EC44,Box 359931, Seattle, WA 98104 USA. RI Metzger, David/D-9499-2012 FU PHS HHS [N01-A1-35176, N01-A1-45200] NR 26 TC 33 Z9 33 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD AUG 18 PY 2000 VL 14 IS 12 BP 1819 EP 1828 DI 10.1097/00002030-200008180-00018 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 348RN UT WOS:000089000400018 PM 10985320 ER PT J AU Sherr, CJ DePinho, RA AF Sherr, CJ DePinho, RA TI Cellular senescence: Mitotic clock or culture shock? SO CELL LA English DT Review ID ONCOGENIC RAS; TELOMERASE; CELLS; APOPTOSIS; P53; IMMORTALIZATION; SUPPRESSION; P16(INK4A); P19(ARF); LOCUS C1 St Jude Childrens Res Hosp, Howard Hughes Med Inst, Memphis, TN 38105 USA. St Jude Childrens Res Hosp, Dept Tumor Cell Biol, Memphis, TN 38105 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, 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 Sherr, CJ (reprint author), St Jude Childrens Res Hosp, Howard Hughes Med Inst, Memphis, TN 38105 USA. EM sherr@stjude.org NR 20 TC 509 Z9 526 U1 4 U2 51 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 18 PY 2000 VL 102 IS 4 BP 407 EP 410 DI 10.1016/S0092-8674(00)00046-5 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 347BX UT WOS:000088908000003 PM 10966103 ER PT J AU Ikura, T Ogryzko, VV Grigoriev, M Groisman, R Wang, J Horikoshi, M Scully, R Qin, J Nakatani, Y AF Ikura, T Ogryzko, VV Grigoriev, M Groisman, R Wang, J Horikoshi, M Scully, R Qin, J Nakatani, Y TI Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis SO CELL LA English DT Article ID GCN5-RELATED N-ACETYLTRANSFERASE; STRAND BREAK REPAIR; RUVB-LIKE PROTEIN; COENZYME-A; CRYSTAL-STRUCTURE; SUPERFAMILY; CHROMATIN; SWI/SNF; COACTIVATOR; COMPONENTS AB It is well known that histone acetylases are important chromatin modifiers and that they play a central role in chromatin transcription. Here, we present evidence for novel roles of histone acetylases. The TIP60 histone acetylase purifies as a multimeric protein complex. Besides histone acetylase activity on chromatin, the TIP60 complex possesses ATPase, DNA helicase, and structural DNA binding activities. Ectopic expression of mutated TIP60 lacking histone acetylase activity results in cells with defective double-strand DNA break repair. Importantly, the resulting cells lose their apoptotic competence, suggesting a defect in the cells' ability to signal the existence of DNA damage to the apoptotic machinery. These results indicate that the histone acetylase TIP60-containing complex plays a role in DNA repair and apoptosis. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. NICHHD, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Baylor Coll Med, Dept Biochem, Houston, TX 77030 USA. Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA. Univ Tokyo, Inst Mol & Cellular Biosci, Tokyo 1130032, Japan. Japan Sci & Technol Corp, Exploratory Res Adv Technol, Horikoshi Gene Selector Project, Tsukuba, Ibaraki 3002635, Japan. RP Nakatani, Y (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. RI Scully, Ralph/F-5008-2013; Ogryzko, Vasily/M-6665-2015 OI Ogryzko, Vasily/0000-0002-8548-1389 FU NCI NIH HHS [K01 CA079576] NR 47 TC 704 Z9 730 U1 2 U2 32 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD AUG 18 PY 2000 VL 102 IS 4 BP 463 EP 473 DI 10.1016/S0092-8674(00)00051-9 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 347BX UT WOS:000088908000008 PM 10966108 ER PT J AU O'Hare, MJ Hou, ST Morris, EJ Cregan, SP Xu, Q Slack, RS Park, DS AF O'Hare, MJ Hou, ST Morris, EJ Cregan, SP Xu, Q Slack, RS Park, DS TI Induction and modulation of cerebellar granule neuron death by E2F-1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYCLIN-DEPENDENT KINASES; TRANSCRIPTION-INDEPENDENT MECHANISMS; ALZHEIMERS-DISEASE BRAIN; S-PHASE ENTRY; CELL-CYCLE; CEREBRAL-ISCHEMIA; PC12 CELLS; RETINOBLASTOMA PROTEIN; INDUCED APOPTOSIS; DNA-SYNTHESIS AB Growing evidence suggests that certain cell cycle regulators also mediate neuronal death. Of relevance, cyclin D1-associated kinase activity is increased and the retinoblastoma protein (Rb), a substrate of the cyclin D1-Cdk4/6 complex, is phosphorylated during K+ deprivation-evoked death of cerebellar granule neurons (CGNs), Cyclin-dependent kinase (CDK) inhibitors block this death, suggesting a requirement for the cyclin D1/Cdk4/6-Rb pathway. However, the downstream target(s) of this pathway are not well defined. The transcription factor E2F-1 is regulated by Rb and is reported to evoke death in proliferating cells when overexpressed. Accordingly, we examined whether E2F-1 was sufficient to evoke death of CGNs and whether it was required for death evoked by low K+. We show that adenovirus-mediated expression of E2F-1 in CGNs results in apoptotic death, which is independent of p53, dependent upon Bax, and associated with caspase 3-like activity. In addition, we demonstrate that levels of E2F-1 mRNA and protein increase during K+ deprivation-evoked death. The increase in E2F-1 protein is blocked by the CDK inhibitor flavopiridol, Finally, E2F-1-deficient neurons are modestly resistant to death induced by low K+. These results indicate that E2F-1 expression is sufficient to promote neuronal apoptosis and that endogenous E2F-1 modulates the death of CGNs evoked by low K+. C1 Univ Ottawa, Neurosci Res Inst, Ottawa, ON K1H 8M5, Canada. Natl Res Council Canada, Inst Biol Sci, Ottawa, ON K1A 0R6, Canada. Massachusetts Gen Hosp, Ctr Canc, Oncol Mol Lab, Charlestown, MA 02129 USA. RP Park, DS (reprint author), Univ Ottawa, Neurosci Res Inst, 451 Smyth Rd, Ottawa, ON K1H 8M5, Canada. RI Cregan, Sean/M-3205-2013 NR 64 TC 117 Z9 120 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 18 PY 2000 VL 275 IS 33 BP 25358 EP 25364 DI 10.1074/jbc.M001725200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 346BB UT WOS:000088849400043 PM 10851232 ER PT J AU Fasshauer, M Klein, J Ueki, K Kriauciunas, KM Benito, M White, MF Kahn, CR AF Fasshauer, M Klein, J Ueki, K Kriauciunas, KM Benito, M White, MF Kahn, CR TI Essential role of insulin receptor substrate-2 in insulin stimulation of Glut4 translocation and glucose uptake in brown adipocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-B; RAT ADIPOSE-CELLS; 3T3-L1 ADIPOCYTES; PHOSPHATIDYLINOSITOL 3-KINASE; POTENTIAL ROLE; GLUCOSE-TRANSPORTER-4 TRANSLOCATION; GLUT4-CONTAINING VESICLES; PHOSPHOINOSITIDE 3-KINASE; GLYCOGEN-SYNTHESIS; GENE-TRANSFER AB Insulin and insulin-like growth factor I signals are mediated via phosphorylation of a family of insulin receptor substrate (IRS) proteins, which may serve both complementary and overlapping functions in the cell. To study the metabolic effects of these proteins in more detail, we established brown adipocyte cell lines from wild type and various IRS knockout (KO) animals and characterized insulin action in these cells in vitro. Preadipocytes derived from both wild type and TRS-S KO mice could be fully differentiated into mature brown adipocytes, In differentiated IRS-2 KO adipocytes, insulin-induced glucose uptake was decreased by 50% compared with their wild type counterparts. This was the result of a decrease in insulin-stimulated Glut4 translocation to the plasma membrane. This decrease in insulin-induced glucose uptake could be partially reconstituted in these cells by retrovirus-mediated reexpression of IRS-2, but not overexpression of IRS-1, Insulin signaling studies revealed a total loss of IRS-2-associated phosphatidylinositol (PI) 3-kinase activity and a reduction in phosphotyrosine-associated PI 3-kinase by 30% (p < 0.05) in the RO cells. The phosphorylation and activity of Akt, a major downstream effector of PI 3-kinase, as well as Akt-dependent phosphorylation of glycogen synthase kinase-3 and p70S6 kinase were not affected by the lack of IRS-2; however, there was a decrease in insulin stimulation of Akt associated with the plasma membrane. These results provide evidence for a critical role of IRS-2 as a mediator of insulin-stimulated Glut4 translocation and glucose uptake in adipocytes, This occurs without effects in differentiation, total activation of Akt and its downstream effecters, but may be caused by alterations in compartmentalization of these downstream signals. C1 Joslin Diabet Ctr, Dept Res, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Med Univ Lubeck, Dept Internal Med 1, D-23538 Lubeck, Germany. Univ Complutense Madrid, Fac Farm, E-28040 Madrid, Spain. RP Kahn, CR (reprint author), Joslin Diabet Ctr, Dept Res, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [DK 33201, DK 5545, DK 36836] NR 45 TC 112 Z9 117 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 18 PY 2000 VL 275 IS 33 BP 25494 EP 25501 DI 10.1074/jbc.M004046200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 346BB UT WOS:000088849400060 PM 10829031 ER PT J AU Higgins, JMG Cernadas, M Tan, K Irie, A Wang, JH Takada, Y Brenner, MB AF Higgins, JMG Cernadas, M Tan, K Irie, A Wang, JH Takada, Y Brenner, MB TI The role of alpha and beta chains in ligand recognition by beta(7) integrins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTERCELLULAR-ADHESION MOLECULE-1; FUNCTION-ASSOCIATED ANTIGEN-1; I-DOMAIN; BINDING-SITE; CRYSTAL-STRUCTURE; E-CADHERIN; A-DOMAIN; MONOCLONAL-ANTIBODY; T-CELLS; ALPHA(E)BETA(7) INTEGRIN AB Integrins alpha(E)beta(7) and alpha(4)beta(7) are involved in localization of leukocytes at mucosal sites. Although both alpha(E)beta(7) and alpha(4)beta(7) utilize the beta(7) chain, they have distinct binding specificities for E-cadherin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1), respectively. We found that mutation of the metal ion-dependent adhesion site (MIDAS) in the alpha(E) A-domain (D190A) abolished E-cadherin binding, as did mutation F298A on the A-domain surface near the MIDAS cleft. A docking model of the A-domain with E-cadherin domain 1 indicates that coordination of the alpha(E) MIDAS metal ion by E-cadherin Glu(31) and a novel projection of Phe(298) into a hydrophobic pocket on E-cadherin provide the basis for the interaction. The location of the binding site on the alpha(E) A-domain resembles that on other integrins, but its structure appears distinctive and particularly adapted to recognize the tip of E-cadherin, a unique integrin ligand. Additionally, mutation of the beta(7) MIDAS motif (D140A) abolished alpha(E)beta(7) binding to E-cadherin and alpha(4)beta(7)-mediated adhesion to MAdCAM-1, and alpha(4) chain mutations that abrogated binding of alpha(4)beta(1) to vascular cell adhesion molecule-1 and fibronectin similarly reduced alpha(4)beta(7) interaction with MAdCAM-1. Thus, although specificity can be determined by the integrin alpha or beta chain, common structural features of both subunits are required for recognition of dissimilar ligands. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp,Lymphocyte Biol Sect, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Pulm & Crit Care Div, Boston, MA 02115 USA. Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA. Scripps Res Inst, Dept Vasc Biol, La Jolla, CA 92037 USA. RP Higgins, JMG (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp,Lymphocyte Biol Sect, Div Rheumatol Immunol & Allergy, Smith Bldg,Rm 538D,1 Jimmy Fund Way, Boston, MA 02115 USA. OI takada, yoshikazu/0000-0001-5481-9589 NR 89 TC 23 Z9 29 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 18 PY 2000 VL 275 IS 33 BP 25652 EP 25664 DI 10.1074/jbc.M001228200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 346BB UT WOS:000088849400080 PM 10837471 ER PT J AU Bookheimer, SY Strojwas, MH Cohen, MS Saunders, AM Pericak-Vance, MA Mazziotta, JC Small, GW AF Bookheimer, SY Strojwas, MH Cohen, MS Saunders, AM Pericak-Vance, MA Mazziotta, JC Small, GW TI Patterns of brain activation in people at risk for Alzheimer's disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CEREBRAL BLOOD-FLOW; E TYPE-4 ALLELE; APOLIPOPROTEIN-E; SENSORY STIMULATION; EPSILON-4 ALLELE; TEMPORAL-LOBE; MEMORY; PERFORMANCE; ASSOCIATION; METABOLISM AB Background: The epsilon 4 allele of the apolipoprotein E gene (APOE) is the chief known genetic risk factor for Alzheimer's disease, the most common cause of dementia late in life. To determine the relation between brain responses to tasks requiring memory and the genetic risk of Alzheimer's disease, we performed APOE genotyping and functional magnetic resonance imaging (MRI) of the brain in older persons with intact cognition. Methods: We studied 30 subjects (age, 47 to 82 years) who were neurologically normal, of whom 16 were carriers of the APOE epsilon 4 allele and 14 were homozygous for the APOE epsilon 3 allele. The mean age and level of education were similar in the two groups. Patterns of brain activation during functional MRI scanning were determined while subjects memorized and recalled unrelated pairs of words and while subjects rested between such periods. Memory was reassessed in 14 subjects two years later. Results: Both the magnitude and the extent of brain activation during memory-activation tasks in regions affected by Alzheimer's disease, including the left hippocampal, parietal, and prefrontal regions, were greater among the carriers of the APOE epsilon 4 allele than among the carriers of the APOE epsilon 3 allele. During periods of recall, the carriers of the APOE epsilon 4 allele had a greater average increase in signal intensity in the hippocampal region (1.03 percent vs. 0.62 percent, P<0.001) and a greater mean (+/-SD) number of activated regions throughout the brain (15.9+/-6.2 vs. 9.4+/-5.5, P = 0.005) than did carriers of the APOE epsilon 3 allele. Longitudinal assessment after two years indicated that the degree of base-line brain activation correlated with degree of decline in memory. Conclusions: Patterns of brain activation during tasks requiring memory differ depending on the genetic risk of Alzheimer's disease and may predict a subsequent decline in memory. (N Engl J Med 2000;343:450-6.) (C)2000, Massachusetts Medical Society. C1 Univ Calif Los Angeles, Inst Neuropsychiat, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Radiol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Mol & Mol Pharmacol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Brain Mapping Ctr, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Alzheimers Dis Res Ctr, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Ctr Aging, Los Angeles, CA 90024 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Small, GW (reprint author), Univ Calif Los Angeles, Inst Neuropsychiat, Dept Psychiat & Biobehav Sci, 88-201,760 Westwood Plaza, Los Angeles, CA 90024 USA. RI Cohen, Mark/C-6610-2011 OI Cohen, Mark/0000-0001-6731-4053 FU NIA NIH HHS [AG13308, P30 AG010123, P30 AG010123-03, P50 AG005128, P50 AG005128-21, P60 AG011268, P60 AG011268-07, R01 AG013308, R01 AG013308-13, U24 AG021886]; NIMH NIH HHS [MH52453, R01 MH052453, R01 MH052453-05]; NINDS NIH HHS [R01 NS031153, P01 NS026630, R01 NS031153-14] NR 34 TC 772 Z9 788 U1 9 U2 48 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 17 PY 2000 VL 343 IS 7 BP 450 EP 456 DI 10.1056/NEJM200008173430701 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 344FC UT WOS:000088747700001 PM 10944562 ER PT J AU Laham, LE Mukhopadhyay, N Roberts, TM AF Laham, LE Mukhopadhyay, N Roberts, TM TI The activation loop in Lck regulates oncogenic potential by inhibiting basal kinase activity and restricting substrate specificity SO ONCOGENE LA English DT Article DE Lck; tyrosine kinase; activation loop; substrate specificity ID RECEPTOR TYROSINE KINASE; AFFINITY PHOSPHOTYROSYL PEPTIDE; CRYSTAL-STRUCTURE; PROTEIN-KINASE; SH2 DOMAIN; C-SRC; INSULIN-RECEPTOR; AUTOPHOSPHORYLATION; PHOSPHORYLATION; MUTATION AB The activities of Src-family non-receptor tyrosine kinases are regulated by structural changes that alter the orientation of key residues within the catalytic domain. In this study, we investigate the effects of activation loop mutations on regulation of the lymphocyte-specific kinase Lck (p56(lck)). Substitution of 5-7 residues amino terminal to the conserved activation loop tyrosine (Y-394) increases kinase activity and oncogenic potential regardless of regulatory C-terminal tail phosphorylation levels (Y-505), while most mutations in the 13 residues carboxyl to Y-394 decrease kinase activity. Phosphorylation of the C-terminal regulatory tail is carried out by the cytosolic tyrosine kinase Csk and we find that mutations upstream or downstream of Y394 or mutation of Y-394 do not affect the level of Y-505 phosphorylation, In addition, we report that mutations on either side of Y-394 affect substrate specificity in vivo. We conclude that the high degree of conservation across the entire activation loop of Src-family kinases is critical for normal regulation of kinase activity and oncogenicity as well as substrate selection. C1 Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Roberts, TM (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA43803-10] NR 33 TC 8 Z9 8 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 17 PY 2000 VL 19 IS 35 BP 3961 EP 3970 DI 10.1038/sj.onc.1203738 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 345PX UT WOS:000088825300001 PM 10962552 ER PT J AU Syngal, S Schrag, D Falchuk, M Tung, N Farraye, FA Chung, D Wright, M Whetsell, A Miller, G Garber, JE AF Syngal, S Schrag, D Falchuk, M Tung, N Farraye, FA Chung, D Wright, M Whetsell, A Miller, G Garber, JE TI Phenotypic characteristics associated with the APC gene I1307K mutation in Ashkenazi Jewish patients with colorectal polyps SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID OVARIAN-CANCER RISK; FAMILY HISTORY; 11307K ALLELE; BREAST-CANCER; JEWS; POLYMORPHISM; COMMUNITY; VARIANT AB Context The I1307K mutation of the APC gene is found in approximately 6% of the Ashkenazi Jewish population and is associated with elevated risk of colorectal cancer. The incidence of the mutation in patients with colorectal adenomas is unknown. Objectives To determine the carrier rate of the I1307K mutation in Ashkenazi Jewish patients with a history of colorectal polyps but without colorectal cancer and to compare phenotypic characteristics and family history of carriers vs noncarriers. Design, Setting, and Patients A total of 231 patients who had at least 1 large bowel polyp diagnosed between January 1, 1992, and January 31, 1999, at 1 of 5 centers in Boston. Mass, were included, of whom 183 were Ashkenazi Jewish. DNA was isolated from cheek swab samples. Main Outcome Measures Presence of the I1307K variant in the APC gene. Results The I1307K variant was identified in 22 (14%) of 161 Ashkenazi Jewish patients with a history of adenomatous polyps and in 1 (5%) of 20 Ashkenazi Jewish patients with hyperplastic polyps. The phenotypic features of adenomas, family history of polyps, colorectal cancer, and other cancers were indistinguishable between I1307K carriers and noncarriers, Conclusions The frequency of the APC I1307K mutation is elevated in Ashkenazi Jewish patients with adenomatous polyps, but not hyperplastic polyps. The I1307K mutation represents a novel paradigm for cancer-predisposing genes, as it is associated with moderately increased risk of neoplasia without other associated distinguishing phenotypic features. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. Genzyme Corp, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Beth Israel Deaconess Med Ctr,Gastrointestinal Un, Boston, MA USA. RP Syngal, S (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. NR 17 TC 25 Z9 25 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 16 PY 2000 VL 284 IS 7 BP 857 EP 860 DI 10.1001/jama.284.7.857 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 342PM UT WOS:000088654400028 PM 10938175 ER PT J AU Sabatine, MS Jang, IK AF Sabatine, MS Jang, IK TI The use of glycoprotein IIb/IIIa inhibitors in patients with coronary artery disease SO AMERICAN JOURNAL OF MEDICINE LA English DT Review ID ISCHEMIC-HEART-DISEASE; MYOCARDIAL-INFARCTION; RANDOMIZED TRIAL; DIABETES-MELLITUS; RECEPTOR BLOCKADE; BALLOON ANGIOPLASTY; CLINICAL OUTCOMES; UNSTABLE ANGINA; TIMI-12 TRIAL; IIB-IIIA AB Platelet membrane glycoprotein IIb/IIIa inhibitors, a new class of potent antiplatelet agents, have been used in the treatment of acute coronary syndromes as well as in the prevention of complications after percutaneous coronary interventions. Approximately 50,000 patients with coronary artery disease have been enrolled in randomized studies of glycoprotein IIb/IIIa inhibitors. The purpose of this article is to review the pharmacology of glycoprotein IIb/IIIa inhibitors, the results of the clinical trials using these agents, and their current use in percutaneous coronary interventions and the treatment of acute coronary syndromes. (C) 2000 by Excerpta Medica, Inc. C1 Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Jang, IK (reprint author), Massachusetts Gen Hosp, Div Cardiol, Bulfinch 105,55 Fruit St, Boston, MA 02114 USA. NR 88 TC 23 Z9 23 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD AUG 15 PY 2000 VL 109 IS 3 BP 224 EP 237 DI 10.1016/S0002-9343(00)00474-5 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 351DP UT WOS:000089142800008 PM 10974186 ER PT J AU Hazzard, WR AF Hazzard, WR TI The department of internal medicine: Hub of the academic health center response to the aging imperative SO ANNALS OF INTERNAL MEDICINE LA English DT Article AB In the 21st century, geriatrics will increasingly dominate U.S. health care as the median age of the population progressively increases. Academic departments of geriatrics have been created in nations that have already experienced this shift. As an alternative strategy that builds on traditional strengths of academic medicine in the United States, departments of internal medicine should lead a multidepartmental, pan-institutional response to the aging imperative. Recognition of gerontology and geriatric medicine as central to the missions of internal medicine in clinical care, education, and research must be increased. In the process, academic departments of internal medicine will develop a high level of geriatric expertise and will launch many programs that address this challenge. Successful development of geriatric programs will serve as a catalyst to strengthen the integration among and between generalists and subspecialists. This will entail developing optimal sites and systems of geriatric care-at different levels of care and over time-that can enhance the geriatric education of medical students, residents, fellows, and practicing physicians. The study of aging and geriatric health care will also become an integral part of departmental research, in its subspecialty divisions as well as its divisions of general internal medicine and geriatrics. This strategy is urgently recommended as both a challenge and an opportunity for all departments of internal medicine. C1 Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. RP Hazzard, WR (reprint author), Vet Affairs Puget Sound Hlth Care Syst, 1660 S Columbian Way, Seattle, WA 98108 USA. NR 4 TC 15 Z9 16 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 AUG 15 PY 2000 VL 133 IS 4 BP 293 EP 296 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 346NG UT WOS:000088877500007 PM 10929171 ER PT J AU Ganda, OP AF Ganda, OP TI Lipoatrophy, lipodystrophy, and insulin resistance SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID INHIBITOR-ASSOCIATED LIPODYSTROPHY; DIABETES-MELLITUS; FAT DISTRIBUTION; ADIPOSE-TISSUE; BODY-FAT; TROGLITAZONE C1 Joslin Diabet Ctr, Boston, MA 02215 USA. RP Ganda, OP (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. FU NCRR NIH HHS [2 MO1-RR001032-25] NR 20 TC 20 Z9 21 U1 0 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD AUG 15 PY 2000 VL 133 IS 4 BP 304 EP 306 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 346NG UT WOS:000088877500010 PM 10929174 ER PT J AU Keire, DA Kobayashi, M Solomon, TE Reeve, JR AF Keire, DA Kobayashi, M Solomon, TE Reeve, JR TI Solution structure of monomeric peptide YY supports the functional significance of the PP-fold SO BIOCHEMISTRY LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; HUMAN NEUROPEPTIDE-Y; PANCREATIC-POLYPEPTIDE; MOLECULAR-STRUCTURE; SECONDARY STRUCTURE; RECEPTOR SUBTYPES; NMR-SPECTROSCOPY; BINDING; EXPRESSION; CLONING AB Peptide YY (PYY) belongs to a family of peptides including neuropeptide Y (NPY) and pancreatic peptide (PP) that regulate numerous functions through both central and peripheral receptors. The solution structure of these peptides is hypothesized to be critically important in receptor selectivity and activation, based on prior demonstration of a stable tertiary conformation of PP called the "PP-fold". Circular dichroism (CD) spectra show a pH-dependent structural transition in the pH range 3-4. Thus we describe the tertiary structure of porcine PYY in water at pH 5.5, 25 degrees C, and 150 mM NaCl, as determined from 2D H-1 NMR data recorded at 500 MHz. A constraint set consisting of 396 interproton distances from NOE data was used as input for distance geometry, simulated annealing, and restrained energy minimization calculations in X-PLOR. The RMSDs of the 20 X-PLOR-generated structures were 0.71 +/- 0.14 and 1.16 +/- 0.17 Angstrom, respectively, for backbone and heavy atom overlays of residues 1-34. The resulting structure consists of two C-terminal helical segments from residues 17 to 22 and 25 to 33 separated by a kink at residues 23, 24, and 25, a turn centered around residues 12-14, and the N-terminus folded near residues 30 and 31. The well-defined portions of the PYY structure reported here bear a marked similarity to the structure of PP. Our findings strongly support the importance of the stable folded structure of this family of peptides for binding and activation of Y receptor subtypes. C1 Univ Calif Los Angeles, CURE, Digest Dis Res Ctr, Greater Los Angles Vet Hlth Care Syst, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Div Digest Dis, Los Angeles, CA 90023 USA. City Hope Natl Med Ctr, Beckman Res Inst, Div Immunol, Duarte, CA 91010 USA. RP Keire, DA (reprint author), Univ Calif Los Angeles, CURE, Digest Dis Res Ctr, Greater Los Angles Vet Hlth Care Syst, Bldg 115,Room 115,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. FU NIDDK NIH HHS [DK-33850, DK41301] NR 42 TC 33 Z9 34 U1 2 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 15 PY 2000 VL 39 IS 32 BP 9935 EP 9942 DI 10.1021/bi992576a PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 345VK UT WOS:000088835700036 PM 10933813 ER PT J AU Stripecke, R Cardoso, AA Pepper, KA Skelton, DG Yu, XJ Mascarenhas, L Weinberg, KI Nadler, LM Kohn, DB AF Stripecke, R Cardoso, AA Pepper, KA Skelton, DG Yu, XJ Mascarenhas, L Weinberg, KI Nadler, LM Kohn, DB TI Lentiviral vectors for efficient delivery of CD80 and granulocyte-macrophage-colony-stimulating factor in human acute lymphoblastic leukemia and acute myeloid leukemia cells to induce antileukemic immune responses SO BLOOD LA English DT Article ID HUMAN HEMATOPOIETIC-CELLS; GM-CSF GENE; TUMOR-CELLS; ANTITUMOR IMMUNITY; MELANOMA-CELLS; PHASE-I; COSTIMULATORY MOLECULES; RETROVIRAL VECTORS; T-LYMPHOCYTES; EXPRESSION AB Cell vaccines engineered to express immunomodulators have shown feasibility in eliminating leukemia in murine models. Vectors for efficient gene delivery to primary human leukemia cells are required to translate this approach to clinical trials, In this study, second-generation lentiviral vectors derived from human immunodeficiency virus 1 were evaluated, with the cytomegalovirus (CMV) promoter driving expression of granulocyte-macrophage-colony-stimulating factor (GMCSF) and CD80 in separate vectors or in a bicistronic vector. The vectors were pseudotyped with vesicular stomatitis virus G glycoprotein and concentrated to high titers (10(8)-10(9) infective particles/ mt). Human acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic myeloid leukemia cell lines transduced with the monocistronic pHR-CD80 vector or the bicistronic pHR-GM/CD vector became 75% to 95% CD80 positive (CD80(+)). More important, transduction of primary human ALL and AML blasts with high-titer lentiviral vectors was consistently successful (40%-95% CD80+), The average amount of GM-CSF secretion by the leukemia cell lines transduced with the pHR-GM-CSF monocistronic vector was 2182.9 pg/10(6) cells per 24 hours. Secretion was markedly lower with the bicistronic pHR-GM/CD vector (average, 225.7 pg/10(6) cells per 24 hours). Lower amounts of CMV-driven messenger RNA were detected with the bicistronic vector, which may account for its poor expression of GM-CSF. Primary ALL cells transduced to express CD80 stimulated T-cell proliferation in an autologous mixed lymphocyte reaction. This stimulation was specifically blocked with monoclonal antibodies reactive against CD80 or by recombinant cytotoxic T-lymphocyte antigen 4-immunoglobulin fusion protein, These results show the feasibility of efficiently transducing primary leukemia cells with lentiviral vectors to express immunomodulators to elicit antileukemic immune responses. (Blood. 2000; 96:1317-1326) (C) 2000 by The American Society of Hematology. C1 Childrens Hosp Los Angeles, Div Res Immunol Bone Marrow Transplantat, Los Angeles, CA 90027 USA. Childrens Hosp Los Angeles, Div Hematol Oncol, Los Angeles, CA 90027 USA. Univ So Calif, Keck Sch Med, Inst Geriatr Med, Los Angeles, CA 90089 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA USA. RP Kohn, DB (reprint author), Childrens Hosp Los Angeles, Div Res Immunol Bone Marrow Transplantat, Mailstop 62,4650 Sunset Blvd, Los Angeles, CA 90027 USA. RI Kohn, Donald/N-5085-2016 OI Kohn, Donald/0000-0003-1840-6087 FU NCI NIH HHS [P01-CA68484] NR 47 TC 78 Z9 84 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 AUG 15 PY 2000 VL 96 IS 4 BP 1317 EP 1326 PG 10 WC Hematology SC Hematology GA 358VQ UT WOS:000089578200017 PM 10942373 ER PT J AU Lecine, P Italiano, JE Kim, SW Villeval, JL Shivdasani, RA AF Lecine, P Italiano, JE Kim, SW Villeval, JL Shivdasani, RA TI Hematopoietic-specific beta 1 tubulin participates in a pathway of platelet biogenesis dependent on the transcription factor NF-E2 SO BLOOD LA English DT Article ID SUPPRESSION SUBTRACTIVE HYBRIDIZATION; LEUCINE ZIPPER PROTEIN; CHICKEN ERYTHROCYTES; MICE LACKING; MYELOPROLIFERATIVE SYNDROME; MURINE MEGAKARYOCYTES; THROMBOXANE SYNTHASE; CELL-LINE; EXPRESSION; ISOTYPES AB The cellular and molecular bases of platelet release by terminally differentiated megakaryocytes represent important questions in cell biology and hematopoiesis. Mice lacking the transcription factor NF-E2 show profound thrombocytopenia, and their megakaryocytes fail to produce proplatelets, the microtubule-based precursors of blood platelets. Using mRNA subtraction between normal and NF-E2-deficient megakaryocytes, cDNA was isolated encoding beta 1 tubulin, the most divergent beta 1 tubulin isoform. In NF-E2-deficient megakaryocytes, beta 1 tubulin mRNA and protein are virtually absent. The expression of beta 1 tubulin Is exquisitely restricted to platelets and megakaryocytes, where it appears late in differentiation and localizes to microtubule shafts and coils within proplatelets. Restoring NF-E2 activity in a megakaryoblastic cell line or in NF-E2-deficient primary megakaryocytes rescues the expression of beta 1 tubulin. Reexpressing beta 1 tubulin in isolation does not, however, restore proplatelet formation in the defective megakaryocytes, indicating that other critical factors are required; indeed, other genes identified by mRNA subtraction also encode structural and regulatory components of the cytoskeleton. These findings provide critical mechanistic links between NF-E2, platelet formation, and selected microtubule proteins, and they also provide novel molecular insights into thrombopoiesis. (Blood. 2000;96:1366-1373) (C) 2000 by The American Society of Hematology. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Shivdasani, RA (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. RI Lecine, Patrick/H-9338-2016 NR 62 TC 103 Z9 108 U1 3 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2000 VL 96 IS 4 BP 1366 EP 1373 PG 8 WC Hematology SC Hematology GA 358VQ UT WOS:000089578200023 PM 10942379 ER PT J AU Leu, AJ Berk, DA Lymboussaki, A Alitalo, K Jain, RK AF Leu, AJ Berk, DA Lymboussaki, A Alitalo, K Jain, RK TI Absence of functional lymphatics within a murine sarcoma: A molecular and functional evaluation SO CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; VEGF-C; FACTOR RECEPTOR-3; VASCULAR TUMORS; EXPRESSION; LIGAND; CANCER; FLT4 AB Despite a clinically recognized association between the lymphatics and metastasis, the biology of tumor-lymphatic interaction is not clearly understood. We report here that functional lymphatic capillaries are absent from the interior of a solid tumor, despite the presence within the tumor of the lymphangiogenic molecule vascular endothelial growth factor (VEGF)-C and endothelial cells bearing its receptor, VEGF receptor 3. Functional lymphatics, enlarged and VEGF receptor 3 positive, sere detected in some tumors only at the tumor periphery (within 100 mu m of the interface with normal tissue). We conclude that although lymphangiogenic factors are present, formation of functional lymphatic vessels is prevented, possibly due to collapse by the solid stress exerted by growing cancer cells. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Univ Helsinki, Mol Canc Biol Lab, SF-00014 Helsinki, Finland. Univ Helsinki, Haartman Inst, Ludwig Inst Canc Res, SF-00014 Helsinki, Finland. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, 100 Blossom St,Cox 7, Boston, MA 02114 USA. RI Berk, David/A-4863-2012; Alitalo, Kari/J-5013-2014 OI Berk, David/0000-0002-3855-6886; Alitalo, Kari/0000-0002-7331-0902 FU NCI NIH HHS [R35-CA-56591] NR 24 TC 296 Z9 313 U1 0 U2 13 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 AUG 15 PY 2000 VL 60 IS 16 BP 4324 EP 4327 PG 4 WC Oncology SC Oncology GA 348AG UT WOS:000088961100006 PM 10969769 ER PT J AU Hansen-Algenstaedt, N Stoll, BR Padera, TP Dolmans, DEJGJ Hicklin, DJ Fukumura, D Jain, RK AF Hansen-Algenstaedt, N Stoll, BR Padera, TP Dolmans, DEJGJ Hicklin, DJ Fukumura, D Jain, RK TI Tumor oxygenation in hormone-dependent tumors during vascular endothelial growth factor receptor-2 blockade, hormone ablation, and chemotherapy SO CANCER RESEARCH LA English DT Article ID SOLID TUMORS; IN-VIVO; IONIZING-RADIATION; THERAPY; ANGIOGENESIS; GRADIENTS; DIFFUSION; ANTIBODY; BIOLOGY; HYPOXIA AB Tumor oxygenation is critical for tumor survival as well as for response to therapy, e.g., radiation therapy, Hormone ablation therapy in certain hormone-dependent tumors and antiangiogenic therapy lead to vessel regression and have also shown beneficial effects when combined with radiation therapy. These findings are counterintuitive because vessel regression should reduce oxygen tension (pO(2)) in tumors, decreasing the effectiveness of radiotherapy. Here we report on the dynamics of pO(2) and oxygen consumption in a hormone-dependent tumor following hormone ablation and during treatment with an anti-VEGFR-2 monoclonal antibody (mAb) or a combination of doxorubicin and cyclophosphamide; the latter combination is not known to cause vessel regression at doses used clinically. Androgen-dependent male mouse mammary carcinoma (Shionogi) was implanted into transparent dorsal skin-fold chambers in male severe combined immunodeficient mice, Thirteen days after the tumors were implanted, mice were treated with antiangiogenic therapy (anti-VEGFR-2 mAb, 1.4 mg/30 g body weight), hormone ablation by castration, or doxorubicin (6.5 mg/kg every 7 days) and cyclophosphamide (100 mg/kg every 7 days). A non-invasive in vivo method was used to measure pO(2) profiles and to calculate oxygen consumption rates (Q(O2)) in tumors, Tumors treated with anti-VEGFR-2 mAb exhibited vessel regression and became hypoxic. Initial vessel regression was followed by a "second wave" of angiogenesis and increases in both pO(2) and Q(O2). Hormone ablation led to tumor regression followed by an increase in pO(2) coincident with regrowth. Chemotherapy led to tumor growth arrest characterized by constant Q(O2) and elevated pO(2). The increased pO(2) during anti-VEGFR-2 mAb and hormone ablation therapy may explain the observed beneficial effects of combining antiangiogenic or hormone therapies with radiation treatment. Thus, understanding the microenvironmental dynamics is critical for optimal scheduling of these treatment modalities. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. MIT, Dept Chem Engn, Cambridge, MA 02139 USA. MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Cambridge, MA 02139 USA. ImClone Syst Inc, Dept Immunol, New York, NY 10014 USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. FU NCI NIH HHS [R35-CA 56591] NR 33 TC 85 Z9 87 U1 0 U2 3 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 AUG 15 PY 2000 VL 60 IS 16 BP 4556 EP 4560 PG 5 WC Oncology SC Oncology GA 348AG UT WOS:000088961100044 PM 10969807 ER PT J AU Pandey, P Saleh, A Nakazawa, A Kumar, S Srinivasula, SM Kumar, V Weichselbaum, R Nalin, C Alnemri, ES Kufe, D Kharbanda, S AF Pandey, P Saleh, A Nakazawa, A Kumar, S Srinivasula, SM Kumar, V Weichselbaum, R Nalin, C Alnemri, ES Kufe, D Kharbanda, S TI Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90 SO EMBO JOURNAL LA English DT Article DE Apaf-1; apoptosis; caspase-9; cytochrome c; Hsp90 ID WD-40 REPEAT REGION; ICE-LIKE PROTEASE; INDUCED APOPTOSIS; POLY(ADP-RIBOSE) POLYMERASE; PROTEOLYTIC ACTIVATION; MOLECULAR CHAPERONES; ICE/CED-3 PROTEASE; CASPASE ACTIVATION; TYROSINE KINASE; TUMOR-CELLS AB The release of cytochrome c from mitochondria results in the formation of an Apaf-1-caspase-9 apoptosome and induces the apoptotic protease cascade by activation of procaspase-3. The present studies demonstrate that heat shock protein 90 (Hsp90) forms a cytosolic complex with Apaf-1 and thereby inhibits the formation of the active complex. Immunodepletion of Hsp90 depletes Apaf-1 and thereby inhibits cytochrome c-mediated activation of caspase-9. Addition of purified Apaf-1 to Hsp90-depleted cytosolic extracts restores cytochrome c-mediated activation of procaspase-9. We also show that Hsp90 inhibits cytochrome c-mediated oligomerization of Apaf-1 and thereby activation of procaspase-9. Furthermore, treatment of cells with diverse DNA-damaging agents dissociates the Hsp90-Apaf-1 complex and relieves the inhibition of procaspase-9 activation. These findings provide the first evidence for a negative cytosolic regulator of cytochrome c-dependent apoptosis and for involvement of a chaperone in the caspase cascade. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Thomas Jefferson Univ, Kimmel Canc Inst, Philadelphia, PA 19107 USA. Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA. Novartis Pharmaceut Corp, Oncol Res, E Hanover, NJ 07936 USA. RP Kharbanda, S (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA75216] NR 76 TC 381 Z9 421 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 AUG 15 PY 2000 VL 19 IS 16 BP 4310 EP 4322 DI 10.1093/emboj/19.16.4310 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 346CM UT WOS:000088853000013 PM 10944114 ER PT J AU Wei, MC Lindsten, T Mootha, VK Weiler, S Gross, A Ashiya, M Thompson, CB Korsmeyer, SJ AF Wei, MC Lindsten, T Mootha, VK Weiler, S Gross, A Ashiya, M Thompson, CB Korsmeyer, SJ TI tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c SO GENES & DEVELOPMENT LA English DT Article DE BID; cytochrome c; BAK; mitochondrial targeting; apoptosis ID PROGRAMMED CELL-DEATH; MITOCHONDRIAL OUTER-MEMBRANE; BCL-2 FAMILY MEMBER; ION-CHANNEL; RECEPTOR OLIGOMERIZATION; APOPTOSIS; BCL-X(L); PROTEIN; MICE; PHOSPHORYLATION AB TNER1/Eas engagement results in the cleavage of cytosolic BID to truncated tBID, which translocates to mitochondria. Immunodepletion and gene disruption indicate BID is required for cytochrome c release. Surprisingly, the three-dimensional structure of this BH3 domain-only molecule revealed two hydrophobic alpha-helices suggesting tBID itself might be a pore-forming protein. Instead, we demonstrate that tBID functions as a membrane-targeted death ligand in which an intact BH3 domain is required for cytochrome c release, but not for targeting. Bak-deficient mitochondria and blocking antibodies reveal tBID binds to its mitochondrial partner BAK to release cytochrome c, a process independent of permeability transition. Activated tBID results in an allosteric activation of BAK, inducing its intramembranous oligomerization into a proposed pore for cytochrome c efflux, integrating the pathway from death receptors to cell demise. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Howard Hughes Med Inst,Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Howard Hughes Med Inst,Dept Med, Boston, MA 02115 USA. Washington Univ, Sch Med, Div Biol & Biomed Sci, St Louis, MO 63110 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. Univ Penn, Dept Med, Philadelphia, PA 19104 USA. Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Korsmeyer, SJ (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Howard Hughes Med Inst,Dept Pathol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [5T32CA09361-19, CA50239, R01 CA050239, R37 CA050239, T32 CA009361] NR 50 TC 853 Z9 876 U1 5 U2 24 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 AUG 15 PY 2000 VL 14 IS 16 BP 2060 EP 2071 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 346LA UT WOS:000088871600008 PM 10950869 ER PT J AU Arenas-Huertero, F Arroyo, A Zhou, L Sheen, J Leon, P AF Arenas-Huertero, F Arroyo, A Zhou, L Sheen, J Leon, P TI Analysis of Arabidopsis glucose insensitive mutants, gin5 and gin6, reveals a central role of the plant hormone ABA in the regulation of plant vegetative development by sugar SO GENES & DEVELOPMENT LA English DT Article DE glucose insensitive; Arabidopsis thaliana; glucose regulation; ABA; abi; hexokinase ID SIGNAL-TRANSDUCTION PATHWAYS; ABSCISIC-ACID; GENE-EXPRESSION; PROTEIN-PHOSPHORYLATION; BETA-AMYLASE; WD PROTEIN; THALIANA; SUCROSE; HEXOKINASE; STRESS AB Sugars have signaling roles in a wide variety of developmental processes in plants. To elucidate the regulatory components that constitute the glucose signaling network governing plant growth and development, we have isolated and characterized two Arabidopsis glucose insensitive mutants, gin5 and gin6, based on a glucose-induced developmental arrest during early seedling morphogenesis. The T-DNA-tagged gin6 mutant abrogates the glucose-induced expression of a putative transcription factor, ABI4, previously shown to be involved in seed-specific abscisic acid (ABA) responses. Thus, ABI4 might be a regulator involved in both glucose- and seed-specific ABA signaling. The characterization of the gin5 mutant, on the other hand, reveals that glucose-specific accumulation of ABA is essential for hexokinase-mediated glucose responses. Consistent with this result, we show that three ABA-deficient mutants (aba1-1, aba2-1, and aba3-2) are also glucose insensitive. Exogenous ABA can restore normal glucose responses in gin5 and aba mutants but not in gin6 plants. Surprisingly, only abi4 and abi5-1 but not other ABA-insensitive signaling mutants (abi1-1, abi2-1, and abi3-1) exhibit glucose insensitivity, indicating the involvement of a distinct ABA signaling pathway in glucose responses. These results provide the first direct evidence to support a novel and central role of ABA in plant glucose responses mediated through glucose regulation of both ABA levels by GIN5 and ABA signaling by GIN6/ABI4. C1 Univ Nacl Autonoma Mexico, Inst Biotecnol, Dept Biol Mol Plantas, Cuernavaca 62271, Morelos, Mexico. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Leon, P (reprint author), Univ Nacl Autonoma Mexico, Inst Biotecnol, Dept Biol Mol Plantas, Cuernavaca 62271, Morelos, Mexico. NR 57 TC 289 Z9 313 U1 3 U2 43 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 AUG 15 PY 2000 VL 14 IS 16 BP 2085 EP 2096 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 346LA UT WOS:000088871600010 PM 10950871 ER PT J AU Sweadner, KJ Rael, E AF Sweadner, KJ Rael, E TI The FXYD gene family of small ion transport regulators or channels: cDNA sequence, protein signature sequence, and expression SO GENOMICS LA English DT Article ID GAMMA-SUBUNIT; MOLECULAR-CLONING; XENOPUS OOCYTES; KINASE-C; NA,K-ATPASE; PHOSPHOLEMMAN; GENERATION; CATION AB A gene family of small membrane proteins, represented by phospholemman and the gamma subunit of Na,K-ATPase, was defined and characterized by the analysis of more than 1000 related ESTs (expressed sequence tags). In addition to new and more complete cDNA sequence for known family members (including MAT-8, CHIF, and RIC), the findings included two new family members and new splicing variants. A large number of EST replicates made it possible to derive curated DNA sequence with higher confidence and accuracy than from the sequencing of individual clones. The family has a core motif of 35 invariant and conserved amino acids centered on a single transmembrane span. Features of each predicted protein product were compared, and tissue distributions were determined. The gene family was named FXYD (pronounced fix-id) in recognition of invariant amino acids in its signature motif, The abundant proteins are involved in the control of ion transport. (C) 2000 Academic Press. C1 Massachusetts Gen Hosp, Ctr Neurosci, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. RP Sweadner, KJ (reprint author), Massachusetts Gen Hosp, Ctr Neurosci, 149-6118,149 13th St, Charlestown, MA 02129 USA. FU NHLBI NIH HHS [HL36271]; NINDS NIH HHS [NS27653] NR 26 TC 292 Z9 306 U1 0 U2 7 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD AUG 15 PY 2000 VL 68 IS 1 BP 41 EP 56 DI 10.1006/geno.2000.6274 PG 16 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 349EM UT WOS:000089030700005 PM 10950925 ER PT J AU Poorkaj, P Peterson, KR Schellenberg, GD AF Poorkaj, P Peterson, KR Schellenberg, GD TI Single-step conversion of P1 and P1 artificial chromosome clones into yeast artificial chromosomes SO GENOMICS LA English DT Article ID TRANSGENIC MICE; HOMOLOGOUS RECOMBINATION; APOLIPOPROTEIN-B; MAMMALIAN-CELLS; DNA FRAGMENTS; YAC DNA; GENE; CLONING; VECTOR; EXPRESSION AB Large insert genomic clones are useful for generating transgenic animals, particularly when specific mutations are introduced. To facilitate manipulation of large genomic sequences, we developed a method of converting Escherichia coli P1 artificial chromosomes (PACs) into yeast artificial chromosomes (YACs). A shuttle vector, pMAX-121, was generated that contains elements needed to generate a YAC (cen4 ars, ura3, his, and two telomere segments) along with similar to 1.3 kb of sequence homologous to P1 and PAC vector sequences. Cotransformation of yeast with the target PAC or P1 clone and pMAX-121 results in two homologous recombination events. The first, between the target clone and pMAX-121, results in a circular molecule. The second is an intramolecular recombination event between the two pMAX-121 telomere sequences, resulting in a linear molecule. The resulting YAC is stably maintained in yeast and can be further modified, using homologous recombination. The method was used to convert a 201-kb PAC containing the human tau gene into a stable linear YAC. A second vector, pLys2-neo, was developed to retrofit the YAC with the yeast lys2 gene, a selectable marker replacing the yeast ura3 gene, and a Pgk-neo cassette that confers G418 resistance to mammalian cells. The resulting YAC can be used for generating transgenic animals and stably transfected cell lines. Also, the lys2 marker facilitates introduction of mutations by homologous recombination. (C) 2000 Academic Press. C1 Vet Affairs Puget Sound Hlth Care Syst, GRECC 182B, Seattle Div, Seattle, WA 98108 USA. Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. Univ Washington, Dept Neurol, Seattle, WA 98195 USA. Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. Univ Kansas, Med Ctr, Dept Biochem & Mol Biol, Sch Med, Kansas City, KS 66160 USA. RP Poorkaj, P (reprint author), Vet Affairs Puget Sound Hlth Care Syst, GRECC 182B, Seattle Div, 1660 S Columbian Way, Seattle, WA 98108 USA. FU NIA NIH HHS [AG05136, P0AG17586, R01AG11762] NR 19 TC 4 Z9 4 U1 1 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD AUG 15 PY 2000 VL 68 IS 1 BP 106 EP 110 DI 10.1006/geno.2000.6267 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 349EM UT WOS:000089030700015 PM 10950935 ER PT J AU Koblin, BA Holte, S Lenderking, B Heagerty, P AF Koblin, BA Holte, S Lenderking, B Heagerty, P CA HIVNET Vaccine Preparedness Study TI Readiness for HIV vaccine trials: Changes in willingness and knowledge among high-risk populations in the HIV network for prevention trials SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE vaccine trials; homosexual men; injection drug users; women; HIV ID EFFICACY TRIALS; UNITED-STATES; FEASIBILITY; PARTICIPATE; MEN AB Longitudinal data were analyzed to determine changes in willingness to participate in HIV vaccine efficacy trials and knowledge of vaccine trial concepts among populations at high risk of HIV-I infection. Gay men (MSM), male and female injection drug users, and non-injecting women at heterosexual risk were recruited(n = 4892). Follow-up visits occurred every 6 months up to 18 months. Willingness was significantly lower at follow-up visits compared with at baseline. Knowledge levels increased for all study populations. Problematic concepts were possible effects of the vaccine on the immune system and lack of knowledge about efficacy of a vaccine before the start of a trial. For concepts concerning safety, blinding, and guarantees of future participation in trials, MSM men had significant increases in knowledge, but little to no change occurred for the other populations. An increase in knowledge was associated with becoming not willing, particularly among MSM with low knowledge levels. At least half of high-risk participants were consistently willing to participate in Future vaccine efficacy trials and with basic vaccine education, knowledge levels increased. Continued educational efforts at the community and individual level are needed to address certain vaccine trial concepts and to increase knowledge levels in all potential study populations. C1 New York Blood Ctr, Lab Epidemiol, New York, NY 10021 USA. Fred Hutchinson Canc Res Ctr, HIVNET Stat Ctr, Seattle, WA 98104 USA. ABT Associates Inc, Cambridge, MA 02138 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Koblin, BA (reprint author), New York Blood Ctr, Lab Epidemiol, 310 E 67th St, New York, NY 10021 USA. FU NCRR NIH HHS [M01RR00096]; NIAID NIH HHS [N01-AI035176, N01-AI-45200] NR 9 TC 54 Z9 55 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 AUG 15 PY 2000 VL 24 IS 5 BP 451 EP 457 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 366YH UT WOS:000090033500008 PM 11035616 ER PT J AU Brander, C Suscovich, T Lee, Y Nguyen, PT O'Connor, P Seebach, J Jones, NG van Gorder, M Walker, BD Scadden, DT AF Brander, C Suscovich, T Lee, Y Nguyen, PT O'Connor, P Seebach, J Jones, NG van Gorder, M Walker, BD Scadden, DT TI Impaired CTL recognition of cells latently infected with Kaposi's sarcoma-associated herpes virus SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MHC CLASS-I; MAJOR HISTOCOMPATIBILITY COMPLEX; PRIMARY-EFFUSION LYMPHOMA; DOWN-REGULATION; ANTIGEN PRESENTATION; T-LYMPHOCYTES; IDENTIFICATION; EXPRESSION; RESPONSES; LINES AB Kaposi's sarcoma-associated herpes virus (KSHV) is a recently identified human gamma 2-herpesvirus associated with Kaposi's sarcoma, primary effusion lymphoma, and Castleman's disease. We reasoned that CTL responses may provide host defense against this virus, and consequently, KSHV may have evolved strategies to evade the CTL-mediated immune surveillance. In this study six B cell lines latently infected with KSHV were found to express reduced levels of HLA class I surface molecules compared with B cell lines transformed by the related gamma-herpesvirus EBV. KSHV-infected cells also required higher concentrations of soluble peptides to induce efficient CTL-mediated lysis than control cell lines and were unable to process and/or present intracellularly expressed Ag, Incubation of the KSHV-infected cell lines with high concentrations of soluble HLA class I binding peptides did not restore the deficient HLA class I surface expression. To assess the underlying mechanisms of these phenomena, TAP-1 and TAP-2 gene expression was analyzed. While no attenuation in TAP-2 expression was observed, TAP-1 expression was significantly reduced in all KSHV cell lines compared with that in controls. These results indicate that KSHV can modulate HLA class I-restricted Ag presentation to CTL, which may allow latently infected cells to escape CTL recognition and persist in the infected host. C1 Massachusetts Gen Hosp, Ctr Canc, AIDS Res Ctr, Boston, MA 02129 USA. Partners AIDS Res Ctr, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. Univ Zurich, Univ Spital Zurich, Zurich, Switzerland. RP Scadden, DT (reprint author), Massachusetts Gen Hosp, Ctr Canc, AIDS Res Ctr, 149 13th St,5212, Boston, MA 02129 USA. FU NCI NIH HHS [CA73580, CA78378] NR 40 TC 56 Z9 58 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2000 VL 165 IS 4 BP 2077 EP 2083 PG 7 WC Immunology SC Immunology GA 342BW UT WOS:000088626200046 PM 10925292 ER PT J AU Ryu, H Lee, JH Kim, KS Jeong, SM Kim, PH Chung, HT AF Ryu, H Lee, JH Kim, KS Jeong, SM Kim, PH Chung, HT TI Regulation of neutrophil adhesion by pituitary growth hormone accompanies tyrosine phosphorylation of Jak2, p125(FAK), and paxillin SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACTIN STRESS FIBERS; SIGNAL-TRANSDUCTION; PHOSPHATIDYLINOSITOL 3-KINASE; RESPIRATORY BURST; SUPEROXIDE ANION; FOCAL ADHESIONS; FACTOR-I; BINDING-SITE; F-ACTIN; KINASE AB Neutrophil adhesion is fundamentally important during the onset of inflammatory responses. The adhesion signaling pathways control neutrophil arrest and extravasation and influence neutrophil shape and function at sites of inflammation. In the present study the intracellular signaling pathways for the adhesion of human neutrophils by pituitary growth hormone (GH) were examined, Pituitary GH triggered the tyrosine phosphorylation of Janus kinase 2 (Jak2) and STAT3 in neutrophils, In addition, pituitary GH treatment resulted in the morphological changes and the tyrosine phosphorylation of focal adhesion kinase (p125(FAK)) and paxillin. Preincubation with genistein, a tyrosine kinase inhibitor, blocked the GH-stimulated adhesion and Jak2, STAT3, p125(FAK), and paxillin phosphorylation. Confocal microscopy revealed that pituitary GH stimulates the focal localization of p125(FAK), paxillin, phosphotyrosine, and filamentous actin filament into the membrane rufflings and uropods of human neutrophils, Immunoprecipitation experiments revealed a physical association of Jak2 with p125(FAK) via STAT3 in vivo. Also an in vitro kinase assay showed an augmentation of p125(FAK) autophosphorylation as a result of pituitary GH treatment. These results suggest that pituitary GH modulates neutrophil adhesion through tyrosine phosphorylation of Jak2, p125(FAK), and paxillin and actin polymerization. C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Kangwon Natl Univ, Coll Nat Sci, Dept Microbiol, Chunchon, Kangwon, South Korea. Wonkwang Univ, Sch Med, Dept Immunol & Bioenergy Qi Med, Inst Biotechnol, Iksan, Chonbuk, South Korea. Wonkwang Univ, Sch Med, Dept Microbiol & Immunol, Iksan, Chonbuk, South Korea. RP Chung, HT (reprint author), Harvard Univ, Inst Med, Beth Israel Deaconess Med Ctr, Dept Neurol, Room 847,77 Ave Louis Pasteur, Boston, MA 02115 USA. NR 62 TC 26 Z9 27 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 AUG 15 PY 2000 VL 165 IS 4 BP 2116 EP 2123 PG 8 WC Immunology SC Immunology GA 342BW UT WOS:000088626200051 PM 10925297 ER PT J AU Kirchhoff, BA Wagner, AD Maril, A Stern, CE AF Kirchhoff, BA Wagner, AD Maril, A Stern, CE TI Prefrontal-temporal circuitry for episodic encoding and subsequent memory SO JOURNAL OF NEUROSCIENCE LA English DT Article DE declarative memory; explicit memory; fMRI; neuroimaging; human memory; prefrontal cortex; medial temporal lobe; parahippocampal gyrus; hippocampus ID POSITRON EMISSION TOMOGRAPHY; HUMAN EXTRASTRIATE CORTEX; VENTRAL VISUAL PATHWAY; WORKING-MEMORY; FRONTAL-CORTEX; FUNCTIONAL-ANATOMY; SEMANTIC DEMENTIA; NOVELTY DETECTION; BRAIN ACTIVITY; RHESUS-MONKEY AB Humans encounter and form memories for multiple types of experiences that differ in content, novelty, and memorability. Critical for understanding memory is determining (1) how the brain supports the encoding of events with differing content and (2) whether neural regions that are sensitive to novelty also influence whether stimuli will be subsequently remembered. This event-related functional magnetic resonance imaging (fMRI) study crossed content (picture/word), novelty (novel/repeated), and subsequent memory (remembered/forgotten) to examine prefrontal and temporal lobe contributions to encoding. Results revealed three patterns of encoding-related activation in anatomically connected inferior prefrontal and lateral temporal structures that appeared to vary depending on whether visuospatial/visuoobject, phonological/lexical, or semantic attributes were processed. Event content also modulated medial temporal lobe activity; word encoding predominately activated the left hemisphere, whereas picture encoding activated both hemispheres. Critically, in prefrontal and temporal regions that were modulated by novelty, the magnitude of encoding activation also predicted whether an event would be subsequently remembered. These results suggest that (1) regions that demonstrate a sensitivity to novelty may actively support encoding processes that impact subsequent explicit memory and (2) multiple content-dependent prefrontal-temporal circuits support event encoding. The similarities between prefrontal and lateral temporal encoding responses raise the possibility that prefrontal modulation of posterior cortical representations is central to encoding. C1 Boston Univ, Dept Psychol, Boston, MA 02215 USA. MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Charlestown, MA 02129 USA. Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. RP Kirchhoff, BA (reprint author), Boston Univ, Dept Psychol, 64 Cummington St, Boston, MA 02215 USA. FU NIA NIH HHS [AG 05788] NR 70 TC 389 Z9 396 U1 8 U2 42 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 15 PY 2000 VL 20 IS 16 BP 6173 EP 6180 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 342ZC UT WOS:000088676400034 PM 10934267 ER PT J AU Mazarati, AM Hohmann, JG Bacon, A Liu, H Sankar, R Steiner, RA Wynick, D Wasterlain, CG AF Mazarati, AM Hohmann, JG Bacon, A Liu, H Sankar, R Steiner, RA Wynick, D Wasterlain, CG TI Modulation of hippocampal excitability and seizures by galanin SO JOURNAL OF NEUROSCIENCE LA English DT Article DE galanin; transgenic mice; seizures; hippocampus; long-term potentiation; glutamate ID TEMPORAL-LOBE EPILEPSY; CENTRAL-NERVOUS-SYSTEM; SUSTAINING STATUS EPILEPTICUS; LONG-TERM POTENTIATION; ELECTRICAL-STIMULATION; RAT HIPPOCAMPUS; NEUROPEPTIDE-Y; PERFORANT PATH; RELEASE; NEURONS AB Previous studies have shown that the expression of the neuropeptide galanin in the hippocampus is altered by seizures and that exogenous administration of galanin into the hippocampus attenuates seizure severity. To address the role of endogenous galanin in modulation of hippocampal excitability and its possible role in seizure mechanisms, we studied two types of transgenic mice: mice with a targeted disruption of the galanin gene (GalKO) and mice that overexpress the galanin gene under a dopamine-beta-hydroxylase promoter (GalOE). GalKO mice showed increased propensity to develop status epilepticus after perforant path stimulation or systemic kainic acid, as well as greater severity of pentylenetetrazol-induced convulsions. By contrast, GalOE mice had increased resistance to seizure induction in all three models. Physiological tests of hippocampal excitability revealed enhanced perforant path-dentate gyrus long-term potentiation (LTP) in GalKO and reduced LTP in GalOE. GalKO showed increased duration of afterdischarge (AD) evoked from the dentate gyrus by perforant path simulation, whereas GalOE had increased threshold for AD induction. Depolarization-induced glutamate release from hippocampal slices was greater in GalKO and lower in GalOE, suggesting that alterations of physiological and seizure responses in galanin transgenic animals may be mediated through modulation of glutamate release. Our data provide further evidence that hippocampal galanin acts as an endogenous anticonvulsant and suggest that genetically induced changes in galanin expression modulate both hippocampal excitability and predisposition to epileptic seizures. C1 Univ Calif Los Angeles, Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Dept Pediat, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Brain Res Inst, Los Angeles, CA 90095 USA. Dept Vet Affairs, Greater Los Angeles Healthcare Syst, Epilepsy Res Labs, Sepulveda, CA 91343 USA. Univ Bristol, Dept Med, Bristol BS2 8HW, Avon, England. Univ Washington, Neurobiol & Behav Program, Seattle, WA 98195 USA. Univ Washington, Dept Obstet & Gynecol, Seattle, WA 98195 USA. Univ Washington, Dept Physiol & Biophys, Seattle, WA 98195 USA. RP Mazarati, AM (reprint author), Univ Calif Los Angeles, Sch Med, Vet Affairs Greater Los Angeles Healthcare Syst, Dept Neurol, 111N1 Epilepsy Res,16111 Plummer St, Sepulveda, CA 91343 USA. FU NICHD NIH HHS [R01-HD27142, U54-HD12626]; NINDS NIH HHS [NS01792] NR 47 TC 151 Z9 155 U1 0 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 AUG 15 PY 2000 VL 20 IS 16 BP 6276 EP 6281 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 342ZC UT WOS:000088676400045 PM 10934278 ER PT J AU Grumet, AE Wyatt, JL Rizzo, JF AF Grumet, AE Wyatt, JL Rizzo, JF TI Multi-electrode stimulation and recording in the isolated retina SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE electrode array; extracellular stimulation; electric stimulation; retina; rabbit; neural recording ID CENTRAL NERVOUS-SYSTEM; ELECTRICAL-STIMULATION; GANGLION-CELLS; RABBIT RETINA; PROSTHESIS; AXONS AB As part of an exploration of the feasibility of an epi-retinal prosthesis, we developed an experimental method to electrically stimulate and record from retinal neurons using a micro-fabricated multi-electrode array. An isolated retina is placed on an array of 10 mu m diameter disk electrodes with the ganglion cell side of the retina facing the electrode surfaces. The retina is bathed in oxygenated Ames' medium and warmed in order to sustain it in vitro for the duration of an experiment. typically 4-9 h. To reduce stimulus artifacts, the electrodes are grouped into two clusters - one used for stimulation and the other for recording - spaced several hundred microns apart, and electrodes are insulated with both silicon nitride and a 10 mu m thick layer of polyimide. Stimuli are delivered to the array using an optically isolated current source stimulator, and the resulting responses recorded with an eight channel nerve response amplifier. Stimulation and recording are performed under computer control. A variety of physiologic measurements is described in order to illustrate the strengths and drawbacks of this method. (C) 2000 Elsevier Science B.V. All rights reserved. C1 MIT, Elect Res Lab, Cambridge, MA 02139 USA. Massachusetts Eye & Ear Infirm, WM Keck Fdn Neural Prosthesis Res Ctr, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. RP Grumet, AE (reprint author), 21 Milton St 1, Somerville, MA 02144 USA. NR 32 TC 109 Z9 113 U1 1 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD AUG 15 PY 2000 VL 101 IS 1 BP 31 EP 42 DI 10.1016/S0165-0270(00)00246-6 PG 12 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 351HN UT WOS:000089151900004 PM 10967359 ER PT J AU Farzan, M Schnitzler, CE Vasilieva, N Leung, D Choe, H AF Farzan, M Schnitzler, CE Vasilieva, N Leung, D Choe, H TI BACE2, a beta-secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FAMILIAL ALZHEIMERS-DISEASE; HEREDITARY CEREBRAL-HEMORRHAGE; DUTCH TYPE; MUTATION; GENE; PEPTIDE; ANGIOPATHY; DEMENTIA; PLAQUES; CELLS AB Production of amyloid-beta protein (A beta) is initiated by a beta-secretase that cleaves the A beta precursor protein (APP) at the N terminus of A beta (the beta site). A recently identified aspartyl protease, BACE, cleaves the beta site and at residue 11 within the A beta region of APP. Here we show that BACE2, a BACE homolog, cleaves at the beta site and more efficiently at a different site within AP. The Flemish missense mutation of APP, implicated in a form of familial Alzheimer's disease, is adjacent to this latter site and markedly increases A beta production by BACE2 but not by BACE. BACE and BACE2 respond identically to conservative beta-site mutations, and alteration of a common active site Arg inhibits beta-site cleavage but not cleavage within A beta by both enzymes. These data suggest that BACE2 contributes to A beta production in individuals bearing the Flemish mutation, and that selective inhibition of these highly similar proteases may be feasible and therapeutically advantageous. C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. Childrens Hosp, Perlmutter Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Farzan, M (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RI Schnitzler, Christine/G-8733-2013; Leung, Doris/R-5447-2016 OI Leung, Doris/0000-0002-2558-7798 NR 29 TC 266 Z9 286 U1 0 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 AUG 15 PY 2000 VL 97 IS 17 BP 9712 EP 9717 DI 10.1073/pnas.160115697 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 345XM UT WOS:000088840500068 PM 10931940 ER PT J AU Brandes, RP Schmitz-Winnenthal, FH Feletou, M Godecke, A Huang, PL Vanhoutte, PM Fleming, I Busse, R AF Brandes, RP Schmitz-Winnenthal, FH Feletou, M Godecke, A Huang, PL Vanhoutte, PM Fleming, I Busse, R TI An endothelium-derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium-dependent vasodilator in resistance vessels of wild-type and endothelial NO synthase knockout mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NITRIC-OXIDE SYNTHASE; VASCULAR SMOOTH-MUSCLE; CAROTID-ARTERY; JUNCTIONAL COMMUNICATION; GLYCYRRHETINIC ACID; BLOOD-VESSELS; GUINEA-PIG; INHIBITION; RABBIT; RELAXATIONS AB In addition to nitric oxide (NO) and prostacyclin (PGl(2)) the endothelium generates the endothelium-derived hyperpolarizing factor (EDHF). We set out to determine whether an EDHF-like response can be detected in wild-type (WT) and endothelial NO synthase knockout mice (eNOS -/-) mice. Vasodilator responses to endothelium-dependent agonists were determined in vivo and in vitro. In vivo, bradykinin induced a pronounced, dose-dependent decrease in mean arterial pressure (MAP) which did not differ between WT and eNOS -/- mice and was unaffected by treatment with N-omega-nitro-L-arginine methyl ester and diclofenac. In the saline-perfuse hindlimb of WT and eNOS -/- mice, marked N-omega-nitro-L-arginine (L-NA, 300 mu mol/liter)- and diclofenac-insensitive vasodilations in response to both bradykinin and acetylcholine (ACh) were observed, which were more pronounced than the agonistinduced vasodilation in the hindlimb of WT in the absence of L-NA. This endothelium-dependent, NO/PGl(2)-independent vasodilatation was sensitive to KCl (40 mM) and to the combination of apamin and charybdotoxin. Cap junction inhibitors (18 alpha-glycyrrhetinic acid, octanol, heptanol) and CB-1 cannabinoid-receptor agonists (Delta 9-tetrahydrocannabinol, HU210) impaired EDHF-mediated vasodilation, whereas inhibition of cytochrome P450 enzymes, soluble guanylyl cyclase, or adenosine receptors had no effect on EDHF-mediated responses. These results demonstrate that in murine resistance vessels the predominant agonist-induced endothelium-dependent vasodilation in vivo and in vitro is not mediated by NO, PGl(2), or a cytochrome P450 metabolite, but by an EDHF-like principle that requires functional gap junctions. C1 Univ Frankfurt Klinikum, Inst Kardiovask Physiol, D-60590 Frankfurt, Germany. Inst Rech Servier, F-92150 Suresnes, France. Univ Dusseldorf, Inst Herz & Kreislaufphysiol, D-40225 Dusseldorf, Germany. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. RP Brandes, RP (reprint author), Univ Frankfurt Klinikum, Inst Kardiovask Physiol, Theodor Stern Kai 7, D-60596 Frankfurt, Germany. RI Vanhoutte, Paul/B-4533-2009; Fleming, Ingrid/L-1225-2014 OI Fleming, Ingrid/0000-0003-1881-3635 NR 37 TC 194 Z9 202 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 15 PY 2000 VL 97 IS 17 BP 9747 EP 9752 DI 10.1073/pnas.97.17.9747 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 345XM UT WOS:000088840500074 PM 10944233 ER PT J AU Davidov, O Zelen, M AF Davidov, O Zelen, M TI Designing cancer prevention trials: a stochastic model approach SO STATISTICS IN MEDICINE LA English DT Article ID BREAST-CANCER; PROBABILITIES AB There is growing interest in the design and implementation of cancer prevention trials. The key idea is to have agents which interfere with carcinogenesis and/or the preclinical stage. In this article we develop multi-stage stochastic models for the planning of cancer prevention trials. For known inputs it is possible to calculate the incidence of disease for the control and intervention groups. Consequently we find designs that balance the required sample size and follow-up time while guaranteeing prespecified error probabilities. Moreover such models can incorporate the mode of action of the intervention as well as compliance. The model has been applied to breast cancer to determine the implications for planning breast cancer intervention trials. Although the model addresses issues in cancer prevention, it is quite general and may be suitable for other chronic diseases. Copyright (C) 2000 John Wiley & Sons, Ltd. C1 Univ Haifa, Dept Stat, IL-31905 Haifa, Israel. Harvard Univ, Dept Biostat, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Davidov, O (reprint author), Univ Haifa, Dept Stat, Mt Carmel, IL-31905 Haifa, Israel. NR 26 TC 7 Z9 7 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD AUG 15 PY 2000 VL 19 IS 15 BP 1983 EP 1995 DI 10.1002/1097-0258(20000815)19:15<1983::AID-SIM534>3.0.CO;2-E 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 342XQ UT WOS:000088671800003 PM 10900447 ER PT J AU Manchester, M Naniche, D Stehle, T AF Manchester, M Naniche, D Stehle, T TI CD46 as a measles receptor: Form follows function SO VIROLOGY LA English DT Review ID COFACTOR PROTEIN CD46; ACCELERATING FACTOR CD55; CELL-MEDIATED-IMMUNITY; VIRUS-BINDING; DOMAINS; DISTINCT; SITE; IDENTIFICATION; MECHANISM; REGIONS C1 Scripps Res Inst, Dept Neuropharmacol, Div Virol, La Jolla, CA 92037 USA. Massachusetts Gen Hosp, Lab Dev Immunol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Manchester, M (reprint author), Scripps Res Inst, Dept Neuropharmacol, Div Virol, 10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. OI Manchester, Marianne/0000-0002-7143-5744 FU NIAID NIH HHS [AI41514, AI36222, AI45716] NR 36 TC 27 Z9 28 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD AUG 15 PY 2000 VL 274 IS 1 BP 5 EP 10 DI 10.1006/viro.2000.0469 PG 6 WC Virology SC Virology GA 347YW UT WOS:000088957600002 PM 10936082 ER PT J AU Green, MJ Farber, NJ Ubel, PA Mauger, DT Aboff, BM Sosman, JM Arnold, RM AF Green, MJ Farber, NJ Ubel, PA Mauger, DT Aboff, BM Sosman, JM Arnold, RM TI Lying to each other - When internal medicine residents use deception with tumor colleagues SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 22nd Annual Meeting of the Society-of-General-Internal-Medicine CY APR 29-MAY 01, 1999 CL SAN FRANCISCO, CALIFORNIA SP Soc Gen Internal Med ID PHYSICIANS ATTITUDES; MISREPRESENTATION; APPLICANTS; STUDENTS; SCHOOL; ETHICS; TRUTH; DISCLOSURE; PATIENT; FRAUD AB Background: While lying is morally problematic, physicians have been known to use deception with their patients and with third parties. Little is known, however, about the use of deception between physicians. Objectives: To determine the likelihood that resident physicians say they would deceive other physicians in various circumstances and to examine how variations in circumstances affect the likelihood of using deception. Method: Two versions of a confidential survey using vignettes were randomly distributed to all internal medicine residents at 4 teaching hospitals in 1998. Survey versions differed by introducing slight variations to each vignette in ways we hypothesized would influence respondents' willingness to deceive. The likelihood that residents say they would use deception in response to each vignette was compared between versions. Results: Three hundred thirty surveys were distributed (response rate, 67%). Of those who responded, 36% indicated they were likely to use deception to avoid exchanging call, 15% would misrepresent a diagnosis in a medical record to protect patient privacy, 14% would fabricate a laboratory value to an attending physician, 6% would substitute their own urine in a drug test to protect a colleague, and 5% would lie about checking a patient's stool for blood to cover up a medical mistake. For some of the scenarios, the likelihood of deceiving was influenced by variations in the vignettes. Conclusions: A substantial percentage of internal medicine residents report they would deceive a colleague in various circumstances, and the likelihood of using deception depends on the context. While lying about clinical issues is not common, it is troubling when it occurs at any time. Medical educators should be aware of circumstances in which residents are likely to deceive, and discuss ways to eliminate incentives to lie. C1 Penn State Univ, Coll Med, Dept Humanities, Hershey, PA 17033 USA. Penn State Univ, Coll Med, Dept Hlth Evaluat Sci, Hershey, PA 17033 USA. Penn State Univ, Milton S Hershey Med Ctr, Gen Internal Med Sect, Hershey, PA 17033 USA. Christiana Care Hlth Syst, Wilmington, DE USA. Vet Affairs Med Ctr, Div Gen Internal Med, Philadelphia, PA USA. Univ Penn, Sch Med, Ctr Bioeth, Philadelphia, PA 19104 USA. Univ Wisconsin, Sch Med, Dept Med, Madison, WI 53706 USA. Univ Pittsburgh, Ctr Bioeth & Hlth Law, Sect Palliat Care & Med Eth, Div Gen Internal Med, Pittsburgh, PA 15260 USA. RP Green, MJ (reprint author), Penn State Univ, Coll Med, Dept Humanities, Campus Box H134,500 Univ Dr, Hershey, PA 17033 USA. NR 39 TC 25 Z9 25 U1 1 U2 2 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 AUG 14 PY 2000 VL 160 IS 15 BP 2317 EP 2323 DI 10.1001/archinte.160.15.2317 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 343MH UT WOS:000088705800010 PM 10927729 ER PT J AU Mylonakis, E Paliou, M Greenbough, TC Flaningan, TP Letvin, NL Rich, JD AF Mylonakis, E Paliou, M Greenbough, TC Flaningan, TP Letvin, NL Rich, JD TI Report of a false-positive HIV test result and the potential use of additional tests in establishing HIV serostatus SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; POPULATION; INFECTION AB Considering the lifelong implications of a positive human immunodeficiency virus (HIV) test result, physicians should be aware of the limitations of tests for HIV. A 43-year-old man had a reactive enzyme-linked immunosorbent assay and an indeterminate result on Western blot analysis. The results of subsequent enzyme-linked immunosorbent assay and Western blot tests were interpreted as positive, and the patient was informed that he had HIV infection. Persistently undetectable plasma HIV-1 RNA, combined with normal physical examination findings, CD4(+) cell count, and CD4/CD8 ratio, prompted further testing, which revealed that the patient was not infected with HIV. False-positive HIV test results are uncommon, but they can occur. In the appropriate clinical setting, follow-up and the use of other laboratory tests, such as determination of plasma viral load, may help identify such cases. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA 02114 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA USA. Brown Univ, Sch Med, Miriam Hosp, Dept Med,Div Clin Immunol, Providence, RI 02912 USA. Univ Massachusetts, Sch Med, Dept Pediat, Program Mol Med, Worcester, MA USA. RP Mylonakis, E (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA 02114 USA. FU NIAID NIH HHS [P30-AI-42853]; NIDA NIH HHS [DA00268] NR 12 TC 21 Z9 23 U1 0 U2 0 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 AUG 14 PY 2000 VL 160 IS 15 BP 2386 EP 2388 DI 10.1001/archinte.160.15.2386 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 343MH UT WOS:000088705800021 PM 10927739 ER PT J AU Hussain, MA Habener, JF AF Hussain, MA Habener, JF TI Glucagon-like peptide 1 increases glucose-dependent activity of the homeoprotein IDX-1 transactivating domain in pancreatic beta-cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID INSULIN GENE-EXPRESSION; ACTIVATED PROTEIN-KINASE; DNA-BINDING ACTIVITY; TRANSCRIPTION FACTOR; MESSENGER-RNA; RIN-5F CELLS; CYCLIC-AMP; LINE; PDX-1; STABILITY AB Both glucose and glucagon-like peptide 1 (GLP-1) stimulate insulin gene transcription in endocrine pancreatic P-cells within the islets of Langerhans. The effects of glucose are mediated by the homeodomain transcription. factor islet duodenum homeobox -1 (IDX-1) that binds to two adenine thymidine-rich (A1 and A2/3) motifs within the rat insulin promoter. Glucose stimulates the activity of the transactivation domain of IDX-1 that lies within the first 80 amino acids of the IDX-1 protein. The effects of GLP-1 on insulin gene expression are primarily conferred by the cAMP responsive element (CRE) within the insulin promoter. GLP-1 stimulates glucose-dependent insulin release from beta-cells, We hypothesize that GLP-1 may augment the effects of glucose on insulin gene transcription, Here we show that GLP-1 stimulates insulin gene transcription independent of the CRE and is glucose-dependent. Furthermore, we show that GLP-1 stimulates the transactivational activity Of IDX-I, (C) 2000 Academic Press. C1 Massachusetts Gen Hosp, Howard Hughes Med Inst, Mol Endocrinol Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Habener, JF (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Mol Endocrinol Lab, 55 Fruit St,Wellman 320, Boston, MA 02114 USA. FU NIDDK NIH HHS [R01 DK 30834, R01 DK 55365] NR 22 TC 20 Z9 21 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 11 PY 2000 VL 274 IS 3 BP 616 EP 619 DI 10.1006/bbrc.2000.3198 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 345LQ UT WOS:000088817800008 PM 10924326 ER PT J AU Liu, HZ Kublaoui, B Pilch, PF Lee, J AF Liu, HZ Kublaoui, B Pilch, PF Lee, J TI Insulin activation of mitogen-activated protein (MAP) kinase and AKT is phosphatidylinositol 3-kinase-dependent in rat adipocytes SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE insulin signaling; PI 3 kinase; MAP kinase ID SIGNAL-TRANSDUCTION PATHWAY; 3-KINASE INHIBITOR; GLUCOSE-TRANSPORT; DNA-SYNTHESIS; SH2 DOMAIN; S6 KINASE; RECEPTOR; STIMULATION; TRANSLOCATION; CELLS AB To explore the mechanism of MAP kinase activation in adipocytes, we examined the possible involvement of several candidate signaling proteins, MAP kinase activity was markedly increased 2-4 min after treatment with insulin and declined to basal levels after 20 min, The insulin-dependent tyrosine phosphorylation of IRS-1 in the internal membrane and its association with phosphatidylinositol 3 (PI3) kinase preceded MAP kinase activation. There was little or no tyrosine phosphorylation of She or association of Grb2 with She or IRS-1. Specific PI3 kinase inhibitors blocked the insulin-mediated activation of MAP kinase. They also decreased the activation of MAP kinase by PMA and EGF but to a much lesser extent, Insulin induced phosphorylation of AKT on serine/threonine residues, and its effect could be blocked by PI3 kinase inhibitors. These results suggest that the insulin-dependent activation of MAP kinase in adipocytes is mediated by the IRS-1/PI3 kinase pathway but not by the Shc/Grb2/SOS pathway. (C) 2000 Academic Press. C1 Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA. RP Lee, J (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. OI Pilch, Paul/0000-0003-1997-0499 FU NIDDK NIH HHS [DK 30425, DK 36424] NR 38 TC 11 Z9 11 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 11 PY 2000 VL 274 IS 3 BP 845 EP 851 DI 10.1006/bbrc.2000.3208 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 345LQ UT WOS:000088817800047 PM 10924365 ER PT J AU Sattler, M Verma, S Shrikhande, G Byrne, CH Pride, YB Winkler, T Greenfield, EA Salgia, R Griffin, JD AF Sattler, M Verma, S Shrikhande, G Byrne, CH Pride, YB Winkler, T Greenfield, EA Salgia, R Griffin, JD TI The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SIGNAL-TRANSDUCTION PATHWAYS; HYDROGEN-PEROXIDE; DNA-DAMAGE; GROWTH-FACTORS; CIGARETTE TAR; PHOSPHORYLATION; TRANSFORMATION; APOPTOSIS; COMPLEX; PHOSPHATASES AB The BCR/ABL oncogene causes chronic myelogenous leukemia, a myeloproliferative disorder characterized by clonal expansion of hematopoietic progenitor cells and myeloid cells, It is shown here that transformation of the hematopoietic cell lines Ba/F3, 32Dcl3, and M07e with BCR/ABL results in an increase in reactive oxygen species (ROS) compared with quiescent, untransformed cells. The increase in ROS was directly due to BCR/ABL because it was blocked by the ABL-specific tyrosine kinase inhibitor STI571, Oxidative stress through ROS is believed to have many biochemical effects, including the potential ability to inhibit protein-tyrosine phosphatases (PTPases), To understand the significance of increased production of ROS, a model system was established in which hydrogen peroxide (H2O2) was added to untransformed cells to mimic the increase in ROS induced constitutively by BCR/ABL. H2O2 substantially reduced total cellular PTPase activity to a degree approximately equivalent to that of pervanadate, a well known PTPase inhibitor. Further, stimulation of untransformed cells with H2O2 or pervanadate increased tyrosine phosphorylation of each of the most prominent known substrates of BCR/ABL, including c-ABL, c-CBL, SHC, and SHP-2. Treatment of the BCR/ABL-expressing cell line MO7/p210 with the reducing agents pyrrolidine dithiocarbamate or N-acetylcysteine reduced the accumulation of ROS and also decreased tyrosine phosphorylation of cellular proteins. Further, treatment of M07e cells with H2O2 or pervanadate increased the tyrosine kinase activity of c-ABL, Drugs that alter ROS metabolism or reactivate PTPases may antagonize BCR/ABL transformation. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Sattler, M (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA75348-03]; NIDDK NIH HHS [DK50654] NR 39 TC 200 Z9 206 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 11 PY 2000 VL 275 IS 32 BP 24273 EP 24278 DI 10.1074/jbc.M002094200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343CC UT WOS:000088683300007 PM 10833515 ER PT J AU Sun, WY Vincent, S Settleman, J Johnson, GL AF Sun, WY Vincent, S Settleman, J Johnson, GL TI MEK kinase 2 binds and activates protein kinase C-related kinase 2 - Bifurcation of kinase regulatory pathways at the level of an MAPK kinase kinase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELLULAR-TRANSFORMATION; SIGNAL-TRANSDUCTION; POTENTIAL EFFECTOR; PUTATIVE TARGET; 2-HYBRID SYSTEM; ADAPTER PROTEIN; SMALL GTPASE; RAT-LIVER; PKN; RHO AB MEK kinase 2 (MEKK2) is a 70-kDa protein serine/threonine kinase that has been shown to function as a mitogen-activated protein kinase (MAPK) kinase kinase, MEKK2 has its kinase domain in the COOH-terminal moiety of the protein. The NH,-terminal moiety of MEKK2 has no signature motif that would suggest a defined regulatory function. Yeast two-hybrid screening was performed to identify proteins that bind MEKK2. Protein kinase C-related kinase 2 (PRK2) was found to bind MEKK2; PRK2 has been previously shown to bind RhoA and the Src homology 3 domain of Nck, PRK2 did not bind MEKK3, which is closely related to MEKK2. The MEKK2 binding site maps to amino acids 637-660 in PRK2, which is distinct from the binding sites for RhoA and Nck. This sequence is divergent in the closely related kinase PRK1, which did not bind MEKK2. In cells, MEKK2 and PRK2 are co-immunoprecipitated and PRK2 is activated by MEKK2, Similarly, purified recombinant MEKK2 activated PRK2 in vitro. MEKK2 activation of PRK2 is independent of MEKK2 regulation of the c-Jun NH,-terminal kinase pathway. MEKK2 activation of PRK2 results in a bifurcation of signaling for the dual control of MAPK pathways and PRK2 regulated responses. C1 Univ Colorado, Hlth Sci Ctr, Dept Pharmacol, Denver, CO 80262 USA. Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02139 USA. Harvard Univ, Sch Med, Charlestown, MA 02139 USA. RP Johnson, GL (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Pharmacol, 4200 E 9th Ave,C-236, Denver, CO 80262 USA. FU NIDDK NIH HHS [DK37871, DK48845]; NIGMS NIH HHS [GM30324] NR 55 TC 22 Z9 25 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 11 PY 2000 VL 275 IS 32 BP 24421 EP 24428 DI 10.1074/jbc.M003148200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343CC UT WOS:000088683300025 PM 10818102 ER PT J AU Chen, M O'Toole, EA Muellenhoff, M Medina, E Kasahara, N Woodley, DT AF Chen, M O'Toole, EA Muellenhoff, M Medina, E Kasahara, N Woodley, DT TI Development and characterization of a recombinant truncated type VII collagen "minigene" - Implication for gene therapy of dystrophic epidermolysis bullosa SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN DERMAL FIBROBLASTS; EPIDERMAL GROWTH-FACTOR; COL7A1 UNDERLIE SEVERE; HUMAN KERATINOCYTES; ANCHORING FIBRILS; ACQUISITA ANTIGEN; BURN WOUNDS; IN-VIVO; PROCOLLAGEN; EXPRESSION AB Dystrophic epidermolysis bullosa (DEB) is an inherited mechano-bullous disorder of skin caused by mutations in the type VII collagen gene. The lack of therapy for DEB provides an impetus to develop gene therapy strategies. However, the full-length 9-kilobase type VII collagen cDNA exceeds the cloning capacity of current viral delivery vectors. In this study, we produced a recombinant type VII minicollagen containing the intact noncollagenous domains, NC1 and NC2, and part of the central collagenous domain using stably transfected human 293 cell clones and purified large quantities of the recombinant minicollagen VII from culture media. Minicollagen VII was secreted as correctly-folded, disulfide-bonded, helical trimers resistant to protease degradation. Purified minicollagen VII bound to fibronectin, laminin-5, type I collagen, and type TV collagen. Furthermore, retroviral-mediated transduction of the minigene construct into DEB keratinocytes tin which type VII collagen was absent) resulted in persistent synthesis and secretion of a 230-kDa recombinant minicollagen VII. In comparison with parent DEB keratinocytes, the gene-corrected DEB keratinocytes demonstrated enhanced cell-substratum adhesion, increased proliferative potential, and reduced cell motility, features that reversed the DEB phenotype toward normal. We conclude that the use of the minicollagen VII may provide a strategy to correct the cellular manifestations of gene defects in DEB. C1 Univ So Calif, Dept Med, Div Dermatol, Inst Med Genet, Los Angeles, CA 90033 USA. Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA 90033 USA. RP Woodley, DT (reprint author), Univ So Calif, Dept Med, Div Dermatol, Inst Med Genet, CRL 108,1303 Mission Rd, Los Angeles, CA 90033 USA. FU NIAMS NIH HHS [R01 AR33625] NR 45 TC 42 Z9 42 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 11 PY 2000 VL 275 IS 32 BP 24429 EP 24435 DI 10.1074/jbc.M003440200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343CC UT WOS:000088683300026 PM 10821839 ER PT J AU Hoffenberg, S Liu, X Nikolova, L Hall, HS Dai, WP Baughn, RE Dickey, BF Barbieri, MA Aballay, A Stahl, PD Knoll, BJ AF Hoffenberg, S Liu, X Nikolova, L Hall, HS Dai, WP Baughn, RE Dickey, BF Barbieri, MA Aballay, A Stahl, PD Knoll, BJ TI A novel membrane-anchored rab5 interacting protein required for homotypic endosome fusion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SMALL GTPASE RAB5; GDP DISSOCIATION INHIBITOR; COILED COILS; NUCLEOTIDE EXCHANGE; BINDING PROTEIN; 2-HYBRID SYSTEM; PLASMA-MEMBRANE; CELL-SURFACE; K562 CELLS; TRANSFERRIN AB The ras-related GTPase rab5 is rate-limiting for homotypic early endosome fusion. We used a yeast two-hybrid screen to identify a rab5 interacting protein, rab5ip. The cDNA sequence encodes a ubiquitous 75-kDa protein with an N-terminal transmembrane domain (TM), a central coiled-coil structure, and a C-terminal region homologous to several centrosome-associated proteins. rab5ip lacking the transmembrane domain (rab5ipTM(-)) had a greater affinity in vitro for rab5-guanosine 5'-O-2-(thio)diphosphate than for rab5-guanosine 5'-3-O-(thio)triphosphate. In transfected HeLa cells, rab5ipTM(-) was partly cytosolic and localized (by immunofluorescence) with a rab5 mutant believed to be in a GDP conformation (GFp-rab5(G78A)) but not with GFP-rab5(Q79L), a GTPase-deficient mutant. rab5ip with the transmembrane domain (rab5ipTM(+)) was completely associated with the particulate fraction and localized extensively with GFP-rab5(wt) in punctate endosome-like structures. Overexpression of rab5ipTM(+) using Sindbis virus stimulated the accumulation of fluid-phase horseradish peroxidase by BHK-81 cells, and homotypic endosome fusion in vitro was inhibited by antibody against rab5ip. rab5ipTM(-) inhibited rab5(wt)-stimulated endosome fusion but did not inhibit fusion stimulated by rab5(Q79L). rab5ip represents a novel rab5 interacting protein that may function on endocytic vesicles as a receptor for rab5-GDP and participate in the activation of rab5. C1 Baylor Coll Med, Dept Med, Div Pulm, Houston, TX 77030 USA. Baylor Coll Med, Dept Physiol & Mol Biophys, Houston, TX 77030 USA. Baylor Coll Med, Dept Microbiol & Immunol, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. Houston Vet Affairs Med Ctr, Houston, TX 77030 USA. Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA. RP Knoll, BJ (reprint author), Univ Houston, Coll Pharm, Dept Pharmcol & Pharmaceut Sci, Bldg SR2,Rm 521D,4800 Calhoun, Houston, TX 77204 USA. RI Stahl, Philip/D-6315-2012; Tang, Amy/L-3226-2016 OI Tang, Amy/0000-0002-5772-2878 NR 57 TC 28 Z9 32 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 11 PY 2000 VL 275 IS 32 BP 24661 EP 24669 DI 10.1074/jbc.M909600199 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343CC UT WOS:000088683300059 PM 10818110 ER PT J AU Wagner, L Oliyarnyk, O Gartner, W Nowotny, P Groeger, M Kaserer, K Waldhausl, W Pasternack, MS AF Wagner, L Oliyarnyk, O Gartner, W Nowotny, P Groeger, M Kaserer, K Waldhausl, W Pasternack, MS TI Cloning and expression of secretagogin, a novel neuroendocrine-and pancreatic islet of Langerhans-specific Ca2+-binding protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CALCIUM-BINDING PROTEINS; INSULIN-SECRETION; KINASE-II; CALBINDIN D28K; RINM5F CELLS; BETA-CELLS; CALRETININ; CA2+; OSCILLATIONS; CALMODULIN AB We have cloned a novel pancreatic beta cell and neuroendocrine cell-specific calcium-binding protein termed secretagogin. The cDNA obtained by immunoscreening a human pancreatic cDNA library using the recently described murine monoclonal antibody D24 contains an open reading frame of 828 base pairs. This codes for a cytoplasmic protein with six putative EF finger hand calcium-binding motifs, The gene could be localized to chromosome 6 by alignment with GenBanb genomic sequence data, Northern blot analysis demonstrated abundant expression of this protein in the pancreas and to a lesser extent in the thyroid, adrenal medulla, and cortex. In addition it was expressed in scant quantity in the gastrointestinal tract (stomach, small intestine, and colon). Thyroid tissue expression of secretagogin was restricted to C-cells, Using a sandwich capture enzyme-linked immunosorbent assay with a detection limit of 6.5 pg/ml, considerable amounts of constitutively secreted protein could be measured in tissue culture supernatants of stably transfected RIN-BF and dog insulinoma (INS-H1) cell clones; however, in stably transfected Jurkat cells, the protein was only secreted upon CD3 stimulation. Functional analysis of transfected cell lines expressing secretagogin revealed an influence on calcium flux and cell proliferation. In RIN-5F cells, the antiproliferative effect is possibly due to secretagogin-triggered down-regulation of substance P transcription. C1 Univ Vienna, Div Clin Endocrinol & Metab, Dept Med 3, A-1090 Vienna, Austria. Univ Vienna, Dept Dermatol, A-1090 Vienna, Austria. Univ Vienna, Dept Clin Pathol, A-1090 Vienna, Austria. Massachusetts Gen Hosp, Infect Dis Unit, Serv Pediat, Boston, MA 02129 USA. Massachusetts Gen Hosp, Infect Dis Unit, Med Serv, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Wagner, L (reprint author), Univ Vienna, Div Clin Endocrinol & Metab, Dept Med 3, Waehringer Guertel 18-20, A-1090 Vienna, Austria. NR 49 TC 88 Z9 95 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 11 PY 2000 VL 275 IS 32 BP 24740 EP 24751 DI 10.1074/jbc.M001974200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343CC UT WOS:000088683300070 PM 10811645 ER PT J AU Wiesel, P Foster, LC Pellacani, A Layne, MD Hsieh, CM Huggins, GS Strauss, P Yet, SF Perrella, MA AF Wiesel, P Foster, LC Pellacani, A Layne, MD Hsieh, CM Huggins, GS Strauss, P Yet, SF Perrella, MA TI Thioredoxin facilitates the induction of heme oxygenase-1 in response to inflammatory mediators SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-BINDING ACTIVITY; SMOOTH-MUSCLE CELLS; NF-KAPPA-B; REDOX REGULATION; TRANSFORMING GROWTH-FACTOR-BETA-1; TRANSCRIPTION FACTORS; DIRECT ASSOCIATION; CARBON-MONOXIDE; STRESS PROTEIN; AP-1 AB Heme oxygenase (HO)-1 is a stress response protein that is regulated by oxidative stress. HO-1 catalyzes the generation of biliverdin, carbon monoxide, and iron from heme. Lipopolysaccharide (LPS) and interleukin (IL)-1 beta induce HO-1 through the binding of nuclear proteins to AP-1 motifs in enhancer regions upstream from the transcription start site. The DNA binding activity of AP-1 proteins depends on the reduction of cysteines in their DNA-binding domains. We found that agents that disrupt free sulfhydryl groups abolish AP-1 binding activity in nuclear proteins obtained from rat aortic smooth muscle cells and macrophages stimulated with IL-1 beta or LPS. Thioredoxin (TRX) may regulate the redox status of nuclear transcription factors in response to oxidative stimuli, thus we determined the role of TRX in the physiologic regulation of HO-1. TRX underwent nuclear translocation in cells stimulated with IL-1 beta and LPS, We transfected macrophages with a heterologous promoter construct containing two AP-1 sites from an upstream enhancer region in the HO-1 promoter. Recombinant TRX induced promoter activity to a level analogous to that induced by LPS, and this TRX response was abolished by mutation of the AP-1 sites. An inhibitor of TRX reductase, used to prevent TRS translocation in the reduced state, decreased HO-1 induction by IL-1 beta and LPS. These data provide the first evidence that TRX contributes to the induction of HO-1 by inflammatory mediators. C1 Brigham & Womens Hosp, Div Cardiovasc, Program Dev Cardiovasc Biol, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Pulm & Crit Care, Boston, MA 02115 USA. Massachusetts Gen Hosp, Cardiac Unit, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Cardiovasc Biol Lab, Boston, MA 02115 USA. Northeastern Univ, Dept Biol, Boston, MA 02115 USA. RP Perrella, MA (reprint author), Brigham & Womens Hosp, Div Cardiovasc, Program Dev Cardiovasc Biol, 75 Francis St, Boston, MA 02115 USA. RI Yet, Shaw-Fang/B-1067-2010; OI Yet, Shaw-Fang/0000-0001-9097-3962 FU NHLBI NIH HHS [HL10113, HL03194, HL60788] NR 38 TC 96 Z9 100 U1 0 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 11 PY 2000 VL 275 IS 32 BP 24840 EP 24846 DI 10.1074/jbc.M000835200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343CC UT WOS:000088683300081 PM 10823822 ER PT J AU Choi, YG Kim, JI Lee, HP Jin, JK Choi, EK Carp, RI Kim, YS AF Choi, YG Kim, JI Lee, HP Jin, JK Choi, EK Carp, RI Kim, YS TI Induction of heme oxygenase-1 in the brains of scrapie-infected mice SO NEUROSCIENCE LETTERS LA English DT Article DE scrapie; astrocytosis; oxidative stress; heme oxygenase-1; neurodegeneration ID NITRIC-OXIDE SYNTHASE; ASTROGLIAL CELLS; PRION DISEASES; MESSENGER-RNA; KAPPA-B; EXPRESSION; HIPPOCAMPUS; STRESS; AGENT; GENE AB Heme oxygenase-1 (HO-1) is an inducible enzyme that catalyzes the rate-limiting step in the degradation of heme to biliverdin, carbon monoxide and iron, and its expression can be used as a marker for oxidative stress. Oxidative stress has been reported to be associated with neurodegenerative diseases including Alzheimer's disease. It is possible that oxidative stress is also involved in the disease process seen in scrapie, the archetype transmissible spongiform encephalopathy. In this study, we report that HO-1 is significantly increased in the scrapie-infected group compared to an age-matched control group. Immunohistochemistry showed a pronounced increase of immunostaining of th is protein in the infected group compared to the minimal amount of staining in the control group. These results support that oxidative stress is closely associated with the pathogenesis of scrapie and that it might contribute to neurodegeneration in this disease. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 Hallym Univ, Hallym Acad Sci, Inst Environm & Life Sci, Kangwon Do 200702, South Korea. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Genet & Aging Unit, Charlestown, MA 02129 USA. New York State Inst Basic Res Dev Disabil, Staten Isl, NY 10314 USA. Hallym Univ, Coll Med, Dept Microbiol, Kangwon Do 200702, South Korea. RP Kim, YS (reprint author), Hallym Univ, Hallym Acad Sci, Inst Environm & Life Sci, 1 Ockcheon-Dong, Kangwon Do 200702, South Korea. NR 22 TC 28 Z9 28 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD AUG 11 PY 2000 VL 289 IS 3 BP 173 EP 176 DI 10.1016/S0304-3940(00)01277-5 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 342DH UT WOS:000088629600005 PM 10961657 ER PT J AU Artandi, SE Chang, S Lee, SL Alson, S Gottlieb, GJ Chin, L DePinho, RA AF Artandi, SE Chang, S Lee, SL Alson, S Gottlieb, GJ Chin, L DePinho, RA TI Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice SO NATURE LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; CARCINOMA IN-SITU; MOUSE TELOMERASE; V(D)J RECOMBINATION; P53-DEFICIENT MICE; HUMAN FIBROBLASTS; EXPRESSION; CELLS; BREAST; METASTASES AB Aged humans sustain a high rate of epithelial cancers such as carcinomas of the breast and colon, whereas mice carrying common tumour suppressor gene mutations typically develop soft tissue sarcomas and lymphomas. Among the many factors that may contribute to this species variance are differences in telomere length and regulation. Telomeres comprise the nucleoprotein complexes that cap the ends of eukaryotic chromosomes and are maintained by the reverse transcriptase, telomerase(1). In human cells, insufficient levels of telomerase lead to telomere attrition with cell division in culture(2) and possibly with ageing and tumorigenesis in vivo(3-5). In contrast, critical reduction in telomere length is not observed in the mouse owing to promiscuous telomerase expression and long telomeres(6-10). Here we provide evidence that telomere attrition in ageing telomerase-deficient p53 mutant mice promotes the development of epithelial cancers by a process of fusion-bridge breakage that leads to the formation of complex non-reciprocal translocations-a classical cytogenetic feature of human carcinomas. Our data suggest a model in which telomere dysfunction brought about by continual epithelial renewal during life generates the massive ploidy changes associated with the development of epithelial cancers. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. CPI Ameripath Lab, Beachwood, OH 44122 USA. Ackerman Acad Dermatopathol, New York, NY 10016 USA. Harvard Univ, Sch Med, Dept Dermatol, 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 DePinho, RA (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. FU NIA NIH HHS [K08 AG001019] NR 32 TC 739 Z9 763 U1 3 U2 31 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 10 PY 2000 VL 406 IS 6796 BP 641 EP 645 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 342PF UT WOS:000088653800051 PM 10949306 ER PT J AU Bromfield, EB Vonsattel, JP Gonzalez, RG Cole, AJ Hoch, DB AF Bromfield, EB Vonsattel, JP Gonzalez, RG Cole, AJ Hoch, DB TI A 23-year-old man with seizures and a lesion in the left temporal lobe - Neurocysticercosis, left temporal lobe end-stage with calcification. Epilepsy. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID CEREBRAL CYSTICERCOSIS; CLASSIFICATION; CHILDREN C1 Brigham & Womens Hosp, Electroencephalog Lab, Boston, MA 02115 USA. Brigham & Womens Hosp, Epilepsy Program, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Bromfield, EB (reprint author), Brigham & Womens Hosp, Electroencephalog Lab, 75 Francis St, Boston, MA 02115 USA. NR 39 TC 10 Z9 10 U1 1 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 10 PY 2000 VL 343 IS 6 BP 420 EP 427 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 342DT UT WOS:000088630500008 ER PT J AU Pandey, P Nakazawa, A Ito, Y Datta, R Kharbanda, S Kufe, D AF Pandey, P Nakazawa, A Ito, Y Datta, R Kharbanda, S Kufe, D TI Requirement for caspase activation in monocytic differentiation of myeloid leukemia cells SO ONCOGENE LA English DT Article DE TPA; differentiation; caspases ID PROTEIN-KINASE-C; ESTER-INDUCED DIFFERENTIATION; SIGNAL-TRANSDUCTION PATHWAY; CYTOCHROME-C; MACROPHAGE DIFFERENTIATION; GENE-EXPRESSION; TRANSCRIPTIONAL REGULATION; INDUCED APOPTOSIS; HL-60 CELLS; RELEASE AB Human myeloid leukemia cells respond to 12-tetradecanoylphorbol-13-acetate (TPA) and other activators of protein kinase C (PKC) with the induction of terminal monocytic differentiation, The present studies demonstrate that TPA treatment of U-937 leukemia cells is associated with release of mitochondrial cytochrome c, activation of caspase-3 and induction of internucleosomal DNA fragmentation. By contrast, the TUR cell variant, which is deficient in PKC beta, failed to respond to TPA with release of cytochrome c and induction of the caspase-3 cascade. Moreover, stable overexpression of PKC beta in TUR cells reconstituted sensitivity to TPA-induced cytochrome c release and activation of caspase-3, The results also demonstrate that treatment of cells with the caspase inhibitor z-VAD-fmk blocks both TPA-induced apoptosis and monocytic differentiation, Similar results were obtained in U-937 cells stably expressing the CrmA caspase inhibitor. These findings demonstrate that TPA induces cytochrome c release by a PKC beta-dependent mechanism and that activation of caspase-mediated signaling is required for induction of the differentiated monocytic phenotype. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Pandey, P (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA29431, CA42802] NR 39 TC 35 Z9 36 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 10 PY 2000 VL 19 IS 34 BP 3941 EP 3947 DI 10.1038/sj.onc.1203751 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 341WQ UT WOS:000088614300013 PM 10951587 ER PT J AU Rigotti, NA Lee, JE Wechsler, H AF Rigotti, NA Lee, JE Wechsler, H TI US college students' use of tobacco products - Results of a national survey SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BINGE-DRINKING; CIGAR SMOKING; PREVALENCE AB Context Adults aged 18 to 24 years, many of whom are in college, represent the youngest legal targets for tobacco industry marketing. Cigarette smoking has been described among college students, but little is known about noncigarette tobacco use by college students or cigar use by adults of any age. Objectives To assess the prevalence of all forms of tobacco use (cigarettes, cigars, pipes, and smokeless tobacco) among US college students and to identify student- and college-level factors associated with use of each product. Design The Harvard College Alcohol Survey, a self-administered survey conducted in 1999. Setting One hundred nineteen nationally representative US 4-year colleges. Subjects A total of 14138 randomly selected students (60% response rate). Main Outcome Measures Self-report of current (in the past 30 days), past-year, and lifetime use of cigarettes, cigars, pipes, smokeless tobacco, and all tobacco products. Results Nearly half (45.7%) of respondents had used a tobacco product in the past year and one third (32.9%) currently used tobacco. Cigarettes accounted for most of the tobacco use (28.5% current prevalence), but cigar use was also substantial (37.1% lifetime prevalence, 23.0% past-year prevalence, and 8.5% current prevalence) and combinations of the 2 were common. Total tobacco use was higher in men than in women (37.9% vs 29.7%; P<.001), despite nearly identical current cigarette smoking rates between the sexes (28.5% for women vs 28.4% for men), because of greater use of cigars (current prevalence, 15.7% vs 3.9%; P<.001) and smokeless tobacco (current prevalence, 8.7% vs 0.4%; P<.001) by men. Tobacco use was significantly higher among white students (P<.001), users of other substances (alcohol and marijuana) (P<.001), and students whose priorities were social rather than educational or athletic (P<.05). Among students who had used both cigars and cigarettes, only 8.9% smoked cigars at an earlier age than they had smoked cigarettes. Conclusion Our study indicates that tobacco use is common among college students and is not limited to cigarettes. College appears to be a time when many students are trying a range of tobacco products and are in danger of developing lifelong nicotine dependence. National efforts to monitor and reduce tobacco use of all types should expand to focus on college students and other young adults. C1 Massachusetts Gen Hosp, Dept Med, Div Gen Med, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Hlth & Social Behav, Boston, MA 02115 USA. RP Rigotti, NA (reprint author), Massachusetts Gen Hosp, Dept Med, Div Gen Med, Tobacco Res & Treatment Ctr, 50 Staniford St,9th Floor, Boston, MA 02114 USA. NR 27 TC 315 Z9 320 U1 3 U2 14 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 9 PY 2000 VL 284 IS 6 BP 699 EP 705 DI 10.1001/jama.284.6.699 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 341JM UT WOS:000088587300027 PM 10927777 ER PT J AU Rigotti, NA AF Rigotti, NA TI A 36-year-old woman who smokes cigarettes SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID SUSTAINED-RELEASE BUPROPION; RANDOMIZED CONTROLLED TRIAL; NICOTINE NASAL SPRAY; DOUBLE-BLIND TRIAL; SMOKING CESSATION; COST-EFFECTIVENESS; HEART-DISEASE; WEIGHT-GAIN; RISK FACTOR; PATCH C1 Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Dept Med, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. RP Rigotti, NA (reprint author), Care of Hartman EE, Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, 330 Brookline Ave,LY318, Boston, MA 02215 USA. NR 64 TC 6 Z9 6 U1 2 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 9 PY 2000 VL 284 IS 6 BP 741 EP 749 DI 10.1001/jama.284.6.741 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 341JM UT WOS:000088587300034 PM 10927784 ER PT J AU Minassian, BA Ianzano, L Meloche, M Andermann, E Rouleau, GA Delgado-Escueta, AV Scherer, SW AF Minassian, BA Ianzano, L Meloche, M Andermann, E Rouleau, GA Delgado-Escueta, AV Scherer, SW TI Mutation spectrum and predicted function of laforin in Lafora's progressive myoclonus epilepsy SO NEUROLOGY LA English DT Article ID PROTEIN-TYROSINE PHOSPHATASES; CORPORA-AMYLACEA; BINDING DOMAIN; SPECIFICITY; IMPORT; GENE; FORM AB Background: Lafora's disease is a progressive myoclonus epilepsy with pathognomonic inclusions (polyglucosan bodies) caused by mutations in the EPM2A gene. EPM2A codes for laforin, a protein with unknown function. Mutations have been reported in the last three of the gene's exons, To date, the first exon has not been determined conclusively. It has been predicted based on genomic DNA sequence analysis including comparison with the mouse homologue. Objectives: 1) To detect new mutations in exon 1 and establish the role of this exon in Lafora's disease. 2) To generate hypotheses about the biological function of laforin based on bioinformatic analyses. Methods: 1) PCR conditions and components were refined to allow amplification and sequencing of the first exon of EPM2A. 2) Extensive bioinformatic analyses of the primary structure of laforin were completed. Results: 1) Seven new mutations were identified in the putative exon 1. 2) Laforin is predicted not to localize to the cell membrane or any of the organelles. If contains all components of the catalytic active site of the family of dual-specificity phosphatases. It contains a sequence predicted to encode a carbohydrate binding domain (coded by exon 1) and two putative glucohydrolase catalytic sites. Conclusions: The identification of mutations in exon 1 of EPM2A establishes its role in the pathogenesis of Lafora's disease. The presence of potential carbohydrate binding and cleaving domains suggest a role for laforin in the prevention of accumulation of polyglucosans in healthy neurons. C1 Hosp Sick Children, Dept Genet, Toronto, ON M5G 1X8, Canada. Hosp Sick Children, Dept Paediat, Div Neurol, Toronto, ON M5G 1X8, Canada. Hosp Sick Children, Bioinformat Supercomp Ctr, Toronto, ON M5G 1X8, Canada. Univ Toronto, Toronto, ON M5G 1X8, Canada. Montreal Neurol Inst, Neurogenet Unit, Montreal, PQ, Canada. McGill Univ, Montreal, PQ H3A 2T5, Canada. Montreal Gen Hosp, Res Inst, Ctr Res Neurosci, Montreal, PQ, Canada. Univ Calif Los Angeles, Sch Med, Dept Neurol, Comprehens Epilepsy Program, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Brain Res Inst, Los Angeles, CA 90024 USA. W Los Angeles DVA Med Ctr, W Los Angeles, CA USA. RP Scherer, SW (reprint author), Hosp Sick Children, Dept Genet, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. RI Howe, Jennifer/I-9013-2012; Scherer, Stephen /B-3785-2013 OI Scherer, Stephen /0000-0002-8326-1999 NR 27 TC 82 Z9 83 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 AUG 8 PY 2000 VL 55 IS 3 BP 341 EP 346 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 342ED UT WOS:000088631500005 PM 10932264 ER PT J AU Wilcox, MA Faraone, SV Neuberg, DS Laird, NM Tsuang, MT AF Wilcox, MA Faraone, SV Neuberg, DS Laird, NM Tsuang, MT TI More evidence for chromosome 10P and schizophrenia. SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Dept Biostat Res, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 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 AUG 7 PY 2000 VL 96 IS 4 MA O5 BP 461 EP 461 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 340ZE UT WOS:000088565900028 ER PT J AU Smoller, JW Lunetta, KL Robins, J AF Smoller, JW Lunetta, KL Robins, J TI The impact of spurious comorbidity and ascertainment bias on genetic association studies. SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 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 AUG 7 PY 2000 VL 96 IS 4 MA O107 BP 487 EP 487 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 340ZE UT WOS:000088565900120 ER PT J AU Smoller, JW Rosenbaum, JF Biederman, J Kennedy, J Kagan, J Snidman, N Faraone, SV Slaugenhaupt, SA AF Smoller, JW Rosenbaum, JF Biederman, J Kennedy, J Kagan, J Snidman, N Faraone, SV Slaugenhaupt, SA TI TDT analysis of glutamate decarboxylase (65-kDa isoform) in behavioral inhibition. SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 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 AUG 7 PY 2000 VL 96 IS 4 MA P362 BP 557 EP 557 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 340ZE UT WOS:000088565900377 ER PT J AU Prinz, WA Grzyb, L Veenhuis, M Kahana, JA Silver, PA Rapoport, TA AF Prinz, WA Grzyb, L Veenhuis, M Kahana, JA Silver, PA Rapoport, TA TI Mutants affecting the structure of the cortical endoplasmic reticulum in Saccharomyces cerevisiae SO JOURNAL OF CELL BIOLOGY LA English DT Article DE SRP receptor; endoplasmic reticulum; cytoskeleton; mitochondria; yeast ID SIGNAL-RECOGNITION PARTICLE; POLYPEPTIDE TRANSLOCATION APPARATUS; LIVER MICROSOMAL SUBFRACTIONS; PROTEIN TRANSLOCATION; MEMBRANE PROTEIN; LIVING CELLS; MITOCHONDRIAL FUSION; ER MEMBRANE; YEAST; RECEPTOR AB We find that the peripheral ER in Saccharomyces cerevisiae forms a dynamic network of interconnecting membrane tubules throughout the cell cycle, similar to the ER in higher eukaryotes. Maintenance of this network does not require microtubule or actin filaments, bur its dynamic behavior is largely dependent on the actin cytoskeleton, We isolated three conditional mutants that disrupt peripheral ER structure. One has a mutation in a component of the COPI coat complex, which is required for vesicle budding. This mutant has a partial defect in ER segregation into daughter cells and disorganized ER in mother cells. A similar phenotype was found in other mutants with defects in vesicular trafficking between ER and Golgi complex, but not in mutants blocked at later steps in the secretory pathway. The other two mutants found in the screen have defects in the signal recognition particle (SRP) receptor,This receptor, along with SRP, targets ribosome-nascent chain complexes to the ER membrane for protein translocation. A conditional mutation in SRP also disrupts ER structure, but other mutants with translocation defects do not. We also demonstrate that, both in wild-type and mutant cells, the ER and mitochondria partially coalign, and that mutations that disrupt ER structure also affect mitochondrial structure. Our data suggest that both trafficking between the ER and Golgi complex and ribosome targeting are important for maintaining ER structure, and that proper ER structure may be required to maintain mitochondrial structure. C1 Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Univ Groningen, Lab Eukaryot Microbiol, GBB, NL-9750 AA Haren, Netherlands. RP Harvard Univ, Sch Med, Dept Cell Biol, 240 Longwood Ave, Boston, MA 02115 USA. EM tom_rapoport@hms.harvard.du NR 61 TC 188 Z9 191 U1 0 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD AUG 7 PY 2000 VL 150 IS 3 BP 461 EP 474 DI 10.1083/jcb.150.3.461 PG 14 WC Cell Biology SC Cell Biology GA 343XM UT WOS:000088727800007 PM 10931860 ER PT J AU Taylor, PR Carugati, A Fadok, VA Cook, HT Andrews, M Carroll, MC Savill, JS Henson, PM Botto, M Walport, MJ AF Taylor, PR Carugati, A Fadok, VA Cook, HT Andrews, M Carroll, MC Savill, JS Henson, PM Botto, M Walport, MJ TI A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE systemic lupus erythematosus; complement deficiency; C1q; transgenic mice; apoptosis ID MOUSE PERITONEAL-MACROPHAGES; SYSTEMIC LUPUS-ERYTHEMATOSUS; LOW-DENSITY-LIPOPROTEIN; RECEPTOR FUNCTION-INVITRO; VITRONECTIN RECEPTOR; DENDRITIC CELLS; CUTTING EDGE; IN-VITRO; PHAGOCYTOSIS; RECOGNITION AB The strongest susceptibility genes for the development of systemic lupus erythematosus (SLE) in humans are null mutants of classical pathway complement proteins. There is a hierarchy of disease susceptibility and severity according to the position of the missing protein in the activation pathway, with the severest disease associated with C1q deficiency. Here we demonstrate, using novel in vivo models of apoptotic cell clearance during sterile peritonitis, a similar hierarchical role for classical pathway complement proteins in vivo in the clearance of apoptotic cells by macrophages. Our results constitute the first demonstration of an impairment in the phagocytosis of apoptotic cells by macrophages in vivo in a mammalian system. Apoptotic cells are thought to be a major source of the autoantigens of SLE, and impairment of their removal by complement may explain the link between hereditary complement deficiency and the development of SLE. C1 Hammersmith Hosp, Imperial Coll, Sch Med, Div Med,Rheumatol Sect, London W12 0NN, England. Hammersmith Hosp, Imperial Coll, Sch Med, Dept Histopathol, London W12 0NN, England. Natl Jewish Med Res Ctr, Dept Pediat, Denver, CO 80206 USA. Univ Nottingham Hosp, Div Renal & Inflammatory Dis, Nottingham NG7 2UH, England. Harvard Univ, Sch Med, Dept Pediat, Ctr Blood Res, Boston, MA 02165 USA. Univ Edinburgh, Sch Med, Ctr Inflammat Res, Edinburgh EH3 9YW, Midlothian, Scotland. RP Walport, MJ (reprint author), Hammersmith Hosp, Imperial Coll, Sch Med, Div Med,Rheumatol Sect, Hammersmith Campus,Du Cane Rd, London W12 0NN, England. OI Walport, Mark/0000-0001-7220-5273; Taylor, Philip/0000-0003-0163-1421 NR 43 TC 481 Z9 503 U1 2 U2 13 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 7 PY 2000 VL 192 IS 3 BP 359 EP 366 DI 10.1084/jem.192.3.359 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 343NQ UT WOS:000088708800006 PM 10934224 ER PT J AU Tager, AM Dufour, JH Goodarzi, K Bercury, SD von Andrian, UH Luster, AD AF Tager, AM Dufour, JH Goodarzi, K Bercury, SD von Andrian, UH Luster, AD TI BLTR mediates leukotriene B-4-induced chemotaxis and adhesion and plays a dominant role in eosinophil accumulation in a murine model of peritonitis SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE receptors; leukotriene; chemotactic factors; inflammation mediators; knockout ID B-4; RECEPTOR; INFLAMMATION; ANTAGONIST; MONOCYTES; PATHWAY; POTENT; MICE AB Leukotriene B-4 (LTB4) is a potent chemoattractant active on multiple leukocytes. including neutrophils, macrophages, and eosinophils, and is implicated in the pathogenesis of a variety of inflammatory processes. A seven transmembrane-spanning, G protein-coupled receptor, called BLTR (LTB4 receptor), has recently been identified as an LTB4 receptor. To determine if BLTR is the sole receptor mediating LTB4-induced leukocyte activation and to determine the role of LTB4 and BLTR in regulating leukocyte function in inflammation in vivo, we generated a BLTR-deficient mouse by targeted gene disruption. This mouse reveals that BLTR alone is responsible for LTB4-mediated leukocyte calcium flux, chemotaxis, and firm adhesion to endothelium in vivo. Furthermore, despite the apparent functional redundancy with other chemoattractant-receptor pairs in vitro, LTB4 and BLTR play an important role in the recruitment and/or retention of leukocytes, particularly eosinophils, to the inflamed peritoneum in vivo. These studies demonstrate that BLTR is the key receptor that mediates LTB4-induced leukocyte activation and establishes a model to decipher the functional roles of BLTR and LTB4 in vivo. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med,Div Rheumatol Allergy & Immunol, Ctr Immunol & Inflammatoy Dis, Boston, MA 02114 USA. Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Luster, AD (reprint author), Massachusetts Gen Hosp, Bldg 149,13th St, Charlestown, MA 02129 USA. RI von Andrian, Ulrich/A-5775-2008 FU NCI NIH HHS [F32 CA088721, F32-CA88721, R01 CA069212]; NHLBI NIH HHS [KO8-HL04087, R01 HL054936, R01-HL54936]; NIAID NIH HHS [R01 AI040618] NR 19 TC 132 Z9 134 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 7 PY 2000 VL 192 IS 3 BP 439 EP 446 DI 10.1084/jem.192.3.439 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 343NQ UT WOS:000088708800014 PM 10934232 ER PT J AU Lei, M Lu, WG Meng, WY Parrini, MC Eck, MJ Mayer, BJ Harrison, SC AF Lei, M Lu, WG Meng, WY Parrini, MC Eck, MJ Mayer, BJ Harrison, SC TI Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch SO CELL LA English DT Article ID P21-ACTIVATED PROTEIN-KINASE; ALDRICH-SYNDROME PROTEIN; HEAVY-CHAIN KINASE; ADAPTER PROTEIN; MEMBRANE LOCALIZATION; CRYSTAL-STRUCTURE; TYROSINE KINASE; ALPHA-PAK; MYOSIN-I; CDC42 AB The p21-activated kinases (PAKs), stimulated by binding with GTP-liganded forms of Cdc42 or Pac, modulate cytoskeletal actin assembly and activate MAP-kinase pathways. The 2.3 Angstrom resolution crystal structure of a complex between the N-terminal autoregulatory fragment and the C-terminal kinase domain of PAK1 shows that GTPase binding will trigger a series of conformational changes, beginning with disruption of a PAK1 dimer and ending with rearrangement of the kinase active site into a catalytically competent state. An inhibitory switch (IS) domain, which overlaps the GTPase binding region of PAK1, positions a polypeptide segment across the kinase cleft. GTPase binding will refold part of the IS domain and unfold the rest. A related switch has been seen in the Wiskott-Aldrich syndrome protein (WASP). C1 Childrens Hosp, Mol Med Lab, Boston, MA 02115 USA. Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Harrison, SC (reprint author), Childrens Hosp, Mol Med Lab, 320 Longwood Ave, Boston, MA 02115 USA. RI Parrini, Maria Carla/J-5390-2016 OI Parrini, Maria Carla/0000-0002-7082-9792 FU NCI NIH HHS [1R01 CA2258-01] NR 57 TC 354 Z9 360 U1 1 U2 11 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD AUG 4 PY 2000 VL 102 IS 3 BP 387 EP 397 DI 10.1016/S0092-8674(00)00043-X PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 342BP UT WOS:000088625600013 PM 10975528 ER PT J AU Shen, EC Stage-Zimmermann, T Chui, P Silver, PA AF Shen, EC Stage-Zimmermann, T Chui, P Silver, PA TI The yeast mRNA-binding protein Npl3p interacts with the cap-binding complex SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PRE-MESSENGER-RNA; CARBOXY-TERMINAL DOMAIN; SACCHAROMYCES-CEREVISIAE; NUCLEAR EXPORT; HNRNP PROTEINS; POLYMERASE-II; SPLICING FACTORS; CYTOPLASM; METHYLTRANSFERASE; RECOGNITION AB A number of RNA-binding proteins are associated with mRNAs in both the nucleus and the cytoplasm. One of these, Np13p, is a heterogeneous nuclear ribonucleoprotein-like protein with some similarity to SR proteins and is essential for growth in the yeast S. cerevisiae. Temperature-sensitive alleles have defects in the export of mRNA out of the nucleus (1). In this report, we define a genetic relationship between NPL3 and the nonessential genes encoding the subunits of the cap-binding complex (CBP80 and CBP20). Deletion of CBP80 or CBP20 in combination with certain temperature-sensitive np13 mutant alleles fail to grow and thus display a synthetic lethal relationship. Further evidence of an interaction between Np13p and the cap-binding complex was revealed by co-immunoprecipitation experiments; Cbp80p and Cbp20p specifically co-precipitate with Np13p. However, the interaction of Np13p with Cbp80p depends on both the presence of Cbp20p and RNA. In addition, we show that Cbp80p is capable of shuttling between the nucleus and the cytoplasm in a manner dependent on the ongoing synthesis of RNA. Taken together, these data support a model whereby mRNAs are co-transcriptionally packaged by proteins including Np13p and cap-binding complex for export out of the nucleus. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Silver, PA (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. FU NIGMS NIH HHS [GM57476, GM19487] NR 44 TC 50 Z9 54 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 4 PY 2000 VL 275 IS 31 BP 23718 EP 23724 DI 10.1074/jbc.M002312200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 340YL UT WOS:000088564200044 PM 10823828 ER PT J AU Tian, M Alt, FW AF Tian, M Alt, FW TI Transcription-induced cleavage of immunoglobulin switch regions by nucleotide excision repair nucleases in vitro SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEAVY-CHAIN GENES; MURINE B-CELLS; CIRCULAR DNA; ENDONUCLEASE ACTIVITY; REPETITIVE SEQUENCES; STRUCTURAL ELEMENTS; RECOMBINATION SITES; COMPLEX-FORMATION; GROWTH FAILURE; XPG PROTEIN AB Immunoglobulin (Tg) heavy chain class switch recombination (CSR) mediates isotype switching during B cell development. CSR occurs between switch (S) regions that precede each Ig heavy chain constant region gene. Various studies have demonstrated that transcription plays an essential role in CSR in vivo. In this study, we show that in vitro transcription of S regions in their physiological orientation induces the formation of stable R loops. Furthermore, we show that the nucleotide excision repair nucleases XPF-ERCC1 and XPG can cleave the R loops formed in the S regions. Based on these findings, we propose that CSR is initiated via a mechanism that involves transcription-dependent S region cleavage by DNA structure-specific endonucleases that function in general DNA repair processes. Such a mechanism also may underlie transcription-dependent mutagenic processes such as somatic hypermutation, and contribute to genomic instability in general. C1 Harvard Univ, Childrens Hosp, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. RP Alt, FW (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. FU NIAID NIH HHS [AI-31531] NR 57 TC 137 Z9 139 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 4 PY 2000 VL 275 IS 31 BP 24163 EP 24172 DI 10.1074/jbc.M003343200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 340YL UT WOS:000088564200102 PM 10811812 ER PT J AU Ball, WJ Wang, ZM Malik, B Kasturi, R Dey, P Short, MK Margolies, MN AF Ball, WJ Wang, ZM Malik, B Kasturi, R Dey, P Short, MK Margolies, MN TI Selection of peptidic mimics of digoxin from phage-displayed peptide libraries by anti-digoxin antibodies SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE digoxin mimotopes; peptidic-digoxin mimics; anti-digoxin antibodies; phage-displayed peptide library; molecular mimicry ID DIGITALIS-LIKE-FACTOR; EPITOPE LIBRARY; BOVINE HYPOTHALAMUS; BINDING-SITE; HUMAN PLASMA; IDENTIFICATION; OUABAIN; INHIBITOR; LIGANDS; AFFINITY AB Since the initial report of the development of methodology to generate high-affinity digitalis-specific (digoxin) antibodies, these antibodies have proven extremely useful tools to monitor digoxin levels in digitalized patients and, as Fab fragments, to reverse toxic digoxin effects in life-threatening digoxin overdoses. These antibodies (both digoxin-specific and ouabain-specific) have been used extensively by investigators for the identification and characterization of putative endogenous digitalis-like factors. In this study, we used two well-characterized mouse anti-digoxin monoclonal antibodies (mAbs), designated 26-10 and 45-20, as binding templates with which to select short bacteriophage-displayed (pIII protein inserted) peptides that are capable of binding to these mAbs and mimicking the conformational structure of digoxin. Selective enrichment from two phage-displayed random peptide Libraries enabled us to isolate and identify distinct 15 and 26 amino acid residue peptide inserts that bind with high avidity and idiotypic specificity to the selecting mAbs. Among these displayed inserts a subset was identified whose mAb binding is inhibited by digoxin and whose corresponding synthetic peptides inhibit phage binding. They, therefore, appear to bind at the mAbs digoxin-binding sites. These data provide the first clear evidence that short polypeptides can serve as surrogates for the low molecular mass hapten digoxin. (C) 2000 Academic Press. C1 Univ Cincinnati, Coll Med, Dept Pharmacol & Cell Biophys, Cincinnati, OH 45267 USA. Hunan Med Univ, Affiliated Hosp 2, Med Res Ctr, Changsha, Peoples R China. Massachusetts Gen Hosp, Dept Surg, E Charlestown, MA 02129 USA. RP Ball, WJ (reprint author), Univ Cincinnati, Coll Med, Dept Pharmacol & Cell Biophys, Cincinnati, OH 45267 USA. FU NHLBI NIH HHS [R01 HL07382, R01 HL-47415, 5 T32 HL07382] NR 52 TC 7 Z9 7 U1 0 U2 2 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD AUG 4 PY 2000 VL 301 IS 1 BP 101 EP 115 DI 10.1006/jmbi.2000.3934 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343MC UT WOS:000088705300009 PM 10926495 ER PT J AU Saint-Ruf, C Panigada, M Azogui, O Debey, P von Boehmer, H Grassi, F AF Saint-Ruf, C Panigada, M Azogui, O Debey, P von Boehmer, H Grassi, F TI Different initiation of pre-TCR and gamma delta TCR signalling SO NATURE LA English DT Article ID T-CELL-RECEPTOR; PROTEIN-TYROSINE KINASE; ALPHA-BETA; LINEAGE COMMITMENT; ANTIGEN RECEPTOR; LIPID RAFTS; SH2 DOMAINS; ACTIVATION; EXPRESSION; MEMBRANES AB Lineage choice is of great interest in developmental biology. In the immune system, the alpha beta and gamma delta lineages of T lymphocytes diverge during the course of the beta-, gamma- and delta-chain rearrangement of T-cell receptor (TCR) genes that takes place within the same precursor cell and which results in the formation of the gamma delta TCR or pre-TCR proteins(1-3). The pre-TCR consists of the TCR beta chain covalently linked to the pre-TCR alpha protein, which is present in immature but not in mature T cells which instead express the TCR alpha chain(4,5). Animals deficient in pre-TCR alpha have few alpha beta lineage cells but an increased number of gamma delta T cells. These gamma delta T cells exhibit more extensive TCR beta rearrangement than gamma delta T cells from wild-type mice(6,7). These observations are consistent with the idea that different signals emanating from the gamma delta TCR and pre-TCR instruct lineage commitment(8). Here we show, by using confocal microscopy and biochemistry to analyse the initiation of signalling, that the pre-TCR but not the gamma delta TCR colocalizes with the p56(lck) Src kinase into glycolipid-enriched membrane domains (rafts) apparently without any need for ligation. This results in the phosphorylation of CD3 epsilon and Zap-70 signal transducing molecules. The results indicate clear differences between pre-TCR and gamma delta TCR signalling. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Fac Med Necker, INSERM, U373, Inst Necker, F-75730 Paris 15, France. Inst Biol Physicochim, Museum Natl Hist Nat, INRA, Unite 806, F-75005 Paris, France. Univ Milan, Dipartimento Biol & Genet Sci Med, I-20133 Milan, Italy. RP von Boehmer, H (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St,Smith 736, Boston, MA 02115 USA. NR 29 TC 129 Z9 130 U1 0 U2 3 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 3 PY 2000 VL 406 IS 6795 BP 524 EP 527 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 340ML UT WOS:000088538000048 PM 10952314 ER PT J AU Clark, EA Golub, TR Lander, ES Hynes, RO AF Clark, EA Golub, TR Lander, ES Hynes, RO TI Genomic analysis of metastasis reveals an essential role for RhoC SO NATURE LA English DT Article ID MELANOMA-CELLS; CANCER; PROGRESSION; EXPRESSION; PROTEIN; GROWTH; GENES; OVEREXPRESSION; TUMORIGENICITY; FIBRONECTIN AB The most damaging change during cancer progression is the switch from a locally growing tumour to a metastatic killer. This switch is believed to involve numerous alterations that allow tumour cells to complete the complex series of events needed for metastasis(1). Relatively few genes have been implicated in these events(2-5.) Here we use an in vivo selection scheme to select highly metastatic melanoma cells. By analysing these cells on DNA arrays, we define a pattern of gene expression that correlates with progression to a metastatic phenotype. In particular, we show enhanced expression of several genes involved in extracellular matrix assembly and of a second set of genes that regulate, either directly or indirectly, the actin-based cytoskeleton. One of these, the small GTPase RhoC, enhances metastasis when overexpressed, whereas a dominant-negative Rho inhibits metastasis. Analysis of the phenotype of cells expressing dominant-negative Rho or RhoC indicates that RhoC is important in tumour cell invasion. The genomic approach allows us to identify families of genes involved in a process, not just single genes, and can indicate which molecular and cellular events might be important in complex biological processes such as metastasis. C1 MIT, Ctr Canc Res, Howard Hughes Med Inst, Cambridge, MA 02139 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. Whitehead Inst MIT Ctr Genome Res, Cambridge, MA 02142 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Hynes, RO (reprint author), MIT, Ctr Canc Res, Howard Hughes Med Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA. NR 29 TC 1100 Z9 1175 U1 3 U2 49 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 3 PY 2000 VL 406 IS 6795 BP 532 EP 535 DI 10.1038/35020106 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 340ML UT WOS:000088538000050 PM 10952316 ER PT J AU Hart, AJ Whalen, PJ Shin, LM McInerney, SC Fischer, H Rauch, SL AF Hart, AJ Whalen, PJ Shin, LM McInerney, SC Fischer, H Rauch, SL TI Differential response in the human amygdala to racial outgroup vs ingroup face stimuli SO NEUROREPORT LA English DT Article; Proceedings Paper CT 29th Annual Meeting of the Society-for-Neuroscience CY OCT 23-28, 1999 CL MIAMI BEACH, FL SP Soc Neurosci DE amygdala; brain; fMRI; neuroimaging; race; social cognition ID FACIAL EXPRESSIONS; COUNTING STROOP; RECOGNITION; RACE AB Here we describe response in the human amygdala to the presentation of racial outgroup vs ingroup faces. Functional magnetic resonance imaging (fMRI) measures of brain activity were acquired while subjects who identified themselves as White or Black viewed photographs of both White and Black faces. Across all subjects, we observed significantly greater blood oxygen-level-dependent (BOLD) signal in the amygdala to outgroup vs ingroup faces, but only during later stimulus presentations. A region of interest (ROI)-based analysis of these voxels revealed a significant interaction between amygdala response to outgroup and ingroup faces over time. Specifically, the greater amygdala activation to outgroup faces during later stimulus presentations was the result of amygdala response habituation to repeated presentations of ingroup faces with sustained responses to outgroup faces. The present results suggest that amygdala responses to human face stimuli are affected by the relationship between the perceived race of the stimulus face and that of the subject. Results are discussed as consistent with a role for the amygdala in encoding socially and/or biologically relevant information. We conclude that researchers seeking to study brain responses to face stimuli in human subjects should consider the relationship between the race of subjects and stimuli as a significant potential source of variance. Moreover, these data provide a foundation for future related studies in the neuroscience of social cognition and race. NeuroReport 11:2351-2355 (C) 2000 Lippincott Williams & Wilkins. C1 Amherst Coll, Dept Psychol, Amherst, MA 01002 USA. Massachusetts Gen Hosp, Psychiat Neuroimaging Res Grp, Boston, MA 02129 USA. Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. Univ Wisconsin, Dept Psychiat, Madison, WI 53719 USA. Univ Wisconsin, Dept Psychol, Madison, WI 53719 USA. Tufts Univ, Dept Psychol, Medford, MA 02155 USA. Univ Uppsala Hosp, PET Ctr, Uppsala, Sweden. RP Amherst Coll, Dept Psychol, Amherst, MA 01002 USA. NR 27 TC 242 Z9 246 U1 6 U2 32 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0959-4965 EI 1473-558X J9 NEUROREPORT JI Neuroreport PD AUG 3 PY 2000 VL 11 IS 11 BP 2351 EP 2355 DI 10.1097/00001756-200008030-00004 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 340ZY UT WOS:000088567600006 PM 10943684 ER PT J AU Andreassen, OA Dedeoglu, A Klivenyi, P Beal, MF Bush, AI AF Andreassen, OA Dedeoglu, A Klivenyi, P Beal, MF Bush, AI TI N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis SO NEUROREPORT LA English DT Article DE copper; copper/zinc superoxide dismutase; familial amyotrophic lateral sclerosis; free radicals; N-acetyl cysteine; oxidation ID SUPEROXIDE-DISMUTASE; NEURON DEGENERATION; APOPTOTIC DEATH; ACETYLCYSTEINE; GLUTATHIONE; MICE; CELLS AB Increasing evidence implicates oxidative damage as a major mechanism in the pathogenesis of amyotrophic lateral sclerosis (ALS). We examined the effect of preventative treatment with N-acetyl-L-cysteine (NAC), an agent that reduces free radical damage. in transgenic mice with a superoxide dismutase (SODI) mutation (G93A), used as an animal model of familial ALS. NAC was administered at 1% concentration in the drinking water from 4-5 weeks of age. The treatment caused a significantly prolonged survival and delayed onset of motor impairment in G93A mice treated with NAC compared to control mice. These results provide further evidence for the involvement of free radical damage in the G93A mice, and support the possibility that NAG, an over-the-counter antioxidant, could be explored in clinical trials for ALS. NeuroReport 11:2491-2493 (C) 2000 Lippincott Williams & Wilkins. C1 Massachusetts Gen Hosp E, Lab Oxidat Biol, Genet & Aging Unit, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Neurochem Lab, Neurol Serv, Boston, MA USA. Cornell Univ, Med Ctr, New York Hosp, Dept Neurol, New York, NY 10021 USA. RP Bush, AI (reprint author), Massachusetts Gen Hosp E, Lab Oxidat Biol, Genet & Aging Unit, Charlestown, MA 02129 USA. RI Bush, Ashley/A-1186-2007 OI Bush, Ashley/0000-0001-8259-9069 NR 22 TC 83 Z9 87 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD AUG 3 PY 2000 VL 11 IS 11 BP 2491 EP 2493 DI 10.1097/00001756-200008030-00029 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 340ZY UT WOS:000088567600031 PM 10943709 ER PT J AU Tearney, GJ Jang, IK Kang, DH Aretz, HT Houser, SL Brady, TJ Schlendorf, K Shishkov, M Bouma, BE AF Tearney, GJ Jang, IK Kang, DH Aretz, HT Houser, SL Brady, TJ Schlendorf, K Shishkov, M Bouma, BE TI Porcine coronary imaging in vivo by optical coherence tomography SO ACTA CARDIOLOGICA LA English DT Article DE ultrasonics; coronary disease; tomography; diagnosis; catheters ID INTRAVASCULAR ULTRASOUND; BIOPSY AB Objective - A high-resolution coronary artery imaging modality has the potential to address important diagnostic and management problems in cardiology. Optical coherence tomography (OCT) is a promising new optical imaging technique with a resolution of approximately 10 mu m The purpose of this study was to use a new OCT catheter to demonstrate the feasibility of performing OCT imaging of normal coronary arteries, intimal dissections, and deployed stents in vivo. Methods and results - Normal coronary arteries, intimal dissections, and stents were imaged in five swine with OCT and compared with intravascular ultrasound (IVUS). In the normal coronary arteries, visualization of al I of the layers of the vessel wall was achieved with a saline flush, including the intima which was not identified by IVUS. Following dissection, detailed layered structures including intimal flaps, intimal defects, and disruption of the medial wall were visualized by OCT. IVUS failed to shaw clear evidence of intimal and medial disruption. Finally, the microanatomic relationships between stents and the vessel walls were clearly identified only by OCT. Conclusions - In this preliminary experiment, we have demonstrated that in vivo OCT imaging of normal coronary arteries, intimal dissections, and deployed stents is feasible, and allows identification of clinically relevant coronary artery morphology with high-resolution and contrast. C1 Massachusetts Gen Hosp, Wellman Labs Photomed, Boston, MA 02114 USA. RP Jang, IK (reprint author), Partners Ctr Innovat Minimall Invas Therapy, Boston, MA 02114 USA. NR 16 TC 47 Z9 52 U1 1 U2 5 PU ACTA CARDIOLOGICA PI BRUSSELS PA AVENUE CIRCULAIRE 138A, 1180 BRUSSELS, BELGIUM SN 0001-5385 J9 ACTA CARDIOL JI Acta Cardiol. PD AUG PY 2000 VL 55 IS 4 BP 233 EP 237 DI 10.2143/AC.55.4.2005745 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 361NL UT WOS:000089729100003 PM 11041121 ER PT J AU McClements, BM Weyman, AE Newell, JB Picard, MH AF McClements, BM Weyman, AE Newell, JB Picard, MH TI Echocardiographic determinants of left ventricular ejection fraction after acute myocardial infarction SO AMERICAN HEART JOURNAL LA English DT Article ID CORONARY-OCCLUSION; ENZYMATIC SIZE; PERFORMANCE; STREPTOKINASE; DYSFUNCTION; PREDICTION; PROGNOSIS; ANTERIOR; SITE; DOG AB Objective This study was performed to determine if factors other than the size of regional dysfunction influence the global left ventricular ejection fraction after acute myocardial infarction. Background Left ventricular ejection fraction is an important prognostic variable after acute myocardial infarction. Although infarct size is known to affect the subsequent global left ventricular ejection fraction, ii remains unclear whether other factors such as site or severity of the wall motion abnormality influence the ejection fraction after acute myocardial infarction. Methods Sixty-nine consecutive patients (mean age 61 +/- 14 years, 46 [67%] male) who did not receive thrombolytic therapy or undergo early revascularization were studied by echocardiography 1 week after Q-wave myocardial infarction. The absolute size of the region of abnormal wall motion (AWM) and the percentage of the endocardium involved (%AWM) were quantitated along with the wall motion score. A severity index was then derived as the mean wall motion score within the region of AWM. Site of myocardial infarction was classified as either anterior or inferior from the endocardial map. Left ventricular ejection fraction was measured by Simpson's method with 2 apical views. Results Twenty-nine (42%) patients had anterior and 40 had inferior myocardial infarction. The mean left ventricular election fraction was significantly lower in anterior than in inferior myocardial infarction (44.8% +/- 11.5% vs 53% +/- 8.6%; P =.001). The mean %AWM was greater in anterior than in inferior myocardial infarction (32.1 +/- 15.5 vs 22.4 +/- 14.1; P =.01). The mean wall motion score was greater in anterior than in inferior myocardial infarction (9.8 +/- 6.4 vs 6.4 +/- 4.4; P =.01). The mean severity index did not differ by site. Multiple regression analysis demonstrated that, in descending order of importance, %AWM, extent of apical involvement, and site of myocardial infarction were independent determinants of global left ventricular ejection fraction. Conclusions For myocardial infarctions of similar size, left ventricular ejection fraction is lower when apical involvement is extensive and the site of infarction is anterior. This site-dependent difference may be related to characteristics specific to the apex. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div,Cardiac Ultrasound Lab, Boston, MA 02114 USA. RP Picard, MH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div,Cardiac Ultrasound Lab, VBK 508,32 Fruit St, Boston, MA 02114 USA. OI Picard, Michael/0000-0002-9264-3243 NR 24 TC 15 Z9 16 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD AUG PY 2000 VL 140 IS 2 BP 284 EP 290 DI 10.1067/mhj.2000.107543 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 344CK UT WOS:000088739900017 PM 10925344 ER PT J AU Singh, JP Larson, MG O'Donnell, CJ Wilson, PF Tsuji, H Lloyd-Jones, DM Levy, D AF Singh, JP Larson, MG O'Donnell, CJ Wilson, PF Tsuji, H Lloyd-Jones, DM Levy, D TI Association of hyperglycemia with reduced heart rate variability (The Framingham Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID DEPENDENT DIABETES-MELLITUS; MYOCARDIAL-INFARCTION; AUTONOMIC NEUROPATHY; INSULIN; MORTALITY; GLUCOSE; EVENTS; RISK AB This study was designed to examine the association of heart rate variability (HRV) with blood glucose levels in a large community-based population. Previous reports have shown HRV to be reduced in diabetics, suggesting the presence of abnormalities in neural regulatory mechanisms. There is scant information about HRV across the spectrum of blood glucose levels in a population-based cohort. One thousand nine hundred nineteen men and women from the Framingham Offspring Study, who underwent ambulatory electrocardiographic recordings at a routine examination, were eligible. HRV variables included the SD of normal RR intervals (SDNN), high-frequency (HF, 0.15 to 0.40 Hz) and low-frequency (LF, 0.04 to 0.15 Hz) power, and LF/HF ratio. Pasting plasma glucose levels were used to classify subjects as normal (<110 mg/dl; n = 1,779), as having impaired fasting glucose levels (110 to 125 mg/dl; n = 56), and as having diabetes mellitus (DM greater than or equal to 126 mg/dl or receiving therapy; n = 84). SDNN, LF and HF power, and LF/HF ratio were inversely related to plasma glucose levels (p <0.0001). SDNN and LF and HF powers were reduced in DM subjects (4.28 +/- 0.03, 6.03 +/- 0.08, and 4.95 +/- 0.09) and in subjects with impaired fasting glucose levels (4.37 +/- 0.04, 6.26 +/- 0.10, and 5.06 +/- 0.11) compared with those with normal fasting glucose (4.51 +/- 0.01, 6.77 +/- 0.02, and 5.55 +/- 0.02, all p <0.005), respectively. After adjusting for covariates (age, sex, heart rate, body mass index, antihypertensive and cardiac medications, systolic and diastolic blood pressures, smoking, and alcohol and coffee consumption), LF power and LF/HF ratio were lower in DM subjects than in those with normal fasting glucose (p <0.005). HRV is inversely associated with plasma glucose levels and is reduced in diabetics as well as in subjects with impaired fasting glucose levels. Additional research is needed to determine if low HRV contributes to the increased cardiovascular morbidity and mortality described in subjects with hyperglycemia. (C) 2000 by Excerpta Medica, Inc. C1 NHLBI, Framingham Heart Study, Framingham, MA USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Div Epidemiol & Prevent Med, Boston, MA 02118 USA. Beth Israel Hosp, Div Cardiol, Boston, MA 02215 USA. Beth Israel Hosp, Div Clin Epidemiol, Boston, MA 02215 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. Kansai Med Univ, Osaka, Japan. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, 5 Thurber St, Framingham, MA USA. RI Lloyd-Jones, Donald/C-5899-2009 NR 28 TC 190 Z9 199 U1 0 U2 9 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD AUG 1 PY 2000 VL 86 IS 3 BP 309 EP 312 DI 10.1016/S0002-9149(00)00920-6 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 338MM UT WOS:000088423900011 PM 10922439 ER PT J AU Chauncey, TR Gooley, TA Lloid, ME Schubert, MM Lilleby, K Holmberg, L Bensinger, WI AF Chauncey, TR Gooley, TA Lloid, ME Schubert, MM Lilleby, K Holmberg, L Bensinger, WI TI Pilot trial of cytoprotection with amifostine given with high-dose chemotherapy and autologous peripheral blood stem cell transplantation SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE amifostine; chemotherapy, high dose; peripheral blood stem cells ID ALLOGENEIC MARROW TRANSPLANTATION; REGIMEN-RELATED TOXICITY; 2 IRRADIATION REGIMENS; BONE-MARROW; RANDOMIZED TRIAL; MYELOID-LEUKEMIA; NITROGEN-MUSTARD; ORAL MUCOSITIS; LUNG-CANCER; PHASE-II AB In an attempt to limit toxicities associated with dose-intensive therapy used for transplant regimens, we performed a pilot study using amifostine with high-dose busulfan (12 mg/kg), melphalan (100 mg/m(2)), and thiotepa (500 mg/m(2)) in 21 patients with a variety of malignancies. After 3 days of oral busulfan, amifostine was given at 910 mg/m(2) IV for 10 minutes, preceding the infusion of each of 2 doses of melphalan and thiotepa given for 4 days. Antiemetic premedication for amifostine was given to all patients. The median patient age was 50 years (range: 32-65 years). Twenty-one patients received 82 separate amifostine infusions. One patient discontinued amifostine after the second dose because of severe nausea and emesis, and two infusions were temporarily held secondary to hypotension. Of these 82 cycles, there was a total of 37 episodes of nausea/vomiting, 28 episodes of sneezing, 11 episodes of flushing, and 1 episode of oral paresthesia. Systolic blood pressure and mean arterial pressure decreased by a mean of 8.4 mm Hg and 5.0 mm Hg, respectively. In general, the infusion was well tolerated. Patients were observed until discharge home (N = 15), until initiation of an additional tandem transplant procedure (N = 4), or until death (N = 2). All twenty-one patients experienced nonhematologic toxicities grade II or greater. Grade II toxicities included mucositis (N = 21), gastrointestinal (N = 3), skin (N = 1), and liver (N = 1), and grade III toxicities included liver (N = 1). Mucositis was also scored according to a detailed toxicity assessment. Mucositis did not appear to be improved with amifostine when compared with a control group of patients not receiving amifostine. Renal dysfunction after transplantation was decreased in the amifostine group, whereas there was no significant effect on posttransplant hepatic dysfunction. Although these data demonstrate the feasibility of delivering parenteral amifostine in conjunction with dose-intensive chemotherapy and autologous peripheral blood stem cell transplantation, there was no evidence of a significant reduction in nonmarrow toxicities. C1 VA Puget Sound Hlth Care Syst, Marrow Transplant Unit, Seattle, WA 98108 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. RP Chauncey, TR (reprint author), VA Puget Sound Hlth Care Syst, Marrow Transplant Unit, S-111-MTU,1660 S Columbian Way, Seattle, WA 98108 USA. FU NCI NIH HHS [CA-47748, CA-15704] NR 44 TC 15 Z9 18 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3732 J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD AUG PY 2000 VL 23 IS 4 BP 406 EP 411 DI 10.1097/00000421-200008000-00019 PG 6 WC Oncology SC Oncology GA 342BM UT WOS:000088625400019 PM 10955873 ER PT J AU Rosen, HR Gretch, D Kaufman, E Quan, S AF Rosen, HR Gretch, D Kaufman, E Quan, S TI Humoral immune response to hepatitis C after liver transplantation: Assessment of a new recombinant immunoblot assay SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID POLYMERASE CHAIN-REACTION; VIRUS-INFECTION; MAJOR GENOTYPES; ANTIBODIES; IDENTIFICATION; SEQUENCES; DIAGNOSIS; SUBTYPES; PROTEINS; VIREMIA AB OBJECTIVE: The immune control of infection with hepatitis C virus (HCV) is poorly understood; vigorous antibody responses to viral proteins seem to coexist with the virus and thus whether they are neutralizing remains controversial. HCV-related liver failure is the leading indication for orthotopic liver transplantation (OLT) worldwide. Attenuated antibody responses in immunosuppressed patients and decreased reliability compared to assessment of HCV RNA has hampered the use of antibody testing post-OLT. The goals of this current analysis were twofold: to determine the sensitivity of a prototype strip immunoblot assay (RIBA 3.0, Chiron Diagnostics) for the diagnosis of HCV post-OLT; to determine if there was a correlation between antibody response and severity of histological recurrence. METHODS: The study was comprised of 76 HCV-positive individuals divided into three patient groups: liver allograft recipients with evidence of mild or no histological recurrence (n = 52), liver allograft recipients with evidence of severe HCV recurrence and allograft cirrhosis (n = 12), and nontransplant patients being enrolled in an induction interferon trial (n = 12). All transplant patients had histological follow-up of at least 1 yr. RESULTS: Sixty of the 64 (94%) HCV-positive OLT recipients had ii reactivity to two or more recombinant antigens; three of the patients who lacked a detectable response had minimal histological recurrence and one had severe recurrence. All nontransplant patients demonstrated 4+ reactivity to at least two antigens, and 55/64 (86%) OLT recipients demonstrated this same level of reactivity. Seven of the nine patients lacking this high level of reactivity had evidence of minimal recurrence. Furthermore, the mean (+/- SEM) level of antibody reactivity for c100 (p = 0.04) and NS5 (p = 0.01) were significantly tower for patients with mild recurrence after OLT, compared to the other groups. The level of antibody reactivity was unrelated to HCV genotype or viral load. CONCLUSIONS: The recently developed RIBA 3.0 assay for detection of antibodies to HCV appears to be highly sensitive for the diagnosis of HCV post-OLT. In general, the level of antibody reactivity was comparable in the transplant patients and in nonimmunosuppressed controls. The pathogenic implications of the relatively diminished humoral response in patients with mild recurrence post-OLT are discussed. (C) 2000 by Am. Cell. of Gastroenterology. C1 Oregon Hlth Sci Univ, Div Gastroenterol Hepatol, Portland Vet Affairs Med Ctr, Portland, OR 97207 USA. Univ Washington, Div Virol, Seattle, WA 98195 USA. Chiron Diagnost, Emeryville, CA USA. RP Rosen, HR (reprint author), Oregon Hlth Sci Univ, Div Gastroenterol Hepatol, Portland Vet Affairs Med Ctr, OHSU 3710 SW US Vet Hosp Rd,POB 1034,P3-G1, Portland, OR 97207 USA. NR 26 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD AUG PY 2000 VL 95 IS 8 BP 2035 EP 2039 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 343KN UT WOS:000088701700031 PM 10950054 ER PT J AU Yoshihashi, H Maeyama, K Kosaki, R Ogata, T Tsukahara, M Goto, Y Hata, J Matsuo, N Smith, RJ Kosaki, K AF Yoshihashi, H Maeyama, K Kosaki, R Ogata, T Tsukahara, M Goto, Y Hata, J Matsuo, N Smith, RJ Kosaki, K TI Imprinting of human GRB10 and its mutations in two patients with Russell-Silver syndrome SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID METHYLATION-SPECIFIC PCR; DISTAL LONG ARM; I RECEPTOR GENE; RING CHROMOSOME-15; UNIPARENTAL DISOMY-7; GROWTH-RETARDATION; HUMAN PEG1/MEST; PROTEIN GRB10; INSULIN; DELETION AB Documentation of maternal uniparental disomy of chromosome 7 in 10% of patients with Russell-Silver syndrome (RSS), characterized by prenatal and postnatal growth retardation and dysmorphic features, has suggested the presence of an imprinted gene on chromosome 7 whose mutation is responsible for the RSS phenotype, Human GRB10 on chromosome 7, a homologue of the mouse imprinted gene Grb10, is a candidate, because GRB10 has a suppressive effect on growth, through its interaction with either the IGF-I receptor or the GH receptor, and two patients with RSS were shown to have a maternally derived duplication of 7p11-p13, encompassing GRB10. In the present study, we first demonstrated that the GRB10 gene is also monoallelically expressed in human fetal brain tissues and is transcribed from the maternally derived allele in somatic-cell hybrids. Hence, human GRB10 is imprinted. A mutation analysis of GRB10 in 58 unrelated patients with RSS identified, within the N-terminal domain of the protein, a P95S substitution in two patients with RSS. In these two cases, the mutant allele was inherited from the mother. The fact that monoallelic GRB10 expression was observed from the maternal allele in this study suggests but does not prove that these maternally transmitted mutant alleles contribute to the RSS phenotype. C1 Keio Univ, Sch Med, Dept Pediat, Div Med Genet,Shinjuku Ku, Tokyo 1608582, Japan. Keio Univ, Sch Med, Pharmacia Upjohn Fund Growth & Dev Res, Shinjuku Ku, Tokyo 1608582, Japan. Keio Univ, Sch Med, Ctr Hlth, Shinjuku Ku, Tokyo 1608582, Japan. Keio Univ, Sch Med, Dept Pathol, Shinjuku Ku, Tokyo 1608582, Japan. Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Mental Retardat & Birth Defect Res, Tokyo, Japan. Yamaguchi Univ, Sch Allied Hlth Sci, Ube, Yamaguchi 755, Japan. Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Kosaki, K (reprint author), Keio Univ, Sch Med, Dept Pediat, Div Med Genet,Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan. RI Kosaki, Kenjiro/K-5350-2013 NR 51 TC 61 Z9 62 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG PY 2000 VL 67 IS 2 BP 476 EP 482 DI 10.1086/302997 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 354YA UT WOS:000089357800021 PM 10856193 ER PT J AU Hsu, CY Bates, DW Kuperman, GJ Curhan, GC AF Hsu, CY Bates, DW Kuperman, GJ Curhan, GC TI Diabetes, hemoglobin A(1c), cholesterol, and the risk of moderate chronic renal insufficiency in an ambulatory population SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE moderate chronic renal insufficiency; epidemiology; diabetes mellitus; hypercholesterolemia ID BLOOD-PRESSURE; SERUM CREATININE; INDEPENDENT PREDICTOR; KIDNEY-FUNCTION; NEPHROPATHY; DISEASE; FAILURE; PROGRESSION; MELLITUS; HYPERTENSION AB Moderate chronic renal insufficiency is common, with 12.5 million individuals in the United States estimated to have a creatinine clearance less than 50 mL/min/1.73 m(2). Little is known about the risk factors for moderate chronic renal insufficiency. We studied 1,428 subjects with Cockcroft-Gault-estimated creatinine clearances greater than 70 mL/min in a hospital-based ambulatory population. Over a mean of 5.7 +/- 1.3 years, 86 subjects developed moderate chronic renal insufficiency, defined as a decrease in creatinine clearance to less than 60 mL/min (1.1 case/100 person-years). Risk factors for moderate chronic renal insufficiency were identified using a proportional hazards model controlling for age, sex, race, systolic blood pressure, and angiotensin-converting enzyme (ACE) inhibitor use. The risk for developing moderate chronic renal insufficiency was associated with diabetes mellitus (relative risk, 2.1; 95% confidence interval [CI], 1.3 to 3.3) and elevated hemoglobin Al, levels. Compared with subjects with normoglycemia (hemoglobin A(1c) less than or equal to 5.7%), the relative risk for moderate chronic renal insufficiency for patients in the upper quartile of hemoglobin Al, (>9.0%) was 2.7 (95% CI, 1.4 to 5.1), The development of moderate chronic renal insufficiency was also independently predicted by elevated maximum serum cholesterol level. Compared with subjects with maximum cholesterol levels of 250 mg/dL or less, the relative risk for those with maximum cholesterol levels greater than 350 mg/dL was 2.4 (95% CI, 1.1 to 5.2). Similar relative risks were obtained when moderate chronic renal insufficiency was defined by the development of an increase in serum creatinine level. Hypercholesterolemia was also associated with moderate chronic renal insufficiency among persons without diabetes. In conclusion, the risk for developing moderate chronic renal insufficiency is increased by diabetes and elevated hemoglobin Al, and serum cholesterol levels. Modification of these risk factors may decrease the incidence of moderate chronic renal insufficiency. (C) 2000 by the National Kidney Foundation, Inc. C1 Univ Calif San Francisco, Div Nephrol, San Francisco, CA 94143 USA. Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. Partners Informat Syst, Boston, MA USA. Massachusetts Gen Hosp, Renal & Gen Med Unit, Boston, MA 02114 USA. RP Hsu, CY (reprint author), Univ Calif San Francisco, Div Nephrol, Room 672 HSE,513 Parnassus Ave, San Francisco, CA 94143 USA. NR 55 TC 50 Z9 50 U1 0 U2 3 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 AUG PY 2000 VL 36 IS 2 BP 272 EP 281 DI 10.1053/ajkd.2000.8971 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 352PM UT WOS:000089227100007 PM 10922305 ER PT J AU Morgan, RO Virnig, BA DeVito, CA Persily, NA AF Morgan, RO Virnig, BA DeVito, CA Persily, NA TI Medicare HMO disenrollment and selective use of medical care: Osteoarthritis-related joint replacement SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID UNITED-STATES; SERVICES; BENEFICIARIES; HIP AB Objective: Recent Medicare health maintenance organization (HMO) disenrollees use a high level of medical services. This study examined admissions for total hip arthroplasty (THA) and osteoarthritis-related knee replacements (OKR) among Medicare HMO disenrollees and continuously enrolled fee-for-service (FFS) beneficiaries to determine whether Medicare beneficiaries are returning to the FFS system to receive quality-of-life enhancing elective care. Study Design: Retrospective analysis of Medicare inpatient claims for elderly Medicare beneficiaries residing in South Florida between 1990 and 1993. Methods: Inpatient admission rates for THA, OKR, and for 2 acute conditions-total hip replacements related to fracture of the hip (HRF) and acute myocardial infarction (AMI)-were estimated for Medicare HMO disenrollees over the 3-month period immediately following their disenrollment, These rates were compared with standardized rates for Medicare FFS enrollees. Results: The annualized adjusted rates of both THA and OKR were 3.5 to 4 times higher among Medicare HMO disenrollees than among FFS beneficiaries (P less than or equal to .0001 for both procedures); substantially smaller differences were noted for HRF (P less than or equal to .05), and no difference was present for AMI. HMO disenrollees and FFS enrollees did not differ in their levels of comorbidity at the time of admission. Conclusions: These data provide indirect evidence that Medicare HMOs in South Florida are rationing THA and OKR and that beneficiaries respond by returning to the FFS system to seek care. This apparent rationing has important implications regarding for the management of serious, but nonemergent, medical conditions within the evolving Medicare system. C1 VA Med Ctr 152, Houston Ctr Qual Care & Utilizat Studies, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Div Hlth Serv Res, Houston, TX 77030 USA. Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. Miami Dept VA Med Ctr, Hlth Serv Res & Dev Ctr, Miami, FL USA. Ctr Geriatr Res Educ & Clin, Miami, FL USA. Univ Miami, Sch Med, Dept Psychiat & Behav Sci, Miami, FL 33152 USA. George Washington Univ, Sch Publ Hlth & Hlth Serv, Washington, DC 20037 USA. RP Morgan, RO (reprint author), VA Med Ctr 152, Houston Ctr Qual Care & Utilizat Studies, 2002 Holcombe Blvd, Houston, TX 77030 USA. RI Morgan, Robert/A-8577-2009 NR 24 TC 6 Z9 6 U1 0 U2 0 PU AMER MED PUBLISHING, M W C COMPANY PI JAMESBURG PA 241 FORSGATE DR, STE 102, JAMESBURG, NJ 08831 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD AUG PY 2000 VL 6 IS 8 BP 917 EP 923 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 345FF UT WOS:000088804200004 PM 11186503 ER PT J AU Ray, J Berkwits, M Davidoff, F AF Ray, J Berkwits, M Davidoff, F TI The fate of manuscripts rejected by a general medical journal SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID IMPACT FACTOR; PUBLISH AB PURPOSE: The fate of research manuscripts that have been rejected by medical journals is of interest to authors, editors, and peer reviewers, but previous studies were conducted before the widespread availability of computerized literature searches. We update the previous investigations of the fate of rejected research manuscripts by using an electronic literature search and a larger sample, a longer follow-up, and more descriptive journal indexes. METHODS: Using a retrospective cohort study design, we examined 350 manuscripts rejected by the Annals of Internal Medicine, a general medical journal, during 1993 and 1994. We assessed the number of manuscripts that were published after initial rejection, time to eventual publication, journal type (general versus specialty), and journal impact factor (higher scores indicated greater impact) and immediacy index. RESULTS: Of 350 rejected manuscripts, 240 (69%, 95% confidence interval [CI]: 64% to 73%) were eventually published after a mean of 552 days (95% CI: 479 to 544 days, range 121 to 1,792 days). Of 226 rejected research articles and reviews, 159 (70%, 95% CI: 64% to 76%) were subsequently published in specialty journals. During 1993 and 1994, the mean impact factor for articles published in the Annals was 9.60 (95% CI: 9.56 to 9.64), compared with a mean of 3.09 (95% CI: 2.80 to 3.37) for the journals in which the rejected articles were subsequently published (mean difference 6.52, 95% CI: 6.24 to 6.81, P < 0.0001). The immediacy index was also lower for these journals. Time to publication had a weak negative correlation with the impact factor of the journal in which the article was published (correlation coefficient -0.15, P = 0.007). CONCLUSIONS: The majority of the manuscripts that were rejected from a large general medical journal were eventually published after an average of 18 months. Most were published in specialty journals with lower impact factor and immediacy index ratings. Am J Med. 2000;109:131-135. (C) 2000 by Excerpta Medica, Inc. C1 Annals Internal Med, Philadelphia, PA USA. McMaster Univ, Dept Med, Hamilton, ON, Canada. McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. Philadelphia VA Med Ctr, Philadelphia, PA USA. Univ Penn, Med Ctr, Div Gen Internal Med, Philadelphia, PA 19104 USA. RP Ray, J (reprint author), 133 Shelborne Ave, Toronto, ON M6B 2M8, Canada. NR 20 TC 44 Z9 45 U1 0 U2 4 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD AUG 1 PY 2000 VL 109 IS 2 BP 131 EP 135 DI 10.1016/S0002-9343(00)00450-2 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 347HP UT WOS:000088922800007 PM 10967154 ER PT J AU Shaywitz, DA Martin, JB Ausiello, DA AF Shaywitz, DA Martin, JB Ausiello, DA TI Patient-oriented research: Principles and new approaches to training SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID CLINICAL RESEARCH AB Remarkable advances in modern biology have enhanced our understanding of disease, permitting us to define-and potentially to treat-illness at the cellular and molecular level. The challenge we now face as physicians and physician-scientists is ensuring that these advances find expression in clinical practice. Thus far, the distance from the bench to the bedside has been surprisingly difficult to span, reflecting the need to develop broader, more integrative approaches to understanding how component molecules and physiologic systems function in the context of the whole person. Although there appears to be a consensus about the need to pursue such integrative, patient-oriented research, a mechanism for training future investigators in this discipline is less well established. In this essay, we present and develop the rationale for a set of underlying principles for patient-oriented research that can be used to guide appropriate training in this field. We also describe briefly a recently established prototype program-the Harvard initiative in Patient-Associated Science: Training, Education, Understanding, and Research (PASTEUR)-that we hope will help cultivate patient-oriented investigators and catalyze the evolution of patient-oriented research into a fully realized academic discipline. Am J Med. 2000;109:136-140. (C) 2000 by Excerpta Medica, Inc. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Ausiello, DA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, 55 Fruit St,GRB 740, Boston, MA 02114 USA. NR 19 TC 17 Z9 17 U1 1 U2 3 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD AUG 1 PY 2000 VL 109 IS 2 BP 136 EP 140 DI 10.1016/S0002-9343(00)00452-6 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 347HP UT WOS:000088922800008 PM 10967155 ER PT J AU Costa, ST Ausiello, D Joiner, K Neilson, EG Taylor, I Wenzel, R AF Costa, ST Ausiello, D Joiner, K Neilson, EG Taylor, I Wenzel, R TI Supporting research in departments of internal medicine: Recommendations for NIH SO AMERICAN JOURNAL OF MEDICINE LA English DT Article C1 Massachusetts Gen Hosp, Harvard Med Sch, Dept Med, Boston, MA 02114 USA. Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA. Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN USA. Univ S Carolina, Dept Med, Columbia, SC 29208 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Internal Med, Richmond, VA 23284 USA. NR 13 TC 2 Z9 2 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD AUG 1 PY 2000 VL 109 IS 2 BP 178 EP 180 DI 10.1016/S0002-9343(00)00462-9 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 347HP UT WOS:000088922800026 PM 10967163 ER PT J AU Guajardo, G Okamoto, Y Gogen, H Shanfeld, JL Dobeck, J Herring, AH Davidovitch, Z AF Guajardo, G Okamoto, Y Gogen, H Shanfeld, JL Dobeck, J Herring, AH Davidovitch, Z TI Immunohistochemical localization of epidermal growth factor in cat paradental tissues during tooth movement SO AMERICAN JOURNAL OF ORTHODONTICS AND DENTOFACIAL ORTHOPEDICS LA English DT Article ID PERIODONTAL-LIGAMENT FIBROBLASTS; OSTEOBLAST-LIKE CELLS; COLLAGEN-SYNTHESIS; EPITHELIAL-CELLS; FACTOR RECEPTORS; BONE-RESORPTION; RAT; DIFFERENTIATION; PROLIFERATION; INVITRO AB Epidermal growth factor enhances proliferation and differentiation of cells during growth, maturation, and tissue healing. The objectives were to localize the epidermal growth factor in paradental cells and to determine the effect of orthodontic treatment on its concentrations in periodontal ligament fibroblasts, alveolar bone surface lining cells, and epithelial rests of Malassez. Sixty male cats, 1 year old, were divided into 2 groups: active and sham, and further divided into 10 time groups. In the active group, 1 maxillary canine was retracted by 80 g force; in the sham group, the animals received an inactive appliance. Sagittal sections of each half maxilla were stained for epidermal growth factor; staining intensity was measured microphotometrically in 10 periodontal ligament fibroblasts, alveolar bone surface lining cells, and epithelial rests of Malassez cells in sites of periodontal ligament tension and compression, and in corresponding sites near control and sham canines. The overall mean staining intensity of the cells of the active group animals was 30.47%, whereas that of the sham group was 21.78% (P < .0001). In all 3 types, cells near the actively treated canines stained significantly darker (P < .0001) than cells near the sham or control canines, particularly between 12 hours and 7 days. These results demonstrate that orthodontic forces increase epidermal growth factor concentrations in paradental cells, suggesting that epidermal growth factor participates in the tissue remodeling that facilitates tooth movement. C1 Harvard Univ, Sch Dent Med, Dept Orthodont, Boston, MA 02115 USA. Univ Tokushima, Dept Orthodont, Fac Dent, Tokushima 770, Japan. Ankara Univ, Dept Orthodont, Sch Dent, TR-06100 Ankara, Turkey. Ohio State Univ, Dept Oral Biol, Columbus, OH 43210 USA. Forsyth Dent Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Univ Oklahoma, Dept Orthodont, Oklahoma City, OK USA. RP Davidovitch, Z (reprint author), 1001 Stanton L Young Blvd, Oklahoma City, OK 73104 USA. NR 80 TC 13 Z9 16 U1 0 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0889-5406 J9 AM J ORTHOD DENTOFAC JI Am. J. Orthod. Dentofac. Orthop. PD AUG PY 2000 VL 118 IS 2 BP 210 EP 219 DI 10.1067/mod.2000.104097 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 344RU UT WOS:000088773300017 PM 10935963 ER PT J AU Lawrence, B Perez-Atayde, A Hibbard, MK Rubin, BP Dal Cin, P Pinkus, JL Pinkus, GS Xiao, S Yi, ES Fletcher, CDM Fletcher, JA AF Lawrence, B Perez-Atayde, A Hibbard, MK Rubin, BP Dal Cin, P Pinkus, JL Pinkus, GS Xiao, S Yi, ES Fletcher, CDM Fletcher, JA TI TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID LARGE-CELL LYMPHOMA; NON-HODGKINS-LYMPHOMA; RECEPTOR TYROSINE KINASE; MONOCLONAL-ANTIBODY ALK1; C-KIT GENE; FUSION PROTEIN; NPM-ALK; EXPRESSION; TROPOMYOSIN; PSEUDOTUMOR AB Inflammatory myofibroblastic tumors (IMTs) are neoplastic mesenchymal proliferations featuring an inflammatory infiltrate composed primarily of lymphocytes and plasma cells. The myofibroblastic cells in some IMTs contain chromosomal rearrangements involving the ALK receptor tyrosine-kinase locus region (chromosome band 2p23). ALK-which is normally restricted in its expression to neural tissues-is expressed strikingly in the IMT cells with 2p23 rearrangements. We now report a recurrent oncogenic mechanism, in IMTs, in which tropomyosin (TPM) N-terminal coiled-coil domains are fused to the ALK. C-terminal kinase domain. We have cloned two ALK fusion genes, TPM4-ALK and TPM3-ALK, which encode similar to 95-kd fusion oncoproteins characterized by constitutive kinase activity and tyrosylphosphorylation. Immunohistochemical and molecular correlations, in other IMTs, implicate non-TPM ALK oncoproteins that are predominantly cytoplasmic or predominantly nuclear, presumably depending on the subcellular localization of the ALK fusion partner. Notably, a TPM3-ALK oncogene was reported recently in anaplastic lymphoma, and TPM3-ALK is thereby the first known fusion oncogene that transforms, in vivo, both mesenchymal and lymphoid human cell lineages. C1 Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Univ Calif San Diego, Med Ctr, Dept Pathol, San Diego, CA 92103 USA. RP Fletcher, JA (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. NR 40 TC 362 Z9 388 U1 1 U2 4 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2000 VL 157 IS 2 BP 377 EP 384 DI 10.1016/S0002-9440(10)64550-6 PG 8 WC Pathology SC Pathology GA 342BJ UT WOS:000088625100006 PM 10934142 ER PT J AU Zhuang, SG Simon, G AF Zhuang, SG Simon, G TI Peroxynitrite-induced apoptosis involves activation of multiple caspases in HL-60 cells SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE poly( adenosine 5 '-diphosphate-ribose) polymerase; lamin B; caspase cysteine protease ID FAS-INDUCED APOPTOSIS; CYTOCHROME-C; NITRIC-OXIDE; POLY(ADP-RIBOSE) POLYMERASE; PROTEASE CASCADE; HUMAN PLATELETS; LAMIN-A; DEATH; PATHWAYS; INVOLVEMENT AB In this study, we show that caspases 2, 3, 6, and 7 were activated during peroxynitrite-induced apoptosis in human leukemia HL-60 cells and that processing of these caspases was accompanied by cleavage of poly(ADP-ribose) polymerase and lamin B. Treatment of cells with DEVD-fluoromethyl ketone (FMK), a selective inhibitor for caspase 3-like proteases, resulted in a marked diminution of apoptotic cells. VAVAD-FMK, an inhibitor of caspase 2, partially inhibited the apoptotic response to peroxynitrite. However, selective inactivation of caspase 6 by VEID-FMK did not affect apoptosis rates. These data suggest that caspase 3-like proteases and caspase 2, but not caspase 6, are required for peroxynitrite-induced apoptosis in this cell type. Moreover, we demonstrate that peroxynitrite treatment stimulated activation of caspases 8 and 9, two initial caspases in the apoptotic signaling pathway, and preincubation of cells with their inhibitor, IETD-FMK, inhibited activation of caspase 3-like proteases and caspase 2 at the concentration that prevents the apoptosis. These observations, together, suggest that caspase 8 and/or caspase 9 mediates activation of caspase 3-like proteases and caspase 2 during the apoptosis induced by peroxynitrite in HL-60 cells. C1 Massachusetts Gen Hosp, Wellman Labs Photomed, Boston, MA 02114 USA. RP Zhuang, SG (reprint author), Massachusetts Gen Hosp, Wellman Labs Photomed, WEL 224,55 Fruit St, Boston, MA 02114 USA. FU NIGMS NIH HHS [GM-30955] NR 49 TC 51 Z9 53 U1 1 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD AUG PY 2000 VL 279 IS 2 BP C341 EP C351 PG 11 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 338FN UT WOS:000088407600009 PM 10913000 ER PT J AU Akiba, Y Guth, PH Engel, E Nastaskin, I Kaunitz, JD AF Akiba, Y Guth, PH Engel, E Nastaskin, I Kaunitz, JD TI Dynamic regulation of mucus gel thickness in rat duodenum SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE fluorescent microspheres; perfusate glycoprotein concentration; indomethacin; periodic acid/Schiff staining; Alcian blue staining; Brunner's glands ID BRUNNERS GLAND SECRETION; INTESTINAL GOBLET CELLS; LUMINAL ACID; MUCIN SECRETION; NITRIC-OXIDE; SURFACE; GLYCOPROTEINS; PENTAGASTRIN; STIMULATION; MUCOSA AB We examined the dynamic regulation of mucus gel thickness (MGT) in vivo in rat duodenum in response to luminal acid, cyclooxygenase (COX) inhibition, and exogenous PGE(2). An in vivo microscopic technique was used to measure MGT with fluorescent microspheres in urethan-anesthetized rats. Duodenal mucosa was topically superfused with pH 7.0 or pH 2.2 solutions with or without PGE(2) and indomethacin treatments. Glycoprotein concentration of duodenal loop perfusates was measured with periodic acid/Schiff (PAS) or Alcian blue (AB) staining. MGT and perfusate glycoprotein concentration were stable during a 35-min perfusion with pH 7.0 solution. Acid exposure increased MGT and PAS- and AB-positive perfusate glycoprotein concentrations. Indomethacin pretreatment increased both PAS- and AB-positive perfusate glycoprotein at baseline; subsequent acid superfusion decreased perfusate glycoproteins and gel thickness. PGE(2) (1 mg/kg iv) simultaneously increased MGT and PAS-positive perfusate glycoprotein concentrations followed by a transient increase in AB-positive glycoprotein concentration, suggesting contributions from goblet cells and Brunner's glands. Parallel changes in MGT and perfusate glycoprotein concentration in response to luminal acid and PGE(2) suggest that rapid MGT variations reflect alterations in the balance between mucus secretion and exudation, which in turn are regulated by a COX-related pathway. Luminal acid and PGE(2) augment mucus secretion from goblet cells and Brunner's glands. C1 Univ Calif Los Angeles, Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, CURE Digest Dis Res Ctr, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Biomath, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Coll Letters & Sci, Los Angeles, CA 90073 USA. RP Kaunitz, JD (reprint author), W Los Angeles Vet Affairs Med Ctr, Bldg 114,Suite 217,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. FU NIDDK NIH HHS [DK-54221] NR 48 TC 44 Z9 46 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD AUG PY 2000 VL 279 IS 2 BP G437 EP G447 PG 11 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 338FQ UT WOS:000088408200025 PM 10915654 ER PT J AU Lu, L Gunja-Smith, Z Woessner, JF Ursell, PC Nissen, T Galardy, RE Xu, Y Zhu, PL Schwartz, GG AF Lu, L Gunja-Smith, Z Woessner, JF Ursell, PC Nissen, T Galardy, RE Xu, Y Zhu, PL Schwartz, GG TI Matrix metalloproteinases and collagen ultrastructure in moderate myocardial ischemia and reperfusion in vivo SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE ventricular function; collagenase; gelatinase; scanning electron microscopy; enzyme inhibitors ID DILATED CARDIOMYOPATHY; CONNECTIVE-TISSUE; PLASMINOGEN-ACTIVATOR; EXTRACELLULAR-MATRIX; STUNNED MYOCARDIUM; PORCINE MYOCARDIUM; FIBRILLAR COLLAGEN; RAT MYOCARDIUM; HEART-FAILURE; EXPRESSION AB Severe ischemic injury or infarction of myocardium may cause activation of matrix metalloproteinases (MMPs) and damage the interstitial matrix. However, it is unknown whether MMP activation and matrix damage occur after moderate ischemia and reperfusion that result in myocardial stunning without infarction, and if so whether such changes contribute to postischemic myocardial expansion and contractile dysfunction. To address these questions, open-chest anesthetized pigs underwent 90 min of regional ischemia (subendocardial blood flow 0.4 +/- 0.1 ml . g(-1) . min(-1)) and 90 min of reperfusion. After ischemia plus reperfusion, histological and ultrastructural examination revealed no myocardial infarction or inflammatory cell infiltration. Myocardial MMP-9 content increased threefold with a fourfold increase in the active form (P < 0.001). Myocardial collagenase content doubled (P < 0.01) but remained in latent form. MMP-2 and tissue inhibitors of metalloproteinases were unaffected. Despite increases in MMPs, collagen ultrastructure (assessed by cell maceration scanning electron microscopy) was unaltered. Intracoronary administration of the MMP inhibitor GM-2487 did not prevent or attenuate myocardial expansion (assessed by regional diastolic dimensions at near-zero left ventricular pressure) or contractile dysfunction. We conclude that although moderate ischemia and reperfusion alter myocardial MMP content and activity, these effects do not result in damage to interstitial collagen, nor do they contribute to myocardial expansion or contractile dysfunction. C1 Univ Colorado, Hlth Sci Ctr, Div Cardiol, Denver, CO 80220 USA. Univ Colorado, Hlth Sci Ctr, Dept Vet Affairs Med Ctr, Cardiol Sect, Denver, CO 80220 USA. Univ Miami, Sch Med, Dept Med, Miami, FL 33101 USA. Univ Miami, Sch Med, Dept Biochem & Mol Biol, Miami, FL 33101 USA. Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. RP Schwartz, GG (reprint author), Denver VA Med Ctr, Cardiol Sect 111B, 1055 Clermont St, Denver, CO 80220 USA. NR 52 TC 47 Z9 50 U1 1 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 AUG PY 2000 VL 279 IS 2 BP H601 EP H609 PG 9 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 340RQ UT WOS:000088549100019 PM 10924059 ER PT J AU Kosslyn, SM Thompson, WL Costantini-Ferrando, MF Alpert, NM Spiegel, D AF Kosslyn, SM Thompson, WL Costantini-Ferrando, MF Alpert, NM Spiegel, D TI Hypnotic visual illusion alters color processing in the brain SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL BLOOD-FLOW; FUNCTIONAL-ANATOMY; HYPNOSIS; CORTEX; SUSCEPTIBILITY; HEMISPHERE; ANALGESIA; TRANCE; PAIN AB Objective: This study was designed to determine whether hypnosis can modulate color perception. Such evidence would provide insight into the nature of hypnosis and its underlying mechanisms. Method: Eight highly hypnotizable subjects were asked to see a color pattern in color, a similar gray-scale pattern in color, the color pattern as gray scale, and the gray-scale pattern as gray scale during positron emission tomography scanning by means of [O-15]CO2. The classic color area in the fusiform or lingual region of the brain was first identified by analyzing the results when subjects were asked to perceive color as color versus when they were asked to perceive gray scale as gray scale. Results: When subjects were hypnotized, color areas of the left and right hemispheres were activated when they were asked to perceive color, whether they were actually shown the color or the gray-scale stimulus. These brain regions had decreased activation when subjects were told to see gray scale, whether they were actually shown the color or gray-scale stimuli. These results were obtained only during hypnosis in the left hemisphere, whereas blood flow changes reflected instructions to perceive color versus gray scale in the right hemisphere, whether or not subjects had been hypnotized. Conclusions: Among highly hypnotizable subjects, observed changes in subjective experience achieved during hypnosis were reflected by changes in brain function similar to those that occur in perception. These findings support the claim that hypnosis is a psychological state with distinct neural correlates and is not just the result of adopting a role. C1 Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Cornell Univ, Weill Med Coll, New York, NY USA. Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. RP Kosslyn, SM (reprint author), Harvard Univ, Dept Psychol, 830 William James Hall,33 Kirkland St, Cambridge, MA 02138 USA. NR 35 TC 159 Z9 164 U1 0 U2 16 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 AUG PY 2000 VL 157 IS 8 BP 1279 EP 1284 DI 10.1176/appi.ajp.157.8.1279 PG 6 WC Psychiatry SC Psychiatry GA 340EL UT WOS:000088520100016 PM 10910791 ER PT J AU Zimmerman, JL Woodruff, PG Clark, S Camargo, CA AF Zimmerman, JL Woodruff, PG Clark, S Camargo, CA CA MARC Investigators TI Relation between phase of menstrual cycle and emergency department visits for acute asthma SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article ID AIRWAY RESPONSIVENESS; ORAL-CONTRACEPTIVES; ESTROGEN; WOMEN AB Hormonal fluctuations during the menstrual cycle are hypothesized to influence the course of asthma among women. A recent study found that almost 50% of emergency department (ED) visits occur during the perimenstrual phase. Our prospective cohort study in 64 EDs examined the relation between phase of menstrual cycle and visits for acute asthma. A total of 288 women with acute asthma were evaluated with a standardized patient interview and medical record review after excluding subjects who were pregnant, on hormonal therapy, postmenopausal, status post hysterectomy, had incomplete reproductive data, or whose ED visit fell more than 28 d after their last menstrual period. Only 13% reported reproductive factors as a personal asthma trigger. For all subjects, ED asthma visits were classified by menstrual phase: 33% were preovulatory (Days 5 to 11), 26% were periovulatory (Days 12 to 18), 20% were postovulatory (Days 79 to 25), and 21% were perimenstrual (Days 26 to 4), p = 0.008. There was no significant association between phase of menstrual cycle and asthma severity. Our data indicate that ED visits for acute asthma among women are more frequent during the preovulatory phase in contrast to other studies reporting more visits in the perimenstrual phase. C1 Ben Taub Gen Hosp, Baylor Coll Med, Dept Internal Med, Houston, TX 77030 USA. Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Channing Lab, Boston, MA 02115 USA. RP Zimmerman, JL (reprint author), Ben Taub Gen Hosp, Baylor Coll Med, Dept Internal Med, 1504 Taub Loop, Houston, TX 77030 USA. FU NHLBI NIH HHS [HL-03533, HL-07427, HL-63253] NR 20 TC 51 Z9 52 U1 0 U2 1 PU AMER LUNG ASSOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD AUG PY 2000 VL 162 IS 2 BP 512 EP 515 PG 4 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 345RP UT WOS:000088829200030 PM 10934079 ER PT J AU Fujino, Y Goddon, S Chiche, JD Hromi, J Kacmarek, RM AF Fujino, Y Goddon, S Chiche, JD Hromi, J Kacmarek, RM TI Partial liquid ventilation ventilates better than gas ventilation SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article ID RESPIRATORY-DISTRESS SYNDROME; ACUTE LUNG INJURY; END-EXPIRATORY PRESSURE; MECHANICAL VENTILATION; NEUTROPHIL ACCUMULATION; VASCULAR CAPACITANCE; PULMONARY-FUNCTION; TIDAL VOLUME; ANIMAL-MODEL; EXCHANGE AB Partial liquid ventilation (PLV) improves oxygenation in several models of lung injury. However, PLV has only been compared with conventional gas ventilation (GV) with low PEEP. Both PLV and GV can markedly improve oxygenation when PEEP is set above the lower corner pressure (Plc) on the inspiratory pressure-volume (P-V) curve of the total respiratory system. We questioned if the use of PEEP set above the Pie during PLV and CV would result in similar gas exchange. Lung injury was induced in 12 sheep by saline lavage before randomization to PLV (n = 6) or CV (n = 6). Animals in the PLV group were filled with perflubron (22 ml/kg) until a meniscus at the teeth was observed. Both groups were then ventilated with pressure control (Fl(O2), 1.0; rate, 20/min; I:E, 1:1) and PEEP (1 cm H2O above the Plc on the inspiratory P-V curve). Peak inspiratory pressure (PIP) was limited to 35 cm H2O. Animals were ventilated for 5 h and then killed for histologic examinations. All 12 animals survived the 5-h ventilation period. After increasing PEEP above Plc, PaO2 increased significantly (p < 0.01) in both the GV and the PLV groups, but it did not differ significantly between groups (p = 0.86) at any time during the experiment. Pa-CO2 and V-D/V-T in CV increased markedly throughout the experiment after increasing PEEP (p < 0.001), but there was no significant change in Pa-CO2 in PLV (p = 0.13). Mean arterial blood pressure, mean pulmonary artery pressure, pulmonary artery occlusion pressure, and central venous pressure, increased and SVR decreased in GV (p < 0.05). The extent and the severity of lung injury in the dependent regions was greater in the GV group (p < 0.05). Both PLV and GV improved oxygenation, but PLV resulted in better ventilation than GV while preserving lung structure when PEEP was set 1 cm H2O above the Plc and PIP limited to 35 cm H2O. C1 Massachusetts Gen Hosp, Resp Care Dept Lab, 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, Resp Care Dept Lab, Ellison 401, Boston, MA 02114 USA. NR 39 TC 26 Z9 30 U1 0 U2 0 PU AMER LUNG ASSOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD AUG PY 2000 VL 162 IS 2 BP 650 EP 657 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 345RP UT WOS:000088829200052 PM 10934101 ER PT J AU Lamkhioued, B Garcia-Zepeda, EA Abi-Younes, S Nakamura, H Jedrzkiewicz, S Wagner, L Renzi, PM Allakhverdi, Z Lilly, C Hamid, Q Luster, AD AF Lamkhioued, B Garcia-Zepeda, EA Abi-Younes, S Nakamura, H Jedrzkiewicz, S Wagner, L Renzi, PM Allakhverdi, Z Lilly, C Hamid, Q Luster, AD TI Monocyte chemoattractant protein (MCP)-4 expression in the airways of patients with asthma - Induction in epithelial cells and mononuclear cells by proinflammatory cytokines SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article ID C-C CHEMOKINES; MESSENGER-RNA EXPRESSION; TUMOR-NECROSIS-FACTOR; BRONCHOALVEOLAR LAVAGE; CHEMOTACTIC PROTEIN-4; EOTAXIN EXPRESSION; BRONCHIAL HYPERRESPONSIVENESS; EOSINOPHIL ACCUMULATION; DIFFERENTIAL REGULATION; TISSUE EOSINOPHILIA AB Chemokines are chemotactic cytokines that play an important role in recruiting leukocytes in allergic inflammation. Monocyte chemo-acctractant protein (MCP)-4 is a CC chemokine with potent chemotactic activities for eosinophils, monocytes, T lymphocytes, and basophils and therefore represents a good candidate to participate in allergic reactions. To determine if MCP-4 plays a role in asthma, we have investigated the expression of MCP-4 messenger RNA (mRNA) and protein in the airways of patients with asthma and normal control subjects by in situ hybridization and immunohistochemistry. We found that MCP-4 mRNA and protein was significantly upregulated in the epithelium and submucosa of bronchial biopsies and in the bronchoalveolar lavage (BAL) cells of patients with asthma compared with normal control subjects (p < 0.01). In addition, MCP-4 protein was significantly elevated in the BAL fluid of patients with atopic asthma when compared with normal control subjects (p < 0.01) and there was a significant correlation between MCP-C eotaxin, and eosinophils. In support of our in situ findings demonstrating MCP-4 expression in epithelial cells and mononuclear cells in vivo, we have found that MCP-4 expression can be induced in these cells in vitro by tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta). Interferon-gamma (IFN-gamma) acted synergistically with TNF-alpha and IL-1 beta in the induction of mRNA MCP-4 mRNA expression in A549 cells, whereas the glucocorticoid dexamethasone diminished the cytokine-induced expression of MCP-4. Our findings demonstrate that MCP-4 is upregulated in the airways of patients with asthma and suggest that MCP-4 plays a role in the recruitment of eosinophils into the airways of patients with asthma. C1 Massachusetts Gen Hosp, Infect Dis Unit, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Pulm & Crit Care Div,Dept Med, Boston, MA 02115 USA. McGill Univ, Meakins Christie Labs, Montreal, PQ, Canada. McGill Univ, Dept Med, Montreal, PQ, Canada. McGill Univ, Dept Pathol, Montreal, PQ, Canada. Univ Montreal, Notre Dame Hosp, CHUM, LC Simard Res Ctr, Montreal, PQ H3C 3J7, Canada. RP Luster, AD (reprint author), Infect Dis Unit, Bldg 149 13th St, Charleston, MA 02129 USA. FU NIAID NIH HHS [AI40618] NR 47 TC 55 Z9 55 U1 0 U2 0 PU AMER LUNG ASSOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD AUG PY 2000 VL 162 IS 2 BP 723 EP 732 PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 345RP UT WOS:000088829200063 PM 10934112 ER PT J AU Kaufman, JA Geller, SC Brewster, DC Fan, CM Cambria, RP LaMuraglia, GM Gertler, JP Abbott, WM Waltman, AC AF Kaufman, JA Geller, SC Brewster, DC Fan, CM Cambria, RP LaMuraglia, GM Gertler, JP Abbott, WM Waltman, AC TI Endovascular repair of abdominal aortic aneurysms: Current status and future directions SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review ID ILIAC ARTERY ANEURYSMS; STENT-GRAFT TREATMENT; OPEN SURGICAL REPAIR; HIGH-RISK PATIENTS; ENDOLUMINAL REPAIR; AORTOILIAC ANEURYSMS; INITIAL EXPERIENCE; AAA TREATMENT; FOLLOW-UP; ENDOLEAKS C1 Massachusetts Gen Hosp, Div Vasc Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Vasc Surg, Boston, MA 02114 USA. RP Kaufman, JA (reprint author), Oregon Hlth Sci Univ, Dotter Intervent Inst, 3181 SW Sam Jackson Pk Rd, Portland, OR 97201 USA. NR 101 TC 35 Z9 38 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2000 VL 175 IS 2 BP 289 EP 302 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 338BD UT WOS:000088397500002 PM 10915659 ER PT J AU Smith, JJ Berlin, L AF Smith, JJ Berlin, L TI Is being sued for malpractice grounds for dismissal from a residency program? SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article C1 Rush N Shore Med Ctr, Dept Radiol, Skokie, IL 60076 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Rush Med Coll, Chicago, IL 60612 USA. RP Berlin, L (reprint author), Rush N Shore Med Ctr, Dept Radiol, 9600 Gross Point Rd, Skokie, IL 60076 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2000 VL 175 IS 2 BP 315 EP 318 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 338BD UT WOS:000088397500007 PM 10915665 ER PT J AU Scott, JA Palmer, EL Fischman, AJ AF Scott, JA Palmer, EL Fischman, AJ TI How well can radiologists using neural network software diagnose pulmonary embolism? SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article ID VENTILATION-PERFUSION SCINTIGRAPHY; CRITERIA; SCANS AB OBJECTIVE. This study evaluated and optimized the performance of an automated artificial neural network image interpreter in the diagnosis of pulmonary embolism on ventilation-perfusion lung scans. The computer interpretations were compared with the interpretations of three experienced observers. MATERIALS AND METHODS. Digital data were obtained from 100 patients with normal findings on chest radiographs who were undergoing both radionuclide ventilation-perfusion scanning and pulmonary angiography. Interpretations of differently trained neural networks were compared with those of three experienced nuclear medicine practitioners unaware of the clinical diagnosis. RESULTS. Machines running neural networks performed similarly to experienced scan interpreters in the detection of pulmonary embolism. Both the human observers and the networks performed best in cases with large emboli. Neural network performance was best in the right lung, when the networks were trained using only cases with large emboli and when networks were trained independently in the right and left lungs. The best predictions resulted from a collaborative interpretation incorporating both the human and computer predictions. CONCLUSION. Computers running artificial neural networks using scan data obtained directly from the anterior and posterior ventilation and perfusion images, without human involvement, perform comparably with experienced observers in patients with normal findings on chest radiographs. Human observers can improve their interpretations by incorporating computer output to formulate diagnostic prediction. The method of training the networks is critical to optimizing performance. C1 Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Scott, JA (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med, Fruit St, Boston, MA 02114 USA. NR 14 TC 11 Z9 11 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2000 VL 175 IS 2 BP 399 EP 405 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 338BD UT WOS:000088397500024 PM 10915682 ER PT J AU Bosch, JL Haaring, C Meyerovitz, MF Cullen, KA Hunink, MGM AF Bosch, JL Haaring, C Meyerovitz, MF Cullen, KA Hunink, MGM TI Cost-effectiveness of percutaneous treatment of iliac artery occlusive disease in the United States SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article ID PERIPHERAL VASCULAR-DISEASE; STENT PLACEMENT; REVASCULARIZATION PROCEDURES; TRANSLUMINAL ANGIOPLASTY AB OBJECTIVE. The costs of percutaneous transluminal angioplasty and stent placement for iliac artery occlusive disease ill the United States were assessed and the cost-effectiveness was evaluated. MATERIALS AND METHODS. Lifetime costs and quality-adjusted life expectancy were estimated using a Markov decision model for a hypothetic cohort of patients with life style-limiting claudication caused by an iliac artery stenosis for whom a percutaneous intervention was indicated. Various percutaneous treatment strategies were evaluated, each consisting of an initial intervention followed by a secondary intervention. Procedures considered were angioplasty alone and angioplasty with selective stent placement. RESULTS. From the perspective of the interventional radiology department, angioplasty with selective stent placement costs more than angioplasty alone ($2926 versus $2106). Taking into account follow-up costs and procedures for long-term failures, the cost differential was reduced because of a lower failure rate of selective stent placement ($13,158 versus $12,458, respectively). Treatment strategies using angioplasty with selective stent placement (as an initial procedure or including reintervention) dominated treatment strategies using angioplasty alone (incremental cost-effectiveness ratio was S7,624-8,519 per quality-adjusted life-year gained). CONCLUSION. Angioplasty with selective stent placement is a cost-effective treatment strategy compared with angioplasty alone in the treatment of intermittent claudication in the United States. C1 Massachusetts Gen Hosp, Dept Radiol, Decis Anal & Technol Assessment Grp, Boston, MA 02114 USA. Univ Utrecht, Med Ctr, Dept Radiol, NL-3584 CX Utrecht, Netherlands. Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. Erasmus Univ, Med Ctr, Dept Epidemiol & Biostat, Program Assessment Radiol Technol, NL-3000 DR Rotterdam, Netherlands. RP Bosch, JL (reprint author), Massachusetts Gen Hosp, Dept Radiol, Decis Anal & Technol Assessment Grp, Zero Emerson Pl,Sta 2H, Boston, MA 02114 USA. NR 18 TC 26 Z9 26 U1 0 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2000 VL 175 IS 2 BP 517 EP 521 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 338BD UT WOS:000088397500046 PM 10915706 ER PT J AU Catalano, OA Hahn, PF Hooper, DC Mueller, PR AF Catalano, OA Hahn, PF Hooper, DC Mueller, PR TI Efficacy of percutaneous abscess drainage in patients with vancomycin-resistant enterococci SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article ID FAECIUM; QUINUPRISTIN/DALFOPRISTIN; MANAGEMENT; INFECTIONS; CHALLENGE AB OBJECTIVE. We reviewed a 4-year experience draining fluid collections infected with vancomycin-resistant enterococci to determine the outcome of percutaneous intervention in patients with this highly resistant and increasingly common organism. MATERIALS AND METHODS. Charts of patients from whom vancomycin-resistant enterococci had been isolated during percutaneous drainage were reviewed to determine patient response to drainage, catheter management, and outcome of treatment. RESULTS. Twenty-one patients underwent percutaneous drainage of 28 fluid collections from which vancomycin-resistant enterococci were isolated, including 16 intraabdominal abscesses, seven biliary or urinary obstructions, and five empyemas. The drainage of 27 (96%) of 28 collections were technically successful. In seven patients, drainage provided the first isolation of vancomycin-resistant enterococci from the patient. Five patients also had blood cultures with positive findings for vancomycin-resistant enterococci, and 14 collections were coinfected with other bacteria or with fungi. Twenty collections (71%) or obstructions were successfully treated with percutaneous drainage. Drainage was unsuccessful in treating eight collections in seven patients. CONCLUSION. Despite high-level antibiotic resistance, fluid collections infected with vancomycin-resistant enterococci can be successfully drained percutaneously, resulting in a favorable likelihood of recovery for patients. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Infect Dis, Infect Control Unit, Boston, MA 02114 USA. RP Hahn, PF (reprint author), Massachusetts Gen Hosp, Dept Radiol, White 270,55 Fruit St, Boston, MA 02114 USA. NR 19 TC 4 Z9 4 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2000 VL 175 IS 2 BP 533 EP 536 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 338BD UT WOS:000088397500049 PM 10915709 ER PT J AU Mangi, AA Berger, DL AF Mangi, AA Berger, DL TI Stump appendicitis SO AMERICAN SURGEON LA English DT Article ID LAPAROSCOPIC APPENDECTOMY AB There has been a recent increase in interest in stump appendicitis with the rapid development of laparoscopic appendectomy. The objective of this study is to determine the frequency, management, and prevention of stump appendicitis in a retrospective review of 2185 cases of appendectomy and right colectomy at the Massachusetts General Hospital from 1960 to 1998. Three patients with stump appendicitis were identified. Patients presented with epigastric or periumbilical pain that radiated to the right lower quadrant. All had focal abdominal signs and a mild to moderate leukocytosis, and all underwent right colectomy. Pathology noted appendiceal stumps 5 mm deep. Two additional patients with chronic abdominal pain had cecal filling defects on barium enema. Endoscopically, these appendiceal stumps were 7 mm deep with impacted fecaliths and pathologic changes consistent with early inflammation. The stumps were resected by snare electrocautery. Stump appendicitis is a very rare entity. Its incidence may be minimized with accurate visualization of the appendiceal base and creation of an appendiceal stump less than 3 mm in depth. There is no correlation between simple ligation or inversion of the stump and stump appendicitis. There should not be a sudden increase in the incidence of this entity if laparoscopic appendectomy is performed properly. C1 Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Berger, DL (reprint author), Massachusetts Gen Hosp, Dept Surg, Wang 465,15 Parkman St, Boston, MA 02114 USA. NR 19 TC 48 Z9 49 U1 0 U2 1 PU SOUTHEASTERN SURGICAL CONGRESS PI ATLANTA PA 141 WEST WIEUCA RD, STE B100, ATLANTA, GA 30342 USA SN 0003-1348 J9 AM SURGEON JI Am. Surg. PD AUG PY 2000 VL 66 IS 8 BP 739 EP 741 PG 3 WC Surgery SC Surgery GA 343AA UT WOS:000088678500010 PM 10966030 ER PT J AU Wexler, HM Molitoris, E Molitoris, D Finegold, SM AF Wexler, HM Molitoris, E Molitoris, D Finegold, SM TI In vitro activity of moxifloxacin against 179 strains of anaerobic bacteria found in pulmonary infections SO ANAEROBE LA English DT Article ID RESPIRATORY-TRACT PATHOGENS; ANTIMICROBIAL AGENTS; BAY-12-8039; 8-METHOXYQUINOLONE; FLUOROQUINOLONE; QUINOLONE AB The activity of moxifloxacin (BAY 12-8039), a new 8-methoxyquinolone, was determined using the NCCLS-approved Wadsworth brucella laked blood agar method and compared to the activities of metronidazole, penicillin G, piperacillin/tazobactam and trovafloxacin. Breakpoints used to define susceptible and resistant categories were, respectively: less than or equal to 8 and greater than or equal to 32 mu g/mL for metronidazole, less than or equal to 2 and greater than or equal to 8 mu g/mL for moxifloxacin and trovafloxacin, less than or equal to 0.5 and greater than or equal to 2 mu g/mL for penicillin G and less than or equal to 32 and greater than or equal to 128 mu g/mL for piperacillin/tazobactam. A total of 179 anaerobic isolates from pulmonary infections were tested. Piperacillin/tazobactam was the most active antimicrobial, inhibiting 99% of strains at the susceptible breakpoint. Ninety-seven percent of these isolates were susceptible to moxifloxacin; 96% to trovafloxacin, 89% to metronidazole and 43% to penicillin G. Geometric mean moxifloxacin MIC values for Bacteroides fragilis and the B. fragilis group were 0.5 and 0.8 mu g/mL, respectively. Eighty-eight percent of B, fragilis and 100% of other B. fragilis group species were susceptible to both moxifloxacin and trovafloxacin. All of the strains of B. fragilis and most of the other B. fragilis group species were resistant to penicillin G. At least 99% of other Bacteroides species, Prevotella, and Fusobacterium strains were susceptible to moxifloxacin, metronidazole, piperacillin/tazobactam and trovafloxacin (88% were susceptible to trovafloxacin at 2 mu g/mL and all were susceptible at 4 mu g/mL). The strains of Clostridium difficile and Clostridium ramosum found in these specimens were both resistant to penicillin G but susceptible to the other agents. All strains of Peptostreptococcus species were susceptible to all of the agents except penicillin G. Activities of the agents against non-spore-forming Gram-positive rods at the intermediate breakpoint were, respectively, moxifloxacin-100%, metronidazole-49%, penicillin G-86%, piperacillin/tazobactam-100%, and trovafloxacin-97%. The promising in vitro activity of moxifloxacin against anaerobic pulmonary isolates warrants further investigation, including clinical correlation studies. C1 Vet Adm Greater Los Angeles Hlth Serv, Med Serv, Los Angeles, CA 90073 USA. Vet Adm Greater Los Angeles Hlth Serv, Res Serv, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Dept Immunol & Microbiol, Los Angeles, CA 90024 USA. RP Wexler, HM (reprint author), VA Wadsworth Med Ctr 691 151J, Microbial Dis Res Lab, Bldg 304,Room E3-224, Los Angeles, CA 90073 USA. NR 18 TC 6 Z9 7 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1075-9964 J9 ANAEROBE JI Anaerobe PD AUG PY 2000 VL 6 IS 4 BP 227 EP 231 DI 10.1006/anae.2000.0348 PG 5 WC Microbiology SC Microbiology GA 343PY UT WOS:000088711800002 ER PT J AU Shin, YS Fink, H Khiroya, R Ibebunjo, C Martyn, J AF Shin, YS Fink, H Khiroya, R Ibebunjo, C Martyn, J TI Prednisolone-induced muscle dysfunction is caused more by atrophy than by altered acetylcholine receptor expression SO ANESTHESIA AND ANALGESIA LA English DT Article ID RAT DIAPHRAGM; CONTRACTILE PROPERTIES; HINDLIMB MUSCLES; SKELETAL-MUSCLE; D-TUBOCURARINE; CORTICOSTEROIDS; GLUCOCORTICOIDS; IMMOBILIZATION; RESISTANCE; EXERCISE AB Large doses of glucocorticoids can alter muscle physiology and susceptibility to neuromuscular blocking drugs by mechanisms not clearly understood. We investigated the effects of moderate and large doses of prednisolone on muscle function and pharmacology, and their relationship to changes in muscle size and acetylcholine receptor (AChR) expression. With institutional approval, 35 Sprague-Dawley rats were randomly allocated to receive daily subcutaneous doses of 10 mg/kg prednisolone (P10 group), 100 mg/kg prednisolone (P100 group), or an equal volume of saline (S group) for 7 days. A fourth group of rats was pair fed (food restricted) with the P100 rats for 7 days (FR group). On Day 8, the nerve-evoked peak twitch tensions, tetanic tensions, and fatigability, and the dose-response curves of sl-tubocurarine in the tibialis cranialis muscle were measured in vivo and related to muscle mass or expression of AChRs. Rate of body weight gain was depressed in the P100, FR, and P10 groups compared with the S group. Tibialis muscle mass was smaller in the P100 group than in the P10 or S groups. The evoked peak twitch and tetanic tensions were less in the P100 group than in the P10 or S groups, however, tension per milligram of muscle mass was greater in the P100 group than in the S group. The 50% effective dose of d-tubocurarine (mu g/kg) in the tibialis muscle was smaller in the P10 (33.6 +/- 5.4) than in the S (61.9 +/- 5.0) or the P100 (71.3 +/- 9.6) groups. AChR expression was less in the P10 group than in the S group. The evoked tensions correlated with muscle mass (r(2) = 0.32, P < 0.001), however, not with expression of AChR. The 50% effective dose of d-tubocurarine did not correlate with muscle mass or AChR expression. Our results suggest that the neuromuscular dysfunction after prednisolone is dose-dependent, and derives primarily from muscle atrophy and derives less so from changes in AChR expression. C1 Chungnam Natl Univ, Coll Med, Dept Anesthesiol, Taejon, South Korea. Harvard Univ, Sch Med, Dept Anesthesiol & Crit Care, Boston, MA USA. Massachusetts Gen Hosp, Anesthesia Serv, Boston, MA 02114 USA. Shriners Burns Hosp, Boston, MA USA. RP Martyn, J (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 32 Fruit St, Boston, MA 02114 USA. EM jmartyn@partners.org NR 33 TC 7 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 EI 1526-7598 J9 ANESTH ANALG JI Anesth. Analg. PD AUG PY 2000 VL 91 IS 2 BP 322 EP 328 DI 10.1097/00000539-200008000-00017 PG 7 WC Anesthesiology SC Anesthesiology GA 338YD UT WOS:000088450100017 ER PT J AU Adrie, C Holzmann, A Hirani, WM Zapol, WM Hurford, WE AF Adrie, C Holzmann, A Hirani, WM Zapol, WM Hurford, WE TI Effects of intravenous Zaprinast and inhaled nitric oxide on pulmonary hemodynamics and gas exchange in an ovine model of acute respiratory distress syndrome SO ANESTHESIOLOGY LA English DT Article DE lavage lung injury; phosphodiesterase inhibitor; pulmonary circulation; sheep ID PHOSPHODIESTERASE INHIBITOR; CYCLIC-GMP; RELAXING FACTOR; SMOOTH-MUSCLE; B 22948; HYPERTENSION; DIPYRIDAMOLE; VASODILATOR; NITROPRUSSIDE; SILDENAFIL AB Background: Inhaled nitric oxide (NO) selectively dilates the pulmonary vasculature and improves gas exchange in acute respiratory distress syndrome. Because of the very short half-life of NO, inhaled NO is administered continuously. Intravenous Zaprinast (2-o-propoxyphenyl-8-azapurin-6-one), a cyclic guanosine monophosphate phosphodiesterase inhibitor, increases the efficacy and prolongs the duration of action of inhaled NO in models of acute pulmonary hypertension. Its efficacy in lung injury models is uncertain, The authors hypothesized that the use of intravenous Zaprinast would have similar beneficial effects when used in combination with inhaled NO to improve oxygenation and dilate the pulmonary vasculature in a diffuse model of acute lung injury. Methods: The authors studied two groups of sheep with lung injury produced by saline lavage. In the first group, 0, 5, 10, and 20 ppm of inhaled NO were administered in a random order before and after an intravenous Zaprinast infusion (2 mg/kg bolus followed by 0.1 mg . kg(-1) . min(-1)). In the second group, inhaled NO was administered at the same concentrations before and after an intravenous infusion of Zaprinast solvent (0.05 M NaOH), Results: After lavage, inhaled NO decreased pulmonary arterial pressure and resistance with no systemic hemodynamic effects, increased arterial oxygen partial pressure, and decreased venous admixture (all P < 0.05). The intravenous administration of Zaprinast alone decreased pulmonary artery pressure but worsened gas exchange (P < 0.05). Zaprinast infusion abolished the beneficial ability of inhaled NO to improve pulmonary gas exchange and reduce pulmonary artery pressure (P < 0.05 vs. control), Conclusions: This study suggests that nonselective vasodilation induced by intravenously administered Zaprinast at the dose used in our study not only worsens gas exchange, but also abolishes the beneficial effects of inhaled NO. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Hurford, WE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RI Hurford, William/G-6386-2013 OI Hurford, William/0000-0003-1201-0313 FU NHLBI NIH HHS [HL 42397] NR 38 TC 14 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD AUG PY 2000 VL 93 IS 2 BP 422 EP 430 DI 10.1097/00000542-200008000-00021 PG 9 WC Anesthesiology SC Anesthesiology GA 340ZB UT WOS:000088565600016 PM 10910492 ER PT J AU Chasan-Taber, L Willet, WC Seddon, JM Stampfer, MJ Rosner, B Colditz, GA Speizer, FE Hankinson, SE AF Chasan-Taber, L Willet, WC Seddon, JM Stampfer, MJ Rosner, B Colditz, GA Speizer, FE Hankinson, SE TI A prospective study of alcohol consumption and cataract extraction among US women SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE cataract; alcohol; cataract extraction; diet; female; prospective studies ID SELF-ADMINISTERED QUESTIONNAIRE; RISK-FACTORS; CIGARETTE-SMOKING; OPACITIES; LENS AB PURPOSE: Alcohol consumption has been implicated in the pathogenesis of cataract in some, but not all analytic studies. To date, no prospective analysis of the relationship between alcohol consumption and cataract has been conducted in women. METHODS: We examined the association between alcohol consumption and cataract extraction in a prospective cohort of female registered nurses. In 1980, 50,461 women were included and others were added as they became 45 years of age for a total of 77,466 women. Information on alcohol consumption and incidence of senile cataract extraction was ascertained during 12 years of follow-up with biennial questionnaires. RESULTS: We observed 1468 cases of cataract extraction in 761,036 person-years of follow-up. Compared to nondrinkers, those consuming alcohol were not at increased risk of cataract, even up to 25 grams or more per day (2 or more drinks) (relative risk [RR] = 1.10, 95% confidence interval [CI] = 0.90, 1.35). Results remained unchanged after controlling for cataract risk factors including cigarette smoking, body mass index, and diabetes. When risk was examined for specific cataract subtypes only, those in the highest category of consumption had a multivariate relative risk of 1.10 (95% CI = 0.74, 1.62) for nuclear cataracts and 1.50 (95% CI = 0.98, 2.30) for posterior subcapsular cataracts only. CONCLUSIONS: These prospective data suggest that there is no substantial overall increased risk of senile cataract due to alcohol intake. The possibility that alcohol consumption leads to a modest increased risk of posterior subcapsular type opacities requiring extraction merits further exploration. Ann Epidemiol 2000;10:347-353. (C) 2000 Elsevier Science Inc. All rights reserved. C1 Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Dept Biostat & Epidemiol, Amherst, MA 01003 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Cambridge, MA 02138 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Cambridge, MA 02138 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Cambridge, MA 02138 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Cambridge, MA 02138 USA. RP Chasan-Taber, L (reprint author), Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Dept Biostat & Epidemiol, 405 Arnold House, Amherst, MA 01003 USA. RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NCI NIH HHS [CA40356]; NEI NIH HHS [EY-09611] NR 20 TC 9 Z9 9 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD AUG PY 2000 VL 10 IS 6 BP 347 EP 353 DI 10.1016/S1047-2797(00)00054-5 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 347RM UT WOS:000088943000002 PM 10964000 ER PT J AU Kim, JY Putman, CM Farkas, J Varvares, M AF Kim, JY Putman, CM Farkas, J Varvares, M TI Paraclinoid internal carotid artery aneurysm presenting as massive epistaxis SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article ID TRAUMATIC PSEUDOANEURYSM; ENDOVASCULAR TREATMENT; DETACHABLE BALLOONS; DIAGNOSIS; THERAPY C1 Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. RP Varvares, M (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. NR 16 TC 7 Z9 10 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 AUG PY 2000 VL 109 IS 8 BP 782 EP 786 PN 1 PG 5 WC Otorhinolaryngology SC Otorhinolaryngology GA 344RQ UT WOS:000088773000015 PM 10961814 ER PT J AU Arozullah, AM Daley, J Henderson, WG Khuri, SF AF Arozullah, AM Daley, J Henderson, WG Khuri, SF CA Natl Vet Adm Surgical Quality Impr TI Multifactorial risk index for predicting postoperative respiratory failure in men after major noncardiac surgery SO ANNALS OF SURGERY LA English DT Article ID AFFAIRS SURGICAL RISK; PULMONARY COMPLICATIONS; MULTIVARIATE-ANALYSIS; ABDOMINAL-SURGERY; THORACIC-SURGERY; ADJUSTMENT; QUALITY; DISEASE; CARE AB Objective To develop and validate a preoperative risk index for predicting postoperative respiratory failure (PRF). Summary Background Data Respiratory failure is an important postoperative complication. Method Based on a prospective cohort study, cases from 44 Veterans Affairs Medical Centers (n = 81,719) were used to develop the models. Cases from 132 Veterans Affairs Medical Centers (n = 99,390) were used as a validation sample. PRF was defined as mechanical ventilation for more than 48 hours after surgery or reintubation and mechanical Ventilation after post-operative extubation. Ventilator-dependent, comatose, do not resuscitate, and female patients were excluded. Results PRF developed in 2,746 patients (3.4%). The respiratory failure risk index was developed from a simplified logistic regression model and included abdominal aortic aneurysm repair, thoracic surgery, neurosurgery, upper abdominal surgery, peripheral vascular surgery, neck surgery, emergency surgery, albumin level less than 30 g/L, blood urea nitrogen level more than 30 mg/dL, dependent functional status, chronic obstructive pulmonary disease, and age. Conclusions The respiratory failure risk index is a validated model for identifying patients at risk for developing PRF and may be useful for guiding perioperative respiratory care. C1 Univ Illinois, Coll Med, Sect Gen Internal Med MC 787, Chicago, IL 60612 USA. Harvard Univ, Sch Med, Vet Affairs Boston Healthcare Syst, Boston, MA USA. Massachusetts Gen Hosp, Partners Hlth Care Syst, Boston, MA 02114 USA. Hines VA Cooperat Studies Program Coordinating Ct, Hines, IL USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Arozullah, AM (reprint author), Univ Illinois, Coll Med, Sect Gen Internal Med MC 787, 840 S Wood St, Chicago, IL 60612 USA. NR 26 TC 242 Z9 252 U1 1 U2 6 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 AUG PY 2000 VL 232 IS 2 BP 242 EP 253 DI 10.1097/00000658-200008000-00015 PG 12 WC Surgery SC Surgery GA 339BE UT WOS:000088457100015 PM 10903604 ER PT J AU Keller, SM Adak, S Wagner, H Johnson, DH AF Keller, SM Adak, S Wagner, H Johnson, DH CA Eastern Cooperative Oncology Grp TI Mediastinal lymph node dissection improves survival in patients with stages II and IIIa non-small cell lung cancer SO ANNALS OF THORACIC SURGERY LA English DT Article; Proceedings Paper CT 36th Annual Meeting of the Society-of-Thoracic-Surgeons CY JAN 31-FEB 02, 2000 CL FT LAUDERDALE, FL SP Soc Thorac Surg ID LYMPHADENECTOMY; TABLES AB Background. Mediastinal lymph node dissection (MLND) is an integral part of surgery for non-small cell lung cancer (NSCLC). To compare the impact of systematic sampling (SS) and complete MLND on the identification of mediastinal lymph node metastases and patient survival, the Eastern Cooperative Oncology Group (ECOG) stratified patients by type of MLND before participation in ECOG 3590 (a randomized prospective trial of adjuvant therapy in patients with completely resected stages II and IIIa NSCLC). Methods. Eligibility requirements for study entry included a thorough investigation of the mediastinal lymph nodes with either SS or complete MLND. The former was defined as removal of at least one lymph node at levels 4, 7, and 10 during a right thoracotomy and at levels 5 and/or 6 and 7 during a left thoracotomy, while the latter required complete removal of all lymph nodes at those levels. Results. Three hundred seventy-three eligible patients were accrued to the study. Among the 187 patients who underwent SS, N1 disease was identified in 40% and N2 disease in 60%. This was not significantly different than the 41% of N1 disease and 59% of N2 disease found among the 186 patients who underwent complete MLND. Among the 222 patients with N2 metastases, multiple levels of N2 disease were documented in 30% of patients who underwent complete MLND and in 12% of patients who had SS (p = 0.001). Median survival was 57.5 months for those patients who had undergone complete MLND and 29.2 months for those patients who had SS (p = 0.004). However, the survival advantage was limited to patients with right lung tumors (66.4 months vs 24.5 months, p < 0.001). Conclusions. In this nonrandomized comparison, SS was as efficacious as complete MLND in staging patients with NSCLC. However, complete MLND identified significantly more levels of N2 disease. Furthermore, complete MLND was associated with improved survival with right NSCLC when compared with SS. (C) 2000 by The Society of Thoracic Surgeons. C1 Beth Israel Deaconess Med Ctr, Dept Surg, New York, NY 10003 USA. Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. Univ S Florida, H Lee Moffitt Canc Ctr, Dept Radiat Oncol, Tampa, FL 33682 USA. Vanderbilt Univ, Dept Med Oncol, Nashville, TN USA. Coordinating Ctr, Brookline, MA USA. RP Beth Israel Deaconess Med Ctr, Dept Surg, 1st Ave & 16th St, New York, NY 10003 USA. EM skeller@bethisraelny.org RI Johnson, David/A-7437-2009 FU NCI NIH HHS [CA-23318, CA-120046, CA-31946] NR 15 TC 181 Z9 200 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD AUG PY 2000 VL 70 IS 2 BP 358 EP 365 DI 10.1016/S0003-4975(00)01673-8 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 346TC UT WOS:000088886300004 PM 10969645 ER PT J AU Torchiana, DF Vine, AJ Titus, JS Hahn, C Shebani, KO Geffin, GA Daggett, WM AF Torchiana, DF Vine, AJ Titus, JS Hahn, C Shebani, KO Geffin, GA Daggett, WM TI The temperature dependence of cardioplegic distribution in the canine heart SO ANNALS OF THORACIC SURGERY LA English DT Article ID MYOCARDIAL BLOOD-FLOW; CARDIAC CONTRACTION; CORONARY-ARTERY; VASOMOTOR TONE; ARRESTED HEART; VASCULAR TONE; HYPOTHERMIA; WARM; METABOLISM; VESSELS AB Background. Cold cardioplegic arrest can produce cooling contracture and suboptimal myocardial protection. This study examines whether cooling contracture is associated with maldistribution of cardioplegic solution, particularly subendocardial hypoperfusion, which may impair recovery. Methods. Canine hearts were arrested by antegrade cold and warm blood cardioplegia in random order. Cardioplegic distribution was measured using radiolabeled microspheres before and just after induction of each period of arrest. Results. With cold cardioplegia, perfusion of left ventricular subepicardial and midwall regions decreased. Subendocardial to subepicardial perfusion ratios increased significantly in the left ventricle as a whole, the anterior and posterior regions of the left ventricular free wall, and the interventricular septum. With warm arrest, transmural flow distribution was not significantly altered from preceding prearrest values. At constant coronary now, coronary perfusion pressure was initially similar after induction of arrest at both temperatures, but it rose subsequently during warm cardioplegia. Conclusions. The data suggest that during normothermic arrest, vasomotor tone regulates cardioplegic distribution, and hyperkalemic vasoconstriction is of slow onset. In the absence of beating and with vasomotion inhibited by hypothermia, cardioplegic distribution during cold arrest appears to be primarily dependent on vascular anatomy. There was no evidence of subendocardial underperfusion during cooling contracture. (C) 2000 by The Society of Thoracic Surgeons. C1 Massachusetts Gen Hosp, Surg Cardiovasc Unit, Dept Surg, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Torchiana, DF (reprint author), Massachusetts Gen Hosp, Surg Cardiovasc Unit, Dept Surg, BUL-119,55 Fruit St, Boston, MA 02114 USA. FU NHLBI NIH HHS [HL12777, HL12322] NR 26 TC 6 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD AUG PY 2000 VL 70 IS 2 BP 614 EP 620 DI 10.1016/S0003-4975(00)01439-9 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 346TC UT WOS:000088886300056 PM 10969689 ER PT J AU Swartz, MN AF Swartz, MN TI Impact of Antimicrobial Agents and Chemotherapy from 1972 to 1998 SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Review ID PENICILLIN-BINDING PROTEINS; STREPTOCOCCUS-PNEUMONIAE; BETA-LACTAMASES; ENTEROBACTER-CLOACAE; RESISTANT; STRAINS; MENINGITIS; GENTAMICIN; THERAPY C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Swartz, MN (reprint author), Massachusetts Gen Hosp, Fruit St, Boston, MA 02114 USA. NR 21 TC 10 Z9 11 U1 0 U2 2 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 AUG PY 2000 VL 44 IS 8 BP 2009 EP 2016 DI 10.1128/AAC.44.8.2009-2016.2000 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 336NB UT WOS:000088308200001 PM 10898668 ER PT J AU Fournier, B Zhao, XL Lu, T Drlica, K Hooper, DC AF Fournier, B Zhao, XL Lu, T Drlica, K Hooper, DC TI Selective targeting of topoisomerase IV and DNA gyrase in Staphylococcus aureus: Different patterns of quinolone-induced inhibition of DNA synthesis SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID ESCHERICHIA-COLI; STREPTOCOCCUS-PNEUMONIAE; BACTERIAL CHROMOSOME; RESISTANT MUTANTS; COUMARIN ACTIVITY; FLUOROQUINOLONES; CIPROFLOXACIN; MUTATIONS; CLEAVAGE; GRLA AB The effect of quinolones on the inhibition of DNA synthesis in Staphylococcus aureus was examined by using single resistance mutations in parC or gyrA to distinguish action against gyrase or topoisomerase IV, respectively, Norfloxacin preferentially attacked topoisomerase IV and blocked DNA synthesis slowly, while nalidixic acid targeted gyrase and inhibited replication rapidly. Ciprofloxacin exhibited an intermediate response, consistent with both enzymes being targeted. The absence of RecA had little influence on target choice by this assay, indicating that differences in rebound (repair) DNA synthesis were not responsible for the results. At saturating drug concentrations, norfloxacin and a gyrA mutant were used to show that topoisomerase IV-nor-floxacin-cleaved DNA complexes are distributed on the S, aureus chromosome at intervals of about 30 kbp, If cleaved complexes block DNA replication, as indicated by previous work, such close spacing of topoisomerase-quinolone-DNA complexes should block replication rapidly (replication forks are likely to encounter a cleaved complex within a minute). Thus, the slow inhibition of DNA synthesis at growth-inhibitory concentrations suggests that a subset of more distantly distributed complexes is physiologically relevant for drug action and is unlikely to be located immediately in front of the DNA replication fork. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Med Serv, Boston, MA 02114 USA. Publ Hlth Res Inst, New York, NY 10016 USA. RP Hooper, DC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, 55 Fruit St, Boston, MA 02114 USA. FU NIAID NIH HHS [AI23988, AI35257, R01 AI023988, R01 AI035257, R37 AI023988] NR 40 TC 58 Z9 60 U1 0 U2 3 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 AUG PY 2000 VL 44 IS 8 BP 2160 EP 2165 DI 10.1128/AAC.44.8.2160-2165.2000 PG 6 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 336NB UT WOS:000088308200024 PM 10898691 ER PT J AU Luterman, JD Haroutunian, V Yemul, S Purohit, D Aisen, PS Mohs, R Pasinetti, GM AF Luterman, JD Haroutunian, V Yemul, S Purohit, D Aisen, PS Mohs, R Pasinetti, GM TI Cytokine gene expression as a function of the clinical progression of Alzheimer disease dementia SO ARCHIVES OF NEUROLOGY LA English DT Article ID GROWTH-FACTOR-BETA; NEUROFIBRILLARY TANGLES; SERUM INTERLEUKIN-6; NEURITIC PLAQUES; BRAIN; TGF-BETA-1; ALPHA(1)-ANTICHYMOTRYPSIN; RESPONSES; ROLES; ALPHA AB Background Inflammatory cytokines have been linked to Alzheimer disease (AD) neurodegeneration, but little is known about the temporal control of their expression in relationship to clinical measurements of AD dementia progression. Design and Main Outcome Measures: We measured inflammatory cytokine messenger RNA (mRNA) expression in postmortem brain specimens of elderly subjects at different clinical stages of dementia and neuropathological dysfunction. Setting and Patients: Postmortem study of nursing home patients. Results: In brains of cognitively normal control subjects, higher interleukin 6 (IL-6) and transforming growth factor beta 1 (TGF-beta 1) mRNA expression was observed in the entorhinal cortex and superior temporal gyrus compared with the occipital cortex. Compared with age-matched controls, subjects with severe/terminal dementia, but not subjects at earlier disease stages, had higher IL-6 and TGF-beta 1 mRNA expression in the entorhinal cortex (P<.01) and superior temporal gyrus (P<.01). When stratified by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropathological criteria, IL-6 mRNA expression in both the entorhinal cortex (P<.05) and superior temporal gyrus (P<.01) correlated with the level of neurofibrillary tangles but not neuritic plaques. However, in the entorhinal cortex, TGF-beta 1 mRNA did not correlate with the level of either neurofibrillary tangles or neuritic plaques. Interestingly, in the superior temporal gyrus, TGF-beta 1 mRNA expression negatively correlated with neurofibrillary tangles (P<.01) and showed no relationship to the pathological features of neuritic plaques. Conclusions: The data are consistent with the hypothesis that cytokine expression may differentially contribute to the vulnerability of independent cortical regions during the clinical progression of AD and suggest that an inflammatory cytokine response to the pathological effects of AD does not occur until the late stages of the disease. These findings have implications for the design of anti-inflammatory treatment strategies. C1 Mt Sinai Med Ctr, Neuroinflammat Res Labs, Dept Psychiat, New York, NY 10029 USA. Mt Sinai Sch Med, Dept Pathol, New York, NY 10029 USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. Bronx Vet Affairs Med Ctr, Dept Psychiat, Bronx, NY USA. Georgetown Univ, Sch Med, Dept Neurol, Washington, DC USA. RP Pasinetti, GM (reprint author), Mt Sinai Med Ctr, Neuroinflammat Res Labs, Dept Psychiat, Box 1229,1 Gustave L Levy Pl, New York, NY 10029 USA. FU NIA NIH HHS [AG16743, AG13799, AG14329] NR 25 TC 118 Z9 125 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD AUG PY 2000 VL 57 IS 8 BP 1153 EP 1160 DI 10.1001/archneur.57.8.1153 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 342PR UT WOS:000088654800008 PM 10927795 ER PT J AU Li, WJ Gragoudas, S Egan, KM AF Li, WJ Gragoudas, S Egan, KM TI Metastatic melanoma death rates by anatomic site after proton beam irradiation for uveal melanoma SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY MAY 09-14, 1999 CL FT LAUDERDALE, FLORIDA SP Assoc Res Vis & Ophthalmol, Natl Hlth Public Serv Award, Childern Hosp Res Fdn ID CILIARY BODY MELANOMA; LONG-TERM SURVIVAL; PROGNOSTIC FACTORS; MICROCIRCULATION ARCHITECTURE; MALIGNANT MELANOMAS; CYTOGENETIC FINDINGS; PLAQUE RADIOTHERAPY; LARGEST NUCLEOLI; FOLLOW-UP; ENUCLEATION AB Background: Ciliary body location is an established prognostic factor for metastasis-related death from uveal melanoma. We evaluated alternative approaches for classifying this covariate when constructing predictive models of patient survival. Methods and Destgn: The analyses were based on a consecutive series of 1848 primary choroidal and/or ciliary body melanoma patients treated with proton beam irradiation (70 cobalt gray equivalent in 5 fractions) at the Harvard Cyclotron Laboratory, Boston, Mass, between July 1975 and December 1995. For each patient, the anatomic site of the tumor was classified according to an estimate of the proportion of the tumor base lying anterior to the ora serrata. Using proportional hazards regression, we estimated relative risk ratios and death rates from melanoma metastasis according to the extent of ciliary body involvement. All estimates were adjusted for other established prognostic factors. Results: Patients were followed up through April 30, 1998; none were lost to follow-up. Of 1848 patients analyzed, 378 died of melanoma metastasis. The median follow-up period among survivors was 9.5 years. Ciliary body origin (>50% of tumor base anterior to the ora serrata) was positively associated with tumor pigmentation (P<.001), tumor height (P<.001), and extrascleral extension of the tumor (P<.001). Compared with tumors involving only the choroid, melanoma-associated death rates increased with the proportion of the tumor base lying within the ciliary body (P=.006); the multivariate-adjusted relative risk ratio for greater than 75% involvement was 2.30 (95% confidence interval [CI], 1.26-4.23). The covariate-adjusted 5-year death rates for ciliary body origin and choroidal origin were 15.9% (95% CI, 11.3%-21.2%) and 9.8% (95% CI, 8.3%-11.7%), respectively. Conclusion: Patients with melanomas of presumed ciliary body origin seem to be subject to a higher risk of death resulting from melanoma metastasis. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Retina Serv, Boston, MA 02114 USA. Univ Massachusetts, Dept Biostat & Epidemiol, Amherst, MA 01003 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Egan, KM (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Retina Serv, Boston, MA 02114 USA. RI Li, Wenjun/F-5634-2015 OI Li, Wenjun/0000-0001-5335-7386 NR 55 TC 33 Z9 34 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD AUG PY 2000 VL 118 IS 8 BP 1066 EP 1070 PG 5 WC Ophthalmology SC Ophthalmology GA 343KZ UT WOS:000088702700006 PM 10922199 ER PT J AU Azar, DT Jain, S Sambursky, R AF Azar, DT Jain, S Sambursky, R TI A new surgical technique of microkeratome-assisted deep lamellar keratoplasty with a hinged flap SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID PENETRATING KERATOPLASTY AB We describe a new surgical technique of microkeratome-assisted deep lamellar keratoplasty for treating patients with corneal stromal disease and normal endothelium. A microkeratome is used to create a hinged anterior stromal flap in the host cornea, and the diseased stroma is resected or ablated. A complementary donor stromal button, prepared using a microkeratome and an artificial anterior chamber, is transplanted prior to repositioning of the nap. The flap may be lifted at a later date, and an excimer laser used to correct residual refractive errors. Notwithstanding the preliminary and theoretical nature of this report, this technique may improve the outcomes of deep lamellar keratoplasty and may allow for decreased postoperative complications. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Corneal & Refract Surg Serv, Boston, MA 02114 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. RP Azar, DT (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Corneal & Refract Surg Serv, 243 Charles St, Boston, MA 02114 USA. NR 10 TC 23 Z9 25 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD AUG PY 2000 VL 118 IS 8 BP 1112 EP 1115 PG 4 WC Ophthalmology SC Ophthalmology GA 343KZ UT WOS:000088702700014 PM 10922207 ER PT J AU Wagenaar, M Schuknecht, H Nadol, J Benraad-van Rens, M Pieke-Dahl, S Kimberling, W Cremers, C AF Wagenaar, M Schuknecht, H Nadol, J Benraad-van Rens, M Pieke-Dahl, S Kimberling, W Cremers, C TI Histopathologic features of the temporal bone in Usher syndrome type I SO ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Article ID INNER-EAR; GENE; LOCALIZATION; CHROMOSOME-11; PROTEIN; MAPS; 1B AB Temporal bones of 2 patients with Usher syndrome type I were examined using light microscopy. In both patients, findings from histopathologic examination of the cochlea were characterized by degeneration of the organ of Corti, which was most marked in the basal turn, atrophy of the stria vascularis, and a decrease in the number of spiral ganglion cells. The cochlear nerve appeared to be diminished. The sensory epithelium of the saccular and utricular maculae of patient 1 was normal for age. The left temporal bone of patient 2, classified as Usher syndrome genetic subtype USH1D or USH1F, demonstrated the typical signs of severe cochleosaccular degeneration. Present cases and cases from the literature were reviewed in search of an explanation for the above-described differences in histologic findings. C1 Univ Nijmegen Hosp, Dept Otolaryngol, NL-6500 HB Nijmegen, Netherlands. Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Inst Deaf & Blind, Beek Ubbergen, Netherlands. Boys Town Natl Res Hosp, Omaha, NE 68131 USA. RP Wagenaar, M (reprint author), Univ Nijmegen Hosp, Dept Otorhinolaryngol, POB 9101, NL-6500 HB Nijmegen, Netherlands. RI Cremers, C.W.R.J./L-4254-2015 NR 25 TC 11 Z9 13 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 AUG PY 2000 VL 126 IS 8 BP 1018 EP 1023 PG 6 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 343LZ UT WOS:000088705000016 PM 10922238 ER PT J AU Houser, SL Mark, EJ AF Houser, SL Mark, EJ TI Bronchocentric granulomatosis with mucus impaction due to bronchogenic carcinoma - An association with clinical relevance SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article AB Objective.-To describe an unexpected inflammatory process associated with malignancy in the lung and to postulate a new mode of pathogenesis. Design.-Retrospective review of surgical pathologic findings. Setting.-Academic hospital pathology department. Patients.-Four patients, 2 men and 2 women, ranging in age from 45 to 74 years, each of whom had a solitary mass on chest radiographs. Interventions.-Pulmonary lobectomy. Main Outcome Measure.-Histopathologic identification of bronchocentric granulomatosis. Results.-Accompanying a bronchogenic carcinoma in each case was a necrotizing chronic granulomatous reaction centered around bronchioles that were plugged with mucus, necrotic detritus from the tumor, lipid, or a combination of these substances. Eosinophils were present in small numbers in one case. The pathologic findings characterize bronchocentric granulomatosis. Conclusions.-The presence of bronchocentric granulomatosis in the biopsy of a mass does not exclude the presence of an accompanying bronchogenic carcinoma associated with obstruction of bronchioles. Bronchocentric granulomatosis in some cases may represent an immunologic response to tumor detritus or lipid, as well as to mucus impaction. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. RP Mark, EJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, 32 Fruit St, Boston, MA 02114 USA. NR 15 TC 4 Z9 5 U1 0 U2 0 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD AUG PY 2000 VL 124 IS 8 BP 1168 EP 1171 PG 4 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 342HH UT WOS:000088638800015 PM 10923078 ER PT J AU Ehde, DM Czerniecki, JM Smith, DG Campbell, KM Edwards, WT Jensen, MP Robinson, LR AF Ehde, DM Czerniecki, JM Smith, DG Campbell, KM Edwards, WT Jensen, MP Robinson, LR TI Chronic phantom sensations, phantom pain, residual limb pain, and other regional pain after lower limb amputation SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE amputation; chronic pain; phantom limb pain; stump pain; sensation; leg; rehabilitation ID STUMP PAIN; AMPUTEES; QUESTIONNAIRE AB Objectives: To determine the characteristics of phantom limb sensation, phantom limb pain, and residual limb pain, and to evaluate pain-related disability associated with phantom limb pain. Design: Retrospective, cross-sectional survey. Six or more months after lower limb amputation, participants (n = 255) completed an amputation pain questionnaire that included several standardized pain measures. Setting: Community-based survey from clinical databases. Participants: A community-based sample of persons with lower limb amputations. Main Outcome Measures: Frequency, duration, intensity, and quality of phantom limb and residual limb pain, and pain-related disability as measured by the Chronic Pain Grade. Results: Of the respondents, 79% reported phantom limb sensations, 72% reported phantom limb pain, and 74% reported residual limb pain. Many described their phantom limb and residual limb pain as episodic and not particularly bothersome. Most participants with phantom limb pain were classified into the two low pain-related disability categories: grade I, low disability/low pain intensity (47%) or grade Il, low disability/high pain intensity (28%). Many participants reported having pain in other anatomic locations, including the back (52%). Conclusions: Phantom limb and residual limb pain are common after a lower limb amputation. For most, the pain is episodic and not particularly disabling. However, for a notable subset, the pain may be quite disabling. Pain after amputation should be viewed from a broad perspective that considers other anatomic sites as well as the impact of pain on functioning. C1 Univ Washington, Sch Med, Dept Rehabil Med, Seattle, WA 98104 USA. Univ Washington, Dept Orthopaed Surg, Seattle, WA 98104 USA. Univ Washington, Dept Anesthesiol, Seattle, WA 98104 USA. Harborview Med Ctr, VA Puget Sound Hlth Care Syst, Seattle, WA USA. VA Ctr Amputat Prosthet & Limb Loss Prevent, Seattle, WA USA. RP Ehde, DM (reprint author), Univ Washington, Sch Med, Dept Rehabil Med, 325 9th Ave,Box 359740, Seattle, WA 98104 USA. RI Robinson , Lawrence/D-8455-2013 FU NICHD NIH HHS [P01 HD/NS33988] NR 22 TC 164 Z9 167 U1 2 U2 12 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 AUG PY 2000 VL 81 IS 8 BP 1039 EP 1044 DI 10.1053/apmr.2000.7583 PG 6 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 349JJ UT WOS:000089041700006 PM 10943752 ER PT J AU Yamamura, MS Gilster, JC Myers, BS Deveney, CW Sheppard, BC AF Yamamura, MS Gilster, JC Myers, BS Deveney, CW Sheppard, BC TI Laparoscopic Heller myotomy and anterior fundoplication for achalasia results in a high degree of patient satisfaction SO ARCHIVES OF SURGERY LA English DT Article; Proceedings Paper CT 71st Annual Session of the Pacific-Coast-Surgical-Association CY FEB 19-22, 2000 CL SAN FRANCISCO, CALIFORNIA SP Pacific Coast Surg Assoc ID BOTULINUM TOXIN INJECTION; ESOPHAGEAL ACHALASIA; GASTROESOPHAGEAL REFLUX; ANTIREFLUX PROCEDURE; ESOPHAGOMYOTOMY; SURGERY; DILATATION; OPERATION; OUTCOMES; EFFICACY AB Hypothesis: Laparoscopic Heller myotomy with anterior fundoplication will alleviate the symptoms of achalasia and result in excellent patient satisfaction. Design: Retrospective study of consecutive patients who underwent laparoscopic Heller myotomy with anterior fundoplication for achalasia between October 1995 and July 1999. A telephone survey assessed symptoms and satisfaction. Patients were asked to quantitate their symptoms on a scale of 0 to 3 (0 = none; 1, mild; 2, moderate; and 3, severe). Setting: University referral center. Patients: Twenty-four patients who underwent laparoscopic Heller myotomy with anterior fundoplication for achalasia. Main Outcome Measures: Postoperative symptoms and satisfaction. Results: Twenty-one patients (88%) were successfully contacted. Mean follow-up was 16.5 months. The laparoscopic approach was successful in all but 3(88%). The mean dysphagia score was 2.81 preoperatively and 0.81 postoperatively (P<.000). The mean chest pain score was 1.57 preoperatively and 0.86 postoperatively (P<.015). The mean supine regurgitation score was 2.10 preoperatively and 0.57 postoperatively (P<.000). The mean upright regurgitation score was 1.57 preoperatively and 0.52 postoperatively (P<.000). The mean heartburn score was 1.57 preoperatively and 0.57 postoperatively (P <.000). Postoperatively, 18 (86%) of 21 patients could swallow bread without difficulty and 17 (89%) of 19 patients could eat meat without difficulty (2 were excluded as they were vegetarians). Twenty (95%) of 21 patients reported improvement after the operation. Conclusions: Laparoscopic Heller myotomy with anterior fundoplication significantly relieves the symptoms of achalasia without causing the symptoms of gastroesophageal reflux disease. This procedure results in excellent overall patient satisfaction. C1 Oregon Hlth Sci Univ, Dept Surg, Portland, OR 97201 USA. Vet Affairs Med Ctr, Portland, OR USA. RP Deveney, CW (reprint author), Portland VA Med Ctr, P8SURG,3710 SW US Vet Hosp Rd, Portland, OR 97201 USA. NR 30 TC 29 Z9 33 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 AUG PY 2000 VL 135 IS 8 BP 902 EP 905 DI 10.1001/archsurg.135.8.902 PG 4 WC Surgery SC Surgery GA 342HN UT WOS:000088639300004 PM 10922249 ER PT J AU Fischer, H Andersson, JLR Furmark, T Fredrikson, M AF Fischer, H Andersson, JLR Furmark, T Fredrikson, M TI Fear conditioning and brain activity: A positron emission tomography study in humans SO BEHAVIORAL NEUROSCIENCE LA English DT Article ID HUMAN AMYGDALA; BLOOD-FLOW; PET; ACTIVATION; EXTINCTION; PROJECTIONS; MECHANISMS; SCANS; ATLAS; FMRI AB Regional cerebral blood flow (rCBF) was measured with (H2O)-O-15 positron emission tomography in 8 healthy women before and after fear conditioning (i.e., paired shocks) and unpaired shocks to videotape cues. Conditioning was supported by enhanced peripheral nervous system recordings and subjective ratings. Fear conditioning increased rCBF in the central gray of the midbrain; bilaterally in the hypothalamus, the thalamus, and the left striatum; and in the right and left anterior cingulate and right prefrontal cortices. Regional CBF was attenuated bilaterally in the right and left prefrontal, temporal (including the amygdala), parietal, and occipital cortices, and in the left orbitofrontal cortex. When compared with unpaired shock presentations, fear conditioning resulted in elevated rCBF in the left cerebellum. Hence, in the present paradigm, only neural activity in the left cerebellum solely reflected processes associated with true Pavlovian conditioning. C1 Uppsala Univ, Dept Psychol, SE-75142 Uppsala, Sweden. Massachusetts Gen Hosp, Psychiat Neuroimaging Res Grp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Univ Uppsala Hosp, Pet Ctr, Uppsala, Sweden. RP Fredrikson, M (reprint author), Uppsala Univ, Dept Psychol, Box 12225, SE-75142 Uppsala, Sweden. OI Furmark, Tomas/0000-0001-6821-9058 NR 52 TC 51 Z9 51 U1 3 U2 6 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD AUG PY 2000 VL 114 IS 4 BP 671 EP 680 DI 10.1037//0735-7044.114.4.671 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 344TV UT WOS:000088775800002 PM 10959525 ER PT J AU Malik, TH Shivdasani, RA AF Malik, TH Shivdasani, RA TI Structure and expression of a novel frizzled gene isolated from the developing mouse gut SO BIOCHEMICAL JOURNAL LA English DT Article DE FzD2; Mfz10; oesophageal epithelium; Wnt receptor ID SIGNALING PATHWAY; WINGLESS SIGNAL; BETA-CATENIN; DROSOPHILA; FAMILY; MUTATIONS; ARMADILLO; CANCER; PRODUCT; HOMOLOG AB The Wnt/APC (adenomatous polyposis coli)/beta-catenin pathway plays a central role in the pathogenesis of colorectal cancer and probably also in normal development of the gastrointestinal tract. Frizzled proteins function as cell-surface receptors for the Wnt family of extracellular ligands. Many components of the Wnt signalling pathway are expressed widely, and determinants of tissue-specific functions are poorly understood. A better understanding of how Wnt signalling regulates tissue-specific development and gut epithelial homoeostasis requires characterization of the many components of this signalling pathway. We therefore wished to identify frizzled genes with limited tissue distribution of expression and isolated Mfz10, a novel member of the mouse family of frizzled genes, from the developing fetal gut. Highest levels of Mfz10 mRNA are detected throughout late embryonic development, in the brain, heart, lung and digestive tract. In adult mice Mfz10 mRNA is detected at highest levels in the heart, brain and lung. Expression in the adult gastrointestinal tract is much weaker, with higher levels in foregut derivatives (oesophagus and stomach) compared with regions derived from the fetal midgut and hindgut; particularly strong mRNA expression is observed in the squamous epithelium of the oesophagus. The amino acid sequence of Mfz10 is nearly identical to that of human FzE2 (also known as FzD2). Interestingly, mRNA levels of human FzD2 are reported to be up-regulated in oesophageal squamous cell carcinomas. These findings suggest a likely role for Mfz10 in the developing and adult foregut. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Shivdasani, RA (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. NR 25 TC 12 Z9 13 U1 0 U2 1 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD AUG 1 PY 2000 VL 349 BP 829 EP 834 PN 3 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343QA UT WOS:000088712000021 PM 10903145 ER PT J AU Pascualy, M Petrie, EC Brodkin, K Peskind, ER Wilkinson, CW Raskind, MA AF Pascualy, M Petrie, EC Brodkin, K Peskind, ER Wilkinson, CW Raskind, MA TI Hypothalamic pituitary adrenocortical and sympathetic nervous system responses to the cold presser test in Alzheimer's disease SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Alzheimer's disease; cortisol; ACTH; norepinephrine; epinephrine; stress ID CORTICOTROPIN-RELEASING HORMONE; DEXAMETHASONE SUPPRESSION TEST; RECEPTOR GENE-EXPRESSION; CA3 PYRAMIDAL NEURONS; CEREBROSPINAL-FLUID; CORTISOL-LEVELS; SENILE DEMENTIA; ADRENAL AXIS; RAT-BRAIN; PLASMA AB Background: Increased basal activity of the hypothalamic-pituitary-adrenocortical (HPA) axis has been repeatedly demonstrated in Alzheimer's disease (AD), and some studies suggest increased basal activity of the sympathetic nervous system (SNS) in this disorder; however, the effects of AD on HPA axis or SNS responses to a standardized aversive stressor have not been examined. The neuroendocrine response to aversive stress may be relevant to the pathophysiology of AD. Methods. Plasma adrenocorticotropic hormone (ACTH), cortisol, norepinephrine (NE), and epinephrine responses to a 1-min cold pressor test (CPT)were measured in nine medically healthy AD outpatients (age 76 +/- 1 years) and nine age- and gender-matched medically healthy cognitively normal older subjects (age 76 +/- 1 year). Results: The cortisol response to CPT was increased in the AD group but the ACTH response did not differ between groups. Basal NE responses to CPT did not differ between groups, the blood pressure response to CPT was higher in the AD subjects. Conclusions: These results suggest increased HPA axis responsiveness to CPT at the level of the adrenal cortex in AD. The results also suggest increased basal sympathoneural activity and increased cardiovascular responsiveness to sympathoneural stimulation in AD under the conditions of this experimental protocol. Increased SNS stimulatory modulation of the adrenal cortex is a possible mechanism contributing to the observed enhanced cortisol response to CPT in these AD subjects. Biol Psychiatry 2000;48:247-254 (C) 2000 Society of Biological Psychiatry. C1 VA Puget Sound Hlth Care Syst, Mental Hlth Serv S116, Educ & Clin Ctr, NW Mental Illness Res, Seattle, WA 98108 USA. VA Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Seattle, WA 98108 USA. Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Raskind, MA (reprint author), VA Puget Sound Hlth Care Syst, Mental Hlth Serv S116, Educ & Clin Ctr, NW Mental Illness Res, 1660 S Columbian Way, Seattle, WA 98108 USA. FU NIA NIH HHS [AG05136, AG08419] NR 61 TC 39 Z9 39 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 1 PY 2000 VL 48 IS 3 BP 247 EP 254 DI 10.1016/S0006-3223(00)00879-9 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 338VK UT WOS:000088443800008 PM 10924668 ER PT J AU Herak-Kramberger, CM Sabolic, I Blanusa, M Smith, PJS Brown, D Breton, S AF Herak-Kramberger, CM Sabolic, I Blanusa, M Smith, PJS Brown, D Breton, S TI Cadmium inhibits vacuolar H(+)ATPase-mediated acidification in the rat epididymis SO BIOLOGY OF REPRODUCTION LA English DT Article ID H+-ATPASE; POSTNATAL-DEVELOPMENT; CAUDA EPIDIDYMIDIS; ANTIGEN RETRIEVAL; EPITHELIAL-CELLS; CHLORIDE; TESTIS; LOCALIZATION; EXPRESSION; TRANSPORT AB In rats, an acidic luminal pH maintains sperm quiescence during storage in the epididymis. We recently showed that vacuolar H(+)ATPase-rich cells in the epididymis and vas deferens are involved in the acidification of these segments. Treatment of rats with cadmium (Cd) leads to alkalinization of this fluid by an unknown mechanism. Because Cd may affect H(+)ATPase function, we examined 1) the in vivo effect of Cd poisoning on H(+)ATPase-rich cell morphology and on the abundance and distribution of the 31-kDa H(+)ATPase subunit in cells along the rat epididymis, and 2) the in vitro effect of Cd on H(+)ATPase activity and function in the isolated vas deferens. Immunofluorescencce and immunoblotting data from rats treated with Cd for 14-15 days (2 mg Cd/kg body mass/day) showed that 1) H(+)ATPase-positive cells regressed to a prepubertal phenotype, and 2) H(+)ATPase was lost from the apical pole of the cell and was redistributed into an intracellular compartment. In experiments in vitro, Cd inhibited bafilomycin-sensitive ATPase activity in isolated total cell membranes and, as measured using a proton-selective extracellular microelectrode, inhibited proton secretion in isolated vas deferens. We conclude that alkalinization of the tubule fluid in the epididymis and vas deferens of Cd-treated rats may result from the loss of functional H(+)ATPase enzyme in the cell apical domain as well as from a direct inhibition of H(+)ATPase function by Cd. C1 Inst Med Res & Occupat Hlth, Unit Mol Toxicol, Zagreb 10001, Croatia. Inst Med Res & Occupat Hlth, Mineral Metab Unit, Zagreb 10001, Croatia. Marine Biol Lab, BioCurrents Res Ctr, Woods Hole, MA 02543 USA. Massachusetts Gen Hosp, Renal Unit, Boston, MA 02129 USA. Massachusetts Gen Hosp, Program Membrane Biol, Boston, MA 02129 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02215 USA. RP Sabolic, I (reprint author), Inst Med Res & Occupat Hlth, Unit Mol Toxicol, Ksaverska Cesta 2,POB 291, Zagreb 10001, Croatia. FU NIDDK NIH HHS [DK 38452] NR 40 TC 24 Z9 25 U1 1 U2 1 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 AUG PY 2000 VL 63 IS 2 BP 599 EP 606 DI 10.1095/biolreprod63.2.599 PG 8 WC Reproductive Biology SC Reproductive Biology GA 339RM UT WOS:000088491700035 PM 10906070 ER PT J AU Schatten, H Wiedemeier, AMD Taylor, M Lubahn, DB Greenberg, NM Besch-Williford, C Rosenfeld, CS Day, JK Ripple, M AF Schatten, H Wiedemeier, AMD Taylor, M Lubahn, DB Greenberg, NM Besch-Williford, C Rosenfeld, CS Day, JK Ripple, M TI Centrosome-centriole abnormalities are markers for abnormal cell divisions and cancer in the transgenic adenocarcinoma mouse prostate (TRAMP) model SO BIOLOGY OF THE CELL LA English DT Article DE cell proliferation; centrosomes; apoptosis; cytoskeleton; prostate cancer ID SEA-URCHIN EGGS; MICROTUBULE ORGANIZING CENTERS; MONOCLONAL-ANTIBODY; CYCLE; ANEUPLOIDY; PROTEIN; GENE; INSTABILITY; EXPRESSION; DIAZEPAM AB We utilized the transgenic adenocarcinoma mouse prostate (TRAMP) model to study the formation of abnormal mitosis in malignant tumors of the prostate. The results presented here are focused on centrosome and centriole abnormalities and the implications for abnormal cell divisions, genomic instability, and apoptosis. Centrosomes are microtubule organizing organelles which assemble bipolar spindles in normal cells but can organize mono-, tri-, and multipolar mitoses in tumor cells, as shown here with histology and electron microscopy in TRAMP neoplastic tissue. These abnormalities will cause unequal distribution of chromosomes and can initiate imbalanced cell cycles in which checkpoints for cell cycle control are lost. Neoplastic tissue of the TRAMP model is also characterized by numerous apoptotic cells. This may be the result of multipolar mitoses related to aberrant centrosome formations. Our results also reveal that centrosomes at the poles in mitotic cancer cells contain more than the regular perpendicular pair of centrioles which indicates abnormal distribution of centrioles during separation to the mitotic poles. Abnormalities in the centriole-centrosome complex are also seen during interphase where the complex is either closely associated with the nucleus or loosely dispersed in the cytoplasm. An increase in centriole numbers is observed during interphase, which may be the result of increased centriole duplication. Alternatively, these centrioles may be derived from basal bodies that have accumulated. in the cell's cytoplasm, after the loss of cell borders. The supernumerary centrioles may participate in the formation of abnormal mitoses during cell division. These results demonstrate multiple abnormalities in the centrosome-centriole complex during prostate cancer that result in abnormal mitoses and may lead to increases in genomic instability and/or apoptosis. (C) 2000 Editions scientifiques et medicales Elsevier SAS. C1 Univ Missouri, Dept Vet Pathobiol, Columbia, MO 65211 USA. Univ Missouri, Canc Res Ctr, Columbia, MO 65211 USA. Univ Missouri, Dept Biochem & Child Hlth, Columbia, MO 65211 USA. Univ Missouri, Genet Area Program, Columbia, MO 65211 USA. Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA. Baylor Coll Med, Scott Dept Urol, Houston, TX 77030 USA. Univ Missouri, Dept Anim Sci, Columbia, MO 65211 USA. Univ Wisconsin, Dept Med, Inst Aging, Madison, WI 53792 USA. Univ Wisconsin, Dept Med, Ctr Comprehens Canc, Madison, WI 53792 USA. William S Middleton Mem Vet Adm Hosp, Madison, WI 53792 USA. RP Schatten, H (reprint author), Univ Missouri, Dept Vet Pathobiol, 1600 E Rollins St, Columbia, MO 65211 USA. NR 40 TC 28 Z9 28 U1 0 U2 2 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 0248-4900 J9 BIOL CELL JI Biol. Cell PD AUG PY 2000 VL 92 IS 5 BP 331 EP 340 DI 10.1016/S0248-4900(00)01079-0 PG 10 WC Cell Biology SC Cell Biology GA 370AY UT WOS:000165101000003 PM 11071042 ER PT J AU Shioda, T AF Shioda, T TI Estimation of Baculovirus titer by beta-galactosidase activity assay of virus preparations SO BIOTECHNIQUES LA English DT Article C1 Massachusetts Gen Hosp, Ctr Canc, Dept Tumor Biol, Charlestown, MA 02129 USA. RP Shioda, T (reprint author), Massachusetts Gen Hosp, Ctr Canc, Dept Tumor Biol, Bldg 149,7th Floor,13th St, Charlestown, MA 02129 USA. NR 6 TC 0 Z9 0 U1 0 U2 1 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD AUG PY 2000 VL 29 IS 2 BP 214 EP 215 PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343AK UT WOS:000088679400009 ER PT J AU Mitsuyasu, RT Anton, PA Deeks, SG Scadden, DT Connick, E Downs, MT Bakker, A Roberts, MR June, CH Jalali, S Lin, AA Pennathur-Das, R Hege, KM AF Mitsuyasu, RT Anton, PA Deeks, SG Scadden, DT Connick, E Downs, MT Bakker, A Roberts, MR June, CH Jalali, S Lin, AA Pennathur-Das, R Hege, KM TI Prolonged survival and tissue trafficking following adoptive transfer of CD4 zeta gene-modified autologous CD4(+) and CD8(+) T cells in human immunodeficiency virus-infected subjects SO BLOOD LA English DT Article ID EPSTEIN-BARR-VIRUS; ALLOGENEIC BONE-MARROW; CLASS-I MOLECULES; HIV-1 INFECTION; LYMPHOCYTE RESPONSES; DISEASE PROGRESSION; CD28 COSTIMULATION; VIRAL REPLICATION; VIVO; IMMUNITY AB We have genetically engineered CD4(+) acid CD8(+) T cells with human immunodeficiency Virus (HIV) specificity by Inserting a gene, CD4 zeta, containing the extracellular domain of human CD4 (which binds HIV env) linked to the zeta (zeta) chain of the T-cell receptor (which mediates T-cell activation), Twenty-four HIV-positive subjects received a single infusion of 2 to 3 x 10(10) autologous CD4 zeta-modified CD4(+) and CD8+ T cells administered with (n = II) or without (n = 13) Interleukin-2 (IL-2), Subjects had CD4 counts greater than 50/mu L and viral loads of at least 1000 copies/ml at entry. T cells were costimulated ex vivo through CD3 and CD28 and expanded for approximately 2 weeks, CD4 zeta was detected in 1% to 3% of blood mononuclear cells at 8 weeks and 0.1% at 1 year after infusion, and survival was not enhanced by IL-2. Trafficking of gene-modified T cells to bulk rectal tissue and/or isolated lamina propria lymphocytes was documented in a subset of 5 of 5 patients at 14 days and 2 of 3 at 1 year. A greater than 0.5 log mean decrease in rectal tissue-associated HIV RNA was observed for at least Iri days, suggesting compartmental antiviral activity of CD4 zeta T cells. CD4+ counts increased by 73/mu L at 8 weeks in the group receiving IL-2, There was no significant mean change in plasma HIV RNA or blood proviral DNA in either treatment arm. This sustained, high-level persistence of gene-modified T cells demonstrates the feasibility of ex vivo T-cell gene therapy in HIV-infected adults and suggests the importance of providing HIV-specific T-helper function. (C) 2000 by The American Society of Hematology. C1 Cell Genesys Inc, Foster City, CA 94404 USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. San Francisco Gen Hosp, San Francisco, CA 94110 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. Stat Collaborat, Washington, DC USA. Specialty Labs, Los Angeles, CA USA. Univ Virginia, Charlottesville, VA 22903 USA. Univ Penn, Philadelphia, PA 19104 USA. RP Hege, KM (reprint author), Cell Genesys Inc, 342 Lakeside Dr, Foster City, CA 94404 USA. FU NCRR NIH HHS [5-MO1-RR00083-37, RR-00865]; NIAID NIH HHS [AI28697] NR 46 TC 206 Z9 214 U1 1 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2000 VL 96 IS 3 BP 785 EP 793 PG 9 WC Hematology SC Hematology GA 337ZQ UT WOS:000088394000001 PM 10910888 ER PT J AU Heinrich, MC Griffith, DJ Druker, BJ Wait, CL Ott, KA Zigler, AJ AF Heinrich, MC Griffith, DJ Druker, BJ Wait, CL Ott, KA Zigler, AJ TI Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor SO BLOOD LA English DT Article ID STEM-CELL FACTOR; GASTROINTESTINAL STROMAL TUMORS; COLONY-STIMULATING FACTOR; BLOOD MONONUCLEAR-CELLS; BONE-MARROW CELLS; WS/WS MUTANT RATS; LUNG-CANCER; GRANULOCYTE-MACROPHAGE; INTERSTITIAL-CELLS; PROTEIN-KINASE AB STI 571 (formerly known as CGP 57148B) is a known inhibitor of the c-abl, bcr-abl, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases, This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia, We sought to extend the activity profile of STI 571 by testing its ability to inhibit the tyrosine kinase activity of c-kit, a receptor structurally similar to PDGFR, We treated a c-kit expressing a human myeloid leukemia cell line, M-07e, with ST1571 before stimulation with Steel factor (SLF). ST1571 inhibited c-kit auto-phosphorylation, activation of mitogen-activated protein (MAP) kinase, and activation of Akt without altering total protein levels of c-kit, MAP kinase, or Akt, The concentration that produced 50% inhibition for these effects was approximately 100 nmol/L, STI 571 also significantly decreased SLF-dependent growth of M-07e cells in a dose-dependent manner and blocked the antiapoptotic activity of SLF, In contrast, the compound had no effect on MAP kinase activation or cellular proliferation in response to granulocyte-macrophage colony-stimulating factor. We also tested the activity of STI 571 in a human mast cell leukemia cell line (HMC-1), which has an activated mutant form of c-kit, STI 571 had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand-dependent activation of the wildtype receptor. These findings show that STI 571 selectively inhibits c-kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival. This compound may be useful in treating cancers associated with increased c-kit kinase activity. (C) 2000 by The American Society of Hematology. C1 Oregon Hlth Sci Univ, Dept Med, Div Hematol & Med Oncol, Portland, OR 97201 USA. Portland Vet Affairs Med Ctr, Portland, OR USA. RP Heinrich, MC (reprint author), R&D 19, 3710 SW US Vet Hosp Rd, Portland, OR 97207 USA. NR 77 TC 718 Z9 752 U1 3 U2 24 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2000 VL 96 IS 3 BP 925 EP 932 PG 8 WC Hematology SC Hematology GA 337ZQ UT WOS:000088394000021 PM 10910906 ER PT J AU Trimble, LA Kam, LW Friedman, RS Xu, Z Lieberman, J AF Trimble, LA Kam, LW Friedman, RS Xu, Z Lieberman, J TI CD3 zeta and CD28 down-modulation on CD8 T cells during viral infection SO BLOOD LA English DT Article ID SIGNAL-TRANSDUCTION MOLECULES; CYTOTOXIC LYMPHOCYTES-T; RECEPTOR ZETA-CHAIN; IN-VIVO; MEDIATED CYTOTOXICITY; IMMUNOLOGICAL MEMORY; HIV-INFECTION; EXPRESSION; COMPLEX; DISEASE AB Down-modulation of CD3 zeta expression on CD8 T lymphocytes occurs, independently of other T-cell receptor (TCR)-CD3 components, in tumor-infiltrating lymphocytes, human immunodeficiency virus infection, and autoimmune disease. These associations suggest that it might be related to chronic antigenic stimulation. CD3 zeta down-modulation was found, however, in CD8 T cells that in response to acute viral infections. In 3 otherwise healthy donors with acute gastroenteritis, infectious mononucleosis, and Epstein-Barr virus/cytomegalovirus/mononucleosis, 30% to 60% of circulating CD8 T cells had down-modulated CD3 zeta to below the level of detection. The CD3 zeta-T cells were also CD28- but expressed the activation markers HLA-DR and CD57. CD3 zeta-CD28-T cells are effector CTL because they express perforin and produce IFN-gamma, but not IL-2, on activation and contain the viral-specific cytotoxic T lymphocyte (CTL). However, CD35-CD28-T cells generally do not express CD25 after anti-CD3 and anti-CD28 stimulation and are not cytotoxic until they are cultured with IL-2 overnight. Cytotoxicity coincides with the re-expression of CD3 zeta but not CD28, Downmodulation of CD3 zeta acid CD28 on effector CTL may control CTL triggering and proliferation to prevent immunopathogenesis. (C) 2000 by The American Society of Hematology. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. RP Lieberman, J (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. RI Lieberman, Judy/A-2717-2015 FU NIAID NIH HHS [AI42519, AI45406] NR 42 TC 52 Z9 53 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 AUG 1 PY 2000 VL 96 IS 3 BP 1021 EP 1029 PG 9 WC Hematology SC Hematology GA 337ZQ UT WOS:000088394000034 PM 10910918 ER PT J AU Nikolic, B Zhao, G Swenson, K Sykes, M AF Nikolic, B Zhao, G Swenson, K Sykes, M TI A novel application of cyclosporine A in nonmyeloablative pretransplant host conditioning for allogeneic BMT SO BLOOD LA English DT Article ID BONE-MARROW TRANSPLANTATION; TOTAL LYMPHOID IRRADIATION; ANTIBODY MAB INJECTIONS; WHOLE-BODY IRRADIATION; T CELL MABS; MONOCLONAL-ANTIBODIES; NEGATIVE SELECTION; MIXED CHIMERISM; THYMIC IRRADIATION; CLONAL DELETION AB The treatment of mice with anti-CD4 and anti-CD8 monoclonal antibodies (mAbs) on day -5, plus 3 Gy whole body irradiation (WBI) and 7 Gy thymic irradiation (TI) on day 0, allows fully major-histocompatibility-complex-mismatched allogeneic bone marrow engraftment and the induction of immunologic tolerance. TI is required in this model to overcome alloreactivity and possibly to make "space" in the recipient thymus so that lasting central tolerance can be achieved. In addition to suppressing mature T cells in the periphery, Cyclosporine A (CYA) and glucocorticoids have a powerful influence on the thymus, In this study, we evaluated whether the administration of CYA to recipient mice for 12 days prior to bone marrow transplant (BMT), of glucocorticosteroids on the day of BMT, or a combination of both, could create space and overcome alloresistance in the thymus by specifically depleting immature and mature thymocytes prior to BMT. High levels of multilineage donor hematopoietic repopulation and specific transplantation tolerance were achieved in mice treated from days -15 to -3 with CYA (20 mg/kg/d subcutaneously), anti-CD4/CD8 mAbs on day -5, followed by 3 Gy WBI and 15 x 10(6) allogeneic bone marrow cells on day 0, VP analysis suggested a central deletional tolerance mechanism. The same treatment without CYA pretreatment allowed only transient chimerism, without tolerance. Corticosteroid treatment abolished the engraftment-promoting and tolerance-inducing effects of CYA, These results demonstrate a novel pretransplantation-only application of CYA, which facilitates allogeneic marrow engraftment with minimal conditioning, by creating thymic space and/or overcoming intrathymic alloresistance. (C) 2000 by The American Society of Hematology. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med,Transplantat Biol Res Ctr, Bone Marrow Transplantat Sect,Surg Serv, Boston, MA 02129 USA. RP Sykes, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Transplantat Biol Res Ctr, Bone Marrow Transplantat Sect,Surg Serv, MGH E,Bldg 149-5102,13th St, Boston, MA 02129 USA. FU NHLBI NIH HHS [R0I HL49915] NR 36 TC 23 Z9 23 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2000 VL 96 IS 3 BP 1166 EP 1172 PG 7 WC Hematology SC Hematology GA 337ZQ UT WOS:000088394000054 PM 10910938 ER PT J AU Burstein, R Cutrer, MF Yarnitsky, D AF Burstein, R Cutrer, MF Yarnitsky, D TI Tbe development of cutaneous allodynia during a migraine attack - Clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine SO BRAIN LA English DT Article DE migraine; headache; allodynia; sensitization; pain ID STEM TRIGEMINAL NEURONS; MUSCLE TENDERNESS; COMMON MIGRAINE; SECONDARY HYPERALGESIA; CHEMICAL-STIMULATION; PAIN THRESHOLDS; HEADACHE; SENSITIVITY; RESPONSES; RAT AB Recently, we showed that most migraine patients exhibit cutaneous allodynia inside and outside their pain-referred areas when examined during a fully developed migraine attack. In this report, we studied the way in which cutaneous allodynia develops by measuring the pain thresholds in the head and forearms bilaterally at several time points during a migraine attack in a 42-year-old male. Prior to the headache, he experienced visual, sensory, motor and speech aura. During the headache, he experienced photo-, phono- and odour-phobia, nausea and vomiting, worsening of the headache by coughing or moving his head, and cutaneous pain when shaving, combing his hair or touching his scalp. Comparisons between his pain thresholds in the absence of migraine and at 1, 2 and 4 h after the onset of migraine revealed the following. (i) After 1 h, mechanical and cold allodynia started to develop in the ipsilateral head but not in any other site. (ii) After 2 h, this allodynia increased on the ipsilateral head and spread to the contralateral head and ipsilateral forearm, (iii) After 4 h, heat allodynia was also detected while mechanical and cold allodynia continued to increase. These clinical observations suggest the following sequence of events along the trigeminovascular pain pathway of this patient. (i) A few minutes after the initial activation of his peripheral nociceptors, they became sensitized; this sensitization can mediate the symptoms of intracranial hypersensitivity. (ii) The barrage of impulses that came from the peripheral nociceptors activated second-order neurons and initiated their sensitization; this sensitization can mediate the development of cutaneous allodynia on the ipsilateral head. (iii) The barrage of impulses that came from the sensitized second-order neurons activated and eventually sensitized third-order neurons; this sensitization can mediate the development of cutaneous allodynia on the contralateral head and ipsilateral forearm at the 2-h point, over 1 h after the appearance of allodynia on the ipsilateral head. This interpretation calls for an early use of anti-migraine drugs that target peripheral nociceptors, before the development of central sensitization. If central sensitization develops, the therapeutic rationale is to suppress it. Because currently available drugs that aim to suppress central sensitization are ineffective, this study stresses the need to develop them for the treatment of migraine. C1 Beth Israel Deaconess Med Ctr, Dept Anesthesia & Crit Care, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA. RP Burstein, R (reprint author), Harvard Inst Med, Dept Anesthesia & Crit Care, Room 830,77 Ave Louis Pasteur, Boston, MA 02115 USA. FU NIDCR NIH HHS [DE-10904]; NINDS NIH HHS [NS-35611-01] NR 38 TC 429 Z9 435 U1 0 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD AUG PY 2000 VL 123 BP 1703 EP 1709 DI 10.1093/brain/123.8.1703 PN 8 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 351EG UT WOS:000089144400015 PM 10908199 ER PT J AU Carbo, N Lopez-Soriano, J Costelli, P Busquets, S Alvarez, B Baccino, FM Quinn, LS Lopez-Soriano, FJ Argiles, JM AF Carbo, N. Lopez-Soriano, J. Costelli, P. Busquets, S. Alvarez, B. Baccino, F. M. Quinn, L. S. Lopez-Soriano, F. J. Argiles, J. M. TI Interleukin-15 antagonizes muscle protein waste in tumour-bearing rats SO BRITISH JOURNAL OF CANCER LA English DT Article DE IL-15; cancer cachexia; protein turnover; skeletal muscle; proteasome; ubiquitin AB Tissue protein hypercatabolism (TPH) is an important feature in cancer cachexia, particularly with regard to the skeletal muscle. The Yoshida AH-130 rat ascites hepatoma is a model system for studying the mechanisms involved in the processes that lead to tissue depletion, since it induces in the host a rapid and progressive muscle wasting, primarily due to TPH. The present study was aimed at investigating if IL-15, which is known to favour muscle fibre hypertrophy, could antagonize the enhanced muscle protein breakdown in this cancer cachexia model. Indeed, IL-15 treatment partly inhibited skeletal muscle wasting in AH-130-bearing rats by decreasing (8-fold) protein degradative rates (as measured by C-14-bicarbonate pre-loading of muscle proteins) to values even lower than those observed in non-tumour bearing animals. These alterations in protein breakdown rates were associated with an inhibition of the ATP-ubiquitin-dependent proteolytic pathway (35% and 41% for 2.4 and 1.2 kb ubiquitin mRNA, and 57% for the C8 proteasome subunit, respectively). The cytokine did not modify the plasma levels of corticosterone and insulin in the tumour hosts. The present data give new insights into the mechanisms by which IL-15 exerts its preventive effect on muscle protein wasting and seem to warrant the implementation of experimental protocols involving the use of the cytokine in the treatment of pathological states characterized by TPH, particularly in skeletal muscle, such as in the present model of cancer cachexia. (C) 2000 Cancer Research Campaign C1 [Carbo, N.; Lopez-Soriano, J.; Busquets, S.; Alvarez, B.; Lopez-Soriano, F. J.; Argiles, J. M.] Univ Barcelona, Fac Biol, Dept Bioquim & Biol Mol, Diagonal 645, E-08071 Barcelona, Spain. [Costelli, P.; Baccino, F. M.] Univ Turin, Dipartimento Med & Oncol Sperimentale, Turin, Italy. [Baccino, F. M.] Ctr CNR Immunogenet & Oncol Sperimentale, Turin, Italy. [Quinn, L. S.] 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, Diagonal 645, E-08071 Barcelona, Spain. OI Busquets, Silvia/0000-0002-9319-3555 FU Fondo de Investigaciones Sanitarias de la Seguridad Social of the Spanish Health Ministry [97/2059]; Direccion General de Investigacion Cientifica y Tecnica from the Spanish Ministry of Education and Science [PB94-0938, HI-1996-0049]; Ministero dell'Universita e della Ricerca Scientifica e Tecnologica, Roma; Consiglio Nazionale delle Ricerche (Special Project ACRO), Roma; Associazione Italiana per la Ricerca sul Cancro, Milano FX Work supported by grants from the Fondo de Investigaciones Sanitarias de la Seguridad Social (97/2059) of the Spanish Health Ministry, the Direccion General de Investigacion Cientifica y Tecnica (PB94-0938 and HI-1996-0049) from the Spanish Ministry of Education and Science, the Ministero dell'Universita e della Ricerca Scientifica e Tecnologica (60% and 40% funds), Roma, the Consiglio Nazionale delle Ricerche (Special Project ACRO), Roma, the Associazione Italiana per la Ricerca sul Cancro, Milano. The authors would like to thank Immunex Corporation (Seattle, WA, USA), which kindly provided IL-15, and Dr MJ Schlesinger and Dr K Tanaka for providing the ubiquitin-specific and proteasome C8 probes, respectively. NR 54 TC 92 Z9 98 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD AUG PY 2000 VL 83 IS 4 BP 526 EP 531 DI 10.1054/bjoc.2000.1299 PG 6 WC Oncology SC Oncology GA V42ZR UT WOS:000209652200019 PM 10945502 ER PT J AU Fisher, CM AF Fisher, CM TI Alien hand phenomena: A review with the addition of six personal cases SO CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES LA English DT Article ID ARTERY TERRITORY INFARCTION; SUPPLEMENTARY MOTOR AREA; CORTICOBASAL DEGENERATION; DISCONNECTION SYNDROME; CALLOSAL-DISCONNECTION; CORPUS-CALLOSUM; APRAXIA; SIGN; DISORDERS; DYSPRAXIA AB This is a comprehensive literature review of the motor abnormalities that have come to be included under the designation of Alien Hand Phenomena (AHP). Some of the disorders are dyspractic in nature - intermanual conflict, mirror movements, interference etc., while others - groping, grasping with inability to release, utilization etc, are frontal lobe reflexes. AHP are mainly associated with two pathological processes: if Infarction or hemorrhage in the territory of the anterior cerebral arteries; and 2) Corticobasal degeneration. included in the review is a description of AHP in six personal cases of corticobasal degeneration. The summary includes a short discussion of the possible anatomy of 'free will' based on AHP. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurol Serv, Boston, MA 02114 USA. RP Fisher, CM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurol Serv, Fruit St, Boston, MA 02114 USA. NR 61 TC 42 Z9 43 U1 1 U2 10 PU CANADIAN J NEUROL SCI INC PI CALGARY PA PO BOX 4220, STATION C EDITORIAL & SUBSCRIPTION SERV, CALGARY, AB T2T 5N1, CANADA SN 0317-1671 J9 CAN J NEUROL SCI JI Can. J. Neurol. Sci. PD AUG PY 2000 VL 27 IS 3 BP 192 EP 203 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA 346JJ UT WOS:000088867000003 PM 10975531 ER PT J AU Mandelblatt, JS Hadley, J Kerner, JF Schulman, KA Gold, K Dunmore-Griffith, J Edge, S Guadagnoli, E Lynch, JJ Meropol, NJ Weeks, JC Winn, R AF Mandelblatt, JS Hadley, J Kerner, JF Schulman, KA Gold, K Dunmore-Griffith, J Edge, S Guadagnoli, E Lynch, JJ Meropol, NJ Weeks, JC Winn, R CA Outcomes Preferences Treatment O TI Patterns of breast carcinoma treatment in older women - Patient preference and clinical and physician influences SO CANCER LA English DT Article DE breast carcinoma; elderly; treatment; patterns of care ID CANCER-PATIENTS; CONSERVING SURGERY; RADIATION-THERAPY; TREATMENT CHOICE; ELDERLY PATIENTS; FOLLOW-UP; STAGE; CARE; AGE; SURVIVAL AB BACKGROUND. Older women have high rates of breast carcinoma, and there are substantial variations in the patterns of care for this population group. METHODS. The authors studied 718 breast carcinoma patients age 67 years and older who were diagnosed with localized disease between 1995 and 1997 from 29 hospitals in 5 regions. Data were collected from patients, charts, and surgeons. Logistic regression analysis was used to evaluate determinants of treatment. RESULTS. Women who were: concerned about body image were 1.8 times more likely (95% confidence interval [95% CI], 1.1-2.8) to receive breast conservation surgery and radiotherapy than women without this preference, controlling for other factors. In contrast, women who preferred receiving no therapy beyond surgery were 3.9 times more likely (95% CI, 2.9-6.1) to undergo mastectomy than other women, after considering other factors. Radiotherapy was omitted after breast conservation 3.4 times more often (95% CI, 2.0-5.6) among women age 80 years and older than among women ages 67-79 years, controlling for covariates. Black women tended to have radiotherapy omitted after breast conservation surgery 2.0 times more often (95% CI, 0.9-4.4) than white women (P = 0.09). Women age 80 years and older also were 70% less likely (odds ratio = 0.3; 95% CI, 0.1-0.8) to receive chemotherapy than women ages 67-79 years, controlling for health, functional status, and other covariates. CONCLUSIONS. After considering other factors, patient preferences and age were found to be associated with breast carcinoma treatment patterns in older women. Further research and training are needed to provide care for the growing population of older women that is both clinically appropriate and consonant with a woman's preferences. (C) 2000 American Cancer Society. C1 Georgetown Univ, Sch Med, Lombardi Canc Ctr, Dept Oncol, Washington, DC 20007 USA. Georgetown Univ, Sch Med, Lombardi Canc Ctr, Dept Med, Washington, DC 20007 USA. Georgetown Univ, Sch Med, Inst Hlth Care Policy & Res, Washington, DC USA. Duke Univ, Sch Med, Med Ctr, Duke Clin Res Inst,Ctr Clin & Genet Econ, Durham, NC USA. Georgetown Univ, Sch Med, Dept Biostat & Biomath, Bethesda, MD USA. Howard Univ, Med Ctr, Dept Radiat Oncol, Washington, DC 20059 USA. Howard Univ, Ctr Canc, Washington, DC 20059 USA. Roswell Pk Canc Inst, Dept Surg, Buffalo, NY 14263 USA. Harvard Univ, Sch Med, Dept Hlth Policy, Boston, MA USA. Washington Hosp Ctr, Inst Canc, Washington, DC 20010 USA. Fox Chase Canc Ctr, Div Med Sci, Philadelphia, PA 19111 USA. Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. Univ Texas, MD Anderson Canc Ctr, Dept Med, Houston, TX 77030 USA. RP Mandelblatt, JS (reprint author), Georgetown Univ, Sch Med, Lombardi Canc Ctr, Dept Oncol, 2233 Wisconsin Ave NW,Suite 440, Washington, DC 20007 USA. FU AHRQ HHS [R01HS08395] NR 60 TC 207 Z9 207 U1 0 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD AUG 1 PY 2000 VL 89 IS 3 BP 561 EP 573 DI 10.1002/1097-0142(20000801)89:3<561::AID-CNCR11>3.0.CO;2-A PG 13 WC Oncology SC Oncology GA 340HN UT WOS:000088527200011 PM 10931455 ER PT J AU Nakase, K Ishimaru, F Avitahl, N Dansako, H Matsuo, K Fujii, K Sezaki, N Nakayama, H Yano, T Fukuda, S Imajoh, K Takeuchi, M Miyata, A Hara, M Yasukawa, M Takahashi, I Taguchi, H Matsue, K Nakao, S Niho, Y Takenaka, K Shinagawa, K Ikeda, K Niiya, K Harada, M AF Nakase, K Ishimaru, F Avitahl, N Dansako, H Matsuo, K Fujii, K Sezaki, N Nakayama, H Yano, T Fukuda, S Imajoh, K Takeuchi, M Miyata, A Hara, M Yasukawa, M Takahashi, I Taguchi, H Matsue, K Nakao, S Niho, Y Takenaka, K Shinagawa, K Ikeda, K Niiya, K Harada, M TI Dominant negative isoform of the Ikaros gene in patients with adult B-cell acute lymphoblastic leukemia SO CANCER RESEARCH LA English DT Article ID DNA-BINDING PROTEINS; TRANSCRIPTION FACTOR; EXPRESSION; MUTATION; PARTNER; HELIOS; FAMILY; AIOLOS AB Gene targeting studies in mice have shown that the transcription factor Ikaros plays an essential role in lymphoid development and as a tumor suppressor in T cells, whereas the related gene Aiolos functions as a tumor suppressor in B cells. We analyzed the expression levels of the Ikaros gene family, Ikaros and Aiolos, in human bone marrow samples from patients with adult acute lymphoblastic leukemia [ALL (n = 46; B-cell ALL = 41; T-cell ALL = 5)]. Overexpression of the dominant negative isoform of Ikaros gene Ik-6 was observed in 14 of 41 B-cell ALL patients by reverse transcription-PCR, and the results were confirmed by sequencing analysis and immunoblotting, None of the other dominant negative isoforms of the Ikaros gene were detected by reverse transcription-PCR analysis, Southern blotting analysis with PstI digestion revealed that those patients with the dominant negative isoform Ik-6 might have small mutations in the Ikaros locus. We did not detect any overexpression of dominant negative isoforms of Aiolos in adult ALL patients. These results suggest that Ikaros plays a key role in human B-cell malignancies through the dominant negative Isoform Ik-6. C1 Okayama Univ, Dept Med, Okayama 7008558, Japan. Okayama Rousai Hosp, Okayama 7008558, Japan. Natl Okayama Hosp, Okayama 7008558, Japan. Okayama Municipal Hosp, Okayama 7008558, Japan. Natl Sanat Minami Okayama Hosp, Okayama 7008558, Japan. Mutual Aid Assoc Publ Sch Teachers, Chugoku Cent Hosp, Fukuyama, Hiroshima 7210975, Japan. Ehime Univ, Dept Med, Matsuyama, Ehime 7910295, Japan. Kochi Municipal Cent Hosp, Kochi 7838505, Japan. Kochi Med Sch, Dept Med, Kochi 7838505, Japan. Kameda Gen Hosp, Kamogawa 2960041, Japan. Kanazawa Univ, Dept Med, Kanazawa, Ishikawa 9208641, Japan. Kyushu Univ, Dept Med, Fukuoka 8128582, Japan. Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. RP Ishimaru, F (reprint author), Okayama Univ, Dept Med, 2-5-1 Shikatacho, Okayama 7008558, Japan. OI Matsuo, Keitaro/0000-0003-1761-6314 NR 20 TC 71 Z9 76 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 AUG 1 PY 2000 VL 60 IS 15 BP 4062 EP 4065 PG 4 WC Oncology SC Oncology GA 342BQ UT WOS:000088625700016 PM 10945610 ER PT J AU Mitsiades, N Poulaki, V Tseleni-Balafouta, S Koutras, DA Stamenkovic, I AF Mitsiades, N Poulaki, V Tseleni-Balafouta, S Koutras, DA Stamenkovic, I TI Thyroid carcinoma cells are resistant to FAS-mediated apoptosis but sensitive to tumor necrosis factor-related apoptosis-inducing ligand SO CANCER RESEARCH LA English DT Article ID FLICE-INHIBITORY PROTEIN; TRAIL-INDUCED APOPTOSIS; HASHIMOTOS-THYROIDITIS; FOLLICULAR CELLS; DEATH DOMAIN; IMMUNE EVASION; IN-VIVO; RECEPTOR; EXPRESSION; FAMILY AB Fas (APO-1/CD95) is a transmembrane protein of the tumor necrosis factor (TNF)/nerve growth factor receptor superfamily that induces apoptosis in susceptible normal and neoplastic cells upon cross-linking by its ligand (FasL). TNF-related apoptosis-inducing ligand (TRAIL) is a more recently identified member of the TNF superfamily that has been shown to selectively kill neoplastic cells by engaging two cell-surface receptors, DR4 and DR5. Two additional TRAIL receptors (DcR1 and DcR2) do not transmit an apoptotic signal and have been proposed to confer protection from TRAIL-induced apoptosis. We addressed the expression of Fas, DR4, and DR5 in thyroid carcinoma cell lines and in 31 thyroid carcinoma specimens by Western blot analysis and immunohistochemistry, respectively, and tested the sensitivity of thyroid carcinoma cell lines to Fas- and TRAIL-induced apoptosis. Fas was found to be expressed in most thyroid carcinoma cell lines and tissue specimens. Although cross-linking of Fas did not induce apoptosis in thyroid carcinoma cell lines, Fas-mediated apoptosis did occur in the presence of the protein synthesis inhibitor cycloheximide, suggesting the presence of a short-hived inhibitor of the Fas pathway in these cells. Cross-linking of Pas failed to induce recruitment and activation of caspase 8, whereas transfection of a constitutively active caspase 8 construct effectively killed the SW579 papillary carcinoma cell line, arguing that the action of the putative inhibitor occurs upstream of caspase 8. By contrast, recombinant TRAIL induced apoptosis in 10 of 12 thyroid carcinoma cell lines tested, by activating caspase-10 at the receptor level and triggering a caspase-mediated apoptotic cascade. Resistance to TRAIL did not correlate with DcR1 or DcR2 protein expression and was overcome by protein synthesis inhibition in 50% of the resistant cell lines. One medullary carcinoma cell line was resistant to Fas- and TRAIL-induced apoptosis, even in the presence of cycloheximide, and to transfection of constitutively active caspase-8, suggesting a different regulation of the apoptotic pathway. Our observations indicate that TRAIL effectively kills carcinomas that originate from the follicular epithelium of the thyroid gland, by inducing caspase-mediated apoptosis, and may provide a potentially potent therapeutic reagent against thyroid cancer. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. Evgenid Hosp, Endocrine Unit, Athens, Greece. NCI, Sect Pediat Tumor Biol & Ultrastruct Pathol, Pathol Lab, NIH, Bethesda, MD 20892 USA. Univ Athens, Dept Pathol, Athens, Greece. RP Mitsiades, N (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Mayer Bldg,Room M557,44 Binney St, Boston, MA 02115 USA. FU NIGMS NIH HHS [GM54176] NR 57 TC 84 Z9 96 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 AUG 1 PY 2000 VL 60 IS 15 BP 4122 EP 4129 PG 8 WC Oncology SC Oncology GA 342BQ UT WOS:000088625700025 PM 10945619 ER PT J AU Del Governatore, M Hamblin, MR Shea, CR Rizvi, I Molpus, KG Tanabe, KK Hasan, T AF Del Governatore, M Hamblin, MR Shea, CR Rizvi, I Molpus, KG Tanabe, KK Hasan, T TI Experimental photoimmunotherapy of hepatic metastases of colorectal cancer with a 17.1A chlorin(e6) immunoconjugate SO CANCER RESEARCH LA English DT Article ID INTERSTITIAL PHOTODYNAMIC THERAPY; OVARIAN-CANCER; MONOCLONAL-ANTIBODY; LIVER METASTASES; FLUENCE RATE; IN-VIVO; MODEL; TUMOR; BIODISTRIBUTION; CARCINOMA AB Photoimmunotherapy (using a monoclonal antibody-targeted photosensitizer and red light) may be a strategy to overcome the Limitations inherent in photodynamic therapy of liver tumors. The aims of this study were (a) to test the efficacy of selective treatment of hepatic metastases of colorectal cancer in an orthotopic murine xenograft using the murine monoclonal antibody 17.1A conjugated to the photosensitizer chlorin(e6), and (b) to compare the tumor response after the same light dose was delivered at two different fluence rates. Based on previous biodistribution studies that had shown that the photoimmunoconjugate with a polyanionic charge had both a higher absolute tumor chlorin(e6) content and a greater tumor:normal liver ratio than those obtained with a photoimmunoconjugate bearing a polycationic charge, mice were treated 3 h after i.v. injection of the polyanionic 17.1A chlorin(e6) conjugate or unconjugated photosensitizer. Red light was delivered into the liver tumor by an interstitial fiber, and tumor response end points were total tumor weight in the short term and survival in the long term. There was a highly significant reduction (<20% of controls; P = 0.0035) in the weight of the tumors in the mice treated with photoimmunotherapy, and the median survival increased from 62.5 to 102 days (P = 0.015). Photodynamic therapy with free chlorin(e6) produced a smaller decrease in tumor weight and a smaller extension of survival, neither of which were statistically significant. A comparison of photoimmunotherapy with 10 J of light delivered at 30 or 300 mW showed that the higher fluence rate prolonged survival significantly more than the Lower fluence rate. This may have been because the high fluence rate gave a contribution of laser-induced hyperthermia to the photodamage. Correlation studies showed that the amount of normal liver remaining at necropsy correlated best with survival. Photoimmunotherapy shows efficacy in destroying liver tumors, and future studies should maximize selectivity to minimize the destruction of normal liver. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatol,Wellman Labs Photomed, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Vincent Mem Obstet & Gynecol Serv,Div Gynecol Onc, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg Oncol, Boston, MA 02114 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Med Dermatol, Durham, NC 27710 USA. RP Hasan, T (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatol,Wellman Labs Photomed, WEL 224,55 Fruit St, Boston, MA 02114 USA. OI Rizvi, Imran/0000-0001-9673-4700; Hamblin, Michael/0000-0001-6431-4605 FU NIAMS NIH HHS [R01 AR40352] NR 41 TC 53 Z9 55 U1 1 U2 4 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 AUG 1 PY 2000 VL 60 IS 15 BP 4200 EP 4205 PG 6 WC Oncology SC Oncology GA 342BQ UT WOS:000088625700036 PM 10945630 ER PT J AU Ropiquet, F Giri, D Kwabi-Addo, B Mansukhani, A Ittmann, M AF Ropiquet, F Giri, D Kwabi-Addo, B Mansukhani, A Ittmann, M TI Increased expression of fibroblast growth factor 6 in human prostatic intraepithelial neoplasia and prostate cancer SO CANCER RESEARCH LA English DT Article ID HUMAN BREAST-CANCER; FACTOR RECEPTOR-4; EPITHELIAL-CELLS; OVER-EXPRESSION; FGF RECEPTORS; FAMILY; AUTOCRINE; INVASION; LINES AB Fibroblast growth factors (FGFs) are known to play an important role in the growth of normal prostatic epithelial cells. In addition to their effects on proliferation, FGFs can promote cell motility, increase tumor angiogenesis, and inhibit apoptosis, all of which play an important role in tumor progression. To determine whether FGFs are overexpressed in human prostate cancers, we analyzed 26 prostate cancer RNAs by reverse transcription-PCR for expression of FGF3, FGF4, and FGF6, which cannot be detected in normal prostate tissue by this technique. Fourteen of 26 prostate cancers expressed FGF6 mRNA. No expression of FGF3 or FGF4 was detected. An ELISA of tissue extracts of normal prostate, high-grade prostatic intraepithelial neoplasia (PIN), and prostate cancer for FGF6 showed that this growth factor was undetectable in normal prostate but was present at elevated levels in 4 of 9 PIN lesions and in 15 of 24 prostate cancers. Immunohistochemical analysis with anti-FGF6 antibody revealed weak staining of prostatic basal cells in normal prostate that was markedly elevated in PIN. In the prostate cancers, the majority of cases revealed expression of FGF6 by the prostate cancer cells themselves. In two cases, expression was present in prostatic stromal cells. Exogenous FGF6 was able to stimulate proliferation of primary prostatic epithelial and stromal cells, immortalized prostatic epithelial cells, and prostate cancer cell lines in tissue culture. FGF receptor 4, which is the most potent FGF receptor for FGF6, is expressed in the human prostate in vivo and in all of the cultured cell lines. Thus, FGF6 is increased in PIN and prostate cancer and can promote the proliferation of the transformed prostatic epithelial cells via paracrine and autocrine mechanisms. C1 Houston Vet Affairs Med Ctr, Res Serv, Houston, TX 77030 USA. Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. RP Ittmann, M (reprint author), Houston Vet Affairs Med Ctr, Res Serv, 2002 Holcombe Blvd, Houston, TX 77030 USA. RI Kwabi-Addo, Bernard/A-6993-2016 OI Kwabi-Addo, Bernard/0000-0003-3692-6350 NR 31 TC 58 Z9 61 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 AUG 1 PY 2000 VL 60 IS 15 BP 4245 EP 4250 PG 6 WC Oncology SC Oncology GA 342BQ UT WOS:000088625700043 PM 10945637 ER PT J AU Stohrer, M Boucher, Y Stangassinger, M Jain, RK AF Stohrer, M Boucher, Y Stangassinger, M Jain, RK TI Oncotic pressure in solid tumors is elevated SO CANCER RESEARCH LA English DT Article ID INTERSTITIAL FLUID PRESSURE; COLLOID OSMOTIC-PRESSURE; PROTEIN CONCENTRATION; HYPERTENSION; PLASMA; ANGIOGENESIS; XENOGRAFT; DELIVERY; ALBUMIN; DOG AB Oncotic and hydrostatic pressure differences control the movement of fluid and large molecules across the microvascular wall of normal and tumor tissues. Recent studies have shown that the interstitial fluid pressure in tumors is elevated and is approximately equal to the microvascular pressure. Whereas oncotic pressure in blood plasma of various species is known, no data are available on the oncotic pressure in the interstitial space of tumors. We hypothesize that because of the leaky nature of tumor vessels, oncotic pressure in tumor interstitium should be close to that in plasma. To this end, we first developed a chronic wick method for the direct measurement of oncotic pressures in the interstitial fluid of tumors grown in mice. We found interstitial oncotic pressures in four human tumor xenografts to be higher than in s.c. tissue and comparable to that in plasma [rhabdomyosarcoma (RD), 24.2 +/- 4.7; squamous cell carcinoma (FaDu), 19.9 +/- 1.9; small cell lung carcinoma (54A), 21.1 +/- 2.8; colon adenocarcinoma (LS174T), 16.7 +/- 3.0 mm Hg; s.c. tissue, 8.2 +/- 2.3; plasma, 20.0 +/- 1.6 mm Hg]. These results support our hypothesis that the oncotic pressure difference across the tumor microvascular wall is low. The high oncotic pressure in tumors is consistent with the elevated interstitial fluid pressure, and it contributes to the suboptimal delivery of large therapeutic agents to neoplastic cells. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Univ Munich, Inst Physiol Physiol Chem & Anim Nutr, D-80539 Munich, Germany. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Cox-7, Boston, MA 02114 USA. FU NCI NIH HHS [R35-CA-56591] NR 25 TC 169 Z9 174 U1 2 U2 14 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 AUG 1 PY 2000 VL 60 IS 15 BP 4251 EP 4255 PG 5 WC Oncology SC Oncology GA 342BQ UT WOS:000088625700044 PM 10945638 ER PT J AU Visioli, F Keaney, JF Halliwell, B AF Visioli, F Keaney, JF Halliwell, B TI Antioxidants and cardiovascular disease; panaceas or tonics for tired sheep? SO CARDIOVASCULAR RESEARCH LA English DT Editorial Material C1 Univ Milan, Inst Pharmacol Sci, I-20133 Milan, Italy. Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. VA Boston Hlth Care Syst, Boston, MA USA. Natl Univ Singapore, Dept Biochem, Singapore 119260, Singapore. RP Visioli, F (reprint author), Univ Milan, Inst Pharmacol Sci, Via Balzaretti 9, I-20133 Milan, Italy. RI Halliwell, Barry/C-8318-2009; Visioli, Francesco/J-9356-2013 OI Visioli, Francesco/0000-0002-1756-1723 NR 5 TC 37 Z9 38 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD AUG PY 2000 VL 47 IS 3 BP 409 EP 409 DI 10.1016/S0008-6363(00)00156-5 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 349QE UT WOS:000089056500001 PM 10963713 ER PT J AU Tomasian, D Keaney, JF Vita, JA AF Tomasian, D Keaney, JF Vita, JA TI Antioxidants and the bioactivity of endothelium-derived nitric oxide SO CARDIOVASCULAR RESEARCH LA English DT Review DE endothelial factors; endothelial function; free radicals; nitric oxide ID LOW-DENSITY-LIPOPROTEIN; CORONARY-ARTERY DISEASE; CHOLESTEROL-FED RABBITS; VASCULAR SMOOTH-MUSCLE; FOREARM RESISTANCE VESSELS; VITAMIN-E CONSUMPTION; DEPENDENT VASODILATION; L-ARGININE; RELAXING FACTOR; SUPEROXIDE-DISMUTASE C1 Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. VA Boston Hlth Care Syst, Boston, MA USA. Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02118 USA. RP Vita, JA (reprint author), Boston Med Ctr, 88 E Newton St, Boston, MA 02118 USA. FU NHLBI NIH HHS [HL52936, HL53398, HL55993] NR 141 TC 79 Z9 87 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD AUG PY 2000 VL 47 IS 3 BP 426 EP 435 DI 10.1016/S0008-6363(00)00103-6 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 349QE UT WOS:000089056500004 PM 10963716 ER PT J AU Husson, H Lugli, SM Ghia, P Cardoso, A Roth, A Brohmi, K Carideo, EG Choi, YS Browning, J Freedman, AS AF Husson, H Lugli, SM Ghia, P Cardoso, A Roth, A Brohmi, K Carideo, EG Choi, YS Browning, J Freedman, AS TI Functional effects of TNF and lymphotoxin alpha 1 beta 2 on FDC-like cells SO CELLULAR IMMUNOLOGY LA English DT Article DE follicular dendritic cells; TNF; lymphotoxin; chemokine; adhesion ID FOLLICULAR DENDRITIC CELLS; TUMOR-NECROSIS-FACTOR; CENTER B-CELLS; ADHESION MOLECULE-1 VCAM-1; ALPHA-DEFICIENT MICE; GERMINAL-CENTERS; CHEMOKINE RECEPTOR; ENDOTHELIAL-CELLS; LYMPHOID-TISSUE; DISTINCT ROLES AB Recent studies suggest that tumor necrosis factor (TNF) family members such as TNF alpha and lymphotoxin alpha beta (LT alpha 1 beta 2) are important in the development of follicular dendritic cells (FDCs) and maintenance of FDC function. In this study we used FDC-like cells (FDC-LC) cultured from normal human tonsil and investigated the effects of TNF and LT alpha 1 beta 2 on expression of adhesion molecules and the production of cytokines and chemokines. TNF and LT alpha 1 beta 2 both increased the expression of VCAM-1 and ICAM-1 on FDC-LC, In addition, IL-4 with LT alpha 1 beta 2 synergistically increased the expression of VCAM-1, but not ICAM-1, Cytokine IL-6 and IL-15 mRNAs were induced following stimulation with TNF and LT alpha 1 beta 2. These two cytokines were present in FDC-LC supernatants by ELISA and increased following TNF and LT alpha 1 beta 2 stimulation. We also examined FDC-LC for chemokines, which affect B cells, including IL-8, SDF-1, MIP3 beta/ELC, and BCA-1/BLC, SDF-1 mRNA and protein were expressed by FDC-LC, and following stimulation with TNF and LT alpha 1 beta 2, decreases in both were observed. Therefore, TNF and LT alpha 1 beta 2 which are produced by activated B cells, increased the expression of adhesion molecules and cytokines from FDC-LC, potentially providing key signals to support germinal center B cell survival and differentiation, (C) 2000 Academic Press. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Alton Ochsner Med Fdn & Ochsner Clin, Cellular Immunol Lab, New Orleans, LA 70121 USA. Biogen, Dept Cell Biol & Immunol, Cambridge, MA 02142 USA. RP Freedman, AS (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. RI Ghia, Paolo/K-7138-2016; OI Ghia, Paolo/0000-0003-3750-7342; Browning, Jeffrey/0000-0001-9168-5233 FU NCI NIH HHS [CA55207, CA66996] NR 64 TC 40 Z9 42 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0008-8749 J9 CELL IMMUNOL JI Cell. Immunol. PD AUG 1 PY 2000 VL 203 IS 2 BP 134 EP 143 DI 10.1006/cimm.2000.1688 PG 10 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 360YQ UT WOS:000089695300007 PM 11006011 ER PT J AU Wood, MW Jones, MA Watson, PR Siber, AM McCormick, BA Hedges, S Rosqvist, R Wallis, TS Galyov, EE AF Wood, MW Jones, MA Watson, PR Siber, AM McCormick, BA Hedges, S Rosqvist, R Wallis, TS Galyov, EE TI The secreted effector protein of Salmonella dublin, SopA, is translocated into eukaryotic cells and influences the induction of enteritis SO CELLULAR MICROBIOLOGY LA English DT Article ID INTESTINAL EPITHELIA; BACTERIAL ENTRY; TYPHIMURIUM; NEUTROPHILS; VIRULENCE; SYSTEM; ATTACHMENT; MECHANISM; MUTATION; CATTLE AB Salmonella-induced enteritis is associated with the induction of an acute intestinal inflammatory response and net fluid secretion into the lumen of infected mucosa. Proteins secreted by the Inv/Spa type III secretion system of Salmonella play a key role in the induction of these responses. We have demonstrated recently that the Inv/Spa-secreted SopB and SopD effector proteins are translocated into eukaryotic cells via a Sip-dependent pathway and act in concert to mediate inflammation and fluid secretion in infected ileal mucosa. Mutations of both sopB and sopD significantly reduced, but did not abrogate, the enteropathogenic phenotype, This indicated that other virulence factors are involved in the induction of enteritis. In this work, we characterize SopA, a secreted protein belonging to the family of Sop effecters of Salmonella dublin. We demonstrate that SopA is translocated into eukaryotic cells and provide evidence suggesting that SopA has a role in the induction of enteritis. C1 Inst Anim Hlth, Compton RG20 7NN, Berks, England. Massachusetts Gen Hosp, Dept Pediat Gastroenterol & Nutr, Charlestown, MA 02129 USA. Umea Univ, Dept Cell & Mol Biol, S-90187 Umea, Sweden. RP Galyov, EE (reprint author), Inst Anim Hlth, Compton RG20 7NN, Berks, England. RI Jones, Michael/G-9945-2011 FU NIDDK NIH HHS [DK-50989] NR 28 TC 76 Z9 80 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 1462-5814 J9 CELL MICROBIOL JI Cell Microbiol. PD AUG PY 2000 VL 2 IS 4 BP 293 EP 303 DI 10.1046/j.1462-5822.2000.00054.x PG 11 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 345GC UT WOS:000088807400004 PM 11207586 ER PT J AU Payne, TH AF Payne, TH TI Computer decision support systems SO CHEST LA English DT Article DE decision support systems, clinical; drug therapy, computer-assisted; hospital information systems; medical informatics; medical records systems, computerized; practice guidelines; therapy, computer-assisted ID PHYSICIAN ORDER ENTRY; MEDICAL RECORD; GUIDELINES; PERFORMANCE; MANAGEMENT; INFORMATION; ERRORS; CARE AB Computer decision support systems are computer applications designed to aid clinicians in making diagnostic and therapeutic decisions in patient care. They can simplify access to data needed to make decisions, provide reminders and prompts at the time of a patient encounter, assist in establishing a diagnosis and in entering appropriate orders, and alert clinicians when new patterns in patient data are recognized. Decision support systems that present patient-specific recommendations in a form that can save clinicians time have been shown to be highly effective, sustainable tools for changing clinician behavior. Designing and implementing such systems is challenging because of the computing infrastructure required, the need for patient data in a machine-processible form, and the changes to existing workflow that may result. Despite these difficulties, there is substantial evidence from trials in a wide range of clinical settings that computer decision support systems help clinicians do a better job caring for patients. As computer-based records and order-entry systems become more common, automated decision support systems will be used more broadly. C1 Univ Washington, VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. RP Payne, TH (reprint author), Univ Washington, VA Puget Sound Hlth Care Syst, 1660 S Columbian Way,Mail Stop S-007-CIM, Seattle, WA 98108 USA. NR 31 TC 50 Z9 52 U1 0 U2 4 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD AUG PY 2000 VL 118 IS 2 SU S BP 47S EP 52S DI 10.1378/chest.118.2_suppl.47S PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 346NW UT WOS:000088878800008 PM 10939999 ER PT J AU Peters, JI Shelledy, DC Jones, AP Lawson, RW Davis, CP LeGrand, TS AF Peters, JI Shelledy, DC Jones, AP Lawson, RW Davis, CP LeGrand, TS TI A randomized, placebo-controlled study to evaluate the role of salmeterol in the in-hospital management of asthma SO CHEST LA English DT Article DE asthma; beta-agonists; salmeterol ID INHALED SALMETEROL; BRONCHIAL-ASTHMA; SALBUTAMOL; AGONISTS; BRONCHOCONSTRICTION; XINAFOATE; SYMPTOMS; THERAPY AB Study objectives: To assess the safety and efficacy of salmeterol xinafoate as an adjunct to conventional therapy for the in-hospital management of acute asthma, Design: A prospective, double-blind, randomized placebo-controlled trial, Setting: Medical wards of a large university-based hospital. Patients: Forty-three patients admitted for an acute exacerbation of asthma, Interventions: Salmeterol (42 mu g) or two puffs of placebo every 12 h in addition to standard therapy (short-acting beta-agonists, corticosteroids, and anticholinergic agents), Results: No clinically adverse effects were seen with the addition of salmeterol to conventional therapy. After salmeterol, there was no difference in pulse, respiratory rate, oxygen saturation by pulse oximetry, severity of symptoms, or dyspnea score. Patients receiving salmeterol had greater FEV1 percent improvements than the placebo group at 12, 24, 36, and 48 h, These findings were not statistically significant. By paired Student's t tests, there were significant improvements in FEV1 (p = 0.03) and FVC (p = 0.03) in the salmeterol group after 48 h of treatment with no comparable improvement in the placebo group. In a subgroup analysis of patients with an initial FEV1 less than or equal to 1.5 L, the absolute FEV1 percent improvement for salmeterol vs placebo was 51% vs 16% at 24 h and 54% vs 40% at 48 h, The relative FEV1 percent improvement for salmeterol vs placebo was 17% vs 8% at 24 h and 18% vs 14% at 48 h, Conclusion: The addition of salmeterol to conventional therapy is safe and may benefit hospitalized patients with asthma, Further studies are needed to clarify its role in the treatment of acute exacerbation of asthma. C1 Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Resp Care, Div Pulm Dis Crit Care Med, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Surg, San Antonio, TX 78284 USA. RP Peters, JI (reprint author), S Texas Vet Hlth Care Syst, Audie L Murphy Mem Vet Hosp Div, Pulm Dis Sect 111E, 7400 Merton Minter Blvd, San Antonio, TX 78284 USA. NR 32 TC 21 Z9 21 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD AUG PY 2000 VL 118 IS 2 BP 313 EP 320 DI 10.1378/chest.118.2.313 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 344VB UT WOS:000088779200010 PM 10936118 ER PT J AU Zahedi, R Braun, M Wetsel, RA Ault, BH Khan, A Welch, TR Frenzke, M Davis, AE AF Zahedi, R Braun, M Wetsel, RA Ault, BH Khan, A Welch, TR Frenzke, M Davis, AE TI The C5a receptor is expressed by human renal proximal tubular epithelial cells SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE complement; renal proximal tubules; C5a receptor ID MESANGIAL CELLS; GROWTH-FACTORS; MESSENGER-RNA; HUMAN-KIDNEY; MEDIATED GLOMERULONEPHRITIS; CELLULAR EXPRESSION; UP-REGULATION; P-SELECTIN; TNF-ALPHA; IN-VIVO AB The C5a receptor is expressed by a variety of cell types. These studies demonstrate by immunohistochemistry that the receptor is present on the surface of proximal and distal tubular epithelial cells from normal kidney. In addition, the receptor was detected on transitional epithelial cells of the ureter and bladder. Primary proximal tubular cultures and a proximal tubular cell line both also expressed the C5a receptor, as demonstrated by immunofluorescence and by FACS analysis. The presence of mRNA encoding the receptor was confirmed by reverse transcriptase-polymerase chain reaction analysis. As opposed to its effect on glomerular mesangial cells, the receptor did not mediate a proliferative response by the proximal tubular cells. C5a also did not enhance the synthesis/secretion of transforming growth factor-beta 1, monocyte chemoattractant protein-1, platelet-derived growth factor-AB or tumour necrosis factor-alpha by cultured proximal tubular cells. Therefore, although the C5a receptor clearly is expressed by proximal tubular cells, clarification of its functional relevance on this cell type awaits further studies. C1 Ctr Blood Res, Boston, MA 02115 USA. NIAID, Clin Invest Lab, Mucosal Immun Sect, Inst Mol Med, Bethesda, MD 20892 USA. Univ Tennessee, Coll Med, Dept Paediat, Memphis, TN USA. Washington Univ, Sch Med, Dept Paediat, St Louis, MO USA. Childrens Hosp Res Fdn, Div Nephrol, Cincinnati, OH 45229 USA. RP Davis, AE (reprint author), Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. FU NIAID NIH HHS [R01 AI025011, AI25011]; NICHD NIH HHS [R01 HD033727, HD33727, R37 HD022082, HD22082] NR 52 TC 41 Z9 45 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD AUG PY 2000 VL 121 IS 2 BP 226 EP 233 DI 10.1046/j.1365-2249.2000.01249.x PG 8 WC Immunology SC Immunology GA 336NK UT WOS:000088309000009 PM 10931135 ER PT J AU Robon, MJ Perell, KL Fang, M Guererro, E AF Robon, MJ Perell, KL Fang, M Guererro, E TI The relationship between ankle plantar flexor muscle moments and knee compressive forces in subjects with and without pain SO CLINICAL BIOMECHANICS LA English DT Article DE osteoarthritis; gait; biomechanics; elderly ID OSTEO-ARTHRITIS; OSTEOARTHRITIS; GAIT; REHABILITATION; POPULATION; OBESITY; DISEASE; WOMEN; AGE AB Objective. The purpose of this study was to compare the compressive knee joint reaction force and ankle plantar flexor muscle moment during the terminal stance phase in symptomatic osteoarthritic and non-symptomatic subjects. Design. The study design was a comparative investigation of walking patterns. Background Patients with knee osteoarthritic symptoms may employ altered gait patterns to reduce the loading of painful joints, Speculation is that decreased ankle plantar flexor moments in the terminal stance phase may he an attempt to minimize compressive knee joint reaction forces. Methods. Twenty community-dwelling men (52-83 years old), ten with knee osteoarthritis and ten non-symptomatic, were studied while walking across a walkway containing two force plates at a comfortable speed. Retroreflective markers were placed in accordance with the Helen Hayes marker system and recorded with six 120 Hz cameras. Three-dimensional kinematics and kinetics were computed. Results. Group means for gait velocity, peak ankle plantar flexor moment and compressive knee joint reaction force were significantly less for the osteoarthritic group relative to the non-symptomatic group. When accounting for the decreased velocity in the osteoarthritic group, however, no group differences were observed. There were significant correlations between all three gait parameters (r > 0.75), but peak ankle plantar flexor moment was the greatest predictor of compressive knee joint reaction force, Conclusions. While no group differences were found for compressive knee joint reaction forces when accounting for gait velocity, it appears that subjects with osteoarthritis utilize gait velocity as a mechanism to reduce compressive knee joint reaction forces. (C) 2000 Published by Elsevier Science Ltd. All rights reserved. C1 Univ Calif Los Angeles, W Los Angeles Healthcare Ctr, PM&R Gait Lab 117G, VA Greater Los Angeles Healthcare Syst,Sch Med, Los Angeles, CA 90073 USA. Ohio State Univ, Coll Med, Columbus, OH 43210 USA. Mt St Marys Coll, Los Angeles, CA USA. Kaiser Permanente Med Ctr, Fresno, CA USA. RP Perell, KL (reprint author), Univ Calif Los Angeles, W Los Angeles Healthcare Ctr, PM&R Gait Lab 117G, VA Greater Los Angeles Healthcare Syst,Sch Med, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 26 TC 24 Z9 24 U1 1 U2 3 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 AUG PY 2000 VL 15 IS 7 BP 522 EP 527 DI 10.1016/S0268-0033(00)00007-3 PG 6 WC Engineering, Biomedical; Orthopedics; Sport Sciences SC Engineering; Orthopedics; Sport Sciences GA 344HV UT WOS:000088753900007 PM 10831812 ER PT J AU Usher, BW O'Brien, TX AF Usher, BW O'Brien, TX TI Recent advances in dobutamine stress echocardiography SO CLINICAL CARDIOLOGY LA English DT Review DE echocardiography; stress testing; dobutamine; diagnostic testing; coronary artery disease ID CORONARY-ARTERY-DISEASE; ACUTE MYOCARDIAL-INFARCTION; EMISSION COMPUTED-TOMOGRAPHY; LEFT-VENTRICULAR FUNCTION; PROGNOSTIC VALUE; CONTRAST ECHOCARDIOGRAPHY; REVERSIBLE DYSFUNCTION; RISK STRATIFICATION; CHEST PAIN; HIBERNATING MYOCARDIUM AB Dobutamine stress echocardiography (DSE) is a reliable cardiac risk stratifier that hac widespread applicability because of its clinical accuracy and cost effectiveness. Dobutamine has positive inotropic and chronotropic effects and is commonly used in patients who cannot exercise or achieve an adequate heart rate response with exercise. Recently available long-term results from several independent clinical trials, combined with enhancements in image quality, have improved the ability to detect significant coronary artery disease and determine myocardial viability. Dobutamine stress echocardiography has an excellent safety profile with clinical results superior to regular exercise electrocardiography and comparable with exercise echocardiography and radionucleotide perfusion stress imaging. Low-dose dobutamine response can accurately predict dysfunctional yet viable myocardial regions that may improve with revascularization. Clinical studies are now available refining the common use of DSE preoperatively in female patients with valvular disease, as well as in the emergency department. Dobutamine stress echocardiography does have some limitations in discriminating particular regions of ischemia when multiple ventricular segments. are involved and when the imaging is suboptimal. It can be applied using minimal additional resources in an otherwise functioning echocardiography laboratory and, with appropriate training, can result in clinical results comparable with those of large-scale multicenter trials. Ongoing improvements in technology and the development of new reagents such as myocardial contrast agents hold promise for further advancement in the near future. C1 Med Univ S Carolina, Dept Med, Div Cardiol, Charleston, SC 29425 USA. Ralph H Johnson Dept Vet Affairs Med Ctr, Med Res Serv, Charleston, SC USA. Ralph H Johnson Dept Vet Affairs Med Ctr, Echocardiog Lab, Charleston, SC USA. Med Univ S Carolina, Gazes Cardiac Res Inst, Charleston, SC 29425 USA. RP O'Brien, TX (reprint author), Med Univ S Carolina, Dept Med, Div Cardiol, 816,CSB,96 Jonathan Lucas St,Suite 816,POB 250623, Charleston, SC 29425 USA. NR 75 TC 9 Z9 11 U1 0 U2 0 PU CLINICAL CARDIOLOGY PUBL CO PI MAHWAH PA PO BOX 832, MAHWAH, NJ 07430-0832 USA SN 0160-9289 J9 CLIN CARDIOL JI Clin. Cardiol. PD AUG PY 2000 VL 23 IS 8 BP 560 EP 570 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 340HP UT WOS:000088527300004 PM 10941540 ER PT J AU Talan, DA Summanen, PH Finegold, SM AF Talan, DA Summanen, PH Finegold, SM TI Ampicillin/sulbactam and cefoxitin in the treatment of cutaneous and other soft-tissue abscesses in patients with or without histories of injection drug abuse SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID SKIN-STRUCTURE INFECTIONS; BACTERIOLOGY; SULBACTAM; EFFICACY AB A randomized, double-blind trial compared the clinical and bacteriologic efficacy of ampicillin/sulbactam (2 g/1 g) and cefoxitin (2 g) administered intravenously every 6 h to patients with (n = 49) or without (n = 47) histories of injection drug abuse who presented with cutaneous or other soft-tissue infections. Cure or improvement occurred in 89.8% of ampicillin/sulbactam-treated patients, compared with 93.6% of cefoxitin-treated patients. The median time to resolution of all symptoms was 10.5 days with ampicillin/sulbactam treatment and 15.5 days with cefoxitin treatment. Mixed aerobic-anaerobic infection was encountered frequently in both treatment groups. A significantly higher percentage of Streptococcus species was found in the major abscesses of the patients with histories of injection drug abuse, compared with those without such histories (37% vs. 19%, respectively; P =.0009). Overall, ampicillin/sulbactam eradicated pathogens from the major abscesses in 100% of patients, whereas the eradication rate with cefoxitin was 97.9%, The 2 drugs were well tolerated. Ampicillin/sulbactam and cefoxitin were equally effective for the empirical treatment of cutaneous or other soft-tissue infections in injection drug abusers and patients who did not inject drugs. C1 Olive View UCLA Med Ctr, Dept Med, Div Emergency Med & Infect Dis, Sylmar, CA 91342 USA. W Los Angeles Vet Affairs Med Ctr, Res Serv, W Los Angeles, CA USA. W Los Angeles Vet Affairs Med Ctr, Infect Dis Sect, W Los Angeles, CA USA. RP Talan, DA (reprint author), Olive View UCLA Med Ctr, Dept Emergency Med, 14445 Olive View Dr,N Annex, Sylmar, CA 91342 USA. NR 31 TC 14 Z9 15 U1 1 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG PY 2000 VL 31 IS 2 BP 464 EP 471 DI 10.1086/313971 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 363MD UT WOS:000089838700010 PM 10987706 ER PT J AU Ryan, ET Calderwood, SB AF Ryan, ET Calderwood, SB TI Cholera vaccines SO CLINICAL INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 48th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene CY NOV 28-DEC 02, 1999 CL WASHINGTON, D.C. SP Amer Soc Trop Med & Hyg ID RECOMBINANT-B-SUBUNIT; VIBRIO-CHOLERAE; WHOLE-CELL; FIELD TRIAL; CVD 103-HGR; ESCHERICHIA-COLI; IMMUNE-RESPONSES; ORAL VACCINES; DOUBLE-BLIND; LIVE AB Cholera causes significant morbidity and mortality worldwide. For travelers, the risk of developing cholera per month of stay in a developing country is similar to 0.001%-0.01%, and cholera may present as traveler's diarrhea. In the United States, only a poorly tolerated, marginally effective, parenterally administered, phenol-inactivated vaccine is available. Outside the United States, 2 additional vaccines are commercially available: an oral killed whole cell-cholera toxin recombinant B subunit vaccine (WC-rBS) and an oral live attenuated Vibrio cholerae vaccine (CVD 103-HgR), These oral vaccines are well tolerated. In field trials, WC-rBS provides 80%-85% protection front cholera caused by V. cholerae serogroup O1 for at least 6 months. In volunteer studies, CVD 103-HgR provides 62%-100% protection against cholera caused by V. cholerae for at least 6 months. No commercially available cholera vaccine protects against disease caused by V. cholerae serogroup O139. New cholera vaccines are being developed. C1 Massachusetts Gen Hosp, Div Infect Dis, Trop & Geog Med Ctr, Travelers Advice & Immunizat Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. RP Ryan, ET (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Trop & Geog Med Ctr, Travelers Advice & Immunizat Ctr, Jackson 504,55 Fruit St, Boston, MA 02114 USA. FU NIAID NIH HHS [R01 AI040725, AI40725, K08 AI01332] NR 36 TC 56 Z9 61 U1 1 U2 7 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG PY 2000 VL 31 IS 2 BP 561 EP 565 DI 10.1086/313951 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 363MD UT WOS:000089838700025 PM 10987721 ER PT J AU Castle, SC AF Castle, SC TI Clinical relevance of age-related immune dysfunction SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID INFLUENZA VACCINATION; PERIPHERAL-BLOOD; DENDRITIC CELLS; NEUTROPHIL FUNCTION; ELDERLY SUBJECTS; UP-REGULATION; IMMUNOSENESCENCE; PROLIFERATION; MACROPHAGES; DECADES AB Immunosenescence is the state of dysregulated immune function that contributes to the increased susceptibility to infection of the elderly. Extensive studies of inbred laboratory animals and very healthy elderly humans have identified changes in immunity; these studies have identified limited phenotypic and functional changes in the T cell component of adaptive immunity. However, no compelling scientific evidence has shown that these changes have direct relevance to the common infections seen in the aged population. This perspective will attempt to shed light on this dilemma. First, it will review clinically relevant infections in the elderly, focusing on influenza and influenza virus vaccination and how chronic illness contributes to increased risk and severity of infection and/or failed vaccine response. Second, key changes in immunity will be reviewed, keeping a perspective of the impact of confounding variables in addition to age but focusing on age-related changes in the interaction of the innate and acquired components of immunity. If the goal is to prevent serious infections in the elderly, it appears that the field of geriatric immunology and/or infectious diseases is faced with the tremendous challenge of studying a very diverse population, including mildly immunocompromised/chronically ill individuals and very healthy elderly. C1 VA Greater Los Angeles Healthcare Syst, GRECC 11G, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. RP Castle, SC (reprint author), VA Greater Los Angeles Healthcare Syst, GRECC 11G, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 35 TC 300 Z9 313 U1 0 U2 8 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG PY 2000 VL 31 IS 2 BP 578 EP 585 DI 10.1086/313947 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 363MD UT WOS:000089838700028 PM 10987724 ER PT J AU Hooper, DC AF Hooper, DC TI Mechanisms of action and resistance of older and newer fluoroquinolones SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID DNA TOPOISOMERASE-IV; STAPHYLOCOCCUS-AUREUS; STREPTOCOCCUS-PNEUMONIAE; QUINOLONE RESISTANCE; ESCHERICHIA-COLI; PRIMARY TARGET; GYRASE; NORA; GENE; MUTATIONS AB The fluoroquinolones interact with 2 bacterial targets, the related enzymes DNA gyrase and topoisomerase IV, both of which are involved in DNA replication. Quinolones form complexes of these enzymes with DNA, complexes that block movement of the DNA-replication fork and thereby inhibit DNA replication. Many older quinolones differ in their relative activities against gyrase and topoisomerase IV in a bacterial cell, having greater potency against gyrase than against topoisomerase TV in many gram-negative bacteria and greater potency against topoisomerase IV than against gyrase in many gram-positive bacteria. Several newer quinolones appear to have more closely balanced activity against these enzymes. Resistance to fluoroquinolones occurs as a result of mutational amino acid substitutions in the subunits of the more sensitive (or primary-target) enzyme within the cell. If however, both enzymes are similarly susceptible to a fluoroquinolone, then the level of resistance caused by a primary-target mutation may be low and may be limited by the sensitivity of the secondary target. Fluoroquinolones also differ in the extent to which common bacterial multidrug efflux pumps affect their activity, with some compounds being unaffected by resistance mechanisms because of overexpression of such pumps. Newer fluoroquinolone interaction with dual targets and avoidance of efflux-resistance mechanisms may each contribute to the lower frequencies of selection of resistant mutants in the laboratory. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA 02114 USA. RP Hooper, DC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, 55 Fruit St, Boston, MA 02114 USA. NR 32 TC 159 Z9 171 U1 1 U2 11 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG PY 2000 VL 31 SU 2 BP S24 EP S28 DI 10.1086/314056 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 364CR UT WOS:000089874900003 PM 10984324 ER PT J AU Lee, A Boone, KB Lesser, I Wohl, M Wilkins, S Parks, C AF Lee, A Boone, KB Lesser, I Wohl, M Wilkins, S Parks, C TI Performance of older depressed patients on two cognitive malingering tests: False positive rates for the Rey 15-item Memorization and Dot Counting Tests SO CLINICAL NEUROPSYCHOLOGIST LA English DT Article AB To our knowledge, no investigations have been undertaken to determine whether depression impacts performance on two commonly used tests to detect malingering of cognitive symptoms, the Rey 15-item Memorization Test and the Rey Dot Counting Test. This is a critical issue because of the high rate of depressive symptoms in patients with neurological conditions. It was hypothesized that depressed individuals, especially those with more severe depression, might be at risk for failing the tests, because these patients exhibit mild deficits in mental speed, visual perceptual/spatial skills, and visual memory, abilities required for successful completion of the malingering tests. However, examination of test performance in 64 older participants with major depression generally revealed very low false positive rates for most test scores, and severity of depression was unrelated to test scores. These results add to accumulating data supporting the validity of these cognitive malingering tests by documenting few false positive identifications. C1 Harbor UCLA Med Ctr, Dept Psychiat, Torrance, CA 90509 USA. W Los Angeles Vet Adm, Los Angeles, CA 90073 USA. Calif Sch Profess Psychol, Los Angeles, CA 90073 USA. RP Boone, KB (reprint author), Harbor UCLA Med Ctr, Dept Psychiat, Box 495,1000 W Carson St,F-9, Torrance, CA 90509 USA. NR 21 TC 16 Z9 16 U1 3 U2 5 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 0920-1637 J9 CLIN NEUROPSYCHOL JI Clin. Neuropsychol. PD AUG PY 2000 VL 14 IS 3 BP 303 EP 308 DI 10.1076/1385-4046(200008)14:3;1-P;FT303 PG 6 WC Psychology, Clinical; Clinical Neurology; Psychology SC Psychology; Neurosciences & Neurology GA 392FV UT WOS:000166401600006 PM 11262705 ER PT J AU Milgrom, P Riedy, CA Weinstein, P Tanner, ACR Manibusan, L Bruss, J AF Milgrom, P Riedy, CA Weinstein, P Tanner, ACR Manibusan, L Bruss, J TI Dental caries and its relationship to bacterial infection, hypoplasia, diet, and oral hygiene in 6-to 36-month-old children SO COMMUNITY DENTISTRY AND ORAL EPIDEMIOLOGY LA English DT Article DE dental caries; diet; prevalence; Streptococcus mutans ID EARLY-CHILDHOOD CARIES; STREPTOCOCCUS-MUTANS; SCHOOL-CHILDREN; INFANTS; COLONIZATION; MICROFLORA; INCREMENT; ERUPTION; SUGARS; MOUTHS AB Caufield et al. (1) have suggested that the acquisition of mutans streptococci in young children most Likely takes place during a "window of infectivity" from 19 to 31 months of age. Objectives and Methods: This study determined the prevalence of dental caries and bacterial infection in a randomly selected sample of 199 children 6 to 36 months old from the island of Saipan in the Commonwealth of the Northern Mariana Islands, USA. The relationships between caries and Streptococcus mutans infection, hypoplasia, diet and oral hygiene behavior were investigated. Results and Conclusions: The overall estimated prevalence of caries was high: 46.8% of the children had white spot lesions and 39.1% had enamel cavitation. Colonization was seen in very young children; S. mutans was detected in 25% of the predentate children. The results of multi-variable modeling support the hypothesis that bacterial infection, diet, and hypoplasia are important in the etiology of dental caries in this population. Adjusted for age and ethnicity, children with a high level of S. mutans detected were 5 times more likely to have dental caries than children with a lower level of S. mutans detected. Hypoplasia and a high cariogenicity score (diet) were also significant independent predictors. The odds of having any white spot lesions or enamel cavitation were 9.6 times greater for children with any hypoplasia, and 7.8 times greater for children with high cariogenicity scores relative to those with lower scores after adjusting for level of S. mutans, age and ethnicity. Sleeping with a bottle, maternal sharing of utensils, and high snacking frequency were not significant predictors of caries in this population. C1 Univ Washington, Dept Dent Publ Hlth Sci, Seattle, WA 98195 USA. Forsyth Inst, Boston, MA USA. Dept Publ Hlth Serv, Saipan, CM USA. RP Milgrom, P (reprint author), Univ Washington, Dept Dent Publ Hlth Sci, Box 357475, Seattle, WA 98195 USA. OI Milgrom, Peter/0000-0003-0784-9181 FU NIDCR NIH HHS [P30 DE-09743, T32 DE-07132] NR 45 TC 108 Z9 117 U1 2 U2 23 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0301-5661 J9 COMMUNITY DENT ORAL JI Community Dentist. Oral Epidemiol. PD AUG PY 2000 VL 28 IS 4 BP 295 EP 306 DI 10.1034/j.1600-0528.2000.280408.x PG 12 WC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health SC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health GA 330QR UT WOS:000087973200008 PM 10901409 ER PT J AU Wirshing, DA AF Wirshing, DA TI Social skills training for schizophrenia: A step by-step guide. SO COMMUNITY MENTAL HEALTH JOURNAL LA English DT Book Review C1 W Los Angeles Vet Affairs Med Ctr, Schizophrenia Res & Treatment Unit, Los Angeles, CA 90073 USA. RP Wirshing, DA (reprint author), W Los Angeles Vet Affairs Med Ctr, Schizophrenia Res & Treatment Unit, 11301 Wilshire Blvd,B-151H,Bldg 210B,Room 15, Los Angeles, CA 90073 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU KLUWER ACADEMIC-HUMAN SCIENCES PRESS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 0010-3853 J9 COMMUNITY MENT HLT J JI Community Ment. Health J. PD AUG PY 2000 VL 36 IS 4 BP 452 EP 453 DI 10.1023/A:1001925315922 PG 2 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 330NC UT WOS:000087967300012 ER PT J AU Burns, JP Mitchell, C Outwater, KM Geller, M Griffith, JL Todres, ID Truog, RD AF Burns, JP Mitchell, C Outwater, KM Geller, M Griffith, JL Todres, ID Truog, RD TI End-of-life care in the pediatric intensive cave unit after the forgoing of life-sustaining treatment SO CRITICAL CARE MEDICINE LA English DT Article DE critical illness; therapy; decision making; life-support care; physician-patient relations; terminal care; statistics; numerical data ID RESPIRATORY-DISTRESS SYNDROME; PHYSICIAN-ASSISTED SUICIDE; CRITICALLY ILL PATIENTS; MECHANICAL VENTILATION; CONSTITUTIONAL RIGHT; CLINICAL MANAGEMENT; SLOW EUTHANASIA; TERMINALLY ILL; SUPREME-COURT; VECURONIUM AB Objective: To describe the attitudes and practice of clinicians in providing sedation and analgesia to dying patients as life-sustaining treatment is withdrawn. Study Design: Prospective case series of 53 consecutive patients who died after the withdrawal of life-sustaining treatment in the pediatric intensive care unit at three teaching hospitals in Boston. Data on the reasons why medications were given were obtained from a self-administered anonymous questionnaire completed by the critical care physician and nurse for each case. Data on what medications were given were obtained from a review of the medical record. Results: Sedatives and/or analgesics were administered to 47 (89%) patients who died after the withdrawal of life-sustaining treatment. Patients who were comatose were less likely to receive these medications. Physicians and nurses cited treatment of pain, anxiety, and air hunger as the most common reasons, and hastening death as the least common reason, for administration of these medications. Hastening death was viewed as an "acceptable, unintended side effect" of terminal care by 91% of physician-nurse matched pairs. The mean dose of sedatives and analgesics administered nearly doubled as life-support was withdrawn, and the degree of escalation in dose did not correlate with clinician's views on hastening death. Conclusion: Clinicians frequently escalate the dose of sedatives or analgesics to dying patients as life-sustaining treatment is withdrawn, citing patient-centered reasons as their principle justification. Hastening death is seen as an unintended consequence of appropriate care, A large majority of physicians and nurses agreed with patient management and were satisfied with the care provided. Care of the dying patient after the forgoing of life-sustaining treatment remains underanalyzed and needs more rigorous examination by the critical care community. C1 Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. Childrens Hosp, Off Eth, Boston, MA 02115 USA. Childrens Hosp, Dept Patient Care Serv, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. New England Med Ctr, Biostat Res Ctr, Boston, MA 02111 USA. St Lukes Hosp, Dept Pediat, Saginaw, MI USA. RP Burns, JP (reprint author), Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. NR 62 TC 78 Z9 82 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD AUG PY 2000 VL 28 IS 8 BP 3060 EP 3066 DI 10.1097/00003246-200008000-00064 PG 7 WC Critical Care Medicine SC General & Internal Medicine GA 346JM UT WOS:000088867300061 PM 10966296 ER PT J AU Lingstrom, P van Houte, J Kashket, S AF Lingstrom, P van Houte, J Kashket, S TI Food starches and dental caries SO CRITICAL REVIEWS IN ORAL BIOLOGY & MEDICINE LA English DT Review DE bioavailability; caries; cariogenicity; eating frequency; microbial flora; pH; plaque; salivation; starch; sucrose ID HEREDITARY FRUCTOSE INTOLERANCE; DIETARY SUCROSE LEVELS; PLAQUE-PH; GLYCEMIC INDEX; STREPTOCOCCUS-MUTANS; WHEAT-STARCH; INTRAORAL DEMINERALIZATION; POTENTIAL CARIOGENICITY; METABOLIC RESPONSES; SUGAR CONSUMPTION AB Sucrose and starches are the predominant dietary carbohydrates in modern societies. While the causal relationship between sucrose and dental caries development is indisputable, the relationship between food starch and dental caries continues to be debated and is the topic of this review The current view of dental caries etiology suggests that in-depth evaluation of the starch-caries relationship requires the consideration of several critical cariogenic determinants. ( I) the intensity (i.e., the amount and frequency) of exposure of tooth surfaces to both sugars and starches, (2) the bioavailability of the starches, (3) the nature of the microbial flora of dental plaque, 0) the pH-lowering capacity of dental plaque, and (5) the flow rate of saliva. Studies of caries in animals, human plaque pH response, and enamel/dentin demineralization leave no doubt that processed food starches in modern human diets possess a significant cariogenic potential. However, the available studies with humans do not provide unequivocal data on their actual cariogenicity. in this regard, we found it helpful to distinguish between two types of situations The first, exemplified by our forebears, people in developing countries, and special subject groups in more modern countries, is characterized by starch consumption in combination with a low sugar intake an eating frequency which is essentially limited to two or three meals per day, and a low-to-negligible caries activity The second, exemplified by people in the more modern societies, e.g.. urban populations is characterized by, starch consumption in combination with significantly increased sugar consumption, an eating frequency of three or more times per day and a significantly elevated caries activity. It is in the first situation that food starches do not appear to be particularly caries-inducive However their contribution to caries development in the second situation is uncertain and requires further clarification. Although food starches do not appear to be particularly caries inducive in the first situation, the possibility cannot be excluded that they contribute significantly to caries activity in modern human populations. The commonly used term "dietary starch content" is misleading, since it represents a large array of single manufactured and processed foods of widely varying composition and potential cariogenicity Hence, increased focus on the cariogenicity of single starchy, foods is warranted. Other aspects of starchy foods consumption, deserving greater attention, include the bioavailability of starches in processed foods. their retentive properties, also in relation to sugars present (starches as co-cariogens), their consumption frequency, the effect of hyposalivation on their cariogenicity, and their impact on root caries. The starch-caries issue is a very complex problem, and much remains uncertain. More focused studies are needed. At present, it appears premature to consider or promote food starches in modern diets as safe for teeth. C1 Univ Gothenburg, Inst Odontol, Dept Cariol, Gothenburg, Sweden. Forsyth Inst, Nutr Sect, Boston, MA 02115 USA. Forsyth Inst, Dept Microbiol, Boston, MA 02115 USA. RP Kashket, S (reprint author), Forsyth Inst, Nutr Sect, 140 Fenway, Boston, MA 02115 USA. FU NIDCR NIH HHS [DE-07493, DE-07009, DE-05253] NR 154 TC 69 Z9 74 U1 1 U2 14 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 1045-4411 J9 CRIT REV ORAL BIOL M JI Crit. Rev. Oral Biol. Med. PD AUG PY 2000 VL 11 IS 3 BP 366 EP 380 PG 15 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 544UM UT WOS:000175180100006 PM 11021636 ER PT J AU Hofman, P Blaauwgeers, HGT Tolentino, MJ Adamis, AP Cardozo, BJN Vrensen, GFJM Schlingemann, RO AF Hofman, P Blaauwgeers, HGT Tolentino, MJ Adamis, AP Cardozo, BJN Vrensen, GFJM Schlingemann, RO TI VEGF-A induced hyperpermeability of blood-retinal barrier endothelium in vivo is predominantly associated with pinocytotic vesicular transport and not with formation of fenestrations SO CURRENT EYE RESEARCH LA English DT Article DE blood-retinal barrier; blood-brain barrier; caveolae; diabetic retinopathy, endothelial growth factors; pinocytotic vesicles; vascular permeability ID VASCULAR-PERMEABILITY FACTOR; GROWTH-FACTOR; BREAKDOWN; VESSELS; ANGIOGENESIS; EYE; MACROMOLECULES; FLUORESCEIN; EXPRESSION; CAVEOLAE AB Purpose. In tissues outside the brain, vascular endothelial growth factor-A (VEGF) causes vascular hyper-permeability by opening of inter-endothelial junctions and induction of fenestrations and vesiculo-vacuolar organelles (VVOs). In preliminary studies, we observed that in blood-retinal barrier endothelium, other cellular mechanisms may underlie increased permeability caused by VEGF. This was further investigated in material of an in in vivo experimental model of VEGF-induced retinopathy. Methods. Two monkeys received 4 intravitreal injections of 0.5 mug VEGF in one eye and PBS in the other eye prior to sacrifice at day 9. One monkey received 12 injections of 1.25 mug VEGF in one eye and PBS in the other eye prior to sacrifice at day 24. As a control, an untreated eye of a fourth monkey was studied. Results. In the high-dose VEGF-injected eye, fluorescein angiography showed intense retinal micro-vascular leakage. This leakage was also demonstrated by immunohistochemistry demonstrating extravasation of endogenous fibrinogen and IgG. However, in these leaky blood vessels the number of pinocytotic vesicles (caveolae) at the endothelial luminal membrane were significantly higher and, only in the VEGF-injected eyes, these pinocytotic vesicles transported plasma IgG. By electron microscopy, no fenestrations or VVOs were found in the endothelial cells of the VEGF-injected eyes. Conclusion. We conclude that increased vascular permeability for plasma proteins induced by VEGF in blood-retinal barrier endothelium is predominantly caused by a mechanism involving active trans-endothelial transport via pinocytotic vesicles and not by formation of endothelial fenestrations or VVOs. C1 Netherlands Ophthalm Res Inst, Dept Morphol, NL-1105 BA Amsterdam, Netherlands. Univ Amsterdam, Acad Med Ctr, Dept Ophthalmol, NL-1105 AZ Amsterdam, Netherlands. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. Leiden Univ, Med Ctr, Dept Ophthalmol, Leiden, Netherlands. RP Hofman, P (reprint author), Netherlands Ophthalm Res Inst, Dept Morphol, Meibergdreef 47, NL-1105 BA Amsterdam, Netherlands. EM p.hofman@ioi.knaw.nl RI li, yang/C-5736-2014 NR 41 TC 62 Z9 66 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0271-3683 EI 1460-2202 J9 CURR EYE RES JI Curr. Eye Res. PD AUG PY 2000 VL 21 IS 2 BP 637 EP 645 DI 10.1076/0271-3683(200008)21:2;1-V;FT637 PG 9 WC Ophthalmology SC Ophthalmology GA 375LW UT WOS:000165375400006 PM 11148600 ER PT J AU Letko, E Bhol, K Foster, CS Ahmed, AR AF Letko, E Bhol, K Foster, CS Ahmed, AR TI Influence of intravenous immunoglobulin therapy on serum levels of anti-beta 4 antibodies in ocular cicatricial pemphigoid - A correlation with disease activity - A preliminary study SO CURRENT EYE RESEARCH LA English DT Article DE ocular cicatricial pemphigoid; mucous membrane pemphigoid; intravenous immunoglobulin; anti-beta 4 antibodies; disease activity ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; IGA BULLOUS DERMATOSIS; BASEMENT-MEMBRANE; IMMUNOFLUORESCENCE ASSAY; MYASTHENIA-GRAVIS; AUTOANTIBODIES; ANTIGEN; LAMININ-5; INTEGRIN; SUBUNITS AB Purpose. To determine any correlation between activity of ocular cicatricial pemphigoid and titer of anti-beta4 antibodies, and any effect of intravenous immunoglobulin (IVIg) therapy on serum levels of anti-beta4 antibodies followed over a 12 month period, using the specific immunoblot assay (IBA). Patients and methods. Eight patients diagnosed with OCP and treated with IVIg as monotherapy were included in the study. Each patient was treated with at least two immunosuppressive agents prior to the institution of IVIg. The presence of anti-beta4 antibodies in the patients' sera was detected by IBA using bovine gingival lysate (BGL) or turner cell line lysate (TCL) as substrates. The activity of OCP was graded based on the conjunctival injection using a scale of zero to four in increments of 0.5 at monthly intervals. To determine the correlation between serum levels of circulating autoantibody and the patients' conjunctival disease activity, the titer of anti-beta4 antibodies was determined at monthly intervals during the course of IVIg therapy. Blood samples were drawn prior to administration of IVIg infusion. The titer was determined by IBA, using serial dilutions of the patients' sera. The highest dilution at which the binding was visible was considered the titer. The dose of IVIg administered was approximately 2-3 g/kg/cycle. The infusion cycles were initially given at monthly intervals, approximately 70 grams daily over four hours for three consecutive days. As clinical improvement was observed, the interval between the cycles was increased, but the dose of IVIg remained the sat-ne for each cycle. To study whether the IVIg has an effect on other antibodies, monthly serum levels of antibodies to tetanus toroid were measured by ELISA. Results. We observed a continuous decrease in mean monthly titer of circulating anti-beta4 antibodies in the patients' sera during IVIg therapy. A decrease in conjunctival inflammation during the course of IVIg was documented by monthly examination in every patient and paralleled the decrease in titer of anti-beta4 antibodies. Since the fifth month of IVIg, therapy, the mean conjunctival inflammation remained less than 0.5, suggesting a clinical remission of OCP. Titers of antibodies to tetanus toroid remained unchanged during the study period. Conclusions. This preliminary study demonstrates a correlation between serum titers of anti-beta4 antibodies and clinical disease activity in patients with OCP. In addition, the study shows that the use of IVIg is associated with a decrease in the serum titer of anti-beta4 antibodies. C1 Harvard Univ, Sch Dent Med, Dept Oral Med & Diagnost Sci, Boston, MA 02115 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Uveitis & Immunol Serv, Boston, MA USA. RP Ahmed, AR (reprint author), Harvard Univ, Sch Dent Med, Dept Oral Med & Diagnost Sci, 188 Longwood Ave, Boston, MA 02115 USA. EM razzaque_ahmed@hms.harvard.edu FU NEI NIH HHS [EY09379-09] NR 33 TC 39 Z9 41 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0271-3683 EI 1460-2202 J9 CURR EYE RES JI Curr. Eye Res. PD AUG PY 2000 VL 21 IS 2 BP 646 EP 654 PG 9 WC Ophthalmology SC Ophthalmology GA 375LW UT WOS:000165375400007 PM 11148601 ER PT J AU Altfeld, M Rosenberg, ES AF Altfeld, M Rosenberg, ES TI The role of CD4(+) T helper cells in the cytotoxic T lymphocyte response to HIV-1 SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; HEPATITIS-C VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; MEDIATED IMMUNE-RESPONSE; ALLOGENEIC BONE-MARROW; LOW VIRAL LOAD; ANTIBODY-RESPONSES; PRIMARY INFECTION; EFFECTOR FUNCTION; IN-VIVO AB Virus-specific CD4(+) T cell help and CD8(+) cytotoxic T cell (CTL) responses are critical for the maintenance of effective immunity in chronic viral infections. HIV-1 infection presents a unique situation in which HIV-l-specific T helper cell responses are characteristically impaired and virus-specific CTLs wane over time as disease progresses; a relationship exists between T cell help and Cn responses in HIV-1 infection. C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02114 USA. Harvard Univ, Sch Med, Charlestown, MA 02114 USA. Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. RP Rosenberg, ES (reprint author), Massachusetts Gen Hosp, Partners AIDS Res Ctr, 13th St,Bldg 149,5th Floor, Charlestown, MA 02114 USA. NR 60 TC 121 Z9 127 U1 0 U2 5 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD AUG PY 2000 VL 12 IS 4 BP 375 EP 380 DI 10.1016/S0952-7915(00)00103-5 PG 6 WC Immunology SC Immunology GA 330UD UT WOS:000087978800003 PM 10899028 ER PT J AU Brander, C Walker, BD AF Brander, C Walker, BD TI Modulation of host immune responses by clinically relevant human DNA and RNA viruses SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID HEPATITIS-C VIRUS; MHC CLASS-I; MAJOR HISTOCOMPATIBILITY COMPLEX; CYTOTOXIC T-CELL; HUMAN CYTOMEGALOVIRUS-INFECTION; CHEMOKINE RECEPTOR US28; HIV-1 NEF PROTEIN; CUTTING EDGE; CORE PROTEIN; NEURONAL APOPTOSIS AB Numerous mechanisms allow viruses to evade host immune surveillance, and new evasion strategies continue to be identified. In addition to interference with antigen processing and presentation, direct viral modulation of host immune responses can also be achieved by altering the host cytokine milieu and the development of immunoregulatory cells. A better understanding of these viral evasion strategies will help to define critical host defense mechanisms and will lead to novel immune-based therapeutic strategies in the future. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Partners AIDS Res Ctr, Charlestown, MA 02129 USA. RP Brander, C (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Partners AIDS Res Ctr, MGH E,5th Floor,149 13th St, Charlestown, MA 02129 USA. NR 98 TC 10 Z9 10 U1 0 U2 0 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 AUG PY 2000 VL 3 IS 4 BP 379 EP 386 DI 10.1016/S1369-5274(00)00108-9 PG 8 WC Microbiology SC Microbiology GA 345LK UT WOS:000088817300010 PM 10972498 ER PT J AU Bauer, TR Hickstein, DD AF Bauer, TR Hickstein, DD TI Gene therapy for leukocyte adhesion deficiency SO CURRENT OPINION IN MOLECULAR THERAPEUTICS LA English DT Article DE CD11/CD18; heterodimer; leukocyte adherence deficiency; neutophil ID RECURRENT BACTERIAL-INFECTIONS; INTEGRIN CD18 SUBUNIT; APE LEUKEMIA-VIRUS; BETA-SUBUNIT; RETROVIRAL VECTORS; PERIPHERAL-BLOOD; MOLECULAR-BASIS; ANIMAL-MODEL; CELLS; LFA-1 AB Leukocyte adhesion deficiency (LAD) is an autosomal recessive immunodeficiency disease characterized by severe, recurrent bacterial infections. In patients with LAD, the leukocytes, particularly the neutrophils, fail to adhere to the endothelial cell wall and migrate to the site of infection. LAD results from heterogeneous molecular defects in the leukocyte integrin CD18, which prevent CD11/CD18 heterodimer formation and surface expression. To date, hematopoietic stem cell transplantation remains the only curative treatment for LAD, however, this approach is limited try transplant-related toxicities and graft-versus-host disease. During the course of the preceding decade we have conducted extensive experimental studies demonstrating that gene transfer of the CD18 subunit corrects the structural and functional defect in LAD leukocytes. These studies provided the support for the initiation of a clinical trial of retroviral-mediated gene transfer of CD18 in two patients with the severe deficiency phenotype or LAD. This review will present an overview of LAD, preclinical CD18 gene transfer studies and the initial results from the current clinical trial. C1 Univ Washington, Dept Med, VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. RP Bauer, TR (reprint author), Univ Washington, Dept Med, VA Puget Sound Hlth Care Syst, 1660 S Columbian Way 151, Seattle, WA 98108 USA. NR 56 TC 28 Z9 30 U1 0 U2 0 PU PHARMAPRESS LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1P 6LB, ENGLAND SN 1464-8431 J9 CURR OPIN MOL THER JI Curr. Opin. Mol. Ther. PD AUG PY 2000 VL 2 IS 4 BP 383 EP 388 PG 6 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 345WR UT WOS:000088838600004 PM 11249768 ER PT J AU Callahan, ST Mansfield, MJ AF Callahan, ST Mansfield, MJ TI Type 2 diabetes mellitus in adolescents SO CURRENT OPINION IN PEDIATRICS LA English DT Review ID POLYCYSTIC-OVARY-SYNDROME; IMPAIRED GLUCOSE-TOLERANCE; INSULIN-RESISTANCE; AFRICAN-AMERICAN; PIMA-INDIANS; ACANTHOSIS NIGRICANS; MINORITY YOUTH; UNITED-STATES; RISK-FACTORS; NIDDM-Y AB Type 2 diabetes mellitus, a significant cause of adult morbidity and mortality, is being diagnosed more frequently in children and adolescents. Genetic predisposition and environmental factors are important determinants for the expression of this disease. Blacks, Hispanic Americans, and Native Americans are known to be at higher risk for type 2 diabetes mellitus as adults and there appears to be increased prevalence of the disease in adolescent members of these groups. Obesity, sedentary lifestyle, and high-fat diet are associated with type 2 diabetes mellitus. A combination of peripheral insulin resistance and relative insulin deficiency results in chronic hyperglycemia The onset of hyperglycemia is usually slow and symptoms such as polyuria and polydipsia are often subtle and may go unrecognized by the patient. The treatment of children and adolescents with type 2 diabetes mellitus is an area of active study. Programs targeting diet modification and increased physical activity are being developed in hopes of delaying or preventing the onset of disease. This paper examines risk factors for the development of type 2 diabetes mellitus, reviews diagnostic criteria, and discusses newly established screening criteria for type 2 diabetes mellitus in children and adolescents. Curr Opin Pediatr 2000 12:310-315 (C) 2000 Lippincott Williams & Wilkins, Inc. C1 Childrens Hosp, Div Adolescent & Young Adult Med, Boston, MA 02115 USA. Childrens Hosp, Dept Pediat, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Callahan, ST (reprint author), Childrens Hosp, Div Adolescent & Young Adult Med, 300 Longwood Ave, Boston, MA 02115 USA. FU PHS HHS [MCJ-MA259195] NR 58 TC 24 Z9 24 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8703 J9 CURR OPIN PEDIATR JI CURR. OPIN. PEDIATR. PD AUG PY 2000 VL 12 IS 4 BP 310 EP 315 DI 10.1097/00008480-200008000-00004 PG 6 WC Pediatrics SC Pediatrics GA 334ZP UT WOS:000088217000004 PM 10943809 ER PT J AU Edge, ASB Spiro, RG AF Edge, ASB Spiro, RG TI A specific structural alteration in the heparan sulphate of human glomerular basement membrane in diabetes SO DIABETOLOGIA LA English DT Article DE glomerular basement membrane; diabetic glomerular basement membrane alterations; 3-O-sulphated glucosamine; heparan sulphate binding; heparan sulphate sulphation sites; hydrazine/nitrous acid fragmentation; iduronic acid; glomerular anionic filter ID SULFATE; PROTEOGLYCANS; MATRIX AB Aims/hypothesis. Heparan sulphate proteoglycan is an important component of the glomerular anionic filtration barrier and its reduced amount in diabetes contributes to glomerular dysfunction. The objective of this study was to determine if there is also an alteration in the sulphation pattern of the diabetic heparan sulphate chains. Methods. The heparan sulphate in the glomerular basement membrane/mesangial matrix from human diabetic and nondiabetic kidneys obtained at autopsy was fragmented by a hydrazine/nitrous acid procedure and after radiolabelling with NaB[H-3](4). the disaccharide products were chromatographically resolved and quantified. Results. Six sulphated disaccharides were identified in both the diabetic and nondiabetic samples and the molar distribution of these was similar, with the notable exception of the iduronic acid-2-O-sulphate alpha 1 --> 4glucosamine-3-O-sulphate species which occurred in the diabetic glomeruli in less than half the amount as in the nondiabetic samples (9.0% compared to 18.7% of total sulphated disaccharides, p < 0.005). Conclusion/interpretation. 3-O-sulphated glucosamine is a rare constituent of heparan sulphate occurring usually in a glucuronic acid beta 1 --> 4glucosamine-3-O-sulphate(+/- 6-O-sulphate) sequence within the antithrombin-binding domain. In the glomerular basement membrane where the 3-O-sulphated glucosamine is present in substantial amounts, however, it occurs exclusively in an iduronic acid-containing sequence. It is likely that the recently discovered 3-O-sulphotransferase variant which specifically acts on the iduronic acid alpha 1 --> 4glucosamine sequence is decreased in human diabetes and moreover that this unusual disaccharide could be a component of a specific heparan sulphate domain which interacts with bioactive proteins. C1 Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Biol Chem, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Spiro, RG (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [DK 17325] NR 10 TC 18 Z9 19 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2000 VL 43 IS 8 BP 1056 EP 1059 DI 10.1007/s001250051489 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 350DB UT WOS:000089084500013 PM 10990084 ER PT J AU Aspelund, G Egan, JM Slezak, LA Sritharan, KC Elahi, D Andersen, DK AF Aspelund, G Egan, JM Slezak, LA Sritharan, KC Elahi, D Andersen, DK TI Glucagon-like peptide-1 and exendin-4 improve glucose tolerance and induce islet cell growth in diabetic rats SO DIABETOLOGIA LA English DT Meeting Abstract C1 Yale Univ, Sch Med, Dept Surg, New Haven, CT 06510 USA. NIA, Gerontol Res Ctr, NIH, Diabet Sect, Baltimore, MD 21224 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2000 VL 43 SU 1 MA 555 BP A144 EP A144 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 351BT UT WOS:000089136700553 ER PT J AU Cohen, SE Chen, D Bradley, RL Kahn, CR AF Cohen, SE Chen, D Bradley, RL Kahn, CR TI The effects of antidiabetic agents on gene expression and metabolism in 3T3-L1 adipocytes SO DIABETOLOGIA LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2000 VL 43 SU 1 MA 578 BP A149 EP A149 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 351BT UT WOS:000089136700576 ER PT J AU Egan, JM Clocquet, AR Greig, NH Hattersley, AT Habener, JF Tack, CJ Elahi, D AF Egan, JM Clocquet, AR Greig, NH Hattersley, AT Habener, JF Tack, CJ Elahi, D TI Decreased insulin secretion in response to glucose and GLP-1 in MODY-3 SO DIABETOLOGIA LA English DT Meeting Abstract C1 NIA, NIH, Baltimore, MD USA. Univ Exeter, Exeter EX4 4QJ, Devon, England. Catholic Univ Nijmegen, NL-6500 HC Nijmegen, Netherlands. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RI Tack, Cees/A-2368-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2000 VL 43 SU 1 MA 67 BP A17 EP A17 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 351BT UT WOS:000089136700067 ER PT J AU Horton, E Clinkingbeard, C Gatlin, M Mallows, S AF Horton, E Clinkingbeard, C Gatlin, M Mallows, S TI Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose spikes in Type 2 diabetes SO DIABETOLOGIA LA English DT Meeting Abstract C1 Joslin Diabet Ctr, Boston, MA 02215 USA. Joslin Diabet Ctr, Boise, ID USA. Novartis Pharmaceut, East Hanover, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2000 VL 43 SU 1 MA 717 BP A186 EP A186 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 351BT UT WOS:000089136700714 ER PT J AU Jonas, JC Laybutt, R Steil, GM Trivedi, N Weir, GC Henquin, JC AF Jonas, JC Laybutt, R Steil, GM Trivedi, N Weir, GC Henquin, JC TI Possible role of cytosolic calcium in glucose stimulation of of c-Myc expression in rat islets. SO DIABETOLOGIA LA English DT Meeting Abstract C1 Univ Louvain, Unite Endocrinol & Metab, Brussels, Belgium. Joslin Diabet Ctr, Islet Cell Biol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2000 VL 43 SU 1 MA 227 BP A57 EP A57 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 351BT UT WOS:000089136700226 ER PT J AU Malecki, MT Klupa, T Moczulski, D Warram, JH Krolewski, AS AF Malecki, MT Klupa, T Moczulski, D Warram, JH Krolewski, AS TI No evidence of association between vitamin D receptor (VDR) gene polymorphisms and type 1 diabetes in Caucasians. SO DIABETOLOGIA LA English DT Meeting Abstract C1 Jagiellonian Univ, Dept Metab Dis, Krakow, Poland. Silesian Sch Med, Dept Internal Med, Boston, MA USA. Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2000 VL 43 SU 1 MA 26 BP A7 EP A7 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 351BT UT WOS:000089136700028 ER PT J AU Sabolinski, M Toole, T Giovino, K Veves, A AF Sabolinski, M Toole, T Giovino, K Veves, A CA Graftskin Diabetic Foot Ulcer Stud TI Graftskin bilayered living skin construct in the treatment of diabetic foot ulcers SO DIABETOLOGIA LA English DT Meeting Abstract C1 Organogenesis Inc, Canton, MA 02021 USA. Joslin Beth Israel Deaconess Foot, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2000 VL 43 SU 1 MA 61 BP A16 EP A16 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 351BT UT WOS:000089136700062 ER PT J AU Vicent, D Ilany, J Neruse, K Yanagisawa, M Kahn, CR AF Vicent, D Ilany, J Neruse, K Yanagisawa, M Kahn, CR TI Insulin receptor in endothelial cells is not required for glucose homeostasis. SO DIABETOLOGIA LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. Univ Texas, SW Med Ctr, Dallas, TX 75235 USA. RI Vicent, David/O-2255-2014 OI Vicent, David/0000-0002-6663-0350 NR 0 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2000 VL 43 SU 1 MA 129 BP A33 EP A33 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 351BT UT WOS:000089136700130 ER PT J AU Weiss, RD Griffin, ML Gallop, R Onken, LS Gastfriend, DR Daley, D Crits-Christoph, P Bishop, S Barber, JP AF Weiss, RD Griffin, ML Gallop, R Onken, LS Gastfriend, DR Daley, D Crits-Christoph, P Bishop, S Barber, JP TI Self-help group attendance and participation among cocaine dependent patients SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE self-help groups; Alcoholics Anonymous; cocaine; treatment; drug abuse ID NATIONAL-INSTITUTE; 12-STEP PROGRAMS AB The authors examined frequency and patterns of self-help group attendance and active participation over a 6-month period among 411 patients receiving treatment in the NIDA Collaborative Cocaine Treatment Study. Nearly two-thirds of patients attended at least one self-help group, and nearly all of these actively participated. Alcoholics Anonymous and Narcotics Anonymous meetings were attended most frequently. Statistical analyses included chi square, one-way analyses of variance, and cluster techniques. While patterns of attendance were relatively consistent over time, findings suggest that a treatment emphasizing the importance of self-help groups is likely to encourage more self-help group attendance and participation over time. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 McLean Hosp, Alcohol & Drug Abuse Treatment Program, Belmont, MA 02478 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. NIDA, Div Clin & Res Serv, Treatment Res Branch, Rockville, MD USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Pittsburgh, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. Brookside Hosp, Nashua, NH USA. RP Weiss, RD (reprint author), McLean Hosp, Alcohol & Drug Abuse Treatment Program, 115 Mill St, Belmont, MA 02478 USA. FU NIDA NIH HHS [K02DA00326, U01DA07090, U01DA07693, U18 DA007090] NR 21 TC 27 Z9 27 U1 2 U2 6 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD AUG 1 PY 2000 VL 60 IS 2 BP 169 EP 177 DI 10.1016/S0376-8716(99)00154-4 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 337RY UT WOS:000088376500007 PM 10940544 ER PT J AU Voss, SE Rosowski, JJ Merchant, SN Thornton, AR Shera, CA Peake, WT AF Voss, SE Rosowski, JJ Merchant, SN Thornton, AR Shera, CA Peake, WT TI Middle ear pathology call affect the ear-canal sound pressure generated by audiologic earphones SO EAR AND HEARING LA English DT Article ID AUDIOMETRY AB Objective: To determine how the ear-canal sound pressures generated by earphones differ between normal and pathologic middle ears. Design: Measurements of ear-canal sound pressures generated by the Etymtic Research ER-3A insert earphone in normal ears (N = 12) were compared with the pressures generated in abnormal ears with mastoidectomy bowls (N = 15), tympanostomy tubes (N = 5), and tympanic-membrane perforations (N = 5), Similar measurements were made with the Telephonics TDH-49 supra-aural earphone in normal ears (N = 10) and abnormal ears with mastoidectomy bowls (N = 10), tympanostomy tubes (N = 4), and tympanic-membrane perforations (N = 5), Results: With the insert earphone, the sound pressures generated in the mastoid-bowl ears were all smaller than the pressures generated in normal ears; from 250 to 1000 Hz the difference in pressure level was nearly frequency independent and ranged from -3 to -15 dB; from 1000 to 4000 Hz the reduction in level increased with frequency and ranged from -5 dB to -35 dB, In the ears with tympanostomy tubes and perforations the sound pressures were always smaller than in normal ears at frequencies below 1000 Hz; the largest differences occurred below 500 Hz and ranged from -5 to -25 dB, With the supra-aural earphone, the sound pressures in ears with the three pathologic conditions were more variable than those with the insert earphone. Generally, sound pressures in the ears with mastoid bowls were lower than those in normal ears for frequencies below about 500 Hz; above about 500 Hz the pressures showed sharp minima and maxima that were not seen in the normal ears. The ears with tympanostomy tubes and tympanic-membrane perforations also showed reduced ear-canal pressures at the lower frequencies, but at higher frequencies these ear-canal pressures were generally similar to the pressures measured in the normal ears. Conclusions: When the middle ear is not normal, ear-canal sound pressures can differ by up to 35 dB from the normal-ear value. Because the pressure level generally is decreased in the pathologic conditions that were studied, the measured hearing loss would exaggerate substantially the actual loss in ear sensitivity. The variations depend on the earphone, the middle ear pathology, and frequency. Uncontrolled variations in ear-canal pressure, whether caused by a poor earphone-to-ear connection or by abnormal middle ear impedance, could be corrected with audiometers that measure sound pressures during hearing tests. C1 Massachusetts Eye & Ear Infirm, Eaton Peabody Lab Auditory Physiol, Boston, MA 02114 USA. MIT, Harvard MIT Div Hlth Sci & Technol, Speech & Hearing Sci Program, Cambridge, MA 02139 USA. MIT, Elect Res Lab, Cambridge, MA 02139 USA. Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. RP Voss, SE (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab Auditory Physiol, 243 Charles St, Boston, MA 02114 USA. NR 19 TC 17 Z9 17 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 J9 EAR HEARING JI Ear Hear. PD AUG PY 2000 VL 21 IS 4 BP 265 EP 274 DI 10.1097/00003446-200008000-00001 PG 10 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 351WW UT WOS:000089183300001 PM 10981602 ER PT J AU Piecyk, M Wax, S Beck, ARP Kedersha, N Gupta, M Maritim, B Chen, S Gueydan, C Kruys, V Streuli, M Anderson, P AF Piecyk, M Wax, S Beck, ARP Kedersha, N Gupta, M Maritim, B Chen, S Gueydan, C Kruys, V Streuli, M Anderson, P TI TIA-1 is a translational silencer that selectively regulates the expression of TNF-alpha SO EMBO JOURNAL LA English DT Article; Proceedings Paper CT EMBO Workshop on Functional Organization of the Cell Nucleus CY AUG 09-12, 1999 CL PRAGUE, CZECH REPUBLIC SP EMBO DE AU-rich element; TIA-1; TNF-alpha; translation ID TUMOR-NECROSIS-FACTOR; 3' UNTRANSLATED REGION; RNA-BINDING PROTEIN; AU-RICH ELEMENTS; P38 MAP KINASE; MESSENGER-RNA; 3'-UNTRANSLATED REGION; RHEUMATOID-ARTHRITIS; C-FOS; SEQUENCE AB TIA-1 and TIAR are related proteins that bind to an AU-rich element (ARE) in the 3' untranslated region of tumor necrosis factor alpha (TNF-alpha) transcripts. To determine the functional significance of this interaction, we used homologous recombination to produce mutant mice lacking TIA-1. Although lipopolysaccharide (LPS)-stimulated macrophages derived from wild-type and TIA-1(-/-) mice express similar amounts of TNF-alpha transcripts, macrophages lacking TIA-1 produce significantly more TNF-alpha protein than wild-type controls. The half-life of TNF-alpha transcripts is similar in wild-type and TIA-1-/- macrophages, indicating that TIA-1 does not regulate transcript stability. Rather, the absence of TIA-1 significantly increases the proportion of TNF-alpha transcripts that associate with polysomes, suggesting that TIA-1 normally functions as a translational silencer. TIA-1 does not appear to regulate the production of interleukin 1 beta, granulocyte-macrophage colony-stimulating factor or interferon gamma, indicating that its effects are, at least partially, transcript specific. Mice lacking TIA-1 are hypersensitive to the toxic effects of LPS, indicating that this translational control pathway may regulate the organismal response to microbial stress. C1 Brigham & Womens Hosp, Div Rheumatol & Immunol, Boston, MA 02115 USA. ETH Zurich, Biochem Lab, CH-8092 Zurich, Switzerland. Free Univ Brussels, IBMM, Chim Biol Lab, B-6041 Gosselies, Belgium. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Anderson, P (reprint author), Brigham & Womens Hosp, Div Rheumatol & Immunol, 1 Jimmy Fund Way, Boston, MA 02115 USA. OI Gueydan, Cyril/0000-0003-3097-7667 NR 59 TC 334 Z9 343 U1 1 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD AUG 1 PY 2000 VL 19 IS 15 BP 4154 EP 4163 DI 10.1093/emboj/19.15.4154 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 343BL UT WOS:000088681800030 PM 10921895 ER PT J AU Dodson, TB Kaban, LB AF Dodson, TB Kaban, LB TI Special considerations for the pediatric emergency patient SO EMERGENCY MEDICINE CLINICS OF NORTH AMERICA LA English DT Article ID MAXILLOFACIAL INFECTIONS; MANDIBULAR FRACTURES; CONDYLAR FRACTURES; MIDFACIAL FRACTURES; FACIAL FRACTURES; CHILDREN; CELLULITIS; GROWTH AB The etiology, diagnosis, and management of infections in children are different than in adults, and few clinicians have extensive experience in these areas. Posttraumatic growth deformities are unique to children and represent the fourth dimension of patient care, that is, changes occurring over time. Pediatric maxillofacial infections and secondary growth deformities associated with orofacial trauma are discussed. C1 Harvard Univ, Sch Dent Med, Dept Oral & Maxillofacial Surg, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. RP Dodson, TB (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, 55 Fruit St,Warren 1201, Boston, MA 02114 USA. NR 39 TC 1 Z9 1 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 0733-8627 J9 EMERG MED CLIN N AM JI Emerg. Med. Clin. N. Am. PD AUG PY 2000 VL 18 IS 3 BP 539 EP + DI 10.1016/S0733-8627(05)70142-5 PG 11 WC Emergency Medicine SC Emergency Medicine GA 347DB UT WOS:000088911200010 PM 10967738 ER PT J AU Walter, R Gottlieb, DJ O'Connor, GT AF Walter, R Gottlieb, DJ O'Connor, GT TI Environmental and genetic risk factors and gene-environment interactions in the pathogenesis of chronic obstructive lung disease SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE air pollution; alpha-1 antitrypsin; environment; genetics; lung disease; obstructive; occupational diseases ID AIR-FLOW OBSTRUCTION; FORCED EXPIRATORY VOLUME; SMALL-AIRWAYS DISEASE; D-BINDING PROTEIN; INTERMEDIATE ALPHA1-ANTITRYPSIN DEFICIENCY; CHRONIC RESPIRATORY-DISEASE; PULMONARY-FUNCTION DECLINE; EMERGENCY ROOM VISITS; AFRICAN GOLD MINERS; CHRONIC-BRONCHITIS AB Current understanding of the pathogenesis of chronic obstructive pulmonary disease (COPD), a source of substantial morbidity and mortality in the United States, suggests that chronic inflammation leads to the airways obstruction and parenchymal destruction that characterize this condition. Environmental factors, especially tobacco smoke exposure, are known to accelerate longitudinal decline of lung function, and there is substantial evidence that upregulation of inflammatory pathways plays a vital role in this process. Genetic regulation of both inflammatory responses and anti-inflammatory protective mechanisms likely underlies the heritability of COPD observed in family studies. In alpha-1 protease inhibitor deficiency, the only genetic disorder known to cause COPD, lack of inhibition of elastase activity, results in the parenchymal destruction of emphysema. Other genetic polymorphisms have been hypothesized to alter the risk of COPD but have not been established as causes of this condition. It is likely that multiple genetic factors interacting with each other and with a number of environmental agents will be found to result in the development of COPD. C1 Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. Boston Univ, Med Ctr, Dept Med, Boston, MA USA. VA Boston Healthcare Syst, Dept Med, Boston, MA USA. RP O'Connor, GT (reprint author), Boston Univ, Sch Med, Ctr Pulm, Room R 304,715 Albany St, Boston, MA 02118 USA. OI O'Connor, George/0000-0002-6476-3926 NR 224 TC 33 Z9 33 U1 0 U2 4 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 2000 VL 108 SU 4 BP 733 EP 742 DI 10.2307/3454410 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 350VH UT WOS:000089121500017 PM 10931792 ER PT J AU Fujikawa, TG Itabashi, HH Wu, AG Shinmei, SS AF Fujikawa, TG Itabashi, HH Wu, AG Shinmei, SS TI Status epilepticus-induced neuronal loss in humans without systemic complications or epilepsy SO EPILEPSIA LA English DT Article DE status epilepticus; seizures; cell death; neuronal necrosis; gliosis ID NEUROLEPTIC MALIGNANT SYNDROME; TEMPORAL-LOBE EPILEPSY; DOMOIC ACID INTOXICATION; NMDA RECEPTOR ANTAGONIST; KAINIC ACID; BRAIN-DAMAGE; LITHIUM-PILOCARPINE; ENTORHINAL CORTEX; LIMBIC SEIZURES; CELL LOSS AB Purpose: To determine the regional distribution of neuronal damage caused strictly by status epilepticus (SE) without systemic complications, underlying brain pathology, or a history of preexisting epilepsy. Methods: The medical records and electroencephalograms (EEGs) of three deceased patients who developed SE in the hospital were reviewed. Their brains were formalin-fixed, and 17 brain regions were selected, embedded in paraffin, and sectioned. Alternate sections were stained with either hematoxylin and eosin and cresyl violet to determine the extent of neuronal loss and gliosis or glial fibrillary astrocytic protein to confirm the extent of astrocytic proliferation. Results: The three patients died 11 to 27 days after the onset of focal motor SE; none had hypotension, hypoxemia, hypoglycemia, or significant hyperthermia. Two patients had no prior seizures and no underlying brain pathology. The third patient, who had leptomeningeal carcinomatosis, had one seizure 2 months before the onset of SE. The duration of SE was 8.8 hours to 3 days. EEGs showed unilateral temporal lobe sharp-wave discharges in one patient and independent temporal lobe sharp-wave discharges bilaterally in the other two patients. In addition to widespread neuronal loss and reactive gliosis in the hippocampus, amygdala, dorsomedial thalamic nucleus, and Purkinje cell layer of the cerebellum we report for the first time periamygdaloid (piriform) and entorhinal cortical damage occurring acutely after SE in humans. Conclusions: In the absence of systemic complications or preexisting epilepsy, SE produces neuronal loss in a distribution similar to that from domoic acid-induced SE in humans and from kainic acid- and pilocarpine-induced SE in rats. C1 VA Greater Los Angeles Healthcare Syst, Neurol Dept 127, Sepulveda Ambulatory Care Ctr, Sepulveda, CA 91343 USA. VA Greater Los Angeles Healthcare Syst, Neurol Dept 127, Nursing Home Care Unit, Sepulveda, CA 91343 USA. VA Greater Los Angeles Healthcare Syst, Expt Neurol Lab, Sepulveda Ambulatory Care Ctr, Sepulveda, CA 91343 USA. VA Greater Los Angeles Healthcare Syst, Expt Neurol Lab, Nursing Home Care Unit, Sepulveda, CA 91343 USA. Univ Calif Los Angeles, Sch Med, Dept Neurol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Dept Pathol, Los Angeles, CA 90024 USA. RP Fujikawa, TG (reprint author), VA Greater Los Angeles Healthcare Syst, Neurol Dept 127, Sepulveda Ambulatory Care Ctr, 16111 Plummer St, Sepulveda, CA 91343 USA. EM dfujikaw@ucla.edu NR 48 TC 22 Z9 23 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 EI 1528-1167 J9 EPILEPSIA JI Epilepsia PD AUG PY 2000 VL 41 IS 8 BP 981 EP 991 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 342TJ UT WOS:000088661000011 ER PT J AU Rowan, AJ AF Rowan, A. James TI What We Owe Our Seniors with Epilepsy-Thoughts on Quality of Life SO EPILEPSY & BEHAVIOR LA English DT Editorial Material C1 Bronx Vet Adm Med Ctr, Bronx, NY 10468 USA. RP Rowan, AJ (reprint author), Bronx Vet Adm Med Ctr, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. NR 1 TC 5 Z9 5 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 1525-5050 J9 EPILEPSY BEHAV JI Epilepsy Behav. PD AUG PY 2000 VL 1 IS 4 BP 215 EP 216 DI 10.1006/ebeh.2000.0087 PG 2 WC Behavioral Sciences; Clinical Neurology; Psychiatry SC Behavioral Sciences; Neurosciences & Neurology; Psychiatry GA V21JM UT WOS:000208203900008 ER PT J AU Walsh, C Ehab Hanna, EH Jang, IK AF Walsh, C Ehab Hanna, EH Jang, IK TI Acute coronary syndromes are common clinical presentation of in-stent stenosis SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Cardiol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG-SEP PY 2000 VL 21 SU S MA 372 BP 36 EP 36 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 351BR UT WOS:000089136600135 ER PT J AU Ammer, R Keane, D Aretz, T Ruskin, J AF Ammer, R Keane, D Aretz, T Ruskin, J TI Persistent atrial fibrillation induces apoptosis in atrial and ventricular myocytes in goats SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Tech Univ Munich, Deutsch Herzzentrum, D-8000 Munich, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG-SEP PY 2000 VL 21 SU S MA 1319 BP 241 EP 241 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 351BR UT WOS:000089136600937 ER PT J AU Hassink, RJ Aretz, TA Keane, D Ruskin, JN AF Hassink, RJ Aretz, TA Keane, D Ruskin, JN TI Extension of atrial myocardium in human pulmonary veins: A morphological and immunohistochemical analysis SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG-SEP PY 2000 VL 21 SU S MA 2036 BP 375 EP 375 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 351BR UT WOS:000089136601457 ER PT J AU Rahimtoola, SH Sethi, GK Henderson, WG Grover, FL Oprian, C Hammermeister, K AF Rahimtoola, SH Sethi, GK Henderson, WG Grover, FL Oprian, C Hammermeister, K CA Participants Vet Adm Cooperative TI Outcomes 15 years after valve replacement with a mechanical versus a bioprosthetic valve: final report of the Veterans Administration randomized trial SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 Univ So Calif, Keck Sch Med, Vet Adm Cooperat Study Valvular Heart Dis, Los Angeles, CA USA. Tucson VA Med Ctr, Vet Adm Cooperat Study Valvular Heart Dis, Tucson, AZ USA. Edward Hines Vet Adm Med Ctr, Vet Adm Cooperat Study Valvular Heart Dis, Hines, IL 60141 USA. Denver VA Med Ctr, Vet Adm Cooperat Study Valvular Heart Dis, Denver, CO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG-SEP PY 2000 VL 21 SU S MA 2076 BP 379 EP 379 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 351BR UT WOS:000089136601474 ER PT J AU Camm, AJ Ruskin, J Marchant, B Evans, D Pratt, C AF Camm, AJ Ruskin, J Marchant, B Evans, D Pratt, C TI Torsade de pointes on dofetilide occurs early and can be effectively treated SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 St George Hosp, London, England. Massachusetts Gen Hosp, Boston, MA 02114 USA. Pfizer Cent Res, Sandwich, Kent, England. Baylor Coll, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG-SEP PY 2000 VL 21 SU S MA P2356 BP 450 EP 450 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 351BR UT WOS:000089136601754 ER PT J AU Poelzl, G Kasai, Y Mochizuki, N Shaul, P Brown, M Mendelsohn, M AF Poelzl, G Kasai, Y Mochizuki, N Shaul, P Brown, M Mendelsohn, M TI Specific association of oestrogen receptor beta with the cell cycle spindle assembly checkpoint protein, Mad2 SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 Univ Innsbruck, Internal Med, Div Cardiol, Innsbruck, Austria. Tufts Univ New England Med Ctr, Mol Cardiac Res Inst, Boston, MA 02111 USA. Int Med Ctr Japan, Dept Pathol, Tokyo, Japan. SW Texas State Univ, Ctr Med, Dept Pediat, Dallas, TX USA. Dana Farber Canc Inst, Harvard Med Sch, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG-SEP PY 2000 VL 21 SU S MA 2591 BP 483 EP 483 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 351BR UT WOS:000089136601875 ER PT J AU Lo, S Lee, DP Herity, NA Ward, MR Filardo, SD Shah, P Makower, J Oesterle, SN Fitzgerald, PJ Yeung, AC AF Lo, S Lee, DP Herity, NA Ward, MR Filardo, SD Shah, P Makower, J Oesterle, SN Fitzgerald, PJ Yeung, AC TI Percutaneous in-situ coronary venous arterialization/bypass: feasibility in human arteriovenous anatomy SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract C1 Stanford Univ, Med Ctr, Dept Cardiovasc Med, Stanford, CA 94305 USA. Massachusetts Gen Hosp, Dept Cardiovasc Med, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG-SEP PY 2000 VL 21 SU S MA P2772 BP 506 EP 506 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 351BR UT WOS:000089136601967 ER PT J AU Garcia-Rodriguez, C Rao, A AF Garcia-Rodriguez, C Rao, A TI Requirement for integration of phorbol 12-myristate 13-acetate and calcium pathways is preserved in the transactivation domain of NFAT1 SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE NFAT; T lymphocyte; calcineurin; calmodulin-dependent kinase ID TRANSCRIPTION FACTOR NFAT1; ACTIVATED T-CELLS; BINDING DOMAINS; NUCLEAR FACTOR; KINASE-IV; NF-AT; CALCINEURIN; GENE; PROMOTER; SIGNALS AB The transcription factor NFAT integrates signals from both calcium- and phorbol ester-stimulated signaling pathways. The calcium signal activates the calmodulin (CaM)-dependent phosphatase calcineurin, which dephosphorylates the regulatory domain of NFAT and promotes its nuclear import, while the phorbol ester signal results in synthesis and activation of Fos and Jun, transcription factors that bind cooperatively with the NFAT DNA-binding domain in the nucleus to mediate the transcription of many target genes. Here we show that transactivation by a GAL4 fusion protein containing the strong acidic N-terminal transactivation domain (TAD) of NFAT1 also requires both calcium and phorbol ester stimulation. The calcium requirement can be mimicked by coexpression of activated versions of two CaM-dependent enzymes, calcineurin and CaM kinase IV. Our data indicate that a 144-amino acid segment of NFAT1, containing the N-terminal TAD but lacking the DNA-binding and Fos/Jun interaction domains, resembles the full-length protein in requiring a combined input from two separate signaling pathways for optimal function in cells. C1 Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Ctr Blood Res, Boston, MA 02115 USA. RP Rao, A (reprint author), Harvard Univ, Sch Med, Dept Pathol, 200 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [CA42471]; NIAID NIH HHS [AI40127] NR 26 TC 15 Z9 15 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD AUG PY 2000 VL 30 IS 8 BP 2432 EP 2436 DI 10.1002/1521-4141(2000)30:8<2432::AID-IMMU2432>3.0.CO;2-F PG 5 WC Immunology SC Immunology GA 346DZ UT WOS:000088856700035 PM 10940935 ER PT J AU Bharadwaj, AK Kasztejna, JP Huq, S Berson, EL Dryja, TP AF Bharadwaj, AK Kasztejna, JP Huq, S Berson, EL Dryja, TP TI Evaluation of the myosin VIIA gene and visual function in patients with Usher syndrome type I SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE myosin VIIA; Usher syndrome; retinitis pigmentosa; hereditary deafness; retinal degeneration; electroretinogram ID RETINITIS-PIGMENTOSA; 1B; HETEROGENEITY; LOCALIZATION; MUTATIONS; CHROMOSOME-11; FAMILIES; MAPS AB Usher syndrome type I (USH1) is a recessively-inherited disorder consisting of retinitis pigmentosa, profound congenital deafness, and vestibular ataxia. It can be caused by mutations in at least six different loci (USH1A-IF). The gene encoding human myosin VIIA (MYO7A) is the USH1B locus. In this study, hh unrelated patients with USH1 were evaluated for defects in MYO7A using single-strand conformation polymorphism analysis and direct genomic sequencing. Twenty-nine per cent of cases were found to have likely pathogenic MYO7A, mutations. A total of 22 likely pathogenic changes were identified, 18 of which were novel. Cosegregation analysis of mutations in five available families showed that the MYO7A changes segregated with the disease in an autosomal recessive fashion. Average visual function as measured by Visual acuity, visual field area, and ERG amplitude was not significantly different between the group of patients with likely pathogenic MYO7A changes and the group in which no likely pathogenic MYO7A changes were detected. (C) 2000 Academic Press. C1 Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Ocular Mol Genet Inst, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02114 USA. RP Dryja, TP (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Ocular Mol Genet Inst, 243 Charles St, Boston, MA 02114 USA. FU NEI NIH HHS [EY08683, EY00169] NR 27 TC 39 Z9 41 U1 0 U2 1 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD AUG PY 2000 VL 71 IS 2 BP 173 EP 181 DI 10.1006/exer.2000.0863 PG 9 WC Ophthalmology SC Ophthalmology GA 344BB UT WOS:000088736800007 PM 10930322 ER PT J AU Lavrovsky, Y Chatterjee, B Clark, RA Roy, AK AF Lavrovsky, Y Chatterjee, B Clark, RA Roy, AK TI Role of redox-regulated transcription factors in inflammation, aging and age-related diseases SO EXPERIMENTAL GERONTOLOGY LA English DT Review DE atherosclerosis; peroxisome proliferator; nuclear factor kappa B ID NF-KAPPA-B; VASCULAR ENDOTHELIAL-CELLS; ACTIVATED RECEPTOR-ALPHA; GLUCOCORTICOID RECEPTOR; GENE-EXPRESSION; NEGATIVE REGULATOR; ANDROGEN RECEPTOR; OXIDIZED LDL; BINDING; OXIDASE AB A progressive rise of oxidative stress due to the altered redox homeostasis appears to be one of the hallmarks of the aging process. Reactive oxygen species (ROS) also serve as signaling agents for inflammation, a systemic defensive reaction against microbial pathogens and other foreign bodies. Changes in the pattern of gene expression through ROS-sensitive transcription factors give rise to both aging and inflammation phenotypes, Chronic oxidative stress and inflammatory reaction also lead to many age-associated diseases such as atherosclerosis and arthritis. Transcription factors that are directly influenced by ROS and proinflammatory cytokines include nuclear factor kappa B (NF-kappa B), activator protein 1 (AP-1), specificity protein 1 (Sp1), peroxisome proliferator-activated receptors (PPARs) and other members of the nuclear receptor superfamily. Here we describe the basic components of the intracellular redox control machinery and their dysregulation with age leading to altered transcription factor function and age-associated pathophysiology. (C) 2000 Elsevier Science Inc. All rights reserved. C1 Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Roy, AK (reprint author), Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. FU NIA NIH HHS [R01 AG019519, R37 AG 10486]; NIAID NIH HHS [R01 AI020866, R37 AI 20866, R37 AI020866]; NIDDK NIH HHS [DK 14744] NR 57 TC 171 Z9 178 U1 0 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD AUG PY 2000 VL 35 IS 5 BP 521 EP 532 DI 10.1016/S0531-5565(00)00118-2 PG 12 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 358TU UT WOS:000089573900002 PM 10978675 ER PT J AU Fujiwara, T Lambert-Messerlian, G Sidis, Y Leykin, L Isaacson, K Toth, T Schneyer, A AF Fujiwara, T Lambert-Messerlian, G Sidis, Y Leykin, L Isaacson, K Toth, T Schneyer, A TI Analysis of follicular fluid hormone concentrations and granulosa cell mRNA levels for the inhibin-activin-follistatin system: relation to oocyte and embryo characteristics SO FERTILITY AND STERILITY LA English DT Article; Proceedings Paper CT 79th Annual Meeting of the Endocrine-Society CY JUN 10-14, 1997 CL MINNEAPOLIS, MINNESOTA SP Endocrine Soc DE inhibin; activin; follistatin; activin receptor; oocyte; follicle ID MATURED BOVINE OOCYTES; OVARIAN FOLLICLES; ALPHA-SUBUNIT; HUMAN-SERUM; IN-VITRO; DEVELOPMENTAL COMPETENCE; MEIOTIC MATURATION; PRECURSOR PROTEINS; MENSTRUAL-CYCLE; II RECEPTORS AB Objective: To explore the potential roles of inhibin, activin, and follistatin in human oocyte development by quantifying their intrafollicular biosynthesis. Design: Prospective, nonrandomized study. Setting: An IVF unit and academic research laboratory. Patient(s): Thirty one patients undergoing IVF. Intervention(s): Human menopausal gonadotropins or human FSH (or both) were administered. Single follicle aspirates (n = 110) were collected for analysis. Main Outcome Measure(s): Concentrations of dimeric, total and pro-alpha C inhibin forms; activin A; follistatin; estradiol; and progesterone were measured in follicular fluids. Granulosa-cell mRNA was analyzed for alpha, beta A, and beta B inhibin and activin subunits; follistatin; activin receptors: and beta-actin. Hormone concentrations and mRNA levels were correlated with oocytes or embryos from the same follicles. Result(s): Levels of progesterone and follistatin were significantly greater in follicles containing MI or MII oocytes than in those containing GV oocytes. Inhibin alpha-subunit mRNA levels were significantly higher in follicles containing maturing oocytes, the highest-quality oocytes, and oocytes that were subsequently fertilized. In contrast, inhibin alpha-subunit mRNA levels were significantly lower in follicles from which higher-quality embryos were obtained. Conclusion(s): Inhibin alpha-subunit biosynthesis is associated with normal oocyte and follicle maturation, but excessive cu-inhibin is associated with poor embryo quality. None of the hormones analyzed were associated with oocyte or embryo quality. (C)2000 by American Society for Reproductive Medicine. (C)2000 by American Society for Reproductive Medicine. C1 Massachusetts Gen Hosp, Reprod Endocrine Unit, Dept Med, Boston, MA 02114 USA. Brown Univ, Women & Infants Hosp, Dept Pathol & Lab Med, Providence, RI USA. Massachusetts Gen Hosp, Dept Obstet & Gynecol, IVF Unit, Boston, MA 02114 USA. RP Schneyer, A (reprint author), Massachusetts Gen Hosp, Reprod Endocrine Unit, Dept Med, BHX-5, Boston, MA 02114 USA. OI Messerlian, Geralyn/0000-0002-9440-3411 FU NICHD NIH HHS [U54HD29164, R01HD31894]; NIDDK NIH HHS [R01DK55838] NR 31 TC 20 Z9 24 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD AUG PY 2000 VL 74 IS 2 BP 348 EP 355 DI 10.1016/S0015-0282(00)00652-X PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 341MW UT WOS:000088595000026 PM 10927057 ER PT J AU Tomasetto, C Karam, SM Ribieras, S Masson, R Lefebvre, O Staub, A Alexander, G Chenard, MP Rio, MC AF Tomasetto, C Karam, SM Ribieras, S Masson, R Lefebvre, O Staub, A Alexander, G Chenard, MP Rio, MC TI Identification and characterization of a novel gastric peptide hormone: The motilin-related peptide SO GASTROENTEROLOGY LA English DT Article ID MOUSE STOMACH; EPITHELIAL-CELLS; CORPUS; DYNAMICS; EXPRESSION; PRECURSOR; MIGRATION; INTESTINE; SEQUENCES; SUBUNIT AB Background & Aims: This study looked for new proteins with expression restricted to the gastric epithelium that may provide insight to the differentiation and function of the gastric unit, Methods: A novel complementary DNA was isolated and sequenced, and its expression was examined in mouse tissues at both messenger RNA and protein levels, Subcellular localization was studied using immunoelectron microscopy. The posttraductional processing of the protein was analyzed in vitro by protein microsequencing and in vivo by Western blotting, Results: We identified a novel protein that is mainly expressed by the secretory granules of the stomach enteroendocrine cells, This protein has sequence similarity with prepromotilin, the precursor of the motilin hormone and the motilin-associated peptide. As for the prepromotilin, a posttraductional maturation leads to a secreted peptide that is further cleaved at a dibasic site and gives rise to the motilin-related peptide (MTLRP) and MTLRP-associated peptide. Conclusions: We have identified and characterized a novel gene encoding the preproMTLRP protein. MTLRP presents similarity to motilin and is specifically expressed by enteroendocrine cells of the stomach and therefore represents a novel hormone. C1 Inst Genet & Biol Mol & Cellulaire, INSERM U184, ULP, CNRS, F-67404 Illkirch, France. Kuwait Univ, Fac Med, Dept Anat, Safat, Kuwait. Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. INSERM U381, Strasbourg, France. CHU Hautepierre, Serv Anat Pathol Gen, F-67098 Strasbourg, France. RP Rio, MC (reprint author), Inst Genet & Biol Mol & Cellulaire, INSERM U184, ULP, CNRS, BP 163, F-67404 Illkirch, France. RI Lefebvre, Olivier/I-2388-2016; Chenard, Marie-Pierre/O-2373-2016; Tomasetto, Catherine/J-2783-2014 OI Lefebvre, Olivier/0000-0001-9130-9174; Tomasetto, Catherine/0000-0002-1811-5848 NR 30 TC 167 Z9 174 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 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2000 VL 119 IS 2 BP 395 EP 405 DI 10.1053/gast.2000.9371 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 350EB UT WOS:000089086800016 PM 10930375 ER PT J AU Jensen, DM AF Jensen, DM TI What to choose for diagnosis of bleeding colonic angiomas: Colonoscopy, angiography, or helical computed tomography angiography? SO GASTROENTEROLOGY LA English DT Editorial Material C1 Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA USA. VA Greater Los Angeles Healthcare Syst, CURE Digest Dis Res Ctr, Los Angeles, CA USA. RP Jensen, DM (reprint author), VA Med Ctr W Los Angeles, 11301 Wilshire Blvd,CURE Bldg 115,Room 318, Los Angeles, CA 90073 USA. FU NIDDK NIH HHS [DK33273, DK41301, 1K24DK02650] NR 9 TC 6 Z9 6 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 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2000 VL 119 IS 2 BP 581 EP 583 DI 10.1053/gast.2000.16275 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 350EB UT WOS:000089086800031 PM 10930391 ER PT J AU Kim, SK Hebrok, M Li, E Oh, SP Schrewe, H Harmon, EB Lee, JS Melton, DA AF Kim, SK Hebrok, M Li, E Oh, SP Schrewe, H Harmon, EB Lee, JS Melton, DA TI Activin receptor patterning of foregut organogenesis SO GENES & DEVELOPMENT LA English DT Article ID SONIC HEDGEHOG; PANCREAS DEVELOPMENT; MOUSE EMBRYOS; MICE; DIFFERENTIATION; GROWTH; CELLS; MORPHOGENESIS; EXPRESSION; NOTOCHORD AB Foregut development produces a characteristic sequence of gastrointestinal and respiratory organs, but the signaling pathways that ensure this developmental order remain largely unknown. Here, mutations of activin receptors ActRIIA and ActRIIB are shown to disrupt the development of posterior foregut-derived organs, including the stomach, pancreas, and spleen. Foregut expression of genes including Shh and Isl1 is shifted in mutant mice. The endocrine pancreas is particularly sensitive to the type and extent of receptor inactivation. ActRIIA(+/-)B(+/-)animals lack axial defects, but have hypoplastic pancreatic islets, hypoinsulinemia, and impaired glucose tolerance. Thus, activin receptor-mediated signaling regulates axial patterning, cell differentiation, and function of foregut-derived organs. C1 Stanford Univ, Dept Dev Biol, Stanford, CA 94305 USA. Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. Univ Florida, Dept Physiol, Gainesville, FL 32610 USA. Max Planck Inst Immunbiol, Dept Dev Biol, D-79108 Freiburg, Germany. Univ Calif San Francisco, Dept Med, Diabet Res Ctr, San Francisco, CA 94143 USA. RP Kim, SK (reprint author), Stanford Univ, Dept Dev Biol, Stanford, CA 94305 USA. NR 32 TC 149 Z9 151 U1 1 U2 6 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 AUG 1 PY 2000 VL 14 IS 15 BP 1866 EP 1871 PG 6 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 342HX UT WOS:000088640100003 PM 10921901 ER PT J AU Hsieh, HL Okamoto, H Wang, ML Ang, LH Matsui, M Goodman, H Deng, XW AF Hsieh, HL Okamoto, H Wang, ML Ang, LH Matsui, M Goodman, H Deng, XW TI FIN219, an auxin-regulated gene, defines a link between phytochrome A and the downstream regulator COP1 in light control of Arabidopsis development SO GENES & DEVELOPMENT LA English DT Article DE Arabidopsis development; COP1 repressor; FIN219 gene; light control; auxin regulation; phytochrome signaling ID LONG HYPOCOTYL MUTANTS; SIGNAL-TRANSDUCTION; PROTEIN; EXPRESSION; THALIANA; RED; DEFICIENT; BINDING; TRANSFORMATION; ELONGATION AB Light signals perceived by photoreceptors are transduced to negatively regulate COP1, a key repressor of photomorphogenic development. To identify genes involved in light inactivation of COP1, a genetic screen was employed to identify extragenic modifier mutations of a temperature-sensitive cop1 allele. One suppressor mutation isolated also exhibited a far-red-specific long hypocotyl phenotype in a wild-type background. Further phenotypic analyses of this new mutation, named fin219, suggested that it defines a novel phytochrome A signaling component. Genetic analysis indicated that FIN219 interacts closely with another phytochrome A signaling component, FHY1. Molecular characterization of FIN219 indicated that it encodes a cytoplasmic localized protein highly similar to the GH3 family of proteins and its expression is rapidly induced by auxin. In contrast to its loss-of-function mutant phenotype, overexpression of FIN219 results in a far-red-specific hyperphotomorphogenic response. Our data suggest that FIN219 may define a critical link for phytochrome A-mediated far-red inactivation of COP1 and a possible cross-talk juncture between auxin regulation and phytochrome signaling. C1 Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RIKEN, Plant Funct Explorat Team, Plant Funct Gen Res Grp, Gen Sci Ctr, Wako, Saitama 3510198, Japan. RP Deng, XW (reprint author), Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA. RI Matsui, Minami/A-5235-2016; OI Matsui, Minami/0000-0001-5162-2668; Hsieh, Hsu-Liang/0000-0003-3201-3677; Okamoto, Haruko/0000-0001-5981-6571 FU NIGMS NIH HHS [GM47850, R01 GM047850, R37 GM047850] NR 53 TC 143 Z9 155 U1 1 U2 16 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 AUG 1 PY 2000 VL 14 IS 15 BP 1958 EP 1970 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 342HX UT WOS:000088640100011 PM 10921909 ER PT J AU Varvares, MA Cheney, ML Gliklich, RE Boyd, JM Goldsmith, T Lazor, J Baron, JCM Montgomery, WW AF Varvares, MA Cheney, ML Gliklich, RE Boyd, JM Goldsmith, T Lazor, J Baron, JCM Montgomery, WW TI Use of the radial forearm fasciocutaneous free flap and Montgomery salivary bypass tube for pharyngoesophageal reconstruction SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE hypopharyngeal carcinoma; pharyngoesophageal reconstruction; radial forearm free flap; salivary bypass tube; neopharyngeal speech ID GASTRIC PULL-UP; CERVICAL ESOPHAGUS; JEJUNAL TRANSPLANTATION; ESOPHAGECTOMY; HYPOPHARYNX AB Background. Head and neck reconstructive surgeons involved in pharyngoesophageal reconstruction have several options available to repair the defect after partial or total laryngopharyngectomy. There is no uniform agreement among head and neck surgeons as to which of the most frequently used techniques offers the best results. Methods. A retrospective study was performed on 20 consecutive patients who had undergone reconstruction of the hypopharynx and cervical esophagus using a radial forearm free flap with Montgomery salivary bypass tube at the Massachusetts Eye and Ear Infirmary in Boston, Massachusetts, and St. Louis University, Department of Otolaryngology-Head and Neck Surgery between 1992 and 1996. This reconstruction was used for primary reconstruction after total or partial laryngopharyngectomy with cervical esophagectomy, partial pharyngectonny sparing the larynx, and for reconstruction of the stenotic neopharynx after laryngectomy. Results. The overall rate of pharyngocutaneous fistula was 20%, and the rate of postoperative stricture was 10%. Of patients reconstructed with this technique, 85% were able to resume oral alimentation, whereas 15% remained G-tube dependent. Of the 18 patients who did not have their larynges remain intact, 6 were able to develop useful tracheoesophageal speech. Conclusions. The results of this study show that the radial forearm fasciocutaneous free flap in combination with the Montgomery salivary bypass tube is extremely useful for reconstruction of partial and circumferential defects of the hypopharynx and cervical esophagus. (C) 2000 John Wiley & Sons, Inc. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol, Boston, MA USA. Harvard Univ, Sch Med, Dept Laryngol, Boston, MA USA. St Louis Univ, Sch Med, Dept Otolaryngol, St Louis, MO USA. Massachusetts Gen Hosp, Dept Speech & Language Pathol, Boston, MA 02114 USA. RP Varvares, MA (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. NR 20 TC 43 Z9 43 U1 0 U2 1 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1043-3074 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD AUG PY 2000 VL 22 IS 5 BP 463 EP 468 DI 10.1002/1097-0347(200008)22:5<463::AID-HED4>3.0.CO;2-S PG 6 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 336ZZ UT WOS:000088334000004 PM 10897105 ER PT J AU Emmons, KM Thompson, B McLerran, D Sorensen, G Linnan, L Basen-Engquist, K Biener, L AF Emmons, KM Thompson, B McLerran, D Sorensen, G Linnan, L Basen-Engquist, K Biener, L TI The relationship between organizational characteristics and the adoption of workplace smoking policies SO HEALTH EDUCATION & BEHAVIOR LA English DT Article ID WORKING WELL TRIAL; CIGARETTE CONSUMPTION; HEALTH; PERSPECTIVE; EMPLOYEES AB Organizational-level variables that are hypothesized to influence the level of smoking policy restrictions and the prevalence of smoking control activities were tested in a sample of 114 worksites that participated in the Working Well Trial, a national trial of worksite health promotion. predictors related to more restrictive policies included smaller size, larger percentage of white-collar workers, larger number of complaints about environmental tobacco smoke, less complexity, more formalization, and having a CEO who valued health and employees' well-being. The number of smoking control activities offered in a worksite was predicted by having a larger blue-collar workforce, a higher percentage of female employees, higher levels of workforce stability, and a CEO who valued health and employees' well-being. Efforts to identify predictors of companies' adoption and implementation of workplace-based policies and interventions are an important part of tobacco control efforts and will enhance future intervention and research efforts. C1 Dana Farber Canc Inst, Div Community Based Res, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Miriam Hosp, Providence, RI 02906 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Massachusetts, Survey Res Ctr, Boston, MA USA. RP Emmons, KM (reprint author), Dana Farber Canc Inst, Div Community Based Res, 44 Binney St, Boston, MA 02115 USA. OI Biener, Lois/0000-0002-4130-8138 NR 34 TC 34 Z9 34 U1 0 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD AUG PY 2000 VL 27 IS 4 BP 483 EP 501 DI 10.1177/109019810002700410 PG 19 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 333DR UT WOS:000088114200009 PM 10929755 ER PT J AU Gammie, SC Huang, PL Nelson, RJ AF Gammie, SC Huang, PL Nelson, RJ TI Maternal aggression in endothelial nitric oxide synthase-deficient mice SO HORMONES AND BEHAVIOR LA English DT Article DE nitric oxide; endothelial nitric oxide synthase; maternal aggression; citrulline; hypothalamus; mice ID LONG-TERM POTENTIATION; RAT-BRAIN; PARAVENTRICULAR NUCLEUS; BEHAVIOR; LACKING; GENE; KNOCKOUT; NEURONS; CELLS; FORMS AB Lactating female rodents protect their pups by expressing fierce aggression, termed maternal aggression, toward intruders. Mice lacking the neuronal nitric oxide synthase gene (nNOS-/-) exhibit significantly impaired maternal aggression, but increased male aggression, suggesting that nitric oxide (NO) produced by nNOS has opposite actions in maternal and male aggression. In contrast, mice lacking the endothelial nitric oxide synthase gene (eNOS-/-) exhibit almost no male aggression, suggesting that NO produced by eNOS facilitates male aggression. In the present study, maternal aggression in eNOS-/- mice was examined and found to be normal relative to wild-type (WT) mice in terms of the percentage displaying aggression, the average number of attacks against a male intruder, and the total amount of time spent attacking the male intruder. The eNOS-/-females also displayed normal pup retrieval behavior. Because a significant elevation of citrulline, an indirect marker of NO synthesis, occurs in neurons of the hypothalamus of lactating WT mice in association with maternal aggression, we examined the brains of eNOS-/females for citrulline immunoreactivity following an aggressive encounter. The aggressive eNOS-/- females exhibited a significant elevation of citrulline in the medial preoptic nucleus and the subparaventricular zone of the hypothalamus relative to unstimulated lactating eNOS-/- females. Taken together, these results suggest that NO produced by eNOS neither facilitates nor inhibits maternal aggression and that NO produced by eNOS has a different role in maternal and male aggression. (C) 2000 Academic press. C1 Johns Hopkins Univ, Dept Psychol, Behav Neuroendocrinol Grp, Baltimore, MD 21218 USA. Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21218 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Gammie, SC (reprint author), Johns Hopkins Univ, Dept Psychol, Behav Neuroendocrinol Grp, 3400 N Charles St,Room 225,Ames Hall, Baltimore, MD 21218 USA. OI Nelson, Randy/0000-0002-8194-4016 FU NIMH NIH HHS [MH 12371-01, MH 57760] NR 35 TC 30 Z9 30 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0018-506X J9 HORM BEHAV JI Horm. Behav. PD AUG PY 2000 VL 38 IS 1 BP 13 EP 20 DI 10.1006/hbeh.2000.1595 PG 8 WC Behavioral Sciences; Endocrinology & Metabolism SC Behavioral Sciences; Endocrinology & Metabolism GA 345HV UT WOS:000088811300002 PM 10924282 ER PT J AU Badgaiyan, RD AF Badgaiyan, RD TI Neuroanatomical organization of perceptual memory: An fMRI study of picture priming SO HUMAN BRAIN MAPPING LA English DT Article DE implicit memory; subliminal stimuli; perceptual representation; extrastriate cortex; area V3A; temporal cortex; picture identification test ID POSITRON-EMISSION-TOMOGRAPHY; EVENT-RELATED FMRI; STEM COMPLETION; IMPLICIT MEMORY; OCCIPITAL-LOBE; VISUAL-CORTEX; RETRIEVAL; EXPLICIT; PET; ACTIVATION AB Neuroanatomical organization of perceptual representation in human memory system is unclear primarily because it has been studied using paradigms that have both, perceptual and conceptual components (e.g., word stem completion and word fragment completion). In the present experiment, functional magnetic resonance imaging (fMRI) technique was used to examine the pattern of cortical activation in a picture identification test in which subjects were asked to identify subliminally presented primed and novel pictures. This test is a modification of the word identification test that is considered a "pure" form of perceptual priming. Results indicate that perceptual priming is associated with reduced activation in the extrastriate cortex and that the memory for subliminally presented stimuli is processed by the same brain areas that process adequate stimuli. The activation pattern observed in picture identification test is different from that reported in the experiments of conceptual priming, suggesting that perceptual and conceptual representation of memory are supported by separate brain mechanisms. (C) 2000 Wiley-Liss, Inc. C1 Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. Harvard Univ, Vet Affairs Med Ctr, Dept Psychiat, Sch Med, Brockton, MA 02401 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Badgaiyan, RD (reprint author), Harvard Univ, Dept Psychol, William James Hall,Room 875,33 Kirkland St, Cambridge, MA 02138 USA. FU NIMH NIH HHS [R01 MH60941, MH57915] NR 45 TC 29 Z9 30 U1 2 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD AUG PY 2000 VL 10 IS 4 BP 197 EP 203 DI 10.1002/1097-0193(200008)10:4<197::AID-HBM50>3.0.CO;2-B PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 341MY UT WOS:000088595200005 PM 10949057 ER PT J AU Cauwels, A Van Molle, W Janssen, B Everaerdt, B Huang, P Fiers, W Brouckaert, P AF Cauwels, A Van Molle, W Janssen, B Everaerdt, B Huang, P Fiers, W Brouckaert, P TI Protection against TNF-induced lethal shock by soluble guanylate cyclase inhibition requires functional inducible nitric oxide synthase SO IMMUNITY LA English DT Article ID NECROSIS-FACTOR-ALPHA; METHYLENE-BLUE; SEPTIC SHOCK; VASCULAR-RESISTANCE; INDUCED SENSITIZATION; INDUCED HYPOTENSION; RECOMBINANT HUMAN; BLOOD-PRESSURE; SMOOTH-MUSCLE; MICE LACKING AB Hypotension and shock observed in sepsis, SIRS, and tumor necrosis factor (TNF) or cytokine-based cancer treatment are the consequence of excessive nitric oxide (NO) production and subsequent soluble guanylate cyclase (sGC)-mediated vascular smooth muscle relaxation. We demonstrate here that, while NO synthase (NOS) inhibitors exacerbated toxicity, inhibitors of sGC activation protected against TNF-induced lethality, bradycardia, and hypotension. Importantly, sGC inhibition did not interfere with the antitumor activity of TNF. Using NOS inhibitors or iNOS-deficient animals, we furthermore observed that no protection against TNF toxicity could be obtained in the absence of NO. These data imply that iNOS- (and not eNOS-) derived NO is an endogenous protective molecule indispensable to survive a TNF challenge and exerting this beneficial effect via sGC-independent mechanisms. C1 State Univ Ghent VIB, Dept Mol Biol, MPET, B-9000 Ghent, Belgium. Univ Maastricht, Dept Pharmacol, Cardiovasc Res Inst Maastricht, NL-6200 MD Maastricht, Netherlands. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Med Serv, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Cauwels, A (reprint author), State Univ Ghent VIB, Dept Mol Biol, MPET, KL Legeganckstr 35, B-9000 Ghent, Belgium. EM anje@dmb.rug.ac.be; peterb@dmb.rug.ac.be NR 55 TC 45 Z9 47 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG PY 2000 VL 13 IS 2 BP 223 EP 231 DI 10.1016/S1074-7613(00)00022-4 PG 9 WC Immunology SC Immunology GA 350ZT UT WOS:000089132100007 PM 10981965 ER PT J AU Feske, S Draeger, R Peter, HH Rao, A AF Feske, S Draeger, R Peter, HH Rao, A TI Impaired NFAT regulation and its role in a severe combined immunodeficiency SO IMMUNOBIOLOGY LA English DT Article; Proceedings Paper CT XXVIIth Annual Meeting of the Clinical Immunology Working Group of the German-Society-for-Immunology CY NOV, 1999 CL FRANKFURT, GERMANY SP German Soc Immunol, Clin Immunol Working Grp ID TRANSCRIPTION FACTOR NFAT1; ACTIVATED T-CELLS; NUCLEAR EXPORT; GENE FAMILY; DEFICIENCY; RECEPTOR; COMPLEX; CALCINEURIN; EXPRESSION; MUTATIONS AB Severe Combined Immunodeficiency (SCID) is a primary immunodeficiency affecting T cells, B cells, or both. Whereas the clinical symptoms are uniformly dominated by recurrent infections, the molecular causes for SCID are very heterogeneous. Mutations in cell surface receptors, signal transduction molecules and transcription factors have been described, including the common gamma chain of the IL-2 (and IL-4, IL-7, IL-9 and IL-15) receptors, the kinase JAK-3, the epsilon and gamma chains of CD3, the protein tyrosine kinase ZAP-70, as well as CIITA and RFX5 involved in MHC class II gene expression. In this work we describe two infants with SCID whose T cells display a severe defect in T cell activation and cytokine transcription due to impaired activation of the transcription factor NFAT. We show that this defect in activation is not due to mutations in the NFAT proteins expressed in T cells or the phosphatase calcineurin which regulates the activation of NFAT. However, nuclear import of NFAT in response to T cell activation was severely compromised in the patients' T cells. A modest degree of nuclear translocation of NFAT was achieved in the patients' T cells when nuclear export was inhibited using lithium chloride. This low level of nuclear NFAT in the nucleus was not sufficient to compensate for the defect in cytokine production in the patients' T cells. However, elevated levels of extracellular calcium led to an increase in cytokine gene transcription by the SCID T cells, suggesting that the underlying genetic defect in the patients involved calcium influx or the initiation of calcium signalling. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Univ Freiburg, Dept Med, Div Clin Immunol & Rheumatol, D-7800 Freiburg, Germany. RP Feske, S (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, Warren Alpert Bldg,200 Longwood Ave, Boston, MA 02115 USA. OI Feske, Stefan/0000-0001-5431-8178 FU NCI NIH HHS [CA42471]; NIAID NIH HHS [AI40127] NR 38 TC 16 Z9 17 U1 0 U2 0 PU GUSTAV FISCHER VERLAG PI JENA PA VILLENGANG 2, D-07745 JENA, GERMANY SN 0171-2985 J9 IMMUNOBIOLOGY JI Immunobiology PD AUG PY 2000 VL 202 IS 2 BP 134 EP 150 PG 17 WC Immunology SC Immunology GA 345KE UT WOS:000088814500004 PM 10993288 ER PT J AU Moss, MH Bush, RK AF Moss, MH Bush, RK TI Patient selection and administration of aeroallergen vaccines SO IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA LA English DT Article ID GRASS-POLLEN IMMUNOTHERAPY; DOUBLE-BLIND TRIAL; CAT-INDUCED ASTHMA; ALLERGEN IMMUNOTHERAPY; HAY-FEVER; RUSH IMMUNOTHERAPY; CLADOSPORIUM-HERBARUM; CLINICAL EFFICACY; MOLD ALLERGY; PRICK TESTS AB Immunotherapy often is used as a treatment fur allergic diseases such as allergic rhinitis and asthma. The acceptance of immunotherapy for treating allergic rhinitis or asthma has been previously limited by the historical lack of adequate numbers of double-blind, placebo-controlled trials of specific allergen immunotherapy involving Large numbers of patients. Nonetheless, numerous studies have shown that immunotherapy for allergic respiratory diseases significantly reduces the severity of symptoms and medication requirements. Criteria can help in selecting patients in whom immunotherapy will be beneficial with minimal risks. C1 William S Middleton Mem Vet Hosp, Madison, WI 53705 USA. Univ Wisconsin Hosp & Clin, Allergy & Immunol Sect, Madison, WI 53792 USA. RP Bush, RK (reprint author), William S Middleton Mem Vet Hosp, 2500 Overlook Terrace, Madison, WI 53705 USA. NR 72 TC 1 Z9 1 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 0889-8561 J9 IMMUNOL ALLERGY CLIN JI Immunol. Allerg. Clin. North Am. PD AUG PY 2000 VL 20 IS 3 BP 533 EP + DI 10.1016/S0889-8561(05)70165-X PG 21 WC Allergy; Immunology SC Allergy; Immunology GA 347YT UT WOS:000088957300006 ER PT J AU Hou, L Sasaki, H Stashenko, P AF Hou, L Sasaki, H Stashenko, P TI Toll-like receptor 4-deficient mice have reduced bone destruction following mixed anaerobic infection SO INFECTION AND IMMUNITY LA English DT Article ID CELL WALL COMPONENTS; BACTERIAL LIPOPOLYSACCHARIDE; ENDOTOXIN-RESISTANT; PERIAPICAL LESIONS; INNATE IMMUNITY; DROSOPHILA TOLL; GENETIC-CONTROL; HOST DEFENSES; CUTTING EDGE; C3H/HEJ MICE AB C3H/HeJ mice have an impaired ability to respond to lipopolysaccharide (LPS) due to a mutation in the gene that encodes Toll-like receptor 4 (TLR4)., The effect of TLR4 deficiency on host responses to endodontic infections is unknown. In the present study, we compared periapical bone destruction, sepsis, and inflammatory cytokine production in LPS-hyporesponsive C3H/HeJ and wild-type control C3H/HeOuJ mice. The mandibular first molars of both strains were subjected to pulpal exposure and infection with a mixture of four anaerobic pathogens, Prevotella intermedia, Fusobacterium nucleatum, Streptococcus intermedius, and Peptostreptococcus micros. At sacrifice on day 21, TLR4-deficient C3H/HeJ mice had significantly reduced periapical bone destruction compared to wild-type C3H/HeOuJ mice (P < 0.001). The decreased bone destruction in C3H/HeJ correlated with reduced expression of the bone resorptive cytokines interleukin 1 alpha (IL-1 alpha) (P < 0.01) and IL-1 beta (P < 0.05) as well as the proinflammatory cytokine IL-12 (P < 0.05). No significant differences were seen in the levels of gamma interferon, tumor necrosis factor alpha (TNF-or), or IL-10 between the two strains. The expression of IL-1 alpha, IL-1 beta, TNF-alpha, IL-10, and IL-12 were all significantly reduced in vitro in macrophages from both TLR4-deficient C3H/HeJ and C57BL/10ScNCr strains, compared to wild-type controls. Notably, the responses of TLR4-deficient macrophages to both gram-positive and gram-negative bacteria were similarly reduced. Neither C3H/HeJ nor C3H/HeOuJ mice exhibited orofacial abscess development or infection dissemination as determined by splenomegaly or cachexia, We conclude that intact TLR function mediates increased proinflammatory responses and bone destruction in response to mixed anaerobic infections. C1 Forsyth Inst, Dept Cytokine Biol, Boston, MA 02115 USA. RP Stashenko, P (reprint author), Forsyth Inst, Dept Cytokine Biol, 140 The Fenway, Boston, MA 02115 USA. FU NIDCR NIH HHS [DE-09018, DE-11664, R01 DE009018, R01 DE011664] NR 45 TC 70 Z9 77 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD AUG PY 2000 VL 68 IS 8 BP 4681 EP 4687 DI 10.1128/IAI.68.8.4681-4687.2000 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 337AY UT WOS:000088336200042 PM 10899873 ER PT J AU Brook, RH McGlynn, EA Shekelle, PG AF Brook, RH McGlynn, EA Shekelle, PG TI Defining and measuring quality of care: a perspective from US researchers SO INTERNATIONAL JOURNAL FOR QUALITY IN HEALTH CARE LA English DT Article DE health care; health services evaluation; quality assessment; quality improvement ID UPPER GASTROINTESTINAL ENDOSCOPY; NEW-YORK-CITY; HEALTH-CARE; CAROTID ENDARTERECTOMY; CORONARY REVASCULARIZATION; MORTALITY DIFFERENCES; VOLUNTARY HOSPITALS; MANAGED CARE; NEW-MEXICO; SYSTEM AB The modern quality field in medicine is about one-third of a century old. The purpose of this paper is to summarize what we know about quality of care and indicate what we can do to improve quality of care in the next century. We assert that quality can be measured, that quality of care varies enormously, that improving quality of care is difficult, that financial incentives directed at the health system level have little effect on quality and that we lack a publicly available tool kit to assess quality. To improve quality of care we will need adequate data and that will require patients to provide information about what happened to them and to allow people to abstract their medical records. It also will require that physicians provide patient information when asked. We also need a strategy to measure quality and then report the results and we need to place in the public domain tool kits that can be used by physicians, administrators, and patient groups to assess and improve quality. Each country should have a national quality report, based on standardized comprehensive and scientifically valid measures, which describes the country's progress in improving quality of care. We can act now. For the 70-100 procedures that dominate what physicians do, we should have a computer-based, prospective system to ensure that physicians ask patients the questions required to decide whether to do the procedure. The patient should verify the responses. Answers from patients should be combined with test results and other information obtained from the patient's physician to produce an assessment of the procedure's appropriateness and necessity. Advanced tools to assess quality, based on data from the patient and medical records, are also currently being developed. These tools could be used to comprehensively assess the quality of primary care across multiple conditions at the country, regional, and medical group level. C1 RAND Corp, Hlth Program, Santa Monica, CA 90407 USA. Univ Calif Los Angeles, Ctr Hlth Sci, Los Angeles, CA USA. Greater Los Angeles Vet Adm Hlth Care Syst, Los Angeles, CA USA. RP Brook, RH (reprint author), RAND Corp, Hlth Program, 1700 Main St,POB 2138, Santa Monica, CA 90407 USA. NR 45 TC 145 Z9 152 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1353-4505 J9 INT J QUAL HEALTH C JI Int. J. Qual. Health Care PD AUG PY 2000 VL 12 IS 4 BP 281 EP 295 DI 10.1093/intqhc/12.4.281 PG 15 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 349TR UT WOS:000089062100005 PM 10985266 ER PT J AU Kaminski, MJ Mroczkowski, TF Krotoski, WA AF Kaminski, MJ Mroczkowski, TF Krotoski, WA TI Dendritic epidermal gamma/delta T cells (DETC) activated in vivo proliferate in vitro in response to Mycobacterium leprae antigens SO INTERNATIONAL JOURNAL OF DERMATOLOGY LA English DT Article ID HEAT-SHOCK PROTEIN; GAMMA-DELTA-CELLS; TUBERCULOSIS; IRRITANTS; STIMULATION; SPECIFICITY; EXPRESSION; RECEPTORS; SKIN AB Background gamma/delta T-cell receptor (TCR)+ dendritic epidermal T cells (DETC) are part of a primitive defense system in the skin; they are capable of responding only to a limited number of antigens. The aim of the present study was to test whether DETC can proliferate in vitro in response to antigens of Mycobacterium leprae. Methods DETC were obtained from CBA mouse ear skin by trypsinization and Histopaque gradient centrifugation. The resulting epidermal cell suspension contained up to 20% DETC, as analyzed by the fluorescence activated cell sorter (FACS) after staining with anti-Thy-1 or anti-gamma/delta TCR monoclonal antibodies (mAbs). The freshly isolated cells, or DETC cultured up to 4 weeks with interleukin-2 (IL-2), were exposed in vitro for up to 6 days to varying doses of the following M. leprae antigens: (1) integral (live) M. leprae bacilli; (2) Dharmendra antigen; and (3) PGL-1 (phenolic glycolipid of M. leprae). The DETC response was assessed by tritiated thymidine (H-3-TdR) incorporation. Results The freshly isolated DETC, or DETC cultured up to 4 weeks with IL-2, did not respond significantly to any of the M. leprae antigens, although at the same time they were able to respond vigorously to concanavalin A (Con A), as positive control. If, however, DETC were isolated from skin, painted 7 days before with croton oil (10 mu L/cm(2) to cause irritant dermatitis, they were able to respond to all M. leprae antigens by a 3-4-fold incrase in the H-3-TdR uptake. The most effective stimulator was a 1 : 1 mixture of Dharmendra and PGL-1 (0.01 mu g/mL), which was as effective as in-fold higher doses of either antigen alone. Cell counts confirmed that increased DNA synthesis was associated with cell proliferation. Experiments employing alpha/beta-TCR CBA murine spleen cells and epidermal cell suspension treated with anti-gamma/delta or anti alpha/beta mAbs+C' proved that only the gamma/delta DETC were the responder cells to M. leprae antigens. Conclusions The results suggest that activation of DETC in vivo may make them responsive to M. leprae antigens. A significant increase in the number of class II major histocompatibility complex (MHC) positive, nondendritic cells was observed in the croton oil-treated epidermis. We hypothesize that croson oil-induced upregulation of class II MHC expression, which endows epidermal cells with antigen-presenting capabilities, might be an important factor in vivo in delivering an immunogenic signal to resident DETC in the skin. C1 Tulane Univ, Med Ctr, Dept Dermatol, New Orleans, LA 70112 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Vet Adm Hosp, San Antonio, TX USA. Gillis W Long Hansens Dis Ctr, Carville, LA USA. RP Mroczkowski, TF (reprint author), Tulane Univ, Med Ctr, Dept Dermatol, 1430 Tulane Ave, New Orleans, LA 70112 USA. NR 29 TC 4 Z9 5 U1 0 U2 2 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0011-9059 J9 INT J DERMATOL JI Int. J. Dermatol. PD AUG PY 2000 VL 39 IS 8 BP 603 EP 608 DI 10.1046/j.1365-4362.2000.00966.x PG 6 WC Dermatology SC Dermatology GA 351KT UT WOS:000089156900008 PM 10971729 ER PT J AU Troulis, MJ Nahlieli, O Castano, F Kaban, LB AF Troulis, MJ Nahlieli, O Castano, F Kaban, LB TI Minimally invasive orthognathic surgery: endoscopic vertical ramus osteotomy SO INTERNATIONAL JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article DE ramus osteotomy; mandible; endoscopic; minimally invasive ID FRACTURES; MANAGEMENT AB The endoscopic procedure for placement and activation of a distraction device for mandibular advancement has been previously reported(20). The purpose of this study was to demonstrate the feasibility of endoscopic exposure, dissection and osteotomy for mandibular set-back. Two cadaver and three anesthetized minipigs were used in this study. Access to the mandibular ramus was achieved through a 2.0 cm submandibular incision. The dissection was carried sharply to the mandible and completed in the subperiosteal plane. Visualization was achieved using a 2.7 mm diameter endoscope (Karl Storz, Germany). Landmarks were identified and a custom-made retractor was inserted into the sigmoid notch. A vertical ramus osteotomy was created (bilaterally) from the sigmoid notch to the mandibular angle. The mandible was set back (average 6 mm) and fixed using 2.0 mm diameter, bicortical screws. Live animals were sacrificed three weeks postoperatively. The mandibles were examined clinically and radiographically to verify proper osteotomy position and clinical union. In all animals, exposure, accurate identification of landmarks, osteotomy placement and screw fixation were achieved. In the live animals (n=3), union between the proximal and distal segments was documented by clinical and radiographic examination. This study demonstrates the feasibility of the EVRO procedure for mandibular set-back in a minipig model. C1 Harvard Univ, Dept Oral & Maxillofacial Surg, Massachusetts Gen Hosp, Sch Dent Med, Boston, MA 02114 USA. Barzilai Med Ctr, Dept Oral & Maxillofacial Surg, Ashkelon, Israel. RP Kaban, LB (reprint author), Harvard Univ, Dept Oral & Maxillofacial Surg, Massachusetts Gen Hosp, Sch Dent Med, Warren Bldg 1201,55 Fruit St, Boston, MA 02114 USA. NR 22 TC 18 Z9 19 U1 0 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0901-5027 J9 INT J ORAL MAX SURG JI Int. J. Oral Maxillofac. Surg. PD AUG PY 2000 VL 29 IS 4 BP 239 EP 242 DI 10.1016/S0901-5027(00)80021-1 PG 4 WC Dentistry, Oral Surgery & Medicine; Surgery SC Dentistry, Oral Surgery & Medicine; Surgery GA 357KE UT WOS:000089498200002 PM 11030392 ER PT J AU Willers, H McCarthy, EE Alberti, M Dahm-Daphi, J Powell, SN AF Willers, H McCarthy, EE Alberti, M Dahm-Daphi, J Powell, SN TI Loss of wild-type p53 function is responsible for upregulated homologous recombination in immortal rodent fibroblasts SO INTERNATIONAL JOURNAL OF RADIATION BIOLOGY LA English DT Article ID DOUBLE-STRAND BREAKS; EMBRYO FIBROBLASTS; ATAXIA-TELANGIECTASIA; MAMMALIAN-CELLS; HIGH-FREQUENCY; DNA; PROTEIN; INSTABILITY; EXPRESSION; MECHANISMS AB Purpose; A correlation between mutations in the tumour suppressor gene p53 and high rates of homologous recombination were previously found in immortal rodent fibroblasts. In the current study, direct evidence was sought that loss of p53 function is mainly responsible for upregulated levels of homologous recombination. Materials and methods: Homologous recombination was assessed in vitro using DNA plasmid substrates that stably integrated into the genome of mouse and rat embryonic fibroblasts. Results: Primary fibroblasts with wild-type p53 displayed a recombination rate of about 1 x 10(-4). This number increased by 33- to 93-fold after spontaneous cellular immortalization, accompanied by loss of p53 function. To exclude potential bias from other gene mutations, wild-type p53 was experimentally disrupted in primary fibroblasts leading to an increase in recombination by one order of magnitude. Conversely, re-introduction of wild-type p53 into p53-null immortal cells reconstituted suppressed recombination rates. Finally, early-passage fibroblast cultures from p53-knock-out mice showed elevated recombination rates, which did not increase further following immortalization. Conclusions: Loss of wild-type P53 is the major genetic determinant of increased homologous recombination frequencies in immortal rodent fibroblasts. Cellular P53 status will be an important factor to consider when performing functional analysis of the increasing number of mammalian proteins that are found to be involved in homologous recombination. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Lab Mol & Cellular Radiat Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Univ Hamburg, Dept Radiooncol, Lab Expt Radiooncol, Hamburg, Germany. RP Powell, SN (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Lab Mol & Cellular Radiat Biol, Cox 3,100 Blossom St, Boston, MA 02114 USA. NR 36 TC 21 Z9 24 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI LONDON PA 11 NEW FETTER LANE, LONDON EC4P 4EE, ENGLAND SN 0955-3002 J9 INT J RADIAT BIOL JI Int. J. Radiat. Biol. PD AUG PY 2000 VL 76 IS 8 BP 1055 EP 1062 PG 8 WC Biology; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 344EY UT WOS:000088747300004 PM 10947118 ER PT J AU Galper, S Recht, A Silver, B Bernardo, MVP Gelman, R Wong, J Schnitt, SJ Connolly, JL Harris, JR AF Galper, S Recht, A Silver, B Bernardo, MVP Gelman, R Wong, J Schnitt, SJ Connolly, JL Harris, JR TI Is radiation alone adequate treatment to the axilla for patients with limited axillary surgery? Implications for treatment after a positive sentinel node biopsy SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article; Proceedings Paper CT 41st Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology CY OCT 30-NOV 04, 1999 CL SAN ANTONIO, TEXAS SP Amer Soc Therapeut Radiol & Oncol DE axillary radiation therapy; sentinel node biopsy ID BREAST-CANCER PATIENTS; CONSERVATIVE SURGERY; LYMPH-NODES; POSTOPERATIVE RADIOTHERAPY; ADJUVANT CHEMOTHERAPY; PREMENOPAUSAL WOMEN; 3-FIELD TECHNIQUE; RANDOMIZED TRIAL; STAGE-I; DISSECTION AB Purpose: To estimate the possible efficacy of axillary radiation therapy (AXRT) following a positive sentinel node biopsy (SNB), we evaluated the risk of regional nodal failure (RNF) for patients with clinical Stage I or II, clinically node-negative invasive breast cancer treated with either no dissection or a limited dissection (LD) defined as removal of 5 nodes or less followed by AXRT. Materials and Methods: From 1978 to 1987, 292 patients underwent AXRT in the absence of axillary dissection; 126 underwent AXRT following LD. The median dose to the axilla was 46 Gy. The median dose to the supraclavicular fossa was 45 Gy. Among patients found to have positive nodes on LD, adjuvant chemotherapy and tamoxifen were administered to 81% and 7% of subjects, respectively. All patients had potential 8-year follow-up. Results: Six of the 418 patients (1.4%) developed RNF as a first site of failure within 8 years. Among these 6 patients (1.4%) with RNF as the first site of failure, 4 had simultaneous distant and regional recurrences; and 2 had isolated axillary failures. Three of the 292 patients (1%) with no axillary dissection, none of 84 patients with pathologically negative nodes and 3 of 42 patients (7%) with pathologically involved nodes had RNP as a first site of failure. Radiation pneumonitis developed in 5 patients (1.2%), brachial plexopathy in 5 (1.2%) and arm edema in 4 (1.2%). In all cases, radiation pneumonitis and brachial plexopathy were transient. Conclusion: These results imply that AXRT may be an effective and safe alternative to completion dissection for treatment of the axilla following a positive SNB. Further studies comparing these two options in specific patient subgroups are needed. (C) 2000 Elsevier Science Inc. C1 Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. Joint Ctr Radiat Therapy, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA USA. Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA USA. MetroWest Med Ctr, Framingham, MA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Galper, S (reprint author), Dana Farber Canc Inst, Dept Biostat, 44 Binney St, Boston, MA 02115 USA. NR 28 TC 45 Z9 45 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD AUG 1 PY 2000 VL 48 IS 1 BP 125 EP 132 DI 10.1016/S0360-3016(00)00631-3 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 341AX UT WOS:000088569800018 PM 10924981 ER PT J AU Wong, JS O'Neill, A Recht, A Schnitt, SJ Connolly, JL Silver, B Harris, JR AF Wong, JS O'Neill, A Recht, A Schnitt, SJ Connolly, JL Silver, B Harris, JR TI The relationship between lymphatic vessel invasion, tumor size, and pathologic nodal status: Can we predict who can avoid a third field in the absence of axillary dissection? SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article; Proceedings Paper CT 40th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology CY OCT 24-29, 1998 CL PHOENIX, ARIZONA SP Amer Soc Therapeut Radiol & Oncol DE breast cancer; lymphatic vessel invasion; axillary lymph nodes; radiotherapy ID STAGE BREAST-CANCER; RADIATION-THERAPY; CONSERVATIVE SURGERY; CONSECUTIVE PATIENTS; CARCINOMA; METASTASES; MANAGEMENT; NODES; INVOLVEMENT; MASTECTOMY AB Purpose: Tangential (2-field) radiation therapy to the breast and lower axilla is typically used in our institution for treating patients with early-stage breast cancer who have 0-3 positive axillary nodes, as determined by axillary dissection, whereas a third supraclavicular/axillary field is added for patients with 4 or more positive nodes. However, dissection may result in complications and added expense. We, therefore, assessed whether clinical or pathologic factors of the primary tumor could reliably predict, in the absence of an axillary dissection, which patients with clinically negative axillary nodes have such limited pathologic nodal involvement that they might be effectively treated with only tangential fields. This would eliminate both the complications of axillary dissection and the added complexity and potential morbidity of a supraclavicular/axillary field. Methods and Materials: In this study, 722 women with clinical Stage I or II unilateral invasive breast cancer of infiltrating ductal histology, with clinically negative axillary nodes, at least 6 lymph nodes recovered on axillary dissection, and central pathology review were treated with breast-conserving therapy from 1968 to 1987. Pathologic nodal status was assessed in relation to clinical T stage, the presence of lymphatic vessel invasion (LVI), age, histologic grade, and the location of the primary tumor. Results: LVI, T stage, and tumor location were each significantly correlated with nodal status on univariate analysis. Ninety-seven percent of LVI-negative patients had 0-3 positive axillary nodes compared to 87% of LVI-positive patients. There was no association between T stage and extent of axillary involvement within LVI-negative and LVI-positive subgroups. In a logistic regression model, only LVI remained a significant predictor of having 4 or more positive nodes, although tumor size was of borderline significance. The odds ratio for LVI (positive vs. negative) as a predictor of having 4 or more positive nodes was 3.9 (95% CI, 2.0-7.6). Conclusion: For patients with clinical T1-2, N0, infiltrating ductal carcinomas, the presence of LVI is predictive of having 4 or more positive axillary nodes. Only 3% of patients with clinical T1-2, N0, LVI-negative breast cancers had 4 or more positive nodes on axillary dissection. Such patients may be reasonable candidates for treatment with tangential radiation fields in the absence of axillary dissection. (C) 2000 Elsevier Science Inc. C1 Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. Joint Ctr Radiat Therapy, Boston, MA 02115 USA. MetroWest Med Ctr, Dept Radiat Oncol, Framingham, MA USA. Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA USA. Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA USA. Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Wong, JS (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 44 Binney St,Level L2, Boston, MA 02115 USA. NR 38 TC 22 Z9 24 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD AUG 1 PY 2000 VL 48 IS 1 BP 133 EP 137 DI 10.1016/S0360-3016(00)00605-2 PG 5 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 341AX UT WOS:000088569800019 PM 10924982 ER PT J AU Hsu, WC Spilker, MH Yannas, IV Rubin, PAD AF Hsu, WC Spilker, MH Yannas, IV Rubin, PAD TI Inhibition of conjunctival scarring and contraction by a porous collagen-glycosaminoglycan implant SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID SMOOTH MUSCLE ACTIN; GRANULATION TISSUE; WOUND CONTRACTION; ARTIFICIAL SKIN; MYOFIBROBLASTS; FIBROBLASTS; TRANSPLANTATION; RECONSTRUCTION; REGENERATION; MEMBRANE AB PURPOSE. TO Study the healing processes of full-thickness wounds in the adult rabbit conjunctiva after grafting with a porous collagen-glycosaminoglycan (CG) copolymer matrix. METHODS. A 7-mm trephine was used to produce lesions of the bulbar conjunctiva down to the level of the bare sclera. Full-thickness removal of the conjunctiva and Tenon's capsule created a reproducible wound bed. Wounds either remained ungrafted (control) or were grafted with CG matrix. In previous studies, this CG matrix has induced partial regeneration of the dermis in the human, the swine, and the guinea pig. Healing of the conjunctival epithelium and underlying stroma was evaluated by histology, immunohistochemistry, and measurement of wound contraction kinetics. RESULTS. By 28 days, ungrafted wounds had closed by contraction (26.4% +/- 5.0% fornix shortening) and the formation of scarlike tissue comprising an aligned array of dense collagen populated with occasional fibroblasts. Grafting of identical defects with CG copolymer matrix resulted in inhibition of wound contraction (6.8% +/- 3.2% fornix shortening) and the formation of a tissue that resembled normal conjunctival stroma, being composed of a loose network of collagen fibers and fibroblasts. Contractile fibroblasts (myofibroblasts) were identified at the edge of both ungrafted and grafted wounds during the period of active contraction. Both ungrafted and grafted wounds were completely re-epithelialized by 28 days. CONCLUSIONS. Implantation of CG copolymer matrix drastically reduced contraction and promoted the formation of a nearly normal subconjunctival stroma. C1 MIT, Dept Mech Engn, Cambridge, MA 02139 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Yannas, IV (reprint author), MIT, Dept Mech Engn, 77 Massachusetts Ave,Room 3-332, Cambridge, MA 02139 USA. NR 50 TC 75 Z9 76 U1 0 U2 12 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 AUG PY 2000 VL 41 IS 9 BP 2404 EP 2411 PG 8 WC Ophthalmology SC Ophthalmology GA 340TT UT WOS:000088551600002 PM 10937547 ER PT J AU Sharon, D Bruns, GAP McGee, TL Sandberg, MA Berson, EL Dryja, TP AF Sharon, D Bruns, GAP McGee, TL Sandberg, MA Berson, EL Dryja, TP TI X-linked retinitis pigmentosa: Mutation spectrum of the RPGR and RP2 genes and correlation with visual function SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID NUCLEOTIDE-EXCHANGE FACTOR; POSITIONAL CLONING; GTPASE REGULATOR; FAMILIES; PHENOTYPE; GENOTYPE; LOCUS; RCC1; HOMOLOGY AB PURPOSE. To assess the frequency of RPGR and RP2 mutations in a set of 85 patients with X-linked retinitis pigmentosa (XLRP) and to compare the visual function of patients with mutations in RPGR versus RP2. METHODS. Eighty-five unrelated patients with XLRP were ascertained, mainly from North America. The single-strand conformation polymorphism (SSCP) and a direct sequencing technique were used to screen their DNA for mutations in the coding region and splice sites of RPGR and RP2. The Snellen visual acuities, visual field areas, and 0.5-Hz and 30-Hz electroretinograms (ERGs) mere measured in male patients. The visual function parameters were compared using multiple regression analysis. RESULTS. A wide spectrum of mutations was found in both genes, including missense, nonsense, splice-site, and frameshift mutations. Twenty putative pathogenic mutations in RPGR, 15 of which were novel, were found in 22 patients (26%), whereas 6 mutations in RP2, 4 of which were novel, were found in 6 patients (7%). A high fraction of the mutations in both genes affected amino acid residues within or adjacent to presumed functional domains. Comparison of visual function between comparably aged patients with mutations in RPGR versus RP2 showed that, on average, patients with RPGR mutations have lower ERG amplitudes and smaller visual field areas. CONCLUSIONS. Mutations in RPGR and RP2 genes together account for approximately 33% of cases of XLRP in North America. Patients with RPGR mutations have less overall retinal function on average than those with RP2 mutations, on the basis of measurements of visual field areas and full-field ERG amplitudes. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Mol Genet Inst, Boston, MA 02114 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02114 USA. Childrens Hosp, Div Genet, Boston, MA 02115 USA. RP Dryja, TP (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, 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 [EY00169, EY08683]; NICHD NIH HHS [HD18658] NR 39 TC 66 Z9 69 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 AUG PY 2000 VL 41 IS 9 BP 2712 EP 2721 PG 10 WC Ophthalmology SC Ophthalmology GA 340TT UT WOS:000088551600043 PM 10937588 ER PT J AU Bailey, GP Sewell, WF AF Bailey, GP Sewell, WF TI Pharmacological characterization of the CGRP receptor in the lateral line organ of Xenopus laevis SO JARO LA English DT Article DE cochlea; vestibular; hair cell; efferents; CGRP; metamorphic ID GENE-RELATED PEPTIDE; SUPERIOR OLIVARY COMPLEX; RAT VAS-DEFERENS; GUINEA-PIG; CALCITONIN-RECEPTOR; MULTIPLE RECEPTORS; INNER-EAR; CORONARY-ARTERY; FINE-STRUCTURE; AMYLIN AB Calcitonin gene-related peptide (CGRP) is a neurotransmitter candidate colocalized with acetylcholine in efferent fibers innervating hair cell organs. We have used the Xenopus laevis lateral line organ to investigate the responses of a hair cell organ to the CGRP family of peptides. Two isoforms of CGRP, r alpha CGRP and r beta -CGRP, and a human analog of alpha -CGRP, h(Tyr degrees) alpha -CGRP, produced dose-dependent increases in efferent nerve fiber discharge rate with EC50 values of approximately 1 muM. Rate increases were 31.2, 18.9, and 10.3%, respectively The peptide fragment rCGRP(8-37) a selective CGRP(1) receptor antagonist, competitively inhibited the response to r alpha -CGRP. Diacetoamidomethyl cysteine CGRP (r[Cys(ACM)(2,7)] alpha -CGRP), a CGRP(2) agonist, did not change discharge rate. Rat amylin did not increase rate until very high concentrations, and then the change was less than 7%. Rat adrenomedullin produced no increase in rate. Responses to r alpha -CGRP developed after metamorphosis. No change in spontaneous discharge rate was observed until postmetamorphic day 6, and then it was only a fraction of the maximal response. This response progressively increased until postmetamorphic day 28, when it reached its maximal value. The most straightforward interpretation of our results is that the effect of CGRP is mediated by the CGRP(1) receptor and that CGRP, of the peptides presently known to exist in the CGRP family, is the most likely endogenous peptide mediating these effects. C1 Massachusetts Eye & Ear Infirm, Eaton Peabody Lab Auditory Physiol, Boston, MA 02114 USA. Boston Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Otolaryngol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. RP Sewell, WF (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab Auditory Physiol, 243 Charles St, Boston, MA 02114 USA. NR 57 TC 7 Z9 7 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1525-3961 J9 JARO JI JARO PD AUG PY 2000 VL 1 IS 1 BP 82 EP 88 DI 10.1007/s101620010007 PG 7 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 425EZ UT WOS:000168278900007 PM 11548239 ER PT J AU Mosko, P AF Mosko, P TI Factors affecting patient satisfaction with follow-up by a nurse practitioner in an outpatient rheumatology clinic - Commentary SO JCR-JOURNAL OF CLINICAL RHEUMATOLOGY LA English DT Editorial Material C1 Philadelphia VA Med Ctr, Philadelphia, PA USA. RP Mosko, P (reprint author), Philadelphia VA Med Ctr, Philadelphia, PA USA. NR 13 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-1608 J9 JCR-J CLIN RHEUMATOL JI JCR-J. Clin. Rheumatol. PD AUG PY 2000 VL 6 IS 4 BP 188 EP 188 PG 1 WC Rheumatology SC Rheumatology GA 343PX UT WOS:000088711700005 ER PT J AU Fava, M Rosenbaum, JF Hoog, SL Tepner, RG Kopp, JB Nilsson, ME AF Fava, M Rosenbaum, JF Hoog, SL Tepner, RG Kopp, JB Nilsson, ME TI Fluoxetine versus sertraline and paroxetine in major depression: tolerability and efficacy in anxious depression SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE fluoxetine; sertraline; paroxetine; SSRI; antidepressant; anxious depression ID DOUBLE-BLIND; ANXIETY; ANTIDEPRESSANT; MULTICENTER; PLACEBO; FAMILY; TRIAL AB Background: Major depression with high levels of anxiety (anxious depression) is a common subtype of depression associated with greater psychosocial impairment and poorer response to antidepressant treatment. It is unclear whether in this population there are differences in efficacy or tolerability across selective serotonin reuptake inhibitors. For this reason, using head-to-head acute treatment comparison, we compared efficacy and tolerability of fluoxetine, sertraline, and paroxetine among depressed patients with high levels of anxiety. Methods: Patients (N = 108) with DSM-IV major depression and high levels of anxiety (a HAM-D-Anxiety/Somatization Factor score greater than or equal to 7) were randomized to fluoxetine, sertraline, or paroxetine treatment in a double-blind fashion. Changes in overall depression and anxiety were assessed. Results: Patients demonstrated similar baseline-to-endpoint improvement in HAM-D-17 and HAM-D-Anxiety/Somatization Factor scores. Patients also demonstrated similar change-over-time improvement in HAM-D-17 and HAM-D-Anxiety/Somatization Factor scores, except at week one where fluoxetine- and sertraline-treated patients had statistically significantly greater improvement than paroxetine-treated patients in the HAM-D-Anxiety/Somatization Factor score. There were no significant differences across treatments in percentages of patients with substantial emergence, any worsening, or improvement at endpoint in individual HAM-D Items 9 (agitation), 10 (psychic anxiety), and 11 (somatic anxiety). Overall, all treatments were well tolerated. Conclusion: These data showed no significant differences in efficacy and tolerability of fluoxetine, sertraline, and paroxetine in patients with high levels of baseline anxiety symptoms during the acute treatment of major depression. Each treatment was similarly effective in improving depression in this subtype df patients with anxious depression. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Massachusetts Gen Hosp, Clin Psychopharmacol Unit, Depress Clin & Res Program, Boston, MA 02114 USA. Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Fava, M (reprint author), Massachusetts Gen Hosp, Clin Psychopharmacol Unit, Depress Clin & Res Program, WAC 812,15 Parkman St, Boston, MA 02114 USA. NR 22 TC 87 Z9 89 U1 2 U2 6 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 AUG PY 2000 VL 59 IS 2 BP 119 EP 126 DI 10.1016/S0165-0327(99)00131-7 PG 8 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 322FX UT WOS:000087500500004 PM 10837880 ER PT J AU Ouyang, Y Virasch, N Hao, P Aubrey, MT Mukerjee, N Bierer, BE Freed, BM AF Ouyang, Y Virasch, N Hao, P Aubrey, MT Mukerjee, N Bierer, BE Freed, BM TI Suppression of human IL-1 beta, IL-2, IFN-gamma, and TNF-alpha production by cigarette smoke extracts SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE cigarette smoking; hydroquinone; catechol; nicotine; cytokine; IL-1 beta; IL-2; IFN-gamma; TNF-alpha; immunosuppression ID NECROSIS-FACTOR-ALPHA; HUMAN ALVEOLAR MACROPHAGES; TOBACCO CARCINOGENESIS; INTERFERON-GAMMA; T-LYMPHOCYTES; REACTIVE METABOLITE; MONONUCLEAR-CELLS; PERIPHERAL-BLOOD; TUMOR PROMOTERS; P-BENZOQUINONE AB Background: Although cigarette smoking is known to have detrimental effects on the immune system, the nature of the immunosuppressive agent or agents is poorly understood. Objective: The purpose of the current study was to evaluate the effects of cigarette smoke extracts from high-tar (unfiltered Camel), medium-tar (Marlboro), and low-tar (Carlton) cigarettes on the in vitro production of IL-1 beta, IL-2, IFN-gamma, and TNF-alpha. Methods: The concentrations of hydroquinone and catechol in cigarette smoke extracts were determined by using HPLC. Human PBMCs were treated with cigarette smoke extracts, hydroquinone, or catechol, and stimulated with anti-CDS and phorbol-12-myristate-13-acetate. Cytokine levels in the supernatants were quantified by ELISA. Results: Pretreatment of PBMCs with cigarette smoke extracts derived from a single high- or low-tar cigarette suppressed the production of IL-1 beta, IL-2, IFN-gamma, and TNF-alpha by greater than 90% without significant loss of cell viability. Nicotine, at a concentration comparable with that found in the highest-tar cigarettes (200 mu g/mL), suppressed the production of IL-2, IFN-gamma, and TNF-alpha by only 21% to 38%. Catechol (50 mu mol/L) inhibited production of IL-2 and IL-1 beta by 62% to 73% but had little effect on TNF-alpha or IFN-gamma production. In contrast, hydroquinone inhibited the production of all 4 cytokines with IC50 values ranging from 3 mu mol/L(IL-1 beta) to 29 mu mol/L (IFN-gamma). However, HPLC determination of the hydroquinone concentrations in cigarette smoke extracts from single Camel (33 +/- 4 mu mol/L), Marlboro (13 +/- 2 mu mol/L), and Carlton (<1 mu mol/L) cigarettes clearly demonstrated that the potent inhibitory effects of the low-tar cigarettes could not be accounted for by either hydroquinone or catechol. Conclusion: These studies indicate that cigarette smoke contains potent inhibitors of cytokine production, at least one of which is present even in low-tar cigarettes. C1 Univ Colorado, Dep Med,Hlth Sci Ctr, Div Clin Immunol & Allergy, Clin Immunol & Histocompatibil Lab, Denver, CO 80262 USA. Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA USA. RP Freed, BM (reprint author), Univ Colorado, Dep Med,Hlth Sci Ctr, Div Clin Immunol & Allergy, Clin Immunol & Histocompatibil Lab, Campus Box B164,4200 E 9th Ave, Denver, CO 80262 USA. FU NHLBI NIH HHS [HL60538]; NIEHS NIH HHS [ES05673] NR 48 TC 155 Z9 159 U1 2 U2 11 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2000 VL 106 IS 2 BP 280 EP 287 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 343NH UT WOS:000088708100010 PM 10932071 ER PT J AU Clarke, MSF Vanderburg, CR Bamman, MM Caldwell, RW Feeback, DL AF Clarke, MSF Vanderburg, CR Bamman, MM Caldwell, RW Feeback, DL TI In situ localization of cholesterol in skeletal muscle by use of a monoclonal antibody SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE immunolocalization; sarcoplasmic reticulum ID SARCOPLASMIC-RETICULUM; INTRACELLULAR CALCIUM; BIOLOGICAL-MEMBRANES; INSULIN-RESISTANCE; CARDIAC-MUSCLE; CELL-MEMBRANE; GROWTH-FACTOR; BINDING; CHANNEL; SARCOLEMMA AB A common perception is that cholesterol, the major structural lipid found in mammalian membranes, is localized nearly exclusively to the plasma membrane of living cells and that it is found in much smaller quantities in internal membranes. This perception is based almost exclusively on cell fractionation studies, in which density gradient centrifugation is used for purification of discrete subcellular membrane fractions. Here we describe a monoclonal antibody, MAb 2C5-6, previously reported to detect purified cholesterol in synthetic membranes (Swartz GM Jr, Gentry MK, Amende LM, Blanchette-Mackie EJ, and Alving CR. Proc Natl Acad Sci USA 85: 1902-1906, 1988), that is capable of detecting cholesterol in situ in the membranes of skeletal muscle sections. Localization of cholesterol, the dihydropyridine receptor of the T tubule, and the Ca2+-ATPase of the sarcoplasmic reticulum (SERCA2) by means of double and triple immunostaining protocols clearly demonstrates that cholesterol is primarily localized to the sarcoplasmic reticulum membranes of skeletal muscle rather than the sarcolemmal or T tubule membranes. The availability of this reagent and its ability to spatially localize cholesterol in situ may provide a greater understanding of the relationship between membrane cholesterol content and transmembrane signaling in skeletal muscle. C1 Univ Space Res Assoc, Div Space Life Sci, Houston, TX 77058 USA. NASA, Lyndon B Johnson Space Ctr, Life Sci Res Labs, Houston, TX 77058 USA. Massachusetts Gen Hosp, Res Space Management Grp, Boston, MA 02114 USA. Univ Alabama, Div Exercise Physiol, Birmingham, AL 35294 USA. Med Coll Georgia, Dept Pharmacol & Toxicol, Augusta, GA 30912 USA. RP Clarke, MSF (reprint author), Univ Space Res Assoc, Div Space Life Sci, 3600 Bay Area Blvd, Houston, TX 77058 USA. NR 46 TC 5 Z9 5 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD AUG PY 2000 VL 89 IS 2 BP 731 EP 741 PG 11 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 347LD UT WOS:000088930200045 PM 10926660 ER PT J AU Estok, DM Harris, WE AF Estok, DM Harris, WE TI A stem design change to reduce peak cement strains at the tip of cemented total hip arthroplasty SO JOURNAL OF ARTHROPLASTY LA English DT Article DE cement strains; distal centralizers ID 10-YEAR FOLLOW-UP; FEMORAL COMPONENT; REPLACEMENT AB A series of 3-dimensional finite element models was created to assess different designs of the tip of the stems of cemented femoral components of total hip arthroplasty that would decrease the peak axial tensile cement strains developed near the tip. Features of stem design that would facilitate positioning the femoral component in a neutral position centered in uniform cement mantle of adequate thickness also were evaluated. These studies showed that a stem that had a narrow tip profile that would accept an externally applied polymethyl methacrylate centralizer shaped similar to a napkin ring and had a gradual transition zone to join the body of the implant achieved these objectives. Such a combination resulted in the reduction of the peak axial strains to less than half the magnitude of the peak strains around a conventional tip (830 vs 1,868 microstrain). The reduction in peak axial strains was to one third the magnitude of the strains developed adjacent to a stem with a hole drilled into the tip to accept the commonly used fin-type polymethyl methacrylate centralizer (830 vs 2,466 microstrain). These goals were achieved because a stem that is designed to accept a napkin ring-style centralizer i) has a lower bending stiffness at the tip of the implant, ii) allows room for a thicker cement mantle, and iii) avoids creating a stress riser adjacent to the edge of the drill hole. The peak cement strains adjacent to a stem of this design are well below the endurance limit of cement as long as the transition zone where the narrow tip meets the body of the implant is gradual. C1 Massachusetts Gen Hosp, Dept Orthopaed Surg, Orthopaed Biomech Lab, Boston, MA 02114 USA. RP Harris, WE (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Orthopaed Biomech Lab, 55 Fruit St, Boston, MA 02114 USA. NR 17 TC 16 Z9 18 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 J9 J ARTHROPLASTY JI J. Arthroplast. PD AUG PY 2000 VL 15 IS 5 BP 584 EP 589 DI 10.1054/arth.2000.6626 PG 6 WC Orthopedics SC Orthopedics GA 349VZ UT WOS:000089067400007 PM 10959996 ER PT J AU Lewis, VO Gebhardt, MC Springfield, DS AF Lewis, VO Gebhardt, MC Springfield, DS TI Parosteal osteosarcoma of the posterior aspect of the distal part of the femur - Oncological and functional results following a new resection technique SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID OSTEO-SARCOMA AB Background: Parosteal osteosarcoma is a low-grade malignant bone tumor that arises from the surface of the metaphysis of long bones. Parosteal osteosarcoma is usually well differentiated and displays a low propensity to metastasize. Wide resection of a parosteal osteosarcoma has been shown to provide a relatively risk-free method of preventing local recurrence. We propose a new method of resection of parosteal osteosarcomas located in the popliteal paraosseous space of the distal part of the femur. This method involves resection of the mass through separate medial and lateral incisions, which allows for wide margins yet limits the amount of dissection of the soft tissues and the neurovascular bundle. Methods: Six patients with parosteal osteosarcoma located in the posterior aspect of the distal part of the femur underwent resection of the lesion and reconstruction with a posterior hemicortical allograft through dual medial and lateral incisions. The patients were evaluated with regard to pain, postoperative function, union of the allograft (osteosynthesis), and the prevalence of local recurrence. Results: The average time until the last follow-up assessment was 4.3 years. No metastases developed, and there were no local recurrences. All patients were free of disease at the last follow-up evaluation. Postoperatively, the average range of motion of the knee was 0 to 122 degrees. Five of the six patients were free of pain at the time of the latest follow-up. Five of the six patients returned to their preoperative active functional status. Conclusions: We recommend resection of a parosteal osteosarcoma located on the posterior surface of the femur through separate medial and lateral incisions. This approach provides minimal dissection of the neurovascular bundle but ample exposure for reconstruction with a hemicortical allograft. C1 Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Lewis, VO (reprint author), Univ Chicago, 5841 N Maryland Ave,MC 3079, Chicago, IL 60637 USA. NR 13 TC 17 Z9 20 U1 0 U2 0 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD AUG PY 2000 VL 82A IS 8 BP 1083 EP 1088 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 343KP UT WOS:000088701800003 PM 10954096 ER PT J AU Ramappa, AJ Lee, FYI Tang, P Carlson, JR Gebhardt, MC Mankin, HJ AF Ramappa, AJ Lee, FYI Tang, P Carlson, JR Gebhardt, MC Mankin, HJ TI Chondroblastoma of bone SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article AB Background: Chondroblastoma of bone is a rare lesion, and few large series have been reported. The purpose of this paper is to report forty-seven cases treated by one group of surgeons and to identify factors associated with more aggressive tumor behavior. Methods: Seventy-three patients,vith chondroblastoma of bone were treated between 1977 and 1998, We were able to obtain historical data, imaging studies, histological findings, and adequate personal or telephone follow-up to determine the outcome for forty-seven patients. Results: The lesions were distributed widely in the skeleton, but most were in the epiphyses or apophyses of the long bones, especially the proximal part of the tibia (eleven tumors) and the proximal part of the humerus (ten tumors). The principal presenting symptoms were pain and limitation of movement. The treatment consisted of a variety of procedures, but the majority of the patients had intralesional curettage and packing with allograft or autograft bone chips or polymethylmethacrylate, Most of the patients had an excellent functional result, although in three osteoarthritis developed in the adjacent joint. Seven patients (15 percent) had a local recurrence; three of them had a second recurrence and one, a third recurrence, One patient died of widespread metastases, and another who had metastases to multiple sites was alive and disease-free after aggressive treatment of the metastatic lesions. Conclusions: While the size of the lesion, the age and gender of the patient, the status of the growth plate, and an aneurysmal-bone-cyst component to the tumor had no significant effect on the recurrence rate, lesions around the hip (the proximal part of the femur, the greater trochanter, and the pel,is) accounted for the majority (five) of the seven recurrent tumors and one of the two metastatic lesions. C1 Massachusetts Gen Hosp, Orthopaed Oncol Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Childrens Hosp, Boston, MA USA. RP Ramappa, AJ (reprint author), Massachusetts Gen Hosp, Orthopaed Serv, Gray 604, Boston, MA 02114 USA. NR 20 TC 79 Z9 94 U1 2 U2 3 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD AUG PY 2000 VL 82A IS 8 BP 1140 EP 1145 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 343KP UT WOS:000088701800011 PM 10954104 ER PT J AU Dearborn, JT Harris, WH AF Dearborn, JT Harris, WH TI Acetabular revision after failed total hip arthroplasty in patients with congenital hip dislocation and dysplasia - Results after a mean of 8.6 years SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID COMPONENTS AB Background: Revision of a total hip arthroplasty in a patient who has had congenital hip dysplasia or dislocation is often more difficult than a standard revision operation. The purpose of this study was to assess the efficacy and complications of use of a cementless hemispherical acetabular component for revision of an acetabular component of a failed total hip replacement in patients whose initial problem was arthritis secondary to congenital dislocation or dysplasia, The mean duration of follow-up was approximately eight years. Methods: We reviewed a consecutive series of sixty-one hips in fifty-three patients who underwent a cementless acetabular revision with use of a hemispherical acetabular component, with or,without concurrent femoral revision. Data were collected prospectively, The mean age of the patients at the time of the index operation was fifty-six years. A mean of 1.9 ipsilateral hip operations had been performed previously. Thirty-nine hips (64 percent) had a so-called high hip center prior to the index revision. With one exception, the uncemented acetabular component was fixed with screws. Fifty-one acetabular components were placed with so-called line-to-line fit, and ten were oversized by one to three millimeters. In thirty eight hips, the femoral component was revised as well. Twenty-nine femora were reconstructed with use of a cemented device, and nine were revised with an uncemented patch-porous-coated femoral stem (a stem on which the porous coating appears in patches). Results: Four patients (five hips) died prior to the five-gear minimum follow-up interval. With the exception of one hip treated with resection arthroplasty because of deep infection, none of the hips in these deceased patients had been revised or had a loose component. One living patient tone hip) had a resection arthroplasty, and one additional patient (two hips) had both stable acetabular components rerevised at the. time of femoral rerevision at another institution because of loosening and osteolysis. One patient refused to return for follow-up, but the components had not been revised, The remaining fifty-two hips in forty-six patients were followed for a mean of 8.6 years (range, 5.0 to 12.7 years). The mean Harris hip score was 80 points (range, 56 to 100 points) at the time of the latest follow-up. No acetabular component had been revised, although two had migrated. No other acetabular component was loose according to our radiographic criteria. Thus, the mechanical failure rate on the acetabular side was 3 percent (two of sixty-one) for the entire series and 4 percent (two of fifty-two) for the patients who had been followed for a mean of 8.6 Sears. On the femoral side, the mechanical failure rate was 3 percent tone of twenty-nine) for the cemented stems and six of nine for the uncemented patch-porous-coated stems. Conclusions: Of the approaches used in this difficult series of patients requiring revision, the hybrid arthroplasty (a cementless acetabular component and a cemented femoral component) yielded overall good results after an intermediate duration of follow-up. C1 Massachusetts Gen Hosp, Orthopaed Biomech Lab, Boston, MA 02114 USA. RP Dearborn, JT (reprint author), Fremont Orthopaed Med Grp, 38690 Stivers St, Fremont, CA 94536 USA. NR 39 TC 20 Z9 24 U1 0 U2 0 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD AUG PY 2000 VL 82A IS 8 BP 1146 EP 1153 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 343KP UT WOS:000088701800012 PM 10954105 ER PT J AU Ring, D Jupiter, JB Quintero, J Sanders, RA Marti, RK AF Ring, D Jupiter, JB Quintero, J Sanders, RA Marti, RK TI Atrophic ununited diaphyseal fractures of the humerus with a bony defect - Treatment by wave-plate osteosynthesis SO JOURNAL OF BONE AND JOINT SURGERY-BRITISH VOLUME LA English DT Article ID GRAFTS; EXTREMITY AB We treated 15 patients with atrophic nonunion of a diaphyseal fracture of the humerus with an associated bony defect using an autogenous cancellous bone graft and a plate to bridge the defect. There were nine men and six women with a mean age of 48 years. The mean length of the bony defect was 3 cm, At a mean follow-up of 30 months only one fracture failed to unite. This suggests that, in the presence of a well-vascularised envelope of muscle, the application of an autogenous cancellous bone graft in conjunction with a bridging plate represents a good alternative to more demanding surgical techniques. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hand Surg Serv, Boston, MA 02114 USA. Hosp Clin San Rafael, Ctr Med Almirante Colon, Bogota, Colombia. Alabama Sports Med & Orthopaed Ctr, Birmingham, AL 35205 USA. Acad Med Centrum, NL-1105 AZ Amsterdam, Netherlands. RP Ring, D (reprint author), 11 Hancock St,Unit 4, Boston, MA 02114 USA. NR 30 TC 48 Z9 49 U1 0 U2 3 PU BRITISH EDITORIAL SOC BONE JOINT SURGERY PI LONDON PA 22 BUCKINGHAM STREET, LONDON WC2N 6ET, ENGLAND SN 0301-620X J9 J BONE JOINT SURG BR JI J. Bone Joint Surg.-Br. Vol. PD AUG PY 2000 VL 82B IS 6 BP 867 EP 871 DI 10.1302/0301-620X.82B6.10124 PG 5 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 345TD UT WOS:000088830500017 PM 10990313 ER PT J AU Azar, DT Primack, JD AF Azar, DT Primack, JD TI Theoretical analysis of ablation depths and profiles in laser in situ keratomileusis for compound hyperopic and mixed astigmatism SO JOURNAL OF CATARACT AND REFRACTIVE SURGERY LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY MAY, 2000 CL FT LAUDERDALE, FLORIDA SP Assoc Res Vis & Ophthalmol ID EC-5000 EXCIMER-LASER; PHOTOREFRACTIVE KERATECTOMY; FOLLOW-UP; PROGRAMS; MYOPIA AB Purpose: To compare the theoretical ablation depths and profiles of 4 treatment strategies for compound hyperopic and mixed astigmatism. Setting: Theoretical analysis. Methods: Corneal contour drawings of theoretical corneal ablation profiles during laser in situ keratomileusis (LASIK) and photoastigmatic refractive keratectomy were made. The depths of tissue ablation in 4 treatment strategies for compound hyperopic astigmatism (Groups 1 to 4) and for mixed astigmatism (Groups 5 to 8) were compared: (1) combined hyperopic spherical and myopic cylindrical treatments (Groups 1 and 5); (2) combined spherical and hyperopic cylindrical treatments (Groups 2 and 6); (3) combined cylindrical treatments (Groups 3 and 7); (4) combined cross-cylinder and spherical equivalent treatments (Groups 4 and 8). Results: In compound hyperopic astigmatism, the 4 approaches resulted in identical final curvatures, but the ablation depths were greatest in Group 1 (combined hyperopic spherical and myopic cylindrical treatments). The smallest amount of ablation occurred in Group 2 (combined hyperopic spherical and hyperopic cylindrical treatments) and Group 3 (combined hyperopic cylindrical treatments), which had similar tissue ablation patterns. In mixed astigmatism, the greatest ablation depth was in Group 5, followed by Group 8, and Groups 6 and 7. The tissue ablation depths and profiles were similar in Groups 6 and 7. Conclusion: The treatment approaches in Groups 2, 3, 6, and 7 (which avoided the use of minus cylinder) resulted in the smallest degree of stromal ablation. Patients with compound hyperopic or mixed astigmatism may benefit from reduced ablation depths by deferring treatment until hyperopic cylindrical and/or combined cylindrical treatments are available. J Cataract Refract Surg 2000; 26:1123-1136 (C) 2000 ASCRS and ESCRS. C1 Massachusetts Eye & Ear Infirm, Corneal Serv, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, External Dis Serv, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, Refract Surg Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA USA. RP Azar, DT (reprint author), Massachusetts Eye & Ear Infirm, Corneal Serv, 243 Charles St, Boston, MA 02114 USA. NR 18 TC 26 Z9 26 U1 0 U2 0 PU AMER SOC CATARACT REFRACTIVE SURGERY PI FAIRFAX PA 4000 LEGATO RD, SUITE 850, FAIRFAX, VA 22030 USA SN 0886-3350 J9 J CATARACT REFR SURG JI J. Cataract. Refract. Surg. PD AUG PY 2000 VL 26 IS 8 BP 1123 EP 1136 DI 10.1016/S0886-3350(00)00524-1 PG 14 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 356XE UT WOS:000089468800016 PM 11008038 ER PT J AU Wang, C Swerdloff, RS Iranmanesh, A Dobs, A Snyder, PJ Cunningham, G Matsumoto, AM Weber, T Berman, N AF Wang, C Swerdloff, RS Iranmanesh, A Dobs, A Snyder, PJ Cunningham, G Matsumoto, AM Weber, T Berman, N CA Testosterone Gel Study Grp TI Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CLINICAL-RESEARCH CENTER; REPLACEMENT THERAPY; LONG-TERM; ANDROGEN REPLACEMENT; PROTEIN-SYNTHESIS; PHARMACOKINETICS; SYSTEM; MASS; BEHAVIOR; EFFICACY AB Testosterone (T) therapy for hypogonadal men should correct the clinical abnormalities of T deficiency, including improvement of sexual function, increase in muscle mass and strength, and decrease in fat mass, with minimal adverse effects. We have shown that administration of a new transdermal T gel formulation to hypogonadal men provided dose proportional increases in serum T levels to the normal adult male range. We now report the effects of 180 days of treatment with this 1% T gel preparation (50 or 100 mg/day, contained in 5 or 10 g gel, respectively) compared to those of a permeation-enhanced T patch (5 mg/day) on defined efficacy parameters in 227 hypogonadal men. In the T gel groups, the T dose was adjusted up or down to 75 mg/day (contained in 7.5 g gel) on day 90 if serum T concentrations were below or above the normal male range. No dose adjustment was made with the T patch group. Sexual function and mood changes were monitored by questionnaire, body composition was determined by dual energy x-ray absorptiometry, and muscle strength was measured by the one repetitive maximum technique on bench and leg press exercises. Sexual function and mood improved maximally on day 30 of treatment, without differences across groups, and showed no further improvement with continuation of treatment. Mean muscle strength in the leg press exercise increased by 11 to 13 kg in all treatment groups by 90 days and did not improve further at 180 days of treatment. Moderate increases were also observed in arm/chest muscle strength. At 90 days of treatment, lean body mass increased more in the 100 mg/day T gel group (2.74 +/- 0.28 kg; P = 0.0002) than in the 50 mg/day T gel (1.28 +/- 0.32 kg) and T patch groups (1.20 +/- 0.26 kg). Fat mass and percent fat were not significantly decreased in the T patch group, but showed decreases in the T gel groups (50 mg/day, -0.90 +/- 0.32 kg; 100 mg/day, -1.05 +/- 0.22 kg). The increase in lean mass and the decrease in fat mass were correlated with the changes in average serum T levels attained after transdermal T replacement. These beneficial effects of T replacement were accompanied by the anticipated increases in hematocrit and hemoglobin but without significant changes in the lipid profile. The increase in mean serum prostate-specific antigen levels (within the normal range) was correlated with serum levels of T. The greatest increases were noted in the 100 mg/day T gel group. Shin irritation was reported in 5.5% of subjects treated with T gel and in 66% of subjects in the permeation-enhanced T patch group. We conclude that T gel replacement improved sexual function and mood, increased lean mass and muscle strength (principally in the legs), and decreased fat mass in hypogonadal men with less skin irritation and discontinuation compared with the recommended dose of the permeation-enhanced T patch. C1 Univ Calif Los Angeles, Los Angeles Cty Harbor Med Ctr, Dept Med, Div Endocrinol, Torrance, CA 90509 USA. Univ Calif Los Angeles, Los Angeles Cty Harbor Med Ctr, Dept Pediat, Div Endocrinol, Torrance, CA 90509 USA. Res & Educ Inst, Torrance, CA 90509 USA. Vet Affairs Med Ctr, Salem, VA 24153 USA. Johns Hopkins Univ, Baltimore, MD 21287 USA. Univ Penn, Med Ctr, Philadelphia, PA 19104 USA. Baylor Coll Med, Vet Affairs Med Ctr, Houston, TX 77030 USA. Univ Washington, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. Duke Univ, Med Ctr, Durham, NC 27705 USA. RP Wang, C (reprint author), Univ Calif Los Angeles, Los Angeles Cty Harbor Med Ctr, Dept Med, Div Endocrinol, 1000 W Carson St, Torrance, CA 90509 USA. FU PHS HHS [M0-00543] NR 44 TC 507 Z9 526 U1 6 U2 32 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2000 VL 85 IS 8 BP 2839 EP 2853 DI 10.1210/jc.85.8.2839 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 381VQ UT WOS:000165784500035 PM 10946892 ER PT J AU Christakis, DA Saint, S Saha, S Elmore, JG Welsh, DE Baker, P Koepsell, TD AF Christakis, DA Saint, S Saha, S Elmore, JG Welsh, DE Baker, P Koepsell, TD TI Do physicians judge a study by its cover? An investigation of journal attribution bias SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE evidence based medicine; meta-analysis; blinding; bias AB The effect of a journal's prestige on readers' impressions of an article is unknown. Two hypotheses were tested: first, that attribution of a study to a " high" prestige journal would be associated with improved impressions and attribution to a "low" prestige journal would be associated with diminished impressions; and second, that formal training in epidemiology and biostatistics would mitigate the effects of this journal attribution bias. The study was designed as a trial among a random sample of 264 internists. Participants were asked to read an article and an abstract from either the Southern Medical Journal (SMJ) or the New England Journal of Medicine (NEJM). Questionnaires were constructed that either attributed the article or abstract to its source or presented it as unattributed. After each article or abstract, respondents were asked to rate the quality of the study, the appropriateness of the methodology employed, the significance of the findings, and its likely effects on their practice. A 20-point impression score was created based on responses to these statements. The effect of attribution to a specific journal and formal epidemiology training on impression scores were assessed using linear regression. Of the 399 eligible participants, 264 questionnaires were returned (response rate 66%). Differences in impression scores associated with attribution of an article or abstract to the NEJM were .71 [95% C.I. (-.44-1.87)] and .50 [95% C.I. (-.87-1.87)] respectively; differences in impression scores associated with attribution of an article or abstract to the SMJ were -.12 [95% C.I. (-1.53-1.30)] and -.95 [95% C.I. (-2.41-.52)]. A stratified analysis demonstrated that epidemiology training did not meaningfully alter the effect of journal attribution on participants' impression scores. If journal attribution bias exists, it is likely to exert small and clinically insignificant effects when physicians read articles carefully. Formal training in epidemiology and biostatistics does not appear to alter these results. (C) 2000 Elsevier science Inc. All rights reserved. C1 Univ Washington, Inst Child Hlth, Seattle, WA 98103 USA. Univ Washington, Div Gen Pediat, Seattle, WA 98195 USA. Univ Michigan, Div Gen Internal Med, Ann Arbor, MI 48109 USA. Oregon Hlth Sci Univ, Portland VA Med Ctr, Div Gen Internal Med, Portland, OR 97201 USA. Univ Washington, Div Gen Internal Med, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Ann Arbor VA Hlth Serv Res & Dev, Ann Arbor, MI USA. Seattle VA Med Ctr, Seattle, WA USA. Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. RP Christakis, DA (reprint author), Univ Washington, Inst Child Hlth, 146 N Canal St,Suite 300, Seattle, WA 98103 USA. NR 11 TC 3 Z9 4 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD AUG PY 2000 VL 53 IS 8 BP 773 EP 778 DI 10.1016/S0895-4356(99)00236-X PG 6 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 347CA UT WOS:000088908400001 PM 10942858 ER PT J AU Patrick, DL Kinne, S Engelberg, RA Pearlman, RA AF Patrick, DL Kinne, S Engelberg, RA Pearlman, RA TI Functional status and perceived quality of life in adults with and without chronic conditions SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article; Proceedings Paper CT 10th National Conference on Disability and Health CY OCT 14-16, 1998 CL DALLAS, TEXAS DE health status; quality of life; chronic conditions; disability evaluation; functional status; depression ID OF-LIFE; PEOPLE; CARE; SATISFACTION; DISABILITIES; DEPRESSION; EXERCISE AB The objective of this study was to evaluate the association between self-reported functional status and quality of life in adults with and without chronic conditions. Data were obtained on functional status (Sickness Impact Profile, SIP), and perceived quality of life (Perceived Quality of Life Scale, PQoL) from 454 persons in nine groups with widely varying levels of functional status and disability. Multiple regression was used to analyze the association controlling for demographic characteristics (age, gender, educational level, income, marital status), self-rated health status, and depressive symptoms. PQoL was lowest for persons using wheelchairs and highest for older well adults. Scores decreased as SIP scores increased. Overall, being older, reporting better functional status, and having fewer depressive symptoms were significantly associated with higher quality of life (adjusted R-2 = 0.60). This pattern held for most subgroups, although the association was much lower for adults with AIDS and younger well adults where ceiling effects were observed in functional status. Functional status and perceived quality of life are highly associated but are distinct in many populations. Depressive symptoms and self-rated health are important mediators of the relationship to include in future studies. Amelioration of depressive symptoms through environmental modification and individual treatment are potential strategies for improving on this association in adults with chronic conditions. (C) 2000 Elsevier Science Inc. All rights reserved. C1 Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. Univ Washington, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. RP Patrick, DL (reprint author), Univ Washington, Dept Hlth Serv, 1959 NE Pacific,Box 357660, Seattle, WA 98195 USA. FU PHS HHS [U48/CCU00954] NR 32 TC 55 Z9 56 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD AUG PY 2000 VL 53 IS 8 BP 779 EP 785 DI 10.1016/S0895-4356(00)00205-5 PG 7 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 347CA UT WOS:000088908400002 PM 10942859 ER PT J AU Ni, HY Denis, CV Subbarao, S Degen, JL Sato, TN Hynes, RO Wagner, DD AF Ni, HY Denis, CV Subbarao, S Degen, JL Sato, TN Hynes, RO Wagner, DD TI Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID GLYCOPROTEIN-IIB-IIIA; VONWILLEBRAND-FACTOR; ARTERY SUBENDOTHELIUM; MONOCLONAL-ANTIBODY; FLOW CONDITIONS; ALPHA-GRANULES; BINDING-SITES; FACTOR-VIII; SHEAR RATE; AGGREGATION AB We used intravital microscopy to observe the formation of platelet plugs in ferric chloride-injured arterioles of live mice. With this model, we evaluated thrombus growth in mice lacking von Willebrand factor (vWF) and fibrinogen (Fg), the two key ligands known to mediate platelet adhesion and aggregation. In vWF(-/-) mice, despite the presence of arterial shear, delayed platelet adhesion occurred and stable thrombi formed, In many mice, a persisting high-shear channel never occluded. Abundant thrombi formed in Fg(-/-) mice, but they detached from the subendothelium, which ultimately caused downstream occlusion in all cases. Surprisingly, mice deficient in both VWF and Fg successfully formed thrombi with properties characteristic of both mutations, leading to vessel occlusion in the majority of vessels, platelets of these doubly deficient mice specifically accumulated fibronectin in their alpha-granules, suggesting that fibronectin could be the ligand supporting the platelet aggregation. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Univ Cincinnati, Cincinnati, OH USA. Childrens Hosp Res Fdn, Cincinnati, OH 45229 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA USA. MIT, Ctr Canc Res, Dept Biol, Cambridge, MA USA. RP Wagner, DD (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. RI Denis , Cecile/A-7649-2011; OI Denis , Cecile/0000-0001-5152-9156; Ni, Heyu/0000-0002-7621-2945 FU NHLBI NIH HHS [P01 HL-414484, R01 HL-47826, R37 HL-41002, R37 HL041002] NR 51 TC 289 Z9 297 U1 0 U2 12 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 2000 VL 106 IS 3 BP 385 EP 392 DI 10.1172/JCI9896 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 342KA UT WOS:000088642700010 PM 10930441 ER PT J AU Koh, TJ Bulitta, CJ Fleming, JV Dockray, GJ Varro, A Wang, TC AF Koh, TJ Bulitta, CJ Fleming, JV Dockray, GJ Varro, A Wang, TC TI Gastrin is a target of the beta-catenin/TCF-4 growth-signaling pathway in a model of intestinal polyposis SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID GLYCINE-EXTENDED GASTRIN; HUMAN COLON-CANCER; BETA-CATENIN; TRANSCRIPTION FACTOR; COLORECTAL-CANCER; BINDING PROTEIN; TRANSGENIC MICE; GENE-EXPRESSION; TUMOR-CELLS; C-MYC AB Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene occur in most colorectal cancers and lead to activation of beta-catenin. Whereas several downstream targets of beta-catenin have been identified (c-myc, cyclin D1, PPAR delta), the precise functional significance of many of these targets has not been examined directly using genetic approaches. Previous studies have shown that the gene encoding the hormone gastrin is activated during colon cancer progression and the less-processed forms of gastrin are important colonic trophic factors. We show here that the gastrin gene is a downstream target of the beta-catenin/TCF-4 signaling pathway and that cotransfection of a constitutively active beta-catenin expression construct causes a threefold increase in gastrin promoter activity. APC(min-/+) mice overexpressing one of the alternatively processed forms of gastrin, glycine-extended gastrin, show a significant increase in polyp number. Gastrin-deficient APC(min-/+) mice, conversely, showed a marked decrease in polyp number and a significantly decreased polyp proliferation rate. Activation of gastrin by beta-catenin may therefore represent an early event in colorectal tumorigenesis and may contribute significantly toward neoplastic progression. The identification of gastrin as a functionally relevant downstream target of the beta-catenin signaling pathway provides a new target for therapeutic modalities in the treatment of colorectal cancer. C1 Massachusetts Gen Hosp, Dept Med, Gastrointestinal Unit, Boston, MA 02114 USA. Univ Liverpool, Physiol Lab, Liverpool L69 3BX, Merseyside, England. RP Massachusetts Gen Hosp, Dept Med, Gastrointestinal Unit, Jackson 724, Boston, MA 02114 USA. EM wang@helix.mgh.harvard.edu RI Varro, Andras/M-2647-2016 OI Varro, Andras/0000-0003-0745-3603 FU NIDDK NIH HHS [R01 DK052778, R01DK52778, K08DK02545-01] NR 45 TC 137 Z9 140 U1 0 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 2000 VL 106 IS 4 BP 533 EP 539 DI 10.1172/JCI9476 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 347EB UT WOS:000088913500010 PM 10953028 ER PT J AU Hata, Y Clermont, A Yamauchi, T Pierce, EA Suzuma, I Kagokawa, H Yoshikawa, H Robinson, GS Ishibashi, T Hashimoto, T Umeda, F Bursell, SE Aiello, LP AF Hata, Y Clermont, A Yamauchi, T Pierce, EA Suzuma, I Kagokawa, H Yoshikawa, H Robinson, GS Ishibashi, T Hashimoto, T Umeda, F Bursell, SE Aiello, LP TI Retinal expression, regulation, and functional bioactivity of prostacyclin-stimulating factor SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; MESSENGER-RNA EXPRESSION; SMOOTH-MUSCLE CELLS; DIABETIC RATS; PROTEIN-KINASE; BLOOD-FLOW; IN-VIVO; VASCULAR-PERMEABILITY; NITRIC-OXIDE; FACTOR PSF AB Prostacyclin-stimulating factor (PSF) acts on vascular endothelial cells to stimulate the synthesis of the vasodilatory molecule prostacyclin (PGI2). We have examined the expression, regulation, and hemodynamic bioactivity of PSF both in whole retina and in cultured cells derived from this tissue. PSF was expressed in all retinal cell types examined in vitro, but immunohistochemical analysis revealed PSF mainly associated with retinal vessels. PSF expression was constitutive in retinal pericytes (RPCs) but could be modulated in bovine retinal capillary endothelial cells (RECs) by cell confluency, hypoxia, serum starvation, high glucose concentrations, or inversely by soluble factors present in early vs. late retinopathy, such as TGF-beta, VEGF, or bFGF. In addition, RPC-conditioned media dramatically increased REC PGI2 production, a response inhibited by blocking PSF with a specific antisense oligodeoxynucleotide (ODN). In vivo, PGI2 increased retinal blood flow (RBF) in control and diabetic animals. Furthermore, the early drop in RBF during the initial weeks after inducing diabetes in rats, as well as the later increase in RBF, both correlated with levels of retinal PSF. RBF also responded to treatment with RPC-conditioned media, and this effect could be partially blocked using the antisense PSF ODN. We conclude that PSF expressed by ocular cells can induce PGI2, retinal vascular dilation, and increased retinal blood flow, and that alterations in retinal PSF expression may explain the biphasic changes in RBF observed in diabetes. C1 Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA. Univ Penn, Scheie Eye Inst, FM Kirby Ctr Mol Ophthalmol, Philadelphia, PA 19104 USA. Kyushu Univ, Fac Med, Dept Internal Med, Fukuoka 812, Japan. Hybridon Inc, Cambridge, MA USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Aiello, LP (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. FU NEI NIH HHS [EY10827]; PHS HHS [36836] NR 58 TC 44 Z9 45 U1 0 U2 2 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 2000 VL 106 IS 4 BP 541 EP 550 DI 10.1172/JCI8338 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 347EB UT WOS:000088913500011 PM 10953029 ER PT J AU Bialek, R Ibricevic, A Aepinus, C Najvar, LK Fothergill, AW Knobloch, J Graybill, JR AF Bialek, R Ibricevic, A Aepinus, C Najvar, LK Fothergill, AW Knobloch, J Graybill, JR TI Detection of Paracoccidioides brasiliensis in tissue samples by a nested PCR assay SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID POLYMERASE CHAIN-REACTION; EXPRESSION; CLONING AB A nested PCR assay for the detection of Paracoccidioides brasiliensis DNA was evaluated, using a sequence of the immunogenic gp43 gene as a target. This gene encodes an outer membrane protein unique to this dimorphic fungus. DNA from six clinical isolates and the ATCC strain 60885 of P. brasiliensis, as well as DNA from closely related fungi, was examined to determine detection limits and cross-reactions. PCR was done on DNA extracts of lung homogenates from 23 experimentally P. brasiliensis-infected and two uninfected BALB/c mice and from 20 Histoplasma capsulatum-infected ICR mice. The results were compared to quantitative cultures. A detection limit of 0.5 fg of specific DNA was determined using cloned plasmid DNA. In all seven P. brasiliensis isolates, the expected 196-bp nested PCR product was found. Their sequences were 100% identical to the gp43 gene sequence in GenBank. DNA extracts of all other, related fungi were negative. The PCR assay was positive in 21 out of 23 culture-positive lung homogenates with concentrations of 1 x 10(3) to 1.3 x 10(7) CFU of P. brasiliensis per g of lung. Uninfected BALB/c mice and H. capsulatum-infected mice samples gave negative results. The high sensitivity and specificity of this new nested PCR assay for the detection of P. brasiliensis in tissue samples were demonstrated. The assay may be useful for diagnosis in human tissue samples. C1 Univ Tubingen Hosp, Inst Trop Med, D-72074 Tubingen, Germany. Univ Tubingen Hosp, Dept Mol Pathol, D-72074 Tubingen, Germany. Audie L Murphy Mem Vet Hosp, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX 78284 USA. RP Bialek, R (reprint author), Univ Tubingen Hosp, Inst Trop Med, Keplerstr 15, D-72074 Tubingen, Germany. NR 13 TC 50 Z9 53 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD AUG PY 2000 VL 38 IS 8 BP 2940 EP 2942 PG 3 WC Microbiology SC Microbiology GA 340XL UT WOS:000088561700025 PM 10921955 ER PT J AU Klastersky, J Paesmans, M Rubenstein, EB Boyer, M Elting, L Feld, R Gallagher, J Herrstedt, J Rapoport, B Rolston, K Talcott, J AF Klastersky, J Paesmans, M Rubenstein, EB Boyer, M Elting, L Feld, R Gallagher, J Herrstedt, J Rapoport, B Rolston, K Talcott, J CA Study Sect Infect Multinatl Assoc TI The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ANTIBIOTIC-THERAPY; PREDICTING BACTEREMIA; EMPIRIC THERAPY; FEVER; CHILDREN; CHEMOTHERAPY; CEFTAZIDIME; MANAGEMENT; AMIKACIN; IDENTIFICATION AB Purpose: Febrile neutropenia remains a potentially life-threatening complication of anticancer chemotherapy, but some patients are at low risk for serious medical complications. The purpose of this study was to develop an internationally validated scoring system to identify these patients. Materials and Methods: Febrile neutropenic cancer patients were observed in a prospective multinational study. Independent factors assessable at fever onset, predicting low risk of complications, on a randomly selected derivation set, were assigned integer weights to develop a risk-index score, which was subsequently tested on ct validation set. Results: On the derivation get (756 patients), predictive factors were a burden of illness indicating absence of symptoms or mild symptoms (weight, 5; odds ratio [OR], 8.21;95% confidence interval [CI], 4.15 to 16.38) or moderate symptoms (weight, 3; OR, 3.70; 95% CI, 2.18 to 6.29); absence of hypotension (weight, 5; OR, 7.62; 95% CI, 2.91 to 19.89); absence of chronic obstructive pulmonary disease (weight, 4; OR, 5.35; 95% CI, 1.86 to 15.46); presence of solid tumor or absence of previous fungal infection in patients with hematologic malignancies (weight, 4,OR, 5.07; 95% CI, 1.97 to 12.95); outpatient status (weight, 3; OR, 3.51; 95% Cl, 2.02 to 6.04); absence of dehydration (weight, 3; OR, 3.81; 95% Cl, 1.89 to 7.73); and age less than 60 years (weight, 2; OR, 2.45; 95% CI, 1.51 to 4.01). On the validation set, a Multinational Association for Supportive Care in Cancer risk-index score greater than or equal to 21 identified law-risk patients with a positive predictive value of 91%, specificity of 68%, and sensitivity of 71%. Conclusion: The risk index accurately identifies patients at low risk for complications and may be used to select patients for testing therapeutic strategies that may be more convenient or cast-effective, (C) 2000 by American Society of Clinical Oncology. C1 Inst Jules Bordet, Med Serv, B-1000 Brussels, Belgium. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Royal Prince Alfred Hosp, Camperdown, NSW, Australia. Ontario Canc Inst, Toronto, ON M4X 1K9, Canada. Geisinger Med Ctr, Danville, PA 17822 USA. Univ Copenhagen, Herlev Hosp, Copenhagen, Denmark. Med Oncol Ctr Rosebank, Johannesburg, South Africa. Pretoria Acad Hosp, Pretoria, South Africa. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Klastersky, J (reprint author), Inst Jules Bordet, Med Serv, 1 Rue Heger Bordet, B-1000 Brussels, Belgium. OI Rapoport, Bernardo/0000-0001-7610-3653 NR 35 TC 507 Z9 533 U1 1 U2 11 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 AUG PY 2000 VL 18 IS 16 BP 3038 EP 3051 PG 14 WC Oncology SC Oncology GA 346TE UT WOS:000088886500015 PM 10944139 ER PT J AU Pande, AC Pollack, MH Crockatt, J Greiner, M Chouinard, G Lydiard, RB Taylor, CB Dager, SR Shiovitz, T AF Pande, AC Pollack, MH Crockatt, J Greiner, M Chouinard, G Lydiard, RB Taylor, CB Dager, SR Shiovitz, T TI Placebo-controlled study of gabapentin treatment of panic disorder SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article ID ALPRAZOLAM; AGORAPHOBIA; VALPROATE; EFFICACY; ANXIETY; PHOBIA AB A randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate the efficacy and safety of gabapentin in relieving the symptoms of panic disorder. One hundred three patients were randomly assigned to receive double-blind treatment with either gabapentin (dosed flexibly between 600 and 3,600 mg/day) or placebo for 8 weeks. No overall drug/placebo difference was observed in scores on the Panic and Agoraphobia Scale (PAS) (p = 0.606). A post hoc analysis was used to evaluate the more severely ill patients as defined by the primary outcome measure (PAS score greater than or equal to 20). In this population, the gabapentin-treated patients showed significant improvement in the PAS change score (p = 0.04). In patients with a PAS score of 20 or greater, women showed a greater response than men regardless of treatment. Adverse events were consistent with the known side effect profile of gabapentin and included somnolence, headache, and dizziness. One patient experienced a serious adverse event during the study. No deaths were reported. The results of this study suggest that gabapentin may have anxiolytic effects in more severely ill patients with panic disorder. C1 Parke Davis Pharmaceut Res, Ann Arbor, MI 48105 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Louis H Lafontaine Hosp, Montreal, PQ, Canada. Univ Washington, Med Ctr, Seattle, WA 98195 USA. Med Univ S Carolina, Charleston, SC 29425 USA. Stanford Sch Med, Dept Psychiat & Behav Serv, Stanford, CA USA. RP Pande, AC (reprint author), Parke Davis Pharmaceut Res, 2800 Plymouth Rd, Ann Arbor, MI 48105 USA. EM atul.pande@wl.com NR 28 TC 172 Z9 174 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 EI 1533-712X J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD AUG PY 2000 VL 20 IS 4 BP 467 EP 471 DI 10.1097/00004714-200008000-00011 PG 5 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 334GF UT WOS:000088178200011 PM 10917408 ER PT J AU Otto, MW Pollack, MH Maki, KM AF Otto, MW Pollack, MH Maki, KM TI Empirically supported treatments for panic disorder: Costs, benefits, and stepped care SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Advancement-of-Behavior-Therapy CY NOV 05-08, 1998 CL WASHINGTON, D.C. SP Assoc Advancement Behav Therapy ID COGNITIVE-BEHAVIOR THERAPY; CONCURRENT MEDICATION TREATMENT; METHODOLOGICAL CONTROVERSIES; ALPRAZOLAM DISCONTINUATION; BENZODIAZEPINE TREATMENT; FOLLOW-UP; AGORAPHOBIA; IMIPRAMINE; METAANALYSIS; MAINTENANCE AB Treatment outcome findings suggest that cognitive-behavioral therapy (CBT) and pharmacotherapy offer similar short-term treatment gains for panic disorder and that CBT may afford more optimal maintenance of treatment gains without the need for ongoing treatment. However, efficacy is not the only consideration for patients, and because of limited health care resources, evaluation of the cost-benefit ratio of these treatments is important, in this article, the authors review estimates of the relative efficacy, acceptability, tolerability, and costs of these treatments; empirically examine the costs and outcome of cognitive-behavioral and pharmacologic interventions as they are delivered in an outpatient clinic specializing in these treatments; and comment on how these data inform a stepped can model of treatment. Analysis of the "services" data indicated that CBT was at least equal to pharmacatherapy in terms of pretreatment severity and acute treatment outcome and that CBT is an especially cost-effective treatment option. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Otto, MW (reprint author), Massachusetts Gen Hosp, WACC-815,15 Parkman St, Boston, MA 02114 USA. NR 55 TC 111 Z9 114 U1 4 U2 11 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD AUG PY 2000 VL 68 IS 4 BP 556 EP 563 DI 10.1037//0022-006X.68.4.556 PG 8 WC Psychology, Clinical SC Psychology GA 345TF UT WOS:000088830700003 PM 10965630 ER PT J AU Takeichi, O Haber, J Kawai, T Smith, DJ Moro, I Taubman, MA AF Takeichi, O Haber, J Kawai, T Smith, DJ Moro, I Taubman, MA TI Cytokine profiles of T-lymphocytes from gingival tissues with pathological pocketing SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE cytokine; periodontal disease; gingival tissue; T-lymphocytes; Th1; Th2; CD4(+); CD8(+) ID HUMAN PERIODONTAL TISSUES; ADOPTIVE TRANSFER; MESSENGER-RNA; CELL SUBSETS; HELPER CELLS; TH2 SUBSETS; IN-VIVO; DISEASE; HYPERSENSITIVITY; CLONES AB Periodontal disease is an infection in which destruction occurs at sites remote from the infection, resulting in pathological pocketing. Intervening between the infection and the destruction is a dense mononuclear inflammatory infiltrate. It has been suggested that this infiltrate might have characteristics and the destructive potential of Th1-type T lymphocytes. To ascertain the nature of the infiltrates we investigated the expression of mRNA for IL-2, IL-5, and IFN-gamma by gingival mononuclear cells (GMC) from healthy (n = 8) or adult periodontitis (AP) patients (n = 25) by using cytokine-specific reverse-transcription/polymerase-L chain-reaction (RT-PCR). GMC, as obtained from patients' tissues, expressed IL-2, IFN-gamma, or IL-5 mRNA. Significantly higher proportions of GMC from AP patients expressed IL-2 and IFN-gamma mRNA than did those from healthy subjects. IFN-gamma was the most consistent cytokine message detected. In other experiments, gingival T-lymphocytes (n = 12) and CD4(+) and CD8(+) gingival T-lymphocytes (n = 16) were isolated from gingival tissues removed surgically from AP patients. AP gingival T-lymphocytes expressed mRNA for IL-2, IFN-gamma, or IL-6 prior to stimulation. After stimulation with Con A, the cells significantly up-regulated IL-5 and IL-6 message expression. Both CD4(+) and CD8(+) gingival T-lymphocytes expressed IFN-gamma, IL-5, and some IL-2. This cumulative cytokine profile observed in these experiments is consistent with the predominance of Th1-type cells in pathological tissues and with Th2-type cells, which can also be present, being up-regulated under appropriate stimulation. Importantly, CD4(+) and CD8(+) lymphocytes were shown to express T1- and T2-type cytokine message, emphasizing the potential for CD8(+) T-lymphocytes to participate in periodontal disease pathology. C1 Forsyth Inst, Dept Immunol, Boston, MA 02115 USA. Nihon Univ, Sch Dent, Dept Endodont, Tokyo 101, Japan. Nihon Univ, Sch Dent, Dept Pathol, Tokyo 101, Japan. RP Taubman, MA (reprint author), Forsyth Inst, Dept Immunol, 140 Fenway, Boston, MA 02115 USA. FU NIDCR NIH HHS [DE-03420] NR 44 TC 92 Z9 95 U1 0 U2 3 PU AMER ASSOC DENTAL RESEARCH PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD AUG PY 2000 VL 79 IS 8 BP 1548 EP 1555 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 359GU UT WOS:000089603800004 PM 11023273 ER PT J AU Yeh, CK Johnson, DA Dodds, MWJ Sakai, S Rugh, JD Hatch, JP AF Yeh, CK Johnson, DA Dodds, MWJ Sakai, S Rugh, JD Hatch, JP TI Association of salivary flow rates with maximal bite force SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE salivary flow; bite force; aging ID MASSETER MUSCLE; PAROTID SECRETION; PERIODONTAL MECHANORECEPTORS; MASTICATORY PERFORMANCE; CRANIOMANDIBULAR INDEX; COMPUTED-TOMOGRAPHY; NATURAL DENTITION; GLAND; HUMANS; DIET AB Mean salivary secretion and bite force decrease with advancing age. Previous studies have shown that salivary flow rates are influenced by mastication. In the present study, we examined the relationship between salivary flow rates and maximal bite force in a community-based sample of men and women 35 years of age or older. Salivary flow rates for unstimulated whole and unstimulated submandibular/sublingual (SMSL) saliva as well as citrate-stimulated parotid and SMSL saliva were measured in 399 subjects. Bite force was assessed with a bilateral force transducer. Pearson correlation analysis yielded significant positive correlations between bite force and flow rates for unstimulated whole saliva (r = 0.24, p < 0.0001), stimulated parotid saliva (r = 0.13, p < 0.03), unstimulated SMSL (r = 0.14, p < 0.0001), and stimulated SMSL (r = 0.16, p < 0.003). When adjusted for age and gender, the partial correlations between bite force and salivary flow rates remained significant for unstimulated whole saliva (r = 0.10, p < 0.05), stimulated parotid saliva (r = 0.13, p < 0.02), and stimulated SMSL saliva (r = 0.14, p < 0.006). Subjects were divided into four groups based on their maximal bite force score (low, medium low, medium high, and high). For each saliva type, the flow rate of the high-bite-force group was significantly greater than that of the low-bite-force group as well as that of the medium-high-bite-force group. These results confirm an age-related decrease in bite force and salivary flow rates and show that, regardless of age or gender, bite force is correlated with salivary flow. C1 Univ Texas, Hlth Sci Ctr, Dept Dent Diagnost Sci 7919, Sch Dent, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Community Dent, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Orthodont, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Psychiat, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, Ctr Geriatr Res Educ & Clin, San Antonio, TX USA. RP Yeh, CK (reprint author), Univ Texas, Hlth Sci Ctr, Dept Dent Diagnost Sci 7919, Sch Dent, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. NR 66 TC 57 Z9 60 U1 1 U2 3 PU AMER ASSOC DENTAL RESEARCH PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD AUG PY 2000 VL 79 IS 8 BP 1560 EP 1565 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 359GU UT WOS:000089603800006 PM 11023275 ER PT J AU Takata, T Zhao, M Uchida, T Wang, T Aoki, T Bartlett, JD Nikai, H AF Takata, T Zhao, M Uchida, T Wang, T Aoki, T Bartlett, JD Nikai, H TI Immunohistochemical detection and distribution of enamelysin (MMP-20) in human odontogenic tumors SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE MMP-20; enamelysin; odontogenic tumor; immunohistochemistry; antibody ID BOVINE ENAMEL; AMELOGENIN; PROTEINS; TOOTH; LOCALIZATION; GENE; METALLOPROTEINASE; AMELOBLASTIN; SEQUENCES; CRYSTALS AB Enamelysin is a tooth-specific protease that was initially isolated from porcine enamel organ and subsequently from human odontoblasts. Since this protease is thought to play important roles in tooth development, the evaluation of enamelysin in odontogenic tumors may aid our understanding of the histogenesis and cell differentiation of such lesions. A monoclonal antibody (203-1C7) was generated against synthesized human enamelysin oligopeptide and was used to assess the immunolocalization of enamelysin in healthy developing tooth germs and various types of odontogenic lesions. In tooth germs, enamelysin expression was detected only in the secretory enamel. Thus, 203-1C7 may serve as an enamel-specific marker in the late stage of enamel matrix development and calcification. In odontogenic lesions, strong enamelysin staining was demonstrated in the immature enamel matrix of ameloblastic fibro-odontomas and odontomas. Furthermore, enamelysin was also detected in globular amyloid masses and calcified foci in calcifying epithelial odontogenic tumors, hyaline droplets, small and large mineralized areas in adenomatoid odontogenic tumors, and a portion of ghost cells in calcifying odontogenic cysts. Positive reactivity was also observed in selected tumor cells in some of these tumors. No intracellular staining for enamelysin was detected in ameloblastomas or the ameloblastic portion of ameloblastic fibro-odontomas. Also, enamelysin was not detected in dentin, dysplastic dentinoid hyaline matrices, and cementum that were present within the tumors examined. Thus, taken together, our results suggest that the enamelysin-specific monoclonal antibody (203-1C7) may be utilized as a marker of early enamel development and that enamelysin may be involved in the pathogenesis of specific odontogenic tumors. C1 Hiroshima Univ, Fac Dent, Dept Oral Pathol, Minami Ku, Hiroshima 7348553, Japan. Hiroshima Univ, Fac Dent, Dept Oral Anat, Minami Ku, Hiroshima 7348553, Japan. Fuji Chem Ind Ltd, Toyama 9338511, Japan. Forsyth Inst, Dept Biomineralizat, Boston, MA 02115 USA. Forsyth Inst, Harvard Forsyth Dept Oral Biol, Boston, MA 02115 USA. RP Takata, T (reprint author), Hiroshima Univ, Fac Dent, Dept Oral Pathol, Minami Ku, 1-2-3 Kasumi, Hiroshima 7348553, Japan. FU NIDCR NIH HHS [R29 DE012098] NR 33 TC 37 Z9 41 U1 0 U2 0 PU AMER ASSOC DENTAL RESEARCH PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD AUG PY 2000 VL 79 IS 8 BP 1608 EP 1613 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 359GU UT WOS:000089603800014 PM 11023283 ER PT J AU Gale, ME Gale, DR AF Gale, ME Gale, DR TI DICOM modality worklist: An essential component in a PACS environment SO JOURNAL OF DIGITAL IMAGING LA English DT Article DE DICOM; PACS; worklist AB The development and acceptance of the digital communication in medicine (DICOM) standard has become a basic requirement for the implementation of electronic imaging in radiology. DICOM is now evolving to provide a standard for electronic communication between radiology and other parts of the hospital enterprise. In a completely integrated filmless radiology department, there are 3 core computer systems, the picture archiving and communication system (PACS), the hospital or radiology information system (HIS, RIS), and the acquisition modality. Ideally, each would have bidirectional communication with the other 2 systems. At a minimum, a PACS must be able to receive and acknowledge receipt of image and demographic data from the modalities. Similarly, the modalities must be able to send images and demographic data to the PACS. Now that basic DICOM communication protocols for query or retrieval, storage, and print classes have become established through both conformance statements and intervendor testing, there has been an increase in interest in enhancing the functionality of communication between the 3 computers. Historically, demographic data passed to the PACS have been generated manually at the modality despite the existence of the same data on the HIS or RIS, In more current sophisticated implementations, acquisition modalities are able to receive patient and study-related data from the HIS or RIS. DICOM Modality Worklist is the missing electronic link that transfers this critical information between the acquisition modalities and the HIS or RIS. This report describes the concepts, issues, and impact of DICOM Modality Worklist implementation in a PACS environment. Copyright (C) 2000 by W.B. Saunders Company. C1 VA Boston Hlth Care Syst, Radiol Serv 114, Boston, MA 02130 USA. RP Gale, ME (reprint author), VA Boston Hlth Care Syst, Radiol Serv 114, 150 S Huntingdon Ave, Boston, MA 02130 USA. NR 7 TC 16 Z9 17 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 0897-1889 J9 J DIGIT IMAGING JI J. Digit. Imaging PD AUG PY 2000 VL 13 IS 3 BP 101 EP 108 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 344PW UT WOS:000088768900001 PM 15359747 ER PT J AU Noble, VE Bontempo, LJ Nadel, ES Brown, DF AF Noble, VE Bontempo, LJ Nadel, ES Brown, DF TI Stridor SO JOURNAL OF EMERGENCY MEDICINE LA English DT Editorial Material 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 8 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0736-4679 J9 J EMERG MED JI J. Emerg. Med. PD AUG PY 2000 VL 19 IS 2 BP 183 EP 186 DI 10.1016/S0736-4679(00)00220-1 PG 4 WC Emergency Medicine SC Emergency Medicine GA 337DY UT WOS:000088343200017 PM 10903470 ER PT J AU Asch, S Connor, SE Hamilton, EG Fox, SA AF Asch, S Connor, SE Hamilton, EG Fox, SA TI Problems in recruiting community-based physicians for health services research SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Review DE physician recruitment methods; health services research ID MAIL SURVEYS; RANDOMIZED TRIAL; RESPONSE RATES; OBSTETRIC CARE; PRACTITIONERS; PREVENTION; WOMEN AB OBJECTIVE: To qualitatively determine factors that are associated with higher participation rates in community-based health services research requiring significant physician participation burden. MEASUREMENTS: A review of the literature was undertaken using medline and the Social Science Research Index to identify health services research studies that recruited large community-based samples of individual physicians and in which the participation burden exceeded that of merely completing a survey. Two reviewers abstracted data on the recruitment methods, and first authors were contacted to supplement published information. MAIN RESULTS: Sixteen studies were identified with participation rates from 2.5% to 91%. Almost all studies used physician recruiters to personally contact potential participants. Recruiters often knew some of the physicians to be recruited, and personal contact with these "known" physicians resulted in greater participation rates. Incentives were generally absent or modest, and at modest levels, did not appear to affect participation rates. Investigators were almost always affiliated with academic institutions, but were divided as to whether this helped or hindered recruitment. HMO-based and minority physicians were more difficult to recruit. Potential participants most often cited time pressures on staff and themselves as the study burden that caused them to decline. CONCLUSIONS: Physician personal contact and friendship networks are powerful tools for recruitment. Participation rates might improve by including HMO and minority physicians in the recruitment process. Investigators should transfer as much of the study burden from participating physicians to project staff as possible. C1 RAND Corp, Santa Monica, CA 90407 USA. W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. PacifiCare Behav Hlth, Van Nuys, CA USA. RP Asch, S (reprint author), RAND Corp, 1700 Main St,POB 2138, Santa Monica, CA 90407 USA. FU NCI NIH HHS [1 RO1 CA65879] NR 25 TC 88 Z9 88 U1 2 U2 10 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD AUG PY 2000 VL 15 IS 8 BP 591 EP 599 DI 10.1046/j.1525-1497.2000.02329.x PG 9 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 349PF UT WOS:000089054300010 PM 10940152 ER PT J AU Rubin, RH AF Rubin, RH TI Prevention and treatment of cytomegalovirus disease in heart transplant patients SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article ID RECIPIENTS; INFECTION; GANCICLOVIR; ANTIBODY; PROPHYLAXIS; THERAPY AB Cytomegalovirus (CMV) remains the most important infection affecting heart-transplant recipients. Treatment of clinical disease is with a two to three-week course of intravenous ganciclovir, which is effective in more than 90% of individuals. However, relapsing disease, particularly in those with primary infection, is an increasing problem, occasionally with the development of ganciclovir-resistant infection. In those instances, foscarnet is needed, despite its nephro- and neurotoxicities. Increasingly, in order to prevent relapse, more prolonged oral courses of anti-viral therapy are being added to the standard two to three-week course of intravenous treatment. In the prevention of CMV disease, those at risk of primary disease (donor seropositive, recipient seronegative) should receive prophylaxis; for seropositive transplant patients, preemptive strategies linked to immunosuppression or viremia monitoring are becoming increasingly prevalent. In the future, as new drugs become available, the essential question will be whether chronic allograft injury (i.e., accelerated coronary artery atherosclerosis) can be prevented with an anti-viral strategy. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Mit Div Hlth Sci & Technol, Ctr Expt Pharmacol & Therapeut, Boston, MA USA. Gordon & Marjorie Osborne Chair Hlth Sci & Techno, Boston, MA USA. RP Rubin, RH (reprint author), Massachusetts Gen Hosp, 32 Fruit St, Boston, MA 02114 USA. NR 15 TC 43 Z9 43 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD AUG PY 2000 VL 19 IS 8 BP 731 EP 735 DI 10.1016/S1053-2498(00)00096-6 PG 5 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 349JF UT WOS:000089041400002 PM 10967265 ER PT J AU Moran, AM Lipshultz, SE Rifai, N O'Brien, P Mooney, H Perry, S Perez-Atayde, A Lipsitz, SR Colan, SD AF Moran, AM Lipshultz, SE Rifai, N O'Brien, P Mooney, H Perry, S Perez-Atayde, A Lipsitz, SR Colan, SD TI Non-invasive assessment of rejection in pediatric transplant patients: Serologic and echocardiographic prediction of biopsy-proven myocardial rejection SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article ID CARDIAC TROPONIN-T; INFANT HEART-TRANSPLANTATION; ALLOGRAFT-REJECTION; INTERNATIONAL SOCIETY; ENDOMYOCARDIAL BIOPSY; VASCULAR REJECTION; INJURY; MARKER AB Background: Cardiac allograft rejection is a multifocal immune process that is currently assessed using biopsy-guided histologic classification systems (International Society for Heart and Lung Transplantation). Cardiac troponin T and I are established serologic markers of global myocyte damage, The use of load-independent measures of contractility have also been shown to accurately assess the presence of ventricular dysfunction. Little is known about their utility in accurately predicting rejection in the pediatric age group. We undertook the present study to compare rejection grade with echocardiographic and serologic estimates of transplant rejection-related myocardial damage. Methods: We compared histologic rejection grades (0 to 4) with patient characteristics, echocardiographic measurements, catheterization measurements, and biochemical markers for 86 evaluations in 37 transplant recipients at Children's Hospital. Results: In univariate analyses, biopsy scores correlated (p < 0.05) inversely with left ventricular systolic function (shortening fraction) and contractility (stress velocity index, SVI), and directly with mitral E-wave amplitude. In multivariate analyses, lower contractility and higher mitral E-wave amplitude remained significantly (p less than or equal to 0.01) associated with rejection (SVI, p = 0.002, odds ratio = 0.393; E wave, p = 0.0002, odds ratio = 228). Most rejection episodes were associated with elevation of biochemical markers of myocardial injury. Although troponin I was weakly associated with differences between rejection grades (p = 0.034), troponin T, creatine kinase-MB fraction, and C-reactive protein did not differ with biopsy-rejection scores. Serum markers had a poor predictive capacity for biopsy-detected rejection. Conclusion: Progressively depressed left ventricular contractility and diastolic function are found with worsening pediatric heart transplant rejection-biopsy score; however, sensitive and specific serum markers do not correspond to the degree of active myocardial injury. The use of echocardiographic measures of contractility is associated with a specificity of 91.8% but low sensitivity of 66.7%. Overall we found poor concordance between serum markers and grade of rejection. It is unclear whether myocardial injury as assessed by serum markers, echocardiography, or histologic scoring is more important for assessment of acute rejection or long-term outcome, but it does not appear that serum and tissue markers of rejection can be used interchangeably. C1 Harvard Univ, Childrens Hosp, Sch Med, Dept Cardiol, Boston, MA 02115 USA. Harvard Univ, Childrens Hosp, Sch Med, Dept Pediat, Boston, MA 02115 USA. Harvard Univ, Childrens Hosp, Sch Med, Dept Lab Med & Pathol, Boston, MA 02115 USA. Univ Rochester, Med Ctr, Div Pediat Cardiol, Rochester, NY 14642 USA. Univ Rochester, Dept Pediat, Rochester, NY 14642 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. RP Moran, AM (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Dept Cardiol, 300 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [CA 68484, CA 55576]; NHLBI NIH HHS [HL 53392] NR 27 TC 31 Z9 32 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD AUG PY 2000 VL 19 IS 8 BP 756 EP 764 DI 10.1016/S1053-2498(00)00145-5 PG 9 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 349JF UT WOS:000089041400006 PM 10967269 ER PT J AU Ligibel, J Seiden, M Spitzer, TR AF Ligibel, J Seiden, M Spitzer, TR TI Panel reactive antibodies in women with ovarian cancer undergoing high-dose chemotherapy with peripheral stem cell rescue: A case control study SO JOURNAL OF HEMATOTHERAPY & STEM CELL RESEARCH LA English DT Article ID PLATELET TRANSFUSIONS; ALLOIMMUNIZATION; HLA AB High-dose chemotherapy with stem cell support is associated with a period of profound thrombocytopenia, During periods of thrombocytopenia, alloreactive antibodies can limit the effectiveness of platelet transfusion. In this institution, women undergoing high-dose chemotherapy with stem cell support for treatment of their ovarian cancer seemed to have a high incidence of panel reactive antibodies (PRA), To evaluate this further, a case-control study was performed comparing pretransplant PRA values in 22 consecutive women undergoing high-dose chemotherapy as intensification therapy for their ovarian cancer and a control group of 51 women receiving similar or identical therapy for their breast cancer. Parity was similar in both groups. Nonparametric t-test comparison of the two groups demonstrated a significantly higher PRA value in women with ovarian cancer compared to those with breast cancer (p = 0.032), Platelet transfusions were more common in women with ovarian cancer as compared to those with breast cancer (5.45/pt and 4.79/pt), although this difference did not reach statistical significance. This finding suggests that alloimmunization may be a more frequent problem in patients with ovarian cancer than in women with breast cancer. C1 Massachusetts Gen Hosp, Dept Med, Div Hematol & Oncol, Boston, MA 02114 USA. RP Seiden, M (reprint author), Massachusetts Gen Hosp, Dept Med, Div Hematol & Oncol, Cox 640,100 Blossom St, Boston, MA 02114 USA. NR 11 TC 0 Z9 0 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 AUG PY 2000 VL 9 IS 4 BP 501 EP 505 DI 10.1089/152581600419170 PG 5 WC Hematology; Medicine, Research & Experimental; Transplantation SC Hematology; Research & Experimental Medicine; Transplantation GA 350JY UT WOS:000089098600016 PM 10982249 ER PT J AU Gong, JL Nikrui, N Chen, DS Koido, S Wu, ZK Tanaka, Y Cannistra, S Avigan, D Kufe, D AF Gong, JL Nikrui, N Chen, DS Koido, S Wu, ZK Tanaka, Y Cannistra, S Avigan, D Kufe, D TI Fusions of human ovarian carcinoma cells with autologous or allogeneic dendritic cells induce antitumor immunity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-ASSOCIATED ANTIGEN; CYTOTOXIC T-LYMPHOCYTES; MONOCLONAL-ANTIBODY; IN-VITRO; BONE-MARROW; HER2/NEU-DERIVED PEPTIDE; CANCER; EXPRESSION; EPITOPES; IDENTIFICATION AB Human ovarian carcinomas express the CA-125, HER2/neu, and MUC1 tumor-associated Ags as potential targets for the induction of active specific immunotherapy, In the present studies, human ovarian cancer cells were fused to human dendritic cells (DC) as an alternative strategy to induce immunity against known and unidentified tumor Ags, Fusions of ovarian cancer cells to autologous DC resulted in the formation of heterokaryons that express the CA-125 Ag and DC-derived costimulatory and adhesion molecules. Similar findings were obtained with ovarian cancer cells fused to allogeneic DC. The fusion cells were functional in stimulating the proliferation of autologous T cells, The results also demonstrate; that fusions of ovarian cancer cells to autologous or allogeneic DC induce cytolytic T cell activity and lysis of autologous tumor cells by a MHC class I-restricted mechanism. These findings demonstrate that fusions of ovarian carcinoma cells and DC activate T cell responses against autologous tumor and that the fusions are functional when generated with either autologous or allogeneic DC. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. RP Gong, JL (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA78378] NR 51 TC 176 Z9 200 U1 3 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2000 VL 165 IS 3 BP 1705 EP 1711 PG 7 WC Immunology SC Immunology GA 337CV UT WOS:000088340600070 PM 10903782 ER PT J AU Dezube, BJ Dahl, TA Wong, TK Chapman, B Ono, M Yamaguchi, N Gillies, SD Chen, LB Crumpacker, CS AF Dezube, BJ Dahl, TA Wong, TK Chapman, B Ono, M Yamaguchi, N Gillies, SD Chen, LB Crumpacker, CS TI A fusion inhibitor (FP-21399) for the treatment of human immunodeficiency virus infection: A phase I study SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HIV-1 REPLICATION; ENTRY AB FP-21399 is a bis(disulfonaphthalene) derivative that prevents human immunodeficiency virus (HIV) infection of uninfected cells by blocking entry of the virus. FP-21399 shows an affinity for lymph nodes. In this phase I study, FP-21399 was administered intravenously over 1 h as a single dose (0.9, 1.7, 2.8, and 4.2 mg/kg) or as a once-weekly infusion (1, 2, and 3 mg/kg) for 4 consecutive weeks to 34 HIV-1 infected patients with CD4(+) cell counts of 50-400 cells/mu L. Concomitant antiretroviral therapy was permitted but not required. The most frequent adverse events involved the transient, dose-dependent appearance of drug- or metabolite-related color in the urine and skin. Plasma drug levels were linear with dose. The drug was cleared, with an elimination half-life of 4 h and a terminal half-life of 1.5-2 days; the terminal half-life represented redistribution and clearance from tissues. FP-21399 administered weekly for 4 weeks was well tolerated. Further studies are necessary to define the role of this fusion inhibitor in the treatment of HIV infection. C1 Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. Lexigen Pharmaceut Inc, Lexington, MA USA. RP Dezube, BJ (reprint author), Beth Israel Deaconess Med Ctr, Div Hematol Oncol, 330 Brookline Ave,CC-913, Boston, MA 02215 USA. FU NCRR NIH HHS [RR01032] NR 5 TC 18 Z9 21 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG PY 2000 VL 182 IS 2 BP 607 EP 610 DI 10.1086/315703 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347WJ UT WOS:000088951900032 PM 10915097 ER PT J AU Young, VB Chien, CC Knox, KA Taylor, NS Schauer, DB Fox, JG AF Young, VB Chien, CC Knox, KA Taylor, NS Schauer, DB Fox, JG TI Cytolethal distending toxin in avian and human isolates of Helicobacter pullorum SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CAMPYLOBACTER-JEJUNI; IDENTIFICATION; GENES; PCR AB Helicobacter pullorum has been isolated from the feces and livers of poultry and is associated with human gastroenteritis. Discrimination of this organism from other enterohepatic Helicobacter species and Campylobacter species has proven difficult. H, pullorum from both avian and human clinical sources has DNA sequence homology and cytotoxic activity that represent a new member of the cytolethal distending toxin (CDT) family of bacterial toxins. CDT is a potential virulence factor in H. pullorum that may serve as a distinguishing phenotype and aid in identification of this organism in veterinary and human clinical samples. C1 MIT, Div Comparat Med, Cambridge, MA 02139 USA. MIT, Div Bioengn & Environm Hlth, Cambridge, MA 02139 USA. Massachusetts Gen Hosp, Dept Med, Infect Dis Unit, Boston, MA 02114 USA. RP Fox, JG (reprint author), MIT, Div Comparat Med, 77 Massachusetts Ave,Rm 16-285C, Cambridge, MA 02139 USA. RI Young, Vincent/B-3179-2009 OI Young, Vincent/0000-0003-3687-2364 FU NCI NIH HHS [CA67529]; NIAID NIH HHS [AI01398]; NIDDK NIH HHS [DK52413] NR 16 TC 67 Z9 67 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG PY 2000 VL 182 IS 2 BP 620 EP 623 DI 10.1086/315705 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347WJ UT WOS:000088951900035 PM 10915100 ER PT J AU Hongcharu, W Taylor, CR Chang, YC Aghassi, D Suthamjariya, K Anderson, RR AF Hongcharu, W Taylor, CR Chang, YC Aghassi, D Suthamjariya, K Anderson, RR TI Topical ALA-photodynamic therapy for the treatment of acne vulgaris SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID PROPIONIBACTERIUM-ACNES; 5-AMINOLEVULINIC ACID; PROTOPORPHYRIN-IX; SEBACEOUS GLANDS; FLUORESCENCE; FOLLICLES; LIGHT; MODEL AB Topical aminolevulinic acid is converted into a potent photosensitizer, protoporphyrin, in human hair follicles and sebaceous glands. Photodynamic therapy with topical aminolevulinic acid was tested for the treatment of acne vulgaris, in an open-label prospective human study. Each of 22 subjects with acne on the back was treated in four sites with aminolevulinic acid plus red light, aminolevulinic acid alone, light alone, and untreated control. Half of the subjects were treated once; half were treated four times. Twenty percent topical aminolevulinic acid was applied with 3 h occlusion, and 150 J per cm(2) broad-band light (550-700 nm) was given. Sebum excretion rate and auto-fluorescence from follicular bacteria were measured before, and 2, 3, 10, and 20 wk after, treatment. Histologic changes and protoporphyrin synthesis in pilosebaceous units were observed from skin biopsies. Aminolevulinic acid plus red light caused a transient acne-like folliculitis. Sebum excretion was eliminated for several weeks, and decreased for 20 wk after photodynamic therapy; multiple treatments caused greater suppression of sebum. Bacterial porphyrin fluorescence was also suppressed by photodynamic therapy. On histology, sebaceous glands showed acute damage and were smaller 20 wk after photodynamic therapy. There was clinical and statistically significant clearance of inflammatory acne by aminolevulinic acid plus red light, for at least 20 wk after multiple treatments and 10 wk after a single treatment. Transient hyperpigmentation, superficial exfoliation, and crusting were observed, which cleared without scarring. Topical aminolevulinic acid plus red light is an effective treatment of acne vulgaris, associated with significant side-effects. Aminolevulinic acid plus red light causes phototoxicity to sebaceous follicles, prolonged suppression of sebaceous gland function, and apparent decrease in follicular bacteria after photodynamic therapy. Potentially, aminolevulinic acid plus red light may be useful for some patients with acne. C1 Harvard Univ, Sch Med,Wellman Labs Photomed, Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. Harvard Univ, Sch Med,Wellman Labs Photomed, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Anderson, RR (reprint author), Harvard Univ, Sch Med,Wellman Labs Photomed, Massachusetts Gen Hosp, Dept Dermatol, BHX 630,50 Blossom St, Boston, MA 02114 USA. NR 26 TC 307 Z9 321 U1 5 U2 38 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2000 VL 115 IS 2 BP 183 EP 192 DI 10.1046/j.1523-1747.2000.00046.x PG 10 WC Dermatology SC Dermatology GA 345FK UT WOS:000088805800007 PM 10951234 ER PT J AU Gerszten, RE Mach, F Sauty, A Rosenzweig, A Luster, AD AF Gerszten, RE Mach, F Sauty, A Rosenzweig, A Luster, AD TI Chemokines, leukocytes, and atherosclerosis SO JOURNAL OF LABORATORY AND CLINICAL MEDICINE LA English DT Review ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; RECEPTOR-DEFICIENT MICE; HUMAN ATHEROMA; EXPRESSION; MACROPHAGES; PLAQUES; CELLS C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Infect Dis Div, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. Univ Hosp Geneva, Fdn Med Res, Div Cardiol, Geneva, Switzerland. RP Luster, AD (reprint author), AIDS Res Ctr, Infect Dis Unit, Bldt 149,13th St, Charlestown, MA 02119 USA. NR 15 TC 63 Z9 68 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0022-2143 J9 J LAB CLIN MED JI J. Lab. Clin. Med. PD AUG PY 2000 VL 136 IS 2 BP 87 EP 92 DI 10.1067/mlc.2000.108154 PG 6 WC Medical Laboratory Technology; Medicine, General & Internal; Medicine, Research & Experimental SC Medical Laboratory Technology; General & Internal Medicine; Research & Experimental Medicine GA 342LK UT WOS:000088645900002 PM 10945236 ER PT J AU Berezovska, O Jack, C McLean, P Aster, JC Hicks, C Xia, WM Wolfe, MS Kimberly, WT Weinmaster, G Selkoe, DJ Hyman, BT AF Berezovska, O Jack, C McLean, P Aster, JC Hicks, C Xia, WM Wolfe, MS Kimberly, WT Weinmaster, G Selkoe, DJ Hyman, BT TI Aspartate mutations in presenilin and gamma-secretase inhibitors both impair Notch1 proteolysis and nuclear translocation with relative preservation of Notch1 signaling SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE Notch; presenilin; nuclear translocation; delta ID AMYLOID PRECURSOR PROTEIN; CELL FATES; NEURONAL DIFFERENTIATION; CAENORHABDITIS-ELEGANS; INTRACELLULAR DOMAIN; DROSOPHILA; NUMB; LOCALIZATION; GENE; BINDING AB It has been hypothesized that a presenilin 1 (PS1)-related enzymatic activity is responsible for proteolytic cleavage of the C-terminal intracellular protein of Notch1, in addition to its role in beta-amyloid protein (A beta) formation from the amyloid precursor protein (APP). We developed an assay to monitor ligand-induced Notch1 proteolysis and nuclear translocation in individual cells: Treatment of full-length Notch1-enhanced green fluorescent protein-transfected Chinese hamster ovary (CHO) cells with a soluble preclustered form of the physiologic ligand Delta leads to rapid accumulation of the C terminus of Notch1 in the nucleus and to transcriptional activation of a C-promoter binding factor 1 (CBF1) reporter construct. Nuclear translocation was blocked by cotransfection with Notch's physiologic inhibitor Numb. Using this assay, we now confirm and extend the observation that PS1 is involved in Notch1 nuclear translocation and signaling in mammalian cells. We demonstrate that the D257A and the D385A PS1 mutations, which had been shown previously to block APP gamma-secretase activity, also prevent Notch1 cleavage and translocation to the nucleus but do not alter Notch1 trafficking to the cell surface, We also show that two APP gamma-secretase inhibitors block Notch1 nuclear translocation with an IC50 similar to that reported for APP gamma-secretase. Notch1 signaling, assessed by measuring the activity of CBF1, a downstream transcription factor, was impaired but not abolished by the PS1 aspartate mutations or gamma-secretase inhibitors. Our results support the hypotheses that (a) PS1-dependent APP gamma-secretase-like enzymatic activity is critical for both APP and Notch processing and (b) the Notch1 signaling pathway remains partially activated even when Notch1 proteolytic processing and nuclear translocation are markedly inhibited. The latter is an important finding from the perspective of therapeutic treatment of Alzheimer's disease by targeting gamma-secretase processing of APP to reduce A beta production. C1 Harvard Univ, Sch Med, Dept Neurol, Alzheimers Dis Res Lab, Charlestown, MA USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. Univ Calif Los Angeles, Sch Med, Dept Biol Chem, Los Angeles, CA 90024 USA. RP Hyman, BT (reprint author), Massachusetts Gen Hosp, Alzheimers Dis Unit, Room 6405,149-13th St, Charlestown, MA 02129 USA. RI xia, weiming/E-5465-2016 OI xia, weiming/0000-0002-7463-3295 FU NIA NIH HHS [AG 14744, P0 AG 15379] NR 47 TC 99 Z9 105 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2000 VL 75 IS 2 BP 583 EP 593 DI 10.1046/j.1471-4159.2000.0750583.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 335EX UT WOS:000088231600016 PM 10899933 ER PT J AU Andreassen, OA Ferrante, RJ Hughes, DB Klivenyi, P Dedeoglu, A Ona, VO Friedlander, RM Beal, MF AF Andreassen, OA Ferrante, RJ Hughes, DB Klivenyi, P Dedeoglu, A Ona, VO Friedlander, RM Beal, MF TI Malonate and 3-nitropropionic acid neurotoxicity are reduced in transgenic mice expressing a caspase-1 dominant-negative mutant SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE Huntington's disease; apoptosis; caspases; mitochondria ID INTERLEUKIN-1-BETA CONVERTING-ENZYME; HUNTINGTONS-DISEASE STRIATUM; CELL-DEATH; DNA FRAGMENTATION; REPEAT LENGTH; APOPTOSIS; INHIBITION; TOXIN; NEURODEGENERATION; MITOCHONDRIA AB Increasing evidence implicates caspase-1-mediated cell death as a major mechanism of neuronal death in neurodegenerative diseases. In the present study we investigated the role of caspase-1 in neurotoxic experimental animal models of Huntington's disease (HD) by examining whether transgenic mice expressing a caspase-1 dominant-negative mutant are resistant to malonate and 3-nitropropionic acid (3-NP) neurotoxicity. Intrastriatal injection of malonate resulted in significantly smaller striatal lesions in mutant caspase-1 mice than those observed in littermate control mice. Caspase-1 was significantly activated following malonate intrastriatal administration in control mice but significantly attenuated in mutant caspase-1 mice. Systemic 3-NP treatment induced selective striatal lesions that were significantly smaller within mutant caspase-1 mice than in littermate control mice. These results provide further evidence of a functional role for caspase-1 in both malonate- and 3-NP-mediated neurotoxin models of HD. C1 New York Hosp, Cornell Med Ctr, Dept Neurol, New York, NY 10021 USA. Massachusetts Gen Hosp, Neurol Serv, Neurochem Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. Brigham & Womens Hosp, Dept Surg, Neurosurg Serv, Boston, MA 02115 USA. Dept Vet Affairs, Bedford VA Med Ctr, Ctr Geriatr Res Educ & Clin, Bedford, MA USA. Cornell Univ, Weill Med Coll, Dept Neurol & Neurosci, New York, NY USA. RP Beal, MF (reprint author), New York Hosp, Cornell Med Ctr, Dept Neurol, 525 E 68th St, New York, NY 10021 USA. RI Friedlander, Robert/A-2845-2016 OI Friedlander, Robert/0000-0003-4423-9219 FU NIA NIH HHS [P01 AG12292, P01 AG14930]; NINDS NIH HHS [NS39258] NR 32 TC 27 Z9 28 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2000 VL 75 IS 2 BP 847 EP 852 DI 10.1046/j.1471-4159.2000.0750847.x PG 6 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 335EX UT WOS:000088231600046 PM 10899963 ER PT J AU Xia, MQ Bacskai, BJ Knowles, RB Qin, SX Hyman, BT AF Xia, MQ Bacskai, BJ Knowles, RB Qin, SX Hyman, BT TI Expression of the chemokine receptor CXCR3 on neurons and the elevated expression of its ligand IP-10 in reactive astrocytes: in vitro ERK1/2 activation and role in Alzheimer's disease SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE chemokine receptor; CXCR3; IP-10; MIP-1 beta; Alzheimer's disease; CNS ID CENTRAL-NERVOUS-SYSTEM; PROTEIN MESSENGER-RNA; MAP-KINASE; GLIAL-CELLS; T-CELLS; NEUROFIBRILLARY TANGLES; INDUCIBLE PROTEIN-10; I-TAC; MICROGLIA; PHOSPHORYLATION AB Inflammatory mediators have been implicated in the pathophysiology of neurodegenerative diseases. Here we report the presence of the chemokine receptor CXCR3 and its ligand, IP-10, in normal and Alzheimer's disease (AD) brains. CXCR3 was detected constitutively on neurons and neuronal processes in various cortical and subcortical regions; IP-10 was observed in a subpopulation of astrocytes in normal brain, and was markedly elevated in astrocytes in AD brains. Many IP-10(+) astrocytes were associated with senile plaques and had an apparently coordinated upregulation of MIP-1 beta. Moreover, we showed that CXCR3 ligands, IP-10 and Mig, were able to activate ERK1/2 pathway in mouse cortical neurons, suggesting a novel mechanism of neuronal-glial interaction. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02129 USA. LeukoSite Inc, Cambridge, MA 02142 USA. RP Hyman, BT (reprint author), Massachusetts Gen Hosp East, Alzheimers Res Unit, 149 13th St,CNY 6405, Boston, MA 02129 USA. FU NIA NIH HHS [P50AG05134] NR 51 TC 127 Z9 131 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD AUG 1 PY 2000 VL 108 IS 1-2 BP 227 EP 235 DI 10.1016/S0165-5728(00)00285-X PG 9 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 338WW UT WOS:000088447100028 PM 10900358 ER PT J AU Zhang, YZ Moheban, DB Conway, BR Bhattacharyya, A Segal, RA AF Zhang, YZ Moheban, DB Conway, BR Bhattacharyya, A Segal, RA TI Cell surface Trk receptors mediate NGF-induced survival while internalized receptors regulate NGF-induced differentiation SO JOURNAL OF NEUROSCIENCE LA English DT Article DE nerve growth factor; neurotrophin; receptor tyrosine kinase; dynamin; endocytosis; survival; Akt ID NERVE GROWTH-FACTOR; SIGNAL-TRANSDUCTION PATHWAYS; RAT SYMPATHETIC NEURONS; TYROSINE KINASE; PC12 CELLS; RETROGRADE TRANSPORT; ANTEROGRADE TRANSPORT; EGF RECEPTOR; DYNAMIN; ENDOCYTOSIS AB Internalization and transport of a ligand-receptor complex are required to initiate cell body responses to target-derived neurotrophin. However, it is not known whether internalized receptors and cell surface receptors initiate the same signaling pathways and biological responses. Here we use a temperature-sensitive mutant of dynamin (G273D) to control the subcellular localization of activated NGF receptors (Trks). We show that dynamin function is required for ligand-dependent endocytosis of Trk receptors. In PC12 cells, nerve growth factor (NGF) stimulation promotes both survival and neuronal differentiation. These distinct biological responses to NGF are controlled by receptors signaling from different locations within the cell. Neuronal differentiation is promoted by catalytically active Trks within endosomes in the cell interior. In contrast, survival responses are initiated by activated receptors at the cell surface where they orchestrate prolonged activation of the kinase Akt. Thus, interactions between Trk receptor tyrosine kinases and intracellular signaling molecules are dictated both by phosphotyrosine motifs within the receptors and by the intracellular location of phosphorylated receptors. C1 Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. RP Segal, RA (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. FU NINDS NIH HHS [NS35148] NR 52 TC 229 Z9 232 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 AUG 1 PY 2000 VL 20 IS 15 BP 5671 EP 5678 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 337JM UT WOS:000088354000017 PM 10908605 ER PT J AU Lim, GP Yang, F Chu, T Chen, P Beech, W Teter, B Tran, T Ubeda, O Ashe, KH Frautschy, SA Cole, GM AF Lim, GP Yang, F Chu, T Chen, P Beech, W Teter, B Tran, T Ubeda, O Ashe, KH Frautschy, SA Cole, GM TI Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease SO JOURNAL OF NEUROSCIENCE LA English DT Article DE inflammation; cytokines; microglia; amyloid; Alzheimer; NSAID ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; TRANSGENIC MICE; AMYLOID PLAQUES; RECEPTOR-GAMMA; MICROGLIA; CYTOKINE; PATHOGENESIS; BRAINS; RISK AB The brain in Alzheimer's disease (AD) shows a chronic inflammatory response characterized by activated glial cells and increased expression of cytokines and complement factors surrounding amyloid deposits. Several epidemiological studies have demonstrated a reduced risk for AD in patients using nonsteroidal anti-inflammatory drugs (NSAIDs), prompting further inquiries about how NSAIDs might influence the development of AD pathology and inflammation in the CNS. We tested the impact of chronic orally administered ibuprofen, the most commonly used NSAID, in a transgenic model of AD displaying widespread microglial activation, age-related amyloid deposits, and dystrophic neurites. These mice were created by overexpressing a variant of the amyloid precursor protein found in familial AD. Transgene-positive (Tg+) and negative (Tg-) mice began receiving chow containing 375 ppm ibuprofen at 10 months of age, when amyloid plaques first appear, and were fed continuously for 6 months. This treatment produced significant reductions in final interleukin-1 beta and glial fibrillary acidic protein levels, as well as a significant diminution in the ultimate number and total area of beta-amyloid deposits. Reductions in amyloid deposition were supported by ELISA measurements showing significantly decreased SDS-insoluble A beta. Ibuprofen also decreased the numbers of ubiquitin-labeled dystrophic neurites and the percentage area per plaque of antiphosphotyrosine-labeled microglia. Thus, the anti-inflammatory drug ibuprofen, which has been associated with reduced AD risk in human epidemiological studies, can significantly delay some forms of AD pathology, including amyloid deposition, when administered early in the disease course of a transgenic mouse model of AD. C1 Univ Calif Los Angeles, Dept Med & Neurol SFVP, Sepulveda VAMC GRECC 11E, Sepulveda, CA 91343 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90095 USA. Greater Los Angeles Vet Affairs Healthcare Syst, Sepulveda, CA 91343 USA. Univ Minnesota, Dept Neurol, Ctr Clin & Mol Neurobiol, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Neurosci, Minneapolis, MN 55455 USA. RP Cole, GM (reprint author), Univ Calif Los Angeles, Dept Med & Neurol SFVP, Sepulveda VAMC GRECC 11E, 16111 Plummer St, Sepulveda, CA 91343 USA. FU NCCIH NIH HHS [R01 AT003008]; NIA NIH HHS [R01 AG010685, AG13471, AG15453, P50 AG016570, R01 AG013741] NR 34 TC 640 Z9 667 U1 4 U2 49 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 1 PY 2000 VL 20 IS 15 BP 5709 EP 5714 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 337JM UT WOS:000088354000022 PM 10908610 ER PT J AU Meara, JG Pilch, BZ Shah, SS Cunningham, MJ AF Meara, JG Pilch, BZ Shah, SS Cunningham, MJ TI Cytokeratin expression in the odontogenic keratocyst SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID JAW CYSTS; EPITHELIA; DIAGNOSIS; TUMORS; CELLS; AID AB Purpose: This study attempted to identify differential cytokeratin expression in cystic jaw lesions using immunohistochemical staining. Patients and Methods: The charts from selected patients treated between 1983 and 1994 for jaw cysts were evaluated. Twenty-four paraffinized specimens were selected randomly for investigation with 5 immunohistochemical stains. The 4 diagnostic categories included ameloblastoma, dentigerous cyst, odontogenic keratocyst (OKC), and recurrent odontogenic keratocyst in patients with nevoid basal cell carcinoma (NBCC) syndrome. The 5 immunohistochemical stains included antibodies to cytokeratins 13, 17, and 18; CAM 5.2; AE 1/3; and carcinoembryonic antigen (CEA). Results: Differential staining of OKCs from patients with and without NBCC syndrome was found only with the antibody to cytokeratin 17. Furthermore, staining of OKCs in syndromic patients appeared to be stronger and more uniform than in nonsyndromic patients. Conclusions: These findings suggest that immunohistochemical staining for cytokeratin 17 may aid in the diagnosis of OKCs and may be used to further subdivide these lesions based on the presence or absence of NBCC syndrome. (C) 2000 American Association of Oral and Maxillofacial Surgeons. C1 Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, Dept ENT Pathol, Boston, MA 02114 USA. RP Cunningham, MJ (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. NR 14 TC 18 Z9 19 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 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD AUG PY 2000 VL 58 IS 8 BP 862 EP 865 DI 10.1053/joms.2000.8205 PG 4 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 352RF UT WOS:000089231100010 PM 10935585 ER PT J AU Petropoulos, AE Cheney, ML Agathos, A Lamothe, A AF Petropoulos, AE Cheney, ML Agathos, A Lamothe, A TI A peripatetic pancreatic pseudocyst in the neck SO JOURNAL OF OTOLARYNGOLOGY LA English DT Article ID MEDIASTINAL MASS C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. RP Cheney, ML (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otolaryngol Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. NR 20 TC 3 Z9 4 U1 0 U2 0 PU DECKER PERIODICALS INC PI HAMILTON PA 4 HUGHSON STREET SOUTH PO BOX 620, LCD 1, HAMILTON, ONTARIO L8N 3K7, CANADA SN 0381-6605 J9 J OTOLARYNGOL JI J. Otolaryngol. PD AUG PY 2000 VL 29 IS 4 BP 247 EP 250 PG 4 WC Otorhinolaryngology SC Otorhinolaryngology GA 352PU UT WOS:000089227700012 PM 11003079 ER PT J AU Casarett, DJ Karlawish, JHT AF Casarett, DJ Karlawish, JHT TI Are special ethical guidelines needed for palliative care research? SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE informed consent; research ethics; human subjects; medical ethics; terminal illness ID INTRACTABLE CANCER PAIN; CLINICAL RESEARCH; INFORMED CONSENT; TERMINAL CANCER; FAMILY MEMBERS; HEALTH-STATUS; LEGAL ISSUES; MANAGEMENT; PERCEPTIONS; TRIAL AB Recent studies have made it clear that there are substantial opportunities to improve end-of-life care. Doing so will,require solid evidence on which to base clinical and polity decisions and this, in turn, will require a focused research effort. However, research that involves patients near the end of life creates numerous ethical challenges. Moreover the inclusion of dying patients in research may make many providers uncomfortable. In short, there seems to he something ethically unique, and uniquely challenging, about palliative care research. This paper considers 4 arguments for this unique status: 1) dying patients are eapecially vulnerable; 2) adequate informed consent may be difficult to obtain; 3) balancing research and clinical roles is particularly difficult; and 4) the risks and benefits of palliative research are difficult to assess. We conclude that the first three of these arguments are weak;, and that special guidelines are not needed. We suggest, however that the fourth argument may have some merit, and should be the focus of discussion among investigators, providers, and patients. (C) U.S. Cancer Pain Relief Committee, 2000. C1 Univ Penn, Ctr Bioeth, Inst Aging, Philadelphia, PA 19104 USA. Univ Penn, Dept Med, Philadelphia, PA 19104 USA. Univ Penn, Div Geriatr Med, Philadelphia, PA 19104 USA. Univ Penn, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. Univ Penn, Alzheimers Dis Res Ctr, Philadelphia, PA 19104 USA. RP Casarett, DJ (reprint author), Univ Penn, Ctr Bioeth, Inst Aging, 3615 Chestnut St, Philadelphia, PA 19104 USA. FU NIA NIH HHS [1K01AG00931-01] NR 75 TC 69 Z9 69 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD AUG PY 2000 VL 20 IS 2 BP 130 EP 139 DI 10.1016/S0885-3924(00)00164-0 PG 10 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 351UY UT WOS:000089177600008 PM 10989251 ER PT J AU Savidge, TC AF Savidge, TC TI Gastrointestinal response to food: Artificial or not? SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Editorial Material ID REARED RAT PUPS; NUTRITION RESEARCH; MILK C1 Massachusetts Gen Hosp, Combined Program Pediat Gastroenterol & Nutr, Dev Gastroenterol Lab, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA USA. RP Savidge, TC (reprint author), Massachusetts Gen Hosp, Combined Program Pediat Gastroenterol & Nutr, Dev Gastroenterol Lab, Charlestown, MA 02129 USA. NR 11 TC 0 Z9 0 U1 0 U2 0 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 AUG PY 2000 VL 31 IS 2 BP 118 EP 120 DI 10.1097/00005176-200008000-00006 PG 3 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA 339BV UT WOS:000088458500006 PM 10941961 ER PT J AU Eckler, K Laufer, MR Perlman, SE AF Eckler, K Laufer, MR Perlman, SE TI Conservative management of bilateral asynchronous adnexal torsion with necrosis in a prepubescent girl SO JOURNAL OF PEDIATRIC SURGERY LA English DT Article DE bilateral ovarian torsion; ovary; abdominal pain; oophoropexy pediatric gynecology ID LAPAROSCOPIC TREATMENT; OVARIAN-FUNCTION; TRANSPOSITION; IRRADIATION; CHILDREN AB Conservative management of ovarian torsion consisting of detorsion and surgical stabilization of the involved ovary, and possibly including the uninvolved ovary, has been described in the adult population. A g-year-old girl with a history of prior ovarian torsion resulting in oophorectomy presented with 72 hours of intermittent abdominal pain, anorexia, and 1 episode of vomiting. The patient had torsion of her remaining ovary diagnosed surgically and was managed with detorsion and oophoropexy, despite the severely necrotic appearance of the ovarian tissue. Postoperative serial ultrasound scans confirmed the viability and position of the ovary. In the prepubertal girl, ovaries may terse despite the absence of enlarging lesions such as tumors or cysts. To maximize the potential success of conservative therapy, torsion always must be included in the differential diagnosis of abdominal pain. Surgical management should attempt to salvage the torsed ovary, despite possible necrotic appearance, and also consider interventions to prevent recurrence, because bilateral torsion is a rare but potentially devastating complication. J Pediatr Surg 35:1248-1251. Copyright (C) 2000 by W.B. Saunders Company. C1 Univ Louisville, Sch Med, Dept Obstet & Gynecol, Louisville, KY 40202 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Vincent Obstet & Gynecol, Boston, MA USA. Harvard Univ, Sch Med, Childrens Hosp, Dept Surg, Boston, MA USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA USA. RP Perlman, SE (reprint author), Univ Louisville, Sch Med, Dept Obstet & Gynecol, 550 S Jackson, Louisville, KY 40202 USA. NR 13 TC 30 Z9 32 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 0022-3468 J9 J PEDIATR SURG JI J. Pediatr. Surg. PD AUG PY 2000 VL 35 IS 8 BP 1248 EP 1251 DI 10.1053/jpsu.2000.8764 PG 4 WC Pediatrics; Surgery SC Pediatrics; Surgery GA 351FE UT WOS:000089146500022 PM 10945705 ER PT J AU Clark, RSB Kochanek, PM Adelson, PD Bell, MJ Carcillo, JA Chen, M Wisniewski, SR Janesko, K Whalen, MJ Graham, SH AF Clark, RSB Kochanek, PM Adelson, PD Bell, MJ Carcillo, JA Chen, M Wisniewski, SR Janesko, K Whalen, MJ Graham, SH TI Increases in bcl-2 protein in cerebrospinal fluid and evidence for programmed cell death in infants and children after severe traumatic brain injury SO JOURNAL OF PEDIATRICS LA English DT Article ID SEVERE HEAD-INJURY; BCL-2-DEFICIENT MICE; REGULATING APOPTOSIS; NEURONAL APOPTOSIS; CYTOCHROME-C; EXPRESSION; BAX; SURVIVAL; RAT; OVEREXPRESSION AB Objectives: To determine whether bcl-2, a protein that inhibits apoptosis, would be increased in cerebrospinal fluid (CSF) in infants and children after traumatic brain injury (TBI) and to examine the association of bcl-2 concentration with clinical variables. Study design: Bcl-2 was measured in CSF from 23 children (aged 2 months-16 years) with severe TBI and from 19 children without TBI or meningitis (control subjects) by enzyme-linked immunosorbent assay CSF oligonucleosome concentration was also determined as a marker of DNA degradation. Brain samples from 2 patients undergoing emergent decompressive craniectomies were analyzed for bcl-2 with Western blot and for DNA fragmentation with TUNEL (terminal deoxynucleotidyl-transerase mediated biotin-dUTP nick-end labeling). Results: CSF bcl-2 concentrations were increased in patients with TBI versus control subjects (P = .01). Bcl-2 was increased in patients with TBI who survived versus those who died (P = .02). CSF oligonucleosome concentration tended to be increased after TBI (P = .07) and was not associated with bcl-2. Brain tissue samples showed an increase in bcl-2 in patients with TBI versus adult brain bank control samples and evidence of DNA fragmentation within cells with apoptotic morphology Conclusions: Bcl-2 may participate in the regulation of cell, death after TBI in infants and children. The increase in bcl-2 seen in patients who survived is consistent with a protective role for this anti-apoptotic protein after TBI. C1 Childrens Hosp Pittsburgh, Div Pediat Crit Care, Dept Anesthesiol & Crit Care Med, Pittsburgh, PA 15213 USA. Childrens Hosp Pittsburgh, Dept Pediat, Pittsburgh, PA 15213 USA. Childrens Hosp Pittsburgh, Dept Neurol Surg, Pittsburgh, PA 15213 USA. Childrens Hosp Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. Childrens Hosp Pittsburgh, Dept Neurol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Safar Ctr Resuscitat Res, Pittsburgh, PA USA. VA Pittsburgh Hlth Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. RP Clark, RSB (reprint author), Childrens Hosp Pittsburgh, Div Pediat Crit Care, Dept Anesthesiol & Crit Care Med, 3705 5th Ave, Pittsburgh, PA 15213 USA. RI Kochanek, Patrick/D-2371-2015; OI Kochanek, Patrick/0000-0002-2627-913X; Wisniewski, Stephen/0000-0002-3877-9860 FU NICHD NIH HHS [5P30 HD28836]; NINDS NIH HHS [KO8 NS01946, R01 NS38620] NR 48 TC 66 Z9 69 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD AUG PY 2000 VL 137 IS 2 BP 197 EP 204 DI 10.1067/mpd.2000.106903 PG 8 WC Pediatrics SC Pediatrics GA 345TZ UT WOS:000088832400013 PM 10931412 ER PT J AU Schwartz, Z Weesner, T van Dijk, S Cochran, DL Mellonig, JT Lohmann, CH Carnes, DL Goldstein, M Dean, DD Boyan, BD AF Schwartz, Z Weesner, T van Dijk, S Cochran, DL Mellonig, JT Lohmann, CH Carnes, DL Goldstein, M Dean, DD Boyan, BD TI Ability of deproteinized cancellous bovine bone to induce new bone formation SO JOURNAL OF PERIODONTOLOGY LA English DT Article DE bone; deproteinized; bone regeneration; osteogenesis ID FREEZE-DRIED BONE; GROWTH FACTOR-BETA; MORPHOGENETIC PROTEIN; POLYACRYLAMIDE GELS; ALLOGRAFT; MATRIX; IMPLANTS; DEFECTS; HYDROXYAPATITE; AUGMENTATION AB Background: Preclinical and clinical studies indicate that deproteinized cancellous bovine bone is osteoconductive and may be osteopromotive. Previous studies using commercial preparations failed to demonstrate the presence of protein, implicating bone-mineral composition and 3-dimensional structure as reasons for clinical success; however, these studies did not examine whether osteoinductive factors might be present in close association with the mineral phase. Methods: Deproteinized cancellous bovine bone was decalcified and any protein present released by chaotropic solvents using the protocol described for purification of bone morphogenetic proteins (BMPs). Three extracts were obtained and tested for their ability to support osteoinduction in the calf muscle of nude mice. Results: Protein content averaged 11 mug/g based on absorbance at 280 nm using bovine serum albumin as a standard. All extracts contained material that stained positively with silver stain after sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE). Western blots of these gels indicated the presence of transforming growth factor-beta (TGF-beta) and BMP-2, All 3 extracts were osteoinductive in the nude mouse model when combined with inactive DFDBA, and bone formation was comparable to that induced by active DFDBA, Deproteinized cancellous bovine bone by itself was not osteoinductive in the nude mouse, but in a clinical case, exhibited osteoclastic resorption with adjacent new bone formation. Conclusions: The results suggest that small amounts of protein are present in deproteinized cancellous bovine bone in close association with the mineral phase, Some of the extracted material has osteoinductive potential and may contain growth factors, This may explain the osteopromotive ability of deproteinized cancellous bovine bone clinically. C1 Univ Texas, Hlth Sci Ctr, Dept Orthopaed, San Antonio, TX 78229 USA. Hebrew Univ Jerusalem, Hadassah Fac Dent Med, Dept Periodont, Jerusalem, Israel. Univ Texas, Hlth Sci Ctr, Dept Periodont, San Antonio, TX 78229 USA. Audie L Murphy Mem Vet Hosp, San Antonio, TX 78284 USA. Univ Gottingen, Dept Orthopaed, D-3400 Gottingen, Germany. Univ Texas, Dept Biochem, San Antonio, TX 78285 USA. RP Boyan, BD (reprint author), Univ Texas, Hlth Sci Ctr, Dept Orthopaed, Mail Code 7774,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. OI Dean, David/0000-0002-4512-9065 NR 64 TC 91 Z9 94 U1 0 U2 3 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 J9 J PERIODONTOL JI J. Periodont. PD AUG PY 2000 VL 71 IS 8 BP 1258 EP 1269 DI 10.1902/jop.2000.71.8.1258 PG 12 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 411GL UT WOS:000167489800006 PM 10972641 ER PT J AU Moor, ACE AF Moor, ACE TI Signaling pathways in cell death and survival after photodynamic therapy SO JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY LA English DT Review DE apoptosis; rescue response; necrosis; photodynamic therapy; signaling pathways ID NF-KAPPA-B; ACTIVATED PROTEIN-KINASE; TRANSITIONAL CARCINOMA-CELLS; ACID SPHINGOMYELINASE GENE; CYTOPLASMIC FREE CALCIUM; PROSTATE-CANCER CELLS; MOUSE LYMPHOMA-CELLS; CYTOCHROME-C RELEASE; INDUCED APOPTOSIS; SINGLET OXYGEN AB Photodynamic therapy (PDT) is a cytotoxic treatment, which can induce cells to initiate a rescue response, or to undergo cell death, either apoptosis or necrosis. The many signaling pathways involved in these processes are the topic of this review. The subcellular localization of the photosensitizer has been shown to be a key factor in the outcome of PDT. Mitochondrial localized photosensitizers are able to induce apoptosis very rapidly. Lysosomal localized photosensitizers can elicit either a necrotic or an apoptotic response. In the plasma membrane, a target for various photosensitizers, rescue responses, apoptosis and necrosis is initiated. Several protein phosphorylation cascades are involved in the regulation of the response to PDT. Finally, a number of stress-induced proteins play a role in the rescue response after PDT. Notably, the induction of apoptosis by PDT might not be crucial for an optimal outcome. Recent studies indicate that abrogation of the apoptotic pathway does alter the clonogenic survival of the cells after PDT. Further studies, both in vitro and especially in vivo could lead to more efficient combination therapies in which signaling pathways, involved in cell death or rescue, are either up- or downregulated before PDT. (C) 2000 Elsevier Science S.A. All rights reserved. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Labs Photomed,Dept Dermatol, Boston, MA 02114 USA. RP Moor, ACE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Labs Photomed,Dept Dermatol, 50 Fruit St, Boston, MA 02114 USA. FU NIAMS NIH HHS [R01 AR40352-03] NR 116 TC 210 Z9 219 U1 1 U2 15 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 1011-1344 J9 J PHOTOCH PHOTOBIO B JI J. Photochem. Photobiol. B-Biol. PD AUG PY 2000 VL 57 IS 1 BP 1 EP 13 DI 10.1016/S1011-1344(00)00065-8 PG 13 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 366YM UT WOS:000090033900001 PM 11100832 ER PT J AU Boppart, MD Asp, S Wojtaszewski, JFP Fielding, RA Mohr, T Goodyear, LJ AF Boppart, MD Asp, S Wojtaszewski, JFP Fielding, RA Mohr, T Goodyear, LJ TI Marathon running transiently increases c-Jun NH2-terminal kinase and p38 gamma activities in human skeletal muscle SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID CELLULAR STRESSES; MAMMALIAN-CELLS; P38 GROUP; PROTEIN; ACTIVATION; EXERCISE; ISOFORMS; PATHWAY; CYTOKINES; MEMBERS AB 1. We examined the: pattern of activation and deactivation of the stress-activated protein kinase signalling molecules c-Jun NH,-terminal kinase (JNK) and p38 kinase in skeletal muscle in response to prolonged strenuous running exercise in human subjects. 2.Male subjects (n = 14; age 32 +/- 2 years; V-O2,V-max 60 +/- 2 ml kg(-1) min(-1)) completed a 42.2 km marathon (mean race time 3 h 35 min). Muscle biopsies were obtained 10 days prior to the marathon, immediattely following the race, and 1, 3 and 5 days after the race. The activation of JNK and p38, including both p38 alpha and p38 gamma, was measured with immune complex assays, The phosphorylation state of p38 (alpha and gamma) and the upstream regulators of JNK and p38, mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 6 (MKK6), were assessed using phosphospecific antibodies. 3. JNK. activity increased 7-fold over basal level immediately post-exercise, but decreased back to basal levels 1, 3 and 5 days after the exercise. p38 gamma phosphorylation (4-fold) and activity (1.5-fold) increased immediately post-exercise and returned to basal levels at 1, 3 and 5 days following exercise. In contrast, p38a phosphorylation and activity did not change over the time course studied. MKK4 and MKK6 phosphorylation increased and decreased in a trend similar to that observed with JNK activity and p38 gamma phosphorylation. Prolonged running exercise did not affect JNK, p38 alpha, or p38 gamma protein expression in the days following the race. 4. This study demonstrates that both JNK and p38 intracellular signalling cascades are robustly, yet transiently increased following prolonged running exercise, The differential activation of title p38 isoforms with exercise in human skeletal muscle indicates that these proteins may have distinct functions in vivo. C1 Brigham & Womens Hosp, Dept Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. Boston Univ, Sargent Coll Hlth & Rehabil Sci, Dept Hlth Sci, Boston, MA 02215 USA. Univ Copenhagen, August Krogh Inst, Copenhagen Muscle Res Ctr, DK-2100 Copenhagen, Denmark. RP Goodyear, LJ (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. RI Wojtaszewski, Jorgen /P-6583-2014 OI Wojtaszewski, Jorgen /0000-0001-9785-6830 FU NIAMS NIH HHS [AR-42238, R01 AR042238]; NIDDK NIH HHS [T32 DK007260, T32 DK07260-22] NR 24 TC 79 Z9 91 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD AUG 1 PY 2000 VL 526 IS 3 BP 663 EP 669 DI 10.1111/j.1469-7793.2000.00663.x PG 7 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 352EX UT WOS:000089202500019 PM 10922016 ER PT J AU Zeitzer, JM Dijk, DJ Kronauer, RE Brown, EN Czeisler, CA AF Zeitzer, JM Dijk, DJ Kronauer, RE Brown, EN Czeisler, CA TI Sensitivity of the human circadian pacemaker to nocturnal light: melatonin phase resetting and suppression SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID BRIGHT LIGHT; PINEAL MELATONIN; BIOLOGICAL CLOCK; PLASMA MELATONIN; RHYTHMS; ENTRAINMENT; EXPOSURE; SHIFTS; HAMSTER; PHOTORECEPTORS AB 1. Ocular exposure to early morning room light can significantly advance the timing of the human circadian pacemaker. The resetting response to such light has a non-linear relationship to illuminance. The dose-response relationship of thr: human circadian pacemaker to late evening light of dim to moderate intensity has not been TI ell established. 2. Twenty-three healthy young male and female volunteers took part in a 9 day protocol in which a single experimental light exposure 6.5 h in duration nias given in the early biological night. The effects of the light exposure on the endogenous circadian phase of the melatonin rhythm and the acute effects of the light exposure on plasma melatonin concentration were calculated. 3. We demonstrate that humans are highly responsive to the phase-delaying effects of light during the early biological night and that both the phase resetting response to light and the acute suppressive effects of light on plasma melatonin follow a logistic dose-response curve, as do many circadian responses to light ill mammals. 4.Contrary to expectations, we found that half of the maximal phase-delaying response achieved in response to a single episode of Evening bright light (similar to 9000 lux (Ix)) carl be obtained with just over 1% of this light (dim room light of similar to 100 lx). The same held true fur the acute suppressive effects of light on plasma melatonin concentrations. This indicates that even small changes in ordinary light exposure during the late evening hours can significantly affect both plasma melatonin concentrations and the entrained phase of the human circadian pacemaker. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med,Endocrine Div,Dept Med, Circadian Neuroendocrine & Sleep Disorders Sect, Boston, MA 02115 USA. Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. Harvard Univ, Div Appl Sci, Cambridge, MA 02138 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care,Stat Res Lab, Boston, MA 02114 USA. MIT, Div Hlth Sci & Technol, Med Educ Ctr 213, Boston, MA 02115 USA. RP Czeisler, CA (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med,Endocrine Div,Dept Med, Circadian Neuroendocrine & Sleep Disorders Sect, 221 Longwood Ave, Boston, MA 02115 USA. RI Dijk, Derk-Jan/D-8387-2011; OI Zeitzer, Jamie/0000-0001-6174-5282 NR 54 TC 430 Z9 436 U1 7 U2 32 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD AUG 1 PY 2000 VL 526 IS 3 BP 695 EP 702 PG 8 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 352EX UT WOS:000089202500022 PM 10922269 ER PT J AU Pando, JA Duray, P Yarboro, C Gourley, MF Klippel, JH Schumacher, HR AF Pando, JA Duray, P Yarboro, C Gourley, MF Klippel, JH Schumacher, HR TI Synovitis occurs in some clinically normal and asymptomatic joints in patients with early arthritis SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE rheumatoid arthritis; reactive arthritis; synovitis; knee ID RHEUMATOID-ARTHRITIS; CHLAMYDIA-TRACHOMATIS; TISSUE; DNA AB Objective. To determine if clinically asymptomatic knee joints in patients with recent onset arthritis reveal histological evidence of synovitis. Methods, As part of a prospective study of patients with synovitis of less than one year duration, we performed blind needle biopsies on the knees of 20 patients who had synovitis elsewhere but no symptoms or detectable swelling or tenderness of the biopsied joint. Results, Histologic evidence of synovitis was observed in 11 knees (55%). All patients with synovitis had evidence of synovial lining cell hyperplasia, increased vascularity, and lymphocytic infiltrates. Five of 6 patients with rheumatoid arthritis (RA) and 5 of 8 with undifferentiated arthritis had histological evidence of synovitis. but none of the 5 with reactive arthritis (ReA) had synovitis in the asymptomatic joints. Histologic evidence of synovitis persisted in some after clinical resolution of previous pain and swelling, while it occurred in others with no history of previous involvement of that knee. Conclusion. Even asymptomatic joints in patients with RA and undifferentiated arthritis of recent onset reveal histologic signs of synovitis. The earliest changes may occur before symptoms. Histologic changes also persist after resolution of previous early symptoms. Evidence of inflammation was not present in asymptomatic joints in our 5 patients diagnosed with ReA. C1 NIAMS, Arthrit & Rheumatism Branch, NIH, Bethesda, MD USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Univ Penn, Div Rheumatol, Philadelphia, PA 19104 USA. Vet Affairs Med Ctr, Philadelphia, PA USA. RP Pando, JA (reprint author), 1305 Savannah Rd, Lewes, DE 19951 USA. NR 23 TC 29 Z9 30 U1 0 U2 1 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 AUG PY 2000 VL 27 IS 8 BP 1848 EP 1854 PG 7 WC Rheumatology SC Rheumatology GA 340PM UT WOS:000088543500007 PM 10955323 ER PT J AU Xue, L Shireman, PK Hampton, B Burgess, WH Greisler, HP AF Xue, L Shireman, PK Hampton, B Burgess, WH Greisler, HP TI The cysteine-free fibroblast growth factor 1 mutant induces heparin-independent proliferation of endothelial cells and smooth muscle cells SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE fibroblast growth factor 1; fibrin glue; thrombin; endothelial cells; smooth muscle cells ID INTIMAL HYPERPLASIA; FACTOR TYPE-1; FACTOR-I; BINDING; RESIDUES; RELEASE; INJURY; RAT AB Background. The structure/function relationships of fibroblast growth factor 1 (FGF-1) are being investigated using site mutation, yielding novel structures with potential clinical applicability for modulating tissue responses to vascular interventions. We generated a mutant FGF-1 in which all three cysteines were converted to serines and then tested the relative mitogenic activities on endothelial cells (ECs) and smooth muscle cells (SMCs) and the molecular stability of the protein to thrombin-induced degradation. Methods. The dose responses of wild-type FGF-1 and the Cys-free mutant in the absence or presence of heparin were tested on ECs and SMCs, Cell proliferation was measured by [H-3]thymidine incorporation. Data were normalized by positive control (20% fetal bovine serum) and expressed as percentage of positive control for comparison. The molecular stability was examined by exposure of the cytokines to thrombin at 37 degrees C for 0.5-24 h and then analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Results. Unlike wild-type FGF-1 which induced only minimal DNA synthesis at concentrations as high as 100 ng/ml, the Cys-free mutant induced a dose-dependent proliferation starting at 1 ng/ml on both ECs and SMCs in the absence of heparin, At 100 ng/ml, Cys-free mutant induced 4-fold more proliferation than wild-type FGF-1 on ECs (76.64 +/- 13.39% vs 14.58 +/- 1.38%, P < 0.01) and 12-fold more proliferation on SMCs (143.52 +/- 9.96 vs 11.25 +/- 3.32, P < 0.01). Heparin 5 U/ml potentiated the mitogenic activity of the Cys-free mutant at low dose range. Both proteins were degraded by thrombin progressively. But the Cys-free mutant showed more susceptibility with accelerated appearance of lower-molecular-weight fragment bands after incubation with thrombin, Conclusions. Conversion of cysteine residues to serine changed the heparin dependency of the growth factor and increased its mitogenic activity and its susceptibility to thrombin-induced degradation. (C) 2000 Academic Press. C1 Loyola Univ, Med Ctr, Dept Surg, Maywood, IL 60153 USA. Loyola Univ, Med Ctr, Dept Cell Biol Neurobiol & Anat, Maywood, IL 60153 USA. US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Dept Surg, Hines, IL 60141 USA. Amer Red Cross, Jerome H Holland Lab, Dept Tissue Biol, Rockville, MD USA. RP Greisler, HP (reprint author), Loyola Univ, Med Ctr, Dept Surg, 2160 S 1st Ave, Maywood, IL 60153 USA. RI Hampton, Brian/G-8427-2015 OI Hampton, Brian/0000-0003-4650-2869 FU PHS HHS [R01-41272] NR 21 TC 13 Z9 14 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 J9 J SURG RES JI J. Surg. Res. PD AUG PY 2000 VL 92 IS 2 BP 255 EP 260 DI 10.1006/jsre.2000.5945 PG 6 WC Surgery SC Surgery GA 339RA UT WOS:000088490700018 PM 10896831 ER PT J AU Stankovic, KM Guinan, JJ AF Stankovic, KM Guinan, JJ TI Medial efferent effects on auditory-nerve responses to tail-frequency tones II: Alteration of phase SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID OUTER HAIR-CELLS; GUINEA-PIG COCHLEA; CROSSED-OLIVOCOCHLEAR-BUNDLE; BASILAR-MEMBRANE MECHANICS; ELECTRICAL-STIMULATION; RECEPTOR POTENTIALS; CHINCHILLA COCHLEA; CA2+ CONCENTRATION; SPIKE INITIATION; FIBER RESPONSES AB It is often assumed that at frequencies in the tuning-curve tail there is a passive, constant coupling of basilar-membrane motion to inner hair cell (IHC) stereocilia. This paper shows changes in the phase of auditory-nerve-fiber (ANF) responses to tail-frequency tones and calls into question whether basilar-membrane-to-IHC coupling is constant. In cat ANFs with characteristic frequencies greater than or equal to 10 kHz, efferent effects on the phase of ANF responses to tail-frequency tones were measured. Efferent stimulation caused substantial changes in ANF phase (Delta Phi) (range -80 degrees to +60 degrees, average -15 degrees, a phase lag) with the largest changes at sound levels near threshold and 3-4 octaves below characteristic frequency (CF). At these tail frequencies, efferent stimulation had much less effect on the phase of the cochlear microphonic (CM) than on ANF phase. Thus, since CM is synchronous with basilar-membrane motion for low-frequency stimuli in the cochlear base, the efferent-induced change in ANF phase is unlikely to be due entirely to a change in basilar-membrane phase. At tail frequencies, ANF phase changed with sound level (often by 90 degrees-180 degrees) and the Delta Phi from a fiber was positively correlated with the slope of its phase-versus-sound-level function at the same frequency, as if Delta Phi were caused by a 2-4 dB increase in sound level. This correlation suggests that the processes that produce the change in ANF phase with sound level at tail frequencies are also involved in producing Delta Phi. It is hypothesized that both efferent stimulation and increases in sound level produce similar phase changes because they both produce a similar mix of cochlear vibrational modes. (C) 2000 Acoustical Society of America. [S0001-4966(00)00808-0]. C1 Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Eaton Peabody Lab Auditory Physiol, Boston, MA 02114 USA. Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. MIT, Elect Res Lab, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Stankovic, KM (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Eaton Peabody Lab Auditory Physiol, 243 Charles St, Boston, MA 02114 USA. FU NIDCD NIH HHS [T32 DC00038, 5 RO1 DC 00235]; NIGMS NIH HHS [T32 GM007753, T3GM 07753] NR 71 TC 11 Z9 11 U1 1 U2 1 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0001-4966 J9 J ACOUST SOC AM JI J. Acoust. Soc. Am. PD AUG PY 2000 VL 108 IS 2 BP 664 EP 678 DI 10.1121/1.429599 PG 15 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA 342BX UT WOS:000088626300026 PM 10955633 ER PT J AU Tsao, H Lerner, LH AF Tsao, H Lerner, LH TI Pigmented purpuric eruption associated with injection medroxyprogesterone acetate SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID DERMATOSIS AB Pigmented purpuric eruptions are characterized clinically by purpura, most commonly petechial, and brownish pigmentation. Although there are several idiopathic variants, several drugs have been associated with these eruptions. We present a patient who experienced pigmented purpura on her lower extremities several months after initiating medroxyprogesterone acetate injection. The eruption cleat-ed several weeks after discontinuation of the medication. C1 Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. NR 14 TC 15 Z9 15 U1 1 U2 1 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 AUG PY 2000 VL 43 IS 2 BP 308 EP 310 DI 10.1067/mjd.2000.106372 PN 1 PG 3 WC Dermatology SC Dermatology GA 340YN UT WOS:000088564400021 PM 10906656 ER PT J AU Hongcharu, W Baldassano, M Gonzalez, E AF Hongcharu, W Baldassano, M Gonzalez, E TI Generalized lichen amyloidosis associated with chronic lichen planus SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article AB The development of lichen amyloidosis in a patient with chronic lichen planus is reported. To our knowledge, this is the first report of the coexistence of these 2 diseases. The disparate response of the 2 conditions to etretinate is discussed. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol,Dermatol Serv, Boston, MA USA. RP Gonzalez, E (reprint author), Dermatol Laser Ctr, MGH-Profess Off Bldg,275 Cambridge St, Boston, MA 02114 USA. NR 9 TC 14 Z9 16 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 AUG PY 2000 VL 43 IS 2 SU S BP 346 EP 348 DI 10.1067/mjd.2000.100966 PN 2 PG 3 WC Dermatology SC Dermatology GA 342FF UT WOS:000088634000006 PM 10901719 ER PT J AU Friedlander, AH Walker, LA Friedlander, IK Felsenfeld, AL AF Friedlander, AH Walker, LA Friedlander, IK Felsenfeld, AL TI Diagnosing and comanaging patients with obstructive sleep apnea syndrome SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article ID MAXILLOMANDIBULAR ADVANCEMENT SURGERY; MANDIBULAR ADVANCEMENT; SURGICAL-MANAGEMENT; HYPOPNEA SYNDROME; ORAL APPLIANCE; UPPER AIRWAY; RISK; PREVALENCE; ATHEROMAS; EFFICACY AB Background, Obstructive sleep apnea syndrome, or OSAS, is a common, but underdiagnosed, disorder that potentially is fatal. It is characterized by repetitive episodes of complete or partial upper airway obstruction leading to absent or diminished : airflow into the lungs. These episodes usually last 10 to 30 seconds and result in loud snoring, a decrease in oxygen saturation, and chronic daytime sleepiness and fatigue. The obstruction is caused by the soft palate, base of the tongue or both collapsing against the pharyngeal walls because of decreased muscle tone during sleep. Potentially fatal systemic illnesses frequently associated with this disorder include hypertension, pulmonary hypertension, heart failure, nocturnal cardiac dysrhythmias, myocardial infarction and ischemic stroke. Clinical Implications, The classic signs and symptoms of OSAS may be recognizable by dental. practitioners. Common findings in the medical history include daytime sleepiness, snoring, hypertension and type 2 diabetes mellitus. Common clinical findings include obesity; a thick neck; excessive fat deposition in the palate, tongue (enlarged) and pharynx; a long soft palate; a retrognathic mandible; and calcified carotid artery atheromas on panoramic and lateral cephalometric radiographs. Conclusions, Dentists cognizant of these signs and symptoms have an opportunity to diagnose patients with occult OSAS. After confirmation of the diagnosis by a physician, dentists can participate in management of the disorder by fabricating mandibular advancement appliances and performing surgical procedures that prevent recurrent airway obstruction. C1 Vet Affairs Outpatient Clin & Nursing Home, Sepulveda, CA USA. Univ Calif Los Angeles, Sch Dent, Los Angeles, CA 90024 USA. W Valley Los Angeles Cty Dept Hlth, Panorama City, CA USA. RP Friedlander, AH (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 43 TC 11 Z9 15 U1 0 U2 0 PU AMER DENTAL ASSN PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD AUG PY 2000 VL 131 IS 8 BP 1178 EP 1184 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 355LR UT WOS:000089387600031 PM 10953534 ER PT J AU Braun, U Kunik, M Stanley, M Stoebner, D Molinari, V Wristers, K Teasdale, T AF Braun, U Kunik, M Stanley, M Stoebner, D Molinari, V Wristers, K Teasdale, T TI A brief cognitive behavioral intervention to improve functioning in elderly patients with chronic obstructive pulmonary disease (COPD) SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract C1 Baylor Coll Med, Houston, TX 77030 USA. Houston VA Med Ctr, Houston, TX USA. Gerontol Soc Amer, Houston, TX 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 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2000 VL 48 IS 8 MA P61 BP S26 EP S26 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 346TK UT WOS:000088887000129 ER PT J AU Cognetti, D Alessi, C Newman, AB Schnelle, J AF Cognetti, D Alessi, C Newman, AB Schnelle, J TI Social interaction and sleep in nursing home residents SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract C1 Univ Calif Los Angeles, Los Angeles, CA USA. Greater Los Angeles Vet Adm Healthcare Syst, Sepulveda, CA 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 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2000 VL 48 IS 8 MA P144 BP S47 EP S47 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 346TK UT WOS:000088887000210 ER PT J AU Grimes, A Mccullough, L Kunik, M Molinari, V Workman, R AF Grimes, A Mccullough, L Kunik, M Molinari, V Workman, R TI Informed consent across psychiatric disorders SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract C1 Baylor Coll Med, Gerontol Soc Amer, Houston, TX 77030 USA. Houston VA Med Ctr, Houston, TX 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 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2000 VL 48 IS 8 MA P452 BP S121 EP S121 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 346TK UT WOS:000088887000508 ER PT J AU Hylek, E Go, A Chang, YC Phillips, K Selby, J Singer, D AF Hylek, E Go, A Chang, YC Phillips, K Selby, J Singer, D TI Increasing age is not associated with poorer anticoagulation control in outpatients with non-valvular atrial fibrillation SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Kaiser Permanente, Div Res, Oakland, CA 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 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2000 VL 48 IS 8 MA P189 BP S58 EP S58 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 346TK UT WOS:000088887000255 ER PT J AU Kim, EC Alessi, C Schnelle, J AF Kim, EC Alessi, C Schnelle, J TI Circadian rhythms of activity and sleep/wake in demented NH residents. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract C1 Univ Calif Los Angeles, Los Angeles, CA USA. Greater Los Angeles VA Healthcare Syst, Sepulveda, CA 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 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2000 VL 48 IS 8 MA P150 BP S48 EP S48 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 346TK UT WOS:000088887000216 ER PT J AU Zaroff, JG Rordorf, GA Ogilvy, CS Picard, MH AF Zaroff, JG Rordorf, GA Ogilvy, CS Picard, MH TI Regional patterns of left ventricular systolic dysfunction after subarachnoid hemorrhage: Evidence for neurally mediated cardiac injury SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; WALL-MOTION; HEART-TRANSPLANTATION; NATURAL-HISTORY; ABNORMALITIES; PHEOCHROMOCYTOMA; CARDIOMYOPATHY; ANEURYSMS; REVERSAL AB Although left ventricular (LV) dysfunction has been described after subarachnoid hemorrhage (SAH), its pathophysiology, regional distribution, and reversibility remain uncertain. To test the hypothesis that regional wall motion patterns in SAH patients do not match the typical patterns observed in coronary artery disease, a segmental wall motion analysis was performed in 30 SAH patients with LV dysfunction. Both regional (n = 21) and global (n = 9) wall motion patterns were observed. Preservation of apical function relative to the base was observed in 17 (57%) of the 30 patients. Many of the wall motion patterns were atypical of coronary artery disease but correlated with the distribution of the myocardial sympathetic nerve terminals. Five subjects had follow-up echocardiograms with resolution of LV dysfunction in all cases. In conclusion, a previously unreported, apex-sparing pattern of LV dysfunction is described, providing indirect evidence for a neurally mediated mechanism of cardiac injury. Limited data indicate that LV dysfunction in SAW patients is potentially reversible. C1 Massachusetts Gen Hosp, Cardiac Ultrasound Lab VBK 508, Boston, MA 02114 USA. RP Picard, MH (reprint author), Massachusetts Gen Hosp, Cardiac Ultrasound Lab VBK 508, 55 Fruit St, Boston, MA 02114 USA. OI Picard, Michael/0000-0002-9264-3243 NR 27 TC 114 Z9 118 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD AUG PY 2000 VL 13 IS 8 BP 774 EP 779 DI 10.1067/mje.2000.105763 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 345NM UT WOS:000088822100010 PM 10936822 ER PT J AU Chang, SW Ashraf, FM Azar, DT AF Chang, SW Ashraf, FM Azar, DT TI Wound healing patterns following perforation sustained during laser in situ keratomileusis SO JOURNAL OF THE FORMOSAN MEDICAL ASSOCIATION LA English DT Article DE laser assisted in situ keratomileusis; LASIK; wound healing; excimer laser; refractive surgery ID CORNEAL LIGHT-SCATTERING; PHOTOREFRACTIVE KERATECTOMY; SMOOTH-MUSCLE; GRANULATION TISSUE; HIGH MYOPIA; CONTRACTION; ACTIN; EXPRESSION; RABBITS; EYES AB Background and purpose: Corneal perforation during laser in situ keratomileusis (LASIK) may interface with flap adhesion and wound healing. The purpose of this study was to investigate wound healing patterns following corneal perforation sustained during LASIK in rabbits. Methods: Forty-two pigmented rabbit eyes underwent LASIK surgery, with 5.0-mm excimer laser treatment under the corneal nap, animals were divided into two groups: group I (n = 19) underwent the regular LASIK procedure with -10.0 D treatment, without perforation; in group II (n = 23), the cornea was perforated with the excimer laser. Treatment was discontinued once perforation was observed, and the corneal flap was replaced without sutures. Slit-lamp biomicroscopy, photography, and scatterometry were performed preoperatively and at 1 and 2 days, 1 week, and weekly up to 1 month, 2 months, and 3 months postoperatively, Animals were killed at 1 day, 1 week, 1 month, and 3 months postoperatively and processed for light microscopic, electron microscopic, and immunohistochemical examinations. Results: In group I, the corneas remained clear throughout the experiment. In all eyes, the interface was not readily discernable clinically or histologically. Cornel wound healing was accompanied by minimal cell infiltration. Epithelial hyperplasia at the flap edge was noted at 1 week. Myofibroblast activation was found at thr epithelial wedge where there was an epithelial basement membrane break. In group II, the anterior chamber was shallow with no iris incarceration at the end of surgery. The corneas were clear (n = 6) ol showed mild to moderate edema (n = 12). Corneal edema peaked at 3.6 +/- 5.0 days and subsided thereafter. Corneal wounds healed similarly to those in group I except at the perforation site. The break in Descemet's membrane and endothelium was covered with a fibrin plug on day 1, which resolved thereafter 1. There was no statistically significant difference in the incidence of postoperative infection (p = 1.0) or flap displacement (p = 0.69) rates between the two treatment groups. The scatterometry index peaked at 2 to 3 weeks postoperatively and was significantly higher in group II than in group I (p < 0.001). Conclusions: Although corneal perforation during LASIK surgery may interfere with immediate postoperative flap adhesion, corneal wound healing following LASIK perforation may be similar to that after an uncomplicated LASIK procedure. C1 Chang Gung Mem Hosp, Dept Ophthalmol, Tao Yuan, Taiwan. Johns Hopkins Univ, Wilmer Eye Inst, Baltimore, MD 21218 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Corneal & Refract Surg Serv, Boston, MA USA. RP Chang, SW (reprint author), Chang Gung Mem Hosp, Dept Ophthalmol, 5 Fu Hsing St, Tao Yuan, Taiwan. NR 24 TC 6 Z9 7 U1 0 U2 2 PU EXCERPTA MEDICA ASIA LTD PI CHAI WAN PA 19/F, EIGHT COMMERCIAL TOWER, 8 SUN YIP ST, CHAI WAN, HONG KONG SN 0929-6646 J9 J FORMOS MED ASSOC JI J. Formos. Med. Assoc. PD AUG PY 2000 VL 99 IS 8 BP 635 EP 641 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 342QV UT WOS:000088657400007 PM 10969507 ER PT J AU Bromley, B Shipp, TD Benacerraf, B AF Bromley, B Shipp, TD Benacerraf, B TI Adenomyosis: Sonographic findings and diagnostic accuracy SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE adenomyosis; pelvis; uterus ID TRANSVAGINAL ULTRASONOGRAPHY; DIFFERENTIAL-DIAGNOSIS; UTERINE ADENOMYOSIS; LEIOMYOMA AB The purposes of this study were to evaluate the accuracy of pelvic sonography in identification of adenomyosis and to characterize the most commonly seen sonographic features. We identified all patients over a 10 year period in whom a prospective diagnosis of adenomyosis was suspected on the basis of sonographic findings and who had undergone hysterectomy at a single hospital. Patients were referred for sonography based on standard indications. Sonographic features used in the diagnosis of adenomyosis consisted of two or more of the following: a mottled inhomogeneous myometrial texture, globular appearing uterus, small cystic spaces within the myometrium, and a "shaggy" indistinct endometrial stripe. Correlation was made with the pathology report on the hysterectomy specimen. Fifty-one women met the study criteria. Forty-three of 51 (84.3%) patients sonographically suspected of having adenomyosis were confirmed as having adenomyosis by pathologic examination. All patients with adenomyosis had a mottled heterogeneous appearing uterus, 95% had a globular uterus, 82% small myometrial lucent areas, and 82% had an indistinct endometrial stripe. Eight patients (15.6%) who had been suspected of having adenomyosis by pelvic sonography did not have adenomyosis reported in the pathology specimen. Six of these eight (75%) patients had multiple small fibroids, one had stage IV endometriosis, and one had a normal uterine specimen with no evidence of pathology. Pelvic sonography provides an accurate diagnosis of adenomyosis in the majority of cases. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Bromley, B (reprint author), Diagnost Ultrasound Associates, 333 Longwood Ave,Suite 400, Boston, MA 02115 USA. NR 15 TC 27 Z9 30 U1 0 U2 0 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 J9 J ULTRAS MED JI J. Ultrasound Med. PD AUG PY 2000 VL 19 IS 8 BP 529 EP 534 PG 6 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 415ZZ UT WOS:000167754600004 PM 10944038 ER PT J AU Marcelli, M Shao, TC Li, XY Yin, H Marani, M Denner, L Teng, B Cunningham, GR AF Marcelli, M Shao, TC Li, XY Yin, H Marani, M Denner, L Teng, B Cunningham, GR TI Induction of apoptosis in BPH stromal cells by adenoviral-mediated overexpression of caspase-7 SO JOURNAL OF UROLOGY LA English DT Article DE benign prostate hyperplasia; apoptosis; caspases ID BENIGN PROSTATIC HYPERPLASIA; TRANSGENIC MICE; GRANZYME-B; GENE; DEATH; EXPRESSION; PROTEASE; FAMILY; CANCER AB Purpose: We hypothesized that expression/activity of critical components of the apoptotic pathway can be used to induce apoptosis of a human prostate cell line derived from benign prostatic hyperplasia (BPH) tissue. Materials and Methods: We analyzed the apoptotic pathway in BPH, cells treated with the powerful inducer of apoptosis, staurosporine (STS), and adenoviruses overexpressing caspase-3, -7, or the control gene lacZ. Results: Twelve hours post-STS, most BPH cells were floating in the culture medium, TUNEL staining was widespread, and DEVDase activity (the catalytic activity of type II caspases) was increased. The pan-caspase inhibitor, Z-VAD-FMK, prevented STS-induced apoptosis, Based on these observations, we performed immunoblot analysis for the three known group II caspases (that is caspase-2, -3 and -7), but none of them was detected with three commercially available antibodies. Nevertheless, in view of the presence of increased DEVDase activity, we reasoned that a group II caspase must be a critical mediator of apoptosis in this model. If correct, we postulated that overexpression and activation of a type II caspase should cause apoptosis. To test this hypothesis, we coupled the cDNAs encoding caspase-3 and caspase-7 to adenoviral vectors and obtained constructs AvC3 and AvC7. Cells infected with AvC3 or AVC7 overexpressed the protein for caspase-3 or -7 within 24 to 48 hours. Caspase-3 overexpression did not cause apoptosis above that observed in cells receiving the control adenovirus expressing the lacZ cDNA (AvLac-Z). In contrast, caspase-7 overexpression induced massive apoptosis, BPH cells were then infected with increasing multiplicity of infection (MOI) of AvC7 and AvlacZ. A positive correlation was found between the amount of caspase-7 expressed and the level of DEVDase activity measured. AVC7 at MOIs of 25:1 and 50:1 induced apoptosis in about 50% of BPH cells at; 72 hours post-infection. This effect was AVC7 specific, because the same MOIs of AvlacZ were not apoptogenic. Conclusions: Adenoviral-mediated overexpression of caspase-7 induces apoptosis of BPH-derived cells. C1 Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Texas Biotechnol Corp, VA Med Ctr, Dept Cell Biol, Houston, TX USA. Univ Texas, Hlth Sci Ctr, Inst Mol Med, Houston, TX USA. RP Cunningham, GR (reprint author), 2002 Holcombe Blvd, Houston, TX 77030 USA. NR 35 TC 15 Z9 18 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2000 VL 164 IS 2 BP 518 EP 525 DI 10.1016/S0022-5347(05)67416-2 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 333JB UT WOS:000088126200087 PM 10893637 ER PT J AU Coull, JJ Romerio, F Sun, JM Volker, JL Galvin, KM Davie, JR Shi, Y Hansen, U Margolis, DM AF Coull, JJ Romerio, F Sun, JM Volker, JL Galvin, KM Davie, JR Shi, Y Hansen, U Margolis, DM TI The human factors YY1 and LSF repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of histone deacetylase 1 SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; TRANSCRIPTION FACTOR LSF; BOX-BINDING PROTEIN; IN-VITRO; ZINC-FINGER; DNA-BINDING; HIV-1 TRANSCRIPTION; CHROMATIN STRUCTURE; FACTOR CP2; ACTIVATION AB Enigmatic mechanisms restore the resting state in activated lymphocytes following human immunodeficiency virus type 1 (HIV-1) infection, rarely allowing persistent nonproductive infection. We detail a mechanism whereby cellular factors could establish virological latency. The transcription factors YY1 and LSF cooperate in repression of transcription from the HIV-1 long terminal repeat (LTR). LSF recruits YY1 to the LTR via the zinc fingers of YY1. The first two zinc fingers were observed to be sufficient for this interaction in vitro. A mutant of LSF incapable of binding DNA blocked repression. Like other transcriptional repressors, YY1 can function via recruitment of histone deacetylase (HDAC). We find that HDAC1 copurifies with the LTR-binding YY1-LSF repressor complex, the domain of YY1 that interacts with HDAC1 is required to repress the HIV-1 promoter, expression of HDAC1 augments repression of the LTR by YY1, and the deacetylase inhibitor trichostatin A blocks repression mediated by YYI. This novel link between HDAC recruitment and inhibition of HIV-1 expression by YY1 and LSF, in the natural context of a viral promoter integrated into chromosomal DNA, is the first demonstration of a molecular mechanism of repression of HUV-1. YY1 and LSF may establish transcriptional and virological latency of HIV, a state that has recently been recognized in vivo and has significant implications for the long-term treatment of AIDS. C1 Univ Texas, SW Med Ctr, Div Infect Dis, Dallas, TX 75390 USA. Univ Maryland, Inst Biotechnol, Inst Human Virol, Baltimore, MD 21201 USA. Univ Manitoba, Fac Med, Dept Biochem & Mol Biol, Winnipeg, MB R3E 0W3, Canada. Dana Farber Canc Inst, Div Mol Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02215 USA. RP Univ Texas, SW Med Ctr, Div Infect Dis, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM david.margolis@email.swmed.edu OI Margolis, David/0000-0001-5714-0002 FU NIAID NIH HHS [AI 41366, AI 45297, R01 AI045297, R56 AI045297]; NIGMS NIH HHS [GM53874, R01 GM053874] NR 76 TC 206 Z9 214 U1 2 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD AUG PY 2000 VL 74 IS 15 BP 6790 EP 6799 DI 10.1128/JVI.74.15.6790-6799.2000 PG 10 WC Virology SC Virology GA 333AE UT WOS:000088105900012 PM 10888618 ER PT J AU Szurek, PF Brooks, BR AF Szurek, PF Brooks, BR TI Synthesis of virus-specific high-mobility DNA after temperature upshift of SC-1 cells chronically infected with moloney murine leukemia virus mutant ts1 SO JOURNAL OF VIROLOGY LA English DT Article ID TS1-INDUCED SPONGIFORM ENCEPHALOMYELOPATHY; RETROVIRAL DNA; REVERSE TRANSCRIPTION; TYPE-1 REPLICATION; TRIPHOSPHATE POOLS; PHYSICAL FORMS; PARALYZED MICE; HOST-RANGE; 3T3 CELLS; INTEGRATION AB Premature termination products of reverse transcription that consist physically of viral minus-sense single-stranded DNA that is shorter than one long terminal repeat and partial DNA duplexes are dramatically increased in the central nervous system (CNS) of FVB/N mice that are infected by ts1, a temperature-sensitive mutant of Moloney murine leukemia virus. Due to their migration in agarose gels, these incomplete physical forms of DNA have been designated high-mobility (HM) DNA, In non-CNS tissues, the level of HM DNA is either low or not detectable. In order to determine the conditions that are necessary for the synthesis of HM DNA in vivo, we have characterized the physical forms of HM DNA that were synthesized in vitro in chronically infected SC-1 cells after temperature upshift, At the permissive temperature of 34 degrees C, the chronically infected SC-1 cells did not synthesize HM DNA. After temperature upshift of the cultured cells from 34 to 37 degrees C, the chronically infected SC-1 cells developed extremely high levels of HM DNA, Following temperature downshift of the cultured cells from 37 to 34 degrees C, a decrease in the level of HM DNA and an increase in the level of unintegrated linear proviral DNA occurred simultaneously. These results suggested that the accumulation of HM DNA both in vitro and in vivo may be the result of superinfection. C1 William S Middleton Mem Vet Hosp, Neurol & Res Serv, Madison, WI 53705 USA. Univ Wisconsin, Madison Med Sch, Dept Neurol, Madison, WI 53705 USA. Univ Wisconsin, Madison Med Sch, Dept Med Microbiol, Madison, WI 53705 USA. RP Brooks, BR (reprint author), William S Middleton Mem Vet Hosp, Neurol & Res Serv, Room B6112,2500 Overlook Terrace, Madison, WI 53705 USA. NR 46 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2000 VL 74 IS 15 BP 7055 EP 7063 DI 10.1128/JVI.74.15.7055-7063.2000 PG 9 WC Virology SC Virology GA 333AE UT WOS:000088105900039 PM 10888645 ER PT J AU Trimble, LA Shankar, P Patterson, M Daily, JP Lieberman, J AF Trimble, LA Shankar, P Patterson, M Daily, JP Lieberman, J TI Human immunodeficiency virus-specific circulating CD8 T lymphocytes have down-modulated CD3 zeta and CD28, key signaling molecules for T-cell activation SO JOURNAL OF VIROLOGY LA English DT Article ID HIV-INFECTED SUBJECTS; RECEPTOR ZETA-CHAIN; DISEASE PROGRESSION; ANTIRETROVIRAL THERAPY; IMMUNE PARAMETERS; NEF PROTEIN; EXPRESSION; COMPLEX; INDIVIDUALS; RESPONSES AB Although human immunodeficiency virus (HIV)-infected subjects without AIDS have a high frequency of HIV-specific CD8 T lymphocytes, cellular immunity is unable to control infection. Freshly isolated lymphocytes often do not lyse HIV-infected targets in 4-h cytotoxicity assays. A large fraction of circulating CD8 T cells from HIV-infected donors down-modulate CD3 zeta, the signaling component of the T-cell receptor complex, which is reexpressed in vitro coincident with the return of cytotoxic function. To investigate further the link between CD3 zeta down-modulation and possible CD8 T-cell functional defects, we used flow cytometry to characterize further the properties of the CD3 zeta-down-modulated subset, HIV-specific CD8 T cells, identified by tetramer staining, are CD3 zeta(-). CD8 T cells with down-modulated CD3 zeta also do not express the key costimulatory receptor CD28 and have the cell surface phenotype of activated or memory T cells (BLA-DR+ CD62L(-)). After T-cell activation, CD3 zeta-down-modulated cells express the activation marker CD69 but not the high-affinity interleukin 2 (IL-2) receptor alpha-chain CD25 and produce gamma interferon but not IL-2. Therefore HIV-specific CD8 T cells have down-modulated key signaling molecules for T-cell activation and costimulation and require exogenous cytokine stimulation, The typical impairment of HIV-specific CD4 T helper cells, which would normally provide specific CD8 T-cell stimulation, means that in vivo CTL function in vivo is compromised in most HIV-infected individuals. In AIDS patients, the functional defect is more severe, since CD3 zeta is not reexpressed even after IL-2 exposure. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Lieberman, J (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. RI Lieberman, Judy/A-2717-2015 FU NIAID NIH HHS [AI 42519, AI 45406] NR 66 TC 103 Z9 105 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2000 VL 74 IS 16 BP 7320 EP 7330 DI 10.1128/JVI.74.16.7320-7330.2000 PG 11 WC Virology SC Virology GA 337DP UT WOS:000088342400014 PM 10906185 ER PT J AU Chen, ZW Shen, Y Kou, ZC Ibegbu, C Zhou, DJ Shen, L Morrison, P Bogle, C McClure, HM Nahmias, AJ Sehgal, PK Letvin, NL AF Chen, ZW Shen, Y Kou, ZC Ibegbu, C Zhou, DJ Shen, L Morrison, P Bogle, C McClure, HM Nahmias, AJ Sehgal, PK Letvin, NL TI Prolonged dominance of clonally restricted CD4(+) T cells in macaques infected with simian immunodeficiency viruses SO JOURNAL OF VIROLOGY LA English DT Article ID RHESUS-MONKEYS; LYMPHOCYTES; REPERTOIRE; RECEPTOR; BETA; RESPONSES; TURNOVER; GAG; INTERLEUKIN-2; PATHOGENESIS AB The repertoire of functional CD4(+) T lymphocytes in human immunodeficiency virus type 1-infected individuals remains poorly understood, To explore this issue, we have examined the clonality of CD4(+) T cells in simian immunodeficiency virus (SIV)-infected macaques by assessing T-cell receptor complementarity-determining region 3 (CDR3) profiles and sequences, A dominance of CD4(+) T cells expressing particular CDR3 sequences was identified within certain V beta-expressing peripheral blood lymphocyte subpopulations in the infected monkeys. Studies were then done to explore whether these dominant CD4(+) T cells represented expanded antigen-specific cell subpopulations or residual cells remaining in the course of virus-induced CD4(+) T-cell depletion, Sequence analysis revealed that these selected CDR3-bearing CD4(+) T-cell clones emerged soon after infection and dominated the CD4(+) T-cell repertoire for up to 14 months. Moreover, inoculation of chronically infected macaques with autologous SIV-infected cell lines to transiently increase plasma viral loads in the monkeys resulted in the dominance of these selected CDR3-bearing CD4(+) T cells. Both the temporal association of the detection of these clonal cell populations with infection and the dominance of these cell populations following superinfection with SIV suggest that these cells may be SIV specific, Finally, the inoculation of staphylococcal enterotoxin B superantigen into SIV-infected macaques uncovered a polyclonal background underlying the few dominant CDR3-bearing CD4(+) T cells, demonstrating that expandable polyclonal CD4(+) T-cell subpopulations persist in these animals. These results support the notions that a chronic AIDS virus infection can induce clonal expansion, in addition to depletion of CD4(+) T cells, and that some of these clones may be SIV specific. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Dana Farber Canc Inst, Boston, MA 02215 USA. Emory Univ, Sch Med, Atlanta, GA 30303 USA. Emory Univ, Yerkes Reg Primate Res Ctr, Atlanta, GA 30322 USA. New England Reg Primate Res Ctr, Southborough, MA 01772 USA. RP Chen, ZW (reprint author), 330 Brookline Ave,RE113, Boston, MA 02215 USA. FU NCRR NIH HHS [RR00165, R01 RR013601, P51 RR000165, RR13601]; NHLBI NIH HHS [HL64560, R01 HL064560]; NIAID NIH HHS [R37 AI020729, R01 AI020729] NR 30 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2000 VL 74 IS 16 BP 7442 EP 7450 DI 10.1128/JVI.74.16.7442-7450.2000 PG 9 WC Virology SC Virology GA 337DP UT WOS:000088342400026 PM 10906197 ER PT J AU Goulder, PJR Lechner, F Klenerman, P McIntosh, K Walker, BD AF Goulder, PJR Lechner, F Klenerman, P McIntosh, K Walker, BD TI Characterization of a novel respiratory syncytial virus-specific human cytotoxic T-lymphocyte epitope SO JOURNAL OF VIROLOGY LA English DT Article ID VIRAL-INFECTION; CELLS; ANTIGEN; REEVALUATION; RECOGNIZE; PATHOLOGY; INFLUENZA; PROTEINS; IMMUNITY; VACCINE AB Respiratory syncytial virus (RSV) infection is a major cause of morbidity in childhood worldwide. The first human RSV-specific cytotoxic T-lymphocyte epitope to be defined is described. This HLA B7-restricted epitope in nucleoprotein (NP) was detectable in four healthy, B7-positive adult subjects using B7-RSV-NP tetrameric complexes to stain CD8+ T cells. C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA. Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA. John Radcliffe Hosp, Nuffield Dept Med, Oxford OX3 9DU, England. RP Goulder, PJR (reprint author), Massachusetts Gen Hosp, Partners AIDS Res Ctr, 13th St,Bldg 149,Rm 5218, Charlestown, MA 02129 USA. FU NIAID NIH HHS [R01 AI028568, R01 AI030914, AI30914, AI28568, R37 AI028568] NR 22 TC 40 Z9 41 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2000 VL 74 IS 16 BP 7694 EP 7697 DI 10.1128/JVI.74.16.7694-7697.2000 PG 4 WC Virology SC Virology GA 337DP UT WOS:000088342400057 PM 10906229 ER PT J AU Eavey, RD Neto, JFL AF Eavey, RD Neto, JFL TI Canal wall window tympanomastoidectomy SO LARYNGOSCOPE LA English DT Article ID CHOLESTEATOMA; CHILDREN; MASTOIDECTOMY; RECURRENT C1 Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. Hosp Criampa Santo Antonio, Div Pediat Otorhinolaryngol, Fundacao Fac Fed Ciencias Med, Dept Otorhinolaryngol, Porto Alegre, RS, Brazil. RP Eavey, RD (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. NR 12 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD AUG PY 2000 VL 110 IS 8 BP 1410 EP 1414 DI 10.1097/00005537-200008000-00036 PG 5 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 341NL UT WOS:000088596400032 PM 10942151 ER PT J AU Lee, S Tallman, MS Oken, MM Cassileth, PA Bennett, JM Wiernik, PH Rowe, JM AF Lee, S Tallman, MS Oken, MM Cassileth, PA Bennett, JM Wiernik, PH Rowe, JM CA Eastern Cooperative Oncology Grp TI Duration of second complete remission compared with first complete remission in patients with acute myeloid leukemia SO LEUKEMIA LA English DT Article DE inversion rate; relapsed or refractory AML; ECOG ID ACUTE MYELOGENOUS LEUKEMIA; BONE-MARROW TRANSPLANTATION; ADULT PATIENTS; POSTREMISSION CHEMOTHERAPY; CYTOSINE-ARABINOSIDE; DOSE CYTARABINE; PHASE-III; THERAPY; INTERLEUKIN-2; DAUNORUBICIN AB The prognosis for patients with acute myeloid leukemia in first relapse is generally poor. The ability to induce a second complete remission (CR) with the same chemotherapy used in initial induction therapy is limited. Remission inversion rate, defined as achieving a longer second CR than the first CR in response to standard chemotherapy for relapse, is important in assessing studies of novel chemotherapy or immunologic treatment strategies for patients with relapsed disease. One hundred and twenty-four patients entered on two Eastern Cooperative Oncology Group (ECOG) studies for patients with relapsed AML were analyzed to determine the remission inversion rate. Twenty-two of the 124 patients (18%; 95% confidence interval 12-26%) experienced a longer second CR duration than the first CR duration by at least 2 months. Inversion of CR duration is thus not a rare event. The inversion frequency reported here establishes a baseline upon which future studies in relapsed disease need to be defined. C1 Northwestern Univ, Sch Med, Div Hematol Oncol, Robert H Lurie Canc Ctr, Chicago, IL 60611 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Virginia Piper Canc Inst, Minneapolis, MN USA. Univ Miami, Sch Med, Miami, FL USA. Univ Rochester, Ctr Canc, Rochester, NY USA. NY Med Coll, Our Lady Mercy Med Ctr, Bronx, NY USA. Rambam Med Ctr, Haifa, Israel. RP Northwestern Univ, Sch Med, Div Hematol Oncol, Robert H Lurie Canc Ctr, 676 N St Clair St,Suite 850, Chicago, IL 60611 USA. NR 30 TC 16 Z9 17 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD AUG PY 2000 VL 14 IS 8 BP 1345 EP 1348 DI 10.1038/sj.leu.2401853 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA 341CB UT WOS:000088572500003 PM 10942227 ER PT J AU Robles, C Kim, KM Oken, MM Bennett, JM Letendre, L Wiernik, PH O'Connel, MJ Cassileth, PA AF Robles, C Kim, KM Oken, MM Bennett, JM Letendre, L Wiernik, PH O'Connel, MJ Cassileth, PA TI Low-dose cytarabine maintenance therapy vs observation after remission induction in advanced acute myeloid leukemia: an Eastern Cooperative Oncology Group Trial (E5483) SO LEUKEMIA LA English DT Article DE low-dose cytarabine; acute myeloid leukemia; maintenance therapy ID ACUTE NONLYMPHOCYTIC LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; CYTOSINE-ARABINOSIDE; MYELODYSPLASTIC SYNDROMES; CHEMOTHERAPY; INFUSION AB The Eastern Cooperative Oncology Group (ECOG) conducted a prospective phase III study in patients with relapsed/refractory acute myeloid leukemia (AML) to evaluate whether administration of repeated courses of low-dose cytarabine (LDAC) maintenance therapy after induction of complete remission in advanced AML would improve disease-free and overall survival, Patients with AML in second/later relapse or refractory disease were first treated with a combination of high-dose cytarabine and amsacrine. Those who achieved complete remission were then randomized to observation or to receive LDAC, 10 mg/m(2) subcutaneously twice a day x2 21 days every 2 months until relapse occurred. Of 86 patients eligible for randomization, 41 patients were assigned to receive LDAC and 45 patients to observation, The median disease-free survival was 7.4 months for patients assigned to LDAC compared to 3.3 months for patients receiving no additional therapy, P=0.084. The median survival from randomization was 10.9 months and 7.0 months for patients receiving LDAC maintenance chemotherapy and observation, respectively (P = 0.615). The data from this study suggest that LDAC maintenance therapy given to patients with advanced AML who achieve complete remission can increase disease-free survival compared to observation, but does not improve overall survival. Nevertheless, because of the ineffectiveness and toxicity of intensive post-remission chemotherapy in this circumstance, LDAC maintenance therapy, a tolerable outpatient regimen, offers the potential for improved quality of life. C1 Univ Miami, Sch Med, Miami, FL USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Virginia Piper Canc Inst, Minneapolis, MN USA. Univ Rochester, Rochester, NY USA. Mayo Clin, Rochester, MN USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Cassileth, PA (reprint author), Sylvester Comprehens Canc Ctr, 1475 NW 12th Ave, Miami, FL 33136 USA. FU NCI NIH HHS [CA11083, CA23318, CA13650] NR 25 TC 15 Z9 15 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD AUG PY 2000 VL 14 IS 8 BP 1349 EP 1353 DI 10.1038/sj.leu.2401850 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA 341CB UT WOS:000088572500004 PM 10942228 ER PT J AU Stone, ME AF Stone, ME TI The lighthouse handbook on vision impairment and vision rehabilitation. SO LIBRARY JOURNAL LA English DT Book Review C1 Massachusetts Gen Hosp, Treadwell Lib, Boston, MA 02114 USA. RP Stone, ME (reprint author), Massachusetts Gen Hosp, Treadwell Lib, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU BOWKER MAGAZINE GROUP CAHNERS MAGAZINE DIVISION PI NEW YORK PA 249 W 17TH ST, NEW YORK, NY 10011 USA SN 0363-0277 J9 LIBR J JI Libr. J. PD AUG PY 2000 VL 125 IS 13 BP 90 EP + PG 2 WC Information Science & Library Science SC Information Science & Library Science GA 347AP UT WOS:000088904300050 ER PT J AU Riddle, JR Hyams, KC Murphy, FM Mazzuchi, JF AF Riddle, JR Hyams, KC Murphy, FM Mazzuchi, JF TI In the borderland between health and disease following the Gulf War SO MAYO CLINIC PROCEEDINGS LA English DT Editorial Material ID VETERANS C1 US Dept Def, Washington, DC USA. USN, Med Res Ctr, Bethesda, MD 20084 USA. US Dept Vet Affairs, Washington, DC USA. RP Riddle, JR (reprint author), USAF, BSC, Skyline 5,Suite 810 Mail,5111 Leesburg Pike, Falls Church, VA 22041 USA. NR 22 TC 7 Z9 7 U1 0 U2 1 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 AUG PY 2000 VL 75 IS 8 BP 777 EP 779 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 341UE UT WOS:000088607400001 PM 10943228 ER PT J AU Geraci, JM AF Geraci, JM TI In-hospital complication occurrence as a screen for quality-of-care problems - What's next? SO MEDICAL CARE LA English DT Editorial Material ID ADVERSE EVENTS; IDENTIFYING COMPLICATIONS; ADMINISTRATIVE DATA; RISK C1 Houston VAMC, Houston, TX 77030 USA. RP Geraci, JM (reprint author), Houston VAMC, 111C,2002 Holcombe Blvd, Houston, TX 77030 USA. NR 22 TC 5 Z9 5 U1 1 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 AUG PY 2000 VL 38 IS 8 BP 777 EP 780 DI 10.1097/00005650-200008000-00001 PG 4 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 337ZP UT WOS:000088393900001 PM 10929989 ER PT J AU Gittell, JH Fairfield, KM Bierbaum, B Head, W Jackson, R Kelly, M Laskin, R Lipson, S Siliski, J Thornhill, T Zuckerman, J AF Gittell, JH Fairfield, KM Bierbaum, B Head, W Jackson, R Kelly, M Laskin, R Lipson, S Siliski, J Thornhill, T Zuckerman, J TI Impact of relational coordination on quality of care, postoperative pain and functioning, and length of stay - A nine-hospital study of surgical patients SO MEDICAL CARE LA English DT Article DE coordination; quality of care; length of stay; clinical outcomes; arthroplasty ID INTENSIVE-CARE; HEALTH SURVEY; OUTCOMES; UNITS; VALIDITY; SERVICES; SF-36; HIP AB BACKGROUND. Health care organizations face pressures from patients to improve the quality of care and clinical outcomes, as well as pressures from managed care to do so more efficiently. Coordination, the management of task interdependencies, is one way that health care organizations have attempted to meet these conflicting demands. OBJECTIVES. The objectives of this study were to introduce the concept of relational coordination and to determine its impact on the quality of care, postoperative pain and functioning; and the length of stay for patients undergoing an elective surgical procedure. Relational coordination comprises frequent, timely, accurate communication, as well as problem-solving, shared goals, shared knowledge, and mutual respect among health care providers. RESEARCH DESIGN. Relational coordination was measured by a cross-sectional questionnaire of health care providers. Quality of care was measured by a cross-sectional postoperative questionnaire of total hip and knee arthroplasty patients. On the same questionnaire, postoperative pain and functioning were measured by the WOMAC osteoarthritis instrument. Length of stay was measured from individual patient hospital records. SUBJECTS. The subjects for this study were 338 care providers and 878 patients who completed questionnaires from 9 hospitals in Boston, MA, New York, NY, and Dallas, TX, between July and December 1997. MEASURES. Quality of care, postoperative pain and functioning, and length of acute hospital stay. RESULTS. Relational coordination varied significantly between sites, ranging from 3.86 to 4.22 (P <0.001). Quality of care was significantly improved by relational coordination (P <0.001) and each of its dimensions. Postoperative pain was significantly reduced by relational coordination (P = 0.041), whereas postoperative functioning was significantly improved by several dimensions of relational coordination, including the frequency of communication (P = 0.044), the strength of shared goals (P = 0.035), and the degree of mutual respect (P = 0.030) among care providers. Length of stay was significantly shortened (53.77%, P <0.001) by relational coordination and each of its dimensions. CONCLUSIONS. Relational coordination across health care providers is associated with improved quality of care, reduced postoperative pain, and decreased lengths of hospital stay for patients undergoing total joint arthroplasty. These findings support the design of formal practices to strengthen communication and relationships among key caregivers on surgical units. C1 Harvard Univ, Sch Business, Boston, MA 02163 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. Tufts Univ, New England Baptist Hosp, Sch Med, Boston, MA 02111 USA. Presbyterian Plano Hosp, Plano, TX USA. Baylor Univ, Med Ctr, Dallas, TX USA. Beth Israel Hosp, New York, NY USA. Hosp Special Surg, New York, NY 10021 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. Hosp Joint Dis & Med Ctr, New York, NY 10003 USA. RP Gittell, JH (reprint author), Harvard Univ, Sch Business, 131 Morgan,Soldiers Field Rd, Boston, MA 02163 USA. NR 38 TC 209 Z9 210 U1 3 U2 33 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 AUG PY 2000 VL 38 IS 8 BP 807 EP 819 DI 10.1097/00005650-200008000-00005 PG 13 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 337ZP UT WOS:000088393900005 PM 10929993 ER PT J AU Yoshida, K Weichselbaum, R Kharbanda, S Kufe, D AF Yoshida, K Weichselbaum, R Kharbanda, S Kufe, D TI Role for Lyn tyrosine kinase as a regulator of stress-activated protein kinase activity in response to DNA damage SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MYELOID-LEUKEMIA CELLS; SIGNAL-TRANSDUCTION PATHWAYS; TUMOR-NECROSIS-FACTOR; C-JUN PROTOONCOGENE; IONIZING-RADIATION; GENE-EXPRESSION; PHOSPHATIDYLINOSITOL 3-KINASE; INDUCED APOPTOSIS; 1-BETA-D-ARABINOFURANOSYLCYTOSINE INCORPORATION; FUNCTIONAL INTERACTION AB The cellular response to DNA damage includes activation of the nuclear Lyn protein tyrosine kinase, Using cells deficient in Lyn expression, the present studies demonstrate that Lyn is required in part for induction of the stress-activated protein kinase (SAPK) in the response to 1-beta-D-arabinofuranosylcytosine (ara-C) and other genotoxic agents, By contrast, exposure of Lyn-deficient cells to ara-C, ionizing radiation, or cisplatin had no effect on activation of extracellular signal-regulated protein kinase or p38 mitogen-activated protein kinase. Similar findings were obtained in cells stably expressing a kinase-inactive, dominant-negative Lyn(K-R) mutant. Coexpression studies demonstrate that Lyn, but not Lyn(K-R), induces SAPK activity. Ln addition, the results demonstrate that Lyn activates SAPK by an MKK7-dependent, SEK1-independent mechanism. As MEKK1 functions upstream to MKK7 and SAPK;, the finding that a dominant-negative MEKK1(K-M) mutant blocks Lyn-induced SAPK activity supports involvement of the MEKK1 --> MKK7 pathway. The results also demonstrate that inhibition of Lyn-induced SAPK activity abrogates the apoptotic response of cells to genotoxic stress. These findings indicate that activation of SAPK by DNA damage is mediated in part by Lyn and that the Lyn --> MEKK1 --> MKK7 --> SAPK is functional in the induction of apoptosis by genotoxic agents. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Chicago, Dept Radiat & Cellular Biol, Chicago, IL 60637 USA. RP Kufe, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [R01 CA029431, CA75216, CA55241, CA29431] NR 75 TC 50 Z9 52 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2000 VL 20 IS 15 BP 5370 EP 5380 DI 10.1128/MCB.20.15.5370-5380.2000 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 334LX UT WOS:000088188900002 PM 10891478 ER PT J AU Spyropoulos, DD Pharr, PN Lavenburg, KR Jackers, P Papas, TS Ogawa, M Watson, DK AF Spyropoulos, DD Pharr, PN Lavenburg, KR Jackers, P Papas, TS Ogawa, M Watson, DK TI Hemorrhage, impaired hematopoiesis, and lethality in mouse embryos carrying a targeted disruption of the Fli1 transcription factor SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MEGAKARYOCYTE-SPECIFIC EXPRESSION; GLYCOPROTEIN-IX PROMOTER; ETS FAMILY; DNA-BINDING; MURINE LEUKEMIA; GENE-EXPRESSION; TRANSGENIC MICE; PROTEINS; GATA; ERYTHROLEUKEMIA AB The Ets family of transcription factors have been suggested to function as key regulators of hematopoeisis. sere we describe aberrant hematopoeisis and hemorrhaging in mouse embryos homozygous for a targeted disruption in the Ets family member, Fli1. Mutant embryos are found to hemorrhage from the dorsal aorta to the lumen of the neural tube and ventricles of the brain (hematorrhachis) on embryonic day 11.0 (E11.0) and are dead by E12.5. Histological examinations and in situ hybridization reveal disorganization of columnar epithelium and the presence of hematomas within the neuroepithelium and disruption of the basement membrane lying between this and mesenchymal tissues, both of which express Fli1 at the time of hemorrhaging. Livers from mutant embryos contain few pronormoblasts and basophilic normoblasts and have drastically reduced numbers of colony forming cells. These defects occur with complete penetrance of phenotype regardless of the genetic background (inbred B6, hybrid 129/B6, or outbred CD1) or the targeted embryonic stem cell line used for the generation of knockout lines. Taken together, these results provide in vivo evidence for the role of Fli1 in the regulation of hematopoiesis and hemostasis. C1 Med Univ S Carolina, Hollings Canc Ctr, Ctr Mol & Struct Biol, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. Ralph H Johnson VA Med Ctr, Charleston, SC 29425 USA. RP Watson, DK (reprint author), Med Univ S Carolina, Hollings Canc Ctr, Ctr Mol & Struct Biol, Charleston, SC 29425 USA. FU NCI NIH HHS [P01 CA078582, P01 CA78582] NR 42 TC 206 Z9 207 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2000 VL 20 IS 15 BP 5643 EP 5652 DI 10.1128/MCB.20.15.5643-5652.2000 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 334LX UT WOS:000088188900025 PM 10891501 ER PT J AU Tsai, EY Falvo, JV Tsytsykova, AV Barczak, AK Reimold, AM Glimcher, LH Fenton, MJ Gordon, DC Dunn, IF Goldfeld, AE AF Tsai, EY Falvo, JV Tsytsykova, AV Barczak, AK Reimold, AM Glimcher, LH Fenton, MJ Gordon, DC Dunn, IF Goldfeld, AE TI A lipopolysaccharide-specific enhancer complex involving Ets, Elk-1, Sp1, and CREB binding protein and p300 is recruited to the tumor necrosis factor alpha promoter in vivo SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NF-KAPPA-B; HUMAN MONOCYTIC CELLS; TRANSCRIPTION FACTORS; GENE-REGULATION; T-CELLS; KINASE PATHWAY; IN-VIVO; C-JUN; ACTIVATION; CBP AB The tumor necrosis factor alpha (TNF-alpha) gene is rapidly activated by lipopolysaccharide (LPS), Here, we show that extracellular signal-regulated kinase (ERK) kinase activity but not calcineurin phosphatase activity is required for LPS-stimulated TNF-alpha gene expression, In LPS-stimulated macrophages, the ERK substrates Ets and Elk-1 bind to the TNF-alpha promoter in vivo. Strikingly, Ets and Elk-1 bind to two TNF-alpha nuclear factor of activated T cells (NFAT)-binding sites, which are required for calcineurin and NFAT-dependent TNF-alpha gene expression in lymphocytes. The transcription factors ATF-2, c-jun, Egr-1, and Sp1 are also inducibly recruited to the TNF-alpha promoter in vivo, and the binding sites for each of these activators are required for LPS-stimulated TNF-alpha gene expression. Furthermore, assembly of the LPS-stimulated TNF-alpha enhancer complex is dependent upon the coactivator proteins CREB binding protein and p300, The finding that a distinct set of transcription factors associates with a fixed set of binding sites on the TNF-alpha promoter in response to LPS stimulation lends new insights into the mechanisms by which complex patterns of gene regulation are achieved. C1 Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. RP Goldfeld, AE (reprint author), Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. FU NIAID NIH HHS [R01 AI032412, AI-32412]; NIGMS NIH HHS [GM-56492, R01 GM056492] NR 60 TC 191 Z9 194 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2000 VL 20 IS 16 BP 6084 EP 6094 DI 10.1128/MCB.20.16.6084-6094.2000 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 340GF UT WOS:000088524200029 PM 10913190 ER PT J AU Bloch, DB Nakajima, A Gulick, T Chiche, JD Orth, D de la Monte, SM Bloch, KD AF Bloch, DB Nakajima, A Gulick, T Chiche, JD Orth, D de la Monte, SM Bloch, KD TI Sp110 localizes to the PML-Sp100 nuclear body and may function as a nuclear hormone receptor transcriptional coactivator SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ACUTE PROMYELOCYTIC LEUKEMIA; PRIMARY BILIARY-CIRRHOSIS; CREB BINDING-PROTEIN; PORE COMPLEX; ALPHA GENE; RAR-ALPHA; PML; BODIES; BROMODOMAIN; T(15-17) AB The nuclear body is a multiprotein complex that may have a role in the regulation of gene transcription. This structure is disrupted in a variety of human disorders including acute promyelocytic leukemia and viral infections, suggesting that alterations in the nuclear body mag have an important role in the pathogenesis of these diseases. In this study, we identified a cDNA encoding a leukocyte-specific nuclear body component designated Sp110, The N-terminal portion of Sp110 was homologous to two previously characterized components of the nuclear body (Sp100 and Sp140). The C-terminal region of Sp110 was homologous to the transcription intermediary factor 1 (TIF1) family of proteins. High levels of Sp110 mRNA were detected in human peripheral blood leukocytes and spleen but not in other tissues, The levels of Sp110 mRNA and protein in the human promyelocytic leukemia cell line NB4 increased following treatment with all-trans retinoic acid (ATRA), and Sp110 localized to PML-Sp100 nuclear bodies in ATRA-treated NB4 cells. Because of the structural similarities between Sp110 and TIF1 proteins, the effect of Sp110 on gene transcription was examined. An Sp110 DNA-binding domain fusion protein activated transcription of a reporter gene in transfected mammalian cells. In addition, Sp110 produced a marked increase in ATRA-mediated expression of a reporter gene containing a retinoic acid response element. Taken together, the results of this study demonstrate that Sp110 is a member of the Sp100/Sp140 family of nuclear body components and that Sp110 may function as a nuclear hormone receptor transcriptional coactivator. The predominant expression of Sp110 in Leukocytes and the enhanced expression of Sp110 in NB4 cells treated with ATRA raise the possibility that Sp110 has a role in inducing differentiation of myeloid cells. C1 Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Massachusetts Gen Hosp, Gen Med Serv, Div Cardiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Neuropathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Arthritis Unit, Boston, MA 02114 USA. RP Bloch, DB (reprint author), Massachusetts Gen Hosp E, CNY 149 13th St, Hillsborough 02129, North Ireland. FU NHLBI NIH HHS [HL55377]; NIAMS NIH HHS [AR-01866]; NIDDK NIH HHS [DK-051179] NR 46 TC 85 Z9 88 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2000 VL 20 IS 16 BP 6138 EP 6146 DI 10.1128/MCB.20.16.6138-6146.2000 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 340GF UT WOS:000088524200034 PM 10913195 ER PT J AU Bastepe, M Juppner, H AF Bastepe, M Juppner, H TI Identification and characterization of two new, highly polymorphic loci adjacent to GNAS1 on chromosome 20q13.3 SO MOLECULAR AND CELLULAR PROBES LA English DT Article DE stimulatory G protein; microsatellite marker; polymorphism information content; heterozygosity ID STIMULATORY-G-PROTEIN; ALBRIGHT HEREDITARY OSTEODYSTROPHY; ADENYLYL-CYCLASE GNAS1; ALPHA-SUBUNIT; GENE; EXPRESSION; MARKERS; MAPS AB GNAS1, which is located in the chromosomal region 20q13.3, gives rise to maternally, paternally or bi-allelically expressed transcripts including the one that encodes the alpha subunit of the stimulatory G protein. Numerous naturally occurring mutations of this gene have been identified in several different disorders including certain forms of pseudohypoparathyroidism, progressive osseous heteroplasia, McCune-Albright syndrome and acromegaly. Polymorphic markers currently employed in the genetic evaluation of these disorders frequently prove uninformative owing to a low heterozygosity value associated with each marker. We searched for potentially polymorphic tandem repeats close to the GNAS1 locus, and identified two new, highly polymorphic loci that are located within a similar to 48-kb region immediately downstream of th is gene. These new microsatellite markers, with their high polymorphism information content, may prove to be useful in genetic studies related to GNAS1 as well as to other genes located in the flanking genomic region. (C) 2000 Academic Press. C1 Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Juppner, H (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Dept Med, 50 Blossom St,WEL 5, Boston, MA 02114 USA. FU PHS HHS [R01 46718-06] NR 23 TC 6 Z9 6 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0890-8508 J9 MOL CELL PROBE JI Mol. Cell. Probes PD AUG PY 2000 VL 14 IS 4 BP 261 EP 264 DI 10.1006/mcpr.2000.0308 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology GA 354RZ UT WOS:000089344600009 PM 10970731 ER PT J AU Monsalve, M Wu, ZD Adelmant, G Puigserver, P Fan, ML Spiegelman, BM AF Monsalve, M Wu, ZD Adelmant, G Puigserver, P Fan, ML Spiegelman, BM TI Direct coupling of transcription and mRNA processing through the thermogenic coactivator PGC-1 SO MOLECULAR CELL LA English DT Article ID RNA-POLYMERASE-II; PRE-MESSENGER-RNA; CARBOXY-TERMINAL DOMAIN; WILMS-TUMOR SUPPRESSOR; NUCLEAR RIBONUCLEOPROTEIN-K; DNA-BINDING PROTEIN; SPLICING FACTORS; ELONGATION-FACTOR; GENE-EXPRESSION; CAPPING ENZYME AB Transcription and mRNA processing are coupled events in vivo, but the mechanisms that coordinate these processes are largely unknown. PGC-1 is a transcriptional coactivator that plays a major role in the regulation of adaptive thermogenesis. PGC-1 also has certain motifs characteristic of splicing factors. We demonstrate here that mutations in the serine- and arginine-rich domain and RNA recognition motif of PGC-1 interfere with the ability of PGC-1 to induce mRNAs of target genes. These mutations also disrupt the ability of PGC-1 to co-localize and associate with RNA processing factors. PGC-1 can alter the processing of an mRNA, but only when it is loaded onto the promoter of the gene. These data demonstrate the coordinated regulation of RNA transcription and processing through PGC-1. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Spiegelman, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. FU NIDDK NIH HHS [DK54477] NR 63 TC 253 Z9 265 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell. PD AUG PY 2000 VL 6 IS 2 BP 307 EP 316 DI 10.1016/S1097-2765(00)00031-9 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 351NY UT WOS:000089166100009 PM 10983978 ER PT J AU Tyagi, RK Lavrovsky, Y Ahn, SC Song, CS Chatterjee, B Roy, AK AF Tyagi, RK Lavrovsky, Y Ahn, SC Song, CS Chatterjee, B Roy, AK TI Dynamics of intracellular movement and nucleocytoplasmic recycling of the ligand-activated androgen receptor in living cells SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID GREEN FLUORESCENT PROTEIN; HUMAN ESTROGEN-RECEPTOR; NUCLEAR EXPORT SIGNAL; GLUCOCORTICOID-RECEPTOR; PROGESTERONE-RECEPTOR; SUBCELLULAR-LOCALIZATION; IMMUNOCYTOCHEMICAL LOCALIZATION; TRANSCRIPTIONAL ACTIVATION; MONOCLONAL-ANTIBODIES; PROSTATE-CANCER AB An expression construct containing the cDNA encoding a modified aequorea green fluorescent protein (GFP) ligated to the 5'-end of the rat androgen receptor (AR) cDNA (GFP-AR) was used to study the intracellular dynamics of the receptor movement in living cells. In three different cell lines, be. PC3, HeLa, and COS1, unliganded GFP-AR was seen mostly in the cytoplasm and rapidly (within 15-60 min) moved to the nuclear compartment after androgen treatment. Upon androgen withdrawal, the labeled AR migrated back to the cytoplasmic compartment and maintained its ability to reenter the nucleus on subsequent exposure to androgen. Under the condition of inhibited protein synthesis by cycloheximide (50 mu g/ml), at least four rounds of receptor recycling after androgen treatment and withdrawal were recorded. Two nonandrogenic hormones, 17 beta-estradiol and progesterone at higher concentrations (10(-7)/10(-6) M), were able to both transactivate the AR-responsive promoter and translocate the GFP-AR into the nucleus. Similarly, antiandrogenic ligands, cyproterone acetate and casodex, were also capable of translocating the cytoplasmic AR into the nucleus albeit at a slower rate than the androgen 5 alpha-dihydrotestosterone (DHT). All AR ligands with transactivation potential, including the mixed agonist/antagonist cyproterone acetate, caused translocation of the GFP-AR into a subnuclear compartment indicated by its punctate intranuclear distribution. However, translocation caused by casodex, a pure antagonist, resulted in a homogeneous nuclear distribution. Subsequent exposure of the casodex-treated cell to DHT rapidly (15-30 min) altered the homogeneous to punctate distribution of the already translocated nuclear AR. When transported into the nucleus either by casodex or by DHT, GFP-AR was resistant to 2 M NaCl extraction, indicating that the homogeneously distributed AR is also associated with the nuclear matrix. Taken together, these results demonstrate that AR requires ligand activation for its nuclear translocation where occupancy by only agonists and partial agonists can direct it to a potentially functional subnuclear location and that one receptor molecule can undertake multiple rounds of hormonal signaling; this indicates that ligand dissociation/inactivation rather than receptor degradation may play a critical role in terminating hormone action. C1 Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78284 USA. Audie L Murphy Mem Vet Affairs Hosp, San Antonio, TX 78284 USA. RP Roy, AK (reprint author), Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, 7703 Floyd Curl Dr, San Antonio, TX 78284 USA. EM roy@uthscsa.edu FU NIA NIH HHS [AG-10486]; NIDDK NIH HHS [DK-14744] NR 53 TC 209 Z9 219 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD AUG PY 2000 VL 14 IS 8 BP 1162 EP 1174 DI 10.1210/me.14.8.1162 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 339VK UT WOS:000088498400004 PM 10935541 ER PT J AU Schmidt-Weber, CB Rao, A Lichtman, AH AF Schmidt-Weber, CB Rao, A Lichtman, AH TI Integration of TCR and IL-4 signals through STAT6 and the regulation of IL-4 gene expression SO MOLECULAR IMMUNOLOGY LA English DT Article DE cytokines; signal transduction; phosphorylation; calcineurin ID INTERLEUKIN-4 GENE; TH2 CELLS; TRANSCRIPTION; ACTIVATION; RESPONSES; DIFFERENTIATION; PROMOTER; PHOSPHORYLATION; IDENTIFICATION; DISRUPTION AB Signals generated by both antigen and cytokines binding to CD4(+) T cells synergize to promote helper T cell subset differentiation. For Th2 cell commitment neither IL-4 nor T cell receptor (TCR) stimulation are sufficient to drive differentiation. Th2 differentiation requires IL-4-receptor mediated signal transducers and activators of transcription 6 (STAT6) activation, but the possibility that IL-4 can directly enhance IL-4 production by T cells has remained unclear. In this report, IL-4 is shown to increase anti-CD3 or ionomycin induced IL-4 mRNA in differentiated murine Th2 cells. Anti-CD3 or ionomycin also enhances IL-4 induction of STAT6 activation, assayed by gel shift analysis of nuclear lysates. Surprisingly, cyclosporin A (CsA) also enhances STAT6 induction. Both ionomycin and CsA also enhance IL-4-induced transcriptional activity of a STAT6-linked promoter-reporter construct. In vitro calcineurin activity reduces STAT6 interactions with DNA, and CsA or FK506 can block this effect of calcineurin. These results indicate that IL-4 and TCR-generated calcium signals interact to maximize IL-4 gene expression and STAT6 activity. Calcineurin-mediated serine dephosphorylation of STAT6 and STAT6 serine phosphorylation may counter-regulate transcriptional activity of STAT6. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol,Immunol Res Div, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Ctr Blood Res, Boston, MA 02115 USA. RP Schmidt-Weber, CB (reprint author), Swiss Inst Allergy & Asthma Res, Obere Str 22, CH-7270 Davos, Switzerland. FU NIAID NIH HHS [2PO1 AI35297] NR 32 TC 6 Z9 6 U1 1 U2 1 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 AUG-SEP PY 2000 VL 37 IS 12-13 BP 767 EP 774 DI 10.1016/S0161-5890(00)00082-1 PG 8 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 413ML UT WOS:000167615900008 PM 11275261 ER PT J AU Eppich, HM Foxall, R Gaynor, K Dombkowski, D Miura, N Cheng, T Silva-Arrieta, S Evans, RH Mangano, JA Preffer, FI Scadden, DT AF Eppich, HM Foxall, R Gaynor, K Dombkowski, D Miura, N Cheng, T Silva-Arrieta, S Evans, RH Mangano, JA Preffer, FI Scadden, DT TI Pulsed electric fields for selection of hematopoietic cells and depletion of tumor cell contaminants SO NATURE BIOTECHNOLOGY LA English DT Article DE stem cells; cell selection; cell purging; electroporation; hematopoiesis ID HUMAN-BONE-MARROW; BREAST-CANCER CELLS; STEM-CELLS; IN-VIVO; ELIMINATION; 4-HYDROPEROXYCYCLOPHOSPHAMIDE; MICROMETASTASES; TRANSPLANTATION; CHEMOTHERAPY; INVITRO AB Purging of tumor cells and selection of stem cells are key technologies for enabling stem cell transplantation and stem cell gene therapy. Here we report a strategy for cell selection based on physical properties of the cells. Exposing cells to an external pulsed electric field (PEF) increases the natural potential difference across the cell membrane until a critical threshold is reached and pore formation occurs, resulting in fatal perturbation of cell physiology. Attaining this threshold is a function of the applied field intensity and cell size, with larger cells porated at lower field intensities than smaller cells. Since hematopoietic stem cells are smaller than other hematopoietic cells and tumor cells, we found that exposure of peripheral blood mononuclear cells (PBMCs) to PEFs caused stepwise elimination of monocytes without affecting the function of smaller lymphocyte populations. Mobilized peripheral blood exposed to PEFs was enriched for CD34(+)/CD38(-) cells and stem cell function was preserved. Furthermore, PEF treatment was able to selectively purge blood preparations of tumor cells and eradicate transplantable tumor. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, AIDS Res Ctr, Boston, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, MGH Canc Ctr, Boston, MA 02129 USA. Sci Res Lab Inc, Somerville, MA 02143 USA. RP Scadden, DT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, AIDS Res Ctr, Boston, MA 02129 USA. OI Foxall, Russell/0000-0001-9821-0708 FU NCI NIH HHS [CA7936401]; NHLBI NIH HHS [HL55718]; NIDDK NIH HHS [DK50234] NR 31 TC 24 Z9 25 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD AUG PY 2000 VL 18 IS 8 BP 882 EP 887 PG 6 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 342VX UT WOS:000088666800027 PM 10932160 ER PT J AU Saito, M Korsmeyer, SJ Schlesinger, PH AF Saito, M Korsmeyer, SJ Schlesinger, PH TI BAX-dependent transport of cytochrome c reconstituted in pure liposomes SO NATURE CELL BIOLOGY LA English DT Article ID PORE FORMATION; MARKER MOLECULES; CELL-DEATH; RELEASE; MITOCHONDRIA; MEMBRANES; APOPTOSIS; KINETICS; BCL-2; MELITTIN C1 Washington Univ, Sch Med, Dept Physiol & Cell Biol, St Louis, MO 63110 USA. Harvard Univ, Sch Med, Howard Hughes Med Inst, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Schlesinger, PH (reprint author), Washington Univ, Sch Med, Dept Physiol & Cell Biol, St Louis, MO 63110 USA. RI Schlesinger, Paul/C-6049-2012 NR 26 TC 343 Z9 356 U1 1 U2 8 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD AUG PY 2000 VL 2 IS 8 BP 553 EP 555 PG 3 WC Cell Biology SC Cell Biology GA 341TE UT WOS:000088605000022 PM 10934477 ER PT J AU Artandi, SE DePinho, RA AF Artandi, SE DePinho, RA TI Mice without telomerase: what can they teach us about human cancer? SO NATURE MEDICINE LA English DT Editorial Material ID COMPARATIVE GENOMIC HYBRIDIZATION; HUMAN-DIPLOID FIBROBLASTS; MOUSE CELLS LACKING; LARGE T-ANTIGEN; LIFE-SPAN; CELLULAR SENESCENCE; TUMOR SUPPRESSION; EPITHELIAL-CELLS; INK4A LOCUS; IMMORTALIZATION AB Unicellular organisms, human cells and mice have provided insights into how the processes of senescence, crisis, genomic instability and cancer in humans. Here, Artandi and DePinho discuss how studies in mice have uncovered a complex interplay between the ARF-p53 pathway, genomic Instability due to telomere dysfunction, and the suppression or promotion of cancer. C1 Dana Farber Canc Inst, Dept Adult Oncol, 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 Artandi, SE (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. NR 40 TC 97 Z9 100 U1 1 U2 8 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 AUG PY 2000 VL 6 IS 8 BP 852 EP 855 DI 10.1038/78595 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 376TX UT WOS:000165473800015 PM 10932211 ER PT J AU Daniels, GH Haber, DA AF Daniels, GH Haber, DA TI Will radioiodine be useful in treatment of breast cancer? SO NATURE MEDICINE LA English DT Editorial Material ID THERAPY AB Expression of a sodium iodide transporter by the thyroid gland causes iodide accumulation, and radioactive iodide is an effective treatment for thyroid cancer. The identification of a similar transporter in mammary tissue indicates that this approach might also be used to treat breast cancer (pages 871-878). C1 Harvard Univ, Sch Med, Dept Med, Thyroid Unit, Boston, MA 02115 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02115 USA. RP Daniels, GH (reprint author), Harvard Univ, Sch Med, Dept Med, Thyroid Unit, Boston, MA 02115 USA. NR 8 TC 17 Z9 18 U1 0 U2 0 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 AUG PY 2000 VL 6 IS 8 BP 859 EP 860 DI 10.1038/78604 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 376TX UT WOS:000165473800016 PM 10932214 ER PT J AU Schuchert, MJ Wright, RD Colson, YL AF Schuchert, MJ Wright, RD Colson, YL TI Characterization of a newly discovered T-cell receptor beta-chain heterodimer expressed on a CD8(+) bone marrow subpopulation that promotes allogeneic stem cell engraftment SO NATURE MEDICINE LA English DT Article ID VERSUS-HOST DISEASE; NATURAL-KILLER-CELLS; ANTIGEN RECEPTOR; GRAFT-REJECTION; IMMATURE THYMOCYTES; MONOCLONAL-ANTIBODY; SUBUNIT COMPOSITION; LYMPHOCYTE-SURFACE; FACILITATING CELLS; CD3 COMPLEXES AB The facilitating cell is a rare CD8(+) bone marrow subpopulation that can enhance allogeneic hematopoietic stem cell engraftment across complete major histocompatibility complex barriers without inducing acute graft-versus-host disease. Here we describe a CD3 epsilon -associated complex on the facilitating cell surface that consists of the T-cell receptor beta -chain disulfide-linked to a previously unknown 33-kilodalton glycoprotein. Provisionally called FCp33, this glycoprotein does not represent any of the known protein chains or surrogates associated with CD3-T-cell receptor beta. Expression of this CD3-T-cell receptor beta -FCp33 complex directly correlates with the facilitating cell's functional ability to enhance allogeneic stem cell engraftment in vivo. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Thorac Surg, Boston, MA 02115 USA. Univ Pittsburgh, Med Ctr Hlth Syst, Dept Surg, Pittsburgh, PA 15261 USA. Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Colson, YL (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Thorac Surg, Boston, MA 02115 USA. FU NIAID NIH HHS [R29-AI4093] NR 43 TC 43 Z9 43 U1 0 U2 0 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 AUG PY 2000 VL 6 IS 8 BP 904 EP 909 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 376TX UT WOS:000165473800034 PM 10932228 ER PT J AU Zisman, A Peroni, OD Abel, ED Michael, MD Mauvais-Jarvis, F Lowell, BB Wojtaszewski, JFP Hirshman, MF Virkamaki, A Goodyear, LJ Kahn, CR Kahn, BB AF Zisman, A Peroni, OD Abel, ED Michael, MD Mauvais-Jarvis, F Lowell, BB Wojtaszewski, JFP Hirshman, MF Virkamaki, A Goodyear, LJ Kahn, CR Kahn, BB TI Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance SO NATURE MEDICINE LA English DT Article ID KNOCKOUT MICE; GLUT4; GLYCOGEN; EXPRESSION; METABOLISM; EXERCISE; TISSUES; BRAIN AB The prevalence of type 2 diabetes mellitus is growing worldwide. By the year 2020, 250 million people will be afflicted(1). Most forms of type 2 diabetes are polygenic with complex inheritance patterns, and penetrance is strongly influenced by environmental factors(2). The specific genes involved are not yet known, but impaired glucose uptake in skeletal muscle is an early, genetically determined defect that is present in nondiabetic relatives of diabetic subjects(3). The rate-limiting step in muscle glucose use is the transmembrane transport of glucose mediated by glucose transporter (GLUT) 4 (ref. 4), which is expressed mainly in skeletal muscle, heart and adipose tissues. GLUT4 mediates glucose transport stimulated by insulin and contraction/exercise. The importance of GLUT4 and glucose uptake in muscle, however, was challenged by two recent observations. Whereas heterozygous GLUT4 knockout mice show moderate glucose intolerance(6), homozygous whole-body GLUT4 knockout (GLUT4-null) mice have only mild perturbations in glucose homeostasis and have growth retardation, depletion of fat stores, cardiac hypertrophy and failure, and a shortened life span(7). Moreover, muscle-specific inactivation of the insulin receptor results in minimal, if any, change in glucose tolerances. To determine the importance of glucose uptake into muscle for glucose homeostasis, we disrupted GLUT4 selectively in mouse muscles. A profound reduction in basal glucose transport and near-absence of stimulation by insulin or contraction resulted. These mice showed severe insulin resistance and glucose intolerance from an early age. Thus, GLUT4-mediated glucose transport in muscle is essential to the maintenance of normal glucose homeostasis. C1 Beth Israel Deaconess Med Ctr, Div Endocrine, Boston, MA 02215 USA. Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Kahn, BB (reprint author), Beth Israel Deaconess Med Ctr, Div Endocrine, Boston, MA 02215 USA. RI Wojtaszewski, Jorgen /P-6583-2014 OI Wojtaszewski, Jorgen /0000-0001-9785-6830 FU NIDDK NIH HHS [DK33201, DK43051, DK46200] NR 25 TC 367 Z9 389 U1 3 U2 35 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 AUG PY 2000 VL 6 IS 8 BP 924 EP 928 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 376TX UT WOS:000165473800038 PM 10932232 ER PT J AU Gotter, AL Manganaro, T Weaver, DR Kolakowski, LF Possidente, B Sriram, S MacLaughlin, DT Reppert, SM AF Gotter, AL Manganaro, T Weaver, DR Kolakowski, LF Possidente, B Sriram, S MacLaughlin, DT Reppert, SM TI A time-less function for mouse Timeless SO NATURE NEUROSCIENCE LA English DT Article ID CIRCADIAN CLOCK; TRANSCRIPTION; LOOP C1 Massachusetts Gen Hosp, Lab Dev Chronobiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Pediat Surg Res Lab, Boston, MA 02114 USA. Univ Texas, Hlth Sci Ctr, Dept Pharmacol, San Antonio, TX 78284 USA. Skidmore Coll, Dept Biol, Saratoga Springs, NY 12866 USA. RP Reppert, SM (reprint author), Massachusetts Gen Hosp, Lab Dev Chronobiol, Boston, MA 02114 USA. FU NICHD NIH HHS [R37HD14427]; NIMH NIH HHS [MH12117]; NINDS NIH HHS [R01NS39303] NR 11 TC 107 Z9 110 U1 2 U2 4 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 AUG PY 2000 VL 3 IS 8 BP 755 EP 756 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 405TU UT WOS:000167177300007 PM 10903565 ER PT J AU Huang, X Poy, F Zhang, RG Joachimiak, A Sudol, M Eck, MJ AF Huang, X Poy, F Zhang, RG Joachimiak, A Sudol, M Eck, MJ TI Structure of a WW domain containing fragment of dystrophin in complex with beta-dystroglycan SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID PROLINE-RICH LIGANDS; MAP INTERPRETATION; PROTEIN; BINDING; SH3; RECOGNITION; PEPTIDE AB Dystrophin and beta-dystroglycan are components of the dystrophin-glcoprotein complex (DGC), a multimolecular assembly that spans the cell membrane and links the actin cytoskeleton to the extracellular basal lamina. Defects in the dystrophin gene are the cause of Duchenne and pecker muscular dystrophies. The C-terminal region of dystrophin binds the cytoplasmic tail of beta-dystroglycan, in part through the interaction of its WW domain with a proline-rich moth in the tail of beta-dystroglycan. Here we report the crystal structure of this portion of dystrophin in complex with the proline-rich binding site in beta-dystroglycan. The structure shows that the dystrophin WW domain is embedded in an adjacent helical region that contains two EF-hand-like domains. The beta-dystroglycan peptide binds a composite surface formed by the WW domain and one of these EF-hands. Additionally, the structure reveals striking similarities in the mechanisms of proline recognition employed by WW domains and SH3 domains. C1 Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA. Argonne Natl Lab, Struct Biol Ctr, Biosci Div, Argonne, IL 60439 USA. CUNY Mt Sinai Sch Med, Dept Biochem & Mol Biol, New York, NY 10029 USA. RP Eck, MJ (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. NR 33 TC 190 Z9 196 U1 2 U2 10 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 AUG PY 2000 VL 7 IS 8 BP 634 EP 638 DI 10.1038/77923 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 340RJ UT WOS:000088548400009 PM 10932245 ER PT J AU Shimaoka, M Shifman, JM Jing, H Takagi, L Mayo, SL Springer, TA AF Shimaoka, M Shifman, JM Jing, H Takagi, L Mayo, SL Springer, TA TI Computational design of an integrin I domain stabilized in the open high affinity conformation SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID FUNCTION-ASSOCIATED ANTIGEN-1; BETA-PROPELLER DOMAIN; PROTEIN DESIGN; CRYSTAL-STRUCTURE; A-DOMAIN; MAC-1 CD11B/CD18; LIGAND-BINDING; DIVALENT-CATION; ALPHA-SUBUNITS; GENE SYNTHESIS AB We have taken a computational approach to design mutations that stabilize a large protein domain of similar to 200 residues in two alternative conformations. Mutations in the hydrophobic core of the alpha M beta 2 integrin I domain were designed to stabilize the crystallographically defined open or closed conformers. When expressed on the cell surface as part of the intact heterodimeric receptor, binding of the designed open and closed I domains to the ligand iC3b, a form of the complement component C3, was either increased or decreased, respectively compared to wild type. Moreover, when expressed in isolation from other integrin domains using an artificial transmembrane domain, designed open I domains were active in ligand binding, whereas designed closed and wild type I domains were inactive, Comparison to a human expert designed open mutant showed that the computationally designed mutants are far more active, Thus, computational design can be used to stabilize a molecule in a desired conformation, and conformational change in the I domain is physiologically relevant to regulation of ligand binding. C1 Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. CALTECH, Howard Hughes Med Inst, Pasadena, CA 91125 USA. CALTECH, Div Biol, Pasadena, CA 91125 USA. RP Springer, TA (reprint author), Ctr Blood Res, 200 Longwood Ave, Boston, MA 02115 USA. NR 42 TC 102 Z9 102 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 AUG PY 2000 VL 7 IS 8 BP 674 EP 678 DI 10.1038/77978 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 340RJ UT WOS:000088548400017 PM 10932253 ER PT J AU Vorgerd, M Schols, L Hardt, C Ristow, M Epplen, JT Zange, J AF Vorgerd, M Schols, L Hardt, C Ristow, M Epplen, JT Zange, J TI Mitochondrial impairment of human muscle in Friedreich ataxia in vivo SO NEUROMUSCULAR DISORDERS LA English DT Article; Proceedings Paper CT 4th International Congress of the World-Muscle-Society CY OCT 14-16, 1999 CL ANTALYA, TURKEY SP World Muscle Soc DE Friedreich ataxia; skeletal muscle; oxidative phosphorylation; mitochondrial function; magnetic resonance spectroscopy ID FRATAXIN; MOUSE AB Friedreich ataxia occurs due to mutations in the gene encoding the mitochondrial protein frataxin. This P-31 magnetic resonance spectroscopy study on the calf muscle of Friedreich ataxia patients provides in vivo evidence of a seven impairment of mitochondrial function. Mitochondrial adenosine triphosphate resynthesis was studied by means of the post-exercise recovery of phosphocreatine. After ischemic exercise in calf muscles of all patients, phosphocreatine recovery was dramatically delayed. Time constants of recovery correlated with mutations of the frataxin gene, the age of the patients, and disease duration. P-31 magnetic resonance spectroscopy represents the first expedient tool for monitoring therapeutic trials in Friedreich ataxia non-invasively. (C) 2000 Elsevier Science B.V. All rights reserved. C1 German Aerosp Ctr, Inst Aerosp Med, D-51170 Cologne, Germany. Ruhr Univ Bochum, Kliniken Bergmannsheil, Dept Neurol, D-44789 Bochum, Germany. Ruhr Univ Bochum, St Josef Hosp, Dept Neurol, D-44791 Bochum, Germany. Ruhr Univ Bochum, Dept Human Mol Genet, D-44780 Bochum, Germany. Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. RP Zange, J (reprint author), German Aerosp Ctr, Inst Aerosp Med, D-51170 Cologne, Germany. RI Ristow, Michael/O-9858-2014; OI Ristow, Michael/0000-0003-2109-2453; Epplen, Joerg T./0000-0002-6087-3327 NR 15 TC 56 Z9 56 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD AUG PY 2000 VL 10 IS 6 BP 430 EP 435 DI 10.1016/S0960-8966(00)00108-5 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 340ZP UT WOS:000088566800007 PM 10899450 ER PT J AU Brown, SP He, SG Masland, RH AF Brown, SP He, SG Masland, RH TI Receptive field microstructure and dendritic geometry of retinal ganglion cells SO NEURON LA English DT Article ID STARBURST AMACRINE CELLS; RABBIT RETINA; CAT RETINA; X-CELLS; Y-CELLS; FUNCTIONAL ARCHITECTURE; SPATIAL SUMMATION; MAMMALIAN RETINA; BIPOLAR CELLS; W-CELLS AB We studied the fine spatial structure of the receptive fields of retinal ganglion cells and its relationship to the dendritic geometry of these cells. Cells from which recordings had been made were microinjected with Lucifer yellow, so that responses generated at precise locations within the receptive field center could be directly compared with that cell's dendritic structure. While many cells with small receptive fields had dome-shaped sensitivity profiles, the majority of large receptive fields were composed of multiple regions of high sensitivity. The density of dendritic branches at any one location did not predict the regions of high sensitivity. Instead, the interactions between a ganglion cell's dendritic tree and the local mosaic of bipolar cell axons seem to define the fine structure of the receptive field center. C1 Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA. Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. RP Masland, RH (reprint author), Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA. RI Brown, Solange/H-1615-2012 NR 56 TC 34 Z9 35 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG PY 2000 VL 27 IS 2 BP 371 EP 383 DI 10.1016/S0896-6273(00)00044-1 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 347YD UT WOS:000088956000020 PM 10985356 ER PT J AU Hoh, BL Ogilvy, CS Butler, WE Loeffler, JS Putman, CM Chapman, PH AF Hoh, BL Ogilvy, CS Butler, WE Loeffler, JS Putman, CM Chapman, PH TI Multimodality treatment of nongalenic arteriovenous malformations in pediatric patients SO NEUROSURGERY LA English DT Article DE arteriovenous malformations; embolization; multimodality; pediatric; radiosurgery; recurrent arteriovenous malformations; surgery ID GAMMA-KNIFE RADIOSURGERY; CONGESTIVE-HEART-FAILURE; TERM FOLLOW-UP; STEREOTAXIC RADIOSURGERY; VASCULAR MALFORMATIONS; MICROSURGICAL RESECTION; ENDOVASCULAR TREATMENT; COMBINED EMBOLIZATION; SURGICAL EXCISION; NATURAL-HISTORY AB OBJECTIVE: Previously reported series of arteriovenous malformations (AVMs) in pediatric patients have primarily used a single-modality treatment approach of either surgery, radiosurgery, or embolization, with significant treatment-related morbidity and mortality. At our institution, we have used a combined multidisciplinary team approach of all three treatment modalities, alone or in combination, to minimize complications and to maximize efficacy in the management of these lesions. METHODS: We retrospectively reviewed 40 consecutive pediatric patients with AVMs seen at our institution from 1991 to 1999. A multidisciplinary team planned the treatment for each AVM. The treatment modality consisted of the following approaches: surgery alone in 14 patients, a combination of endovascular embolization and surgery in 6 patients, radiosurgery alone in 11 patients, a combination of endovascular embolization and radiosurgery in 2 patients, and a combination of radiosurgery and surgery in 2 patients. Four patients are receiving ongoing multistaged treatment far reduction of the nidus size for eventual surgical resection or radiosurgical obliteration of large, complex lesions. In one patient, no treatment was recommended. RESULTS: The clinical outcomes for the overall series were 95.0% excellent or good (Glasgow Outcome Scale score 5 or 4), 2.5% fair (Glasgow Outcome Scale score 3), and 2.5% dead. Radiographic efficacy in the patients who have completed treatment was 92.9% complete obliteration of their AVMs and 7.1% incomplete obliteration. Of the 10 patients who had seizures, 9 are seizure-free. CONCLUSION: A combined multimodality approach of surgery, radiosurgery, and embolization in managing AVMs in pediatric patients can improve outcomes and minimize morbidity and mortality. C1 Massachusetts Gen Hosp, Brain Aneurysm AVM Ctr, Neurosurg Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Radiat Oncol Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Intervent Neuroradiol Serv, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Neurosurg Serv, Boston, MA USA. RP Ogilvy, CS (reprint author), Massachusetts Gen Hosp, Brain Aneurysm AVM Ctr, Neurosurg Serv, VBK-710,Fruit St, Boston, MA 02114 USA. NR 94 TC 52 Z9 54 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD AUG PY 2000 VL 47 IS 2 BP 346 EP 357 DI 10.1097/00006123-200008000-00015 PG 12 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 339WZ UT WOS:000088502000036 PM 10942007 ER PT J AU King, JT AF King, JT TI How many neurosurgeons does it take to write a research article? Authorship proliferation in neurosurgical research SO NEUROSURGERY LA English DT Article DE authorship; bibliometrics; neurosurgery; research ID MULTIPLE AUTHORSHIP; CITATION ANALYSIS; JOURNALS; COAUTHORSHIP; TRENDS; PUBLICATIONS; FREQUENCY; PUBLISH; PERISH; TOOL AB OBJECTIVE: Authorship proliferation in biomedical research has become rampant; the proportion of single-author articles is decreasing, the percentage of multiauthor articles is increasing, and the number of authors per publication is increasing. To determine whether authorship trends in the North American neurosurgical literature parallel trends observed in other areas of the biomedical literature, I studied original neurosurgical research articles published in the past 50 years. METHODS: I sampled clinical, anatomic, and laboratory investigations in Neurosurgery and the Journal of Neurosurgery at 10-year intervals from 1945 to 1995. For each research article, I determined the number of authors, the countries of origin, and the educational degrees of the authors. RESULTS: The mean number of authors per article has increased steadily in the past 50 years, from 1.8 (standard deviation, +/-0.8) authors per article in 1945 to 4.6 (standard deviation, +/-2.1) authors in 1995. The proportion of single-author articles is decreasing; these articles accounted for 43% of articles in 1945 and only 3% of articles in 1995. Increases in the proportions of non-M.D. authors and of articles originating outside the United States were also observed. CONCLUSION: The proliferation of multiauthor articles and the decrease in the proportion of single-author articles in the neurosurgical literature parallel trends observed in many other areas of biomedical research. Possible explanations include larger research teams, variable or absent journal criteria for defining authorship, and the increased awarding of "gift" authorships. C1 Univ Pittsburgh, Dept Neurol Surg, Pittsburgh, PA 15213 USA. VA Pittsburgh Healthcare Syst, Neurosurg Sect, Pittsburgh, PA USA. VA Pittsburgh Healthcare Syst, Ctr Hlth Serv Res, Pittsburgh, PA USA. Univ Pittsburgh, Ctr Res Hlth Care, Dept Med, Pittsburgh, PA 15213 USA. RP King, JT (reprint author), Univ Pittsburgh, Dept Neurol Surg, 200 Lothrop St,B-400 PUH, Pittsburgh, PA 15213 USA. NR 40 TC 45 Z9 45 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD AUG PY 2000 VL 47 IS 2 BP 435 EP 440 DI 10.1097/00006123-200008000-00032 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 339WZ UT WOS:000088502000085 PM 10942017 ER PT J AU Chen, GTY AF Chen, GTY TI The Marks et al article reviewed SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID TREATMENT PLANNING SYSTEM C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Div Biophys, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Chen, GTY (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Div Biophys, Boston, MA 02114 USA. NR 11 TC 0 Z9 0 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD AUG PY 2000 VL 14 IS 8 BP 1201 EP + PG 2 WC Oncology SC Oncology GA 368QT UT WOS:000090129600018 ER PT J AU Wong, JR Wang, CC AF Wong, JR Wang, CC TI The Ali/Al-Sarraf article reviewed SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID ADVANCED NASOPHARYNGEAL CARCINOMA; CHEMOTHERAPY; RADIOTHERAPY; CANCER; RECURRENT; SURVIVAL C1 Morristown Mem Hosp, Dept Radiat Oncol, Morristown, NJ 07962 USA. Columbia Univ, Coll Phys & Surg, New York, NY USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. RP Wong, JR (reprint author), Morristown Mem Hosp, Dept Radiat Oncol, Morristown, NJ 07962 USA. NR 17 TC 0 Z9 0 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD AUG PY 2000 VL 14 IS 8 BP 1235 EP 1237 PG 3 WC Oncology SC Oncology GA 368QT UT WOS:000090129600023 ER PT J AU Ambati, BK Ambati, J Azar, N Stratton, L Schmidt, EV AF Ambati, BK Ambati, J Azar, N Stratton, L Schmidt, EV TI Periorbital and orbital cellulitis before and after the advent of Haemophilus influenzae type B vaccination SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY MAY 09-14, 1999 CL FT LAUDERDALE, FLORIDA SP Assoc Res Vis & Ophthalmol, Natl Hlth Public Serv Award, Childern Hosp Res Fdn ID UNITED-STATES; MANAGEMENT; CHILDHOOD AB Objective: To evaluate the effect of the introduction of the Haemophilus influenzae B (Hib) vaccine (introduced first in 1985, then extended in 1990 to children at least 2 months of age) on the epidemiologic features of periorbital and orbital cellulitis. Design: Retrospective, comparative case series. Participants: Three hundred fifteen pediatric inpatients. Methods: Children at Massachusetts General Hospital and Massachusetts Eye and Ear Infirmary with discharge diagnosis of periorbital or orbital cellulitis from 1980 through 1998 were reviewed. Main Outcome Measures: Case rate, culture-positive isolates, and associated conditions. Results: A total of 297 cases of periorbital cellulitis and 18 cases of orbital cellulitis were reviewed. Before 1990, there were 27 cases of Hib-related cellulitis (11.7% of total in that period), whereas after 1990, there were only three (3.5% of total; P = 0.028). The number of cases per year was significantly lower after 1990 (21.2 +/- 10.4 vs, 8.7 +/- 3.9; P = 0.008), as were the number of positive culture isolates (for any organism) after 1990 (76 [33.0%] vs. 9 [10.6%]; P < 0.001). The medical conditions most commonly associated with periorbital cellulitis were sinusitis (44 [14.5%]) and upper respiratory infections (73 [26.6%]), All cases of orbital cellulitis were associated with sinusitis. Conclusions: The introduction of the Hib vaccine coincided with a sharp decline not only in the number of periorbital and orbital cellulitis cases related to H. influenzae, but also in the annual case rate. These data are consistent with a facilitative role for H. influenzae in the development of cellulitis secondary to other pathogens. They also may support restriction of the spectrum of antibiotics used to manage these conditions. Ophthalmology 2000;107:1450-1453 (C) 2000 by the American Academy of Ophthalmology. C1 Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. RP Ambati, BK (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. NR 17 TC 43 Z9 46 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD AUG PY 2000 VL 107 IS 8 BP 1450 EP 1453 DI 10.1016/S0161-6420(00)00178-0 PG 4 WC Ophthalmology SC Ophthalmology GA 339EW UT WOS:000088465500013 PM 10919886 ER PT J AU Shiuey, Y Ambati, BK Adamis, AP AF Shiuey, Y Ambati, BK Adamis, AP CA Viral Conjunctivitis Study Grp TI A randomized, double-masked trial of topical ketorolac versus artificial tears for treatment of viral conjunctivitis SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Academy-of-Ophthalmology CY OCT, 1999 CL ORLANDO, FLORIDA SP Amer Acad Opthalmol ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ADENOVIRAL REPLICATION; OCULAR INFECTION; OPHTHALMOLOGY; 0.5-PERCENT; RABBITS AB Objective: To determine if topical ketorolac 0.5% relieves the symptoms and signs of viral conjunctivitis better than artificial tears. Design: Randomized, controlled trial. Participants: One hundred seventeen patients with a clinical diagnosis of viral conjunctivitis were randomized to the treatment group or control group. Methods: Physicians and patients were masked to treatment. Patients in the treatment group received topical ketorolac 0.5% four times daily. Patients in the control group received artificial tears four times daily. Symptom and sign scores were recorded on the day of recruitment and at the time of a follow-up examination 3 to 4 days later. Main Outcome Measures: Change in six symptoms of conjunctivitis (overall discomfort, itching, foreign body sensation, tearing, redness, and lid swelling) and four signs of conjunctivitis (conjunctival injection, conjunctival chemosis, conjunctival mucus, and lid edema). Adverse effects were also studied. Results: A total of 105 patients returned for their 3- to 4-day follow-up. Both the artificial tear and ketorolac groups showed improvement in all symptom scores at their 3- to 4-day follow-up visit. There was no statistically significant difference between the change in symptom scores between the treatment group and control group in any symptom category except redness. Patients in the control group were more likely to report improvement in redness than those in the treatment group, P = 0.012. There was no statistically significant difference between the change in sign scores between the treatment and control groups. Ketorolac 0.5% was more likely to produce stinging than artificial tears, 59.2% versus 18.8%, P < 0.001. Conclusions: Topical ketorolac 0.5% used four times daily is no better than artificial tears at relieving the symptoms or signs of viral conjunctivitis and produces more stinging than artificial tears. Ophthalmology 2000; 107:1512-1517 (C) 2000 by the American Academy of Ophthalmology. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Shiuey, Y (reprint author), 331 Bloomfield Ave, Nutley, NJ 07110 USA. NR 13 TC 21 Z9 22 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD AUG PY 2000 VL 107 IS 8 BP 1512 EP 1517 DI 10.1016/S0161-6420(00)00177-9 PG 6 WC Ophthalmology SC Ophthalmology GA 339EW UT WOS:000088465500027 PM 10919900 ER PT J AU Foster, CS AF Foster, CS TI Association of preoperative tear function with surgical outcome in severe Stevens-Johnson syndrome - Discussion SO OPHTHALMOLOGY LA English DT Editorial Material C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02114 USA. RP Foster, CS (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, 243 Charles St, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD AUG PY 2000 VL 107 IS 8 BP 1523 EP 1523 DI 10.1016/S0161-6420(00)00215-3 PG 1 WC Ophthalmology SC Ophthalmology GA 339EW UT WOS:000088465500029 ER PT J AU Letko, E Bhol, K Foster, CS Ahmed, AR AF Letko, E Bhol, K Foster, CS Ahmed, AR TI Linear IgA bullous disease limited to the eye: A diagnostic dilemma - Response to intravenous immunoglobulin therapy SO OPHTHALMOLOGY LA English DT Article ID IMMUNE THROMBOCYTOPENIC PURPURA; BASEMENT-MEMBRANE ZONE; GAMMA-GLOBULIN; DERMATOSIS; CHILDHOOD; ADULTS; ANTIBODIES; AUTOIMMUNE; INFUSIONS; ANTIGEN AB Purpose: To report on a diagnostic dilemma and treatment challenge in a patient with chronic cicatrizing conjunctivitis without involvement of skin and other mucous membranes persisting for 6 years and not responding to topical and systemic steroids. Design: interventional case report. Methods: We performed direct immunofluorescence of the conjunctiva with fluorescein-conjugated rabbit antihuman antibodies against immunoglobulin A, G, and M, complement 3 component, and fibrinogen. To investigate the presence of circulating antibodies in patient's serum, indirect immunofluorescence using normal human conjunctiva, normal human skin, and monkey esophagus as substrate was done. In addition, we did immunoblot. analysis using normal human epidermis as substrate to determine the molecular weight of an antigen. The patient was treated with intravenous immunoglobulin (IVIg). The correlation between the titer of circulating antibodies and the activity of conjunctival inflammation at various intervals during the course of IVIg therapy was demonstrated by immunoblot assay with serial dilutions of the patient's serum. The highest dilution at which the binding was visible was considered the titer. Results: Direct immunofluorescence of the conjunctiva and indirect immunofluorescence with both salt split skin and conjunctiva as substrate disclosed linear deposition of immunoglobulin A (IgA) at the epithelial basement membrane. Immunoblot analysis demonstrated the presence of IgA circulating antibodies in patient's serum directed against a 97kDa protein in human epidermis. A continuous decrease in the titer of these antibodies correlating to improvement of clinical symptoms was observed during IVIg therapy. Conclusions: Use of a nonconventional diagnostic tool (immunoblot analysis), in addition to conventional immunohistologic studies, might be helpful in establishing the diagnosis of patients with chronic cicatrizing conjunctivitis. On the basis of results of these laboratory tests and clinical presentation, we believe that this patient has linear IgA bullous disease limited to the eye. IVIg therapy decreased the titer of circulating antibodies and induced a remission in this patient. Ophthalmology 2000; 107:1524-1528 (C) 2000 by the American Academy of Ophthalmology. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Uveitis & Immunol Serv, Boston, MA USA. RP Foster, CS (reprint author), Massachusetts Eye & Ear Infirm, Serv Immunol, 243 Charles St, Boston, MA 02114 USA. NR 23 TC 33 Z9 33 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD AUG PY 2000 VL 107 IS 8 BP 1524 EP 1528 DI 10.1016/S0161-6420(00)00245-1 PG 5 WC Ophthalmology SC Ophthalmology GA 339EW UT WOS:000088465500030 PM 10919903 ER PT J AU Domankevitz, Y Waldman, J Lin, CP Anderson, RR AF Domankevitz, Y Waldman, J Lin, CP Anderson, RR TI Selective delivery of laser energy to biological tissue based on refractive-index differences SO OPTICS LETTERS LA English DT Article AB We report a novel method for selective laser energy delivery into biological tissues based on refractive-index differences. As a specific example, Ho:YAG laser energy is delivered into fat preferentially over other soft tissue, despite the fact that water has a higher absorption coefficient at this wavelength than fat. (C) 2000 Optical Society of America OCIS codes: 170.3660, 170.3880, 170.6390. C1 Massachusetts Gen Hosp, Wellman Labs Photomed, Boston, MA 02114 USA. Univ Massachusetts, Dept Phys & Appl Phys, Lowell, MA 01854 USA. RP Domankevitz, Y (reprint author), Massachusetts Gen Hosp, Wellman Labs Photomed, Boston, MA 02114 USA. NR 9 TC 5 Z9 6 U1 0 U2 3 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 0146-9592 J9 OPT LETT JI Opt. Lett. PD AUG 1 PY 2000 VL 25 IS 15 BP 1104 EP 1106 DI 10.1364/OL.25.001104 PG 3 WC Optics SC Optics GA 338AQ UT WOS:000088396300014 PM 18064285 ER PT J AU Zeitels, SM AF Zeitels, SM TI The evolution of the assessment and treatment of paralytic dysphonia SO OTOLARYNGOLOGIC CLINICS OF NORTH AMERICA LA English DT Article ID VOCAL CORD; LARYNGEAL PARALYSIS; LARYNGOPLASTIC PHONOSURGERY; RE-INNERVATION; REINNERVATION; CONFIGURATION; SYNKINESIS; EXPERIENCE; GLOTTIS; VOICE AB Vocal fold paralysis has been an omnipresent disorder throughout the annals of laryngologic history since the origin of the specialty in 1858. The attendant complexity of laryngoscopic presentation, physiologic dysfunction, and surgical rehabilitation have led to a rich heritage of scientific investigations that can be traced through the past 140 years. The following historical summary provides the reader with a working knowledge of past experiences that connect to current initiatives and portend future progress. C1 Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Div Laryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Zeitels, SM (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Div Laryngol, 243 Charles St, Boston, MA 02114 USA. NR 76 TC 2 Z9 3 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 0030-6665 J9 OTOLARYNG CLIN N AM JI Otolaryngol. Clin. N. Am. PD AUG PY 2000 VL 33 IS 4 BP 803 EP + DI 10.1016/S0030-6665(05)70245-0 PG 15 WC Otorhinolaryngology SC Otorhinolaryngology GA 349XR UT WOS:000089071300010 PM 10918662 ER PT J AU Zeitels, SM AF Zeitels, SM TI New procedures for paralytic dysphonia - Adduction arytenopexy, goretex medialization laryngoplasty, and cricothyroid subluxation SO OTOLARYNGOLOGIC CLINICS OF NORTH AMERICA LA English DT Article ID PHONOSURGERY AB Laryngoplastic phonosurgery has evolved to be a dominant treatment modality for paralytic dysphonia. The postoperative vocal outcome from the combined use of adduction arytenopexy, Goretex medialization laryngoplasty, and cricothyroid subluxation is such that most patients will have a normal phonation time and more than two octaves of dynamic range with minimal acoustic perturbation. With the addition of the adduction arytenopexy and cricothyroid subluxation procedures to the armamentarium of the phonosurgeon, all parameters for static reconstruction of the paralyzed vocal fold have been addressed. C1 Massachusetts Eye & Ear Infirm, Div Laryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Zeitels, SM (reprint author), Massachusetts Eye & Ear Infirm, Div Laryngol, 243 Charles St, Boston, MA 02114 USA. NR 18 TC 24 Z9 24 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 0030-6665 J9 OTOLARYNG CLIN N AM JI Otolaryngol. Clin. N. Am. PD AUG PY 2000 VL 33 IS 4 BP 841 EP + DI 10.1016/S0030-6665(05)70247-4 PG 14 WC Otorhinolaryngology SC Otorhinolaryngology GA 349XR UT WOS:000089071300012 PM 10918664 ER PT J AU Shalaby, AA Demers, PA Sager, PT Bersohn, MM AF Shalaby, AA Demers, PA Sager, PT Bersohn, MM TI Placement of a defibrillation lead in the left subclavian vein from the right cephalic vein SO PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY LA English DT Article DE defibrillation threshold; ICD implant; active can; left-handed ID IMPLANTATION AB This case report highlights the feasibility and stability of transvenous placement of a second defibrillation lead in the left subclavian vein from a right cephalic vein approach. This was undertaken in a right-sided implant of an active can cardioverter defibrillator to lower defibrillation thresholds that would have otherwise precluded implant. C1 VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Univ Pittsburgh, Pittsburgh, PA USA. ELA Med, Plymouth, MN USA. RP Bersohn, MM (reprint author), Cardiol 111E, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 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 AUG PY 2000 VL 23 IS 8 BP 1318 EP 1319 DI 10.1111/j.1540-8159.2000.tb00954.x PG 2 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA 343RC UT WOS:000088714500024 PM 10962762 ER PT J AU Decosterd, I Woolf, CJ AF Decosterd, I Woolf, CJ TI Spared nerve injury: an animal model of persistent peripheral neuropathic pain SO PAIN LA English DT Article DE nerve injury; peripheral neuropathic pain; animal models; denervation ID RAT SPINAL-CORD; EXPERIMENTAL ANESTHESIA DOLOROSA; SUPERFICIAL DORSAL HORN; SCIATIC-NERVE; CUTANEOUS HYPERALGESIA; MYELINATED AFFERENTS; SENSORY NEURONS; ADULT-RAT; ALLODYNIA; HYPERSENSITIVITY AB Peripheral neuropathic pain is produced by multiple etiological factors that initiate a number of diverse mechanisms operating at different sites and at different times and expressed both within, and across different disease states. Unraveling the mechanisms involved requires laboratory animal models that replicate as far as possible, the different pathophysiological changes present in patients. It is unlikely that a single animal model will include the full range of neuropathic pain mechanisms. A feature of several animal models of peripheral neuropathic pain is partial denervation. In the most frequently used models a mixture of intact and injured fibers is created by loose ligation of either the whole (Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988;33:87-107) or a tight ligation of a part (Seltzer Z, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 1990;43:205-218) of a large peripheral nerve, or a tight ligation of an entire spinal segmental nerve (Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992;50.355-363). We have developed a variant of partial denervation, the spared nerve injury model. This involves a lesion of two of the three terminal branches of the sciatic nerve (tibial and common peroneal nerves) leaving the remaining sural nerve intact. The spared nerve injury model differs from the Chung spinal segmental nerve, the Bennett chronic constriction injury and the Seltzer partial sciatic nerve injury models in that the co-mingling of distal intact axons with degenerating axons is restricted, and it permits behavioral testing of the noninjured skin territories adjacent to the denervated areas. The spared nerve injury model results in early (<24 h), prolonged (>6 months), robust tall animals are responders) behavioral modifications. The mechanical (von Frey and pinprick) sensitivity and thermal (hot and cold) responsiveness is increased in the ipsilateral sural and to a lesser extent saphenous territories, without any change in heat thermal thresholds. Crush injury of the tibial and common peroneal nerves produce similar early changes, which return, however to baseline at 7-9 weeks. The spared nerve injury model may provide, therefore, an additional resource for unraveling the mechanisms responsible for the production of neuropathic pain. (C) 2000 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Woolf, CJ (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, 149 13th St,Room 4310, Charlestown, MA 02129 USA. FU NINDS NIH HHS [NS38253-01] NR 56 TC 797 Z9 905 U1 12 U2 73 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD AUG PY 2000 VL 87 IS 2 BP 149 EP 158 DI 10.1016/S0304-3959(00)00276-1 PG 10 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 345KA UT WOS:000088814100005 PM 10924808 ER PT J AU Brunicardi, FC Dyen, Y Brostrom, Y Kleinman, R Colonna, J Gelabert, H Gingerich, R AF Brunicardi, FC Dyen, Y Brostrom, Y Kleinman, R Colonna, J Gelabert, H Gingerich, R TI The circulating hormonal milieu of the endocrine pancreas in healthy individuals, organ donors, and the isolated perfused human pancreas SO PANCREAS LA English DT Review DE insulin; C-peptide; glucagon; pancreatic polypeptide; glucose; Islet of langerhans ID SPLANCHNIC NEURAL REGULATION; POSTPRANDIAL PLASMA-GLUCOSE; RELEASE-INHIBITING HORMONE; C-PEPTIDE CONCENTRATIONS; INSULIN-SECRETION RATES; GLUCAGON-SECRETION; DIABETES-MELLITUS; GROWTH-HORMONE; ORAL GLUCOSE; SOMATOSTATIN SECRETION AB Although basal circulating levels of individual islet cell hormones have been measured, few studies compared the molar ratios of the major hormones secreted by the endocrine pancreas. This study examined the basal levels of four major islet hormones: insulin, C-peptide (C-P), glucagon (G), and pancreatic polypeptide (PP) in normal subjects, in organ donors with brain death, and in the isolated perfused human pancreas. Basal blood samples were taken from normal, fasted control subjects (NCs). Pancreata were obtained from 17 organ donors (ODs) with donor portal vein (DPV) and radial arterial (DRA) blood samples taken before organ procurement. Single-pass perfusion was performed on the procured pancreata, and after rewarming and equilibration, basal samples were collected from the splenic vein (SV) for 30 min. Radioimmunoassays of insulin, C-P, G, and PP were performed on all samples, and basal levels of all hormones were expressed as a common unit, femtomoles per milliliter. The data suggest that in the basal state, these four major islet hormones circulate in a relatively constant molar ratio. The ratio of the hormones is altered in brain death and with in vitro perfusion of the pancreas. The isolated perfused human pancreas secretes a relatively constant molar ratio of these hormones; however, this ratio is markedly different from the circulating ratio seen in either the NC group or the OD group. We conclude that a relatively constant hormonal milieu is secreted from the normal endocrine pancreas, and this hormonal milieu is altered after brain death and with isolation and perfusion of the human pancreas. C1 Baylor Coll Med, Dept Surg, Houston, TX 77030 USA. W Los Angeles Vet Affairs Med Ctr, Dept Surg, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Dept Surg, Los Angeles, CA 90024 USA. Linco Labs, St Louis, MO USA. RP Brunicardi, FC (reprint author), Baylor Coll Med, Dept Surg, 6550 Fannin,Suite 1625, Houston, TX 77030 USA. FU NIDDK NIH HHS [R29 DK 46441-01] NR 112 TC 9 Z9 9 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD AUG PY 2000 VL 21 IS 2 BP 203 EP 211 DI 10.1097/00006676-200008000-00014 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 339VH UT WOS:000088498200014 PM 10975715 ER PT J AU Frazier, AL Fisher, L Camargo, CA Tomeo, C Colditz, G AF Frazier, AL Fisher, L Camargo, CA Tomeo, C Colditz, G TI Association of adolescent cigar use with other high-risk behaviors SO PEDIATRICS LA English DT Article DE adolescent; cigar; cigarette; smokeless tobacco; tobacco; alcohol; binge drinking; physical activity; self-esteem ID SMOKING INITIATION; PARENTAL SMOKING; TOBACCO INDUSTRY; SUBSTANCE USE; SELF-ESTEEM; DRUG-USE; CHILDREN; INVOLVEMENT; CALIFORNIA; ELEMENTARY AB Objectives. To describe the association of cigar use with use of cigarettes, smokeless tobacco, and alcohol among adolescents; and to examine the association of self-esteem, physical activity, and use of tobacco promotional items with cigar use. Methods. A cross-sectional study of 7104 girls and 5499 boys 10 to 15 years of age in 1997. Data were collected from self-report questionnaires. Results. The prevalence of cigar use increased with age among both girls and boys. Among 11-year-olds, only 1% of girls and 3% of boys had used a cigar, whereas among 15-year-olds, 11% of girls and 25% of boys had used a cigar. Cigar users were much more likely than nonusers to have experimented with cigarettes (girls, odds ratio [OR]: 23.6; 95% confidence interval [CI]: 17.2-32.3; boys, OR: 21.3; 95% CI: 17.1-26.6), smokeless tobacco (girls, OR: 7.5; 95% CI: 4.5-12.4; boys, OR: 13.0; 95% CI: 9.8-17.4), and alcohol (girls, OR: 6.6; 95% CI: 4.8-9.1; boys, OR: 6.8; 95% CI: 5.3-8.8). There was a strong association between cigar use and binge drinking, especially among boys (girls, OR: 11.6; 95% CI: 7.9-16.9; boys, OR: 34.8; 95% CI: 19.4-62.3). Cigar users reported more hours of weekly physical activity than did nonusers. Additionally, cigar users were more likely to report high social self-esteem and to possess a tobacco promotional item. Conclusions. Adolescents who use cigars are more likely to use other tobacco products and alcohol, to report high social self-esteem, and to possess tobacco promotional items. Health care professionals and teachers should include cigar use in discussions with adolescents addressing substance use. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Channing Lab, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Frazier, AL (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Channing Lab, 181 Longwood Ave, Boston, MA 02115 USA. RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NHLBI NIH HHS [HL03533]; NIDDK NIH HHS [DK46834] NR 42 TC 16 Z9 16 U1 1 U2 1 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 AUG PY 2000 VL 106 IS 2 BP art. no. EP e26 DI 10.1542/peds.106.2.e26 PG 7 WC Pediatrics SC Pediatrics GA 340MM UT WOS:000088538100012 PM 10920182 ER PT J AU Gill-Body, KM Beninato, M Krebs, DE AF Gill-Body, KM Beninato, M Krebs, DE TI Relationship among balance impairments, functional performance, and disability in people with peripheral vestibular hypofunction SO PHYSICAL THERAPY LA English DT Article; Proceedings Paper CT Annual Conference and Exposition of the American-Physical-Therapy-Association CY JUN 06, 1999 CL WASHINGTON, D.C. SP Amer Phys Therapy Assoc DE balance; disability; dizziness handicap inventory; posturography; vestibular hypofunction ID DIZZINESS HANDICAP INVENTORY; COMPUTERIZED DYNAMIC POSTUROGRAPHY; PHYSICAL THERAPY; REHABILITATION; REACH; DYSFUNCTION AB Background and Purpose. Physical therapy interventions are often based on assumed relationships among impairments, functional performance, and disability. The purposes of this study were (1) to describe balance impairments, functional performance, and disability in subjects with unilateral peripheral vestibular hypofunction (UVH) and bilateral peripheral vestibular hypofunction (BVH), (2) to examine the relationship among these factors, and (3) to determine whether disability can be explained by commonly used tests of balance and functional performance. Subjects. Participants were 85 subjects (mean age = 62.5 years, SD = 16.5) with UVH (n = 41) or BVH (n = 44) diagnosed by vestibular function tests and clinical examination. Methods. Each subject completed the Dizziness Handicap Inventory (DHI) to obtain a measure of disability. Functional performance was measured with a modified Timed Up & Go Test (TUG). Balance impairments were measured with computerized posturography and balance tests. Descriptive statistics, correlational analyses, and stepwise regressions were performed. Results. Subjects with BVH had poorer balance but similar TUG scores and perceived levels of disability, as compared with subjects with UVH. Weak to moderate correlations existed among balance measurements, TUG scores, and DHI scores. Balance impairments and TUG scores together explained 78% of the variance in DHI scores of the subjects with BVH, whereas balance impairments along explained 13% of the variance in DHI scores of the subjects with UVH. Conclusion and Discussion. Balance impairments and functional performance appear to be more closely related to disability in individuals with BVH as compared with those with UVH. Clinical tests of balance impairments and functional performance appear to be useful in explaining disability. C1 Massachusetts Gen Hosp, Inst Hlth Profess, Grad Programs Phys Therapy, Boston, MA 02114 USA. Massachusetts Gen Hosp, Phys Therapy Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Biomot Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. MIT, Cambridge, MA 02139 USA. RP Gill-Body, KM (reprint author), Massachusetts Gen Hosp, Inst Hlth Profess, Grad Programs Phys Therapy, 101 Merrimac St, Boston, MA 02114 USA. FU NIA NIH HHS [R01AG11255]; PHS HHS [H133G60045] NR 30 TC 49 Z9 54 U1 2 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 AUG PY 2000 VL 80 IS 8 BP 748 EP 758 PG 11 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA 340GZ UT WOS:000088525900002 PM 10911413 ER PT J AU Rigotti, NA Arnsten, JH McKool, KM Wood-Reid, KM Pasternak, RC Singer, DE AF Rigotti, NA Arnsten, JH McKool, KM Wood-Reid, KM Pasternak, RC Singer, DE TI Smoking by patients in a smoke-free hospital: Prevalence, predictors, and implications SO PREVENTIVE MEDICINE LA English DT Article DE smoking (prevention and control); nicotine dependence; hospitals; patient compliance ID CESSATION PROGRAM; RANDOMIZED TRIAL; SURGERY; QUIT AB Background. No-smoking policies are now mandated in all U.S. hospitals. They require hospitalized smokers to abstain temporarily from tobacco. Little is known about patients' compliance with these policies or about their effects on patients' comfort and subsequent smoking behavior. Hospitalization in a smoke-free hospital might precipitate nicotine withdrawal in smokers, but it might also offer smokers an opportunity to stop smoking. Methods. To assess the prevalence, predictors, and implications of smoking during hospitalization, we analyzed data from a cohort of 650 adult smokers who were admitted to an urban teaching hospital and participating in a smoking intervention trial. We measured nicotine withdrawal symptoms at study entry (24-48 h after admission) and patients' self-reports of smoking while hospitalized, compliance with the hospital no-smoking policy (smoking prohibited indoors but permitted outdoors), and smoking status 1 and 6 months after discharge. Results. One-quarter of smokers admitted to a smoke-free hospital reported smoking during their hospital stay, although only 4% of smokers admitted violating policy by smoking indoors. Within 48 h of admission, 55% of smokers reported cigarette cravings and 29% of smokers reported difficulty refraining from smoking. Smokers with cigarette cravings were more likely to smoke while hospitalized (OR 3.6; 95% CI: 1.9-6.7). Those with nicotine withdrawal symptoms were more likely to violate the hospital no-smoking policy (OR 6.8; 95% CI: 5.3-8.3). Abstaining from tobacco use while hospitalized was a strong independent predictor of continued abstinence after discharge (OR 3.8; 95% CI: 1.4-10.3). Conclusions. Smoking by patients in a smoke-free hospital was common. Craving for cigarettes and symptoms consistent with nicotine withdrawal occurred frequently in hospitalized smokers and were associated with smoking during hospitalization, which was itself strongly linked with continuing to smoke after discharge. Pharmacologic treatment of cigarette cravings in hospitalized smokers could potentially improve patient comfort, increase compliance with hospital no-smoking policies, and promote smoking cessation after hospital discharge, This approach deserves further study. (C) 2000 American Health Foundation and Academic Press. C1 Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Div Cardiochirurg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Rigotti, NA (reprint author), Massachusetts Gen Hosp, Gen Internal Med Unit, S-50-9, Boston, MA 02114 USA. FU NCI NIH HHS [CA01673] NR 35 TC 52 Z9 54 U1 1 U2 5 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD AUG PY 2000 VL 31 IS 2 BP 159 EP 166 DI 10.1006/pmed.2000.0695 PN 1 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 344DH UT WOS:000088742000011 PM 10938217 ER PT J AU Keen, N Staskawicz, B Mekalanos, J Ausubel, F Cook, RJ AF Keen, N Staskawicz, B Mekalanos, J Ausubel, F Cook, RJ TI Pathogens and hosts: The dance is the same, the couples are different SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material C1 Univ Calif Riverside, Dept Plant Pathol, Riverside, CA 92521 USA. Univ Calif Berkeley, Dept Plant & Microbial Biol, Berkeley, CA 94720 USA. Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Washington State Univ, Dept Plant Pathol, Pullman, WA 99164 USA. Washington State Univ, Dept Crop & Soil Sci, Pullman, WA 99164 USA. RP Keen, N (reprint author), Univ Calif Riverside, Dept Plant Pathol, Riverside, CA 92521 USA. NR 0 TC 8 Z9 8 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 AUG 1 PY 2000 VL 97 IS 16 BP 8752 EP 8753 DI 10.1073/pnas.97.16.8752 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 341UL UT WOS:000088608000003 PM 10922030 ER PT J AU Rahme, LG Ausubel, FM Cao, H Drenkard, E Goumnerov, BC Lau, GW Mahajan-Miklos, S Plotnikova, J Tan, MW Tsongalis, J Walendziewicz, CL Tompkins, RG AF Rahme, LG Ausubel, FM Cao, H Drenkard, E Goumnerov, BC Lau, GW Mahajan-Miklos, S Plotnikova, J Tan, MW Tsongalis, J Walendziewicz, CL Tompkins, RG TI Plants and animals share functionally common bacterial virulence factors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article; Proceedings Paper CT National Academy of Sciences Colloquium on Virulence and Defense in Host-Pathogen Interactions: Common Features Between Plants and Animals CY DEC 09-11, 1999 CL ARNOLD & MABEL BECKMAND CTR, IRVINE, CALIFORNIA HO ARNOLD & MABEL BECKMAND CTR ID TO-CELL COMMUNICATION; SYRINGAE PV SYRINGAE; PSEUDOMONAS-AERUGINOSA; CAENORHABDITIS-ELEGANS; ESCHERICHIA-COLI; PHOSPHOLIPASE-C; GENE; PATHOGENICITY; ELASTASE; PROTEIN AB By exploiting the ability of Pseudomonas aeruginosa to infect a variety of vertebrate and nonvertebrate hosts, we have developed model systems that use plants and nematodes as adjuncts to mammalian models to help elucidate the molecular basis of P. aeruginosa pathogenesis. Our studies reveal a remarkable degree of conservation in the virulence mechanisms used by P. aeruginosa to infect hosts of divergent evolutionary origins. C1 Harvard Univ, Sch Med, Dept Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Shriners Burn Inst, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Soc Fellows, Cambridge, MA 02138 USA. RP Rahme, LG (reprint author), Harvard Univ, Sch Med, Dept Surg, Boston, MA 02114 USA. NR 62 TC 249 Z9 255 U1 1 U2 12 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 1 PY 2000 VL 97 IS 16 BP 8815 EP 8821 DI 10.1073/pnas.97.16.8815 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 341UL UT WOS:000088608000013 PM 10922040 ER PT J AU Myszka, DG Sweet, RW Hensley, P Brigham-Burke, M Kwong, PD Hendrickson, WA Wyatt, R Sodroski, J Doyle, ML AF Myszka, DG Sweet, RW Hensley, P Brigham-Burke, M Kwong, PD Hendrickson, WA Wyatt, R Sodroski, J Doyle, ML TI Energetics of the HIV gp120-CD4 binding reaction SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; EXTERIOR ENVELOPE GLYCOPROTEIN; SOLUBLE CD4; CONFORMATIONAL-CHANGES; ATOMIC-STRUCTURE; PROTEINS; NEUTRALIZATION; RECEPTOR; ANTIBODY; SURFACE AB HIV infection is initiated by the selective interaction between the cellular receptor CD4 and gp120, the external envelope glycoprotein of the virus. We used analytical ultracentrifugation, titration calorimetry, and surface plasmon resonance biosensor analysis to characterize the assembly state, thermodynamics, and kinetics of the CD4-gp120 interaction. The binding thermodynamics were of unexpected magnitude; changes in enthalpy, entropy, and heat capacity greatly exceeded those described for typical protein-protein interactions. These unusual thermodynamic properties were observed with both intact gp120 and a deglycosylated and truncated form of gp120 protein that lacked hypervariable loops V1, V2, and V3 and segments of its N and C termini. Together with previous crystallographic studies, the large changes in heat capacity and entropy reveal that extensive structural rearrangements occur within the core of gp120 upon CD4 binding. CD spectral studies and slow kinetics of binding support this conclusion. These results indicate considerable conformational flexibility within gp120, which may relate to viral mechanisms for triggering infection and disguising conserved receptor-binding sites from the immune system. C1 Univ Utah, Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT 84112 USA. SmithKline Beecham Pharmaceut, Dept Immunol, King Of Prussia, PA 19406 USA. SmithKline Beecham Pharmaceut, Dept Biol Struct, King Of Prussia, PA 19406 USA. Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. Columbia Univ, Howard Hughes Med Inst, New York, NY 10032 USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Myszka, DG (reprint author), Univ Utah, Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT 84112 USA. FU NCI NIH HHS [P30 CA042014, P30 CA006516]; NIAID NIH HHS [AI 31783, AI 39420, AI 49895, P30 AI028691, P30 AI042848, R01 AI031783, R01 AI039420, R01 AI040895] NR 43 TC 336 Z9 341 U1 0 U2 22 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 1 PY 2000 VL 97 IS 16 BP 9026 EP 9031 DI 10.1073/pnas.97.16.9026 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 341UL UT WOS:000088608000049 PM 10922058 ER PT J AU Tsai, M Wedemeyer, J Ganiatsas, S Tam, SY Zon, LI Galli, SJ AF Tsai, M Wedemeyer, J Ganiatsas, S Tam, SY Zon, LI Galli, SJ TI In vivo immunological function of mast cells derived from embryonic stem cells: An approach for the rapid analysis of even embryonic lethal mutations in adult mice in vivo SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FC-EPSILON-RI; ACTIVATED PROTEIN-KINASE; C-KIT LIGAND; IN-VITRO; MOUSE; DIFFERENTIATION; SEK1; PRECURSORS; CULTURE; HEPARIN AB An important goal of tissue engineering is to achieve reconstitution of specific functionally active cell types by transplantation of differentiated cell populations derived from normal or genetically altered embryonic stem cells in vitro. We find that mast cells derived in vitro from wild-type or genetically manipulated embryonic stem cells can survive and orchestrate immunologically specific IgE-dependent reactions after transplantation into mast cell-deficient Kit(W)/Kit(W-v) mice. These findings define a unique approach for analyzing the effects of mutations of any genes that are expressed in mast cells, including embryonic lethal mutations, in vitro or in vivo. C1 Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. Harvard Univ, Childrens Hosp, Sch Med, Howard HUghes Med Inst,Div Hematol Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Galli, SJ (reprint author), Stanford Univ, Sch Med, Dept Pathol, 300 Pasteur Ave,L-235, Stanford, CA 94305 USA. FU NCI NIH HHS [R01 CA072074, CA 72074]; NIAID NIH HHS [R01 AI023990, AI 23990, R37 AI023990, AI 41995] NR 34 TC 67 Z9 68 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 AUG 1 PY 2000 VL 97 IS 16 BP 9186 EP 9190 DI 10.1073/pnas.160254997 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 341UL UT WOS:000088608000077 PM 10908668 ER PT J AU Baird, A Walz, K Gaudette, T Boas, D Kagan, J AF Baird, A Walz, K Gaudette, T Boas, D Kagan, J TI Frontal lobe development: An MRS study SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD AUG PY 2000 VL 37 SU 1 BP S25 EP S25 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 364PJ UT WOS:000089900500107 ER PT J AU Karlsgodt, K Gastfriend, DR Breiter, HC Elman, I AF Karlsgodt, K Gastfriend, DR Breiter, HC Elman, I TI Lifetime years of cocaine use and baseline depressive symptomatology predict subjective but not hemodynamic responses to doses of cocaine SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Karlsgodt, Katherine/H-2964-2013 OI Karlsgodt, Katherine/0000-0003-3332-4231 NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD AUG PY 2000 VL 37 SU 1 BP S54 EP S54 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 364PJ UT WOS:000089900500221 ER PT J AU Siegle, GJ Steinhauer, SR AF Siegle, GJ Steinhauer, SR TI Pupillary and reaction-time assessment of interference of emotional and nonemotional information on subsequent processing SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD AUG PY 2000 VL 37 SU 1 BP S90 EP S90 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 364PJ UT WOS:000089900500366 ER PT J AU Siegle, GJ AF Siegle, GJ TI Pupillary and reaction time assessment of attention to emotional information in depression SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD AUG PY 2000 VL 37 SU 1 BP S15 EP S15 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 364PJ UT WOS:000089900500066 ER PT J AU Snidman, N Kagan, J Rosenbaum, JF Biederman, J AF Snidman, N Kagan, J Rosenbaum, JF Biederman, J TI Child cardiovascular correlates of parent psychopathology SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD AUG PY 2000 VL 37 SU 1 BP S92 EP S92 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 364PJ UT WOS:000089900500375 ER PT J AU Steinhauer, SR Condray, R Kasparek, A Siegle, GJ AF Steinhauer, SR Condray, R Kasparek, A Siegle, GJ TI Pharmacological dissociation of autonomic pathways contributing to pupillary dilation after motor activity SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 Univ Pittsburgh, Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD AUG PY 2000 VL 37 SU 1 BP S95 EP S95 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 364PJ UT WOS:000089900500385 ER PT J AU Steinhauer, SR Condray, R Kasparek, A AF Steinhauer, SR Condray, R Kasparek, A TI Inhibition of the pupillary light reaction by cognitive activity: Evidence for dual parasympathetic components SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD AUG PY 2000 VL 37 SU 1 BP S94 EP S94 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 364PJ UT WOS:000089900500384 ER PT J AU Steinhauer, SR Condray, R AF Steinhauer, SR Condray, R TI Mechanisms of cognitive modulation in schizophrenia as determined by pupillary motility SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract C1 Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD AUG PY 2000 VL 37 SU 1 BP S15 EP S15 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 364PJ UT WOS:000089900500064 ER PT J AU Moosavi, SH Topulos, GP Hafer, A Lansing, RW Adams, L Brown, R Banzett, RB AF Moosavi, SH Topulos, GP Hafer, A Lansing, RW Adams, L Brown, R Banzett, RB TI Acute partial paralysis alters perceptions of air hunger, work and effort at constant P-CO2 and V-E SO RESPIRATION PHYSIOLOGY LA English DT Article DE hyperpnea, volitional; mammals, humans; paralysis, respiratory sensations; sensation, respiratory, central motor control ID PARTIAL CURARIZATION; RESPIRATORY SENSATIONS; LUNG-VOLUME; BREATHLESSNESS; DRIVE; DISSOCIATION; TUBOCURARINE; DESCRIPTORS; EXERCISE; DYSPNEA AB Breathing sensations of AIR HUNGER, WORK and EFFORT may depend on projections of central motor discharge (corollary discharge) to the forebrain. Source of motor drive (brainstem or cortex) may determine what is perceived. To test the effect of changing motor discharge at constant ventilation, we induced partial neuromuscular blockade during hypercapnic hyperpnea (31 +/- 9 L min(-1); PETCO2 = 49 +/- 2 Torr) and during matched volitional hyperpnea (34 +/- 5 L min(-1); PETCO2 = 41 +/- 1 Torr). Decline of vital capacity was similar between conditions (39%). Ventilation was unchanged with paralysis, indicating increased respiratory motor drive to maintain hyperpnea. Sensations were rated on a seven point ordinal scale. Median EFFORT and WORK increased 3-3.5 points with paralysis during both forms of hyperpnea (P < 0.02, Wilcoxon signed rank). Median AIR HUNGER increased 2.5 points with paralysis during hypercapnic (P < 0.02) but not during volitional hyperpnea. Data suggests that EFFORT and WORK arise from motor cortex activity (subjects reported engaging volitional control when paralyzed even during hypercapnia) and suggests that AIR HUNGER arises from medullary motor activity. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Harvard Univ, Sch Publ Hlth, Physiol Program, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Anesthesiol, Boston, MA 02115 USA. Univ Arizona, Dept Psychol, Tucson, AZ 85721 USA. Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London W6 8RF, England. Boston VA Hlth Care Syst, Pulm & Crit Care Med Sect, Boston, MA 02132 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Moosavi, SH (reprint author), Harvard Univ, Sch Publ Hlth, Physiol Program, 665 Huntington Ave,Room 309,Bldg 1, Boston, MA 02115 USA. FU NHLBI NIH HHS [HL46690] NR 36 TC 23 Z9 26 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0034-5687 J9 RESP PHYSIOL JI Respir. Physiol. PD AUG PY 2000 VL 122 IS 1 BP 45 EP 60 DI 10.1016/S0034-5687(00)00135-3 PG 16 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 341WE UT WOS:000088613300005 PM 10936600 ER PT J AU Percy, LA Fang, MA AF Percy, LA Fang, MA TI Geropharmacology for the rheumatologist SO RHEUMATIC DISEASE CLINICS OF NORTH AMERICA LA English DT Article ID LOW-DOSE METHOTREXATE; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; 2ND-LINE ANTIRHEUMATIC DRUGS; ELDERLY PATIENTS; SERUM CREATININE; CONTROLLED TRIAL; THERAPEUTIC USE; DOUBLE-BLIND; BLOOD-FLOW; ARTHRITIS AB Drug administration to older patients with rheumatic disease is a challenge because they are more likely to have adverse drug reactions compared with younger patients. Elderly patients are at risk for adverse drug effects because they often have multiple acute and chronic illnesses and are on several prescription and over-the-counter medications. This article will enhance the practitioner's understanding of how disease and age modulate the pharmacokinetics and pharmacodynamics of medications commonly prescribed for rheumatic disorders. Minimizing the number of drugs prescribed, starting medications at low doses and increasing slowly, and monitoring for toxicity are especially important in the elderly. With judicious use of medications, the quality of life of older patients with rheumatic disease can be enhanced. C1 Univ Calif San Francisco, Sch Pharm, San Francisco, CA 94143 USA. Univ So Calif, Sch Pharm, Los Angeles, CA USA. Univ Pacific, Sch Pharm, Stockton, CA 95211 USA. Western Univ Hlth Sci, Sch Pharm, Pomona, CA USA. VA Greater Los Angeles Healthcare Syst, Geriatr Pharm Practice Residency, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Ctr Geriatr Res Educ & Clin, Los Angeles, CA USA. VA Greater Los Angeles Healthcare Syst, Palliat Treatment Program, Los Angeles, CA USA. RP Percy, LA (reprint author), VA GLAHS, GRECC 11G, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 75 TC 9 Z9 9 U1 1 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-857X J9 RHEUM DIS CLIN N AM JI Rheum. Dis. Clin. North Am. PD AUG PY 2000 VL 26 IS 3 BP 433 EP + DI 10.1016/S0889-857X(05)70150-2 PG 24 WC Rheumatology SC Rheumatology GA 350HD UT WOS:000089094200003 PM 10989506 ER PT J AU Salmon, H Johnson, I Germana, S Haller, GW Sachs, DH Leguern, C AF Salmon, H Johnson, I Germana, S Haller, GW Sachs, DH Leguern, C TI Dendritic cells enriched from swine thymus co-express CD1, CD2 and major histocompatibility complex class II and actively stimulate alloreactive T lymphocytes SO SCANDINAVIAN JOURNAL OF IMMUNOLOGY LA English DT Article ID SURFACE MARKER ANALYSIS; BONE-MARROW; MONOCLONAL-ANTIBODIES; MOUSE THYMUS; MINIATURE SWINE; ANTILYMPHOCYTE-SERUM; NEGATIVE SELECTION; PHENOTYPE; TOLERANCE; SPLEEN AB Initial characterization and partial purification of thymic dendritic cells (DC) from miniature swine were carried out with the ultimate goal of using these cells to induce transplantation tolerance in this preclinical animal model. Immunohistochemical analysis of swine thymic tissue sections has shown DC to be large cells located in the medullary and the cortico-medullary regions as evidenced by the presence of surrounding Hassal bodies. These cells exhibit membrane processes and express the CD1, granulocyte/macrophage (G/M), and major histocompatibility complex (MHC) class II surface antigens, as well as the S100 cytosolic and nuclear markers found in humans to be specific for DC. Dendritic cells were purified from thymi following collagenase treatment, Percoll gradient centrifugation, and adhesion steps to plastic. Cells similar in morphology and phenotype to those described in tissue sections were detected in the lighter density layers of the gradient and represented 0.02% of the starting cell number. Removal of plastic nonadherent cells showed enrichment levels similar to those reported for murine and human DC. Two-colour flow cytometric analysis of purified pig DC identified these cells as MHC class IIhi, CD1(+), CD2(+), and G/M+. The dendritic nature of these cells was confirmed by their potent ability to stimulate alloreactive T lymphocytes. Modification of porcine thymic DC by transfer of allogeneic MHC genes and reinjection into the DC donor should permit testing of the role of this DC subset in the induction of transplantation tolerance. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 01229 USA. RP Salmon, H (reprint author), INRA, Pathol Infect & Immunol Lab, F-37380 Nouzilly, France. RI salmon, henri/B-2605-2010 FU NHLBI NIH HHS [5RO1 HL46532]; NIAID NIH HHS [1RO1 AI33053, 2RO1 AI31046] NR 54 TC 13 Z9 13 U1 0 U2 3 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0300-9475 J9 SCAND J IMMUNOL JI Scand. J. Immunol. PD AUG PY 2000 VL 52 IS 2 BP 164 EP 172 PG 9 WC Immunology SC Immunology GA 336MM UT WOS:000088306200009 PM 10931384 ER PT J AU Baksh, S Burakoff, SJ AF Baksh, S Burakoff, SJ TI The role of calcineurin in lymphocyte activation SO SEMINARS IN IMMUNOLOGY LA English DT Review DE calcineurin; T lymphocyte; NFAT; apoptosis; immunophilins ID TRANSCRIPTION FACTOR NFAT1; DEPENDENT PROTEIN-KINASE; T-LYMPHOCYTES; RYANODINE RECEPTOR; NUCLEAR FACTOR; KAPPA-B; NF-AT; PHOSPHATASE-ACTIVITY; GENE-EXPRESSION; CYCLOSPORINE-A AB Lymphokine gene transcription involves numerous signal transduction molecules and second messengers. The serine/threonine phosphatase calcineurin has been demonstrated to play a central role in. the immediate, early activation of numerous lymphokines (such as interleukin [IL]-2) and in the regulation of cell surface receptors such as CD40L, CD95, and recently CD25 alpha (the a chain of the IL-2 receptor). In addition to lymphocyte activation, calcineurin functions include control of neuronal signaling; muscle contraction, muscle hypertrophy and cellular death. Therefore, calcineurin not only plays a vital role in the regulation of T lymphocyte function, but also functions in cellular environments outside the immune system. C1 Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Baksh, S (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. NR 72 TC 38 Z9 42 U1 0 U2 2 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD AUG PY 2000 VL 12 IS 4 BP 405 EP 415 DI 10.1006/smim.2000.0221 PG 11 WC Immunology SC Immunology GA 359KF UT WOS:000089609500007 PM 10995587 ER PT J AU Posner, MR Colevas, AD Tishler, RB AF Posner, MR Colevas, AD Tishler, RB TI The role of induction chemotherapy in the curative treatment of squamous cell cancer of the head and neck SO SEMINARS IN ONCOLOGY LA English DT Review ID PHASE-III TRIAL; STAGE-IV HEAD; LARYNX PRESERVATION; RANDOMIZED TRIAL; CARCINOMA; RADIOTHERAPY; FLUOROURACIL; CISPLATIN; DOCETAXEL; NEOADJUVANT C1 Dana Farber Canc Inst, Head & Neck Oncol Program, Dept Adult Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Posner, MR (reprint author), Dana Farber Canc Inst, Head & Neck Oncol Program, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. NR 32 TC 35 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 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD AUG PY 2000 VL 27 IS 4 SU 8 BP 13 EP 24 PG 12 WC Oncology SC Oncology GA 351BM UT WOS:000089136200003 PM 10952434 ER PT J AU Reppert, SM AF Reppert, SM TI Cellular and molecular basis of circadian timing in mammals SO SEMINARS IN PERINATOLOGY LA English DT Review ID RAT SUPRACHIASMATIC NUCLEUS; PERIOD HOMOLOGS; FIRING RHYTHMS; CLOCK; LIGHT; EXPRESSION; NEURONS; MPER1; GLUTAMATE; MECHANISM C1 Massachusetts Gen Hosp, Lab Dev Chronobiol, MassGen Hosp Children, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Reppert, SM (reprint author), Massachusetts Gen Hosp, Lab Dev Chronobiol, MassGen Hosp Children, Jackson 1226, Boston, MA 02114 USA. NR 30 TC 19 Z9 21 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 0146-0005 J9 SEMIN PERINATOL JI Semin. Perinatol. PD AUG PY 2000 VL 24 IS 4 BP 243 EP 246 DI 10.1053/sper.2000.9122 PG 4 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 353CG UT WOS:000089255700003 PM 10975430 ER PT J AU Hutter, MM Glasgow, RE Mulvihill, SJ AF Hutter, MM Glasgow, RE Mulvihill, SJ TI Does the participation of a surgical trainee adversely impact patient outcomes? A study of major pancreatic resections in California SO SURGERY LA English DT Article; Proceedings Paper CT 61st Annual Meeting of the Society-of-University-Surgeons CY FEB 10-12, 2000 CL TORONTO, CANADA SP Soc Univ Surgeons ID HOSPITAL VOLUME; MORTALITY; CANCER; OPERATIONS; SURGERY AB Background Some patients have concerns regarding. the impact of surgical trainees on the quality of care that they receive in teaching hospital. No population-based data exist that describe outcomes of surgical procedures in teaching and nonteaching hospitals; however institutional data suggest that teaching hospital provide high-quality care. We hypothesized that the presence of a general surgery residency program (GSRP) is associated with superior outcomes for Pancreatic resection, a complex surgical procedure. Methods. A retrospective, population-based, risk-adjusted analysis of 5696 patients who underwent major pancreatic resection compares the outcomes of patients treated at hospitals with a GSRP (GSRP+) and those hospital without a GSRP (GSRP-). Results. GSRP+ hospitals had a lower operative mortality rate (8.3 % vs 11.0 %; P < .001), a lower percentage of patients discharged to another acute care hospital or skilled nursing facility (6.5% vs 13.0%; P < .001), and a longer length of stay compared with GSRP- hospitals (22.1 +/- 0.4 days vs 19.6 +/- 0.3 days; P < .001). The observed difference in hospital mortality rates was not significant after an adjustment was made for patient mix and hospital volume (9.7% vs 10.0%). However outcomes were found in the university teaching hospitals, as compared with the affiliated teaching and the nonteaching hospitals (5.3% [P < .001] vs 11.4% vs 21.0%; risk adjusted, 8.0% [P < .05] vs 10.9% vs 10.0%). Conclusions. The presence of surgical trainees does not have an adverse impact on the quality of care for One complex procedure, pancreatectomy and is associated with superior operative mortality rate in university teaching hospitals. C1 Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Mulvihill, SJ (reprint author), Univ Calif San Francisco, Dept Surg, 533 Parnassus Ave,Room U-122, San Francisco, CA 94143 USA. FU NIDDK NIH HHS [DK07573] NR 22 TC 39 Z9 39 U1 0 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 AUG PY 2000 VL 128 IS 2 BP 286 EP 292 DI 10.1067/msy.2000.107416 PG 7 WC Surgery SC Surgery GA 342LM UT WOS:000088646100026 PM 10923006 ER PT J AU Goss, G Demetri, G AF Goss, G Demetri, G TI Medical management of unresectable, recurrent low-grade retroperitoneal liposarcoma: integration of cytotoxic and non-cytotoxic therapies into multimodality care SO SURGICAL ONCOLOGY-OXFORD LA English DT Article DE liposarcoma; retroperitoneum; chemotherapy; differentiation; troglitazone ID ACTIVATED RECEPTOR-GAMMA; SOFT-TISSUE SARCOMAS; DEDIFFERENTIATED LIPOSARCOMA; RETINOIC ACID; DIFFERENTIATION; CHROMOSOMES; TUMORS; LIGAND AB Liposarcomas of the retroperitoneum are rare tumors, and best managed by an expert multidisciplinary team consisting of a surgical oncologist with appropriate medical oncology and radiation oncology collaboration. For large tumors, surgical excision with wide margins is difficult to achieve, and even wide margins cannot ensure that microscopic remnants of residual disease will not grow back in the,future. For these reasons, even following expert resection, local recurrence is common. For patients with recurrent and unresectable liposarcoma, treating the sarcoma while maintaining quality of life becomes the major therapeutic goal. Importantly, patients with advanced recurrent disease demonstrate the need for multidisciplinary team involvement, with timely consideration of palliative surgical, radiation therapy, and chemotherapy options. Such patients also represent ideal candidates for investigational approaches aimed at identifying new agents with which to treat this disease. In addition to the development of new cytotoxic agents, patients may be candidates for novel strategies such as differentiation therapies or anti-angiogenic approaches. The recent explosion of knowledge regarding the cytogenetics, molecular, and cellular biology of liposarcomas allows us to remain positive that new translational therapies will be developed to improve the clinical outcomes of patients with these diseases. Current strategies, such as the use of PPAR gamma ligands to differentiate liposarcomas, will soon be tested in major national collaborative trials, and the cooperation of surgeons and medical oncologists at all levels of community and academic practice will be crucial to obtain answers in this field. This review will summarize an illustrative case in the process of describing the natural history and potential interventions which should be considered for patients with this disease. (C) 2000 Published by Elsevier Science Ltd. C1 Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA. RP Goss, G (reprint author), Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, 44 Binney St, Boston, MA 02115 USA. NR 26 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0960-7404 J9 SURG ONCOL JI Surg. Oncol.-Oxf. PD AUG PY 2000 VL 9 IS 2 BP 53 EP 59 DI 10.1016/S0960-7404(00)00023-2 PG 7 WC Oncology; Surgery SC Oncology; Surgery GA 381QW UT WOS:000165775400003 PM 11094323 ER PT J AU Xia, Y Li, J Bertino, A Kuter, DJ AF Xia, Y Li, J Bertino, A Kuter, DJ TI Thrombopoietin and the TPO receptor during platelet storage SO TRANSFUSION LA English DT Review ID PROGRAMMED CELL-DEATH; HUMAN MEGAKARYOCYTE GROWTH; C-MPL LIGAND; VASCULAR ENDOTHELIAL-CELLS; COLONY-STIMULATING FACTOR; MTT COLORIMETRIC ASSAY; IN-VITRO; BCL-2 PROTECTION; ERYTHROPOIETIN ACTION; POLYETHYLENE-GLYCOL AB BACKGROUND: For most cells, the addition of a specific growth factor has improved cellular viability by preventing programmed cell death (apoptosis). To determine whether the platelet-specific hematopoietic growth factor thrombopoietin (TPO) might improve platelet viability, endogenous TPO and the platelet TPO receptor were analyzed during storage, and the effect of recombinant TPO on platelet viability was assessed. STUDY DESIGN AND METHODS: During platelet storage, TPO stability was assessed by SDS-PAGE, TPO receptor function was measured, and the platelet TPO receptor was characterized by a I-125-rHuTPO competitive-binding assay. A recombinant TPO, pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), was added to platelet concentrates during storage, and its effect on pH, LDH, and metabolic activity was determined. RESULTS: During storage, the molecular weight and concentration of endogenous TPO (125 +/- 19 pg/mL) and exogenous TPO (5720 +/- 140 pg/mL) were constant for 12 days; the number (33 +/- 4), binding affinity (149 +/- 33 pM), and function of the platelet TPO receptors were constant for 7 days. Metabolic activity measured with the MTT and MTS assays closely correlated with changes in the pH and LDH. The addition of PEG-rHuMGDF did not alter the pH, LDH, or metabolic activity of platelets during storage, but it did increase by 65 percent the uptake of S-35-methionine into platelets. Finally, platelet concentrates obtained from donors treated with PEG-rHuMGDF retained normal metabolic activity for 12 days, as compared with 5 to 6 days for normal platelet concentrates. CONCLUSIONS: TPO and its platelet receptor are present in normal amounts and have normal function during platelet storage. The addition of recombinant TPO increased platelet methionine transport but did not alter platelet viability during storage. Other means to prevent apoptosis during platelet storage should be considered, and the measurement of platelet metabolic activity by MTT and MTS assays may assist this effort. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hematol Oncol Unit, Boston, MA 02114 USA. RP Kuter, DJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hematol Oncol Unit, 100 Blossom St, Boston, MA 02114 USA. FU NHLBI NIH HHS [HL61222, HL54838] NR 102 TC 12 Z9 13 U1 1 U2 3 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD AUG PY 2000 VL 40 IS 8 BP 976 EP 987 DI 10.1046/j.1537-2995.2000.40080976.x PG 12 WC Hematology SC Hematology GA 346GN UT WOS:000088862800016 PM 10960526 ER PT J AU Watts, A Foley, A Awwad, M Treter, S Lambrigts, D Buhler, L Gojo, S Basker, M Oravec, G Sachs, DH Andrews, D Cooper, DKC AF Watts, A Foley, A Awwad, M Treter, S Lambrigts, D Buhler, L Gojo, S Basker, M Oravec, G Sachs, DH Andrews, D Cooper, DKC TI Plasma perfusion by apheresis through a Gal immunoaffinity column successfully depletes anti-Gal antibody: Experience with 275 aphereses in baboons SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 5th Congress of the International-Xenotransplantation-Association CY OCT 24-28, 1999 CL NAGOYA, JAPAN SP Int Xenotransplant Assoc, Pharmaceut Manufacturers Assoc Tokyo, Osaka Pharmaceut Manufacturers Assoc, Suzuken Mem Fdn, Novartis Pharma AG, Novartis Pharma KK, Fujisawa Healthcare Inc, Fujisawa GmbH, Fujisawa Pharmaceut Co Ltd, F Hoffmann La Roche Ltd, Nippon Roche KK, Biotransplant Inc, Nextran Inc C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transpantat Biol Res Ctr, Boston, MA 02129 USA. BioTransplant Inc, Charlestown, MA USA. RP Cooper, DKC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transpantat Biol Res Ctr, MGH E,Bldg 149,13th St, Boston, MA 02129 USA. NR 2 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD AUG PY 2000 VL 32 IS 5 BP 860 EP 860 DI 10.1016/S0041-1345(00)01011-3 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 344CV UT WOS:000088740800014 PM 10936245 ER PT J AU Gopfert, C Buhler, L Wise, R Basker, M Gojo, S Imai, M Alwayn, I Sachs, DH Sackstein, R Cooper, DKC Robson, SC AF Gopfert, C Buhler, L Wise, R Basker, M Gojo, S Imai, M Alwayn, I Sachs, DH Sackstein, R Cooper, DKC Robson, SC TI Von Willebrand factor concentration, multimeric patterns, and cleaving protease activity in baboons undergoing xenogeneic peripheral blood stem cell transplantation SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 5th Congress of the International-Xenotransplantation-Association CY OCT 24-28, 1999 CL NAGOYA, JAPAN SP Int Xenotransplant Assoc, Pharmaceut Manufacturers Assoc Tokyo, Osaka Pharmaceut Manufacturers Assoc, Suzuken Mem Fdn, Novartis Pharma AG, Novartis Pharma KK, Fujisawa Healthcare Inc, Fujisawa GmbH, Fujisawa Pharmaceut Co Ltd, F Hoffmann La Roche Ltd, Nippon Roche KK, Biotransplant Inc, Nextran Inc C1 Harvard Univ, Sch Med, Immunobiol Res Ctr, Boston, MA 02215 USA. Massachusetts Gen Hosp, TBRC, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, IRC, Boston, MA 02215 USA. RP Gopfert, C (reprint author), Harvard Univ, Sch Med, Immunobiol Res Ctr, 99 Brookline Ave, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD AUG PY 2000 VL 32 IS 5 BP 990 EP 990 DI 10.1016/S0041-1345(00)01079-4 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 344CV UT WOS:000088740800084 PM 10936315 ER PT J AU Basker, M Alwayn, IPJ Treter, S Harper, D Buhler, L Andrews, D Thall, A Lambrigts, D Awwad, M White-Scharf, M Sachs, DH Cooper, DKC AF Basker, M Alwayn, IPJ Treter, S Harper, D Buhler, L Andrews, D Thall, A Lambrigts, D Awwad, M White-Scharf, M Sachs, DH Cooper, DKC TI Effect of B cell/plasma cell depletion or suppression on anti-Gal antibody in the baboon SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 5th Congress of the International-Xenotransplantation-Association CY OCT 24-28, 1999 CL NAGOYA, JAPAN SP Int Xenotransplant Assoc, Pharmaceut Manufacturers Assoc Tokyo, Osaka Pharmaceut Manufacturers Assoc, Suzuken Mem Fdn, Novartis Pharma AG, Novartis Pharma KK, Fujisawa Healthcare Inc, Fujisawa GmbH, Fujisawa Pharmaceut Co Ltd, F Hoffmann La Roche Ltd, Nippon Roche KK, Biotransplant Inc, Nextran Inc C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. Bio Transplant Inc, Boston, MA USA. RP Cooper, DKC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, MGH E,Bldg 149,13th St, Boston, MA 02129 USA. NR 1 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD AUG PY 2000 VL 32 IS 5 BP 1009 EP 1009 DI 10.1016/S0041-1345(00)01087-3 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 344CV UT WOS:000088740800092 PM 10936323 ER PT J AU Down, JD Awwad, M Kurilla-Mahon, B Moran, K Ericsson, T Oldmixon, B Lachance, A Watts, A Treter, S Nash, K Gojo, S Sachs, DH White-Scharf, ME Cooper, DKC AF Down, JD Awwad, M Kurilla-Mahon, B Moran, K Ericsson, T Oldmixon, B Lachance, A Watts, A Treter, S Nash, K Gojo, S Sachs, DH White-Scharf, ME Cooper, DKC TI Increases in autologous hematopoietic progenitors in the blood of baboons following irradiation and treatment with porcine stem cell factor and interleukin-3 SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 5th Congress of the International-Xenotransplantation-Association CY OCT 24-28, 1999 CL NAGOYA, JAPAN SP Int Xenotransplant Assoc, Pharmaceut Manufacturers Assoc Tokyo, Osaka Pharmaceut Manufacturers Assoc, Suzuken Mem Fdn, Novartis Pharma AG, Novartis Pharma KK, Fujisawa Healthcare Inc, Fujisawa GmbH, Fujisawa Pharmaceut Co Ltd, F Hoffmann La Roche Ltd, Nippon Roche KK, Biotransplant Inc, Nextran Inc ID TRANSPLANTATION C1 BioTransplant Inc, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. RP Down, JD (reprint author), BioTransplant Inc, 3rd Ave,Charlestown Navy Yard, Charlestown, MA 02129 USA. NR 3 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD AUG PY 2000 VL 32 IS 5 BP 1045 EP 1046 DI 10.1016/S0041-1345(00)01111-8 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 344CV UT WOS:000088740800114 PM 10936345 ER PT J AU Abe, M Chen, AM Qi, J Sachs, DH Sykes, M Yang, YG AF Abe, M Chen, AM Qi, J Sachs, DH Sykes, M Yang, YG TI Porcine stem cell factor facilitates long-lasting porcine hematopoietic engraftment in murine recipients SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 5th Congress of the International-Xenotransplantation-Association CY OCT 24-28, 1999 CL NAGOYA, JAPAN SP Int Xenotransplant Assoc, Pharmaceut Manufacturers Assoc Tokyo, Osaka Pharmaceut Manufacturers Assoc, Suzuken Mem Fdn, Novartis Pharma AG, Novartis Pharma KK, Fujisawa Healthcare Inc, Fujisawa GmbH, Fujisawa Pharmaceut Co Ltd, F Hoffmann La Roche Ltd, Nippon Roche KK, Biotransplant Inc, Nextran Inc C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Surg Serv,Transplantat Biol Res Ctr, Boston, MA 02129 USA. RP Yang, YG (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Surg Serv,Transplantat Biol Res Ctr, MGH E,Bldg 149-5102,13th St, Boston, MA 02129 USA. FU NHLBI NIH HHS [R01HL49915, R01HL54038]; NIAID NIH HHS [P01AI39755] NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD AUG PY 2000 VL 32 IS 5 BP 1047 EP 1047 DI 10.1016/S0041-1345(00)01112-X PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 344CV UT WOS:000088740800115 PM 10936346 ER PT J AU Wu, A Yamada, K Awwad, M Shimizu, A Watts, A Murphy, M Gojo, S Neville, D Cooper, DKC Sykes, M Sachs, DH AF Wu, A Yamada, K Awwad, M Shimizu, A Watts, A Murphy, M Gojo, S Neville, D Cooper, DKC Sykes, M Sachs, DH TI Experience with porcine thymic transplantation in baboons SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 5th Congress of the International-Xenotransplantation-Association CY OCT 24-28, 1999 CL NAGOYA, JAPAN SP Int Xenotransplant Assoc, Pharmaceut Manufacturers Assoc Tokyo, Osaka Pharmaceut Manufacturers Assoc, Suzuken Mem Fdn, Novartis Pharma AG, Novartis Pharma KK, Fujisawa Healthcare Inc, Fujisawa GmbH, Fujisawa Pharmaceut Co Ltd, F Hoffmann La Roche Ltd, Nippon Roche KK, Biotransplant Inc, Nextran Inc C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. BioTransplant Inc, Boston, MA USA. RP Sachs, DH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, MGH E,Bldg 149,CNY, Boston, MA 02129 USA. NR 1 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD AUG PY 2000 VL 32 IS 5 BP 1048 EP 1048 DI 10.1016/S0041-1345(00)01113-1 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 344CV UT WOS:000088740800116 PM 10936347 ER PT J AU Alwayn, IPJ Buhler, L Basker, M Goepfert, C Kawai, T Kozlowski, T Ierino, F Sachs, DH Sackstein, R Robson, SC Cooper, DKC AF Alwayn, IPJ Buhler, L Basker, M Goepfert, C Kawai, T Kozlowski, T Ierino, F Sachs, DH Sackstein, R Robson, SC Cooper, DKC TI Coagulation/thrombotic disorders associated with organ and cell xenotransplantation SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 5th Congress of the International-Xenotransplantation-Association CY OCT 24-28, 1999 CL NAGOYA, JAPAN SP Int Xenotransplant Assoc, Pharmaceut Manufacturers Assoc Tokyo, Osaka Pharmaceut Manufacturers Assoc, Suzuken Mem Fdn, Novartis Pharma AG, Novartis Pharma KK, Fujisawa Healthcare Inc, Fujisawa GmbH, Fujisawa Pharmaceut Co Ltd, F Hoffmann La Roche Ltd, Nippon Roche KK, Biotransplant Inc, Nextran Inc 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, MGH E,Bldg 149,13th St, Boston, MA 02129 USA. NR 2 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD AUG PY 2000 VL 32 IS 5 BP 1099 EP 1099 DI 10.1016/S0041-1345(00)01141-6 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 344CV UT WOS:000088740800145 PM 10936376 ER PT J AU Buhler, L Awwad, M Basker, M Gojo, S Thall, A Down, JD Sykes, M Andrews, D Sackstein, R White-Scharf, ME Sachs, DH Cooper, DKC AF Buhler, L Awwad, M Basker, M Gojo, S Thall, A Down, JD Sykes, M Andrews, D Sackstein, R White-Scharf, ME Sachs, DH Cooper, DKC TI A nonmyeloablative regimen with CD40L blockade leads to humoral and cellular hyporesponsiveness to pig hematopoietic cells in baboons SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 5th Congress of the International-Xenotransplantation-Association CY OCT 24-28, 1999 CL NAGOYA, JAPAN SP Int Xenotransplant Assoc, Pharmaceut Manufacturers Assoc Tokyo, Osaka Pharmaceut Manufacturers Assoc, Suzuken Mem Fdn, Novartis Pharma AG, Novartis Pharma KK, Fujisawa Healthcare Inc, Fujisawa GmbH, Fujisawa Pharmaceut Co Ltd, F Hoffmann La Roche Ltd, Nippon Roche KK, Biotransplant Inc, Nextran Inc C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02129 USA. Biotransplant Inc, Charlestown, MA USA. RP Cooper, DKC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, MGH E,Bldg 149-9019,13th St, Boston, MA 02129 USA. NR 2 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD AUG PY 2000 VL 32 IS 5 BP 1100 EP 1100 DI 10.1016/S0041-1345(00)01142-8 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 344CV UT WOS:000088740800146 PM 10936377 ER PT J AU Buhler, L Awwad, M Treter, S Basker, M Ericson, T Lachance, A Oldmixon, B Kurilla-Mahon, B Gojo, S Huang, C Thall, A Down, JD White-Scharf, ME Sachs, DH Cooper, DKC AF Buhler, L Awwad, M Treter, S Basker, M Ericson, T Lachance, A Oldmixon, B Kurilla-Mahon, B Gojo, S Huang, C Thall, A Down, JD White-Scharf, ME Sachs, DH Cooper, DKC TI Induction of mixed hematopoietic chimerism in the pig-to-baboon model SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 5th Congress of the International-Xenotransplantation-Association CY OCT 24-28, 1999 CL NAGOYA, JAPAN SP Int Xenotransplant Assoc, Pharmaceut Manufacturers Assoc Tokyo, Osaka Pharmaceut Manufacturers Assoc, Suzuken Mem Fdn, Novartis Pharma AG, Novartis Pharma KK, Fujisawa Healthcare Inc, Fujisawa GmbH, Fujisawa Pharmaceut Co Ltd, F Hoffmann La Roche Ltd, Nippon Roche KK, Biotransplant Inc, Nextran Inc ID TOLERANCE; REGIMEN C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. Biotransplant Inc, Charlestown, MA USA. RP Cooper, DKC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, MGH E,Bldg 149-9019,13th St, Boston, MA 02129 USA. NR 4 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD AUG PY 2000 VL 32 IS 5 BP 1101 EP 1101 DI 10.1016/S0041-1345(00)01143-X PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 344CV UT WOS:000088740800147 PM 10936378 ER PT J AU Buhler, L Treter, S McMorrow, I Neethling, FA Alwayn, I Awwad, M Thall, A Cooper, DKC LeGuern, C Sachs, DH AF Buhler, L Treter, S McMorrow, I Neethling, FA Alwayn, I Awwad, M Thall, A Cooper, DKC LeGuern, C Sachs, DH TI Injection of porcine anti-idiotypic antibodies to primate anti-Gal antibodies leads to active inhibition of serum cytotoxicity in a baboon SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 5th Congress of the International-Xenotransplantation-Association CY OCT 24-28, 1999 CL NAGOYA, JAPAN SP Int Xenotransplant Assoc, Pharmaceut Manufacturers Assoc Tokyo, Osaka Pharmaceut Manufacturers Assoc, Suzuken Mem Fdn, Novartis Pharma AG, Novartis Pharma KK, Fujisawa Healthcare Inc, Fujisawa GmbH, Fujisawa Pharmaceut Co Ltd, F Hoffmann La Roche Ltd, Nippon Roche KK, Biotransplant Inc, Nextran Inc ID INVIVO C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. BioTransplant Inc, Charlestown, MA USA. RP Cooper, DKC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, MGH E,Bldg 149-9019,13th St, Boston, MA 02129 USA. NR 2 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD AUG PY 2000 VL 32 IS 5 BP 1102 EP 1102 DI 10.1016/S0041-1345(00)01144-1 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 344CV UT WOS:000088740800148 PM 10936379 ER PT J AU Benson, CB Genest, DR Bernstein, MR Soto-Wright, V Goldstein, DP Berkowitz, RS AF Benson, CB Genest, DR Bernstein, MR Soto-Wright, V Goldstein, DP Berkowitz, RS TI Sonographic appearance of first trimester complete hydatidiform moles SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Article DE first trimester; hydatidiform mole; pregnancy; ultrasound ID GESTATIONAL TROPHOBLASTIC DISEASE; MOLAR PREGNANCIES; DIAGNOSIS; ULTRASOUND; SPECTRUM AB Objective Complete hydatidiform moles are now being diagnosed earlier in gestation, thus the clinical presentation and pathologic findings of complete molar pregnancy have changed. We studied the sonographic appearance of first trimester moles and the ability of ultrasound to detect them. Methods We reviewed the sonographic interpretation and sonograms, when available, from all patients with first trimester complete moles diagnosed at our institution from January 1988 to March 1996. Results Of the 24 patients in gestational age at time of the sonogram was 8.7 +/- 2.0 weeks (mean +/-SD) with a range of 5.7-12.3 weeks. The initial sonographic interpretation was a complete mole in 17 (71%) cases, partial mole versus failed pregnancy in two (8%), and failed pregnancy in five (21%) cases. Of the 22 patients with sonograms available for review interpretation on review of the images was a complete mole in 18 (82 %) cases, partial mole versus failed pregnancy in one (5%), and failed pregnancy in three (14%) cases. The typical sonographic appearance of a first trimester complete mole was a complex, echogenic, intra-uterine mass containing many small cystic spaces. Conclusion The majority of first trimester complete moles demonstrate a typical ultrasound appearance such that the diagnosis can be made with ultrasound in most cases. C1 Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, New England Trophoblast Dis Ctr,Div Gynecol Oncol, Dept Radiol, Boston, MA USA. Harvard Univ, Sch Med, New England Trophoblast Dis Ctr,Div Gynecol Oncol, Dept Pathol, Boston, MA USA. Harvard Univ, Sch Med, New England Trophoblast Dis Ctr,Div Gynecol Oncol, Dept Obstet Gynecol & Reprod Biol, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Benson, CB (reprint author), Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. NR 11 TC 37 Z9 39 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD AUG PY 2000 VL 16 IS 2 BP 188 EP 191 DI 10.1046/j.1469-0705.2000.00201.x PG 4 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 382DB UT WOS:000165802200015 PM 11117091 ER PT J AU Meier, M King, GL AF Meier, M King, GL TI Protein kinase C activation and its pharmacological inhibition in vascular disease SO VASCULAR MEDICINE LA English DT Review DE cardiovascular disease; diabetes mellitus; diabetic vascular complications; diacylglycerol (DAG); protein kinase C (PKC) ID NITRIC-OXIDE SYNTHASE; GLOMERULAR MESANGIAL CELLS; GROWTH-FACTOR-BETA; DEPENDENT DIABETES-MELLITUS; SMOOTH-MUSCLE CELLS; RETINAL BLOOD-FLOW; ELEVATED GLUCOSE-LEVELS; MESSENGER-RNA EXPRESSION; SODIUM-POTASSIUM-ATPASE; HUMAN ENDOTHELIAL-CELLS AB Vascular complications in diabetes mellitus are known to be associated with the activation of the protein kinase C (PKC) pathway through the de novo synthesis of diacylglycerol (DAG) from glycolytic intermediates. Specific PKC isoforms, mainly the beta- and delta -isoforms, have been shown to be persistently activated in diabetic mellitus. Multiple studies have reported that the activation of PKC leads to increased production of extracellular matrix and cytokines, enhances contractility, permeability and vascular cell proliferation, induces the activation of cytosolic phospholipase A(2) and inhibits the activity of Na+K+-ATPase. These events are not only frequently observed in diabetes mellitus but are also involved in the actions of vasoactive agents or oxidative stress. Inhibition of PKC by two different kinds of PKC inhibitors - LY333531, a selective PKC-p-isoform inhibitor, and vitamin E, d-alpha-tocopheron -were able to prevent or reverse the various vascular dysfunctions in vitro and in vivo. Clinical studies using these compounds are now ongoing to evaluate the significance of DAG-PKC pathway activation in the development of vascular complications in diabetic patients. C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02115 USA. RP King, GL (reprint author), 1 Joslin Pl, Boston, MA 02215 USA. FU NEI NIH HHS [EY-05110-15, EY-09178-07]; NIDDK NIH HHS [DK-53105-02] NR 193 TC 84 Z9 90 U1 0 U2 1 PU ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1358-863X J9 VASC MED JI Vasc. Med. PD AUG PY 2000 VL 5 IS 3 BP 173 EP 185 DI 10.1177/1358836X0000500307 PG 13 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 374TX UT WOS:000165361400007 PM 11104300 ER PT J AU Robson, SC Cooper, DKC d'Apice, AJF AF Robson, SC Cooper, DKC d'Apice, AJF TI Disordered regulation of coagulation and platelet activation in xenotransplantation SO XENOTRANSPLANTATION LA English DT Article DE coagulation; endothelial cells; molecular incompatibility; platelets; xenotransplantation ID THROMBOTIC THROMBOCYTOPENIC PURPURA; VON-WILLEBRAND-FACTOR; ACTIVABLE FIBRINOLYSIS INHIBITOR; ENDOTHELIAL-CELL ACTIVATION; BONE-MARROW TRANSPLANTATION; DECAY-ACCELERATING FACTOR; FACTOR PATHWAY INHIBITOR; PRIMATE CARDIAC XENOTRANSPLANTATION; ATP-DIPHOSPHOHYDROLASE ACTIVITY; DISCORDANT XENOGRAFT REJECTION AB Rejection of xenografts is associated with vascular-based inflammation, thrombocytopenia and the consumption of coagulation factors that may evolve into disseminated intravascular coagulation (DIC). Similarly, bone marrow-derived cellular xenotransplantation procedures are associated with endothelial cell activation and thrombotic microangiopathic injury. These complications generally develop despite the best available measures for depletion of xenoreactive natural antibody, inhibition of complement activation and suppression of T- and B-cell mediated immune responses. The mechanisms underlying the DIC and thrombotic microangiopathy associated with xenotransplantation are unclear. A proposed primary biological dysfunction of xenografts with respect to regulation of clotting could amplify vascular injury, promote immunological responses and independently contribute to graft failure. Disordered thromboregulation could have deleterious effects, comparable to unregulated complement activation, in the pathogenesis of xenograft rejection and may therefore represent a substantive barrier to xenotransplantation. C1 Harvard Univ, Sch Med, Dept Med, Newark Beth Israel Med Ctr, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA USA. St Vincents Hosp, Immunol Res Ctr, Melbourne, Vic 3065, Australia. RP Robson, SC (reprint author), Beth Israel Deaconess Med Ctr, Ctr Immunobiol, REs N,99 Brookline Ave, Boston, MA 02115 USA. NR 100 TC 99 Z9 103 U1 3 U2 6 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2000 VL 7 IS 3 BP 166 EP 176 DI 10.1034/j.1399-3089.2000.00067.x PG 11 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 360TE UT WOS:000089682700002 PM 11021661 ER PT J AU Watts, A Foley, A Awwad, M Treter, S Oravec, G Buhler, L Alwayn, IPJ Kozlowski, T Lambrigts, D Gojo, S Basker, M White-Scharf, ME Andrews, D Sachs, DH Cooper, DKC AF Watts, A Foley, A Awwad, M Treter, S Oravec, G Buhler, L Alwayn, IPJ Kozlowski, T Lambrigts, D Gojo, S Basker, M White-Scharf, ME Andrews, D Sachs, DH Cooper, DKC TI Plasma perfusion by apheresis through a Gal immunoaffinity column successfully depletes anti-Gal antibody: experience with 320 aphereses in baboons SO XENOTRANSPLANTATION LA English DT Article DE anti-Gal antibodies; baboon; extracorporeal immunoadsorption; plasmapheresis; xenotransplantation ID ANTI-GAL-ALPHA-1-3GAL ANTIBODY; TOLERANCE INDUCTION; NATURAL ANTIBODIES; BONE-MARROW; IN-VITRO; KIDNEY; CELLS; IMMUNOADSORPTION; EPITOPES; REMOVAL AB Background: Anti-Gal alpha 1-3Gal (Gal) antibodies (Gal Ab) contribute to the rejection of porcine organs transplanted into primates. Extracorporeal immunoadsorption (EIA) has been developed to eliminate Gal Ab from the circulation. Methods: Between 1995 and 1999 we performed 320 EIAs in baboons using a COBE-Spectra apheresis unit incorporating a synthetic Gal immunoaffinity column. Three plasma volumes were immunoadsorbed on each occasion. The 221 consecutive EIAs performed in 41 immunosuppressed baboons between January 1997 and April 1999 form the basis of this review. Of these 41 baboons, 29 underwent a series of three or four EIAs at daily intervals, seven had multiple series of three EIAs, and the remainder underwent single or double EIAs. Serum Gal Ab levels were monitored by ELISA before and at intervals after the course of EIA. Results: There were two fatal complications, one from a respiratory mishap (unrelated to the EIA) and one from persistent hypotension unresponsive to therapeutic interventions. Seven procedures (3%) were terminated early owing to technical difficulties and/or persistent hypotension. Mean pre-EIA Gal Ab levels in naive baboons were 33.1 mu g/ml (IgM) and 14.5 mu g/ml (IgG). Immediately after three consecutive EIAs, IgM was depleted by a mean of 97.3% and IgG by 99.4%. By 18 to 24 h later, Gal Ab was returning but depletion remained at 80.1% (IgM) and 84.7% (IgG). The subsequent rate of return of Gal Ab depended on the immunomodulatory protocol used. Conclusions: (1) With appropriate monitoring, EIA is an acceptably safe procedure, even in small(<10 kg) baboons. (2) Three consecutive EIAs are effective in removing >97% of Gal Ab. (3) In the majority of cases, return of Gal Ab begins within 24 h, irrespective of the immunomodulatory protocol. C1 Harvard Univ, Transplantat Biol Res Ctr, Massachusetts Gen Hosp E, Sch Med, Boston, MA 02129 USA. BioTransplant Inc, Charlestown, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Hematol, Boston, MA USA. RP Cooper, DKC (reprint author), Harvard Univ, Transplantat Biol Res Ctr, Massachusetts Gen Hosp E, Sch Med, MGH E,Bldg 149-9019,13th St, Boston, MA 02129 USA. FU NIAID NIH HHS [5PO1 AI39755] NR 22 TC 42 Z9 47 U1 0 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2000 VL 7 IS 3 BP 181 EP 185 DI 10.1034/j.1399-3089.2000.00068.x PG 5 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 360TE UT WOS:000089682700004 PM 11021663 ER PT J AU Auchincloss, H AF Auchincloss, H TI Literature update 2000, part 1 SO XENOTRANSPLANTATION LA English DT Review C1 Massachusetts Gen Hosp, Transplantat Unit, Surg Serv, Boston, MA 02114 USA. RP Auchincloss, H (reprint author), Massachusetts Gen Hosp, Transplantat Unit, Surg Serv, GRB 504, Boston, MA 02114 USA. NR 77 TC 0 Z9 0 U1 0 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD AUG PY 2000 VL 7 IS 3 BP 230 EP 234 DI 10.1034/j.1399-3089.2000.00079.x PG 5 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 360TE UT WOS:000089682700010 PM 11021669 ER PT J AU Hayashi, T AF Hayashi, T TI New therapy reduces AIDS passed to fetuses and costs less SO YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN LA Japanese DT Review DE nevirapine; vertical-transmission; AZT; HIV; HAART ID HIV-1; TRANSMISSION; ZIDOVUDINE; INFANT; PAN AB The AIDS clinical group protocol of zidovudine (AZT) prophylaxis regimen for HIV-1-infected pregnant women and their babies has been associated with a decrease in vertical HIV-1 transmission in non-breastfeeding women in developmental countries. However, scientists furthermore compared the safety and efficacy of short-course nevirapine or AZT during labour and the first week of life. In an advancement that promises to significantly reduce the incidence of AIDS in children in developing countries, scientists have found a simple new way with nevirapine to prevent mother-to-child transmission of the AIDS virus that also is less costly and markedly more effective than the standard therapy with AZT in the third world. The more practical therapy comes from substituting one marketed drug, nevirapine, for the standard drug, AZT. The cost for the two doses of nevirapine was $4, compared with $268 for AZT regimen now used in developing countries and $815 for the much longer and more complicated course used in the U.S. and other developing countries. It is proposed that wide-scale use of nevirapine in developing countries could potentially prevent 300000 to 400000 newborns each year from beginning life infected with HIV. C1 MIT, Massachusetts Gen Hosp East, Whitehead Inst Biomed Res, Immunobiol Lab, Charlestown, MA 02129 USA. RP MIT, Massachusetts Gen Hosp East, Whitehead Inst Biomed Res, Immunobiol Lab, Bldg 149,Room 3503,13th St, Charlestown, MA 02129 USA. NR 26 TC 1 Z9 1 U1 0 U2 0 PU PHARMACEUTICAL SOC JAPAN PI TOKYO PA 2-12-15 SHIBUYA, SHIBUYA-KU, TOKYO, 150-0002, JAPAN SN 0031-6903 J9 YAKUGAKU ZASSHI JI Yakugaku Zasshi-J. Pharm. Soc. Jpn. PD AUG PY 2000 VL 120 IS 8 BP 683 EP 687 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 339ZQ UT WOS:000088508100004 PM 10946618 ER PT J AU Sawasdikosol, S Pratt, JC Meng, WY Eck, MJ Burakoff, SJ AF Sawasdikosol, S Pratt, JC Meng, WY Eck, MJ Burakoff, SJ TI Adapting to multiple personalities: Cbl is also a RING finger ubiquitin ligase SO BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER LA English DT Review DE Cbl; TCR signal transduction; ubiquitin ligase; adapter protein; protein tyrosine kinase ID GROWTH-FACTOR RECEPTOR; PHOSPHOTYROSINE-BINDING DOMAIN; SYK TYROSINE KINASES; C-CBL; SIGNAL-TRANSDUCTION; NEGATIVE REGULATOR; T-CELLS; V-CBL; PHOSPHATIDYLINOSITOL 3-KINASE; IN-VIVO C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Mol Pharmacol & Ped, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Chem, Boston, MA 02115 USA. RP Sawasdikosol, S (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. NR 65 TC 23 Z9 23 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-419X J9 BBA-REV CANCER JI Biochim. Biophys. Acta-Rev. Cancer PD JUL 31 PY 2000 VL 1471 IS 1 BP M1 EP M12 DI 10.1016/S0304-419X(00)00013-5 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Oncology SC Biochemistry & Molecular Biology; Biophysics; Oncology GA 353TH UT WOS:000089291200001 PM 11004605 ER PT J AU McCoy, SL Hausman, FA Deffebach, ME Bakke, A Merkens, LS Bennett, RM Hefeneider, SH AF McCoy, SL Hausman, FA Deffebach, ME Bakke, A Merkens, LS Bennett, RM Hefeneider, SH TI Quantification of DNA binding to cell-surfaces by flow cytometry SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE flow cytometry; DNA binding; isoparametric analysis ID EPIDERMAL GROWTH-FACTOR; FACTOR RECEPTOR; PLASMID DNA; CPG MOTIFS; QUANTITATION; INVOLVEMENT; MACROPHAGES; TRANSPORT; ANTIGEN; GAMMA AB DNA binding to cell-surfaces has been documented in several studies. The interaction of DNA with cells has been shown to have therapeutic potential as a non-viral form of gene delivery and DNA vaccination. Recently, bacterial DNA binding and internalization has been demonstrated in some cells to trigger secretion of cytokines and cell activation. Previous studies to quantify DNA. binding to cells have used radiolabeled DNA. Here we report a non-radioactive assay for quantification of cell-surface DNA binding based on the isoparametric analysis of flow cytometric data as described by Chatelier et al., Embo J., 5 (1986) 1181. This assay has the advantage over previously used procedures in not employing radioactive material and being able to discriminate viable from non-viable cells that bind DNA. With the importance of understanding the interaction of DNA with cells, this assay may have application for the identification and characterization of reagents designed to either enhance or inhibit DNA binding to cells. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Portland Vet Affairs Med Ctr, Dept Immunol & Pulmonol, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Div Med, Portland, OR 97201 USA. Targeted Gene Delivery Inc, Portland, OR USA. RP Hefeneider, SH (reprint author), Portland Vet Affairs Med Ctr, Dept Immunol, 3710 SW US Vet Hosp Rd, Portland, OR 97201 USA. OI Bennett, Robert/0000-0002-7526-3425 FU NCI NIH HHS [R43 CA78140]; NIAMS NIH HHS [R1AR34298]; NIDCD NIH HHS [R01DC03573] NR 23 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD JUL 31 PY 2000 VL 241 IS 1-2 BP 141 EP 146 DI 10.1016/S0022-1759(00)00205-2 PG 6 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 342JJ UT WOS:000088641200013 PM 10915856 ER PT J AU Wang, ZZ Wang, Y Li, ZF Li, J Dong, ZW AF Wang, ZZ Wang, Y Li, ZF Li, J Dong, ZW TI Humanization of a mouse monoclonal antibody neutralizing TNF-alpha by guided selection SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE tumor necrosis factor alpha; phage display; recombinant antibody libraries; human antibody ID TUMOR-NECROSIS-FACTOR; HYPERVARIABLE REGIONS; RHEUMATOID-ARTHRITIS; FAB FRAGMENTS; V(H) SEGMENTS; SEPTIC SHOCK; REPERTOIRE; LIBRARIES; AFFINITY; REVEALS AB With the advent of phage display antibody libraries, humanization of murine antibodies can be achieved by epitope guided selection. In present study, guided selection was applied to the humanization of the mouse mAb Z8 that is directed to human TNF-alpha and can neutralize the cytotoxicity of TNF-alpha. First, the Z8 Fd gene was paired as a template with a repertoire of human kappa chains, and displayed on the filamentous phage, forming a hybrid phage antibody library. Selected by four rounds of panning against TNF-alpha, hybrid antibody fragments that bound to TNF-alpha and contained human kappa chains were obtained. Meanwhile human Fd genes were selected by pairing the human Fd repertoire with the Z8 kappa chain and performing the same procedure of panning. One of the isolated human Fd genes (huFd2), which showed the strongest reactivity, was chosen to pair with 12 of selected human kappa chains. Two of the resulting human Fabs (huFd2-hu kappa 1 and huFd2-hu kappa 2), with same Fd and different kappa chains, bound to TNF-alpha specifically. Their human origin was proved by ELISA and sequencing analysis. The human Fabs competitive ELISA and in vitro TNF-alpha neutralization assay demonstrated that the human Fabs resembled its parental mouse mAb Z8 in that they both recognized the same epitope and neutralized the cytotoxicity of TNF-alpha. These results suggest that guided selection is a promising strategy in murine mAb humanization. (C) 2000 Elsevier Science BN. All rights reserved. C1 Navy Gen Hosp, Cent Lab, Beijing 100037, Peoples R China. Beijing Med Univ, Beijing Inst Canc Res, Beijing 100034, Peoples R China. Canc Hosp, Chinese Acad Med Sci, Beijing 100020, Peoples R China. RP Wang, ZZ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Immunopathol Unit, Warren 5,32 Fruit St, Boston, MA 02114 USA. NR 34 TC 14 Z9 17 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD JUL 31 PY 2000 VL 241 IS 1-2 BP 171 EP 184 DI 10.1016/S0022-1759(00)00203-9 PG 14 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 342JJ UT WOS:000088641200016 PM 10915859 ER PT J AU Warren, KS Wu, JC Pinet, F Fishman, RC AF Warren, KS Wu, JC Pinet, F Fishman, RC TI The genetic basis of cardiac function: dissection by zebrafish (Danio rerio) screens SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT Discussion Meeting on Philosophical Transactions of the Royal-Society-of-London CY NOV 16-17, 1999 CL LONDON, ENGLAND SP Royal Soc London DE zebrafish; genetic screen; cardiac development; cardiac function; single-gene mutation; contractility disorder ID HEART-FAILURE; DILATED CARDIOMYOPATHY; NEUREGULIN RECEPTOR; COMPLEX; MODEL; MICE; SARCOGLYCAN; DISRUPTION; MUTATIONS; STRESS AB The vertebrate heart differs from chordate ancestors both structurally and functionally. Genetic units of form, termed 'modules', are identifiable by mutation, both in zebrafish and mouse, and correspond to feature recently acquired in evolution, such as the ventricular chamber or endothelial lining of the vessels and heart. Zebrafish (Danio rerio) genetic screens have provided a reasonably inclusive set of such genes. Normal cardiac function may also be disrupted by single-gene mutations in zebrafish. Individual mutations may perturb contractility or rhythm generation. The zebrafish mutations which principally disturb cardiac contractility fall into two broad phenotypic categories, 'dilated' and 'hypertrophic'. Interestingly, these correspond to the two primary types of heart failure in humans. These disorders of early cardiac function provide candidate genes to be examined in complex human heart diseases, including arrhythmias and heart failure. C1 Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. Coll France, INSERM, U36, F-75005 Paris, France. RP Fishman, RC (reprint author), Massachusetts Gen Hosp E, Cardiovasc Res Ctr, 149 13th St,4th Floor, Charlestown, MA 02129 USA. EM fishman@cvrc.mgh.harvard.edu RI Pinet, Florence/F-2892-2013 FU NHLBI NIH HHS [5R01HL49579-07]; NIDDK NIH HHS [5R01DK55383-02] NR 30 TC 25 Z9 26 U1 0 U2 2 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD JUL 29 PY 2000 VL 355 IS 1399 BP 939 EP 944 PG 6 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 342ZN UT WOS:000088677400009 PM 11128987 ER PT J AU Ioannidis, JPA Havlir, DV Tebas, P Hirsch, MS Collier, AC Richman, DD AF Ioannidis, JPA Havlir, DV Tebas, P Hirsch, MS Collier, AC Richman, DD TI Dynamics of HIV-1 viral load rebound among patients with previous suppression of viral replication SO AIDS LA English DT Article DE viral rebound; mathematical modeling; viral load; HIV-1; antiretroviral therapy; viral fitness ID ANTIRETROVIRAL THERAPY; IN-VIVO; REVERSE-TRANSCRIPTASE; INFECTION; PLASMA; RNA; DISCONTINUATION; MAINTENANCE; FITNESS AB Objective: To model the dynamics of HIV-1 rebound in patients receiving suboptimal therapy after suppression of plasma viremia to < 200 copies/ml by triple combination therapy. Design: Mathematical modeling of data from 23 patients switched to indinavir maintenance therapy after viral replication was suppressed with a combination of indinavir, zidovudine and lamivudine. Modeling of HIV-I rebound among 23 patients on zidovudine/lamivudine maintenance was also performed for comparison. Methods: Evaluation of slopes of rebound and of their heterogeneity; calculation of the basic reproductive number (R-o, the number of newly infected cells arising from each productively infected cell); regression analyses for predictors of the slope of rebound. Results: Rebound of plasma HIV RNA followed a sigmoid curve with an initial exponential phase. There was significant heterogeneity in the slopes of rebound for individual patients (P < 0.001). In the indinavir maintenance rebounds, the average initial slope was estimated to be 0.587/day (doubling time 1.2 days). The slopes of rebound in patients on zidovudine/lamivudine maintenance tended to be less steep on average (P = 0.025). Among patients taking indinavir maintenance, the average R-o for the initial rebound of viremia was 4.3; in multivariate regressions, the slope of rebound was steeper during early rebound and in patients with higher viral load at the start of triple therapy or a higher CD4 cell count when indinavir monotherapy was initiated. The slope was less steep in patients with a greater increase in the number of CD4 cells during triple therapy. Conclusions: The rates of viral load increase among patients with viral rebound while receiving less than triple therapy are similar to those reported in patients interrupting therapy. Variability among patients may depend on viral fitness, target cell availability and extent of immune reconstitution. (C) 2000 Lippincott Williams & Wilkins. C1 Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, Clin & Mol Epidemiol Unit, GR-45110 Ioannina, Greece. Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Infect Dis Unit, Boston, MA USA. Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. Univ Calif San Diego, Dept Pathol, San Diego, CA 92103 USA. Vet Affairs Med Ctr, San Diego, CA 92161 USA. Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. Univ Washington, Sch Med, AIDS Clin Trials Unit, Seattle, WA USA. RP Ioannidis, JPA (reprint author), Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, Clin & Mol Epidemiol Unit, GR-45110 Ioannina, Greece. RI Tebas, Pablo/A-7061-2008; Ioannidis, John/G-9836-2011 FU NIAID NIH HHS [AI 36214, AI 38858, AI27670] NR 27 TC 15 Z9 15 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 JUL 28 PY 2000 VL 14 IS 11 BP 1481 EP 1488 DI 10.1097/00002030-200007280-00003 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 349AL UT WOS:000089021600002 PM 10983634 ER PT J AU O'Neill, T Dwyer, AJ Ziv, Y Chan, DW Lees-Miller, SP Abraham, RH Lai, JH Hill, D Shiloh, Y Cantley, LC Rathbun, GA AF O'Neill, T Dwyer, AJ Ziv, Y Chan, DW Lees-Miller, SP Abraham, RH Lai, JH Hill, D Shiloh, Y Cantley, LC Rathbun, GA TI Utilization of oriented peptide libraries to identify substrate motifs selected by ATM SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DEPENDENT PROTEIN-KINASE; ATAXIA-TELANGIECTASIA GENE; NIJMEGEN BREAKAGE SYNDROME; SEVERE COMBINED IMMUNODEFICIENCY; COMBINED IMMUNE-DEFICIENCY; 3-KINASE RELATED KINASES; DNA-DAMAGE CHECKPOINT; CELL-CYCLE REGULATION; V(D)J RECOMBINATION; IONIZING-RADIATION AB The ataxia telangiectasia mutated (ATM) gene encodes a serine/threonine protein kinase that plays a critical role in genomic surveillance and development. Here, we use a peptide library approach to define the in vitro substrate specificity of ATM kinase activity. The peptide library analysis identified an optimal sequence with a central core motif of LSQE that is preferentially phosphorylated by ATM. The contributions of the amino acids surrounding serine in the LSQE motif were assessed by utilizing specific peptide libraries or individual peptide substrates. All amino acids comprising the LSQE sequence were critical for maximum peptide substrate suitability for ATM. The DNA-dependent protein kinase (DNA-PK), a Ser/Thr kinase related to ATM and important in DNA repair, was compared with ATM in terms of peptide substrate selectivity. DNA-PK was found to be unique in its preference of neighboring amino acids to the phosphorylated serine. Peptide library analyses defined a preferred amino acid motif for ATM that permits clear distinctions between ATM and DNA-PK kinase activity. Data base searches using the library-derived ATM sequence identified previously characterized substrates of ATM, as well as novel candidate substrate targets that may function downstream in ATM-directed signaling pathways. C1 Harvard Univ, Childrens Hosp, Sch Med, Dept Pediat,Ctr Blood Res, Boston, MA 02115 USA. Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. Univ Calgary, Dept Biol Sci, Calgary, AB T2N 1N4, Canada. Univ Calgary, Dept Biol Chem, Calgary, AB T2N 1N4, Canada. Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. Harvard Univ, Beth Israel Deaconess Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. Oncogene Sci Inc, Cambridge, MA 02142 USA. RP Rathbun, GA (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Dept Pediat,Ctr Blood Res, 200 Longwood Ave, Boston, MA 02115 USA. RI Cantley, Lewis/D-1800-2014 OI Cantley, Lewis/0000-0002-1298-7653 FU NIGMS NIH HHS [GM56203, GM57018, R01 GM056203] NR 65 TC 116 Z9 118 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 28 PY 2000 VL 275 IS 30 BP 22719 EP 22727 DI 10.1074/jbc.M001002200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 338KV UT WOS:000088419400019 PM 10801797 ER PT J AU Amano, S Scott, IC Takahara, K Koch, M Champliaud, MF Gerecke, DR Keene, DR Hudson, DL Nishiyama, T Lee, S Greenspan, DS Burgeson, RE AF Amano, S Scott, IC Takahara, K Koch, M Champliaud, MF Gerecke, DR Keene, DR Hudson, DL Nishiyama, T Lee, S Greenspan, DS Burgeson, RE TI Bone morphogenetic protein 1 is an extracellular processing enzyme of the laminin 5 gamma 2 chain SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROCOLLAGEN C-PROTEINASE; JUNCTIONAL EPIDERMOLYSIS-BULLOSA; DROSOPHILA EMBRYO; GENE; EXPRESSION; IDENTIFICATION; CLEAVAGE; CHORDIN; FAMILY; BMP-1 AB Epithelial cells maintained in culture medium containing low calcium proteolytically process laminin 5 (alpha 3 beta 3 gamma 2) within the alpha 3 and gamma 2 chains (1). Experiments were designed to identify the enzyme(s) responsible for the laminin 5 processing and the sites of proteolytic cleavage. To characterize the nature of laminin 5 processing, we determined the N-terminal amino acid sequences of the proteolytic fragments produced by the processing events. The results indicate that the first alpha 3 chain cleavage (200-165 kDa alpha 3) occurs within subdomain G4 of the G domain. The second cleavage (165-145 kDa alpha 3) occurs within the Ina domain, 11 residues N-terminal to the start of domain II. The gamma chain is cleaved within the second epidermal growth factor-like repeat of domain III. The sequence cleaved within the gamma 2 chain matches the consensus sequence for the cleavage of type I, II, and III procollagens by bone morphogenetic protein-1 (BMP-1), also known as type I procollagen C-proteinase (2). Recombinant BMP-1 cleaves gamma 2 in vitro, both within intact laminin 5 and at the predicted site of a recombinant gamma 2 short arm. alpha 3 is also cleaved by BMP-1 in vitro, but the cleavage site is yet to be determined. These results show the laminin alpha 3 and gamma 2 chains to be substrates for BMP-1 in vitro. We speculate that gamma 2 cleavage is required for formation of the laminin 5-6 complex. and that this complex is directly involved in assembly of the interhemidesmosomal basement membrane. This further suggests that BMP-1 activity facilitates basement membrane assembly, but not hemidesmosome assembly, in the laminin 5-rich dermal-epidermal-junction basement membrane in vivo. C1 Massachusetts Gen Hosp, MGH Harvard Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. Shiseido Res Ctr, Life Sci Res Labs, Yokohama, Kanagawa 2368643, Japan. Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53706 USA. Shriners Hosp Crippled Childrens, Portland, OR 97201 USA. RP Burgeson, RE (reprint author), Massachusetts Gen Hosp, MGH Harvard Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. RI Nishiyama, Toshio/C-5434-2013 FU NIAMS NIH HHS [AR 35689, AR 38923, AR 43621] NR 45 TC 165 Z9 172 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 28 PY 2000 VL 275 IS 30 BP 22728 EP 22735 DI 10.1074/jbc.M002345200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 338KV UT WOS:000088419400020 PM 10806203 ER PT J AU Cohen, GB Rangan, VS Chen, BK Smith, S Baltimore, D AF Cohen, GB Rangan, VS Chen, BK Smith, S Baltimore, D TI The human thioesterase II protein binds to a site on HIV-1 Nef critical for CD4 down-regulation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACYL-COA THIOESTERASE; CELL-SURFACE CD4; CYCLOPHILIN-A; TYPE-1 NEF; ADAPTER COMPLEXES; TARGETING SIGNAL; ESCHERICHIA-COLI; T-LYMPHOCYTES; SH3 DOMAIN AB A HIV-I Nef affinity column was used to purify a 35-kDa Nef-interacting protein from T-cell lysates. The 35-kDa protein was identified by peptide microsequence analysis as the human thioesterase II (hTE) enzyme, an enzyme previously identified in a yeast two-hybrid screen as a potential Nef-interacting protein. Immunofluorescence studies showed that hTE localizes to peroxisomes and that coexpression of Nef and hTE leads to relocalization of Nef to peroxisomes. Interaction of Nef and hTE was abolished by point mutations in Nef at residues Asp(108), Leu(112), Phe(121), Pro(122), and Asp(123). All of these mutations also abrogated the ability of Nef to down-regulate CD4 from the surface of HIV-infected cells. Eased on the x-ray and NMR structures of Nef, these residues define a surface on Nef critical for CD4 down-regulation. A subset of these mutations also affected the ability of Nef to down-regulate major histocompatibility complex class I. These results, taken together with previous studies, identify a region on Nef critical for most of its known functions. However, not all Nef alleles bind to hTE with high affinity, so the role of hTE during HIV infection remains uncertain. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr AIDS Res, Charlestown, MA 02129 USA. Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. MIT, Whitehead Inst, Dept Biol, Cambridge, MA 02139 USA. CALTECH, Off President, Pasadena, CA 91125 USA. RP Baltimore, D (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr AIDS Res, Charlestown, MA 02129 USA. EM baltimore@caltech.edu NR 61 TC 44 Z9 45 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 28 PY 2000 VL 275 IS 30 BP 23097 EP 23105 DI 10.1074/jbc.M000536200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 338KV UT WOS:000088419400067 PM 10807905 ER PT J AU Baid, S Cosimi, AB Tolkoff-Rubin, N Colvin, RB Williams, WW Pascual, M AF Baid, S Cosimi, AB Tolkoff-Rubin, N Colvin, RB Williams, WW Pascual, M TI Renal disease associated with hepatitis C infection after kidney and liver transplantation SO TRANSPLANTATION LA English DT Editorial Material ID CRYOGLOBULINEMIC MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS; VIRUS-ASSOCIATED GLOMERULONEPHRITIS; INTERFERON-ALPHA TREATMENT; NON-HODGKINS-LYMPHOMA; MIXED CRYOGLOBULINEMIA; ALLOGRAFT RECIPIENTS; VIRAL-INFECTION; THROMBOTIC MICROANGIOPATHY; LONG-TERM; FIBRILLARY GLOMERULONEPHRITIS C1 Massachusetts Gen Hosp, Dept Med, Renal Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Transplantat Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Pascual, M (reprint author), Massachusetts Gen Hosp, Dept Med, Renal Unit, Box MZ 70, Boston, MA 02114 USA. NR 81 TC 40 Z9 41 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 JUL 27 PY 2000 VL 70 IS 2 BP 255 EP 261 DI 10.1097/00007890-200007270-00001 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 341DA UT WOS:000088574700001 PM 10933143 ER PT J AU Cooke, KR Hill, GR Gerbitz, A Kobzik, L Martin, TR Crawford, JM Brewer, JP Ferrara, JLM AF Cooke, KR Hill, GR Gerbitz, A Kobzik, L Martin, TR Crawford, JM Brewer, JP Ferrara, JLM TI Tumor necrosis factor-alpha neutralization reduces lung injury after experimental allogeneic bone marrow transplantation SO TRANSPLANTATION LA English DT Article ID VERSUS-HOST DISEASE; IDIOPATHIC-PNEUMONIA-SYNDROME; CELL-MEDIATED CYTOTOXICITY; GALACTOSAMINE-TREATED MICE; TOTAL-BODY IRRADIATION; DONOR T-CELLS; INTERSTITIAL PNEUMONITIS; INFLAMMATORY RESPONSE; PULMONARY RESPONSES; FAS LIGAND AB Background, Idiopathic pneumonia syndrome (IPS) is a frequent and potentially fatal complication of bone marrow transplantation (BR;TT), We have previously shown that experimental TPS is associated with increased levels of lipopolysaccaride (LPS) and tumor necrosis factor-alpha (TNF alpha) in the bronchoalveolar lavage (BAL) fluid, and that administration of LPS to animals with extensive graft versus host exacerbated underlying lung injury (Blood 1996; 88: 3230). Methods. Lethally irradiated CBA mice received BMT from allogeneic (BIO,ER) or syngeneic (CBA) donors. The role of TNF alpha in the exacerbation of pulmonary toxicity caused by LPS injection and in the evolution of TPS after allogeneic BMT was examined by neutralizing TNFa after BMT using a soluble binding protein (rhTNFR:Fc). Results. Five weeks after BR IT, administration of rhTNFR:Fc dramatically reduced mortality and prevented the exacerbation of lung injury caused by LPS administration, This protective effect was associated with preservation of pulmonary function and with marked reductions of cells, neutrophils, and EPS in the BAL fluid of treated animals. TNF alpha neutralization from week 4 to 6 after allogeneic BMT effectively halted the progression of systemic GVHD and significantly reduced, but did not prevent lung injury that developed during the treatment period. Conclusions. We conclude that TNF alpha is central to early LPS induced toxicity in this model and is a significant, but not the exclusive contributor to the development of IFS after allogeneic BMT. C1 Univ Michigan, Ctr Canc, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Pediat, Blood & Marrow Transplantat Program, Ann Arbor, MI 48109 USA. Dana Farber Canc Inst, Div Pediat Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Childrens Hosp, Div Pediat Pulmonol, Boston, MA 02115 USA. Univ Florida, Coll Med, Dept Pathol, Gainesville, FL 32610 USA. RP Cooke, KR (reprint author), Univ Michigan, Ctr Canc, Dept Internal Med, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. RI Ain, Kenneth/A-5179-2012; Hill, Geoffrey/O-2630-2016 OI Ain, Kenneth/0000-0002-2668-934X; Hill, Geoffrey/0000-0003-2994-0429 FU NHLBI NIH HHS [HL 03565, HL55162]; NIDDK NIH HHS [DK39512] NR 66 TC 80 Z9 84 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 JUL 27 PY 2000 VL 70 IS 2 BP 272 EP 279 DI 10.1097/00007890-200007270-00006 PG 8 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 341DA UT WOS:000088574700006 PM 10933148 ER PT J AU Kawai, T Wee, SL Bazin, H Latinne, D Phelan, J Boskovic, S Ko, DSC Hong, HZ Mauiyyedi, S Nadazdin, O Abrahamian, G Preffer, F Colvin, RB Sachs, DH Cosimi, AB AF Kawai, T Wee, SL Bazin, H Latinne, D Phelan, J Boskovic, S Ko, DSC Hong, HZ Mauiyyedi, S Nadazdin, O Abrahamian, G Preffer, F Colvin, RB Sachs, DH Cosimi, AB TI Association of natural killer cell depletion with induction of mixed chimerism and allograft tolerance in non-human primates SO TRANSPLANTATION LA English DT Article ID MARROW GRAFT-REJECTION; BONE-MARROW; T-CELLS; PHENOTYPIC CHARACTERIZATION; CYNOMOLGUS MONKEYS; TRANSPLANTATION; MICE; REGIMEN; RECIPIENTS; PREVENTION AB Background. Nonmyeloablative T cell depletion followed by donor bone marrow infusion has proved to be an effective approach to induction of mixed chimerism and tolerance of organ allografts in non-human primates. To help define the mechanisms involved we have compared T cell depletion with ATG versus anti-CD2 monoclonal antibody with respect to establishment of mixed chimerism and induction of tolerance. Method. Both nonmyeloablative regimens included low dose total body irradiation (1.5 Gy x 2), thymic irradiation (7 Gy), splenectomy and kidney plus donor bone marrow transplantation, followed by a 4-week posttransplant course of cyclosporine. In addition, the ATG group (13 recipients) received antithymocyte globulin, although the LOCD2b group (10 recipients! were treated with an anti-CD2 monoclonal antibody (LOCD2b). Results, In the ATG group, 11 of 13 monkeys developed multilineage chimerism and 9 survived for more than 100 days without kidney allograft rejection. In contrast, 0/10 monkeys in the LOCD2b group developed chimerism, 5 died of infection and 5 suffered progressive rejection; only 1 recipient survived beyond 100 days. Sequential monitoring of peripheral blood mononuclear cells revealed greater T cell (CD3+) depletion in the LOCD2b-treated animals compared to those receiving ATG. However, NK cells (CD16+CD8+) mere significantly more depleted in the ATG group and NK function remained abrogated longer after ATG than LOCD2b treatment (3 weeks vs. <5 days). Conclusion. Despite excellent T cell depletion by LoCD2b, ATG was more effective in inducing chimerism and tolerance, This difference correlated with an ti-NR activity of the two reagents. These data suggest that NK cells may also resist engraftment of allogeneic bone marrow cells in this model. C1 Massachusetts Gen Hosp, Transplantat Unit, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02114 USA. RP Kawai, T (reprint author), Massachusetts Gen Hosp, Transplantat Unit, Dept Surg, Boston, MA 02114 USA. FU NHLBI NIH HHS [P0I-HL18646]; NIAID NIH HHS [R01 AI037692, R01 AI037692-09, R21 AI037692, R21 AI037692-06]; PHS HHS [R0I A137692-05] NR 36 TC 30 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 JUL 27 PY 2000 VL 70 IS 2 BP 368 EP 374 DI 10.1097/00007890-200007270-00023 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 341DA UT WOS:000088574700023 PM 10933165 ER PT J AU Hadigan, C Corcoran, C Basgoz, N Davis, B Sax, P Grinspoon, S AF Hadigan, C Corcoran, C Basgoz, N Davis, B Sax, P Grinspoon, S TI Metformin in the treatment of HIV lipodystrophy syndrome - A randomized controlled trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ANTIRETROVIRAL THERAPY HAART; INSULIN-RESISTANCE; PROTEASE INHIBITORS; GLUCOSE-TOLERANCE; DIABETES-MELLITUS; INFECTED WOMEN; HEART-DISEASE; FAT; HYPERINSULINEMIA; RISK AB Context A syndrome of lipodystrophy, characterized by fat redistribution and insulin resistance, has been estimated to affect the majority of human immunodeficiency virus (HIV)-infected individuals who are treated with combination antiretroviral therapy. There are no proven therapies for the metabolic disturbances associated with HIV lipodystrophy syndrome. Objective To determine the safety and efficacy of metformin therapy in HIV-infected patients with fat redistribution and abnormal glucose homeostasis. Design and Setting Randomized, double-blind, placebo-controlled pilot study conducted in a university hospital between December 1998 and January 2000, Patients Twenty-six HIV-infected, nondiabetic patients with fat redistribution and abnormal oral glucose tolerance test (OGTT) results, hyperinsulinemia, or both. Interventions Patients were randomly assigned to receive metformin, 500 mg twice daily (n=14), or identical placebo (n=12), for 3 months. Main Outcome Measures Insulin area under the curve (AUC), calculated 120 minutes following a 75-g OGTT at baseline vs at 3-month follow-up and compared between treatment groups. Results Patients treated with metformin demonstrated significant reductions in mean (SEM) insulin AUC 120 minutes after OGTT (-2930 [912] vs -414 [432] mu IU/mL [-20349 (6334) vs -2875 {3000} pmol/L]; P=.01), weight (-1.3 [0.6] vs 1.1[0.4] kg; P=.005), and diastolic blood pressure (-5 [4] vs 5 [2] mm Hg; P=.009) vs controls, respectively. Metformin therapy was associated with a decrease in visceral abdominal fat (VAT; -1115 [819] vs 1191 [699] mm(2); P=.08) and a proportional reduction in subcutaneous abdominal fat (SAT); the VAT-SAT ratio was unchanged in metformin-treated vs placebo-treated patients. No increase in lactate or liver transaminase levels was observed with metformin treatment. Mild diarrhea was the most common adverse effect of metformin. No patient discontinued therapy because of adverse effects. Conclusions This study suggests that a relatively low dosage of metformin reduces insulin resistance and related cardiovascular risk parameters in HIV-infected patients with lipodystrophy. C1 Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Combined Program Pediat Gastroenterol & Nutr, Boston, MA USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Infect Dis, Boston, MA USA. RP Grinspoon, S (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Bulfinch 457B, Boston, MA 02114 USA. FU NCRR NIH HHS [M01-RR300088]; NIDDK NIH HHS [T32-DK07703, K23-DK02844] NR 26 TC 244 Z9 249 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 26 PY 2000 VL 284 IS 4 BP 472 EP 477 DI 10.1001/jama.284.4.472 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 335QB UT WOS:000088254200034 PM 10904511 ER PT J AU Albert, MS Drachman, DA AF Albert, MS Drachman, DA TI Alzheimer's disease - What is it, how many people have it, and why do we need to know? SO NEUROLOGY LA English DT Editorial Material ID PREVALENCE; DEMENTIA; DIAGNOSIS C1 Massachusetts Gen Hosp, Gerontol Res Unit, Boston, MA 02129 USA. Univ Massachusetts, Dept Neurol, Worcester, MA 01605 USA. RP Albert, MS (reprint author), Massachusetts Gen Hosp, Gerontol Res Unit, Bldg 149,13th St, Boston, MA 02129 USA. NR 14 TC 23 Z9 24 U1 0 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 JUL 25 PY 2000 VL 55 IS 2 BP 166 EP 168 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 337FA UT WOS:000088345700002 PM 10908884 ER PT J AU McMahon, FG Fujioka, K Singh, BN Mendel, CM Rowe, E Rolston, K Johnson, F Mooradian, AD AF McMahon, FG Fujioka, K Singh, BN Mendel, CM Rowe, E Rolston, K Johnson, F Mooradian, AD TI Efficacy and safety of sibutramine in obese white and African American patients with hypertension - A 1-year, double-blind, placebo-controlled, multicenter trial SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID CORONARY HEART-DISEASE; DEPENDENT DIABETES-MELLITUS; WEIGHT-LOSS; FOLLOW-UP; CARDIOVASCULAR-DISEASE; REUPTAKE INHIBITOR; ENERGY-EXPENDITURE; INSULIN-RESISTANCE; FAT DISTRIBUTION; UNITED-STATES AB Background: Obesity is a highly prevalent medical condition and is commonly accompanied by hypertension. This study assessed the efficacy and safety of treatment with sibutramine hydrochloride for promoting and maintaining weight loss in obese patients with controlled hypertension, including a subset analysis of African American patients. Patients and Methods: Obese patients with a body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) between 27 and 40 and a history of hypertension controlled with a calcium channel blocker (with or without concomitant thiazide diuretic treatment) were randomized to receive sibutramine (n=150) or placebo (n=74) with minimal behavioral intervention for 52 weeks. African Americans constituted 36% of enrolled patients. Efficacy assessments were body weight and related parameters (BMI and waist and hip circumferences), metabolic parameters (serum levels of triglycerides, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], total cholesterol, glucose, and uric acid), and quality-of-life measures. Safety assessments included recording of blood pressure, pulse rate, adverse events, and reasons for discontinuation. Results: For patients receiving sibutramine, weight loss occurred during the first 6 months of the trial and was maintained to the end of the 12-month treatment period. Among patients receiving sibutramine, 40.1% lost 5% or more of body weight (5% responders) and 13.4% lost 10% or more of body weight (10% responders) compared with 8.7% and 4.3% of patients in the placebo group, respectively (P<.05). Changes in body weight were similar among African Americans and whites. Sibutramine-induced weight loss was associated with significant improvements in serum levels of triglycerides, HDL-C, glucose, and uric acid. Waist circumference and quality-of-life measures also improved significantly in patients receiving sibutramine. Sibutramine-treated patients had small but statistically significant mean increases in diastolic blood pressure (2.0 mm Hg) and pulse rate (4.9 beats/min) compared with placebo-treated patients (-1.3 mm Hg and 0.0 beats/min; P<.05); these changes were similar among African Americans and whites. Most adverse events were mild to moderate in severity and transient. The most common adverse event resulting in discontinuation among patients receiving sibutramine was hypertension (5.3% of patients receiving sibutramine vs 1.4% of patients receiving placebo). Conclusions: In obese patients with controlled hypertension, sibutramine was an effective and well-tolerated treatment for weight loss and maintenance. Sibutramine-induced weight loss resulted in improvements in serum levels of triglycerides, HDL-C, uric acid, and glucose, and in waist circumference and quality-of-life measures. Blood pressure and heart rate increased by a small amount. Efficacy and safety profiles for sibutramine among African American and white obese patients with controlled hypertension were similar. C1 Clin Res Ctr, New Orleans, LA 70112 USA. Scripps Clin, San Jose, CA USA. Univ Calif Los Angeles, Los Angeles, CA USA. W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. Knoll Pharmaceut Co, Mt Olive, NJ USA. St Louis Univ, Sch Med, Dept Internal Med, Div Endocrinol, St Louis, MO USA. RP McMahon, FG (reprint author), Clin Res Ctr, 147 S Liberty, New Orleans, LA 70112 USA. NR 56 TC 157 Z9 164 U1 0 U2 4 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 JUL 24 PY 2000 VL 160 IS 14 BP 2185 EP 2191 DI 10.1001/archinte.160.14.2185 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 335FM UT WOS:000088233300015 PM 10904462 ER PT J AU Fortini, ME Skupski, MP Boguski, MS Hariharan, IK AF Fortini, ME Skupski, MP Boguski, MS Hariharan, IK TI A survey of human disease gene counterparts in the Drosophila genome SO JOURNAL OF CELL BIOLOGY LA English DT Article ID P53; DEGENERATION; SUPPRESSION; INTERACTS; MUTATIONS; HOMOLOG; KINASE; MDM2 C1 Univ Penn, Sch Med, Dept Genet, Stellar Chance Labs, Philadelphia, PA 19104 USA. Celera Genom, Rockville, MD 20850 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. RP Fortini, ME (reprint author), Univ Penn, Sch Med, Dept Genet, Stellar Chance Labs, Room 709C,422 Curie Blvd, Philadelphia, PA 19104 USA. RI Tang, Amy/L-3226-2016 OI Tang, Amy/0000-0002-5772-2878 FU NEI NIH HHS [R01EY11632]; NIA NIH HHS [R01 AG014583, R01AG14583]; NINDS NIH HHS [R01 NS036084, R01NS36084] NR 28 TC 103 Z9 110 U1 1 U2 20 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 JUL 24 PY 2000 VL 150 IS 2 BP F23 EP F29 DI 10.1083/jcb.150.2.F23 PG 7 WC Cell Biology SC Cell Biology GA 339DM UT WOS:000088462400002 PM 10908582 ER PT J AU Mukherjee, S AF Mukherjee, S TI Take your medicine - Why cheap AIDS drugs for Africa might be dangerous. SO NEW REPUBLIC LA English DT Article C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Mukherjee, S (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NEW REPUBLIC INC PI WASHINGTON PA 1220 19TH ST NW SUITE 600, WASHINGTON, DC 20036 USA SN 0028-6583 J9 NEW REPUBLIC JI New Repub. PD JUL 24 PY 2000 VL 223 IS 4 BP 16 EP 16 PG 1 WC Political Science SC Government & Law GA 335NJ UT WOS:000088249300009 ER PT J AU Cook, IA Leuchter, AF Witte, E Abrams, M Uijtdehaage, SHJ Stubbeman, W Rosenberg-Thompson, S Anderson-Hanley, C Dunkin, JJ AF Cook, IA Leuchter, AF Witte, E Abrams, M Uijtdehaage, SHJ Stubbeman, W Rosenberg-Thompson, S Anderson-Hanley, C Dunkin, JJ TI Neurophysiologic predictors of treatment response to fluoxetine in major depression (vol 85, pg 263, 1999) SO PSYCHIATRY RESEARCH LA English DT Correction C1 Univ Calif Los Angeles, Sch Med, Neuropsychiat Inst Hosp, Quantitat EEG Lab, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. RP Cook, IA (reprint author), Univ Calif Los Angeles, Sch Med, Neuropsychiat Inst Hosp, Quantitat EEG Lab, 760 Westwood Plaza, Los Angeles, CA 90024 USA. NR 1 TC 0 Z9 0 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 JUL 24 PY 2000 VL 95 IS 1 BP 87 EP 87 DI 10.1016/S0165-1781(00)00170-0 PG 1 WC Psychiatry SC Psychiatry GA 341AP UT WOS:000088569100010 ER PT J AU Friedlander, AH Friedlander, IK Pogrel, MA AF Friedlander, AH Friedlander, IK Pogrel, MA TI Dentistry's role in the diagnosis and co-management of patients with sleep apnoea/hypopnoea syndrome SO BRITISH DENTAL JOURNAL LA English DT Article ID POSITIVE AIRWAY PRESSURE; COLLEGE-OF-PHYSICIANS; APNEA SYNDROME; ORAL APPLIANCE; PREVALENCE; ATHEROMAS; ACCIDENTS; OBESITY; DEVICES; TRIAL AB The sleep apnoea/hypopnoea syndrome (SAHS) is characterized by repeated upper airway narrowing or collapse during sleep. The obstruction is caused by the soft palate and/or base of tongue collapsing against the pharyngeal walls because of decreased muscle tone. These episodes are accompanied by hypoxaemia, surges in blood pressure, brief arousal from sleep and pronounced snoring. individuals with occult disease are at heightened risk of motorway accidents because of excessive sleepiness, sustained hypertension, myocardial infarction, and stroke. The signs and symptoms of SAHS may be recognisable in the dental practice. Common findings in the medical history include daytime sleepiness, snoring, hypertension, and type 2 diabetes mellitus. Common clinical findings include merle gender, obesity, increased neck circumference, excessive fat deposition in the palate, tongue (macroglossia) and pharynx, a long soft palace, a small recessive mandible and maxilla, and calcified carotid artery atheromas on panoramic and lateral cephalometric radiographs. Dentists who recognise these signs and symptoms have an opportunity ca diagnose patients with occult SAHS. After confirmation of the diagnosis by a physician, dentists can participate in the management of the disorder by fabricating mandibular advancement appliances that enlarge the retroglossal space by anterior displacement of the tongue and performing corrective upper airway surgery that prevents recurrent airway obstruction. C1 VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Med Ctr, Hosp Dent Serv, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Dent, Los Angeles, CA 90024 USA. Los Angeles Cty Dept Hlth, Panorama City, CA USA. VA Sepulveda Dent Serv, Sepulveda, CA USA. Univ Calif San Francisco, Sch Dent, Dept Oral & Maxillofacial Surg, San Francisco, CA 94143 USA. RP Friedlander, AH (reprint author), VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 56 TC 14 Z9 14 U1 0 U2 4 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0610 J9 BRIT DENT J JI Br. Dent. J. PD JUL 22 PY 2000 VL 189 IS 2 BP 76 EP 80 DI 10.1038/sj.bdj.4800687a PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 344JF UT WOS:000088754900019 PM 10975158 ER PT J AU Amory, JK Anawalt, BD Paulsen, CA Bremner, WJ AF Amory, JK Anawalt, BD Paulsen, CA Bremner, WJ TI Klinefelter's syndrome SO LANCET LA English DT Article ID MEN C1 Univ Washington, Populat Ctr Res Reprod, Seattle, WA 98195 USA. Univ Washington, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. RP Amory, JK (reprint author), Univ Washington, Populat Ctr Res Reprod, Seattle, WA 98195 USA. NR 8 TC 20 Z9 23 U1 0 U2 1 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUL 22 PY 2000 VL 356 IS 9226 BP 333 EP 335 DI 10.1016/S0140-6736(00)02517-4 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 336MJ UT WOS:000088305900039 PM 11071204 ER PT J AU Ghosh-Choudhury, N Ghosh-Choudhury, G Celeste, A Ghosh, PM Moyer, M Abboud, SL Kreisberg, J AF Ghosh-Choudhury, N Ghosh-Choudhury, G Celeste, A Ghosh, PM Moyer, M Abboud, SL Kreisberg, J TI Bone morphogenetic protein-2 induces cyclin kinase inhibitor p21 and hypophosphorylation of retinoblastoma protein in estradiol-treated MCF-7 human breast cancer cells SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE BMP-2; pRb; p21; breast cancer cell ID DEPENDENT KINASES; IN-VIVO; EXPRESSION; RECEPTOR; GENE; AMPLIFICATION; ACTIVATION; GROWTH; PROGRESSION; REGULATORS AB The biologic effects and mechanisms by which bone morphogenetic proteins (BMPs) function in breast cancer cells are not well defined. A member of this family of growth and differentiation factors, BMP-2, inhibited both basal and estradiol-induced growth of MCF-7 breast tumor cells in culture. Flow cytometric analysis showed that in the presence of BMP-2, 62% and 45% of estradiol-stimulated MCF-7 cells progressed to S-phase at 24 h and 48 h, respectively. Estradiol mediates growth of human breast cancer cells by stimulating cyclins and cyclin-dependent kinases (CDKs). BMP-2 significantly increased the Level of the cyclin kinase inhibitor, p21, which in turn associated with and inactivated cyclin D1. BMP-2 inhibited estradiol-induced cyclin D1-associated kinase activity. Also estradiol-induced CDK2 activity was inhibited by BMP-2. This inhibition of CDK activity resulted in hypophosphorylation of retinoblastoma protein thus keeping it in its active form. These data provide the first evidence by which BMP-2 inhibits estradiol-induced proliferation of human breast cancer cells. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Texas, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78284 USA. S Texas Vet Hlth Care Syst, GRECC, San Antonio, TX USA. Genet Inst, Boston, MA USA. RP Ghosh-Choudhury, N (reprint author), Univ Texas, Hlth Sci Ctr, Dept Pathol, 7703 Floyd Curl Dr, San Antonio, TX 78284 USA. FU NIDDK NIH HHS [DK-50190] NR 49 TC 66 Z9 69 U1 0 U2 1 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 JUL 21 PY 2000 VL 1497 IS 2 BP 186 EP 196 DI 10.1016/S0167-4889(00)00060-4 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 338VW UT WOS:000088444800002 PM 10903423 ER PT J AU Roberts, JD Chiche, JD Weimann, J Steudel, W Zapol, WM Bloch, KD AF Roberts, JD Chiche, JD Weimann, J Steudel, W Zapol, WM Bloch, KD TI Nitric oxide inhalation decreases pulmonary artery remodeling in the injured lungs of rat pups SO CIRCULATION RESEARCH LA English DT Article DE inhaled nitric oxide; pulmonary hypertension; proliferation; congenital heart disease; bronchopulmonary dysplasia ID SMOOTH-MUSCLE CELLS; DEPENDENT PROTEIN-KINASE; CONGENITAL HEART-DISEASE; PLATELET-AGGREGATION; LEUKOCYTE ADHESION; GROWTH-FACTOR; DNA-SYNTHESIS; HYPERTENSION; PROLIFERATION; NEWBORN AB Vascular injury causes the muscularization of peripheral pulmonary arteries, which is more pronounced in the infant than in the adult lung. Although inhaled NO gas attenuates pulmonary artery remodeling in hypoxic rats, whether or not it protects the lung by mitigating vasoconstriction is unknown. This investigation tested whether inhaled NO decreases the muscularization of injured pulmonary arteries in rat pups by modulating vascular tone. One week after monocrotaline administration, the percentage of muscularized rat pup lung arteries was increased by >3-fold. Nevertheless, monocrotaline exposure did not cause right ventricular hypertrophy, pulmonary hypertension, or vasoconstriction. in addition, it did not increase the expression of markers of inflammation (interleukin-1 beta, intercellular adhesion molecule-1, and E-selectin) or of platelet-mediated thrombosis (GPIb alpha). Continuous inhalation of 20 ppm NO gas prevented the neomuscularization of the pulmonary arteries in pups with lung injury. Moreover, a 3-fold increase in cell proliferation and 30% decrease in cell numbers in pulmonary arteries caused by monocrotaline exposure was prevented by NO inhalation. These data indicate that inhaled NO protects infants against pulmonary remodeling induced by lung injury by mechanisms that an independent of pulmonary tone, inflammation, or thrombosis. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pediat, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA 02114 USA. RP Roberts, JD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. FU NHLBI NIH HHS [HL-04237, HL-42397, K08 HL004237, K08 HL004237-01, HL-55377] NR 49 TC 43 Z9 45 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JUL 21 PY 2000 VL 87 IS 2 BP 140 EP 145 PG 6 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 339RQ UT WOS:000088492000012 PM 10903998 ER PT J AU Majumder, PK Pandey, P Sun, XG Cheng, KD Datta, R Saxena, S Kharbanda, S Kufe, D AF Majumder, PK Pandey, P Sun, XG Cheng, KD Datta, R Saxena, S Kharbanda, S Kufe, D TI Mitochondrial translocation of protein kinase C delta in phorbol ester-induced cytochrome C release and apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MONOCYTIC DIFFERENTIATION; PROTEOLYTIC ACTIVATION; CELLS; CASPASE-8; COMPLEX; SIGNAL; DATP AB Apoptosis is induced by the release of cytochrome c from mitochondria to the cytoplasm. The present studies demonstrate that the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) induces translocation of protein kinase C (PKC) delta from the cytoplasm to mitochondria. The results also show that translocation of PKC delta results in release of cytochrome c, The functional significance of this event is further supported by the demonstration that PKC delta translocation is required for TPA-induced apoptosis, These findings demonstrate that translocation of PKC delta to mitochondria is responsible, at least in part, for inducing cytochrome c release and apoptosis. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Lovelace Resp Res Inst, Albuquerque, NM 87115 USA. RP Kufe, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA42082]; NIGMS NIH HHS [GM58200] NR 24 TC 238 Z9 242 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 21 PY 2000 VL 275 IS 29 BP 21793 EP 21796 DI 10.1074/jbc.C000048200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 337LY UT WOS:000088363800005 PM 10818086 ER PT J AU Shimizu, M Potts, JT Gardella, TJ AF Shimizu, M Potts, JT Gardella, TJ TI Minimization of parathyroid hormone - Novel amino-terminal parathyroid hormone fragments with enhanced potency in activating the type-1 parathyroid hormone receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID (PTH)/PTH-RELATED PEPTIDE RECEPTOR; PTH-RELATED PEPTIDE; RAT OSTEO-SARCOMA; ADENYLYL-CYCLASE; BIOLOGICAL-ACTIVITY; EXTRACELLULAR LOOP; PHOSPHOLIPASE-C; CROSS-LINKING; BINDING; REGION AB The amino-terminal and carboxyl-terminal portions of the 1-34 fragment of parathyroid hormone (PTH) contain the major determinants of receptor activation and receptor binding, respectively. We investigated how the amino-terminal signaling portion of PTH interacts with the receptor by utilizing analogs of the weakly active fragment, rat (r) PTH(1-14)NH2, and cells transfected with the wild-type human PTH-1 receptor (hP1R-WT) or a truncated PTH-1 receptor which lacked most of the amino-terminal extracellular domain (hP1R-delNt). Of 132 mono-substituted PTH(1-14) analogs, most having substitutions in the (1-9) region were inactive in assays of cAMP formation in LLC-PK1 cells stably expressing hP1R-WT, whereas most having substitutions in the (10-14) region were active, Several substitutions (e.g. Ser(3) --> Ala, Asn(10) --> Ala or Gin, Leu(11) --> Arg, Gly(12) --> Ala, Kis(14) --> Trp) enhanced activity 2-10-fold. These effects were additive, as [Ala(3,10,12),Arg(11),Trp(14)] rPTH(1-14)NH2 was 220-fold more potent than rPTH(1-14)NH2 (EC50 = 0.6 +/- 0.1 and 133 +/- 16 mu m respectively). Native rPTH(1-11) was inactive, but [Ala(3,10),Arg(11)]rPTH(1-11)NH2 achieved maximal cAMP stimulation (EC50 = 17 mu M). The modified PTH fragments induced cAMP formation with hP1R-delNt in COS-7 cells as potently as they did with hP1R-WT; PTH(1-34) was 6,000-fold weaker with hP1R-delNt than with hP1R-WT. The most potent analog, [Ala(3,10,12),Arg(11),Trp(14)]rPTH(1-14)NH2, stimulated inositol phosphate production with hP1R-WT, The results show that short NH2-terminal peptides of PTH can be optimized for considerable gains in signaling potency through modification of interactions involving the regions of the receptor containing the transmembrane domains and extracellular loops. C1 Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Gardella, TJ (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. FU NIDDK NIH HHS [DK-11794] NR 43 TC 73 Z9 76 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 21 PY 2000 VL 275 IS 29 BP 21836 EP 21843 DI 10.1074/jbc.M909861199 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 337LY UT WOS:000088363800013 PM 10777513 ER PT J AU Yalamanchili, P Lu, CF Oxvig, C Springer, TA AF Yalamanchili, P Lu, CF Oxvig, C Springer, TA TI Folding and function of I domain-deleted Mac-1 and lymphocyte function-associated antigen-1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTERCELLULAR-ADHESION MOLECULE-1; INTEGRIN CR3 CD11B/CD18; BETA-PROPELLER DOMAIN; COMPLEMENT RECEPTOR TYPE-3; GLYCOPROTEIN-IIB-IIIA; LEUKOCYTE ADHESION; ALPHA-SUBUNIT; BINDING-SITE; CRYSTAL-STRUCTURE; LIGAND-BINDING AB In those integrins that contain it, the I domain is a major ligand recognition site. The I domain is inserted between beta-sheets 2 and 3 of the predicted beta-propeller domain of the integrin alpha subunit, We deleted the I domain from the integrin alpha(M) and alpha(L) subunits to give I-less Mac-1 and lymphocyte function-associated antigen-1 (LFA-1), respectively. The I-less alpha(M) and alpha(L) subunits were expressed in association with the wild-type beta(2) subunit on the surface of transfected cells and bound to all the monoclonal antibodies mapped to the putative beta-propeller and C-terminal regions of the a, and a, subunits, suggesting that the folding of these domains is independent of the I domain. I-less Mac-1 bound to the ligands iC3b and factor X, but this binding was reduced compared with wild-type Mac-1. In contrast, I-less Mac-1 did not bind to fibrinogen or denatured bovine serum albumin. Binding to iC3b and factor X by I-less Mac-1 was inhibited by the function-blocking antibody CBRM1/32, which binds to the beta-propeller domain of the a, subunit, I-less LFA-1 did not bind its ligands intercellular adhesion molecule-1 and -3. Thus, the I domain is not essential for the folding, heterodimer formation, and surface expression of Mac-1 and LFA-1 and is required for binding to some ligands, but not others. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Springer, TA (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, 200 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [CA31799] NR 57 TC 58 Z9 60 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 21 PY 2000 VL 275 IS 29 BP 21877 EP 21882 DI 10.1074/jbc.M908868199 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 337LY UT WOS:000088363800019 PM 10764808 ER PT J AU Lau, OD Courtney, AD Vassilev, A Marzilli, LA Cotter, RJ Nakatani, Y Cole, PA AF Lau, OD Courtney, AD Vassilev, A Marzilli, LA Cotter, RJ Nakatani, Y Cole, PA TI p300/CBP-associated factor histone acetyltransferase processing of a peptide substrate SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SEROTONIN N-ACETYLTRANSFERASE; MELATONIN RHYTHM ENZYME; CATALYTIC MECHANISM; COACTIVATORS P300; CRYSTAL-STRUCTURE; COENZYME-A; DNA-DAMAGE; ACETYLATION; PCAF; BINDING AB p300/CBP-associated factor (PCAF) is a histone acetyltransferase that; plays an important role in the remodeling of chromatin and the regulation of gene expression. It has been shown to catalyze preferentially acetylation of the epsilon-amino group of lysine 14 in histone H3, In this study, the kinetic mechanism of PCAF was evaluated with a 20-amino acid peptide substrate derived from the amino terminus of histone H3 (H3-20) and recombinant bacterially expressed PCAF catalytic domain (PCAF(cat)). The enzymologic behavior of full-length PCAF and PCAF(cat) were shown to be similar. PCAF-catalyzed acetylation of the substrate H3-20 was shown to be specific for Lys-14, analogous to its behavior with the full-length histone H3 protein. Two-substrate kinetic analysis displayed an intersecting line pattern, consistent with a ternary complex mechanism for PCAF, The dead-end inhibitor analog desulfo-CoA was competitive versus acetyl-CoA and noncompetitive versus H3-20, The dead-end analog inhibitor H3-20 K14A was competitive versus H3-20 and uncompetitive versus acetylCoA The potent bisubstrate analog inhibitor H3-CoA-20 was competitive versus acetyl-CoA and noncompetitive versus H3-20. Taken together, these inhibition patterns support an ordered BiBi kinetic mechanism for PCAF in which acetyl-CoA binding precedes H3-20 binding. Viscosity experiments suggest that diffusional release of product is not rate-determining for PCAF catalysis, These results provide a mechanistic framework for understanding the detailed catalytic behavior of an important subset of the histone acetyltransferases and have significant implications for molecular regulation of and inhibitor design for these enzymes. C1 Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Cole, PA (reprint author), Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Rm 316,Hunterian Bldg,725 N Wolfe St, Baltimore, MD 21205 USA. NR 35 TC 82 Z9 82 U1 2 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 21 PY 2000 VL 275 IS 29 BP 21953 EP 21959 DI 10.1074/jbc.M003219200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 337LY UT WOS:000088363800029 PM 10777508 ER PT J AU Walker, AK See, R Batchelder, C Kophengnavong, T Gronniger, JT Shi, Y Blackwell, TK AF Walker, AK See, R Batchelder, C Kophengnavong, T Gronniger, JT Shi, Y Blackwell, TK TI A conserved transcription motif suggesting functional parallels between Caenorhabditis elegans SKN-1 and Cap'n'Collar-related basic leucine zipper proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-BINDING DOMAIN; GATA-FACTOR; BZIP; NRF2; GENE; E1A; ACTIVATION; INDUCTION; ELEMENTS; P300 AB In Caenorhabditis elegans, the predicted transcription factor SKN-1 is required for embryonic endodermal and mesodermal specification and for maintaining differentiated intestinal cells post-embryonically. The SKN-1 DNA-binding region is related to the Cap'n'Collar (CNC) family of basic leucine zipper proteins, but uniquely, SKN-1 binds DNA as a monomer. CNC proteins are absent in C, elegans, however; and their involvement in the endoderm and mesoderm suggests some functional parallels to SKN-1, Using a cell culture assay, we show that SKN-1 induces transcription and contains three potent activation domains. The functional core of one domain is a short motif, the DIDLID element, which is highly conserved in a subgroup of vertebrate CNC proteins. The DIDLID element is important for SKN-1-driven transcription, suggesting a likely significance in other CNC proteins. SKN-1 binds to and activates transcription through the p300/cAMP-rrespossvv element-binding protein-binding protein (CBP) coactivator, supporting the genetic prediction that SKN-1 recruits the C, elegans p300/CBP ortholog, CBP-1, The DIDLID element appears to act independently of p300/CBP, however, suggesting a distinct conserved target. The evolutionarily preservation of the DIDLID transcriptional element supports the model that SKN-1 and some CNC proteins interact with analogous cofactors and may have preserved some similar functions despite having divergent DNA-binding domains. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Blackwell, TK (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, 200 Longwood Ave, Boston, MA 02115 USA. FU NIDDK NIH HHS [DK09416]; NIGMS NIH HHS [GM50900, GM58012] NR 38 TC 39 Z9 46 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 21 PY 2000 VL 275 IS 29 BP 22166 EP 22171 DI 10.1074/jbc.M001746200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 337LY UT WOS:000088363800058 PM 10764775 ER PT J AU Zang, Q Lu, CF Huang, CC Takagi, J Springer, TA AF Zang, Q Lu, CF Huang, CC Takagi, J Springer, TA TI The top of the inserted-like domain of the integrin lymphocyte function-associated antigen-1 beta subunit contacts the alpha subunit beta-propeller domain near beta-sheet 3 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTERCELLULAR-ADHESION MOLECULE-1; LIGAND-BINDING REGION; I-DOMAIN; A-DOMAIN; CELL-ADHESION; MONOCLONAL-ANTIBODIES; CRITICAL RESIDUES; CRYSTAL-STRUCTURE; IMMUNE-SYSTEM; AMINO-ACIDS AB We find that monoclonal antibody YTA-1 recognizes an epitope formed by a combination of the integrin alpha(L) and beta(2) subunits of LFA-1, Using human/mouse chimeras of the alpha(L) and beta(2) subunits, we determined that YTA-1 binds to the predicted inserted (I)-like domain of the beta(2) subunit and the predicted beta-propeller domain of the cu, subunit, Substitution into mouse LFA-1 of human residues Ser(302) and Arg(303) of the beta(2) subunit and Pro(78), Thr(79) Asp(80), Ile(365), and Asn(367) Of the alpha(L) subunit is sufficient to completely reconstitute YTA-1 reactivity. Antibodies that bind to epitopes that are nearby in models of the I-like and beta-propeller domains compete with YTA-1 monoclonal antibody for binding. The predicted beta-propeller domain of integrin alpha subunits contains seven beta-sheets arranged like blades of a propeller around a pseudosymmetry axis. The antigenic residues cluster on the bottom of this domain in the 1-2 loop of blade 2, and on the side of the domain in beta-strand 4 of blade 3. The I domain is inserted between these blades on the top of the beta-propeller domain. The antigenic residues in the beta subunit localize to the top of the I-like domain near the putative Mg2+ ion binding site. Thus, the I-like domain contacts the bottom or side of the beta-propeller domain near beta-sheets 2 and 3, YTA-1 preferentially reacts with activated LFA-1 and is a function-blocking antibody, suggesting that conformational movements occur near the interface it defines between the LFA-1 alpha and beta subunits. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Springer, TA (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, 200 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [CA31798] NR 56 TC 28 Z9 28 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 21 PY 2000 VL 275 IS 29 BP 22202 EP 22212 DI 10.1074/jbc.M002883200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 337LY UT WOS:000088363800063 PM 10781608 ER PT J AU Ford, HL Landesman-Bollag, E Dacwag, CS Stukenberg, PT Pardee, AB Seldin, DC AF Ford, HL Landesman-Bollag, E Dacwag, CS Stukenberg, PT Pardee, AB Seldin, DC TI Cell cycle-regulated phosphorylation of the human SIX1 homeodomain protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CASEIN KINASE-II; DNA-BINDING; HOMEOBOX GENES; SITE; ACTIVATION; CK2; IDENTIFICATION; EXPRESSION; DROSOPHILA; TISSUE AB Human SIX1 (HSIX1) is a member of the Six class of homeodomain proteins implicated in muscle, eye, head, and brain development. To further understand the role of HSIX1 in the cell cycle and cancer, we developed an HSIX1-specific antibody to study protein expression at various stages of the cell cycle. Our previous work demonstrated that HSIX1 mRNA expression increases as cells exit S phase and that overexpression of HSIX1 can attenuate a DNA damage-induced G(2) cell cycle checkpoint. Overexpression of HSIX1 mRNA was observed in 44% of primary breast cancers and 90% of metastatic lesions. Now wt? demonstrate that HSIX1 is a nuclear phosphoprotein that becomes hyperphosphorylated at mitosis in both MCF7 cells and in Xenopus extracts. The pattern of phosphorylation observed in mitosis is similar to that seen by treating recombinant HSIX1 with casein kinase II (CK2) in vitro, Apigenin, a selective CK2 inhibitor, diminishes interphase and mitotic phosphorylation of HSIX1. Treatment of MCF7 cells with apigenin leads to a dose-dependent arrest at the G(2)/M boundary, implicating CK2, like HSIX1, in the G(2)/M transition. HSIX1 hyperphosphorylated in vitro by CK2 loses its ability to bind the MEF3 sites of the aldolase A promoter (pM), and decreased binding to pM is observed during mitosis, Because CK2 and HSIX1 have both been implicated in cancer and in cell cycle control, we propose that HSIX1, whose activity is regulated by CK2, is a relevant target of CK2 in G(2)/M checkpoint control and that both molecules participate in the same pathway whose dysregulation leads to cancer. C1 Dana Farber Canc Inst, Div Canc Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Boston Univ, Med Ctr, Dept Med & Pathol, Boston, MA 02118 USA. RP Ford, HL (reprint author), Dana Farber Canc Inst, Div Canc Biol, D610B,44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [1F32 CA79197-01] NR 45 TC 88 Z9 90 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 21 PY 2000 VL 275 IS 29 BP 22245 EP 22254 DI 10.1074/jbc.M002446200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 337LY UT WOS:000088363800068 PM 10801845 ER PT J AU Aspinwall, CA Qian, WJ Roper, MG Kulkarni, RN Kahn, CR Kennedy, RT AF Aspinwall, CA Qian, WJ Roper, MG Kulkarni, RN Kahn, CR Kennedy, RT TI Roles of insulin receptor substrate-1, phosphatidylinositol 3-kinase, and release of intracellular Ca2+ stores in insulin-stimulated insulin secretion in beta-cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHOLIPASE C-GAMMA; PANCREATIC-ISLETS; TYROSINE PHOSPHORYLATION; CYTOSOLIC CA2+; S6 KINASE; GLUCOSE; EXOCYTOSIS; ACTIVATION; IRS-2; GENE AB The signaling pathway by which insulin stimulates insulin secretion and increases in intracellular free Ca2+ concentration ([Ca2+](i)) in isolated mouse pancreatic beta-cells and clonal beta-cells was investigated. Application of insulin to single beta-cells resulted in increases in [Ca2+](i) that were of lower magnitude, slower onset, and longer lifetime than that observed with stimulation with tolbutamide, Furthermore, the increases in [Ca2+](i) originated from interior regions of the cell rather than from the plasma membrane as with depolarizing stimuli. The insulin-induced [Ca2+](i) changes and insulin secretion at single beta-cells were abolished by treatment with 100 nM wortmannin or 1 mu M thapsigargin; however, they were unaffected by 10 mu M U73122, 20 mu M nifedipine, or removal of Ca2+ from the medium. Insulin-stimulated insulin secretion was also abolished by treatment with 2 mu M bisin-dolylmaleimide I, but [Ca2+](i) changes were unaffected. In an insulin receptor substrate-1 gene disrupted beta-cell tumor line, insulin did not evoke either [Ca2+](i) changes or insulin secretion. The data suggest that autocrine-activated increases in [Ca2+](i) are due to release of intracellular Ca2+ stores, especially the endoplasmic reticulum, mediated by insulin receptor substrate-1 and phosphatidylinositol 3-kinase, Autocrine activation of insulin secretion is mediated by the increase in [Ca2+](i) and activation of protein kinase C. C1 Univ Florida, Dept Chem, Gainesville, FL 32611 USA. Harvard Univ, Sch Med, Div Res, Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 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; Aspinwall, Craig/0000-0002-4359-5812 FU NIDDK NIH HHS [DK 33201, DK31036, DK46960] NR 46 TC 118 Z9 128 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 21 PY 2000 VL 275 IS 29 BP 22331 EP 22338 DI 10.1074/jbc.M909647199 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 337LY UT WOS:000088363800079 PM 10764813 ER PT J AU Ma, QP Tian, L Woolf, CJ AF Ma, QP Tian, L Woolf, CJ TI Resection of sciatic nerve re-triggers central sprouting of A-fibre primary afferents in the rat SO NEUROSCIENCE LETTERS LA English DT Article DE sciatic nerve; central sprouting; A-fibre; C-fibre; nerve injury; primary afferent ID TRANSGANGLIONIC DEGENERATIVE ATROPHY; SPINAL-CORD; CENTRAL TERMINALS; DORSAL HORN; HORSERADISH-PEROXIDASE; TRANSPORT; AXOTOMY; NEURONS; FIBERS; NGF AB We have investigated whether nerve injury or target deprivation is responsible for the injury induced central sprouting of A-fibres. Cholera toxin B subunit conjugated horseradish peroxidase was used to trace the termination of A-fibre primary afferents. Transection of the sciatic nerve induces central sprouting of sciatic myelinated A-fibre primary afferents into the spinal dorsal horn lamina II, which normally is the termination site of unmyelinated C-fibre primary afferents. The sprouting A-fibre terminals withdrew from lamina II after six to eight months. A second cut to the previously sectioned and ligated sciatic nerve re-triggered the central sprouting of A-fibre primary afferents into the spinal dorsal horn lamina II, suggesting that nerve injury per se rather than the deprivation of target tissues is the cause of central sprouting of A-fibre primary afferents. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 UCL, Dept Anat & Dev Biol, London WC1E 6BT, England. Capital Med Univ, Xuanwu Hosp, Dept Neurol, Beijing 100053, Peoples R China. Massachusetts Gen Hosp, Dept Anaesthesia & Crit Care, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Ma, QP (reprint author), Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Dept Pharmacol, Terlings Pk, Harlow CM20 2QR, Essex, England. EM qingping_ma@merck.com NR 17 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUL 21 PY 2000 VL 288 IS 3 BP 215 EP 218 DI 10.1016/S0304-3940(00)01242-8 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 336RN UT WOS:000088316900013 PM 10889346 ER PT J AU Muller, JE AF Muller, JE TI Triggering of cardiac events by sexual activity: Findings from a case-crossover analysis SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article; Proceedings Paper CT Symposium on Sexual Activity and Cardiac Risk: The Princeton Conference CY JUN, 1999 CL PRINCETON, NEW JERSEY SP Univ Med & Dent, Robert Wood Johnson Med Sch ID ACUTE MYOCARDIAL-INFARCTION; CARDIOVASCULAR EVENTS; CIRCADIAN VARIATION; PHYSICAL EXERTION; RISK; ONSET AB Although anecdotal reports have suggested that sexual activity increases the risk of acute myocardial infarction (MI), controlled studies to evaluate the magnitude of this risk have only recently been conducted. Using on epidemiologic technique celled the case-crossover method, the Myocardial Infarction Onset Study (MIOS) has provided quantitative data on sexual activity as a trigger of MI onset. Sexual activity was found to double the relative risk of acute MI in healthy individuals and patients with a prior history of angina or MI, However, the absolute risk of sexually triggered MI remains extremely low, because the baseline risk of MI is low for most individuals and the increased risk due to sexual activity is transient. Regular exercise also was found to reduce the risk of MI by sexual activity. Given that >12 million people in the United States have coronary artery disease, these findings should be more widely disseminated to reassure patients that, in most cases, sexual activity carries little risk of causing a cardiac event. In the future, advances in research on the triggering of MI ore likely to yield new approaches to the prevention of cardiovascular events through prospective identification of the vulnerable plaques that lead to coronary thrombosis, and prophylactic measures to sever the link between triggers and their potentially disastrous consequences. (C) 2000 by Excerpta Medica, Inc. C1 Massachusetts Gen Hosp, Div Cardiol, CIMIT, Boston, MA 02114 USA. RP Muller, JE (reprint author), Massachusetts Gen Hosp, Div Cardiol, CIMIT, 100 Charles River Plaza,Suite 400, Boston, MA 02114 USA. NR 29 TC 29 Z9 28 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 JUL 20 PY 2000 VL 86 IS 2A SI SI BP 14F EP 18F PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 337DC UT WOS:000088341300005 PM 10899271 ER PT J AU DeBusk, R Drory, Y Goldstein, I Jackson, G Kaul, S Kimmel, SE Kostis, JB Kloner, RA Lakin, M Meston, CM Mittleman, M Muller, JE Padma-Nathan, H Rosen, RC Stein, RA Zusman, R AF DeBusk, R Drory, Y Goldstein, I Jackson, G Kaul, S Kimmel, SE Kostis, JB Kloner, RA Lakin, M Meston, CM Mittleman, M Muller, JE Padma-Nathan, H Rosen, RC Stein, RA Zusman, R TI Management of sexual dysfunction in patients with cardiovascular disease: Recommendations of the Princeton Consensus Panel SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article; Proceedings Paper CT Symposium on Sexual Activity and Cardiac Risk: The Princeton Conference CY JUN, 1999 CL PRINCETON, NEW JERSEY SP Univ Med & Dent, Robert Wood Johnson Med Sch AB Sexual dysfunction is highly prevalent in both sexes and adversely effects patients' quality of life and well being. Given the frequent association between sexual dysfunction and cardiovascular disease, in addition to the potential cardiac risk of sexual activity itself, a consensus panel was convened to develop recommendations for clinical management of sexual dysfunction in patients with cardiovascular disease. Based upon a review of the research and presentations by invited experts, a classification system was developed for stratification of patients into high, low, and intermediate categories of cardiac risk. The large majority of patients are in the low-risk category, which includes patients with (1) controlled hypertension; (2) mild, stable angina; (3) successful coronary revascularization; (4) a history of uncomplicated myocardial infarction (MI); (5) mild valvular disease; and (6) no symptoms and <3 cardiovascular risk factors. These patients con be safely encouraged to initiate or resume sexual activity or to receive treatment for sexual dysfunction. An important exception is the use of sildenafil in patients taking nitrates in any form. patients in the intermediate-risk category include those with (1) moderate angina; (2) a recent MI (<6 weeks); (3) left ventricular dysfunction and/or class II congestive heart failure; (4) nonsustained low-risk arrhythmias; and (5) greater than or equal to 3 risk factors for coronary artery disease. These patients should receive further cardiologic evaluation before restratification into the low- or high-risk category. Finally, patients in the high-risk category include those with (1) unstable or refractory angina; (2) uncontrolled hypertension; (3) congestive heart failure (class III or IV); (4) very recent MI (<2 weeks); (5) highrisk arrhythmias; (6) obstructive cardiomyopathies; and (7) moderate-to-severe valvular disease. These patients should be stabilized by specific treatment for their cardiac condition before resuming sexual activity or being treated for sexual dysfunction. A simple algorithm is provided for guiding physicians in the management of sexual dysfunction in patients with varying degrees of cardiac risk. (C) 2000 by Excerpta Medica, Inc. C1 Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Med, New Brunswick, NJ 08903 USA. Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. Chaim Sheba Med Ctr, Cardiac Rehabil Inst, IL-52621 Tel Hashomer, Israel. Boston Univ, Med Ctr, Boston, MA USA. St Thomas Hosp, Ctr Cardiothorac, London, England. Cedars Sinai Med Ctr, Div Cardiol, Los Angeles, CA 90048 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Good Samaritan Hosp, Inst Heart, Los Angeles, CA USA. Cleveland Clin Fdn, Dept Urol, Cleveland, OH 44195 USA. Univ Texas, Dept Psychol, Austin, TX 78712 USA. Beth Israel Deaconess Med Ctr, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Male Clin, Beverly Hills, CA USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Psychiat, New Brunswick, NJ 08903 USA. Brooklyn Hosp Ctr, Div Cardiol, Brooklyn, NY USA. Harvard Univ, Sch Med, Boston, MA USA. RP Kostis, JB (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Med, 1 Robert Wood Johnson Pl,POB 19, New Brunswick, NJ 08903 USA. NR 18 TC 38 Z9 40 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 20 PY 2000 VL 86 IS 2A SI SI BP 62F EP 68F PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 337DC UT WOS:000088341300016 PM 10899282 ER PT J AU Garman, SC Wurzburg, BA Tarchevskaya, SS Kinet, JP Jardetzky, TS AF Garman, SC Wurzburg, BA Tarchevskaya, SS Kinet, JP Jardetzky, TS TI Structure of the Fc fragment of human IgE bound to its high-affinity receptor Fc epsilon RI alpha SO NATURE LA English DT Article ID HUMAN-IMMUNOGLOBULIN-E; MEDIATED EFFECTOR FUNCTIONS; BINDING-SITE; CRYSTAL-STRUCTURE; GAMMA-RII; MONOCLONAL-ANTIBODY; IDENTIFICATION; SUBUNIT; COMPLEX; GLYCOSYLATION AB The initiation of immunoglobulin-E (IgE)-mediated allergic responses requires the binding of IgE antibody to its high-affinity receptor, Fc epsilon RI. Crosslinking of Fc epsilon RI initiates an intracellular signal transduction cascade that triggers the release of mediators of the allergic response. The interaction of the crystallizable fragment (Fc) of IgE (IgE-Fc) with Fc epsilon RI is a key recognition event of this process and involves the extracellular domains of the Fc epsilon RI alpha-chain. To understand the structural basis for this interaction, we have solved the crystal structure of the human IgE-Fc-Fc epsilon RI alpha complex to 3.5-Angstrom resolution. The crystal structure reveals that one receptor binds one dimeric IgE-Fc molecule asymmetrically through interactions at two sites, each involving one C epsilon 3 domain of the IgE-Fc. The interaction of one receptor with the IgE-Fc blocks the binding of a second receptor, and features of this interaction are conserved in other members of the Fc receptor family. The structure suggests new approaches to inhibiting the binding of IgE to Fc epsilon RI for the treatment of allergy and asthma. C1 Northwestern Univ, Dept Biochem Mol Biol & Cell Biol, Evanston, IL 60208 USA. Beth Israel Deaconness Med Ctr, Dept Pathol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Jardetzky, TS (reprint author), Northwestern Univ, Dept Biochem Mol Biol & Cell Biol, 2153 Sheridan Rd, Evanston, IL 60208 USA. NR 50 TC 230 Z9 244 U1 0 U2 13 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 20 PY 2000 VL 406 IS 6793 BP 259 EP 266 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 335PM UT WOS:000088251900038 PM 10917520 ER PT J AU Allen, JS Sheffer, EC Pena, CS Scully, RE Perakis, CR AF Allen, JS Sheffer, EC Pena, CS Scully, RE Perakis, CR TI A 74-year-old man with unrelenting dysphagia - Adenocarcinoma, grade 2, of the distal esophagus probably arising in Barrett's epithelium. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID ACHALASIA SECONDARY; GASTRIC CARDIA; CARCINOMA; PSEUDOACHALASIA; NEOPLASIA; FEATURES; CANCER C1 Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA 02115 USA. RP Allen, JS (reprint author), Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. NR 39 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 20 PY 2000 VL 343 IS 3 BP 199 EP 205 DI 10.1056/NEJM200007203430308 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 335HY UT WOS:000088239100008 ER PT J AU Podolsky, DK AF Podolsky, DK TI Going the distance - The case for true colorectal-cancer screening SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID SENSITIVITY; COLONOSCOPY C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Podolsky, DK (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 20 TC 121 Z9 124 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 20 PY 2000 VL 343 IS 3 BP 207 EP 208 DI 10.1056/NEJM200007203430309 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 335HY UT WOS:000088239100009 PM 10900282 ER PT J AU Hannan, KM Kennedy, BK Cavanaugh, AH Hannan, RD Hirschler-Laszkiewicz, I Jefferson, LS Rothblum, LI AF Hannan, KM Kennedy, BK Cavanaugh, AH Hannan, RD Hirschler-Laszkiewicz, I Jefferson, LS Rothblum, LI TI RNA polymerase I transcription in confluent cells: Rb downregulates rDNA transcription during confluence-induced cell cycle arrest SO ONCOGENE LA English DT Article DE retinoblastoma protein; ribosomal RNA; transcription; confluence; cell cycle ID RIBOSOMAL DNA-TRANSCRIPTION; RETINOBLASTOMA GENE-PRODUCT; UPSTREAM BINDING-FACTOR; FACTOR-TIF-IA; FACTOR UBF; INITIATION-FACTOR; CARDIOMYOCYTE HYPERTROPHY; NEONATAL CARDIOMYOCYTES; C-FOS; PROMOTER AB When 3T6 cells are confluent, they withdraw from the cell cycle. Concomitant with cell cycle arrest significant reduction in RNA polymerase I transcription (80% decrease at 100% confluence) is observed. In the present study, we examined mechanism(s) through which transcription of the ribosomal genes is coupled to cell cycle arrest induced by cell density. Interestingly with an increase in cell density (from 3-43% confluence), a significant accumulation in the cellular content of hyperphosphorylated Rb was observed. As cell density increased further, the hypophosphorylated form of Rb became predominant and accumulated in the nucleoli, Co-immunoprecipitation experiments demonstrated there was also a significant rise in the amount of hypophosphorylated Rb associated with the rDNA transcription factor UBF, This increased interaction between Rb and UBF correlated with the reduced rate of rDNA transcription. Furthermore, overexpression of recombinant Rb inhibited UBF-dependent activation of transcription from a cotransfected rDNA reporter in either confluent or exponential cells. The amounts or activities of the rDNA transcription components we examined did not significantly change with cell cycle arrest. Although the content of PAF53, a polymerase associated factor was altered marginally (decreased 38%), the time course and magnitude of the decrease did not correlate with the reduced rate of rDNA transcription. The results presented support a model wherein regulation of the binding of UBF to Rb and, perhaps the cellular content of PAF53, are components of the mechanism through which cell cycle and rDNA transcription are linked. C1 Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. Massachusetts Gen Hosp, Ctr Canc, Dept Mol Oncol, Charlestown, MA 02129 USA. RP Rothblum, LI (reprint author), Penn State Univ, Coll Med, Sigfried & Janet Weis Ctr Res, Henry Hood Res Program, Danville, PA 17822 USA. OI Hannan, Ross/0000-0002-2166-4493 FU NIDDK NIH HHS [DK13499, DK15658]; NIGMS NIH HHS [GM48991] NR 52 TC 58 Z9 58 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUL 20 PY 2000 VL 19 IS 31 BP 3487 EP 3497 DI 10.1038/sj.onc.1203690 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 337FJ UT WOS:000088346500005 PM 10918607 ER PT J AU Wang, WL Healy, ME Sattler, M Verma, S Lin, J Maulik, G Stiles, CD Griffin, JD Johnson, BE Salgia, R AF Wang, WL Healy, ME Sattler, M Verma, S Lin, J Maulik, G Stiles, CD Griffin, JD Johnson, BE Salgia, R TI Growth inhibition and modulation of kinase pathways of small cell lung cancer cell lines by the novel tyrosine kinase inhibitor STI 571 SO ONCOGENE LA English DT Article DE small cell lung cancer; c-Kit and stem cell factor; STI 571; signal transduction in lung cancer; cell motility ID C-KIT; BCR-ABL; EXPRESSION; COEXPRESSION; PAXILLIN AB Small cell lung cancer (SCLC) is an aggressive cancer characterized by several autocrine growth mechanisms including stem cell factor and its receptor c-Kit, In order to arrive at potentially new and novel therapy for SCLC, we have investigated the effects of the tyrosine kinase inhibitor, STI 571, on SCLC cell lines. It has been previously reported that STI 571 does not only inhibit cellular Abl tyrosine kinase activity but also the PDGF receptor and c-Kit tyrosine kinases at similar concentrations (approximately 0.1 mu M). There is no expression of the PDGF-receptor, and the Abl kinase is not activated by SCLC, but over 70% of SCLC contain the c-Kit receptor. Utilizing this preliminary data, we have determined that three (NCI-H69, NCI-H146 and NCI-H209) of five (including NCI-H82 and NCI-H249) SCLC cell lines had detectable c-Kit receptors and were inhibited in growth and viability at concentrations 1-5 mu M of STI 571 after 48 h of treatment. The SCLC cell lines, NCI-H69, NCI-H146 and NCI-H209, showed a dose-response (tested between 0.1-10 mu M) inhibition of tyrosine phosphorylation of c-git as well as in vitro kinase activity (at 5 mu M) of c-Kit in response to STI 571, STI 571 inhibited cell motility, as assessed by time-lapsed video microscopy, within 6 h of STI 571 treatment (5 mu M). STI 571 also decreased intracellular levels of reactive oxygen species (ROS) by at least 60%, at a concentration (5 mu M) that also inhibited cell growth. Cell cycle analysis of STI 571 responsive cells showed that cells were generally slowed in G2/M phase, but there was no arrest at G1/S, A downstream phosphorylation target of c-Kit, Akt, was not phosphorylated in response to stem cell factor in the presence of STI 571, These data imply that STI 571 inhibits growth of SCLC cells through a mechanism that involves inactivation of the tyrosine kinase c-Kit, The effectiveness of STI 571 in this study suggests this drug may be useful in a clinical trial, for patients with SCLC. C1 Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Salgia, R (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Dana 530C,44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA75348-03] NR 23 TC 204 Z9 215 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUL 20 PY 2000 VL 19 IS 31 BP 3521 EP 3528 DI 10.1038/sj.onc.1203698 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 337FJ UT WOS:000088346500008 PM 10918610 ER PT J AU Sesmilo, G Biller, BMK Llevadot, J Hayden, D Hanson, G Rifai, N Klibanski, A AF Sesmilo, G Biller, BMK Llevadot, J Hayden, D Hanson, G Rifai, N Klibanski, A TI Effects of growth hormone administration on inflammatory and other cardiovascular risk markers in men with growth hormone deficiency - A randomized, controlled clinical trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID C-REACTIVE PROTEIN; CORONARY HEART-DISEASE; AVERAGE CHOLESTEROL LEVELS; PLACEBO-CONTROLLED TRIAL; INTIMA-MEDIA THICKNESS; RECOMBINANT HUMAN GH; NESTED CASE-CONTROL; MYOCARDIAL-INFARCTION; BODY-COMPOSITION; HYPOPITUITARY ADULTS AB Background: Growth hormone-deficient adults have increased cardiovascular mortality. Growth hormone replacement may affect cardiovascular risk. Inflammation plays an important role in atherosclerosis, and inflammatory markers are predictive of cardiovascular events. Objective: To investigate the effect of growth hormone replacement on inflammatory and other cardiovascular risk factors. Design: Randomized, single-blind, placebo-controlled trial. Patients: 40 men with adult-onset growth hormone deficiency. Intervention: Growth hormone or placebo given for 18 months at a dose adjusted for normal serum insulin-like growth factor I level. Measurements: Anthropometric, hemoglobin A(1c), and central fat values were assessed every 6 months. Levels of glucose, insulin, insulin-like growth factor I, and lipids were measured at 1, 3, 6, 12, and 18 months. C-reactive protein, serum amyloid polypeptide A, interleukin-6, and lipoprotein(a) levels were determined at baseline and 6 and 18 months. Results: C-reactive protein and interleukin-6 levels decreased in growth hormone recipients compared with placebo recipients (differences between groups, -1.9+/-0.6 mg/L [P=0.0027] and -1.3+/-0.5 ng/L [P=0.013], respectively). Changes in serum amyloid polypeptide A levels between groups did not reach statistical significance (difference between groups, -2.4+/-1.2 mg/L; P = 0.056). Serum cholesterol levels, low-density lipoprotein cholesterol levels, and ratios of total cholesterol to high-density lipoprotein cholesterol decreased in growth hormone recipients in the first 3 months compared with placebo recipients (differences between groups, -0.86 +/- 0.17 mmol/L [-33.2 +/- 6.6 mg/dL] [P < 0.001], -0.63 +/- 0.20 mmol/L [-24.5 +/- 5.9 mg/dL] [P < 0.001], and -0.56 +/- 0.26 [P = 0.040], respectively), but the decrease was not maintained from month 6 to month 18. Lipoprotein(a) levels increased (difference between groups, 22.0 +/- 8.0 mg/L; P = 0.0096). Short-term increases occurred in glucose levels, insulin levels, and insulin-to-glucose ratios (differences between groups, 0.54 +/- 0.16 mmol/L [9.6 +/- 2.8 mg/dL] [P = 0.0018], 37.9 +/- 9.6 pmol/L [P < 0.001], and 6.0 +/- 1.8 [P = 0.0025], respectively), but only the increase in glucose level was maintained over the long term (difference between groups, 0.56 +/- 0.17 mmol/L [10.0 +/- 3.1 mg/dL]; P = 0.0026). Hemoglobin A,, values did not change. Truncal fat-to-total fat ratios decreased (difference between groups, -0.018 +/- 0.007; P = 0.0087), Conclusions: Long-term growth hormone replacement in men reduces levels of inflammatory cardiovascular risk markers, decreases central fat, and increases lipoprotein(a) and glucose levels without affecting lipid levels. C1 Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Childrens Hosp, Boston, MA 02115 USA. RP Klibanski, A (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, 55 Fruit St,Bulfinch 457B, Boston, MA 02114 USA. FU NCRR NIH HHS [RR 1066]; NIDDK NIH HHS [DK08783] NR 67 TC 178 Z9 185 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 JUL 18 PY 2000 VL 133 IS 2 BP 111 EP 122 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 335RL UT WOS:000088258500004 PM 10896637 ER PT J AU Ikushima, H Munakata, Y Ishii, T Iwata, S Terashima, M Tanaka, H Schlossman, SF Morimoto, C AF Ikushima, H Munakata, Y Ishii, T Iwata, S Terashima, M Tanaka, H Schlossman, SF Morimoto, C TI Internalization of CD26 by mannose 6-phosphate/insulin-like growth factor II receptor contributes to T cell activation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DIPEPTIDYL PEPTIDASE-IV; ADENOSINE-DEAMINASE BINDING; LEUKEMIA INHIBITORY FACTOR; IMMUNE-RESPONSE; INTRACELLULAR TRAFFICKING; SURFACE EXPRESSION; PERIPHERAL-BLOOD; ANTIGEN RECEPTOR; LYMPHOCYTES-T; RETINOIC ACID AB CD26 is a T cell activation antigen known to bind adenosine deaminase and have dipeptidyl peptidase IV activity. Cross-linking of CD26 and CD3 with immobilized mAbs can deliver a costimulatory signal that contributes to T cell activation. Our earlier studies revealed that cross-linking of CD26 induces its internalization. the phosphorylation of a number of proteins involved in the signaling pathway. and subsequent T cell proliferation. Although these findings suggest the importance of internalization in the function of CD26, CD26 has only 6 aa residues in its cytoplasmic region with no known motif for endocytosis. In the present study, we have identified the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGFIIR) as a binding protein for CD26 and that mannose 6-phosphate (M6P) residues in the carbohydrate moiety of CD26 are critical for this binding. Activation of peripheral blood T cells results in the mannose 6 phosphorylation of CD26. In addition, the cross-linking of CD26 with an anti-CD26 antibody induces not only capping and internalization of CD26 but also colocalization of CD26 with M6P/IGFIIR. Finally, both internalization of CD26 and the T cell proliferative response induced by CD26-mediated costimulation were inhibited by the addition of M6P, but not by glucose 6-phosphate or mannose l-phosphate. These results indicate that internalization of CD26 after crosslinking is mediated in part by MGP/IGFIIR and that the interaction between mannose 6-phosphorylated CD26 and M6P/IGFIIR may play an important role in CD26-mediated T cell costimulatory signaling. C1 Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Tokyo, Inst Med Sci, Dept Clin Immunol, Minato Ku, Tokyo 1088639, Japan. Univ Tokyo, Inst Med Sci, Ctr AIDS Res, Minato Ku, Tokyo 1088639, Japan. RP Morimoto, C (reprint author), Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. RI Iwata, Satoshi/A-8819-2011 FU NIAID NIH HHS [AI12069]; NIAMS NIH HHS [AR33713] NR 40 TC 66 Z9 69 U1 1 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 JUL 18 PY 2000 VL 97 IS 15 BP 8439 EP 8444 DI 10.1073/pnas.97.15.8439 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 335YF UT WOS:000088273900047 PM 10900005 ER PT J AU Kogai, T Schultz, JJ Johnson, LS Huang, M Brent, GA AF Kogai, T Schultz, JJ Johnson, LS Huang, M Brent, GA TI Retinoic acid induces sodium/iodide symporter gene expression and radioiodide uptake in the MCF-7 breast cancer cell line SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID THYROID NA+/I SYMPORTER; IODIDE TRANSPORT; TRANSCRIPTION FACTOR; GROWTH-INHIBITION; MAMMARY-GLAND; MESSENGER-RNA; FRTL-5 CELLS; THYROTROPIN; APOPTOSIS; PROTEIN AB The sodium/iodide symporter (NIS) stimulates iodide uptake in normal lactating breast, but is not known to be active in nonlactating breast or breast cancer. We studied NIS gene regulation and iodide uptake in MCF-7 cells, an estrogen receptor (ER)-positive human breast cancer cell line. All-trans retinoic acid (tRA) treatment stimulated iodide uptake in a time- and dose-dependent fashion up to approximate to 9.4-fold above baseline. Stimulation with selective retinoid compounds indicated that the induction of iodide uptake was mediated by retinoic acid receptor. Treatment with tRA markedly stimulated NIS mRNA and immunoreactive protein ( approximate to 68 kDa). tRA stimulated NIS gene transcription approximate to 4-fold, as shown by nuclear run-on assay. No induction of iodide uptake was observed with RA treatment of an ER-negative human breast cancer cell line, MDA-MB 231, or a normal human breast cell line, MCF-12A. The iodide efflux rate of tRA-treated MCF-7 cells was slow (t(1/2) = 24 min), compared with that in FRTL-5 thyroid cells (t(1/2) = 3.9 min), favoring iodide retention in MCF-7 cells. An in vitro clonogenic assay demonstrated selective cytotoxicity with I-131 after tRA stimulation of MCF-7 cells. tRA up-regulates NIS gene expression and iodide uptake in an ER-positive breast cancer cell line. Stimulation of radioiodide uptake after systemic retinoid treatment may be useful for diagnosis and treatment of some differentiated breast cancers. C1 W Los Angeles Vet Affairs Med Ctr, Mol Endocrinol Lab, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Dept Physiol, Los Angeles, CA 90073 USA. RP Brent, GA (reprint author), W Los Angeles Vet Affairs Med Ctr, Mol Endocrinol Lab, 11301 Wilshire Blvd,Bldg 114,Room 230, Los Angeles, CA 90073 USA. NR 54 TC 101 Z9 104 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 JUL 18 PY 2000 VL 97 IS 15 BP 8519 EP 8524 DI 10.1073/pnas.140217197 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 335YF UT WOS:000088273900061 PM 10890895 ER PT J AU Biswas, DK Cruz, AP Gansberger, E Pardee, AB AF Biswas, DK Cruz, AP Gansberger, E Pardee, AB TI Epidermal growth factor-induced nuclear factor kappa B activation: A major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PROTEIN-KINASE-C; MAMMARY EPITHELIAL-CELLS; GENE-EXPRESSION; SELECTIVE INHIBITOR; PROLIFERATION; PROMOTER; TARGET; D1; SUPERACTIVATION; DIFFERENTIATION AB The epidermal growth factor (EGF) family of receptors (EGFR) is overproduced in estrogen receptor (ER) negative (-) breast cancer cells. An inverse correlation of the level of EGFR and ER is observed between ER- and ER positive (+) breast cancer cells. A comparative study with EGFR-overproducing ER- and low-level producing ER+ breast cancer cells suggests that EGF is a major growth-stimulating factor for ER- cells. An outline of the pathway for the EGF-induced enhanced proliferation of ER- human breast cancer cells is proposed. The transmission of mitogenic signal induced by EGF-EGFR interaction is mediated via activation of nuclear factor kappa B (NF-kappa B). The basal level of active NF-kappa B in ER- cells is elevated by EGF and inhibited by anti-EGFR antibody (EGFR-Ab), thus qualifying EGF as a NF-kappa B activation factor. NF-kappa B transactivates the cell-cycle regulatory protein, cyclin D1. which causes increased phosphorylation of retinoblastoma protein, more strongly in ER- cells. An inhibitor of phosphatidylinositol 3 kinase, Ly294-002, blocked this event. suggesting a role of the former in the activation of NF-kappa B by EGF. Go6976. a well-characterized NF-kappa B inhibitor, blocked EGF-induced NF-kappa B activation and up-regulation of cell-cycle regulatory proteins. This low molecular weight compound also caused apoptotic death, predominantly more in ER- cells. Thus Go6976 and similar NF-kappa B inhibitors are potentially novel low molecular weight therapeutic agents for treatment of ER- breast cancer patients. C1 Dana Farber Canc Inst, Div Canc Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Biswas, DK (reprint author), Dana Farber Canc Inst, Div Canc Biol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA61253-07] NR 57 TC 239 Z9 250 U1 1 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 JUL 18 PY 2000 VL 97 IS 15 BP 8542 EP 8547 DI 10.1073/pnas.97.15.8542 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 335YF UT WOS:000088273900065 PM 10900013 ER PT J AU Leissring, MA Yamasaki, TR Wasco, W Buxbaum, JD Parker, I LaFerla, FM AF Leissring, MA Yamasaki, TR Wasco, W Buxbaum, JD Parker, I LaFerla, FM TI Calsenilin reverses presenilin-mediated enhancement of calcium signaling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID AMYLOID-BETA-PEPTIDE; ALZHEIMERS-DISEASE; ENDOPLASMIC-RETICULUM; FIBROBLASTS; APOPTOSIS; CELLS; CHANNELS; NEURONS; SORCIN AB Most cases of autosomal-dominant familial Alzheimer's disease are linked to mutations in the presenilin genes (PS1 and PS2). In addition to modulating beta-amyloid production, presenilin mutations also produce highly specific and selective alterations in intracellular calcium signaling. Although the molecular mechanisms underlying these changes are not known, one candidate molecular mediator is calsenilin, a recently identified calcium-binding protein that associates with the C terminus of both PS1 and PS2. In this study, we investigated the effects of calsenilin on calcium signaling in Xenopus oocytes expressing either wild-type or mutant PS1. In this system, mutant PS1 potentiated the amplitude of calcium signals evoked by inositol 1,4,5-trisphosphate and also accelerated their rates of decay. We report that calsenilin coexpression reverses both of these potentially pathogenic effects. Notably, expression of calsenilin alone had no discernable effects on calcium signaling, suggesting that calsenilin modulates these signals by a mechanism independent of simple calcium buffering. Our findings further suggest that the effects of presenilin mutations on calcium signaling are likely mediated through the C-terminal domain, a region that has also been implicated in the modulation of beta-amyloid production and cell death. C1 Univ Calif Irvine, Lab Mol Neuropathogenesis, Irvine, CA 92697 USA. Univ Calif Irvine, Mol & Cellular Neurobiol Lab, Dept Neurobiol & Behav, Irvine, CA 92697 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Genet & Aging Unit, Charlestown, MA 02129 USA. CUNY Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. RP LaFerla, FM (reprint author), Univ Calif Irvine, Lab Mol Neuropathogenesis, 1109 Gillespie Neurosci Res Facil, Irvine, CA 92697 USA. OI Buxbaum, Joseph/0000-0001-8898-8313 FU NIA NIH HHS [T32 AG000096, AG16361, AG16573, P50 AG005138, P50 AG016573, R01 AG015801, R01 AG016361]; NIGMS NIH HHS [GM4807] NR 30 TC 66 Z9 68 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 JUL 18 PY 2000 VL 97 IS 15 BP 8590 EP 8593 DI 10.1073/pnas.97.15.8590 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 335YF UT WOS:000088273900073 PM 10900016 ER PT J AU Beversdorf, DQ Smith, BW Crucian, GP Anderson, JM Keillor, JM Barrett, AM Hughes, JD Felopulos, GJ Bauman, ML Nadeau, SE Heilman, KM AF Beversdorf, DQ Smith, BW Crucian, GP Anderson, JM Keillor, JM Barrett, AM Hughes, JD Felopulos, GJ Bauman, ML Nadeau, SE Heilman, KM TI Increased discrimination of "false memories" in autism spectrum disorder SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID OLDER ADULTS; ILLUSORY MEMORIES; RECOGNITION; YOUNGER AB Individuals with autism spectrum disorder (ASD) have impaired ability to use context, which may manifest as alterations of relatedness within the semantic: network. However, impairment in context use may be more difficult to detect in high-functioning adults with ASD. To test context use in this population, we examined the influence of context on memory by using the "false memory" test. In the false memory task, lists of words were presented to high-functioning subjects with ASD and matched controls. Each list consists of words highly related to an index word not on the list. Subjects are then given a recognition test. Positive responses to the index words represent false memories. We found that individuals with ASD are able to discriminate false memory items from true items significantly better than are control subjects. Memory in patients with ASD may be more accurate than in normal individuals under certain conditions. These results also suggest that semantic representations comprise a less distributed network in high-functioning adults with ASD. Furthermore, these results may be related to the unusually high memory capacities found in some individuals with ASD. Research directed at defining the range of tasks performed superiorly by high-functioning individuals with ASD will be important for optimal vocational rehabilitation. C1 Ohio State Univ, Med Ctr, Dept Neurol, Columbus, OH 43210 USA. Baystate Med Ctr, Springfield, MA 01199 USA. Univ Florida, Coll Med, Dept Neurol, Gainesville, FL 32610 USA. Def & Civil Inst Environm Med, Toronto, ON M3M 3B9, Canada. Penn State Univ, Coll Med, Dept Med, Div Neurol, Hershey, PA 17033 USA. Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD 20814 USA. Massachusetts Gen Hosp, Dept Child Psychiat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pediat Neurol, Boston, MA 02114 USA. Ctr Geriatr Res Educ & Clin, Gainesville, FL 32610 USA. Dept Vet Adm Med Ctr, Neurol Serv, Gainesville, FL 32610 USA. Brain Rehabil Ctr, Gainesville, FL 32610 USA. RP Beversdorf, DQ (reprint author), Ohio State Univ, Med Ctr, Dept Neurol, 1654 Upham Dr, Columbus, OH 43210 USA. EM beversdorf-1@medctr.osu.edu RI Beversdorf, David/M-2786-2016; OI Beversdorf, David/0000-0002-0298-0634; Barrett, A.M./0000-0002-0789-2887 FU NINDS NIH HHS [K08 NS002085] NR 30 TC 57 Z9 59 U1 4 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 18 PY 2000 VL 97 IS 15 BP 8734 EP 8737 DI 10.1073/pnas.97.15.8734 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 335YF UT WOS:000088273900098 PM 10900024 ER PT J AU Liberman, MC O'Grady, DF Dodds, LW McGee, J Walsh, EJ AF Liberman, MC O'Grady, DF Dodds, LW McGee, J Walsh, EJ TI Afferent innervation of outer and inner hair cells is normal in neonatally de-efferented cats SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE olivocochlear; cochlea; development ID GAMMA-AMINOBUTYRIC-ACID; DEVELOPING RAT COCHLEA; POSTNATAL MATURATION; IMMUNOCYTOCHEMICAL DETECTION; GLUTAMATE-DECARBOXYLASE; HORSERADISH-PEROXIDASE; FIBERS; SYNAPSES; BUNDLE; LIGHT AB It has been hypothesized that normal pruning of exuberant branching of afferent neurons in the developing cochlea is caused by the arrival of the olivocochlear efferent neurons and the resulting competition for synaptic sites on hair cells. This hypothesis was supported by a report that afferent innervation density on mature outer hair cells (OHCs) is elevated in animals deefferented at birth, before the olivocochlear system reaches the outer hair cell area (Pujol and Carlier [1982] Dev. Brain Res. 3:151-154). In the current study, this claim was evaluated quantitatively at the electron microscopic level in four cats that were de-efferented at birth and allowed to survive for 6-11 months. A semiserial section analysis of 156 OHCs from de-efferented and normal ears showed that, although de-efferentation essentially was complete in all four cases, the number and distribution of afferent terminals on OHCs was indistinguishable from normal, and the morphology of afferent synapses was normal in both the inner hair cell area and the OHC area. Thus, the postnatal presence of an efferent system is not; required for the normal development of cochlear afferent innervation, and the synaptic competition hypothesis is not supported. (C) 2000 Wiley-Liss, Inc. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. Boys Town Natl Res Hosp, Omaha, NE 68131 USA. Creighton Univ, Sch Med, Dept Biomed Sci, Omaha, NE 68131 USA. Creighton Univ, Sch Med, Dept Otolaryngol, Omaha, NE 68131 USA. RP Liberman, MC (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. FU NIDCD NIH HHS [DC00034, DC00215, DC0188, P30 DC005209] NR 55 TC 10 Z9 10 U1 1 U2 6 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 JUL 17 PY 2000 VL 423 IS 1 BP 132 EP 139 PG 8 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 325JW UT WOS:000087673300011 PM 10861542 ER PT J AU Fratazzi, C N, M Arbeit, RD Carini, C Gerken, TA Ardman, B Remold-O'Donnell, E Remold, HG AF Fratazzi, C N, M Arbeit, RD Carini, C Gerken, TA Ardman, B Remold-O'Donnell, E Remold, HG TI A macrophage invasion mechanism for mycobacteria implicating the extracellular domain of CD43 SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE mycobacteria; CD43; macrophages; tumor necrosis factor alpha; interleukin 10 ID TUMOR-NECROSIS-FACTOR; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; MEDIATES ENHANCED PHAGOCYTOSIS; AVIUM COMPLEX; HUMAN-MONOCYTES; T-LYMPHOCYTES; FACTOR-ALPHA; HUMAN-PLASMA; TUBERCULOSIS; RECEPTOR AB We studied the role of CD43 (leukosialin/sialophorin), the negatively charged sialoglycoprotein of leukocytes, in the binding of mycobacteria to host cells. CD CD43-transfected HeLa cells bound Mycobacterium avium, but not Salmonella typhimurium or Shigella flexneri. Quantitative bacteriology showed that macrophages (M phi) from wild-type mice (CD43(+/+)) bound M. avium, Mycobacterium bovis (bacillus Calmette-Guerin), and Mycobacterium tuberculosis (strain H37Rv), whereas M phi from CD43 knockout mice (CD43(-/-)) did not. Fluorescence microscopy demonstrated chat the associated M. avium had been ingested by the CD43(+/+) M phi. The inability of CD43(-/-) M phi to bind M. avium could be restored by addition of galactoglycoprotein (Galgp), the extracellular mucin portion of CD43. The effect of Galgp is not due to opsonization of the bacteria, but required its interaction with the M phi; other mucins had no effect. CD43 expression by the M phi was also required for optimal induction by M. avium of tumor necrosis factor (TNF)-alpha production, which likewise could be reconstituted by Galgp. In contrast, interleukin (IL)-10 production by M. avium-infected M phi was CD43 independent, demonstrating discordant regulation of TNF-alpha and IL-10. These findings describe a novel role of CD43 in promoting stable interaction of mycobacteria with receptors on the M phi enabling the cells to respond specifically with TNF-alpha production. C1 Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Vet Adm Med Ctr, Dept Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Harvard Univ, Sch Publ Hlth, Dept Trop Publ Hlth, Boston, MA 02115 USA. Case Western Reserve Univ, WA Bernbaum Ctr Cyst Fibrosis Res, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Biochem, Cleveland, OH 44106 USA. Tufts Univ, Dept Pathol, Boston, MA 02111 USA. Tufts Univ, New England Med Ctr Hosp, Tupper Res Inst, Dept Med, Boston, MA 02111 USA. RP Remold-O'Donnell, E (reprint author), Brigham & Womens Hosp, Dept Med, Smith Bldg,Rm 526B,75 Francis St, Boston, MA 02115 USA. FU NIAID NIH HHS [AI29880, AI31006, AI41710, R01 AI039574] NR 48 TC 32 Z9 35 U1 0 U2 0 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 JUL 17 PY 2000 VL 192 IS 2 BP 183 EP 191 DI 10.1084/jem.192.2.183 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 335TP UT WOS:000088261100005 PM 10899905 ER PT J AU Sato, N Ahuja, SK Quinones, M Kostecki, V Reddick, RL Melby, PC Kuziel, WA Ahuja, SS AF Sato, N Ahuja, SK Quinones, M Kostecki, V Reddick, RL Melby, PC Kuziel, WA Ahuja, SS TI CC chemokine receptor (CCR)2 is required for Langerhans cell migration and localization of T helper cell type 1 (Th1)-inducing dendritic cells: Absence of CCR2 shifts the Leishmania major-resistant phenotype to a susceptible state dominated by Th2 cytokines, B cell outgrowth, and sustained neutrophilic inflammation SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE infectious immunity; chemokine; cytokine; knockout; T helper cell ID SECONDARY LYMPHOID ORGANS; IN-VIVO; FLUORESCEIN ISOTHIOCYANATE; CUTANEOUS LEISHMANIASIS; MICE LACKING; IMMUNE-RESPONSE; TREATED MICE; BALB/C MICE; INFECTION; EXPRESSION AB There is growing evidence that chemokines and their receptors regulate the movement and interaction of antigen-presenting cells such as dendritic cells (DCs) and T cells. We tested the hy pothesis that the CC chemokine receptor (CCR)2 and CCR5 and the chemokine macrophage inflammatory protein (MIP)-1 alpha, a ligand for CCR5, influence DC migration and localization. We found that deficiency of CCR2 but not CCR5 or MIP-1 alpha led to distinct defects in DC biology. Langerhans cell (skin DC) density in CCR2-null mice was normal, and their ability to migrate into the dermis was intact; however, their migration to the draining lymph nodes was markedly impaired. CCR2-null mice had lower numbers of DCs in the spleen, and this was primarily due to a reduction in the CD8 alpha(+) T helper cell type 1 (Th1)-inducing subset of DCs. Additionally, there was a block in the Leishmania major infection-induced relocalization of splenic DCs from the marginal zone to the T cell areas. We propose that these DC defects, in conjunction with increased expression of B lymphocyte chemoattractant, a B cell-specific chemokine, may collectively contribute to the striking B cell outgrowth and Th2 cytokine-biased nonhealing phenotype that we observed in CCR2-deficient mice infected with L. major. This disease phenotype in mice with an L. major-resistant genetic background but lacking CCR2 is strikingly reminiscent of that observed typically in mice with an L. major-susceptible genetic background. Thus, CCR2 is an important determinant of not only DC migration and localization but also the development of protective cell-mediated immune responses to L. major. C1 S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX 78284 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. Univ Texas, Sect Mol Genet & Microbiol, Austin, TX 78712 USA. Univ Texas, Inst Mol & Cellular Biol, Austin, TX 78712 USA. RP Ahuja, SS (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med, Mail Code 7880,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. NR 69 TC 198 Z9 202 U1 0 U2 3 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 JUL 17 PY 2000 VL 192 IS 2 BP 205 EP 218 DI 10.1084/jem.192.2.205 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 335TP UT WOS:000088261100007 PM 10899907 ER PT J AU DeBusk, R Drory, Y Goldstein, I Jackson, G Kaul, S Kimmel, SE Kostis, JB Kloner, RA Lakin, M Meston, CM Mittleman, M Muller, JE Padma-Nathan, H Rosen, RC Stein, RA Zusman, R AF DeBusk, R Drory, Y Goldstein, I Jackson, G Kaul, S Kimmel, SE Kostis, JB Kloner, RA Lakin, M Meston, CM Mittleman, M Muller, JE Padma-Nathan, H Rosen, RC Stein, RA Zusman, R TI Management of sexual dysfunction in patients with cardiovascular disease: Recommendations of the Princeton Consensus Panel SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article AB Sexual dysfunction is highly prevalent in both sexes and adversely affects patients' quality of life and well being. Given the frequent association between sexual dysfunction and cardiovascular disease, in addition to the potential cardiac risk of sexual activity itself, a consensus panel was convened to develop recommendations for clinical management of sexual dysfunction in patients with cardiovascular disease. Based upon a review of the research and presentations by invited experts, a classification system was developed for stratification of patients into high, low, and intermediate categories of cardiac risk. The large majority of patients are in the low-risk category, which includes patients with (1) controlled hypertension; (2) mild, stable angina; (3) successful coronary revascularization; (4) a history of uncomplicated myocardial infarction (MI); (5) mild valvular disease; and (6) no symptoms and <3 cardiovascular risk factors. These patients can be safely encouraged to initiate or resume sexual activity or to receive treatment for sexual dysfunction. An important exception is the use of sildenafil in patients taking nitrates in any form. Patients in the intermediate-risk category include those with (1) moderate angina; (2) a recent MI (<6 weeks); (3) left ventricular dysfunction and/or class II congestive heart failure; (4) nonsustained low-risk arrhythmias; and (5) greater than or equal to 3 risk factors for coronary artery disease. These patients should receive further cardiologic evaluation before restratification into the low- or high-risk category. Finally, patients in the high-risk category include those with (1) unstable or refractory angina; (2) uncontrolled hypertension; (3) congestive heart failure (class III or IV); (4) very recent MI (<2 weeks); (5) highrisk arrhythmias; (6) obstructive cardiomyopathies; and (7) moderate-to-severe valvular disease. These patients should be stabilized by specific treatment for their cardiac condition before resuming sexual activity or being treated for sexual dysfunction. A simple algorithm is provided for guiding physicians in the management of sexual dysfunction in patients with varying degrees of cardiac risk. (C)2000 by Excerpta Medica, Inc. C1 Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Med, New Brunswick, NJ 08903 USA. Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. Chaim Sheba Med Ctr, Cardiac Rehabil Inst, IL-52621 Tel Hashomer, Israel. Boston Univ, Med Ctr, Boston, MA USA. St Thomas Hosp, Ctr Cardiothorac, London, England. Cedars Sinai Med Ctr, Div Cardiol, Los Angeles, CA 90048 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Hosp Good Samaritan, Inst Heart, Los Angeles, CA 90017 USA. Cleveland Clin Fdn, Dept Urol, Cleveland, OH 44195 USA. Univ Texas, Dept Psychol, Austin, TX 78712 USA. Beth Israel Deaconess Med Ctr, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Male Clin, Beverly Hills, CA USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Psychiat, Piscataway, NJ 08854 USA. Brooklyn Hosp Ctr, Div Cardiol, Brooklyn, NY USA. Harvard Univ, Sch Med, Boston, MA USA. RP Kostis, JB (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Med, 1 Robert Wood Johnson Pl,POB 19, New Brunswick, NJ 08903 USA. RI Kloner, Robert/B-2971-2012 NR 17 TC 179 Z9 187 U1 0 U2 6 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 JUL 15 PY 2000 VL 86 IS 2 BP 175 EP 181 DI 10.1016/S0002-9149(00)00896-1 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 333HR UT WOS:000088125300010 PM 10913479 ER PT J AU Manoach, DS Gollub, RL Benson, ES Searl, MM Goff, DC Halpern, E Saper, CB Rauch, SL AF Manoach, DS Gollub, RL Benson, ES Searl, MM Goff, DC Halpern, E Saper, CB Rauch, SL TI Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex and basal ganglia during working memory performance SO BIOLOGICAL PSYCHIATRY LA English DT Article DE working memory; prefrontal cortex; schizophrenia; basal ganglia; functional magnetic resonance imaging; functional brain mapping ID PARIETAL CORTEX; FUNCTIONAL MRI; FRONTAL-CORTEX; BRAIN ACTIVITY; TASK; DEFICITS; CIRCUITS; DISORDER; SYMPTOMS; MONKEY AB Background: Working memory (WM) deficits in schizophrenia have been associated with dorsolateral prefrontal cortex (DLPFC) dysfunction in neuroimaging studies. We previously found increased DLPFC activation in schizophrenic versus normal subjects during WM performance (Manoach et al 1999b), We now have investigated whether schizophrenic subjects recruit different brain regions, particularly the basal ganglia and thalamus, components of frontostriatal circuitry thought to mediate WM. Methods: We examined regional brain activition in nine normal and nine schizophrenic subjects during WM performance using functional magnetic resonance imaging. Subjects performed a modified version of the Sternberg Item Recognition Paradigm that included a monetary reward for correct responses. We compared high and low WM load conditions to each other and to a non-WM baseline condition. We examined activation in both individual subjects and averaged group data. Results: Relative to normal subjects, schizophrenic subjects exhibited deficient WM performance, at least an equal magnitude of right DLPFC activation, significantly greater left DLPFC activation and increased spatial heterogeneity of DLPFC activation. Furthermore, only the schizophrenic group activated the basal ganglia and thalamus, even when matched for task performance with the normal group. Conclusions: Aberrant WM performance and brain activation in schizophrenia may reflect dysfunction of frontostriatal circuitry that subserves WM, Future studies will elucidate the contribution of the anatomical components of this circuitry to WM deficits. Biol Psychiatry 2000;48: 99-109 (C) 2000 Society of Biological Psychiatry. C1 Beth Israel Deaconess Med Ctr, Behav Neurol Unit, Boston, MA 02215 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Manoach, DS (reprint author), Beth Israel Deaconess Med Ctr, Behav Neurol Unit, 330 Brookline Ave, Boston, MA 02215 USA. OI Gollub, Randy L./0000-0002-9434-4044 NR 58 TC 342 Z9 350 U1 3 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 15 PY 2000 VL 48 IS 2 BP 99 EP 109 DI 10.1016/S0006-3223(00)00227-4 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 335TC UT WOS:000088260000002 PM 10903406 ER PT J AU Faraone, SV Seidman, LJ Kremen, WS Toomey, R Pepple, JR Tsuang, MT AF Faraone, SV Seidman, LJ Kremen, WS Toomey, R Pepple, JR Tsuang, MT TI Neuropsychologic functioning among the nonpsychotic relatives of schizophrenic patients: The effect of genetic loading SO BIOLOGICAL PSYCHIATRY LA English DT Article DE genetics; neuropsychology; endophenotypes; multiplex families ID CARD-SORTING-TEST; SEX-DIFFERENCES; PERFORMANCE; DEFICIT; IDENTIFICATION; TRANSMISSION; SIBLINGS; MEMORY C1 Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Mental Hlth Ctr, S Easton, MA 02375 USA. Brockton W Roxbury Vet Affairs Med Ctr, Brockton, MA USA. Massachusetts Gen Hosp, Psychiat Serv, Boston, MA 02114 USA. Harvard Univ, Inst Psychiat Epidmiol & Genet, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Univ Calif Davis, Dept Psychiat, Sacramento, CA 95817 USA. Univ Calif Davis, Napa Psychiat Res Ctr, Napa State Hosp, Napa, CA USA. RP Faraone, SV (reprint author), Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Mental Hlth Ctr, Suite 255,750 Washington St, S Easton, MA 02375 USA. OI Faraone, Stephen/0000-0002-9217-3982 FU NIMH NIH HHS [1 R37MH43518-01, 1 R01MH41874-01, 5 UO1 MH46318-02] NR 26 TC 148 Z9 153 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 15 PY 2000 VL 48 IS 2 BP 120 EP 126 DI 10.1016/S0006-3223(99)00263-2 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 335TC UT WOS:000088260000004 PM 10903408 ER PT J AU Altshuler, LL Bartzokis, G Grieder, T Curran, J Jimenez, T Leight, K Wilkins, J Gerner, R Mintz, J AF Altshuler, LL Bartzokis, G Grieder, T Curran, J Jimenez, T Leight, K Wilkins, J Gerner, R Mintz, J TI An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Review DE amygdala; bipolar; limbic; hippocampus; schizophrenia; temporal lobe ID FIRST-EPISODE SCHIZOPHRENIA; MONOZYGOTIC TWINS DISCORDANT; CAUDATE NUCLEI VOLUMES; CEREBRAL BLOOD-FLOW; MAGNETIC-RESONANCE; VENTRICULAR ENLARGEMENT; ALZHEIMERS-DISEASE; PREFRONTAL CORTEX; BRAIN MORPHOLOGY; BASAL GANGLIA AB Background: Hippocampal atrophy has been described in postmortem and magnetic resonance imaging studies of schizophrenia The specificity of this finding to schizophrenia remains to be determined, The neuropathology of bipolar disorder is understudied, and temporal lobe structures have only recently been evaluated. Methods: Twenty-four bipolar, 20 schizophrenic, and 18 normal comparison subjects were evaluated using magnetic resonance brain imaging, Image data were acquired using a three-dimensional spoiled GRASS sequence, and brain images were reformatted in three planes. Temporal lobe structures including the amygdala, hippocampus, parahippocampus, and total temporal lobe were measured to obtain volumes for each structure in the three subject groups, Severity of symptoms in both patient groups was assessed at the time the magnetic resonance images were obtained. Results: Hippocampal volumes were significantly smaller in rite schizophrenic group than in both bipolar and normal comparison subjects, Further, amygdala volumes were significantly larger in the bipolar group than in both schizophrenic and normal comparison subjects. Conclusions: The results suggest differences in affected limbic structures in patients with schizophrenia and bipolar disorder. These specific neuroanatomic abnormalities may shed light on the underlying pathophysiology and presentation of the two disorders. Biol Psychiatry 2000; 48:147-162 (C) 2000 Society of Biological Psychiatry. C1 Univ Calif Los Angeles, Mood Disorders Program, Dept Psychiat, Inst Neuropsychiat, Los Angeles, CA 90095 USA. W Los Angeles Vet Affairs Med Ctr, Psychiat Serv, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Med Ctr, Dept Radiol Sci, Los Angeles, CA USA. Univ Arkansas Med Sci, Dept Psychiat, Little Rock, AR 72205 USA. Little Rock VA Med Ctr, Psychiat Serv, Little Rock, AR USA. RP Altshuler, LL (reprint author), Univ Calif Los Angeles, Mood Disorders Program, Dept Psychiat, Inst Neuropsychiat, 300 UCLA Med Plaza,Suite 1544, Los Angeles, CA 90095 USA. RI Bartzokis, George/K-2409-2013 NR 121 TC 258 Z9 263 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 15 PY 2000 VL 48 IS 2 BP 147 EP 162 DI 10.1016/S0006-3223(00)00836-2 PG 16 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 335TC UT WOS:000088260000007 PM 10903411 ER PT J AU Raje, N Anderson, KC AF Raje, N Anderson, KC TI Introduction: the evolving role of bisphosphonate therapy in multiple myeloma SO BLOOD LA English DT Editorial Material ID CELL-LINES; IN-VITRO; ANTITUMOR-ACTIVITY; SKELETAL EVENTS; APOPTOSIS; PAMIDRONATE; ADHESION; PROTEIN; GROWTH; THALIDOMIDE C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Anderson, KC (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 30 TC 15 Z9 18 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 15 PY 2000 VL 96 IS 2 BP 381 EP 383 PG 3 WC Hematology SC Hematology GA 335GB UT WOS:000088234800001 PM 10887095 ER PT J AU Million, RP Van Etten, RA AF Million, RP Van Etten, RA TI The Grb2 binding site is required for the induction of chronic myeloid leukemia-like disease in mice by the Bcr/Abl tyrosine kinase SO BLOOD LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; BCR-ABL ONCOGENE; SIGNAL-TRANSDUCTION PATHWAYS; HEMATOPOIETIC-CELL LINES; MYELOPROLIFERATIVE DISEASE; PHILADELPHIA-CHROMOSOME; V-ABL; BONE-MARROW; SH2 DOMAIN; TRANSFORMATION AB The BCR/ABL oncogene results from a balanced translocation between chromosomes 9 and 22 and is found in patients with chronic myeloid leukemia (CML) and in some patients with acute B-lymphoid leukemia. The Bcr/Abl fusion protein is a constitutively active tyrosine kinase that stimulates several intracellular signaling pathways, including activation of Ras through direct binding of the SH2-containing adapter protein Grb2 to Bcr tyrosine 177, A tyrosine-to-phenylalanine mutation (Y177F) at this site blocks the co-association of Bcr/Abl and Grb2 in vivo and impairs focus formation by Bcr/Abl in fibroblasts. However, the Bcr/Abl Y177F mutant can transform hematopoietic cell lines and primary bone marrow cells in vitro, so the importance of the Bcr/Abl-Grb2 interaction to myeloid and lymphoid leukemogenesis in vivo is unclear. We have recently demonstrated the efficient induction of CML-like myeloproliferative disease by BCR/ABL in a murine bone marrow transduction/transplantation model system. The Y177F mutation greatly attenuates the myeloproliferative disease induced by BCR/ABL, with mice developing B- and T-lymphoid leukemias of longer latency. In addition, the v-abl oncogene of Abelson murine leukemia virus, whose protein product lacks interaction with Grb2, is completely defective for the induction of CML-like disease. these results suggest that direct binding of Grb2 is required for the efficient induction of CML-like myeloproliferative disease by oncogenic Abl proteins. (C) 2000 by The American Society of Hematology. C1 Harvard Univ, Sch Med, Dept Genet, Ctr Blood Res, Boston, MA 02115 USA. RP Van Etten, RA (reprint author), Harvard Univ, Sch Med, Dept Genet, Ctr Blood Res, 200 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [CA09595, CA57593] NR 43 TC 100 Z9 103 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 JUL 15 PY 2000 VL 96 IS 2 BP 664 EP 670 PG 7 WC Hematology SC Hematology GA 335GB UT WOS:000088234800038 PM 10887132 ER PT J AU Choi, SJ Cruz, JC Craig, F Chung, H Devlin, RD Roodman, GD Alsina, M AF Choi, SJ Cruz, JC Craig, F Chung, H Devlin, RD Roodman, GD Alsina, M TI Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma SO BLOOD LA English DT Article ID HUMAN-BONE-MARROW; MONOCLONAL-ANTIBODIES; CELL-FORMATION; B-CELLS; DISEASE; PLASMA; INTERLEUKIN-6; CULTURES; PROTEIN-1-ALPHA; HEMATOPOIESIS AB This study was designed to determine if macrophage inhibitory protein-1 alpha (MIP-1 alpha), a recently described osteoclast (OCL) stimulatory factor,(1) was present in marrow from patients with multiple myeloma (MM) and possibly involved in the bone destructive process. MIP-1 alpha, but not interleukin-1 beta (IL-1 beta), tumor necrosis factor-beta (TNF-beta), or interleukin-6 (IL-6), messenger RNA was elevated in freshly isolated bone marrow from 3 of 4 patients with MM compared to normal controls. Furthermore, enzyme-linked immunosorbent assays of freshly Isolated bone marrow plasma detected increased concentrations of hMIP-1 alpha (range, 75-7784 pg/mL) in 8 of 13 patients (62%) with active myeloma, in 3 of 18 patients (17%) with stable myeloma (range, 75-190.3), as well as in conditioned media from 4 of 5 lymphoblastoid cell lines (LCLs) derived from patients with MM, Mildly elevated levels of MIP-1 alpha were detected in 3 of 14 patients (21%) with other hematologic diagnoses (range, 80.2-118.3, median value of 95 pg/mL) but not in normal controls (8 of 7), MIP-1 alpha was not detected in the peripheral blood of any patients with MM, In addition, recombinant hMIP-1 alpha induced OCL formation in human bone marrow cultures. Importantly, addition of a neutralizing antibody to MIP-1 alpha to human bone marrow cultures treated with freshly isolated marrow plasma from patients with MM blocked the increased OCL formation induced by these marrow samples but had no effect on control levels of OCL formation. Thus, high levels of MIP-1 alpha are expressed in marrow samples from patients with MM, but not in marrow from patients with other hematologic disorders or controls, and support an important role for MIP-1 alpha as one of the major factors responsible for the increased OCL stimulatory activity in patients with active MM. (C) 2000 by The American Society of Hematology. C1 151 Audie L Murphy Vet Adm Hosp, Res Serv, San Antonio, TX 78284 USA. 151 Audie L Murphy Vet Adm Hosp, Gen Clin Res Ctr, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Hematol & Pathol, San Antonio, TX 78284 USA. St Francis Hosp & Med Ctr, Hartford, CT USA. Cheil Gen Hosp, Seoul, South Korea. RP Alsina, M (reprint author), 151 Audie L Murphy Vet Adm Hosp, Res Serv, 7400 Merton Minter Blvd, San Antonio, TX 78284 USA. FU NCI NIH HHS [CA40035, CA69136] NR 28 TC 268 Z9 274 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 15 PY 2000 VL 96 IS 2 BP 671 EP 675 PG 5 WC Hematology SC Hematology GA 335GB UT WOS:000088234800039 PM 10887133 ER PT J AU Xiao, S McCarthy, JG Aster, JC Fletcher, JA AF Xiao, S McCarthy, JG Aster, JC Fletcher, JA TI ZNF198-FGFR1 transforming activity depends on a novel proline-rich ZNF198 oligomerization domain SO BLOOD LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; CHRONIC MYELOMONOCYTIC LEUKEMIA; ATYPICAL MYELOPROLIFERATIVE DISORDER; PROTEIN INTERACTION SITES; ETV6-NTRK3 GENE FUSION; NON-HODGKINS-LYMPHOMA; T-CELL LYMPHOMA; C-KIT; CHROMOSOMAL TRANSLOCATION; CLINICOPATHOLOGICAL ENTITY AB An acquired chromosomal translocation, t(8;13)(p11;q11-12), observed in a distinctive type of stem cell leukemia/lymphoma syndrome, leads to the fusion of the 5' portion of ZNF198 and the 3' portion of FGFR1. ZNF198-FGFR1 fusion transcripts encode 4 to 10 zinc fingers, a proline-rich region, and the intracellular portion of the FGFR1 (fibroblast growth factor receptor 1) receptor tyrosine kinase, We demonstrate that the ZNF198 proline-rich region constitutes a novel self-association domain. When fused to the intracellular domain of FGFR1, the ZNF198 proline-rich region is sufficient to cause oligomerization, FGFR1 tyrosine kinase activation, and transformation of Ba/F3 cells to IL-3 independent growth. C1 Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. RP Xiao, S (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. FU NCI NIH HHS [R01 CA72791] NR 61 TC 54 Z9 56 U1 1 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 JUL 15 PY 2000 VL 96 IS 2 BP 699 EP 704 PG 6 WC Hematology SC Hematology GA 335GB UT WOS:000088234800043 PM 10887137 ER PT J AU Greenberg, DB Jonasch, E Gadd, MA Ryan, BF Everett, JR Sober, AJ Mihm, MA Tanabe, KK Ott, M Haluska, FG AF Greenberg, DB Jonasch, E Gadd, MA Ryan, BF Everett, JR Sober, AJ Mihm, MA Tanabe, KK Ott, M Haluska, FG TI Adjuvant therapy of melanoma with interferon-alpha-2b is associated with mania and bipolar syndromes - Gabapentin may serve as a mood stabilizer SO CANCER LA English DT Article DE medical oncology; melanoma; interferon; side effects; mania; mood instability; depression; gabapentin ID RESECTED CUTANEOUS MELANOMA; RANDOMIZED CONTROLLED TRIAL; COOPERATIVE-ONCOLOGY-GROUP; ALPHA; DISORDERS; BRAIN; ALFA AB BACKGROUND. The use of a high dose regimen of interferon-alpha-2b, (IFN) has recently been demonstrated to benefit patients with resected high risk melanoma. The incidence of melanoma is rising rapidly, and the use of this regimen is becoming increasingly common. IFN has been associated with numerous psychiatric side effects. METHODS, The authors describe four melanoma patients treated with adjuvant IFN who developed a manic-depressive syndrome or mood instability with therapy, and they review the literature on mania and the mixed affective syndromes associated with IFN. RESULTS. The authors suggest that IFN may induce a mixed affective instability, and that patients risk developing hypomania or mania as IFN doses fluctuate or as IFN-induced depression is treated with antidepressants alone. Mania is particularly associated with dose reductions or pauses in IFN treatment. The risk of mood fluctuation continues after treatment with IFN stops, and patients should be monitored for 6 months following completion of therapy. Gabapentin appeared effective as monotherapy for acute mania, as an antianxiety agent, as a hypnotic, and as a mood stabilizer in these individual cases. CONCLUSIONS. Mania and mood instability can occur in patients being treated with IFN therapy for melanoma. In this study, gabapentin was an effective moodstabilizing agent for these patients. (C) 2000 American Cancer Society. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Haluska, FG (reprint author), Massachusetts Gen Hosp, GRJ 1021,55Fruit St, Boston, MA 02114 USA. NR 23 TC 49 Z9 52 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 0008-543X J9 CANCER JI Cancer PD JUL 15 PY 2000 VL 89 IS 2 BP 356 EP 362 DI 10.1002/1097-0142(20000715)89:2<356::AID-CNCR21>3.0.CO;2-Z PG 7 WC Oncology SC Oncology GA 336RA UT WOS:000088315700020 PM 10918166 ER PT J AU Domchek, SM Younger, J Finkelstein, DM Seiden, MV AF Domchek, SM Younger, J Finkelstein, DM Seiden, MV TI Predictors of skeletal complications in patients with metastatic breast carcinoma SO CANCER LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 15-18, 1999 CL ATLANTA, GEORGIA SP Amer Soc Clin Oncol DE metastatic breast carcinoma; skeletal complications; predictors; bisphosphonates ID BONE METASTASES; COMBINATION CHEMOTHERAPY; PAMIDRONATE TREATMENT; MULTIPLE-MYELOMA; CONTROLLED TRIAL; CLINICAL COURSE; CANCER PATIENTS; CLODRONATE; BISPHOSPHONATES; MORBIDITY AB BACKGROUND. The high rate of incidence of skeletal complications in women with metastatic breast carcinoma appears to contribute significantly to their morbidity. Although recent trials have demonstrated the efficacy of bisphosphonates in preventing skeletal complications in selected patients, to the authors' knowledge the incidence rate of skeletal complications in an unselected population of women with metastatic breast carcinoma is unknown. The current study was designed to examine the incidence rate of skeletal complications in a large unselected group of women with metastatic breast carcinoma to determine predictors of these complications. METHODS. All women (n = 718) diagnosed with metastatic breast carcinoma between 1981-1991 at the study institution were studied retrospectively. RESULTS. Greater than 50% of the women developed skeletal complications; among these women, 51% had > 1 complication. Approximately 80% of those with bone-limited disease at the time of diagnosis developed complications, as did 60% of those with bone and visceral disease and 21% of those with no bone disease. By univariate analysis, the site of initial metastatic disease, abnormal alkaline phosphatase, and a disease free interval of < 3 years were predictive of skeletal complications. Multivariate analysis revealed that bone involvement at the time of diagnosis was predictive of subsequent skeletal complications. CONCLUSIONS. In this large retrospective study with extensive follow-up, skeletal complications were extremely common and repetitive, although complications predated patient death by greater than or equal to 1 year in the group of women presenting with any bone disease. The presence of bone disease at the time of initial presentation was predictive of skeletal complications. In this group of patients, the authors were unable to identify a subgroup with a low rate of skeletal complications. (C) 2000 American Cancer Society. C1 Massachusetts Gen Hosp, Dept Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Biostat, Boston, MA 02114 USA. RP Domchek, SM (reprint author), Dana Farber Canc Inst, Dept Oncol, Dana 1212,44 Binney St, Boston, MA 02115 USA. OI Finkelstein, Dianne/0000-0001-9564-8181 NR 22 TC 59 Z9 60 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 0008-543X J9 CANCER JI Cancer PD JUL 15 PY 2000 VL 89 IS 2 BP 363 EP 368 DI 10.1002/1097-0142(20000715)89:2<363::AID-CNCR22>3.0.CO;2-3 PG 6 WC Oncology SC Oncology GA 336RA UT WOS:000088315700021 PM 10918167 ER PT J AU Baish, JW Jain, RK AF Baish, JW Jain, RK TI Fractals and cancer SO CANCER RESEARCH LA English DT Article ID TUMOR VASCULAR ARCHITECTURE; RETINAL-VESSELS; DIABETIC-RETINOPATHY; DIGITAL MAMMOGRAMS; GROWTH-FACTOR; BONE-MARROW; ANGIOGENESIS; DIMENSION; GEOMETRY; TISSUE AB Recent studies have shown that fractal geometry, a vocabulary of irregular shapes, can be useful Fur describing the pathological architecture of tumors and, perhaps more surprisingly, for yielding insights into the mechanisms of tumor growth and angiogenesis that complement those obtained by modern molecular methods. This article outlines the basic methods of Fractal geometry and discusses the value and limitations of applying this nets tool to cancer research. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol,Edwin L Steele Lab, Boston, MA 02114 USA. Bucknell Univ, Dept Mech Engn, Lewisburg, PA 17837 USA. RP Jain, RK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol,Edwin L Steele Lab, Boston, MA 02114 USA. FU NCI NIH HHS [R15-CA/OD74366, R35-CA-56591] NR 71 TC 332 Z9 349 U1 1 U2 25 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 JUL 15 PY 2000 VL 60 IS 14 BP 3683 EP 3688 PG 6 WC Oncology SC Oncology GA 337ML UT WOS:000088365300001 PM 10919633 ER PT J AU Chakrabarti, S Price, BD Tetradis, S Fox, EA Zhang, YZ Maulik, G Makrigiorgos, GM AF Chakrabarti, S Price, BD Tetradis, S Fox, EA Zhang, YZ Maulik, G Makrigiorgos, GM TI Highly selective isolation of unknown mutations in diverse DNA fragments: Toward new multiplex screening in cancer SO CANCER RESEARCH LA English DT Article ID MULTISTEP NATURE; POINT MUTATIONS; ABASIC SITES; ASSAY; DEPURINATION; GLYCOSYLASE; ENZYME; ACID; P53 AB Cancer research would greatly benefit from technologies that allow simultaneous screening of several unknown gene mutations. Lack of such methods currently hampers the large-scale detection of genetic alterations in complex DNA samples. We present a novel mismatch-rapture methodology for the highly efficient isolation and amplification of mutation-containing DNA from diverse nucleic acid fragments of unknown sequence. To demonstrate the potential of this method, heteroduplexes with a single A/G mismatch are formed via cross-hybridization of mutant C(T-->G) and wild-type DNA-fragment populations. Aldehydes are uniquely introduced at the position of mismatched adenines via the Escherichia coli glycosylase, MutY, Subsequent treatment with a biotinylated hydroxylamine results in highly specific and covalent biotinylation of the site of mismatch. For PCR amplification synthetic Linkers are then Ligated to the DNA fragments, Biotinylated DNA is then isolated and PCR amplified. Mutation-containing DNA fragments can subsequently be sequenced to identify type and position of mutation. This method correctly detects a single T-->G transversion introduced into a 7-kb plasmid containing full-length cDNA from the p53 gene, In the presence of a high excess wild-type DNA (1:1000 mutant:normal plasmids) or in the presence of diverse DNA fragment sizes, the DNA fragments containing the mutation are readily detectable and can be isolated and amplified, The present Aldehyde-Linker-Based Ultrasensitive Mismatch Scanning has a current limit of detection of one base substitution in 7 Mb of DNA and increases the Limit for unknown mutation scanning by two to three orders of magnitude. Homozygous and heterozygous p53 regions (G-->T, exon 4) from genomic DNA are also examined, and correct identification of mutations is demonstrated. This method should allow large-scale detection of genetic alterations in cancer samples without any assumption as to the genes of interest. C1 Harvard Univ, Sch Med, Dept Radiat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Mol Diagnost Lab, Boston, MA 02115 USA. Univ Calif Los Angeles, Sch Dent, Los Angeles, CA 90095 USA. RP Makrigiorgos, GM (reprint author), Harvard Univ, Sch Med, Dept Radiat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. FU NCI NIH HHS [1R21/R33 CA832340-01, K04 CA69296] NR 26 TC 13 Z9 13 U1 1 U2 4 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 JUL 15 PY 2000 VL 60 IS 14 BP 3732 EP 3737 PG 6 WC Oncology SC Oncology GA 337ML UT WOS:000088365300010 PM 10919642 ER PT J AU Li, WJ Judge, H Gragoudas, ES Seddon, JM Egan, KM AF Li, WJ Judge, H Gragoudas, ES Seddon, JM Egan, KM TI Patterns of tumor initiation in choroidal melanoma SO CANCER RESEARCH LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; NORMAL HUMAN EYES; UVEAL MELANOMA; MALIGNANT-MELANOMA; HOST FACTORS; COUNT; RISK; RADIATION; EXPOSURE; SUNLIGHT AB This study attempts to document the occurrence of tumors with respect to clock hour location and distance from the manila and to evaluate tumor location in relation to retinal topography and light dose distribution on the retinal sphere. Analysis of patterns of tumor initiation may provide new evidence to clarify the controversy regarding the possible light-related etiology of choroidal melanoma, Incident cases of choroidal and ciliary body melanoma in Massachusetts residents diagnosed between 1984 and 1993 were the basis fur analysis. Conventional fundus drawings and photos were used to assess the initiation site of each tumor. The Initiation site was defined as the intersect between the largest tumor diameter and the largest perpendicular diameter of the tumor. Initiation sites were recorded using spherical coordinates, The retinal sphere was divided into tit mutually exclusive sectors defined according to clock hour and anteroposterior distance From the macula. Rates of initiation were computed for each sector, overall, and according to gender and other clinical factors, Results were similar in left and right eyes; therefore, these were combined in analysis. Tumor initiation had a predilection for the macula (P < 0.0001). Overall, no significant clock hour preference was observed (P = 0.63), However, the parafoveal zone showed a strong circular trend (P < 0.01), with highest rates occurring in the temporal region, and the lowest rates occurring in the nasal region. Rates of occurrence in six progressively more anterior concentric zones (designated as the foveal, parafoveal, posterior, peripheral, anterior, and ciliary body zones) were 21.4 14.2, 12.1, 8.9, 4.5, and 4.3 counts per spherical unit per 1000 eyes, respectively. Concentric zone location did not vary by gender (P = 0.93) or laterality (P = 0.78). However, posterior location was associated,vith light iris color (P = 0.01). Tumor diameters were largest in the peripheral region of the fundus and smallest in the macular and ciliary body zone (P < 0.001), Clock hour location was not influenced by gender (P = 0.74), laterality (P = 0.53), iris color (P = 0.84), or tumor diameter (P = 0.73), Results suggest that tumor initiation is not uniformly distributed, with rates of occurrence concentrated in the macular area and decreasing monotonically with distance from the macula to the ciliary body, This pattern is consistent with the retinal topography and correlates positively with the dose distribution of solar light on the retinal sphere. C1 Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Retina Serv, Boston, MA 02114 USA. Univ Massachusetts, Dept Biostat & Epidemiol, Amherst, MA 01003 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02114 USA. RP Egan, KM (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Retina Serv, 243 Charles St, Boston, MA 02114 USA. RI Li, Wenjun/F-5634-2015 OI Li, Wenjun/0000-0001-5335-7386 NR 36 TC 39 Z9 39 U1 1 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 JUL 15 PY 2000 VL 60 IS 14 BP 3757 EP 3760 PG 4 WC Oncology SC Oncology GA 337ML UT WOS:000088365300015 PM 10919647 ER PT J AU Li, SJ Yan, T Yang, JQ Oberley, TD Oberley, LW AF Li, SJ Yan, T Yang, JQ Oberley, TD Oberley, LW TI The role of cellular glutathione peroxidase redox regulation in the suppression of tumor cell growth by manganese superoxide dismutase SO CANCER RESEARCH LA English DT Article ID KAPPA-B-ALPHA; OXIDATIVE STRESS; ANTIOXIDANT ENZYMES; CU,ZN-SUPEROXIDE DISMUTASE; SIGNAL-TRANSDUCTION; MALIGNANT PHENOTYPE; PARAQUAT RESISTANCE; RAT HEPATOCYTES; CARCINOMA-CELLS; S-TRANSFERASES AB Manganese-containing superoxide dismutase (MnSOD) is an essential primary antioxidant enzyme that converts superoxide radical to hydrogen peroxide and molecular oxygen within the mitochondrial matrix. Cytosolic glutathione peroxidase (GPX) converts hydrogen peroxide into water, MnSOD is reduced in a variety of tumor types and has been proposed to be a new kind of tumor suppressor gene, but the mechanism(s) by which MnSOD suppresses malignancy is unclear. According to the enzymatic reactions catalyzed by MnSOD and cytosolic GPX, change in the cellular redox status, especially change attributable to accumulation of hydrogen peroxide or other hydroperoxides, is a possible reason to explain the suppression of tumor growth observed in MnSOD-overexpressing cells. To test this possible mechanism, we transfected human cytosolic GPX cDNA into human glioma cells overexpressing MnSOD. The results showed that GPX overexpression not only reversed the tumor cell growth inhibition caused by MnSOD overexpression but also altered the cellular contents of total glutathione, reduced glutathione, oxidized glutathione, and Intracellular reactive oxygen species, Overexpression of GPX also inhibited degradation of the inhibitory subunit alpha of nuclear factor-kappa B. These results suggest that hydrogen peroxide or other hydroperoxides appear to be key reactants in the tumor suppression by MnSOD overexpression, and growth inhibition correlates with the intracellular redox status. This work suggests that manipulations that inhibit peroxide removal should enhance the tumor suppressive effect of MnSOD overexpression. C1 Univ Iowa, Coll Med, Med Labs B180, Radiat Res Lab, Iowa City, IA 52242 USA. William S Middleton Mem Vet Hosp, Pathol Serv, Madison, WI 53705 USA. Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53705 USA. RP Oberley, LW (reprint author), Univ Iowa, Coll Med, Med Labs B180, Radiat Res Lab, Iowa City, IA 52242 USA. FU NCI NIH HHS [CA 66081] NR 61 TC 198 Z9 203 U1 1 U2 8 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 JUL 15 PY 2000 VL 60 IS 14 BP 3927 EP 3939 PG 13 WC Oncology SC Oncology GA 337ML UT WOS:000088365300039 PM 10919671 ER PT J AU King, CR AF King, CR TI What is the T-pot for prostate cancer? Radiobiological implications of the equivalent outcome with I-125 or Pd-103 SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material ID LINEAR-QUADRATIC MODEL; RADIOTHERAPY; CARCINOMA; BRACHYTHERAPY; SENSITIVITY; TUMORS; CELLS C1 Boston Univ, Sch Med, Dept Radiat Oncol, Boston, MA 02118 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP King, CR (reprint author), Boston Univ, Sch Med, Dept Radiat Oncol, 88 E Newton St, Boston, MA 02118 USA. NR 18 TC 14 Z9 14 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2000 VL 47 IS 5 BP 1165 EP 1167 DI 10.1016/S0360-3016(00)00543-5 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 334TW UT WOS:000088202600001 PM 10939883 ER PT J AU Colson, YL Schuchert, MJ Ildstad, ST AF Colson, YL Schuchert, MJ Ildstad, ST TI The abrogation of allosensitization following the induction of mixed allogeneic chimerism SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BONE-MARROW TRANSPLANTATION; T-CELL DEPLETION; IMMUNE-RESPONSE; HOST-DISEASE; ANTIGEN; TOLERANCE; RAT; ENGRAFTMENT; INVITRO; MEMORY AB The association of preformed anti-donor Abs with the hyperacute rejection of bone marrow and solid organ allografts and the persistence of the anti-donor immune response secondary to immunologic memory make allosensitization an absolute contraindication to transplantation. Mixed allogeneic (A + B->A) bone marrow chimerism has been demonstrated to confer donor-specific tolerance in nonsensitized recipients, but has not been evaluated in the setting of allosensitization. The current study documents that despite significant anti-donor sensitization, mixed allogeneic engraftment is possible and provides a marked advantage over fully allogeneic (B->A) models. Moreover, the acceptance of donor skin grafts and loss of circulating anti-donor Abs suggest that allosensitization can be abrogated with the induction of stable mixed allogeneic chimerism. C1 Dana Farber Canc Inst, Div Pediat Oncol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Thorac Surg, Boston, MA 02115 USA. Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15261 USA. Univ Louisville, Inst Cellular Therapeut, Louisville, KY 40202 USA. RP Colson, YL (reprint author), Dana Farber Canc Inst, Div Pediat Oncol, Mayer 615,44 Binney St, Boston, MA 02115 USA. FU NIAID NIH HHS [R01-AI30615, R29-AI40933]; NIDDK NIH HHS [DK43901] NR 35 TC 20 Z9 24 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 JUL 15 PY 2000 VL 165 IS 2 BP 637 EP 644 PG 8 WC Immunology SC Immunology GA 332QU UT WOS:000088085600006 PM 10878335 ER PT J AU Lewinsohn, DM Briden, AL Reed, SG Grabstein, KH Alderson, MR AF Lewinsohn, DM Briden, AL Reed, SG Grabstein, KH Alderson, MR TI Mycobacterium tuberculosis-reactive CD8(+) T lymphocytes: The relative contribution of classical versus nonclassical HLA restriction SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTIGEN-PRESENTING CELLS; BOVIS BCG; INFECTION; MICE; RESISTANCE; RESPONSES; ALPHA; LUNGS; MACROPHAGES; RECOGNITION AB Previous studies in mice and humans models have suggested an important role for CD8(+) T cells in host defense to Mycobacterium tuberculosis (Mtb), In humans, CD8(+) Mtb-reactive T cells have been described that are HLA-A2-, B52-, as well as CD1-restricted, Recently, we have described Mtb-specific CD8(+) T cells that are neither HLA-A-, B-, or C- nor group 1 CD1-restricted, At present, little is known about the relative contribution of each of these restriction specificities to the overall CD8(+) response to Mtb, An IFN-gamma enzyme-linked immunospot assay was used to determine the frequency of Mtb-reactive CD8(+) T cells directly from PBMC, The effector cell frequency among five healthy; purified protein derivative-positive subjects was 1/7,600 +/- 4,300 compared with 1/16,000 +/- 7,000 in six purified protein derivative-negative controls. To determine the frequencies of classically, CD1-, and nonclassically restricted cells, a limiting dilution analysis was performed. In one purified protein derivative-positive subject, 192 clones were generated using Mtb-infected dendritic cells (DC), clones were assessed for reactivity against control autologous DC, Mtb-infected autologous DC, and HLA-mismatched CD1(+) targets (DC), as well as HLA-mismatched CD1(-) targets (macrophages), Of the 96 Mtb-reactive CD8(+) T cell clones, four (4%) were classically restricted and 92 (96%) were nonclassically restricted. CD1-restricted cells were not detected. Of the classically restricted cells, two were HLA-B44 restricted and one was HLA-B14 restricted. These results suggest that while classically restricted CD8(+) lymphocytes can be detected, they comprise a relatively small component of the overall CD8(+) T cell response to Mtb, Further definition of the nonclassical response may aid development of an effective vaccine against tuberculosis. C1 Oregon Hlth Sci Univ, Portland Vet Affairs Med Ctr, Div Pulm & Crit Care Med, Portland, OR 97207 USA. Corixa Corp, Seattle, WA 98104 USA. RP Lewinsohn, DM (reprint author), Oregon Hlth Sci Univ, Portland Vet Affairs Med Ctr, Div Pulm & Crit Care Med, R&D 11,3710 US Vet Rd, Portland, OR 97207 USA. RI Lewinsohn, David/I-4936-2013 OI Lewinsohn, David/0000-0001-9906-9494 FU NIAID NIH HHS [1K08AI01644] NR 33 TC 73 Z9 75 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2000 VL 165 IS 2 BP 925 EP 930 PG 6 WC Immunology SC Immunology GA 332QU UT WOS:000088085600038 PM 10878367 ER PT J AU Chen, DX Lan, J Pei, W Chen, J AF Chen, DX Lan, J Pei, W Chen, J TI Detection of DNA base-excision repair activity for oxidative lesions in adult rat brain mitochondria SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE mitochondria; oxidative stress; DNA damage; base excision repair; brain ID BLUE PLUS LIGHT; POLYMERASE-GAMMA; PARKINSONS-DISEASE; XENOPUS-LAEVIS; RINR-38 CELLS; DAMAGE; SITES; AGE; GLYCOSYLASE; STRESS AB Endogenous oxidative damage to brain mitochondrial DNA and consequential disturbances of gene expression and mitochondrial dysfunction have long been implicated in aging and the pathogenesis of neurodegenerative diseases. It has yet to be determined, however, whether mitochondria in brain cells contain an active DNA repair system and, if so, how this system functions. Therefore, the capacity for the repair of defined types of oxidative DNA lesions has been investigated in adult rat brain mitochondria. Using in vitro DNA incorporation repair assay, we have detected base excision repair (BER) activity for the common oxidative DNA adduct 8-hydroxyl-2'-deoxyguanine (8-oxodG) in mitochondria protein extracts from cortical tissues and cultured primary cortical neurons and astrocytes. The levels of BER activity were both protein concentration-dependent and repair-incubation time-dependent. To resolve the BER pathway, the activity of essential BER enzymes was examined in mitochondria using oligonucleotide incision assay, DNA polymerase assay, and DNA ligase assay employing specific DNA substrates. Mitochondrial extracts were able to remove specifically 8-oxodG, uracil, and the apurinic/apyrimidinic abasic site from substrates. Moreover, a gamma-like DNA polymerase activity and a DNA ligase activity were detected in mitochondiral extracts, based on the formation of specific repair products. These results demonstrate that adult brain mitochondria possess an active BER system for repairing oxidative DNA lesions. This repair system appears to function by sequential actions of DNA repair enzymes that are homologous to, but not identical to, that in the nucleus. Thus, BER may represent an endogenous protective mechanism against oxidative damage to mitochondrial, as well as nuclear, genomes in brain cells. (C) 2000 Wiley-Liss, Inc. C1 Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Inst Brain & Aging, Pittsburgh, PA USA. Vet Affairs Pittsburgh Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. RP Chen, J (reprint author), Univ Pittsburgh, Sch Med, Dept Neurol, S506 Biomed Sci Tower, Pittsburgh, PA 15213 USA. FU NINDS NIH HHS [NS36736, NS38560] NR 54 TC 36 Z9 37 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 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JUL 15 PY 2000 VL 61 IS 2 BP 225 EP 236 DI 10.1002/1097-4547(20000715)61:2<225::AID-JNR13>3.0.CO;2-0 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 331AJ UT WOS:000087994500013 PM 10878595 ER PT J AU Johnson, J Rickman, DW Brecha, NC AF Johnson, J Rickman, DW Brecha, NC TI Somatostatin and somatostatin subtype 2A expression in the mammalian retina SO MICROSCOPY RESEARCH AND TECHNIQUE LA English DT Article DE bipolar cells; photoreceptors; amacrine cells; horizontal cells; neuropeptides ID ROD BIPOLAR CELLS; IMMUNOREACTIVE AMACRINE CELLS; C-LIKE IMMUNOREACTIVITY; ADULT CAT RETINA; RABBIT RETINA; RAT RETINA; CHROMATOGRAPHIC CHARACTERIZATION; HIPPOCAMPAL-NEURONS; RECEPTOR SUBTYPE; CHICKEN RETINA AB This review discusses the expression and cellular localization of the neuropeptide somatostatin (SRIF) and one of the SRIF subtype (sst) receptors, sst, in the mammalian retina. SRIF immunoreactivity is predominantly localized to a sparse population of amacrine and displaced amacrine cells in the ganglion cell layer in several mammalian retinas including the rat, rabbit, cat, and primate. These cells, characterized by multiple processes, form a sparse network in the inner plexiform layer (IPL) in all retinal regions. Very few processes are also in the outer plexiform layer. In contrast to the predominant distribution of SRIF processes to the IPL, there is a widespread distribution of sst(2A) immunoreactivity to both the inner and outer retina in all mammalian retinas studied to date. In rabbit retina, sst(2A) immunoreactivity is predominant in rod bipolar cells and in sparse wide-field amacrine cells. In the rat retina, sst(2A) immunoreactivity is localized to several neuronal cell types-cone photoreceptors, horizontal cells, rod and cone bipolar cells, and amacrine cells. Reverse-transcriptase-polymerase chain reaction analysis found that set, mRNA is expressed in the rat retina, while sst(2A) mRNA is not detected. Finally, in the primate retina sst(2) immunoreactivity is predominant in cone photoreceptors, with additional immunostained cell bodies and processes in the inner retina. These findings indicate that SRIF may modulate several neuronal cell types in the retina, and that it has a broad influence on both scotopic and photopic visual pathways. (C) 2000 Wiley-Liss. Inc. C1 Univ Calif Los Angeles, Med Ctr, Sch Med, Dept Neurobiol,CHS, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. Univ Calif San Francisco, Dept Ophthalmol, San Francisco, CA 94143 USA. Univ Iowa, Dept Ophthalmol & Visual Sci, Iowa City, IA USA. CURE, Digest Dis Res Ctr, Los Angeles, CA USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Brecha, NC (reprint author), Univ Calif Los Angeles, Med Ctr, Sch Med, Dept Neurobiol,CHS, 10833 Le Conte Ave,Box 951763, Los Angeles, CA 90095 USA. FU NEI NIH HHS [EY11389, EY07026, EY04067] NR 64 TC 27 Z9 27 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 1059-910X J9 MICROSC RES TECHNIQ JI Microsc. Res. Tech. PD JUL 15 PY 2000 VL 50 IS 2 BP 103 EP 111 DI 10.1002/1097-0029(20000715)50:2<103::AID-JEMT2>3.0.CO;2-X PG 9 WC Anatomy & Morphology; Biology; Microscopy SC Anatomy & Morphology; Life Sciences & Biomedicine - Other Topics; Microscopy GA 336PB UT WOS:000088310800002 PM 10891874 ER PT J AU Renatus, M Zhou, Q Stennicke, HR Snipas, SJ Turk, D Bankston, LA Liddington, RC Salvesen, GS AF Renatus, M Zhou, Q Stennicke, HR Snipas, SJ Turk, D Bankston, LA Liddington, RC Salvesen, GS TI Crystal structure of the apoptotic suppressor CrmA in its cleaved form SO STRUCTURE WITH FOLDING & DESIGN LA English DT Article DE apoptosis; caspase; protease; protease inhibitor; serpin; viral countermeasures ID INTERLEUKIN-1-BETA CONVERTING-ENZYME; VIRUS SERPIN CRMA; COWPOX VIRUS; 3-DIMENSIONAL STRUCTURE; PROTEINASE-INHIBITORS; PLASMINOGEN-ACTIVATOR; ANTITHROMBIN-III; GRANZYME-B; RESOLUTION; CASPASES AB Background: Cowpox virus expresses the serpin CrmA (cytokine response modifier A) in order to avoid inflammatory and apoptotic responses of infected host cells. The targets of CrmA are members of the caspase family of proteases that either initiate the extrinsic pathway of apoptosis (caspases 8 and 10) or trigger activation of the pro-inflammatory cytokines interleukin-1 beta and interleukin-18 (caspase 1). Results: We have determined the structure of a cleaved form of CrmA to 2.26 Angstrom resolution. CrmA has the typical fold of a cleaved serpin, even though it lacks the N-terminal half of the A helix, the entire D helix, and a portion of the E helix that are present in all other known serpins. The reactive-site loop of CrmA was mutated to contain the optimal substrate recognition sequence for caspase 3; however, the mutation only marginally increased the ability of CrmA to inhibit caspase 3. Superposition of the reactive-site loop of alpha 1-proteinase inhibitor on the cleaved CrmA structure provides a model for Virgin CrmA that can be docked to caspase 1, but not to caspase 3. Conclusions: CrmA exemplifies viral economy, selective pressure having resulted in a 'minimal' serpin that lacks the regions not needed for structural integrity or inhibitory activity. The docking model provides an explanation for the selectivity of CrmA. Our demonstration that engineering optimal substrate recognition sequences into the CrmA reactive-site loop fails to generate a good caspase 3 inhibitor is consistent with the docking model. C1 Burnham Inst, Program Apoptosis & Cell Death Res, La Jolla, CA 92037 USA. Harvard Univ, Ctr Blood Res, Sch Med, Boston, MA 02115 USA. Jozef Stefan Inst, Dept Biochem & Mol Biol, Ljubljana, Slovenia. Burnham Inst, Program Cell Adhes Extracellular Matrix Biol, La Jolla, CA 92037 USA. RP Salvesen, GS (reprint author), Burnham Inst, Program Apoptosis & Cell Death Res, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. FU NHLBI NIH HHS [HL51399] NR 48 TC 41 Z9 41 U1 1 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0969-2126 J9 STRUCT FOLD DES JI Struct. Fold. Des. PD JUL 15 PY 2000 VL 8 IS 7 BP 789 EP 797 DI 10.1016/S0969-2126(00)00165-9 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 334NM UT WOS:000088192600012 PM 10903953 ER PT J AU van den Brink, MRM Moore, E Horndasch, KJ Crawford, JM Murphy, GF Burakoff, SJ AF van den Brink, MRM Moore, E Horndasch, KJ Crawford, JM Murphy, GF Burakoff, SJ TI Fas ligand-deficient gld mice are more susceptible to graft-versus-host-disease SO TRANSPLANTATION LA English DT Article ID BONE-MARROW TRANSPLANTATION; CONFER IMMUNE PRIVILEGE; INDUCED APOPTOSIS; T-LYMPHOCYTES; DIFFERENTIAL EXPRESSION; PROGENITOR CELLS; UP-REGULATION; CD95 LIGAND; TUMOR-CELLS; LPR GENE AB Background. The Fas/Fas ligand (FasL) pathway plays an important role in a number of apoptotic processes that could be important for the development of graft-versus-host disease (GVHD) after bone marrow transplantation (BMT), such as cytolysis of target cells by cytotoxic T cells, regulation of inflammatory responses, peripheral deletion of autoimmune cells, costimulation of T cells, and activation-induced cell death. Methods. To study the role of the Fas/FasL pathway in the complex pathophysiology of graft versus host disease (GVHD), we used FasL-deficient B6.gld mice as recipients in a Major Histocompatibility Antigen Complex-matched minor Histocompatibility Antigen-mismatched murine model for GVHD after allogeneic BMT (C3H.SW-->B6). Results. We found a significantly higher morbidity and mortality from GVHD compared to control B6 recipients. Histopathological analysis of the GVHD target organs demonstrated that B6.gld recipients developed significantly more thymic and intestinal GVHD. B6.gld recipients with GVHD demonstrated an increased expansion of donor T cells and monocytes/macrophages compared to control B6 recipients, whereas serum TNF-alpha levels were equivalent in B6.gld recipients and control B6 recipients. Conclusion. This study demonstrates that the expression of FasL in the BMT recipient is important for the host's ability to control GVHD. C1 Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Div Hematol & Oncol, Boston, MA 02215 USA. Univ Florida, Coll Med, Dept Pathol Immunol & Lab Med, Gainesville, FL 32610 USA. Thomas Jefferson Med Ctr, Dept Pathol, Philadelphia, PA 19107 USA. RP van den Brink, MRM (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, Mailbox 111,1275 York Ave, New York, NY 10021 USA. FU NCI NIH HHS [R01 CA40358, 5PO1 CA39542]; NIDDK NIH HHS [R01 DK39512] NR 58 TC 19 Z9 19 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 JUL 15 PY 2000 VL 70 IS 1 BP 184 EP 191 PG 8 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 339UK UT WOS:000088496100034 PM 10919598 ER PT J AU Farrell, JJ Cosimi, AB Chung, RT AF Farrell, JJ Cosimi, AB Chung, RT TI Idiopathic giant esophageal ulcers in a renal transplant patient responsive to steroid therapy SO TRANSPLANTATION LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; THALIDOMIDE TREATMENT; ULCERATION; INFECTION; EFFICACY; AIDS AB Idiopathic giant esophageal ulcers in immunocompromised patients have been described only in patients with acquired immunodeficiency syndrome. A solitary report of an idiopathic giant esophageal ulcer in an immunocompetent patient exists. We describe a ease of idiopathic esophageal ulceration ultimately responsive to steroid therapy in a 31-year old immunosuppressed, human immunodeficiency virus-negative renal transplant patient. The case is described with particular reference to the evaluation, differential diagnosis, and therapeutic response to steroids. Similarities in presentation and treatment to giant esophageal ulcers in human immunodeficiency virus infection suggest an underlying immune defect as the likely cause. This is the first described case of giant esophageal ulceration responsive to steroids in an immunosuppressed human immunodeficiency virus-negative patient. This entity should be added to the differential diagnosis of esophageal ulceration in solid organ transplant recipients. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Med Serv, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Unit, Boston, MA 02114 USA. RP Chung, RT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Med Serv, GRJ 724,55 Fruit St, Boston, MA 02114 USA. NR 11 TC 7 Z9 7 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 JUL 15 PY 2000 VL 70 IS 1 BP 230 EP 232 PG 3 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 339UK UT WOS:000088496100047 PM 10919611 ER PT J AU Choudhury, GG Ricono, JM AF Choudhury, GG Ricono, JM TI Increased effect of interferon gamma on PDGF-induced c-fos gene transcription in glomerular mesangial cells: Differential effect of the transcriptional coactivator CBP on STAT1 alpha activation SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE PDGF; interferon gamma; c-fos; sis-inducible element ID SERUM RESPONSE ELEMENT; GROWTH-FACTOR; MEDIATED ACTIVATION; SIGNAL-TRANSDUCTION; DNA-SYNTHESIS; KINASE; PROMOTER; TYROSINE; RECEPTOR; PATHWAYS AB We have previously shown that interferon gamma (IFN gamma) synergistically increases PDGF-induced DNA synthesis in mesangial cells. To examine the mechanism, we studied its effect on PDGF-induced c-fos gene transcription using a reporter mesangial cell in which firefly luciferase gene is driven by c-fos promoter. IFN gamma significantly enhanced PDGF-induced c-fos transcription, We have shown previously that PDGF-induced c-fos transcription in mesangial cells is mediated by the ternary complex factor Elk-1. Using a GAL-4 DNA binding-domain-Elk-1 transactivation domain fusion protein-based reporter assay we showed that the increased effect of IFN gamma was not mediated by Elk-1 transactivation. Gel mobility shift assay of lysates of mesangial cells treated with a combination of IFN gamma and PDGF using sis-inducible DNA element (SIE) showed increased STAT1 alpha-SIE complex formation as compared to the PDGF alone. To investigate the transcriptional consequences of this observation, stable reporter mesangial cells in which luciferase gene is driven by four copies of SIE was used, IFN gamma and PDGF in combination significantly increased SIE-dependent transcription as compared to PDGF or IFN gamma alone. Using an antibody in the gel mobility shift assay we showed that the PDGF-induced STE-STAT1 alpha complex recruited the transcriptional coactivator CBP. However, the STA1 alpha-SIE complex formed in the presence of IFN gamma and PDGF did not contain CBP. Taken together, our data provide the first evidence that the synergistic effect of IFN gamma on PDGF-induced DNA synthesis may be the result of increased c-fos gene transcription via SIE. This effect occurs in the presence of increased activation of STAT1 alpha without recruitment of the transcriptional coactivator CBP. (C) 2000 Academic Press. C1 Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78284 USA. S Texas Vet hlth Care Syst, Ctr Geriatr Res Educ & Clin, San Antonio, TX USA. RP Choudhury, GG (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med, Floyd Curl Dr, San Antonio, TX 78284 USA. NR 42 TC 5 Z9 6 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 14 PY 2000 VL 273 IS 3 BP 1069 EP 1077 DI 10.1006/bbrc.2000.3081 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 337LX UT WOS:000088363700048 ER PT J AU Fujii, N Hayashi, T Hirshman, MF Smith, JT Habinowski, SA Kaijser, L Mu, J Ljungqvist, O Birnbaum, MJ Witters, LA Thorell, A Goodyear, LJ AF Fujii, N Hayashi, T Hirshman, MF Smith, JT Habinowski, SA Kaijser, L Mu, J Ljungqvist, O Birnbaum, MJ Witters, LA Thorell, A Goodyear, LJ TI Exercise induces isoform-specific increase in 5 ' AMP-activated protein kinase activity in human skeletal muscle SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE AMPK; exercise; glucose transport; skeletal muscle; contraction, human ID ACETYL-COA CARBOXYLASE; GLUT4 TRANSLOCATION; GLUCOSE-TRANSPORT; DYNAMIC EXERCISE; CREATINE-KINASE; MALONYL-COA; CONTRACTION; HEXOKINASE; ACTIVATION; SUBFAMILY AB The 5'AMP-activated protein kinase (AMPK) is stimulated by contractile activity in rat skeletal muscle. AMPK has emerged as an important signaling intermediary in the regulation of cell metabolism being linked to exercise-induced changes in muscle glucose and fatty acid metabolism. In the present study, we determined the effects of exercise on isoform-specific AMPK activity (alpha 1 and alpha 2) in human skeletal muscle. Needle biopsies of vastus lateralis muscle were obtained from seven healthy subjects at rest, after 20 and 60 min of cycle ergometer exercise at 70% of VO(2)max, and 30 min following the 60 min exercise bout. In comparison to the resting state, AMPK alpha 2 activity significantly increased at 20 and 60 min of exercise, and remained at a higher level with 30 min of recovery. AMPK al activity tended to slightly decrease with 20 min of exercise at 70%VO(2)max; however, the change was not statistically significant. AMPK alpha 1 activities were at basal levels at 60 min of exercise and 30 min of recovery. On a separate day, the same subjects exercised for 20 min at 50% of VO(2)max. Exercise at this intensity did not change alpha 2 activity, and similar to exercise at 70% of VO(2)max, there was no significant change in alpha 1 activity. In conclusion, exercise at a higher intensity for only 20 min leads to increases in AMPK alpha 2 activity but not alpha 1 activity. These results suggest that the alpha 2-containing AMPK complex, rather than al, may be involved in the metabolic responses to exercise in human skeletal muscle. (C) 2000 Academic Press. C1 Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. Dartmouth Coll, Sch Med, Dept Med & Biochem, Endocrine Metab Div, Hanover, NH 03755 USA. Karolinska Inst, Huddinge Univ Hosp, Dept Surg, S-14186 Huddinge, Sweden. Karolinska Inst, Huddinge Univ Hosp, Dept Clin Physiol, S-14186 Huddinge, Sweden. Univ Penn, Sch Med, Dept Med, Howard Hughes Med Inst, Philadelphia, PA 19104 USA. Karolinska Inst, Ersta Hosp, Ctr Gastrointestinal Dis, S-11691 Stockholm, Sweden. RP Goodyear, LJ (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. RI Fujii, Nobuharu/J-2724-2014; OI Fujii, Nobuharu/0000-0002-0974-3033; Birnbaum, Morris/0000-0001-9972-8680 FU NIAMS NIH HHS [AR42338, AR45670] NR 37 TC 220 Z9 238 U1 0 U2 4 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 14 PY 2000 VL 273 IS 3 BP 1150 EP 1155 DI 10.1006/bbrc.2000.3073 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 337LX UT WOS:000088363700062 PM 10891387 ER PT J AU Prass, K Wiegand, F Schumann, P Ahrens, M Kapinya, K Harms, C Liao, WJ Trendelenburg, G Gertz, K Moskowitz, MA Knapp, F Victorov, IV Megow, D Dirnagl, U AF Prass, K Wiegand, F Schumann, P Ahrens, M Kapinya, K Harms, C Liao, WJ Trendelenburg, G Gertz, K Moskowitz, MA Knapp, F Victorov, IV Megow, D Dirnagl, U TI Hyperbaric oxygenation induced tolerance against focal cerebral ischemia in mice is strain dependent SO BRAIN RESEARCH LA English DT Article DE C57BL/6 mouse; oxygen free radical; preconditioning; SV129 mouse; stroke ID ARTERY OCCLUSION; BRAIN; RATS AB SV129 or C57BL/6 mice were exposed to hyperbaric oxygenation (HBO, 5 days, 1 h every day, 100% O-2 at 3 atm absolute). One day after the 5th HBO session focal cerebral ischemia was induced. In SV129 mice, HBO induced tolerance against permanent focal cerebral ischemia (n = 42, mean infarct volume reduction 27%, P = 0.001), but not against transient (30 or 60 min) focal cerebral ischemia. In the C57BL/6 strain of mice, HBO did not induce tolerance against focal cerebral ischemia, even when the duration of ischemia or the HBO protocol were modified. For the first time we demonstrate that HBO can induce tolerance to focal cerebral ischemia, but this effect is strain dependent. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Humboldt Univ, Dept Neurol, Berlin, Germany. Univ Essen Gesamthsch, Dept Neurol, D-4300 Essen, Germany. Univ Caen, CNRS, UMR 6551, F-14032 Caen, France. Russian Acad Med Sci, Brain Res Inst, Moscow, Russia. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Stroke Res Lab, Charlestown, MA USA. RP Dirnagl, U (reprint author), Humboldt Univ, Dept Neurol, Berlin, Germany. RI Moskowitz, Michael/D-9916-2011; Victorov, Ilya/C-4680-2012; Gertz, Karen/J-1603-2015; OI Harms, Christoph/0000-0002-2063-2860; Dirnagl, Ulrich/0000-0003-0755-6119 NR 20 TC 72 Z9 83 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUL 14 PY 2000 VL 871 IS 1 BP 146 EP 150 DI 10.1016/S0006-8993(00)02264-2 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 336BF UT WOS:000088281500018 PM 10882793 ER PT J AU Huang, CC Zang, Q Takagi, J Springer, TA AF Huang, CC Zang, Q Takagi, J Springer, TA TI Structural and functional studies with antibodies to the integrin beta 2 subunit - A model for the I-like domain SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID VON-WILLEBRAND-FACTOR; LEUKOCYTE ADHESION DEFICIENCY; FUNCTION-ASSOCIATED ANTIGEN-1; FUNCTION-ASSOCIATED MOLECULE-1; CELL-SURFACE EXPRESSION; LIGAND-BINDING REGION; CRYSTAL-STRUCTURE; A-DOMAIN; MONOCLONAL-ANTIBODIES; CONFORMATIONAL-CHANGES AB To establish a structure and function map of the beta 2 integrin subunit, we mapped the epitopes of a panel of beta 2 monoclonal antibodies including function-blocking, nonblocking, and activating antibodies using human/mouse beta 2 subunit chimeras. Activating antibodies recognize the C-terminal half of the cysteine-rich region, residues 522-612. Antibodies that do not affect ligand binding map to residues 1-98 and residues 344-521. Monoclonal antibodies to epitopes within a predicted I-like domain (residues 104-341) strongly inhibit LFA-1-dependent adhesion. These function-blocking monoclonal antibodies were mapped to specific residues with human --> mouse knockout or mouse --> human knock-in mutations. Combinatorial epitopes involving residues distant in the sequence provide support for a specific alignment between the beta-subunit and I domains that was used to construct a three-dimensional model. Antigenic residues 133, 332, and 339 are on the first and last predicted alpha-helices of the I-like domain, which are adjacent on its "front," Other antigenic residues in beta 2 and in other integrin beta subunits are present on the front. No antigenic residues are present on the "back" of the domain, which is predicted to be in an interface with other domains, such as the alpha subunit beta-propeller domain. Most mutations in the beta 2 subunit in leukocyte adhesion deficiency are predicted to be buried in the beta 2 subunit I-like domain. Two long insertions are present relative to alpha-subunit I-domains. One is tied down to the back of the I-like domain by a disulfide bond. The other corresponds to the "specificity-determining loop" defined in beta 1 and beta 3 integrins and contains the antigenic residue Glu(175) in a disulfide-bonded loop located near the "top" of the domain. C1 Ctr Blood Res, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Pfizer Inc, Cent Res, Groton, CT 06340 USA. Biogen Inc, Cambridge, MA 02142 USA. RP Springer, TA (reprint author), Ctr Blood Res, Dept Pathol, 200 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [CA 31798] NR 80 TC 84 Z9 85 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 JUL 14 PY 2000 VL 275 IS 28 BP 21514 EP 21524 DI 10.1074/jbc.M002286200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 335EM UT WOS:000088230600075 PM 10779511 ER PT J AU Tracey, I Becerra, L Chang, I Breiter, H Jenkins, L Borsook, D Gonzalez, RG AF Tracey, I Becerra, L Chang, I Breiter, H Jenkins, L Borsook, D Gonzalez, RG TI Noxious hot and cold stimulation produce common patterns of brain activation in humans: a functional magnetic resonance imaging study SO NEUROSCIENCE LETTERS LA English DT Article DE functional magnetic resonance imaging; pain; thermal; brain imaging; brain ID PAIN; HEAT AB We used functional magnetic resonance imaging ( fMRI) to determine whether similar brain regions activate during noxious hot and cold stimulation. Six male subjects underwent whole brain fMRI during phasic delivery of noxious hot (46 degrees C) and noxious cold (5 degrees C) stimulation to the dorsum of the left hand. Mid-brain regions activated included thalamus, basal ganglia and insula. Cortical areas activated included cingulate, somatosensory, premotor and motor cortices, as well as prefrontal and inferior parietal cortex. Most regions activated bilaterally but with stronger activation contralateral to the stimulus. Noxious cold stimulation produced significantly increased volumes of activation compared to noxious heat in prefrontal areas only. Our results suggest a similar network of regions activate common to the perception of pain produced by either noxious hot or cold stimulation. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Boston, MA 02129 USA. Univ Oxford, John Radcliffe Hosp, Dept Clin Neurol, Ctr Funct MRI Brain, Oxford OX3 9DU, England. Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Neural Plast Res Lab, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. RP Gonzalez, RG (reprint author), Massachusetts Gen Hosp, GRB 285,Fruite St, Boston, MA 02114 USA. FU NIDA NIH HHS [DA012581]; NIDCR NIH HHS [DE12734]; NINDS NIH HHS [NS34626] NR 19 TC 108 Z9 112 U1 0 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUL 14 PY 2000 VL 288 IS 2 BP 159 EP 162 DI 10.1016/S0304-3940(00)01224-6 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 334QZ UT WOS:000088198300019 PM 10876085 ER PT J AU Januzzi, JL Stern, TA Pasternak, RC DeSanctis, RW AF Januzzi, JL Stern, TA Pasternak, RC DeSanctis, RW TI The influence of anxiety and depression on outcomes of patients with coronary artery disease SO ARCHIVES OF INTERNAL MEDICINE LA English DT Review ID ACUTE MYOCARDIAL-INFARCTION; ISCHEMIC-HEART-DISEASE; VENTRICULAR-FIBRILLATION THRESHOLD; WESTERN COLLABORATIVE GROUP; EXERCISE TRAINING-PROGRAMS; IN-HOSPITAL SYMPTOMS; LONG-TERM MORTALITY; CARDIAC REHABILITATION; ELECTROCONVULSIVE-THERAPY; FOLLOW-UP AB For years, patients with cardiac disease have been thought to exhibit characteristic emotional features. However, the modern understanding of the relationship between affective disorders and the heart may be traced to the mid-19th century, with the publication of Williams' seminal text regarding "nervous and sympathetic palpitations of the heart."(1) This was followed through the late 1800s by numerous works that described the concept of neurologically based, or "neurasthenic," cardiac disorders. In the 20th century, large advances occurred in the area of mo-ed-related issues that pertained to coronary artery disease (CAD) and sudden cardiac death (SCD). In his 1910 Lumleian lecture, Sir William Osler described his typical patient with angina pectoris as "a man whose engine is always set full speed ahead" and further noted his patients with cardiac disease to be "worriers."(2) The Menningers,(3) in early psychoanalytic studies, described a characteristic tendency to suppress anger among patients with CAD, as did Helen Flanders Dunbar,(4) a pioneer of psychosomatic medicine. More recently, Stewart Wolf, in his 1969 lecture "Psychosocial Forces in Myocardial Infarction and Sudden Death," commented on a phenomenon of "joyless striving" among his patients with heart disease.(5). C1 Massachusetts Gen Hosp, Dept Med, Cardiac Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP DeSanctis, RW (reprint author), Massachusetts Gen Hosp, Dept Med, Cardiac Unit, Boston, MA 02114 USA. NR 132 TC 132 Z9 141 U1 3 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 JUL 10 PY 2000 VL 160 IS 13 BP 1913 EP 1921 DI 10.1001/archinte.160.13.1913 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 330XZ UT WOS:000087988000004 PM 10888966 ER PT J AU Sleckman, BP Bassing, CH Hughes, MM Okada, A D'Auteuil, M Wehrly, TD Woodman, BB Davidson, L Chen, JZ Alt, FW AF Sleckman, BP Bassing, CH Hughes, MM Okada, A D'Auteuil, M Wehrly, TD Woodman, BB Davidson, L Chen, JZ Alt, FW TI Mechanisms that direct ordered assembly of T cell receptor beta locus V, D, and J gene segments SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CODING-END SEQUENCE; V(D)J RECOMBINATION; ALLELIC EXCLUSION; TCR-ALPHA; REARRANGEMENT; INITIATION; ACCESSIBILITY; ELEMENTS AB T cell receptor (TCR) beta variable region genes are assembled in progenitor T cells from germ-line V beta, D beta, and J beta segments via an ordered two-step process in which D beta to J beta rearrangements occur on both alleles before appendage of a V beta to a preexisting DJ beta complex. Direct joining of V beta segments to nonrearranged D beta or J beta segments, while compatible with known restrictions on the V(D)J recombination mechanism, are infrequent within the endogenous TCR beta locus. We have analyzed mechanisms that mediate ordered V beta, D beta, and J beta assembly via an approach in which TCR beta minilocus recombination substrates were introduced into embryonic stem cells and then analyzed for rearrangement in normal thymocytes by recombinase-activating gene 2-deficient blastocyst complementation. These analyses demonstrated that V beta segments are preferentially targeted for rearrangement to D beta as opposed to J beta segments. In addition, we further demonstrated that V beta segments can be appended to nonrearranged endogenous D beta segments in which we have eliminated the ability of D beta segments to join to J beta segments. Our findings are discussed in the context of the mechanisms that regulate the ordered assembly and utilization of V, D, and J segments. C1 Harvard Univ, Childrens Hosp, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. Ctr Blood Res, Boston, MA 02115 USA. Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. RP Alt, FW (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. FU NIAID NIH HHS [R01 AI020047, AI01297, AI20047, R37 AI020047] NR 29 TC 55 Z9 55 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 JUL 5 PY 2000 VL 97 IS 14 BP 7975 EP 7980 DI 10.1073/pnas.130190597 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 331ZK UT WOS:000088048400058 PM 10869424 ER PT J AU Bonner-Weir, S Taneja, M Weir, GC Tatarkiewicz, K Song, KH Sharma, A O'Neil, JJ AF Bonner-Weir, S Taneja, M Weir, GC Tatarkiewicz, K Song, KH Sharma, A O'Neil, JJ TI In vitro cultivation of human islets from expanded ductal tissue SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BETA-CELLS; ENDOCRINE PANCREAS; GROWTH-FACTOR; CULTURE; DIFFERENTIATION; PROLIFERATION; EXPRESSION; MATRIX; RAT; TRANSPLANTATION AB A major obstacle to successful islet transplantation for both type 1 and 2 diabetes is an inadequate supply of insulin-producing tissue. This need for transplantable human islets has stimulated efforts to expand existing pancreatic islets and/or grow new ones. To test the hypothesis that human adult duct tissue could be expanded and differentiated in vitro to form islet cells, digested pancreatic tissue that is normally discarded from eight human islet isolations was cultured under conditions that allowed expansion of the ductal cells as a monolayer whereupon the cells were overlaid with a thin layer of Matrigel. With this manipulation, the monolayer of epithelial cells formed three-dimensional structures of ductal cysts from which 50- to 150-mu m diameter islet-like clusters of pancreatic endocrine cells budded. Over 3-4 weeks culture the insulin content per flask increased 10- to 15-fold as the DNA content increased up to 7-fold. The cultivated human islet buds were shown by immunofluorescence to consist of cytokeratin 19-positive duct cells and hormone-positive islet cells. Double staining of insulin and non-p cell hormones in occasional cells indicated immature cells still in the process of differentiation. Insulin secretion studies were done over 24 h in culture, Compared with their basal secretion at 5 mM glucose, cysts/cultivated human islet buds exposed to stimulatory 20 mM glucose had a 2.3-fold increase in secreted insulin. Thus, duct tissue from human pancreas can be expanded in culture and then be directed to differentiate into glucose responsive islet tissue in vitro. This approach may provide a potential new source of pancreatic islet cells for transplantation. C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. RP Bonner-Weir, S (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. NR 28 TC 692 Z9 778 U1 2 U2 23 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 JUL 5 PY 2000 VL 97 IS 14 BP 7999 EP 8004 DI 10.1073/pnas.97.14.7999 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 331ZK UT WOS:000088048400062 PM 10884429 ER PT J AU Lu, YC Friedman, R Kushner, N Doling, A Thomas, L Touzjian, N Starnbach, M Lieberman, J AF Lu, YC Friedman, R Kushner, N Doling, A Thomas, L Touzjian, N Starnbach, M Lieberman, J TI Genetically modified anthrax lethal toxin safely delivers whole HIV protein antigens into the cytosol to induce T cell immunity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PROTECTIVE ANTIGEN; IN-VIVO; MEDIATED DELIVERY; LYMPHOCYTES; EPITOPES; TRANSLOCATION; BINDING; GP160; NEF AB Bacillus anthrax lethal toxin can be engineered to deliver foreign proteins to the cytosol for antigen presentation to CD8 T cells. Vaccination with modified toxins carrying 8-9 amino acid peptide epitopes induces protective immunity in mice. To evaluate whether large protein antigens can be used with this system, recombinant constructs encoding several HIV antigens up to 500 amino acids were produced. These candidate HIV vaccines are safe in animals and induce CD8 T cells in mice. Constructs encoding gag p24 and nef stimulate gag-specific CD4 proliferation and a secondary cytotoxic T lymphocyte response in HIV-infected donor peripheral blood mononuclear cells in vitro. These results lay the foundation for future clinical vaccine studies. C1 Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. RP Lu, YC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, 665 Huntington Ave, Boston, MA 02115 USA. RI Lieberman, Judy/A-2717-2015 FU NIAID NIH HHS [AI41526, AI42671, AI47539] NR 27 TC 36 Z9 43 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 JUL 5 PY 2000 VL 97 IS 14 BP 8027 EP 8032 DI 10.1073/pnas.97.14.8027 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 331ZK UT WOS:000088048400067 PM 10884430 ER PT J AU Bearer, EL Breakefield, XO Schuback, D Reese, TS LaVail, JH AF Bearer, EL Breakefield, XO Schuback, D Reese, TS LaVail, JH TI Retrograde axonal transport of herpes simplex virus: Evidence for a single mechanism and a role for tegument SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SQUID GIANT-AXON; CYTOPLASMIC DYNEIN; PROTEIN; AXOPLASM; CELLS; MOTILITY; ORGANELLES; INFECTION; DYNACTIN; KINESIN AB Herpes simplex virus type I (HSV) typically enters peripheral nerve terminals and then travels back along the nerve to reach the neuronal cell body, where it replicates or enters latency. To monitor axoplasmic transport of HSV, we used the giant axon of the squid, Loligo pealei, a well known system for the study of axoplasmic transport. To deliver HSV into the axoplasm, viral particles stripped of their envelopes by detergent were injected into the giant axon, thereby bypassing the infective process. Labeling the viral tegument protein, VP16, with green fluorescent protein allowed viral particles moving inside the axon to be imaged by confocal microscopy. Viral particles moved 2.2 +/- 0.26 mu m/sec in the retrograde direction, a rate comparable to that of the transport of endogenous organelles and of virus in mammalian neurons in culture. Electron microscopy confirmed that 96% of motile (stripped) viral particles had lost their envelope but retained tegument, and Western blot analysis revealed that these particles had retained protein from capsid but not envelope. We conclude that (i) HSV recruits the squid retrograde transport machinery; (ii) viral tegument and capsid but not envelope are sufficient for this recruitment; and (iii) the giant axon of the squid provides a unique system to dissect the viral components required for transport and to identify the cellular transport mechanisms they recruit. C1 Marine Biol Lab, Woods Hole, MA 02543 USA. Brown Univ, Dept Pathol & Lab Med, Providence, RI 02912 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. NINCDS, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Anat & Ophthalmol, San Francisco, CA 94143 USA. RP Bearer, EL (reprint author), Marine Biol Lab, Woods Hole, MA 02543 USA. FU NEI NIH HHS [EYO8773]; NIGMS NIH HHS [GM47638] NR 45 TC 89 Z9 96 U1 0 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 JUL 5 PY 2000 VL 97 IS 14 BP 8146 EP 8150 DI 10.1073/pnas.97.14.8146 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 331ZK UT WOS:000088048400087 PM 10884436 ER PT J AU Go, AS Hylek, EM Phillips, KA Borowsky, LH Henault, LE Chang, YC Selby, JV Singer, DE AF Go, AS Hylek, EM Phillips, KA Borowsky, LH Henault, LE Chang, YC Selby, JV Singer, DE TI Implications of stroke risk criteria on the anticoagulation decision in nonvalvular atrial fibrillation - The anticoagulation and risk factors in atrial fibrillation (ATRIA) study SO CIRCULATION LA English DT Article DE fibrillation; anticoagulants; risk factors; stroke AB Background-Warfarin dramatically reduces the risk of stroke in patients with nonvalvular atrial fibrillation (NVAF) but increases the likelihood of bleeding, Accurately identifying patients who need anticoagulation is critical. We assessed the potential impact of prominent stroke risk classification schemes on this decision in a large sample of patients with NVAF. Methods and Results-We used clinical and electrocardiographic databases to identify 13559 ambulatory patients with NVAF from July 1996 through December 1997, We compared the proportion of patients classified as having a low enough stroke risk to receive aspirin using published criteria from the Atrial Fibrillation Investigators (AFI), American College of Chest Physicians (ACCP), and the Stroke Prevention in Atrial Fibrillation Investigators (SPAF), In this cohort, AFI criteria classified 11% as having a low stroke risk, compared with 23% for ACCP and 29% for SPAF (kappa range, 0.44 to 0.85). This 2- to-3-fold increase in low stroke risk patients by ACCP and SPAF criteria primarily resulted from the inclusion of many older subjects (65 to 75 years +/- men >75 years) with no additional clinical stroke risk factors. Conclusions-The age threshold for assigning an increased stroke risk has a dramatic impact on whether to recommend warfarin in populations of patients with NVAF, Large, prospective studies with many stroke events are needed to precisely determine the relationship of age to stroke risk in AF and to identify which AF subgroups are at a sufficiently low stroke risk to forego anticoagulation. C1 Kaiser Permanente Med Care Program, Div Res, Oakland, CA 94611 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Massachusetts Gen Hosp, Dept Med, Div Gen Med, Clin Epidemiol Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Go, AS (reprint author), Kaiser Permanente Med Care Program, Div Res, 3505 Broadway St, Oakland, CA 94611 USA. FU NIA NIH HHS [AG15478] NR 13 TC 88 Z9 91 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 4 PY 2000 VL 102 IS 1 BP 11 EP 13 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 329VG UT WOS:000087928700005 PM 10880408 ER PT J AU Streit, M Velasco, P Riccardi, L Spencer, L Brown, LF Janes, L Lange-Asschenfeldt, B Yano, K Hawighorst, T Iruela-Arispe, L Detmar, M AF Streit, M Velasco, P Riccardi, L Spencer, L Brown, LF Janes, L Lange-Asschenfeldt, B Yano, K Hawighorst, T Iruela-Arispe, L Detmar, M TI Thrombospondin-1 suppresses wound healing and granulation tissue formation in the skin of transgenic mice SO EMBO JOURNAL LA English DT Article DE blood vessels; skin; transgenic mice; wound healing ID ENDOTHELIAL GROWTH-FACTOR; TUMOR-GROWTH; IN-VITRO; FACTOR EXPRESSION; ANGIOGENESIS; CELLS; DIFFERENTIATION; KERATINOCYTES; CARCINOMA; RECEPTOR AB The function of the endogenous angiogenesis inhibitor thrombospondin-1 (TSP-1) in tissue repair has remained controversial. We established transgenic mice with targeted overexpression of TSP-1 in the skin, using a keratin 14 expression cassette. TSP-1 transgenic mice were healthy and fertile, and did not show any major abnormalities of normal skin vascularity, cutaneous vascular architecture, or microvascular permeability. However, healing of full-thickness skin wounds was greatly delayed in TSP-1 transgenic mice and was associated with reduced granulation tissue formation and highly diminished wound angiogenesis, Moreover, TSP-1 potently inhibited fibroblast migration in vivo and in vitro. These findings demonstrate that TSP-1 preferentially interfered with wound healing-associated angiogenesis, rather than with the angiogenesis associated with normal development and skin homeostasis, and suggest that therapeutic application of angiogenesis inhibitors might potentially be associated with impaired wound vascularization and tissue repair. C1 Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. RP Detmar, M (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Bldg 149,13th St, Charlestown, MA 02129 USA. FU NCI NIH HHS [CA 6410, CA69184, R01 CA069184] NR 53 TC 134 Z9 137 U1 2 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD JUL 3 PY 2000 VL 19 IS 13 BP 3272 EP 3282 DI 10.1093/emboj/19.13.3272 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 333LY UT WOS:000088132600011 PM 10880440 ER PT J AU Yoo, CC Levine, MS McLarney, JK Rubesin, SE Herlinger, H AF Yoo, CC Levine, MS McLarney, JK Rubesin, SE Herlinger, H TI Value of barium studies for predicting primary versus secondary non-Hodgkin's gastrointestinal lymphoma SO ABDOMINAL IMAGING LA English DT Article DE gastrointestinal lymphoma; non-Hodgkin's gastrointestinal lymphoma; barium studies ID PRIMARY GASTRIC LYMPHOMA; ESOPHAGEAL LYMPHOMA; TRACT; POLYPOSIS AB Background: To determine the predictive value of a single lesion versus multifocal disease for differentiating primary and secondary gastrointestinal (GI) lymphoma on barium studies. Methods: Our study group consisted of 90 cases of non-Hodgkin's GI lymphoma from the radiologic archives of the Armed Forces Institute of Pathology in which barium studies had been performed. Each of those studies was reviewed jointly by two of the authors to determine in a blinded fashion whether the patients had a single lesion or multifocal disease (defined as two or more discrete lesions). Medical and pathologic records were then reviewed to determine whether these patients had primary (defined as lymphoma arising in the GI tract) or secondary (defined as disseminated lymphoma with associated GI tract involvement) GI lymphoma. The final clinical diagnosis was then correlated with the radiographic findings to test the hypothesis that a single lesion is more likely to be associated with primary GI lymphoma and that multifocal disease is more likely to be associated with secondary GI lymphoma. Results: Sixty-eight patients had a single lesion in the GI tract on barium studies; 52 (76%) of these patients had primary GI lymphoma and 16 (24%) had secondary GI lymphoma. Another 22 patients had multifocal disease on barium studies; 20 (91%) of these patients had secondary GI lymphoma and two (9%) had primary GI lymphoma. Conclusion: The predictive value of a single lesion for primary GI lymphoma on barium studies was 76%, and the predictive value of multifocal disease for secondary GI lymphoma was 91%. Thus, our data suggest that it is often possible to differentiate these two forms of GI lymphoma on the basis of the radiographic findings. C1 Hosp Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. Armed Forces Inst Pathol, Dept Radiol Pathol, Washington, DC 20306 USA. RP Levine, MS (reprint author), Massachusetts Gen Hosp, Dept Radiol, 32 Fruit St, Boston, MA 02114 USA. NR 21 TC 8 Z9 13 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0942-8925 J9 ABDOM IMAGING JI Abdom. Imaging PD JUL-AUG PY 2000 VL 25 IS 4 BP 368 EP 372 DI 10.1007/s002610000055 PG 5 WC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging SC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging GA 328VJ UT WOS:000087871300005 PM 10926188 ER PT J AU Gibbs, MA Camargo, CA Rowe, BH Silverman, RA AF Gibbs, MA Camargo, CA Rowe, BH Silverman, RA TI State of the art: Therapeutic controversies in severe acute asthma SO ACADEMIC EMERGENCY MEDICINE LA English DT Editorial Material DE acute asthma; asthma; controversies; beta agonists; corticosteroids; leukotriene-modifying agents ID LEUKOTRIENE-RECEPTOR ANTAGONIST; RANDOMIZED CONTROLLED TRIAL; PLACEBO-CONTROLLED TRIAL; CHURG-STRAUSS-SYNDROME; TO-MODERATE ASTHMA; INDUCED BRONCHOCONSTRICTION; 5-LIPOXYGENASE INHIBITOR; DOUBLE-BLIND; CONTINUOUS NEBULIZATION; ALBUTEROL AB This is a transcript of the 1999 SAEM State-of-the-Art session on "Therapeutic Controversies in Severe Acute Asthma," presented at the 1999 SAEM annual meeting in Boston. The aim of this session was to address some of the current controversies in the management of acute asthma exacerbations, a major issue in emergency medicine. Despite many recent advances in asthma management, morbidity and mortality remain high. While many of us have strong feelings on how asthma patients should be treated, many of our assertions are not based on good science, and there are numerous areas of controversy. This discussion focuses on the controversy over beta agonist treatment for acute asthma, the physiology of corticosteroids in asthma, and the emergency use of leukotriene-modifying agents. C1 Carolinas Med Ctr, Dept Emergency Med, Charlotte, NC 28232 USA. Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. Univ Alberta, Div Emergency Med, Edmonton, AB, Canada. Long Isl Jewish Med Ctr, Dept Emergency Med, New York, NY USA. RP Gibbs, MA (reprint author), Carolinas Med Ctr, Dept Emergency Med, POB 32861, Charlotte, NC 28232 USA. NR 69 TC 16 Z9 17 U1 0 U2 1 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD JUL PY 2000 VL 7 IS 7 BP 800 EP 815 DI 10.1111/j.1553-2712.2000.tb02275.x PG 16 WC Emergency Medicine SC Emergency Medicine GA 331HF UT WOS:000088012200013 PM 10917332 ER PT J AU Vidal, R Calero, M Piccardo, P Farlow, MR Unverzagt, FW Mendez, E Jimenez-Huete, A Beavis, R Gallo, G Gomez-Tortosa, E Ghiso, J Hyman, BT Frangione, B Ghetti, B AF Vidal, R Calero, M Piccardo, P Farlow, MR Unverzagt, FW Mendez, E Jimenez-Huete, A Beavis, R Gallo, G Gomez-Tortosa, E Ghiso, J Hyman, BT Frangione, B Ghetti, B TI Senile dementia associated with amyloid beta protein angiopathy and tau perivascular pathology but not neuritic plaques in patients homozygous for the APOE-epsilon 4 allele SO ACTA NEUROPATHOLOGICA LA English DT Article DE Alzheimer's disease; cerebral amyloid angiopathy; amyloid beta protein; neurofibrillary tangles; senile plaques ID HEREDITARY CEREBRAL-HEMORRHAGE; APOLIPOPROTEIN-E EPSILON-4; TANGLE PREDOMINANT FORM; LEWY BODY DISEASE; ALZHEIMERS-DISEASE; DUTCH TYPE; GENE; MUTATION; VARIANT; PRECURSOR AB Amyloid beta protein deposition in cortical and leptomeningeal vessels, causing the most common type of cerebral amyloid angiopathy, is found in sporadic and familial Alzheimer's disease (AD) and is the principal feature in the hereditary cerebral hemorrhage with amyloidosis, Dutch type. The presence of the Apolipoprotein E (APOE)-epsilon 4 allele has been implicated as a risk factor for AD and the development of cerebral amyloid angiopathy in AD. We report clinical, pathological and biochemical studies on two APOE-epsilon 4 homozygous subjects, who had senile dementia and whose main neuropathological feature was a severe and diffuse amyloid angiopathy associated with perivascular tau neurofibrillary pathology. Amyloid beta protein and ApoE immunoreactivity were observed in leptomeningeal vessels as well as in medium-sized and small vessels and capillaries in the parenchyma of the neocortex, hippocampus, thalamus, cerebellum, midbrain, pens, and medulla. The predominant peptide form of amyloid beta protein was that terminating at residue Val(40), as determined by immunohistochemistry, amino acid sequence and mass spectrometry analysis. A crown of tau-immunopositive cell processes was consistently present around blood vessels. DNA sequence analysis of the Amyloid Precursor Protein gene and Presenilin-1 (PS-1) gene revealed no mutations. In these APOE-epsilon 4 homozygous patients, the pathological process differed from that typically seen in AD in that they showed a heavy burden of perivascular tau-immunopositive cell processes associated with severe amyloid beta protein angiopathy, neurofibrillary tangles, some cortical Lewy bodies and an absence of neuritic plaques. These cases emphasize the concept that tau deposits may be pathogenetically related to amyloid beta protein deposition. C1 Indiana Univ, Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA. NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USA. NYU, Sch Med, Dept Neurol, New York, NY 10016 USA. NYU, Sch Med, Dept Psychiat, New York, NY 10016 USA. Ctr Nacl Biotecnol, Unidad Anal Estructal Prot, Madrid, Spain. Massachusetts Gen Hosp, Alzheimer Res Unit, Charleston, MA 02129 USA. RP Ghetti, B (reprint author), Indiana Univ, Sch Med, Dept Pathol & Lab Med, 635 Barnhill Dr, Indianapolis, IN 46202 USA. RI Calero, Miguel/H-5691-2015 OI Calero, Miguel/0000-0001-5366-3324 FU NIA NIH HHS [AG08721, AG10973, U24 AG021886]; NIAMS NIH HHS [AR02594] NR 45 TC 42 Z9 45 U1 0 U2 2 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 JUL PY 2000 VL 100 IS 1 BP 1 EP 12 PG 12 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 328KJ UT WOS:000087849800001 PM 10912914 ER PT J AU Ali, SF Haung, P Itzhak, Y AF Ali, SF Haung, P Itzhak, Y TI Role of peroxynitrite in methamphetamine-induced dopaminergic neurotoxicity and sensitization in mice SO ADDICTION BIOLOGY LA English DT Article; Proceedings Paper CT XXI Collegium-Internationale-Neuropsycho-Pharmacologium Meeting CY JUL, 1998 CL GLASGOW, SCOTLAND SP Collegium Int Neuropsycho Pharmacologium ID NITRIC-OXIDE SYNTHASE; INDUCED BEHAVIORAL SENSITIZATION; HEAT-SHOCK-PROTEIN; SEROTONERGIC NEUROTOXICITY; ENVIRONMENTAL-TEMPERATURE; PHARMACOLOGICAL AGENTS; INDUCED HYPERTHERMIA; LIPID-PEROXIDATION; STRIATAL DOPAMINE; DEFICIENT MICE AB Methamphetamine (METH)-induced dopaminergic neurotoxicity is thought to be associated with the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Recently, we have reported that copper/zinc(CuZn)-superoxide dismutase transgenic mice are resistant to METH-induced neurotoxicity. In the present study, we examined the role of the neuronal nitric oxide synthase (nNOS), susceptibility of nNOS knockout (KO) mice and sensitization to psychostimulants after neurotoxic doses of METH. Male Swiss Webster mice were treated with or without 7-nitroindazole (7-NI) along with METH (5 mg/kg,ip,q 3 h x 3) and were sacrificed 72 h after the last METH injection. Dopamine (DA) and dopamine transporter (DAT) binding sites were determined in striatum from saline and METH-treated animals. 7-NI completely protected against the depletion of DA, and DAT in striatum. In follow-up experiments nNOS KO mice along with appropriate control (C57BL/6N, SV129 and B6FSV129) mice were treated with METH (5 mg/kg,ip, q 3 h x 3) and were sacrificed 72 h after dosing. This schedule of METH administrations resulted in only 10-20% decrease in tissue content of DA and no apparent change in the number of DAT binding sites in nNOS KO mice. However, this regime of METH resulted in a significant decrease in the content of DA as well as DAT binding sires in the wild-type animals. Pre-exposure to single or multiple doses of METH resulted in a marked locomotion sensitization in response to METH. However, the nNOS KO mice show no sensitization in response to METH after single or multiple injections of METH. Therefore, these studies strongly suggest the role of peroxynitrite, nNOS and DA system in METH-induced neurotoxicity and behavioral sensitization. C1 US FDA, Natl Ctr Toxicol Res, Neurochem Lab, Div Neurotoxicol, Jefferson, AR 72079 USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charleston, MA USA. Univ Miami, Sch Med, Dept Psychiat & Behav Sci, Miami, FL USA. RP Ali, SF (reprint author), US FDA, Natl Ctr Toxicol Res, Neurochem Lab, Div Neurotoxicol, HFT-132, Jefferson, AR 72079 USA. NR 62 TC 3 Z9 3 U1 0 U2 0 PU CARFAX PUBLISHING PI BASINGSTOKE PA RANKINE RD, BASINGSTOKE RG24 8PR, HANTS, ENGLAND SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD JUL PY 2000 VL 5 IS 3 BP 331 EP 341 DI 10.1111/j.1369-1600.2000.tb00200.x PG 11 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 339TB UT WOS:000088493000012 PM 20575850 ER PT J AU Pettinati, HM Volpicelli, JR Kranzler, HR Luck, G Rukstalis, MR Cnaan, A AF Pettinati, HM Volpicelli, JR Kranzler, HR Luck, G Rukstalis, MR Cnaan, A TI Sertraline treatment for alcohol dependence: Interactive effects of medication and alcoholic subtype SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article; Proceedings Paper CT 37th Annual Meeting of the American-College-of-Neuropsychopharmacology CY DEC 11-18, 1998 CL LAS CROABAS, PUERTO RICO SP Amer Coll Neuropsychopharmacol DE alcoholism; alcoholic subtypes; SSRI pharmacotherapy; sertraline ID PLACEBO-CONTROLLED TRIAL; ETHANOL INTAKE; B ALCOHOLICS; DOUBLE-BLIND; FLUOXETINE; TRYPTOPHAN; ONSET; CONSUMPTION; BEHAVIOR; DRINKERS AB Background: Characteristic behaviors of some alcohol-dependent individuals, e.g., binge drinking, comorbid psychopathology, and some types of alcohol-related problems, have been linked to abnormalities in serotonergic neurotransmission. However, studies that have evaluated serotonergic pharmacotherapy for reducing drinking have yielded conflicting results. One explanation for these findings is a general failure to distinguish alcohol subgroups that may be differentiated on the basis of serotonergic abnormalities. However, in 1996, Kranzler and colleagues reported that Type B alcoholics, who are characterized by high levels of premorbid vulnerability, alcohol dependence severity, and comorbid psychopathology, showed less favorable drinking outcomes in response to treatment with fluoxetine, a serotonin reuptake inhibitor, than with placebo. This medication effect was not seen in Type A alcoholics, i.e., those with lower risk/severity of alcoholism and psychopathology. The aim of the present study was to explore the validity of differential responding by alcohol-dependent subtypes using the serotonin reuptake inhibitor, sertraline. Methods: A k-means clustering procedure was applied to a sample of alcohol-dependent subjects enrolled in a 14-week, placebo-controlled trial of 200 mg/day of sertraline, classifying them into lower-risk severity (Type A: n = 55) and higher-risk/severity (Type B: n = 45) subgroups. Results: A significant interaction between alcoholic subtype and medication condition was found, confirming the findings of Kranzler and colleagues that alcoholic subtypes responded differentially to serotonergic medication. Somewhat at variance with their results, however, the present study showed that the lower risk/severity (Type A) subjects had more favorable outcomes when treated with sertraline compared to placebo. Conclusions: Alcoholic subtypes differentially responded to sertraline when used as a treatment to reduce alcohol drinking, with one subtype having more favorable outcomes. Subtyping alcoholics may help to resolve conflicting findings in the literature on serotonergic treatment of alcohol dependence. C1 Univ Penn, Sch Med, Dept Psychiat, Addict Treatment Res Ctr, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Psychiat, Ctr Study Addict, Philadelphia, PA 19104 USA. Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. Univ Connecticut, Sch Med, Alcohol Res Ctr, Dept Psychiat, Farmington, CT USA. RP Pettinati, HM (reprint author), Univ Penn, Sch Med, Dept Psychiat, Addict Treatment Res Ctr, Philadelphia, PA 19104 USA. FU NIAAA NIH HHS [K02-AA00239, R01-AA09544] NR 53 TC 144 Z9 148 U1 2 U2 6 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 JUL PY 2000 VL 24 IS 7 BP 1041 EP 1049 DI 10.1097/00000374-200007000-00015 PG 9 WC Substance Abuse SC Substance Abuse GA 334XV UT WOS:000088212400015 PM 10924008 ER PT J AU Encke, J Wands, JR AF Encke, J Wands, JR TI Ethanol inhibition: The humoral and cellular immune response to hepatitis C virus NS5 protein after genetic immunization SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE hepatitis C virus; nonstructural proteins; DNA immunization; ethanol inhibition ID ALCOHOLIC LIVER-DISEASE; CYTOKINE-EXPRESSING PLASMIDS; HEPATOCELLULAR-CARCINOMA; B VIRUS; DNA VACCINATION; CORE PROTEIN; INFECTION; RNA; PREVALENCE; ANTIBODIES AB Background: The combination of chronic hepatitis C virus (HCV) and ethanol may increase viral replication, impair cellular immunity, and result in severe and progressive liver disease. Because HCV nonstructural proteins play a major role in viral elimination, we examined the cellular and humoral immune responses after genetic immunization against NS5 in a chronic ethanol mouse model. Methods: Mice were fed an ethanol or isocaloric pair-fed control liquid diet and were immunized with HCV NS5-expression plasmid. Results: The humoral and cellular arms of the immune system were significantly impaired in ethanol-fed mice. Abstinence partially reversed the inhibitory effects on antibody levels and the CD4+ proliferative immune response but did not restore the CD8+ cytotoxic T-cell response to this HCV nonstructural protein. Furthermore, we determined whether murine interleukin-2 coadministration with the NS5 expression plasmid would reverse the inhibitory effects of chronic ethanol consumption; again, partial restoration was observed for B-cell and CD4+ T-cell activity, but not for cytotoxic T cells. Conclusions: These results suggest that the high rate of chronic HCV infection in alcoholics may be due to ethanol's effects on antiviral immune responses. C1 Harvard Univ, Sch Med, Mol Hepatol Lab, Massachusetts Gen Hosp,Canc Ctr, Charlestown, MA USA. RP Wands, JR (reprint author), Rhode Isl Hosp, Liver Res Ctr, 55 Claverick St,4th Floor, Providence, RI 02903 USA. FU NCI NIH HHS [CA-35711]; NIAAA NIH HHS [AA-20169, AA-02666] NR 46 TC 31 Z9 31 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 JUL PY 2000 VL 24 IS 7 BP 1063 EP 1069 DI 10.1097/00000374-200007000-00018 PG 7 WC Substance Abuse SC Substance Abuse GA 334XV UT WOS:000088212400018 PM 10924011 ER PT J AU Meisenhelder, JB Chandler, EN AF Meisenhelder, JB Chandler, EN TI Prayer and health outcomes in church members SO ALTERNATIVE THERAPIES IN HEALTH AND MEDICINE LA English DT Article ID RELIGIOUS SERVICES; MEDICAL OUTCOMES; DEPRESSION; ATTENDANCE; MORTALITY; RELIABILITY; VALIDITY; OLDER; RISK AB Context . This study adds to the existing research on religion and health by focusing on the specific practice of prayer and its relationship to health outcomes. Objectives . The purpose of this study is to examine the relationship of frequency of prayer to 8 categories of physical and mental health. Design . The Presbyterian Church, USA, performed data collection as part of an ongoing research program. Members of the Presbyterian Church were randomly selected from the national population and surveyed by mail on their frequency of prayer and their health status, as measured by the Medical Outcomes Study Short-form 36 Health Survey. C1 Massachusetts Gen Hosp, Inst Hlth Profess, Boston, MA 02114 USA. RP Chandler, EN (reprint author), Massachusetts Gen Hosp, Inst Hlth Profess, Boston, MA 02114 USA. NR 51 TC 14 Z9 14 U1 0 U2 0 PU INNOVISION COMMUNICATIONS PI ALISO VIEJO PA 101 COLUMBIA, ALISO VIEJO, CA 92656 USA SN 1078-6791 J9 ALTERN THER HEALTH M JI Altern. Ther. Health Med. PD JUL PY 2000 VL 6 IS 4 BP 56 EP 60 PG 5 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 330YM UT WOS:000087989300009 PM 10895514 ER PT J AU Ortiz, F Fitten, LJ AF Ortiz, F Fitten, LJ TI Barriers to healthcare access for cognitively impaired older Hispanics SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE access barrier; aged; cognitively impaired; dementia; elderly; healthcare access; Hispanics ID ILLNESS RATING-SCALE; MEXICAN-AMERICANS; ELDERLY HISPANICS; MENTAL-HEALTH; PSYCHOLOGICAL DISTRESS; ALZHEIMERS-DISEASE; LOS-ANGELES; SERVICES; COMMUNITY; PREVALENCE AB This study describes the development of the Barriers to Healthcare Access Survey (BHAS) used to evaluate seven barrier factors believed to influence healthcare access Fur elderly Hispanics with memory or cognitive problems. This study further reports the results: of the BHAS applied to a community sample of cognitively impaired older Hispanics and their caregivers. The study includes (1) The BHAS's development and procedures to establish instrument validity and reliability; (2) Interviews with the BHAS on 65 cognitively impaired Hispanics who were undergoing full diagnostic assessment for dementia and their caregivers. The most frequently perceived healthcare barriers reported in our study were related to (1) personal beliefs (38%), (2) language proficiency (33%), and (3) economic status (13%). The BHAS possesses the requisite psychometric properties to be an effective instrument for an initial survey of perceived barriers to access health care for low-education, cognitively impaired, elderly Hispanic patients. The findings suggest that perceptions regarding illness, health consequences of aging, and beliefs about the utility of medicine do, in fact, influence healthcare use by older Hispanic patients with dementia. Language proficiency and economic status remain common barriers among elderly Hispanic subgroups, but when these barriers are experienced by the cognitively impaired, serious healthcare implications: ensue, especially delay in early diagnosis and treatment. C1 Greater Los Angeles Vet Affairs Healthcare Syst, N Hills, CA 91343 USA. Univ Calif Los Angeles, Sch Med, Alzheimers Dis Res Ctr, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA USA. RP Ortiz, F (reprint author), Greater Los Angeles Vet Affairs Healthcare Syst, Sepulveda Campus,16111 Plummer St 116A-9, N Hills, CA 91343 USA. FU NIA NIH HHS [P50AG16570] NR 57 TC 34 Z9 34 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD JUL-SEP PY 2000 VL 14 IS 3 BP 141 EP 150 DI 10.1097/00002093-200007000-00005 PG 10 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 350PP UT WOS:000089110600005 PM 10994655 ER PT J AU Giugliano, RP McCabe, CH Sequeira, RF Frey, MJ Henry, TD Piana, RN Tamby, JF Jensen, BK Nicolas, SB Jennings, LK Wise, RJ Braunwald, E AF Giugliano, RP McCabe, CH Sequeira, RF Frey, MJ Henry, TD Piana, RN Tamby, JF Jensen, BK Nicolas, SB Jennings, LK Wise, RJ Braunwald, E CA TIMI 15A 15B Investigators TI First report of an intravenous and oral glycoprotein IIb/IIIa inhibitor (RPR 109891) in patients with recent acute coronary syndromes: Results of the TIMI 15A and 15B trials SO AMERICAN HEART JOURNAL LA English DT Article ID PLATELET-AGGREGATION; BINDING; INDUCTION AB Background RPR 109891 is a modified tetrapeptide glycoprotein IIb/IIIa inhibitor available in intravenous and oral formulations. Two phase II dose-ranging studies were performed to investigate pharmacodynamics and safety in acute coronary syndromes. Methods The Thrombolysis In Myocardial Infarction (TIMI) 15A trial was a randomized, open-label, study of RPR 109891 administered intravenously for 24 to 96 hours in 91 patients. TIMI 15B was a randomized, double-blind comparison of intravenous RPR 109891 plus 4 weeks of oral RPR 109891 (n = 142) compared with placebo (n = 50). Results Intravenous RPR 109891 exhibited a dose-response inhibition of platelet aggregation; mean inhibition after a bolus ranged from 53% to 92%, and at steady state 49% to 98%. Oral RPR 109891 demonstrated less platelet inhibition (peaks, range 48% to 59%; troughs, range 18% to 39%). Mean glycoprotein IIb/IIIa receptor occupancy and platelet inhibition were highly correlated (r = 0.82, 95% confidence interval 0.74-0.88). There were trends for increased major hemorrhage (10% vs 6%, P = .57), thrombocytopenia <90,000 cells/mm(3) (13% vs 4%, P = .11), and profound thrombocytopenia <20,000 (3.5% vs 0%, P = .33) with intravenous plus oral RPR 109891 compared with placebo. In 3 of 5 cases of profound thrombocytopenia, RPR 109891 had been interrupted because of bypass surgery, and a precipitous fall in platelet count occurred after the first postoperative oral dose. Conclusions Intravenous RPR 109891 is a potent, predictable, dose-related platelet inhibitor. Oral RPR 109891 (less than or equal to 600 mg/d) achieves moderate platelet inhibition. Interrupted glycoprotein IIb/IIIa blockade may be associated with a higher risk of profound thrombocytopenia and deserves closer examination in future studies. C1 Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Jackson Mem Hosp, Div Cardiol, Miami, FL 33136 USA. Heart Ctr Sarasota, Sarasota, FL USA. Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. Rhone Poulenc Rorer, Collegeville, PA USA. Rhone Poulenc Rorer, Antony, France. Univ Tennessee, Vasc Biol Program, Memphis, TN USA. RP Giugliano, RP (reprint author), TIMI Study Off, 333 Longwood Ave,Suite 402, Boston, MA 02115 USA. NR 16 TC 20 Z9 21 U1 1 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 JUL PY 2000 VL 140 IS 1 BP 81 EP + DI 10.1067/mhj.2000.107172 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 334CX UT WOS:000088168900015 PM 10874267 ER PT J AU Lewin, S Goldberg, L Dec, GW AF Lewin, S Goldberg, L Dec, GW TI The spectrum of pulmonary abnormalities on computed chest tomographic imaging in patients with advanced heart failure SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article AB Noncontrast chest computed tomographic imaging was performed in 71 consecutive patients with advanced heart failure during initial cardiac transplant evaluation. Benign mediastinal adenopathy (nodes >1.0 cm in diameter) was detected in 35% of this group. C1 Massachusetts Gen Hosp, Div Cardiol, Heart Failure & Transplantat Ctr, Heart Failure & Transplantat Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Buffalo, Sch Med, Buffalo, NY USA. Univ Penn, Div Cardiol, Philadelphia, PA 19104 USA. RP Dec, GW (reprint author), Massachusetts Gen Hosp, Div Cardiol, Heart Failure & Transplantat Ctr, Heart Failure & Transplantat Serv, Bigelow 645 Fruit St, Boston, MA 02114 USA. NR 3 TC 15 Z9 15 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 1 PY 2000 VL 86 IS 1 BP 98 EP + DI 10.1016/S0002-9149(00)00837-7 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 327UU UT WOS:000087812900021 PM 10867103 ER PT J AU Huang, LW Garrett, AP Schorge, JO Muto, MG Bell, DA Welch, WR Berkowitz, RS Mok, SC AF Huang, LW Garrett, AP Schorge, JO Muto, MG Bell, DA Welch, WR Berkowitz, RS Mok, SC TI Distinct allelic loss patterns in papillary serous carcinoma of the peritoneum SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE peritoneal carcinoma; loss of heterozygosity; BRCA1; ovarian cancer ID EPITHELIAL OVARIAN CARCINOMAS; TUMOR-SUPPRESSOR GENES; DELETION UNIT; HUMAN BORDERLINE; BRCA1 GENE; CANCER; EXTRAOVARIAN; MUTATIONS; SURFACE; GRADE AB Tumor and normal tissues from 55 patients with papillary serous carcinoma of the peritoneum (PSCP) were analyzed Polymerase chain reaction amplification of tandem repeat polymorphism was used to screen for loss of heterozygosity (LOH). We mapped 22 oligonucleotide primers to chromosomes 1p, 3p, 6q, 7q, 9p, 11p, 17p, 17q, and Xq. Germline BRCA1 mutation status of 43 patients was determined previously. High frequencies (>30%) of LOH in PSCP were observed on 6q, 9p, 17p, 17q, and Xq. Compared with allelic loss of serous epithelial ovarian carcinoma (SEOC), the frequency of LOH was significantly lower in PSCP on 1p, 7q, 11p, 17p, and 17q. Of 43 cases screened for germline BRCA1 mutations, 9 cases were identified with mutations. The frequencies of LOH were not significantly different among the BRCA1-related and BRCA1-unrelated PSCP cases. The high LOH rate identified on 6q, 9p, 17p, 17q, and Xq in PSCP suggests that candidate turner suppressor genes residing in these regions may be important for the development of the tumor. Compared with allelic loss of SEOC, PSCP exhibits a significantly lower frequency of LOH on chromosomes 1p36, 7q31.3, 11p15.1, 17p13.1, and 17q21. An increase in susceptibility to the acquisition of allelic loss in BRCA1-related PSCP cannot be identified. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol,Lab & Div Gynecol Oncol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Shin Kong Wu Ho Su Mem Hosp, Dept Obstet & Gynecol, Taipei, Taiwan. RP Mok, SC (reprint author), Lab Gynecol Oncol, BLI-449,221 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [R01CA69453, R01CA63381, R01CA69291] NR 29 TC 11 Z9 11 U1 0 U2 0 PU AMER SOC CLIN PATHOLOGISTS 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 JUL PY 2000 VL 114 IS 1 BP 93 EP 99 PG 7 WC Pathology SC Pathology GA 327WV UT WOS:000087818000011 PM 10884804 ER PT J AU Vakil, N Rhew, D Soll, A Ofman, JJ AF Vakil, N Rhew, D Soll, A Ofman, JJ TI The cost-effectiveness of diagnostic testing strategies for Helicobacter pylori SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID UREA BREATH TEST; PEPTIC-ULCER DISEASE; DYSPEPTIC PATIENTS; NONINVASIVE TESTS; UNITED-STATES; ENZYME-IMMUNOASSAY; GOLD STANDARD; ANTIBODY-TEST; PRIMARY-CARE; FLEXSURE HP AB OBJECTIVE: Several noninvasive methods are now available for diagnosing Helicobacter pylori infection. Because the prevalence of H. pylori infection is variable in patients requiring testing, the optimal testing strategies may vary under different conditions. The aim of this study was to evaluate the cost-effectiveness of competing diagnostic strategies for H. pylori in patients with varying H. pylori prevalence. METHODS: A decision analysis was performed comparing the costs per number of correct diagnoses achieved by alternative sequential testing strategies. Estimates of H. pylori prevalence and test characteristics were derived from a systematic review of the MEDLINE bibliographic database. Cost estimates were derived from the 2000 Medicare Fee Schedule. RESULTS: The enzyme-linked immunosorbent assay (ELISA) test had the lowest cost per correct diagnosis at low (30%), intermediate (60%), and high (90%) prevalence ($90-$95/correct diagnosis), but its diagnostic accuracy was low (80-84%). At low and intermediate prevalence the stool test was more accurate (93%), with an average cost of $126-$127 per correct diagnosis. Additional confirmatory testing of positive or negative tests increased the diagnostic accuracy of the stool test, but had high incremental costs. ELISA testing was preferable when prevalence rates were very high (90%), and using a confirmatory urea breath test for negative ELISA tests increased the diagnostic accuracy to 96%, with modest incremental costs. If the cost of the breath test was <$50 or if the cost of the stool test is >$82, breath testing became preferable to stool testing. If the cost of the stool test fell to <$20, it became preferable to ELISA. Similarly, if the cost of the ELISA serology was >$39 then stool testing became preferable at all prevalence rates. Fingerstick whole blood tests were not cost-effective. CONCLUSIONS: The choice of an initial test for H. pylori detection depends on the prevalence of H. pylori infection and the value placed on increased diagnostic accuracy. Al though ELISA results in the lowest cost-effectiveness ratios, in patients at low-intermediate pretest probability of infection, the stool test provides increased accuracy, with modest incremental costs. (C) 2000 by Am. Cell. of Gastroenterology. C1 Univ Wisconsin, Sch Med, Sinai Samaritan Med Ctr, Div Gastroenterol,Dept Med, Milwaukee, WI 53233 USA. Zynx Hlth Inc, Los Angeles, CA USA. W Los Angeles Vet Affairs Med Ctr, Dept Med, Los Angeles, CA 90073 USA. Cedars Sinai Med Ctr, Div Gastroenterol, Dept Med, Los Angeles, CA 90048 USA. Cedars Sinai Med Ctr, Div Gastroenterol, Dept Hlth Serv Res, Los Angeles, CA 90048 USA. RP Vakil, N (reprint author), Univ Wisconsin, Sch Med, Sinai Samaritan Med Ctr, Div Gastroenterol,Dept Med, 945 N 12th St,Room 4040, Milwaukee, WI 53233 USA. NR 89 TC 53 Z9 54 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD JUL PY 2000 VL 95 IS 7 BP 1691 EP 1698 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 335DX UT WOS:000088229000013 PM 10925969 ER PT J AU Goodman, FR Bacchelli, C Brady, AF Brueton, LA Fryns, JP Mortlock, DP Innis, JW Holmes, LB Donnenfeld, AE Feingold, M Beemer, FA Hennekam, RCM Scambler, PJ AF Goodman, FR Bacchelli, C Brady, AF Brueton, LA Fryns, JP Mortlock, DP Innis, JW Holmes, LB Donnenfeld, AE Feingold, M Beemer, FA Hennekam, RCM Scambler, PJ TI Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID URINARY-TRACT ABNORMALITIES; 2 UNRELATED FAMILIES; HOXD13; GENE; COMPLEX; UPDATE AB Hand-foot-genital syndrome (HFGS) is a rare, dominantly inherited condition affecting the distal limbs and genitourinary tract. A nonsense mutation in the homeobox of HOXA13 has been identified in one affected family, making HFGS the second human syndrome shown to be caused by a HOX gene mutation. We have therefore examined HOXA13 in two new and four previously reported families with features of HFGS. In families 1, 2, and 3, nonsense mutations truncating the encoded protein N-terminal to or within the homeodomain produce typical limb and genitourinary abnormalities; in family 4, an expansion of an N-terminal polyalanine tract produces a similar phenotype; in family 5, a missense mutation, which alters an invariant domain, produces an exceptionally severe limb phenotype; and in family 6, in which limb abnormalities were atypical, no HOXA13 mutation could be detected. Mutations in HOXA13 can therefore cause more-severe limb abnormalities than previously suspected and may act by more than one mechanism. C1 Inst Child Hlth, Mol Med Unit, London WC1N 1EH, England. Northwick Pk Hosp, Kennedy Galton Ctr, London, England. Katholieke Univ Leuven, Ctr Human Genet, Louvain, Belgium. Stanford Univ, Beckman Ctr, Dept Dev Biol, Stanford, CA 94305 USA. Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. Harvard Univ, Massachusetts Gen Hosp, Dept Genet & Teratol, Boston, MA USA. Penn Hosp, Genet Sect, Philadelphia, PA USA. Natl Birth Defects Ctr, Waltham, MA USA. Univ Med Ctr, Dept Med Genet, Utrecht, Netherlands. Univ Amsterdam, Dept Pediat, Amsterdam, Netherlands. Univ Amsterdam, Inst Human Genet, Amsterdam, Netherlands. RP Goodman, FR (reprint author), Inst Child Hlth, Mol Med Unit, 30 Guilford St, London WC1N 1EH, England. RI Scambler, Peter/C-4998-2008; Mortlock, Douglas/C-9981-2010; Morlock, Doug/C-3482-2012 OI Scambler, Peter/0000-0002-1487-4628; FU NIAMS NIH HHS [P60 AR20557]; NICHD NIH HHS [HD34059] NR 28 TC 126 Z9 134 U1 1 U2 5 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL PY 2000 VL 67 IS 1 BP 197 EP 202 DI 10.1086/302961 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 347JY UT WOS:000088926900021 PM 10839976 ER PT J AU Korosi, A Kahn, T Kalb, T Uribarri, J AF Korosi, A Kahn, T Kalb, T Uribarri, J TI Marked hyperlactatemia associated with severe alkalemia in a patient with thrombotic thrombocytopenic purpura SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE alkalosis; lactate; thrombotic thrombocytopenic purpura (TTP); hypoxia ID METABOLIC ALKALOSIS; PH AB This report describes a case of severe alkalemia associated with a blood lactate level greater than 13 mEq/L in a patient without evidence of hypotension or hypoxemia. The patient, who had the clinical manifestations of thrombotic thrombocytopenic purpura (TTP), developed the alkalemia from an acute respiratory alkalosis superimposed on an existing metabolic alkalosis. Profound alkalemia may impair oxygen delivery because of stronger hemoglobin-oxygen affinity, vasoconstriction, and alterations in the redox potential of cytochrome c. We suggest that the synergistic effects of a sudden, extreme alkalemia and the localized tissue hypoxia that resulted from extensive microvascular thrombi secondary to TTP caused the patient's hyperlactatemia. (C) 2000 by the National Kidney Foundation, Inc. C1 Mt Sinai Med Ctr, Div Nephrol, New York, NY 10029 USA. Mt Sinai Med Ctr, Dvi Pulmonol, New York, NY 10029 USA. Bronx Vet Affairs Med Ctr, Renal Sect, Bronx, NY USA. RP Korosi, A (reprint author), Mt Sinai Med Ctr, Div Nephrol, Box 1243,1 Gustave L Levy Pl, New York, NY 10029 USA. NR 13 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 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUL PY 2000 VL 36 IS 1 BP art. no. EP e6 DI 10.1053/ajkd.2000.8303 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 331FM UT WOS:000088007700041 PM 10873905 ER PT J AU Romero-Rangel, T Stavrou, P Cotter, J Rosenthal, P Baltatzis, S Foster, CS AF Romero-Rangel, T Stavrou, P Cotter, J Rosenthal, P Baltatzis, S Foster, CS TI Gas-permeable scleral contact lens therapy in ocular surface disease SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID MEDICAL APPLICATIONS; DISORDERS AB PURPOSE: To describe the therapeutic benefits of nonfenestrated gas-permeable scleral contact lenses in the management of patients with ocular surface disease. METHODS: The charts of 49 consecutive patients (76 eyes) with ocular surface disease whose management included the use of gas-permeable scleral contact lenses were reviewed. We also developed a questionnaire to assess the impact of lens wear on subjective aspects of activities of daily living. RESULTS: The mean age of the 49 patients was 44.6 years (range, 3 to 87 years); 31 patients were female and 18 mere male. The most common indication for fitting of the lenses was Stevens-Johnson syndrome (54 [71%] of the 76 eyes). Other indications included ocular cicatricial pemphigoid, exposure keratitis, toxic epidermal necrolysis, postherpetic keratitis, congenital deficiency of meibomian glands, superior limbal keratoconjunctivitis, Sjogren syndrome, and inflammatory corneal degeneration. The mean follow-up was 33.6 months (range, 2 to 144 months). Improvement in best corrected visual acuity (defined as a gain of 2 or more Snellen lines) was observed in 40 (53%) of the eyes, Zn eight (53%) of the 15 eyes with active corneal epithelial defects at the time of lens fitting, the defects healed, whereas in the remaining seven eyes the corneal epithelial defects remained unchanged. Forty-five (92%) of the 49 patients reported improvement in their quality of life as a result of reduction of photophobia and discomfort. The mean wearing time of the gas-permeable scleral contact lenses was 13.7 hours per day (range, 4 to 18 hours), Many patients had preparatory surgical procedures before lens fitting (for example, punctal occlusion or mucous membrane grafting), and some had visual rehabilitation surgical procedures (for example, keratoplasty and/or cataract surgery) after lens fitting. CONCLUSIONS: Gas-permeable scleral contact lens wear provides an additional effective strategy in the surface management and visual rehabilitation of patients with severe ocular surface disease. (C) 2000 by Elsevier Science inc. All rights reserved. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med,Ocular Immunol & Uveitis Serv, Dept Ophthalmol,Hilles Immunol Lab, Boston, MA 02114 USA. Boston Fdn Sight, Boston, MA USA. Univ Athens, Athens, Greece. RP Foster, CS (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med,Ocular Immunol & Uveitis Serv, Dept Ophthalmol,Hilles Immunol Lab, 243 Charles St, Boston, MA 02114 USA. NR 34 TC 94 Z9 96 U1 1 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD JUL PY 2000 VL 130 IS 1 BP 25 EP 32 DI 10.1016/S0002-9394(00)00378-0 PG 8 WC Ophthalmology SC Ophthalmology GA 355UN UT WOS:000089407100004 PM 11004256 ER PT J AU Rosenthal, P Cotter, JM Baum, J AF Rosenthal, P Cotter, JM Baum, J TI Treatment of persistent corneal epithelial defect with extended wear of a fluid-ventilated gas-permeable scleral contact lens SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID OCULAR-SURFACE; TRANSPLANTATION; KERATITIS; RISK AB PURPOSE: To report treatment of persistent corneal epithelial defects unresponsive to other therapies by extended wear of a fluid-ventilated gas-permeable scleral contact lens. METHODS: In this retrospective study, 14 eyes of 13 consecutive patients referred for the treatment of persistent corneal epithelial defects that failed to heal with conventional therapies or developed epithelial defects after penetrating keratoplasty for persistent corneal epithelial defects were fitted with. an extended-wear gas-permeable scleral lens. These included seven eyes of six patients with Stevens-Johnson syndrome and seven eyes of seven patients who did not have Stevens-Johnson syndrome. Twelve eyes had undergone recent penetrating keratoplasty. All 14 eyes were fitted with a gas-permeable scleral contact lens designed to avoid the intrusion of air bubbles under its optic. An antibiotic and corticosteroid were added to the lens fluid reservoir or instilled before each lens insertion in 12 of 14 eyes. The lenses were worn continuously except for brief periods of removal for purposes of cleaning, replacement of the lens fluid reservoir, and examination and photography of the cornea, RESULTS: Five of the seven persistent corneal epithelial defects associated with Stevens-Johnson syndrome healed. The persistent corneal epithelial defects of four of these eyes re-epithelialized within 7 days, and a fifth healed in 27 days of gas-permeable scleral lens extended wear. A sixth persistent corneal epithelial defect that failed to heal initially re-epithelialized after a subsequent penetrating keratoplasty and gas-permeable scleral lens extended wear. The seventh eye healed after 3 days of gas-permeable scleral lens extended wear, but the persistent corneal epithelial defect subsequently recurred. Three of seven non-Stevens-Johnson syndrome persistent corneal epithelial defects re-epithelialized within 36 hours, 6 days, and 36 days, respectively. Of the six (six of 14) persistent corneal epithelial defects that failed to heal with a gas-permeable scleral lens extended wear, one subsequently healed after multiple amniotic membrane grafts, Microbial keratitis occurred in four eyes (four of 14) and graft failure in one eye, all of which required repeat penetrating keratoplasty. CONCLUSION: Extended wear of an appropriately designed gas-permeable scleral contact lens was effective in promoting the healing of persistent corneal epithelial defects in some eyes that failed to heal after other therapeutic measures. Re-epithelialization appears to be aided by a combination of oxygenation, moisture, and protection of the fragile epithelium afforded by the scleral lens. However, microbial keratitis represents a significant risk. (C) 2000 by Elsevier Science Inc. All rights reserved. C1 Boston Eye Associates, Boston Fdn Sight, Boston, MA USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Rosenthal, P (reprint author), 1244 Boylston St,Suite 202, Chestnut Hill, MA 02467 USA. NR 15 TC 70 Z9 72 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD JUL PY 2000 VL 130 IS 1 BP 33 EP 41 DI 10.1016/S0002-9394(00)00379-2 PG 9 WC Ophthalmology SC Ophthalmology GA 355UN UT WOS:000089407100005 PM 11004257 ER PT J AU Senger, DR Van de Water, L AF Senger, DR Van de Water, L TI VEGF expression by epithelial and stromal cell compartments - Resolving a controversy SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Editorial Material ID ENDOTHELIAL GROWTH-FACTOR; VASCULAR-PERMEABILITY FACTOR; MESSENGER-RNA STABILITY; FACTOR VPF/VEGF; FACTOR GENE; HYPOXIA; ANGIOGENESIS; INDUCTION; RECEPTORS; TUMORS C1 Beth Israel Med Ctr, Dept Pathol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA USA. Shriners Burns Hosp, Boston, MA USA. RP Senger, DR (reprint author), Beth Israel Med Ctr, Dept Pathol, Boston, MA 02215 USA. FU NCI NIH HHS [CA77357, R01 CA077357]; NIGMS NIH HHS [GM56442, R01 GM056442] NR 33 TC 12 Z9 12 U1 0 U2 2 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUL PY 2000 VL 157 IS 1 BP 1 EP 3 DI 10.1016/S0002-9440(10)64508-7 PG 3 WC Pathology SC Pathology GA 332TL UT WOS:000088089500001 PM 10880367 ER PT J AU Nau, GJ Chupp, GL Emile, JF Jouanguy, E Berman, JS Casanova, JL Young, RA AF Nau, GJ Chupp, GL Emile, JF Jouanguy, E Berman, JS Casanova, JL Young, RA TI Osteopontin expression correlates with clinical outcome in patients with mycobacterial infection SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID CALMETTE-GUERIN INFECTION; INTERFERON-GAMMA-RECEPTOR; ATHEROSCLEROTIC PLAQUES; BACTERIAL-INFECTION; GENETIC-RESISTANCE; BCG INFECTION; MICE LACKING; TUBERCULOSIS; DEFICIENCY; SUSCEPTIBILITY AB Osteopontin (OPN) is a protein flat Is expressed in chronic Inflammatory diseases including tuberculosis, and its deficiency predisposes to more severe mycobacterial Infections in mice. However, no reports have identified altered OPN expression in, or correlated these alterations to, infections in humans. The data presented herein identify alterations in the tissue expression of OPN protein and describe an inverse correlation between these levels and disease progression after inoculation of Mycobacterium bovis bacillus Calmette-Guerin vaccine in humans. Patients with regional adenitis and good clinical outcomes had abundant OPN in infected lymph nodes. This pattern of OPN accumulation was also observed in patients infected by M. avium-intracellulare. In contrast, patients with disseminated infection and histologically ill-defined granulomas had no significant osteopontin accumulation in infected lymph nodes; these patients had either deficiencies in the interferon-gamma receptor 1 or idiopathic Immune defects, The level of OPN protein expression was inversely correlated with disseminated infection and, of particular interest, with death of the patient. We conclude that osteopontin expression correlates with an effective immune and inflammatory response when humans are challenged by a mycobacterial infection and that osteopontin contributes to human resistance against mycobacteria. C1 Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. MIT, Dept Biol, Cambridge, MA USA. Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. Univ Paris Sud, Hop Paul Brousse, Serv Anat Pathol, Villejuif, France. Necker Enfants Malad Med Sch, Lab Human Genet Infect Dis, Paris, France. Vet Adm Med Ctr, Boston, MA USA. RP Young, RA (reprint author), Whitehead Inst Biomed Res, 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 [AI01305, AI37869]; NICHD NIH HHS [N01-HD-6-2915] NR 38 TC 61 Z9 62 U1 0 U2 3 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUL PY 2000 VL 157 IS 1 BP 37 EP 42 DI 10.1016/S0002-9440(10)64514-2 PG 6 WC Pathology SC Pathology GA 332TL UT WOS:000088089500007 PM 10880373 ER PT J AU Giri, D Ittmann, M AF Giri, D Ittmann, M TI Interleukin-1 alpha is a paracrine inducer of FGF7, a key epithelial growth factor in benign prostatic hyperplasia SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID FACTOR GENE-EXPRESSION; FIBROBLASTS; CELLS AB Benign prostatic hyperplasia (BPN) is an extremely common disease of older men In which there is benign overgrowth of the prostatic transition zone, leading to obstruction of urine outflow, FGF7, a potent growth factor for prostatic epithelial cells, is increased by threefold in BPH and is correlated with increased epithelial proliferation in this condition. Immunohistochemistry of normal and hyperplastic prostate revealed that FGF7-expressing fibroblastic cells were present in higher numbers near the epithelial acini, implying that epithelial cells may express a factor that induces FGF7 expression by stromal cells. Conditioned medium (CM) from primary cultures of prostatic epithelial cells was capable of inducing a two- to sixfold increase in time expression of FGF7 by primary stromal cultures. Blocking experiments with neutralizing anti-interleukin-1 alpha(I1-1 alpha) antibodies and IL-1Ra, an I1-1 alpha receptor antagonist, show that this inducing activity was due to the presence of I1-1 alpha in the epithelial CM. Analysis of normal prostatic peripheral zone and BPH tissue by enzyme-linked immunoabsorption assay reveal that I1-1 alpha is present at increased levels in hyperplastic prostate and that levels of I1-1 alpha correlate strongly with tissue FGF7 concentration In BPH, Therefore I1-1 alpha is produced by prostatic epithelial cells and can induce FGF7, a potent epithelial growth factor, which can in turn lead to further epithelial growth and increased I1-1 alpha secretion, thus establishing a double paracrine loop that is functionally equivalent to an autocrine growth loop. This double paracrine loop may play a key role in the abnormal proliferation of the transition zone, which is critical to the pathogenesis of BPH. C1 Houston Dept Vet Affairs Med Ctr, Res Serv 151, Houston, TX 77030 USA. Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. RP Ittmann, M (reprint author), Houston Dept Vet Affairs Med Ctr, Res Serv 151, 2002 Holcombe Blvd, Houston, TX 77030 USA. FU NIDDK NIH HHS [R01 DK054170, R01 DK54170] NR 21 TC 47 Z9 48 U1 0 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUL PY 2000 VL 157 IS 1 BP 249 EP 255 DI 10.1016/S0002-9440(10)64535-X PG 7 WC Pathology SC Pathology GA 332TL UT WOS:000088089500028 PM 10880394 ER PT J AU Cataldo, AM Peterhoff, CM Troncosco, JC Gomez-Isla, T Hyman, BT Nixon, RA AF Cataldo, AM Peterhoff, CM Troncosco, JC Gomez-Isla, T Hyman, BT Nixon, RA TI Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome - Differential effects of APOE genotype and presenilin mutations SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID SMALL GTPASE RAB5; GLUT3 GLUCOSE-TRANSPORTER; APOLIPOPROTEIN-E GENOTYPE; CENTRAL-NERVOUS-SYSTEM; PRECURSOR PROTEIN; CATHEPSIN-D; ENDOPLASMIC-RETICULUM; LYSOSOMAL SYSTEM; BINDING PROTEIN; NEURONAL ENDOCYTOSIS AB Endocytosis is critical to the function and fate of molecules important to Alzheimer's disease (AD) etiology, including the beta protein precursor (PPP), amyloid beta (A beta) peptide, and apolipoprotein E (ApoE), Early endosomes, a major site of A beta peptide generation, are markedly enlarged within neurons in the Alzheimer brain, suggesting altered endocytic pathway (EP) activity. Here, we show that neuronal EP activation is a specific and very early response in AD. To evaluate endocytic activation, we used markers of internalization (rab5, rabaptin 5) and recycling (rab4), and found that enlargement of rab5-positive early endosomes In the AD brain was associated with elevated levels of rab4 immunoreactive protein and translocation of rabaptin 5 to endosomes, implying that both endocytic uptake and recycling are activated. These abnormalities were evident in pyramidal neurons of the neocortex at preclinical stages of disease when Alzheimer-like neuropathology, such as A beta deposition, was restricted to the entorhinal region. In Down syndrome, early endosomes were significantly enlarged in some pyramidal neurons as early as 28 weeks of gestation, decades before classical AD neuropathology develops. Markets of EP activity were only minimally influenced by normal aging and other neurodegenerative diseases studied. Inheritance of the epsilon 4 allele of APOE, however, accentuated early endosome enlargement at preclinical stages of AD. By contrast, endosomes were normal in size at advanced stages of familial AD caused by mutations of presenilin 1 or 2, indicating that altered endocytosis is not a consequence of A beta deposition. These results identify EP activation as the earliest known intraneuronal change to occur in sporadic AD, the most common form of AD. Given the important role of the EP in A beta peptide generation and ApoE function, early endosomal abnormalities provide a mechanistic Link between EP alterations, genetic susceptibility factors, and A beta generation and suggest differences that may be involved in A beta generation and beta amyloidogenesis in subtypes of AD. C1 Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. NYU, Sch Med, New York, NY USA. Johns Hopkins Univ, Sch Med, Dept Pathol Neuropathol & Neurol, Baltimore, MD USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Cataldo, AM (reprint author), Nathan S Kline Inst Psychiat Res, 140 Old Orangeburg Rd, Orangeburg, NY 10962 USA. FU NIA NIH HHS [AG 10916, AG14762] NR 73 TC 326 Z9 330 U1 1 U2 12 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUL PY 2000 VL 157 IS 1 BP 277 EP 286 DI 10.1016/S0002-9440(10)64538-5 PG 10 WC Pathology SC Pathology GA 332TL UT WOS:000088089500031 PM 10880397 ER PT J AU Takeuchi, A Irizarry, MC Duff, K Saido, TC Ashe, KH Hasegawa, M Mann, DMA Hyman, BT Iwatsubo, T AF Takeuchi, A Irizarry, MC Duff, K Saido, TC Ashe, KH Hasegawa, M Mann, DMA Hyman, BT Iwatsubo, T TI Age-related amyloid beta deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid beta precursor protein Swedish mutant is not associated with global neuronal loss SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID SENILE PLAQUES; DISEASE; APOPTOSIS; MUTATION; HIPPOCAMPUS; PHENOTYPE; DEMENTIA; CORTEX; CELLS; MOUSE AB To analyze the relationship between the deposition of amyloid beta peptides (A beta) and neuronal loss in transgenic models of Alzheimer's disease (AD), we examined the frontal neocortex (Fc) and CA1 portion of hippocampus (CA1) in PSAPP mice doubly expressing AD-associated mutant presenilin 1 (PS1) and Swedish-type mutant beta amyloid precursor protein (APPsw) by morphometry of A beta burden and neuronal counts. Deposition of hp was detected as early as 3 months of age in the Fc and CA1 of PSAPP mice and progressed to cover 28.3% of the superior frontal cortex and 18.4% of CA1 at 12 months: similar to 20- (Fc) and similar to 40- (CA1) fold greater deposition than in APPsw mice. There was no significant difference in neuronal counts in either CA1 or the frontal cortex between nontransgenic (non-tg), PS1 transgenic, APPsw, and PSAPP mice at 3 to 12 months of age. In the PSAPP mice, there was disorganization of the neuronal architecture by compact amyloid plaques, and the average number of neurons was 8 to 10% fewer than the other groups (NS, P > 0.10) in CA1 and 2 to 20% fewer in frontal cortex (NS, P = 0.31), There was no loss of total synaptophysin immunoreactivity in the Fe or dentate gyrus molecular layer of the 12-month-old PSAPP mice. Thus, although co-expression of mutant PS1 with Swedish mutant beta APP leads to marked cortical and limbic A beta deposition in an age-dependent manner, it does not result in the dramatic neuronal loss in hippocampus and association cortex characteristic of AD. C1 Univ Tokyo, Grad Sch Pharmaceut Sci, Dept Neuropathol & Neurosci, Tokyo 1130033, Japan. Massachusetts Gen Hosp, Alzheimer Dis Res Unit, Charlestown, MA USA. NYU, Nathan Kline Inst, Orangeburg, NY USA. RIKEN, Brain Sci Inst, Lab Proteolyt Neurosci, Wako, Saitama 35101, Japan. Univ Minnesota, Ctr Clin & Mol Neurobiol, Minneapolis, MN USA. Univ Minnesota, Dept Neurol, Minneapolis, MN USA. Univ Minnesota, Dept Neurosci, Minneapolis, MN USA. Univ Manchester, Dept Pathol Sci, Manchester, Lancs, England. RP Iwatsubo, T (reprint author), Univ Tokyo, Grad Sch Pharmaceut Sci, Dept Neuropathol & Neurosci, 7-3-1 Bunkyoku Hongo, Tokyo 1130033, Japan. FU NIA NIH HHS [AG00793] NR 49 TC 172 Z9 180 U1 1 U2 5 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUL PY 2000 VL 157 IS 1 BP 331 EP 339 DI 10.1016/S0002-9440(10)64544-0 PG 9 WC Pathology SC Pathology GA 332TL UT WOS:000088089500037 PM 10880403 ER PT J AU Keire, DA Mannon, P Kobayashi, M Walsh, JH Solomon, TE Reeve, JR AF Keire, DA Mannon, P Kobayashi, M Walsh, JH Solomon, TE Reeve, JR TI Primary structures of PYY, [Pro(34)]PYY, and PYY-(3-36) confer different conformations and receptor selectivity SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE peptide YY; Y-1 receptor; Y-2 receptor; circular dichroism; nuclear magnetic resonance; three-dimensional structure ID AMPHIPHILIC SECONDARY STRUCTURES; HUMAN NEUROPEPTIDE-Y; PEPTIDE-YY; PANCREATIC-POLYPEPTIDE; AQUEOUS-SOLUTION; Y-2 RECEPTORS; ANALOGS; BINDING; DYNAMICS; CELLS AB We synthesized PYY-(1-36) (nonselective between Y-1 and Y-2 receptor subtype agonists), [Pro(34)]-PYY (selective for Y-1), and PYY-(3-36) (selective for Y-2) to determine whether solution conformation plays a role in receptor subtype selectivity. The three peptides exhibited the expected specificities in displacing labeled PYY-(1-36) from cells transfected with Y-1 receptors (dissociation constants = 0.42, 0.21, and 1,050 nM, respectively) and from cells transfected with Y2 receptors (dissociation constants = 0.03, 710, and 0.11 nM, respectively) for PYY-(1-36), [Pro(34)]PYY, and PYY-(3-36). Sedimentation equilibrium analyses revealed that the three PYY analogs were 80-90% monomer at the concentrations used for the subsequent circular dichroism (CD) and H-1-nuclear magnetic resonance (NMR) studies. CD analysis measured helicities for PYY-(1-36), [Pro(34)]PYY, and PYY-(3-36) of 42%, 31%, and 24%, suggesting distinct differences in secondary structure. The backbone H-1-NMR resonances of the three peptides further substantiated marked conformational differences. These patterns support the hypothesis that Y-1 and Y-2 receptor subtype binding affinities depend on the secondary and tertiary solution state structures of PYY and its analogs. C1 Greater Los Angeles Vet Affairs Healthcare Syst, CURE Digest Dis Res Ctr, Los Angeles, CA 90073 USA. City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. Vet Affairs Med Ctr, Durham, NC 27705 USA. Duke Univ, Med Ctr, Durham, NC 27705 USA. Univ Calif Los Angeles, Sch Med, Div Digest Dis, Los Angeles, CA 90095 USA. RP Reeve, JR (reprint author), Greater Los Angeles Vet Affairs Healthcare Syst, CURE Digest Dis Res Ctr, Rm 115,Bld 115, Los Angeles, CA 90073 USA. FU NIDDK NIH HHS [DK-41301, DK-33850] NR 30 TC 81 Z9 82 U1 0 U2 6 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 JUL PY 2000 VL 279 IS 1 BP G126 EP G131 PG 6 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 333RN UT WOS:000088144700015 PM 10898754 ER PT J AU Wiener, SM Hoyt, RF Deleonardis, JR Clevenger, RR Jeffries, KR Nagashima, K Mandel, M Owens, J Eckhaus, M Lutz, RJ Safer, B AF Wiener, SM Hoyt, RF Deleonardis, JR Clevenger, RR Jeffries, KR Nagashima, K Mandel, M Owens, J Eckhaus, M Lutz, RJ Safer, B TI Manometric changes during retrograde biliary infusion in mice SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE drug delivery; polarized epithelia; tight junction; cholestasis ID BILE-DUCT LIGATION; GENE-TRANSFER; HEPATOCELLULAR-CARCINOMA; RAT-LIVER; IN-VIVO; CHOLESTASIS; COMPLEX; HEPATOBILIARY; CANALICULI; JUNCTIONS AB The manometric, ultrastructural, radiographic, and physiological consequences of retrograde biliary infusion were determined in normostatic and cholestatic mice. Intraluminal biliary pressure changed as a function of infusion volume, rate, and viscosity. Higher rates of constant infusion resulted in higher peak intraluminal biliary pressures. The pattern of pressure changes observed was consistent with biliary ductular and/or canalicular filling followed by leakage at a threshold pressure. Retrograde infusion with significant elevations in pressure led to paracellular leakage of lanthanum chloride, radiopaque dye, and [C-14] sucrose with rapid systemic redistribution via sinusoidal and subsequent hepatic venous drainage. Chronic extrahepatic bile duct obstruction resulted in significantly smaller peak intrabiliary pressures and lower levels of paracellular leakage. These findings indicate that under both normostatic and cholestatic conditions elevated intrabiliary volumes/pressures result in an acute pressure-dependent physical opening of tight junctions, permitting the movement of infusate from the intrabiliary space into the subepithelial tissue compartment. Control of intraluminal pressure may potentially permit the selective delivery of macromolecules >18-20 Angstrom in diameter to specific histological compartments. C1 NHLBI, Mol Hematol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Lab Anim Med & Surg, NIH, Bethesda, MD 20892 USA. NCI, Lab Cell & Mol Struct, Frederick Canc Res & Dev Ctr, Frederick, MD 21270 USA. NIH, Pathol Serv, Diagnost & Surg Sect, Vet Resources Program,Natl Ctr Res Resources, Bethesda, MD 20892 USA. NIH, Bioengn & Phys Sci Program, Off Res Serv, Off Director, Bethesda, MD 20892 USA. RP Wiener, SM (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit GRJ 722, 55 Fruit St, Boston, MA 02114 USA. NR 37 TC 13 Z9 13 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 JUL PY 2000 VL 279 IS 1 BP G49 EP G66 PG 18 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 333RN UT WOS:000088144700007 PM 10898746 ER PT J AU Griffin, JL White, LT Lewandowski, ED AF Griffin, JL White, LT Lewandowski, ED TI Substrate-dependent proton load and recovery of stunned hearts during pyruvate dehydrogenase stimulation SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE myocardium; reperfusion; nuclear magnetic resonance spectroscopy; dichloroacetate ID CYTOSOLIC FREE CALCIUM; FATTY-ACID METABOLISM; ISCHEMIC RAT HEARTS; DICHLOROACETATE; OXIDATION; LACTATE; MYOCARDIUM; FAILURE; EFFICIENCY; ACTIVATION AB Stimulation of pyruvate dehydrogenase (PDH) improves functional recovery of postischemic hearts. This study examined the potential for a mechanism mediated by substrate-dependent proton production and intracellular pH. After 20 min of ischemia, isolated rabbit hearts were reperfused with or without 5 mM dichloroacetate (DCA) in the presence of either 5 mM glucose, 5 mM glucose + 2.5 mM lactate, or 5 mM glucose + 2.5 mM pyruvate. DCA inhibits PDH kinase, increasing the proportion of dephosphorylated, active PDH. Unlike pyruvate or glucose alone, lactate + glucose did not support the effects of DCA on the recovery of rate-pressure product (RPP) (without DCA, RPP = 14,000 +/- 1,200, n = 6; with DCA, RPP = 13,700 +/- 1,800, n = 9). Intracellular pH, from P-31 nuclear magnetic resonance spectra, returned to normal within 2.1 min of reperfusion with all substrates except for lactate 1 glucose 1 DCA or lactate 1 DCA, which delayed pH recovery for up to 12 min (at 2.1 min pH = 6.00 +/- 0.08, lactate + glucose + DCA; pH = 6.27 +/- 0.34, for lactate + DCA). Hearts were also reperfused after 10 min of ischemia with 0.5 mM palmitate + 5 mM DCA and either 2.5 mM pyruvate or 2.5 mM lactate. Again, intracellular pH recovery was delayed in the presence of lactate. PDH activation in the presence of lactate also decreased coupling of oxidative metabolism to mechanical work. These findings have implications for therapeutic use of stimulated carbohydrate oxidation in stunned hearts. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. RP Lewandowski, ED (reprint author), Univ Illinois, Coll Med, Dept Physiol & Biophys, MC901,835 S Walcott,Rm E202 MSB, Chicago, IL 60612 USA. FU NHLBI NIH HHS [R01 HL-49244] NR 36 TC 16 Z9 16 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 JUL PY 2000 VL 279 IS 1 BP H361 EP H367 PG 7 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 336LE UT WOS:000088302100042 PM 10899076 ER PT J AU Xiao, YF Wright, SN Wang, GK Morgan, JP Leaf, A AF Xiao, YF Wright, SN Wang, GK Morgan, JP Leaf, A TI Coexpression with beta(1)-subunit modifies the kinetics and fatty acid block of hH(1 alpha) Na+ channels SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE alpha-subunit; cardiac sodium ion channel; polyunsaturated fatty acids ID RAT VENTRICULAR MYOCYTES; SINGLE SODIUM-CHANNELS; HUMAN SKELETAL-MUSCLE; BETA(1) SUBUNIT; ALPHA-SUBUNITS; FUNCTIONAL EXPRESSION; CARDIAC MYOCYTES; LIDOCAINE BLOCK; XENOPUS OOCYTES; BETA-1 SUBUNITS AB Voltage-gated cardiac Na+ channels are composed of alpha- and beta(1)-subunits. In this study beta(1)-subunit was cotransfected with the alpha- subunit of the human cardiac Na+ channel (hH1(alpha)) in human embryonic kidney (HEK293t) cells. The effects of this coexpression on the kinetics and fatty acid-induced suppression of Na+ currents were assessed. Current density was significantly greater in HEK293t cells coexpressing alpha- and beta(1)-subunits (I-Na,I-alpha beta) than in HEK293t cells expressing alpha-subunit alone (I-Na,I-alpha). Compared with I-Na,I-alpha, the voltage-dependent inactivation and activation of I-Na,I-alpha beta were significantly shifted in the depolarizing direction. In addition, coexpression with beta(1)-subunit prolonged the duration of recovery from inactivation. Eicosapentaenoic acid [EPA, C20:5(n-3)] significantly reduced I-Na,I-alpha beta in a concentration-dependent manner and at 5 mu M shifted the midpoint voltage of the steady-state inactivation by -22 +/- 1 mV. EPA also significantly accelerated channel transition from the resting state to the inactivated state and prolonged the recovery time from inactivation. Docosahexaenoic acid [C22: 6(n-3)], alpha-linolenic acid [C18:3(n-3)], and conjugated linoleic acid [C18:2(n-6)] at 5 mu M significantly inhibited both I-Na,I-alpha beta and I-Na,I-alpha. In contrast, saturated and monounsaturated fatty acids had no effects on I-Na,I-alpha beta. This finding differs from the results for I-Na,I-alpha, which was significantly inhibited by both saturated and unsaturated fatty acids. Our data demonstrate that functional association of beta(1)-subunit with hH1(alpha) modifies the kinetics and fatty acid block of the Na+ channel. C1 Harvard Univ, Sch Med, Div Cardiovasc,Beth Israel Deaconess Med Ctr, Harvard Thorndike Lab,Dept Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Charles A Dana Res Inst, Boston, MA 02215 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA 02215 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Anesthesia, Boston, MA 02215 USA. Murray State Univ, Dept Sci Biol, Murray, KY 42071 USA. RP Xiao, YF (reprint author), Harvard Univ, Sch Med, Div Cardiovasc,Beth Israel Deaconess Med Ctr, Harvard Thorndike Lab,Dept Med, 330 Brookline Ave, Boston, MA 02215 USA. FU NHLBI NIH HHS [HL-62284]; NIDA NIH HHS [DA-11762]; NIDDK NIH HHS [DK-38165] NR 43 TC 71 Z9 73 U1 1 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 JUL PY 2000 VL 279 IS 1 BP H35 EP H46 PG 12 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 336LE UT WOS:000088302100005 PM 10899039 ER PT J AU Silver, RB Breton, S Brown, D AF Silver, RB Breton, S Brown, D TI Potassium depletion increases proton pump (H+-ATPase) activity in intercalated cells of cortical collecting duct SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE proton-adenosinetriphosphatase; bafilomycin; intracellular pH; 2 ',7 '-bis( 2-carboxyethyl)-5(6)-carboxyfluorescein; immunocytochemistry ID INTRACELLULAR PH; TURTLE BLADDER; DISTAL TUBULE; K-ATPASE; RAT; SECRETION; MEMBRANE; EXOCYTOSIS; MECHANISMS; SUBTYPES AB Intercalated cells (ICs) from kidney collecting ducts contain proton-transporting ATPases (H+-ATPases) whose plasma membrane expression is regulated under a variety of conditions. It has been shown that net proton secretion occurs in the distal nephron from chronically K+-depleted rats and that upregulation of tubular H+-ATPase is involved in this process. However, regulation of this protein at the level of individual cells has not so far been examined. In the present study, H+-ATPase activity was determined in individually identified ICs from control and chronically K+-depleted rats (9-14 days on a low-K+ diet) by monitoring K+ and Na+-independent H+ extrusion rates after an acute acid load. Split-open rat cortical collecting tubules were loaded with the intracellular pH (pH(i)) indicator 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein, and pH(i) was determined by using ratiometric fluorescence imaging. The rate of pH(i) recovery in ICs in response to an acute acid load, a measure of plasma membrane H+-ATPase activity, was increased after K+ depletion to almost three times that of controls. Furthermore, the lag time before the start of pH(i) recovery after the cells were maximally acidified fell from 93.5 +/- 13.7 s in controls to 24.5 +/- 2.1 s in K+-depleted rats. In all ICs tested, Na+- and K+ independent pH(i) recovery was abolished in the presence of bafilomycin (100 nM), an inhibitor of the H+-ATPase. Analysis of the cell-to-cell variability in the rate of pH(i) recovery reveals a change in the distribution of membrane-bound proton pumps in the IC population of cortical collecting duct from K+-depleted rats. Immunocytochemical analysis of collecting ducts from control and K+-depleted rats showed that K+-depletion increased the number of ICs with tight apical H+ ATPase staining and decreased the number of cells with diffuse or basolateral H+-ATPase staining. Taken together, these data indicate that chronic K+ depletion induces a marked increase in plasma membrane H+ ATPase activity in individual ICs. C1 Cornell Univ, Joan & Sanford I Weill Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Program Membrane Biol, Charlestown, MA 02129 USA. RP Silver, RB (reprint author), Cornell Univ, Joan & Sanford I Weill Med Coll, Dept Physiol & Biophys, 1300 York Ave, New York, NY 10021 USA. EM rbsilve@mail.med.cornell.edu FU NIDDK NIH HHS [DK-42956, DK-45828] NR 29 TC 21 Z9 21 U1 0 U2 1 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 JUL PY 2000 VL 279 IS 1 BP F195 EP F202 PG 8 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 333RM UT WOS:000088144600020 PM 10894802 ER PT J AU Tsuang, MT Stone, WS Faraone, SV AF Tsuang, MT Stone, WS Faraone, SV TI Toward reformulating the diagnosis of schizophrenia SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Review ID DEVELOPMENTAL BRAIN ABNORMALITIES; BIPOLAR AFFECTIVE-DISORDER; NONPSYCHOTIC RELATIVES; SCHIZOTYPAL DISORDER; HIPPOCAMPAL DAMAGE; ROSCOMMON FAMILY; MAJOR PSYCHOSES; GENOME SCAN; GENETICS; LINKAGE AB Objective: The authors assess implications of DSM criteria for schizophrenia by reviewing the criteria's 1) emphasis on psychotic features, 2) dissociation of symptoms from their etiology, 3) exclusive reliance on clinical features but exclusion of biological indicators, and 4) classification of schizophrenia as a discrete category. The authors then discuss alternative conceptions of schizophrenia that take into account recent data concerning its genetic and neurodevelopmental origins and its pathophysiological substrates. Method: The historical development of diagnostic criteria for schizophrenia is reviewed in the context of recent published data on the biology and development of schizophrenia. Results: Growing evidence suggests that symptoms of psychosis may be a common end-state in a variety of disorders, including schizophrenia, rather than a reflection of the specific etiology of schizophrenia. Features occurring before the advent of psychosis that are clinical, biological, and/ or neuropsychological in nature may constitute evidence of a genetic predisposition toward schizophrenia ("schizotaxia") and may provide more specific information about the genetic, pathophysiological, and developmental origins of schizophrenia. Conclusions: The success of efforts to treat and prevent schizophrenia will depend to an important extent on an accurate understanding of its causes. This goal can be furthered by conducting field trials to develop research criteria to assess the value of a developmentally sensitive, biologically informed approach to classification that would consider schizotaxia with psychosis (schizophrenia) and schizotaxia alone as distinct diagnostic conditions. C1 Harvard Univ, Sch Med, Massachusetts Mental Hlth Ctr, Dept Psychiat, Boston, MA 02115 USA. Brockton W Roxbury Vet Affairs Med Ctr, Boston, MA USA. Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Psychiat Serv, Boston, MA 02114 USA. Harvard Inst Psychiat Epidemiol & Genet, Boston, MA USA. RP Tsuang, MT (reprint author), Harvard Univ, Sch Med, Massachusetts Mental Hlth Ctr, Dept Psychiat, 74 Fenwood Rd, Boston, MA 02115 USA. OI Faraone, Stephen/0000-0002-9217-3982 FU NIMH NIH HHS [MH-46318, MH-41879, MH-43518] NR 78 TC 131 Z9 135 U1 1 U2 9 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 JUL PY 2000 VL 157 IS 7 BP 1041 EP 1050 DI 10.1176/appi.ajp.157.7.1041 PG 10 WC Psychiatry SC Psychiatry GA 329WJ UT WOS:000087931200002 PM 10873908 ER PT J AU Faraone, SV Biederman, J Mick, E Williamson, S Wilens, T Spencer, T Weber, W Jetton, J Kraus, I Pert, J Zallen, B AF Faraone, SV Biederman, J Mick, E Williamson, S Wilens, T Spencer, T Weber, W Jetton, J Kraus, I Pert, J Zallen, B TI Family study of girls with attention deficit hyperactivity disorder SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID DSM-IV ADHD; DEFICIT/HYPERACTIVITY DISORDER; CONDUCT DISORDER; SEX-DIFFERENCES; RISK-FACTORS; ENVIRONMENTAL-INFLUENCES; PSYCHIATRIC ILLNESS; LATENT CLASS; CHILDREN; COMORBIDITY AB Objective: Because attention deficit hyperactivity disorder (ADHD) is relatively infrequent among girls, little is known about the causes of ADHD in girls. To help fill this gap in the literature, the authors assessed the familial transmission of ADHD in families ascertained through girls. Method: Interviewers who were blind to diagnosis administered structured psychiatric interviews to 140 girls with ADHD and their 417 first-degree relatives and to 122 girls without ADHD and their 369 first-degree relatives. Results: The relatives of the ADHD girls had a significantly higher prevalence of ADHD, according to either the DSM-III-R or DSM-IV definition, than the relatives of the comparison girls. However, this did not differ from the prevalence the authors reported previously for families of boys with ADHD. Like the boys' families, the relatives of the girl probands also had significantly higher prevalences of antisocial, mood, anxiety, and substance use disorders, although the prevalence of familial antisocial disorders was lower than had been observed in the boys' families. There was no association between the DSM-IV subtypes of the probands and relatives. Conclusions: The familial transmission of ADHD and comorbid disorders generalizes to families of girls with ADHD. Neither proband gender nor subtype influences the familial transmission of ADHD. C1 Massachusetts Gen Hosp, Pediat Psychopharmacol Unit ACC 725, Child Psychiat Serv, Boston, MA 02114 USA. Harvard Pilgrim Community Hlth Plan, Boston, MA USA. RP Faraone, SV (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit ACC 725, Child Psychiat Serv, Fruit St, Boston, MA 02114 USA. OI Mick, Eric/0000-0001-8505-8145; Faraone, Stephen/0000-0002-9217-3982 FU NIMH NIH HHS [MH-41314] NR 47 TC 97 Z9 99 U1 2 U2 7 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 JUL PY 2000 VL 157 IS 7 BP 1077 EP 1083 DI 10.1176/appi.ajp.157.7.1077 PG 7 WC Psychiatry SC Psychiatry GA 329WJ UT WOS:000087931200008 PM 10873914 ER PT J AU O'Malley, ME Halpern, E Mueller, PR Gazelle, GS AF O'Malley, ME Halpern, E Mueller, PR Gazelle, GS TI Helical CT protocols for the abdomen and pelvis: A survey SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article ID ACUTE FLANK PAIN; CONTRAST MATERIAL; LIVER METASTASES; CONVENTIONAL CT; RENAL MASSES; APPENDICITIS; DIAGNOSIS; TUMOR AB OBJECTIVE. We surveyed members of the Society of Computed Body Tomography/Magnetic Resonance to evaluate current techniques used for helical CT in the abdomen and pelvis. MATERIALS AND METHODS. The survey was distributed to 70 members (36 institutions) of the Society of Computed Body Tomography/Magnetic Resonance, The survey included general questions related to abdominal and pelvic helical CT and also asked the members to write a protocol for 12 hypothetical requisitions. RESULTS. Thirty-two members (46%) responded, representing 28 institutions (78%). The number of protocols for helical CT of the abdomen and pelvis at each institution ranges from ? to 35 (median, Il). IV contrast material is administered for 90% (median) of abdominal and pelvic CT examinations. Nonionic contrast material is used for 68% (median) of these examinations, IV contrast material is used by 100% of institutions for turner staging protocols except for one institution that does not use IV contrast material for lymphoma staging. Fifty percent of the institutions obtain two- or three-phases of liver images for breast cancer staging. For all protocols, the average collimation and reconstruction interval is 7 mm except for renal (5 mm) and adrenal (4 mm) protocols. Rectal contrast material is administered most commonly for colon cancer staging (39% of institutions). CONCLUSION. There is a wide range in the number of protocols used for helical CT in the abdomen and pelvis among the responding institutions. Most protocols include use of nonionic IV contrast material injected at a rate of 3 ml/sec and a collimation of 7 mm. C1 Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Decis Anal & Technol Assessment DATA Grp, Boston, MA 02114 USA. RP O'Malley, ME (reprint author), Toronto Gen Hosp, Dept Med Imaging, 200 Elizabeth St, Toronto, ON M5G 2C4, Canada. NR 19 TC 26 Z9 26 U1 0 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD JUL PY 2000 VL 175 IS 1 BP 109 EP 113 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 325DH UT WOS:000087660700021 PM 10882257 ER PT J AU Yantiss, RK Spiro, IJ Compton, CC Rosenberg, AE AF Yantiss, RK Spiro, IJ Compton, CC Rosenberg, AE TI Gastrointestinal stromal tumor versus intra-abdominal fibromatosis of the bowel wall - A clinically important differential diagnosis SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE intra-abdominal fibromatosis; gastrointestinal stromal tumor; immunohistochemistry; ultrastructure ID FAMILIAL ADENOMATOUS POLYPOSIS; AUTONOMIC NERVE TUMORS; DESMOID TUMOR; INTERSTITIAL-CELLS; PROGNOSTIC FACTORS; GARDNERS-SYNDROME; MUSCLE TUMORS; MANAGEMENT; PROLIFERATION; RADIOTHERAPY AB Intra-abdominal fibromatosis (IAF) is an uncommon benign neoplasm that usually occurs in the mesentery or retroperitoneum and may, on occasion, mimic a gastrointestinal stromal tumor (GIST). Differentiating between these two entities is important clinically because IAF is a benign tumor whereas GISTs frequently have malignant potential. In this study, the authors identified 13 cases of IAF with prominent involvement of the bower wall as well as 35 GISTs of the small intestine, colon, or mesentery and analyzed their clinical, gross, histologic, immunophenotypic. and ultrastructural characteristics to identify important distinguishing features. Patients with IAF were younger (mean, 34 yrs) than patients with GIST (mean, 54 yrs). Both types of tumors tended to be large, but GISTs were soft and lobulated with hemorrhage, necrosis, or cystification whereas IAFs were firm, tan, and homogeneous. Histologic features characteristic of GIST included the presence of spindle or epithelioid cells with variable architecture, mitotic activity (range, <1-95 mitoses/50 high-power fields [hpf]; mean, 15 mitoses/50 hpf), nuclear atypia, and myxoid or hyalinized stroma. Necrosis and hemorrhage were seen in 16 and 25 tumors, respectively. In contrast, IAFs were composed of broad, sweeping fascicles of monotonous spindle cells with mitotic activity (range, <3-11 mitoses/50 hpf; mean, 4 mitoses/50 hpf), bland nuclear features, and finely collagenous stroma. Necrosis, hemorrhage, and myxoid degeneration were not seen. Immunohistochemical studies performed on a limited number of GISTs and IAFs demonstrated that cells expressed vimentin (100% GIST and IAF), CD117 (88% GIST and 75% IAF), CD34 (42% GIST and 0% IAF), smooth muscle actin (63% GIST and 75% IAF), muscle actin (75% GIST and 75% IAF), desmin (8% GIST and 50% IAF), and S-100 protein (16% GIST and 0% IAF). Ultrastructural analysis of 21 GISTs revealed incomplete smooth muscle differentiation in some tumors whereas IAFs were shown to have complete myofibroblastic/fibroblastic differentiation. Information regarding clinical outcome was available on 29 patients and revealed that three patients with histologically benign GISTs were alive with no evidence of disease at 5 months to 6 years (mean, 3.5 yrs) and one patient with a histologically benign tumor died of disease after 7 years. Of patients with histologically malignant GIST, one died of surgical complications. 10 were alive without disease at 1 to 13 years (mean, 5.4 yrs), four were alive with disease at 4 months to 15 years (mean, 3.8 yrs), three had disseminated disease at operation, and seven were dead of disease at 10 months to 3 years (mean, 2.2 yrs). Follow up of eight patients with IAF demonstrated that five were alive without disease at 4 months to 15 years (mean, 5.3 yrs) and three had recurrences at 1 (two patients) and 2 years (one patient). In summary, IAFs can have many features (large size, infiltration of adjacent structures, mitotic activity) that can cause diagnostic confusion with GISTs and, importantly, the degree of mitotic activity present in IAFs may overlap that seen in malignant GISTs. These entities can be distinguished primarily by their light microscopic and ultrastructural features but there is a notable overlap in their immunohistochemical profiles. The distinction between these neoplasms is important because then are important clinical implications for the patient. C1 Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Rosenberg, AE (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. NR 48 TC 115 Z9 129 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 JUL PY 2000 VL 24 IS 7 BP 947 EP 957 DI 10.1097/00000478-200007000-00006 PG 11 WC Pathology; Surgery SC Pathology; Surgery GA 329WU UT WOS:000087932100006 PM 10895817 ER PT J AU Ryan, ET Dhar, U Khan, WA Salam, MA Faruque, ASG Fuchs, GJ Calderwood, SB Bennish, ML AF Ryan, ET Dhar, U Khan, WA Salam, MA Faruque, ASG Fuchs, GJ Calderwood, SB Bennish, ML TI Mortality, morbidity, and microbiology of endemic cholera among hospitalized patients in Dhaka, Bangladesh SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID EL-TOR CHOLERA; VIBRIO-CHOLERAE; DIARRHEAL DISEASES; O139 BENGAL; RISK-FACTORS; INFECTION; STRAINS; PROTECTION; EPIDEMIC; EMERGENCE AB Mortality and morbidity associated with cholera acquired in a modern endemic setting have not been well defined. In Dhaka Bangladesh from 1986 to 1996, we found that causative agents of cholera shifted over time, varying by serogroup, biotype, and serotype. At the International Centre for Diarrhoeal Disease Research (ICDDR,B: Centre for Health and Population Research) in 1996, 19,100 cholera patients were treat-ed, 887 (4.6%) were admitted, and 33 died (mortality rate = 3.7% of cholera inpatients, 0.14% of all cholera patients). When cholera inpatients who were discharged improved were compared with those who died, bacteremia (odds ratio [OR] = 10.5, 95% confidence interval [CI] = 2.9-37.9), radiographic evidence of pneumonia (OR = 3.1, 95% CI = 1.2-7.7), and acidosis as estimated by the serum bicarbonate value (OR = 0.893, 95% CI = 0.825-0.963) were independently associated with death by multivariate analysis. Pneumonia was the leading cause of death and accounted for two-thirds of all deaths among individuals with cholera in this study. Death in hospitalized patients with cholera acquired in a modern endemic setting is, therefore, extremely rare, and most frequently due to concomitant infection, especially pneumonia. C1 Massachusetts Gen Hosp, Div Infect Dis, Trop & Geog Med Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. Int Ctr Diarrhoeal Dis Res, Ctr Hlth & Populat Res B, Div Clin Sci, Dhaka 1000, Bangladesh. Louisiana State Univ, Sch Med, Dept Pediat, New Orleans, LA 70112 USA. New England Med Ctr, Tupper Res Inst, Div Geog Med & Infect Dis, Boston, MA 02111 USA. RP Ryan, ET (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Trop & Geog Med Ctr, Jackson 504,55 Fruit St, Boston, MA 02114 USA. FU NIAID NIH HHS [AI-40725, AI/HDO1671-01, AI/K0801332, R01 AI040725]; NICHD NIH HHS [HD39165, U01 HD039165] NR 55 TC 29 Z9 29 U1 1 U2 4 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUL-AUG PY 2000 VL 63 IS 1-2 BP 12 EP 20 PG 9 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 431JZ UT WOS:000168629200003 PM 11357989 ER PT J AU Lewis, KP Appadurai, IR Pierce, ET Halpern, EF Bode, RH AF Lewis, KP Appadurai, IR Pierce, ET Halpern, EF Bode, RH TI Prophylactic amrinone for weaning from cardiopulmonary bypass SO ANAESTHESIA LA English DT Article DE surgery, cardiovascular; heart; pharmacology, amrinone ID HEART-FAILURE; SURGERY; THERAPY; ARTERY AB This prospective, randomised, double-blind, controlled clinical study was performed at a single tertiary referral centre to test the hypothesis that the prophylactic administration of amrinone before separation of a patient from cardiopulmonary bypass decreases the incidence of failure to wean, and to identify those patients who could be predicted to benefit from such pre-emptive management. Two hundred and thirty-four patients, scheduled to undergo elective cardiac surgery, were randomly allocated to receive either a bolus dose of 1.5 mg.kg(-1) amrinone over 15 min, followed by an infusion of 10 mu g.kg(-1).min(-1), or a bolus of placebo of equal volume followed by an infusion of placebo. Treatment with amrinone or placebo was initiated upon release of the aortic cross-clamp, before weaning from cardiopulmonary bypass. Anaesthetic technique, monitoring and myocardial preservation methods were standardised for both groups. Significantly fewer patients failed to wean in the group that received prophylactic amrinone than in the control group (7 vs. 21%, p = 0.002). Amrinone improved weaning success regardless of left ventricular ejection fraction, although this benefit was statistically significant only in the group with left ventricular ejection fractions > 55%. Of the 32 patients who failed to wean from cardiopulmonary bypass, 14 had normal pre-operative left ventricular ejection fractions. C1 Boston Univ, Med Ctr, Dept Anesthesiol, Boston, MA 02118 USA. Univ Wales Hosp, Dept Anaesthet, Cardiff, S Glam, Wales. Massachusetts Gen Hosp, Data Anal & Technol Assessment Grp, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Pierce, ET (reprint author), Boston Univ, Med Ctr, Dept Anesthesiol, E Newton St, Boston, MA 02118 USA. NR 20 TC 7 Z9 7 U1 1 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0003-2409 J9 ANAESTHESIA JI Anaesthesia PD JUL PY 2000 VL 55 IS 7 BP 627 EP 633 DI 10.1046/j.1365-2044.2000.01372.x PG 7 WC Anesthesiology SC Anesthesiology GA 330CV UT WOS:000087946000002 PM 10919416 ER PT J AU Washington, DL Stevens, CD Shekelle, PG Baker, DW Fink, A Brook, RH AF Washington, DL Stevens, CD Shekelle, PG Baker, DW Fink, A Brook, RH TI Safely directing patients to appropriate levels of care: Guideline-driven triage in the emergency service SO ANNALS OF EMERGENCY MEDICINE LA English DT Article; Proceedings Paper CT Va Health Services Research and Development National Meeting CY FEB 24-26, 1999 CL WASHINGTON, D.C. SP VA Hlth Serv Res & Dev Natl ID PUBLIC HOSPITAL EMERGENCY; REFUSING CARE; CONSEQUENCES; DEPARTMENTS; PHYSICIAN; LEAVE AB Study objective: We sought to develop and Validate standardized clinical criteria to identify patients presenting to the emergency department whose care may be safely deferred to a later date in a nonemergency setting. Methods: Using a modified Delphi process, a 17-member multidisciplinary physician panel developed explicit, standardized, deferred-care criteria. In a prospective cohort design, emergency nurses at a tertiary care Veterans Administration (VA) Medical Center, using the criteria, screened 1,187 consecutive ambulatory adult patients presenting with abdominal pain, musculoskeletal symptoms, or respiratory infection symptoms. Patients meeting deferred-care criteria were offered the option of an appointment within 1 week in the ambulatory care clinic at the study site; ail other patients were offered same-day care. As outcome measures, we assessed nonelective hospitalizations for related conditions occurring within 7 days of evaluation at our facility or any other VA facility within a 300-mile radius, and we assessed 30-day all-cause mortality. Results: Two hundred twenty-six (19%) patients met screening criteria for deferred care. Patients meeting deferred-care criteria experienced zero (95% confidence interval, 0% to 1.2%) related nonelective VA hospitalizations within 7 days of evaluation, and none died within 30 days. By contrast, 68 (7%) of 961 (95% confidence interval, 5.5% to 8.9%) patients who did not meet deferred-care criteria were hospitalized nonelectively for related conditions, and 5 (0.5%) died. Conclusion: By using hospitalization and 30-day mortality as safety gauges, standardized clinical criteria can identify, at presentation, VA ED users who may be safely cared for at a later dale in a nonemergency setting. These guidelines apply to a significant proportion of VA ED users with common ambulatory conditions. These criteria deserve testing in other ED settings. C1 VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Ctr Hlth Sci, Dept Med, Los Angeles, CA 90024 USA. Harbor UCLA Med Ctr, Dept Emergency Med, Torrance, CA 90509 USA. Case Western Reserve Univ, Sch Med, Dept Med, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Epidemiol Biostat, Cleveland, OH 44106 USA. Metrohlth Med Ctr, Cleveland, OH 44106 USA. Univ Calif Los Angeles, Sch Publ Hlth, Dept Hlth Sci, Los Angeles, CA 90024 USA. RAND, Hlth Sci Program, Santa Monica, CA USA. RP Washington, DL (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Med, 11301 Wilshire Blvd,111G, Los Angeles, CA 90073 USA. NR 27 TC 18 Z9 18 U1 1 U2 1 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD JUL PY 2000 VL 36 IS 1 BP 15 EP 22 DI 10.1067/mem.2000.107003 PG 8 WC Emergency Medicine SC Emergency Medicine GA 330YG UT WOS:000087988700003 PM 10874230 ER PT J AU Klein, C Pramstaller, PP Kis, B Page, CC Kann, M Leung, J Woodward, H Castellan, CC Scherer, M Vieregge, P Breakefield, XO Kramer, PL Ozelius, LJ AF Klein, C Pramstaller, PP Kis, B Page, CC Kann, M Leung, J Woodward, H Castellan, CC Scherer, M Vieregge, P Breakefield, XO Kramer, PL Ozelius, LJ TI Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: Expanding the phenotype SO ANNALS OF NEUROLOGY LA English DT Article ID RECESSIVE JUVENILE PARKINSONISM; AUTOSOMAL-DOMINANT; LINKAGE ANALYSIS; ALPHA-SYNUCLEIN; LEWY BODY; DISEASE; GENE; DEMENTIA; MUTATION; INHERITANCE AB A gene for autosomal recessive parkinsonism, PARK;? (parkin), has recently been identified on chromosome 6q and shown to be mutated in Japanese and European families, mostly with early-onset parkinsonism. Here we present a large pedigree from South Tyrol (a region of northern Italy) with adult-onset, clinically typical tremor-dominant parkinsonism of apparently autosomal dominant inheritance. Haplotype analysis excluded linkage to the chromosome 2p, 4p, and 4q regions that harbor genes associated with autosomal dominant parkinsonism, but implicated the parkin locus on chromosome 6q. Compound heterozygous deletions in the parkin gene (one large and one truncating) were identified in 4 affected male siblings. The patients were clinically indistinguishable from most patients with idiopathic Parkinson's disease. None of them displayed any of the clinical hallmarks described in patients with previously reported parkin mutations, including diurnal fluctuations, benefit from sleep, foot dystonia, hyperreflexia, and early susceptibility to levodopa-induced dyskinesias. Two affected female individuals carried one (truncating) of the two deletions in a heterozygous state with an apparently normal allele. We conclude that the phenotypic spectrum associated with mutations in the parkin gene is broader than previously reported, suggesting that this gene may be important in the etiology of the more frequent late-onset typical Parkinson's disease. C1 Albert Einstein Coll Med, Bronx, NY 10461 USA. Massachusetts Gen Hosp, Mol Neurogenet Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA. Med Univ Lubeck, Dept Neurol, D-23538 Lubeck, Germany. Reg Gen Hosp, Dept Neurol, Bolzano Bozen, Italy. Reg Gen Hosp, Dept Genet, Bolzano Bozen, Italy. Oregon Hlth Sci Univ, Dept Neurol, Portland, OR 97201 USA. RP Ozelius, LJ (reprint author), Albert Einstein Coll Med, 1300 Morris Pk Ave, Bronx, NY 10461 USA. RI Kis, Bernhard/A-8731-2008; Pramstaller, Peter/C-2357-2008 OI Kis, Bernhard/0000-0003-3244-9737; FU NINDS NIH HHS [NS38372] NR 35 TC 164 Z9 171 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JUL PY 2000 VL 48 IS 1 BP 65 EP 71 DI 10.1002/1531-8249(200007)48:1<65::AID-ANA10>3.0.CO;2-L PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 330JP UT WOS:000087959200011 PM 10894217 ER PT J AU Souba, WW Wilmore, DW AF Souba, WW Wilmore, DW TI Judging surgical research: How should we evaluate performance and measure value? SO ANNALS OF SURGERY LA English DT Article ID ACADEMIC SURGERY; JIM INTERVIEW; FORCES; MD AB Objective To establish criteria to evaluate performance in surgical research, and to suggest strategies to optimize research in the future. Summary Background Data Research is an integral component of the academic mission, focusing on important clinical problems, accounting for surgical advances, and providing training and mentoring for young surgeons, With constraints on healthcare resources, there is increasing pressure to generate clinical revenues at the expense of the time and effort devoted to surgical research. An approach that would assess the value of research would allow prioritization of projects. Further, alignment of high-priority research projects with clinical goals would optimize research gains and maximize the clinical enterprise. Methods The authors reviewed performance criteria applied to industrial research and modified these criteria to apply to surgical research. They reviewed several programs that align research objectives with clinical goals. Results Performance criteria were categorized along several dimensions: internal measures (quality, productivity, innovation, learning, and development), customer satisfaction, market share, and financial indices (cost and profitability), A "report card" was proposed to allow the assessment of research in an individual department or division. Conclusions The department's business strategy can no longer be divorced from its research strategy. Alignment between research and clinical goals will maximize the department's objectives but will create the need to modify existing hierarchical structures and reward systems, Such alignment appears to be the best way to ensure the success of surgical research in the future. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg, Boston, MA USA. RP Souba, WW (reprint author), Penn State Coll Med, Dept Surg, H051,500 Univ Dr, Hershey, PA 17033 USA. NR 18 TC 16 Z9 16 U1 0 U2 3 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 JUL PY 2000 VL 232 IS 1 BP 32 EP 41 DI 10.1097/00000658-200007000-00005 PG 10 WC Surgery SC Surgery GA 329RF UT WOS:000087921100005 PM 10862192 ER PT J AU Basker, MR Cooper, DKC AF Basker, MR Cooper, DKC TI Oesophageal syncope SO ANNALS OF THE ROYAL COLLEGE OF SURGEONS OF ENGLAND LA English DT Article DE syncope; oesophagus; swallowing; dysrhythmia ID COMPLETE ATRIOVENTRICULAR-BLOCK; DE-GLUTITION SYNCOPE; CAROTID-SINUS HYPERSENSITIVITY; SWALLOW SYNCOPE; DEGLUTITION SYNCOPE; GLOSSOPHARYNGEAL NEURALGIA; SEIZURES; HEART AB Oesophageal syncope is loss of consciousness on swallowing, which is thought to be associated with an abnormal vagovagal reflex that leads to transient bradycardia. Patients with this potentially lethal condition may present to neurologists, cardiologists or gastroenterologists. It may be associated with cardio-active drug therapy, previous myocardial infarction, or with an organic lesion of the lower oesophagus. Barium and manometric studies, in association with ECG monitoring, should, therefore, be carried out in all cases. In many patients, however, it appears to be a functional abnormality for which no cause can be determined. In the absence of a condition necessitating surgical correction, medical therapy in the form of anticholinergic or sympathomimetic agents is occasionally helpful. Total denervation of the affected portion of the oesophagus has successfully prevented further symptoms, but insertion of a programmed cardiac pacemaker is currently the definitive treatment of choice. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Transplantat Biol Res Ctr,MGH E, Boston, MA 02129 USA. RP Cooper, DKC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Transplantat Biol Res Ctr,MGH E, Bldg 149-9019,13th St, Boston, MA 02129 USA. NR 57 TC 11 Z9 11 U1 0 U2 1 PU ROYAL COLL SURGEONS ENGLAND PI LONDON PA 35-43 LINCOLN'S INN FIELDS, LONDON WC2A 3PN, ENGLAND SN 0035-8843 J9 ANN ROY COLL SURG JI Ann. R. Coll. Surg. Engl. PD JUL PY 2000 VL 82 IS 4 BP 249 EP 253 PG 5 WC Surgery SC Surgery GA 342MP UT WOS:000088648800005 PM 10932658 ER PT J AU Schwarze, ML Menard, MT Fuchimoto, Y Huang, CA Houser, S Mawulawde, K Allison, KS Sachs, DH Madsen, JC AF Schwarze, ML Menard, MT Fuchimoto, Y Huang, CA Houser, S Mawulawde, K Allison, KS Sachs, DH Madsen, JC TI Mixed hematopoietic chimerism induces long-term tolerance to cardiac allografts in miniature swine SO ANNALS OF THORACIC SURGERY LA English DT Article; Proceedings Paper CT 36th Annual Meeting of the Society-of-Thoracic-Surgeons CY JAN 31-FEB 02, 2000 CL FT LAUDERDALE, FLORIDA SP Soc Thorac Surg ID MAJOR HISTOCOMPATIBILITY COMPLEX; BONE-MARROW TRANSPLANTATION; STAGE RENAL-DISEASE; ALLOGENEIC CHIMERISM; CYNOMOLGUS MONKEYS; DONOR; IMMUNOSUPPRESSION; VASCULOPATHY; INDUCTION; ANTIGEN AB Background. Tolerance to cardiac allografts has not been achieved in large animals using methods that are readily applicable to human recipients. We investigated the effects of mixed hematopoietic chimerism on cardiac allograft survival and chronic rejection in miniature swine Methods. Recipients were T-cell depleted using a porcine CD3 immunotoxin, and each received either of two nonmyeloablative preparative regimens previously demonstrated to permit the establishment of stable mixed hematopoietic chimerism across MHC-matched, minor-antigen-mismatched histocompatibility barriers. Five to 12 months after the chimerism was induced, hearts from the original cell donors were heterotopically transplanted into the stable mixed chimeras. Results. Cardiac allografts transplanted into untreated recipients across similar minor antigen barriers were rejected within 44 days (within 21, 28, 35, 39, 44 days among individual study subjects). In contrast, hearts transplanted into the mixed chimeras were all accepted long term ( > 153, > 225, > 286, > 362 days) without immunosuppressive drugs and developed minimal vasculopathy. Conclusions. Mixed hematopoietic chimerism, established in miniature swine using clinically relevant, nonmyeloablative conditioning regimens, permits long-term cardiac allograft survival without chronic immunosuppressive therapy, significant vasculopathy, or graft-versus-host disease. (Ann Thorac Surg 2000; 70:131-9) (C) 2000 by The Society of Thoracic Surgeons. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg,Div Cardiac Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg,Transplantat Biol Res Ctr, Boston, MA 02114 USA. RP Madsen, JC (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg,Div Cardiac Surg, EDR 105,55 Fruit St, Boston, MA 02114 USA. FU NHLBI NIH HHS [2RO1-HL54211-04] NR 24 TC 34 Z9 37 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD JUL PY 2000 VL 70 IS 1 BP 131 EP 138 DI 10.1016/S0003-4975(00)01564-2 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 336TB UT WOS:000088318100032 PM 10921697 ER PT J AU Torchiana, DF Vine, AJ Shebani, KO Kantor, HL Titus, JS Lu, CZ Daggett, WM Geffin, GA AF Torchiana, DF Vine, AJ Shebani, KO Kantor, HL Titus, JS Lu, CZ Daggett, WM Geffin, GA TI Cardioplegia and ischemia in the canine heart evaluated by P-31 magnetic resonance spectroscopy SO ANNALS OF THORACIC SURGERY LA English DT Article ID WARM-BLOOD CARDIOPLEGIA; VENTRICULAR PRESSURE; ARRESTED HEART; METABOLISM; PRESERVATION; HYPOTHERMIA; CALCIUM; BYPASS; FLOW AB Background. Warm continuous blood cardioplegia provides excellent protection, but must be interrupted by ischemic intervals to aid visualization. We hypothesized that (1) as ischemia is prolonged, the reduced metabolic rate offered by cooling gives the advantage to hypothermic cardioplegia; and (2) prior cardioplegia mitigates the deleterious effects of normothermic ischemia. Methods. Isolated cross-perfused canine hearts underwent cardioplegic arrest followed by 45 minutes of global ischemia at 10 degrees C or 37 degrees C, or 45 minutes of normothermic ischemia without prior cardioplegia. Left ventricular function was measured at baseline and during 2 hours of recovery. Metabolism was continuously evaluated by phosphorus-31 magnetic resonance spectroscopy. Results. Adenosine triphosphate was 71% +/- 4%, 71% +/- 7%, and 38% +/- 5% of baseline at 30 minutes, and 71% +/- 4%, 48% +/- 5%, and 39% +/- 6% at 42 minutes of ischemia in the cold ischemia, warm ischemia, and normothermic ischemia without prior cardioplegia groups, respectively. Left ventricular systolic function, left ventricular relaxation, and high-energy phosphate levels recovered fully after cold cardioplegia and ischemia. Prior cardioplegia delayed the decline in intracellular pH during normothermic ischemia initially by 9 minutes, and better preserved left ventricular relaxation during recovery, but did not ameliorate the severe postischemic impairment of left ventricular systolic function, marked adenosine triphosphate depletion, and creatine phosphate increase. Left ventricular distensibility decreased in all groups. Conclusions. When cardioplegia is followed by prolonged ischemia, better protection is provided by hypothermia than by normothermia. Prior cardioplegia confers little advantage on recovery after prolonged normothermic ischemia but delays initial ischemic metabolic deterioration, which would contribute to the safety of brief interruptions of warm cardioplegia. (Ann Thorac Surg 2000;70:197-205) (C) 2000 by The Society of Thoracic Surgeons. C1 Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Cardiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Torchiana, DF (reprint author), Massachusetts Gen Hosp, Dept Surg, BUL119,Fruit St, Boston, MA 02114 USA. FU NHLBI NIH HHS [HL12777] NR 26 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD JUL PY 2000 VL 70 IS 1 BP 197 EP 205 DI 10.1016/S0003-4975(00)01341-2 PG 9 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 336TB UT WOS:000088318100045 PM 10921708 ER PT J AU Cambria, RP AF Cambria, RP TI Epidural versus subdural spinal cord cooling: Cerebrospinal fluid temperature and pressure changes - Invited commentary SO ANNALS OF THORACIC SURGERY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Cambria, RP (reprint author), Massachusetts Gen Hosp, WACC 458,15 Parkman St, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD JUL PY 2000 VL 70 IS 1 BP 228 EP 228 DI 10.1016/S0003-4975(00)01545-9 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 336TB UT WOS:000088318100050 ER PT J AU Daggett, WM AF Daggett, WM TI Entire septal patch technique for postinfarction ventricular septal rupture - Invited commentary SO ANNALS OF THORACIC SURGERY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Daggett, WM (reprint author), Massachusetts Gen Hosp, Dept Surg, Bulfinch 119, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD JUL PY 2000 VL 70 IS 1 BP 274 EP 275 DI 10.1016/S0003-4975(00)01486-7 PG 2 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 336TB UT WOS:000088318100064 ER PT J AU Bonassar, LJ Grodzinsky, AJ Srinivasan, A Davila, SG Trippel, SB AF Bonassar, LJ Grodzinsky, AJ Srinivasan, A Davila, SG Trippel, SB TI Mechanical and physicochemical regulation of the action of insulin-like growth factor-I on articular cartilage SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE IGF-I; cartilage biomechanics; matrix assembly; physical stimuli; chondrocyte metabolism ID NEWLY SYNTHESIZED PROTEOGLYCANS; BIOSYNTHETIC RESPONSE; DYNAMIC COMPRESSION; INDIVIDUAL CELLS; RETINOIC ACID; FLUID-FLOW; EXPLANTS; CULTURE; JOINT; CHONDROCYTES AB The development and maintenance of healthy joints is a complex process involving many physical and biological stimuli. This study investigates the interaction between insulin-like growth factor-I (IGF-I) and static mechanical compression in the regulation of articular cartilage metabolism. Bovine cartilage explants were treated with concentrations of IGF-I from 0 to 300 ng/ml in the presence or absence of 0-50% static compression, and the transient and steady-state incorporation of [H-3]proline and [S-35]sulfate into matrix components were measured. In parallel studies, cartilage explants were treated with 0-300 ng/ml IGF-I at media pH ranging from 6.4 to 7.2 and the steady-state incorporation of [H-3]proline and [S-35]sulfate was measured. The effect of 50% static compression on IGF-I transport was determined by measuring the uptake of I-125-labeled IGF-I into cartilage explants, Static compression decreased both [H-3]proline and [S-35]sulfate incorporation in a dose-dependent manner in the presence or absence of IGF-I. IGF-I increased [H-3]proline and [S-35]sulfate incorporation in a dose-dependent manner in the presence or absence of compression, but the anabolic effect of the growth factor was lessened when the tissue was compressed by 50%. The response of cartilage explants to IGF-I was similarly lessened in unstrained tissue cultured in media at pH 6.4, a condition which results in a similar intratissue pH to that when cartilage is compressed by 50%. The characteristic time constant (tau) for IGF-I stimulation of cartilage explants was approximately 24 h, while tau for inhibition of biosynthesis by static compression was approximately 2 h, Samples which mere both com-pressed and treated with IGF-I demonstrated an initial decrease in biosynthetic activity at 2 h, followed by an increase at 24 h, Static compression did not alter tau for [I-125]labeled IGF-I transport into cartilage but decreased the concentration of I-125-labeled IGF-I in the tissue at equilibrium. (C) 2000 Academic Press. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Orthopaed Res Labs, Boston, MA 02114 USA. MIT, Ctr Biomed Engn, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. RP Bonassar, LJ (reprint author), Univ Massachusetts, Sch Med, Tissue Engn Lab, Room S2-725,55 Lake Ave N, Worcester, MA 01655 USA. RI Bonassar, Lawrence/C-2103-2016 OI Bonassar, Lawrence/0000-0003-1094-6433 FU NIAMS NIH HHS [AR33263, AR31068] NR 36 TC 70 Z9 73 U1 1 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JUL 1 PY 2000 VL 379 IS 1 BP 57 EP 63 DI 10.1006/abbi.2000.1820 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 329WR UT WOS:000087931900007 PM 10864441 ER PT J AU Stafford, RS Farhat, JH Misra, B Schoenfeld, DA AF Stafford, RS Farhat, JH Misra, B Schoenfeld, DA TI National patterns of physician activities related to obesity management SO ARCHIVES OF FAMILY MEDICINE LA English DT Article ID PRIMARY-CARE PRACTITIONERS; UNITED-STATES; HEALTH PROMOTION; COST AB Context: National physician practices related to the clinical recognition and management of obesity are unknown. Objectives: To estimate national patterns of office-based, obesity-related practices and to determine the independent predictors of these practices. Design: Serial cross-sectional surveys of physician office visits. Setting: Ambulatory medical care in the United States. Patients: We analyzed 55 858 adult physician office visits sampled in the 1995-1996 National Ambulatory Medical Care Surveys. Data from the Third National Health and Nutrition Examination Surveys, 1988-1994 were used to assess and, then, adjust for the underreporting of obesity. Main Outcome Measures: Reporting of obesity at office visits and physician counseling for weight loss, exercise, and diet among patients identified as obese. Results: Physicians reported obesity in only 8.6% of 1995-1996 National Ambulatory Medical Care Surveys visits. The 22.7% prevalence rate of the Third National Health and Nutrition Examination Surveys, 1988-1994 suggests that physicians reported obesity in only 38% of their obese patients. Among visits by patients identified as obese, physicians frequently provided counseling for weight loss (35.5%), exercise (32.8%), and diet (41.5%). Adjusted for population prevalence; however, each service was provided to no more than one quarter of all obese patients. While patients with obesity-related comorbidities were treated more aggressively, in these patients, weight loss counseling occurred at only 52% of the visits. Conclusions: Specific interventions to address obesity are infrequent in visits to US physicians. Obesity is underreported and interventions are only moderately likely among patients identified as obese, even for those with serious obesity-related comorbidities. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Hlth Policy, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Sch Publ Hlth,Biostat Ctr, Boston, MA 02114 USA. RP Stafford, RS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Hlth Policy, 50 Staniford St,9th Floor, Boston, MA 02114 USA. FU AHRQ HHS [HS07892]; NHLBI NIH HHS [K08-HL03548]; NIDDK NIH HHS [P30 DK40561] NR 28 TC 141 Z9 142 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1063-3987 J9 ARCH FAM MED JI Arch. Fam. Med. PD JUL PY 2000 VL 9 IS 7 BP 631 EP + DI 10.1001/archfami.9.7.631 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 334DA UT WOS:000088169300013 PM 10910311 ER PT J AU Kyosseva, SV Elbein, AD Hutton, TL Griffin, WST Mrak, RE Sturner, WQ Karson, CN AF Kyosseva, SV Elbein, AD Hutton, TL Griffin, WST Mrak, RE Sturner, WQ Karson, CN TI Increased levels of transcription factors Elk-1, cyclic adenosine monophosphate response element-binding protein, and activating transcription factor 2 in the cerebellar vermis of schizophrenic patients SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article; Proceedings Paper CT International Congress on Schizophrenia Research CY APR 17-21, 1999 CL SANTA FE, NEW MEXICO ID SIGNAL-TRANSDUCTION; KINASE CASCADES; NERVOUS-SYSTEM; NITRIC-OXIDE; RAT-BRAIN; CREB; STIMULATION; PHOSPHORYLATION; MEMORY; GENE AB Background: We investigated the levels of transcription factors associated with activation of the mitogen-activated protein (MAP) kinase pathway in schizophrenics using postmortem brain samples. These studies were done to determine whether our previous findings of abnormal levels of the MAP kinases in the cerebellar vermis were linked to additional downstream targets of this signal transduction pathway. Method: We measured the protein levels of 3 transcription factors in nuclear fractions of postmortem samples from cerebellar vermis of 10 patients with schizophrenia and 13 control subjects: Elk-l, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and activating transcription factor 2 (ATF-2). Studies in rats examined the postmortem stability and effect of haloperidol and risperidone on levels of Elk-l, cAMP, and ATF-2 proteins. Results: We found a significant increase in the protein levels of Elk-l (mean +/-SD, 4489 +/- 659 vs 2915 +/- 583 arbitrary densitometric units [P < .001]), CREB (mean +/- SD, 2149 +/- 1061 vs 904 +/- 711 arbitrary densitometric units [P = .003 ]) and ATF-2 (mean +/- SD, 1421 +/- 854 vs 512 +/- 394 arbitrary densitometric units [P = .003]) in the cerebellar vermis of schizophrenic subjects. Complementary studies in rats indicate that these findings can not be attributed to subacute treatment with antipsychotic medications. Conclusion: Taken together with the alterations of MAP kinases previously reported, and the findings of elevations of downstream transcription targets, we suggest that the MAP kinase signal transduction pathway contributes to the cerebellar abnormalities in schizophrenia. C1 Univ Arkansas Med Sci, Dept Biochem & Mol Biol, Little Rock, AR 72205 USA. Univ Arkansas Med Sci, Dept Psychiat, Little Rock, AR 72205 USA. Univ Arkansas Med Sci, Dept Pathol, Little Rock, AR 72205 USA. Ctr Geriatr Res Educ & Clin, Little Rock, AR USA. Mental Illness Res Educ Clin Ctr, Little Rock, AR USA. Cent Arkansas Vet Healthcare Syst, Little Rock, AR USA. State Arkansas Med Examiners Off, Little Rock, AR USA. RP Karson, CN (reprint author), VA Boston Healthcare Syst, 150 S Huntington Ave, Boston, MA 02130 USA. FU NHLBI NIH HHS [HL 17783]; NIMH NIH HHS [5RO1 MH45729-03] NR 47 TC 25 Z9 25 U1 1 U2 3 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 JUL PY 2000 VL 57 IS 7 BP 685 EP 691 DI 10.1001/archpsyc.57.7.685 PG 7 WC Psychiatry SC Psychiatry GA 331TR UT WOS:000088035200006 PM 10891039 ER PT J AU Oliveiva, J Ay, H Schaefer, PW Buonanno, FS Chang, YC Gonzalez, RG Koroshetz, WJ AF Oliveiva, J Ay, H Schaefer, PW Buonanno, FS Chang, YC Gonzalez, RG Koroshetz, WJ TI Diffusion-weighted magnetic resonance imaging identifies the "clinically relevant" small-penetrator infarcts SO ARCHIVES OF NEUROLOGY LA English DT Article ID LACUNAR INFARCTION; ACUTE STROKE; TIME-COURSE; MR; EXPERIENCE AB Background: Most patients initially seen with a clinical syndrome consistent with a small-penetrator infarct (SPI) also harbor multiple, chronic, hyperintense, white matter lesions on conventional magentic resonance imaging tie, T2-weighted image [T2WI] and fluid-attenuation inversion recovery [FLAIR] imaging). Diffusion-weighted imaging (DWI) can identify the clinically relevant "index infarction" in such circumstances, since it differentiates between acute and chronic lesions. Objective: To determine the clinical and radiological predictors associated with misidentification of an SPI as acute using T2WI and FLAIR images in patients with an acute SPI seen on DWI. Patients: Sixty-seven consecutive patients who had an SPI. Methods: Two independent examiners, provided with brief clinical information, but blinded to DWI findings, sought a clinically appropriate lesion on T2WI and FLAIR imaging in 67 consecutive patients found to have an SPI seen on DWI. Results: The index infarction based on evaluation of T2WI or FLAIR images was in a different location than the acute lesion as identified by DWI in 9 (13%) and 11 (16%) of 67 patients, respectively. Both T2WI and FLAIR imaging were rated normal in another 9% of the patients. Multivariate analysis showed that small lesion size (<10 mm) was the only predictor of misidentifying the clinically appropriate lesion on conventional magnetic resonance imaging (P<.01). Conclusions: T2-weighted imaging and FLAIR imaging fail to identify the clinically relevant SPI in almost one quarter of the patients found to have a lesion on DWI. The characteristics of DWI make it well suited for the detection of acute small infarcts. Diffusion-weighted imaging is necessary to consistently define the clinical-anatomical relations in patients initially seen with SPIs. C1 Massachusetts Gen Hosp, Dept Neurol, Stroke Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Neuroradiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Oliveiva, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol Stroke Serv, Blake 1291 B,55 Fruit St, Boston, MA 02114 USA. FU NINDS NIH HHS [5P50NS108288-22, NS34626, R01NS28371] NR 22 TC 23 Z9 24 U1 0 U2 0 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 JUL PY 2000 VL 57 IS 7 BP 1009 EP 1014 DI 10.1001/archneur.57.7.1009 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 333TB UT WOS:000088145900013 PM 10891983 ER EF