FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Mathew, P Valentine, MB Bowman, LC Rowe, ST Nash, MB Valentine, VA Cohn, SL Castleberry, RP Brodeur, GM Look, AT AF Mathew, P Valentine, MB Bowman, LC Rowe, ST Nash, MB Valentine, VA Cohn, SL Castleberry, RP Brodeur, GM Look, AT TI Detection of MYCN gene amplification in neuroblastoma by fluorescence in situ hybridization: A pediatric oncology group study SO NEOPLASIA LA English DT Article DE neuroblastoma; fluorescence in situ hybridization; MYCN gene; gene amplification; double minute chromatin bodies ID N-MYC; INSITU HYBRIDIZATION; NEURO-BLASTOMA; STAGE AB To assess the utility of fluorescence in situ hybridization (FISH) for analysis of MYCN gene amplification in neuroblastoma, we compared this assay with Southern blot analysis using tumor specimens collected from 232 patients with presenting characteristics typical of this disease. The FISH technique identified MYCN amplification in 47 cases, compared with 39 by Southern blotting, thus increasing the total number of positive cases by 21%. The major cause of discordancy was a low fraction of tumor cells (less than or equal to 30% replacement) in clinical specimens, which prevented an accurate estimate of MYCN copy number by Southern blotting. With FISH, by contrast, it was possible to analyze multiple interphase nuclei of tumor cells, regardless of the proportion of normal peripheral blood, bone marrow, or stromal cells in clinical samples. Thus, FISH could be performed accurately with very small numbers of tumor cells from touch preparations of needle biopsies, Moreover, this procedure allowed us to discern the heterogeneous pattern of MYCN amplification that is characteristic of neuroblastoma. We conclude that FISH improves the detection of MYCN gene amplification in childhood neuroblastomas in a clinical setting, thus facilitating therapeutic decisions based on the presence or absence of this prognostically important biologic marker. C1 St Jude Childrens Res Hosp, Dept Expt Oncol, Memphis, TN 38105 USA. St Jude Childrens Res Hosp, Dept Hematol Oncol, Memphis, TN 38105 USA. Northwestern Univ, Dept Pediat, Chicago, IL 60611 USA. Northwestern Univ, Dept Tumor Cell Biol, Chicago, IL 60611 USA. Childrens Mem Hosp, Chicago, IL 60614 USA. Univ Florida, Pediat Oncol Grp, Gainesville, FL 32611 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Univ Penn, Philadelphia, PA 19104 USA. RP Look, AT (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St,Mayer 630, Boston, MA 02115 USA. OI Cohn, Susan/0000-0001-5749-7650 FU NCI NIH HHS [CA 21765, CA 31566, P30 CA021765] NR 17 TC 48 Z9 50 U1 0 U2 1 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD MAR-APR PY 2001 VL 3 IS 2 BP 105 EP 109 DI 10.1038/sj.neo.7900146 PG 5 WC Oncology SC Oncology GA 429AQ UT WOS:000168494200002 PM 11420745 ER PT J AU Jara, A Gonzalez, S Felsenfeld, AJ Chacon, C Valdivieso, A Jalil, R Chuaqui, B AF Jara, A Gonzalez, S Felsenfeld, AJ Chacon, C Valdivieso, A Jalil, R Chuaqui, B TI Failure of high doses of calcitriol and hypercalcaemia to induce apoptosis in hyperplastic parathyroid glands of azotaemic rats SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE apoptosis; calcitriol; hypercalcaemia; parathyroid gland; parathyroid hormone; rat ID CHRONIC-RENAL-FAILURE; VITAMIN-D METABOLITES; SEVERE SECONDARY HYPERPARATHYROIDISM; CELL-PROLIFERATION; CALCIUM RECEPTOR; UREMIC PATIENTS; PULSE THERAPY; HORMONE; 1,25-DIHYDROXYCHOLECALCIFEROL; PHOSPHATE AB Background. Whether calcitriol administration, which is used to treat secondary hyperparathyroidism in dialysis patients, induces regression of parathyroid-gland hyperplasia remains a subject of interest and debate. If regression of the parathyroid gland were to occur, the presumed mechanism would be apoptosis. However, information on whether high doses of calcitriol can induce apoptosis of parathyroid cells in hyperplastic parathyroid glands is lacking. Consequently, high doses of calcitriol were given to azotaemic rats and the parathyroid glands were evaluated for apoptosis. Methods. Rats were either sham-operated (two groups) or underwent a two-stage 5/6 nephrectomy (three groups). For the first 4 weeks, all rats were given a high (1.2%) phosphorus (P) diet to stimulate parathyroid gland growth and then were changed to a normal (0.6%) P diet for 2 weeks. At week 7, three of the five groups were given high doses of calcitriol (500 pmol/100 g body weight) intraperitoneally every 24 h during 72 h before sacrifice. The five groups during week 7 were: (i) normal renal function (NRF) + 0.6% P diet, (ii) NRF + 0.6% P + calcitriol; (iii) renal failure (RF)+0.6% P; (iv) RF+1.2% P+calcitriol; and (v) RF+0.6% P+calcitriol. Parathyroid glands were removed at sacrifice and the TUNEL stain was performed to detect apoptosis. Results, At sacrificer the respective serum calcium values in calcitriol-treated groups (groups 2, 4, and 5) were 15.52+/-0.26, 13.41+/-0.39 and 15.12+/-0.32 mg/dl. In group 3, PTH was 178 +/- 42 pg/ml, but in calcitriol-treated groups, PTH values were suppressed, 8+/-1 (group 2), 12 +/- 2 (group 4), and 7 +/- 1 pg/ml (group 5). Despite, the severe hypercalcaemia and marked PTH suppression in calcitriol-treated groups, the percentage of apoptotic cells in the parathyroid glands was very low (range 0.08+/-0.04 to 0.25+/-0.20%) and not different among the five groups. Conclusions. We found no evidence in hyperplastic parathyroid glands that apoptosis could be induced in azotaemic rats by the combination of high doses of calcitriol and severe hypercalcaemia despite the marked reduction in PTH levels that was observed. C1 Pontificia Univ Catolica Chile, Dept Nephrol, Santiago, Chile. Pontificia Univ Catolica Chile, Dept Pathol, Santiago, Chile. W Los Angeles Vet Affairs Med Ctr, Dept Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Los Angeles, CA 90073 USA. RP Jara, A (reprint author), Pontificia Univ Catolica Chile, Dept Nephrol, Marcoleta 345, Santiago, Chile. NR 43 TC 18 Z9 18 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD MAR PY 2001 VL 16 IS 3 BP 506 EP 512 DI 10.1093/ndt/16.3.506 PG 7 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 412HQ UT WOS:000167549300012 PM 11239023 ER PT J AU Sperling, R Bates, J Cocchiarella, A Rentz, D Schacter, D Rosen, B Albert, M AF Sperling, R Bates, J Cocchiarella, A Rentz, D Schacter, D Rosen, B Albert, M TI Functional MRI studies in aging and AD SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, NMR Ctr, Boston, MA 02114 USA. Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR-APR PY 2001 VL 22 IS 2 MA 9 BP 333 EP 333 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 405HW UT WOS:000167154800027 ER PT J AU Johnson, KA Killiany, R Jones, KJ Becker, JA Hilson, J Sandor, T Kikinis, R Jolesz, F Albert, MS AF Johnson, KA Killiany, R Jones, KJ Becker, JA Hilson, J Sandor, T Kikinis, R Jolesz, F Albert, MS TI MRI volumetric sampling of SPECT perfusion in prodromal Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR-APR PY 2001 VL 22 IS 2 MA 19 BP 336 EP 336 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 405HW UT WOS:000167154800037 ER PT J AU Killiany, R Gomez-Isla, T Moss, M Kikinis, R Sandor, T Jolesz, F Tanzi, R Jones, K Hyman, B Albert, M AF Killiany, R Gomez-Isla, T Moss, M Kikinis, R Sandor, T Jolesz, F Tanzi, R Jones, K Hyman, B Albert, M TI Use of MRI to predict who will get Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract C1 Boston Univ, Boston, MA 02215 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR-APR PY 2001 VL 22 IS 2 MA 21 BP 336 EP 336 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 405HW UT WOS:000167154800039 ER PT J AU Hyman, BT AF Hyman, BT TI Molecular and anatomical studies in Alzheimer's disease SO NEUROLOGIA LA English DT Article DE Alzheimer disease; beta amyloid; dementia; multiphoton microscopy ID AMYLOID BETA-PEPTIDE; APOLIPOPROTEIN-E GENOTYPE; SENILE PLAQUES; NEUROFIBRILLARY TANGLES; NEURONAL LOSS; NEUROPATHOLOGICAL CRITERIA; 2-PHOTON EXCITATION; DEMENTIA SEVERITY; PYRAMIDAL NEURONS; TRANSGENIC MICE AB This chapter builds on the themes developed during the last 10 years of studying the neuroanatomical basis of Alzheimer's disease (AD) from a neural systems perspective. Indirect evidence suggests that Abeta deposits are a dynamic lesion, and that a subset of Abeta deposits that stain for thioflavine S (thioS) are a critical lesion in terms of effects on neurons and their processes. Parallel studies in transgenic mice point to the same conclusion. Finally, we will discuss recent studies, using a remarkable microscropy tool that we have developed - an application of multiphoton microscopy - for in vivo histology, and in vivo functional imaging in living, anesthetized transgenic mice. Resolution is well below a micrometer, and cortical depths up to similar to300 microns beneath the skull can be imaged; the mice recover uneventfully and can be reimaged days to months later. With this new technique, we can, for the first time, study dynamic processes of Abeta deposition and resolution in a living brain. C1 Massachusetts Gen Hosp, Alzheimer Res Unit, Charlestown, MA 02129 USA. RP Hyman, BT (reprint author), Massachusetts Gen Hosp, Alzheimer Res Unit, 149 13th St,Rm 6405, Charlestown, MA 02129 USA. NR 49 TC 9 Z9 11 U1 0 U2 0 PU EDICIONES DOYMA S/L PI BARCELONA PA TRAV DE GRACIA 17-21, 08021 BARCELONA, SPAIN SN 0213-4853 J9 NEUROLOGIA JI Neurologia PD MAR PY 2001 VL 16 IS 3 BP 100 EP 104 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 511BL UT WOS:000173243800002 PM 11333778 ER PT J AU Quinn, J Kaye, J AF Quinn, J Kaye, J TI The neurology of aging SO NEUROLOGIST LA English DT Review DE memory impairment; dementia; aging; balance; gait ID MILD COGNITIVE IMPAIRMENT; HEALTHY OLDEST-OLD; PLASMA-CATECHOLAMINE RESPONSES; ONSET ALZHEIMER-DISEASE; ADULT AGE-DIFFERENCES; COMMUNITY POPULATION; WORKING-MEMORY; RECALL PERFORMANCE; PERCEPTUAL SPEED; MUSCLE STRENGTH AB BACKGROUND- Several neurologic signs that are considered pathologic in younger patients are known to appear in the absence of pathology in older patients. At the same lime, disorders of the nervous sytem are a major cause of morbidity in the aging population. Dementia is a particularly common condition in the aging population, with a steadily increasing incidence with age. REVIEW SUMMARY- The neurologic findings in the elderly are reviewed, starting with the noncognitive portion of the neurologic examination and proceeding to cognitive changes. This literature review raises several questions regarding the nature of brain aging and late-life dementia, which are explored additionally in a review of the findings of the Oregon Brain Aging Study. This is a longitudinal study of exceptionally healthy subjects older than 85 years of age in which longitudinal clinical and neuropsychologic data are complemented by longitudinal volumetric brain magnetic resonance imaging data. Neuropathologic examination of the brain has also been completed for the first cohort of brains coming to autopsy. CONCLUSIONS- The neurology of healthy aging is characterized by the appearance of specific neurologic signs, a very gradual decline in some cognitive functions, and minimal loss of brain volume. With increasing age, even in the healthiest elderly, there is an increased incidence of dementia, which is characterized by increased rates of cognitive decline and brain volume loss. The pathology associated with this dementia is classical Alzheimer disease pathology. It is possible for elderly subjects to be spared cognitive decline, brain volume loss, and Alzheimer pathology, even into the eleventh decade. Although this phenotype represents the exception rather than the rule, additional investigations of healthy aging hold promise for elucidating the mechanisms responsible for both pathologic and successful brain aging. C1 Oregon Hlth Sci Univ, Dept Neurol, Portland, OR 97210 USA. Portland VA Med Ctr, Portland, OR USA. OI Kaye, Jeffrey/0000-0002-9971-3478 NR 168 TC 1 Z9 1 U1 2 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1074-7931 J9 NEUROLOGIST JI Neurologist PD MAR PY 2001 VL 7 IS 2 BP 98 EP 112 PG 15 WC Clinical Neurology SC Neurosciences & Neurology GA 412TJ UT WOS:000167570200003 ER PT J AU Chang, DC Reppert, SM AF Chang, DC Reppert, SM TI The circadian clocks of mice and men SO NEURON LA English DT Review ID SUPRACHIASMATIC NUCLEUS; PERIPHERAL-TISSUES; GENE-EXPRESSION; PATHWAYS C1 Massachusetts Gen Hosp, MassGen Hosp Children, Lab Dev Chronobiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02114 USA. RP Reppert, SM (reprint author), Massachusetts Gen Hosp, MassGen Hosp Children, Lab Dev Chronobiol, Boston, MA 02114 USA. NR 20 TC 32 Z9 33 U1 2 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD MAR PY 2001 VL 29 IS 3 BP 555 EP 558 DI 10.1016/S0896-6273(01)00230-6 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 418BA UT WOS:000167868900004 PM 11301014 ER PT J AU Tolias, AS Moore, T Smirnakis, SM Tehovnik, EJ Siapas, AG Schiller, PH AF Tolias, AS Moore, T Smirnakis, SM Tehovnik, EJ Siapas, AG Schiller, PH TI Eye movements modulate visual receptive fields of V4 neurons SO NEURON LA English DT Article ID SUPERIOR TEMPORAL SULCUS; RHESUS-MONKEY; AREA V4; PREFRONTAL CORTEX; PARIETAL CORTEX; ATTENTION; MACAQUE; SACCADES; REPRESENTATION; RESPONSES AB The receptive field, defined as the spatiotemporal selectivity of neurons to sensory stimuli, is central to our understanding of the neuronal mechanisms of perception. However, despite the fact that eye movements are critical during normal vision, the influence of eye movements on the structure of receptive fields has never been characterized. Here, we map the receptive fields of macaque area V4 neurons during saccadic eye movements and find that receptive fields are remarkably dynamic. Specifically, before the initiation of a saccadic eye movement, receptive fields shrink and shift towards the saccade target. These spatiotemporal dynamics may enhance information processing of relevant stimuli during the scanning of a visual scene, thereby assisting the selection of saccade targets and accelerating the analysis of the visual scene during free viewing. C1 MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02114 USA. MIT, Ctr Learning & Memory, Cambridge, MA 02139 USA. RP Tolias, AS (reprint author), Max Planck Inst Biol Cybernet, Spemannstr 38, Tubingen, Germany. NR 45 TC 167 Z9 168 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD MAR PY 2001 VL 29 IS 3 BP 757 EP 767 DI 10.1016/S0896-6273(01)00250-1 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 418BA UT WOS:000167868900024 PM 11301034 ER PT J AU Seaton, BE Goldstein, G Allen, DN AF Seaton, BE Goldstein, G Allen, DN TI Sources of heterogeneity in schizophrenia: The role of neuropsychological functioning SO NEUROPSYCHOLOGY REVIEW LA English DT Review DE schizophrenia; diagnosis; subtyping; cognition ID TEMPORAL-LOBE EPILEPSY; NEGATIVE SYMPTOMS; 1ST-EPISODE SCHIZOPHRENIA; COGNITIVE HETEROGENEITY; NEUROCOGNITIVE DEFICITS; IDENTIFYING SUBTYPES; PREFRONTAL CORTEX; MEMORY IMPAIRMENT; DYSFUNCTION; CLASSIFICATION AB Although schizophrenia is often characterized as a heterogeneous disorder, efforts to validate stable and meaningful subtypes have met with limited success. Thus, the issue of whether schizophrenia reflects a continuum of severity or a number of discrete subtypes remains controversial. This review evaluates efforts to establish subtypes based upon a model that includes causes, characteristics, and course and outcomes of heterogeneity. Emphasis is placed on empirical classification studies utilizing cognitive tests or symptom rating scales, sometimes in conjunction with neuroimaging procedures. Results of recent cluster analytic studies are reviewed that produced evidence of four or five clusters, varying in level and pattern of performance. Although this research typically generated meaningful subtypes, it was often the case that there was little correspondence between subtyping systems based upon cognitive function and those based upon symptom profile. It was concluded that there may be different mechanisms for producing cognitive and symptomatic heterogeneity, and that diversity in presentations of schizophrenia reflects a combination of continuities in severity of the disorder with a number of meaningful and stable subtypes. C1 VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15206 USA. Mercy Med Ctr N Iowa, Mason City, IA USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Univ Nevada, Las Vegas, NV 89154 USA. RP Goldstein, G (reprint author), VA Pittsburgh Healthcare Syst, 7180 Highland Dr,151R, Pittsburgh, PA 15206 USA. EM ggold@nb.net NR 105 TC 41 Z9 41 U1 2 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1040-7308 J9 NEUROPSYCHOL REV JI Neuropsychol. Rev. PD MAR PY 2001 VL 11 IS 1 BP 45 EP 67 DI 10.1023/A:1009013718684 PG 23 WC Psychology, Clinical; Neurosciences SC Psychology; Neurosciences & Neurology GA 432GX UT WOS:000168684800003 PM 11392562 ER PT J AU Kyosseva, SV Owens, S Elbein, AD Karson, CN AF Kyosseva, SV Owens, S Elbein, AD Karson, CN TI Differential and region-specific activation of mitogen-activated protein kinases following chronic administration of phencyclidine in rat brain SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE phencyclidine; rat cerebellum; signal transduction; ERK; JNK; p38 MAP kinase ID SIGNAL-REGULATED KINASE; CENTRAL-NERVOUS-SYSTEM; MAP KINASE; TYROSINE PHOSPHORYLATION; ELECTROCONVULSIVE SHOCK; GLUTAMATERGIC DYSFUNCTION; TRANSDUCTION CASCADE; COGNITIVE DYSMETRIA; CEREBELLAR VERMIS; STRIATAL NEURONS AB We have previously demonstrated elevation of the extracellular signal-regulated kinase (ERK) pathway in the cerebellum from patients with schizophrenia, an illness that may involve dysfunction of the N-methyl-D-aspartate (NMDA) receptor. Since the NMDA antagonist, phencyclidine (PCP), produces schizophrenic-like symptoms in humans, and abnormal behavior in animals, we examined the effects of chronic PCP administration in time- and dose-dependent manner on ERK and two other members of mitogen-activated protein kinase family, c-Jun N-terminal protein kinase (JNK) and p38, in rat brain. Osmotic pumps for PCP (18 mg/kg/day) and saline (controls) were implanted subcutaneously in rats for three, 10, and 20 days. Using Western blot analysis, we found no change at three days, but a significant increase in the phosphorylation of ERK1, ERK2 and MEK in the cerebellum at 10- and 20-days of continuous PCP infusion. For the experiments involving various doses of PCP; rats were infused with PCP at concentrations of 2.5, 10, 18, or 25 mg/kg/day, or saline for 10 days. We observed a dose dependent elevation in the phosphorylation of ERK1 and ERK2 only in the cerebellum but not in brainstem, frontal cortex or hippocampus. The activities of JNK and p38 were unchanged in all investigated brain regions including cerebellum. These results demonstrate that chronic infusion of PCP in rats produces a differential and brain region-specific activation of MAP kinases, suggesting a role for the ERK signaling pathway in PCP abuse and perhaps in schizophrenia. (C) 2001 American College of Neuropsychopharmacology. Published by Elsevier Science Inc. 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 Pharmacol & Toxicol, Little Rock, AR 72205 USA. VA Boston Healthcare Syst, Boston, MA USA. RP Kyosseva, SV (reprint author), Univ Arkansas Med Sci, Dept Biochem & Mol Biol, 4301 W Markham St, Little Rock, AR 72205 USA. FU NHLBI NIH HHS [HL-17783]; NIMH NIH HHS [MH60739, MH45729] NR 71 TC 28 Z9 29 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2001 VL 24 IS 3 BP 267 EP 277 DI 10.1016/S0893-133X(00)00180-9 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 400KZ UT WOS:000166871900005 PM 11166517 ER PT J AU Ojemann, RG AF Ojemann, RG TI Retrosigmoid approach to acoustic neuroma (vestibular schwannoma) SO NEUROSURGERY LA English DT Article DE acoustic neuroma; operative technique; retrosigmoid approach; suboccipital approach; vestibular schwannoma AB THE RETROSIGMOID APPROACH for the microsurgical removal of an acoustic neuroma (vestibular schwannoma) is described, and perioperative medical management of the patient is discussed. The techniques for monitoring facial and cochlear nerve function are presented. The supine-oblique position, skin incision, bone removal, dural opening, and initial exposure are outlined. Important points in the technique for removing acoustic neuromas and preserving hearing, when possible, are described and illustrated. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Ojemann, RG (reprint author), Massachusetts Gen Hosp, Fruit St, Boston, MA 02114 USA. NR 10 TC 37 Z9 45 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD MAR PY 2001 VL 48 IS 3 BP 553 EP 558 DI 10.1097/00006123-200103000-00018 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 408AH UT WOS:000167304000048 PM 11270545 ER PT J AU Shekelle, PG AF Shekelle, PG TI Are appropriateness criteria ready for use in clinical practice? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID CAROTID ENDARTERECTOMY; UNDERUSE; CARE; REVASCULARIZATION; VALIDITY C1 Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA 90073 USA. RP Shekelle, PG (reprint author), Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA 90073 USA. NR 14 TC 32 Z9 32 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 MAR 1 PY 2001 VL 344 IS 9 BP 677 EP 678 DI 10.1056/NEJM200103013440912 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 405TR UT WOS:000167177100012 PM 11228286 ER PT J AU Goetzl, L Shipp, TD Cohen, A Zelop, CM Repke, JT Lieberman, E AF Goetzl, L Shipp, TD Cohen, A Zelop, CM Repke, JT Lieberman, E TI Oxytocin dose and the risk of uterine rupture in trial of labor after cesarean SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID DELIVERY; SEGMENT AB Objective: To examine the association between uterine rupture and oxytocin use in trial of labor after cesarean. Methods: A case-control study was performed. Cases were all women with uterine ruptures who received oxytocin during a trial of labor after a single cesarean delivery within a 12-year period (n = 24). Four controls undergoing trial of labor after a single cesarean delivery were matched to each case by 500 g birth weight category, year of birth, and by induction or augmentation (n = 96). The study had an 80% power to detect a 40% increase in oxytocin duration or a 65% increase in total oxytocin dose. Results: No significant differences were seen in initial oxytocin dose, maximum dose, or time to maximum dose. Although women with uterine ruptures had higher exposure to oxytocin as measured by mean total oxytocin dose (544 mU higher) and oxytocin duration (54 minutes longer), these differences were not statistically significant. Women with uterine rupture who received oxytocin were more likely to have experienced an episode of uterine hyperstimulation (37.5% compared with 20.8%, P = .05). However, the positive predictive value of hyperstimulation for uterine rupture was only 2.8%. Conclusion: Although no significant differences in exposure to oxytocin were detected between cases of uterine rupture and controls, the rarity of uterine rupture limited our power to detect small differences in exposure. In women receiving oxytocin, uterine rupture is associated with an increase in uterine hyperstimulation, but the clinical value of hyperstimulation for predicting uterine rupture is limited. (C) 2001 by The American College of Obstetricians and Gynecologists. C1 Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX USA. Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. Univ Nebraska, Med Ctr, Dept Obstet & Gynecol, Omaha, NE USA. RP Goetzl, L (reprint author), 1921 N Blvd, Houston, TX 77098 USA. NR 8 TC 25 Z9 26 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAR PY 2001 VL 97 IS 3 BP 381 EP 384 DI 10.1016/S0029-7844(00)01171-6 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 405JD UT WOS:000167155500011 PM 11239641 ER PT J AU Zelop, CM Shipp, TD Cohen, A Repke, JT Lieberman, E AF Zelop, CM Shipp, TD Cohen, A Repke, JT Lieberman, E TI Trial of labor after 40 weeks' gestation in women with prior cesarean SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID UTERINE RUPTURE; DELIVERY AB Objective: To compare outcomes in women with prior cesareans delivering at or before 40 weeks' gestation with those delivering after 40 weeks. Methods: We reviewed labor outcomes over 12 years at one institution for women with one prior cesarean and no other deliveries who had a trial of labor at term. We analyzed the rates of symptomatic uterine rupture and cesarean for term deliveries before or after 40 weeks and stratified for spontaneous and induced labor. Potential confounding by birth weight was controlled using logistic regression. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated. Results: Of 2775 women with one prior scar and no other deliveries, 1504 delivered at or before 40 weeks and 1271 delivered after 40 weeks. For spontaneous labor, rupture rate at or before 40 weeks was 0.5% compared with 1.0% after 40 weeks (P = .2, adjusted OR 2.1, CI 0.7, 5.7). For induced labor, uterine rupture rates were 2.1% at or before 40 weeks and 2.6% after 40 weeks (P = .7, adjusted OR 1.1, CI 0.4, 3.4). For spontaneous labor, rate of cesareans during subsequent trials of labor at or before 40 weeks was 25% compared with 33.5% after 40 weeks (P = .001, adjusted OR 1.5, CI 1.2, 1.8). For induced labor, rate of cesareans during subsequent trials of labor at or before 40 weeks was 33.8% compared with 43% after 40 weeks (P = .03, adjusted OR 1.5, CI 1.1, 2.2). Conclusion: The risk of uterine rupture does not increase substantially after 40 weeks but is increased with induction of labor regardless of gestational age; Because spontaneous labor after 40 weeks is associated with a cesarean rate similar to that following induced labor before 40 weeks, awaiting spontaneous labor after 40 weeks does not decrease the likelihood of successful vaginal delivery. (C) 2001 by The American College of Obstetricians and Gynecologists. C1 Lenox Hill Hosp, Dept Obstet & Gynecol, New York, NY 10021 USA. Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. Univ Nebraska, Med Ctr, Dept Obstet & Gynecol, Omaha, NE 68182 USA. RP Zelop, CM (reprint author), Lenox Hill Hosp, Dept Obstet & Gynecol, 100 E 77th St, New York, NY 10021 USA. NR 4 TC 29 Z9 31 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAR PY 2001 VL 97 IS 3 BP 391 EP 393 DI 10.1016/S0029-7844(00)01175-3 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 405JD UT WOS:000167155500013 PM 11239643 ER PT J AU Rachid, MD Yoo, SH Azar, DT AF Rachid, MD Yoo, SH Azar, DT TI Phototherapeutic keratectomy for decentration and central islands after photorefractive keratectomy SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Academy-of-Ophthalmology CY NOV 08-11, 1998 CL NEW ORLEANS, LOUISIANA SP Amer Acad Ophthalmol ID CORNEAL TOPOGRAPHY; FOLLOW-UP; MYOPIA; RETREATMENT; REGRESSION; ABLATION; KERATOMILEUSIS; MANAGEMENT AB Purpose: To determine visual outcomes after treatment of decentration and central islands occurring after photorefractive keratectomy (PRK), Design: Retrospective, noncomparative case series. Participants: Patients In = 14) who exhibited decentration or central islands after PRK and photoastigmatic keratectomy (PARK). Methods: Fourteen eyes with post-PRK decentration (group I) or central islands (group II) were treated by transepithelial phototherapeutic keratectomy guided by epithelial fluorescence without modulating agents, and subsequently were treated with PRK or PARK. Mean follow-up time was 9 months (range, 45 days-21 months). Main Outcome Measures: We analyzed pre- and postoperative keratometry, refractive errors, uncorrected visual acuity (UCVA), best-corrected visual acuity, and haze. In group I, we also measured pre- and postoperative decentration; in group II, we compared pre- and postoperative central island power. Results: Group I showed improvement in centration (P = 0.003), Group II showed decreased central island power (P = 0.18), -LogMAR UCVA improved from 0.59 (20/80(+1)) to 0.17 (20/30) IP = 0.03) and from 0.74 (20/100(-1)) to 0.21 (20/30(-1)) (P = 0.01) after retreatment of groups I and II, respectively. Conclusions: Retreatment of patients having decentration and central islands after PRK results in improved visual outcomes. (C) 2001 by the American Academy of Ophthalmology. C1 Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Boston, MA USA. Schepens Eye Res Inst, Boston, MA USA. RP Azar, DT (reprint author), Massachusetts Eye & Ear Infirm, Corneal & Refract Surg Serv, 243 Charles St, Boston, MA 02114 USA. FU NEI NIH HHS [EY10101] NR 39 TC 9 Z9 9 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 MAR PY 2001 VL 108 IS 3 BP 545 EP 552 DI 10.1016/S0161-6420(00)00595-9 PG 8 WC Ophthalmology SC Ophthalmology GA 405AN UT WOS:000167135200032 PM 11237909 ER PT J AU Bursell, SE Cavallerano, JD Cavallerano, AA Clermont, AC Birkmire-Peters, D Aiello, LP Aiello, LM AF Bursell, SE Cavallerano, JD Cavallerano, AA Clermont, AC Birkmire-Peters, D Aiello, LP Aiello, LM CA Joslin Vision Network Res Team TI Stereo nonmydriatic digital-video color retinal imaging compared with early treatment diabetic retinopathy study seven standard field 35-mm stereo color photos for determining level of diabetic retinopathy SO OPHTHALMOLOGY LA English DT Article ID FOLLOW-UP; FUNDUS PHOTOGRAPHY; PRACTICE PATTERNS; EYE DISEASE; MELLITUS; CARE; AGREEMENT; CAMERA; KAPPA; IMPLEMENTATION AB Objective: To evaluate the ability to determine clinical levels of diabetic retinopathy, timing of next appropriate retinal evaluation, and necessity of referral to ophthalmology specialists using stereoscopic nonmydriatic digital-video color retinal images as compared with Early Treatment Diabetic Retinopathy Study (ETDRS) seven standard field 35-mm stereoscopic color fundus photographs. Design: Prospective, clinic-based, comparative instrument validation study. Participants: Fifty-four patients (108 eyes) with type 1 or type 2 diabetes mellitus selected after chart review from a single center to include the full spectrum of diabetic retinopathy. Methods: Nonsimultaneous 45 degrees -field stereoscopic digital-video color images (JVN images) were obtained from three fields with the Joslin Vision Network (JVN) system before pupil dilation. Following pupil dilation, ETDRS seven standard field 35-mm stereoscopic color 30 degrees fundus photographs (ETDRS photos) were obtained. Joslin Vision Network images and ETDRS photos were graded on a lesion-by-lesion basis by two independent, masked readers to assess ETDRS clinical level of diabetic retinopathy. An independent ophthalmology retina specialist adjudicated interreader disagreements in a masked fashion. Main Outcome Measures: Determination of ETDRS clinical level of diabetic retinopathy, timing of next ophthalmic evaluation of diabetic retinopathy, and need for prompt referral to ophthalmology specialist. Results: There was substantial agreement (kappa = 0.65) between the clinical level of diabetic retinopathy assessed from the undilated JVN images and the dilated ETDRS photos. Agreement was excellent (kappa = 0.87) for suggested referral to ophthalmology specialists for eye examinations. Comparison of individual lesions between the JVN images and the ETDRS photos and for interreader comparisons were comparable to the prior ETDRS study. Conclusions: Undilated digital-video images using the JVN system were comparable photographs for the determination of diabetic retinopathy level. The results validate the agreement between nonmydriatic JVN images and dilated ETDRS photographs and suggest that this digital technique may be an effective telemedicine tool for remotely determining the level of diabetic retinopathy, suggesting timing of next retinal evaluation and identifying the need for prompt referral to ophthalmology specialists. Thus, the JVN system would be an appropriate tool for facilitating increased access of diabetic patients into recommended eye evaluations, but should not be construed as a paradigm that would replace the need for comprehensive eye examinations. C1 Harvard Univ, Sch Med, Beetham Eye Inst, Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. Tripler Army Med Ctr, Honolulu, HI 96859 USA. RP Aiello, LM (reprint author), Harvard Univ, Sch Med, Beetham Eye Inst, Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. NR 57 TC 143 Z9 151 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD MAR PY 2001 VL 108 IS 3 BP 572 EP 585 DI 10.1016/S0161-6420(00)00604-7 PG 14 WC Ophthalmology SC Ophthalmology GA 405AN UT WOS:000167135200036 PM 11237913 ER PT J AU Nadol, JB AF Nadol, JB TI Histopathology of residual and recurrent conductive hearing loss after stapedectomy SO OTOLOGY & NEUROTOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Otological-Society CY MAY 12-13, 2000 CL ORLANDO, FLORIDA SP Amer Otol Soc DE otosclerosis; stapedectomy; conductive hearing loss ID REVISION STAPES SURGERY; LASER AB Hypothesis: Histopathologic examination of temporal bones from patients who had undergone stapedectomy may provide information concerning the causes of both residual and recurrent conductive hearing loss (CHL). Background: Although closure of the air-bone gap to within 10 dB occurs in approximately 90% of primary stapedectomies, a residual CHL occurs in approximately 10% and recurrent CHL may occur in up to 35% of cases. Putative causes of failure of surgery as determined during revision include erosion of the incus, bony regrowth at the oval window, and displacement of the prosthesis. Most reports on the histopathologic findings of temporal bones from such patients have focused on complications of surgery, with little attempt to correlate postoperative air-bone gap with the observed histopathology. Methods: A retrospective review of the author's collection of temporal bones ascertained 22 cases with postoperative CHL of 10 dB or greater (air-bone gap averaged at 500, 1000, 2000, 3000, and 4000 Wt, using postoperative air- and bone-conduction levels) after stapedectomy. These temporal bones were prepared by standard methodology for light microscopy. Results: Of the 22 cases with postoperative CHL equal to or greater than 10 dB, there were 19 with residual CHL, 2 with recurrent CHL, and 1 with both residual and recurrent CHL. The most common histopathologic correlates of residual and recurrent hearing loss included resorptive osteitis of the incus (64%); obliteration of the round window by otosclerosis (23%); the prosthesis lying on a residual footplate fragment (23%); the prosthesis abutting the bony margin of the oval window (18%); adhesions in the middle ear (14%); and new bone formation in the oval window (14%). Conclusions: Histopathologic examination of temporal bones from patients who in life had undergone stapedectomy provides useful information concerning causes of both residual and recurrent CHL. These data provide a basis for improving both surgical technique and prosthesis design. C1 Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Nadol, JB (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. NR 23 TC 15 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 J9 OTOL NEUROTOL JI Otol. Neurotol. PD MAR PY 2001 VL 22 IS 2 BP 162 EP 169 DI 10.1097/00129492-200103000-00008 PG 8 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 413GE UT WOS:000167601300009 PM 11300263 ER PT J AU Takeoka, M Soman, TB Shih, VE Caviness, VS Krishnamoorthy, KS AF Takeoka, M Soman, TB Shih, VE Caviness, VS Krishnamoorthy, KS TI Carbamyl phosphate synthetase 1 deficiency: A destructive encephalopathy SO PEDIATRIC NEUROLOGY LA English DT Article ID ORNITHINE TRANSCARBAMYLASE DEFICIENCY; UREA CYCLE DISORDERS; HYPERAMMONEMIC RATS; AMINO-ACIDS; DEFECTS; THERAPY; AMMONIA; COMA AB Carbamyl phosphate synthetase I is a urea cycle enzyme. Severe deficiency of carbamyl phosphate synthetase I presents in the neonatal period as hyperammonemic encephalopathy with altered consciousness and occasional seizures after feeding begins. Episodes of altered consciousness with or without seizures and focal neurologic deficits are seen later with patients of partial carbamyl phosphate synthetase I deficiency. Fatal cerebral edema with brain herniation may develop on occasion. Three patients presenting with carbamyl phosphate synthetase I deficiency are reported with neuroimaging and pathologic findings illustrating the destructive encephalopathy with acute cerebral edema, followed by diffuse cerebral atrophy and occasional cystic encephalomalacia. The deterioration in carbamyl phosphate synthetase I deficiency occurs during the hyperammonemic crises. This deficiency may be difficult to treat despite the current advances in treatment strategies, especially in neonatal-onset patients with low carbamyl phosphate synthetase I activity. (C) 2001 by Elsevier Science Inc. All rights reserved. C1 Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Takeoka, M (reprint author), Keio Univ, Sch Med, Dept Pediat, Child Neurol Serv,Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan. NR 24 TC 15 Z9 16 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0887-8994 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD MAR PY 2001 VL 24 IS 3 BP 193 EP 199 DI 10.1016/S0887-8994(00)00259-9 PG 7 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 426FG UT WOS:000168338700003 PM 11301219 ER PT J AU Hammer, M Yaroslavsky, AN Schweitzer, D AF Hammer, M Yaroslavsky, AN Schweitzer, D TI A scattering phase function for blood with physiological haematocrit SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID OPTICAL-PROPERTIES; LIGHT-SCATTERING; CELLS AB Though the optics of red blood cells as well as whole blood has been studied extensively, an effective scattering phase function for whole blood is still needed. The interference of waves scattered by neighbouring cells cannot be neglected in highly concentrated suspensions such as whole blood. As a result, the phase function valid for single erythrocytes may fail to describe a single scattering process in whole blood with physiological haematocrit (Hct approximate to 0.4). In this study we compared the results obtained in goniophotometric measurements of blood samples with the results of angle-resolved Monte Carlo simulations. The results show that a Henyey-Greenstein phase function with an anisotropy factor of 0.972 is an adequate approximation for the effective scattering phase function of whole blood with high haematocrit at a wavelength of 514 nm. C1 Univ Jena, Dept Ophthalmol, D-07740 Jena, Germany. Massachusetts Gen Hosp, Wellman Labs Photomed, Dept Dermatol, Boston, MA 02114 USA. RP Hammer, M (reprint author), Univ Jena, Dept Ophthalmol, Bachstr 18, D-07740 Jena, Germany. NR 19 TC 38 Z9 38 U1 0 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD MAR PY 2001 VL 46 IS 3 BP N65 EP N69 DI 10.1088/0031-9155/46/3/402 PG 5 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 411VR UT WOS:000167520400023 PM 11277234 ER PT J AU Bednar, MM Harrigan, EP Anziano, RJ Camm, AJ Ruskin, JN AF Bednar, MM Harrigan, EP Anziano, RJ Camm, AJ Ruskin, JN TI The QT interval SO PROGRESS IN CARDIOVASCULAR DISEASES LA English DT Review ID TORSADES-DE-POINTES; ACUTE MYOCARDIAL-INFARCTION; POLYMORPHIC VENTRICULAR-TACHYCARDIA; DIABETIC AUTONOMIC NEUROPATHY; INDEPENDENT RISK FACTOR; SUDDEN CARDIAC DEATH; INCREASES PLASMA-CONCENTRATIONS; PNEUMOCYSTIS-CARINII PNEUMONIA; GRAPEFRUIT JUICE ALTERS; Q-T PROLONGATION C1 Pfizer Inc, Worldwide Clin Dev CNS, Groton, CT 06340 USA. Univ London St Georges Hosp, Sch Med, London SW17 0RE, England. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Bednar, MM (reprint author), Pfizer Inc, Worldwide Clin Dev CNS, Eastern Point Rd, Groton, CT 06340 USA. NR 329 TC 161 Z9 165 U1 1 U2 9 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0033-0620 J9 PROG CARDIOVASC DIS JI Prog. Cardiovasc. Dis. PD MAR-APR PY 2001 VL 43 IS 5 SU 1 BP 1 EP 45 DI 10.1053/pcad.2001.21469 PG 45 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 412YA UT WOS:000167580900001 PM 11269621 ER PT J AU Caroff, SN AF Caroff, SN TI Plagues, prions, and paranoia: The neuropsychiatry of infectious disease SO PSYCHIATRIC ANNALS LA English DT Editorial Material C1 Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Dept Vet Affairs Med Ctr, Inpatient Serv, Philadelphia, PA 19104 USA. RP Caroff, SN (reprint author), Univ Penn, Sch Med, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD MAR PY 2001 VL 31 IS 3 BP 148 EP + PG 5 WC Psychiatry SC Psychiatry GA 410ZN UT WOS:000167473500002 ER PT J AU Gliatto, MF Caroff, SN AF Gliatto, MF Caroff, SN TI Neurosyphilis: A history and clinical review SO PSYCHIATRIC ANNALS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; SYPHILIS; INFECTION; THERAPY; ADULTS C1 Dept Vet Affairs Med Ctr, Dept Psychiat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. RP Gliatto, MF (reprint author), Dept Vet Affairs Med Ctr, Dept Psychiat, 38th St & Woodland Ave, Philadelphia, PA 19104 USA. NR 41 TC 3 Z9 3 U1 1 U2 2 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD MAR PY 2001 VL 31 IS 3 BP 153 EP 161 PG 9 WC Psychiatry SC Psychiatry GA 410ZN UT WOS:000167473500003 ER PT J AU Caroff, SN Mann, SC Gliatto, MF Sullivan, KA Campbell, EC AF Caroff, SN Mann, SC Gliatto, MF Sullivan, KA Campbell, EC TI Psychiatric manifestations of acute viral encephalitis SO PSYCHIATRIC ANNALS LA English DT Article ID HERPES-SIMPLEX ENCEPHALITIS; MIMICKING FUNCTIONAL-PSYCHOSIS; IMMUNE-DEFICIENCY SYNDROME; HIV-INFECTION; MONOAMINE METABOLISM; VIRUS ENCEPHALITIS; CATATONIC SYNDROME; AIDS; LETHARGICA; DISORDERS C1 Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. Dept Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. RP Caroff, SN (reprint author), VA Med Ctr 116A, Univ Ave, Philadelphia, PA 19104 USA. NR 81 TC 8 Z9 9 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD MAR PY 2001 VL 31 IS 3 BP 193 EP 204 PG 12 WC Psychiatry SC Psychiatry GA 410ZN UT WOS:000167473500007 ER PT J AU Centorrino, F Hernan, MA Drago-Ferrante, G Rendall, M Apicella, A Langar, G Baldessarini, RJ AF Centorrino, F Hernan, MA Drago-Ferrante, G Rendall, M Apicella, A Langar, G Baldessarini, RJ TI Factors associated with noncompliance with psychiatric outpatient visits SO PSYCHIATRIC SERVICES LA English DT Article ID MEDICATION; APPOINTMENTS; PREDICTORS; DISORDERS AB Adherence to recommended services is essential for long-term effectiveness of ambulatory treatment programs, hut factors associated with such adherence are not securely established. We evaluated attendance at 896 scheduled psychiatric clinic visits for 62 patients at a major psychiatric teaching hospital, Visit adherence was found to be significantly higher among patients in an acute stage of illness, those with a personality disorder, those with a post-high-school education, and those living alone. Adherence was also higher when visits were routinely scheduled, when the intervisit interval was shorter, and when the visit entailed psychotherapy rather than pharmacotherapy. C1 Harvard Univ, Sch Med, Consolidated Dept Psychiat, Belmont, MA 02178 USA. Massachusetts Gen Hosp, McLean Div, Bipolar & Psychot Disorders Program, Belmont, MA USA. Harvard Univ, Sch Publ Hlth, Expt Therapeut Res Unit, Cambridge, MA 02138 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Cambridge, MA 02138 USA. RP Centorrino, F (reprint author), McLean Hosp, 115 Mill St, Belmont, MA 02478 USA. FU NIMH NIH HHS [MH-34370] NR 10 TC 47 Z9 49 U1 0 U2 1 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1075-2730 J9 PSYCHIATR SERV JI Psychiatr. Serv. PD MAR PY 2001 VL 52 IS 3 BP 378 EP 380 DI 10.1176/appi.ps.52.3.378 PG 3 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 408MG UT WOS:000167329500019 PM 11239109 ER PT J AU Waters, GS Caplan, D AF Waters, GS Caplan, D TI Age, working memory, and on-line syntactic processing in sentence comprehension SO PSYCHOLOGY AND AGING LA English DT Article ID INDIVIDUAL-DIFFERENCES; ALZHEIMERS-DISEASE; LANGUAGE COMPREHENSION; APHASIC PATIENTS; CAPACITY THEORY; RESOURCE; SPAN; TASK; DISORDERS; ADULTS AB One hundred twenty-seven individuals who ranged in age from 18 to 90 years were tested on a reading span test and on measures of on-line and off-line sentence processing efficiency. Older participants had reduced working-memory spans compared with younger participants. The on-line measures were sensitive to local increases in processing load, and the off-line measures were sensitive to the syntactic complexity of the sentences. Older and younger participants showed similar effects of syntactic complexity on the on-line measures. There was some evidence that older participants were more affected than younger participants by syntactic complexity on the off-line measures. The results support the hypothesis that on-line processes involved in recognizing linguistic forms and determining the literal, preferred, discourse-coherent meaning of sentences constitute a domain of language processing that relies on its own processing resource or working-memory system. C1 Massachusetts Gen Hosp, Neuropsychol Lab, Boston, MA 02114 USA. Boston Univ, Dept Commun Disorders, Boston, MA 02215 USA. RP Waters, GS (reprint author), 635 Commonwealth Ave, Boston, MA 02215 USA. FU NIA NIH HHS [AG009661] NR 64 TC 75 Z9 79 U1 2 U2 7 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0882-7974 J9 PSYCHOL AGING JI Psychol. Aging PD MAR PY 2001 VL 16 IS 1 BP 128 EP 144 DI 10.1037/0882-7974.16.1.128 PG 17 WC Gerontology; Psychology, Developmental SC Geriatrics & Gerontology; Psychology GA 472VC UT WOS:000171004800011 PM 11302362 ER PT J AU Kampman, KM Alterman, AI Volpicelli, JR Maany, I Muller, ES Luce, DD Mulholland, EM Jawad, AF Parikh, GA Mulvaney, FD Weinrieb, RM O'Brien, CP AF Kampman, KM Alterman, AI Volpicelli, JR Maany, I Muller, ES Luce, DD Mulholland, EM Jawad, AF Parikh, GA Mulvaney, FD Weinrieb, RM O'Brien, CP TI Cocaine withdrawal symptoms and initial urine toxicology results predict treatment attrition in outpatient cocaine dependence treatment SO PSYCHOLOGY OF ADDICTIVE BEHAVIORS LA English DT Article ID ABSTINENCE SYMPTOMATOLOGY; DSM-IV; ABUSERS; PSYCHOTHERAPY; INPATIENT; USERS AB This study evaluated the ability of cocaine withdrawal symptoms, measured by the Cocaine Selective Severity Assessment (CSSA) and initial urine toxicology results, to predict treatment attrition among 128 cocaine dependent veterans participating in a 4-week day hospital treatment program. The CSSA was administered and a urine toxicology screen was obtained at intake and at the start of the day hospital (about 1 week later). The combination of a positive urine toxicology screen and a high CSSA score at intake predicted failure to complete treatment. Urine toxicology results at the start of the day hospital, but not at intake, predicted failure to complete treatment. Among participants without other psychiatric illness, high CSSA scores at intake, predicted failure to complete treatment. The presence of cocaine withdrawal symptoms and a positive urine toxicology screen are clinically useful predictors of treatment attrition. C1 Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Dept Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. Childrens Hosp, Div Biostat & Epidemiol, Philadelphia, PA 19104 USA. RP Kampman, KM (reprint author), Univ Penn, Treatment Res Ctr, 3900 Chestnut St, Philadelphia, PA 19104 USA. FU NIDA NIH HHS [K20 DA00238, Y01 DA30012] NR 31 TC 86 Z9 87 U1 1 U2 3 PU EDUCATIONAL PUBLISHING FOUNDATION PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0893-164X J9 PSYCHOL ADDICT BEHAV JI Psychol. Addict. Behav. PD MAR PY 2001 VL 15 IS 1 BP 52 EP 59 DI 10.1037/0893-164X.15.1.52 PG 8 WC Substance Abuse; Psychology, Multidisciplinary SC Substance Abuse; Psychology GA 472DC UT WOS:000170967200008 PM 11255939 ER PT J AU Springer, S Fife, A Lawson, W Hui, JCK Jandorf, L Cohn, PF Fricchione, G AF Springer, S Fife, A Lawson, W Hui, JCK Jandorf, L Cohn, PF Fricchione, G TI Psychosocial effects of enhanced external counterpulsation in the angina patient: A second study SO PSYCHOSOMATICS LA English DT Article ID CORONARY-ARTERY DISEASE; ACUTE MYOCARDIAL-INFARCTION; RISK-FACTORS; MENTAL STRESS; HEART-DISEASE; DEPRESSION; PECTORIS; ISCHEMIA; HOSTILITY; PROGNOSIS AB Enhanced external counterpulsation (EECP) is a noninvasive technique that has shown promise in the treatment of ischemic coronary artery disease. Patients undergoing EECP were tested for alterations in psychosocial state associated with treatment. Overall perception of health and quality of life improved with EECP. There was also significant improvement in levels of depression, anxiety, and somatization but no change in levels of anger or hostility. On most measures, change was more significant for subjects who showed objective evidence of resolution of ischemia. Given the known predictive relationship between depression and mortality from cardiac disease, the improvement in depression scores through EECP indicates a finding of potential importance that may warrant further study in future research. C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. SUNY Stony Brook, Div Cardiol, Dept Med, Stony Brook, NY 11794 USA. SUNY Stony Brook, Dept Surg, Stony Brook, NY 11794 USA. Mt Sinai Sch Med, Ruttenberg Canc Ctr, New York, NY USA. Carter Ctr, Atlanta, GA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Springer, S (reprint author), Massachusetts Gen Hosp, Dept Psychiat, WAC 812,55 Fruit St, Boston, MA 02114 USA. NR 41 TC 19 Z9 20 U1 0 U2 0 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD MAR-APR PY 2001 VL 42 IS 2 BP 124 EP 132 DI 10.1176/appi.psy.42.2.124 PG 9 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 406QR UT WOS:000167227100007 PM 11239125 ER PT J AU Pitman, RK Lanes, DM Williston, SK Guillaume, JL Metzger, LJ Gehr, GM Orr, SP AF Pitman, RK Lanes, DM Williston, SK Guillaume, JL Metzger, LJ Gehr, GM Orr, SP TI Psychophysiologic assessment of posttraumatic stress disorder in breast cancer patients SO PSYCHOSOMATICS LA English DT Article ID COMBAT VETERANS; IMAGERY; PTSD; PREVALENCE; WOMEN AB The authors performed psychodiagnostic, psychometric, and psychophysiologic evaluations on 37 patients referred by local surgeons approximately 2 years after tissue diagnosis of Stage I to III breast cancer: The Clinician-Administered Posttraumatic Stress Disorder (PTSD) Scale (CAPS) was used to classify patients into the following groups: "Current PTSD" (n = 5) "Past PTSD" (n = 7), and "Never had PTSD" (n = 25). Individualized "scripts" portraying personal life events were tape recorded and played back to the patients in the laboratory. Current PTSD patients showed significantly higher heart rate, skin conductance, and corrugator electromyogram responses during imagery of their personal breast cancer experiences than Past and Never patients. Physiologic responses were significantly and positively correlated with CAPS scores. These results provide psychophysiologic support for the proposition that a diagnosis of with a life-threatening illness can cause PTSD. C1 VA Res Serv, Manchester, NH USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. RP Pitman, RK (reprint author), PTSD Res Lab, MGH East,Bldg 149,13th St, Boston, MA 02129 USA. NR 23 TC 35 Z9 36 U1 0 U2 3 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD MAR-APR PY 2001 VL 42 IS 2 BP 133 EP 140 DI 10.1176/appi.psy.42.2.133 PG 8 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 406QR UT WOS:000167227100008 PM 11239126 ER PT J AU Bechtold, KT Horner, MD Labbate, LA Windham, WK AF Bechtold, KT Horner, MD Labbate, LA Windham, WK TI The construct validity and clinical utility of the Frank Jones story as a brief screening measure of cognitive dysfunction SO PSYCHOSOMATICS LA English DT Article ID MINI-MENTAL STATE; ALZHEIMERS-DISEASE; INSTRUMENTS AB The use of quick and easily administered screening measures of cognitive functioning htrs become increasingly important in clinical settings. A number of brief screening instruments are available, but few have been thoroughly examined for their validity and clinical utility: The Frank Jones Story is a 2-minute screening procedure proposed to measure problem solving by asking patients to explain an absurd proposition. The authors used this screen to help them classify 155 patients as cognitively impaired or unimpaired based on a full neuropsychological evaluation. Overall, the total score on the Frank Jones Story was a good predictor of intact functioning for patients. that were unimpaired but was poor at predicting cognitive dysfunction. However; various subscores of the test reflected differing patterns of sensitivity and specificity for cognitive impairment. These data suggest that the Frank Jones Story might have some utility for initial screening for cognitive dysfunction. C1 Ralph H Johnson VA Med Ctr, Mental Hlth Serv 116, Charleston, SC 29401 USA. So Illinois Univ, Dept Psychol, Carbondale, IL 62901 USA. Med Univ S Carolina, Inst Psychiat, Charleston, SC 29425 USA. Coll Charleston, Charleston, SC 29401 USA. RP Horner, MD (reprint author), Ralph H Johnson VA Med Ctr, Mental Hlth Serv 116, 109 Bee St, Charleston, SC 29401 USA. NR 16 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD MAR-APR PY 2001 VL 42 IS 2 BP 146 EP 149 DI 10.1176/appi.psy.42.2.146 PG 4 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 406QR UT WOS:000167227100010 PM 11239128 ER PT J AU Mischoulon, D McColl-Vuolo, R Howarth, S Lagomasino, IT Alpert, JE Nierenberg, AA Fava, M AF Mischoulon, D McColl-Vuolo, R Howarth, S Lagomasino, IT Alpert, JE Nierenberg, AA Fava, M TI Management of major depression in the primary care setting SO PSYCHOTHERAPY AND PSYCHOSOMATICS LA English DT Article DE depression; Hispanic; primary care; minority ID MENTAL-HEALTH SERVICES; STRUCTURED CLINICAL INTERVIEW; PSYCHOLOGICAL DISTRESS; MEDICAL OUTCOMES; SELF-REPORT; DISORDERS; QUESTIONNAIRE; EPIDEMIOLOGY; RECOGNITION; PREVALENCE AB Background: Patients treated in community clinics, particularly those of minority status, may rely more heavily on primary care physicians (PCPs) for the diagnosis and management of depression. We wished to determine how PCPs in a community clinic setting initially manage patients newly diagnosed with major depression. Methods: 698 patients were screened for major depression by the Structural Clinical interview for DSM-III-R in a community-based primary care health center. Forty outpatients (29 Hispanic) were found to suffer from major depression. A letter explaining positive findings was sent to the patients' PCPs. Medical record charts were reviewed 3 months later to determine the PCP's management following the diagnosis. Results: Of the 38 patients who remained in the study at 3 months, 20 (53%) received no intervention from the PCP by the end of 3 months after diagnosis, and of these, 14 were Hispanic. Five (13%) were prescribed an antidepressant by the PCP. Nine (24%) were referred to mental health services for medication, psychotherapy or combination treatment. Four (11%) ere prescribed an antidepressant and then referred to mental health services. Differences between management of Hispanic and non-Hispanic patients were not statistically significant. Conclusions: Independent screening by psychiatrists in primary care settings may not be adequate enough to ensure appropriate management of depression by PCPs. Possible explanations may include time constraints during primary care visits, patient and/or physician reticence, and insufficient education of PCPs about depression. Copyright (C) 2001 S. Karger AG, Basel. C1 Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. RP Mischoulon, D (reprint author), WAC 812,15 Parkman St, Boston, MA 02114 USA. OI Alpert, Jonathan/0000-0002-4332-908X FU NIMH NIH HHS [5T32MH19126-10] NR 50 TC 22 Z9 24 U1 2 U2 4 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0033-3190 J9 PSYCHOTHER PSYCHOSOM JI Psychother. Psychosom. PD MAR-APR PY 2001 VL 70 IS 2 BP 103 EP 107 DI 10.1159/000056233 PG 5 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 410TQ UT WOS:000167455600006 PM 11244391 ER PT J AU Rybak, LD Rosenthal, DI AF Rybak, LD Rosenthal, DI TI Radiological imaging for the diagnosis of bone metastases SO QUARTERLY JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE neoplasm metastasis; bone neoplasms secondary; tomography, emission computed; magnetic resonance imaging; radiography ID BREAST-CANCER PATIENTS; VERTEBRAL METASTASES; SKELETAL METASTASES; PROSTATE-CANCER; MARROW IMMUNOSCINTIGRAPHY; EMISSION-TOMOGRAPHY; MULTIPLE-MYELOMA; CT GUIDANCE; SCINTIGRAPHY; MR AB Primary neoplasms of the skeleton are rare, but metastatic involvement is, unfortunately, a common occurrence. This is particularly true for certain primary tumors. Skeletal metastases are clinically significant because of associated symptoms, complications such as pathological fracture and their profound significance for staging, treatment and prognosis. Detection of bone metastases is, thus, an important part of treatment planning. The frequency with which metastases are detected varies considerably with the type of primary tumor and with the methodology utilized for detection. Four main modalities are utilized clinically: plain film radiography, CT scan, nuclear imaging and magnetic resonance imaging. In this discussion, we will review literature on the radiology of skeletal metastases with respect to lesion detection, assessment of response to treatment and possible therapeutic implications. The bulk of the discussion will focus on MRT and nuclear studies since most of the recent advances have been made in these areas. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. RP Rosenthal, DI (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, WAC 515,15 Parkman St, Boston, MA 02114 USA. NR 70 TC 88 Z9 111 U1 0 U2 2 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 0392-0208 J9 Q J NUCL MED JI Q. J. Nucl. Med. PD MAR PY 2001 VL 45 IS 1 BP 53 EP 64 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 448GU UT WOS:000169619800008 PM 11456376 ER PT J AU Kirrane, RM Mitropoulou, V Nunn, M Silverman, J Siever, LJ AF Kirrane, RM Mitropoulou, V Nunn, M Silverman, J Siever, LJ TI Physostigmine and cognition in schizotypal personality disorder SO SCHIZOPHRENIA RESEARCH LA English DT Article DE cognitive impairment; physostigmine; schizotypal personality disorder ID VISUOSPATIAL WORKING-MEMORY; CHOLINE-ACETYLTRANSFERASE; NICOTINIC RECEPTORS; SCHIZOPHRENIA; PERFORMANCE; AMPHETAMINE; CHALLENGE; RATS AB There is evidence that reduced cholinergic activity may play a role in the pathophysiology of cognitive impairment in the schizophrenia spectrum. We tested the effects of physostigmine, an anticholinesterase inhibitor, on visuospatial working memory as evaluated by the Dot test, and on verbal learning and recall as measured by a serial learning task in patients with schizotypal personality disorder. Physostigmine tended to improve the Dot test, but not serial verbal learning performance in these patients. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Mt Sinai Med Ctr, Dept Psychiat, New York, NY USA. Bronx Vet Adm Med Ctr, Dept Psychiat, New York, NY USA. RP Siever, LJ (reprint author), Mt Sinai Med Ctr, Dept Psychiat, New York, NY USA. FU NCRR NIH HHS [5 MO1 RR00071] NR 24 TC 25 Z9 26 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD MAR 1 PY 2001 VL 48 IS 1 BP 1 EP 5 DI 10.1016/S0920-9964(00)00059-1 PG 5 WC Psychiatry SC Psychiatry GA 419RN UT WOS:000167962600001 PM 11278149 ER PT J AU Allen, DN Goldstein, G Weiner, C AF Allen, DN Goldstein, G Weiner, C TI Differential neuropsychological patterns of frontal- and temporal-lobe dysfunction in patients with schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE differential neuropsychological patterns; frontal- and temporal-lobe dysfunction ID CEREBRAL BLOOD-FLOW; COGNITIVE HETEROGENEITY; EPISODE SCHIZOPHRENIA; BRAIN-DYSFUNCTION; MONOZYGOTIC TWINS; EPILEPSY; MEMORY; IDENTIFICATION; ABNORMALITIES; ACTIVATION AB The frontal and temporal lobes have been implicated as pathogenic sites for schizophrenia, although there is a marked heterogeneity of brain function and structure between individual patients. It is currently unclear whether some patients with schizophrenia exhibit primarily frontal lobe dysfunction, while others exhibit primarily temporal-lobe dysfunction. The current investigation examined this issue in a preliminary way by using neurocognitive tests to discriminate test performances of patients with schizophrenia from patients without schizophrenia who had definitive neurological evidence of either frontal- or temporal-lobe dysfunction. Of the patients with schizophrenia, 20.7% were classified as having a frontal lobe dysfunction profile, while 19.3% had a temporal lobe dysfunction profile. Results further clarify neurobiological heterogeneity in schizophrenia by demonstrating that a substantial number of patients with schizophrenia exhibit either primarily frontal- or temporal-lobe dysfunction. Results may partially explain the inadequacy of neurobiological models for schizophrenia that do not consider these differential patterns of dysfunction. (C) 2001 Elsevier Science B.V. All rights reserved. C1 VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. Univ Nevada, Las Vegas, NV 89154 USA. Univ Pittsburgh, Pittsburgh, PA 15206 USA. RP Goldstein, G (reprint author), VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. NR 45 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD MAR 1 PY 2001 VL 48 IS 1 BP 7 EP 15 DI 10.1016/S0920-9964(00)00115-8 PG 9 WC Psychiatry SC Psychiatry GA 419RN UT WOS:000167962600002 PM 11278150 ER PT J AU Caro, I AF Caro, I TI Dermatomyositis SO SEMINARS IN CUTANEOUS MEDICINE AND SURGERY LA English DT Article ID JUVENILE RHEUMATOID-ARTHRITIS; INCLUSION-BODY MYOSITIS; TERM FOLLOW-UP; POLYMYOSITIS-DERMATOMYOSITIS; INVOLVEMENT; CANCER; FEATURES; CHILDREN; COHORT; RISK AB Dermatomyositis is a disease that has a characteristic skin eruption that may occur with or without a proximal myopathy. The disease with cutaneous features only is classified as amyopathic dermatomyositis. The origin is unknown, but autoimmune factors are believed to play an important role. Autoantibodies are found in most patients and some have myositis-specific antibodies. Systemic changes may occur and there appears to be a relationship to internal malignancy, particularly in older patients. Juvenile disease has an associated vasculopathy. Treatment includes systemic corticosteroids and other immunosuppressive agents. The cutaneous changes may be difficult to treat, Copyright (C) 2001 by W.B. Saunders Company. C1 Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. RP Caro, I (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Dermatol, Sch Med, Bartlett 610,55 Fruit St, Boston, MA 02114 USA. NR 63 TC 7 Z9 7 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 1085-5629 J9 SEMIN CUTAN MED SURG JI Semin. Cutan. Med. Surg. PD MAR PY 2001 VL 20 IS 1 BP 38 EP 45 DI 10.1053/sder.2001.23095 PG 8 WC Dermatology; Surgery SC Dermatology; Surgery GA 412DD UT WOS:000167538000005 PM 11308135 ER PT J AU Ojemann, RG AF Ojemann, RG TI Ectopic arachnoid granulomatosis: A case report - Commentary SO SURGICAL NEUROLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ojemann, RG (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 1 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 0090-3019 J9 SURG NEUROL JI Surg. Neurol. PD MAR PY 2001 VL 55 IS 3 BP 186 EP 186 DI 10.1016/S0090-3019(01)00401-3 PG 1 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 424NK UT WOS:000168238200020 ER PT J AU Nikas, DC Danks, RA Black, PM AF Nikas, DC Danks, RA Black, PM TI Tumor surgery under local anesthesia SO TECHNIQUES IN NEUROSURGERY LA English DT Article DE brain tumors; local anesthesia; brain mapping; localization; imaging; epilepsy surgery; eloquent cortex ID BRAIN MAPPING TECHNIQUES; TEMPORAL-LOBE EPILEPSY; PROTON MR SPECTROSCOPY; ELECTRICAL-STIMULATION; EVOKED-POTENTIALS; MOTOR CORTEX; FUNCTIONAL MRI; HUMAN LANGUAGE; LOCALIZATION; ORGANIZATION AB Resection, or even biopsy, of an intraaxial mass lesion in close relation to eloquent cortex carries a major risk for neurologic deficit. In such lesions, craniotomy under local anesthesia and monitored sedation is a safe technique that allows maximal resection of the lesion, with a low risk of new neurologic deficit. We have assessed the safety and effectiveness of this technique, demonstrated its usefulness in gross total or substantial tumor resection, found that there was no additional operative morbidity or usage of hospital resources. The technique also involves a level of stress that remains within the tolerance level of the average adult. Operating under local anesthesia proved an important tool for localization of function and exploration of eloquent cortex, as well as for the safe removal of epileptogenic areas. A number of other noninvasive strategies have been described and are currently the subject of great interest. Although these are promising new techniques, cortical mapping under local anesthesia was one of the most important steps in our progress toward a more exact localization of function in the cerebral cortex, and apart from a research tool in neurophysiology remains an important adjunct for the management of brain tumors by defining the limits of safe resection. C1 Childrens Hosp, Neurosurg Serv, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. Monash Med Ctr, Dept Neurosci, Clayton, Vic 3168, Australia. Brigham & Womens Hosp, Neurosurg Serv, Boston, MA 02115 USA. Dana Farber Canc Inst, Neurosurg Serv, Boston, MA 02115 USA. RP Black, PM (reprint author), Childrens Hosp, Neurosurg Serv, 300 Longwood Ave, Boston, MA 02115 USA. NR 57 TC 7 Z9 7 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-2855 J9 TECH NEUROSURG JI Tech. Neurosurg. PD MAR PY 2001 VL 7 IS 1 BP 70 EP 84 DI 10.1097/00127927-200103000-00009 PG 15 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 450RQ UT WOS:000169757200009 ER PT J AU Greene, MF AF Greene, MF TI Diabetic embryopathy 2001: Moving beyond the "diabetic milieu" SO TERATOLOGY LA English DT Editorial Material ID CONGENITAL-MALFORMATIONS; GLYCEMIC CONTROL; PREGNANCY; INFANTS; MOTHERS; WOMEN; RATS; ORGANOGENESIS; POPULATION; PREVENTION C1 Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. RP Greene, MF (reprint author), Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. NR 23 TC 15 Z9 17 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0040-3709 J9 TERATOLOGY JI Teratology PD MAR PY 2001 VL 63 IS 3 BP 116 EP 118 DI 10.1002/tera.1021 PG 3 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 417PY UT WOS:000167844400003 PM 11283967 ER PT J AU Bauer, KA AF Bauer, KA TI Conventional fibrinolytic assays for the evaluation of patients with venous thrombosis: Don't bother SO THROMBOSIS AND HAEMOSTASIS LA English DT Editorial Material ID DEEP-VEIN THROMBOSIS; PLASMINOGEN-ACTIVATOR INHIBITOR; COAGULATION-FACTOR-V; THROMBOEMBOLIC DISEASE; PROTEIN-C; FACTOR-XI; FAMILY; HYPOFIBRINOLYSIS; THROMBOPHILIA; GENE C1 VA Boston Healthcare Syst, Hematol Sect, W Roxbury, MA 02132 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. RP Bauer, KA (reprint author), VA Boston Healthcare Syst, Hematol Sect, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. NR 24 TC 7 Z9 7 U1 0 U2 0 PU F K SCHATTAUER VERLAG GMBH PI STUTTGART PA P O BOX 10 45 43, LENZHALDE 3, D-70040 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD MAR PY 2001 VL 85 IS 3 BP 377 EP 378 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 414ND UT WOS:000167672000002 PM 11307800 ER PT J AU Li, TS AF Li, TS TI Disease model: photoreceptor degenerations SO TRENDS IN MOLECULAR MEDICINE LA English DT Review AB Retinal diseases can be caused by genetic or non-genetic factors, and typically involve specific cell layers within the retina. A large number of simple Mendelian gene defects are known to affect the photoreceptor cell layer. As photoreceptor dells cannot be maintained in vitro, the study of animal models is instrumental in understanding the disease process and in testing therapeutic approaches. This review briefly summarizes those animal models of photoreceptor diseases with defined genotypes. C1 Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02114 USA. RP Li, TS (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Berman Gund Lab Study Retinal Degenerat, 243 Charles St, Boston, MA 02114 USA. NR 5 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4914 J9 TRENDS MOL MED JI Trends Mol. Med PD MAR PY 2001 VL 7 IS 3 BP 133 EP 135 DI 10.1016/S1471-4914(00)01902-X PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 453TL UT WOS:000169932500009 PM 11286785 ER PT J AU vanSonnenberg, E Wittich, GR Goodacre, BW Casola, G D'Agostino, HB AF vanSonnenberg, E Wittich, GR Goodacre, BW Casola, G D'Agostino, HB TI Percutaneous abscess drainage: Update SO WORLD JOURNAL OF SURGERY LA English DT Article ID GUIDED TRANSVAGINAL DRAINAGE; INTRA-ABDOMINAL ABSCESSES; PYOGENIC LIVER-ABSCESS; INTRAABDOMINAL ABSCESSES; CATHETER DRAINAGE; PELVIC ABSCESSES; PANCREATIC PSEUDOCYSTS; DIVERTICULAR ABSCESSES; COMPUTED-TOMOGRAPHY; RADIOLOGIC GUIDANCE AB During the approximately 20 years that percutaneous abscess drainage (PAD) has been an extant procedure and as the millennium begins, PAD has become, by consensus, the treatment of choice for abscesses. Indications for PAD continue to expand, and currently almost all abscesses are considered amenable. On occasion, PAD is an adjunctive procedure that provides a beneficial temporizing effect for the surgeon who eventually must operate for a coexisting problem such as a bowel leak Simple unilocular abscesses are cured almost uniformly by PAD; more complicated abscesses, such as those with enteric fistulas (e.g., diverticular abscess) or pancreatic abscesses, have cure rates ranging from 65% to 90%. Various catheters and insertion techniques have proven effective. Ultrasonography, computed tomography, and fluoroscopy are the staple modalities that guide PAD. PAD is the prototype interventional radiology procedure, providing detection of the abscess by imaging, needling for diagnosis, and catheterization for therapy. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Texas, Med Branch, Dept Radiol, Galveston, TX 77555 USA. Univ Washington, Sch Med, Dept Radiol, Seattle, WA 98195 USA. Univ Calif San Diego, Med Ctr, Dept Radiol, San Diego, CA 92103 USA. Louisiana State Univ, Sch Med, Dept Radiol, Shreveport, LA 71130 USA. RP vanSonnenberg, E (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. NR 84 TC 87 Z9 92 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0364-2313 J9 WORLD J SURG JI World J.Surg. PD MAR PY 2001 VL 25 IS 3 BP 362 EP 372 PG 11 WC Surgery SC Surgery GA 426PP UT WOS:000168357800018 PM 11343195 ER PT J AU Cole, J Tsou, R Wallace, K Gibran, N Isik, F AF Cole, J Tsou, R Wallace, K Gibran, N Isik, F TI Comparison of normal human skin gene expression using cDNA microarrays SO WOUND REPAIR AND REGENERATION LA English DT Article; Proceedings Paper CT Meeting of the Plastic-Surgery-Research-Council CY MAY, 2000 CL SEATTLE, WASHINGTON SP Plast Surg Res Council ID TISSUE MICROARRAYS; PROTEIN; APOPTOSIS; COMPLEX; RNA AB Perturbations in normal wound healing may be traced to perturbations in gene expression in uninjured skin. In order to decipher normal and abnormal genetic responses to cutaneous injury, baseline gene expression in uninjured skin must first be defined. There is little data on gene expression profiles of normal human skin, i.e., which genes tend to be variable in expression and which tend to remain comparable. Therefore this study was designed to determine the degree of variability in human skin mRNA expression. Samples of normal skin were obtained from 9 healthy females undergoing breast reduction surgery. RNA was extracted, reverse transcribed into radiolabeled cDNA and hybridized onto cDNA microarrays of similar to 4400 genes. Gene expression intensities from the 9 samples were normalized and compared as a ratio of highest/lowest expression intensity. Deviation greater than 2 standard deviations from the mean of each gene was used as a cut-off. Seventy-one genes (1.7%) were substantially variable in their expression. These included genes coding for transport proteins, gene transcription, cell signaling proteins, and cell surface proteins. We found minimal variability in the matrix genes, growth factor genes and other groups of genes that are the most often studied in wound healing research. A small but definite variability in gene expression across 9 samples of clinically comparable specimens of normal skin was detected. This is in keeping with clinical observations of the variability in normal skin across individuals. These data provide high-throughput comparison of normal skin gene expression and suggest new molecules that may be studied in skin biology and perhaps, wound repair. C1 Univ Washington, Med Ctr, Dept Surg, Seattle, WA 98195 USA. VA Puget Sound Hlth Care Syst, Dept Surg, Seattle, WA USA. Univ Washington, Harborview Med Ctr, Seattle, WA 98104 USA. RP Isik, F (reprint author), Univ Washington, Med Ctr, Dept Surg, Box 356410,1959 NE Pacific St, Seattle, WA 98195 USA. FU NIGMS NIH HHS [R01 GM57426] NR 36 TC 32 Z9 35 U1 0 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1067-1927 J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD MAR-APR PY 2001 VL 9 IS 2 BP 77 EP 85 DI 10.1046/j.1524-475x.2001.00077.x PG 9 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA 432JV UT WOS:000168689200003 PM 11350645 ER PT J AU Lee, SJ Fairclough, D Antin, JH Weeks, JC AF Lee, SJ Fairclough, D Antin, JH Weeks, JC TI Discrepancies between patient and physician estimates for the success of stem cell transplantation SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BONE-MARROW TRANSPLANTATION; SHARED DECISION-MAKING; NON-HODGKINS-LYMPHOMA; CANCER-PATIENTS; INFORMED CONSENT; ADJUVANT THERAPY; DISEASE; EXPECTATIONS; PROGNOSIS; REMISSION AB Context Stem cell transplantation is associated with considerable morbidity and mortality. The extent to which patients and their physicians correctly estimate these risks is unknown. Objective To measure the expectations of patients and physicians prior to stem cell transplantation and correlate them with actual outcomes after transplantation. Design Prospective cohort study with baseline questionnaire administered July 1996 through November 1999 and follow-up to May 2000. Setting Tertiary care transplant center in the United States. Participants Of 458 surveys mailed, evaluable returned surveys were included for 313 autologous and allogeneic stem cell transplantation patients and their physicians, Main Outcome Measures Patient and physician expectations prior to transplantation (measured on 6-point Likert scales) of treatment related mortality, cure with transplantation, and cure without transplantation; actual treatment-related mortality and disease-free survival among patients with at least 1 year of follow-up after transplantation (n=263). Results Both patients and physicians were fairly accurate in estimating treatment-related mortality when actual mortality was less than 30%. However, in situations in which mortality was higher than 30%, such as with allogeneic transplantation for intermediate or advanced disease, physician expectations were lower, while patients remained optimistic. Similarly, physicians provided lower estimates of disease-free survival in cases of intermediate or advanced disease while patient expectations remained high and constant regardless of disease stage. Conclusions Patients and their physicians have the most concordant and accurate expectations when the outcome of stem cell transplantation is likely to be favorable, However, patients with more advanced disease fail to recognize the higher risks associated with their situations. C1 Dana Farber Canc Inst, Dept Adult Oncol, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. AMC Canc Res Ctr, Denver, CO USA. RP Lee, SJ (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Ctr Outcomes & Policy Res, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA75267-03] NR 20 TC 62 Z9 62 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 FEB 28 PY 2001 VL 285 IS 8 BP 1034 EP 1038 DI 10.1001/jama.285.8.1034 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 403ME UT WOS:000167046400025 PM 11209174 ER PT J AU Bernardo, MVP Harrington, DP AF Bernardo, MVP Harrington, DP TI Sample size calculations for the two-sample problem using the multiplicative intensity model SO STATISTICS IN MEDICINE LA English DT Article ID BREAST-CANCER PATIENTS; COX REGRESSION-MODEL; ONCOLOGY-GROUP TRIAL; CLINICAL-TRIALS; EVENT; TIME; TAMOXIFEN; DURATION; THERAPY AB In this paper we propose formulae for calculating the expected number of events or, alternatively, the required trial duration, for clinical trials involving two treatment groups in which patients may potentially experience multiple events and the data will be analysed using a multiplicative intensity (MI) model. We use a partial likelihood-based approach and examine in detail two MI models: one that includes a binary treatment variable as the only covariate and a three-state Markov process model in which a binary time-varying covariate is added to the previous model. For the simpler model, our formula coincides with those derived by Cook using full likelihood methods. We present applications of the derived formulae to chronic granulomatous disease and breast cancer data sets. Copyright (C) 2001 John Wiley & Sons, Ltd. C1 Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Cambridge, MA 02138 USA. RP Bernardo, MVP (reprint author), Dana Farber Canc Inst, Dept Biostat Sci, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA 39929] NR 18 TC 14 Z9 14 U1 1 U2 1 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD FEB 28 PY 2001 VL 20 IS 4 BP 557 EP 579 DI 10.1002/sim.693 PG 23 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 402CK UT WOS:000166968300006 PM 11223901 ER PT J AU Bozkurt, B Torre-Amione, G Warren, MS Whitmore, J Soran, OZ Feldman, AM Mann, DL AF Bozkurt, B Torre-Amione, G Warren, MS Whitmore, J Soran, OZ Feldman, AM Mann, DL TI Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure SO CIRCULATION LA English DT Article DE heart failure; myocardial contraction; growth substances; cytokines; tumor necrosis factor ID CARDIOMYOPATHY AB Background-Previously, we showed that tumor necrosis factor (TNF) antagonism with etanercept, a soluble TNF receptor, was well tolerated and that it suppressed circulating levels of biologically active TNF for 14 days in patients with moderate heart failure. However, the effects of sustained TNF antagonism in heart failure are not known. Methods and Results-We conducted a randomized, double-blind, placebo-controlled, multidose trial of etanercept in 47 patients with NYHA class III to IV heart failure. Patients were treated with biweekly subcutaneous injections of etanercept 5 mg/m(2) (n=16) or 12 mg/m(2) (n=15) or with placebo (n=16) for 3 months. Doses of 5 and 12 mg/m(2) etanercept were safe and well tolerated for 3 months. Treatment with etanercept led to a significant dose-dependent improvement in left ventricular (LV) ejection fraction and LV remodeling, and there was a trend toward an improvement in patient functional status, as determined by clinical composite score. Conclusion-Treatment with etanercept for 3 months was safe and well-tolerated in patients with advanced heart failure, and it resulted in a significant dose-dependent improvement in LV structure and function and a trend toward improvement in patient functional status. C1 Houston VA Med Ctr, Winters Ctr Heart Failure Res 151C, Dept Med, Houston, TX 77030 USA. Baylor Coll Med, Houston, TX 77030 USA. Univ Pittsburgh, Med Ctr Hlth Syst, Cardiovasc Inst, Pittsburgh, PA USA. Methodist Hosp, Houston, TX 77030 USA. Immunex Corp, Seattle, WA USA. RP Mann, DL (reprint author), Houston VA Med Ctr, Winters Ctr Heart Failure Res 151C, Dept Med, 2002 Holcombe Blvd, Houston, TX 77030 USA. OI Mann, Douglas /0000-0002-2516-0145 FU NHLBI NIH HHS [P50 HL-O6H] NR 5 TC 241 Z9 261 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 27 PY 2001 VL 103 IS 8 BP 1044 EP 1047 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 412NW UT WOS:000167562100012 PM 11222463 ER PT J AU Durante, W Liao, L Reyna, SV Peyton, KJ Schafer, AI AF Durante, W Liao, L Reyna, SV Peyton, KJ Schafer, AI TI Transforming growth factor-beta(1) stimulates L-arginine transport and metabolism in vascular smooth muscle cells - Role in polyamine and collagen synthesis SO CIRCULATION LA English DT Article DE muscle, smooth; amino acids; collagen ID AMINO-ACID TRANSPORTER; RAT-LIVER ARGINASE; GENE-EXPRESSION; NITRIC-OXIDE; FACTOR-BETA; GROWTH-FACTOR-BETA-1; HYPERPLASIA; RECEPTOR; IDENTIFICATION; BIOSYNTHESIS AB Background-Transforming growth factor-beta (1) (TGF-beta (1)) contributes to arterial remodeling by stimulating vascular smooth muscle cell (VSMC) growth and collagen synthesis at sites of vascular injury. Because L-arginine is metabolized to growth-stimulatory polyamines and to the essential collagen precursor L-proline, we examined whether TGF-beta (1) regulates the transcellular transport and metabolism of L-arginine by VSMCs. Methods and Results-TGF-beta (1) increased L-arginine uptake, and this was associated with a selective increase in cationic amino acid transporter-1 (CAT-1) mRNA. In addition, TGF-beta (1) stimulated L-arginine metabolism by inducing arginase I mRNA and arginase activity. TGF-beta (1) also stimulated L-ornithine catabolism by elevating ornithine decarboxylase (ODC) and ornithine aminotransferase (OAT) activity. TGF-beta (1) markedly increased the capacity of VSMCs to generate the polyamine putrescine and L-proline from extracellular L-arginine. The TGF-beta (1)-mediated increase in putrescine and L-proline production was reversed by methyl-L-arginine, a competitive inhibitor of cationic amino acid transport, or by hydroxy-L-arginine, an arginase inhibitor. Furthermore, the formation of putrescine was inhibited by the ODC inhibitor cu-difluoromethylornithine, and L-proline generation was blocked by the OAT inhibitor L-canaline. L-Canaline also inhibited TGF-beta (1)-stimulated type I collagen synthesis. Conclusions-These results demonstrate that TGF-beta (1) stimulates polyamine and L-proline synthesis by inducing the genes that regulate the transport and metabolism of L-arginine. In addition, they show that TGF-beta (1)-stimulated collagen production is dependent on L-proline formation. The ability of TGF-beta (1) to upregulate L-arginine transport and direct its metabolism to polyamines and L-proline may contribute to arterial remodeling at sites of vascular damage. C1 Baylor Coll Med, Houston VA Med Ctr, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Baylor Coll Med, Dept Pharmacol, Houston, TX 77030 USA. RP Durante, W (reprint author), Baylor Coll Med, Houston VA Med Ctr, Bldg 109,Room 130,2002 Holcombe Blvd, Houston, TX 77030 USA. FU NHLBI NIH HHS [HL-36045, HL-59976, HL-62467] NR 37 TC 90 Z9 95 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 27 PY 2001 VL 103 IS 8 BP 1121 EP 1127 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 412NW UT WOS:000167562100025 PM 11222476 ER PT J AU Shoulson, I Penney, J McDermott, M Kieburtz, K Schwid, SR Kayson, E Chase, T Fahn, S Greenamyre, JT Lang, A Siderowf, A Pearson, N Harrison, M Rost-Ruffner, E Colcher, A Lloyd, M Matthews, M Pahwa, R McGuire, D Lew, MF Schuman, S Marek, K Broshjeit, S Factor, S Brown, D Feigin, A Mazurkiewicz, J Ford, B Jennings, D Dillon, S Comella, C Blasucci, L Janko, K Shulman, L Wiener, W Bateman-Rodriguez, D Carrion, A Suchowersky, O Lafontaine, AL Pantella, C Siemers, E Belden, J Davies, R Lannon, M Grimes, D Gray, P Martin, W Kennedy, L Adler, C Newman, S Hammerstad, J Stone, C Lewitt, P Bardram, K Mistura, K Miyasaki, J Johnston, L Cha, JHJ Tennis, M Panisset, M Hall, J Tetrud, J Friedlander, J Hauser, R Gauger, L Rodnitzky, R Deleo, A Dobson, J Seeberger, L Dingmann, C Tarsy, D Ryan, P Elmer, L Ruzicka, D Stacy, M Brewer, M Locke, B Baker, D Casaceli, C Day, D Florack, M Hodgeman, K Laroia, N Nobel, R Orme, C Rexo, L Rothenburgh, K Sulimowicz, K Watts, A Wratni, E Tariot, P Cox, C Leventhal, C Alderfer, V Craun, AM Frey, J McCree, L McDermott, J Cooper, J Holdich, T Read, B AF Shoulson, I Penney, J McDermott, M Kieburtz, K Schwid, SR Kayson, E Chase, T Fahn, S Greenamyre, JT Lang, A Siderowf, A Pearson, N Harrison, M Rost-Ruffner, E Colcher, A Lloyd, M Matthews, M Pahwa, R McGuire, D Lew, MF Schuman, S Marek, K Broshjeit, S Factor, S Brown, D Feigin, A Mazurkiewicz, J Ford, B Jennings, D Dillon, S Comella, C Blasucci, L Janko, K Shulman, L Wiener, W Bateman-Rodriguez, D Carrion, A Suchowersky, O Lafontaine, AL Pantella, C Siemers, E Belden, J Davies, R Lannon, M Grimes, D Gray, P Martin, W Kennedy, L Adler, C Newman, S Hammerstad, J Stone, C Lewitt, P Bardram, K Mistura, K Miyasaki, J Johnston, L Cha, JHJ Tennis, M Panisset, M Hall, J Tetrud, J Friedlander, J Hauser, R Gauger, L Rodnitzky, R Deleo, A Dobson, J Seeberger, L Dingmann, C Tarsy, D Ryan, P Elmer, L Ruzicka, D Stacy, M Brewer, M Locke, B Baker, D Casaceli, C Day, D Florack, M Hodgeman, K Laroia, N Nobel, R Orme, C Rexo, L Rothenburgh, K Sulimowicz, K Watts, A Wratni, E Tariot, P Cox, C Leventhal, C Alderfer, V Craun, AM Frey, J McCree, L McDermott, J Cooper, J Holdich, T Read, B CA Parkinson Study Grp TI A randomized, controlled trial of remacemide for motor fluctuations in Parkinson's disease SO NEUROLOGY LA English DT Article ID LEVODOPA-INDUCED DYSKINESIAS; MONOAMINE-DEPLETED RATS; NMDA RECEPTOR SUBUNITS; L-DOPA; GLUTAMATE ANTAGONIST; RESPONSE ALTERATIONS; SUBTHALAMIC NUCLEUS; BASAL GANGLIA; MONKEYS; PHOSPHORYLATION AB Background: Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa. Methods: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy. Results: Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant. Conclusion: Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD. C1 Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14642 USA. Clin Trials Coordinat Ctr, Rochester, NY USA. Univ Virginia, Ctr Hlth Sci, Charlottesville, VA USA. Penn Hosp, Philadelphia, PA 19107 USA. Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. Univ So Calif, Sch Med, Los Angeles, CA USA. Yale Univ, Sch Med, New Haven, CT USA. Albany Med Coll, Albany, NY 12208 USA. N Shore Univ Hosp, Manhasset, NY USA. Columbia Presbyterian Med Ctr, New York, NY 10032 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. Univ Miami, Miami, FL 33152 USA. Univ Calgary, Med Clin, Calgary, AB, Canada. Indiana Univ, Sch Med, Indianapolis, IN USA. Brown Univ, Mem Hosp Rhode Isl, Pawtucket, RI 02860 USA. Ottawa Civic Hosp, Ottawa, ON K1Y 4E9, Canada. Univ Alberta, Edmonton, AB, Canada. Mayo Clin, Scottsdale, AZ USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Sinai Clin Neurosci Ctr, W Bloomfield, MI USA. Toronto Western Hosp, Toronto, ON M5T 2S8, Canada. Massachusetts Gen Hosp, Boston, MA 02114 USA. McGill Ctr Studies Aging, Montreal, PQ, Canada. Parkinsons Inst, Sunnyvale, CA USA. Univ S Florida, Tampa, FL USA. Univ Iowa, Iowa City, IA USA. Colorado Neurol Inst, Englewood, CO USA. Beth Israel Deaconess Med Ctr, Boston, MA USA. Univ Michigan, Ann Arbor, MI 48109 USA. Barrow Neurol Inst, Phoenix, AZ 85013 USA. RP Schwid, SR (reprint author), Univ Rochester, Med Ctr, Dept Neurol, 601 Elmwood Ave,Box 605, Rochester, NY 14642 USA. RI Greenamyre, J. Timothy/B-4049-2011; OI Miyasaki, Janis/0000-0002-6372-6007 FU NCRR NIH HHS [M01-RR00044, M01-RR01066] NR 39 TC 37 Z9 38 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD FEB 27 PY 2001 VL 56 IS 4 BP 455 EP 462 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 405HT UT WOS:000167154500008 PM 11222787 ER PT J AU Knudsen, KA Rosand, J Karluk, D Greenberg, SM AF Knudsen, KA Rosand, J Karluk, D Greenberg, SM TI Clinical diagnosis of cerebral amyloid angiopathy: Validation of the Boston Criteria SO NEUROLOGY LA English DT Article ID HEMORRHAGE AB The authors performed clinical-pathologic correlation to assess the validity of the Boston diagnostic criteria for cerebral amyloid angiopathy (CAA). Thirteen subjects were diagnosed clinically with probable CAA from among 39 patients with available pathologic tissue in a prospective cohort of subjects aged greater than or equal to 55 years with primary lobar hemorrhage. All 13 individuals were confirmed neuropathologically as having CAA. This small pathologic series indicates that the diagnosis of probable CAA can be made during life with high accuracy. C1 Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, CS Kubik Lab Neurpathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurol, Clin Trials Unit, Boston, MA 02114 USA. RP Greenberg, SM (reprint author), Massachusetts Gen Hosp, Neurol Clin Trials Unit, Wang ACC 836, Boston, MA 02114 USA. FU NIA NIH HHS [AG00725] NR 10 TC 453 Z9 476 U1 2 U2 20 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD FEB 27 PY 2001 VL 56 IS 4 BP 537 EP 539 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 405HT UT WOS:000167154500024 PM 11222803 ER PT J AU Williamson, PTF Watts, JA Addona, GH Miller, KW Watts, A AF Williamson, PTF Watts, JA Addona, GH Miller, KW Watts, A TI Dynamics and orientation of N+(CD3)(3)-bromoacetylcholine bound to its binding site on the nicotinic acetylcholine receptor SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE H-2 NMR; structure; P-31 NMR ID SOLID-STATE NMR; NUCLEAR-MAGNETIC-RESONANCE; TORPEDO-CALIFORNICA; POSTSYNAPTIC MEMBRANES; ELECTRIC ORGAN; H-2 NMR; BACTERIORHODOPSIN; CHROMOPHORE; AGONIST; PROTEIN AB Dynamic and structural information has been obtained for an analogue of acetylcholine while bound to the agonist binding site on the nicotinic acetylcholine receptor (nAcChoR), using wide-line deuterium solid-state NMR, Analysis of the deuterium lineshape obtained at various temperatures from unoriented nAcChoR membranes labeled with deuterated bromoacetylcholine (BAC) showed that the quaternary ammonium group of the ligand is well constrained within the agonist binding site when compared with the dynamics observed in the crystalline solids. This motional restriction would suggest that a high degree of complementarity exists between the quaternary ammonium group of the ligand and the protein within the agonist binding site. nAcChoR membranes were uniaxially oriented by isopotential centrifugation as determined by phosphorous NMR of the membrane phospholipids. Analysis of the deuterium NMR lineshape of these oriented membranes enriched with the nAcChoR labeled with N+(CD3)(3)-BAC has enabled us to determine that the angle formed between the quaternary ammonium group of the BAC and the membrane normal is 42 degrees in the desensitized form of the receptor. This measurement allows us to orient in part the bound ligand within the proposed receptor binding site. C1 Univ Oxford, Dept Biochem, Biomembrane Struct Unit, Oxford OX1 3QU, England. Massachusetts Gen Hosp, Dept Anesthesia, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02114 USA. RP Watts, A (reprint author), Univ Oxford, Dept Biochem, Biomembrane Struct Unit, S Parks Rd, Oxford OX1 3QU, England. RI Williamson, Philip/A-3362-2008 OI Williamson, Philip/0000-0002-0231-8640 FU NIAAA NIH HHS [AA07040] NR 46 TC 27 Z9 28 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 27 PY 2001 VL 98 IS 5 BP 2346 EP 2351 DI 10.1073/pnas.031361698 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 407EH UT WOS:000167258900046 PM 11226242 ER PT J AU Lu, CF Shimaoka, M Ferzly, N Oxvig, C Takagi, J Springer, TA AF Lu, CF Shimaoka, M Ferzly, N Oxvig, C Takagi, J Springer, TA TI An isolated, surface-expressed I domain of the integrin alpha L beta 2 is sufficient for strong adhesive function when locked in the open conformation with a disulfide bond SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FUNCTION-ASSOCIATED ANTIGEN-1; POLYMERASE CHAIN-REACTION; BETA-PROPELLER DOMAIN; LIGAND-BINDING; OVERLAP EXTENSION; CRYSTAL-STRUCTURE; CELL-ADHESION; A-DOMAIN; SUBUNIT; LFA-1 AB We introduced disulfide bonds to lock the integrin alphaL beta2 I domain in predicted open, ligand binding or closed, nonbinding conformations. Transfectants expressing alphaL beta2 heterodimers containing locked-open but not locked-closed or wild-type I domains constitutively adhered to intercellular adhesion molecule-1 (ICAM-1) substrates. Locking the I domain closed abolished constitutive and activatable adhesion. The isolated locked-open I domain bound as well as the activated alphaL beta2 heterodimer, and binding was abolished by reduction of the disulfide, Lovastatin, which binds under the conformationally mobile C-terminal alpha -helix of the I domain, inhibited binding to ICAM-1 by alphaL beta2 with wild-type, but not locked-open I domains. These data establish the importance of conformational change in the alphaL I domain for adhesive function and show that this domain is sufficient for full adhesive activity. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Anesthesia, 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 [R37 CA031798, R01 CA031798, CA31798] NR 40 TC 105 Z9 106 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 FEB 27 PY 2001 VL 98 IS 5 BP 2387 EP 2392 DI 10.1073/pnas.041606398 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 407EH UT WOS:000167258900053 PM 11226249 ER PT J AU Lu, CF Shimaoka, M Zang, Q Takagi, J Springer, TA AF Lu, CF Shimaoka, M Zang, Q Takagi, J Springer, TA TI Locking in alternate conformations of the integrin alpha L beta 2 I domain with disulfide bonds reveals functional relationships among integrin domains SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FUNCTION-ASSOCIATED ANTIGEN-1; INTERCELLULAR-ADHESION MOLECULE-1; BETA-PROPELLER DOMAIN; BINDING-SITE; A-DOMAIN; ALPHA-SUBUNITS; ANTIBODY; AFFINITY; CD18; PROMOTES AB We used integrin alphaL beta2 heterodimers containing I domains locked open (active) or closed (inactive) with disulfide bonds to investigate regulatory interactions among domains in integrins, mAbs to the alphaL I domain and beta2 I-like domain inhibit adhesion of wild-type alphaL beta2 to intercellular adhesion molecule-1. However, with alphaL beta2 containing a locked open I domain, mAbs to the I domain were subdivided into subsets (i) that did not inhibit, and thus appear to inhibit by favoring the closed conformation, and tin that did inhibit, and thus appear to bind to the ligand binding site. Furthermore, alphaL beta2 containing a locked open I domain was completely resistant to inhibition by mAbs to the beta2 I-like domain, but became fully susceptible to inhibition after disulfide reduction with DTT. This finding suggests that the I-like domain indirectly contributes to ligand binding by regulating opening of the I domain in wild-type alphaL beta2. Conversely, locking the I domain closed partially restrained conformational change of the I-like domain by Mn2+, as measured with mAb m24, which we map here to the beta2 I-like domain. By contrast, locking the I domain closed or open did not affect constitutive or Mn2+-induced exposure of the KIM127 epitope in the beta2 stalk region. Furthermore, locked open I domains, in alphaL beta2 complexes or expressed in isolation on the cell surface, bound to intercellular adhesion molecule-1 equivalently in Mg2+ and Mn2+. These results suggest that Mn2+ activates alphaL beta2 by binding to a site other than the I domain, most likely the I-like domain of beta2. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Anesthesia, 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 [R01 CA031798, CA31798, R37 CA031798] NR 33 TC 148 Z9 151 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 FEB 27 PY 2001 VL 98 IS 5 BP 2393 EP 2398 DI 10.1073/pnas.041618598 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 407EH UT WOS:000167258900054 PM 11226250 ER PT J AU Fukumura, D Gohongi, T Kadambi, A Izumi, Y Ang, J Yun, CO Buerk, DG Huang, PL Jain, RK AF Fukumura, D Gohongi, T Kadambi, A Izumi, Y Ang, J Yun, CO Buerk, DG Huang, PL Jain, RK TI Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FLK-1/KDR ACTIVATION; DEFICIENT MICE; VEGF; CELLS; MICROCIRCULATION; PATHWAY; CANCER; GENE; PROSTACYCLIN; INHIBITION AB Nitric oxide (NO) plays a critical role in vascular endothelial growth factor (VEGF)-induced angiogenesis and vascular hyperpermeability, However, the relative contribution of different NO synthase (NOS) isoforms to these processes is not known. Here, we evaluated the relative contributions of endothelial and inducible NOS (eNOS and iNOS, respectively) to angiogenesis and permeability of VEGF-induced angiogenic vessels. The contribution of eNOS was assessed by using an eNOS-deficient mouse, and iNOS contribution was assessed by using a selective inhibitor [L-N-6-(1-iminoethyl) lysine, L-NIL] and an iNOS-deficient mouse. Angiogenesis was induced by VEGF in type I collagen gels placed in the mouse cranial window. Angiogenesis, vessel diameter, blood flow rate, and vascular permeability were proportional to NO levels measured with microelectrodes: Wild-type (WT) greater than or equal to WT with L-NIL or iNOS(-/-) > eNOS(-/-) greater than or equal to eNOS(-/-) with L-NIL. The role of NOS in VEGF-induced acute vascular permeability increase in quiescent vessels also was determined by using eNOS- and iNOS-deficient mice. VEGF superfusion significantly increased permeability in both WT and iNOS-/- mice but not in eNOS(-/-) mice. These findings suggest that eNOS plays a predominant role in VEGF-induced angiogenesis and vascular permeability. Thus, selective modulation of eNOS activity is a promising strategy for altering angiogenesis and vascular permeability in vivo. C1 Massachusetts Gen Hosp, Edwin L Steele Lab, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Univ Penn, Sch Med, Dept Physiol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Bioengn, Philadelphia, PA 19104 USA. RP Fukumura, D (reprint author), Massachusetts Gen Hosp, Edwin L Steele Lab, 100 Blossom St, Boston, MA 02114 USA. RI Buerk, Donald/F-6888-2014; Yun, Chae-Ok/P-3698-2015; OI Yun, Chae-Ok/0000-0002-9466-4531 FU NCI NIH HHS [R24-CA85140, R24 CA085140, R35-CA56591]; NEI NIH HHS [EY09269, R01 EY009269]; NHLBI NIH HHS [HL57818, R01 HL057818]; NINDS NIH HHS [NS33335, R01 NS033335] NR 44 TC 552 Z9 566 U1 1 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 27 PY 2001 VL 98 IS 5 BP 2604 EP 2609 DI 10.1073/pnas.041359198 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 407EH UT WOS:000167258900090 PM 11226286 ER PT J AU Martin, KJ Graner, E Li, Y Price, LM Kritzman, BM Fournier, MV Rhei, E Pardee, AB AF Martin, KJ Graner, E Li, Y Price, LM Kritzman, BM Fournier, MV Rhei, E Pardee, AB TI High-sensitivity array analysis of gene expression for the early detection of disseminated breast tumor cells in peripheral blood SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE breast cancer; hematogeneous dissemination of tumor cells cDNA; prognostic markers; differential display ID POLYMERASE-CHAIN-REACTION; CANCER-CELLS; CARCINOMA-CELLS; BONE-MARROW; RT-PCR; MAMMARY; MASPIN; MDM-2; CYTOKERATIN-19; SURVIVAL AB Early detection is an effective means of reducing cancer mortality. Here, we describe a highly sensitive high-throughput screen that can identify panels of markers for the early detection of solid tumor cells disseminated in peripheral blood. The method is a two-step combination of differential display and high-sensitivity cDNA arrays. In a primary screen, differential display identified 170 candidate marker genes differentially expressed between breast tumor cells and normal breast epithelial cells. In a secondary screen, high-sensitivity arrays assessed expression levels of these genes in 48 blood samples, 22 from healthy volunteers and 26 from breast cancer patients. Cluster analysis identified a group of 12 genes that were elevated in the blood of cancer patients. Permutation analysis of individual genes defined five core genes (P less than or equal to 0.05, PERMAX test). As a group, the 12 genes generally distinguished accurately between healthy volunteers and patients with breast cancer. Mean expression levels of the 12 genes were elevated in 77% (10 of 13) untreated invasive cancer patients, whereas cluster analysis correctly classified volunteers and patients (P = 0.0022, Fisher's exact test). Quantitative real-time PCR confirmed array results and indicated that the sensitivity of the assay (1:2 x 10(8) transcripts) was sufficient to detect disseminated solid tumor cells in blood. Expression-based blood assays developed with the screening approach described here have the potential to detect and classify solid tumor cells originating from virtually any primary site in the body. C1 Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. RP Pardee, AB (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RI Graner, Edgard/K-4411-2012 FU NCI NIH HHS [R01 CA61253-08A1] NR 39 TC 99 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 FEB 27 PY 2001 VL 98 IS 5 BP 2646 EP 2651 DI 10.1073/pnas.041622398 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 407EH UT WOS:000167258900097 PM 11226293 ER PT J AU Aballay, A Ausubel, FM AF Aballay, A Ausubel, FM TI Programmed cell death mediated by ced-3 and ced-4 protects Caenorhabditis elegans from Salmonella typhimurium-mediated killing SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PSEUDOMONAS-AERUGINOSA; NEMATODE; PATHOGENESIS; APOPTOSIS; MODEL; HOST; INFECTION; GENETICS AB Programmed cell death (PCD) in mammals has been implicated in several disease states including cancer, autoimmune disease, and neurodegenerative disease. In Caenorhabditis elegans, PCD is a normal component of development. We find that Salmonella typhimurium colonization of the C. elegans intestine leads to an increased level of cell death in the worm gonad. S. typhimurium-mediated germ-line cell death is not observed in C. elegans ced-3 and ced-4 mutants in which developmentally regulated cell death is blocked, and ced-3 and ced-4: mutants are hypersensitive to S. typhimurium-mediated killing. These results suggest that PCD may be involved in the C. elegans defense response to pathogen attack. C1 Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Ausubel, FM (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Wellman 10, Boston, MA 02114 USA. RI Tang, Amy/L-3226-2016 OI Tang, Amy/0000-0002-5772-2878 FU NIGMS NIH HHS [GM48707, R01 GM048707, R37 GM048707] NR 30 TC 134 Z9 150 U1 3 U2 15 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 27 PY 2001 VL 98 IS 5 BP 2735 EP 2739 DI 10.1073/pnas.041613098 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 407EH UT WOS:000167258900113 PM 11226309 ER PT J AU Vila, M Jackson-Lewis, V Vukosavic, S Djaldetti, R Liberatore, G Offen, D Korsmeyer, SJ Przedborski, S AF Vila, M Jackson-Lewis, V Vukosavic, S Djaldetti, R Liberatore, G Offen, D Korsmeyer, SJ Przedborski, S TI Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PROGRAMMED CELL-DEATH; TROPHIC FACTOR DEPRIVATION; SUBSTANTIA-NIGRA; DEFICIENT MICE; CYTOCHROME-C; TYROSINE-HYDROXYLASE; NEURONAL DEATH; NITRIC-OXIDE; TOXIN MPTP; IN-VIVO AB 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages dopaminergic neurons in the substantia nigra pars compacta (SNpc) as seen in Parkinson's disease. Here, we show that the proapoptotic protein Bax is highly expressed in the SNpc and that its ablation attenuates SNpc developmental neuronal apoptosis. In adult mice, there is an up-regulation of Bax in the SNpc after MPTP administration and a decrease in Bcl-2. These changes parallel MPTP-induced dopaminergic neurodegeneration. We also show that mutant mice lacking Bax are significantly more resistant to MPTP than their wild-type littermates. This study demonstrates that Bax plays a critical role in the MPTP neurotoxic process and suggests that targeting Bax may provide protective benefit in the treatment of Parkinson's disease. C1 Columbia Univ, Dept Neurol, New York, NY 10032 USA. Columbia Univ, Dept Pathol, New York, NY 10032 USA. Felsenstein Res Ctr, IL-69978 Petah Tiqwa, Israel. 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. RP Przedborski, S (reprint author), Columbia Univ, Dept Neurol, BB-307,650 W 168th St, New York, NY 10032 USA. FU NINDS NIH HHS [P50 NS038370, P50 NS38370, R01 NS038586, R01 NS38586, R29 NS37345] NR 43 TC 233 Z9 239 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 FEB 27 PY 2001 VL 98 IS 5 BP 2837 EP 2842 DI 10.1073/pnas.051633998 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 407EH UT WOS:000167258900131 PM 11226327 ER PT J AU Mylonakis, E Ryan, ET Calderwood, SB AF Mylonakis, E Ryan, ET Calderwood, SB TI Clostridium difficile-associated diarrhea - A review SO ARCHIVES OF INTERNAL MEDICINE LA English DT Review ID BOVINE IMMUNOGLOBULIN CONCENTRATE; ANTIBIOTIC-ASSOCIATED COLITIS; PLACEBO-CONTROLLED TRIAL; SERUM ANTIBODY-RESPONSE; TOXIN-A-RECEPTOR; PSEUDOMEMBRANOUS COLITIS; RISK-FACTORS; RHO-PROTEINS; SACCHAROMYCES-BOULARDII; HOSPITALIZED-PATIENTS AB Clostridium difficile causes 300 000 to 3 000 000 cases of diarrhea and colitis in the United States every year. Antibiotics most frequently associated with the infection are clindamycin, ampicillin, amoxicillin, and cephalosporins, but all antibiotics may predispose patients to C difficile infection. The clinical presentation varies from asymptomatic colonization to mild diarrhea to severe debilitating disease, with high fever, severe abdominal pain, paralytic ileus, colonic dilation (or megacolon): or even perforation. The most sensitive and specific test available for diagnosis of C difficile infection is a tissue culture assay for the cytotoxicity of toxin B. However, this test takes 1 to 3 days to complete and requires tissue culture facilities. Detection of C difficile toxin by means of enzyme-linked immunoassay is more rapid and inexpensive. A minority of patients may require more than 1 stool assay to detect toxin. Oral metronidazole or oral vancomycin hydrochloride for 10 to 14 days are equally effective at resolving clinical symptoms; oral metronidazole is preferred in most cases because of lowered cost and less selective pressure for vancomycin-resistant organisms. Approximately 15% of patients experience relapse after initial therapy and require retreatment, sometimes with an extended, tapering regimen. Immunity appears to be incomplete and predominantly mediated by serum IgG to toxin A. Measures for preventing the spread of the pathogen, appropriate diagnostic testing, and treatment may avert morbidity and mortality due to C difficile-associated diarrhea. C1 Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. RP Calderwood, SB (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Gray Jackson 504,55 Fruit St, Boston, MA 02114 USA. FU NIAID NIH HHS [AI01332, AI40725, R01 AI040725] NR 106 TC 170 Z9 183 U1 1 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD FEB 26 PY 2001 VL 161 IS 4 BP 525 EP 533 DI 10.1001/archinte.161.4.525 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 404AT UT WOS:000167075800005 PM 11252111 ER PT J AU Wee, CC Rigotti, NA Davis, RB Phillips, RS AF Wee, CC Rigotti, NA Davis, RB Phillips, RS TI Relationship between smoking and weight control efforts among adults in the United States SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID BODY-WEIGHT; CIGARETTE-SMOKING; CONTROL BEHAVIORS; YOUNG-ADULTS; CESSATION; WOMEN; ADOLESCENTS; POPULATION; HEALTH; COHORT AB Background: The effect of weight control concerns on smoking among adults is unclear. We examined the association between smoking behavior and weight control efforts among US adults. Methods: A total of 17317 adults responded to the Year 2000 Supplement of the 1995 National Health Interview Survey (83% combined response rate). Respondents provided sociodemographic and health information, including their smoking history and whether they were trying to lose weight, maintain weight, or gain weight. Results: Rates of smoking were lower among adults who were trying to lose or maintain weight than among those not trying to control weight (25% vs 31%; P<.001). After adjustment for sex, race, education, income, marital status, region of the country, and body mass index, the relationship between trying to lose weight and current smoking varied according to age. Among adults younger than 30 years, those trying to lose weight were more likely to smoke currently (odds ratio, 1.36 [95% confidence interval, 1.09-1.70]),whereas older adults trying to lose weight were as likely or less likely to smoke compared with adults not trying to control weight. After adjustment, smokers of all ages who were trying to lose weight were more likely to express a desire to quit smoking. Results were similar after stratification by sex and body mass index. Conclusions: Adults younger than 30 years are more likely to smoke if they are trying to lose weight. However, smokers of all ages who are trying to lose weight are more likely to want to stop smoking. Patients' weight control efforts should not discourage clinicians from counseling about smoking cessation. Education about smoking and healthy weight control methods should target young adults. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02215 USA. RP Wee, CC (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, 330 Brookline Ave,Libby 330, Boston, MA 02215 USA. FU AHRQ HHS [1 F32 HS00137-01] NR 42 TC 36 Z9 37 U1 2 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 FEB 26 PY 2001 VL 161 IS 4 BP 546 EP 550 DI 10.1001/archinte.161.4.546 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 404AT UT WOS:000167075800007 PM 11252113 ER PT J AU Li, YQ Kufe, D AF Li, YQ Kufe, D TI The human DF3/MUC1 carcinoma-associated antigen signals nuclear localization of the catenin p120(ctn) SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE MUC1; cytoplasmic tail; p120(ctn); nuclear signals ID E-CADHERIN; TYROSINE PHOSPHORYLATION; BETA-CATENIN; EPISIALIN MUC1; ALPHA-CATENIN; CELL-ADHESION; SUBSTRATE; EXPRESSION; PROTEIN; DF3 AB The human DF3/MUC1 glycoprotein is aberrantly overexpressed by carcinoma cells. The present studies show that MUC1 associates with the Armadillo protein, p120(ctn). The cytoplasmic domain of MUC1 binds directly to p120, The functional significance of the MUC1-p120 association is supported by the demonstration that MUC1 induces nuclear localization of p120, These findings demonstrate that MUC1 confers cell membrane to nuclear signaling by interactions with p120, (C) 2001 Academic Press C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 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 [CA87421] NR 23 TC 47 Z9 49 U1 1 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 FEB 23 PY 2001 VL 281 IS 2 BP 440 EP 443 DI 10.1006/bbrc.2001.4383 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 407FR UT WOS:000167262000029 PM 11181067 ER PT J AU Spiegelman, BM Flier, JS AF Spiegelman, BM Flier, JS TI Obesity and the regulation of energy balance SO CELL LA English DT Review ID MITOCHONDRIAL UNCOUPLING PROTEIN; HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; MELANIN-CONCENTRATING HORMONE; ACTIVATED RECEPTOR-GAMMA; ADIPOSE-TISSUE; NEUROPEPTIDE-Y; BODY-WEIGHT; TRANSGENIC MICE; GENE-EXPRESSION; FOOD-INTAKE C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Spiegelman, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. NR 100 TC 1274 Z9 1322 U1 22 U2 137 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD FEB 23 PY 2001 VL 104 IS 4 BP 531 EP 543 DI 10.1016/S0092-8674(01)00240-9 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 405VP UT WOS:000167181500008 PM 11239410 ER PT J AU Merscher, S Funke, B Epstein, JA Heyer, J Puech, A Lu, MM Xavier, RJ Demay, MB Russell, RG Factor, S Tokooya, K Jore, BS Lopez, M Pandita, RK Lia, M Carrion, D Xu, H Schorle, H Kobler, JB Scambler, P Wynshaw-Boris, A Skoultchi, AI Morrow, BE Kucherlapati, R AF Merscher, S Funke, B Epstein, JA Heyer, J Puech, A Lu, MM Xavier, RJ Demay, MB Russell, RG Factor, S Tokooya, K Jore, BS Lopez, M Pandita, RK Lia, M Carrion, D Xu, H Schorle, H Kobler, JB Scambler, P Wynshaw-Boris, A Skoultchi, AI Morrow, BE Kucherlapati, R TI TBX1 is responsible for cardiovascular defects in Velo-Cardio-Facial/DiGeorge syndrome SO CELL LA English DT Article ID CONGENITAL HEART-DISEASE; DIGEORGE-SYNDROME REGION; HOLT-ORAM-SYNDROME; NEURAL CREST CELLS; FACIAL-SYNDROME; 22Q11 DELETIONS; MOLECULAR DEFINITION; MICE DEFICIENT; GENE; MUTATIONS AB Velo-cardio-facial syndrome (VCFS)/DiGeorge syndrome (DGS) is a human disorder characterized by a number of phenotypic features including cardiovascular defects. Most VCFS/DGS patients are hemizygous for a 1.5-3.0 Mb region of 22q11. To investigate the etiology of this disorder, we used a cre-loxP strategy to generate mice that are hemizygous for a 1.5 Mb deletion corresponding to that on 22q11. These mice exhibit significant perinatal lethality and have conotruncal and parathyroid defects. The conotruncal defects can be partially rescued by a human BAC containing the TBX1 gene. Mice heterozygous for a null mutation in Tbx1 develop conotruncal defects. These results together with the expression patterns of Tbx1 suggest a major role for this gene in the molecular etiology of VCFS/DGS. C1 Yeshiva Univ Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA. Univ Penn, Div Cardiovasc, Philadelphia, PA 19104 USA. Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA. Univ London, Coll Med, Inst Child Hlth, London, England. Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Forschungszentrum Karlsruhe, Inst Genet & Toxikol, D-76133 Karlsruhe, Germany. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med,Dept Otol & Laryngol, HP Mosher Laryngol Res Lab, Boston, MA 02114 USA. RP Morrow, BE (reprint author), Yeshiva Univ Albert Einstein Coll Med, Dept Mol Genet, 1300 Morris Pk Ave, Bronx, NY 10461 USA. RI Scambler, Peter/C-4998-2008; PUECH, Anne/A-7470-2013; Schorle, Hubert/M-5001-2016 OI Scambler, Peter/0000-0002-1487-4628; Schorle, Hubert/0000-0001-8272-0076 FU NHLBI NIH HHS [HL 62974, HL61475]; NICHD NIH HHS [HD34980] NR 36 TC 534 Z9 540 U1 4 U2 20 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD FEB 23 PY 2001 VL 104 IS 4 BP 619 EP 629 DI 10.1016/S0092-8674(01)00247-1 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 405VP UT WOS:000167181500015 PM 11239417 ER PT J AU Pahlavani, MA Vargas, DA AF Pahlavani, MA Vargas, DA TI Aging but not dietary restriction alters the activation-induced apoptosis in rat T cells SO FEBS LETTERS LA English DT Article DE activation-induced cell death; T cell; aging; dietary restriction; rat ID CALORIC RESTRICTION; DNA FRAGMENTATION; HEPATOCYTE PROLIFERATION; FAS ANTIGEN; F344 RATS; DEATH; EXPRESSION; MICE; LYMPHOCYTES; AGE AB The aim of this study was to determine if aging or dietary restriction (DR) alters activation-induced cell death, which is known to regulate cell proliferation and eliminate the high number of activated cells during an immune response, Splenic T cells were isolated from young (4-6 months) and old (25-26 months) Fischer 344 rats that had free access to food, ad libitum (AL), and from dietary-restricted (DR) old (25-26 months) rats that beginning at 6 weeks of age mere fed 60% (40% food-restricted) of the diet consume by the AL rats, T cells were incubated with anti-CD3 antibody, or staphylococcal enterotoxin B (primary stimulus) for 72-96 h, followed by restimulation with anti-CD3 (secondary stimulus) for 72 h, Activation-induced apoptosis was assessed by DNA fragmentation and the expression of Fas/CD95 receptor and Fas ligand (Fas-L) was measured by flow cytometry, We found that the amount of DNA fragmentation was significantly (P < 0.05) higher in the stimulated and restimulated T cells from AL old rats and DR old rats compared to young rats. The increase in DNA fragmentation with age was paralleled by an increase in the proportion of the cells expressing Fas and Fas-L, However, DR had no significant effect on the age-related increase in DNA fragmentation or the expression of Fas or Fas-L, We also measured the levels of Bcl-2 and Bas protein and found that the level of Bcl-2 decreased and Pax increased with age and that DR had no effect on the age-related changes in the level of Bcl-2 or Bax protein. These results demonstrate that aging but not DR alters activation-induced apoptosis in rat T cells. (C) 2001 Federation of European Biochemical Societies, Published by Elsevier Science B.V. All rights reserved. C1 S Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr 182, San Antonio, TX 78284 USA. Audie L Murphy Mem Vet Hosp, San Antonio, TX 78284 USA. Univ Texas, Dept Physiol, Ctr Hlth Sci, San Antonio, TX 78284 USA. RP Pahlavani, MA (reprint author), S Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr 182, 7400 Merton Minter Blvd, San Antonio, TX 78284 USA. FU NIA NIH HHS [AG00677, AG14088] NR 52 TC 21 Z9 23 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD FEB 23 PY 2001 VL 491 IS 1-2 BP 114 EP 118 DI 10.1016/S0014-5793(01)02184-6 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 407AC UT WOS:000167248400025 PM 11226431 ER PT J AU Linseman, DA Heidenreich, KA Fisher, SK AF Linseman, DA Heidenreich, KA Fisher, SK TI Stimulation of M-3 muscarinic receptors induces phosphorylation of the Cdc42 effecter activated Cdc42Hs-associated kinase-1 via a Fyn tyrosine kinase signaling pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FOCAL ADHESION KINASE; HUMAN NEUROBLASTOMA-CELLS; SUBCELLULAR-LOCALIZATION; LYSOPHOSPHATIDIC ACID; ALZHEIMERS-DISEASE; NEURITE RETRACTION; NERVOUS-SYSTEM; GROWTH-FACTOR; RHO; GTPASES AB The tyrosine kinase, activated Cdc42Hs-associated kinase-1 (ACR-1), is a specific effector of the Rho family GTPase Cdc42. GTP-bound Cdc42 has been shown to facilitate neurite outgrowth elicited by activation of muscarinic cholinergic receptors (mAChRs). Because tyrosine kinase activity is a requirement for neuritogenesis in several cell systems, we investigated whether endogenous mAChRs (principally of the M-3 subtype) expressed in human SN-SY5Y neuroblastoma cells would signal to ACK-1. Incubation of cells with the cholinergic agonist oxotremorine-M (Oxo-M) induced an approximately 6-fold increase in the tyrosine phosphorylation of ACK-1 which was inhibited by atropine. ACK-1 phosphorylation was blocked by Clostridium difficile toxin B, an inhibitor of Rho family GTPases. In contrast, disruption of the actin cytoskeleton with cytochalasin D stimulated ACK-1 phosphorylation, and moreover, addition of Oxo-M 60 cells preincubated with this agent elicited a further increase in phosphorylation, indicating that an intact cytoskeleton is not required for mAChR signaling to ACH-1. Although stimulation of M-3 mAChRs induces bath an increase in intracellular Ca2+ and activation of protein kinase C (PKC), neither of these second messenger pathways was required for receptor-stimulated ACK-1 phosphorylation. Instead, inhibition of PKC resulted in a 2-fold increase in Oxo-M-stimulated ACK-1 phosphorylation, whereas acute activation of PRC with phorbol ester decreased ACK-1 phosphorylation. The agonist-induced tyrosine phosphorylation of ACK-1 was blocked by inhibitors of Src family kinases, and ACK-1 was coprecipitated with Fyn (but not Src) in an agonist-dependent manner. Finally, scrape loading cells with glutathione S-transferase fusion proteins of either the Fyn-SH2 or Fyn-SH3 domain significantly attenuated mAChR-stimulated ACK-1 tyrosine phosphorylation, The data are the first to shaw phosphorylation of ACK-1 after stimulation of a receptor coupled to neurite outgrowth and indicate that a Rho family GTPase (i.e, Cdc42) and Fyn are essential upstream elements of this signaling pathway. C1 Denver Vet Affairs Med Ctr, Denver, CO 80220 USA. Univ Michigan, Mental Hlth Res Inst, Dept Pharmacol, Ann Arbor, MI 48104 USA. Univ Michigan, Mental Hlth Res Inst, Neurosci Lab, Ann Arbor, MI 48104 USA. RP Linseman, DA (reprint author), Denver Vet Affairs Med Ctr, 111H,Rm 9C120,1055 Clermont St, Denver, CO 80220 USA. FU NIGMS NIH HHS [GM07767]; NIMH NIH HHS [MH12193]; NINDS NIH HHS [NS23831] NR 55 TC 36 Z9 36 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 FEB 23 PY 2001 VL 276 IS 8 BP 5622 EP 5628 DI 10.1074/jbc.M006812200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 404RU UT WOS:000167115100031 PM 11087735 ER PT J AU Xiong, Y Kern, P Chang, HC Reinherz, EL AF Xiong, Y Kern, P Chang, HC Reinherz, EL TI T cell receptor binding to a pMHCII ligand is kinetically distinct from and independent of CD4 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MHC CLASS-II; IMMUNODEFICIENCY-VIRUS GP120; TCR FAB FRAGMENT; ALPHA-BETA; SIGNAL-TRANSDUCTION; CRYSTAL-STRUCTURE; TYROSINE KINASE; LYMPHOCYTES-T; ANTIGEN RECEPTOR; ATOMIC-STRUCTURE AB Immune recognition of pMHCII ligands by a helper T lymphocyte involves its antigen-specific T cell receptor (TCR) and CD4 coreceptor. We have characterized the binding of both molecules to the same pMHCII. The D10 ap TCR heterodimer binds to conalbumin/I-A(k) with virtually identical kinetics and affinity as the single chain V alphaV beta domain module (scD10) (Kd = 6-8 muM). The CD4 ectodomain does not alter either interaction. Moreover, CD4 alone demonstrates weak pMHCII binding (K-d = 200 muM), with no discernable affinity for the cup TCR heterodimer. Hence, rather than providing a major contribution to binding energy, the critical role for the coreceptor in antigen-specific activation likely results from transient inducible recruitment of the CD4 cytoplasmic tail-associated lck tyrosine kinase to the pMHCII-ligated TCR complex. C1 Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Reinherz, EL (reprint author), Dana Farber Canc Inst, Immunobiol Lab, 44 Binney St, Boston, MA 02115 USA. FU NIAID NIH HHS [AI19807, AI43649] NR 69 TC 68 Z9 68 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 FEB 23 PY 2001 VL 276 IS 8 BP 5659 EP 5667 DI 10.1074/jbc.M009580200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 404RU UT WOS:000167115100036 PM 11106664 ER PT J AU Dammann, O Phillips, TM Allred, EN O'Shea, TM Paneth, N Van Marter, LJ Bose, C Ehrenkranz, RA Bednarek, FJ Naples, M Leviton, A AF Dammann, O Phillips, TM Allred, EN O'Shea, TM Paneth, N Van Marter, LJ Bose, C Ehrenkranz, RA Bednarek, FJ Naples, M Leviton, A CA Elgan Study Investigators TI Mediators of fetal inflammation in extremely low gestational age newborns SO CYTOKINE LA English DT Article DE cytokines; growth factors; infant; premature; inflammation ID NECROSIS-FACTOR-ALPHA; COLONY-STIMULATING FACTOR; AMNIOTIC-FLUID; ENDOTHELIAL-CELLS; CEREBRAL-PALSY; PRETERM LABOR; BRONCHOPULMONARY DYSPLASIA; CYTOKINES INTERLEUKIN-6; INTRAUTERINE INFECTION; BRAIN-DAMAGE AB To establish levels of mediators of inflammation in cord blood and postnatal serum from extremely low gestational age newborns (ELGANs, less than or equal to 28 weeks), we measured sixteen markers of inflammation by recycling immunoaffinity chromatography in 15 ELGANs who had serum sampled at days 2-5. Median levels of IL-1, IL-6, IL-8, IL-11, IL-13, TNF-alpha, G-CSF, M-CSF, GM-CSF, MTP-1 alpha, and RANTES mere considerably higher than published values of these inflammatory mediators from term newborns. In three of eight ELGANS who had serial measurements taken, levels of IL-1, IL-6, IL-8, IL-11, TNF-alpha, G-CSF, and MIP-1 alpha declined from initially very high levels to reach an apparent baseline towards the end of the first postnatal week. In these same three infants, GM-CSF and TGF-beta1 levels increased continuously during the first week. In the other five ELGANs, no consistent changes were observed, We speculate, that in some ELGANs, a fetal systemic inflammatory response is characterized by an antenatal wave of pro-inflammatory cytokines, followed by a second, postnatal wave of anti-inflammatory cytokines. Large epidemiologic studies are needed to clarify relationships among inflammation markers and their expression in the fetal and neonatal circulation over time. Such studies would also add to our understanding of the possible role of inflammatory mediators in the pathophysiology of the major complications of extreme prematurity. (C) 2001 Academic Press. C1 Childrens Hosp, Neuroepidemiol Unit, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. William Beaumont Hosp, Royal Oak, MI 48073 USA. DeVos Childrens Hosp, Grand Rapids, MI 49503 USA. Univ Massachusetts, Sch Med, Worcester, MA 01655 USA. Univ N Carolina, Chapel Hill, NC 27599 USA. New England Med Ctr, Boston, MA 02111 USA. George Washington Univ, Med Ctr, Washington, DC 20037 USA. E Carolina Univ, Sch Med, Greenville, NC 27858 USA. Yale Univ, Sch Med, New Haven, CT 06520 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Michigan State Univ, Sparrow Hosp, E Lansing, MI 48823 USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC 27157 USA. NIH, DBEPS, ORS, Bethesda, MD 20892 USA. Univ Chicago, Chicago, IL 60637 USA. Childrens Hosp, Baystate Med Ctr, Springfield, MA 01199 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Dammann, O (reprint author), Childrens Hosp, Neuroepidemiol Unit, CA505,300 Longwood Ave, Boston, MA 02115 USA. NR 30 TC 61 Z9 63 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 1043-4666 J9 CYTOKINE JI Cytokine PD FEB 21 PY 2001 VL 13 IS 4 BP 234 EP 239 DI 10.1006/cyto.2000.0820 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 410CB UT WOS:000167421500006 PM 11237431 ER PT J AU Johnson, BE AF Johnson, BE TI Is more better? Chemotherapy for patients with extensive-stage small-cell lung cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID COLONY-STIMULATING FACTOR; PHASE-III; CISPLATIN; ETOPOSIDE C1 Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Adult Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Adult Oncol, Rm D1234,44 Binney St, Boston, MA 02115 USA. NR 8 TC 4 Z9 4 U1 0 U2 0 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 21 PY 2001 VL 93 IS 4 BP 254 EP 255 DI 10.1093/jnci/93.4.254 PG 2 WC Oncology SC Oncology GA 403NK UT WOS:000167049200002 PM 11181764 ER PT J AU Torre-Amione, G Young, JB Durand, JB Bozkurt, B Mann, DL Kobrin, I Pratt, CM AF Torre-Amione, G Young, JB Durand, JB Bozkurt, B Mann, DL Kobrin, I Pratt, CM TI Hemodynamic effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients with class III to IV congestive heart failure SO CIRCULATION LA English DT Article DE endothelin; hemodynamics; heart failure ID ETA-RECEPTOR; HYPERTROPHY; EXPRESSION; THERAPY; SYSTEM; VASOCONSTRICTION; HYPERTENSION; BLOCKADE; ET(A) AB Background--Endothelin-1, a powerful mediator of vasoconstriction, is increased in patients with congestive heart failure and appears to be a prognostic marker that strongly is correlated with the severity of disease. However, little is known about the potential immediate beneficial effects of acute blockade of the endothelin system in patients with symptomatic left ventricular dysfunction. We assessed the hemodynamic effects and safety of tezosentan, an intravenous dual endothelin receptor antagonist, in patients with moderate to severe heart failure. Methods and Results--This randomized placebo-controlled study evaluated the hemodynamic effects: of 6-hour infusions of tezosentan at 5, 20, 50, and 100 mg/h compared with placebo in 61 patients with New York Heart Association class III to IV heart failure. Plasma endothelin-l and tezosentan concentrations were also determined. Treatment with tezosentan caused a dose-dependent increase in cardiac index ranging from 24.4% to 49.9% versus 3.0% with placebo. Tezosentan also dose-dependently reduced pulmonary capillary wedge pressure and pulmonary and systemic vascular resistances, with no change in heart rate. No episodes of ventricular tachycardia or hypotension requiring drug termination were observed during tezosentan infusion. Tezosentan administration resulted in dose-related increased plasma endothelin-1 concentrations. Conclusions--The present study demonstrated that tezosentan can be safely administered to patients with moderate to severe heart failure and that by virtue of its ability to antagonize the effects of endothelin-l, it induced vasodilatory responses leading to a significant improvement in cardiac index. Further studies are under way to determine the clinical effects of tezosentan in the setting of acute heart failure. C1 Methodist Hosp, Winters Ctr Heart Failure Res, Eugene & Judith Campbell Labs Cardiac Transplanta, Houston, TX 77030 USA. Methodist Hosp, DeBakey Heart Ctr, Houston, TX 77030 USA. Baylor Coll Med, Houston VA Med Ctr, Houston, TX 77030 USA. Cleveland Clin Fdn, Kaufman Ctr Heart Failure, Cleveland, OH 44195 USA. Actel Ltd, Allschwil, Switzerland. RP Torre-Amione, G (reprint author), Baylor Coll Med, Texas Med Ctr, Cardiol Sect, 1 Baylor Plaza, Houston, TX 77030 USA. OI Mann, Douglas /0000-0002-2516-0145 NR 34 TC 80 Z9 87 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 FEB 20 PY 2001 VL 103 IS 7 BP 973 EP 980 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 412NV UT WOS:000167562000011 PM 11181472 ER PT J AU Chapman, RG Ostuni, E Liang, MN Meluleni, G Kim, E Yan, L Pier, G Warren, HS Whitesides, GM AF Chapman, RG Ostuni, E Liang, MN Meluleni, G Kim, E Yan, L Pier, G Warren, HS Whitesides, GM TI Polymeric thin films that resist the adsorption of proteins and the adhesion of bacteria SO LANGMUIR LA English DT Article ID SELF-ASSEMBLED MONOLAYERS; CARBOXYLIC ANHYDRIDE GROUPS; SURFACE-PLASMON RESONANCE; POLY(ETHYLENE GLYCOL); POLYETHYLENE GLYCOLS; SOLID-SURFACES; MODEL SYSTEM; BINDING; OXIDE); GOLD AB This paper describes the design and preparation of thin polymeric films that resist the adsorption of proteins and the adhesion of bacteria to an extent comparable to, or better than, self-assembled monolayers (SAMs) that present tri(ethylene glycol) groups. These polymeric films were prepared by the reaction of a polyamine, for example, poly(ethylenimine), with a SAM that presented interchain carboxylic anhydride groups, and by the subsequent conversion of the amino groups of the polymer to amido groups on reaction with acyl chlorides. Polyamines functionalized with acetyl chloride produced films that resisted the adsorption of protein and the adhesion of bacteria to a useful extent. Functionalization of the polyamine with acyl chlorides that were derivatives of oligo(ethylene glycol) resulted in films that were 1-10 times more resistant than those obtained by acetylation. The removal of hydrogen bond donor groups from the surface of the polyamines upon acylation seems to be important for the generation of films that resist the attachment of proteins and bacteria. C1 Harvard Univ, Dept Chem & Biol Chem, Cambridge, MA 02138 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dept Med, Boston, MA 02115 USA. Surface Logix Inc, Brighton, MA 02135 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Infect Dis Unit, Charlestown, MA 02129 USA. RP Whitesides, GM (reprint author), Harvard Univ, Dept Chem & Biol Chem, 12 Oxford St, Cambridge, MA 02138 USA. NR 56 TC 259 Z9 264 U1 7 U2 83 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD FEB 20 PY 2001 VL 17 IS 4 BP 1225 EP 1233 DI 10.1021/la001222d PG 9 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 403WC UT WOS:000167064600038 ER PT J AU Ay, I Sugimori, H Finklestein, SP AF Ay, I Sugimori, H Finklestein, SP TI Intravenous basic fibroblast growth factor (bFGF) decreases DNA fragmentation and prevents downregulation of Bcl-2 expression in the ischemic brain following middle cerebral artery occlusion in rats SO MOLECULAR BRAIN RESEARCH LA English DT Article DE basic fibroblast growth factor; apoptosis; focal ischemia; Bcl-2 ID PROGRAMMED CELL-DEATH; REDUCES INFARCT SIZE; HIPPOCAMPAL-NEURONS; FOCAL ISCHEMIA; BAX; APOPTOSIS; MODEL; MICE; REDUCTION; GLUTAMATE AB In previous studies, we showed that basic fibroblast growth factor (bFGF) reduced infarct volume when infused intravenously in animal models of focal cerebral ischemia. Tn the current study, we examined the potential mechanism of infarct reduction by bFGF, especially effects on apoptosis within the ischemic brain. We found that bFGF decreased DNA fragmentation in the ischemic hemisphere, as assessed by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) histochemical methods combined with morphological criteria, bFGF also prevented reduction of immunoreactivity of the anti-apoptotic protein Bcl-2 in the ischemic hemisphere, but did not alter immunoreactivity of the pro-apoptotic proteins Bax, Caspase-1, or Caspase-3. These changes in TUNEL histochemistry and Bcl-2 immunoreactivity were especially prominent in cortex at the borders ('penumbra') of infarcts, spared by bFGF treatment. We conclude that the infarct-reducing effects of bFGF may be due, in part, to prevention of downregulation of Bcl-2 expression and decreased apoptosis in the ischemic brain. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Massachusetts Gen Hosp, Dept Neurol, CNS Growth Factor Res Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Finklestein, SP (reprint author), Massachusetts Gen Hosp, Dept Neurol, CNS Growth Factor Res Lab, Boston, MA 02114 USA. NR 40 TC 43 Z9 45 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD FEB 19 PY 2001 VL 87 IS 1 BP 71 EP 80 DI 10.1016/S0169-328X(00)00285-0 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 406EP UT WOS:000167202200008 ER PT J AU Hettiaratchy, S Butler, PEM Lee, WPA AF Hettiaratchy, S Butler, PEM Lee, WPA TI Lessons from hand transplantations SO LANCET LA English DT Editorial Material C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Plast Surg, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA USA. Royal Free Hosp, Dept Plast Surg, London NW3 2QG, England. RP Lee, WPA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Plast Surg, Boston, MA 02114 USA. NR 7 TC 31 Z9 32 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD FEB 17 PY 2001 VL 357 IS 9255 BP 494 EP 495 DI 10.1016/S0140-6736(00)04037-X PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 402WT UT WOS:000167011700005 PM 11229664 ER PT J AU Xiao, YF Ke, QG Wang, SY Yang, YK Wang, GK Morgan, JP Leaf, A AF Xiao, YF Ke, QG Wang, SY Yang, YK Wang, GK Morgan, JP Leaf, A TI Point mutations in alpha-subunit of human cardiac Na+ channels alter Na+ current kinetics SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE human cardiac Na+ channel; alpha-subunit; point mutation; activation; inactivation ID POLYUNSATURATED FATTY-ACIDS; RAT VENTRICULAR MYOCYTES; SINGLE SODIUM-CHANNELS; LOCAL-ANESTHETICS; ANTIARRHYTHMIC DRUGS; INACTIVATION; BATRACHOTOXIN; RECEPTOR; CELLS; STATE AB Dietary polyunsaturated fatty acids (PUFAs) prevent ischemia-induced fatal cardiac arrhythmias in animals and probably in humans. This action results from inhibition of ion currents for Na+, Ca2+, and possibly other ions. To extend understanding of this protection we are seeking a possible binding site for the PUFAs on the alpha -subunit of the human cardiac Na+ channel, hH1(alpha), transiently expressed in HEK293t cells. Three mutated single amino acid substitutions with lysine were made in the alpha -subunit at Domain 4-Segment 6 (D4-S6) for F1760, Y1767 and at D1-S6 for N406. These are in the putative sites of binding of local anesthetics and batrachotoxin, respectively. The mutants F1760K, Y1767K, and N406K, separately and to different extents, affected the current density, the steady-state inactivation potential, accelerated inactivation, delayed recovery from inactivation, and affected voltage-dependent block, but did not affect activation of the hH1(alpha). It is essential to learn that single point mutations in D1-S6 and D4-S6 alone significantly modify the kinetics of human cardiac hH1(alpha) Na+ currents. The effects of PUFAs on these mutant channels will be the subject of subsequent reports. (C) 2001 Academic Press. C1 Beth Israel Deaconess Med Ctr, Charles A Dana Res Inst, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc, Harvard Thorndike Lab, Boston, MA 02215 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Brigham & Womens Hosp, Dept Anesthesia, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. SUNY Albany, Dept Biol, Albany, NY 12222 USA. RP Leaf, A (reprint author), Massachusetts Gen Hosp E, 149 13th St, Charlestown, MA 02129 USA. FU NHLBI NIH HHS [HL62284]; NIDA NIH HHS [DA11762]; NIDDK NIH HHS [DK38165]; NIGMS NIH HHS [GM35401] NR 29 TC 11 Z9 11 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 FEB 16 PY 2001 VL 281 IS 1 BP 45 EP 52 DI 10.1006/bbrc.2001.4309 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 404TM UT WOS:000167116900008 PM 11178958 ER PT J AU Bjorbaek, C Buchholz, RM Davis, SM Bates, SH Pierroz, DD Gu, H Neel, BG Myers, MG Flier, JS AF Bjorbaek, C Buchholz, RM Davis, SM Bates, SH Pierroz, DD Gu, H Neel, BG Myers, MG Flier, JS TI Divergent roles of SHP-2 in ERK activation by leptin receptors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TYROSINE-PHOSPHATASE SHP-2; OBESE GENE-PRODUCT; SIGNAL-TRANSDUCTION; OB/OB MICE; CYTOKINE RECEPTORS; NEUROPEPTIDE-Y; MESSENGER-RNA; DIABETIC MICE; OB RECEPTOR; DB/DB MICE AB The protein tyrosine phosphatase SHP-2 has been proposed to serve as a regulator of leptin signaling, but its specific roles are not fully examined. To directly investigate the role of SHP-2, we employed dominant negative strategies in transfected cells. We show that a catalytically inactive mutant of SHP-2 blocks leptin-stimulated ERK phosphorylation by the long leptin receptor, ObRb. SHP-2, lacking two C-terminal tyrosine residues, partially inhibits ERK phosphorylation. We find similar effects of the SHP-2 mutants after examining stimulation of an ERK-dependent egr-1 promoter-construct by leptin. We also demonstrate ERK phosphorylation and egr-1 mRNA expression in the hypothalamus by leptin. Analysis of signaling by ObRb lacking intracellular tyrosine residues or by the short leptin receptor, ObRa, enabled us to conclude that two pathways are critical for ERK activation. One pathway does not require the intracellular domain of ObRb, whereas the other pathway requires tyrosine residue 985 of ObRb. The phosphatase activity of SHP-2 is required for both pathways, whereas activation of ERK via Tyr-985 of ObRb also requires tyrosine phosphorylation of SHP-2. SHP-2 is thus a positive regulator of ERK by leptin receptors, and both the adaptor function and the phosphatase activity of SHP-2 are critical for this regulation. C1 Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Canc Biol Program, Boston, MA 02215 USA. Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Flier, JS (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol, 99 Brookline Ave, Boston, MA 02215 USA. RI Gu, Haihua/G-6364-2011 FU NCI NIH HHS [R01-CA-49152, CA72144]; NIDDK NIH HHS [DK-R37-28082, R01-DK-56731, DK-50693] NR 63 TC 233 Z9 247 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 FEB 16 PY 2001 VL 276 IS 7 BP 4747 EP 4755 DI 10.1074/jbc.M007439200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 428WH UT WOS:000168484300031 PM 11085989 ER PT J AU Stipp, CS Orlicky, D Hemler, ME AF Stipp, CS Orlicky, D Hemler, ME TI FPRP, a major, highly stoichiometric, highly specific CD81 and CD9-associated protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RECEPTOR REGULATORY PROTEIN; LEUKEMIA-VIRUS TYPE-1; MHC CLASS-II; TRANSMEMBRANE-4 SUPERFAMILY; CELL-SURFACE; MONOCLONAL-ANTIBODY; PLASMA-MEMBRANE; B-LYMPHOCYTES; T-CELLS; ANTIPROLIFERATIVE ANTIBODY-1 AB CD81 and CD9, members of the transmembrane-4 superfamily (TM4SF; tetraspanins), form extensive complexes with other TM4SF proteins, integrins, and other proteins, especially in mild detergents. In moderately stringent Brij 96 lysis conditions, CD81 and CD9 complexes are virtually identical to each other, but clearly distinct from other TM4SF complexes. One of the most prominent proteins within CD81 and CD9 complexes is identified here as FPRP, the 133-kDa prostaglandin F-2 alpha receptor regulatory protein. FPRP, a cell-surface Ig superfamily protein, associates specifically with CD81 or with CD81 and CD9, but not with integrins or other TM4SF proteins. In contrast to other CD81- and CD9-associating proteins, FPRP associates at very high stoichiometry, with essentially 100% of cell-surface FPRP on 293 cells being CD81- and CD9-associated. Also, CD81.CD9.FPRP complexes have a discrete size (<4 x 10(6) Da) as measured by gel permeation chromatography and remain intact after disruption of cholesterol-rich membrane microdomains by methyl--cyclodextrin. Although CD81 associated with both alpha (3) integrin and FPRP in 293 cells, the alpha (3)beta (1).CD81 and CD81.CD9.FPRP complexes were distinct, as determined by immunoprecipitation and immunodepletion experiments. In conclusion, our data affirm the existence of distinct TM4SF complexes with unique compositions and specifically characterize FPRP as the most robust, highly stoichiometric CD81- and/or CDS-associated protein yet described. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Univ Colorado, Hlth Sci Ctr, Ctr Canc, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Pathol, Denver, CO 80262 USA. RP Hemler, ME (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Rm D-1430,44 Binney St, Boston, MA 02115 USA. FU NIGMS NIH HHS [GM38903] NR 71 TC 98 Z9 100 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 FEB 16 PY 2001 VL 276 IS 7 BP 4853 EP 4862 DI 10.1074/jbc.M009859200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 428WH UT WOS:000168484300045 PM 11087758 ER PT J AU Armstrong, JM Chen, JF Schwarzschild, MA Apasov, S Smith, PT Caldwell, C Chen, P Figler, H Sullivan, G Fink, S Linden, J Sitkovsky, M AF Armstrong, JM Chen, JF Schwarzschild, MA Apasov, S Smith, PT Caldwell, C Chen, P Figler, H Sullivan, G Fink, S Linden, J Sitkovsky, M TI Gene dose effect reveals no G(s)-coupled A(2A) adenosine receptor reserve in murine T-lymphocytes: studies of cells from A(2A)-receptor-gene-deficient mice SO BIOCHEMICAL JOURNAL LA English DT Article DE apoptosis; cAMP; gene targeting; purinergic receptors; thymocytes ID PURINERGIC RECEPTOR; EXTRACELLULAR ATP; EXPRESSION; SPARE; INHIBITION; RESPONSES; ACTIVATION; DEFICIENCY; AGONISTS; SUBSETS AB Agonist binding to extracellular A(2A) adenosine receptors (A(2A)Rs) inhibits the activation of virtually all tested functions of T-cells and can induce apoptosis in thymocytes. The evaluation of levels of expression of these immunosuppressive receptors is expected to clarify whether the absence of spare A(2A)Rs (no 'receptor reserve') might be one of the mechanisms of attenuation of the effects of extracellular adenosine on T-cells. A(2A) transcript is found in T-cells and functional receptors can be demonstrated, but the density of receptor on T-cells is too low to be detected by radioligand binding. Studies of direct radioligand binding to murine brain with the selective A(2A)R agonist [H-3]CGS21680 (2-{4-[(2-carboxyethyl)-phenyl]ethylamino}-5'-N-ethylcarbox-amidoadenosine) established that striata levels of A(2A)R are virtually absent from A(2A) knock-out mice. Mice that are heterozygous (A(2A)R(+/-)) for the A(2A)R express significantly decreased levels of A(2A)R. To test for the presence of spare receptors in T-cells we took advantage of this gene dose effect and examined whether the decrease in the number of receptors in thymocytes from A(2A)R(+/-) mice was proportionately reflected in a decrease in the functional cAMP response of T-cells to adenosine. cAMP accumulation and apoptosis induced by adenosine and by A(2A)R agonist are of a lower magnitude in T-cells from A(2A)R(+/-) heterozygous mice than in T-cells from A(2A)R(+/+) littermate control mice. These results indicate that there is no A(2A)R reserve in murine T-cells. Strongly decreased adenosine-triggered cAMP increases were detected in thymocytes from A(2A)R(-/-) mice, suggesting that A(2A) adenosine receptors cannot fully compensate for the loss of A(2A)Rs in murine T-cells. We conclude that the number of A(2A)Rs is the limiting factor in determining the maximal cAMP response of T-lymphocytes to extracellular adenosine, thereby minimizing the immunosuppressive effects of extracellular adenosine. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20982 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurobiol Lab, Boston, MA 02129 USA. Univ Virginia, Hlth Sci Ctr, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA. RP Sitkovsky, M (reprint author), NIAID, Immunol Lab, NIH, Bethesda, MD 20982 USA. FU NIDA NIH HHS [DA07496] NR 36 TC 53 Z9 55 U1 0 U2 0 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD FEB 15 PY 2001 VL 354 BP 123 EP 130 DI 10.1042/0264-6021:3540123 PN 1 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 403ZR UT WOS:000167073400016 PM 11171087 ER PT J AU Gillessen, S Mach, N Small, C Mihm, M Dranoff, G AF Gillessen, S Mach, N Small, C Mihm, M Dranoff, G TI Overlapping roles for granulocyte-macrophage colony-stimulating factor and interleukin-3 in eosinophil homeostasis and contact hypersensitivity SO BLOOD LA English DT Article ID FACTOR-DEFICIENT MICE; PULMONARY ALVEOLAR PROTEINOSIS; LIGAND-TREATED MICE; GM-CSF; DENDRITIC CELLS; HEMATOPOIETIC-CELLS; ANTITUMOR IMMUNITY; LYMPHOID ORGANS; TRANSGENIC MICE; LUNG-DISEASE AB Studies of mice rendered deficient in granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) have established unique roles for these cytokines in pulmonary homeostasis, resistance to infection, and antigen-specific T- and B-cell responses, In addition to these distinctive properties, however, GM-CSF and IL-3 also stimulate the development and activation of hematopoietic cells in many similar ways, raising the possibility that each factor might partially compensate for the other's absence in singly deficient mice. To test whether endogenous GM-CSF and IL-3 mediate redundant functions in vivo, we generated mice lacking both cytokines through sequential gene targeting experiments in embryonic stem (ES) cells. Surprisingly, doubly deficient animals, but not single knockouts, showed increased numbers of circulating eosinophils, Doubly deficient mice, moreover, developed weaker contact hypersensitivity reactions to haptens applied epicutaneously then mice deficient in either factor alone. Together, these findings delineate overlapping roles for GM-CSF and IL-3 in hematopoiesis and immunity. (C) 2001 by The American Society of Hematology. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Univ Hosp Geneva, Dept Internal Med, Div Oncol, Geneva, Switzerland. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Dranoff, G (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Dana 510E,44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA74886] NR 55 TC 25 Z9 26 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 15 PY 2001 VL 97 IS 4 BP 922 EP 928 DI 10.1182/blood.V97.4.922 PG 7 WC Hematology SC Hematology GA 400HY UT WOS:000166867200018 PM 11159518 ER PT J AU Peyvandi, F Carew, JA Perry, DJ Hunault, M Khanduri, U Perkins, SJ Mannucci, PM Bauer, KA AF Peyvandi, F Carew, JA Perry, DJ Hunault, M Khanduri, U Perkins, SJ Mannucci, PM Bauer, KA TI Abnormal secretion and function of recombinant human factor VII as the result of modification to a calcium binding site caused by a 15-base pair insertion in the F7 gene SO BLOOD LA English DT Article ID BLOOD-COAGULATION FACTOR; TISSUE FACTOR; ENDOPLASMIC-RETICULUM; FACTOR-IX; DEFICIENCY; PROTEIN; MUTATIONS; IDENTIFICATION; DEGRADATION; PROTEASOME AB A case of a novel mutation in the F7 gene that results in factor VII coagulant activity (VII:c) of less than 1% and VII antigen (VII:Ag) levels of 10% is presented. DNA analysis revealed a homozygous 15-base pair (bp) in-frame insertion-type mutation at nucleotide 10554, This insertion consisted of a duplication of residues leucine (L)213 to aspartic acid (D)217 (leucine, serine, glutamic acid, histidine, and aspartic acid), probably arising by slipped mispairing between 2 copies of a direct repeat (GCGAGCACGAC) separated by 4 bp, Molecular graphic analyses showed that the insertion is located at the surface of the catalytic domain in an exposed loop stabilized by extensive salt-bridge and hydrogen bond formation at which the calcium binding site is located. The mutation probably interferes with protein folding during VII biosynthesis and/or diminishes functional activity through the loss of calcium binding, In vitro expression studies demonstrated that the levels of VII:Ag in lysates of cells transfected with wild type VII (VIIWT) were equivalent to those with mutant type VII (VIIMT), but the level of secreted VIIMT was 5% to 10% that of VIIWT. Pulse chase studies demonstrated that VIIMT did not accumulate intracellularly, and studies with inhibitors of protein degradation showed that recombinant VIIMT was partially degraded in the pre-Golgi compartment, Accordingly, only small amounts of VIIMT with undetectable procoagulant activity were secreted into conditioned media. These results demonstrate that a combination of secretion and functional defects is the mechanism whereby this insertion causes VII deficiency. (C) 2001 by The American Society of Hematology. C1 IRCCS, Maggiore Hosp, Angelo Bianchi Bonomi Hemophilia & Thrombosis Ctr, Milan, Italy. Harvard Univ, Sch Med, VA Boston Healthcare Syst, Dept Med,Hematol Sect, Boston, MA 02115 USA. Univ Milan, I-20122 Milan, Italy. UCL Royal Free & Univ Coll Med Sch, Dept Hematol, Hemophilia Ctr, London, England. UCL Royal Free & Univ Coll Med Sch, Dept Hematol, Hemostasis Unit, London, England. UCL Royal Free & Univ Coll Med Sch, Dept Biochem & Mol Biol, London, England. Sultan Qaboos Univ, Coll Med, Dept Hematol, Muscat, Oman. RP Peyvandi, F (reprint author), Angelo Bianchi Bonomi Hemophilia & Thrombosis Ctr, Via Pace 9, I-20122 Milan, Italy. EM flora.peyvandi@unimi.it RI Mannucci, Pier/C-3102-2014; OI Peyvandi, Flora/0000-0001-7423-9864 NR 26 TC 13 Z9 14 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 FEB 15 PY 2001 VL 97 IS 4 BP 960 EP 965 DI 10.1182/blood.V97.4.960 PG 6 WC Hematology SC Hematology GA 400HY UT WOS:000166867200023 PM 11159523 ER PT J AU Arico, M Imashuku, S Clementi, R Hibi, S Teramura, T Danesino, C Haber, DA Nichols, KE AF Arico, M Imashuku, S Clementi, R Hibi, S Teramura, T Danesino, C Haber, DA Nichols, KE TI Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene SO BLOOD LA English DT Article ID ENCODING GENE; HETEROGENEITY; INFECTION; XLP AB The hemophagocytic lymphohistiocytoses (HLH) comprise a heterogeneous group of disorders characterized by dysregulated activation of T cells and macrophages, Although some patients with HLH harbor perforin gene mutations, the cause of the remaining cases is not known. The phenotype of HLH bears a strong resemblance to X-linked lymphoproliferative disease (XLP), an Epstein-Barr virus (EBV)- associated immunodeficiency resulting from defects in SH2D1A, a small SH2 domain-containing protein expressed in T lymphocytes and natural killer cells. Here it is shown that 4 of 25 male patients with HLH who were examined harbored germline SH2D1A mutations. Among these 4 patients, only 2 had family histories consistent with XLP. On the basis of these findings, it is suggested that all male patients with EBV-associated hemophagocytosis be screened for mutations in SH2D1A, Patients identified as having XLP should undergo genetic counseling, and be followed long-term for development of lymphoma and hypogammaglobulinemia. C1 Childrens Hosp Philadelphia, Div Pediat Oncol, Philadelphia, PA 19104 USA. IRCCS, Policlin S Matteo, Dept Pediat, Pavia, Italy. Kyoto Prefectural Univ Med, Childrens Res Hosp, Kyoto, Japan. Univ Pavia, I-27100 Pavia, Italy. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Nichols, KE (reprint author), Childrens Hosp Philadelphia, Div Pediat Oncol, 34th St & Civ Ctr Blvd, Philadelphia, PA 19104 USA. FU NIAID NIH HHS [K11-AI01331]; Telethon [E.0755] NR 20 TC 105 Z9 116 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 15 PY 2001 VL 97 IS 4 BP 1131 EP 1133 DI 10.1182/blood.V97.4.1131 PG 3 WC Hematology SC Hematology GA 400HY UT WOS:000166867200047 PM 11159547 ER PT J AU Dias, SD Rudd, CE AF Dias, SD Rudd, CE TI CTLA-4 blockade of antigen-induced cell death SO BLOOD LA English DT Article ID T-LYMPHOCYTE ANTIGEN-4; MULTIORGAN TISSUE DESTRUCTION; CLATHRIN-ASSOCIATED PROTEIN; TYROSINE PHOSPHORYLATION; IN-VIVO; PHOSPHATIDYLINOSITOL 3-KINASE; CTLA-4-DEFICIENT MICE; CUTTING EDGE; ACTIVATION; INDUCTION AB While cytotoxic T lymphocyte antigen-4 (CTLA-4) negatively regulates T-cell receptor (TCR)-driven interleukin (IL)-2 production and proliferation, little is known regarding whether the coreceptor has the capacity to inhibit other events, such as Fas ligand (FasL) expression and antigen- induced cell death (AICD), In this study, it is shown that CTLA-4 expressed in a T-cell hybridoma can elicit a potent block of fasL expression end AICD, Inhibition occurred independently of CTLA-4 blockage of IL-2 production and was partially reversed by a single mutation in the cytoplasmic YVKM motif. These findings indicate that CTLA-4 can block TCR signaling prior to bifurcation of signals leading to IL-2 production end apoptosis. C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Div Tumor Immunol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Rudd, CE (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Div Tumor Immunol, 44 Binney St, Boston, MA 02115 USA. NR 44 TC 19 Z9 19 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 FEB 15 PY 2001 VL 97 IS 4 BP 1134 EP 1137 PG 4 WC Hematology SC Hematology GA 400HY UT WOS:000166867200048 ER PT J AU Goggins, WB Finkelstein, DM Tsao, H AF Goggins, WB Finkelstein, DM Tsao, H TI Evidence for an association between cutaneous melanoma and non-Hodgkin lymphoma SO CANCER LA English DT Article DE cutaneous melanoma; non-Hodgkin lymphoma; SEER; second cancer ID MALIGNANT-MELANOMA; PANCREATIC-CANCER; ULTRAVIOLET-RADIATION; DEATH-CERTIFICATE; UNITED-STATES; SKIN-CANCER; 2ND CANCERS; RISK; OCCUPATION; SWEDEN AB BACKGROUND. Over the past 2 decades both cutaneous melanoma (CM) and non-Hodgkin lymphoma (NHL) incidence rates have increased substantially. One approach to better understanding the etiologic basis for these increases is to examine the risk of NHL in CM survivors and the risk of CM in NHL survivors. METHODS. To explore the possible association between CM and NHL, the authors followed cohorts of CM and NHL patients registered through the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program between 1973 and 1996 and identified patients who developed CM after NHL and NHL after CM. The number of observed cases then were compared with the number of expected cases to see if CM survivors were at an increased risk of NI-IL or if NHL survivors were at an increased risk of CM. RESULTS. Between 1973 and 1996, 54,803 CM patients and 62,597 NHL patients who met the authors' inclusion criteria were identified through SEER. The authors found statistically significant elevated risks of NHL among CM survivors (standardized incidence ratio [SIR], 1.42; 95% confidence interval [CI], 1.23-1.63) and CM among NHL survivors (SIR, 1.75; 95% CI, 1.48-2.07). CONCLUSIONS. These results support an association between CM and NHL. Although detection bias and posttherapy effects may explain part of this association, shared genetic or etiologic factors, such as sunlight exposure, also may play a role. (C) 2001 American Cancer Society. C1 Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. Hong Kong Baptist Univ, Dept Math, Kowloon, Hong Kong, Peoples R China. Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Melanoma Ctr, Div Oncol, Boston, MA 02114 USA. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Bartlett 622,48 Blossom St, Boston, MA 02114 USA. NR 48 TC 43 Z9 43 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD FEB 15 PY 2001 VL 91 IS 4 BP 874 EP 880 DI 10.1002/1097-0142(20010215)91:4<874::AID-CNCR1076>3.0.CO;2-O PG 7 WC Oncology SC Oncology GA 403TD UT WOS:000167057800035 PM 11241258 ER PT J AU Musher, DM Mediwala, R Phan, HM Chen, G Baughn, RE AF Musher, DM Mediwala, R Phan, HM Chen, G Baughn, RE TI Nonspecificity of assaying for IgG antibody to pneumolysin in circulating immune complexes as a means to diagnose pneumococcal pneumonia SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID COMMUNITY-ACQUIRED PNEUMONIA; STREPTOCOCCUS-PNEUMONIAE; ETIOLOGY; POLYSACCHARIDE; INFECTIONS; CHILDREN; VACCINE; TRIAL AB Detection of immunoglobulin G (IgG) antibody to pneumolysin (PLY) in precipitated circulating immune complexes (CICs) has been used to diagnose pneumococcal pneumonia. With care to include appropriate controls, we precipitated and dissociated CICs and then assayed for IgG antibody to PLY. We detected IgG antibody to PLY in CICs that were precipitated from serum samples that were obtained at the time of admission to the hospital from 5 (23%) of 22 healthy adults, 7 (44%) of 16 subjects with stable chronic obstructive pulmonary disease, 10 (63%) of 16 subjects colonized with Streptococcus pneumoniae, and 9 (60%) of 15 patients with nonbacteremic pneumococcal pneumonia. Of the 16 patients with bacteremic pneumococcal pneumonia, 4 (25%) had IgG antibody to PLY at the time of admission, and 8 (50%) had IgG antibody to PLY in convalescence. Levels of IgG antibody in CICs closely correlated with serum levels of IgG antibody to PLY, implicating precipitation of free serum antibody in tests with false-positive results. Detection of IgG antibody to PLY in precipitated CICs is not a reliable method for diagnosing pneumococcal pneumonia. C1 Houston Vet Affairs Med Ctr, Med Serv, Infect Dis Sect, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Baylor Coll Med, Dept Microbiol Immunol, Houston, TX 77030 USA. Baylor Coll Med, Dept Dermatol, Houston, TX 77030 USA. RP Musher, DM (reprint author), Houston Vet Affairs Med Ctr, Med Serv, Infect Dis Sect, 111G,Room 4B-370,2002 Holcombe Blvd, Houston, TX 77030 USA. NR 23 TC 28 Z9 28 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD FEB 15 PY 2001 VL 32 IS 4 BP 534 EP 538 DI 10.1086/318709 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 400DX UT WOS:000166857900002 PM 11181114 ER PT J AU Mootha, VK Wei, MC Buttle, KF Scorrano, L Panoutsakopoulou, V Mannella, CA Korsmeyer, SJ AF Mootha, VK Wei, MC Buttle, KF Scorrano, L Panoutsakopoulou, V Mannella, CA Korsmeyer, SJ TI A reversible component of mitochondrial respiratory dysfunction in apoptosis can be rescued by exogenous cytochrome c SO EMBO JOURNAL LA English DT Article DE apoptosis; cytochrome c; Fas; mitochondria ID BCL-X-L; CELL-DEATH; PERMEABILITY TRANSITION; OUTER-MEMBRANE; PROTEASE CASCADE; MAMMALIAN-CELLS; BAX; RELEASE; PATHWAY; INHIBITION AB Multiple apoptotic pathways release cytochrome c from the mitochondrial intermembrane space, resulting in the activation of downstream caspases. In vivo activation of Fas (CD95) resulted in increased permeability of the mitochondrial outer membrane and depletion of cytochrome c stores. Serial measurements of oxygen consumption, NADH redox state and membrane potential revealed a loss of respiratory state transitions, This tBID-induced respiratory failure did not require any caspase activity. At early time points, re-addition of exogenous cytochrome c markedly restored respiratory functions. Over time, however, mitochondria showed increasing irreversible respiratory dysfunction as well as diminished calcium buffering. Electron microscopy and tomographic reconstruction revealed asymmetric mitochondria with blebs of herniated matrix, distended inner membrane and partial loss of cristae structure. Thus, apoptogenic redistribution of cytochrome c is responsible for a distinct program of mitochondrial respiratory dysfunction, in addition to the activation of downstream caspases. 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. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. New York State Dept Hlth, Wadsworth Ctr Labs & Res, Resource Visualizat Biol Complex, Albany, NY 12201 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. RI Scorrano, Luca/A-6652-2008; OI Scorrano, Luca/0000-0002-8515-8928; Panoutsakopoulou, Vily/0000-0002-1569-1508 FU NCCIH NIH HHS [5T32AT09361]; NCI NIH HHS [CA50239-13, R01 CA050239, R37 CA050239]; NCRR NIH HHS [P41 RR001219, RR01219] NR 60 TC 119 Z9 126 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD FEB 15 PY 2001 VL 20 IS 4 BP 661 EP 671 DI 10.1093/emboj/20.4.661 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 404FR UT WOS:000167087200004 PM 11179211 ER PT J AU Johnson, FB Marciniak, RA McVey, M Stewart, SA Hahn, WC Guarente, L AF Johnson, FB Marciniak, RA McVey, M Stewart, SA Hahn, WC Guarente, L TI The Saccharomyces cerevisiae WRN homolog Sgs1p participates in telomere maintenance in cells lacking telomerase SO EMBO JOURNAL LA English DT Article DE ALT; replicative senescence; SGS1; telomeres; Werner syndrome ID WERNER-SYNDROME PROTEIN; ROTHMUND-THOMSON-SYNDROME; SYNDROME DNA HELICASE; SYNDROME GENE; LIFE-SPAN; CELLULAR IMMORTALIZATION; FUNCTIONAL INTERACTION; MOUSE TELOMERASE; BLOOMS-SYNDROME; YEAST AB Werner syndrome (WS) is marked by early onset of features resembling aging, and is caused by loss of the RecQ family DNA helicase WRN. Precisely how loss of WRN leads to the phenotypes of WS is unknown. Cultured WS fibroblasts shorten their telomeres at an increased rate per population doubling and the premature senescence this loss induces can be bypassed by telomerase. Here we show that WRN co-localizes with telomeric factors in telomerase-independent immortalized human cells, and further that the budding yeast RecQ family helicase Sgs1p influences telomere metabolism in yeast cells lacking telomerase. Telomerase-deficient sgs1 mutants show increased rates of growth arrest in the G(2)/M phase of the cell cycle as telomeres shorten. In addition, telomerase-deficient sgs1 mutants have a defect in their ability to generate survivors of senescence that amplify telomeric TG(1-3) repeats, and SGS1 functions in parallel with the recombination gene RAD51 to generate survivors. Our findings indicate that Sgs1p and WRN function in telomere maintenance, and suggest that telomere defects contribute to the pathogenesis of WS and perhaps other RecQ helicase diseases. C1 68280 MIT, Dept Biol, Cambridge, MA 02139 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA USA. RP Guarente, L (reprint author), 68280 MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RI Stewart, Sheila/C-5213-2012 NR 63 TC 183 Z9 188 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD FEB 15 PY 2001 VL 20 IS 4 BP 905 EP 913 DI 10.1093/emboj/20.4.905 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 404FR UT WOS:000167087200027 PM 11179234 ER PT J AU Oberley, TD Verwiebe, E Zhong, WX Kang, SW Rhee, SG AF Oberley, TD Verwiebe, E Zhong, WX Kang, SW Rhee, SG TI Localization of the thioredoxin system in normal rat kidney SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE thioredoxin; thioredoxin reductase; peroxiredoxin; reactive oxygen species; kidney; free radicals ID LEUKEMIA-DERIVED FACTOR; DNA-BINDING ACTIVITY; MAMMALIAN PEROXIREDOXIN; REDOX REGULATION; GROWTH-FACTOR; ANTIOXIDANT ENZYMES; HYDROGEN-PEROXIDE; REDUCTASE; CELLS; SELENOCYSTEINE AB Components of the thioredoxin system were localized in normal rat kidney using immunoperoxidase techniques at the light microscopic level and immunogold techniques at the ultrastructural level. Results from both methods were similar. Thioredoxin, thioredoxin reductases, and peroxiredoxins showed cell-type-specific localization, with the same cell types (proximal and distal tubular epithelial, papillary collecting duct, and transitional epithelial cells) previously identified as having high amounts of antioxidant enzyme immunoreactive proteins and oxidative damage products also having high levels of proteins of the thioredoxin system. In addition, peroxiredoxins II and IV were found in high levels in the cytoplasm of red blood cells, identified in kidney blood vessels. While thioredoxin and thioredoxin reductase 1 were found in all subcellular locations in kidney cells, thioredoxin reductase 2 was found predominantly in mitochondria. Thioredoxin reductase 1 was identified in rat plasma, suggesting it is a secreted protein. Peroxiredoxins often had specific subcellular locations, with peroxiredoxins III and V found in mitochondria and peroxiredoxin IV found in lysosomes. Our results emphasize the complex nature of the thioredoxin system, demonstrating unique cell-type and organelle specificity. (C) 2001 Elsevier Science Inc. C1 William S Middleton Mem Vet Hosp, Pathol & Lab Med Serv, Madison, WI 53705 USA. Univ Wisconsin, Sch Med, Dept Pathol & Lab Med, Madison, WI USA. NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. RP Oberley, TD (reprint author), William S Middleton Mem Vet Hosp, Pathol & Lab Med Serv, 2500 Overlook Terrace,Room A35, Madison, WI 53705 USA. NR 56 TC 89 Z9 89 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD FEB 15 PY 2001 VL 30 IS 4 BP 412 EP 424 DI 10.1016/S0891-5849(00)00486-X PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 401YD UT WOS:000166955900009 PM 11182297 ER PT J AU Rottkamp, CA Raina, AK Zhu, XW Gaier, E Bush, AI Atwood, CS Chevion, M Perry, G Smith, MA AF Rottkamp, CA Raina, AK Zhu, XW Gaier, E Bush, AI Atwood, CS Chevion, M Perry, G Smith, MA TI Redox-active iron mediates amyloid-beta toxicity SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE amyloid-beta; Alzheimer disease; free radicals; iron; neurotoxicity; oxidative stress ID ALZHEIMERS-DISEASE; FREE-RADICALS; A-BETA; PROTEIN; AGGREGATION; PEPTIDE; DEPOSITION; OXIDATION AB While amyloid-beta toxicity is mediated by oxidative stress and can be attenuated by antioxidants, the actual biochemical mechanism underlying neurotoxicity remains to be established. However, since aggregated amyloid-beta can interact with transition metals, such as iron, both in vitro and in vivo, we suspected that bound iron might be the mediator of toxicity such that holo- and apo-amyloid would have differential effects on cellular viability. Here we demonstrate that when amyloid-beta is pretreated with the iron chelator deferoxamine, neuronal toxicity is significantly attenuated while conversely, incubation of holo-amyloid-beta with excess free iron restores toxicity to original levels. These data, taken together with the known sequelae of amyloid-beta, suggest that the toxicity of amyloid-beta is mediated, at least in part, via redox-active iron that precipitates lipid peroxidation and cellular oxidative stress. (C) 2001 Elsevier Science Inc. C1 Case Western Reserve Univ, Inst Pathol, Cleveland, OH 44106 USA. Massachusetts Gen Hosp, Harvard Med Sch, Lab Oxidat Biol, Charlestown, MA USA. Hebrew Univ Jerusalem, Hadassah Med Sch, IL-91010 Jerusalem, Israel. Hebrew Univ Jerusalem, Hadassah Sch Dent Med, IL-91010 Jerusalem, Israel. RP Smith, MA (reprint author), Case Western Reserve Univ, Inst Pathol, 2085 Adelbert Rd, Cleveland, OH 44106 USA. RI Smith, Mark/A-9053-2009; Zhu, Xiongwei/A-9629-2009; Perry, George/A-8611-2009; Bush, Ashley/A-1186-2007 OI Perry, George/0000-0002-6547-0172; Bush, Ashley/0000-0001-8259-9069 FU NINDS NIH HHS [NS38648] NR 20 TC 257 Z9 268 U1 1 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD FEB 15 PY 2001 VL 30 IS 4 BP 447 EP 450 DI 10.1016/S0891-5849(00)00494-9 PG 4 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 401YD UT WOS:000166955900012 PM 11182300 ER PT J AU Rieger, DK Reichenberger, E McLean, W Sidow, A Olsen, BR AF Rieger, DK Reichenberger, E McLean, W Sidow, A Olsen, BR TI A double-deletion mutation in the Pitx3 gene causes arrested lens development in aphakia mice SO GENOMICS LA English DT Article ID LIM-DOMAIN; HOMEOBOX GENE; MOUSE GENOME; EYE DEVELOPMENT; CHROMOSOMAL LOCALIZATION; TRANSCRIPTION FACTOR; KAPPA-B; FAMILY; EXPRESSION; MAP AB The recessive aphakia (ak) mouse mutant is characterized by bilateral microphthalmia due to a failure of lens morphogenesis. We fine-mapped the ak locus to the interval between D19Umil and D19Mit9, developed new polymorphic markers, and mapped candidate genes by construction of a BAC contig. The Pitx3 gene, known to be expressed in lens primordia, shows zero recombination with the ak mutation on our inter-subspecific intercross panel representing 1170 meioses. A recent report described a deletion in the intergenic region between Gbf1 and Pitx3 as the possible ak mutation. Our results differ in that we find not only the distant intergenic deletion, but also a much larger deletion directly in the Pitx3 gene, eliminating exon 1 and extending into intron 1 and the promoter region. Pitx3 transcript levels are severely reduced in ak/ak mice from E11.5 to newborn (5 +/- 1% of the wildtype levels at E13.5), while an involvement of the flanking Gbf1 and Cig30 genes in the aberrant lens development is highly unlikely based on expression analysis. We conclude that the ak mutation consists of two deletions, the larger of which removes part of Pitx3, indicating a crucial role of this gene in early lens development. (C) 2001 Academic Press. C1 Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Harvard Univ, Sch Dent Med, Harvard Forsyth Dept Oral Biol, Boston, MA 02115 USA. Forsyth Inst, Boston, MA 02115 USA. SUMC R248B, Dept Pathol, Stanford, CA 94305 USA. SUMC R248B, Dept Genet, Stanford, CA 94305 USA. RP Rieger, DK (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, 240 Longwood Ave, Boston, MA 02115 USA. FU NEI NIH HHS [1 F32 EY07020-01]; NIAMS NIH HHS [AR36820, AR36819] NR 63 TC 98 Z9 100 U1 0 U2 2 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 FEB 15 PY 2001 VL 72 IS 1 BP 61 EP 72 DI 10.1006/geno.2000.6464 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 412KN UT WOS:000167553700007 PM 11247667 ER PT J AU Schwartz, CL Thompson, EB Gelber, RD Young, ML Chilton, D Cohen, HJ Sallan, SE AF Schwartz, CL Thompson, EB Gelber, RD Young, ML Chilton, D Cohen, HJ Sallan, SE TI Improved response with higher corticosteroid dose in children with acute lymphoblastic leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CELL LINE; C-MYC; DEXAMETHASONE; SUPPRESSION AB Purpose: We investigated whether there was a dose-response relationship for the use of corticosteroids in childhood acute lymphoblastic leukemia (ALL). Patients and Methods: Three hundred sixty-nine patients, ages 1 to 18 years with ALL, were randomly assigned to receive one of four different doses of corticosteroid (prednisolone 40 mg/m(2)/d or dexamethasone 6, 18, or 150 mg/m(2)/d) administered as a 3-day, single-drug window before initiation of standard, multidrug induction chemotherapy. Corticosteroid drug response was measured by reduction in bone marrow blast counts and absolute peripheral blast counts after 3 days. Glucocarticoid receptor (GCR) number and the effective concentration of dexamethasone resulting in a 50% reduction of leukemic cell viability in vitro (EC-50) were evaluated at days 0 and 3. Results: Increasing dexamethasone doses resulted in greater marrow blast response (P = .007), with a similar trend in peripheral-blood blast response. High-dose carticosteroid regimens (dexamethasone 18 or 150 mg/m2/d) elicited better responses than standard doses of dexamethasone or prednisone (bone marrow, P = .002; peripheral blasts, P = .05). Among patients treated with standard-dose corticosteroids, 38% with resistant (EC-50 > 10(-7)) peripheral blasts had a good response compared with 92% with sensitive (EC-50 < 10(-7)) peripheral blasts (P = .01). In contrast, there was no differential response according to EC-50 group after high-dose corticosteroids. Similarly, an association between response and GCR on peripheral-blood blasts was noted after standard-dose corticosteroid regimens but not after high-dose corticosteroid regimens. Conclusion: Response of ALL to glucacorticoid therapy increased with dose. Higher-dose corticosteroid treatment abrogated the effect of relative drug insensitivity and of low GCR on peripheral blasts. C1 Johns Hopkins Oncol Ctr, Div Pediat Oncol CMC800, Baltimore, MD 21287 USA. Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. Univ Texas, Med Branch, Galveston, TX 77550 USA. Stanford Univ, Med Ctr, Palo Alto, CA 94304 USA. RP Schwartz, CL (reprint author), Johns Hopkins Oncol Ctr, Div Pediat Oncol CMC800, 600 N Wolfe St, Baltimore, MD 21287 USA. FU NCI NIH HHS [CA06516, CA68484] NR 15 TC 49 Z9 53 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 15 PY 2001 VL 19 IS 4 BP 1040 EP 1046 PG 7 WC Oncology SC Oncology GA 406MH UT WOS:000167219400016 PM 11181667 ER PT J AU Earle, CC Tsai, JS Gelber, RD Weinstein, MC Neumann, PJ Weeks, JC AF Earle, CC Tsai, JS Gelber, RD Weinstein, MC Neumann, PJ Weeks, JC TI Effectiveness of chemotherapy for advanced lung cancer in the elderly: Instrumental variable and propensity analysis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; HEALTH-CARE; ADMINISTRATIVE DATABASES; DEMAND; WEAK AB Purpose: To compare the effectiveness of chemotherapy given to elderly patients in routine practice for stage IV non-small-cell lung cancer (NSCLC) with the efficacy observed in randomized trials. Patients and Methods: We used instrumental variable analysis (IVA) and propensity scores (PS) to simulate the conditions of a randomized trial in a retrospective cohort of patients over age 65 from the Survival, Epidemiology, and End Results (SEER) tumor registry. Geographic variation in chemotherapy use served as the instrument for the IVA analysis, and propensity scores were calculated with a logistic model based on patient disease and sociodemographic characteristics. Results: Among 6,232 elderly patients, the instrumental variable estimate indicated an increase in median survival of 33 days and an improvement in I-year survival of 9% attributable to chemotherapy. In a Cox regression model, chemotherapy administration was associated with a hazard ratio of 0.81 (95% confidence interval, 0.76 to 0.85). When survival was analyzed separately within propensity score quintiles, the hazard ratios were all similar, ranging from 0.78 to 0.85. These results are comparable with those of a large meta-analysis, which found a hazard ratio of 0.87 in the subgroup of patients over age 65. Conclusion: Chemotherapy for stage IV NSCLC seems to have effectiveness for elderly patients and those with comorbid conditions that is similar to the efficacy seen in randomized trials containing mostly younger, highly selected patients. All suitable patients should be given the opportunity to consider palliative chemotherapy for metastatic NSCLC. C1 Dana Farber Canc Ctr, Ctr Outcomes & Policy Res, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Dana Farber Canc Ctr, Ctr Outcomes & Policy Res, Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Ctr Risk Anal, Program Econ Evaluat Med Technol, Boston, MA 02115 USA. RP Earle, CC (reprint author), Dana Farber Canc Ctr, Ctr Outcomes & Policy Res, Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA 72663] NR 32 TC 166 Z9 177 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 15 PY 2001 VL 19 IS 4 BP 1064 EP 1070 PG 7 WC Oncology SC Oncology GA 406MH UT WOS:000167219400019 PM 11181670 ER PT J AU Forastiere, AA Leong, T Rowinsky, E Murphy, BA Vlock, DR DeConti, RC Adams, GL AF Forastiere, AA Leong, T Rowinsky, E Murphy, BA Vlock, DR DeConti, RC Adams, GL TI Phase III comparison of high-dose paclitaxel plus cisplatin plus granulocyte colony-stimulating factor versus low-dose paclitaxel plus cisplatin in advanced head and neck cancer: Eastern Cooperative Oncology Group Study E1393 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 33rd Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 17-21, 1997 CL DENVER, COLORADO SP Amer Soc Clin Oncol ID SQUAMOUS-CELL CARCINOMA; METHOTREXATE; FLUOROURACIL; TOXICITY AB Purpose: To determine dose-response effects and the activity of paclitaxel combined with cisplatin in patients with incurable squamous cell carcinoma of the head and neck. Patients and Methods: Two hundred ten patients with locally advanced, recurrent, or metastatic disease were randomly placed in either Arm A, paclitaxel 200 mg/m(2) (24-hour infusion) + cisplatin 75mg/m(2) + granulocyte colony-stimulating factor, or Arm B, paclitaxel 135 mg/m(2) (24-hour infusion) + cisplatin 75 mg/m(2). Cycles were repeated every 3 weeks until progression or a total of 12 cycles for complete responses. Primary outcomes were event-free and overall survival. Results: No significant differences in outcomes were observed between the high- and low-dose paclitaxel regimens. The estimated median survival was 7.3 months (95% confidence interval, 6.0 to 8.6). The 1-year survival rate was 29%, and event-free survival was 4.0 months. The objective response rate (complete response plus partial response) war 35% for the high-dose patients and 36% for the low-dose patients. Myelosuppression was the most frequent toxicity: grade 3 or 4 granulocytopenia, 70% of patients in Arm A and 78% in Arm a; febrile neutropenia, 27% of patients in Arm A and 39% in Arm a. Grade 5 toxicities occurred in 22 patients (10.5%). Treatment was terminated early in 31% because of excessive toxicity or patient refusal. Conclusion: This phase III multicenter trial showed (1) no advantage for high-dose paclitaxel and (2) excessive hematologic toxicity associated with both regimens. Therefore, neither of the paclitaxel regimens evaluated in this trial can be recommended. C1 Johns Hopkins Oncol Ctr, Baltimore, MD 21205 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Vanderbilt Univ, Nashville, TN USA. Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. Fairview Univ, Med Ctr, Minneapolis, MN USA. RP Forastiere, AA (reprint author), Johns Hopkins Oncol Ctr, Bunting Blaustein Canc Res Bldg,1650 Orleans St, Baltimore, MD 21205 USA. FU NCI NIH HHS [CA16116, CA20365, CA21115, CA23318, CA49957, CA66636] NR 17 TC 107 Z9 107 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 15 PY 2001 VL 19 IS 4 BP 1088 EP 1095 PG 8 WC Oncology SC Oncology GA 406MH UT WOS:000167219400022 PM 11181673 ER PT J AU Posner, MR Glisson, B Frenette, G Al-Sarraf, M Colevas, AD Norris, CM Seroskie, JD Shin, DM Olivares, R Garay, CA AF Posner, MR Glisson, B Frenette, G Al-Sarraf, M Colevas, AD Norris, CM Seroskie, JD Shin, DM Olivares, R Garay, CA TI Multicenter phase I-II trial of docetaxel, cisplatin, and fluorouracil induction chemotherapy for patients with locally advanced squamous cell cancer of the head and neck SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ADVANCED LARYNGEAL CARCINOMA; HIGH-DOSE LEUCOVORIN; RANDOMIZED TRIAL; ORGAN PRESERVATION; ONCOLOGY-GROUP; 5-FU INFUSION; SURVIVAL; THERAPY; RECURRENT AB Purpose: We conducted a phase I-II, multi-institutional trial to determine the maximum-tolerated dose (MTD) of cisplatin in an induction chemotherapy regimen of docetaxel, cisplatin, and fluorouracil for squamous cell cancer of the head and neck (SCCHN) and to determine the safety, tolerability, and efficacy of the regimen at MTD. Patients and Methods: A total of 43 patients with previously untreated, locally advanced, curable SCCHN were entered. Overall, 29 patients (67%) had N2 or N3 nodal disease and nine (21%) had T4 primary tumors. All patients received docetaxel 75 mg/m(2) on day 1; cisplatin at 75 (level I) or 100 (level II) mg/m2 on day 1; and a continuous flourouracil infusion at 1,000 mg/m(2)/d on days 1 through 4. Patients were treated with prophylactic antibiotics on days 5 through 15. Cycles were repeated every 21 days for a total of three cycles. Patients then received definitive therapy based on institutional preferences. Results: Thirteen patients were treated at level I, and 30 patients were treated at level II. All 43 patients were assessable for toxicity. There were no major differences in toxicity between level I and level II. Cisplatin-associated grade 3 or 4 hypomagnesemia or hypocalcemia occurred in 13 (30%) and hearing lass in two patients (5%). Grade 3 or 4 neutropenia was observed in 41 patients (95%) and febrile neutropenia occurred in eight (19%). There was one serious infection (2%). There were 17 (40% [95% confidence interval [CI], 25% to 56%]) clinical complete responders (CR), 23 (54% [95% CI, 39% to 69%]) partial responders (PR), one (2%) with no change, and two (5%) unassessable patients. Major responses (CR, PR) were abserved in 40 (93% [95% CI, 81% to 99%]) patients. Primary site CR was documented in 24 (54%) of patients. Postchematherapy primary site biopsies were performed in 25 patients (58%) and pathologically negative biopsy was obtained in 11 (92%) of 12 primary site clinical CRs and seven (54%) of 13 with PR or no change. Overall, negative biopsies were obtained in 18 patients (72%). Conclusion: TPF induction chemotherapy can be delivered safely with a cisplatin dose of 100 mg/m2 in previously untreated patients with SCCHN. The regimen is associated with ct high rate of primary site clinical and pathologic CRs. Phase III comparison with cisplatinum and fluorouracil chemotherapy is warranted. C1 Dana Farber Canc Inst, Head & Neck Oncol Program, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg, Boston, MA 02115 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Blumenthal Canc Ctr, Charlotte, NC USA. Providence Canc Ctr, Southfield, MI USA. Aventis Pharmaceut, Collegeville, PA USA. RP Posner, MR (reprint author), Dana Farber Canc Inst, Head & Neck Oncol Program, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. RI Ray, Dana/C-3470-2013; Shin, Dong Moon/G-9649-2013 NR 33 TC 109 Z9 114 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 15 PY 2001 VL 19 IS 4 BP 1096 EP 1104 PG 9 WC Oncology SC Oncology GA 406MH UT WOS:000167219400023 PM 11181674 ER PT J AU Soiffer, RJ Weller, E Alyea, EP Mauch, P Webb, IL Fisher, DC Freedman, AS Schlossman, RL Gribben, J Lee, S Anderson, KC Marcus, K Stone, RM Antin, JH Ritz, J AF Soiffer, RJ Weller, E Alyea, EP Mauch, P Webb, IL Fisher, DC Freedman, AS Schlossman, RL Gribben, J Lee, S Anderson, KC Marcus, K Stone, RM Antin, JH Ritz, J TI CD6+donor marrow T-cell depletion as the sole form of graft-versus-host disease prophylaxis in patients undergoing allogeneic bone marrow transplant from unrelated donors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; TOTAL-LYMPHOID IRRADIATION; COUNTERFLOW CENTRIFUGAL ELUTRIATION; CHRONIC MYELOID-LEUKEMIA; SELECTIVE DEPLETION; SIBLING DONORS; LYMPHOCYTES-T; PREVENTION; RECIPIENTS; METHOTREXATE AB Purpose: The role of donor marrow T-cell depletion (TCD) in preventing graft-versus-host disease (GVHD) after transplantation of unrelated allogeneic marrow remains undefined. Because different TCD methodologies differ in the degree and specificity with which T cells are removed, it is likely that transplant outcomes would depend on which technique is used. Herein, we report results in the first 48 recipients of unrelated marrow using CD6+ TCD as the sole form of GVHD prophylaxis. Patients and Methods: Median age of patients was 46 years (20 to 58 years). Donors were matched at A/B HLA loci. Ablation consisted of cyclophosphamide and fractionated total-body irradiation (TBI; 14 Gy). To facilitate engraftment, patients also received 7.5 Gy (22 points) or 4.5 Gy (26 points) of total lymphoid irradiation (TLI) before admission. No additional immune suppressive prophylaxis was administered. Granulocyte colony-stimulating factor was administered daily from day +1 to engraftment. Results: All 48 patients demonstrated neutrophil engraftment. An absolute neutrophil count of 500 x 10(6)/L. was achieved at a median of 12 days (range, 9 to 23 days). There were no cases of late graft failure. The number of CD34+ cells infused/kg was associated with speed of platelet and neutrophil recovery. The dose of TLI did not influence engraftment. Grades 2-4 acute GVHD occurred in 42% of patients (95% confidence interval [CI], 0.28 to 0.57). Mortality at day 100 was 19%. There have been only five relapses. Estimated 2-year survival war 44% (95% CI, 0.28 to 0.59) for the entire group, 58% for patients less than 50 years of age. In multivariable analysis, age less than 50 years (P = .002), cytomegalovirus seronegative status (P = .04), and early disease status at bone marrow transplant (P = .05) were associated with superior survival. Conclusion: CD6+ TCD does not impede engraftment of unrelated bone marrow after low-dose TLI, cyclophosphamide, and TBI. CD6+ TCD as the sole form of GVHD prophylaxis results in on incidence of GVHD that compares favorably with many adult studies of unrelated transplantation using unmanipulated marrow and immune-suppressive medications, especially in light of the median age of our patients (46 years). Although event-free survival in patients less than 50 years of age is very encouraging, older patients experience frequent transplantation-related complications despite TCD. C1 Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. RP Soiffer, RJ (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. RI Ritz, Jerome/C-7929-2009 OI Ritz, Jerome/0000-0001-5526-4669 FU NIAID NIH HHS [AI 29530] NR 43 TC 33 Z9 35 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 15 PY 2001 VL 19 IS 4 BP 1152 EP 1159 PG 8 WC Oncology SC Oncology GA 406MH UT WOS:000167219400030 PM 11181681 ER PT J AU Wekerle, T Kurtz, J Sayegh, MH Ito, H Wells, AD Bensinger, S Shaffer, J Turka, LA Sykes, M AF Wekerle, T Kurtz, J Sayegh, MH Ito, H Wells, AD Bensinger, S Shaffer, J Turka, LA Sykes, M TI Peripheral deletion after bone marrow transplantation with costimulatory blockade has features of both activation-induced cell death and passive cell death SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INHIBITS MULTIPLE FORMS; MATURE T-CELLS; CLONAL DELETION; LYMPHOCYTES-T; NEGATIVE SELECTION; TRANSGENIC MICE; ENTEROTOXIN-B; APOPTOSIS; BCL-2; FAS AB Two major pathways of death of previously activated T cells have been described: activation-induced cell death can be triggered by restimulating activated T cells with high concentrations of Ag, is Fas-dependent, is not influenced by proteins of the Eel family, and is blocked by cyclosporin A; in contrast, passive cell death is induced by the withdrawal of growth factors and activation stimuli, is Fas-independent, and is blocked by Eel family proteins. We examined the role of these two forms of cell death in the peripheral deletion of donor-reactive host T cells after allogeneic bone marrow transplantation and costimulatory blockade with anti-CD154 plus CTLA4Ig in two murine models. The substantial decline in donor-reactive CD4 cells seen in wild-type recipients 1 wk after bone marrow transplantation with costimulatory blockade was largely inhibited in Fas-deficient recipients and in Bcl-x(L)-transgenic recipients. We observed these effects both in a model involving low-dose total body irradiation and a conventional dose of bone marrow, and in a radiation-free regimen using high-dose bone marrow transplantation. Furthermore, cyclosporin A did not completely block the deletion of donor-reactive CD4(+) T cells in recipients of bone marrow transplantation with costimulatory blockade, Thus, the deletion of donor-reactive T cells occurring early after bone marrow transplantation with costimulatory blockade has features of both activation-induced cell death and passive cell death. Furthermore, these in vivo data demonstrate for the first time the significance of in vitro results indicating that proteins of the Eel family can prevent Fas-mediated apoptosis under certain circumstances. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med,Transplantat Biol Res Ctr, Bone Marrow Transplantat Sect, Boston, MA 02129 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Lab Immunogenet & Transplantat, Boston, MA 02115 USA. Univ Penn, Dept Med, Philadelphia, PA 19104 USA. RP Sykes, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Transplantat Biol Res Ctr, Bone Marrow Transplantat Sect, MGH East,Bldg 149-5102,13th St, Boston, MA 02129 USA. OI Wekerle, Thomas/0000-0001-5159-2796 FU NHLBI NIH HHS [R01 HL49915] NR 39 TC 81 Z9 84 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2001 VL 166 IS 4 BP 2311 EP 2316 PG 6 WC Immunology SC Immunology GA 400QA UT WOS:000166882000021 PM 11160287 ER PT J AU Sasada, T Reinherz, EL AF Sasada, T Reinherz, EL TI A critical role for CD2 in both thymic selection events and mature T cell function SO JOURNAL OF IMMUNOLOGY LA English DT Article ID POSITIVE SELECTION; ALPHA-BETA; NEGATIVE SELECTION; MICE LACKING; LOW-AFFINITY; THYMOCYTE DEVELOPMENT; ANTIGEN RECOGNITION; ADAPTER PROTEIN; LYMPHOCYTES-T; MHC COMPLEX AB To examine the function of CD2 in vivo, N15 TCR transgenic (tg) RAG-2(-/-) H-2(b) mice bearing a single TCR specific for the vesicular stomatitis virus octapeptide bound to the H-2K(b) molecule were compared on a wild-type or CD2(-/-) background. In N15tg RAG-(2-/-) CD2(-/-) mice, thymic dysfunction is evident by 6 wk with a pre-TCR block in the CD4(-)CD8(-) double negative thymocytes at the CD25+CD44- stage. Moreover, mature N15tg RAG-2(-/-) CD2(-/-) T cells are similar to 100-fold less responsive to vesicular `stomatitis virus octapeptide and unresponsive to weak peptide agonists, as judged by IFN-gamma production. Repertoire analysis shows substantial differences in V alpha usage between non-tg C57BL/6 (B6) and B6 CD2(-/-) mice. Collectively, these findings show that CD2 plays a role in pre-TCR function in double-negative thymocytes, TCR selection events during thymocyte development, and TCR-stimulated cytokine production in mature T cells. The Journal of Immunology, 2001, 166: 2394-2403. C1 Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Reinherz, EL (reprint author), Dana Farber Canc Inst, Immunobiol Lab, 44 Binney St, Boston, MA 02115 USA. FU NIAID NIH HHS [AI21226] NR 77 TC 29 Z9 33 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2001 VL 166 IS 4 BP 2394 EP 2403 PG 10 WC Immunology SC Immunology GA 400QA UT WOS:000166882000032 PM 11160298 ER PT J AU Baron, C Sachs, DH LeGuern, C AF Baron, C Sachs, DH LeGuern, C TI A particular TCR beta variable region used by T cells infiltrating kidney transplants SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RECEPTOR ALPHA-CHAIN; GENE SEGMENTS; ANTIGEN RECEPTOR; MINIATURE SWINE; DIVERSITY; MURINE; REPERTOIRE; ALLOGRAFTS; TOLERANCE; REARRANGEMENT AB Immune tolerance to MHC class II identical renal grafts is achievable in miniature swine following a short immunosuppressive treatment, Like in clinical transplants, swine-accepted allografts are primarily infiltrated by CD8(+) T cells, which are noncytotoxic to the renal tissue. However, the actual specificity and function of these intragraft-infiltrating lymphocytes remain poorly understood. To develop the molecular tools to study TCR-associated functions of graft-infiltrating cells in a preclinical transplantation model, we have determined the nucleotide sequence of 19 pig V beta, 12 J beta, and two D beta. Sequence comparisons identified 17 different V beta families and two J beta clusters homologous to the human J beta1 and J beta2. The fact that the pig J beta1 segments were always found joined to the D beta1-like sequence in numerous rearranged TCR beta cDNA suggests the existence of two D-J clusters in swine. These results also imply that the polymorphism of the porcine TCR beta segments is similar to that found in human. Finally, we report the discovery of a new and functional V beta subfamily named V beta 100, which exhibited similarity to the murine V beta2 sequence but had no described V beta homolog in humans. Pilot spectratyping studies on V beta usage revealed a clonal dominance of V beta 100(+) T cell subsets among infiltrating cells in two accepted grafts. The Journal of Immunology, 2001, 166: 2589-2596. C1 Harvard Univ, Transplantat Biol Res Ctr, Massachusetts Gen Hosp, Sch Med, Boston, MA 02129 USA. RP LeGuern, C (reprint author), Harvard Univ, Transplantat Biol Res Ctr, Massachusetts Gen Hosp, Sch Med, MGH E,Bldg 149-9019,13th St, Boston, MA 02129 USA. FU NHLBI NIH HHS [2PO1 HL18646]; NIAID NIH HHS [2RO1 AI33053, 2RO1 AI31046] NR 26 TC 16 Z9 19 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2001 VL 166 IS 4 BP 2589 EP 2596 PG 8 WC Immunology SC Immunology GA 400QA UT WOS:000166882000054 PM 11160320 ER PT J AU Lian, JP Crossley, L Zhan, Q Huang, RY Coffer, P Toker, A Robinson, D Badwey, JA AF Lian, JP Crossley, L Zhan, Q Huang, RY Coffer, P Toker, A Robinson, D Badwey, JA TI Antagonists of calcium fluxes and calmodulin block activation of the p21-activated protein kinases in neutrophils SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GUINEA-PIG NEUTROPHILS; TYROSINE PHOSPHORYLATION; COUPLED RECEPTORS; RAPID ACTIVATION; ADAPTER PROTEIN; BINDING PROTEIN; INHIBITION; COMPONENT; CASCADE; FAMILY AB Neutrophils stimulated with fMLP or a variety of other chemoattractants that bind to serpentine receptors coupled to heterotrimeric G proteins exhibit rapid activation of two p21-activated protein kinases (Paks) with molecular masses of similar to 63 and 69 kDa (gamma- and alpha -Pak). Previous studies have shown that products of phosphatidylinositol 3-kinase and tyrosine kinases are required for the activation of Paks, We now report that a variety of structurally distinct compounds which interrupt different stages in calcium/calmodulin (CaM) signaling block activation of the 63- and 69-kDa Paks in fMLP-stimulated neutrophils. These antagonists included selective inhibitors of phospholipase C (1-[6-((17 beta -3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole- 2,5-dione), the intracellular Ca2+ channel (8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate), CaM (N-(6-aminohexyl)-5chloro-1-naphthalenesulfonamide; N-(4-aminobutyl)-5-chloro-1-naphthalenesulfonamide: trifluoperazine), and CaM-activated protein kinases (N- [2-(N-(chlorocinnamyl)-N-methylaminomethyl)phenyl]-N-[2-hydroxyethyl]-4-methoxybenzenesulfonamide). This inhibition was dose-dependent with IC50 values very similar to those that interrupt CaM-dependent reactions in vitro. In contrast, less active analogues of these compounds (1-[6-((17 beta -3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-2,5-pyrro- lidinedione; N-(6-aminohexyl)-1-naphthalenesulfonamide; N-(4-aminobutyl)-1-naphthalenesulfonamide; promethazine; 2-[N-(4-methoxybenzenesulfonyl)]amino-N- (4-chlorocinnamyl)-N-methylbenzyl-amine]) did not affect activation of Paks in these cells. CaM antagonists (N-(6-aminohexyl)-5-chloro-l-naphthalenesulfonamide: trifluoperazine), but not their less-active analogues (N-(6-aminohexyl)-1-naphthalenesulfonamide; promethazine), were also found to block activation of the small GTPases Pas and Pac in stimulated neutrophils along with the extracellular signal-regulated kinases, These data strongly suggest that the Ca2+/CaM complex plays a major role in the activation of a number of enzyme systems in neutrophils that are regulated by small GTPases. C1 Brigham & Womens Hosp, Ctr Expt Therapeut & Reperfus Injury, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. Boston Biomed Res Inst, Boston, MA 02114 USA. Univ Utrecht Hosp, Dept Pulm Dis, Utrecht, Netherlands. Massachusetts Gen Hosp, Arthrit Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Badwey, JA (reprint author), Brigham & Womens Hosp, Ctr Expt Therapeut & Reperfus Injury, Dept Anesthesiol Perioperat & Pain Med, 75 Francis St,Thorn Bldg,Room 703, Boston, MA 02115 USA. RI Coffer, Paul/A-5769-2009 FU NIAID NIH HHS [AI 23323]; NIDCR NIH HHS [P01 DE 13499 , +]; NIDDK NIH HHS [DK 50015] NR 55 TC 19 Z9 19 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2001 VL 166 IS 4 BP 2643 EP 2650 PG 8 WC Immunology SC Immunology GA 400QA UT WOS:000166882000061 PM 11160327 ER PT J AU Kim, HA Ratner, N Roberts, TM Stiles, CD AF Kim, HA Ratner, N Roberts, TM Stiles, CD TI Schwann cell proliferative responses to cAMP and Nf1 are mediated by cyclin D1 SO JOURNAL OF NEUROSCIENCE LA English DT Article DE Schwann cell; platelet-derived growth factor; cAMP; cyclin D1; cell cycle; neurofibromatosis ID NEUROFIBROMATOSIS TYPE-1 GENE; PROTEIN-KINASE-A; GLIAL GROWTH-FACTOR; VONRECKLINGHAUSEN NEUROFIBROMATOSIS; SERUM COMPONENTS; ACTIVATION; PURIFICATION; MECHANISM; INDUCTION; LINEAGE AB In most mammalian cells, the cAMP-dependent protein kinase A pathway promotes growth arrest and cell differentiation. However in Schwann cells, the reverse is true. Elevated levels of cAMP function as the cofactor to a broad range of mitogenic cues in culture and in animals. Previous studies have suggested that cAMP acts at an early point in the Schwann cell mitogenic response, perhaps by stimulating the expression of growth factor receptors. We show here that cAMP acts downstream rather than upstream of growth factor receptor expression. The essential function(s) of cAMP is exerted as Schwann cells progress through the G(1) phase of the cell cycle. Ectopic expression studies using an inducible retroviral vector show that the G(1) phase requirement for cAMP can be alleviated by a single protein, cyclin D1. We show, in addition, that at least one function of the Nf1 tumor suppressor is to antagonize the accumulation of cAMP and the expression of cyclin D1 in Schwann cells. Thus a G(1) phase-specific protein, cyclin D1, accounts for two salient features of Schwann cell growth control: the promitotic response to cAMP and the antimitotic response to the Nf1 tumor suppressor. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Univ Cincinnati, Coll Med, Dept Cell Biol, Cincinnati, OH 45267 USA. RP Stiles, CD (reprint author), Dana Farber Canc Inst, SM1070,1 Jimmy Fund Way, Boston, MA 02115 USA. FU NICHD NIH HHS [HD24926]; NINDS NIH HHS [NS28804] NR 35 TC 79 Z9 81 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 15 PY 2001 VL 21 IS 4 BP 1110 EP 1116 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 399NR UT WOS:000166819700007 PM 11160381 ER PT J AU Clayton, JD Kyriacou, CP Reppert, SM AF Clayton, JD Kyriacou, CP Reppert, SM TI Keeping time with the human genome SO NATURE LA English DT Article AB The cloning and characterization of 'clock gene' families has advanced our understanding of the molecular control of the mammalian circadian clock. We have analysed the human genome for additional relatives, and identified new candidate genes that may expand our knowledge of the molecular workings of the circadian clock. This knowledge could lead to the development of therapies for treating jet lag and sleep disorders, and add to our understanding of the genetic contribution of clock gene alterations to sleep and neuropsychiatric disorders. The human genome will also aid in the identification of output genes that ultimately control circadian behaviours. C1 Massachusetts Gen Hosp, MassGen Hosp Children, Lab Dev Chronobiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England. RP Reppert, SM (reprint author), Massachusetts Gen Hosp, MassGen Hosp Children, Lab Dev Chronobiol, Boston, MA 02114 USA. NR 15 TC 58 Z9 59 U1 1 U2 4 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 15 PY 2001 VL 409 IS 6822 BP 829 EP 831 DI 10.1038/35057006 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 401QC UT WOS:000166938800047 PM 11237000 ER PT J AU Sachidanandam, R Weissman, D Schmidt, SC Kakol, JM Stein, LD Marth, G Sherry, S Mullikin, JC Mortimore, BJ Willey, DL Hunt, SE Cole, CG Coggill, PC Rice, CM Ning, ZM Rogers, J Bentley, DR Kwok, PY Mardis, ER Yeh, RT Schultz, B Cook, L Davenport, R Dante, M Fulton, L Hillier, L Waterston, RH McPherson, JD Gilman, B Schaffner, S Van Etten, WJ Reich, D Higgins, J Daly, MJ Blumenstiel, B Baldwin, J Stange-Thomann, NS Zody, MC Linton, L Lander, ES Altshuler, D AF Sachidanandam, R Weissman, D Schmidt, SC Kakol, JM Stein, LD Marth, G Sherry, S Mullikin, JC Mortimore, BJ Willey, DL Hunt, SE Cole, CG Coggill, PC Rice, CM Ning, ZM Rogers, J Bentley, DR Kwok, PY Mardis, ER Yeh, RT Schultz, B Cook, L Davenport, R Dante, M Fulton, L Hillier, L Waterston, RH McPherson, JD Gilman, B Schaffner, S Van Etten, WJ Reich, D Higgins, J Daly, MJ Blumenstiel, B Baldwin, J Stange-Thomann, NS Zody, MC Linton, L Lander, ES Altshuler, D CA Int SNP Map Working Grp TI A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms SO NATURE LA English DT Article ID LIPOPROTEIN-LIPASE GENE; COMMON DISEASE GENES; LINKAGE DISEQUILIBRIUM; CANDIDATE GENES; DNA-SEQUENCES; SNP MAP; DIVERSITY; IDENTIFICATION; POPULATIONS; DISCOVERY AB We describe a map of 1.42 million single nucleotide polymorphisms (SNPs) distributed throughout the human genome, providing an average density on available sequence of one SNP every 1.9 kilobases. These SNPs were primarily discovered by two projects: The SNP Consortium and the analysis of clone overlaps by the International Human Genome Sequencing Consortium. The map integrates all publicly available SNPs with described genes and other genomic features. We estimate that 60,000 SNPs fall within exon (coding and untranslated regions), and 85% of exons are within 5 kb of the nearest SNP. Nucleotide diversity varies greatly across the genome, in a manner broadly consistent with a standard population genetic model of human history. This high-density SNP map provides a public resource for defining haplotype variation across the genome, and should help to identify biomedically important genes for diagnosis and therapy. C1 Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. MIT, Dept Biol, Cambridge, MA 02142 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Altshuler, D (reprint author), 9 Cambridge Ctr, Cambridge, MA 02139 USA. EM drb@sanger.ac.uk; altshul@genome.wi.mit.edu RI Altshuler, David/A-4476-2009; Kwok, Pui-Yan/F-7725-2014; Ning, Zemin/D-2411-2013; Schaffner, Stephen/D-1189-2011; OI Altshuler, David/0000-0002-7250-4107; Kwok, Pui-Yan/0000-0002-5087-3059; Ning, Zemin/0000-0003-4359-776X; Schultz, Brian/0000-0003-4964-976X; sachidanandam, ravi/0000-0001-9844-4459 NR 44 TC 1848 Z9 1968 U1 17 U2 154 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 15 PY 2001 VL 409 IS 6822 BP 928 EP 933 DI 10.1038/35057149 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 401QC UT WOS:000166938800060 PM 11237013 ER PT J AU Abi-Younes, S Si-Tahar, M Luster, AD AF Abi-Younes, S Si-Tahar, M Luster, AD TI The CC chemokines MDC and TARC induce platelet activation via CCR4 SO THROMBOSIS RESEARCH LA English DT Article DE MDC; TARC; CCR4; chemokine and platelets ID MACROPHAGE-DERIVED CHEMOKINE; ATOPIC-DERMATITIS; REGULATED CHEMOKINE; ASTHMATIC-PATIENTS; BRONCHIAL-ASTHMA; FACTOR-I; T-CELLS; RECEPTOR; RANTES; EXPRESSION AB While chemokines have received considerable attention for their role in leukocyte chemotaxis, their effects on platelets have not been well described. We found that two CC chemokine receptor 4 (CCR4) ligands, macrophage-derived chemokine (MDC) and thymus and activation-regulated chemokine (TARC) induce concentration-dependent platelet aggregation and calcium flux. Flow cytometric analysis revealed the expression of CCR4 on platelets and a monoclonal antibody (mAb) to CCR4 inhibited MDC- and TARC-induced platelet aggregation, confirming that this effect is mediated through their common receptor CCR4. MDC fully desensitized TARC-induced calcium mobilization in platelets, while TARC was unable to completely desensitize a subsequent MDC response, which is similar to observations made in Th2 CD4(+) lymphocytes and CCR4-transfected cells. Aspirin (ASA) treatment of platelets allowed reversible primary aggregation but inhibited irreversible complete aggregation, suggesting that MDC- and TARC-induced full platelet aggregation is dependent on cyclooxygenase metabolites of arachidonic acid. MDC and TARC were unable to induce platelet aggregation and platelet secretion in washed human platelets, even though they induced a calcium flux, suggesting that plasma components are required for MDC- and TARC-induced platelet aggregation. Since Th2-type cytokines induce the release of MDC and TARC from cells and the expression of these chemokines is increased in Th2-type inflammation, we hypothesize that MDC and TARC may play a role in platelet activation seen in Th2 diseases, such as asthma and atopic dermatitis. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Massachusetts Gen Hosp E, Bldg 149,13th St, Charlestown, MA 02129 USA. EM luster@helix.mgh.harvard.edu RI SI-TAHAR, Mustapha/L-4149-2014 OI SI-TAHAR, Mustapha/0000-0002-5792-7742 NR 55 TC 60 Z9 64 U1 2 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0049-3848 J9 THROMB RES JI Thromb. Res. PD FEB 15 PY 2001 VL 101 IS 4 BP 279 EP 289 DI 10.1016/S0049-3848(00)00402-3 PG 11 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 410AW UT WOS:000167418700008 PM 11248289 ER PT J AU Zhang, WT Godillot, AP Wyatt, R Sodroski, J Chaiken, I AF Zhang, WT Godillot, AP Wyatt, R Sodroski, J Chaiken, I TI Antibody 17b binding at the coreceptor site weakens the kinetics of the interaction of envelope glycoprotein gp120 with CD4 SO BIOCHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; CONFORMATIONAL-CHANGES; RECEPTOR-BINDING; TRANSMEMBRANE GLYCOPROTEIN; ATOMIC-STRUCTURE; HIV-1 ENTRY; HTLV-III; GP41; EPITOPES AB HIV-1 utilizes CD4 and the chemokine coreceptor for viral entry. The coreceptor CCR5 binding site on gp120 partially overlaps with the binding epitope of 17b, a neutralizing antibody of HIV-1. We designed a multicomponent biosensor assay to investigate the kinetic mechanism of interaction between gp120 and its receptors and the cooperative effect of the CCR5 binding site on the CD4 binding site, using 17b as a surrogate of CCR5. The Env gp120 proteins from four viral strains (JRFL, YU2, 89.6, and HXB2) and their corresponding C1-, V1/V2-, C5-deleted mutants (Delta JRFL, Delta YU2, Delta 89.6, and Delta HXB2) were tested in this study. We found that, across the primary and lab-adapted virus strains, 17b reduced the affinity of all four full-length Env gp120s for sCD4 by decreasing the on-rate and increasing the off-rate. This effect of 17b on full-length gp120 binding to sCD4 contrasts with the enhancing effect of sCD4 on gp120-17b interaction. For the corresponding loop-deleted mutants of Env gp120, the off-rates of the gp120-sCD4 interaction were greatly reduced in the presence of 17b, resulting in higher affinities (except for that of Delta HXB2). The results suggest that, when 17b is prebound to full-length gp120, the V 1/V2 loops may be relocated to a position that partially blocks the CD4-binding site, leading to weakening of the CD4 interaction. Given the fact that the 17b binding epitope partially overlaps with the binding site of CCR5, the kinetic results suggest that coreceptor CCR5 binding could have a similar "release" effect on the gp120-CD4 interaction by increasing the off-rate of the latter. The results also suggest that the neutralizing effect of 17b may arise not only from partially blocking the CCR5 binding site but also from reducing the CD4 binding affinity of gp120. This negative cooperative effect of 17b may provide insight into approaches to designing antagonists for viral entry. C1 Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Chaiken, I (reprint author), 909 Stellar Change Labs,422 Curie Blvd, Philadelphia, PA 19104 USA. FU NIAID NIH HHS [P30-AI45008]; NIGMS NIH HHS [P01-GM 56550-01] NR 36 TC 42 Z9 44 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 13 PY 2001 VL 40 IS 6 BP 1662 EP 1670 DI 10.1021/bi001397m PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 401RM UT WOS:000166942100019 PM 11327825 ER PT J AU Golomb, MR Durand, ML Schaefer, PW McDonald, CT Maia, M Schwamm, LH AF Golomb, MR Durand, ML Schaefer, PW McDonald, CT Maia, M Schwamm, LH TI A case of immunotherapy-responsive eastern equine encephalitis with diffusion-weighted imaging SO NEUROLOGY LA English DT Article ID DISEASES C1 Massachusetts Gen Hosp, Massachusetts Eye & Ear Infirm, Infect Dis Serv, Boston, MA 02114 USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Div Infect Dis Lab, Boston, MA USA. Prot Design Labs Inc, Fremont, CA USA. RP Schwamm, LH (reprint author), Massachusetts Gen Hosp, Massachusetts Eye & Ear Infirm, Infect Dis Serv, 55 Fruit St,VBK 915, Boston, MA 02114 USA. OI Schwamm, Lee/0000-0003-0592-9145 NR 7 TC 12 Z9 12 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 FEB 13 PY 2001 VL 56 IS 3 BP 420 EP 421 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 401DK UT WOS:000166911700032 PM 11171919 ER PT J AU Roth, GJ AF Roth, GJ TI A new "kid" on the platelet thrombin receptor "block": Glycoprotein Ib-IX-V SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID RESPONSIVENESS; ACTIVATION C1 Vet Affairs Puget Sound Hlth Care Syst, Seattle Div, Seattle, WA 98108 USA. Univ Washington, Seattle, WA 98108 USA. RP Roth, GJ (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Seattle Div, Seattle, WA 98108 USA. NR 11 TC 5 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 FEB 13 PY 2001 VL 98 IS 4 BP 1330 EP 1331 DI 10.1073/pnas.98.4.1330 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 401VL UT WOS:000166949200005 PM 11171948 ER PT J AU Addo, MM Altfeld, M Rosenberg, ES Eldridge, RL Philips, MN Habeeb, K Khatri, A Brander, C Robbins, GK Mazzara, GP Goulder, PJR Walker, BD AF Addo, MM Altfeld, M Rosenberg, ES Eldridge, RL Philips, MN Habeeb, K Khatri, A Brander, C Robbins, GK Mazzara, GP Goulder, PJR Walker, BD CA HIV Controller Study Collaboration TI The HIV-1 regulatory proteins Tat and Rev are frequently targeted by cytotoxic T lymphocytes derived from HIV-1-infected individuals SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CTL ESCAPE VIRUS; VACCINE DEVELOPMENT; PRIMARY INFECTION; FINE SPECIFICITY; RAPID SELECTION; VIREMIA; CELLS; AIDS; PROGRESSION AB The HIV-1 regulatory proteins Rev and Tat are expressed early in the virus life cycle and thus may be important targets for the immune control of HIV-1-infection and for effective vaccines. However, the extent to which these proteins are targeted in natural HIV-1 infection as well as precise epitopes targeted by human cytotoxic T lymphocytes (CTL) remain to be defined. In the present study, 57 HIV-1-infected individuals were screened for responses against Tat and Rev by using overlapping peptides spanning the entire Tat and Rev proteins. CD8+ T cell responses against Tat and Rev were found in up to 19 and 37% of HIV-1-infected individuals, respectively, indicating that these regulatory proteins are important targets for HIV-l-specific CTL. Despite the small size of these proteins, multiple CTL epitopes were identified in each. These data indicate that Tat and Rev are frequently targeted by CTL in natural HIV-1 infection and may be important targets for HIV vaccines. C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Therion Biol Corp, Cambridge, MA 02142 USA. RP Walker, BD (reprint author), Massachusetts Gen Hosp East, 149 13th St, Charlestown, MA 02129 USA. RI Robbins, Gregory/F-7988-2011 FU NIAID NIH HHS [R01 AI030914, AI28568, AI30914, AI46995, R01 AI028568, R01 AI046995, R37 AI028568] NR 39 TC 149 Z9 156 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 13 PY 2001 VL 98 IS 4 BP 1781 EP 1786 DI 10.1073/pnas.98.4.1781 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 401VL UT WOS:000166949200085 PM 11172028 ER PT J AU Chen, JF Moratalla, R Impagnatiello, F Grandy, DK Cuellar, B Rubinstein, M Beilstein, MA Hackett, E Fink, JS Low, MJ Ongini, E Schwarzschild, MA AF Chen, JF Moratalla, R Impagnatiello, F Grandy, DK Cuellar, B Rubinstein, M Beilstein, MA Hackett, E Fink, JS Low, MJ Ongini, E Schwarzschild, MA TI The role of the D2 dopamine receptor (D2R) in A(2A) adenosine receptor (A(2A)R)-mediated behavioral and cellular responses as revealed by A(2A) and D-2 receptor knockout mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID C-FOS EXPRESSION; 6-HYDROXYDOPAMINE-LESIONED RATS; ACETYLCHOLINE-RELEASE; GENE-EXPRESSION; DEFICIENT MICE; BASAL GANGLIA; CYCLIC-AMP; ACTIVATION; STRIATUM; ANTAGONISTS AB The A(2A)R is largely coexpressed with D(2)Rs and enkephalin mRNA in the striatum where it modulates dopaminergic activity. Activation of the A(2A)R antagonizes D2R-mediated behavioral and neurochemical effects in the basal ganglia through a mechanism that may involve direct A(2A)R-D2R interaction. However, whether the D2R is required for the A(2A)R to exert its neural function is an open question. In this study, we examined the role of D(2)Rs in A(2A)R-induced behavioral and cellular responses, by using genetic knockout (KO) models (mice deficient in A(2A)Rs or D(2)Rs or both). Behavioral analysis shows that the A(2A)R agonist 2-4-(2-carboxyethyl)henethylamino-5'-N-ethylcarbox-amidoadenosine reduced spontaneous as well as amphetamine-induced locomotion in both D-2 KO and wild-type mice. Conversely, the nonselective adenosine antagonist caffeine and the A(2A)R antagonist 8-(3-chlorostyryl)caffeine produced motor stimulation in mice lacking the DIR, although the stimulation was significantly attentuated. At the cellular level, A(2A)R inactivation counteracted the increase in enkephalin expression in striatopallidal neurons caused by D2R deficiency. Consistent with the D-2 KO phenotype, A(2A)R inactivation partially reversed both acute D2R antagonist (haloperidol)-induced catalepsy and chronic haloperidol-induced enkephalin mRNA expression. Together, these results demonstrate that A(2A)Rs elicit behavioral and cellular responses despite either the genetic deficiency or pharmacological blockade of D(2)Rs. Thus, A(2A)R-mediated neural functions are partially independent of D(2)Rs. Moreover, endogenous adenosine acting at striatal A(2A)Rs may be most accurately viewed as a facilitative modulator of striatal neuronal activity rather than simply as an inhibitory modulator of D2R neurotransmission. C1 Massachusetts Gen Hosp, Dept Neurol, Mol Neurobiol Lab, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. CSIC, Inst Cajal, E-28002 Madrid, Spain. Schering Plough Res Inst, I-20132 Milan, Italy. Oregon Hlth Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA. Univ Buenos Aires, CONICET, INGEBI, RA-1428 Buenos Aires, DF, Argentina. Univ Buenos Aires, Dept Biol Sci, RA-1428 Buenos Aires, DF, Argentina. RP Chen, JF (reprint author), Massachusetts Gen Hosp, Dept Neurol, Mol Neurobiol Lab, Boston, MA 02129 USA. RI Moratalla, Rosario/H-9280-2015 OI Moratalla, Rosario/0000-0002-7623-8010 FU NIDA NIH HHS [DA12062, DA07496]; NINDS NIH HHS [NS373403] NR 46 TC 163 Z9 165 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 13 PY 2001 VL 98 IS 4 BP 1970 EP 1975 DI 10.1073/pnas.98.4.1970 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 401VL UT WOS:000166949200117 PM 11172060 ER PT J AU Sasaki, Y Hadjikhani, N Fischl, B Liu, AK Marret, S Dale, AM Tootell, RBH AF Sasaki, Y Hadjikhani, N Fischl, B Liu, AK Marret, S Dale, AM Tootell, RBH TI Local and global attention are mapped retinotopically in human occipital cortex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN VISUAL-CORTEX; SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; SPATIAL-FREQUENCY; SELECTIVE ATTENTION; FUNCTIONAL-ANALYSIS; CORTICAL SURFACE; HEMISPHERIC-SPECIALIZATION; CONTRAST SENSITIVITY; MAGNIFICATION FACTOR AB Clinical evidence suggests that control mechanisms for local and global attention are lateralized in the temporal-parietal cortex. However, in the human occipital (visual) cortex, the evidence for lateralized local/global attention is controversial. To clarify this matter, we used functional MRI to map activity in the human occipital cortex, during local and global attention, with sustained visual fixation. Data were analyzed in a flattened cortical format, relative to maps of retinotopy and spatial frequency peak tuning, Neither local nor global attention was lateralized in the occipital cortex, Instead, local attention and global attention appear to be special cases of visual spatial attention, which are mapped consistently with the maps of retinotopy and spatial frequency tuning, in multiple visual cortical areas. C1 Massachusetts Gen Hosp, Dept Radiol, NMR Ctr, Charlestown, MA 02129 USA. RP Sasaki, Y (reprint author), Massachusetts Gen Hosp, Dept Radiol, NMR Ctr, 149 13th St, Charlestown, MA 02129 USA. RI Hadjikhani, Nouchine/C-2018-2008; Dale, Anders/A-5180-2010; OI Hadjikhani, Nouchine/0000-0003-4075-3106; Marrett, Sean/0000-0001-8179-6511 FU NEI NIH HHS [EY07980]; NINDS NIH HHS [R01 NS39581] NR 51 TC 76 Z9 86 U1 4 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 13 PY 2001 VL 98 IS 4 BP 2077 EP 2082 DI 10.1073/pnas.98.4.2077 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 401VL UT WOS:000166949200135 PM 11172078 ER PT J AU Wright, CI Fischer, H Whalen, PJ McInerney, S Shin, LM Rauch, SL AF Wright, CI Fischer, H Whalen, PJ McInerney, S Shin, LM Rauch, SL TI Differential prefrontal cortex and amygdala habituation to repeatedly presented emotional stimuli SO NEUROREPORT LA English DT Article DE cerebral cortex; facial expressions; functional magnetic resonance imaging; human; limbic system ID FACIAL EXPRESSIONS; FAMILIARITY; RECOGNITION; ACTIVATION; FEAR; FMRI AB Repeated presentations of emotional facial expressions were used to assess habituation in the human brain using fMRI. Significant fMRI signal decrement was present in the left dorsolateral prefrontal and premotor cortex, and right amygdala. Within the left prefrontal cortex greater habituation to happy vs fearful stimuli was evident, suggesting devotion of sustained neural resources for processing of threat vs safety signals. In the amygdala, significantly greater habituation was observed on the right compared to the left. In contrast, the left amygdala was significantly more activated than the right to the contrast of fear vs happy. We Speculate that the right amygdala is part of a dynamic emotional stimulus detection system, while the left is specialized for sustained stimulus evaluations. NeuroReport 12:379-383 (C) 2001 Lippincott Williams & Wilkins. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Psychiat Neuroimaging Grp, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Charlestown, MA 02129 USA. Brigham & Womens Hosp, Dept Neurol, Brigham Behav Neurol Grp, Boston, MA 02115 USA. Univ Wisconsin, Dept Psychol, Madison, WI 53719 USA. Univ Wisconsin, Dept Psychiat, Madison, WI 53719 USA. Tufts Univ, Dept Psychol, Medford, MA 02155 USA. RP Wright, CI (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Psychiat Neuroimaging Grp, 13th St,Bldg 149,CNY-9, Charlestown, MA 02129 USA. FU NIMH NIH HHS [MH-60219] NR 33 TC 305 Z9 307 U1 3 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD FEB 12 PY 2001 VL 12 IS 2 BP 379 EP 383 DI 10.1097/00001756-200102120-00039 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 397NQ UT WOS:000166702100039 PM 11209954 ER PT J AU Vidal, M AF Vidal, M TI A biological atlas of functional maps SO CELL LA English DT Review ID GENOME; ELEGANS; GENES C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Vidal, M (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. NR 24 TC 144 Z9 153 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD FEB 9 PY 2001 VL 104 IS 3 BP 333 EP 339 DI 10.1016/S0092-8674(01)00221-5 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 402RZ UT WOS:000167003100004 PM 11239391 ER PT J AU Eastcott, JW Holmberg, CJ Dewhirst, FE Esch, TR Smith, DJ Taubman, MA AF Eastcott, JW Holmberg, CJ Dewhirst, FE Esch, TR Smith, DJ Taubman, MA TI Oligonucleotide containing CpG motifs enhances immune response to mucosally or systemically administered tetanus toxoid SO VACCINE LA English DT Article DE oligodeoxynucleotide; CpG motifs; mucosal immunity ID MYCOBACTERIUM-BOVIS BCG; B SURFACE-ANTIGEN; BACTERIAL-DNA; INTERFERON-PRODUCTION; GAMMA PRODUCTION; POTENT ENHANCER; CUTTING EDGE; CELL; OLIGODEOXYNUCLEOTIDES; ACTIVATION AB Oligodeoxynucleotides (ODN) containing unmethylated CpG dinucleotides induce proliferation of B cells and activation of macrophages and thus stimulation of the immune system. We tested an oligonucleotide containing an unmethylated CpG dinucleotide flanked by two 5' purines and two 3' pyrimidines (GAGAACGCTCGACCTTCGAT) for the ability to affect antibody levels to tetanus toroid (Tt). Groups of male Rowett rats (n = 5-6/group) received colloidal aluminium hydroxide (Al(OH)(3)) either alone, or with Tt bound to the Al(OH)(3), or with Tt bound to Al(OH)(3) with the addition of the CpG oligonucleotide. Antigens were administered subcutaneously in the salivary gland vicinity once, or by gastric intubation on 3 consecutive days. On day 124 all animals were given a boost with the same material by the same route. Serum IgG and saliva IgA antibody to Tt was determined by ELISA. Serum antibody levels were significantly higher in ODN + Tt treated rats than in Tt-alone rats immunized by either route after primary or booster immunizations. Thus, administration of an ODN containing unmethylated CpG motifs along with an immunogen bound to Al(OH)(3) can result in enhanced specific antibody when administered by intragastric as well as subcutaneous routes. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Forsyth Inst, Dept Immunol, Boston, MA 02115 USA. Forsyth Inst, Dept Mol Genet, Boston, MA 02115 USA. RP Taubman, MA (reprint author), Forsyth Inst, Dept Immunol, 140 Fenway, Boston, MA 02115 USA. FU NIDCR NIH HHS [DE-04733] NR 30 TC 44 Z9 47 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD FEB 8 PY 2001 VL 19 IS 13-14 BP 1636 EP 1642 DI 10.1016/S0264-410X(00)00422-9 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 402NN UT WOS:000166995200012 PM 11166886 ER PT J AU Nathan, DG Fontanarosa, PB Wilson, JD AF Nathan, DG Fontanarosa, PB Wilson, JD TI Opportunities for medical research in the 21st century SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 JAMA, Chicago, IL 60610 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. RP Fontanarosa, PB (reprint author), JAMA, 515 N State St, Chicago, IL 60610 USA. NR 5 TC 17 Z9 18 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 FEB 7 PY 2001 VL 285 IS 5 BP 533 EP 534 DI 10.1001/jama.285.5.533 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 397TV UT WOS:000166714200006 PM 11176853 ER PT J AU Silberstein, LE Toy, P AF Silberstein, LE Toy, P TI Research opportunities in transfusion medicine SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HEMATOPOIETIC STEM-CELLS; VERSUS-HOST DISEASE; BLOOD COMPONENTS; INACTIVATION AB In recent years, the translation of basic research in transfusion medicine has led to development of novel cellular therapies using well-characterized cell populations isolated from either bone marrow or blood (eg, hematopoietic stem and progenitor cells, T lymphocytes, dendritic cells). Refinements in cell therapies will make possible optimal stem cell engraftment, gene therapy, immunotherapy of cancer and infectious disease, and even solid organ regeneration. Moreover, the immune consequences of transfusion therapy are better appreciated and opportunities are at hand to prevent or blunt unwanted immune responses, such as platelet refractoriness and graft-vs-host disease. Transfusion medicine has become a broad, multidisciplinary field that has evolved beyond issues related to blood procurement and storage. The next series of advances in transfusion medicine will complement the current approaches of donor blood screening and viral/bacterial inactivation steps to ensure a safe and adequate blood supply. C1 Harvard Univ, Sch Med, Boston, MA USA. Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. RP Silberstein, LE (reprint author), Childrens Hosp, Dana Farber Canc Inst, Joint Program Transfus Med, Bader 4,300 Longwood Ave, Boston, MA 02115 USA. NR 29 TC 2 Z9 2 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 FEB 7 PY 2001 VL 285 IS 5 BP 577 EP 580 DI 10.1001/jama.285.5.577 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 397TV UT WOS:000166714200015 PM 11176862 ER PT J AU Livingston, DM Shivdasani, R AF Livingston, DM Shivdasani, R TI Toward mechanism-based cancer care SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PROGRAMMED CELL-DEATH; RETINOBLASTOMA PROTEIN; BCL-2; GENE; LEUKEMIA; ELEGANS; HOMOLOG; MICE AB in the past 25 years, research has elucidated molecular mechanisms directing key aspects of tumor cell behavior. Detailed understanding of these mechanisms has already changed methods for diagnosis, prognosis, and treatment. with continuing advances in cancer science and the emergence of-new technologies for applying basic science to clinical practice, new methods based on molecular mechanisms will dominate cancer care and prevention. C1 Dana Farber Canc Inst, Div Neoplast Dis Mech, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Livingston, DM (reprint author), Dana Farber Canc Inst, Div Neoplast Dis Mech, 44 Binney St, Boston, MA 02115 USA. NR 31 TC 14 Z9 15 U1 0 U2 0 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 FEB 7 PY 2001 VL 285 IS 5 BP 588 EP 593 DI 10.1001/jama.285.5.588 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 397TV UT WOS:000166714200017 PM 11176864 ER PT J AU Grange, RW Isotani, E Lau, KS Kamm, KE Huang, PL Stull, JT AF Grange, RW Isotani, E Lau, KS Kamm, KE Huang, PL Stull, JT TI Nitric oxide contributes to vascular smooth muscle relaxation in contracting fast-twitch muscles SO PHYSIOLOGICAL GENOMICS LA English DT Article DE endothelial nitric oxide synthase; neuronal nitric oxide synthase; exercise hyperemia; skeletal muscle ID SKELETAL-MUSCLE; STRIATED-MUSCLE; BLOOD-FLOW; MYOSIN PHOSPHORYLATION; FUNCTIONAL HYPEREMIA; MUSCULAR-DYSTROPHY; RELAXING FACTOR; SYNTHASE; EXERCISE; DILATION AB During skeletal muscle contraction, NO derived from neuronal nitric oxide synthase (nNOS) in skeletal muscle fibers or from endothelial cells (eNOS) may relax vascular smooth muscle contributing to functional hyperemia. To examine the relative importance of these pathways, smooth muscle myosin regulatory light chain (smRLC) phosphorylation was assessed as an index of vascular tone in isolated extensor digitorum longus (EDL) muscles from C57, nNOS(-/-), and eNOS(-/-) mice. The smRLC phosphorylation (in mol phosphate per mol smRLC) in C57 resting muscles (0.12 +/- 0.04) was increased 3.7-fold (0.44 +/- 0.03) by phenylephrine (PE). Reversal of this increase with electrical stimulation (to 0.19 +/- 0.03; P < 0.05) was partially blocked by N--nitro-L-arginine (NLA). In nNOS(-/-) EDL, the PE-induced increase in smRLC phosphorylation (0.10 +/- 0.02 to 0.49 +/- 0.04) was partially decreased by stimulation (0.25 +/- 0.04). In eNOS(-/-) EDL, the control value for smRLC was increased (0.24 +/- 0.04), and PE-induced smRLC phosphorylation (0.36 +/- 0.06) was decreased by stimulation even in the presence of NLA (to 0.20 +/- 0.02; P < 0.05). These results suggest that in addition to NO-independent mechanisms, NO derived from both nNOS and eNOS plays a role in the integrative vascular response of contracting skeletal muscle. C1 Univ Texas, SW Med Ctr, Dept Physiol, Dallas, TX 75235 USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02129 USA. RP Grange, RW (reprint author), Virginia Polytech Inst & State Univ, Dept Human Nutr Foods & Exercise, Blacksburg, VA 24061 USA. FU NHLBI NIH HHS [HL-06296] NR 42 TC 59 Z9 60 U1 1 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD FEB 7 PY 2001 VL 5 IS 1 BP 35 EP 44 PG 10 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 399MG UT WOS:000166816500004 PM 11161004 ER PT J AU Casarett, D Kutner, JS Abrahm, J AF Casarett, D Kutner, JS Abrahm, J CA End Life Care Consensus Panel TI Life after death: A practical approach to grief and bereavement SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID CONJUGAL BEREAVEMENT; COMPLICATED GRIEF; SUICIDAL IDEATION; ADAPTATION; INTERVENTION; DEPRESSION; PREDICTORS; DISTINCT; SUPPORT; SPOUSES AB This consensus paper describes the essential skills that clinicians need to help persons who are experiencing grief after the death of a loved one. Four aspects of the grieving process are reviewed: anticipatory grief, acute grief, normal grief reactions, and complicated grief. Techniques for assessment and recommendations about interventions and indications for referral are provided for each aspect. C1 Univ Colorado, Hlth Sci Ctr, Denver, CO USA. Univ Penn, Ctr Bioeth, Philadelphia, PA 19104 USA. Univ Penn, Inst Aging, Philadelphia, PA 19104 USA. Vet Affairs Med Ctr, Philadelphia, PA USA. RP Casarett, D (reprint author), Amer Coll Phys, Amer Soc Internal Med, Ctr Eth & Professionalism, 190 N Independence Mall W, Philadelphia, PA 19106 USA. NR 44 TC 29 Z9 29 U1 3 U2 11 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD FEB 6 PY 2001 VL 134 IS 3 BP 208 EP 215 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 397KR UT WOS:000166695300005 PM 11177334 ER PT J AU Nathan, DM AF Nathan, DM TI Inhaled insulin for type 2 diabetes: Solution or distraction? SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID MELLITUS; EFFICACY C1 Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. RP Nathan, DM (reprint author), Massachusetts Gen Hosp, Diabet Unit, Bulfinch 408,Fruit St, Boston, MA 02114 USA. NR 19 TC 10 Z9 10 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD FEB 6 PY 2001 VL 134 IS 3 BP 242 EP 244 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 397KR UT WOS:000166695300009 PM 11177338 ER PT J AU Assil, IQ Qi, LJ Arai, M Shomali, M Abou-Samra, AB AF Assil, IQ Qi, LJ Arai, M Shomali, M Abou-Samra, AB TI Juxtamembrane region of the amino terminus of the corticotropin releasing factor receptor type 1 is important for ligand interaction SO BIOCHEMISTRY LA English DT Article ID VASOACTIVE INTESTINAL POLYPEPTIDE; FACTOR CRF RECEPTOR; FUNCTIONAL EXPRESSION; PEPTIDE RECEPTOR; UROTENSIN-I; EXTRACELLULAR DOMAINS; BINDING DETERMINANTS; CHIMERIC RECEPTORS; AGONIST-BINDING; XENOPUS-LAEVIS AB The functional properties of the amino terminus (NT) of the corticotropin releasing factor (CRF) receptor type 1 (R1) were studied by use of murine (m) CRFR1 and rat (r) parathyroid hormone (PTH)/parathyroid hormone-related peptide receptor (PTH1R) chimeras. The chimeric receptor CXP, in which the NT of mCRFR1 was annealed to the TMs of PTH1R, and the reciprocal hybrid, PXC, bound radiolabeled analogues of sauvagine and PTH(3-34), respectively. Neither hybrid bound radiolabeled CRF or PTH(1-34). CRF and PTH(1-34) weakly stimulated intracellular cAMP accumulation in COS-7 cells transfected with PXC and CXP, respectively. Thus the NT is required for ligand binding and the TMs are required for agonist-stimulated cAMP accumulation. Replacing individual intercysteine segments of PXC with their mCRFR1 counterparts did not rescue CRF or sauvagine radioligand binding or stimulation of cAMP accumulation. Replacement of residues 1-31 of mCRFR1 with their PTH1R counterparts resulted in a chimeric receptor, PEG, which had normal CRFR1 functional properties. In addition, a series of chimeras (F1PEC-F6PEC) were generated by replacement of the NT intercysteine residues of PEC with their PTH1R counterparts. Only F1PEC, F2PEC, and F3PEC showed detectable CRF and sauvagine radioligand binding. All of the PEC chimeras except F5PEC increased cAMP accumulation. These data indicate that the Cys(68-)Glu(109) domain is important for binding and that the Cys(87)-Cys(102) region plays an important role in CRFR1 activation. C1 Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Abou-Samra, AB (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. OI Abou-Samra, Abdul/0000-0001-8735-1142 NR 44 TC 26 Z9 28 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 6 PY 2001 VL 40 IS 5 BP 1187 EP 1195 DI 10.1021/bi001758y PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 399YQ UT WOS:000166842200006 PM 11170443 ER PT J AU Mann, DL AF Mann, DL TI Tumor necrosis factor and viral myocarditis - The fine line between innate and inappropriate immune responses in the heart SO CIRCULATION LA English DT Editorial Material DE tumor necrosis factor; myocarditis; cytokines; inflammation ID FACTOR-ALPHA; DILATED CARDIOMYOPATHY; TRANSGENIC MICE; EXPRESSION; ENDOTOXIN; GENE C1 Houston Vet Adm Med Ctr, Houston, TX 77030 USA. Winters Ctr Heart Failure Res, Houston, TX USA. Baylor Coll Med, Dept Med, Cardiol Sect, Houston, TX 77030 USA. RP Mann, DL (reprint author), Houston Vet Adm Med Ctr, Cardiol Res 151C,2002 Holcombe Blvd, Houston, TX 77030 USA. OI Mann, Douglas /0000-0002-2516-0145 NR 15 TC 24 Z9 26 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 6 PY 2001 VL 103 IS 5 BP 626 EP 629 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 412NT UT WOS:000167561800004 PM 11156870 ER PT J AU Simon, JA Hsia, J Cauley, JA Richards, C Harris, F Fong, J Barrett-Connor, E Hulley, SB AF Simon, JA Hsia, J Cauley, JA Richards, C Harris, F Fong, J Barrett-Connor, E Hulley, SB CA HERS Res Grp TI Postmenopausal hormone therapy and risk of stroke - The Heart and Estrogen-progestin Replacement Study (HERS) SO CIRCULATION LA English DT Article DE cerebrovascular disorders; hormones; stroke ID CARDIOVASCULAR-DISEASE; FOLLOW-UP; CIGARETTE-SMOKING; ISCHEMIC STROKE; WOMEN; MORTALITY; COHORT; USERS; PARTICIPANTS; POPULATION AB Background-Observational studies have shown that postmenopausal hormone therapy may increase, decrease, or have no effect on the risk of stroke. To date, no clinical trial has examined this question. To investigate the relation between estrogen plus progestin therapy and risk of stroke among postmenopausal women, we analyzed data collected from the Heart & Estrogen-progestin Replacement Study (HERS), a secondary coronary heart disease prevention trial. Methods and Results-Postmenopausal women (n=2763) were randomly assigned to take conjugated estrogen plus progestin or placebo. Primary outcomes for these analyses were stroke incidence and stroke death during a mean follow-up of 4.1 years. The number of women with strokes was compared with the number of women without strokes. A total of 149 women (5%) had 1 or more strokes, 85% of which were ischemic, resulting in 26 deaths, Hormone therapy was not significantly associated with risk of nonfatal stroke (relative hazard [RH] 1.18; 95% CI 0.83 to 1.66), fatal stroke (RH 1.61; 95% CI 0.73 to 3.55), ortransient ischemic attack (RH 0.90; 95% CI 0.57 to 1.42). Independent predictors of stroke events included increasing age, hypertension, diabetes, current cigarette smoking, and atrial fibrillation. Black women were at increased risk compared with white women, and unexpectedly, body mass index was inversely associated with stroke risk. Conclusions-Hormone therapy with conjugated equine estrogen and progestin had no significant effect on the risk for stroke among postmenopausal women with coronary disease. C1 San Francisco VA Med Ctr, Med Serv, Gen Internal Med Sect, San Francisco, CA 94121 USA. Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. George Washington Univ, Dept Med, Washington, DC USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. Wyeth Ayerst Res, Radnor, PA USA. Univ Calif San Diego, Sch Med, Dept Family Med & Prevent Med, San Diego, CA 92103 USA. RP Simon, JA (reprint author), San Francisco VA Med Ctr, Med Serv, Gen Internal Med Sect, Gen Internal Med 111A1,4150 Clement St, San Francisco, CA 94121 USA. RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 33 TC 251 Z9 263 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 6 PY 2001 VL 103 IS 5 BP 638 EP 642 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 412NT UT WOS:000167561800007 PM 11156873 ER PT J AU Haq, S Choukroun, G Lim, H Tymitz, KM del Monte, F Gwathmey, J Grazette, L Michael, A Hajjar, R Force, T Molkentin, JD AF Haq, S Choukroun, G Lim, H Tymitz, KM del Monte, F Gwathmey, J Grazette, L Michael, A Hajjar, R Force, T Molkentin, JD TI Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure SO CIRCULATION LA English DT Article DE calcineurin; cardiomyopathy; mitogen-activated protein kinases ID CARDIAC-HYPERTROPHY; CALCINEURIN; APOPTOSIS; STRESS; EXPRESSION; KINASES; DISEASE AB Background-Left ventricular failure is commonly preceded by a period of hypertrophy. Intriguingly, many of the signaling pathways that have been implicated in the regulation of hypertrophy, including the 3 mitogen-activated protein kinases (MAPKs: extracellular signal-regulated kinase, stress-activated protein kinase, and p38), protein phosphatase, calcineurin, and the protein kinase Akt and its target glycogen synthase kinase-3 (GSK-3), also regulate the apoptotic response. Methods and Results-To understand the mechanisms that might regulate the progression of heart failure, we analyzed the activity of these signaling pathways in the hearts of patients with advanced heart failure, patients with compensated cardiac hypertrophy, and normal subjects. In patients with hypertrophy, neither the MAPK nor the Akt/GSK-3 pathways were activated, and the dominant signaling pathway was calcineurin. In failing hearts, calcineurin activity was increased but less so than in the hypertrophied hearts, and all 3 MAPKs and Akt were activated (and, accordingly, GSK-3 beta was inhibited), irrespective of whether the underlying diagnosis was ischemic or idiopathic cardiomyopathy. Conclusions-In the failing heart, there is a clear prohypertrophic activity profile, likely occurring in response to increased systolic wall stress and neurohormonal mediators. However, with the activation of these hypertrophic pathways, potent proapoptotic and antiapoptotic signals may also be generated. Therapies directed at altering the balance of activity of these signaling pathways could potentially alter the progression of heart failure. C1 Massachusetts Gen Hosp, Cardiol Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Renal Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Childrens Hosp, Div Mol Cardiovasc Biol, Cincinnati, OH 45229 USA. Univ Cincinnati, Cincinnati, OH USA. Boston Univ, Sch Med, Boston, MA 02215 USA. RP Force, T (reprint author), New England Med Ctr, Mol Cardiol Res Inst, Box 8486,750 Washington St, Boston, MA 02111 USA. OI Force, Thomas/0000-0002-0450-8659 FU NHLBI NIH HHS [HL50361, HL52318, HL57623, HL61688, HL62927, HL69562]; NIDDK NIH HHS [DK50282]; NIEHS NIH HHS [T32ES07051] NR 21 TC 279 Z9 291 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 6 PY 2001 VL 103 IS 5 BP 670 EP 677 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 412NT UT WOS:000167561800012 PM 11156878 ER PT J AU Kelleher, AD Long, C Holmes, EC Allen, RL Wilson, J Conlon, C Workman, C Shaunak, S Olson, K Goulder, P Brander, C Ogg, G Sullivan, JS Dyer, W Jones, I McMichael, AJ Rowland-Jones, S Phillips, RE AF Kelleher, AD Long, C Holmes, EC Allen, RL Wilson, J Conlon, C Workman, C Shaunak, S Olson, K Goulder, P Brander, C Ogg, G Sullivan, JS Dyer, W Jones, I McMichael, AJ Rowland-Jones, S Phillips, RE TI Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE human immunodeficiency virus; immune escape; selection; CD8(+) T lymphocyte; phylogenetic analysis ID IMMUNODEFICIENCY-VIRUS TYPE-1; DYNAMICS IN-VIVO; REVERSE-TRANSCRIPTASE; GENETIC-VARIATION; ZIDOVUDINE TREATMENT; PRIMARY INFECTION; PERIPHERAL-BLOOD; DRUG-RESISTANCE; CAPSID PROTEIN; CYCLOPHILIN-A AB The immune response to HIV-1 in patients who carry human histocompatibility leukocyte antigen (HLA)-B27 is characterized by an immunodominant response to an epitope in p24 gag (amino acids 263-272. KRWIILGLNK). Substitution of lysine (K) or glycine (G) for arginine (R) at HIV-1 gag residue 264 (R264K and R264G) results in epitopes that bind to HLA-B27 poorly We have detected a R264K mutation in four patients carrying HLA-B27. In three of these patients the mutation occurred late, coinciding with disease progression. In another it occurred within 1 yr of infection and was associated with a virus of syncytium-inducing phenotype. In each case, R264K was tightly associated with a leucine to methionine change at residue 268. After the loss of the cytotoxic T lymphocyte (CTL) response to this epitope and in the presence of high viral load, reversion to wild-type sequence was observed. In a fifth patient, a R264G mutation was detected when HIV-1 disease progressed. Its occurrence was associated with a glutamic acid to aspartic acid mutation at residue 260. Phylogenetic analyses indicated that these substitutions emerged under natural selection rather than by genetic drift or linkage. Outgrowth of CTL escape viruses required high viral loads and additional, possibly compensatory, mutations in the gag protein. C1 John Radcliffe Hosp, Inst Mol Med, MRC Human Immunol, Oxford OX3 9DS, England. John Radcliffe Hosp, Nuffield Dept Clin Med, Oxford OX3 9DU, England. Univ Oxford, Dept Zool, Oxford OX1 3PS, England. AIDS Res Inst, Darlinghurst, NSW 2010, Australia. Hammersmith Hosp, Imperial Coll Sch Med, Dept Infect Dis, London W12 ONN, England. Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA. Australian Red Cross Blood Serv, Sydney, NSW 2000, Australia. Univ Reading, Sch Anim & Microbial Sci, Reading RG6 6AH, Berks, England. RP Kelleher, AD (reprint author), Univ New S Wales, Natl Ctr HIV Epidemiol & Clin Res, 376 Victoria St, Sydney, NSW 2010, Australia. OI Allen, Rachel/0000-0001-9834-8475; Holmes, Edward/0000-0001-9596-3552 NR 54 TC 355 Z9 364 U1 0 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD FEB 5 PY 2001 VL 193 IS 3 BP 375 EP 385 DI 10.1084/jem.193.3.375 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 400ZQ UT WOS:000166902900010 PM 11157057 ER PT J AU Macias, W Carlson, R Rajadhyaksha, A Barczak, A Konradi, C AF Macias, W Carlson, R Rajadhyaksha, A Barczak, A Konradi, C TI Potassium chloride depolarization mediates CREB phosphorylation in striatal neurons in an NMDA receptor-dependent manner SO BRAIN RESEARCH LA English DT Article DE CREB; striatum; L-type Ca2+ channel; potassium chloride depolarization; NMDA receptor; c-fos ID INTRACELLULAR CA2+ CONCENTRATION; TRANSCRIPTION FACTOR CREB; ELEMENT-BINDING-PROTEIN; RAT HIPPOCAMPAL-NEURONS; GAMMA-AMINOBUTYRIC-ACID; GENE-EXPRESSION; CALCIUM CHANNELS; PARKINSONS-DISEASE; PRODYNORPHIN GENE; BASAL GANGLIA AB Potassium chloride (KCl)-depolarization has been used to study the properties of L-type Ca2+ channel-mediated signal transduction in hippocampal neurons. Calcium influx through L-type Ca2+ channels stimulates a second messenger pathway that transactivates genes under the regulatory control of the Ca2+- and cyclic AMP-responsive element (CRE). Here, we show that in striatal neurons, but not in hippocampal neurons, CRE binding protein (CREB) phosphorylation and CRE-mediated gene expression after KCl-depolarization depends on functional NMDA receptors. This difference in NMDA receptor dependence is not due to different properties of L-type Ca2+ channels in either neuronal type, but rather to different neuron-intrinsic properties. Despite this variation, the second messenger pathway activated by KCI requires Ca2+/calmodulin (CaM) kinase for CREB phosphorylation in both neuronal types. We conclude that depolarization by KCl works differently in striatal and hippocampal neurons. (C) 2001 Elsevier Science BN. All rights reserved. C1 McLean Hosp, Lab Neuroplast, Belmont, MA 02478 USA. Massachusetts Gen Hosp, Mol & Dev Neurosci Lab, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Konradi, C (reprint author), McLean Hosp, Lab Neuroplast, MRC 218,115 Mill St, Belmont, MA 02478 USA. FU NIDA NIH HHS [DA07134, R01 DA007134, R01 DA007134-14] NR 50 TC 19 Z9 20 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD FEB 2 PY 2001 VL 890 IS 2 BP 222 EP 232 DI 10.1016/S0006-8993(00)03163-2 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 397CW UT WOS:000166676600004 PM 11164788 ER PT J AU Augustine, JG de la Calle, A Knarr, G Buchner, J Frederick, CA AF Augustine, JG de la Calle, A Knarr, G Buchner, J Frederick, CA TI The crystal structure of the Fab fragment of the monoclonal antibody MAK33 - Implications for folding and interaction with the chaperone BiP SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHAIN BINDING-PROTEIN; HEAVY-CHAIN; PEPTIDE-BINDING; MOLTEN GLOBULE; IN-VITRO; ASSOCIATION; SPECIFICITY; ISOMERASE; COMPLEX; DOMAIN AB The Feb fragment of the murine monoclonal antibody, MAK33, directed against human creatine kinase of the muscle-type, was crystallized and the three-dimensional structure was determined to 2.9 Angstrom. The antigen-binding surface of MAK33 shows a convex overall shape typical for immunoglobulins binding large antigens, The structure allows us to analyze the environment of cis-prolylpeptide bonds whose isomerization is of key importance in the folding process. These residues seem to be involved with not only domain stability but also seem to play a role in the association of heavy and light chains, reinforcing the importance of beta -strand recognition in antibody assembly. The structure also allows the localization of segments of primary sequence postulated to represent binding sites for the ER-specific chaperone BiP within the context of the entire Feb fragment. These sequences are found primarily in beta -strands that are necessary for interactions between the individual domains. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Tech Univ Munich, Inst Organ Chem & Biochem, D-85747 Garching, Germany. RP Frederick, CA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, SM1036,44 Binney St, Boston, MA 02115 USA. RI Buchner, Johannes/A-2651-2010 NR 43 TC 22 Z9 22 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 FEB 2 PY 2001 VL 276 IS 5 BP 3287 EP 3294 DI 10.1074/jbc.M005221200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 398YW UT WOS:000166784900041 PM 11036070 ER PT J AU Zhang, D Pasternack, MS Beresford, PJ Wagner, L Greenberg, AH Lieberman, J AF Zhang, D Pasternack, MS Beresford, PJ Wagner, L Greenberg, AH Lieberman, J TI Induction of rapid histone degradation by the cytotoxic T lymphocyte protease granzyme A SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA FRAGMENTATION; PROTEOLYTIC DIGESTION; MEDIATED CYTOTOXICITY; CHROMATIN CONDENSATION; MYELOID LEUKEMOGENESIS; PUTATIVE ONCOGENE; LIMIT PEPTIDES; PHOSPHATASE 2A; TARGET-CELLS; A BINDS AB The cytotoxic T lymphocyte protease granzyme A induces caspase-independent cell death in which DNA single-strand nicking is observed instead of oligonucleosomal fragmentation. Granzyme A is a specific tryptase that concentrates in the nucleus of targeted cells and synergistically enhances DNA fragmentation induced by the caspase activator granzyme B. Here we show that granzyme A treatment of isolated nuclei enhances DNA accessibility to exogenous endonucleases. In vitro and after cell loading with perforin, GrnA completely degrades histone H1 and cleaves core histones into similar to 16kDa fragments. Histone digestion provides a mechanism for unfolding compacted chromatin and facilitating endogenous DNase access to DNA during T cell and natural killer cell granule-mediated apoptosis. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Univ Manitoba, Manitoba Inst Cell Biol, Winnipeg, MB R3E 0V9, Canada. RP Lieberman, J (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. RI Lieberman, Judy/A-2717-2015 FU NIAID NIH HHS [AI45587] NR 58 TC 66 Z9 69 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 FEB 2 PY 2001 VL 276 IS 5 BP 3683 EP 3690 DI 10.1074/jbc.M005390200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 398YW UT WOS:000166784900091 PM 11060286 ER PT J AU Green, CA Fenn, DS Moussaoui, D Kadri, N Hoffman, WF AF Green, CA Fenn, DS Moussaoui, D Kadri, N Hoffman, WF TI Quality of life in treated and never-treated schizophrenic patients SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Article DE quality of life; schizophrenia; therapeutics; signs and symptoms; dyskinesias; cross-cultural comparison ID OF-LIFE; MENTAL-ILLNESS; FAMILY STIGMA; CONSEQUENCES; COUNTRIES; INSIGHT; DRUGS AB Objective: To evaluate quality of life (QOL) among treated and never-treated schizophrenic patients. Method: QOL ratings were obtained for (a) 112 Moroccan participants with schizophrenia who had never received neuroleptic medications, (b) matched samples of chronically-medicated schizophrenic patients in Morocco and the United States and (c) matched community controls in both countries. Results: QOL ratings were generally higher for US groups, although Moroccan controls obtained higher ratings than US controls for some domains. QOL ratings were higher for controls compared to patients within each country, although US patients' scores were similar to controls on some dimensions. We found no differences between treated and untreated Moroccan patients for any QOL domain, although relationships among predictors were different. Conclusion: Within the context of Moroccan culture, benefits of medications alone are not evident in QOL scores. QOL appears to be a complex construct influenced by different factors within each of the groups studied. C1 Kaiser Permanente Ctr Hlth Res, Portland, OR 97227 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Univ Psychiat Ctr Ibn Rochd, Casablanca, Morocco. Portland VA Med Ctr, Portland, OR USA. RP Green, CA (reprint author), Kaiser Permanente Ctr Hlth Res, 3800 N Interstate Ave, Portland, OR 97227 USA. RI Green, Carla/D-2534-2017 OI Green, Carla/0000-0002-0000-4381 FU NIMH NIH HHS [R01-MH52351-01] NR 44 TC 18 Z9 18 U1 2 U2 9 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-690X J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PD FEB PY 2001 VL 103 IS 2 BP 131 EP 142 DI 10.1034/j.1600-0447.2001.00088.x PG 12 WC Psychiatry SC Psychiatry GA 402LV UT WOS:000166989400009 PM 11167316 ER PT J AU McKay, JR Merikle, E Mulvaney, FD Weiss, RV Koppenhaver, JM AF McKay, JR Merikle, E Mulvaney, FD Weiss, RV Koppenhaver, JM TI Factors accounting for cocaine use two years following initiation of continuing care SO ADDICTION LA English DT Article ID SUBSTANCE-ABUSE TREATMENT; ADDICTION SEVERITY INDEX; OUTPATIENT TREATMENT; TREATMENT SERVICES; DRINKING BEHAVIOR; ALCOHOL ABUSERS; SOCIAL SUPPORT; OPIOID ADDICTS; SELF-EFFICACY; DRUG-ABUSERS AB Aims. To examine the relationship between various interpersonal, intrapersonal and situational factors assessed at 6, 12 and 18 months after entrance to continuing care, and cocaine use in subsequent periods. Design. A randomized clinical trial with a 2-year follow-up. Setting. An outpatient US Veterans Administration substance abuse treatment program. Participants. Cocaine-dependent male veterans (N = 132) entering continuing care. Interventions. 12-Step focused group treatment vs. individualized relapse prevention continuing care. Measurements. Motivation, coping and mood, social support, co-morbid problem severity, treatment attendance, self-help participation and cocaine use variables were assessed at each follow-up. Findings. During the 2-year follow-up, patients used cocaine on fewer than 8% of the days in each of the four 6-month periods, which represented a highly significant decrease in relation to cocaine use prior to treatment. In univariate analyses, abstinence commitment, self-efficacy, positive mood, support from family, employment, attendance in continuing care and self-help participation at two or more of the follow-ups predicted less cocaine use in subsequent 6-month periods. Readiness to change and medical, psychiatric, legal and family/social problem severities either did not predict, or were inconsistently related to, subsequent cocaine use. In multivariate analyses, degree of self-help participation emerged as the strongest and most consistent predictor of cocaine use. However, when current cocaine use at each follow-up was controlled, none of the predictors was significant at more than one follow-up point. There was little evidence of interactions between treatment condition and the predictor variables. Conclusions. Continued self-help participation and the early achievement of cocaine abstinence appear to be important factors in the maintenance of good cocaine use outcomes over extended periods. The results also highlight the importance of controlling for various post-treatment factors when evaluating the relationship between any one factor and subsequent outcome, as many of the factors that were significant predictors in the univariate analyses were no longer significant when other factors were controlled. C1 Univ Penn, Treatment Res Ctr, Dept Psychiat, Philadelphia, PA 19104 USA. Vet Affairs Med Ctr, Philadelphia, PA USA. Pfizer Inc, Groton, CT 06340 USA. DeltaMetr, Philadelphia, PA USA. RP McKay, JR (reprint author), Univ Penn, Treatment Res Ctr, Dept Psychiat, 3900 Chestnut St, Philadelphia, PA 19104 USA. RI Reis, Aline/G-9573-2012 FU NIDA NIH HHS [K02 DA00361, P50 DA05186, R29 DA08399] NR 59 TC 68 Z9 68 U1 5 U2 9 PU CARFAX PUBLISHING PI BASINGSTOKE PA RANKINE RD, BASINGSTOKE RG24 8PR, HANTS, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD FEB PY 2001 VL 96 IS 2 BP 213 EP 225 DI 10.1046/j.1360-0443.2001.9622134.x PG 13 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 402HR UT WOS:000166981500004 PM 11182866 ER PT J AU Norris, PJ Rosenberg, ES AF Norris, PJ Rosenberg, ES TI Cellular immune response to human immunodeficiency virus SO AIDS LA English DT Article; Proceedings Paper CT Satellite Symposium on the Role of Immunotherapy in the Treatment of HIV held at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy CY SEP 26-29, 1999 CL SAN FRANCISCO, CALIFORNIA DE HAART; HIV-1; CD4+T helper cells; CD8+cytotoxic T lymphocytes; structured treatment interruption; immunotherapy ID CYTOTOXIC T-LYMPHOCYTES; LOW VIRAL LOAD; ANTIRETROVIRAL THERAPY; HIV-1 INFECTION; IN-VIVO; COMBINATION THERAPY; CELLS; DISCONTINUATION; RECONSTITUTION; PERSISTENCE AB Despite recent success with the use of highly active antiretroviral therapy, eradication of HIV type 1 appears beyond the capabilities of presently available therapy. Therefore, greater emphasis has been given to finding mechanisms that promote immunologic control of viral replication rather than eradication. Although the correlates of immune protection in HIV-1 infection remain undefined, increasing evidence indicates that HIV-1-specific cellular immune responses may play a critical role in antiviral control. Vigorous HIV-1-specific CD4+ T-helper cell and CD8+ cytotoxic T-lymphocyte responses may play a critical role in control of viral replication in the absence of antiretroviral therapy, which has been demonstrated in individuals with long-term nonprogressive infection. However, in chronic, progressive HIV-1 infection, virus-specific T-helper cell responses are typically weak or absent in all stages of disease, and HIV-1-specific cytotoxic T-lymphocyte responses wane over time, presumably due to the lack of HIV-1-specific T helper cells. Effective treatment of individuals during acute HIV-1 seroconversion syndrome appears to restore HIV-1-specific T-helper cell responses, which are otherwise only observed in persons with long-term nonprogressive infection. This observation, along with anecdotal reports of individuals successfully controlling viral replication after treating acute HIV-1 infection, provides immunologic rationale for structured treatment interruption and other immunotherapeutic approaches designed to augment HIV-1-specific immune responses. (C) 2001 Lippincott Williams & Wilkins. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr AIDS Res, Boston, MA 02144 USA. Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02144 USA. RP Rosenberg, ES (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr AIDS Res, 55 Fruit St, Boston, MA 02144 USA. NR 31 TC 19 Z9 19 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD FEB PY 2001 VL 15 SU 2 BP S16 EP S21 DI 10.1097/00002030-200102002-00004 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 410ZF UT WOS:000167470400004 PM 11424972 ER PT J AU Cho, E Hung, S Willett, WC Spiegelman, D Rimm, EB Seddon, JM Colditz, GA Hankinson, SE AF Cho, E Hung, S Willett, WC Spiegelman, D Rimm, EB Seddon, JM Colditz, GA Hankinson, SE TI Prospective study of dietary fat and the risk of age-related macular degeneration SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE age-related macular degeneration; diet; fats; fatty acids; fish; food-frequency questionnaire; Health Professionals Follow-up Study; men; Nurses' Health Study; prospective studies; women ID FOOD FREQUENCY QUESTIONNAIRE; CORONARY HEART-DISEASE; RETINITIS-PIGMENTOSA; UNITED-STATES; ACIDS; WOMEN; REPRODUCIBILITY; MACULOPATHY; METABOLISM; VALIDITY AB Background: The relation between intakes of total fat and specific types of fat and age-related macular degeneration (AMD) remains unclear. Objective: Our objective was to examine prospectively the association between fat intake and AMD. Design: We conducted a prospective follow-up study of participants in the Nurses' Health Study and the Health Professionals Follow-up Study. At baseline (1984 for women and 1986 for men), the study included 42743 women and 29746 men aged greater than or equal to 50 y with no diagnosis of AMD who were followed until 1996. Fat intake was assessed with a food-frequency questionnaire. Results: We accrued 567 patients with AMD with a visual loss of 20/30 or worse. The pooled multivariate relative risk (RR) for the highest compared with the lowest quintile of total fat intake was 1.54 (95% CI: 1.17, 2.01: P for trend = 0.008). Linolenic acid was positively associated with risk of AMD (top versus bottom quintile of RR: 1.49; 95% CI: 1.15, 1.94; P for trend = 0.0009). Docosahexaenoic acid had a modest inverse relation with AMD (top versus bottom quintile of RR: 0.70; 95% CI: 0.52, 0.93; P for trend = 0.05), and >4 servings of fish/wk was associated with a 35% lower risk of AMD compared with less than or equal to3 servings/mo (RR: 0.65; 95% CI: 0.46, 0.91; P for trend = 0.009). Conclusions: Total fat intake was positively associated with risk of AMD, which may have been due to intakes of individual fatty acids, such as linolenic acid, rather than to total fat intakes per se. A high intake of fish may reduce the risk of AMD. C1 Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med,Dept Med, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Epidemiol Unit, Boston, MA USA. RP Cho, E (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NCI NIH HHS [CA 40356, CA 55075]; NEI NIH HHS [EY 09611]; NHLBI NIH HHS [HL 35464] NR 29 TC 195 Z9 207 U1 1 U2 8 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD FEB PY 2001 VL 73 IS 2 BP 209 EP 218 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 395HU UT WOS:000166575600010 PM 11157315 ER PT J AU Page, DL Gray, R Allred, CC Dressler, LG Hatfield, AK Martino, S Robert, NJ Wood, WC AF Page, DL Gray, R Allred, CC Dressler, LG Hatfield, AK Martino, S Robert, NJ Wood, WC TI Prediction of node-negative breast cancer outcome by histologic grading and S-phase analysis by flow cytometry - An Eastern Cooperative Oncology Group study (2192) SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE breast cancer; histologic grading; S-phase analysis; flow cytometry ID SCARFF-BLOOM-RICHARDSON; TERM-FOLLOW-UP; PROGNOSTIC-FACTORS; DUCTAL CARCINOMA; RISK-FACTORS; TUMOR GRADE; CHEMOTHERAPY; INDEX; P53; PROLIFERATION AB Histologic evaluation and reporting of invasive breast cancer has effectively used Nottingham combined histologic grade (NCHG). This approach to predict outcome in invasive breast cancer has not been tested in multicenter cooperative trials. Histologic slides from selected breast cancer cases entered on node-negative Eastern Cooperative Oncology Group trials were assigned grades. Two pathologists evaluated cases for NCHG defined from differentiation. mitotic index, and nuclear grade. The study population consisted of separate samples from low- and high-risk strata, where low risk was estrogen receptor positive with a tumor size of less than 3 cm and high risk was estrogen receptor negative or tumor size greater than or equal to 3 cm. The rate of agreement was generally good, with 80% of cases classified the same for mitotic count and 76% of the cases classified the same for combined grade. There were no cases disagreeing from the lowest to the highest of the three categories. The median follow-up is 11.6 years, but for analysis of survival, this was truncated at 5 years. Mitotic index and combined grade as assessed by both pathologists showed significant associations with survival. High combined histologic grade was predictive for response to cyclophosphamide/methotrexate/5-fluorouracil (CMF) with survival differences at 5 years of 30% in the treated high-grade patients over the un-treated patients. Overall, it is clear that pathologists can have close agreement in assignment of combined histologic grades, with highly significant prediction in univariate and borderline significance in multivariate analysis in prognostication of time to recurrence as well as survival. Thus, stratification used in these trials was highly prognostic as hoped, leaving a role for histologic grading in these relatively large tumors, more powerful than S-phase analysis in this series. In the subgroups of high-risk patients randomized between CMF and observation, there was a suggestion that the high-combined-grade group was predictive of treatment efficacy. We conclude that a combined histologic grade with defined criteria may be reliably assigned by practiced pathologists using readily available criteria, and that the measure may be of use in prognostication and prediction of therapeutic responsiveness when done in a technically ideal fashion. C1 Vanderbilt Univ, Med Ctr N, Dept Pathol, Nashville, TN 37232 USA. Dana Farber Canc Ctr, Boston, MA USA. Univ Texas San Antonio, San Antonio, TX 78285 USA. Univ N Carolina, Chapel Hill, NC USA. Carle Canc Ctr, Urbana, IL USA. Van Nuys Breast Ctr, Van Nuys, CA USA. Fairfax Hosp, Falls Church, VA USA. Emory Univ, Atlanta, GA 30322 USA. RP Page, DL (reprint author), Vanderbilt Univ, Med Ctr N, Dept Pathol, Nashville, TN 37232 USA. EM david.page@mcmail.vanderbilt.edu FU NCI NIH HHS [CA22433, CA23318, CA49957] NR 67 TC 40 Z9 40 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-3732 EI 1537-453X J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD FEB PY 2001 VL 24 IS 1 BP 10 EP 18 DI 10.1097/00000421-200102000-00002 PG 9 WC Oncology SC Oncology GA 404GA UT WOS:000167088000002 PM 11232942 ER PT J AU Pandya, KJ Yeap, BY Weiner, LM Krook, JE Erban, JK Schinella, RA Davis, TE AF Pandya, KJ Yeap, BY Weiner, LM Krook, JE Erban, JK Schinella, RA Davis, TE TI Megestrol and tamoxifen in patients with advanced endometrial cancer - An Eastern Cooperative Oncology Group study (E4882) SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE endometrial cancer; megestrol; tamoxifen; treatment ID CARCINOMA; ADENOCARCINOMA; RECURRENT; RECEPTORS; ESTROGEN AB To investigate the effect of adding tamoxifen to megestrol in the hormonal therapy for advanced endometrial cancer, 66 patients were entered in this study. Initially. 41 patients were randomized to either the standard progestin therapy of megestrol or to the combination of megestrol and tamoxifen between October 1982 and October 1984. The megestrol arm was terminated because of poor accrual and 25 patients were directly assigned to the combination arm. Among the 20 eligible cases on the megestrol arm, the response rate of 20% consisted of 1 complete response and 3 partial responses. The response rate on the megestrol plus tamoxifen arm was 19% with 1 (2%) complete response and 7 (17%) partial responses among 42 eligible cases. The median survival times were 12.0 months and 8.6 months, respectively. Only mild and moderate toxicities were observed on megestrol compared with more toxic complications observed on the combination of megestrol and tamoxifen, including a life-threatening case of pulmonary embolism. Although we could not carry out a comparative evaluation as intended, we conclude that the combination of megestrol and tamoxifen offers no clinical advantage over megestrol alone in the treatment of advanced endometrial carcinoma. C1 Univ Rochester, Med Ctr, Hematol Oncol Unit, Rochester, NY 14642 USA. Stanford Univ, Stanford, CA 94305 USA. NYU Med Ctr, New York, NY 10016 USA. Tufts New England Med Ctr, Boston, MA USA. Duluth Clin, Duluth, MN USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Pandya, KJ (reprint author), Univ Rochester, Med Ctr, Hematol Oncol Unit, 601 Elmwood Ave,Box 704, Rochester, NY 14642 USA. FU NCI NIH HHS [CA23318, CA18281, CA11083] NR 19 TC 26 Z9 29 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 FEB PY 2001 VL 24 IS 1 BP 43 EP 46 DI 10.1097/00000421-200102000-00007 PG 4 WC Oncology SC Oncology GA 404GA UT WOS:000167088000007 PM 11232948 ER PT J AU Murphy, BA Leong, T Burkey, B Langer, C Forastiere, A AF Murphy, BA Leong, T Burkey, B Langer, C Forastiere, A TI Lack of efficacy of topotecan in the treatment of metastatic or recurrent squamous carcinoma of the head and neck - An Eastern Cooperative Oncology Group trial (E3393) SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE squamous carcinoma; head and neck cancer; topotecan; metastatic disease; treatment ID PHASE-II; CANCER AB Recurrent or metastatic squamous carcinoma of the head and neck (RMSCHN) is a modestly chemoresponsive tumor; however. currently available agents have failed to improve survival. New active agents are needed for the treatment of this disease. Topotecan is a topoisomerase inhibitor that demonstrated initial promising activity in squamous carcinoma of the head and neck. The Eastern Cooperative Oncology Group conducted a phase II trial of topotecan to determine the efficacy and toxicity of a weekly treatment schedule in patients with RMSCHN. Patients with metastatic or locally recurrent squamous carcinoma of the head and neck were treated with topotecan 1.5 mg/m(2) X 24 hours by continuous infusion on days 1, 8, 15, and 22 of each 35-day cycle. Patients were stratified in two cohorts: chemonaive and previously treated. Sixteen chemonaive and 16 previously treated patients were registered on study. Grade III/IV neutropenia and anemia occurred in 16% and 18% of patients, respectively. No responses were observed in either cohort. Median survival for previously untreated patients was 4.6 months and 3.2 months for previously treated patients. Topotecan failed to demonstrate efficacy in patients with RMSCHN. Further evaluation of this agent is not planned. C1 Vanderbilt Univ, Dept Med, Div Hematol Oncol, Nashville, TN USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Johns Hopkins Univ, Sch Med, Johns Hopkins Oncol Ctr, Baltimore, MD 21205 USA. RP Murphy, BA (reprint author), Vanderbilt Clin, Dept Med, Div Hematol Oncol, 1956, Nashville, TN 37232 USA. FU NCI NIH HHS [CA 16116, CA 49957, CA 21115] NR 10 TC 3 Z9 3 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 FEB PY 2001 VL 24 IS 1 BP 64 EP 66 DI 10.1097/00000421-200102000-00011 PG 3 WC Oncology SC Oncology GA 404GA UT WOS:000167088000011 PM 11232952 ER PT J AU Terriff, CM Tee, AM AF Terriff, CM Tee, AM TI Citywide pharmaceutical preparation for bioterrorism SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article DE antidotes; anti-infective agents; biological warfare; disaster planning; dosage; dosage schedules; drug distribution; patient information; pharmacists, hospital; pharmacy, institutional, hospital; public health; vaccines ID PUBLIC-HEALTH MANAGEMENT; BIOLOGICAL WEAPON; SMALLPOX; THREAT; TERRORISM; ANTHRAX AB One community's efforts to become pharmaceutically prepared for an attack with biological agents is described. In response to recent bioterrorist activities, including a local scare in 1999 involving anthrax, the pharmacy department at Deaconess Medical Center in Spokane, Washington, was asked to develop plan for bioterrorism preparedness. A literature search was conducted, and resources, such as the Centers for Disease Control and Prevention, were contacted. For each biological agent, information was compiled about symptom onset, treatment, postexposure prophylaxis, patient isolation precautions, and the availability of antidotes at local hospitals. A procedure was developed for obtaining antidotes that might not be available or stocked in sufficient quantitives. After being reviewed by appropriate authorities, the information was presented to area hospitals and trauma centers, drug wholesalers, hospital risk-management personnel, and emergency management personnel. In May 2000 dozens of emergency and medical personnel attended a day-long program on domestic prepared ness. Citywide cooperation was obtained on how to respond to a mass exposure to a bioterrorism agent. The job of a pharmacist during a bioterrorism strike is to rapidly disseminate antidotes and information, provide dosage and vaccination schedules for both treatment and prophylaxis, and counsel patients. Medical facilities in Spokane have cooperated to make the community more prepared for a bioterrorist attack. C1 Deaconess Med Ctr, Dept Pharm, Spokane, WA 99210 USA. Washington State Univ, Coll Pharm, Spokane, WA USA. RP Terriff, CM (reprint author), Deaconess Med Ctr, Dept Pharm, 800 W 5th Ave, Spokane, WA 99210 USA. NR 15 TC 8 Z9 8 U1 0 U2 1 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD FEB 1 PY 2001 VL 58 IS 3 BP 233 EP 237 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 398VR UT WOS:000166777600009 PM 11217178 ER PT J AU Rosenberg, BJ Barbeau, EM Moure-Eraso, R Levenstein, C AF Rosenberg, BJ Barbeau, EM Moure-Eraso, R Levenstein, C TI The work environment impact assessment: A methodologic framework for evaluating health-based interventions SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE work environment; impact assessment; intervention; intervention research ID MICE AB Background A new conceptual framework is needed to evaluate health-based interventions based on the premise that like the environment, workplaces are complex ecologies. The proposed Work Environment Impact Assessment (WEIA) is analogous to Environmental Impact Assessment (EIA), a concept and method developed 30 years ago in the environmental policy arena to evaluate potential consequences of human activity for the natural environment. WEIA entails identifying and evaluating both intended and unintended consequences, or outcomes, associated with a particular intervention. Because the workplace is a complex ecology, changes in one aspect may lead to changes in other aspects. WEIA calls for a systematic and comprehensive approach to the total work environment. Methods To illustrate the utility of WEIA we use this approach to evaluate an intervention to reduce the public's exposure to the pesticide Alar(R), which had been used on apples until it was withdrawn from the market in 1989. Results While this intervention did indeed reduce the public's exposure to Alar, it also led to other unintended consequences, namely new ergonomic hazards for apple pickers, increased stress levels in the orchards for both pickers and growers, as well as new worker and perhaps public, exposure to potent neurotoxins. Conclusions The goal of using WEIA is not to engage in a risk-risk debate that stalls worthwhile interventions. Rather we propose that by conducting a Work Environment Impact Assessment, all possible positive and negative "ripple" effects stemming from an intervention can be considered, so that the intervention can be designed to achieve maximum benefit. Am. J. Ind. Med. 39:218-226, 2001. (C) 2001 Wiley-Liss, Inc. C1 Tufts Univ, Sch Med, Dept Family Med & Community Hlth, Boston, MA 02111 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth & Social Behav, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Univ Massachusetts, Dept Work Environm, Lowell, MA USA. RP Rosenberg, BJ (reprint author), Tufts Univ, Sch Med, Dept Family Med & Community Hlth, 136 Harrison Ave, Boston, MA 02111 USA. NR 33 TC 17 Z9 17 U1 3 U2 10 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD FEB PY 2001 VL 39 IS 2 BP 218 EP 226 DI 10.1002/1097-0274(200102)39:2<218::AID-AJIM1009>3.0.CO;2-4 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 398KV UT WOS:000166756400010 PM 11170164 ER PT J AU Robinson, JP Fulton-Kehoe, D Martin, DC Franklin, GM AF Robinson, JP Fulton-Kehoe, D Martin, DC Franklin, GM TI Outcomes of pain center treatment in Washington State workers' compensation SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE historical cohort studies; musculoskeletal diseases; pain clinics; pain; intractable; treatment outcome; workers compensation ID LOW-BACK-PAIN; RANDOMIZED CONTROLLED TRIALS; FUNCTIONAL RESTORATION; FOLLOW-UP; REHABILITATION PROGRAM; NEGLECTED TOPICS; DISABILITY; RETURN; LITIGATION; INPATIENT AB Background Injured workers with chronic pain who have failed conventional therapies often receive treatment at pain centers. This study evaluated the effect of pain center treatment on time loss status of Washington State injured workers. The primary hypothesis was that treatment at a pain center would lead to a reduction in the probability of a worker's receiving time loss benefits at a 2-year follow-up. Methods A population-based retrospective cohort study was performed on 2,032 Washington State workers' compensation patients who underwent pain center evaluations. Subjects who received pain center treatment were compared to those who were evaluated but not treated with respect to time loss status at 2-year follow-up. Results Univariate analysis revealed that at 2-year follow-up, 35% of treated subjects were receiving time loss payments vs, 40% of evaluated only subjects (P < 0.05). Subjects who were younger female, and less chronic were more likely to undergo pain center treatment and were less likely to be on time loss at 2-year follow-up. In multivariate analyses, which statistically controlled baseline differences between the two groups, there was no difference between treated subjects and evaluated only subjects. Conclusions There was no evidence that pain center treatment alters 2-year time loss status of already disabled workers. Am, J. Ind. Med. 39:227-236, 2001. (C) 2001 Wiley-Liss, Inc. C1 Univ Washington, Pain Ctr, Seattle, WA 98103 USA. Univ Washington, Sch Publ Hlth & Community Med, Dept Environm Hlth, Seattle, WA 98195 USA. Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. Univ Washington, Sch Med, Dept Neurol, Seattle, WA USA. RP Robinson, JP (reprint author), Univ Washington, Pain Ctr, 1914 N 34th St,Suite 101, Seattle, WA 98103 USA. NR 66 TC 5 Z9 5 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 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD FEB PY 2001 VL 39 IS 2 BP 227 EP 236 DI 10.1002/1097-0274(200102)39:2<227::AID-AJIM1010>3.0.CO;2-W PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 398KV UT WOS:000166756400011 PM 11170165 ER PT J AU Fried, L Bernardini, J Piraino, B AF Fried, L Bernardini, J Piraino, B TI Charlson comorbidity index as a predictor of outcomes in incident peritoneal dialysis patients SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article; Proceedings Paper CT 20th Annual PD Conference CY FEB 27-29, 2000 CL SAN FRANCISCO, CALIFORNIA DE end-stage renal disease (ESRD); peritoneal dialysis; mortality; comorbidity; risk factors ID CO-MORBIDITY; MORTALITY; HEMODIALYSIS; SURVIVAL; IMPACT; DEATH; RISK AB A previous study at our center used the Charlson Comorbidity Index (CCI) (an index of comorbidity that includes age) to predict outcomes in a mixed group of incident and prevalent dialysis patients. The purpose of this study was to examine the usefulness of the CCI as a predictor in incident peritoneal dialysis (PD) patients and to examine whether it was a better predictor than simply the number of comorbid conditions or other known predictors, such as age, albumin level, diabetes, and cardiovascular disease. Since 1990, we have collected prospectively comorbidity data at the start of PD, All patients with known comorbidity and serum albumin and who did not have a prior history of hemodialysis or transplant were included (n = 268). Time at risk began at day 1 of PD training. Cox proportional hazards best subset selection was used to screen models to predict patient survival. Candidate models were analyzed further for proportionality and other model assumptions. Univariate analysis showed that significant predictors of mortality were CCI (chi-square = 43.3, P < 0.0001), age (chi-square = 23.7, P < 0.0001), cardiac disease (chi-square = 19.9, P < 0.0001), number of comorbid conditions (chi-square = 15.6, P < 0.0001), serum albumin at the start of dialysis (chi-square = 15.3, P = 0.0001), and diabetes (chi-square = 4, P < 0.05). In multivariate analysis, CCI alone was the best predictor, The addition of serum albumin did not improve the model significantly (chi-square = 51.86 versus 49.34). For every increase of 1 in the CCI score, the relative risk of death was 1.54 (95% confidence interval, 1.36 to 1.74). CCI alone scored at the start of PD is a strong predictor of patient survival in incident end-stage renal disease patients on PD. This simple-to-calculate index would be useful to adjust for confounding in future studies and in the adjustment of case mix if Medicare moves to a capitated payment system. (C) 2001 by the National Kidney Foundation, Inc. C1 Univ Pittsburgh, Sch Med, Renal Electrolyte Div, Pittsburgh, PA 15213 USA. VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. RP Fried, L (reprint author), Univ Pittsburgh, Sch Med, Renal Electrolyte Div, 938 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15213 USA. OI Piraino, Beth/0000-0001-5061-0841 NR 29 TC 145 Z9 153 U1 1 U2 7 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 FEB PY 2001 VL 37 IS 2 BP 337 EP 342 DI 10.1053/ajkd.2001.21300 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 396QE UT WOS:000166647400012 PM 11157375 ER PT J AU Norbash, AM Singer, RJ AF Norbash, AM Singer, RJ TI Videographic assessment of the embolic characteristics of three polymeric compounds: Ethylene vinyl alcohol, cellulose acetate, and liquid urethane SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID FLOW DYNAMICS; ARTERIOVENOUS-MALFORMATIONS; ENDOVASCULAR TREATMENT; EXPERIMENTAL ANEURYSMS; CAROTID-ARTERY; EMBOLIZATION; THROMBOSIS; COPOLYMER; MODEL; STENTS AB BACKGROUND AND PURPOSE: Aneurysms have been clinically and experimentally treated with various surgical and endovascular methods, including endovascular polymer instillation, Additional tools may help to identify advantages and disadvantages of polymeric aneurysm treatment, We assessed the value of high-resolution videography to compare in vitro embolization characteristics of ethylene vinyl alcohol copolymer (VIN), cellulose acetate polymer (ACE), and urethane copolymer (UCO), METHODS: In a "neck-up" glass aneurysm model, solutions of 8% and 12% VIN, 8% and 12% ACE, and 8% UCO were introduced through a microcatheter into a xanthan gum solution at three flow rates: full physiological (62 cm/s), half physiological, and pow arrest, Each formulation was then introduced into a "neck-down" aneurysm model at flow arrest, for a total of 20 experiments. Results were tabulated for six different categories: outflow tail formation, inflow-zone polymer-mass deformation, inflow-zone migration, detachment tail formation, adherent mass pullout, and conjectural net effect, RESULTS: Of the 20 experiments, nine had unacceptable results because of potential clinical complications. The results were unacceptable in four of eight VIN experiments, four of eight ACE experiments, and one of four UCO experiments. VIN performance was more dependent on how arrest than the more viscous ACE. The growth of the ACE solutions was most circumferential, with balloonlike growth characteristics, little inflow-zone effects, and fewer outflow tails than seen with VIN, All compounds had the potential for partial catheter adhesion and catheter-adhesing tails. UCO had the highest percentage of favorable results and the lowest percentage of unfavorable results, CONCLUSION: Videographic analysis allows detailed assessment of the dynamic embolization characteristics of polymers, revealing potential advantages of compounds such as UCO. C1 Harvard Univ, Brigham & Womens Hosp, Dept Neuroradiol, Div Intervent Neuroradiol, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Div Vasc Neurosurg, Boston, MA 02115 USA. RP Norbash, AM (reprint author), Harvard Univ, Brigham & Womens Hosp, Dept Neuroradiol, Div Intervent Neuroradiol, ASB1,L1,Room 015,75 Francis St, Boston, MA 02115 USA. NR 22 TC 12 Z9 12 U1 0 U2 1 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD FEB PY 2001 VL 22 IS 2 BP 334 EP 340 PG 7 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 403NL UT WOS:000167049300022 PM 11156779 ER PT J AU Kassoff, A Kassoff, J Mehu, M Buehler, J Eglow, M Kaufman, F Kieval, S Margherio, RR Cox, MS Garretson, B Hassan, T Ruby, A Trese, MT Werner, JC Williams, GA Regan, V Manatrey, P Cumming, K Lewis, B Zajechowski, M Falk, R Streasick, P Szydlowski, L McIver, F Bridges, C Stanley, C Klein, ML Robertson, JE Wilson, DJ Beardsley, C Smith, G Howard, S Dreyer, RF Ma, C Chenoweth, RG Zilis, JD Crider, H Parker, S Sherman, K Martin, D Aaberg, TM Aaberg, TM Sternberg, P Curtis, L Gilman, J Myles, B Armiger, D Capone, A Saperstein, D Stribling, B Swords, R Orth, DH Flood, TP Civantos, J deBustros, S Packo, KH Merrill, PT MacLeod, C Morrison, C Bryant, DA Doherty, D Sandoval, S Seddon, JM Pinnolis, MK Jones-Devonish, DA Evans, C Davis, N Callahan, C Walsh, D Dubois, J Burton, I Rosenberg, NJ Patel, P Crouse, VD Snow, KK Chew, EY Ferris, FL Csaky, K Dabas, KH Goodman, L Kim, YJ Mercer, R Palmer, MC Ciatto, PF Kuehl, E Kivitz, I Koutsandreas, D Nashwinter, R Haughey, M Babilonia-Ayukawa, G La-Reau, A McCarthy, SA Ayres, LM Lopez, P Randall, A Friberg, TR Eller, A Gorin, MB Alexander, J Mack, B Paine, MK Corbin, PS Curtin, DY Ostroska, PP Warnicki, J Fijewski, E Bressler, SB Bressler, NM Cassel, G Finkelstein, D Goldberg, M Haller, JA Ratner, L Schachat, AP Sherman, SH Sunness, JS Schnenning, S Sackett, C Belt, J Cain, D Emmert, D Herring, M George, T Wheeler, S Elman, MJ Ballinger, R Betancourt, A Glasser, D Lammlein, J Seff, R Shuman, M Starr, J Carrigan, A Mathews, T Sotirakos, P Cain, T Ringrose, C Chandra, SR Davis, MD Ip, M Klein, R Nork, TM Stevens, T Blodi, B Gottlieb, J Walker, W Soderling, B Schmitz, M Perkins, T Blatz, M Harrison, B Knutson, G Neider, M Peterson, J Krolnik, D Somers, G Myers, FL Davis, MD Klein, BEK Klein, R Hubbard, L Armstrong, J Neider, M Wabers, H Kastorff, L Lang, K Badal, D Geithman, PL Miner, KD Dohm, KL Onofrey, JA Esser, B Hurtenbach, C Fisher, MR Robinson, NL Baliker, J Gai, C Craanen, S Webster, M Elledge, J Reed, S Bent, W Glander, KE Osterby, KR Reimers, J Magli, YL Brickbauer, J Ansay, S King, WN Miller, D Sowell, A Gunter, E Bowman, B Lindblad, AS Ederer, F Milton, RC Clemons, T Gensler, G Keller, A Entler, G Stine, E Brunson, K Berlin, SH Pallas, S Mengers, SA Scholl, PR Anand, R Ferris, FL Chew, EY Sperduto, R Kurinij, N AF Kassoff, A Kassoff, J Mehu, M Buehler, J Eglow, M Kaufman, F Kieval, S Margherio, RR Cox, MS Garretson, B Hassan, T Ruby, A Trese, MT Werner, JC Williams, GA Regan, V Manatrey, P Cumming, K Lewis, B Zajechowski, M Falk, R Streasick, P Szydlowski, L McIver, F Bridges, C Stanley, C Klein, ML Robertson, JE Wilson, DJ Beardsley, C Smith, G Howard, S Dreyer, RF Ma, C Chenoweth, RG Zilis, JD Crider, H Parker, S Sherman, K Martin, D Aaberg, TM Aaberg, TM Sternberg, P Curtis, L Gilman, J Myles, B Armiger, D Capone, A Saperstein, D Stribling, B Swords, R Orth, DH Flood, TP Civantos, J deBustros, S Packo, KH Merrill, PT MacLeod, C Morrison, C Bryant, DA Doherty, D Sandoval, S Seddon, JM Pinnolis, MK Jones-Devonish, DA Evans, C Davis, N Callahan, C Walsh, D Dubois, J Burton, I Rosenberg, NJ Patel, P Crouse, VD Snow, KK Chew, EY Ferris, FL Csaky, K Dabas, KH Goodman, L Kim, YJ Mercer, R Palmer, MC Ciatto, PF Kuehl, E Kivitz, I Koutsandreas, D Nashwinter, R Haughey, M Babilonia-Ayukawa, G La-Reau, A McCarthy, SA Ayres, LM Lopez, P Randall, A Friberg, TR Eller, A Gorin, MB Alexander, J Mack, B Paine, MK Corbin, PS Curtin, DY Ostroska, PP Warnicki, J Fijewski, E Bressler, SB Bressler, NM Cassel, G Finkelstein, D Goldberg, M Haller, JA Ratner, L Schachat, AP Sherman, SH Sunness, JS Schnenning, S Sackett, C Belt, J Cain, D Emmert, D Herring, M George, T Wheeler, S Elman, MJ Ballinger, R Betancourt, A Glasser, D Lammlein, J Seff, R Shuman, M Starr, J Carrigan, A Mathews, T Sotirakos, P Cain, T Ringrose, C Chandra, SR Davis, MD Ip, M Klein, R Nork, TM Stevens, T Blodi, B Gottlieb, J Walker, W Soderling, B Schmitz, M Perkins, T Blatz, M Harrison, B Knutson, G Neider, M Peterson, J Krolnik, D Somers, G Myers, FL Davis, MD Klein, BEK Klein, R Hubbard, L Armstrong, J Neider, M Wabers, H Kastorff, L Lang, K Badal, D Geithman, PL Miner, KD Dohm, KL Onofrey, JA Esser, B Hurtenbach, C Fisher, MR Robinson, NL Baliker, J Gai, C Craanen, S Webster, M Elledge, J Reed, S Bent, W Glander, KE Osterby, KR Reimers, J Magli, YL Brickbauer, J Ansay, S King, WN Miller, D Sowell, A Gunter, E Bowman, B Lindblad, AS Ederer, F Milton, RC Clemons, T Gensler, G Keller, A Entler, G Stine, E Brunson, K Berlin, SH Pallas, S Mengers, SA Scholl, PR Anand, R Ferris, FL Chew, EY Sperduto, R Kurinij, N CA Age-Related Eye Disease Study Res TI The age-related eye disease study (AREDS) system for classifying cataracts from photographs: AREDS report No. 4 SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article AB PURPOSE: To describe the system for grading cataracts from photographs in the Age Related Eye Disease Study (AREDS). METHODS: The system for grading cataracts in AREDS uses photographs taken in a standardized fashion with specially modified cameras at 11 clinical centers, The photographs are evaluated by graders for quality and cataract severity at a central reading center, The area of lens involvement is used to assess the severity of cortical and posterior subcapsular opacities, Optical density of nuclear opacity is graded against a series of seven standard photographs. Contemporaneous variability in grading is evaluated periodically by having a second examiner regrade a subset of the photographs. Temporal variability is assessed by annually regrading a subset of photographs. RESULTS: Photographs of 925 eyes, most with no or early lens opacities, were regraded to assess intergrader reliability. For cortical opacities, there was an absolute difference of 10% or greater of area involved in 1.9% of the replicate gradings. For posterior subcapsular opacities an absolute difference of 5% of area involved was noted in 2.8% of the regraded photographs. For nuclear opacities, absolute differences of 1.5 or more steps were observed in 0.6% of eyes. There was little evidence of temporal drift in grading any of the three types of opacity during four annual regrades. CONCLUSIONS: We have demonstrated a high degree of reliability in grading the severity of lens opacities in a large study cohort with mostly early lens changes, the type of cohort most likely to be entered in clinical trials involving cataract prevention. The Age-Related Eye Disease Study System for Classifying Cataracts From Photographs could be useful in studies where there is a need to standardize data collection over time and across different data collection sites. Limitations of the system include the cost of implementation and, currently, the limited amount of data on grading reproducibility for more advanced lens opacities. (Am J Ophthalmol 2001;131:167-175. (C) 2001 by Elsevier Science Inc. All rights reserved). C1 Associated Retinal Consultants PC, Royal Oak, MI USA. Devers Eye Inst, Portland, OR USA. Emory Univ, Atlanta, GA 30322 USA. Ingalls Mem Hosp, Harvey, IL USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. NEI, Ctr Clin, Bethesda, MD USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Univ Wisconsin, Madison, WI 53706 USA. Univ Wisconsin, Reading Ctr, Madison, WI 53706 USA. Ctr Dis Control & Prevent, Cent Lab, Atlanta, GA USA. NEI, Project Off, Bethesda, MD USA. NIH, Div Contracts & Grants, Bethesda, MD USA. Bausch & Lomb Pharmaceut, Rochester, NY USA. EMMES Corp, AREDS Coordinating Ctr, Potomac, MD 20854 USA. RP Kassoff, A (reprint author), EMMES Corp, AREDS Coordinating Ctr, 11325 7 Locks Rd, Potomac, MD 20854 USA. NR 3 TC 149 Z9 150 U1 0 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 FEB PY 2001 VL 131 IS 2 BP 167 EP 175 PG 9 WC Ophthalmology SC Ophthalmology GA 400KK UT WOS:000166870600002 ER PT J AU Yu, Q Stamenkovic, I AF Yu, Q Stamenkovic, I TI Angiopoietin-2 is implicated in the regulation of tumor angiogenesis SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID RECEPTOR TYROSINE KINASE; TIE2 RECEPTOR; EXPRESSION; GROWTH; CELLS; VASCULOGENESIS; ENDOTHELIUM; MITOGEN; LIGAND; GENE AB We addressed the effect of angiopoietin expression on tumor growth and metastasis. Overexpression of angiopoietin-2 (Ang-2) in Lewis lung carcinoma and TA3 mammary carcinoma cells inhibited their ability to form metastatic tumors and prolonged the survival of mice injected with the corresponding transfectants. In contrast, angiopoietin-1 (Ang-l) overexpression had no detectable effect on the ability of either tumor type to disseminate. Tumors derived from Ang-2-overexpressing cells displayed aberrant angiogenic vessels that took the form of vascular cords or aggregated vascular endothelial cells with few associated smooth muscle cells. These vascular cords or aggregates were accompanied by endothelial and tumor cell apoptosis, suggesting that an imbalance in Ang-2 expression with respect to Ang-1 and vascular endothelial growth factor may disrupt angiogenesis and tumor survival in vivo. Our observations suggest that Ang-2 may play an important role in regulating tumor angiogenesis. C1 Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Stamenkovic, I (reprint author), Massachusetts Gen Hosp, Mol Pathol Unit, 149 13th St,7th Floor, Charlestown, MA 02129 USA. FU NCI NIH HHS [CA55735]; NIGMS NIH HHS [GM54176] NR 32 TC 75 Z9 83 U1 0 U2 0 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD FEB PY 2001 VL 158 IS 2 BP 563 EP 570 DI 10.1016/S0002-9440(10)63998-3 PG 8 WC Pathology SC Pathology GA 401KC UT WOS:000166925900025 PM 11159193 ER PT J AU Boppart, MD Hirshman, MF Sakamoto, K Fielding, RA Goodyear, LJ AF Boppart, MD Hirshman, MF Sakamoto, K Fielding, RA Goodyear, LJ TI Static stretch increases c-Jun NH2-terminal kinase activity and p38 phosphorylation in rat skeletal muscle SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE contraction; extracellular signal-regulated kinase; soleus; extensor digitorum longus ID ACTIVATED PROTEIN-KINASE; GROWTH-FACTOR-I; MECHANICAL STRETCH; CARDIAC MYOCYTES; HYPERTROPHY; EXPRESSION; CELLS; EXERCISE; PATHWAY; INSULIN AB Physical exercise and contraction increase c-Jun NH2-terminal kinase (JNK) activity in rat and human skeletal muscle, and eccentric contractions activate JNK to a greater extent than concentric contractions in human skeletal muscle. Because eccentric contractions include a lengthening or stretch component, we compared the effects of isometric contraction and static stretch on JNK and p38, the stress-activated protein kinases. Soleus and extensor digitorum longus (EDL) muscles dissected from 50- to 90-g male Sprague-Dawley rats were subjected to 10 min of electrical stimulation that produced contractions and/or to 10 min of stretch (0.24 N tension, 20-25% increase in length) in vitro. In the soleus muscle, contraction resulted in a small, but significant, increase in JNK activity (1.8-fold above basal) and p38 phosphorylation (4-fold). Static stretch had a much more profound effect on the stress-activated protein kinases, increasing JNK activity 19-fold and p38 phosphorylation 21-fold. Increases in JNK activation and p38 phosphorylation in response to static stretch were fiber-type dependent, with greater increases occurring in the soleus than in the EDL. Immunohistochemistry performed with a phosphospecific antibody revealed that activation of JNK occurred within the muscle fibers. These studies suggest that the stretch component of a muscle contraction may be a major contributor to the increases in JNK activity and p38 phosphorylation observed after exercise in vivo. C1 Brigham & Womens Hosp, Dept Med, Joslin Diabet Ctr, Div Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Boston Univ, Dept Hlth Sci, Sargent Coll Hlth & Rehabil Sci, Boston, MA 02215 USA. RP Goodyear, LJ (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. FU NIAMS NIH HHS [AR-42238]; NIDDK NIH HHS [T32 DK-07260-22] NR 33 TC 66 Z9 76 U1 0 U2 5 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 FEB PY 2001 VL 280 IS 2 BP C352 EP C358 PG 7 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 392NB UT WOS:000166416600016 PM 11208531 ER PT J AU Chen, MC Goliger, J Bunnett, N Soll, AH AF Chen, MC Goliger, J Bunnett, N Soll, AH TI Apical and basolateral EGF receptors regulate gastric mucosal paracellular permeability SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE epidermal growth factor receptors; transforming growth factor receptors; gastric mucosal defense; paracellular pathway ID EPIDERMAL GROWTH-FACTOR; TYROSINE PHOSPHORYLATION; FACTOR-ALPHA; EPITHELIAL-CELLS; LOCALIZATION; PEPTIDES; CULTURE; KINASE; SOMATOSTATIN; MONOLAYERS AB Previous studies found that monolayers formed from canine oxyntic epithelial cells in primary culture displayed remarkable resistance to apical acidification and both mitogenic and migratory responses to epidermal growth factor (EGF) treatment. In our present studies, we found that EGF increased transepithelial resistance (TER) but not short-circuit current in these monolayers. Parallel effects of EGF on decreasing mannitol flux and increasing TER implicate direct regulation of paracellular permeability. EGF acting at either apical and basolateral receptors rapidly increased TER, but the apical response was sustained whereas the basolateral response was transient. I-125-labeled EGF binding revealed specific apical binding, but receptor numbers were 25-fold lower than on the basolateral surface. Both apical and basolateral EGF activated tyrosine phosphorylation of EGF receptors (EGFR), beta -catenin, and cellular substrate as evident on confocal microscopy. Although apical EGF activated a lesser degree of receptor autophosphorylation than basolateral EGF, phosphorylation of beta -catenin was equally prominent with apical and basolateral receptor activation. Together, these findings indicate that functional apical and basolateral EGFR exist on primary canine gastric epithelial cells and that these receptors regulate paracellular permeability. The sustained effect of apical EGFR activation and prominent phosphorylation of beta -catenin suggest that apical EGFR may play a key role in this regulation. C1 Univ Calif Los Angeles, W Los Angeles Vet Affairs Med Ctr, Sch Med, CURE Digest Dis Res Ctr, Los Angeles, CA USA. Univ Calif San Francisco, Sch Med, Dept Surg & Physiol, San Francisco, CA 94143 USA. RP Chen, MC (reprint author), Vet Adm Wadsworth Hosp Ctr, Bldg 115,Rm 215,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. FU NIDDK NIH HHS [DK-19984, DK-30444] NR 36 TC 14 Z9 14 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 FEB PY 2001 VL 280 IS 2 BP G264 EP G272 PG 9 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 391FR UT WOS:000166346400013 PM 11208549 ER PT J AU Sang, Q Goyal, RK AF Sang, Q Goyal, RK TI Swallowing reflex and brain stem neurons activated by superior laryngeal nerve stimulation in the mouse SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE c-fos expression; solitary subnuclei; nucleus ambiguus; dorsal motor nucleus of vagus; swallowing program generator ID LOWER ESOPHAGEAL SPHINCTER; UPPER ALIMENTARY-TRACT; VISCEROTOPIC REPRESENTATION; MEDULLA-OBLONGATA; PREMOTOR NEURONS; RAT; CAT; AFFERENTS; NUCLEUS; LOCALIZATION AB The purpose of the present study was to identify vagal subnuclei that participate in reflex swallowing in response to electrical stimulation of the left superior laryngeal nerve (SLN). SLN stimulation at 10 Hz evoked primary peristalsis, including oropharyngeal and esophageal peristalsis, and LES relaxation. It also induced c-fos expression in interneurons in the interstitial (SolI), intermediate (SolIM), central (SolCe), dorsomedial (SolDM) and commissural (SolC) solitary subnuclei. Neurons in parvicellular reticular nucleus (PCRt) and area postrema (AP) and motoneurons in the semicompact (NAsc), loose (NAl), and compact (NAc) formations of the nucleus ambiguus and both rostral (DMVr) and caudal (DMVc) parts of the dorsal motor nucleus of vagus were also activated. The activated neurons represent all neurons concerned with afferent SLN-mediated reflexes, including the swallowing-related neurons. SLN stimulation at 5 Hz elicited oropharyngeal and LES but not esophageal responses and evoked c-fos expression in neurons in SolI, SolIM, SolDM, PCRt, AP, NAsc, NAl, and DMVc but not in SolCe, NAc, or DMVr. These data are consistent with the role of SolI, SolIM, SolDM, NAsc, NAl, and DMVc circuit in oropharyngeal peristalsis and LES relaxation and SolCe, NAc, DMVc, and DMVr in esophageal peristalsis and LES responses. C1 VA Boston Hlth Care Syst, Res & Dev, W Roxbury Div, Ctr Swallowing & Motil Disorders, W Roxbury, MA 02132 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Goyal, RK (reprint author), VA Boston Hlth Care Syst, Res & Dev, W Roxbury Div, Ctr Swallowing & Motil Disorders, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. FU NIDDK NIH HHS [DK-31092] NR 34 TC 22 Z9 22 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 FEB PY 2001 VL 280 IS 2 BP G191 EP G200 PG 10 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 391FR UT WOS:000166346400004 PM 11208540 ER PT J AU Tavakkolizadeh, A Berger, UV Shen, KR Levitsky, LL Hediger, MA Ashley, SW Whang, EE Rhoads, DB AF Tavakkolizadeh, A Berger, UV Shen, KR Levitsky, LL Hediger, MA Ashley, SW Whang, EE Rhoads, DB TI Diurnal rhythmicity in intestinal SGLT-1 function, V-max, and mRNA expression topography SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE intestinal sugar absorption; Ussing chamber; sodium-glucose cotransporter; in situ hybridization; enzyme kinetics ID TRANSPORTER MESSENGER-RNA; CRYPT-VILLUS SITE; PLASMA-GLUCOSE; RATS; INSULIN; RESPONSES AB Mechanisms underlying the circadian rhythmicity in intestinal sugar absorption remain unclear. To test whether this rhythmicity is caused by changes in Na+-glucose cotransporter 1 (SGLT-1) function, we measured phloridzin-inhibitable sugar fluxes as an index of SGLT-1 activity. Jejunum obtained from rats killed at 6-h intervals during a 12-h light-dark cycle (CT0 is circadian time 0 h, time of light onset) were mounted in Ussing chambers, and 3-O-methylglucose (3-OMG) fluxes were calculated before and after addition of phloridzin. 3-OMG-induced change in short-circuit current and absorptive flux were significantly greater at CT9 than at CT3. This increase was phloridzin inhibitable. Kinetic studies indicated a significant increase in SGLT-1 maximal velocity (V-max) at CT9. Food intake between CT3 and CT9 was <10% of the daily total, indicating that the increased SGLT-1 activity was anticipatory. Diurnicity of SGLT-1 mRNA was confirmed by Northern blotting. Expression topography analyzed by in situ hybridization revealed more intense labeling along the entire villus axis at CT9 and CT15 compared with CT3 and CT21. We conclude that diurnicity in intestinal sugar absorption is caused by periodicity in SGLT-1 V-max. C1 Harvard Univ, Pediat Endocrine Unit, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Membrane Biol Program, Boston, MA 02115 USA. RP Rhoads, DB (reprint author), Harvard Univ, Pediat Endocrine Unit, Massachusetts Gen Hosp, Sch Med, 55 Fruit St,BHX410, Boston, MA 02114 USA. FU NICHD NIH HHS [HD-31215]; NIDDK NIH HHS [DK-54399, DK-47326] NR 32 TC 42 Z9 42 U1 0 U2 3 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 FEB PY 2001 VL 280 IS 2 BP G209 EP G215 PG 7 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 391FR UT WOS:000166346400006 PM 11208542 ER PT J AU Takata, M Filippov, G Liu, HL Ichinose, F Janssens, S Bloch, DB Bloch, KD AF Takata, M Filippov, G Liu, HL Ichinose, F Janssens, S Bloch, DB Bloch, KD TI Cytokines decrease sGC in pulmonary artery smooth muscle cells via NO-dependent and NO-independent mechanisms SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE interleukin-1 beta; tumor necrosis factor-alpha; nitric oxide; guanosine 3 ',5 '-cyclic monophosphate ID SOLUBLE GUANYLATE-CYCLASE; NITRIC-OXIDE SYNTHASE; MOLECULAR-CLONING; MESSENGER-RNA; EXPRESSION; SHOCK; GENE; LUNG AB Exposure of rat pulmonary artery smooth muscle cells (rPASMC) to cytokines leads to nitric oxide (NO) production by NO synthase 2 (NOS2). NO stimulates cGMP synthesis by soluble guanylate cyclase (sGC), a heterodimer composed of alpha (1)- and beta (1)-subunits. Prolonged exposure of rPASMC to NO decreases sGC subunit mRNA and protein levels. The objective of this study was to determine whether levels of NO produced endogenously by NOS2 are sufficient to decrease sGC expression in rPASMC. Interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) increased NOS2 mRNA levels and decreased sGC subunit mRNA levels. Exposure of rPASMC to IL-1 beta and TNF-alpha for 24 h decreased sGC subunit protein levels and NO-stimulated sGC enzyme activity. L-N-6-(1-iminoethyl) lysine (NOS2 inhibitor) or 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (sGC inhibitor) partially prevented the cytokine-mediated decrease in sGC subunit mRNA levels. However, cytokines also decreased sGC subunit mRNA levels in PASMC derived from NOS2-deficient mice. These results demonstrate that levels of NO and cGMP produced in cytokine-exposed PASMC are sufficient to decrease sGC subunit mRNA levels. In addition, cytokines can decrease sGC subunit mRNA levels via NO-independent mechanisms. C1 Harvard Univ, Sch Med, Dept Med, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Anesthesia, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Arthrit Unit, Charlestown, MA 02129 USA. Univ Leuven VIB, Univ Hosp Gasthuisberg, Ctr Transgene Technol & Gene Therapy, B-3000 Leuven, Belgium. Univ Leuven, Univ Hosp Gasthuisberg, Cardiac Unit, B-3000 Leuven, Belgium. RP Bloch, KD (reprint author), Massachusetts Gen Hosp E, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. EM blochk@helix.mgh.harvard.edu FU NHLBI NIH HHS [T32-HL-07208, HL-55377, HL-42397] NR 22 TC 47 Z9 48 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD FEB PY 2001 VL 280 IS 2 BP L272 EP L278 PG 7 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 393BU UT WOS:000166450000011 PM 11159006 ER PT J AU Frankle, WG Shera, D Berger-Hershkowitz, H Evins, AE Connolly, C Goff, DC Henderson, DC AF Frankle, WG Shera, D Berger-Hershkowitz, H Evins, AE Connolly, C Goff, DC Henderson, DC TI Clozapine-associated reduction in arrest rates of psychotic patients with criminal histories SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID MENTAL-ILLNESS; SCHIZOPHRENIA; SERVICE; JAIL AB Objective: The authors examined the relationship between treatment with clozapine and rates of arrest of psychotic outpatients with criminal histories. Method: Patients who had been given a DSM-IV psychotic diagnosis were selected from an urban outpatient clinic database. Background checks performed on 360 patients identified 165 (45.8%) with positive criminal histories in Massachusetts. The authors reviewed the charts of these patients to determine several variables, including whether and when they had received clozapine. A Poisson regression model was used to regress arrest rates against the variables of age, sex, onset of illness, birth cohort, and clozapine treatment. Risk ratios (i.e., percent change in arrest rates) were then calculated by computing the exponential of the Poisson regression coefficients. Results: The 165 patients included in the analysis had a total of 1,126 arrests. The mean number of arrests was 6.8. Differences were found between the 65 patients who received clozapine and the 100 patients who did not in number of arrests, sex, and onset of illness. The regression revealed significantly higher arrest rate estimates associated with more recent birth cohort (4.8%) and with onset of illness (64.6%) and lower arrest rate estimates associated with higher levels of education (11.6%), receiving clozapine (32.6%), and receiving clozapine during specific periods of time (68.9%). Conclusions: Clozapine's effect on arrest rates in this group of patients is large enough to warrant further investigation. The data indicate that clozapine may reduce recidivism in subjects with criminal histories who are in need of antipsychotic medication. C1 Massachusetts Gen Hosp, Dept Psychiat, Schizophrenia Program, Boston, MA 02114 USA. Massachusetts Gen Hosp, Biostat Unit, Boston, MA 02114 USA. Freedom Trail Clin, Boston, MA USA. Harvard Univ, Sch Med, Consolidated Dept Psychiat, Cambridge, MA 02138 USA. RP Frankle, WG (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Schizophrenia Program, MGH McLean Residency,50 Staniford St,5th Floor, Boston, MA 02114 USA. OI Frankle, William/0000-0003-0356-4197 NR 22 TC 24 Z9 24 U1 1 U2 2 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD FEB PY 2001 VL 158 IS 2 BP 270 EP 274 DI 10.1176/appi.ajp.158.2.270 PG 5 WC Psychiatry SC Psychiatry GA 398MZ UT WOS:000166761400017 PM 11156810 ER PT J AU Wilens, TE Spencer, TJ Biederman, J Girard, K Doyle, R Prince, J Polisner, D Solhkhah, R Comeau, S Monuteaux, MC Parekh, A AF Wilens, TE Spencer, TJ Biederman, J Girard, K Doyle, R Prince, J Polisner, D Solhkhah, R Comeau, S Monuteaux, MC Parekh, A TI A controlled clinical trial of bupropion for attention deficit hyperactivity disorder in adults SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 39th Annual Meeting of the New-Clinical-Drug-Evaluation-Unit CY JUN 01-04, 1999 CL BOCA RATON, FLORIDA SP New Clin Drug Evaluat Unit ID SUBSTANCE USE DISORDERS; UTAH RATING-SCALE; DEFICIT/HYPERACTIVITY DISORDER; DOUBLE-BLIND; PSYCHIATRIC STATUS; CONDUCT DISORDER; FOLLOW-UP; CHILDREN; ADHD; ADOLESCENTS AB Objective: Despite the increasing recognition of attention deficit hyperactivity disorder (ADHD) in adults, there is a paucity of controlled pharmacological trials demonstrating the effectiveness of compounds used in treatment, particularly nonstimulants. The authors report results from a controlled investigation to determine the anti-ADHD efficacy of bupropion in adult patients with DSM-IV ADHD. Method: This was a double-blind, placebo-controlled, randomized, parallel, 6-week trial comparing patients receiving sustained-release bupropion (up to 200 mg b.i.d.) (N=21) to patients receiving placebo (N=19). The authors used standardized structured psychiatric instruments for diagnosis of ADHD. To measure improvement, they used separate assessments of ADHD, depression, and anxiety symptoms at baseline and each weekly visit. Results: Of the 40 subjects (55% male) enrolled in the study, 38 completed the study. Bupropion treatment was associated with a significant change in ADHD symptoms at the week-6 endpoint (42% reduction), which exceeded the effects of placebo (24% reduction). In analyses using a cutoff of 30% or better reduction to denote response, 76% of the subjects receiving bupropion improved, compared to 37% of the subjects receiving placebo. Similarly, in analyses using Clinical Global Impression scale scores, 52% of the subjects receiving bupropion reported being "much improved" to "very improved," compared to 11% of the subjects receiving placebo. Conclusions: These results indicate a clinically and statistically significant effect of bupropion in improving ADHD in adults. The results suggest a therapeutic role for bupropion in the armamentarium of agents for ADHD in adults, while further validating the continuity of pharmacological responsivity of ADHD across the lifespan. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Psychopharmacol Clin, Boston, MA 02114 USA. RP Wilens, TE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Psychopharmacol Clin, ACC 725, Boston, MA 02114 USA. FU NIDA NIH HHS [DA-11315]; NIMH NIH HHS [MH-011175] NR 54 TC 154 Z9 155 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 FEB PY 2001 VL 158 IS 2 BP 282 EP 288 DI 10.1176/appi.ajp.158.2.282 PG 7 WC Psychiatry SC Psychiatry GA 398MZ UT WOS:000166761400019 PM 11156812 ER PT J AU Smith, JJ Maida, TR Agraz, JA AF Smith, JJ Maida, TR Agraz, JA TI Medicare coverage for new medical technology: The basics of health care financing administration policy SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Ctr Integrat Innovat Technol & Med, CMIT, Boston, MA 02114 USA. Boston Univ, Sch Law, Boston, MA 02215 USA. RP Smith, JJ (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. NR 11 TC 0 Z9 0 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 FEB PY 2001 VL 176 IS 2 BP 313 EP 316 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 395RB UT WOS:000166594100006 PM 11159063 ER PT J AU Saini, S AF Saini, S TI Opinion - Radiologic measurement of tumor size in clinical trials: Past, present, and future SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Editorial Material ID CANCER C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Saini, S (reprint author), Massachusetts Gen Hosp, Dept Radiol, 32 Fruit St, Boston, MA 02114 USA. NR 5 TC 36 Z9 36 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 FEB PY 2001 VL 176 IS 2 BP 333 EP 334 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 395RB UT WOS:000166594100010 PM 11159068 ER PT J AU Chahud, F Young, RH Remulla, JF Khadem, JJ Dryja, TP AF Chahud, F Young, RH Remulla, JF Khadem, JJ Dryja, TP TI Bilateral diffuse uveal melanocytic proliferation associated with extraocular cancers - Review of a process particularly associated with gynecologic cancers SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE eye; uveal melanocytic hyperplasia; paraneoplastic syndrome; carcinoma; gynecologic cancer ID FIBROBLAST-GROWTH-FACTOR; CELL-CARCINOMA; MELANOMA; RETINOPATHY; TUMORS; BLINDNESS; RECOVERIN; LESIONS; PROTEIN; LUNG AB We reviewed cases of a paraneoplastic syndrome in which uveal melanocytes proliferated and led to blindness. Eighteen cases were derived from the literature, and two were taken from our institution. The average patient age at the time of the diagnosis was 63 years (range, 34-89 years). There were 13 women and 7 men. In approximately half of the cases, the ocular symptoms antedated those of the inciting tumor. Most of the inciting tumors were poorly differentiated carcinomas. The most common tumors were from the female genital tract (ovary and uterus) among the women patients and from the lung among the men. Tumors from the breast were rare tone possible case), and tumors of the prostate were conspicuously absent. All five inciting tumors whose histopathology was reviewed expressed neuron-specific enolase. but none prominently expressed antigens more specific for neuroendocrine carcinomas such as chromogranin or synaptophysin. It is our experience that many general pathologists are not aware of this unique paraneoplastic syndrome. Our report is the first to document a statistically significant association between this syndrome and gynecologic cancers. C1 Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Cogan Eye Pathol Lab, Boston, MA USA. Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Dryja, TP (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. FU NEI NIH HHS [EY08683] NR 31 TC 20 Z9 22 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD FEB PY 2001 VL 25 IS 2 BP 212 EP 218 DI 10.1097/00000478-200102000-00009 PG 7 WC Pathology; Surgery SC Pathology; Surgery GA 397LG UT WOS:000166696700009 PM 11176070 ER PT J AU Maluf, HM Swanson, PE Koerner, FC AF Maluf, HM Swanson, PE Koerner, FC TI Solid low-grade in situ carcinoma of the breast - Role of associated lesions and E-cadherin in differential diagnosis SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE breast carcinoma; ductal carcinoma in situ solid type; lobular carcinoma in situ; E-cadherin; immunohistochemistry ID INFILTRATING DUCTAL CARCINOMA; IN-SITU; EXPRESSION; CANCER; MUTATIONS; GENE AB Low-grade solid in situ carcinomas of the breast are difficult to classify. The authors investigated 12 cases of in situ carcinomas with equivocal features and correlated their histologic attributes with those of the associated invasive carcinomas as well as with E-cadherin expression in both in situ and invasive disease. E-cadherin-positive in situ lesions were invariably associated with invasive carcinomas of the ductal type. In situ carcinomas that were E-cadherin negative were associated with invasive carcinomas of the lobular type in five of six cases. In all cases, the invasive carcinomas showed the same pattern of E-cadherin reactivity as the in situ lesions. Sharply defined cellular membranes, necrosis, and occasional microacini were seen in both E-cadherin-positive and negative in situ carcinomas, whereas intracytoplasmic lumina and a noncohesive appearance were seen only in E-cadherin-negative lesions. C1 Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Maluf, HM (reprint author), Washington Univ, Sch Med, Dept Pathol, Div Surg Pathol, Box 8118,660 S Euclid Ave, St Louis, MO 63110 USA. NR 26 TC 39 Z9 40 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD FEB PY 2001 VL 25 IS 2 BP 237 EP 244 DI 10.1097/00000478-200102000-00012 PG 8 WC Pathology; Surgery SC Pathology; Surgery GA 397LG UT WOS:000166696700012 PM 11176073 ER PT J AU Nielsen, GP Mangham, DC Grimer, RJ Rosenberg, AE AF Nielsen, GP Mangham, DC Grimer, RJ Rosenberg, AE TI Chordoma periphericum - A case report SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE parachordoma; chordoma; chordoma periphericum ID EXTRASKELETAL MYXOID CHONDROSARCOMA; SARCOMA; TUMORS; LIGHT; BONE AB The authors describe a tumor that had the histologic and ultrastructural features and immunohistochemical profile of on axial chordoma, but arose in the distal ulna. A skeletal survey failed to show any other site of involvement. The turner was resected. and the patient remains free of disease 2 1/2 years later. Rare tumors with the histologic features of chordoma have been reported in appendicular locations. Chordoma periphericum. a tumor that has the potential to metastasize. needs to be distinguished from parachordoma because no classic parachordoma has been reported to disseminate. C1 Harvard Univ, Dept Pathol, Massachusetts Gen Hosp, Sch Med,James Homer Wright Pathol Labs, Boston, MA 02114 USA. Royal Orthopaed Hosp, Dept Musculoskeletal Pathol, Birmingham B31 2AP, W Midlands, England. RP Nielsen, GP (reprint author), Harvard Univ, Dept Pathol, Massachusetts Gen Hosp, Sch Med,James Homer Wright Pathol Labs, Fruit St, Boston, MA 02114 USA. NR 21 TC 25 Z9 26 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD FEB PY 2001 VL 25 IS 2 BP 263 EP 267 DI 10.1097/00000478-200102000-00016 PG 5 WC Pathology; Surgery SC Pathology; Surgery GA 397LG UT WOS:000166696700016 PM 11176077 ER PT J AU Bird, TD Schellenberg, GD AF Bird, TD Schellenberg, GD TI The case of the missing tau, or, why didn't the mRNA bark? SO ANNALS OF NEUROLOGY LA English DT Editorial Material ID ALZHEIMER DEGENERATIVE DEMENTIA; FRONTOTEMPORAL DEMENTIA; MUTATIONS; CHROMOSOME-17; GENE; CONSENSUS; MISSENSE; PROTEIN; FTDP-17 C1 Univ Washington, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. RP Bird, TD (reprint author), Univ Washington, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. NR 22 TC 1 Z9 1 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD FEB PY 2001 VL 49 IS 2 BP 144 EP 145 DI 10.1002/1531-8249(20010201)49:2<144::AID-ANA33>3.0.CO;2-J PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 402CJ UT WOS:000166968200003 PM 11220733 ER PT J AU Mathisen, DJ AF Mathisen, DJ TI Use of omentum for mediastinal tracheostomy after total laryngoesophagectomy - Invited commentary SO ANNALS OF THORACIC SURGERY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Gen Thorac Surg Unit, Boston, MA 02114 USA. RP Mathisen, DJ (reprint author), Massachusetts Gen Hosp, Gen Thorac Surg Unit, Boston, MA 02114 USA. 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 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD FEB PY 2001 VL 71 IS 2 BP 413 EP 413 DI 10.1016/S0003-4975(00)02379-1 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 402MQ UT WOS:000166992500004 ER PT J AU Posner, MR AF Posner, MR TI Docetaxel in squamous cell cancer of the head and neck SO ANTI-CANCER DRUGS LA English DT Article; Proceedings Paper CT Meeting on Docetaxel in Perspective CY MAY 21, 2000 CL NEW ORLEANS, LOUISIANA DE head and neck; SCCHN; docetaxel; cisplatin; 5-fluorouracil; leucovorin; TPLF ID PHASE-II TRIAL; ACTIVE-DRUG; CARCINOMA; CISPLATIN; 5-FLUOROURACIL; CHEMOTHERAPY; FLUOROURACIL; TAXOTERE(R); LEUCOVORIN; APOPTOSIS AB Single-agent docetaxel induces a response in 21-42% of patients with recurrent squamous cell cancer of the head and neck (SCCHN). When used in combination with 5-fluorouracil (5-FU), response rates (RRs) of between 24 and 27% have been reported. In contrast, in combination with cisplatin, docetaxel has achieved a RR of 33% in previously treated patients and 86% in a subgroup of chemotherapy-naive advanced stage patients. The docetaxel/ cisplatin combination appears to be highly active. High-dose induction chemotherapy for patients with locally advanced but potentially curable SCCHN is producing promising results: following combination therapy involving docetaxel, cisplatin, 5-FU and leucovorin (TPFL), RR are high and 75% of patients are alive at 2 years. Intermediate-dose induction chemotherapy involving docetaxel is also promising: the TAX 708 trial found an excellent 93% RR in 41 evaluable patients treated with docetaxel plus cisplatin and 5-FU (TPF). The rate of pathological complete response was also high. The toxicities with TPF therapy were similar to those seen with cisplatin/5-FU regimens without docetaxel. A phase III trial of this approach is currently being conducted. [(C) 2001 Lippincott Williams & Wilkins]. C1 Dana Farber Canc Inst, Head & Neck Oncol Program, Dept Adult Oncol, Boston, MA 02115 USA. RP Posner, MR (reprint author), Dana Farber Canc Inst, Head & Neck Oncol Program, Dept Adult Oncol, Boston, MA 02115 USA. NR 18 TC 16 Z9 17 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4973 J9 ANTI-CANCER DRUG JI Anti-Cancer Drugs PD FEB PY 2001 VL 12 SU 1 BP S21 EP S24 PG 4 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 418LA UT WOS:000167892600005 PM 11340900 ER PT J AU Gonzalez, GM Sutton, DA Thompson, E Tijerina, R Rinaldi, MG AF Gonzalez, GM Sutton, DA Thompson, E Tijerina, R Rinaldi, MG TI In vitro activities of approved and investigational antifungal agents against 44 clinical isolates of basidiomycetous fungi SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID SCHIZOPHYLLUM-COMMUNE; INFECTION; PATIENT; LUNG AB The in vitro activity of amphotericin B, fluconazole, flucytosine, itraconazole, voriconazole, and posaconazole was evaluated against 44 clinical isolates of filamentous basidiomycetous fungi. No statistically significant differences were noted between Schizophyllum commune (n = 5), Coprinus species (n = 8), Bjerkandera adusta (n = 14), and sterile, uncharacterized basidiomycetes (n = 17). C1 Univ Texas, Hlth Sci Ctr, Dept Pathol, Fungus Testing Lab, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX 78229 USA. Univ Autonoma Nuevo Leon, Fac Med, Dept Microbiol, Monterrey, Nuevo Leon, Mexico. RP Gonzalez, GM (reprint author), Univ Texas, Hlth Sci Ctr, Dept Pathol, Fungus Testing Lab, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. NR 15 TC 43 Z9 44 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 FEB PY 2001 VL 45 IS 2 BP 633 EP 635 DI 10.1128/AAC.45.2.633-635.2001 PG 3 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 394TP UT WOS:000166539600043 PM 11158771 ER PT J AU Fisher, DE AF Fisher, DE TI The p53 tumor suppressor: Critical regulator of life & death in cancer SO APOPTOSIS LA English DT Review DE apoptosis; caspase; p53; tumor suppressor ID WILD-TYPE P53; TATA-BINDING PROTEIN; CELL-CYCLE ARREST; APOPTOSIS IN-VIVO; DNA-DAMAGE; P53-DEPENDENT APOPTOSIS; TRANSCRIPTIONAL ACTIVATION; TETRAMERIZATION DOMAIN; P53-MEDIATED APOPTOSIS; SV40-TRANSFORMED CELLS AB p53 is the most commonly mutated or deleted known gene in human cancer. The consequences of its disruption are profound, either in the germlines of patients with Li-Fraumeni Syndrome, or in mice with targeted gene knockouts. Abundant evidence suggests that p53 exerts regulation of cell cycle progression as well as apoptotic cell death, both in response to identical environmental or metabolic stressors. The specific decision of cell cycle arrest vs. death may underlie p53's differential ability to trigger death in cancer cells and arrest with repair in non-cancer cells, thus producing a therapeutic index pertinent to cancer therapy. Indeed, p53 status is likely to correlate with prognosis in many human cancers and in multiple animal tumor models. The mechanistic basis for p53's functions are still emerging, and will hopefully yield new therapeutic strategies applicable to treatment of the many poor-prognosis, p53-deficient human malignancies. C1 Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Fisher, DE (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, D630-C,44 Binney St, Boston, MA 02115 USA. NR 115 TC 59 Z9 72 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 1360-8185 J9 APOPTOSIS JI Apoptosis PD FEB PY 2001 VL 6 IS 1-2 BP 7 EP 15 DI 10.1023/A:1009659708549 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 403LZ UT WOS:000167045800002 PM 11321044 ER PT J AU Irwin, MS Kaelin, WG AF Irwin, MS Kaelin, WG TI Role of the newer p53 family proteins in malignancy SO APOPTOSIS LA English DT Review DE p53; p63; p73; apoptosis; tumor suppressor; EEC syndrome ID TUMOR-SUPPRESSOR P53; HUMAN BLADDER-CANCER; KINASE C-ABL; P73 GENE; P53-RELATED PROTEIN; MUTATIONAL ANALYSIS; CELL-LINES; CHROMOSOME 1P36.3; BREAST-CANCER; TRANSCRIPTIONAL ACTIVITIES AB The most recently identified members of the p53 family, p63 and p73, share certain structural and functional similarities with p53. Both p63 and p73 can bind to canonical p53-DNA-binding sites, transactivate the promoters of known p53 target genes and induce apoptosis. Despite these similarities there are many important differences. In contrast to p53, p63 and p73 give rise to multiple distinct protein isoforms that have different functional properties. Upstream signaling pathways involved in the activation of p63 and p73 differ from those involved in p53 activation. Only a subset of the DNA damaging agents that induce p53 can induce p73. Cellular and viral oncoproteins can discriminate between p53 and the newer family members. In addition, the levels of p63 and p73 are affected by certain states of cellular differentiation. Finally, it is becoming clear that the newest members of the p53 family are not classical tumor suppressor genes. In contrast to the high prevalence of p53 mutations in human cancers, p63 and p73 mutations are rare. Indeed, levels of p73 increase during malignant progression. In addition, unlike p53-/- mice, mice lacking p63 and p73 do not develop tumors, but instead have significant developmental abnormalities. Mutations in p63 have also been detected in humans with the ectodermal dysplastic syndrome EEC. Further studies are required to determine whether qualitative or quantitative differences in the expression of p63 and p73 isoforms are important in the development of human cancers. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Howard Hughes Med Inst, Coconut Grove, FL 33133 USA. RP Irwin, MS (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. NR 112 TC 64 Z9 73 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 1360-8185 J9 APOPTOSIS JI Apoptosis PD FEB PY 2001 VL 6 IS 1-2 BP 17 EP 29 DI 10.1023/A:1009663809458 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 403LZ UT WOS:000167045800003 PM 11321038 ER PT J AU Hayashi, T Faustman, DL AF Hayashi, T Faustman, DL TI Implications of altered apoptosis in diabetes mellitus and autoimmune disease SO APOPTOSIS LA English DT Review DE apoptosis; Lmp2; NF-kappa B; NOD; proteasome ID NF-KAPPA-B; SYSTEMIC-LUPUS-ERYTHEMATOSUS; BETA-CELL DESTRUCTION; FAS LIGAND EXPRESSION; UBIQUITIN-PROTEASOME PATHWAY; NECROSIS-FACTOR-ALPHA; IN-VITRO APOPTOSIS; COMPLEX CLASS-I; INTERFERON-GAMMA; NOD MICE AB Lymphocyte development, selection and education represent tightly controlled immune processes that normally prevent autoimmunity. Lymphocyte development requires cellular selection through apoptosis to remove potentially autoreactive cells. Dysregulated apoptosis, both interrupted as well as accetuated apoptosis, are now demonstrated as central defects in diverse human and murine autoimmune disease. In murine models of autoimmune lupus, mutations in cell death receptor CD95 (Fas) and its ligand CD95L (FasL) have been identified; these errors create a lymphoid system resistant to apoptosis. In contract, select lymphoid subpopulations of auto immune diabetic mice have accelerated apoptosis due to faulty activation of transcription factor NF-kappaB that normally protects against apoptotic death. The genetic basis of interrupted NF-kappaB in diabetes is a gene defect in an essential subunit of the proteasome. Although no specific gene in most common forms of human autoimmune disease has been identified, functional assays repeatedly demonstrate apoptotic defects in multiple cellular signaling pathways for cell death. C1 Massachusetts Gen Hosp, Immunobiol Lab, Charlestown, MA 02139 USA. Harvard Univ, Sch Med, Charlestown, MA 02139 USA. RP Faustman, DL (reprint author), Massachusetts Gen Hosp E, Immunobiol Lab, Bldg 149,13th St, Charlestown, MA 02139 USA. NR 121 TC 19 Z9 20 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 1360-8185 J9 APOPTOSIS JI Apoptosis PD FEB PY 2001 VL 6 IS 1-2 BP 31 EP 45 DI 10.1023/A:1009667926296 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 403LZ UT WOS:000167045800004 PM 11321039 ER PT J AU Chauhan, D Anderson, KC AF Chauhan, D Anderson, KC TI Apoptosis in multiple myeloma: Therapeutic implications SO APOPTOSIS LA English DT Article DE apoptosis; multiple myeloma; signal transduction ID ACTIVATED PROTEIN-KINASE; SHP-2 TYROSINE PHOSPHATASE; MARROW STROMAL CELLS; NF-KAPPA-B; SIGNAL-TRANSDUCTION; INTERFERON-GAMMA; GROWTH-FACTOR; PHOSPHOTYROSINE PHOSPHATASE; RETINOBLASTOMA PROTEIN; DOWN-REGULATION AB Apoptosis is the primary means by which most radio- and chemotherapy modalities kill cancer cells, and abnormalities in the apoptotic pathways may contribute to disease pathogenesis of cancer. Multiple Myeloma (MM) is a hematological malignancy which will affect 14,000 new individuals in the United States in 2001 and remains irreversibly fatal despite all available therapies. The current review focuses on the studies of apoptotic and survival signaling pathways in MM cells, which have both identified novel apoptotic and anti-apoptotic proteins and provided targets for novel therapeutics. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Anderson, KC (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA 78373] NR 85 TC 18 Z9 18 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 1360-8185 J9 APOPTOSIS JI Apoptosis PD FEB PY 2001 VL 6 IS 1-2 BP 47 EP 55 DI 10.1023/A:1009620027205 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 403LZ UT WOS:000167045800005 PM 11321040 ER PT J AU Rana, A Sathyanarayana, P Lieberthal, W AF Rana, A Sathyanarayana, P Lieberthal, W TI Role of apoptosis of renal tubular cells in acute renal failure: Therapeutic implications SO APOPTOSIS LA English DT Review DE acute renal failure; apoptosis; Bcl-2; MAPK; necrosis ID ACTIVATED PROTEIN-KINASE; NF-KAPPA-B; SIGNAL-TRANSDUCTION PATHWAY; CYTOSOLIC PHOSPHOLIPASE A(2); CYTOCHROME-C RELEASE; BCL-X-L; MAP KINASE; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHOINOSITIDE 3-KINASE; TYROSINE PHOSPHORYLATION AB Acute renal failure (ARF) can be defined as a sudden loss of renal function and is a common and serious clinical problem. There are many causes of ARF but the most common cause results from injury to the renal tubular epi-thelial cells (RTECs). RTECs can be injured by schemia or by cytotoxic agents and, once injured, can die by necrosis or apotosis. In general, necrosis occurs in response to any severe injury, which leads to the biochemical collapse of the cell. Milder forms of the same types of injury cause apoptosis. At the cellular level there are fundamental differences between necrosis and apoptosis. Necrosis results from the additive effect of a number of independent biochemical events that are activated by severe depletion of cell energy stores. By contrast, apoptosis occurs via a coordinated, predictable and pre-determined pathway. These biochemical differences between apoptosis and necrosis have important therapeutic implications. Once a cell has been severely injured, necrosis is difficult to prevent. By contrast, the apoptotic pathway can potentially be modulated to maintain cell viability. The components of the apoptotic pathway that are potentially amenable to therapeutic modulation are discussed in detail in this review. C1 Cardiovasc Res Inst, Temple, TX 76504 USA. Massachusetts Gen Hosp, Diabet Res Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Boston Univ, Sch Med, Evans Dept Clin Res, Dept Nephrol, Boston, MA 02118 USA. RP Rana, A (reprint author), Cardiovasc Res Inst, 1901 S 1st St,Bldg 162, Temple, TX 76504 USA. FU NIDDK NIH HHS [DK52898, DK58306]; NIGMS NIH HHS [GM55835] NR 171 TC 64 Z9 79 U1 1 U2 4 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 1360-8185 J9 APOPTOSIS JI Apoptosis PD FEB PY 2001 VL 6 IS 1-2 BP 83 EP 102 DI 10.1023/A:1009680229931 PG 20 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 403LZ UT WOS:000167045800008 PM 11321045 ER PT J AU McGinty, D Alam, MN Szymusiak, R Nakao, M Yamamoto, M AF McGinty, D Alam, MN Szymusiak, R Nakao, M Yamamoto, M TI Hypothalamic sleep-promoting mechanisms: Coupling to thermoregulation SO ARCHIVES ITALIENNES DE BIOLOGIE LA English DT Article ID EYE-MOVEMENT SLEEP; NEURONAL FIRING MODE; BASAL FOREBRAIN; CIRCADIAN PACEMAKER; CELLULAR MECHANISMS; BODY-TEMPERATURE; WAKING DISCHARGE; RATS; WAKEFULNESS; LESIONS C1 Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. Tohoku Univ, Grad Sch Informat Sci, Sendai, Miyagi 9808579, Japan. RP McGinty, D (reprint author), Vet Adm Greater Los Angeles Healthcare Syst, Sepulveda Branch, Neurophysiol Res, Los Angeles, CA 91343 USA. FU NIMH NIH HHS [MH47480] NR 56 TC 22 Z9 22 U1 0 U2 1 PU UNIV PISA PI PISA PA LUNGARNO A PACINOTTI 43, 56100 PISA, ITALY SN 0003-9829 J9 ARCH ITAL BIOL JI Arch. Ital. Biol. PD FEB PY 2001 VL 139 IS 1-2 BP 63 EP 75 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 403AV UT WOS:000167021100008 PM 11256188 ER PT J AU Szymusiak, R Steininger, T Alam, N McGinty, D AF Szymusiak, R Steininger, T Alam, N McGinty, D TI Preoptic area sleep-regulating mechanisms SO ARCHIVES ITALIENNES DE BIOLOGIE LA English DT Article ID POSTERIOR LATERAL HYPOTHALAMUS; EYE-MOVEMENT SLEEP; BASAL FOREBRAIN; WAKING DISCHARGE; LOCUS-COERULEUS; RETICULAR-FORMATION; NERVOUS-SYSTEM; NEURONS; RATS; CAT C1 Univ Calif Los Angeles, Dept Med, VA Greater Los Angeles Healthcare Syst, Res Serv 151A3, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Psychol, VA Greater Los Angeles Healthcare Syst, Res Serv 151A3, Los Angeles, CA 90024 USA. RP Szymusiak, R (reprint author), Univ Calif Los Angeles, Dept Med, VA Greater Los Angeles Healthcare Syst, Res Serv 151A3, Los Angeles, CA 90024 USA. NR 66 TC 44 Z9 47 U1 0 U2 1 PU UNIV PISA PI PISA PA LUNGARNO A PACINOTTI 43, 56100 PISA, ITALY SN 0003-9829 J9 ARCH ITAL BIOL JI Arch. Ital. Biol. PD FEB PY 2001 VL 139 IS 1-2 BP 77 EP 92 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 403AV UT WOS:000167021100009 PM 11256189 ER PT J AU Anderson, RR AF Anderson, RR TI Regarding tattoos - Is that sunlight, or an oncoming train at the end of the tunnel? SO ARCHIVES OF DERMATOLOGY LA English DT Editorial Material ID SWITCHED RUBY-LASER; COSMETIC TATTOO; PICOSECOND C1 Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. RP Anderson, RR (reprint author), Massachusetts Gen Hosp, Dept Dermatol, BHX-6,50 Blossom St, Boston, MA 02114 USA. NR 14 TC 15 Z9 15 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD FEB PY 2001 VL 137 IS 2 BP 210 EP 212 PG 3 WC Dermatology SC Dermatology GA 401JJ UT WOS:000166924200013 PM 11176693 ER PT J AU Byne, W Buchsbaum, MS Kemether, E Hazlett, EA Shinwari, A Mitroupoulou, V Siever, LJ AF Byne, W Buchsbaum, MS Kemether, E Hazlett, EA Shinwari, A Mitroupoulou, V Siever, LJ TI Magnetic resonance imaging of the thalamic mediodorsal nucleus and pulvinar in schizophrenia and schizotypal personality disorder SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; MEDICATED SCHIZOPHRENICS; MORPHOMETRIC ANALYSIS; GLUCOSE-METABOLISM; NEUROLEPTIC-NAIVE; PREFRONTAL CORTEX; CEREBRAL-CORTEX; OUTPUT CHANNELS; BASAL GANGLIA; VOLUME AB Background: The importance of neuronal interactions in development, the cortical dependence of many thalamic nuclei, and the phenomenon of transsynaptic degeneration suggest possible abnormalities in thalamic nuclei with connections to other brain regions implicated in schizophrenia. Because frontal and temporal lobe volumes are diminished in schizophrenia, Volume loss could characterize their primary thalamic relay nuclei (mediodorsal nucleus [MDN] and pulvinar). Methods: Tracers delineated the thalamus, MDN, and pulvinar on contiguous 1.2-mm magnetic resonance images in 12 schizophrenic patients, 12 with schizotypal personality disorder (SPD), and 12 normal control subjects. The MDN and pulvinar were rendered visible by means of a Sobel intensity-gradient filter. Results: Pixel overlap for delineation of all structures by independent tracers was at least 80%; intraclass correlations were r=0.78 for MDN and r=0.83 for pulvinar. Pulvinar volume was smaller in schizophrenic (1.22+/-0.24 cm(3)) and SPD (1.20+/-0.23 cm(3)) patients than controls (1.37+/-0.25 cm(3)). Differences for MDN were not statistically significant; however, when expressed as percentage of total brain volume, pulvinar and MDN together were reduced in SPD (0.14%) and schizophrenic (0.15%) patients vs controls (0.16%). Reductions were more prominent in the left hemisphere, with MDN reduced only in the schizophrenic group, and pulvinar in both patient groups. Total thalamic volume did not differ among the 3 groups. Conclusions: Measurement of MDN and pulvinar in magnetic resonance images is feasible and reproducible. Schizophrenic and SPD patients have volume reduction in the pulvinar, but only schizophrenic patients show reduction relative to brain volume in MDN. C1 Bronx Vet Affairs Med Ctr, Dept Psychiat 1F29, Bronx, NY 10468 USA. Mt Sinai Sch Med, New York, NY USA. Pilgrim Psychiat Ctr, W Brentwood, NY USA. RP Byne, W (reprint author), Bronx Vet Affairs Med Ctr, Dept Psychiat 1F29, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. FU NIMH NIH HHS [MH40071, MH55989, MH60023] NR 65 TC 143 Z9 144 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 FEB PY 2001 VL 58 IS 2 BP 133 EP 140 DI 10.1001/archpsyc.58.2.133 PG 8 WC Psychiatry SC Psychiatry GA 399YV UT WOS:000166842600004 PM 11177115 ER PT J AU Wang, F Frisbie, JH Klein, MA AF Wang, F Frisbie, JH Klein, MA TI Solitary rectal ulcer syndrome (colitis cystica profunda) in spinal cord injury patients: 3 case reports SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Academy-of-Physical-Medicine-and-Rehabilitation CY NOV 12-13, 1999 CL WASHINGTON, D.C. SP Amer Acad Phys Med & Rehabil DE colitis; ulcerative; colonic diseases; functional; rehabilitation; spinal cord injuries AB Clinically indicated endoscopic examinations of 56 patients with spinal cord injury (SCI) (31 for bleeding) were performed over a 3-year period, of which 3 (6%) showed solitary rectal ulcer syndrome (SRUS). The presentation was rectal bleeding or mucoid discharge. The endoscopic appearance wax multiple pseudopolyps and occasional mucosal ulcers extending proximally 8 to 40cm from the anus. Mucosal biopsy specimens showed distorted mucosal glands and displaced smooth muscle fibers wrapping around the glands, the hallmark of SRUS. The affected patients had routinely used suppositories and digital stimulation for bowel care and had been paralyzed 7 to 50 years. None had rectal prolapse. These cases show that SRUS (colitis cystica profunda) can be found among patients with SCI. C1 Dept Vet Affairs Med Ctr, Spinal Cord Injury Serv, W Roxbury, MA 02132 USA. Dept Vet Affairs Med Ctr, Pathol Serv, W Roxbury, MA 02132 USA. Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Frisbie, JH (reprint author), Dept Vet Affairs Med Ctr, Spinal Cord Injury Serv, 1400 Vet Foreign Wars Pkwy, W Roxbury, MA 02132 USA. NR 8 TC 7 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 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD FEB PY 2001 VL 82 IS 2 BP 260 EP 261 DI 10.1053/apmr.2001.16341 PG 2 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 400AG UT WOS:000166846000020 PM 11239322 ER PT J AU Merfeld, DM AF Merfeld, DM TI Must all action halt during sensorimotor mismatch? SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material ID GRAVITY; MONKEY AB Gray's target article presents a model of consciousness that includes several ideas similar to those developed over the past century to explain how sensorimotor information is interpreted by the nervous system. This commentary discusses these ideas and introduces some additional hypotheses, also derived from sensorimotor investigations, that might help improve Gray's model. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Jenks Vestibular Physiol Lab, Boston, MA 02114 USA. RP Merfeld, DM (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Jenks Vestibular Physiol Lab, Boston, MA 02114 USA. NR 10 TC 2 Z9 2 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-9863 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD FEB PY 2001 VL 24 IS 1 BP 189 EP + DI 10.1017/S0140525X01233937 PG 3 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 458DJ UT WOS:000170177700079 ER PT J AU Goldvasser, D McGibbon, CA Krebs, DE AF Goldvasser, D McGibbon, CA Krebs, DE TI High curvature and jerk analyses of arm ataxia SO BIOLOGICAL CYBERNETICS LA English DT Article ID POINTING MOVEMENTS; CEREBELLAR-ATAXIA; ABNORMAL CONTROL; BRAIN INJURY; COORDINATION; QUANTIFICATION; DYNAMICS; MOTION AB We investigated high curvature analysis (HCA) and integrated absolute jerk (IAJ) for differentiating healthy and cerebellopathy (CB) patients performing pointing tasks. Seventeen CB patients and seventeen healthy controls were required to move a pointer at their preferred pace between two 50.8 cm laterally spaced targets while standing with their arm extended in front of their body. HCA was used to quantify the frequency of sharp turns in the horizontal-plane (anterior-posterior and medio-lateral) velocity trajectory of the hand-held pointer. IAJ was assessed by integration of absolute jerk (second time derivative of velocity) time histories in the anterior-posterior and medio-lateral directions. HCA scores and IAJ scores were then compared between CB patients and healthy controls, for both analyses, higher scores indicate less smooth movements. We hypothesized that CB patients would have less smooth movement trajectories than healthy controls due to upper extremity ataxia associated with cerebellar disease and degeneration. We found that CB patients had higher HCA scores than healthy controls (P = 0.014). Although CB patients had higher IAJ scores in both anterior-posterior (P = 0.060) and medio-lateral (P = 0.231) directions compared to the healthy controls, the differences were not significant. The difference in sensitivity between the HCA and the IAJ analysis might be explained by primitive neural activation commands, ubiquitous though only evident with some cerebellar dysfunctions, which produce submovements which are themselves minimal jerk curves. We conclude that HCA may be a useful tool for quantifying upper extremity ataxia in CB patients performing a repeated pointing task. C1 Massachusetts Gen Hosp, Biomot Lab, Boston, MA 02114 USA. MGH Inst Hlth Profess, Boston, MA USA. Harvard Univ, Sch Med, Dept Orthoped, Boston, MA USA. RP Goldvasser, D (reprint author), Massachusetts Gen Hosp, Biomot Lab, Boston, MA 02114 USA. FU NIA NIH HHS [R01-AG11255] NR 25 TC 16 Z9 17 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-1200 J9 BIOL CYBERN JI Biol. Cybern. PD FEB PY 2001 VL 84 IS 2 BP 85 EP 90 DI 10.1007/s004220000201 PG 6 WC Computer Science, Cybernetics; Neurosciences SC Computer Science; Neurosciences & Neurology GA 393ZU UT WOS:000166500200002 PM 11205353 ER PT J AU Wedeen, VJ Reese, TG Napadow, VJ Gilbert, RJ AF Wedeen, VJ Reese, TG Napadow, VJ Gilbert, RJ TI Demonstration of primary and secondary muscle fiber architecture of the bovine tongue by diffusion tensor magnetic resonance imaging SO BIOPHYSICAL JOURNAL LA English DT Article ID WEIGHTED MRI; WATER; ANISOTROPY AB The myoarchitecture of the tongue is comprised of a complex array of muscle fiber bundles, which form the structural basis for lingual deformations during speech and swallowing. We used magnetic resonance imaging of the water diffusion tensor to display the primary and secondary fiber architectural attributes of the excised bovine tongue. Fiber orientation mapping provides a subdivision of the tongue into its principal intrinsic and extrinsic muscular components, The anterior tongue consists of a central region of orthogonally oriented intrinsic fibers surrounded by an axially oriented muscular sheath. The posterior tongue consists principally of a central region of extrinsic fibers, originating at the inferior surface and projecting in a fan-like manner in the superior, lateral, and posterior directions, and lateral populations of extrinsic fibers directed posterior-inferior and posterior-superior. Analysis of cross-fiber anisotropy indicates a basic contrast of design between the extrinsic and the intrinsic fibers. Whereas the extrinsic muscles exhibit a uniaxial architecture typical of skeletal muscle, the intrinsic core muscles, comprised of the verticalis and the transversus muscles, show strong cross-fiber anisotropy. This pattern is consistent with the theory that the tongue's core functions as a muscular hydrostat in that conjoint contraction of the transverse and vertical fibers enable the tissue to expand at right angles to these fibers. These findings suggest that three-dimensional analysis of diffusion tensor magnetic resonance imaging provides a structural basis for understanding the micromechanics of the mammalian tongue. C1 Massachusetts Gen Hosp, NMR Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. MIT, Dept Mech Engn, Cambridge, MA 02139 USA. RP Wedeen, VJ (reprint author), Massachusetts Gen Hosp E, Dept Radiol, NMR Ctr, 149 13th St, Charlestown, MA USA. NR 19 TC 42 Z9 46 U1 0 U2 3 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD FEB PY 2001 VL 80 IS 2 BP 1024 EP 1028 PG 5 WC Biophysics SC Biophysics GA 398PP UT WOS:000166765100044 PM 11159469 ER PT J AU Yuan, J Melder, RJ Jain, RK Munn, LL AF Yuan, J Melder, RJ Jain, RK Munn, LL TI Lateral view flow system for studies of cell adhesion and deformation under flow conditions SO BIOTECHNIQUES LA English DT Article ID ENDOTHELIAL-CELLS; BLOOD-CELLS; L-SELECTIN; ERYTHROCYTES; LEUKOCYTES; VELOCITY; SURFACES; VENULES AB Physical interactions between circulating cells and the vascular wall play a central role in inflammation, metastasis, atherosclerosis, and therapeutic cell delivery. Unfortunately, traditional in vitro flow assays cannot be used to visualize the details of cell-surface interactions in blood flow because of inappropriate geometry and the poor penetration of light in erythrocyte solutions. To overcome these obstacles, we have developed an agarose-cast cylindrical vessel system to examine the profiles of cells interacting with surfaces under flow conditions. This design allows observation and quantification of cell deformations as cells adhere to surfaces under dynamic flow conditions without modifying the microscope or optical path. Furthermore, our flow system is uniquely suited for monitoring the profiles of adherent leukocytes deforming in response to erythrocyte suspension flow. We have used this flow system to study the role of erythrocytes in leukocyte-substrate interactions. Our results show that the cell deformation index (the ratio of the cell length of cell height) is higher in erythrocyte solutions compared to erythrocyte-free saline. This novel lateral view flow system provides a powerful technique for visualizing and quantifying the morphological changes of cells in contact with substrates exposed to shear stress. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Munn, LL (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 7, Boston, MA 02114 USA. RI Munn, Lance/L-3950-2016 OI Munn, Lance/0000-0003-0698-7232 FU NHLBI NIH HHS [R01 HL064240, K02 HL073237-01, R01-HL64240, R01 HL064240-01, K02 HL073237] NR 26 TC 14 Z9 14 U1 0 U2 3 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD FEB PY 2001 VL 30 IS 2 BP 388 EP + PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 400ZL UT WOS:000166902500027 PM 11233608 ER PT J AU Chernock, RD Cherla, RP Ganju, RK AF Chernock, RD Cherla, RP Ganju, RK TI SHP2 and cbl participate in alpha-chemokine receptor CXCR4-mediated signaling pathways SO BLOOD LA English DT Article ID TYROSINE-PHOSPHATASE SHP-2; SARCOMA-ASSOCIATED HERPESVIRUS; PROTEIN-COUPLED RECEPTOR; GROWTH-FACTOR RECEPTOR; CELL ANTIGEN RECEPTOR; T-CELLS; PHOSPHATIDYLINOSITOL 3-KINASE; FOCAL ADHESION; HIV-1 ENTRY; IN-VIVO AB Stromal cell-derived factor (SDF)-1 alpha, and its receptor, CXCR4, play an important role in cell migration, embryonic develop ment, and human immunodeficiency virus infection. However, the cellular signaling pathways that mediate these processes are not fully elucidated. We and others have shown that the binding of SDF-1 alpha to CXCR4 activates phosphatidylinositol-3 kinase (PI-3 kinase), p44/42 mitogen-associated protein kinase, and the transcription factor nuclear factor-kappaB, and it also enhances the tyrosine phosphorylation and association of proteins involved in the formation of focal adhesions. In this study, we examined the role of phosphatases in CXCR4-mediated signaling pathways. We observed significant inhibition of SDF-1 alpha -induced migration by phosphatase inhibitors in CXCR4-transfected pre-B lymphoma L1.2 cells, Jurkat T cells, and peripheral blood lymphocytes. Further studies revealed that SDF-1 alpha stimulation induced robust tyrosine phosphorylation in the SH2-containing phosphatase SHP2, SHP2 associated with the CXCR4 receptor and the signaling molecules SHIP, cbl, and fyn, Overexpression of wild-type SHP2 increased SDF-1 alpha -induced chemotaxis. Enhanced activation of fyn and lyn kinases and the tyrosine phosphorylation of cbl were also observed, In addition, SDF-1 alpha stimulation enhanced the association of cbl with PI-3 kinase, Crk-L, and 14-3-3 beta proteins. Our results suggest that CXCR4-mediated signaling is regulated by SHP2 and cbl, which collectively participate in the formation of a multimeric signaling complex. (C) 2001 by The American Society of Hematology. C1 Harvard Univ, Inst Med, BIDMC, Div Expt Med,Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, BIDMC, Div Hematol Oncol, Boston, MA 02115 USA. RP Ganju, RK (reprint author), Harvard Univ, Inst Med, BIDMC, Div Expt Med,Sch Med, 4 Blackfan Circle,Room 343, Boston, MA 02115 USA. FU NCI NIH HHS [CA76950] NR 76 TC 68 Z9 74 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 1 PY 2001 VL 97 IS 3 BP 608 EP 615 DI 10.1182/blood.V97.3.608 PG 8 WC Hematology SC Hematology GA 397LV UT WOS:000166697900003 PM 11157475 ER PT J AU Elias, AD Richardson, P Avigan, D Ibrahim, J Joyce, R Demetri, G Levine, J Warren, D Arthur, T Reich, E Wheeler, C Frei, E Ayash, L AF Elias, AD Richardson, P Avigan, D Ibrahim, J Joyce, R Demetri, G Levine, J Warren, D Arthur, T Reich, E Wheeler, C Frei, E Ayash, L TI A short course of induction chemotherapy followed by two cycles of high-dose chemotherapy with stem cell rescue for chemotherapy naive metastatic breast cancer SO BONE MARROW TRANSPLANTATION LA English DT Article DE metastatic cancer; hematopoietic stem cell support; double transplant; phase I ID PROGRESSION-FREE SURVIVAL; COMBINATION CHEMOTHERAPY; INTENSIVE CHEMOTHERAPY; AUTOLOGOUS MARROW; PROGENITOR CELLS; BONE-MARROW; PHASE-II; SUPPORT; TRIAL; TAXOL AB A single cycle of high-dose chemotherapy with stem cell support (HDC) in women with responsive metastatic breast cancer (BC) consistently achieves over 50% complete and near complete response (CR/nCR). This significant cytoreduction results in a median event-free survival (EFS) of 8 months, and approximately 20% 3-year and 16% 5-year EFS in selected patients. To improve long-term outcomes, new strategies to treat minimal residual tumor burden are needed, Increased total dose delivered can be achieved with two cycles of HDC. Critical design issues include shortening induction chemotherapy to avoid development of drug resistance and the use of different agents for each HDC cycle. We have determined the maximum tolerated dose (MTD) for paclitaxel combined with high-dose melphalan in the context of a double transplant and explored the impact of a short induction phase. Between June 1994 and August 1996, we enrolled 32 women with metastatic BC on to this phase I double transplant trial. Induction consisted of doxorubicin 30 mg/m(2)/day days 1-3 given for 2 cycles every 14 days with G-CSF 5 mug/kg s,c, days 4-12, Stem cell collection was performed by leukapheresis in each cycle when the WBC recovered to above 1000/mul. Patients with stable disease or better response to induction were eligible to proceed with HDC. HDC regimen I(TxM) included paclitaxel with dose escalation from 0 to 300 mg/m(2) given on day 1 and melphalan 180 mg/m2 in two divided doses given on day 3. HDC regimen II was CTCb (cyclophosphamide 6 g/m(2), thiotepa 500 mg/m(2), and carboplatin 800 mg/m(2) total doses) delivered by 96-h continuous infusion. At the first dose level of 150 mg/m(2) paclitaxel by 3 h infusion, four of five patients developed dose-limiting toxicity consisting of diffuse skin erythema and capillary leak syndrome. Only two of these five completed the second transplant. Subsequently, paclitaxel was delivered by 24-h continuous infusion together with 96 h of dexamethasone and histamine receptor blockade. This particular toxicity was not observed again. No toxic deaths occurred and dose-limiting toxicity was not encountered. Three patients were removed from study prior to transplant: one for insurance refusal and two for disease progression, All others completed both cycles of transplant, Complete and near complete response (CR/nCR) after completion of therapy was achieved in 23 (72%) of 32 patients. The median EFS is 26 months. The median overall survival has not yet been reached. At a median follow-up of 58 months, EFS and overall survival are 41% and 53%, respectively. This double transplant approach is feasible, safe, and tolerable. Treatment duration is only 14 weeks and eliminates lengthy induction chemotherapy. The observed event-free and overall survivals are promising and are better than expected following a single transplant. Whilst selection biases may in part contribute to this effect, a much larger phase II double transplant trial is warranted in preparation for a potential randomized comparison of standard therapy vs single vs double transplant. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Elias, AD (reprint author), Univ Colorado, Hlth Sci Ctr, 4200 E 9th Ave, Denver, CO 80220 USA. FU NCI NIH HHS [CA13849] NR 52 TC 8 Z9 9 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD FEB PY 2001 VL 27 IS 3 BP 269 EP 278 DI 10.1038/sj.bmt.1702780 PG 10 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 404GU UT WOS:000167089700005 PM 11277174 ER PT J AU Vaina, LM Cowey, A Eskew, RT LeMay, M Kemper, T AF Vaina, LM Cowey, A Eskew, RT LeMay, M Kemper, T TI Regional cerebral correlates of global motion perception - Evidence from unilateral cerebral brain damage SO BRAIN LA English DT Article DE brain damage; motion processing; visual areas ID POSITRON EMISSION TOMOGRAPHY; SUPERIOR TEMPORAL SULCUS; TRANSCRANIAL MAGNETIC STIMULATION; FIRST-ORDER MOTION; CORTICAL AREAS MT; VISUAL-MOTION; MACAQUE MONKEY; FUNCTIONAL-ANATOMY; DIRECTION DISCRIMINATION; SELECTIVE IMPAIRMENT AB The used a psychophysical task to measure sensitivity to motion direction in 50 stroke patients with unilateral brain lesions and 85 control subjects. Subjects were asked to discriminate the overall direction of motion in dynamic stochastic random dot displays in which only a variable proportion of the spots moved in a single direction while the remainder moved randomly, Behavioural and neurophysiological evidence shows that the middle temporal (MT/V5) and middle superior temporal (MST) areas in the macaque monkey are indispensably involved in the perception of this type of motion, In human subjects too, lesions in the same region disrupt performance on this task. Here we assessed more extensively the correlation between direction sensitivity for global motion and the anatomical locus of the lesion, Thresholds for perceiving the direction of global motion were impaired in the visual field contralateral to the lesion in patients with lesions in the occipitoparietal and parietotemporal areas involving the human analogue of areas MT/V5 and MST, but not by lesions in the occipito-temporal or anterior frontal areas, Patients with lesions involving the anterior temporal or parietal lobes displayed poor performance for stimuli presented in either visual field, which is consistent with the large and bilateral receptive fields in these areas in monkeys. The perception of global motion was also more impaired in the centripetal than the centrifugal direction in the hemifield contralateral to the MT/V5 lesion. Surprisingly, thresholds were normal in all patients when the displays contained static but not dynamic visual noise, suggesting that their deficit reflects an inability to filter out dynamic noise, Although frequent repeated testing of some patients whose lesion involved the human homologue of MT was accompanied by an improvement in performance, this was no greater than in other patients who received training on different motion tasks. C1 Boston Univ, Dept Biomed Engn, Brain & Vis Res Res Lab, Boston, MA 02215 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. NE Univ, Dept Psychol, Boston, MA USA. Univ Oxford, Dept Expt Psychol, Oxford OX1 2JD, England. RP Vaina, LM (reprint author), Boston Univ, Dept Biomed Engn, Brain & Vis Res Res Lab, 44 Cummington St, Boston, MA 02215 USA. FU NEI NIH HHS [R01 EY007861, EY09712, EY2-RO1-0781] NR 75 TC 51 Z9 53 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD FEB PY 2001 VL 124 BP 310 EP 321 DI 10.1093/brain/124.2.310 PN 2 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 403TZ UT WOS:000167059700006 PM 11157558 ER PT J AU Koenen, KC Driver, KL Oscar-Berman, M Wolfe, J Folsom, S Huang, MT Schlesinger, L AF Koenen, KC Driver, KL Oscar-Berman, M Wolfe, J Folsom, S Huang, MT Schlesinger, L TI Measures of prefrontal system dysfunction in posttraumatic stress disorder SO BRAIN AND COGNITION LA English DT Article DE posttraumatic stress disorder; frontal brain systems; neuropsychology; comparative neuropsychology ID TO-SAMPLE PERFORMANCE; PARKINSONS-DISEASE; HIPPOCAMPAL VOLUME; OBJECT ALTERNATION; DELAYED-RESPONSE; COMBAT VETERANS; WORKING-MEMORY; NEUROPSYCHOLOGY; ATTENTION; DEFICITS AB Clinical observations have suggested that individuals who have suffered traumatic stressful events exhibit disruption in abilities mediated by frontal brain systems. Therefore, this study employed tasks sensitive to frontal lobe dysfunction, including delayed response (DR), delayed alternation (DA), object alternation (OA), delayed matching-to-sample (DMTS), and delayed nonmatching-to-sample (DNMTS), with participants having posttraumatic stress disorder (PTSD). Compared to controls, the PTSD participants were unimpaired on DA and DMTS, but they showed deficits on DR, OA, and DNMTS tasks. This pattern of results suggests disruption of functioning in selective prefrontal brain systems. Results are discussed in the context of the neuropsychological features of PTSD, as well as possible neuropathological and etiological underpinnings of this disorder. (C) 2001 Academic Press. C1 Boston Univ, Sch Med, Div Psychiat, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Dept Vet Affairs Med Ctr, Psychol Res Serv, Boston, MA USA. Dept Vet Affairs Med Ctr, Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA USA. Columbia Sch Publ Hlth, Boston, MA USA. Univ Toronto, Dept Psychiat, Toronto, ON, Canada. RP Oscar-Berman, M (reprint author), Boston Univ, Sch Med, Div Psychiat, M-902,715 Albany St, Boston, MA 02118 USA. EM kckds@hotmail.com RI Koenen, Karestan/K-5402-2014 OI Koenen, Karestan/0000-0003-3293-4281 FU NIAAA NIH HHS [R37-AA07112]; NIMH NIH HHS [F31 MH011954, F31 MH011954-01]; PHS HHS [K05-00219] NR 62 TC 69 Z9 74 U1 2 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0278-2626 J9 BRAIN COGNITION JI Brain Cogn. PD FEB PY 2001 VL 45 IS 1 BP 64 EP 78 DI 10.1006/brcg.2000.1256 PG 15 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 403UF UT WOS:000167060300006 PM 11161363 ER PT J AU Caplan, D AF Caplan, D TI The measurement of chance performance in aphasia, with specific reference to the comprehension of semantically reversible passive sentences: A note on issues raised by Caramazza, Capitani, Rey, and Berndt (2001) and Drai, Grodzinsky, and Zurif (2001) SO BRAIN AND LANGUAGE LA English DT Editorial Material ID BROCA APHASIA; AGRAMMATISM; NEUROPSYCHOLOGY; MORPHOLOGY; ASSIGNMENT; SPEAKING; MEMORY; ROLES C1 Massachusetts Gen Hosp, Neuropsychol Lab, Dept Neurol, Boston, MA 02114 USA. RP Caplan, D (reprint author), Massachusetts Gen Hosp, Neuropsychol Lab, Dept Neurol, Vincent Burnham 827,Fruit St, Boston, MA 02114 USA. FU NIDCD NIH HHS [DC00942] NR 26 TC 20 Z9 20 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0093-934X J9 BRAIN LANG JI Brain Lang. PD FEB PY 2001 VL 76 IS 2 BP 193 EP 201 DI 10.1006/brln.2000.2354 PG 9 WC Audiology & Speech-Language Pathology; Linguistics; Neurosciences; Psychology, Experimental SC Audiology & Speech-Language Pathology; Linguistics; Neurosciences & Neurology; Psychology GA 405VT UT WOS:000167181800008 PM 11254258 ER PT J AU Soriano, SG Sullivan, LJ Venkatakrishnan, K Greenblatt, DJ Martyn, JAJ AF Soriano, SG Sullivan, LJ Venkatakrishnan, K Greenblatt, DJ Martyn, JAJ TI Pharmacokinetics and pharmacodynamics of vecuronium in children receiving phenytoin or carbamazepine for chronic anticonvulsant therapy SO BRITISH JOURNAL OF ANAESTHESIA LA English DT Article DE complications, epilepsy; neuromuscular block, vecuronium; children ID INDUCED NEUROMUSCULAR BLOCKADE; ACETYLCHOLINE-RECEPTORS; INDUCED RESISTANCE; DRUG-INTERACTIONS; PROTEIN-BINDING; D-TUBOCURARINE; UP-REGULATION; PLASMA; SUCCINYLCHOLINE; GLYCOPROTEIN AB The pharmacokinetics and time course of action of vecuronium in normal children and children receiving anticonvulsant drugs for prolonged periods were characterized. A bolus dose of vecuronium 0.15 mg kg(-1) was administered i.v. to 10 non-epileptic children and to 10 children on phenytoin and 10 children on carbamazepine, who were matched for age and weight. Plasma concentrations of vecuronium, 3-OH desacetylvecuronium (the primary metabolite of vecuronium) and at-acid glycoprotein (AAG) were determined. Pharmacokinetic variables were derived from plasma samples collected before and after administration of vecuronium. Neuromuscular transmission was monitored by evoked compound electromyography. Recovery of the first twitch of the train-of-four (T-1/T-0) and the recovery index (RI), the time for 25-75% recovery of T-1/T-0, were determined. The elimination half-life of vecuronium was significantly reduced in both anticonvulsant groups compared with control [control 48.2 (SD 40.3), phenytoin 23.5 (13.1), carbamazepine 18.4 (16.6) min, P<0.05]. Vecuronium clearance was increased in both anticonvulsant groups [control 9.0 (3.6), phenytoin 15.1 (8.9), carbamazepine 18.8 (13.1) ml kg(-1) min(-1), 0.05 3 times that of baseline in 13 of /14 patients (92.9%), suggesting some degree of Leydig cell insufficiency. CONCLUSIONS. The results of the current study show a high risk of gonadal dysfunction in men exposed to cyclophosphamide during childhood as part of a VAC/Adria-VAC chemotherapy regimen. Exposure prior to puberty was not found to be protective, and the risk of infertility appeared to increase with higher doses of therapy. To the authors' knowledge the clinical significance of impaired Leydig cell function beginning at a young age is unknown and merits further study. (C) 2001 American Cancer Society. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, David B Berini Jr Qual Life Clin, Boston, MA 02115 USA. Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Kenney, LB (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, David B Berini Jr Qual Life Clin, 44 Binney St,D307B, Boston, MA 02115 USA. NR 33 TC 128 Z9 145 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 FEB 1 PY 2001 VL 91 IS 3 BP 613 EP 621 DI 10.1002/1097-0142(20010201)91:3<613::AID-CNCR1042>3.0.CO;2-R PG 9 WC Oncology SC Oncology GA 402GC UT WOS:000166976800021 PM 11169946 ER PT J AU Nichols, KE Malkin, D Garber, JE Fraumeni, JF Li, FP AF Nichols, KE Malkin, D Garber, JE Fraumeni, JF Li, FP TI Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID FRAUMENI-SYNDROME FAMILY; TUMOR-SUPPRESSOR GENE; ADRENAL-CORTICAL CARCINOMA; TP53 SPLICING MUTATION; CHOROID-PLEXUS TUMORS; BREAST-CANCER; PRONE FAMILY; ADRENOCORTICAL CARCINOMA; OLIGOMERIZATION DOMAIN; MALIGNANT-MELANOMA AB Germ-line p53 mutations are associated with dominantly inherited Li-Fraumeni syndrome (LFS), which features early-onset sarcomas of bone and soft tissues, carcinomas of the breast and adrenal cortex, brain tumors, and acute leukemias. However, carriers of germ-line p53 mutations may also be at increased risk of other cancers. To clarify the tumor spectrum associated with inherited p53 mutations, we examined cancer occurrences among our series of 45 families, plus 140 other affected cases and kindreds reported in the literature. The analyses included all cancers in patients with a germ-line p53 mutation and their first-degree relatives with nearly 50% likelihood of being a carrier. Data were abstracted on tumor types and ages at diagnosis in eligible family members, and duplicate reports were excluded. Among 738 evaluable cancers, 569 (77%) were the six tumor types (breast and adrenocortical carcinomas, sarcomas of the bone and soft tissues, brain tumors, and leukemias) associated with LFS, The remaining 169 (23%) cancers included diverse carcinomas of the lung and gastrointestinal tract, lymphomas, and other neoplasms that occurred at much earlier ages than expected in the general population. Unusually early ages at diagnosis are characteristic of hereditary cancers and suggest that carriers of germ-line p53 mutations are at increased risk of a wide range of neoplasms. Future studies addressing age-specific penetrance and site-specific cancer risks can increase the utility of LFS as a model for understanding the role of p53 alterations in carcinogenesis and for designing diagnostic and preventive interventions for the broad array of neoplasms in this syndrome. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Li, FP (reprint author), Dana Farber Canc Inst, Smith 201,44 Binney St, Boston, MA 02115 USA. NR 91 TC 181 Z9 186 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2001 VL 10 IS 2 BP 83 EP 87 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 401HR UT WOS:000166922600001 PM 11219776 ER PT J AU Ichikawa, T Petros, WP Ludeman, SM Fangmeier, J Hochberg, FH Colvin, OM Chiocca, EA AF Ichikawa, T Petros, WP Ludeman, SM Fangmeier, J Hochberg, FH Colvin, OM Chiocca, EA TI Intraneoplastic polymer-based delivery of cyclophosphamide for intratumoral bioconversion by a replicating oncolytic viral vector SO CANCER RESEARCH LA English DT Article ID INTERSTITIAL CHEMOTHERAPY; METABOLITES; 4-HYDROPEROXYCYCLOPHOSPHAMIDE; THERAPY; GLIOMA AB rRp450 is an oncolytic herpesvirus that expresses the CYP2B1 cDNA, responsible for bioconverting cyclophosphamide (CPA) into the active metabolites 4-hydroxyCPA/aldophosphamide (AP). However, formal proof of prodrug activation is lacking. We report that activation of CPA in cells infected with rRp450 generates a time-dependent increase of diffusible 4-hydroxyCPA/AP. For in vivo applications, a CPA-impregnated polymer was implanted into human tumor xenografts inoculated with rRp450. The area under the curve for 4-hydroxyCPA/AP was 806 mug/g of tumor tissue/h when CPA was administered via intraneoplastic polymer and 3 mug/g of tumor tissue/h when CPA was administered i.p. Therefore, (a) a lytic virus expressing a "suicide" gene can activate a prodrug; and (b) within rRp450-infected tumor, more prolonged and higher concentrations of activated metabolites are generated by intraneoplastic compared with systemic administration of prodrug. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neurosurg Serv,Mol Neurooncol Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neurol Serv, Boston, MA 02114 USA. Duke Univ, Ctr Comprehens Canc, Durham, NC 27710 USA. RP Chiocca, EA (reprint author), Massachusetts Gen Hosp, CNY6,East Bldg,13th St, Charlestown, MA 02129 USA. FU NCI NIH HHS [P01 CA692460] NR 20 TC 30 Z9 35 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2001 VL 61 IS 3 BP 864 EP 868 PG 5 WC Oncology SC Oncology GA 403AJ UT WOS:000167020100015 PM 11221871 ER PT J AU Fan, LJ Iyer, J Zhu, SX Frick, KK Wada, RK Eskenazi, AE Berg, PE Ikegaki, N Kennett, RH Frantz, CN AF Fan, LJ Iyer, J Zhu, SX Frick, KK Wada, RK Eskenazi, AE Berg, PE Ikegaki, N Kennett, RH Frantz, CN TI Inhibition of N-myc expression and induction of apoptosis by iron chelation in human neuroblastoma cells SO CANCER RESEARCH LA English DT Article ID HUMAN NEURO-BLASTOMA; TRANS-RETINOIC ACID; PROTEIN-KINASE-C; RIBONUCLEOTIDE REDUCTASE; DNA-SYNTHESIS; TRANSCRIPTIONAL REGULATION; GENE-EXPRESSION; AMPLIFICATION; HYDROXYUREA; MECHANISM AB Neuroblastoma is the second most common solid malignancy of childhood. Enhanced expression of the amplified N-myc gene in the tumor tells may be associated with poor patient prognosis and may contribute to tumor development and progression. The use of deferoxamine mesylate (DFO), an iron chelator, to treat neuroblastoma is being investigated in national clinical studies. We show here by TUNEL assay and DNA laddering that DFO induces apoptosis in cultured human neuroblastoma cells, which is preceded by a decrease in the expression of N-myc and the altered expression of some other oncogenes (up-regulating c-fos and down-regulating c-myb) but not housekeeping genes. The decrease in N-myc expression is iron-specific but does not result from inhibition of ribonucleotide reductase, because specific inhibition of this iron-containing enzyme by hydroxyurea does not affect N-myc protein levels. Nuclear run-on and transient reporter gene expression experiments show that the decrease in N-myc expression occurs at the level of initiation of transcription and by inhibiting N-myc promoter activity. Comparison across neuroblastoma fell lines of the amount of residual cellular N-myc protein with the extent of apoptosis measured as pan-caspase activity after 48 h of iron chelation reveals no correlation, suggesting that the decrease in N-myc expression is unlikely to mediate apoptosis, In conclusion, chelation of cellular iron by DFO may alter the expression of multiple genes affecting the malignant phenotype by multiple pathways, Given the clinical importance of N-myc overexpression in neuroblastoma malignancy, decreasing N-myc expression by DFO might be useful as an adjunct to current therapy. C1 Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. Univ Rochester, Sch Med & Dent, Dept Pediat, Rochester, NY 14642 USA. NCI, Pediat Oncol Branch, NIH, Gaithersburg, MD 20877 USA. Canc Res Ctr Hawaii, Honolulu, HI 96813 USA. Kapiolani Hlth Res Inst, Honolulu, HI 96813 USA. George Washington Univ, Dept Biochem & Mol Biol, Washington, DC 20037 USA. Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. Wheaton Coll, Dept Biol, Wheaton, IL 60187 USA. Childrens Hosp, Dept Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Fan, LJ (reprint author), Univ Maryland, Sch Med, Dept Pediat, Room 10-044A,BRB,655 W Baltimore St, Baltimore, MD 21201 USA. FU NINDS NIH HHS [NS34432] NR 50 TC 49 Z9 52 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2001 VL 61 IS 3 BP 1073 EP 1079 PG 7 WC Oncology SC Oncology GA 403AJ UT WOS:000167020100050 PM 11221835 ER PT J AU Simmons, ML Lamborn, KR Takahashi, M Chen, PC Israel, MA Berger, MS Godfrey, T Nigro, J Prados, M Chang, S Barker, FG Aldape, K AF Simmons, ML Lamborn, KR Takahashi, M Chen, PC Israel, MA Berger, MS Godfrey, T Nigro, J Prados, M Chang, S Barker, FG Aldape, K TI Analysis of complex relationships between age, p53, epidermal growth factor receptor, and survival in glioblastoma patients SO CANCER RESEARCH LA English DT Article ID PROGNOSTIC-SIGNIFICANCE; BRAIN-TUMORS; PROLIFERATION MARKERS; ASTROCYTIC TUMORS; LABELING INDEX; GLIOMAS; OVEREXPRESSION; EXPRESSION; MUTATIONS; GENE AB Glioblastoma multiforme (GBM) carries a dismal prognosis. However, a range of survival times exists, and parameters that define prognostic groups may help to optimize treatment. To identify such prognostic groups, we analyzed tumor tissue from 110 cases of newly diagnosed GEM from two clinical protocols. Similar to other studies, we found no association of epidermal growth factor receptor (EGFR) overexpression (as assessed by immunohistochemistry), p53 immunopositivity, or p53 mutation with survival in the entire sample, However, EGFR overexpression showed trends toward worse prognosis in patients younger than the median age, but better prognosis in patients older than the median age. This interaction of EGFR with age group was statistically significant and led us to focus our further analyses on the younger patients. In this group, a statistically significant association of EGFR overexpression with worse survival was identified in the p53-negative but not p53-positive tumors. We found a similar result after screening these cases for mutations in p53: EGFR overexpression was negatively associated with survival only in the p53 wild-type cases. To confirm this unexpected result, this finding was reproduced in a validation sample of an additional 42 tumors from younger patients on the same two clinical protocols. This complex relationship between EGFR and p53 in younger patients remained in a multivariate analysis that incorporated additional prognostic variables. The results suggest that analysis of prognostic markers in GEM is complex, and maximal information may require analysis of subgroups based on age and the status of specific markers such as p53, In addition, they suggest a specific group of patients on which to focus promising therapies targeting EGFR. C1 Univ Calif San Francisco, Sch Med, Dept Pathol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Med, Dept Epidemiol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Med, Dept Neurol Surg, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Med, Ctr Canc, San Francisco, CA 94143 USA. Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Aldape, K (reprint author), Univ Calif San Francisco, Sch Med, Dept Pathol Neuropathol, San Francisco, CA 94143 USA. RI Godfrey, Tony/A-5572-2013 OI Godfrey, Tony/0000-0002-3283-6983 FU NCI NIH HHS [P01 CA13525, CA 62399-01, P30 CA082103, P30 CA82103-01] NR 34 TC 210 Z9 222 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2001 VL 61 IS 3 BP 1122 EP 1128 PG 7 WC Oncology SC Oncology GA 403AJ UT WOS:000167020100057 PM 11221842 ER PT J AU Sen, J AF Sen, J TI Signal transduction in thymus development SO CELLULAR AND MOLECULAR BIOLOGY LA English DT Review DE thymus; T-cell development; signal transduction; gene expression ID T-CELL DEVELOPMENT; RECEPTOR-GAMMA-CHAIN; SEVERE COMBINED IMMUNODEFICIENCY; ACTIVATED PROTEIN-KINASE; DEFECTIVE LYMPHOID DEVELOPMENT; IMMATURE CD4+CD8+ THYMOCYTES; TRANSCRIPTION FACTOR GATA-3; PHOSPHATASE-DEFICIENT MICE; P56(LCK) TYROSINE KINASE; INHIBITS MULTIPLE FORMS AB Reciprocal interaction between bone marrow derived lymphoid precursor cells and the thymic environment leads, through a series of developmental events, to the generation of a diverse repertoire of functional T-cells. During thymopoiesis fetal liver or bone marrow derived precursors enter the thymus and develop into mature T-cells in response to cues derived from the environment. The thymic micro-environment provides signals to the lymphoid cells as a result of cell-cell interactions, locally produced cytokines, chemokines and hormones. Developing thymocytes, in turn, influence the thymic stroma to form a supportive micro-environment. Stage-specific signals provide an exquisite balance between cellular proliferation, differentiation, cell survival and death. The result of this intricate signaling concert is the production of the requisite numbers of well educated self-restricted T-cells. Mature T-cells are exported to the peripheral lymphoid organs, where, upon encountering antigen, naive T-cells further mature into effector cells that provide cytolytic or T helper functions. While there are extra-thymic locations for T-cell development, majority of T-cells in peripheral lymphoid organs are thymus derived. In mice and humans, T-cells develop throughout life although the efficacy declines significantly with age. It is not clear if this is a direct consequence of deterioration of the thymic environment by involution, a paucity of bone marrow derived precursors, or both. However, new data clearly shows that the involuted adult thymus retains the ability to generate new T-cells. Recent advances have revealed many components of an exquisitely balanced signaling cascades that regulate cell fate, cellular proliferation and cell death in the thymus. This article describes fundamental features of developing thymocytes and the thymic micro-environment as they relate to the signaling pathways. C1 Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Div Pediat Hematol & Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Sen, J (reprint author), Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Div Pediat Hematol & Oncol, 44 Binney St, Boston, MA 02115 USA. NR 169 TC 18 Z9 19 U1 0 U2 1 PU CELLULAR & MOLECULAR BIOLOGY PI NOISY-LE-GRAND PA PROF R WEGMANN RESIDENCE HAUSSMANN 1 AVENUE DU PAVE NEUF, 93160 NOISY-LE-GRAND, FRANCE SN 0145-5680 J9 CELL MOL BIOL JI Cell. Mol. Biol. PD FEB PY 2001 VL 47 IS 1 BP 197 EP 215 PG 19 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 416CB UT WOS:000167761400021 PM 11292256 ER PT J AU Zhao, Y Rodriguez-Barbosa, JI Zhao, GL Shaffer, J Arn, JS Sykes, M AF Zhao, Y Rodriguez-Barbosa, JI Zhao, GL Shaffer, J Arn, JS Sykes, M TI Maturation and function of mouse T-cells with a transgenic TCR positively selected by highly disparate xenogeneic porcine MHC SO CELLULAR AND MOLECULAR BIOLOGY LA English DT Article DE thymus; positive selection; T-cells; xenograft; transplantation ID PIG THYMUS GRAFTS; II-DEFICIENT MICE; NEGATIVE SELECTION; CLONAL DELETION; HEMATOPOIETIC-CELLS; HELPER-CELLS; TOLERANCE; LYMPHOCYTES; NAIVE; DIFFERENTIATION AB Remarkably normal cellular immune function, along with specific T-cell tolerance to highly disparate xenogeneic donors, can be achieved by grafting fetal pig thymus (FP THY) tissue to T and NK cell-depleted, thymectomized (ATX) mice. Porcine MHC can mediate positive selection of mouse CD4(+) T-cells with a mouse MHC-restricted TCR in FP THY-grafted, T- and NK cell-depleted, ATX TCR-transgenic "AND" mice. However, functional studies were not performed on transgenic mouse T-cells selected in a FP THY graft. We have now performed further studies to confirm the ability of porcine MHC to mediate the positive selection of mouse T-cells with a mouse MHC-restricted TCR, and to exclude the possibility that the maturation of mouse T-cells with a mouse MHC-restricted TCR in FP THY grafts in ATX "AND" mice is a special case. For this purpose, TCR-transgenic mice with an unrelated transgenic TCR ["3A9", specific for hen egg lysozyme (HEL) peptide 46-61 presented by I-A(k)] were employed. Similar to FP THY-grafted ATX "AND" mice, large numbers of mouse CD4 single positive thymocytes expressing the transgenic TCR (V beta8.2) and expressing a mature phenotype (Qa-2(high) and heat stable antigen, HSA(low)) were detected in FP THY grafts. Porcine thymus grafting led to a high level of peripheral repopulation with mouse naive-type (CD44(low) CD45RB(high) CD62L(high)) CD4(+) cells expressing the transgenic TCR in T and NK cell-depleted ATX "3A9" mice, regardless of whether the recipients had a positive selecting or a non-selecting, class II deficient MHC background. The mouse CD4(+) T-cells expressing the "3A9" TCR showed efficient primary proliferative responses to the protein antigen (HEL) when it was presented by mouse class II+ antigen presenting cells (APC) in vitro. These results, collectively, support the general conclusion that discordant xenogeneic porcine MHC can mediate positive selection of mouse T-cells with mouse MHC-restricted TCR. This study has implications for the potential clinical use of xenogeneic thymus transplantation to reconstitute cellular immunity in the setting of thymic insufficiency or thymectomy, and hence for its applicability to the induction of xenograft tolerance and in the treatment of immunodeficiency diseases. C1 Harvard Univ, Sch Med,Massachusetts Gen Hosp, Bone Marrow Transplantat Sect, Surg Serv,Transplantat Biol Res Ctr, Boston, MA 02129 USA. RP Sykes, M (reprint author), Harvard Univ, Sch Med,Massachusetts Gen Hosp, Bone Marrow Transplantat Sect, Surg Serv,Transplantat Biol Res Ctr, MGH E,Bldg 149-5102,13th St, Boston, MA 02129 USA. RI RODRIGUEZ-BARBOSA, JOSE IGNACIO/C-7808-2011 FU NHLBI NIH HHS [HL186461]; NIAID NIH HHS [P01-AI39755] NR 57 TC 9 Z9 9 U1 0 U2 0 PU CELLULAR & MOLECULAR BIOLOGY PI NOISY-LE-GRAND PA PROF R WEGMANN RESIDENCE HAUSSMANN 1 AVENUE DU PAVE NEUF, 93160 NOISY-LE-GRAND, FRANCE SN 0145-5680 J9 CELL MOL BIOL JI Cell. Mol. Biol. PD FEB PY 2001 VL 47 IS 1 BP 217 EP 228 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 416CB UT WOS:000167761400022 PM 11292257 ER PT J AU Ryan, DP Supko, JG Eder, JP Seiden, MV Demetri, G Lynch, TJ Fischman, AJ Davis, J Jimeno, J Clark, JW AF Ryan, DP Supko, JG Eder, JP Seiden, MV Demetri, G Lynch, TJ Fischman, AJ Davis, J Jimeno, J Clark, JW TI Phase I and pharmacokinetic study of esteinascidin 743 administered as a 72-hour continuous intravenous infusion in patients with solid malignancies SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 13-18, 1999 CL ATLANTA, GEORGIA SP Amer Soc Clin Oncol ID PERFORMANCE LIQUID-CHROMATOGRAPHY; TUNICATE ECTEINASCIDIA-TURBINATA; POTENT ANTITUMOR-ACTIVITY; MARINE NATURAL PRODUCT; CARIBBEAN TUNICATE; CRYSTAL-STRUCTURES; ANTICANCER DRUG; MINOR-GROOVE; HUMAN PLASMA; GUANINE N2 AB Ecteinascidin 743 (ET-743) is a cytotoxic tetrahydroisoquinoline alkaloid that covalently binds to DNA in the minor groove. The in vitro chemosensitivity of cancer cells to ET-743 is markedly enhanced by prolonging the duration of exposure to the drug. A Phase I study of ET-743 given as a 72-h continuous i.v. infusion every 21 days was performed. Characteristics of the 21 adult patients with refractory solid tumors enrolled in the study were as follows: (a) 12 men; (b) 9 women; (c) median age, 59 years; (d) Eastern Cooperative Oncology Group performance status less than or equal to1, 20 patients; and (e) two prior regimens of chemotherapy, 7 patients. Dose limiting toxicity (DLT) was defined by typical criteria, except that grade 3 transaminitis did not constitute a DLT. There were no DLTs in the six patients evaluated at the first two dose levels of 600 and 900 mug/m(2), Reversible grade 4 transaminitis occurred in two of nine patients after treatment with the first cycle of therapy at the third dose level of 1200 mug/m(2). Another patient experienced grade 4 rhabdomyolysis, renal failure requiring hemodialysis, grade 4 neutropenia, and grade 3 thrombocytopenia during the second cycle of therapy with this dose. The maximum tolerated dose was 1200 mug/m(2), and an additional six patients were enrolled at an intermediate dose level of 1050 mug/m(2). This well-tolerated dose was established as the recommended Phase II dose. The disposition of ET-743 was distinctly biexponential, and a departure from linear pharmacokinetic behavior was evident at the 1200-mug/m(2) dose level. Pharmacokinetic parameters determined at 1050 mug/m(2) were (mean +/- SD): maximum plasma concentration, 318 +/- 147 pg/ml; initial disposition phase half-life, 9.0 +/- 10.3 min; terminal phase half-life, 69.0 +/- 56.7 h; and total plasma clearance, 28.4 +/- 22.5 liters/h/m(2). Prolonged systemic exposure to concentrations of the agent that are cytotoxic in vitro were achieved. Toxicity of the drug is clearly schedule-dependent, because increasing the duration of infusion from 3 or 24 h to 72 h results in decreased myelosuppression and comparable hepatotoxicity. Although there were no objective responses to therapy, clear evidence of antitumor activity was observed in a patient with epithelioid mesothelioma, as confirmed by positron emission tomography studies. A Phase II trial to assess the efficacy of ET-743 against this highly refractory neoplasm has been initiated on the basis of this observation. The therapeutically optimal administration schedule remains to be established, inasmuch as there have been indications of activity against a variety of tumors during Phase I studies when the drug was infused over times ranging from 1 to 72 h. Characterizing the pharmacokinetics of ET-743 during the course of Phase II trials and Phase I combination studies is recommended to assure that this promising new anticancer drug can be used with an acceptable margin of safety. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. Pharm Mar S A, Clin Res & Dev, Madrid, Spain. RP Ryan, DP (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Cox Bldg,Room 640, Boston, MA 02114 USA. NR 46 TC 103 Z9 106 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB PY 2001 VL 7 IS 2 BP 231 EP 242 PG 12 WC Oncology SC Oncology GA 405LE UT WOS:000167160200004 PM 11234874 ER PT J AU Katznelson, L Kleinberg, D Vance, ML Stravou, S Pulaski, KJ Schoenfeld, DA Hayden, DL Wright, ME Woodburn, CJ Klibanski, A AF Katznelson, L Kleinberg, D Vance, ML Stravou, S Pulaski, KJ Schoenfeld, DA Hayden, DL Wright, ME Woodburn, CJ Klibanski, A TI Hypogonadism in patients with acromegaly: data from the multi-centre acromegaly registry pilot study SO CLINICAL ENDOCRINOLOGY LA English DT Article ID HUMAN GROWTH-HORMONE; PITUITARY-ADENOMAS; INSULIN RESISTANCE; FACTOR-I; EPIDEMIOLOGY; SURVIVAL AB OBJECTIVE Because acromegaly is an uncommon disorder, epidemiological data regarding the demographics of the disease such as the prevalence of hypogonadism have been limited. In order to derive clinical and epidemiological information, including underlying hormonal factors, regarding hypogonadism in patients with acromegaly, we performed a pilot study designed to develop a multi-centre acromegaly patient registry. DESIGN AND MEASUREMENTS Medical records of patients with acromegaly seen between 1976 and 1996 at three Institutions were reviewed, and data were entered into a database using a secure internet website. Hypogonadism was defined as amenorrhoea in women and testosterone deficiency in men. Subanalysis was performed in patients with microadenomas and women less than 50 years of age, to include women of reproductive age. RESULTS Information was available on 363 patients, of whom 54% were women. The mean age at diagnosis was 41 +/- 13 years. In subjects less than 50 years of age, hypogonadism was present in 59%. Hyperprolactinaemia was present in 45% and 21% of hypogonadal and eugonadal patients of reproductive age, respectively (P = 0.0003). GH levels were higher in patients with hypogonadism (P = 0.03). In patients < 50 years of age with microadenomas, hypogonadism was present in nine of the 22 (41%) patients, including 55% of the women and 27% of the men (P = ns). Hyperprolactinaemia was present in three of the 10 and four of the 14 of microadenoma patients with hypogonadism and eugonadism, respectively. CONCLUSION We developed a web-based acromegaly patient registry and used it to show that hypogonadism is a frequent consequence of acromegaly, even in patients with microadenomas, who are not at risk from hypopituitarism due to local mass effects. We also demonstrated that prolactin and GH hypersecretion contribute to the pathogenesis of hypogonadism in acromegaly, and that hypogonadism may occur in microadenoma patients even in the absence of hyperprolactinaemia. C1 Massachusetts Gen Hosp, Neuroendocrine Unit, Neuroendocrine Clin Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Gen Clin Res Ctr, Ctr Biostat, Boston, MA 02114 USA. NYU Med Ctr, New York, NY 10016 USA. Univ Virginia, Med Ctr, Charlottesville, VA 22903 USA. RP Katznelson, L (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Neuroendocrine Clin Ctr, 55 Fruit St,BUL 457B, Boston, MA 02114 USA. FU NCRR NIH HHS [M01RR01066] NR 24 TC 32 Z9 35 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD FEB PY 2001 VL 54 IS 2 BP 183 EP 188 DI 10.1046/j.1365-2265.2001.01214.x PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 402JX UT WOS:000166984800007 PM 11207632 ER PT J AU Thind, PK Tow, DE Drum, DE Nagel, S AF Thind, PK Tow, DE Drum, DE Nagel, S TI An unexpected pericardial effusion SO CLINICAL NUCLEAR MEDICINE LA English DT Article DE pericardial effusion; myocardial perfusion; Tc-99m sestamibi C1 VA Boston Hlth Care Syst, W Roxbury Div, Nucl Med Sect, Boston, MA USA. Harvard Univ, Sch Med, Joint Program Nucl Med, Boston, MA USA. RP Tow, DE (reprint author), Vet Adm Med Ctr W Roxbury, 1400 VFW Pkwy, Boston, MA 02132 USA. NR 2 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-9762 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD FEB PY 2001 VL 26 IS 2 BP 171 EP 172 DI 10.1097/00003072-200102000-00028 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 392VV UT WOS:000166434000028 PM 11201490 ER PT J AU Gill, TJ Moezzi, DM Oates, KM Sterett, WI AF Gill, TJ Moezzi, DM Oates, KM Sterett, WI TI Arthroscopic reduction and internal fixation of tibial plateau fractures in skiing SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article AB Arthroscopic reduction and interval fixation of tibial plateau fractures can facilitate restoration of articular congruity while permitting rigid fracture stabilization. Twenty-five patients who underwent arthroscpoic reduction and internal fixation of a tibial plateau fracture were reviewed. The average age of the patients was 45. At a mean followup of 24 months, 76% of patients rated their result as excellent and 16% as good. Eighty-four percent returned to full sporting activity. There were no episodes of nonunion, failure of fixation, wound infection, deep venous thrombosis, compartment syndrome, or arthrofibrosis. Preoperative fracture depression averaged 7.7 mm (range, 1-18 mm). Fracture depression at final followup averaged 0.8 mm (range, 05 mm). Sixty-four percent of patients had associated intraarticular injury diagnosed and treated at the time of arthroscopy. Arthroscopic reduction and internal fixation provides an accurate assessment of, and allows definitive treatment for, intraarticular injuries associated with tibial plateau fractures. The technique allows less soft tissue stripping than with traditional arthrotomy, better visualization of the articular surface, early return to physical activities, and obviates the need for meniscal detachment and repair. C1 Massachusetts Gen Hosp, Dept Orthoped, Boston, MA 02114 USA. Tufts Univ, Dept Orthoped Surg, Boston, MA 02111 USA. Steadman Hawkins Clin, Vail, CO USA. RP Gill, TJ (reprint author), Massachusetts Gen Hosp, Dept Orthoped, WACC-508,15 Parkman St, Boston, MA 02114 USA. NR 12 TC 20 Z9 29 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD FEB PY 2001 IS 383 BP 243 EP 249 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 397XD UT WOS:000166722800029 PM 11210961 ER PT J AU Hylek, EM AF Hylek, EM TI Oral anticoagulants - Pharmacologic issues for use in the elderly SO CLINICS IN GERIATRIC MEDICINE LA English DT Article ID ATRIAL-FIBRILLATION; RISK-FACTORS; BLEEDING COMPLICATIONS; SEPARATED ENANTIOMORPHS; STROKE PREVENTION; WARFARIN THERAPY; RACEMIC WARFARIN; DRUG-METABOLISM; HUMAN-LIVER; VITAMIN-K AB Clinical indications for oral anticoagulant therapy have greatly expanded, particularly among the elderly. Optimal use of oral anticoagulants in the geriatric population requires an understanding of the mechanism of action of warfarin and the pharmacokinetic and pharmacodynamic differences in this age group. Many factors affect the dose response of warfarin and the stability of anticoagulation control, including age, medications, diet, and comorbid illness. Important considerations in the initiation of warfarin dosing and the long-term management of anticoagulation in the elderly are discussed. C1 Massachusetts Gen Hosp, Div Gen Internal Med, Clin Epidemiol Unit, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Hylek, EM (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, Clin Epidemiol Unit, Dept Med, 50 Staniford St,9th Floor,923, Boston, MA 02114 USA. NR 69 TC 43 Z9 43 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 0749-0690 J9 CLIN GERIATR MED JI Clin. Geriatr. Med. PD FEB PY 2001 VL 17 IS 1 BP 1 EP + DI 10.1016/S0749-0690(05)70102-6 PG 14 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 402GL UT WOS:000166977800002 PM 11270124 ER PT J AU Beyth, RJ AF Beyth, RJ TI Hemorrhagic complications of oral anticoagulant therapy SO CLINICS IN GERIATRIC MEDICINE LA English DT Article ID NONRHEUMATIC ATRIAL-FIBRILLATION; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; CEREBRAL AMYLOID ANGIOPATHY; DEEP-VEIN THROMBOSIS; PEPTIC-ULCER DISEASE; CASE-FATALITY RATES; BLEEDING COMPLICATIONS; PULMONARY-EMBOLISM; STROKE PREVENTION; ELDERLY PATIENTS AB Although the efficacy of anticoagulant therapy has been established for many conditions that are prevalent among the elderly population, the decision to initiate anticoagulant therapy in the elderly population is not straightforward because elderly patients with multiple comorbidities and varying levels of functional status are not routinely included in clinical trials of efficacy. The true benefits of anticoagulant therapy will be realized when health care providers and elderly patients can accurately assess the absolute risk versus the benefit associated with anticoagulant therapy. C1 Houston Vet Affairs Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. RP Beyth, RJ (reprint author), Houston Vet Affairs Med Ctr, Houston Ctr Qual Care & Utilizat Studies, 39A,2002 Holcombe Blvd, Houston, TX 77030 USA. FU NIA NIH HHS [K08-AG00712] NR 81 TC 16 Z9 16 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 0749-0690 J9 CLIN GERIATR MED JI Clin. Geriatr. Med. PD FEB PY 2001 VL 17 IS 1 BP 49 EP + DI 10.1016/S0749-0690(05)70105-1 PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 402GL UT WOS:000166977800005 PM 11270133 ER PT J AU Singer, DE Go, AS AF Singer, DE Go, AS TI Antithrombotic therapy in atrial fibrillation SO CLINICS IN GERIATRIC MEDICINE LA English DT Article ID RISK-FACTORS; TRANSESOPHAGEAL ECHOCARDIOGRAPHY; STROKE PREVENTION; WARFARIN USE; NATIONAL PATTERNS; CONTROLLED TRIAL; SELF-MANAGEMENT; ANTICOAGULATION; ASPIRIN; THROMBOEMBOLISM AB Atrial fibrillation is a hallmark of aging, affecting 6% of individuals aged 65 years or older. Atrial fibrillation also increases the risk for ischemic stroke by fivefold. A consistent series of randomized, controlled trials have demonstrated that long-term anticoagulation largely reverses the risk for stroke posed by atrial fibrillation. This article reviews these trials and other studies bearing on the optimal intensity of anticoagulation for atrial fibrillation, the selection of patients with atrial fibrillation for long-term anticoagulation, and the efficacy of aspirin as an alternative stroke-preventive agent. C1 Massachusetts Gen Hosp, Dept Med, Div Gen Med, Clin Epidemiol Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Kaiser Permanente Med Care Program, Div Res, Oakland, CA 94611 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Singer, DE (reprint author), Massachusetts Gen Hosp, Dept Med, Div Gen Med, Clin Epidemiol Unit, S50-9, Boston, MA 02114 USA. FU NIA NIH HHS [AG 15478] NR 55 TC 8 Z9 10 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0749-0690 J9 CLIN GERIATR MED JI Clin. Geriatr. Med. PD FEB PY 2001 VL 17 IS 1 BP 131 EP + DI 10.1016/S0749-0690(05)70110-5 PG 18 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 402GL UT WOS:000166977800010 PM 11270126 ER PT J AU Mendez, MF AF Mendez, MF TI Generalized auditory agnosia with spared music recognition in a left-hander. Analysis of a case with a right temporal stroke SO CORTEX LA English DT Article DE auditory agnosia; cortical auditory disorders; amusia; word deafness ID PURE WORD DEAFNESS; BILATERAL LESIONS; CORTICAL DEAFNESS; PERCEPTION; DISORDERS; DAMAGE; HEMORRHAGE; APHASIA; DEFECT; CORTEX AB After a right temporoparietal stroke, a left-handed man lost the ability to understand speech and environmental sounds but developed greater appreciation for music. The patient had preserved reading and writing but poor verbal comprehension. Slower speech, single syllable words, and minimal written cues greatly facilitated his verbal comprehension. On identifying environmental sounds, he made predominant acoustic errors. Although he failed to name melodies, he could match, describe, and sing them. The patient had normal hearing except for presbyacusis, right-ear dominance for phonemes, and normal discrimination of basic psychoacoustic features and rhythm. Further testing disclosed difficulty distinguishing tone sequences and discriminating two clicks and short-versus-long tones, particularly in the left ear. Together, these findings suggest impairment in a direct route for temporal analysis and auditory word forms in his right hemisphere to Wernicke's area in his left hemisphere. The findings further suggest a separate and possibly rhythm-based mechanism for music recognition. C1 Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90024 USA. RP Mendez, MF (reprint author), VA Greater Los Angeles Healthcare Syst, Neurobehav Unit 116AF, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 56 TC 19 Z9 21 U1 3 U2 5 PU MASSON DIVISIONE PERIODICI PI MILAN PA VIA FRATELLI BRESSAN 2, 20126 MILAN, ITALY SN 0010-9452 J9 CORTEX JI Cortex PD FEB PY 2001 VL 37 IS 1 BP 139 EP 150 DI 10.1016/S0010-9452(08)70563-X PG 12 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 417BD UT WOS:000167814700012 PM 11292159 ER PT J AU Boulton, SJ Vincent, S Vidal, M AF Boulton, SJ Vincent, S Vidal, M TI Use of protein-interaction maps to formulate biological questions SO CURRENT OPINION IN CHEMICAL BIOLOGY LA English DT Review ID FUNCTIONAL GENOMIC ANALYSIS; C-ELEGANS; SACCHAROMYCES-CEREVISIAE; ENERGY-TRANSFER; YEAST; PATHWAY; PROSPECTS; SELECTION; SYSTEM; CELLS AB Protein-interaction mapping approaches generate functional information for large numbers of genes that are predicted from complete genome sequences. This information, released as databases available on the Internet, is likely to transform the way biologists formulate and then address their questions of interest. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. MGH Canc Ctr, Oncol Mol Lab, Charlestown, MA 02129 USA. RP Vidal, M (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [P01CA80111-02, 7R33CA81658-02]; NHGRI NIH HHS [5RO1HG01715-02] NR 37 TC 7 Z9 7 U1 0 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1367-5931 J9 CURR OPIN CHEM BIOL JI Curr. Opin. Chem. Biol. PD FEB PY 2001 VL 5 IS 1 BP 57 EP 62 DI 10.1016/S1367-5931(00)00168-X PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 403PK UT WOS:000167051500009 PM 11166649 ER PT J AU Ivan, M Kaelin, WG AF Ivan, M Kaelin, WG TI The von Hippel-Lindau tumor suppressor protein SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; BIOLOGICALLY-ACTIVE PRODUCT; POLYCYSTIC KIDNEY-DISEASE; UBIQUITIN LIGASE COMPLEX; RENAL-CARCINOMA CELLS; SOCS-BOX MOTIF; GENE-PRODUCT; ELONGIN-C; TYROSINE-HYDROXYLASE; NERVOUS-SYSTEM AB The von Hippel-Lindau tumor suppressor protein (pVHL) has been shown to bind directly to the alpha subunits of the heterodimeric transcription factor HIF (hypoxia inducible factor). pVHL directs the polyubiquitination and, hence, destruction of HIF in the presence of oxygen. Loss of pVHL function leads to deregulation of HIF target genes, which play critical roles in angiogenesis. C1 Dana Farber Canc Inst, Howard Hughes Med Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Ivan, M (reprint author), Dana Farber Canc Inst, Howard Hughes Med Inst, 44 Binney St, Boston, MA 02115 USA. RI Ivan, Mircea/A-8109-2012 NR 79 TC 151 Z9 160 U1 0 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD FEB PY 2001 VL 11 IS 1 BP 27 EP 34 DI 10.1016/S0959-437X(00)00152-0 PG 8 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 397XM UT WOS:000166723900004 PM 11163147 ER PT J AU Ezekowitz, RAB Hoffmann, J AF Ezekowitz, RAB Hoffmann, J TI Innate immunity - Still blossoming - Editorial overview SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review C1 Harvard Univ, Sch Med, MassGen Hosp Children, Lab Dev Immunol, Boston, MA 02114 USA. Inst Biol Mol & Cellulaire, CNRS, UPR 9022, F-67084 Strasbourg, France. RP Ezekowitz, RAB (reprint author), Harvard Univ, Sch Med, MassGen Hosp Children, Lab Dev Immunol, 15 Parkman St, Boston, MA 02114 USA. NR 1 TC 3 Z9 3 U1 0 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD FEB PY 2001 VL 13 IS 1 BP 53 EP 54 DI 10.1016/S0952-7915(00)00181-3 PG 2 WC Immunology SC Immunology GA 395DW UT WOS:000166564300008 ER PT J AU Gadjeva, M Thiel, S Jensenius, JC AF Gadjeva, M Thiel, S Jensenius, JC TI The mannan-binding-lectin pathway of the innate immune response SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID SERINE-PROTEASE MASP; COMPLEMENT ACTIVATION; HALOCYNTHIA-RORETZI; MOLECULAR-CLONING; IN-VITRO; COMPONENT; RECEPTOR; SYSTEM; COLLECTINS; MECHANISM AB Dramatic progress has been achieved during the past year in our understanding of how the complement system is activated via the mannan-binding-lectin pathway. Surprising discoveries have changed our concepts of the complexes that are formed upon engagement of mannan-binding lectin with its serine proteases. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 01215 USA. Aarhus Univ, Dept Med Microbiol & Immunol, DK-8000 Aarhus, Denmark. RP Gadjeva, M (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, 221 Longwood Ave, Boston, MA 01215 USA. NR 47 TC 75 Z9 83 U1 1 U2 6 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD FEB PY 2001 VL 13 IS 1 BP 74 EP 78 DI 10.1016/S0952-7915(00)00185-0 PG 5 WC Immunology SC Immunology GA 395DW UT WOS:000166564300012 PM 11154921 ER PT J AU Conlin, PR AF Conlin, PR TI Efficacy and safety of angiotensin receptor blockers: A review of losartan in essential hypertension SO CURRENT THERAPEUTIC RESEARCH-CLINICAL AND EXPERIMENTAL LA English DT Review DE angiotensin receptor blocker; efficacy; hypertension; losartan; safety ID QUALITY-OF-LIFE; BLOOD-PRESSURE; ANTIHYPERTENSIVE EFFICACY; II ANTAGONISTS; DOUBLE-BLIND; HYDROCHLOROTHIAZIDE; TOLERABILITY; TRIAL; AMLODIPINE; ENALAPRIL AB Background: Current guidelines and results from recent clinical trials have refocused attention on the treatment of hypertension. Emphasis has been placed on identifying patients at high risk and treating to lower levels of blood pressure, particularly in patients with diabetes or target organ damage. Due to their proven benefits, diuretics and beta-blockers continue to be suggested as initial therapy for patients with essential hypertension. However, many acknowledge that antihypertensive therapy needs to be individualized, taking into account patient demographic characteristics, concomitant diseases that may be affected beneficially or adversely by the antihypertensive agent chosen, quality of life, cost, and use of other drugs that may lead to drug interactions. Most patients will require combination therapy to achieve adequate blood pressure control. Therefore, a number of antihypertensive agents may be appropriate for first-line or add-on therapy. Objective: The objective of this article was to review current treatment options for hypertension, with particular emphasis on the angiotensin receptor blockers (ARBs). Losartan, the most widely studied agent of this class, is also discussed. Methods: Selected references were sought from MEDLlNE(R) (1990-2000) describing the pharmacology antihypertensive efficacy, and tolerability of ARBs. Results: In hypertensive patients, losartan has been compared with other antihypertensive agents, including enalapril, amlodipine, and nifedipine gastrointestinal therapeutic system. In each case, an antihypertensive regimen of losartan once daily with or without hydrochlorothiazide showed comparable blood pressure-lowering effects. Losartan has also consistently demonstrated an excellent tolerability profile, with an overall incidence of adverse effects similar to that of placebo. Subtle pharmacologic differences exist among the agents of the ARE class. However, a recent meta-analysis suggested that no clinically dr statistically significant difference in antihypertensive efficacy exists among them. Conclusions: ARBs such as losartan are effective with once-daily dosing and have an excellent safety profile. These agents are clearly a useful first-line or add-on treatment option in patients with hypertension. C1 Brigham & Womens Hosp, Div Endocrinol Hypertens, Boston, MA 02115 USA. VA Boston Healthcare Syst, Med Serv, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Conlin, PR (reprint author), Brigham & Womens Hosp, Div Endocrinol Hypertens, 221 Longwood Ave, Boston, MA 02115 USA. NR 37 TC 11 Z9 12 U1 1 U2 6 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0011-393X J9 CURR THER RES CLIN E JI Curr. Ther. Res.-Clin. Exp. PD FEB PY 2001 VL 62 IS 2 BP 79 EP 91 DI 10.1016/S0011-393X(01)80019-9 PG 13 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 412GM UT WOS:000167546700001 ER PT J AU Christian, MM Cox, DO Smith, CV Onouye, T Moy, RL AF Christian, MM Cox, DO Smith, CV Onouye, T Moy, RL TI Ocular damage due to chlorhexidine versus eyeshield thermal injury SO DERMATOLOGIC SURGERY LA English DT Article ID CORNEAL AB BACKGROUND. Ocular damage may occur from a number of mechanisms during laser use. OBJECTIVE. To review issues relevant to ocular protection during laser resurfacing. METHODS. The authors were consulted to evaluate the thermal energy transferred from the outer to the inner (ie, corneal contact) surface of stainless steel eyeshields following direct exposure to the carbon dioxide (CO2) resurfacing laser beam. Measurements were obtained using thermocouples (attached to the inner surface of the eyeshields) and analyzed with a computer-based acquisition system. RESULTS. A maximum eyeshield temperature increase of 13 degreesC above the ambient temperature was noted following one pass with a CO2 resurfacing laser (Sharplan continuous CO2 laser with Clinicon SureScan scanner, 15 W, 950 mu sec pulse duration, square spot of 9 mm). CONCLUSION. The eyeshields analyzed in this study minimized thermal transfer following a single direct hit with a CO2 resurfacing laser. An understanding of the potential mechanisms of ocular injury is essential in preventing its occurrence. C1 Univ Texas, SW Med Ctr, Dallas, TX USA. Cox & Co, Los Angeles, CA USA. Quan Smith Associates, Santa Monica, CA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Calif Los Angeles, W Los Angeles Vet Affairs Med Ctr, Div Dermatol, Los Angeles, CA USA. RP Christian, MM (reprint author), 5323 Harry Hines Blvd, Dallas, TX 75235 USA. NR 13 TC 6 Z9 6 U1 1 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1076-0512 J9 DERMATOL SURG JI Dermatol. Surg. PD FEB PY 2001 VL 27 IS 2 BP 153 EP 157 DI 10.1046/j.1524-4725.2001.00221.x PG 5 WC Dermatology; Surgery SC Dermatology; Surgery GA 405QF UT WOS:000167170000011 PM 11207689 ER PT J AU Long, FX Schipani, E Asahara, H Kronenberg, H Montminy, M AF Long, FX Schipani, E Asahara, H Kronenberg, H Montminy, M TI The CREB family of activators is required for endochondral bone development SO DEVELOPMENT LA English DT Article DE CREB; phosphorylation; Indian hedgehog; mouse; bone ID HORMONE-RELATED PEPTIDE; ELEMENT-BINDING PROTEIN; PARATHYROID-HORMONE; CYCLIC-AMP; INDIAN HEDGEHOG; TRANSGENIC MICE; TRANSCRIPTION FACTORS; GENE; CHONDROCYTES; GROWTH AB We have evaluated the importance of the CREB family of transcriptional activators for endochondral bone formation by expressing a potent dominant negative CREB inhibitor (A-CREB) in growth plate chondrocytes of transgenic mice. A-CREB transgenic mice exhibited short-limbed dwarfism and died minutes after birth, apparently due to respiratory failure from a diminished rib cage circumference. Consistent with the robust Ser133 phosphorylation and, hence, activation of CREB in chondrocytes within the proliferative zone of wild-type cartilage during development, chondrocytes in A-CREB mutant cartilage exhibited a profound decrease in proliferative index and a delay in hypertrophy, Correspondingly, the expression of certain signaling molecules in cartilage, most notably the Indian hedgehog (Ihh) receptor patched (Ptch), was lower in A-CREB expressing versus wild-type chondrocytes, CREB appears to promote Ptch expression in proliferating chondrocytes via an Ihh-independent pathway; phospho-CREB levels were comparable in cartilage from Ihh(-/-) and wild-type mice. These results demonstrate the presence of a distinct signaling pathway in developing bone that potentiates Ihh signaling and regulates chondrocyte proliferation, at least in part, via the CREB family of activators. C1 Salk Inst Biol Studies, Peptide Biol Labs, La Jolla, CA 92037 USA. Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Montminy, M (reprint author), Salk Inst Biol Studies, Peptide Biol Labs, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. FU NIGMS NIH HHS [GM19621, GM37828] NR 40 TC 69 Z9 70 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD FEB PY 2001 VL 128 IS 4 BP 541 EP 550 PG 10 WC Developmental Biology SC Developmental Biology GA 407VF UT WOS:000167290900008 PM 11171337 ER PT J AU Higaki, Y Hirshman, MF Fujii, N Goodyear, LJ AF Higaki, Y Hirshman, MF Fujii, N Goodyear, LJ TI Nitric oxide increases glucose uptake through a mechanism that is distinct from the insulin and contraction pathways in rat skeletal muscle SO DIABETES LA English DT Article ID ACTIVATED PROTEIN-KINASE; SYNTHASE ACTIVITY; TRANSPORT; TRANSLOCATION; WORTMANNIN; EXPRESSION; SUBFAMILY; GLUT4; CELL AB Insulin, contraction, and the nitric oxide (NO) donor, sodium nitroprusside (SNP), all increase glucose transport in skeletal muscle. Some reports suggest that NO is a critical mediator of insulin- and/or contraction-stimulated transport. To determine if the mechanism leading to NO-stimulated glucose uptake is similar to the insulin- or contraction-dependent signaling pathways, isolated soleus and extensor digitorum longus (EDL) muscles from rats were treated with various combinations of SNP (maximum 10 mmol/l), insulin (maximum 50 mU/ml), electrical stimulation to produce contractions (maximum 10 min), wortmannin (100 nmol/I), and/or the NO synthase (NOS) inhibitor N-G-monomethyl-L-arginine (L-NMMA) (0.1 mmol/l). The combinations of SNP plus insulin and SNP plus contraction both had fully additive effects on 2-deoxyglucose uptake. Wortmannin completely inhibited insulin-stimulated glucose transport and only slightly inhibited SNP-stimulated 2-deoxyglucose uptake, whereas L-NMMA. did not inhibit contraction-stimulated 2-deoxyglucose uptake. SNP significantly increased the activity of the alpha1 catalytic subunit of 5' AMP-activated protein kinase (AMPK), a signaling molecule that has been implicated in mediating glucose transport in fuel-depleted cells. Addition of the NOS inhibitor N-G-nitro-L-arginine methyl ester (L-NAME) (1 mg/ml) to the drinking water of rats for 2 days failed to affect the increase in muscle 2-deoxyglucose uptake in response to treadmill exercise. These data suggest that NO stimulates glucose uptake through a mechanism that is distinct from both the insulin and contraction signaling pathways. C1 Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Goodyear, LJ (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. RI Fujii, Nobuharu/J-2724-2014 OI Fujii, Nobuharu/0000-0002-0974-3033 FU NIAMS NIH HHS [AR-42238, AR-45670] NR 39 TC 165 Z9 170 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2001 VL 50 IS 2 BP 241 EP 247 DI 10.2337/diabetes.50.2.241 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 401AJ UT WOS:000166904500004 PM 11272132 ER PT J AU Suzuma, I Hata, Y Clermont, A Pokras, F Rook, SL Suzuma, K Feener, EP Aiello, LP AF Suzuma, I Hata, Y Clermont, A Pokras, F Rook, SL Suzuma, K Feener, EP Aiello, LP TI Cyclic stretch and hypertension induce retinal expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 - Potential mechanisms for exacerbation of diabetic retinopathy by hypertension SO DIABETES LA English DT Review ID SMOOTH-MUSCLE CELLS; HUMAN MESANGIAL CELLS; PERMEABILITY FACTOR; ANGIOTENSIN-II; MACULAR DEGENERATION; CHOROIDAL NEOVASCULARIZATION; RISK-FACTORS; SIGNAL-TRANSDUCTION; UP-REGULATION; DEVELOPMENTAL EXPRESSION AB Systemic hypertension exacerbates diabetic retinopathy and other coexisting ocular disorders through mechanisms that remain largely unknown. Increased vascular permeability and intraocular neovascularization characterize these conditions and are complications primarily mediated by vascular endothelial growth factor (VEGF). Because systemic hypertension increases vascular stretch, we evaluated the expression of VEGF, VEGF-R2 (kinase insert domain-containing receptor [KDR]), and VEGF-R1 (fms-like tyrosine kinase [Flt]) in bovine retinal endothelial cells (BRECs) undergoing clinically relevant cyclic stretch and in spontaneously hypertensive rat (SHR) retina. A single exposure to 20% symmetric static stretch increased KDR mRNA expression 3.9 +/- 1.1-fold after 3 h (P = 0.002), with a gradual return to baseline within 9 h. In contrast, BRECs exposed to cardiac-profile cyclic stretch at 60 cpm continuously accumulated KDR mRNA in a transcriptionally mediated, time-dependent and stretch-magnitude-dependent manner. Exposure to 9% cyclic stretch increased KDR mRNA expression 8.7 +/- 2.9-fold (P = 0.011) after 9 h and KDR protein concentration 1.8 +/- 0.3-fold (P = 0.005) after 12 h. Stretched-induced VEGF responses were similar. Scatchard binding analysis demonstrated a 180 +/- 40%, (P = 0.032) increase in high-affinity VEGF receptor number with no change in affinity. Cyclic stretch increased basal thymidine uptake 60 +/- 10% (P < 0.001) and VEGF-stimulated thymidine uptake by 2.6 +/- 0.2-fold (P = 0.005). VEGF-NAb reduced cyclic stretch-induced thymidine uptake by 65%. Stretched-induced KDR expression was not inhibited by AT1 receptor blockade using candesartan. Hypertension increased retinal. KBR expression 67 +/- 42% (P < 0.05) in SHR rats compared with normotensive WKY control animals. When hypertension was reduced using captopril or candesartan, retinal KDR expression returned to baseline levels. VEGF reacted similarly, but Flt expression did not change. These data suggest a novel molecular mechanism that would account for the exacerbation of diabetic retinopathy by concomitant hypertension, and may partially explain the principal clinical manifestations of hypertensive retinopathy itself. Furthermore, these data imply that anti-VEGF therapies may prove therapeutically effective for hypertensive retinopathy and/or ameliorating the deleterious effects of coexistent hypertension on VEGF-associated disorders such as diabetic retinopathy. C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Aiello, LP (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02115 USA. FU NEI NIH HHS [EY-10827]; NIDDK NIH HHS [DK-48358, P30 DK036836]; PHS HHS [36836] NR 102 TC 84 Z9 91 U1 0 U2 9 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2001 VL 50 IS 2 BP 444 EP 454 DI 10.2337/diabetes.50.2.444 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 401AJ UT WOS:000166904500031 PM 11272159 ER PT J AU Bonner-Weir, S AF Bonner-Weir, S TI beta-cell turnover - Its assessment and implications SO DIABETES LA English DT Article; Proceedings Paper CT 1st Servier-IGIS Symposium CY MAR 23-25, 2000 CL ST JEAN CAP FERRAT, FRANCE ID ENDOCRINE PANCREAS; RAT PANCREAS; INSULIN-SECRETION; RENAL HYPERTROPHY; DIABETIC RATS; NEONATAL RAT; ISLET CELLS; IN-VIVO; B-CELLS; APOPTOSIS AB The pancreatic beta -cells are responsible for the maintenance of the body's glucose levels within a very narrow range; their population is dynamic and undergoes compensatory changes to maintain euglycemia. The structural parameters that allow mass changes (replication, neogenesis, cell volume changes, and cell death) can now be assessed and have proved to be powerful tools. Changes in one parameter can dramatically affect the beta -cell mass. Unfortunately, conclusions are often drawn on measurements that do not assess beta -cell mass but only relative volumes. Throughout the lifetime of a mammal, low levels of beta -cell replication and apoptosis are balanced and result in a slowly increasing mass. The balance allows gradual replacement of the beta -cell population; thus, beta -cells should be considered a slowly renewed tissue. Two major implications of beta -cell turnover are that 1) at any time, the beta -cells would be at different ages and 2) any limitation on replacement could have dire consequences for glucose homeostasis. 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. OI Bonner-Weir, Susan/0000-0003-4682-0656 NR 51 TC 115 Z9 120 U1 1 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2001 VL 50 SU 1 BP S20 EP S24 DI 10.2337/diabetes.50.2007.S20 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 401ZA UT WOS:000166958400005 PM 11272192 ER PT J AU Burks, DJ White, MF AF Burks, DJ White, MF TI IRS proteins and beta-cell function SO DIABETES LA English DT Article; Proceedings Paper CT 1st Servier-IGIS Symposium CY MAR 23-25, 2000 CL ST JEAN CAP FERRAT, FRANCE ID INSULIN-RECEPTOR SUBSTRATE-1; AMINO-ACID POLYMORPHISM; SIGNAL-TRANSDUCTION; TYROSINE PHOSPHORYLATION; PHOSPHOTYROSINE PROTEIN; DOCKING PROTEIN; RAT PANCREAS; IGF-I; MICE; EXPRESSION AB Insulin receptor substrate (IRS) proteins mediate a variety of the metabolic and growth-promoting actions of insulin and IGF-1. After phosphorylation by activated receptors, these intracellular signaling molecules recruit various downstream effector pathways including phosphatidylinositol 3-kinase and Grb2. Ablation of the IRS-2 gene produces a diabetic phenotype; mice lacking IRS-2 display peripheral insulin resistance and beta -cell dysfunction characterized by a 50% reduction in beta -cell mass. In contrast, deletion of IRS-1 retards somatic growth and enhances beta -cell mass. IRS1(-/-) mice are 50% smaller than controls but have a twofold increase in pancreatic beta -cell mass. Thus, observations from these recently developed animal models implicate the IRS signaling systems in the response of classical insulin target tissues, and they suggest a critical role for these proteins in the regulation of beta -cell function. In humans, type 2 diabetes generally occurs when insulin-secretory reserves fail to compensate for peripheral insulin resistance. Study and identification of the signals downstream of IRS proteins in beta -cells may provide unique insights into the compensatory mechanisms by which these cells respond to insulin resistance. Therefore, the intent of this review is to summarize recent observations regarding the regulation of beta -cell function by members of the IRS protein family. C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Howard Hughes Med Inst, Boston, MA 02215 USA. Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. RP White, MF (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Howard Hughes Med Inst, 1 Joslin Pl, Boston, MA 02215 USA. EM whitemor@joslab.harvard.edu NR 54 TC 100 Z9 109 U1 0 U2 7 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2001 VL 50 SU 1 BP S140 EP S145 DI 10.2337/diabetes.50.2007.S140 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 401ZA UT WOS:000166958400037 PM 11272176 ER PT J AU Hull, RL Verchere, CB Andrikopoulos, S Wang, F Vidal, J Kahn, SE AF Hull, RL Verchere, CB Andrikopoulos, S Wang, F Vidal, J Kahn, SE TI Oophorectomy promotes islet amyloid formation in human islet amyloid polypeptide transgenic mice SO DIABETES LA English DT Article; Proceedings Paper CT 1st Servier-IGIS Symposium CY MAR 23-25, 2000 CL ST JEAN CAP FERRAT, FRANCE C1 Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98108 USA. Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. RP Hull, RL (reprint author), Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, 1660 S Columbian Way, Seattle, WA 98108 USA. NR 4 TC 3 Z9 3 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2001 VL 50 SU 1 BP S184 EP S185 DI 10.2337/diabetes.50.2007.S184 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 401ZA UT WOS:000166958400048 PM 11272188 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 Potential role of the early response gene c-myc in beta-cell adaptation to changes in glucose concentration SO DIABETES LA English DT Meeting Abstract C1 Univ Catholique Louvain, Unit Endocrinol & Metab, B-1200 Brussels, Belgium. Joslin Diabet Ctr, Unit Endocrinol & MEtab, Boston, MA 02215 USA. RI Jonas, Jean-Christophe/C-6766-2011 OI Jonas, Jean-Christophe/0000-0001-9882-5438 NR 1 TC 5 Z9 5 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2001 VL 50 SU 1 BP S137 EP S137 DI 10.2337/diabetes.50.2007.S137 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 401ZA UT WOS:000166958400035 PM 11272174 ER PT J AU Laybutt, R Hasenkamp, W Groff, A Grey, S Jonas, JC Kaneto, H Sharma, A Bonner-Weir, S Weir, G AF Laybutt, R Hasenkamp, W Groff, A Grey, S Jonas, JC Kaneto, H Sharma, A Bonner-Weir, S Weir, G TI beta-cell adaptation to hyperglycemia SO DIABETES LA English DT Article; Proceedings Paper CT 1st Servier-IGIS Symposium CY MAR 23-25, 2000 CL ST JEAN CAP FERRAT, FRANCE C1 Joslin Diabet Ctr, Boston, MA 02215 USA. RP Laybutt, R (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. RI Grey, Shane/B-3020-2008; Jonas, Jean-Christophe/C-6766-2011 OI Grey, Shane/0000-0003-2160-1625; Jonas, Jean-Christophe/0000-0001-9882-5438 NR 5 TC 13 Z9 14 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2001 VL 50 SU 1 BP S180 EP S181 DI 10.2337/diabetes.50.2007.S180 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 401ZA UT WOS:000166958400046 PM 11272186 ER PT J AU Porte, D Kahn, SE AF Porte, D Kahn, SE TI beta-cell dysfunction and failure in type 2 diabetes - Potential mechanisms SO DIABETES LA English DT Article; Proceedings Paper CT 1st Servier-IGIS Symposium CY MAR 23-25, 2000 CL ST JEAN CAP FERRAT, FRANCE ID ISLET AMYLOID POLYPEPTIDE; JAPANESE-AMERICAN MEN; TRANSGENIC MICE; B-CELL; SULFONYLUREA THERAPY; INSULIN SENSITIVITY; PROINSULIN LEVELS; MELLITUS; HYPERGLYCEMIA; AMYLIN AB Type 2 diabetes is characterized by a progressive loss of beta -cell function throughout the course of the disease. The pattern of loss is an initial defect in early or first-phase insulin secretion, followed by a decreasing maximal capacity of glucose to potentiate all nonglucose signals. Last, a defective steady-state and basal insulin secretion develops, leading to complete beta -cell failure requiring insulin treatment. This functional loss exceeds the expected impact of a 20-50% loss of beta -cells reported at autopsy, which has been associated with amyloid deposits. This review summarizes the nature of the amyloid deposition process and its association with disproportionate hyperproinsulinemia. It reviews recent studies in IAPP (islet-amyloid polypeptide, or amylin) transgenic mice developing islet amyloid deposits and hyperglycemia to suggest that the process of amyloid fibril formation impairs function early and leads to beta -cell failure and eventual death. Based on the known association of amyloid deposits and relative hyperproinsulinemia, it is hypothesized that fibril formation begins during impaired glucose tolerance after other factors cause the initial defects in early insulin secretion and insulin action. Thus, the process that leads to beta -cell loss is implicated in the deposition of amyloid and the late unrelenting progressive hyperglycemia now found in all patients despite current therapies. C1 VA San Diego Hlth Care Syst, La Jolla, CA 92161 USA. Univ Calif San Diego, San Diego, CA 92103 USA. Univ Washington, Seattle, WA 98195 USA. Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. RP Porte, D (reprint author), VA San Diego Hlth Care Syst, 111G, La Jolla, CA 92161 USA. FU NIDDK NIH HHS [DK17047, DK12829, DK50703] NR 35 TC 140 Z9 146 U1 2 U2 11 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2001 VL 50 SU 1 BP S160 EP S163 DI 10.2337/diabetes.50.2007.S160 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 401ZA UT WOS:000166958400041 PM 11272181 ER PT J AU Sharma, A Taneja, M Rietz, P Weitekamp, J Bonner-Weir, S AF Sharma, A Taneja, M Rietz, P Weitekamp, J Bonner-Weir, S TI Novel pancreatic precursor cell lines for studying beta-cell differentiation SO DIABETES LA English DT Article; Proceedings Paper CT 1st Servier-IGIS Symposium CY MAR 23-25, 2000 CL ST JEAN CAP FERRAT, FRANCE C1 Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. RP Sharma, A (reprint author), Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, 1 Joslin Pl, Boston, MA 02215 USA. NR 4 TC 2 Z9 3 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2001 VL 50 SU 1 BP S42 EP S43 DI 10.2337/diabetes.50.2007.S42 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 401ZA UT WOS:000166958400012 PM 11272199 ER PT J AU Weir, GC Laybutt, DR Kaneto, H Bonner-Weir, S Sharma, A AF Weir, GC Laybutt, DR Kaneto, H Bonner-Weir, S Sharma, A TI beta-cell adaptation and decompensation during the progression of diabetes SO DIABETES LA English DT Article; Proceedings Paper CT 1st Servier-IGIS Symposium CY MAR 23-25, 2000 CL ST JEAN CAP FERRAT, FRANCE ID INDUCED INSULIN-SECRETION; CIRCULATING FATTY-ACIDS; RAT PANCREATIC-ISLETS; MYC TARGET GENES; C-MYC; CHRONIC HYPERGLYCEMIA; GLUCOSE-TOLERANCE; RENAL HYPERTROPHY; MALONYL-COA; MODEL AB Inadequate beta -cell function is an essential component of all forms of diabetes. The most obvious problem is a failure to maintain sufficient beta -cell mass and function to cope with whatever insulin resistance is present. The most striking functional defect is a loss of acute glucose-induced insulin secretion (GIIS). This review discusses the ways in which beta -cells successfully adapt to increased demand and then decompensate as diabetes develops. Successful adaptation is achieved through increased beta -cell mass and increased insulin secretion. The hypothesis is explored that beta -cells exposed to the diabetic milieu lose their differentiation, which leads to loss of specialized functions such as GIIS. This concept has been strengthened by the finding of dedifferentiation of beta -cells in a rat model of partial pancreatectomy that includes a reduction of insulin gene expression, which may further contribute to decreased insulin production. Another finding was increased expression of c-Myc, which probably contributes to an increase in the expression of lactate dehydrogenase and the development of beta -cell hypertrophy. Arguments are developed that the beta -cell changes found in diabetes are better correlated with increased glucose levels than with nonesterified fatty acid levels, thus supporting the importance of glucose toxicity. C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol,Res Div, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Weir, GC (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol,Res Div, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [DK-36836, DK-35449] NR 45 TC 195 Z9 208 U1 0 U2 6 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2001 VL 50 SU 1 BP S154 EP S159 DI 10.2337/diabetes.50.2007.S154 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 401ZA UT WOS:000166958400040 PM 11272180 ER PT J AU Perkins, BA Olaleye, D Zinman, B Bril, V AF Perkins, BA Olaleye, D Zinman, B Bril, V TI Simple screening tests for peripheral neuropathy in the diabetes clinic SO DIABETES CARE LA English DT Article ID SEMMES-WEINSTEIN MONOFILAMENTS; LOWER-EXTREMITY AMPUTATION; FOOT ULCERATION; SURAL-NERVE; MICROVASCULAR COMPLICATIONS; INSULIN-TREATMENT; POLYNEUROPATHY; MELLITUS; RISK; REPRODUCIBILITY AB OBJECTIVE- The utility of rapid and reliable sensory tests appropriate for the diagnosis of neuropathy in the diabetes clinic, rather than as prognostic tools for the prediction of foot complications, has been unclear because of limitations inherent in previous studies. Although clinical practice guidelines recommend annual screening for neuropathy, they are unable to support specific recommendations for screening maneuvers because of a lack of evidence for the validity of screening tests in the medical literature. The objective of this study was to assess the operating characteristics of four simple sensory screening maneuvers as compared with standardized electrophysiological tests in the diagnosis of distal symmetrical polyneuropathy. RESEARCH DESIGN AND METHODS- We assessed four simple tests (the 10-g Semmes-Weinstein monofilament examination [SWME], superficial pain sensation, vibration testing by the on-off method, and vibration testing by the timed method) in 478 subjects with independent blinded evaluations compared against the criterion standard of nerve conduction studies. We present receiver-operating characteristic (ROC) curves, positive and negative likelihood ratios, and sensitivity and specificity values for each test. RESULTS- The four simple screening maneuvers reveal similar operating characteristics. Cutoff points by ROC curve analyses reveal that a positive or abnormal test is represented by five incorrect responses of eight stimuli applied. A negative or normal test is represented by one ar fewer incorrect responses of right stimuli applied. By these criteria, the point estimates of the positive Likelihood ratios for vibration testing by the on-off method, vibration testing by the timed method. the SWME, and superficial pain sensation test are 26.6, 18.5, 10.2, and 9.2, respectively. The point estimates of the negative likelihood ratios are 0.33, 0.51, 0.34, and 0.50, respectively. The screening tests showed comparable sensitivity and specificity results. The 10-g SWME, superficial pain test, and vibration testing by the on-off method are rapid, each requiring similar to 60 s to administer. The timed vibration test takes longer, and the interpretation is more complicated. The combination of two simple tests (e.g., the 10-g SWME and vibration testing by the on-off method) does not add value to each individual screening test. CONCLUSIONS- Annual screening for diabetic neuropathy should be conducted using superficial pain sensation testing, SWME, or vibration testing by the on-off method. The reported operating characteristics for each sensory modality can be applied to positive findings on the physical examination of individual patients to predict the likelihood of neuropathy. C1 Univ Hlth Network, Toronto Gen Hosp, Toronto, ON M5G 2C4, Canada. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. SAS Inst, PharmaHlth Technol, Cary, NC USA. Univ Toronto, Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. RP Bril, V (reprint author), Univ Hlth Network, Toronto Gen Hosp, EN 11-209,200 Elizabeth St, Toronto, ON M5G 2C4, Canada. RI Zinman, Bernard/E-7266-2013 NR 39 TC 194 Z9 217 U1 3 U2 11 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2001 VL 24 IS 2 BP 250 EP 256 DI 10.2337/diacare.24.2.250 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 397EU UT WOS:000166681000011 PM 11213874 ER PT J AU Veves, A Falanga, V Armstrong, DG Sabolinski, ML AF Veves, A Falanga, V Armstrong, DG Sabolinski, ML CA Apligraf Diabetic Foot Ulcer Study TI Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers - A prospective randomized multicenter clinical trial SO DIABETES CARE LA English DT Article ID GROWTH-FACTOR; ULCERATION AB OBJECTIVE- We assessed in a randomized prospective trial the effectiveness of Graftskin, a living skin equivalent, in treating noninfected nonischemic chronic plantar diabetic foot ulcers. RESEARCH DESIGN AND METHODS- In 24 centers in the U.S., 208 patients were randomly assigned to ulcer treatment either with Graftskin (112 patients) or saline-moistened gauze (96 patients, control group). Standard state-of-the-art adjunctive therapy which included extensive surgical debridement and adequate foot off-loading, was provided in both groups. Graftskin was applied at the beginning of the study and weekly thereafter for a maximum of 4 weeks (maximum of five applications) or earlier if complete healing occurred. The major outcome of complete wound healing was assessed by intention to treat at the 12-week follow-up visit. RESULTS- At the 12-week follow-up visit, 63 (56%) Graftskin-treated patients achieved complete wound healing compared with 36 (38%) in the control group (P = 0.0042). The Kaplan-Meier median time to complete closure was 65 days for Graftskin, significantly lower than the 90 days observed in the control group (P = 0.0026). The odds ratio for complete healing for a Graftskin-treated ulcer compared with a control-treated ulcer was 2.14 (95% CI 1.23-3.74). The rate of adverse reactions was similar bem een the two groups with the exception of osteomyelitis and lower-limb amputations, both of which were less frequent in the Graftskin group. CONCLUSIONS- Application of Graftskin for a maximum of 4 weeks results in a higher healing rate when compared with state-of-the-art currently available treatment and is not associated with any significant side effects. Graftskin may be a very useful adjunct for the management of diabetic foot ulcers that are resistant to the currently available standard of care. C1 Joslin Beth Israel Deaconess Foot Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. Roger Williams Med Ctr, Dept Dermatol & Skin Surg, Providence, RI USA. Boston Univ, Sch Med, Boston, MA 02118 USA. So Arizona Vet Affairs Med Ctr, Dept Surg, Tucson, AZ USA. Organgenesis, Canton, MA USA. RP Veves, A (reprint author), Joslin Beth Israel Deaconess Foot Ctr, 1 Deaconess Rd, Boston, MA 02215 USA. NR 24 TC 341 Z9 355 U1 2 U2 14 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2001 VL 24 IS 2 BP 290 EP 295 DI 10.2337/diacare.24.2.290 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 397EU UT WOS:000166681000018 PM 11213881 ER PT J AU Hamdy, O Abou-Elenin, K LoGerfo, FW Horton, ES Veves, A AF Hamdy, O Abou-Elenin, K LoGerfo, FW Horton, ES Veves, A TI Contribution of nerve-axon reflex-related vasodilation to the total skin vasodilation in diabetic patients with and without neuropathy SO DIABETES CARE LA English DT Article ID NITRIC-OXIDE; ENDOTHELIAL DYSFUNCTION; SODIUM-NITROPRUSSIDE; FOOT ULCERATION; MICROCIRCULATION; RISK; MELLITUS; ACETYLCHOLINE; REACTIVITY; MECHANISMS AB OBJECTIVE- To examine the contribution of nerve-axon reflex-related vasodilation to total acetylcholine-induced vasodilation in the skin of normal and diabetic subjects. RESEARCH DESIGN AND METHODS- The skin microcirculation was evaluated at the forearm level in 69 healthy subjects and 42 nonneuropathic diabetic patients and at the foot level in 27 healthy subjects and 101 diabetic patients (33 with neuropathy 23 with Charcot arthropathy, 32 with peripheral vascular disease and neuropathy, and 13 without complications). Two single-point laser probes were used to measure total and neurovascular vasodilation response to the iontophoresis of 1% acetylcholine, 1% sodium nitroprusside, and deionized water. RESULTS- The neurovascular response to acetylcholine was significantly higher than the response to sodium nitroprusside and deionized water (P < 0.01). At the forearm level, the contribution of neurovascular response to the total response to acetylcholine was 35% in diabetic patients and 31% in control subjects. At the foot level, thf contribution was 29% in diabetic patients without neuropathy and 36% in control subjects, while it nas significantly diminished in the three neuropathic groups. A significantly lower nonspecific nerve-axon-related vasodilation was observed during the iontophoresis of sodium nitroprusside, which does nut specifically stimulate the C nociceptive fibers. CONCLUSIONS- Neurovascular vasodilation accounts for approximately one-third of thr total acetylcholine-induced vasodilation at both the forearm and foot levels. The presence of diabetic neuropathy results in reduction of both the total vasodilatory response to acetylcholine and the percentage contribution of neurovascular vasodilation to the total response. Acetylcholine and sodium nitroprusside cause vasodilation in the skin microcirculation through different pathways. C1 Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Surg,Microcirculat Lab, Boston, MA 02215 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Surg,Joslin Beth Israel Deaconess Foot Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Med,Clin Res Ctr, Boston, MA 02115 USA. RP Veves, A (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Surg,Microcirculat Lab, Palmer 317,West Campus,1 Deaconess Rd, Boston, MA 02215 USA. NR 27 TC 52 Z9 54 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2001 VL 24 IS 2 BP 344 EP 349 DI 10.2337/diacare.24.2.344 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 397EU UT WOS:000166681000027 PM 11213890 ER PT J AU Zrebiec, JF Jacobson, AM AF Zrebiec, JF Jacobson, AM TI What attracts patients with diabetes to an internet support group? A 21-month longitudinal website study SO DIABETIC MEDICINE LA English DT Article DE internet; diabetes; support groups; website ID HEALTH-CARE; INFORMATION AB Aims To establish and evaluate a web-based educational and emotional resource for patients with diabetes and their family members. Methods A total of 47 365 user visits over a 21-month period to three internet discussion groups about diabetes were tracked for user activity, characteristics and level of satisfaction. Results The primary domains of users were the US (70%) and Canada (4%). Of all users, 7.55% posted messages, while 92.45% read messages posted by others. The average length of use was 15 min 5 s. Forty-four per cent posted messages to the nutrition discussion, 38% posted messages to the motivational discussion, and 18% posted messages to the family discussion. The most common postings addressed nutrition (42%), the emotional impact of diabetes (18%), managing high or low blood glucose levels (10%), and complications (8%). Respondents to the satisfaction survey were 64% female, 43% were insulin and 37% non-insulin users. Eighty-four per cent were older than 30 years, 34% had recently diagnosed diabetes and 32% had diabetes > 10 years. Forty-three per cent visited more than three times. Seventy-nine per cent of all respondents rated participation in the chat as having a positive effect on coping with diabetes. Conclusions A professionally moderated internet discussion group is actively visited by a broad base of patients and families, and appears to be a useful strategy for engaging patients with chronic disease for emotional support and information exchange. C1 Joslin Diabet Ctr, Behav & Mental Hlth Unit, Boston, MA 02215 USA. RP Zrebiec, JF (reprint author), Joslin Diabet Ctr, Behav & Mental Hlth Unit, 1 Joslin Pl, Boston, MA 02215 USA. FU PHS HHS [R01-42315] NR 16 TC 53 Z9 53 U1 0 U2 4 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0742-3071 J9 DIABETIC MED JI Diabetic Med. PD FEB PY 2001 VL 18 IS 2 BP 154 EP 158 DI 10.1046/j.1464-5491.2001.00443.x PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 415QW UT WOS:000167735000012 PM 11251681 ER PT J AU Cacciola, JS Alterman, AI Rutherford, MJ McKay, JR Mulvaney, FD AF Cacciola, JS Alterman, AI Rutherford, MJ McKay, JR Mulvaney, FD TI The relationship of psychiatric comorbidity to treatment outcomes in methadone maintained patients SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE methadone; treatment outcome; personality disorders; psychiatric diagnosis; comorbidity ID STRUCTURED CLINICAL INTERVIEW; ADDICTION SEVERITY INDEX; TEST-RETEST RELIABILITY; TREATED OPIATE ADDICTS; PERSONALITY-DISORDERS; DRUG PROBLEMS; SADS-L; ALCOHOL; DIAGNOSIS; PREDICTORS AB The authors examined the relationship of comorbid non-substance use psychiatric disorders to preadmission problem status and treatment outcomes in 278 methadone maintenance patients. Recent admissions were assigned DSM-III-R Axis I and II diagnoses according to structured diagnostic interviews. The Addiction Severity Index was administered at admission to assess past and current substance use and psychosocial problems and again 7 months later. Treatment retention and month 7 drug urinalysis results were also obtained. Across substance use and psychosocial domains, participants showed significant and comparable levels of improvement regardless of comorbidity. Comorbid participants received more concurrent psychiatric treatment which may have accounted for the lack of differential improvement among groups. Nevertheless. psychiatric comorbidity was associated with poorer psychosocial and medical status at admission and follow-up and participants with the combination of Axis I and II comorbidity had the most severe problems. Admission and month 7 substance use were, for the most part. not related to psychiatric comorbidity, although there was a trend indicating more treatment attrition for participants with personality disorders. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Penn, Sch Med, Vet Affairs Med Ctr, Ctr Studies Addict, Philadelphia, PA 19104 USA. RP Cacciola, JS (reprint author), Univ Penn, Sch Med, Vet Affairs Med Ctr, Ctr Studies Addict, Bldg 3,Univ & Civ Ctr Blvd, Philadelphia, PA 19104 USA. FU NIDA NIH HHS [DA05186, R01 DA-05858-04] NR 32 TC 93 Z9 95 U1 1 U2 8 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 FEB 1 PY 2001 VL 61 IS 3 BP 271 EP 280 DI 10.1016/S0376-8716(00)00148-4 PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 390ZG UT WOS:000166329200008 PM 11164691 ER PT J AU Weisberg, E Griffin, JD AF Weisberg, E Griffin, JD TI Mechanisms of resistance imatinib (ST1571) in preclinical models and in leukemia patients SO DRUG RESISTANCE UPDATES LA English DT Review ID CHRONIC MYELOGENOUS LEUKEMIA; TYROSINE KINASE INHIBITOR; ABL-POSITIVE CELLS; IN-VIVO; PHILADELPHIA-CHROMOSOME; BCR/ABL; GENE; STI571; TRANSFORMATION; INTERLEUKIN-3 AB The tyrosine kinase inhibitor imatinib (ST 157I,Glivec) blocks the activity of the BCR/ABL oncogene and induces hematologic remissions in the majority of patients with chronic myeloid leukemia (CML). Glivec is an aminopyrimidine derivative that interacts with the ATP-binding site within the kinase domain of ABL and several other tyrosine kinases, including c-KIT, PDGF beta receptor, and ARG. The compound is currently in phase III clinical trials. Although patients with chronic phase CML have been found to develop drug resistance only rarely so far, patients in more advanced phases of the leukemia develop resistance frequently. The available information on Glivec resistance will be reviewed. (C) 2001 Harcourt Publishers Ltd. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Griffin, JD (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. NR 51 TC 43 Z9 45 U1 0 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1368-7646 J9 DRUG RESIST UPDATE JI Drug Resist. Update PD FEB PY 2001 VL 4 IS 1 BP 22 EP 28 DI 10.1054/drup.2001.0180 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 416MZ UT WOS:000167785900005 PM 11512149 ER PT J AU Dirks, DD Takayanagi, S Moshfegh, A Noffsinger, PD Fausti, SA AF Dirks, DD Takayanagi, S Moshfegh, A Noffsinger, PD Fausti, SA TI Examination of the neighbor-hood activation theory in normal and hearing-impaired listeners SO EAR AND HEARING LA English DT Article ID SPOKEN-WORD RECOGNITION; STIMULUS VARIABILITY; SPEECH-PERCEPTION; MODEL AB Objective: Experiments were conducted to examine the effects of lexical information on word recognition among normal hearing listeners and individuals with sensorineural hearing loss. The lexical factors of interest were incorporated in the Neighborhood Activation Model (NAM). Central to this model is the concept that words are recognized relationally in the context of other phonemically similar words. NAM: suggests that words in the mental lexicon are organized into similarity neighborhoods and the listener is required to select the target word from competing lexical items. Two structural characteristics of similarity neighborhoods that influence word recognition have been identified; "neighborhood density" or the number of phonemically similar words (neighbors) for a particular target item and "neighborhood frequency" or the average frequency of occurrence of all the items within a neighborhood. A third lexical factor, "word frequency" or the frequency of occurrence of a target word in the language, is assumed to optimize the word recognition process by biasing the system toward choosing a high frequency over a low frequency word. Design: Three experiments were performed. In the initial experiments, word recognition for consonant-vowel-consonant (CVC) monosyllables was assessed in young normal hearing listeners by systematically partitioning the items into the eight possible lexical conditions that could be created by two levels of the three lexical factors, word frequency (high and low), neighborhood density thigh and low), and average neighborhood frequency thigh and low). Neighborhood structure and word frequency were estimated computationally using a large, on-line lexicon-based Webster's Pocket Dictionary. From this program 400 highly familiar, monosyllables were selected and partitioned into eight orthogonal lexical groups (50 words/group). The 400 words were presented randomly to normal hearing listeners in speech-shaped noise (Experiment 1) and "in quiet" (Experiment 2) as well as to an elderly group of listeners with sensorineural hearing loss in the speech-shaped noise (Experiment 3). Results: The results of three experiments verified predictions of NAM in both normal hearing and hearing-impaired listeners. In each experiment, words from low density neighborhoods were recognized more accurately than those from high density neighborhoods. The presence of high frequency neighbors (average neighborhood frequency) produced poorer recognition performance than comparable conditions with low frequency neighbors. Word frequency was found to have a highly significant effect on word recognition. Lexical conditions with high word frequencies produced higher performance scores than conditions with low frequency words. Conclusion: The results supported the basic tenets of NAM theory and identified both neighborhood structural properties and word frequency as significant lexical factors affecting word recognition when listening in noise and "in quiet." The results of the third experiment permit extension of NAM: theory to individuals with sensorineural hearing loss. Future development of speech recognition tests should allow for the effects of higher level cognitive (lexical) factors on lower level phonemic processing. C1 Univ Calif Los Angeles, Sch Med, Div Head & Neck Surg, Rehabil Ctr, Los Angeles, CA 90095 USA. Vet Adm Med Ctr, Natl Ctr Rehabilitat Auditory Res, Portland, OR USA. Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Dirks, DD (reprint author), Univ Calif Los Angeles, Sch Med, Div Head & Neck Surg, Rehabil Ctr, Bldg 31-24, Los Angeles, CA 90095 USA. NR 18 TC 31 Z9 31 U1 2 U2 4 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 FEB PY 2001 VL 22 IS 1 BP 1 EP 13 DI 10.1097/00003446-200102000-00001 PG 13 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 403EC UT WOS:000167028800001 PM 11271971 ER PT J AU Kokkotou, EG Tritos, NA Mastaitis, JW Slieker, L Maratos-Flier, E AF Kokkotou, EG Tritos, NA Mastaitis, JW Slieker, L Maratos-Flier, E TI Melanin-concentrating hormone receptor is a target of leptin action in the mouse brain SO ENDOCRINOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; BODY-WEIGHT; NEUROPEPTIDE-Y; RAT-BRAIN; GENE; HYPOTHALAMUS; PEPTIDE; SLC-1; MICE AB Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that is important in the regulation of energy homeostasis. MCH signals via a seven-transmembrane G protein-coupled receptor, which is coupled to G alpha (i). This receptor was initially cloned in rat and human and designated SLC-1 because of its homology to the somatostatin receptor. In rat brain, it is expressed in a pattern that mirrors the previously described pattern of projections of MCH-immunoreactive fibers. In the present study we cloned the mouse MCH receptor (MCH-R) ortholog by a rapid amplification of 5'- and 3'-cDNA ends approach and have found it to be 98% homologous with the rat sequence. We have characterized MCH-R messenger RNA distribution in the mouse brain by in situ hybridization and have shown MCH-R to be expressed in diverse brain areas implicated in the regulation of feeding, body adiposity, and sensory integration of smell and gustatory inputs, including the hypothalamus [paraventricular nucleus (magnocellular part) and dorsomedial, ventromedial, and arcuate nucleus], areas of the olfactory pathway, and the nucleus of the solitary tract. We also studied MCH-R regulation and found that MCH-R expression is increased 7-fold by 48-h fasting or genetic leptin deficiency (ob/ob mice) and is completely blunted by leptin administration. In contrast, MCH-R messenger RNA expression remains unaltered in genetic MCH deficiency. Our findings suggest that MCH-R constitutes a central target of leptin action in the mammalian brain. C1 Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. Eli Lilly & Co, Res Labs, Indianapolis, IN 46285 USA. RP Maratos-Flier, E (reprint author), Joslin Diabet Ctr, Room 620,1 Joslin Pl, Boston, MA 02215 USA. NR 23 TC 100 Z9 103 U1 0 U2 0 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2001 VL 142 IS 2 BP 680 EP 686 DI 10.1210/en.142.2.680 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 398GC UT WOS:000166747700021 PM 11159839 ER PT J AU Jonsson, KB John, MR Gensure, RC Gardella, TJ Juppner, H AF Jonsson, KB John, MR Gensure, RC Gardella, TJ Juppner, H TI Tuberoinfundibular peptide 39 binds to the parathyroid hormone (PTH)/PTH-related peptide receptor, but functions as an antagonist SO ENDOCRINOLOGY LA English DT Article ID MESSENGER-RIBONUCLEIC-ACID; PTH-RELATED PEPTIDE; PROTEIN-RECEPTOR; CROSS-LINKING; TERMINAL REGION; AMINO-TERMINUS; AGONIST; LIGAND; IDENTIFICATION; HYPOTHALAMUS AB The tuberoinfundibular peptide TIP39 [TIP-(1-39)], which exhibits only limited amino acid sequence homology with PTH and PTH-related peptide (PTHrP), stimulates cAMP accumulation in cells expressing the PTH2 receptor (PTH2R), but it is inactive at the PTK/ PTHrP receptor (PTH1R). However, when using either I-125-labeled rat [Nle(8.21),Tyr(34)]pTH-(1-34)amide (rPTH) or I-125-labeled human [Tyr36]PTHrP-(1-36)amide [PTHrP-(1-36)] for radioreceptor studies, TIP-(1-39) bound to LLCPK1 cells stably expressing the PTH1R (HKrk-B7 cells), albeit with weak apparent affinity (243 +/- 52 and 210 +/- 64 nM, respectively). In comparison to the parent peptide, the apparent binding affinity of TIP-(3-39) was about 3-fold higher, and that of TIP-(9-39) was about 5.5-fold higher. However, despite their improved ICS, values at the PTH1R, both truncated peptides failed to stimulate cAMP accumulation in HKrk-B7 cells. In contrast, the chimeric peptide PTHrP-(1-20)/TLP-(23-39) bound to HKrk-B7 cells with affinities of 31 +/- 8.2 and 11 +/- 4.0 nM when using radiolabeled rPTH and PTHrP-(1-36), respectively, and it stimulated cAMP accumulation in HKrk-B7 and SaOS-2 cells with potencies (EC50, 1.40 +/- 0.3 and 0.38 +/- 0.12 nM, respectively) and efficacies (maximum levels, 39 +/- 8 and 31 +/- 3 pmol/well, respectively) similar to those of PTH-(1-34) and PTHrP-(1-36). In both cell lines, TIP(9-39) and, to a lesser extent, TIP-(1-39) inhibited the actions of the three agonists with efficiencies similar to those of [Leu(11),D-Trp(12),Trp(23),Tyr(36)] PTHrP-(7-36)amide, an established PTH1R antagonist. Taken together, the currently available data suggest that the carboxyl-terminal portion of TIP-(1-39) interacts efficiently with the PTH1R, at sites identical to or closely overlapping those used by PTH-(1-34) and PTHrP-(1-36). The amino-terminal residues of TIP(1-39), however, are unable to interact productively with the PTH1R, thus enabling TIP-(1-39) and some of its truncated analogs to function as an antagonist at this receptor. C1 Massachusetts Gen Hosp, Endocrine Unit, Dept Med & Pediat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Juppner, H (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Dept Med & Pediat, Wellman 5, Boston, MA 02114 USA. NR 31 TC 29 Z9 31 U1 0 U2 2 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2001 VL 142 IS 2 BP 704 EP 709 DI 10.1210/en.142.2.704 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 398GC UT WOS:000166747700024 PM 11159842 ER PT J AU Divieti, P Inomata, N Chapin, K Singh, R Juppner, H Bringhurst, FR AF Divieti, P Inomata, N Chapin, K Singh, R Juppner, H Bringhurst, FR TI Receptors for the carboxyl-terminal region of PTH(1-84) are highly expressed in osteocytic cells SO ENDOCRINOLOGY LA English DT Article ID PARATHYROID-HORMONE FRAGMENTS; PTH/PTHRP RECEPTOR; PERIPHERAL METABOLISM; MESSENGER-RNA; PEPTIDE; BONE; PTH; CALCIUM; COMMUNICATION; SPECTROSCOPY AB PTH is a potent systemic regulator of cellular differentiation and function in bone. It acts upon cells of the osteoblastic Lineage via the G protein-coupled type-1 PTH/PTH-related peptide receptor (PTH1R). Carboxyl fragments of intact PTH(1-84) (C-PTH fragments) are cosecreted with it by the parathyroid glands in a calcium-dependent manner and also are generated via proteolysis of the hormone in peripheral tissues. Receptors that recognize C-PTH fragments (CPTHRs) have been described previously in osteoblastic and chondrocytic cells. To directly study CPTHRs in bone cells, we isolated clonal, conditionally transformed cell lines from fetal calvarial bone of mice that are homozygous for targeted ablation of the PTH1R gene and transgenically express a temperature-sensitive mutant SV40 T antigen. Cells with the highest specific binding of the CPTHR radio-ligand I-125-[Tyr(34)]hPTH(19-84) exhibited a stellate, dendritic appearance suggestive of an osteocytic phenotype and expressed 6- to 10-fold more CPTHR sites/cell than did osteoblastic cells previously isolated from the same bones. In these osteocytic (OC) cells, expression of mRNAs for CD44, connexin 43, and osteocalcin was high, whereas that for alkaline phosphatase and cbfa-1/osf-2 was negligible. The CPTHR radioligand was displaced completely by hPTH(1-84), hPTH(19-84) and hPTH(24-84) (IC(50)s = 20-50 nM) and by kPTH(39-84) (IC50 = 500 nM) but only minimally (24%) by 10,000 nM hPTH(1-34). CPTHR binding was down-regulated dose dependently by hPTH(1-84), an effect mimicked by ionomycin and active phorbol ester. Human PTH(1-84) and hPTH(39-84) altered connexin 43 expression and increased apoptosis in OC cells. Apoptosis induced by PTH(1-84) was blocked by the caspase inhibitor DEVD, We conclude that osteocytes, the most abundant cells in bone, may be principal target cells for unique actions of intact PTH(1-84) and circulating PTH C-fragments that are mediated by CPTHRs. C1 Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Chugai Pharmaceut Co Ltd, Shizuoka, Japan. RP Divieti, P (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Wellman 5, Boston, MA 02114 USA. NR 41 TC 110 Z9 116 U1 0 U2 0 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2001 VL 142 IS 2 BP 916 EP 925 DI 10.1210/en.142.2.916 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 398GC UT WOS:000166747700047 PM 11159865 ER PT J AU Ross, J Kearse, LA Barlow, MK Houghton, KJ Cosgrove, GR AF Ross, J Kearse, LA Barlow, MK Houghton, KJ Cosgrove, GR TI Alfentanil-induced epileptiform activity: A simultaneous surface and depth electroencephalographic study in complex partial epilepsy SO EPILEPSIA LA English DT Article DE depth electroencephalography; complex partial epilepsy; alfentanil ID HIGH-DOSE FENTANYL; TEMPORAL-LOBE EPILEPSY; GRAND MAL SEIZURE; ANESTHESIA; OPIATE; METABOLISM; INDUCTION; INFUSION; ABSENCE; BRAIN AB Purpose: Alfentanil is a high potency mu opiate receptor agonist commonly used during presurgical induction of anesthesia. This and other opiate receptor agonists have demonstrated proconvulsant effects in animals, but these properties have been less consistently demonstrated in humans. Most human scalp EEG studies have failed to demonstrate induction of epileptiform activity with these agents, which is inconsistent with findings using intracranial EEG. Simultaneous scalp and depth EEG recordings have yet to be performed in this setting. The relationship between opiate dose and proconvulsant activity is unclear. Methods: Simultaneous scalp and depth electrode recordings were performed on five patients with complex partial epilepsy (CPE) who underwent alfentanil anesthesia induction before depth electrode removal. Consecutive equal bolus doses of alfentanil were administered to each patient according to strict time intervals so as to assess their correlation with any induced epileptiform activity. Results: Epileptiform activity was induced by alfentanil in three of five patients. Two of these patients had electrographic seizures. Epileptiform activity was only detected from the depth electrodes, occurring within 2 min of the first bolus dose in all three cases. Further increase or spread of epileptiform activity did not occur despite cumulative bolus doses of alfentanil. Conclusions: Alfentanil is proconvulsant in patients with CPE. Induced seizures may be subclinical and lack a scalp EEG correlate. There is a complex dose-response relationship. Alfentanil induction of anesthesia should be approached with caution in patients with CPE. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesiol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, Boston, MA USA. RP Ross, J (reprint author), New England Neurol Associates, 220 Sutton St, N Andover, MA 01845 USA. NR 35 TC 14 Z9 17 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD FEB PY 2001 VL 42 IS 2 BP 220 EP 225 DI 10.1046/j.1528-1157.2001.4220220.x PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 407XN UT WOS:000167296200009 PM 11240593 ER PT J AU Pryor, FM Gidal, B Ramsay, RE DeToledo, J Morgan, RO AF Pryor, FM Gidal, B Ramsay, RE DeToledo, J Morgan, RO TI Fosphenytoin: Pharmacokinetics and tolerance of intramuscular loading doses SO EPILEPSIA LA English DT Article DE fosphenytoin; pharmacokinetics; tolerance; acute repetitive seizures; intramuscular injection ID INTRAVENOUS PHENYTOIN; EPILEPTIC PATIENTS; DIPHENYLHYDANTOIN; LORAZEPAM; DIAZEPAM; KINETICS AB Purpose: Fosphenytoin (FPHT; Cerebyx) is well absorbed when given intramuscularly (IM). All prior pharmacokinetic studies had the first plasma sample obtained 30 min after IM administration. The objectives of this study were to determine the rate and extent of FPHT absorption and to evaluate the tolerability of IM FPHT compared with IM saline. Methods: This was an open-label, double-blinded study in which patients received 10 mg/kg dose of IM FPHT in one gluteus and IM saline in the other gluteus. Half the patients received saline injection of equal volume to FPHT (up to 19.5 mL); the other half received 2 mL of saline. Neurologic examination, vital signs, PHT blood samples. injection site examination, and subjective pain scores at injection site were obtained before and at timed intervals for 6 h. Results. Total PHT serum concentrations 10 mug/mL were obtained in 5 min in 14.3% of patients and in 26.3% after 10 min. More than half the patients had therapeutic serum concentrations at 30 min; 45.8% of patients reported no pain at either the FPHT or saline injection site. No significant difference in pain was noted between FPHT and saline injection sites at 60 min and thereafter. Early decrease in blood pressure occurred but was not clinically significant. Classic PHT-induced central nervous system (CNS) side effects were evident in one third of patients within 1 h after injection, Conclusions: (a) LM FPHT is rapidly absorbed (therapeutic levels achieved as early as 5-20 min). (b) IM FPHT is well tolerated by most patients irrespective of injection volume. C1 Univ Miami, Sch Med, Miami, FL USA. Univ Wisconsin, Madison, WI USA. Houston VA Med Ctr, Houston, TX USA. Baylor Coll Med, Houston, TX 77030 USA. RP Pryor, FM (reprint author), Miami VA Med Ctr, Neurol Serv 127, 1201 NW 16 St, Miami, FL 33125 USA. RI Ramsay, R. Eugene/D-4491-2011 NR 22 TC 12 Z9 12 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD FEB PY 2001 VL 42 IS 2 BP 245 EP 250 DI 10.1046/j.1528-1157.2001.20800.x PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 407XN UT WOS:000167296200013 PM 11240597 ER PT J AU Rubin, BP Skarin, AT Pisick, E Rizk, M Salgia, R AF Rubin, BP Skarin, AT Pisick, E Rizk, M Salgia, R TI Use of cytokeratins 7 and 20 in determining the origin of metastatic carcinoma of unknown primary, with special emphasis on lung cancer SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE carcinoma; CK7; CK20; cytokeratins; lung cancer; unknown primary ID MONOCLONAL-ANTIBODIES; DIFFERENTIAL-DIAGNOSIS; GASTROINTESTINAL CARCINOMAS; ADENOCARCINOMAS; KERATIN-7; MARKER; EXPRESSION; EPITHELIA; IMMUNOPEROXIDASE; PATTERNS AB Metastatic carcinoma of unknown primary is a common problem, accounting for up to 10-15% of all solid tumours at presentation. Proper identification of the site of origin has prognostic and therapeutic significance. Prior immunohistochemical methods to identify the site of origin have been useful in a limited number of cases. Differential cytokeratin staining may be useful in this setting, particularly in identifying metastases from lung cancer. We have identified 144 cases of metastatic carcinoma of unknown primary to bone, lung or liver at Brigham and Women's Hospital between 1 January 1997 and 1 July 1998, Cytokeratin (CK) 7 and CK20 were used in 75 of these cases to narrow down the possible sites of the primary tumours. All of these cases were ambiguous as to the site of the primary tumour. Forty-five cases were CK7 + /CK20-, 15 cases were CK7-/CK20-, 9 cases were CK7-/CK20 + and 6 cases were CK7 + /CK20 +. Three of the cases were selected for detailed presentation and discussion as well as a discussion of the pertinent literature. Overall, the CK7 + /CK20- phenotype favours a lung primary, the CK7 + /CK20 + phenotype strongly favours transitional cells (urothelial) carcinoma, the CK7-/CK20 + phenotype favours colorectal carcinoma, while the CK7-/ CK20- profile is not helpful. (C) 2001 Lippincott Williams & Wilkins. C1 Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Dana Farber Canc Inst, Div Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Salgia, R (reprint author), Brigham & Womens Hosp, Dept Med, Dana 1234B,44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA75348-04] NR 36 TC 46 Z9 50 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-8278 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD FEB PY 2001 VL 10 IS 1 BP 77 EP 82 DI 10.1097/00008469-200102000-00009 PG 6 WC Oncology SC Oncology GA 410XD UT WOS:000167465600009 PM 11263595 ER PT J AU Kohler, H Schulz, S Wiebalck, A AF Kohler, H Schulz, S Wiebalck, A TI Pain management in children: Assessment and documentation in burn units SO EUROPEAN JOURNAL OF PEDIATRIC SURGERY LA English DT Article DE pain; burns; children AB Burns are considered to be among the most painful types of trauma, Especially the pain of children is often unsatisfactorily treated. This study investigates the assessment and documentation of pain by physicians and nurses in children suffering from burns. Pain management was considered sufficient in 80% of ventilated patients and in 60% of non-ventilated patients. The minority of the staff regarded pain management as sufficient during dressing changes after the acute phase and during nursing care. Thirty-eight per cent of the physicians and 58% of the nurses documented the pain. Standardized documentation was used by fewer than 20% of the staff, Pain documentation was not considered relevant for further therapy by 48% of the physicians. More than half of all participants believed that an improvement of the pain therapy performed in their hospital was necessary. Standardized documentation, an algorithm for the application of analgesics, and more training in pain management were desired by many staff members. C1 Univ Dusseldorf, Childrens Hosp, D-4000 Dusseldorf, Germany. Ruhr Univ Bochum, Clin Bergmannsheil, Dept Anaesthesiol Intens Care & Pain Therapy, D-4630 Bochum, Germany. RP Kohler, H (reprint author), Massachusetts Gen Hosp, Dept Pediat Gastroenterol & Nutr, 149 13th St, Charlestown, MA 02129 USA. NR 21 TC 11 Z9 11 U1 0 U2 1 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0939-7248 J9 EUR J PEDIATR SURG JI Eur. J. Pediatr. Surg. PD FEB PY 2001 VL 11 IS 1 BP 40 EP 43 DI 10.1055/s-2001-12196 PG 4 WC Pediatrics; Surgery SC Pediatrics; Surgery GA 424ZA UT WOS:000168262800009 PM 11370982 ER PT J AU McLellan, AT AF McLellan, AT TI Moving toward a "third generation" of contingency management studies in the drug abuse treatment field: Comment on Silverman et al. (2001) SO EXPERIMENTAL AND CLINICAL PSYCHOPHARMACOLOGY LA English DT Editorial Material AB The power of positively reinforced contingency management procedures has been definitively proven in the drug abuse field-even among the most severely affected clients. This study by K. Silverman, D. Svikis, E. Robles, M. L. Stitzer, and G. E. Bigelow (2001) and other studies like it have clearly moved the contingency management work out of controlled, contrived settings and into the real world. Suggestions are offered for moving the next generation of studies toward less complicated populations and using more robust reinforcements within the constraints of contemporary financial and administrative boundaries. C1 Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. Vet Affairs Med Ctr, Dept Psychiat, Philadelphia, PA USA. RP McLellan, AT (reprint author), Treatment Res Inst, 600 Publ Ledger Bldg,150 S Independence Mall W, Philadelphia, PA 19106 USA. NR 1 TC 7 Z9 7 U1 1 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1064-1297 J9 EXP CLIN PSYCHOPHARM JI Exp. Clin. Psychopharmacol. PD FEB PY 2001 VL 9 IS 1 BP 29 EP 32 DI 10.1037/1064-1297.9.1.29 PG 4 WC Psychology, Biological; Psychology, Clinical; Pharmacology & Pharmacy; Psychiatry SC Psychology; Pharmacology & Pharmacy; Psychiatry GA 472JZ UT WOS:000170981700005 PM 11519631 ER PT J AU Kradin, R Rodberg, G Zhao, LH Leary, C AF Kradin, R Rodberg, G Zhao, LH Leary, C TI Epinephrine yields translocation of lymphocytes to the lung SO EXPERIMENTAL AND MOLECULAR PATHOLOGY LA English DT Article DE T-lymphocytes; NK cells; lymph node; stress; epinephrine; lung ID CHEMICAL SYMPATHECTOMY; IMMUNE-SYSTEM; STRESS AB Previous studies have demonstrated that acute stress leads to the appearance of T-lymphocytes in skin and bone marrow In order to examine the effects of adrenergic stimulation on the traffic of immune lymphocytes to the lung, C57BL/6 mice were injected with epinephrine subcutaneously, and changes in lymphocyte representation in lung, hilar lymph node, spleen, and blood were examined at 30 min. Cytofluorimetric lymphocyte subset analysis showed that epinephrine increased "memory" CD4+ lymphocytes in enzymatic digests of lung but decreased their representation in spleen. NK1.1+ lymphocytes were concomitantly increased in lung and decreased in spleen. Next, lymphocytes in spleen or popliteal lymph nodes were labeled with the Hoechst lipophilic red dye PKH26 in vivo 48 h prior to epinephrine injection. PKH26 + lymphocytes were identified in lung tissue at 30 min postepinephrine but not in controls. Lymphocyte traffic was inhibited by propanolol. We conclude that epinephrine promotes rapid shifts in immune lymphocytes from lymphoid tissues into lung and blood. Directed traffic of immune lymphocytes may be a feature of the adaptive immune response to stress at mucosal barrier surfaces. (C) 2001 Academic Press. C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Kradin, R (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren 501, Boston, MA 02114 USA. FU PHS HHS [R0I A139054] NR 14 TC 15 Z9 15 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4800 J9 EXP MOL PATHOL JI Exp. Mol. Pathol. PD FEB PY 2001 VL 70 IS 1 BP 1 EP 6 DI 10.1006/exmp.2000.2342 PG 6 WC Pathology SC Pathology GA 410TH UT WOS:000167454900001 PM 11170785 ER PT J AU Ladetto, M Sametti, S Donovan, JW Ferrero, D Astolfi, M Mitterer, M Ricca, I Drandi, D Corradini, P Coser, P Pileri, A Gribben, JC Tarella, C AF Ladetto, M Sametti, S Donovan, JW Ferrero, D Astolfi, M Mitterer, M Ricca, I Drandi, D Corradini, P Coser, P Pileri, A Gribben, JC Tarella, C TI A validated real-time quantitative PCR approach shows a correlation between tumor burden and successful ex vivo purging in follicular lymphoma patients SO EXPERIMENTAL HEMATOLOGY LA English DT Article DE real-time PCR; bcl-2 rearrangement; minimal residual disease; ex vivo purging; follicle center lymphoma ID POLYMERASE-CHAIN-REACTION; NON-HODGKINS-LYMPHOMA; BONE-MARROW TRANSPLANTATION; MINIMAL RESIDUAL DISEASE; BLOOD PROGENITOR CELLS; COLONY-STIMULATING FACTOR; HIGH-DOSE CHEMOTHERAPY; MOLECULAR REMISSIONS; BCL-2 TRANSLOCATION; ENGRAFTMENT AB Objective. Purging procedures are increasingly used to provide stem cell collections devoid of contaminating tumor cells, In follicle center lymphoma (FCL), most approaches eradicate polymerase chain reaction (PCR)-detectable disease in only a fraction of harvests undergoing ex vivo manipulation, In this study we evaluated whether there is a relationship between tumor burden of stem cell harvests and successful clearance of PCR-detectable disease following ex vivo manipulation, Materials and Methods. To address this issue, we developed a real-time PCR approach for quantitative measurement of tumor contamination using the bcl-2 rearrangement. Real-time PCR was used to evaluate the relationship between tumor burden of stem-cell harvests and purging effectiveness in PCR+ samples derived from 10 FCL patients, Ex vivo purging was performed using the MaxSep cell separator (Baxter Immunotherapy, Deerfield, IL, USA), Results. Our real-time PCR method proved effective, sensitive, accurate, and reproducible. Four collections were successfully cleared of minimal residual disease (MRD) whereas six remained PCR+, Real-time PCR showed that the four collections successfully cleared of MRD had a prepurging tumor burden significantly lower than those remaining PCR+ (p = 0.04), Conclusion, This study provides the first evidence that evaluation of tumor burden in stem-cell harvests by real-time PCR can predict the effectiveness of therapeutic intervention in non-Hodgkin's lymphoma. Based on these findings, we foresee a more widespread use of this technique to evaluate the impact of different therapeutic approaches in FCL. (C) 2001 International Society for Experimental Hematology, Published by Elsevier Science Inc. C1 Azienda Osped S Giovanni Battista, Div Univ Ematol, Turin, Italy. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Div ematol & Trapianto Midollo Osseo, Bozen Bolzano, Italy. RP Ladetto, M (reprint author), Cattedra Ematol, Via Genova 3, I-10126 Turin, Italy. RI drandi, daniela/Q-6504-2016; OI LADETTO, Marco/0000-0002-8283-2681 NR 38 TC 45 Z9 45 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD FEB PY 2001 VL 29 IS 2 BP 183 EP 193 DI 10.1016/S0301-472X(00)00651-2 PG 11 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 401EG UT WOS:000166913900007 PM 11166457 ER PT J AU Mahajan, S Gollob, JA Ritz, J Frank, DA AF Mahajan, S Gollob, JA Ritz, J Frank, DA TI CD2 stimulation leads to the delayed and prolonged activation of STAT1 in T cells but not NK cells SO EXPERIMENTAL HEMATOLOGY LA English DT Article DE signal transduction; transcription factors; adhesion molecules; phosphorylation ID NATURAL-KILLER-CELLS; CILIARY NEUROTROPHIC FACTOR; TYROSINE PHOSPHORYLATION; SIGNALING PATHWAY; TARGETED DISRUPTION; IMMUNE-RESPONSE; FUNCTIONAL-ROLE; LYMPHOCYTES-T; RECEPTOR; PROTEIN AB Objective. T lymphocytes can be activated by soluble factors such as cytokines or through direct cell-tell interactions, Although cytokine receptors are known to signal through STAT family transcription factors, the mechanisms by which other cell-surface molecules, such as CD2, transduce signals is unclear. The goal of this study was to determine whether stimulation of T cells through CD2 recapitulates aspects of cytokine-induced T-cell activation by use of STAT transcription factors, Materials and methods. T cells were treated with anti-CD2 antibodies or cells bearing the natural CD2 ligand CD58, after which signaling through STAT transcription factors was assessed. Results, Stimulation of CD2 on primary T lymphocytes leads to the tyrosine phosphorylation, nuclear translocation, and DNA binding of STAT1. In contrast to stimulation by cytokines, the activation of STAT1 in response to CD2 ligation is delayed and does not involve Jak kinases, Furthermore, while STAT phosphorylation induced by cytokines is generally transient, STAT1 phosphorylation following CD2 stimulation persists for a period of days. Transcription of key target genes such as IRF1 and c-fos proceeds with delayed kinetics following CD2 stimulation, suggesting that this unique pattern of STAT activation mag lead to a distinct cellular response following CD2 ligation, This pathway appears to be restricted to T cells, as stimulation of CD2 on NK cells does not lead to STAT1 activation. Conclusion. Stimulation of T cells through cell-surface molecules such as CD2 involves activation of STAT transcription factors, thus recapitulating elements of cytokine signaling. (C) 2001 International Society for Experimental Hematology, Published by Elsevier Science Inc. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Frank, DA (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Mayer 522B,44 Binney St, Boston, MA 02115 USA. RI Ritz, Jerome/C-7929-2009 OI Ritz, Jerome/0000-0001-5526-4669 FU NCI NIH HHS [CA41619] NR 54 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD FEB PY 2001 VL 29 IS 2 BP 209 EP 220 DI 10.1016/S0301-472X(00)00652-4 PG 12 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 401EG UT WOS:000166913900010 PM 11166460 ER PT J AU Nakajima, A Wada, K Miki, H Kubota, N Nakajima, N Terauchi, Y Ohnishi, S Saubermann, LJ Kadowaki, T Blumberg, RS Nagai, R Matsuhashi, N AF Nakajima, A Wada, K Miki, H Kubota, N Nakajima, N Terauchi, Y Ohnishi, S Saubermann, LJ Kadowaki, T Blumberg, RS Nagai, R Matsuhashi, N TI Endogenous PPAR gamma mediates anti-inflammatory activity in murine ischemia-reperfusion injury SO GASTROENTEROLOGY LA English DT Article ID PROLIFERATOR-ACTIVATED RECEPTORS; DYSFUNCTION; MECHANISMS; ADHESION; DISEASE; INHIBIT; COLITIS; ALPHA AB Background & Aims: Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor whose activation has been linked to several physiologic pathways including those related to the regulation of intestinal inflammation. We sought to determine whether PPAR gamma could function as an endogenous anti-inflammatory pathway in a murine model of intestinal ischemia-reperfusion (I/R) injury. Methods: PPAR gamma -deficient and wildtype mice were examined for their response to I/R procedure. Treatment with a PPAR gamma -specific ligand was also performed. Results: In a murine model of intestinal I/R injury, we observed more severe injury in PPAR gamma -deficient mice and protection against local and remote tissue injury in mice treated with a PPAR gamma -activating ligand, BRL-49653. Activation of PPAR gamma resulted in down-regulation of intercellular adhesion molecule 1 expression by intestinal endothelium and tissue tumor necrosis factor alpha messenger RNA levels most likely by inhibition of the NF-kappaB pathway. Conclusions: These data strongly suggest that an endogenous PPAR gamma pathway exists in tissues that may be amenable to therapeutic manipulation in I/R-related injuries. C1 Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Med, Ctr Expt Therapeut & Reperfus Injury, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Med Ctr, Gastroenterol Sect, Boston, MA USA. Univ Tokyo, Dept Gastroenterol, Tokyo, Japan. Univ Tokyo, Dept Metab Dis, Tokyo, Japan. Univ Tokyo, Dept Cardiovasc Dis, Tokyo, Japan. RP Blumberg, RS (reprint author), Brigham & Womens Hosp, Div Gastroenterol, Thorn 1419,75 Francis St, Boston, MA 02115 USA. RI Kubota, Naoto/N-7892-2015 FU NIDDK NIH HHS [DK44319, DK51362, DK53056] NR 25 TC 173 Z9 186 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 FEB PY 2001 VL 120 IS 2 BP 460 EP 469 DI 10.1053/gast.2001.21191 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 397PX UT WOS:000166705000019 PM 11159886 ER PT J AU Podolsky, DK AF Podolsky, DK TI Introduction SO GASTROENTEROLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Podolsky, DK (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, GRJ 719,32 Fruit St, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD FEB PY 2001 VL 120 IS 3 SI SI BP 593 EP 593 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 403GU UT WOS:000167034800001 ER PT J AU Uko, GP Fraser, PA Awdeh, ZL Fici, DA Crawford, KD Larsen, CE Alper, CA AF Uko, GP Fraser, PA Awdeh, ZL Fici, DA Crawford, KD Larsen, CE Alper, CA TI Hepatitis B surface antigen- and tetanus toxoid-specific clonal expansion of CD4(+) cells in vitro determined by TCRBV CDR3 length and nucleotide sequence SO GENES AND IMMUNITY LA English DT Article DE CD4(+) PBMC; monoclonality/oligoclonality; spectratyping; recall antigen ID T-LYMPHOCYTES; RHEUMATOID-ARTHRITIS; RECEPTOR REPERTOIRE; IMMUNE-RESPONSE; NONRESPONDERS; HBSAG; USAGE; POPULATION; SELECTION; TRACKING AB We demonstrate activation of primary human TCRBV-specific CD4(+) cells in vitro towards hepatitis B surface antigen (HBsAg) and tetanus toroid (TT) without the use of cell lines, clones or added cytokines. By multiplex PCR analysis and spectratyping, antigen-activated cells exhibited clonal T cell receptor expansion within specific and limited TCRBV families. The expanded CD4(+) T cells were CD45RO. Three of four unrelated HBsAg responders showed CD4(+) expansion within the TCRBV16 family. The response comprised predominantly single CDR3 sequences in all three donors and was completely monoclonal in one of them. However, the CDR3 lengths and sequences differed among the responders. Clonality induced by HBsAg in TCRBV16 was specific, reproducible and distinct from that induced by TT in terms of sequence, nucleotide addition and diversify (BD) or junctional (BJ) element usage. Thus, for the first time, we show monoclonal or oligoclonal expansion of primary human CD4(+) peripheral blood mononuclear cells (PBMC) in vitro in response to nominal protein antigen without manipulations utilizing exogenous IL-2. The ability to induce monoclonal/ oligoclonal responses to HBsAg now permits motif identification studies for determining the T cell role in nonresponsiveness to the HBsAg vaccine. Genes and Immunity (2001) 2, 11-19. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Alper, CA (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. FU NHLBI NIH HHS [HL-29583]; NIAID NIH HHS [AI-35630] NR 25 TC 6 Z9 7 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD FEB PY 2001 VL 2 IS 1 BP 11 EP 19 DI 10.1038/sj.gene.6363729 PG 9 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 407WL UT WOS:000167293700003 PM 11294562 ER PT J AU Nakatani, Y AF Nakatani, Y TI Histone acetylases - versatile players SO GENES TO CELLS LA English DT Review ID IN-VIVO; ACETYLTRANSFERASE ACTIVITY; GENE ACTIVATION; YEAST GCN5P; DNA-BINDING; TRANSCRIPTION; COMPLEX; PCAF; CORE; TIP60 AB Genomic DNA in eukaryotes is tightly packed in the form of a highly ordered chromatin structure. In view of this tight packing, one of the most important questions in biology is how the transcriptional machinery regulates target genes in chromatin. Reversible modification of histones by acetylation is involved in transcriptional activation as well as repression in chromatin contexts. Recent studies with highly purified histone acetylases have provided insights into the mechanisms whereby acetylases contribute to transcriptional control. Furthermore, they suggest the possibility that histone acetylases could play roles in various forms of DNA metabolism as well as in transcription in chromatin contexts. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Nakatani, Y (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 56 TC 45 Z9 45 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 1356-9597 J9 GENES CELLS JI Genes Cells PD FEB PY 2001 VL 6 IS 2 BP 79 EP 86 DI 10.1046/j.1365-2443.2001.00411.x PG 8 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 420KG UT WOS:000168003700001 PM 11260253 ER PT J AU Maciejewski, ML Dowd, B Call, KT Feldman, R AF Maciejewski, ML Dowd, B Call, KT Feldman, R TI Comparing mortality and time until death for medicare HMO and FFS beneficiaries SO HEALTH SERVICES RESEARCH LA English DT Article DE prepaid health plans; managed care; fee-for-service plans; system comparisons; elderly ID MANAGED CARE; PLAN; DEMONSTRATIONS; ENROLLEES; CANCER AB Objective. To compare adjusted mortality rates of TEFRA-risk HMO enrollees and disenrollees with rates of beneficiaries enrolled in the Medicare fee-for-service sector (FFS), and to compare the time until death for decedents in these three groups. Data Source. Data are from the 124 counties with the largest TEFRA-risk HMO enrollment using 1993-1994 Medicare Denominator files for beneficiaries enrolled in the FFS and TEFRA-risk HMO sectors. Study Design. A retrospective study that tracks the mortality rates and time until death of a random sample of 1,240,120 Medicare beneficiaries in the FFS sector and 1,526,502 enrollees in HMOs between April 1, 1993 and April 1, 1994. A total of 58,201 beneficiaries switched from an HMO to the FFS sector and were analyzed separately. Principal Findings. HMO enrollees have lower relative odds of mortality than a comparable group of FFS beneficiaries. Conversely, HMO disenrollees have higher relative odds of mortality than comparable FFS beneficiaries. Among decedents in the three groups, HMO enrollees lived longer than FFS beneficiaries, who in turn lived longer than HMO disenrollees. Conclusions. Medicare TEFRA-risk HMO enrollees appear to be, on average, healthier than beneficiaries enrolled in the FFS sector, who appear to be in turn healthier than HMO disenrollees. These health status differences persist, even after controlling for beneficiary demographics and county-level variables that might confound the relationship between mortality and the insurance sector. C1 VA Puget Sound Hlth Care Syst, HSR&D 125, NW Ctr Outcomes Res Older Adults, Seattle, WA 98108 USA. Univ Washington, Seattle, WA 98195 USA. Univ Minnesota, Minneapolis, MN USA. RP Maciejewski, ML (reprint author), VA Puget Sound Hlth Care Syst, HSR&D 125, NW Ctr Outcomes Res Older Adults, 1660 S Columbian Way, Seattle, WA 98108 USA. NR 21 TC 25 Z9 25 U1 0 U2 0 PU HEALTH ADMINISTRATION PRESS PI CHICAGO PA C/O FOUNDATION AMER COLL HEALTHCARE EXECUTIVES ONE N FRANKLIN ST, STE 1700, CHICAGO, IL 60606-3491 USA SN 0017-9124 J9 HEALTH SERV RES JI Health Serv. Res. PD FEB PY 2001 VL 35 IS 6 BP 1245 EP 1265 PG 21 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 404AJ UT WOS:000167075000004 PM 11221818 ER PT J AU Perrillo, RP Wright, T Rakela, J Levy, G Schiff, E Gish, R Martin, P Dienstag, J Adams, P Dickson, R Anschuetz, G Bell, S Condreay, L Brown, N AF Perrillo, RP Wright, T Rakela, J Levy, G Schiff, E Gish, R Martin, P Dienstag, J Adams, P Dickson, R Anschuetz, G Bell, S Condreay, L Brown, N CA Lamivudine N Amer Transplant Grp TI A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis SO HEPATOLOGY LA English DT Article ID B IMMUNE GLOBULIN; SURFACE-ANTIGEN; COMBINATION LAMIVUDINE; INTERFERON-ALFA; VIRUS; INFECTION; PROPHYLAXIS; RECIPIENTS; CIRRHOSIS; RECURRENCE AB Seventy-seven liver transplant candidates were enrolled in a multicenter study in which patients were treated with lamivudine (100 mg daily) without the adjunctive use of hepatitis B immune globulin. Treatment was begun while patients awaited liver transplantation and continued after transplantation. All were hepatitis B surface antigen (HBsAg) positive, and 61% had detectable hepatitis B e antigen (HBeAg) and HBV DNA when treatment was begun. Forty-seven underwent liver transplantation and 30 did not. Median study participation was 38 months (range, 2.7-48.5) in the transplanted patients and 26 months (range, 0.1-37) in the nontransplanted group. Twenty-five of 42 (60%) transplanted patients with 12 or more weeks of posttransplantation follow-up were HBsAg negative at the last study visit. At treatment week 156, 13 of 22 (59%) remained HBsAg negative, and all 9 reinfected patients were HBV-DNA positive before treatment. In the nontransplanted patients, HBeAg was initially detectable in 20 of 27 (74%) but this decreased to 3 of 17 (18%) after 104 weeks of treatment, and significant improvement in biochemical parameters was observed. HBV-DNA polymerase mutants were detected in 15 (21%) and 6 (20%) of the transplanted and nontransplanted patients, respectively. When compared with historical cohorts, lamivudine-treated patients appeared to have improved survival, and transplanted patients had a decrease in the rate of recurrent HBV infection. Lamivudine therapy was partially effective in preventing recurrent HBV infection when given before and after transplantation. Thus, future trials using a combination of HBIg and lamivudine are needed to assess the optimal prophylactic therapy. C1 Alton Ochsner Med Fdn & Ochsner Clin, Sect Gastroenterol & Hepatol, New Orleans, LA 70121 USA. Vet Affairs Med Ctr, Div Gastroenterol, San Francisco, CA 94121 USA. Univ Pittsburgh, Med Ctr, Div Gastroenterol, Pittsburgh, PA USA. Toronto Gen Hosp, Toronto, ON, Canada. Univ Miami, Med Ctr, Ctr Liver Dis, Miami, FL 33152 USA. Calif Pacific Med Ctr, San Francisco, CA USA. Univ Calif Los Angeles, Med Ctr, Div Gastroenterol, Los Angeles, CA 90024 USA. Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Hlth Sci Ctr, London, ON, Canada. Univ Florida, Gainesville, FL USA. Glaxo Wellcome, Res Triangle Pk, NC USA. RP Perrillo, RP (reprint author), Alton Ochsner Med Fdn & Ochsner Clin, Sect Gastroenterol & Hepatol, 1514 Jefferson Highway, New Orleans, LA 70121 USA. NR 35 TC 278 Z9 316 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD FEB PY 2001 VL 33 IS 2 BP 424 EP 432 DI 10.1053/jhep.2001.21554 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 397QF UT WOS:000166705800014 PM 11172345 ER PT J AU Novitsky, V Flores-Villanueva, PO Chigwedere, P Gaolekwe, S Bussman, H Sebetso, G Marlink, R Yunis, EJ Essex, M AF Novitsky, V Flores-Villanueva, PO Chigwedere, P Gaolekwe, S Bussman, H Sebetso, G Marlink, R Yunis, EJ Essex, M TI Identification of most frequent HLA class I antigen specificities in Botswana: Relevance for HIV vaccine design SO HUMAN IMMUNOLOGY LA English DT Article DE HLA; HIV-1; HIV-1 vaccine; Botswana; Southern Africa ID T-LYMPHOCYTE RESPONSES; TYPE-1 INFECTION; DNA VACCINES; PROGRESSION; ASSOCIATION; AIDS; NOMENCLATURE; VOLUNTEERS; PEPTIDES; ALLELES AB Since the mid-1990s, southern African countries have been experiencing an expansion of human immunodeficiency virus type 1 (HIV-1) infection caused by HIV-1 subtype C. To facilitate the design of an HLA-based HIV vaccine, we studied the distribution of the HLA class I antigen specificities in Botswana, a southern African country with a high prevalence of HIV infection. Botswana's highly efficient health care system and its central geographical location within southern Africa suggests that it might be an appropriate candidate site for future trials of an HLA-based HIV vaccine. Specificities of HLA class I genes have been investigated in DNA samples obtained from 161 persons of Botswana origin by polymerase chain reaction (PCR) with sequence-specific primers. We identified 2 HLA-A, 7 HLA-B, and 5 HLA-C specificities that were observed at high frequencies in the Botswana population: A30, A02, A23, A68, B58, B72, B42, B8, B18, B44, B45, Cw7, Cw2, Cw17, Cw6, and Cw4. HLA-A30, A02, A23, A68, B58, Cw2, Cw4, Cw6, Cw7, and Cw17 were observed at frequencies of more than 10%. The frequency of HLA-A30 was 27.3%. HLA-B58 (17.9%) was the most frequent generic HLA-B type. Other frequent antigen specificities detected for the HLA-B were B72 (9.6%), B42! (9.3%), Be (7.4%), B18 (7.4%), B44 (7.4%), and B45 (6.4%). Analysis of haplotype frequencies revealed that haplotypes HLA-A30/HLA-B58 (6.7%), A30/B42 (6.1%), A30/B8 (4.1%), A30/B45 (3.2%), and A23/B58 (2.5%) were the most frequent among two-locus haplotypes. The comparison of HIV-positive patients and noninfected controls for HLA class I specificities confirmed the previously described association of A2/A6802 supertype with resistance to HIV. Our study suggested an increased resistance to HIV infection associated with A68 rather than A2. Wie also found that the generic HLA-B58 type was associated with increased susceptibility to HIV infection. Our findings suggest that the design of an HLA-based HIV vaccine that includes multiple CTL epitopes restricted by identified common III,A class I specificities might target up to 97.5% of the population in Botswana. The results of this study extend the HLA map to a southern African country that has high rates of HIV and also provide a database for the design of an (C) American Society for Histocompatibility and Immunogenetics, 2001. Published by Elsevier Science Inc. C1 Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Princess Marina Hosp, Natl Hlth Lab, Gaborone, Botswana. Princess Marina Hosp, Botswana Harvard HIV Reference Lab, Gabrone, Botswana. RP Essex, M (reprint author), Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, FXB-402,651 Huntington Ave, Boston, MA 02115 USA. FU FIC NIH HHS [D43 TW00004]; NCI NIH HHS [R35 CA39805]; NIAID NIH HHS [AI47067] NR 41 TC 36 Z9 38 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0198-8859 J9 HUM IMMUNOL JI Hum. Immunol. PD FEB PY 2001 VL 62 IS 2 BP 146 EP 156 DI 10.1016/S0198-8859(00)00236-6 PG 11 WC Immunology SC Immunology GA 405CZ UT WOS:000167141200008 PM 11182225 ER PT J AU Weng, LP Gimm, O Kum, JB Smith, WM Zhou, XP Wynford-Thomas, D Leone, G Eng, C AF Weng, LP Gimm, O Kum, JB Smith, WM Zhou, XP Wynford-Thomas, D Leone, G Eng, C TI Transient ectopic expression of PTEN in thyroid cancer cell lines induces cell cycle arrest and cell type-dependent cell death SO HUMAN MOLECULAR GENETICS LA English DT Article ID TUMOR-SUPPRESSOR GENE; PTEN/MMAC1 MUTATIONS; PHOSPHATASE-ACTIVITY; GLIOBLASTOMA CELLS; GERMLINE MUTATIONS; SOMATIC MUTATIONS; COWDEN-SYNDROME; BREAST CANCERS; GLIOMA-CELLS; HUMAN BRAIN AB The tumour suppressor gene PTEN/MMAC1/TEP1 has been implicated in a variety of human cancers and several inherited hamartoma tumour syndromes, including Cowden syndrome, which has a high risk of breast and thyroid cancer. We have previously reported that overexpression of PTEN in MCF-7 breast cancer cells induces cell cycle arrest and apoptosis. In this study, we analysed PTEN status at both the structural and expression levels and explored PTENs growth-suppressive effects on thyroid. We found that 1 of 10 thyroid cancer lines [follicular thyroid carcinoma FTC-133] had hemizygous deletion and a splice variant IVS4-19G-->A in the remaining allele, Four lines, including FTC-133, express PTEN mRNA at low levels. In general, PTEN protein levels correlated with mRNA levels, except for NPA87, which has low levels of transcript and relatively high levels of PTEN protein. Transient expression of PTEN in seven thyroid cancer cell lines resulted in G(1) arrest in two well differentiated papillary thyroid cancer lines (PTCs) and both G(1), arrest and cell death in the remaining five lines, including three FTCs, one poorly differentiated PTC and one undifferentiated thyroid cancer. The level of phosphorylated Akt was inversely correlated with the endogenous level of PTEN protein and overexpression of PTEN-blocked Akt phosphorylation in all cells analysed. Our results suggest that downregulation of PTEN expression at the mRNA level plays a role in PTENinactivation in thyroid cancer and PTEN exerts its tumour-suppressive effect on thyroid cancer through the inhibition of cell cycle progression alone or both cell cycle progression and cell death. C1 Ohio State Univ, Ctr Comprehens Canc, Human Canc Genet Program, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Clin Canc Genet Program, Columbus, OH 43210 USA. Ohio State Univ, Dept Internal Med, Div Human Genet, Columbus, OH 43210 USA. Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Div Human Canc Genet, Columbus, OH 43210 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Univ Wales, Sch Med, Dept Pathol, Cardiff CF4 4XN, S Glam, Wales. Univ Cambridge, Canc Res Campaign, Human Canc Genet Res Grp, Cambridge CB2 2QQ, England. RP Eng, C (reprint author), Ohio State Univ, Ctr Comprehens Canc, Human Canc Genet Program, 420 W 12th Ave,Suite 690 TMRF, Columbus, OH 43210 USA. OI Eng, Charis/0000-0002-3693-5145 FU NCI NIH HHS [P30CA16058] NR 55 TC 66 Z9 74 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD FEB 1 PY 2001 VL 10 IS 3 BP 251 EP 258 DI 10.1093/hmg/10.3.251 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 399AN UT WOS:000166788800011 PM 11159944 ER PT J AU Schmidt, WA Boudousquie, AC Vetto, JT Pommier, RF Alexander, P Thurmond, A Scanlan, RM Jones, MK AF Schmidt, WA Boudousquie, AC Vetto, JT Pommier, RF Alexander, P Thurmond, A Scanlan, RM Jones, MK TI Lymph nodes in the human female breast: A review of their detection and significance SO HUMAN PATHOLOGY LA English DT Review DE lymph nodes; breast; fine needle aspiration; triple test; imaging; mammography; ultrasound ID FINE-NEEDLE ASPIRATION; CANCER; APPEARANCE; DIAGNOSIS; CYTOLOGY; LESIONS AB Our experience led us to test the hypothesis that lymph nodes are nor uncommon within the substance of the human female breast mound. The following specimen types and sources were used to survey the presence of intramammary lymph nodes in the human female breast mound: (1) cadaver breasts; (2) community hospital breast specimens; and (3) university and VA hospital specimens. We found true lymph nodes within and associated with breast specific tissue (ie, tissue that includes duct and gland structures), thereby validating the hypothesis posed. We discuss the significance of these findings in terms of our dominant patient care paradigm (the Triple Test-physical examination, imaging, and fine-needle aspiration [FNA]) and the choice of patient care management options. We conclude the following: lymph nodes occur in any quadrant of the breast mound; recognizing the possibility of intramammary lymph nodes is important when choosing between patient management options; intramammary lymph nodes can be sampled by FNA; intramammary lymph nodes can contain various disease processes; and in the Oregon Health Sciences University Multidisciplinary Breast Clinic, these intramammary lymph nodes are commonly identified by imaging methods and are more likely to be sampled by FNA than either by core or excisional biopsy. HUM PATHOL 32:178-187. Copyright (C) 2001 by W.B. Saunders Company. C1 Oregon Hlth Sci Univ, Dept Pathol Surg & Radiol, Portland, OR 97201 USA. Portland Vet Affairs Med Ctr, Portland, OR USA. Meridian Pk Hosp, Dept Radiol, Tualatin, OR USA. Meridian Pk Hosp, Dept Pathol, Tualatin, OR USA. Kaiser Sunnyside Med Ctr, Dept Radiol, Clackamas, OR USA. RP Schmidt, WA (reprint author), Vet Affairs Med Ctr, Pathol & Lab Med Serv P5Path, POB 1034,3710 SW US Vet Hosp Rd, Portland, OR 97207 USA. NR 36 TC 17 Z9 17 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD FEB PY 2001 VL 32 IS 2 BP 178 EP 187 DI 10.1053/hupa.2001.21571 PG 10 WC Pathology SC Pathology GA 407LU UT WOS:000167273700006 PM 11230705 ER PT J AU Greenwald, RJ Boussiotis, VA Lorsbach, RB Abbas, AK Sharpe, AH AF Greenwald, RJ Boussiotis, VA Lorsbach, RB Abbas, AK Sharpe, AH TI CTLA-4 regulates induction of anergy in vivo SO IMMUNITY LA English DT Article ID CELL-CYCLE PROGRESSION; CD4(+) T-CELLS; IN-VIVO; TOLERANCE INDUCTION; PERIPHERAL TOLERANCE; CUTTING EDGE; ACTIVATION; ANTIGEN; CD28; COSTIMULATION AB The requirement for CTLA-4 during the induction of peripheral T cell tolerance in vivo was investigated using naive TCR transgenic T cells lacking CTLA-4. CTLA-4(-/-) T cells are resistant to tolerance induction, as demonstrated by their proliferative responses, IL-2 production, and progression into the cell cycle. Following exposure to a tolerogenic stimulus in vivo and restimulation in vitro, wild-type T cells are blocked at the late G1 to S restriction point of the cell cycle. In contrast, CTLA-4(-/-) T cells enter into the S phase of the cell cycle, as shown by downregulation of p27(kip1), elevated cdk2 kinase activity, and Rb hyperphosphorylation. Thus, CTLA-4 has an essential role in determining the outcome of T cell encounter with a tolerogenic stimulus. C1 Harvard Univ, Sch Med, Div Immunol Res, Dept Pathol,Brigham & Womens Hosp, Cambridge, MA 02138 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Sharpe, AH (reprint author), Harvard Univ, Sch Med, Div Immunol Res, Dept Pathol,Brigham & Womens Hosp, Cambridge, MA 02138 USA. FU NHLBI NIH HHS [T32HL07627]; NIAID NIH HHS [AI35297, AI40614, AI41584, AI43552, F32AI10415] NR 46 TC 273 Z9 284 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD FEB PY 2001 VL 14 IS 2 BP 145 EP 155 DI 10.1016/S1074-7613(09)00096-X PG 11 WC Immunology SC Immunology GA 404HZ UT WOS:000167092500005 PM 11239447 ER PT J AU Ehmann, UK Calderwood, SK Stevenson, MA AF Ehmann, UK Calderwood, SK Stevenson, MA TI Gap-junctional communication between feeder cells and recipient normal epithelial cells correlates with growth stimulation SO IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL LA English DT Article DE connexins; tissue culture; mammary cells; cell proliferation; cell junctions ID MAMMARY-GLAND; INTERCELLULAR COMMUNICATION; DEVELOPMENTAL REGULATION; CONNEXIN EXPRESSION; PROTEIN EXPRESSION; TRANSFORMED-CELLS; HUMAN BREAST; RAT; DIFFERENTIATION; CONTACT AB LA7 rat mammary tumor cells stimulate the proliferation, in culture, of three normal epithelial cell types, namely mouse mammary, rat mammary, and mouse thymic cells. Cap-junctional communication between LA7 feeders and mouse mammary cells was demonstrated by microinjection of lucifer yellow, which traveled from LA7 to the surrounding mouse mammary cells. The amount of H-3-uridine exchange between feeder and recipient mouse mammary, rat mammary and mouse thymus cells correlated with the growth rate induced by the feeders. Cells of the Madin Darby canine kidney (MDCK) line, which do not appreciably stimulate mouse mammary cell growth when used as feeder cells, also exchange little H-3-uridine with them. Expression of connexins Cx43, 32, and 26 was studied in all these cell lines and strains by immunocytochemistry. Mouse mammary cells expressed Cx26, and a few mouse thymic cells expressed Cx32. LA7, mouse mammary, mouse thymic, and rat mammary cells all expressed easily detectable amounts of the gap-junction protein Cx43, in contrast to MDCK cells, which expressed only a hint of the protein. These results suggest that gap junctions composed of Cx43 are those by which the normal epithelial cells communicate with the LA feeders. Thus, the ability of feeder cells to stimulate proliferation in recipients correlates with the expression of Cx43 in both members of the feeder/recipient pair and the capacity to form functional gap junctions between these cells. C1 Vet Affairs Palo Alto Hlth Care Syst, Vet Affairs Med Ctr, Dept Pathol & Lab Serv, Palo Alto, CA 94304 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ehmann, UK (reprint author), Vet Affairs Palo Alto Hlth Care Syst, Vet Affairs Med Ctr, Dept Pathol & Lab Serv, 3801 Miranda Ave, Palo Alto, CA 94304 USA. NR 43 TC 3 Z9 3 U1 0 U2 0 PU SOC IN VITRO BIOLOGY PI LARGO PA 9315 LARGO DR WEST, STE 25, LARGO, MD 20774 USA SN 1071-2690 J9 IN VITRO CELL DEV-AN JI In Vitro Cell. Dev. Biol.-Anim. PD FEB PY 2001 VL 37 IS 2 BP 100 EP 110 PG 11 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 422WA UT WOS:000168141200009 ER PT J AU Balto, K Sasaki, H Stashenko, P AF Balto, K Sasaki, H Stashenko, P TI Interleukin-6 deficiency increases inflammatory bone destruction SO INFECTION AND IMMUNITY LA English DT Article ID BLOOD MONONUCLEAR-CELLS; ACUTE-PHASE RESPONSE; PERIAPICAL LESIONS; GENE-EXPRESSION; HUMAN-MONOCYTES; PARATHYROID-HORMONE; TRANSGENIC MICE; CYTOKINE GENES; IN-VIVO; IL-6 AB Periapical bone destruction occurs as a consequence of pulpal infection. In previous studies, we showed that interleukin-1 (IL-1) is the primary stimulator of bone destruction in this model. IL-6 is a pleiotropic cytokine that is induced in these infections and has both pro- and anti-inflammatory activities. In the present study, we determined the role of IL-6 in regulating IL-1 expression and bone resorption, The first molars of IL-6 knockouts (IL-6(-/-)) and wild-type mice were subjected to surgical pulp exposure and infection with a mixture of four common pulpal pathogens, including Prevotella intermedia, Fusobacterium nucleatum, Peptostreptococcus micros, and Streptococcus intermedius. Mice were killed after 21 days, and bone destruction and cytokine expression were determined, Surprisingly, bone destruction was significantly increased in IL-6(-/-) mire versus that in wild-type mice (by 30%; P < 0.001). In a second experiment, the effects of chronic (IL-6-/-) IL-6 deficiency and short-term IL-6 deficiency induced by in vivo antibody neutralization were determined, Both IL-6(-/-) (30%; P < 0.001) and anti-IL-6 antibody-treated mice (40%; P < 0.05) exhibited increased periapical bone resorption, compared to wild-type controls, The increased bone resorption in IL-6-deficient animals correlated with increases in osteoclast numbers, as well as with elevated expression of bone-resorptive cytokines IL-1 and IL-1 beta, in periapical lesions and with decreased expression of the anti-inflammatory cytokine IL-10, These data demonstrate that endogenous IL-6 expression has significant anti-inflammatory effects in modulating infection-stimulated bone destruction in vivo. C1 Forsyth Inst, Dept Cytokine Biol, Boston, MA 02115 USA. Harvard Univ, Sch Dent Med, Dept Endodont, Boston, MA 02115 USA. RP Stashenko, P (reprint author), Forsyth Inst, Dept Cytokine Biol, 140 Fenway, Boston, MA 02115 USA. FU NIDCR NIH HHS [DE-09018, DE-11664, R01 DE009018, R01 DE011664] NR 49 TC 71 Z9 73 U1 0 U2 3 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 FEB PY 2001 VL 69 IS 2 BP 744 EP 750 DI 10.1128/IAI.69.2.744-750.2001 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 394MW UT WOS:000166528700015 PM 11159963 ER PT J AU Loeb, M Bentley, DW Bradley, S Crossley, K Garibaldi, R Gantz, N McGeer, A Muder, RR Mylotte, J Nicolle, LE Nurse, B Paton, S Simor, AE Smith, P Strausbaugh, L AF Loeb, M Bentley, DW Bradley, S Crossley, K Garibaldi, R Gantz, N McGeer, A Muder, RR Mylotte, J Nicolle, LE Nurse, B Paton, S Simor, AE Smith, P Strausbaugh, L TI Development of minimum criteria for the initiation of antibiotics in residents of long-term-care facilities: Results of a consensus conference SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID NURSING-HOME PATIENTS; ASYMPTOMATIC BACTERIURIA; RESISTANT ENTEROCOCCI; DIAGNOSING PNEUMONIA; PHYSICAL-EXAMINATION; INFECTION-CONTROL; ANTIMICROBIAL USE; TRANSMISSION; COLONIZATION; THERAPY AB Establishing a clinical diagnosis of infection in residents of long-term-care facilities (LTCFs) is difficult. As a result, deciding when to initiate antibiotics can be particularly challenging. This article describes the establishment of minimum criteria for the initiation of antibiotics in residents of LTCFs. Experts in this area were invited to participate in a consensus conference. Using a modified delphi approach, a questionnaire and selected relevant articles were sent to participants who were asked to rank individual signs and symptoms with respect to their relative importance. Using the results of the weighting by participants, a modification of the nominal group process was used to achieve consensus. Criteria for initiating antibiotics for skin and soft-tissue infections, respiratory infections, urinary infections, and fever where the focus of infection is unknown were developed. C1 McMaster Univ, Div Infect Dis & Med Microbiol, Hamilton, ON, Canada. Hamilton Civ Hosp, Hamilton, ON, Canada. St Louis Univ, Sch Med, Dept Internal Med, St Louis, MO USA. St Louis Vet Affairs VA Med Ctr, Ctr Geriatr Res Educ & Clin, St Louis, MO USA. VA Med Ctr, GRECC, Ann Arbor, MI USA. VA Med Ctr, Educ Serv, Minneapolis, MN USA. Polyclin Med Ctr, Dept Med, Harrisburg, PA USA. Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. Mt Sinai Hosp, Dept Infect Control, Toronto, ON M5G 1X5, Canada. Univ Toronto, Toronto, ON, Canada. Univ Pittsburgh, Med Ctr, VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15260 USA. Erie Cty Med Ctr, Buffalo, NY USA. Univ Manitoba, Dept Med, Hlth Sci Ctr, Winnipeg, MB R3T 2N2, Canada. Hosp Special Care, New Britain, CT USA. Hlth Canada, Lab Ctr Dis Prevent & Control, Ottawa, ON K1A 0L2, Canada. Sunnybrook & Womens Coll, Hlth Sci Ctr, Toronto, ON, Canada. Univ Toronto, Toronto, ON, Canada. Univ Nebraska, Med Ctr, Omaha, NE USA. Portland VA Med Ctr, Portland, OR USA. RP Loeb, M (reprint author), Hamilton Hlth Sci Corp, 711 Concess St,Henderson Gen Hosp Site, Hamilton, ON L8V 1C3, Canada. RI mcgeer, allison /H-7747-2014 OI mcgeer, allison /0000-0001-5647-6137 NR 33 TC 145 Z9 147 U1 1 U2 10 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD FEB PY 2001 VL 22 IS 2 BP 120 EP 124 DI 10.1086/501875 PG 5 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 401NQ UT WOS:000166934300014 PM 11232875 ER PT J AU Collins, JF AF Collins, JF TI Stress and gut inflammation: The perception becomes reality SO INFLAMMATORY BOWEL DISEASES LA English DT Article C1 Portland VA Med Ctr, Dept Med, Portland, OR USA. RP Collins, JF (reprint author), Portland VA Med Ctr, Dept Med, Portland, OR USA. NR 1 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD FEB PY 2001 VL 7 IS 1 BP 80 EP 81 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 402VH UT WOS:000167008500017 ER PT J AU Shellito, PC AF Shellito, PC TI The ABCs of ileal pouch design SO INFLAMMATORY BOWEL DISEASES LA English DT Article C1 Massachusetts Gen Hosp, Colon & Rectal Surg Serv, Boston, MA 02114 USA. RP Shellito, PC (reprint author), Massachusetts Gen Hosp, Colon & Rectal Surg Serv, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD FEB PY 2001 VL 7 IS 1 BP 81 EP 81 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 402VH UT WOS:000167008500018 ER PT J AU Kishi, N Tang, ZY Maeda, Y Hirai, A Mo, R Ito, M Suzuki, S Nakao, K Kinoshita, T Kadesch, T Hui, CC Artavanis-Tsakonas, S Okano, H Matsuno, K AF Kishi, N Tang, ZY Maeda, Y Hirai, A Mo, R Ito, M Suzuki, S Nakao, K Kinoshita, T Kadesch, T Hui, CC Artavanis-Tsakonas, S Okano, H Matsuno, K TI Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis SO INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE LA English DT Article DE Deltex; Notch; neurogenesis; cell signaling; E47; C2C12 cell ID SPLIT COMPLEX GENES; EGF-LIKE REPEATS; DROSOPHILA-MELANOGASTER; XENOPUS-EMBRYOS; CELL FATE; INTRACELLULAR DOMAIN; RBP-J; NEURONAL DIFFERENTIATION; TRANSMEMBRANE PROTEIN; LATERAL INHIBITION AB Notch signaling plays an important role in cell-fate specification in multicellular organisms by regulating cell-cell communication. The Drosophila deltex gene encodes a modulator of the Notch pathway that has been shown to interact physically with the Ankyrin repeats of Notch. We isolated four distinct cDNAs corresponding to mouse homologs of deltex - mouse Deltex1 (MDTX1), mouse Deltex2 (MDTX2), mouse Deltex2 DeltaE (MDTX2 DeltaE), and mouse Deltex3 (MDTX3). Deduced amino acid sequences of these four cDNAs showed a high degree of similarity to Drosophila Deltex and its human homolog, DTX1 throughout their lengths, even though they possess distinct structural features. MDTX proteins formed homotypic and heterotypic multimers. We found that these genes were expressed in the central, peripheral nervous system and in the thymus, overlapping with those of mouse Notch1. In mammalian tissue culture cells, overexpression of any of the four mouse deltex homologs suppressed the transcriptional activity of E47, a basic helix-loop-helix (bHLH) protein: in a manner similar to suppression by an activated form of human Notch1 or human DTX1. In addition, overexpression of MDTX2 and MDTX2 DeltaE in C2C12 cells under differentiation-inducing conditions suppressed the expression of myogenin, one of the myogenic transcriptional factors; this was also similar to a previously reported activity of constitutively activated Notch. Furthermore, misexpression of any of the MDTX genes in Xenopus embryos resulted in an expansion of the region expressing the neural cell adhesion molecule (N-CAM) gene, a marker for the neuroepithelium. Collectively, our results suggest that these mouse deltex homologs are involved in vertebrate Notch signaling and regulation of neurogenesis. (C) 2001 ISDN. Published by Elsevier Science Ltd. All rights reserved. C1 Osaka Univ, Grad Sch Med, Biomed Res Ctr, Dept Neurosci,Div Neuroanat, Osaka 5650871, Japan. Univ Penn, Howard Hughes Med Inst, Philadelphia, PA 19104 USA. Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. Osaka Univ, Microbial Dis Res Inst, Dept Immunoregulat, Osaka 5650871, Japan. Kwansei Gakuin Univ, Fac Sci, Nishinomiya, Hyogo 6628501, Japan. Hosp Sick Children, Res Inst, Program Dev Biol, Toronto, ON M5G 1X8, Canada. Japan Sci & Technol Corp, Core Res Evolut Sci & Technol, Kawaguchi, Saitama 3320012, Japan. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Charlestown, MA 02129 USA. Keio Univ, Sch Med, Dept Physiol, Shinjuku Ku, Tokyo 1608582, Japan. RP Okano, H (reprint author), Osaka Univ, Grad Sch Med, Biomed Res Ctr, Dept Neurosci,Div Neuroanat, 2-2 Yamadaoka, Osaka 5650871, Japan. RI Kishi, Noriyuki/L-1379-2013; Hidokano, Hideyuki/J-5973-2013 NR 93 TC 55 Z9 61 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0736-5748 J9 INT J DEV NEUROSCI JI Int. J. Dev. Neurosci. PD FEB PY 2001 VL 19 IS 1 BP 21 EP 35 DI 10.1016/S0736-5748(00)00071-X PG 15 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 413KY UT WOS:000167612400003 PM 11226752 ER PT J AU Aarsland, D Cummings, JL Larsen, JP AF Aarsland, D Cummings, JL Larsen, JP TI Neuropsychiatric differences between Parkinson's disease with dementia and Alzheimer's disease SO INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Parkinson's disease; dementia; neuropsychiatric symptoms; Alzheimer's disease ID PROGRESSIVE SUPRANUCLEAR PALSY; EXPLICIT MEMORY; LEWY BODIES; HUNTINGTONS; IMPAIRMENT; DISORDERS; DIAGNOSIS; SYMPTOMS; SIGNS AB Objective. To compare the profile of neuropsychiatric symptoms in patients with Parkinson's disease with dementia (PDD) and patients with Alzheimer's disease (AD). Design. Cross-sectional survey of a population-based sample of patients with PDD and AD patients matched for age, sex, and Mini-Mental State Examination (MMSE) score. Method. Patients were diagnosed according to published criteria for PD and AD. The diagnosis of dementia in PD was made according to DSM-III-R, and was based on clinical interview of the patient and a relative, psychometric testing (including MMSE, Dementia Rating Scale and tests assessing memory, executive functions and visuospatial functioning) and physical examination. The Neuropsychiatric Inventory (NPI) was administered to all patients. Results. One or more psychiatric symptoms was reported in 95% of AD and 83% of PDD patients. Hallucinations were more severe in PD patients, while aberrant motor behavior, agitation, disinhibition, irritability, euphoria, and apathy were more severe in AD. In PDD, apathy was more common in mild Hoehn and Yahr stages, while delusions increased with more severe motor and cognitive disturbances. In PDD, only delusions correlated with the MMSE score. Conclusions. Neuropsychiatric symptoms are common and severe in patients with PDD, with important implications for the management of these patients. AD and PDD patients have different neuropsychiatric profiles, suggesting different underlying mechanisms. Cognitive impairment, psychopathology, and motor features progress independently in PDD patients Copyright (C) 2001 John Wiley Br Sons, Ltd. C1 Rogaland Psychiat Hosp, Geriatr Psychiat Serv, N-4095 Stavanger, Norway. Univ Calif Los Angeles, Sch Med, Dept Neurol, 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, Behav Neurosci Sect, Psychiat Serv, Los Angeles, CA 90073 USA. Rogaland Psychiat Hosp, Dept Neurol, N-4095 Stavanger, Norway. RP Aarsland, D (reprint author), Rogaland Psychiat Hosp, Geriatr Psychiat Serv, PO 1163 Hillevag, N-4095 Stavanger, Norway. OI Aarsland, Dag/0000-0001-6314-216X FU NIA NIH HHS [AG 16570] NR 43 TC 77 Z9 80 U1 1 U2 6 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0885-6230 J9 INT J GERIATR PSYCH JI Int. J. Geriatr. Psychiatr. PD FEB PY 2001 VL 16 IS 2 BP 184 EP 191 DI 10.1002/1099-1166(200102)16:2<184::AID-GPS304>3.0.CO;2-K PG 8 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 401RC UT WOS:000166941200009 PM 11241724 ER PT J AU Verma, S Orengo, CA Kunik, ME Hale, D Molinari, VA AF Verma, S Orengo, CA Kunik, ME Hale, D Molinari, VA TI Tolerability and effectiveness of atypical antipsychotics in male geriatric inpatients SO INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE olanzapine; risperidone; geriatric; psychosis; tolerability AB Background. The atypical antipsychotics are gradually becoming the mainstay of treatment for psychosis in the elderly. The present study examines the effectiveness and tolerability of risperidone and olanzapine treatment in 34 matched male patients admitted to a VA Medical Center geriatric inpatient unit. Methods. The Positive and Negative Syndrome Scale for Schizophrenia (PANSS), the Cohen-Mansfield Agitation Inventory (CMAI), the Rating Scale for Side-Effects, the Extra-Pyramidal Rating Scale, and the Mini-Mental State Examination were administered at admission and discharge. Results. T-tests at admission and discharge across groups indicate that the patients as a whole were performing significantly better following their stay on the CMAI (t(30)=4.31, p=0.000), the GAF (t(31)=9.73, p=0.000), the PANSS total score (t(29)=3.82, p=0.001), and the positive symptom portion of the PANSS (t(28)=4.29, p=0.000). Conclusions. No significant differences were detected between the two groups with regard to length of hospitalization, or reduction in scores on the PANSS, or CMAI, however the daily cost of risperidone was 1/3 as much as olanzapine (p=0.00). The two treatments were comparable in the elderly men evaluated in this study. Copyright (C) 2001 John Wiley & Sons, Ltd. C1 Baylor Coll Med, Dept Psychiat & Behav Sci, Houston, TX 77030 USA. Houston Vet Affairs Med Ctr, Psychiat Serv, Houston, TX USA. Vet Integrated Serv Network 16, Mental Illness Res Educ & Clin Ctr, New York, NY USA. VAMC, Houston Ctr Qual Care & Utilizat Studies, Houston, TX USA. Univ Houston, Houston, TX USA. VAMC, Psychiat Serv, Houston, TX USA. RP Orengo, CA (reprint author), Baylor Coll Med, Dept Psychiat, 1 Baylor Plaza, Houston, TX 77030 USA. NR 14 TC 16 Z9 17 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0885-6230 J9 INT J GERIATR PSYCH JI Int. J. Geriatr. Psychiatr. PD FEB PY 2001 VL 16 IS 2 BP 223 EP 227 DI 10.1002/1099-1166(200102)16:2<223::AID-GPS323>3.0.CO;2-R PG 5 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 401RC UT WOS:000166941200014 PM 11241729 ER PT J AU Newton, TL Bane, CMH AF Newton, TL Bane, CMH TI Cardiovascular correlates of behavioral dominance and hostility during dyadic interaction SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Article DE cardiovascular reactivity; dominance; hostility; dyadic interaction ID CORONARY HEART-DISEASE; SOCIAL SUPPORT; CONTESTED DOMINANCE; REACTIVITY; RESPONSES; HEALTH; MODEL; PSYCHOPHYSIOLOGY; PRESSURE; SEVERITY AB The present study examined cardiovascular correlates of expression of, and exposure to, naturally occurring behavioral dominance and hostility during dyadic social interaction. Unacquainted men and women undergraduates participated in three mixed-gender interactions with the same partner while their blood pressure and heart rate were assessed. Videotaped records of the interactions were coded for behavioral dominance and hostility. Exposure effects were apparent for women's systolic blood pressure and men's heart rate, with significantly greater reactivity shown by participants whose partners exhibited more dominance or hostility, respectively. Also, women's expression of dominance was positively and significantly associated with their heart rate reactivity. In addition to providing further evidence that emotion-related features of the social environment contribute to cardiovascular reactivity, these results illustrate that dominance merits attention as a correlate of cardiac stress reactivity, independent of hostility. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Boston Univ, Sch Med, Boston Vet Adm Med Ctr, Natl Ctr PTSD,Women Hlth Sci Div, Boston, MA 02130 USA. Univ Miami, Miami, FL 33152 USA. RP Newton, TL (reprint author), Boston Univ, Sch Med, Boston Vet Adm Med Ctr, Natl Ctr PTSD,Women Hlth Sci Div, 150 S Huntington Ave, Boston, MA 02130 USA. NR 47 TC 15 Z9 15 U1 5 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD FEB PY 2001 VL 40 IS 1 BP 33 EP 46 DI 10.1016/S0167-8760(00)00124-0 PG 14 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 397FY UT WOS:000166683700003 PM 11166106 ER PT J AU Pruschy, M Rocha, S Zaugg, K Tenzer, A Hess, C Fisher, DE Glanzmann, C Bodis, S AF Pruschy, M Rocha, S Zaugg, K Tenzer, A Hess, C Fisher, DE Glanzmann, C Bodis, S TI Key targets for the execution of radiation-induced tumor cell apoptosis: The role of p53 and caspases SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article; Proceedings Paper CT 1st International Conference on Translational Research and Pre-Clinical Strategies in Clinical Radio-Oncology (ICTR 2000) CY MAR 05-08, 2000 CL LUGANO, SWITZERLAND SP NCI, Radiat Res Soc, Amer Coll Radiol, European ch Oncol, European Org Res & Treatment Canc, Swiss League Against Canc DE apoptosis; p53; caspase; tumor cell ID ANTICANCER AGENTS; CANCER-THERAPY; IN-VIVO; P53-DEPENDENT APOPTOSIS; MUTANT P53; DEATH; GENE; ACTIVATION; INHIBITION; MECHANISMS AB In many human hematologic and solid malignancies, intrinsic or acquired treatment resistance remains a major obstacle for successful cancer therapy, The molecular understanding of how tumor cells respond to chemotherapy and ionizing radiation is rapidly evolving, Induction of programmed cell death, apoptosis, is one important strategy Fur successful canter therapy. This has been shown convincingly for oncogene-transformed normal cells as well as tumor cells of lymphoid origin. However, the relevance of apoptosis in solid human malignancies is less clear. Loss of apoptosis might be linked to specific mutations in the often tissue-specific apoptotic pathways due to aberrations in the stress-related signal transduction cascades. Restoration of a dysfunctional apoptotic program In cancer tissue where apoptosis has been identified as an important mechanism for tissue homeostasis is one rational approach for innovative cancer therapy, In this review, we focus on the relevance of the tumor suppressor p53 for apoptosis-induction and successful cancer therapy outlining the importance of an intact caspase machinery for apoptosis execution. Strategies are discussed to overcome treatment resistance acid a high apoptotic threshold in human malignancies where apoptosis is the dominant mode of cell death acid the status of p53 is an important determinant for apoptosis induction. (C) 2001 Elsevier Science Inc. C1 Univ Zurich Hosp, Dept Radiat Oncol, CH-8091 Zurich, Switzerland. ETH Zurich, Dept Biochem, CH-8092 Zurich, Switzerland. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Bodis, S (reprint author), Univ Zurich Hosp, Dept Radiat Oncol, Ramistr 100, CH-8091 Zurich, Switzerland. OI Rocha, Sonia/0000-0002-2413-4981 NR 48 TC 27 Z9 30 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 FEB 1 PY 2001 VL 49 IS 2 BP 561 EP 567 DI 10.1016/S0360-3016(00)01480-2 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 397QV UT WOS:000166707700035 PM 11173155 ER PT J AU Chae, JH Nahas, Z Li, XB George, MS AF Chae, JH Nahas, Z Li, XB George, MS TI Transcranial magnetic stimulation in psychiatry: research and therapeutic applications SO INTERNATIONAL REVIEW OF PSYCHIATRY LA English DT Article ID HUMAN MOTOR CORTEX; RESISTANT MAJOR DEPRESSION; RTMS IMPROVES MOOD; PREFRONTAL CORTEX; NEUROPSYCHIATRIC TOOL; SCHIZOPHRENIA; EXCITABILITY; EPILEPSY; TMS; RESPONSES AB Transcranial magnetic stimulation (TMS) is a new, non-invasive procedure where a localized pulsed magnetic field to the surface of the head depolarizes underlying superficial neurons. The magnetic field is generated by passing powerful, brief electrical currents through a conducting coil, held close to the scalp. This electrically generated magnetic field passes unimpeded through the skull (transcranial) and is focused in the cortex (stimulation). The earliest research uses of TMS were in neurology, where TMS was used to examine central and peripheral nerve conduction as well as to study motor cortex. More recently, this technology has been widely used to map various brain functions such as visual information processing, language, memory, emotion, and movement. The ability to excite or inhibit local areas of the brain has raised the possibility of whether TMS might be a novel therapeutic tool for various psychiatric disorders. Here we review the methodology of TMS and its emerging research and therapeutic applications in psychiatry. C1 Catholic Univ Korea, Dept Psychiat, Seoul, South Korea. Med Univ S Carolina, Dept Psychiat, Charleston, SC USA. Med Univ S Carolina, Dept Radiol, Charleston, SC USA. Med Univ S Carolina, Dept Neurol, Charleston, SC USA. Ralph H Johnson Vet Hosp, Charleston, SC USA. RP Chae, JH (reprint author), Med Univ S Carolina, Inst Psychiat & Behav Sci, Funct Neuroimaging Div, POB 250861,Room 502 N,67 President St, Charleston, SC 29425 USA. NR 63 TC 2 Z9 2 U1 1 U2 4 PU CARFAX PUBLISHING PI BASINGSTOKE PA RANKINE RD, BASINGSTOKE RG24 8PR, HANTS, ENGLAND SN 0954-0261 J9 INT REV PSYCHIATR JI Int. Rev. Psych. PD FEB PY 2001 VL 13 IS 1 BP 18 EP 23 DI 10.1080/09540260020024150 PG 6 WC Psychiatry SC Psychiatry GA 415AV UT WOS:000167699100004 ER PT J AU Kumari, S Bhol, KC Simmons, RK Razzzaque, MS Letko, E Foster, CS Ahmed, AR AF Kumari, S Bhol, KC Simmons, RK Razzzaque, MS Letko, E Foster, CS Ahmed, AR TI Identification of ocular cicatricial Pemphigoid antibody binding site(s) in human beta 4 integrin SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID CELL-ADHESION; EPIDERMOLYSIS-BULLOSA; EXTRACELLULAR-MATRIX; CYTOPLASMIC DOMAIN; MONONUCLEAR-CELLS; PASSIVE TRANSFER; SUBUNIT; AUTOANTIBODIES; ANTIGEN; DISEASES AB PURPOSE. To identify specific site(s) on human beta4 molecule to which sera from ocular cicatricial pemphigoid (OCP) patients bind and to determine its role in the process of blister formation. METHODS. Clone the fragments representing the extracellular and intracellular domain of beta4 molecule from normal human conjunctival mRNA into an expression vector; map the region to which sera from OCP patients bind by Western blot analysis. Determine the role of the immunodominant region in pathogenesis by demonstrating the ability of the rabbit antibody to the immunodominant region to produce separation of basement membrane zone (BMZ) from the basal epithelial layer when incubated with normal human conjunctiva in an in vitro organ culture model. RESULTS. Majority of the OCP sera tested bound to the C-terminal end of the intracellular domain IC3.0 of the human beta4 integrin. Further subcloning of IC3.0 demonstrated that a smaller fragment extending from 1489 aa to 1572 aa (IC3.4) was responsible for this binding. This region may have multiple antibody binding sites. Antibody to human IC3.0 and IC3.4 produced in rabbit, resulted in BMZ separation, histologically identical with that observed when normal human conjunctiva was cultured with OCP sera in an human conjunctival organ culture model. CONCLUSIONS. These observations identify IC3.4 as the antibody binding site for sera of OCP patients and suggest a possible role for it in blister formation. Indirectly it highlights certain important aspects of the structural and functional dynamics of the biology of the hemidesmosomes and basement membranes. C1 Harvard Univ, Sch Dent Med, Dept Oral Med & Diagnost Sci, Boston, MA 02115 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Immunol & Uveitis Serv, Boston, MA 02115 USA. RP Razzzaque, MS (reprint author), Harvard Univ, Sch Dent Med, Dept Oral Med & Diagnost Sci, 188 Longwood Ave, Boston, MA 02115 USA. FU NEI NIH HHS [EY08379] NR 48 TC 28 Z9 29 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD FEB PY 2001 VL 42 IS 2 BP 379 EP 385 PG 7 WC Ophthalmology SC Ophthalmology GA 401NG UT WOS:000166933300012 PM 11157870 ER PT J AU Woodward, AL Spergel, JM Alenius, H Mizoguchi, E Bhan, AK Castigli, E Brodeur, SR Oettgen, HC Geha, RS AF Woodward, AL Spergel, JM Alenius, H Mizoguchi, E Bhan, AK Castigli, E Brodeur, SR Oettgen, HC Geha, RS TI An obligate role for T-cell receptor alpha beta T+ cells but not T-cell receptor gamma delta T+ cells, B cells, or CD40/CD40L interactions in a mouse model of atopic dermatitis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE atopic dermatitis; alpha beta T cells; gamma delta T cells; B cells; CD40L; CD40 ID INFLAMMATORY RESPONSES; ALLERGIC DERMATITIS; IMMUNE-RESPONSE; IN-SITU; MICE; CD40; LYMPHOCYTES; HYPERRESPONSIVENESS; AEROALLERGEN; EXPRESSION AB Background: We recently described a murine model of atopic dermatitis (AD) elicited by epicutaneous sensitization with ovalbumin (OVA). The skin lesions in these mice were characterized by a dermal infiltrate consisting of eosinophils and T cells and by increased expression of the T(H)2 cytokines IL-4 and IL-5. Epicutaneous sensitization induces a rise in the levels of serum total IgE and OVA-specific antibodies, further indicating that it elicits a predominantly T(H)2 response. Objective: This study was undertaken to assess the roles of T cells, B cells, and CD40L-CD40 interactions in AD. Methods: Mice with targeted gene deletions were sensitized with OVA. Histologic and immunohistochemical examinations, as well as measurements of IL-4 mRNA, were performed on OVA-sensitized skin. Total and antigen-specific serum IgE levels were determined. Results: RAG2(-/-) mice, which lack both T and B cells, did not exhibit cellular infiltration, induction of dermal IL-4 mRNA, or elevation of serum IgE after OVA sensitization: all of these features were present in B-cell-deficient IgH(-/-) mice. T-cell receptor alpha (-/-) mice did not display cellular infiltration, IL-4 mRNA expression, or increased IgE levels after OVA sensitization, but these responses were elicited in T-cell receptor delta (-/-) mice after sensitization. Absence of CD40 had no effect on these responses. Conclusion: These results suggest that alpha beta T cells, but not gamma delta T cells, B cells, or CD40L-CD40 interactions, are critical for skin inflammation and the T(H)2 response in AD. C1 Harvard Univ, Childrens Hosp, Sch Med, Div Immunol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Pathol, Immunopathol Unit, Boston, MA 02114 USA. RP Geha, RS (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Div Immunol, Enders 8,300 Longwood Ave, Boston, MA 02115 USA. FU NIAID NIH HHS [AI-31136, AI-31541, AI-42202] NR 28 TC 39 Z9 42 U1 0 U2 2 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 FEB PY 2001 VL 107 IS 2 BP 359 EP 366 DI 10.1067/mai.2001.112695 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 403YV UT WOS:000167071400025 PM 11174205 ER PT J AU Alenius, HT Laouini, D Woodward, A Mizoguchi, E Bhan, AK Castigli, E Oettgen, HC Geha, RS AF Alenius, HT Laouini, D Woodward, A Mizoguchi, E Bhan, AK Castigli, E Oettgen, HC Geha, RS TI Mast cells regulate expression of cytokines and levels of circulating IgE in allergen induced skin inflammation SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Childrens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 777 BP S236 EP S237 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300773 ER PT J AU Bannert, N Farzan, M Ochi, H Price, K Sodroski, J Boyce, JA AF Bannert, N Farzan, M Ochi, H Price, K Sodroski, J Boyce, JA TI Infection of human mast cell progenitors by HIV-1 SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 925 BP S282 EP S283 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300921 ER PT J AU Clark, S Brenner, BE Cydulka, RK Gaeta, TJ Bock, SA Camargo, CA AF Clark, S Brenner, BE Cydulka, RK Gaeta, TJ Bock, SA Camargo, CA TI Multicenter study of emergency department visits for food allergy SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Brooklyn Hosp Ctr, Brooklyn, NY USA. Case Western Reserve Univ, Metrohlth Med Ctr, Cleveland, OH USA. Methodist Hosp, Brooklyn, NY USA. Boulder Valley Asthma & Allergy Clin, Boulder, CO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 649 BP S196 EP S196 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300645 ER PT J AU Keahey, L Bulloch, B Becker, A Pollack, CV Clark, S Camargo, CA AF Keahey, L Bulloch, B Becker, A Pollack, CV Clark, S Camargo, CA TI Oxygen saturation as a predictor of admission in children presenting to the emergency department with acute asthma SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Childrens Hosp, Winnipeg, MB R3A 1S1, Canada. Maricopa Med Ctr, Phoenix, AZ USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 750 BP S228 EP S228 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300746 ER PT J AU Nguyen, ADK Sanchez, H AF Nguyen, ADK Sanchez, H TI Expression of an Alt a 1 subunit in Pichia pastoris SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 William S Middleton Mem Vet Hosp, Madison, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 69 BP S20 EP S21 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300070 ER PT J AU Nguyen, R Yusin, J Klaustermeyer, WB Katz, RM AF Nguyen, R Yusin, J Klaustermeyer, WB Katz, RM TI Hypersensitivity reaction to allopurinol: Successful skin testing and desensitization SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Univ Calif Los Angeles Hosp, W Los Angeles VA, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 29 BP S9 EP S9 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300030 ER PT J AU Pivniouk, V Swat, W Snapper, S Alt, F Geha, RS AF Pivniouk, V Swat, W Snapper, S Alt, F Geha, RS TI Impaired signaling via the high affinity IgE receptor in Vav deficient and WASP efficient mast cells SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Childrens Hosp, Boston, MA 02115 USA. Howard Hughes Med Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 487 BP S148 EP S148 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300486 ER PT J AU Sanchez, H AF Sanchez, H TI Pulmonary responses in an animal model of Alternaria sensitivity SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 William S Middleton Mem Vet Hosp, Madison, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 173 BP S50 EP S50 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300173 ER PT J AU Yu, FC Gibbon, GW Klaustermeyer, WB AF Yu, FC Gibbon, GW Klaustermeyer, WB TI Severe refractory atopic dermatitis responsive to a short course of low-dose cyclosporin SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Greater Los Angeles VA Med Ctr, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2001 VL 107 IS 2 SU S MA 252 BP S75 EP S75 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 405RE UT WOS:000167172300252 ER PT J AU Muratoglu, OK Bragdon, CR O'Connor, DO Jasty, M Harris, WH AF Muratoglu, OK Bragdon, CR O'Connor, DO Jasty, M Harris, WH TI A novel method of cross-linking ultra-high-molecular-weight polyethylene to improve wear, reduce oxidation, and retain mechanical properties - Recipient of the 1999 HAP Paul Award SO JOURNAL OF ARTHROPLASTY LA English DT Article DE cross-linking; ultra-high-molecular-weight polyethylene; wear; oxidation resistance; mechanical properties ID UHMWPE; JOINTS AB Increasing cross-linking has been shown in vitro and in vivo to improve markedly the wear resistance of ultra-high-molecular-weight polyethylene (UHMWPE). The reduction in the mechanical properties of polyethylene under certain methods used to produce cross-linking has been a concern, however. These reductions are known to result from the processes used to increase the cross-link density and could affect the device performance in vivo. We present a novel method of increasing the cross-link density of UHMWPE in which UHMWPE is irradiated in air at art elevated temperature with a high-dose-rate electron beam and subsequently is melt-annealed. This treatment improves markedly the wear resistance of the polymer as tested in a hip simulator, while maintaining the mechanical properties of the material within national and international standards. This method leads to the absence of delectable free radicals in the polymer and, as a result, excellent resistance to oxidation of the polymer. C1 Massachusetts Gen Hosp, Orthopaed Biomech & Biomat Lab, Boston, MA 02114 USA. RP Muratoglu, OK (reprint author), Massachusetts Gen Hosp, Orthopaed Biomech & Biomat Lab, GRJ 1206, Boston, MA 02114 USA. NR 39 TC 360 Z9 368 U1 5 U2 47 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 FEB PY 2001 VL 16 IS 2 BP 149 EP 160 DI 10.1054/arth.2001.20540 PG 12 WC Orthopedics SC Orthopedics GA 400PA UT WOS:000166879600002 PM 11222887 ER PT J AU Lee, EW Kim, HT AF Lee, EW Kim, HT TI Early fatigue failures of cemented, forged, cobalt-chromium femoral stems at the neck-shoulder junction SO JOURNAL OF ARTHROPLASTY LA English DT Article DE hip arthroplasty; femoral component; fracture; laser arching ID TOTAL HIP-REPLACEMENT; COMPONENT; FRACTURE AB Femoral component fracture is a rare bur well-documented complication after total hip arthroplasty, Historically, most stem fractures have occurred at the middle third of the implant, where proximal stem loosening and solid distal stem fixation result in cantilever bending and eventual fatigue failure. In contrast, we report 2 early fatigue failures of well-positioned, well-fixed, cemented, forged, cobalt-chromium femoral components at the neck-shoulder junction. A contributing factor to the implant failures was heavy laser etching in a region of the implant subjected to high stresses, leading to decreased fatigue resistance and subsequent fracture. C1 Univ Calif San Francisco, San Francisco VA Med Ctr, Orthopaed Surg Sect, San Francisco, CA 94143 USA. RP Kim, HT (reprint author), 4150 Clement St, San Francisco, CA 94121 USA. NR 8 TC 27 Z9 28 U1 1 U2 5 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 FEB PY 2001 VL 16 IS 2 BP 236 EP 238 DI 10.1054/arth.2001.20542 PG 3 WC Orthopedics SC Orthopedics GA 400PA UT WOS:000166879600016 PM 11222901 ER PT J AU Beversdorf, DQ Anderson, JM Manning, SE Anderson, SL Nordgren, RE Felopulos, GJ Bauman, ML AF Beversdorf, DQ Anderson, JM Manning, SE Anderson, SL Nordgren, RE Felopulos, GJ Bauman, ML TI Brief report: Macrographia in high-functioning adults with autism spectrum disorder SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE autism; Asperger syndrome; motor control; handwriting ID ASPERGER SYNDROME; MICROGRAPHIA; INFARCTION; DISEASE AB The initial description of Asperger syndrome commented on the poor handwriting and motor coordination difficulties of individuals with this condition. Early descriptions of autism do not remark upon such difficulties. Recent evidence, however, suggests that individuals with both conditions have a similar motor control impairment. Handwriting has not been formally assessed in this context. Our study compared handwriting size between individuals with autism spectrum disorder and age- and IQ-matched control subjects. Macrographia was observed among subjects with autism spectrum disorder which remained statistically significant when covaried with educational level. This finding may correlate with the anatomical abnormalities present in the cerebellum of individuals with autism spectrum disorder. C1 Ohio State Univ, Ctr Med, Dept Neurol, Columbus, OH 43210 USA. Massachusetts Gen Hosp, NMR Ctr, Boston, MA 02114 USA. Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. Dartmouth Hitchcock Med Ctr, Dept Pediat, Lebanon, NH 03756 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pediat Neurol, Boston, MA 02114 USA. RP Beversdorf, DQ (reprint author), Ohio State Univ, Ctr Med, Dept Neurol, 1654 Upham Dr, Columbus, OH 43210 USA. RI Beversdorf, David/M-2786-2016 OI Beversdorf, David/0000-0002-0298-0634 NR 26 TC 23 Z9 24 U1 0 U2 4 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD FEB PY 2001 VL 31 IS 1 BP 97 EP 101 DI 10.1023/A:1005622031943 PG 5 WC Psychology, Developmental SC Psychology GA 445WC UT WOS:000169480700011 PM 11439759 ER PT J AU Gensler, TJ Hottelet, M Zhang, CH Schlossman, S Anderson, P Utz, PJ AF Gensler, TJ Hottelet, M Zhang, CH Schlossman, S Anderson, P Utz, PJ TI Monoclonal antibodies derived from BALB/c mice immunized with apoptotic Jurkat T cells recognize known autoantigens SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE apoptosis; autoantibodies; autoimmunity; SLE ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; 28S RIBOSOMAL-RNA; INTERMEDIATE FILAMENTS; RHEUMATIC DISEASES; GRANZYME-B; PROTEIN; AUTOANTIBODIES; KERATINOCYTES; LYMPHOCYTES; VIMENTIN AB It has been postulated that post-translational modifications and relocalization of proteins during apoptosis may lead to presentation of these molecules to the immune system in such a way that normal mechanisms of tolerance are bypassed. In the present study, Jurkat cells were induced to undergo apoptosis by treatment with the chemotherapeutic agent Ara-C. BALB/c mice were then immunized with the apoptotic cells and hybridomas were generated. Using an indirect immunofluorescence assay, the monoclonal antibodies produced were screened by flow cytometry for those monoclonal antibodies demonstrating reactivity with permeabilized apoptotic Jurkat cells but not with non permeabilized normal or apoptotic Jurkat cells. Of 281 monoclonal antibodies, 20 monoclonal antibodies with these properties were selected for further analysis. Using P-32- or S-35-metabolically labelled Jurkat cells, these selected monoclonal antibodies were screened for their ability to recognize autoantigens by immunoprecipitation and Western blotting. Well characterized autoimmune sera were then used to confirm the identity of autoantigens by immunoblotting. We demonstrate that immunization of normal mice with apoptotic Jurkat cells results in the formation of antibodies targeting multiple autoantigens or autoantigen complexes, including Ku, rRNPs, snRNPs and vimentin. These findings are consistent with the hypothesis that apoptosis can contribute to the development of autoimmunity. (C) 2001 Academic Press. C1 Stanford Univ, Sch Med, Div Rheumatol & Immunol, Dept Med, Stanford, CA 94305 USA. Brigham & Womens Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Med, Div Tumor Immunol, Boston, MA 02115 USA. RP Utz, PJ (reprint author), Stanford Univ, Sch Med, Div Rheumatol & Immunol, Dept Med, CCSR Bldg,Room 2215-A,300 Pasteur Dr, Stanford, CA 94305 USA. FU NCI NIH HHS [CA67929]; NIAID NIH HHS [AI33600, AI12069, K0AI01521]; NIAMS NIH HHS [T32 AR07530] NR 49 TC 31 Z9 31 U1 0 U2 3 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD FEB PY 2001 VL 16 IS 1 BP 59 EP 69 DI 10.1006/jaut.2000.0464 PG 11 WC Immunology SC Immunology GA 404CG UT WOS:000167079400007 PM 11221997 ER PT J AU Brandon, LD Goldberg, MB AF Brandon, LD Goldberg, MB TI Periplasmic transit and disulfide bond formation of the autotransported Shigella protein IcsA SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ACTIN-BASED MOTILITY; ESCHERICHIA-COLI; INTERCELLULAR SPREAD; FLEXNERI VIRULENCE; DSBA; SECRETION; IDENTIFICATION; LOCALIZATION; SEQUENCE; CLEAVAGE AB The Shigella outer membrane protein IcsA belongs to the family of type V secreted (autotransported) virulence factors. Members of this family mediate their own translocation across the bacterial outer membrane: the carboxy-terminal beta domain forms a beta barrel channel in the outer membrane through which the amino-terminal OL domain passes. IcsA, which is localized at one pole of the bacterium, mediates actin assembly by Shigella, which is essential for bacterial intracellular movement and intercellular dissemination. Here, we characterize the transit of IcsA across the periplasm during its secretion. We show that an insertion in the dsbB gene, whose gene product mediates disulfide bond formation of many periplasmic intermediates, does not affect the surface expression or unipolar targeting of IcsA. However, IcsA forms one disulfide bond in the periplasm in a DsbA/DsbB-dependent fashion. Furthermore, cellular fractionation studies reveal that IcsA has a transient soluble periplasmic intermediate. Our data also suggest that IcsA is folded in a proteinase K-resistant state in the periplasm, From these data, we propose a novel model for the secretion of IcsA that may be applicable to other autotransported proteins. C1 Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Goldberg, MB (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 55 Fruit St,GRJ504, Boston, MA 02114 USA. FU NIAID NIH HHS [AI35817, R01 AI035817] NR 32 TC 71 Z9 73 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD FEB PY 2001 VL 183 IS 3 BP 951 EP 958 DI 10.1128/JB.183.3.951-958.2001 PG 8 WC Microbiology SC Microbiology GA 393FX UT WOS:000166459500019 PM 11208794 ER PT J AU Hood, JK Hwang, WW Silver, PA AF Hood, JK Hwang, WW Silver, PA TI The Saccharomyces cerevisiae cyclin Clb2p is targeted to multiple subcellular locations by cis- and trans-acting determinants SO JOURNAL OF CELL SCIENCE LA English DT Article DE Saccharomyces cerevisiae; cyclins; Clb2p; bud tip; bud neck; nuclear localization ID NUCLEAR-PROTEIN EXPORT; RAN-BINDING-PROTEIN; YEAST-CELL CYCLE; GENE-PRODUCT; BUDDING YEAST; G1 CYCLINS; RNA-EXPORT; S-PHASE; LOCALIZATION; MITOSIS AB The cyclin-dependent kinase Cdc28p associates with the cyclin Clb2p to induce mitosis in the yeast Saccharomyces cerevisiae. Several cell cycle regulatory proteins have been shown to require specific nuclear transport events to exert their regulatory functions, Therefore, we investigated the subcellular localization of wild-type Clb2p and several mutant versions of the protein using green fluorescent protein (GFP) fusion constructs. Wild-type Clb2p is primarily nuclear at all points of the cell. A point mutation in a potential leucine-rich nuclear export signal (NES) enhances the nuclear localization of the protein, and Delta yrb2 cells exhibit an apparent Clb2p nuclear export defect. Clb2p contains a bipartite nuclear localization signal (NLS), and its nuclear Localization requires the alpha and beta importins (Srp1p and Kap95p), as well as the yeast Ran GTPase and its regulators. Deletion of the Clb2p NLS causes increased cytoplasmic. localization of the protein, as well as accumulation at the bud neck. These data indicate that Clb2p exists in multiple places in the yeast cell, possibly allowing Cdc28p to locally phosphorylate substrates at distinct subcellular sites. C1 Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Silver, PA (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA09362] NR 39 TC 42 Z9 43 U1 0 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD FEB PY 2001 VL 114 IS 3 BP 589 EP 597 PG 9 WC Cell Biology SC Cell Biology GA 404EL UT WOS:000167084400013 PM 11171327 ER PT J AU Graham, SH Chen, J AF Graham, SH Chen, J TI Programmed cell death in cerebral ischemia SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Review DE AIF; bcl-2; caspases; Fas; mitochondria ID INTERLEUKIN-1-BETA CONVERTING-ENZYME; APOPTOSIS-INDUCING FACTOR; HIPPOCAMPAL CA1 NEURONS; TRAUMATIC BRAIN INJURY; CYTOCHROME-C RELEASE; GLOBAL-ISCHEMIA; CAENORHABDITIS-ELEGANS; ARTERY OCCLUSION; RAT-BRAIN; BCL-X AB Programmed cell death (PCD) is an ordered and tightly controlled set of changes in gene expression and protein activity that results in neuronal cell death during brain development. This article reviews the molecular pathways by which PCD is executed in mammalian cells and the potential relation of these pathways to pathologic neuronal cell death. Whereas the classical patterns of apoptotic morphologic change often do not appear in the brain after ischemia, there is emerging biochemical and pharmacologic evidence suggesting a role for PCD in ischemic brain injury. The most convincing evidence for the induction of PCD after ischemia includes the altered expression and activity in the ischemic brain of deduced key death-regulatory genes. Furthermore, studies have shown that alterations in the activity of these gene products by peptide inhibitors, viral vector-mediated gene transfer. antisense oligonucleotides, or transgenic mouse techniques determine, at least in part, whether ischemic neurons live or die after stroke. These studies provide strong support for the hypothesis that PCD contributes to neuronal cell death caused by ischemic injury. However, many questions remain regarding the precise pathways that initiate, sense, and transmit cell death signals in ischemic neurons and the molecular mechanisms by which neuronal cell death is executed at different stages of ischemic injury. Elucidation of these pathways and mechanisms may lead to the development of novel therapeutic strategies for brain injury after stroke and related neurologic disorders. C1 Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15213 USA. Vet Affairs Pittsburgh Hlth Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. RP Graham, SH (reprint author), Univ Pittsburgh, Sch Med, Dept Neurol, 526 S BST, Pittsburgh, PA 15213 USA. FU NINDS NIH HHS [NS37459, NS35965, NS36736] NR 85 TC 332 Z9 368 U1 2 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD FEB PY 2001 VL 21 IS 2 BP 99 EP 109 DI 10.1097/00004647-200102000-00001 PG 11 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 399XK UT WOS:000166839400001 PM 11176275 ER PT J AU White, KE Jonsson, KB Carn, G Hampson, G Spector, TD Mannstadt, M Lorenz-Depiereux, B Miyauchi, A Yang, IM Ljunggren, O Meitinger, T Strom, TM Juppner, H Econs, MJ AF White, KE Jonsson, KB Carn, G Hampson, G Spector, TD Mannstadt, M Lorenz-Depiereux, B Miyauchi, A Yang, IM Ljunggren, O Meitinger, T Strom, TM Juppner, H Econs, MJ TI The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ONCOGENIC OSTEOMALACIA; HORMONE AB The gene mutated in autosomal dominant hypophosphatemic rickets (ADHR), a phosphate wasting disorder, has been identified as FGF-23, a protein that shares sequence homology with fibroblast growth factors (FGFs). Patients with ADHR display many of the clinical and laboratory characteristics that are observed in patients with oncogenic hypophosphatemic osteomalacia (OHO), a disorder thought to arise by the secretion of a phosphate wasting factor from different mesenchymal tumors. In the present studies, we therefore investigated whether FGF-23 is a secreted factor and whether it is abundantly expressed in OHO tumors. After transient transfection of OK-E, COS-7, and HEK293 cells with the plasmid encoding full-length FGF-23, all three cell lines efficiently secreted two protein species into the medium that were approximately 32 and 12 kDa upon SDS-PAGE and subsequent Western blot analysis using an affinity-purified polyclonal antibody to FGF-23. Furthermore, Northern blot analysis using total RNA from five different OHO tumors revealed extremely high levels of FGF-23 mRNA, and Western blot analysis of extracts from a sixth tumor detected the 32 kDa FGF-23 protein species. In summary, FGF-23, the gene mutated in ADHR, is a secreted protein and its mRNA is abundantly expressed by several different OHO tumors. Our findings indicate that FGF-23 may be a candidate phosphate wasting factor, previously designated "phosphatonin". C1 Indiana Univ, Sch Med, Dept Med, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. Massachusetts Gen Hosp, MassGen Hosp Children, Endocrine Unit, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. St Thomas Hosp, Twin Res Unit, London SE1 7EH, England. St Thomas Hosp, Dept Chem Pathol, London SE1 7EH, England. Univ Munich, Klinikum Innenstadt, Abt Med Genet, D-80336 Munich, Germany. Kobe Univ, Sch Med, Dept Med, Kobe, Hyogo 650, Japan. Natl Sanatorium Hyogo Chuo Hosp, Sanda 6691515, Japan. Univ Uppsala, Dept Med Sci, S-75185 Uppsala, Sweden. Kuyunghee Univ, Dept Internal Med, Seoul, South Korea. RP Econs, MJ (reprint author), Indiana Univ, Sch Med, Dept Med, Indianapolis, IN 46202 USA. EM mecons@iupui.edu RI Spector, Tim/F-6533-2012; Meitinger, Thomas/O-1318-2015 NR 13 TC 217 Z9 224 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2001 VL 86 IS 2 BP 497 EP 500 DI 10.1210/jc.86.2.497 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 402TU UT WOS:000167004900008 PM 11157998 ER PT J AU Rietschel, P Hadigan, C Corcoran, C Stanley, T Neubauer, G Gertner, J Grinspoon, S AF Rietschel, P Hadigan, C Corcoran, C Stanley, T Neubauer, G Gertner, J Grinspoon, S TI Assessment of growth hormone dynamics in human immunodeficiency virus-related lipodystrophy SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PROTEASE INHIBITORS; INSULIN-RESISTANCE; OBESE SUBJECTS; ZUCKER RATS; FACTOR-I; SECRETION; MEN; PYRIDOSTIGMINE; GH; RESPONSIVENESS AB Human immunodeficiency virus (HIV) lipodystrophy (LIPO) is characterized by increased visceral adiposity, peripheral fat atrophy, dyslipidemia, and insulin resistance. GH concentrations are known to vary inversely with excess weight and body fat but have not been investigated in HIV lipodystrophy. Twenty-one subjects with HIV LIPO, 20 HIV-infected nonlipodystrophy subjects (NONLIPO), and 20 control (C) subjects were prospectively recruited for this study and compared. Subjects in the three groups were all male, age-matched [median, 47 yr old (interquartile range, 37-50) LIPO; 41 (37-44) NONLIPO; and 43 (37-49) C], and body mass index matched [median, 24.3 kg/m(2) (interquartile range, 22.2-26.6) LIPO; 24.4 (23.3-25.9) NONLIPO; and 24.8 (22.7-26.1) C] (P > 0.05 for all comparisons). Visceral abdominal fat [16,124 mm(2) (11,246 -19,790) LIPO; 7,559 (5,134-11,201) NONLIPO; and 8,803 (6,165-11,623) C; P < 0.01 LIFO vs. NONLIPO and LIFO vs. C] and the ratio of visceral abdominal fat to sc abdominal fat [1.37 (0.71-2.44) LIPO vs. 0.57 (0.47-0.78) NONLIPO vs. 0.55 (0.41-0.71) C, P < 0.01 LIPO vs. NONLIPO and LIPO vs. C] were significantly increased in the LIPO subjects but were not significantly different between NONLIPO and C. The mean overnight GH concentration, determined from frequent sampling every 20 min (from 2000 h to 0800 h) was decreased in the LIFO subjects [0.38 mug/L (0.13-0.67) LIFO vs. 0.96 (0.53-1.30) NONLIPO us. 0.81 (0.49-1.03) C, P < 0.05 LIFO vs. NONLIPO and LIFO vs. C] and not significantly different between NONLIPO and C. Pulse analysis demonstrated decreased baseline GH [0.08 g/L (0.06-0.21) LIPO vs. 0.19 (0.10-0.32) NONLIPO vs. 0.17 (0.12-0.57) C, P < 0.05 LIFO vs. NONLIPO and LIFO vs. C] and GH peak amplitude [1.06 g/L (0.46-1.94) LIFO vs. 2.47 (1.22-3.43) NONLIPO and 2.27 (1.36-4.25) C, P < 0.05 LIPO vs. NONLIPO and LIFO vs. C] in the LIFO subjects but no significant difference in pulse frequency. No significant differences were observed between NONLIPO and C for any GH parameter. Insulin-like growth factor-I was not different between the groups. Total body fat (r = -0.40, P = 0.01) and visceral fat (r = -0.58, P = 0.0001) correlated inversely with mean overnight GH concentrations in the HIV-infected patients. In a multivariate regression model, controlling for age, body mass index, body fat, and visceral fat, only visceral fat was a significant predictor of mean GH concentrations (P = 0.0036, r(2) for model = 0.40). These data demonstrate normal GH pulse frequency and insulinlike growth factor-I concentrations but reduced mean GH concentrations, basal GH concentrations, and GH pulse amplitude in patients with HIV lipodystrophy. Increased visceral adiposity is the strongest predictor of reduced GH concentrations in HIV lipodystrophy. Further studies are necessary to determine the clinical significance of reduced GH in patients with HIV lipodystrophy. C1 Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Gen Clin Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Serono Labs Inc, Norwell, MA 02061 USA. RP Grinspoon, S (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Bulfinch 457B, Boston, MA 02114 USA. EM sgrinspoon@partners.org FU NCRR NIH HHS [M01-RR-01066]; NIDDK NIH HHS [P32-DK-07028] NR 30 TC 121 Z9 122 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2001 VL 86 IS 2 BP 504 EP 510 DI 10.1210/jc.86.2.504 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 402TU UT WOS:000167004900010 PM 11158000 ER PT J AU Leder, BZ Smith, MR Fallon, MA Lee, MLT Finkelstein, JS AF Leder, BZ Smith, MR Fallon, MA Lee, MLT Finkelstein, JS TI Effects of gonadal steroid suppression on skeletal sensitivity to parathyroid hormone in men SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID BONE-MINERAL DENSITY; POSTMENOPAUSAL WOMEN; TOTAL 1,25-DIHYDROXYVITAMIN-D; CIRCULATING FREE; HYPOGONADAL MEN; ESTROGEN; INTERLEUKIN-6; OSTEOPOROSIS; EXPRESSION; NAFARELIN AB Hypogonadism is associated with osteoporosis in men. GnRH-agonist-induced hypogonadism increases bone turnover and bone loss in men, but the mechanism underlying these changes is unknown. To determine whether gonadal steroid deprivation increases the skeletal sensitivity to PTH or blunts the ability of PTH to promote 1,25-dihydroxyvitamin D formation, we infused human PTH-(1-34) at a dose of 0.55 U/kg.h for 24 h, in 11 men (ages, 50-82 yr) with locally advanced, node-positive, or biochemically recurrent prostate cancer but no evidence of bone metastases. PTH infusions were performed before initiation of GnRH agonist therapy (leuprolide acetate, 22.5 mg im, every 3 months) and again after 6 months of confirmed GnRH agonist-induced hypogonadism. Serum osteocalcin (OC), bone-specific alkaline phosphatase (BSAP), N-telopeptide (NTX), whole-blood ionized calcium, and 1,25-dihydroxyvitamin D were measured at baseline and every 6 h during each PTH infusion. Urinary NTX and free deoxypyridinoline (DPD) were assessed on spot morning samples before PTH infusion and on 24-h samples collected during the PTH infusions. Sex steroid levels were lowered to the castrate range in all subjects. Baseline serum NTX levels (drawn before PTH infusion) increased from 9.1 +/- 3.7 before leuprolide therapy to 13.9 +/- 5.0 nmol bone collagen equivalents (BCE)/L after leuprolide therapy (P = 0.003). Spot urine NTX collected before PTH infusion increased from 28 +/- 8 before leuprolide therapy to 49 +/- 17 nmol BCE/mmol creatinine after leuprolide therapy (P < 0.001), and urinary DPD increased from 4.7 +/- 1.1 to 7.4 +/- 1.8 nmol BCE/mmol creatinine (P < 0.001). Baseline serum OC and BSAP levels drawn before each PTH infusion did not change before us. after leuprolide therapy. Serum NTX levels increased significantly during PTH infusion pre-GnRH agonist therapy (P < 0.001), and the rate of increase was greater after 6 months of GnRH agonist-induced hypogonadism (P < 0.01 for the difference in rates of change before and after GnRH agonist administration). Serum OC and BSAP levels decreased during PTH infusion (P < 0.001 for OC and P = 0.002 for BSAP), but the rates of decrease did not differ before or after leuprolide therapy (P = 0.45 for OC and P = 0.19 far BSAP). Whole-blood ionized calcium levels increased during PTH infusion (P < 0.001), and the rate of increase was greater after GnRH agonist-induced hypogonadism (P = 0.068). Serum 1,25-dihydroxyvitamin D levels increased in response to PTH infusion before leuprolide therapy (P = 0.022), but there was no difference in the rate of increase before or after leuprolide therapy (P = 0.66). The incremental increase in urinary NTX excretion, but not DPD, during PTH infusion was greater after 6 months of leuprolide therapy (P = 0.029 for NTX, P = 0.578 for DPD). We conclude that suppression of sex steroids in elderly men increases the skeletal responsiveness to the bone resorbing effects of PTH infusion but does not affect the response of bone formation markers or 1,25-dihydroxyvitamin D to PTH. Changes in skeletal sensitivity to PTH may play an important role in the pathogenesis of hypogonadal bone loss in men. C1 Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Hematol Oncol Unit, Boston, MA 02114 USA. Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. RP Leder, BZ (reprint author), Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA 02114 USA. EM bleder@partners.org FU NCRR NIH HHS [5M01-RR-1066-20, RR-1066]; NIDDK NIH HHS [K24-DK-02759] NR 36 TC 37 Z9 39 U1 1 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2001 VL 86 IS 2 BP 511 EP 516 DI 10.1210/jc.86.2.511 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 402TU UT WOS:000167004900011 PM 11158001 ER PT J AU Wilkinson, CW Petrie, EC Murray, SR Colasurdo, EA Raskind, MA Peskind, ER AF Wilkinson, CW Petrie, EC Murray, SR Colasurdo, EA Raskind, MA Peskind, ER TI Human glucocorticoid feedback inhibition is reduced in older individuals: Evening study SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PITUITARY-ADRENAL AXIS; DEXAMETHASONE SUPPRESSION TEST; CORTISOL SUPPRESSION; PLASMA-CORTISOL; CIRCADIAN RHYTHMICITY; NORMAL VOLUNTEERS; RAT-BRAIN; AGE; GENDER; ADRENOCORTICOTROPIN AB We have previously shown that when tested in the morning, older men and women, pretreated with metyrapone to block endogenous cortisol synthesis, exhibit delayed suppression of plasma ACTH in response to cortisol infusion. To confirm this finding and to determine whether aging-related changes in feedback responsiveness are exaggerated near the time of the circadian nadir in adrenocortical secretion, we performed a similar study in the evening. Healthy young (20-35 yr, n = 22) and old (>65 yr, n = 21) men and women were administered metyrapone orally (750 mg) at 1600 and 1900 h, followed by a cortisol infusion of 0.06 mg/kg/h for 150 min. Blood samples were taken at 15-min intervals for 4 h following infusion onset for measurement of plasma ACTH, cortisol, 11-deoxycortisol, and corticosteroid binding globulin. When corrections were made for differences in circulating cortisol concentrations achieved among age and gender subgroups, feedback inhibition of ACTH was found to be significantly greater in young than in old subjects of both genders. Our studies support the hypothesis that glucocorticoid responses to stress in aging individuals are likely to be prolonged due to blunted and delayed inhibition of ACTH secretion, thus increasing the total exposure to glucocorticoids. C1 VA Puget Sound Hlth Care Syst, GRECC 182B, Seattle, WA 98108 USA. VA Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA 98108 USA. Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Wilkinson, CW (reprint author), VA Puget Sound Hlth Care Syst, GRECC 182B, 1660 S Columbian Way, Seattle, WA 98108 USA. EM wilkinso@u.washington.edu NR 50 TC 65 Z9 66 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2001 VL 86 IS 2 BP 545 EP 550 DI 10.1210/jc.86.2.545 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 402TU UT WOS:000167004900017 PM 11158007 ER PT J AU Miller, KK Sesmilo, G Schiller, A Schoenfeld, D Burton, S Klibanski, A AF Miller, KK Sesmilo, G Schiller, A Schoenfeld, D Burton, S Klibanski, A TI Androgen deficiency in women with hypopituitarism SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GROWTH-HORMONE DEFICIENCY; BONE-MINERAL DENSITY; PLASMA-CONCENTRATIONS; POSTMENOPAUSAL WOMEN; ADRENAL ANDROGEN; ADULT PATIENTS; GH DEFICIENCY; SEX STEROIDS; TESTOSTERONE; MEN AB Androgen deficiency in men is associated with severe osteopenia, alterations in body composition including an increase in fat mass, and decreased libido. Little is known about the pathophysiology, metabolic consequences, or gender-specific effects of androgen deficiency in women. Acquired hypopituitarism in women is characterized by central hypogonadism and/or hypoadrenalism and therefore may affect critical sources of androgen production in women. We hypothesized that serum androgen levels would be decreased in women with hypopituitarism. We therefore determined serum androgen levels in 55 women with hypopituitarism and 92 controls. This included 4 subsets of hypopituitary women: 1) women less than 50 yr old not receiving estrogen, 2) women less than 50 yr old receiving estrogen, 3) women more than 50 yr old not receiving estrogen, and 4) women more than 50 yr old receiving estrogen. Premenopausal controls with regular menstrual cycles were studied in the early follicular phase, midcycle, and luteal phase during one cycle. All other subjects were studied 3 times during the month at comparable intervals to mimic these 3 time points of the normal menstrual cycle. Serum testosterone, fr-ee testosterone, androstenedione, and dehydroepiandrosterone sulfate levels were markedly reduced in all 4 groups of women with hypopituitarism compared with controls (P < 0.0001). Moreover, serum testosterone, free testosterone, and androstenedione levels were lower in women with central hypoadrenalism and hypogonadism than in subjects with hypoadrenalism or hypogonadism alone (P < 0.025). Mean DHEAS levels were decreased in hypopituitary women with both hypogonadism and hypoadrenalism compared with those in women with hypogonadism alone (P < 0.0001). These data demonstrate hypoandrogenemia in women with hypopituitarism. The physiological consequences of low androgen levels in this population remain to be determined. C1 Massachusetts Gen Hosp, Neuroendocrine Unit, Dept Med, Clin Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Klibanski, A (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Dept Med, Clin Res Ctr, Bulfinch 457B, Boston, MA 02114 USA. EM aklibanski@partners.org FU NCRR NIH HHS [M01-RR-01066] NR 44 TC 74 Z9 76 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2001 VL 86 IS 2 BP 561 EP 567 DI 10.1210/jc.86.2.561 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 402TU UT WOS:000167004900019 PM 11158009 ER PT J AU Gipson, IK Moccia, R Spurr-Michaud, S Argueso, P Gargiulo, AR Hill, JA Offner, GD Keutmann, HT AF Gipson, IK Moccia, R Spurr-Michaud, S Argueso, P Gargiulo, AR Hill, JA Offner, GD Keutmann, HT TI The amount of MUC5B mucin in cervical mucus peaks at midcycle SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID VON-WILLEBRAND FACTOR; MOLECULAR-CLONING; CHROMOSOMAL LOCALIZATION; GENOMIC ORGANIZATION; SIALOMUCIN COMPLEX; TERMINAL SEQUENCE; HUMAN ENDOCERVIX; GASTRIC MUCIN; IDENTIFICATION; GENES AB The physical character and amount of mucus secreted by the endocervix changes dramatically during the menstrual cycle to facilitate sperm migration at the time of midcycle ovulation. Mucins are highly glycosylated, high-molecular-weight proteins, which are the major structural components of the protective mucus gel covering all wet-surfaced epithelia, including that of the endocervix. We have previously demonstrated that the endocervical epithelium expresses messenger RNA (mRNA) of three of the large gel-forming mucins, designated MUC5AC, MUC5B, and MUC6, with mRNA of MUC5B predominating. Because mucin protein levels may be regulated posttranscriptionally, measurement of MUC5B protein levels with cycle are needed for correlation to mRNA levels. Measurement of specific mucin gene products within mucus secretions has been limited by availability of specific, well-characterized antibodies and by volume requirements of the isolation protocols for mucins, which include CsCl density centrifugation and fraction isolation. To measure MUC5B protein within the cervical mucus through the hormone cycle, we developed a polyclonal antibody specific to the mucin. The antibody, designated no. 799, is to a synthetic peptide mimicking a 19-amino-acid segment of an intercysteine-rich region within the D4 domain in the 3' region of the MUC5B protein. It recognizes native as well as denatured MUC5B on immunoblot, is preadsorbable with its peptide, and binds to apical secretory vesicles of epithelia expressing MUC5B. We used the MUC5B antibody along with a cervical mucin standard cervical mucin isolate in enzyme-linked immunosorbent assay to determine the relative amount of MUC5B mucin in samples of human cervical mucus taken through the menstrual cycle. We demonstrate a peak of MUC5B mucin in human cervical mucus collected at midcycle, compared with mucus from early or late in the cycle. This peak in MUC5B content coincides with the change in mucus character that occurs at midcycle, suggesting that this large mucin species may be important to sperm transit to the uterus. C1 Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Boston Univ, Med Ctr, Boston, MA 02118 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Gipson, IK (reprint author), Harvard Univ, Sch Med, Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM gipson@vision.eri.harvard.edu FU NICHD NIH HHS [R01-HD-33171] NR 50 TC 59 Z9 60 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2001 VL 86 IS 2 BP 594 EP 600 DI 10.1210/jc.86.2.594 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 402TU UT WOS:000167004900024 PM 11158014 ER PT J AU Hadigan, C Meigs, JB Rabe, J D'Agostino, RB Wilson, PWF Lipinska, I Tofler, GH Grinspoon, S AF Hadigan, C Meigs, JB Rabe, J D'Agostino, RB Wilson, PWF Lipinska, I Tofler, GH Grinspoon, S TI Increased PAI-1 and tPA antigen levels are reduced with metformin therapy in HIV-infected patients with fat redistribution and insulin resistance SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; GLUCOSE-TOLERANCE; CARDIOVASCULAR RISK; DISEASE; TISSUE AB Cardiovascular disease (CVD) risk associated with fat redistribution seen among HIV-infected individuals remains unknown, but: may be increased due to hyperlipidemia, hyperinsulinemia, increased visceral adiposity, and a prothrombotic state associated with these metabolic abnormalities. In this study we characterized plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPA) antigen levels, markers of fibrinolysis and increased CVD risk, in HIV lipodystrophic patients compared to controls. Furthermore, we investigated the effect of treatment with metformin on PAI-1 and tPA antigen levels in patients with HIV-associated fat redistribution. Eighty-six patients age 43+/-1 yr, BMI 26.1+/-0.5 kg/m(2)) with HIV and fat redistribution were compared to 258 age- and BMI-matched subjects from the Framingham Offspring study. In addition, 25 HIV-infected patients with fat redistribution and fasting insulin > 15 muU/mL [104 pmol/L] or impaired glucose tolerance, but without diabetes mellitus were enrolled in a placebo-controlled treatment study of metformin 500mg twice dairy. PAI-1 and tPA antigen levels were significantly increased in patients with HIV related fat redistribution compared to Framingham control subjects (46.1+/-1.4 vs 18.9+/-0.9 mug/L PAI-1, 16.6+/-0.8 vs. 8.0+/-0.3 mug/L tPA, P=0.0001). Among patients with HIV infection, a multivariate regression analysis including age, sex, waist-to-hip ratio, BMI, smoking status, protease inhibitor use and insulin area under the curve (AUC), found gender and insulin AUC were significant predictors of tPA antigen. Twelve weeks of metformin treatment resulted in decreased tPA antigen levels (-1.9+/-1.4 vs +1.4+/-1.0 mug/L in the placebo-treated group P=0.02). Similarly, metformin resulted in improvement in PAI-1 levels (-8.7+/-2.3 vs +1.7+/-2.9 mug/L, P=0.03). Change in insulin AUC correlated significantly with change in tPA antigen (r=0.43, P=0.03). PAI-1 and tPA antigen, markers of impaired fibrinolysis and increased CVD risk, are increased in association with hyperinsulinemia in patients with HIV and fat redistribution. Metformin reduces PAI-1 and tPA antigen concentrations in these patients and may ultimately improve associated CVD risk. C1 Massachusetts Gen Hosp, Neuroendocrine Unit, Div Gen Med, Boston, MA 02114 USA. Framingham Heart Study, Boston, MA USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Hadigan, C (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Div Gen Med, 55 Fruit St, Boston, MA 02114 USA. FU NCRR NIH HHS [M01-RR3000088]; NIDDK NIH HHS [K23-DK02844, R01-DK59535] NR 21 TC 106 Z9 110 U1 1 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2001 VL 86 IS 2 BP 939 EP 943 DI 10.1210/jc.86.2.939 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 402TU UT WOS:000167004900082 PM 11158071 ER PT J AU Letvin, NL Walker, BD AF Letvin, NL Walker, BD TI HIV versus the immune system: another apparent victory for the virus SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID CYTOTOXIC T-LYMPHOCYTES; ANTIRETROVIRAL THERAPY; VIREMIA; INFECTION; MEMORY; RESPONSES; EFFECTOR; ANTIGEN; CELLS; PROSTITUTES C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Partner AIDS Res Ctr, Boston, MA 02129 USA. Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Boston, MA 02215 USA. RP Walker, BD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Partner AIDS Res Ctr, 149 13th St,Room 5212D, Boston, MA 02129 USA. NR 24 TC 8 Z9 8 U1 0 U2 1 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 FEB PY 2001 VL 107 IS 3 BP 273 EP 275 DI 10.1172/JCI12174 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 399XR UT WOS:000166840000007 PM 11160150 ER PT J AU Calvi, LM Sims, NA Hunzelman, JL Knight, MC Giovannetti, A Saxton, JM Kronenberg, HM Baron, R Schipani, E AF Calvi, LM Sims, NA Hunzelman, JL Knight, MC Giovannetti, A Saxton, JM Kronenberg, HM Baron, R Schipani, E TI Activated parathyroid hormone/parathyroid hormone-related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID (PTH)/PTH-RELATED PEPTIDE RECEPTOR; PRIMARY HYPERPARATHYROIDISM; OSTEOPROGENITOR CELLS; FIBROUS DYSPLASIA; EXPRESSION; MICE; HISTOMORPHOMETRY; PROLIFERATION; RATS; CHONDRODYSPLASIA AB Parathyroid hormone (PTH), an important regulator of calcium homeostasis, targets most of its complex actions in bone to cells of the osteoblast lineage. Furthermore, PTH is known to stimulate osteoclastogenesis indirectly through activation of osteoblastic cells. To assess the role of the PTH/PTH-related protein receptor (PPR) in mediating the diverse actions of PTH on bone in vivo, we generated mice that express, in cells of the osteoblastic lineage, one of the the constitutively active re ccp tors described in Jansen's metaphyseal chondrodysplasia. In these transgenic mice, osteoblastic function was increased in the trabecular and endosteal compartments, whereas it was decreased in the periosteum. In trabecular bone of the transgenic mice, there was an increase in osteoblast precursors, as well as in mature osteoblasts. Osteoblastic expression of the constitutively active PPR induced a dramatic increase in osteoclast number in both trabecular and compact bone in transgenic animals. The net effect of these actions was a substantial increase in trabecular bone volume and a decrease in cortical bone thickness of the long bones, These findings, for the first time to our knowledge, identify the PPR as a crucial mediator of both bone-forming and bone-resorbing actions of PTH, and they underline the complexity and heterogeneity of the osteoblast population and/or their regulatory microenvironment. C1 Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Yale Univ, Sch Med, New Haven, CT USA. RP Schipani, E (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St, Boston, MA 02114 USA. OI Calvi, Laura Maria/0000-0001-6969-239X FU NIAMS NIH HHS [AR-44855, AR-45354, P50 AR044855]; NIDDK NIH HHS [DK-07028, F32 DK060317, F32 DK060317-01, T32 DK007028] NR 31 TC 211 Z9 215 U1 0 U2 4 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 FEB PY 2001 VL 107 IS 3 BP 277 EP 286 DI 10.1172/JCI11296 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 399XR UT WOS:000166840000008 PM 11160151 ER PT J AU Chung, UI Schipani, E McMahon, AP Kronenberg, HM AF Chung, UI Schipani, E McMahon, AP Kronenberg, HM TI Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID HORMONE-RELATED PEPTIDE; PARATHYROID-HORMONE; SONIC-HEDGEHOG; BLOMSTRAND-CHONDRODYSPLASIA; INACTIVATING MUTATION; POLARIZING ACTIVITY; RECEPTOR; GENE; DIFFERENTIATION; EXPRESSION AB Vertebrate skeletogenesis requires a well-coordinated transition from chondrogenesis to osteogenesis. Hypertrophic chondrocytes in the growth plate play a pivotal role in this transition. Parathyroid hormone-related peptide (PTHrP), synthesized in the periarticular growth plate, regulates the site at which hypertrophy occurs. By comparing PTH/PTHrP recepfor(-/-)/wild-type (PPR-/-/wild-type) chimeric mice with Ihh(-/-);PPR-/-/wild-type chimeric and Ihh(-/-)/wild-type chimeric mice, we provide in vivo evidence that Indian hedgehog(Ihh), synthesized by prehypertrophic and hypertrophic chondrocytes, regulates the site of hypertrophic differentiation by signaling to the periarticular growth plate and also determines the site of hone collar formation in the adjacent perichondrium. By providing crucial local signals from prehypertrophic and hypertrophic chondrocytes to both chondrocytes and preosteoblasts, Ihh couples chondrogenesis to osteogenesis in endochondral bone development. C1 Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. RP Kronenberg, HM (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Wellman 503, Boston, MA 02114 USA. FU NIDDK NIH HHS [P01 DK056246, P01 DK56246] NR 33 TC 242 Z9 249 U1 1 U2 8 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 FEB PY 2001 VL 107 IS 3 BP 295 EP 304 DI 10.1172/JCI11706 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 399XR UT WOS:000166840000010 PM 11160153 ER PT J AU Ludwig, DS Tritos, NA Mastaitis, JW Kulkarni, R Kokkotou, E Elmquist, J Lowell, B Flier, JS Maratos-Flier, E AF Ludwig, DS Tritos, NA Mastaitis, JW Kulkarni, R Kokkotou, E Elmquist, J Lowell, B Flier, JS Maratos-Flier, E TI Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID NEUROPEPTIDE-Y; FEEDING-BEHAVIOR; LEPTIN; GENE; HYPOTHALAMUS; HYPERPHAGIA; PATHWAYS; PEPTIDES; POMC; RATS AB Several lines of investigation suggest that the hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates body weight in mammals. Obese mice lacking functional leptin overexpress the MCH message in the fed or fasted state. Acute intracerebroventricular injection of MCH increases energy intake in rats. Mice lacking the MCH gene are lean. To test the hypothesis that chronic overexpression of MCH in mice causes obesity we produced transgenic mice that overexpress MCH (MCH-OE) in the lateral hypothalamus at approximately twofold higher levels than normal mice. On the FVB genetic background, homozygous transgenic animals fed a high-fat diet ate 10% more and were 12% heavier at 13 weeks of age than wild-type animals, and they had higher systemic leptin levels. Blood glucose levels were higher both preprandially and after an intraperitoneal glucose injection. MCH-OE animals were insulin-resistant, as demonstrated by markedly higher plasma insulin levels and a blunted response to insulin; MCH-OE animals had only a 5% decrease in blood glucose after insulin administration, compared with a 31% decrease in wild-type animals. MCH-OE animals also exhibited a twofold increase in islet size. To evaluate the contribution of genetic background to the predisposition to obesity seen in MCH-OE mice, the transgene was bred onto the C57BL/6J background. Heterozygote C57BL/6J mice expressing the transgene showed increased body weight on a standard diet, confirming that MCH overexpression can lead to obesity. C1 Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. Childrens Hosp, Dept Med, Boston, MA 02115 USA. Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA. RP Maratos-Flier, E (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [1K08 DK-02440, DK-09825, F32 DK009825, P01 DK056116, R01 DK-56113, R01 DK-56116] NR 28 TC 426 Z9 443 U1 0 U2 11 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 FEB PY 2001 VL 107 IS 3 BP 379 EP 386 DI 10.1172/JCI10660 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 399XR UT WOS:000166840000019 PM 11160162 ER PT J AU Yano, K Brown, LF Detmar, M AF Yano, K Brown, LF Detmar, M TI Control of hair growth and follicle size by VEGF-mediated angiogenesis SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID VASCULAR-PERMEABILITY FACTOR; DERMAL PAPILLA CELLS; TRANSGENIC MICE; FACTOR VPF/VEGF; TUMOR-CELLS; EXPRESSION; SKIN; INHIBITOR; RECEPTORS; OVEREXPRESSION AB The murine hair follicle undergoes pronounced cyclic expansion and regression, leading to rapidly changing demands for its vascular support. Our study aimed to quantify the cyclic changes of perifollicular vascularization and to characterize the biological role of VEGF for hair growth, angiogenesis, and follicle cycling. We found a significant increase in perifollicular vascularization during the growth phase (anagen) of the hair cycle, followed by regression of angiogenic blood vessels during the involution (catagen) and the resting (telogen) phase. Perifollicular angiogenesis was temporally and spatially correlated with upregulation of VEGF mRNA expression by follicular keratinocytes of the outer root sheath, but not by dermal papilla cells. Transgenic overexpression of VEGF in outer root sheath keratinocytes of hair follicles strongly induced perifollicular vascularization, resulting in accelerated hair regrowth after depilation and in increased size of hair follicles and hair shafts. Conversely, systemic treatment with a neutralizing anti-VEGF antibody led to hair growth retardation and reduced hair follicle size. No effects of VEGF treatment or VEGF blockade were observed in mouse vibrissa organ cultures, which lack a functional vascular system. These results identify VEGF as a major mediator of hair follicle growth and cycling and provide the first direct evidence that improved follicle vascularization promotes hair growth and increases hair follicle and hair size. C1 Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Dept Dermatol, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA USA. Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Detmar, M (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Dept Dermatol, Bldg 149,13th St, Charlestown, MA 02129 USA. FU NCI NIH HHS [CA-69184, CA-86410, R01 CA069184, R01 CA086410] NR 48 TC 196 Z9 226 U1 0 U2 14 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 FEB PY 2001 VL 107 IS 4 BP 409 EP 417 DI 10.1172/JCI11317 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 403YY UT WOS:000167071700005 PM 11181640 ER PT J AU Nucci, M Akiti, T Barreiros, G Silveira, F Revankar, SG Sutton, DA Patterson, TF AF Nucci, M Akiti, T Barreiros, G Silveira, F Revankar, SG Sutton, DA Patterson, TF TI Nosocomial fungemia due to Exophiala jeanselmei var. jeanselmei and a Rhinocladiella species: Newly described causes of bloodstream infection SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID AMBULATORY PERITONEAL-DIALYSIS; CATHETER-ASSOCIATED FUNGEMIA; DERMATITIDIS; PATIENT; FUNGI; PATHOGENS AB Fungi have become increasingly important causes of nosocomial bloodstream infections. The major cause of nosocomial fungemia has been Candida spp, but increasingly molds and other yeasts have caused disease. Exophiala jeanselmei and members of the genus Rhinocladiella are dematiaceous moulds, which have been infrequently associated with systemic infection and have not been described as causes of fungemia. In this paper, the occurrence of 23, cases of fungemia due to these organisms over a 10-month period is reported and the clinical characteristics of patients and outcomes are described. The majority of patients were immunosuppressed; 21 of 23 (91%) had received blood products and 78% had a central venous catheter, All patients had at least one manifestation of fever, but only one patient had signs or symptoms suggesting deep-seated infection. Antifungal therapy was given to 19 of the 23 patients; of those who did not receive therapy, 3 died prior to the culture result and 1 had been discharged without therapy. Antifungal susceptibility of the organisms showed activity of amphotericin B, itraconazole, and the new triazole antifungals voriconazole and posaconazole. E. jeanselmei and Rhinocladiella species are potential causes of nosocomial fungemia and may be associated with systemic infection. C1 Univ Fed Rio de Janeiro, Hosp Univ Clementino Fraga Filho, Mycol Lab, BR-21941 Rio De Janeiro, Brazil. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78284 USA. S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA. RP Nucci, M (reprint author), Univ Fed Rio de Janeiro, Hosp Univ Clementino Fraga Filho, Mycol Lab, Av Brigadeiro Trompovsky S-N, BR-21941 Rio De Janeiro, Brazil. RI Nucci, Marcio/G-4515-2012 OI Nucci, Marcio/0000-0003-4867-0014 NR 31 TC 37 Z9 39 U1 0 U2 2 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 FEB PY 2001 VL 39 IS 2 BP 514 EP 518 DI 10.1128/JCM.39.2.514-518.2001 PG 5 WC Microbiology SC Microbiology GA 398VA UT WOS:000166776100015 PM 11158099 ER PT J AU Korzets, A Weinberger, M Chagnac, A Goldschmied-Reouven, A Rinaldi, MG Sutton, DA AF Korzets, A Weinberger, M Chagnac, A Goldschmied-Reouven, A Rinaldi, MG Sutton, DA TI Peritonitis due to Thermoascus taitungiacus (anamorph Paecilomyces taitungiacus) SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID FUNGAL PERITONITIS; VARIOTII INFECTION; FILAMENTOUS FUNGI; DIALYSIS; PATIENT; LILACINUS; IDENTIFICATION; TAIWAN; MOLD AB The first case of human disease due to the thermophilic ascomycete Thermoascus taitungiacus (the teleomorph of Paecilomyces taitungiacus) is presented. T. taitungiacus was recovered from four dialysate fluid specimens of a 57-year-old patient undergoing chronic peritoneal dialysis. Identification was based upon cylindrical conidia, reddish orange nonostiolate ascomata, lack of growth at 20 degreesC, thermotolerance, and ascospores that appeared pale yellow, elliptical, thick walled, and predominately echinulate by light microscopy but irregularly verrucose by scanning electron microscopy. C1 Rabin Med Ctr, Dept Internal Med & Infect Dis C, IL-49100 Petah Tiqwa, Israel. Rabin Med Ctr, Dept Nephrol, IL-49100 Petah Tiqwa, Israel. Chaim Sheba Med Ctr, Mycol Unit, IL-52621 Tel Hashomer, Israel. Tel Aviv Univ, Sackler Sch Med, Ramat Aviv, Israel. S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA. Univ Texas, Hlth Sci Ctr, Dept Pathol, Fungus Testing Lab, San Antonio, TX 78284 USA. RP Weinberger, M (reprint author), Rabin Med Ctr, Dept Internal Med & Infect Dis C, Beilinson Campus, IL-49100 Petah Tiqwa, Israel. NR 29 TC 7 Z9 8 U1 0 U2 2 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 FEB PY 2001 VL 39 IS 2 BP 720 EP 724 DI 10.1128/JCM.39.2.720-724.2001 PG 5 WC Microbiology SC Microbiology GA 398VA UT WOS:000166776100050 PM 11158134 ER PT J AU Backstrand, KH Ng, AK Takvorian, RW Jones, EL Fisher, DC Molnar-Griffin, BJ Silver, B Tarbell, NJ Mauch, PM AF Backstrand, KH Ng, AK Takvorian, RW Jones, EL Fisher, DC Molnar-Griffin, BJ Silver, B Tarbell, NJ Mauch, PM TI Results of a prospective trial of mantle irradiation alone for selected patients with early-stage Hodgkins's disease SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CONTROLLED CLINICAL-TRIALS; PROGNOSTIC FACTORS; ANTIBODY-RESPONSE; LAPAROTOMY; COMPLICATIONS; RADIOTHERAPY; CHILDHOOD; CHEMOTHERAPY; EXPERIENCE; MANAGEMENT AB Purpose: To determine the efficacy of mantle radiation therapy alone in selected patients with early-stage Hodgkin's disease. Patients and Methods: Between October 1988 and June 2000, 87 selected patients with pathologic stage (PS) IA to IIA or clinical stage (CS) IA Hodgkin's disease were entered onto a single-arm prospective trial of treatment with mantle irradiation alone. Eighty-three of 87 patients had greater than or equal to 1 year of follow-up after completion of mantle irradiation and were included for analysis in this study. Thirty-seven patients had PS IA, 40 had PS IIA, and six had CS IA disease. Histologic distribution was as follows: nodular sclerosis (n = 64), lymphocyte predominant (n = 15), mixed cellularity (n = 3), and unclassified (n = 1). Median follow-up time was 61 months. Results: The 5-year actuarial rates of freedom from treatment failure (FFTF) and overall survival were 86% and 100%, respectively. Eleven of 83 patients relapsed at a median time of 27 months. Nine of the 1 1 relapses contained at least a component below the diaphragm. All 11 patients who developed recurrent disease were alive without evidence of Hodgkin's disease at the time of last follow-up. The 5-year FFTF in the 43 stage I patients was 92% compared with 78% in the 40 stage II patients (P = .04). Significant differences in FFTF were not seen by histology (P = .26) or by European Organisation for Research and Treatment of Cancer I-I-SE eligibility (P = .25). Conclusion: Mantle irradiation alone in Selected patients with early-stage Hodgkin's disease is associated with disease control rates comparable to those seen with extended field irradiation. The FFTF is especially favorable among stage I patients. (C) 2001 by American Society of Clinical Oncology. C1 Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Radiat Oncol, Massachusetts Gen Hosp, Boston, MA USA. Duke Univ, Dept Radiat Oncol, Durham, NC USA. RP Mauch, PM (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,ASB1-L2, Boston, MA 02115 USA. NR 26 TC 10 Z9 10 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2001 VL 19 IS 3 BP 736 EP 741 PG 6 WC Oncology SC Oncology GA 399GK UT WOS:000166803100018 PM 11157025 ER PT J AU Kilbridge, KL Weeks, JC Sober, AJ Haluska, FG Slingluff, CL Atkins, MB Sock, DE Kirkwood, JM Nease, RF AF Kilbridge, KL Weeks, JC Sober, AJ Haluska, FG Slingluff, CL Atkins, MB Sock, DE Kirkwood, JM Nease, RF TI Patient preferences for adjuvant interferon alfa-2b treatment SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID METASTATIC MALIGNANT-MELANOMA; RESECTED CUTANEOUS MELANOMA; COOPERATIVE-ONCOLOGY-GROUP; PHASE-II TRIAL; MULTIFACTORIAL ANALYSIS; PROGNOSTIC FACTORS; SURVIVAL; HEALTH AB Purpose: Although trials of adjuvant interferon alfa-2b (IFN alpha -2b) in high-risk melanoma patients suggest improvement in disease-free survival, it is unclear whether treatment offers improvement in overall survival. Widespread use of adjuvant IFN alpha -2b has been tempered by its significant toxicity. To quantify the trade-offs between IFN alpha -2b toxicity and survival, we assessed patient utilities for health states associated with IFN therapy. Utilities are measures of preference for a particular health state on a scale of 0 (death) to 1 (perfect health). Patients and Methods: We assessed utilities for health states associated with adjuvant IFN among 107 low-risk melanoma patients using the standard gamble technique. Health states described four IFN alpha -2b Sb toxicity scenarios and the following three posttreatment outcomes: disease-free health and melanoma recurrence (with or without IFN alpha -2b) leading to cancer death. We also asked patients the improvement in 5-year disease-free survival they would require to tolerate IFN. Results: Utilities for melanoma recurrence with or without IFN alpha -2b were significantly lower than utilities for all IFN alpha -2b toxicities but were not significantly different from each other. At least half of the patients were willing to tolerate mild-moderate and severe IFN alpha -2b toxicity for 4% and 10% improvements, respectively, in 5-year disease free survival. Conclusion: On average, patients rate quality of life with melanoma recurrence much lower than even severe IFN alpha- 2b toxicity. These results suggest that recurrence-free survival is highly valued by patients. The utilities measured in our study can be applied directly to quality-of-life determinations in clinical trials of adjuvant IFN alpha -2b to measure the net benefit of therapy. (C) 2001 by American Society of Clinical Oncology. C1 Univ Virginia Hlth Syst, HSC, Dept Hlth Evaluat Sci, Charlottesville, VA 22908 USA. Univ Virginia Hlth Syst, Dept Internal Med, Charlottesville, VA 22908 USA. Univ Virginia Hlth Syst, Dept Surg, Charlottesville, VA 22908 USA. Dana Farber Canc Inst, Ctr OUtcomes & Policy Res, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Univ Pittsburgh, Div Med Oncol, Pittsburgh, PA USA. Washington Univ, Sch Med, Lab Med Decis Sci, St Louis, MO USA. RP Kilbridge, KL (reprint author), Univ Virginia Hlth Syst, HSC, Dept Hlth Evaluat Sci, POB 800821, Charlottesville, VA 22908 USA. NR 21 TC 54 Z9 54 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2001 VL 19 IS 3 BP 812 EP 823 PG 12 WC Oncology SC Oncology GA 399GK UT WOS:000166803100028 PM 11157035 ER PT J AU Villalona-Calero, MA Eder, JP Toppmeyer, DL Allen, LF Fram, R Velagapudi, R Myers, M Amato, A Kagen-Hallet, K Razvillas, B Kufe, DW Von Hoff, DD Rowinsky, EK AF Villalona-Calero, MA Eder, JP Toppmeyer, DL Allen, LF Fram, R Velagapudi, R Myers, M Amato, A Kagen-Hallet, K Razvillas, B Kufe, DW Von Hoff, DD Rowinsky, EK TI Phase I and pharmacokinetic study of LU79553, a DNA intercalating bisnaphthalimide, in patients with solid malignancies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LEUKEMIA GROUP-B; BIS-NAPHTHALIMIDES; ANTITUMOR-ACTIVITY; AMONAFIDE; MITONAFIDE; CANCER; HEART; DOXORUBICIN; ADRIAMYCIN; INFUSION AB Purpose: To determine the maximum-tolerated dose and characterize the pharmacokinetic behavior of LU79553, a novel bisnaphthalimide antineoplastic agent, when administered as a daily intravenous infusion for 5 days every 3 weeks. Patients and Methods: Patients with advanced solid malignancies received escalating doses of LU79553. plasma sampling and urine collections were performed on both days 1 and 5 of the first course. Results: Thirty patients received 105 courses of LU79553 at doses ranging from 2 to 24 mg/m(2)/d. Proximal myopathy, erectile dysfunction, and myelosuppression precluded the administration of multiple courses at doses above 18 mg/m(2)/d. These toxicities were intolerable in two of six patients after receiving three courses at the 24-mg/m(2)/d dose level. At the 18-mg/m(2)/d dose, one of six patients developed febrile neutropenia and grade 2 proximal myopathy after three courses of LU79553. The results of electrophysiologic, histopathologic, and ultrastructural studies supported a drug-induced primary myopathic process. A patient with a platinum- and taxane resistant papillary serous carcinoma of the peritoneum experienced a partial response lasting 22 months. Pharmacokinetics were dose-independent, optimally described by a three-compartment model, and there was modest drug accumulation over the 5 days of treatment. Conclusion: Although no dose-limiting events were noted in the first two courses of LU79553, cumulative muscular toxicity precluded repetitive treatment with LU79553 at doses above 18 mg/m(2)/d, which is the recommended dose for subsequent disease-directed evaluations. the preliminary antitumor activity noted is encouraging, but the qualitative and cumulative nature of the principal toxicities, as well as the relatively small number of patients treated repetitively, mandate that rigorous and long-term toxicologic monitoring be performed in subsequent evaluations of this unique agent. (C) 2001 by American Society of Clinical Oncology. C1 Inst Drug Dev, Canc Therapy & Res Ctr, San Antonio, TX USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Dana Farber Partners Canc Care, Boston, MA USA. Inst Canc, New Brunswick, NJ USA. Knoll Pharmaceut Co, Mt Olive, NJ USA. RP Villalona-Calero, MA (reprint author), Ohio State Univ, Arthur G James Canc Hosp, B406 Starling Loving Hall,320 W 10th Ave, Columbus, OH 43210 USA. FU NCRR NIH HHS [MO1 RR01346] NR 40 TC 26 Z9 28 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2001 VL 19 IS 3 BP 857 EP 869 PG 13 WC Oncology SC Oncology GA 399GK UT WOS:000166803100033 PM 11157040 ER PT J AU Keuthen, NJ Fraim, C Deckersbach, T Dougherty, DD Baer, L Jenike, MA AF Keuthen, NJ Fraim, C Deckersbach, T Dougherty, DD Baer, L Jenike, MA TI Longitudinal follow-up of naturalistic treatment outcome in patients with trichotillomania SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID BEHAVIORAL TREATMENT; CLOMIPRAMINE; PROFILE AB Background: Little is known about the longitudinal course of treatment outcome in patients with trichotillomania. The authors conducted a second follow-up assessment on a cohort of hair pullers previously studied. Method: Forty-four subjects completed a hair-pulling questionnaire and paper-and-pencil measures of hair-pulling severity and impact, psychosocial functioning, depression, anxiety, and self-esteem Mean time elapsed between the first and second follow-up assessment was 2.5 years (index evaluation to first follow-up = 3.5 years). Results: Twenty-seven subjects (61.4%) had active treatment since the first follow-up. No significant changes in hair pulling, depression, anxiety, or psychosocial functioning were reported from first to second follow-up. Self-esteem scores significantly worsened during this period (p = .000). A trend toward worsening also existed for psychosocial impact scores. Comparison of scores at index evaluation with second follow-up still showed significant improvement over time for hair pulling (p = .001) but significant worsening in self-esteem (p = .000). Treatment and responder status were unrelated to clinical functioning, with the exception of depression and psychosocial impact. Conclusion: Although hair pullers exhibit initial improvement with treatment, scale scores plateau or worsen by second follow-up. Significant worsening in self-esteem at second follow-up may be related to the absence of further improvements in hair-pulling severity. Future research should focus on the interrelationships among self-esteem, depression, and hair pulling during treatment for this disorder. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Charlestown, MA USA. RP Keuthen, NJ (reprint author), OCD Clin, MGH-E 9106,149 13th St, Charlestown, MA 02129 USA. RI Citations, TLC SAB/C-4006-2011 NR 25 TC 29 Z9 29 U1 0 U2 1 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD FEB PY 2001 VL 62 IS 2 BP 101 EP 107 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 407RH UT WOS:000167284200006 PM 11247093 ER PT J AU Rapaport, MH Pollack, MH Clary, CM Mardekian, J Wolkow, R AF Rapaport, MH Pollack, MH Clary, CM Mardekian, J Wolkow, R TI Panic disorder and response to sertraline: The effect of previous treatment with benzodiazepines SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article; Proceedings Paper CT CINP Biannual Meeting CY JUL 22-25, 1998 CL GLASGOW, SCOTLAND SP CINP ID DOUBLE-BLIND; MULTICENTER TRIAL; PLACEBO; AGORAPHOBIA; ALPRAZOLAM; ANXIETY AB More than 50% of patients who seek psychiatric care for panic disorder have previously received prescriptions for a benzodiazepine (BZ). Research on the treatment of generalized anxiety suggests that a history of BZ exposure might decrease the efficacy and tolerability of treatment with a serotonergic anxiolytic. This study examines the effect of prior BZ treatment on the efficacy and tolerability of sertraline treatment for panic disorder. Data were pooled (N = 705) from four double-blind, placebo-controlled studies of the efficacy of sertra-line for the treatment of panic. Two of the studies were 12-week fixed-dose studies with starting doses of 50 mg, whereas 2 mere flexible-dose studies of 10-week duration with starting doses of 25 mg. The effect of study treatment on the frequency of panic attacks, Clinical Global Impressions (CGI) Improvement Scale, and tolerability was examined for patients with or without prior BZ treatment. The efficacy of sertraline was not affected by prior treatment with BZs. The mean endpoint reduction in panic attack frequency was identical in patients with or without prior BZ use: 79% vs. 80% (not significant). A history of good versus poor response to prior BZ treatment did not significantly influence CGI responder rates for sertraline-treated patients (67% vs. 61%, respectively). Sertraline CGI responder rates were significantly greater than placebo response, which mas 47% for the good-response prior-BZ subgroup (p = 0.007), and 36% for the poor-response BZ subgroup (p = 0.013). Placebo response was lower in patients with any prior BZ use by 10%, on an intent-to-treat last-observation-carried-forward analysis (p = 0.106) and by 15% on a completer analysis (p = 0.045). Prior BZ use did not influence either rates of adverse events or discontinuation rates within the first 3 weeks in patients treated with either sertraline or placebo. Sertraline is both well-tolerated and has significant efficacy in patients with panic disorder, including the subset of patients with panic disorder who have previously been treated with BZs. C1 Univ Calif San Diego, Dept Psychiat, Psychopharmacol Res Program, La Jolla, CA 92093 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Pfizer Inc, New York, NY USA. RP Rapaport, MH (reprint author), Univ Calif San Diego, Dept Psychiat, Psychopharmacol Res Program, La Jolla, CA 92093 USA. NR 20 TC 2 Z9 2 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD FEB PY 2001 VL 21 IS 1 BP 104 EP 107 DI 10.1097/00004714-200102000-00019 PG 4 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 393PN UT WOS:000166479000018 PM 11199932 ER PT J AU Kumar, AM Bontempo, LJ Nadel, ES Brown, DFM AF Kumar, AM Bontempo, LJ Nadel, ES Brown, DFM TI A rare cause of congestive heart failure 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 6 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 FEB PY 2001 VL 20 IS 2 BP 153 EP 157 DI 10.1016/S0736-4679(00)00305-X PG 5 WC Emergency Medicine SC Emergency Medicine GA 403NC UT WOS:000167048500009 PM 11207410 ER PT J AU Dretler, SP Spencer, BA AF Dretler, SP Spencer, BA TI CT and stone fragility SO JOURNAL OF ENDOUROLOGY LA English DT Article ID UNENHANCED HELICAL CT; LITHOTRIPSY MONOTHERAPY; URETERAL CALCULI; URINARY CALCULI; RENAL CALCULI; FLANK PAIN; SPIRAL CT; RADIOGRAPHY; TOMOGRAPHY AB Informed selection of treatment requires knowledge of the size and composition of a calculus. Spiral CT has a growing role in the detection of calculi, with an overall accuracy in excess of 95%, Moreover, the margin of error in determining stone size does not exceed 3.6%, and stone volume is underestimated by <5%. Pixelograms, the compilation of multiple points of attenuation, may provide clues to stone composition and durility. C1 Massachusetts Gen Hosp, Kidney Stone Ctr, Dept Urol, Boston, MA 02114 USA. RP Dretler, SP (reprint author), Massachusetts Gen Hosp, Kidney Stone Ctr, Dept Urol, Boston, MA 02114 USA. NR 21 TC 42 Z9 47 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0892-7790 J9 J ENDOUROL JI J. Endourol. PD FEB PY 2001 VL 15 IS 1 BP 31 EP 36 DI 10.1089/08927790150500926 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 403MH UT WOS:000167046700005 PM 11248917 ER PT J AU Cook, RL Sereika, SM Hunt, SC Woodward, WC Erlen, JA Conigliaro, J AF Cook, RL Sereika, SM Hunt, SC Woodward, WC Erlen, JA Conigliaro, J TI Problem drinking and medication adherence among persons with HIV infection SO JOURNAL OF GENERAL 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 DE adherence; alcohol; HIV infection ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL THERAPY; PATIENT COMPLIANCE; HEALTH; DISEASE; USERS AB OBJECTIVE: To examine the relation between problem drinking and medication adherence among persons with HIV infection, DESIGN: Cross-sectional survey. SETTING/PARTICIPANTS: Two hundred twelve persons with HN infection who visited 2 outpatient clinics between December 1997 and February 1998. MEASUREMENTS AND MAIN RESULTS: Nineteen percent of subjects reported problem drinking during the previous month, 14% missed at least 1 dose of medication within the previous 24 hours, and 30% did not take their medications as scheduled during the previous week. Problem drinkers were slightly more likely to report a missed dose (17% vs 12%, P =.38] and significantly more likely to report taking medicines off schedule (45% vs 26%, P =.02). Among drinking subtypes, taking medications off schedule was significantly associated with both heavy drinking (high quantity/frequency) (adjusted odds ratio [OR], 4.70: 95% confidence interval [95% CI], 1.49 to 14.84; P<.05) and hazardous drinking (adjusted OR, 2.64; 95% CI, 1.07 to 6.53: P<.05), Problem drinkers were more likely to report missing medications because of forgetting (48% vs 35%, P =.10), running out of medications (15% vs 8%, P =.18), and consuming alcohol or drugs (26% vs 3%, P <.001). CONCLUSION: Problem drinking is associated with decreased medication adherence, particularly with taking medications off schedule during the previous week. Clinicians should assess for alcohol problems, link alcohol use severity to potential adherence problems. and monitor outcomes in both alcohol consumption and medication adherence. C1 Univ Pittsburgh, Sch Med, Ctr Res Chron Disorders, Pittsburgh, PA 15213 USA. VA Pittsburgh Hlth Care Syst, Ctr Res Hlth Care, Pittsburgh, PA USA. VA Pittsburgh Hlth Care Syst, Div Gen Internal Med, Pittsburgh, PA USA. Bornemann Internal Med, Reading, PA USA. RP Cook, RL (reprint author), Univ Pittsburgh, Sch Med, Ctr Res Chron Disorders, E820 UPMC Montefiore,200 Lothrop St, Pittsburgh, PA 15213 USA. NR 35 TC 169 Z9 173 U1 1 U2 2 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 FEB PY 2001 VL 16 IS 2 BP 83 EP 88 DI 10.1046/j.1525-1497.2001.00122.x PG 6 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 406VE UT WOS:000167236100002 PM 11251758 ER PT J AU Atlas, SJ Deyo, RA AF Atlas, SJ Deyo, RA TI Evaluating and managing acute low back pain in the primary care setting SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Review DE acute low back pain; evaluation; management; review; primary care ID RANDOMIZED CONTROLLED TRIAL; LUMBAR SPINAL STENOSIS; BED REST; FOLLOW-UP; PHYSICAL-EXAMINATION; MAGNETIC-RESONANCE; GENERAL-PRACTICE; CLINICAL-TRIAL; UNITED-STATES; CORTICOSTEROID INJECTIONS AB Acute low back pain is a common reason for patient calls or visits to a primary care clinician. Despite a large differential diagnosis, the precise etiology is rarely identified, although musculoligamentous processes are usually suspected, For most patients, back symptoms are nonspecific, meaning that there is no evidence for radicular symptoms or underlying systemic disease. Because episodes of acute, nonspecific low back pain are usually self-limited, many patients treat themselves without contacting their primary care clinician, When patients do call or schedule a visit, evaluation and management by primary care clinicians is appropriate. The history and physical. examination usually provide clues to the rare but potentially serious causes of low back pain, as well as identify patients at risk for prolonged recovery, Diagnostic testing, including plain x-rays, is often unnecessary during the initial evaluation, For patients with acute, nonspecific low back pain, the primary emphasis of treatment should be conservative care, time, reassurance, and education. Current recommendations focus on activity as tolerated (though not active exercise while pain is severe) and minimal if any bed rest. Referral for physical treatments is most appropriate for patients whose symptoms are not improving over 2 to 4 weeks. Specialty referral should be considered for patients with a progressive neurologic deficit, failure of conservative therapy, or an uncertain or serious diagnosis. The prognosis for most patients is good, although recurrence is common. Thus, educating patients about the natural history of acute low back pain and how to prevent future episodes can help ensure reasonable expectations. C1 Harvard Univ, Massachusetts Gen Hosp, Div Gen Med, Sch Med, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Med Practices Evaluat Ctr,Med Serv, Sch Med, Boston, MA 02114 USA. Univ Washington, Ctr Cost & Outcomes Res, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. RP Atlas, SJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Div Gen Med, Sch Med, 50 Staniford St, Boston, MA 02114 USA. RI Abbott, J./B-2976-2008 OI Abbott, J./0000-0001-6468-7284 FU AHRQ HHS [HS-08194, HS-06334, HS-09804, R01 HS009804] NR 101 TC 88 Z9 94 U1 2 U2 13 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 FEB PY 2001 VL 16 IS 2 BP 120 EP 131 DI 10.1046/j.1525-1497.2001.91141.x PG 12 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 406VE UT WOS:000167236100008 PM 11251764 ER PT J AU Hwang, SW O'Connell, JJ Lebow, JM Bierer, MF Orav, EJ Brennan, TA AF Hwang, SW O'Connell, JJ Lebow, JM Bierer, MF Orav, EJ Brennan, TA TI Health care utilization among homeless adults prior to death SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article DE homeless persons; death; delivery of health care; health services accessibility ID ANTIRETROVIRAL THERAPY; URBAN HOMELESS; MEDICAL-CARE; MORTALITY; POPULATION; INFECTION; MORBIDITY; BOSTON; LIFE AB This study characterizes health care utilization prior to death in a group of 558 homeless adults in Boston. In the year before death, 27 percent of decedents had no outpatient visits, emergency department visits, or hospitalizations except those during which death occurred. However, 21 percent of homeless decedents had a health care contact within one month of death, and 21 percent had six or more outpatient visits in the year before death. Injection drug users and persons with HIV infection were more likely to have had contact with the health care system. This study concludes that homeless persons may be underusing health care services even when they are at high risk of death. Because a subset of homeless persons had extensive health care contacts prior to death, opportunities to prevent deaths may have been missed, and some deaths may not have been preventable through medical intervention. C1 St Michaels Hosp, Inner City Hlth Program, Toronto, ON M5B 1W8, Canada. Massachusetts Gen Hosp, Boston Hlth Care Homeless Program, Boston, MA 02118 USA. Cambridge Hlth Alliance, Somerville Primary Care, Cambridge, MA 02139 USA. Brigham & Womens Hosp, Div Gen Med, Clin Initiat Dev Program, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. RP Hwang, SW (reprint author), St Michaels Hosp, Inner City Hlth Program, Shuter Wing 2-026,30 Bond St, Toronto, ON M5B 1W8, Canada. RI Hwang, Stephen/D-2297-2011 OI Hwang, Stephen/0000-0002-1276-1101 NR 22 TC 35 Z9 35 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-2089 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD FEB PY 2001 VL 12 IS 1 BP 50 EP 58 PG 9 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 393NZ UT WOS:000166477700004 PM 11217228 ER PT J AU Heitner, T Moor, A Garrison, JL Marks, C Hasan, T Marks, JD AF Heitner, T Moor, A Garrison, JL Marks, C Hasan, T Marks, JD TI Selection of cell binding and internalizing epidermal growth factor receptor antibodies from a phage display library SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE receptor mediated endocytosis; epidermal growth factor receptor; phage antibody library; single chain Fv; scFv; tumor targeting ID HUMAN MONOCLONAL-ANTIBODIES; SINGLE-CHAIN FV; BREAST-CANCER; EGF RECEPTOR; TUMOR-CELLS; IN-VITRO; EXPRESSION; AFFINITY; PROTEIN; DIMERIZATION AB The first step in developing a targeted cancer therapeutic is generating a ligand that binds to a receptor which is either tumor specific or sufficiently overexpressed in tumors to provide targeting specificity. For this work, we generated human monoclonal antibodies to the EGF receptor (EGFR), an antigen overexpressed on many solid tumors, single chain Fv (scFv) antibody fragments were directly selected by panning a phage display library on tumor cells (A431) overexpressing EGFR or Chinese hamster ovary cells (CHO/EGFR cells) transfected with the EGFR gene and recovering endocytosed phage from within the cell. Three unique scFvs were isolated, two from selections on A431 cells and two from selections on CHO/EGFR cells. All three scFv bound native receptor as expressed on a panel of tumor cells and did not bind EGFR negative cells. Phage antibodies and multivalent immunoliposomes constructed from scFv were endocytosed by EGFR expressing cells as shown by confocal microscopy. Native scFv primarily stained the cell surface, with less staining intracellularly. The results demonstrate how phage antibodies binding native cell surface receptors can be directly selected on overexpressing cell lines or transfected cells. Use of a transfected cell line allows selection of antibodies to native receptors without the need for protein expression and purification, significantly speeding the generation of targeting antibodies to genomic sequences. Depending upon the format used, the antibodies can be used to deliver molecules to the cell surface or intracellularly. (C) 2001 Elsevier Science BN. All rights reserved. C1 Univ Calif San Francisco, Dept Anesthesia, San Francisco Gen Hosp, San Francisco, CA 94110 USA. Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco Gen Hosp, San Francisco, CA 94110 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Labs Photomed, Boston, MA 02114 USA. RP Marks, JD (reprint author), Univ Calif San Francisco, Dept Anesthesia, San Francisco Gen Hosp, Room 3C-38, San Francisco, CA 94110 USA. FU NCI NIH HHS [5 P50 CA58207]; NIAMS NIH HHS [R01 AR40352-03] NR 40 TC 62 Z9 71 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD FEB 1 PY 2001 VL 248 IS 1-2 BP 17 EP 30 DI 10.1016/S0022-1759(00)00340-9 PG 14 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 405ZA UT WOS:000167189400003 PM 11223066 ER PT J AU West, CA He, C Su, M Rawn, J Swanson, S Hay, JB Mentzer, SJ AF West, CA He, C Su, M Rawn, J Swanson, S Hay, JB Mentzer, SJ TI Stochastic regulation of cell migration from the efferent lymph to oxazolone-stimulated skin SO JOURNAL OF IMMUNOLOGY LA English DT Article ID REGIONAL LYMPH; LYMPHOCYTES; NODES; ANTIBODY; KINETICS; SITES; SHEEP; MICE AB The systemic immune response is a dynamic process involving the trafficking of lymphocytes from the Ag-stimulated lymph node to the peripheral tissue. Studies in sheep have demonstrated several phases of cell output in the efferent lymph after Ag stimulation. When skin contact sensitizers are used as Ag, the efferent lymph cell output peaks similar to 96 h after Ag stimulation and is temporally associated with the recruitment of cells into the skin. To investigate the relative contribution of this high-output phase of efferent lymphocytes to lymphocytic inflammation in the skin, we used a common contact sensitizer 2-phenyl-4-ethoxymethylene-5-oxazolone (oxazolone) to stimulate the skin and draining prescapular lymph node of adult sheep. The efferent lymph ducts draining the Ag-stimulated and contralateral control lymph nodes were cannulated throughout the experimental period. The lymphocytes leaving the lymph nodes during the 72-h period before maximum infiltration were differentially labeled with fluorescent tracers, reinjected into the arterial circulation, and tracked to the site of Ag stimulation. Quantitative tissue cytometry of the skin at the conclusion of the injection period (96 h after Ag stimulation) demonstrated more migratory cells derived from the Ag-stimulated lymph node than the contralateral control (median 18.5 vs 15.5 per field; p < 0.05). However, when corrected for total cell output of the lymph node, the Ag-stimulated migratory cells were 3.8-fold more prevalent in the skin than the contralateral control cells. These results suggest that the in situ immune response generally mirrors the frequency of recruitable lymphocytes in the peripheral blood. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Lab Immunophysiol,Harvard Surg Res Labs, Boston, MA 02115 USA. Univ Toronto, Dept Immunol, Toronto, ON, Canada. RP Mentzer, SJ (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Lab Immunophysiol,Harvard Surg Res Labs, Room G09,JFB,44 Binney St, Boston, MA 02115 USA. NR 49 TC 16 Z9 16 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 FEB 1 PY 2001 VL 166 IS 3 BP 1517 EP 1523 PG 7 WC Immunology SC Immunology GA 396EE UT WOS:000166622700013 PM 11160191 ER PT J AU Lee, RS Rusche, JR Maloney, ME Sachs, DH Sayegh, MH Madsen, JC AF Lee, RS Rusche, JR Maloney, ME Sachs, DH Sayegh, MH Madsen, JC TI CTLA4Ig-induced linked regulation of allogeneic T cell responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; IN-VIVO; LYMPHOCYTES-T; TOLERANCE; INDUCTION; TRANSPLANTATION; COSTIMULATION; BLOCKADE; ANTIGEN; SUPPRESSION AB The mechanisms by which CTLA4Ig exerts its powerful immunomodulatory effects are not clear. We show here that CTLA4Ig can induce linked regulation of allogeneic porcine T cell responses in vitro. Naive miniature swine SLA(dd) T cells were rendered hyporesponsive to specific allogeneic Ag after coculturing with MHC-mismatched SLA(cc) stimulators in the presence of CTLA4Ig, These Ag-specific hyporesponsive T cells were subsequently able to actively inhibit the allogeneic responses of naive syngeneic T cells in an MHC-linked fashion, as the responses of naive SLA(dd) responders against specific SLA(cc) and (SLA(ac))F-1 stimulators were inhibited, but allogeneic responses against a 1:1 mixture of SLA(aa) (I-a, IIa) and SLA(cc) (I-c, IIc) were maintained. This inhibition could be generated against either class I or class II Ags, was radiosensitive, and required cell-cell contact. Furthermore, the mechanism of inhibition was not dependent upon a deletional, apoptotic pathway, but it was reversed by anti-IL-10 mAb. These data suggest that CTLA4Ig-induced inhibition of naive allogeneic T cell responses can be mediated through the generation of regulatory T cells via an IL-10-dependent mechanism. C1 Massachusetts Gen Hosp, Dept Surg, Div Cardiac Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. Repligen Corp, Needham, MA 02494 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Renal Div,Lab Immunogenet & Transplantat, Boston, MA 02115 USA. RP Madsen, JC (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Cardiac Surg, EDR 105, Boston, MA 02114 USA. FU NHLBI NIH HHS [R01-HL54211] NR 43 TC 24 Z9 25 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2001 VL 166 IS 3 BP 1572 EP 1582 PG 11 WC Immunology SC Immunology GA 396EE UT WOS:000166622700020 PM 11160198 ER PT J AU Melby, PC Chandrasekar, B Zhao, WG Coe, JE AF Melby, PC Chandrasekar, B Zhao, WG Coe, JE TI The hamster as a model of human visceral leishmaniasis: Progressive disease and impaired generation of nitric oxide in the face of a prominent Th1-like cytokine response SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; TRANSFORMING-GROWTH-FACTOR; ACUTE CHAGASIC CARDIOMYOPATHY; DEPENDENT KILLING MECHANISM; IFN-GAMMA; IMMUNE-RESPONSE; L-ARGININE; KALA-AZAR; IN-VIVO; ACTIVATED MACROPHAGES AB Active human visceral leishmaniasis (VL) is characterized by a progressive increase in visceral parasite burden, cachexia, massive splenomegaly, and hypergammaglobulinemia. In contrast, mice infected with Leishmania donovani, the most commonly studied model of VL, do not develop overt, progressive disease. Furthermore, mice control Leishmania infection through the generation of NO, an effector mechanism that does not have a clear role in human macrophage antimicrobial function. Remarkably, infection of the Syrian hamster (Mesocricetus auratus) with L. donovani reproduced the clinicopathological features of human VL, and investigation into the mechanisms of disease in the hamster revealed striking differences from the murine model. Uncontrolled parasite replication in the hamster liver, spleen, and bone marrow occurred despite a strong Th1-like cytokine (IL-2, IFN-gamma, and TNF/lymphotoxin) response in these organs, suggesting impairment of macrophage effector function. Indeed, throughout the course of infection, inducible NO synthase (iNOS, NOS2) mRNA or enzyme activity in liver or spleen tissue was not detected. In contrast, NOS2 mRNA and enzyme activity was readily detected in the spleens of infected mice. The impaired hamster NOS2 expression could not be explained by an absence of the NOS2 gene, overproduction of IL-4, defective TNF/lymphotoxin production (a potent second signal for NOS2 induction), or early dominant production of the deactivating cytokines IL-10 and TGF-beta. Thus, although a Th1-like cytokine response was prominent, the major antileishmanial effector mechanism that is responsible for control of infection in mice was absent throughout the course of progressive VL in the hamster. C1 Univ Texas, Hlth Sci Ctr, Dept Med, Div Infect Dis, San Antonio, TX 78284 USA. S Texas Vet Hlth Care Syst, Dept Vet Affairs Med Ctr, Med Serv, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Microbiol, San Antonio, TX 78284 USA. NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Melby, PC (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med, Div Infect Dis, 7703 Floyd Curl Dr, San Antonio, TX 78284 USA. NR 54 TC 150 Z9 153 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2001 VL 166 IS 3 BP 1912 EP 1920 PG 9 WC Immunology SC Immunology GA 396EE UT WOS:000166622700061 PM 11160239 ER PT J AU Call, SA Saag, MS Westfall, AO Raper, JL Pham, SV Tolson, JM Hellmann, NS Cloud, GA Johnson, VA AF Call, SA Saag, MS Westfall, AO Raper, JL Pham, SV Tolson, JM Hellmann, NS Cloud, GA Johnson, VA TI Phenotypic drug susceptibility testing predicts long-term virologic suppression better than treatment history in patients with human immunodeficiency virus infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) CY SEP 26-29, 1999 CL SAN FRANCISCO, CALIFORNIA ID PROTEASE INHIBITOR THERAPY; ANTIRETROVIRAL THERAPY; REVERSE-TRANSCRIPTASE; RESISTANCE MUTATIONS; CONTROLLED TRIAL; SALVAGE THERAPY; HIV-INFECTION; ZIDOVUDINE; FAILURE; LAMIVUDINE AB To assess the value of phenotypic drug susceptibility testing as a predictor of antiretroviral treatment response in human immunodeficiency virus (HIV)-infected people, drug susceptibility testing was performed retrospectively on plasma samples collected at baseline in a cohort of 86 antiretroviral-experienced, HIV-infected people experiencing treatment failure and initiating a new antiretroviral treatment regimen. Two separate criteria for reduced drug susceptibility were evaluated. In multivariate analyses, phenotypic susceptibility was an independent predictor of time to treatment failure (adjusted hazards ratio [HR], 0.70; 95% confidence interval [CI], 0.55-0.90; and adjusted HR, 0.76; 95% CI, 0.61-0.95, with reduced drug susceptibility cutoffs defined as 4.0-fold and 2.5-fold higher than reference virus IC50 values, respectively). Previous protease inhibitor experience was also a significant independent predictor. Notably, drug susceptibility predicted on the basis of treatment history alone was not predictive of time to treatment failure. In this cohort, phenotypic testing results enhanced the ability to predict sustained long-term suppression of virus load. C1 Univ Alabama, Sch Med, Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA. Univ Alabama, Sch Med, Div Gen Internal Med, Birmingham, AL 35294 USA. Univ Alabama, Sch Med, Div Infect Dis, Birmingham, AL 35294 USA. Univ Alabama, Sch Med, Biostat Unit, Birmingham, AL 35294 USA. Glaxo Wellcome Inc, Res Triangle Pk, NC 27709 USA. ViroLogic, S San Francisco, CA USA. RP Johnson, VA (reprint author), Univ Alabama, Sch Med, Birmingham Vet Affairs Med Ctr, THT 229,1530 3rd Ave S, Birmingham, AL 35294 USA. FU NIAID NIH HHS [AI40876, P30 AI37767, AI32775] NR 33 TC 23 Z9 24 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 1 PY 2001 VL 183 IS 3 BP 401 EP 408 DI 10.1086/318078 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 390DG UT WOS:000166280000006 PM 11133371 ER PT J AU Rosenzweig, M Marks, DF DeMaria, MA Connole, M Johnson, RP AF Rosenzweig, M Marks, DF DeMaria, MA Connole, M Johnson, RP TI Identification of primitive hematopoietic progenitor cells in the rhesus macaque SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article DE bone marrow cells; hematopoietic progenitors; rhesus macaque ID BONE-MARROW CELLS; COLONY-STIMULATING FACTOR; LONG-TERM-CULTURE; HUMAN GM-CSF; STEM-CELLS; CORD-BLOOD; PERIPHERAL-BLOOD; IN-VIVO; FUNCTIONAL-PROPERTIES; LIMITING DILUTION AB The close phylogenetic relationship of macaques to humans has resulted in their widespread use as a preclinical model for bone marrow transplantation and stem cell gene therapy. To facilitate fur ther use of this model. we undertook analysis of hematopoietic cells using multiparametric flow cytometric analysis. Rhesus CD34(+) CD38(-) cells displayed a number of characteristics of primitive hematopoietic cells, including low forward and orthogonal scatter and the lack of expression of lineage-specific markers or human lymphocyte antigen-DR. Four-color flow cytometric analysis demonstrated that rhesus CD34(+) CD38(-) cells were heterogenous with respect to Thy-1 expression and were CD59(dim), Quantitative limiting dilution long-term culture-initiating cell (LTC-IC) analysis demonstrated that CD34(+) CD38(-) cells were approximately 150-fold enriched for LTC-IC as compared with unfractionated bone marrow, and occurred at a frequency similar to that previously reported in humans. Thus, as in humans, the CD34(+)38(-) population of rhesus macaque bone marrow is enriched for primitive, multipotent hematopoietic progenitor cells. C1 New England Reg Primate Res Ctr, Div Immunol, Harvard Med Sch, Southborough, MA 01772 USA. Massachusetts Gen Hosp, AIDS Res Ctr, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Infect Dis Unit, Charlestown, MA 02129 USA. RP Rosenzweig, M (reprint author), New England Reg Primate Res Ctr, Div Immunol, Harvard Med Sch, 1 Pine Hill Dr, Southborough, MA 01772 USA. FU NCRR NIH HHS [RR00168]; NIAID NIH HHS [AI39423, AI36550] NR 50 TC 3 Z9 3 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD FEB PY 2001 VL 30 IS 1 BP 36 EP 45 DI 10.1111/j.1600-0684.2001.300105.x PG 10 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 430LV UT WOS:000168576100005 PM 11396862 ER PT J AU Gulley, ML AF Gulley, ML TI Molecular diagnosis of Epstein-Barr virus-related diseases SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Review ID POLYMERASE-CHAIN-REACTION; NON-HODGKINS-LYMPHOMA; POSTTRANSPLANTATION LYMPHOPROLIFERATIVE DISORDERS; HUMAN-IMMUNODEFICIENCY-VIRUS; IN-SITU HYBRIDIZATION; NASOPHARYNGEAL CARCINOMA; INSITU HYBRIDIZATION; SMALL RNAS; INFECTIOUS-MONONUCLEOSIS; IMMUNOCOMPETENT PATIENTS AB Epstein-Barr virus (EBV) is the causative agent of Infectious mononucleosis, and it may also be found in a wide variety of benign and malignant lesions including oral hairy leukoplakia, inflammatory pseudotumor, Hodgkin's disease, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, and gastric carcinoma. Molecular testing is increasingly Important in the diagnosis and monitoring of patients affected by these diseases. In biopsy tissues, molecular detection of EBV-encoded RNA transcripts by in situ hybridization remains the gold standard for proving that a histopathological lesion is EBV-related, EBV-encoded RNA hybridization and EBV LMP1 immunostains are used routinely to detect latent EBV in tissues affected try posttransplant lymphoproliferative disorder (PTLD) or in enlarged nodes from patients with infectious mononucleosis. Traditional serology is the best test for evaluating acute versus remote infection in healthy individuals. High serological titers serve as a tumor marker for some EBV-related malignancies, but titers are not a dependable tumor marker in Immunocompromised hosts. EBV viral load testing by quantitative DNA amplification of blood samples Is a promising new laboratory test that has proven useful for early diagnosis and monitoring patients with PTLD, Recent studies suggest a role for EBV viral load testing in nasopharyngeal carcinoma, Hodgkin's disease, and AIDS patients with brain lymphoma. Further research is needed to define more fully the clinical utility of viral load tests In the full spectrum of EBV-associated diseases. Gene expression profiling Is on the horizon as a means to improve subclassification of EBV-related diseases and to predict response to therapy. C1 Univ Texas, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78284 USA. Audie L Murphy Mem Vet Hosp, San Antonio, TX 78284 USA. RP Gulley, ML (reprint author), Univ Texas, Hlth Sci Ctr, Dept Pathol, 7703 Floyd Curl Dr, San Antonio, TX 78284 USA. NR 71 TC 129 Z9 140 U1 3 U2 7 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD FEB PY 2001 VL 3 IS 1 BP 1 EP 10 DI 10.1016/S1525-1578(10)60642-3 PG 10 WC Pathology SC Pathology GA 401GN UT WOS:000166920000001 PM 11227065 ER PT J AU Brown, AM Sheu, RKF Mohs, R Haroutunian, V Blass, JP AF Brown, AM Sheu, RKF Mohs, R Haroutunian, V Blass, JP TI Correlation of the clinical severity of Alzheimer's disease with an aberration in mitochondrial DNA (antDNA) SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE Alzheimer; CO1; mitochondria; mtDNA; neurodegeneration; pathogenesis ID KETOGLUTARATE DEHYDROGENASE COMPLEX; AMYLOID BETA-PEPTIDE; HUMAN NUCLEAR GENOME; APOLIPOPROTEIN-E; RAT-BRAIN; OXIDATIVE DAMAGE; MUTATIONS; DEMENTIA; ABNORMALITIES; METABOLISM AB Controversy exists about which of the well-established neurobiological abnormalities in Alzheimer's disease (AD) relate directly to the clinical disabilities. Because of an interest in the mitochondrial lesion in AD, we tested the correlation between clinical disability (measured by the Clinical Dementia Rating [CDR] scale) and an anomaly in mitochondrial DNA (mtDNA) in AD brain. Simultaneous polymerase chain reaction (PCR) amplification of the CO1 gene in mtDNA and CO1 pseudogenes in nuclear DNA (nDNA) were performed in samples from AD and non-AD brain, and the ratios of mtDNA/nDNA amplicons calculated. This approach utilizes PCR amplification of endogenous nDNA as a normalization standard for the amplification of mtDNA. We examined total DNA from the brains of Caucasian residents of a Jewish nursing home (86 AD and 26 non-AD "controls"). These patients had been closely followed clinically until death and then autopsied. In this sample, the degree of cognitive impairment in the AD patients correlated with the reduction in the amplification of the mtDNA gene (rho = 0.23; p = 0.034), but not with the density of neuritic plaques (p = 0.109). These results agree with the suggestion that the well-documented impairment in brain-energy metabolism in AD may be a direct cause of the clinical disability. C1 Burke Med Res Inst, Dementia Res Serv, White Plains, NY 10605 USA. Cornell Univ, Weill Med Coll, Dept Biochem, New York, NY 10021 USA. Cornell Univ, Weill Med Coll, Dept Neurol & Neurosci, New York, NY 10021 USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. Bronx Vet Affairs Med Ctr, Bronx, NY 10468 USA. Cornell Univ, Weill Med Coll, Dept Med, New York, NY 10021 USA. RP Blass, JP (reprint author), Burke Med Res Inst, Dementia Res Serv, 785 Mamaroneck Ave, White Plains, NY 10605 USA. NR 41 TC 21 Z9 21 U1 1 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD FEB PY 2001 VL 16 IS 1 BP 41 EP 48 DI 10.1385/JMN:16:1:41 PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 429NW UT WOS:000168524700005 PM 11345519 ER PT J AU Hagerty, T Morgan, WW Elango, N Strong, R AF Hagerty, T Morgan, WW Elango, N Strong, R TI Identification of a glucocorticoid-responsive element in the promoter region of the mouse tyrosine hydroxylase gene SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE gene promoter; gene transcription; glucocorticoid response element; tyrosine hydroxylase ID PC12 PHEOCHROMOCYTOMA CELLS; DOPAMINE BETA-HYDROXYLASE; THYMIDINE KINASE GENE; CYCLIC-AMP; MEMBRANE DEPOLARIZATION; MESSENGER-RNAS; RECEPTOR; TRANSCRIPTION; EXPRESSION; INDUCTION AB it has been known for nearly 30 years that glucocorticoid receptor stimulation induces increased tyrosine hydroxylase (TH) gene expression. However, the mechanism mediating this effect has remained elusive. Sequences with homology to known glucocorticoid-responsive elements (GRE) have been identified in the 5' flanking region of the TH gene of several vertebrate species, but none has been shown to be functional. To identify the GRE element(s) in the TH promoter, we generated chimeric constructs in which different lengths of the 5' flanking sequences of the mouse TH gene (3.6, 1.1 and 0.8 kb) were ligated to a luciferase reporter gene. Dexamethasone treatment increased luciferase expression only in cells transiently transfected with the construct containing 3.6 kb of the TH 5' flanking DNA. Go-administration of mifepristone (RU486), a glucocorticoid receptor antagonist, blocked this effect. We identified a TH-GRE sequence (5'-GGCACAGTGTGGTCT) in the mouse 5' flanking DNA between -2435 and -2421 from the transcription start. Responsiveness to dexamethasone was lost following deletion of this sequence. To determine the ability of this element to function in a heterologous promoter, we prepared a chimeric construct in which the TH-GRE sequence was cloned just upstream of a minimal thymidine kinase (TK) promoter. Promoter activity was increased 2-fold in dexamethasone-treated PC12 cells transfected with the TH-GRE-TK construct. These results provide strong evidence that the 15 base-pair sequence in the 5' flanking DNA of the mouse TH gene functions as a glucocorticoid response element. This is the first report identifying a functional glucocorticoid response element in the promoter region of the TH gene of any species. C1 Audie L Murphy Mem Vet Hosp, Educ & Clin Ctr 182, Dept Geriatr Med, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Pharmacol, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78284 USA. RP Strong, R (reprint author), Audie L Murphy Mem Vet Hosp, Educ & Clin Ctr 182, Dept Geriatr Med, 7400 Merton Minter Blvd, San Antonio, TX 78284 USA. FU NIDDK NIH HHS [DK 52543] NR 34 TC 33 Z9 35 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2001 VL 76 IS 3 BP 825 EP 834 DI 10.1046/j.1471-4159.2001.00072.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 397UG UT WOS:000166715300021 PM 11158254 ER PT J AU Sapp, E Kegel, KB Aronin, N Hashikawa, T Uchiyama, Y Tohyama, K Bhide, PG Vonsattel, JP DiFiglia, M AF Sapp, E Kegel, KB Aronin, N Hashikawa, T Uchiyama, Y Tohyama, K Bhide, PG Vonsattel, JP DiFiglia, M TI Early and progressive accumulation of reactive microglia in the Huntington disease brain SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE human brain; huntingtin; Huntington disease; mutant huntingtin; nuclear inclusions; reactive microglia; thymosin beta 4 ID NEURONAL INTRANUCLEAR INCLUSIONS; CENTRAL-NERVOUS-SYSTEM; ALZHEIMERS-DISEASE; THYMOSIN BETA(4); SUBSTANTIA-NIGRA; PREFRONTAL CORTEX; XENOPUS-LAEVIS; RAT-BRAIN; G-ACTIN; EXPRESSION AB Microglia may contribute to cell death in neurodegenerative diseases. We studied the activation of microglia in affected regions of Huntington disease (HD) brain by localizing thymosin beta -4 (T beta4), which is increased in reactive microglia. Activated microglia appeared in the neostriatum, cortex, and globus pallidus and the adjoining white matter of the HD brain, but not in control brain. In the striatum and cortex, reactive microglia occurred in all grades of pathology, accumulated with increasing grade, and grew in density in relation to degree of neuronal loss. The predominant morphology of activated microglia differed in the striatum and cortex. Processes of reactive microglia were conspicuous in low-grade HD, suggesting an early microglia response to changes in neuropil and axons and in the grade 2 and grade 3 cortex, were aligned with the apical dendrites of pyramidal neurons. Some reactive microglia contacted pyramidal neurons with huntingtin-positive nuclear inclusions. The early and proximate association of activated microglia with degenerating neurons in the HD brain implicates a role for activated microglia in HD pathogenesis. C1 Massachusetts Gen Hosp, Lab Cellular Neurobiol, Dept Neurol, Charlestown, MA 02129 USA. Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. Univ Massachusetts, Sch Med, Dept Cell Biol, Worcester, MA USA. RIKEN, Brain Sci Inst, Lab Neural Architecture, Wako, Saitama, Japan. Osaka Univ, Sch Med, Dept Anat, Osaka, Japan. Iwate Med Univ, Sch Med, Ctr Electron Microscopy & Bioimaging Res, Dept Neuroanat, Morioka, Iwate 020, Japan. RP DiFiglia, M (reprint author), Massachusetts Gen Hosp, Lab Cellular Neurobiol, Dept Neurol, MGH E, Charlestown, MA 02129 USA. FU NINDS NIH HHS [NS16367] NR 62 TC 215 Z9 221 U1 0 U2 7 PU AMER ASSN NEUROPATHOLOGISTS INC PI LAWRENCE PA 1041 NEW HAMPSHIRE ST, LAWRENCE, KS 66044 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD FEB PY 2001 VL 60 IS 2 BP 161 EP 172 PG 12 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 402VD UT WOS:000167008100006 PM 11273004 ER PT J AU Christie, RH Bacskai, BJ Zipfel, WR Williams, RM Kajdasz, ST Webb, WW Hyman, BT AF Christie, RH Bacskai, BJ Zipfel, WR Williams, RM Kajdasz, ST Webb, WW Hyman, BT TI Growth arrest of individual senile plaques in a model of Alzheimer's disease observed by in vivo multiphoton microscopy SO JOURNAL OF NEUROSCIENCE LA English DT Article DE amyloid; transgenic; Alzheimer; two-photon; in vivo imaging; senile plaque; microglia ID AMYLOID PLAQUES; TRANSGENIC MICE; AGGREGATION; DISAGGREGATION; DYNAMICS AB In Alzheimer's disease, amyloid-beta peptide aggregates in the extracellular space to form senile plaques. The process of plaque deposition and growth has been modeled on the basis of in vitro experiments in ways that lead to divergent predictions: either a diffusion-limited growth model in which plaques grow by first-order kinetics, or a dynamic model of continual deposition and asymmetrical clearance in which plaques reach a stable size and stop growing but evolve morphologically over time. The models have not been tested in vivo because plaques are too small (by several orders of magnitude) for conventional imaging modalities. We now report in vivo multiphoton laser scanning imaging of thioflavine S-stained senile plaques in the Tg2576 transgenic mouse model of Alzheimer's disease to test these biophysical models and show that there is no detectable change in plaque size over extended periods of time. Qualitatively, geometric features remain unchanged over time in the vast majority of the 349 plaques imaged and re-imaged. Intervals as long as 5 months were obtained. Nonetheless, rare examples of growth or shrinkage of individual plaques do occur, and new plaques appear between imaging sessions. These results indicate that thioflavine S-positive plaques appear and then are stable, supporting a dynamic feedback model of plaque growth. C1 Massachusetts Gen Hosp, Alzheimers Dis Res Unit, Charlestown, MA 02129 USA. Cornell Univ, Sch Appl & Engn Phys, Ithaca, NY 14853 USA. RP Hyman, BT (reprint author), Massachusetts Gen Hosp, Alzheimers Dis Res Unit, CNY 6405,149 13th St, Charlestown, MA 02129 USA. RI Webb, Watt/B-5905-2011; Zipfel, Warren/B-4059-2016 OI Zipfel, Warren/0000-0003-2640-329X FU NIA NIH HHS [P01 AG15453, AG08487]; NIGMS NIH HHS [T32 GM007753, T32GM07753] NR 19 TC 142 Z9 148 U1 0 U2 12 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 1 PY 2001 VL 21 IS 3 BP 858 EP 864 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 398WF UT WOS:000166778900016 PM 11157072 ER PT J AU Krakauer, JW Pine, ZM Ghilardi, MF Ghez, C AF Krakauer, JW Pine, ZM Ghilardi, MF Ghez, C TI Learning of visuomotor transformations for vectorial planning of reaching trajectories (vol 20, pg 8916, 2000) SO JOURNAL OF NEUROSCIENCE LA English DT Correction DE vectorial planning; motor learning; visuomotor transformations; reaching movements; psychophysics; generalization ID ARM MOVEMENTS; MOTOR; DIRECTION; ERRORS; ADAPTATION; VARIABILITY; ACCURACY; BIASES; SPACE AB The planning of visually guided reaches is accomplished by independent specification of extent and direction. We investigated whether this separation of extent and direction planning for well practiced movements could be explained by differences in the adaptation to extent and directional errors during motor learning. We compared the time course and generalization of adaptation with two types of screen cursor transformation that altered the relationship between hand space and screen space. The first was a gain change that induced extent errors and required subjects to learn a new scaling factor. The second was a screen cursor rotation that induced directional errors and required subjects to learn new reference axes. Subjects learned a new scaling factor at the same rate when training with one or multiple target distances, whereas learning new reference axes took longer and was less complete when training with multiple compared with one target direction. After training to a single target, subjects were able to transfer learning of a new scaling factor to previously unvisited distances and directions. In contrast, generalization of rotation adaptation was incomplete; there was transfer across distances and arm configurations but not across directions. Learning a rotated reference frame only occurred after multiple target directions were sampled during training. These results suggest the separate processing of extent and directional errors by the brain and support the idea that reaching movements are planned as a hand-centered vector whose extent and direction are established via learning a scaling factor and reference axes. C1 Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Ctr Neurobiol & Behav, Dept Neurobiol & Behav, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA. Univ Calif San Francisco, Ctr Aging, San Francisco, CA 94143 USA. San Francisco Vet Adm Med Ctr, Div Geriatr, San Francisco, CA USA. CNR, INB, I-20133 Milan, Italy. RP Ghez, C (reprint author), Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Ctr Neurobiol & Behav, Dept Neurobiol & Behav, 1051 Riverside Dr, New York, NY 10032 USA. NR 39 TC 0 Z9 0 U1 1 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 1 PY 2001 VL 21 IS 3 BP A1 EP A9 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 398WF UT WOS:000166778900039 ER PT J AU Ascoli, V Signoretti, S Onetti-Muda, A Pescarmona, E Della-Rocca, C Nardi, F Mastroianni, CM Gastaldi, R Pistilli, A Gaidano, G Carbone, A Lo-Coco, F AF Ascoli, V Signoretti, S Onetti-Muda, A Pescarmona, E Della-Rocca, C Nardi, F Mastroianni, CM Gastaldi, R Pistilli, A Gaidano, G Carbone, A Lo-Coco, F TI Primary effusion lymphoma in HIV-infected patients with multicentric Castleman's disease SO JOURNAL OF PATHOLOGY LA English DT Article DE Kaposi's sarcoma; primary effusion lymphoma; multicentric Castleman's disease; human herpesvirus-8; body cavity; lambda light chain ID EPSTEIN-BARR-VIRUS; POLYMERASE-CHAIN-REACTION; SYSTEMIC LYMPHOPROLIFERATIVE DISORDER; ACQUIRED IMMUNODEFICIENCY SYNDROME; NON-HODGKINS-LYMPHOMA; KAPOSIS-SARCOMA; NODE HYPERPLASIA; DNA-SEQUENCES; MORPHOLOGIC FEATURES; POEMS SYNDROME AB Multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL) are two B-cell lymphoproliferative diseases associated with Kaposi's sarcoma-associated herpes virus/human herpesvirus-8 (KSHV/HHV-8). Although MCD is considered a prelymphoma state, it is not known whether a pathogenetic link exists between MCD and PEL, This paper reports the clinicopathological features of four cases of PEL (two pericardial, one pleural, and one peritoneal) developing in the context of HIV-associated MCD. Effusions, lymph nodes, spleen, and additional tissues from three autopsies were examined for morphology/immunophenotype, search for HHV-8 DNA, and assessment of immunoglobulin heavy chain gene (IgH) configuration using polymerase chain reaction (PCR)-based techniques. MCD and PEL samples contained HHV-8 DNA, Clonal IgH rearrangements were detected only in PEL, whereas MCD tissues were polyclonal. Light-chain immunostaining confirmed B-cell clonality in PEL (two lambda, one kappa, one not tested) and polyclonality in MCD, The autopsies revealed different morphological variants of visceral KS and multi-organ atypical infiltrates exhibiting immunoblastic/plasmablastic features reminiscent of PEL morphology, with a restriction of lambda-positive cells. In two cases, using microdissection and IgH PCR analysis, multiple/discrete bands were found in the infiltrates, compatible with polyclonality/oligoclonality. The case showing an oligoclonal IgH ladder contained a rearrangement of identical junctional size to the PEL clone; however, further analysis with PEL-derived clonotypic primers and sequencing of PCR products showed no amplification and nucleotide diversity, respectively, indicating that the two B-cell populations examined were clonally unrelated. These data show that MCD and PEL may co-exist in HIV-infected patients, suggesting a relevant association between these two HHV-8-related disorders. Although a definite clonal relationship between MCD and PEL was not demonstrated, it is hypothesized that in some MCD cases, within expanded polyclonal B-cell populations secondary to HHV-8 infection, clonal expansions may occur that localize into a body cavity, i.e. PEL, Copyright (C) 2000 John Wiley & Sons, Ltd. C1 Univ La Sapienza, Dipartimento Med Sperimentale & Patol, I-00161 Rome, Italy. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Univ La Sapienza, Dipartimento Malattie Infettive & Tropicali, Rome, Italy. Univ La Sapienza, Dipartimento Biotecnol Cellulann & Ematol, Rome, Italy. Univ Piemonte Orientale Amedeo Avogadro, Dipartimento Sci Med, Div Med Interna, Novara, Italy. IRCCS, Ctr Riferimento Oncol, Aviano, Italy. RP Ascoli, V (reprint author), Univ La Sapienza, Dipartimento Med Sperimentale & Patol, Viale Regina Elena 324, I-00161 Rome, Italy. RI Onetti Muda, Andrea/G-5384-2012; OI MASTROIANNI, Claudio Maria/0000-0002-1286-467X NR 45 TC 28 Z9 28 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0022-3417 J9 J PATHOL JI J. Pathol. PD FEB PY 2001 VL 193 IS 2 BP 200 EP 209 PG 10 WC Oncology; Pathology SC Oncology; Pathology GA 396CU UT WOS:000166619400010 PM 11180167 ER PT J AU Blais, MA Hilsenroth, MJ Castlebury, F Fowler, JC Baity, MR AF Blais, MA Hilsenroth, MJ Castlebury, F Fowler, JC Baity, MR TI Predicting DSM-IV Cluster B personality disorder criteria from MMPI-2 and Rorschach data: A test of incremental validity SO JOURNAL OF PERSONALITY ASSESSMENT LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-of-Personality-Assessment CY FEB 20, 1998 CL BOSTON, MASSACHUSETTS SP Soc Personal Assessment ID RESPONSE-FREQUENCY; TEST USAGE; SCALES; INDEXES; INTERRELATIONSHIPS; ADOLESCENTS; RELIABILITY; BORDERLINE; MODELS; MCMI AB Despite their frequent conjoint clinical use, the incremental validity of Rorschach (Rorschach, 1921/1942) and MMPI (Hathaway & McKinley, 1943) data has not been adequately established, nor has any study to date explored the incremental validity of these tests for predicting Diagnostic and Statistical Manual of Mental Disorders (4th ed. [DSM-IV]; American Psychiatric Association, 1995) personality disorders (PDs). In a reanalysis of existing data, we used select Rorschach variables and the MMPI PD scales to predict DSM-IV antisocial, borderline, histrionic, and narcissistic PD criteria in a sample of treatment-seeking outpatients. The correlational findings revealed a limited relation between Rorschach and MMPI-2 (Butcher, Dahlstrom, Graham, Tellegen, Sr. Kaemmer, 1989) variables, with only 5 of 30 correlations reaching significance (p < .05). Hierarchical regression analyses showed that both the MMPI and Rorschach data add incrementally in the prediction of DSM-IV borderline and narcissistic PD total criteria scores. The findings were less clear for the incremental value of Rorschach and MMPI-2 data in predicting the total number of DSM-IV histrionic PD criteria, which were best predicted by Rorschach data, and antisocial PD criteria, which were best predicted by MMPI-2 data. In addition to providing evidence of the incremental validity of Rorschach data, these findings also shed light on the psychological characteristics of the DSM-IV Cluster B PDs. C1 Massachusetts Gen Hosp, Inpatient Psychiat Serv, Boston, MA 02114 USA. Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. Austen Riggs Ctr, Erik H Erikson Inst Training & Res, Stockbridge, MA USA. RP Blais, MA (reprint author), Massachusetts Gen Hosp, Inpatient Psychiat Serv, Blake 11,55 Fruit St, Boston, MA 02114 USA. NR 63 TC 39 Z9 40 U1 0 U2 13 PU LAWRENCE ERLBAUM ASSOC INC PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430-2262 USA SN 0022-3891 J9 J PERS ASSESS JI J. Pers. Assess. PD FEB PY 2001 VL 76 IS 1 BP 150 EP 168 DI 10.1207/S15327752JPA7601_9 PG 19 WC Psychology, Clinical; Psychology, Social SC Psychology GA 398MK UT WOS:000166760100009 PM 11206295 ER PT J AU Huang, X Keskin, SS Gullu, G Olmez, I AF Huang, X Keskin, SS Gullu, G Olmez, I TI Wet deposition flux of trace elements to the Adirondack region SO JOURNAL OF RADIOANALYTICAL AND NUCLEAR CHEMISTRY LA English DT Article AB Wet deposition samples from two locations in the Adirondack region of New York were analyzed for trace elemental composition by instrumental neutron activation analysis. Annual fluxes of the measured species were determined by precipitation-weighted and linear-regression methods. Despite several episodes of high deposition fluxes, the cumulative areal wet deposition of trace elements increased fairly linearly (r(2)>0.9) over the two year sampling period at both sites. This implies that short duration sampling programs may be used to estimate long-term fluxes and cumulative wet deposition impacts. Based on the magnitude of their fluxes. the measured species have been divided into four groups: acidic onions, electroneutral balancing cations. and minor and trace elements anthropogenic origin. C1 MIT, Nucl Reactor Lab, Cambridge, MA 02139 USA. RP Huang, X (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 7 TC 2 Z9 2 U1 1 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0236-5731 J9 J RADIOANAL NUCL CH JI J. Radioanal. Nucl. Chem. PD FEB PY 2001 VL 247 IS 2 BP 317 EP 323 DI 10.1023/A:1006749517167 PG 7 WC Chemistry, Analytical; Chemistry, Inorganic & Nuclear; Nuclear Science & Technology SC Chemistry; Nuclear Science & Technology GA 410YR UT WOS:000167469100008 ER PT J AU Chen, HJL Bloch, KJ AF Chen, HJL Bloch, KJ TI Hypocomplementemic urticarial vasculitis, Jaccoud's arthropathy, valvular heart disease, and reversible tracheal stenosis: A surfeit of syndromes SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE hypocomplementemic urticarial vasculitis; Jaccoud's arthropathy; valvular heart disease ID SYSTEMIC LUPUS-ERYTHEMATOSUS; AIRWAY-OBSTRUCTION; IGG AUTOANTIBODIES; C1Q AB We describe a patient who, during 29 years of observation, manifested polyarthralgia and polyarthritis leading to progressive deformity of the joints of hands and feet (without loss of cartilage or erosion of bone): persistent urticaria made worse by cold and accompanied by hypocomplementemia; and progressive cardiac valvular disease with mitral and aortic stenosis and regurgitation. In 1996, she developed subglottic tracheal stenosis that resolved by the end of 1997 without a change in treatment, which has consisted of low dose azathioprine, glucocorticoid, and nonsteroidal antiinflammatory drugs. Tests for cryoprecipitable protein, antineutrophil cytoplasmic antibodies, antinuclear antibody, and rheumatoid factor were negative. Skin biopsy was consistent with "leukocytoclastic vasculitis." The pathogenesis of this remarkable combination of syndromes is unknown. C1 Massachusetts Gen Hosp, Clin Immunol Unit, Gen Med Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Allergy Unit, Gen Med Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Bloch, KJ (reprint author), Massachusetts Gen Hosp, Clin Immunol Unit, Gen Med Serv, Bulfinch 422,55 Fruit St, Boston, MA 02114 USA. NR 14 TC 13 Z9 15 U1 0 U2 0 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD FEB PY 2001 VL 28 IS 2 BP 383 EP 386 PG 4 WC Rheumatology SC Rheumatology GA 402EP UT WOS:000166973300033 PM 11246684 ER PT J AU Rubin, JP Cober, SR Butler, PEM Randolph, MA Gazelle, GS Ierino, FL Sachs, DH Lee, WPA AF Rubin, JP Cober, SR Butler, PEM Randolph, MA Gazelle, GS Ierino, FL Sachs, DH Lee, WPA TI Injection of allogeneic bone marrow cells into the portal vein of swine in utero SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE fetus; bone marrow; tolerance; portal vein; ultrasound; chimerism ID MINIATURE SWINE; STEM-CELLS; TRANSPLANTATION; INUTERO; ALLOGRAFTS; CHIMERISM; TOLERANCE; MONKEYS; MICE AB The ability to safely manipulate the immune system of the developing fetus carries the hope of effective treatment strategies for certain congenital disorders that can be diagnosed during gestation. One possible intervention is the induction of specific transplantation tolerance to an adult donor who could provide tissue after birth without the need for immunosuppression. Although the introduction of allogeneic stem cells to a developing immune system has been shown to result in hematopoietic chimerism, donor-specific transplantation tolerance has not been demonstrated in a large animal model. In previous reports of in utero stem-cell transplantation, the cells were injected into the fetus by an intraperitoneal route. We sought to improve upon this technique of cell transplantation by developing a method for the safe delivery of allogeneic stem cells directly into the hepatic circulation of fetal swine. In the second phase of our study, we determined if adult allogeneic bone marrow cells delivered to the fetus by this intravascular route could result in result in hematopoietic chimerism and donor-specific transplantation tolerance. A method of successful intravascular injection was designed in which a laparotomy was performed on a sow at midgestation (50-55 days) to administer 1 cc of inoculum into the portal vein of each fetus using transuterine ultrasound guidance and a 25-gauge spinal needle. In one sow, 10 piglets were injected with saline to test safety, and 8 piglets were born. For transplantation of stem cells to the fetuses, donor bone marrow was harvested from a genetically defined miniature swine. In one sow the marrow was injected without T-cell depletion resulting in abortion. In the third sow, the marrow was depleted of T-cells to less than 0.01% using magnetic beads conjugated to anti-CDS monoclonal antibodies. No chimerism was detected in these offspring. Only in the fourth sow where the T-cell depletion was reduced to about 1% of the cells in the inoculum did one animal demonstrate chimerism. This piglet showed reproducible blood chimerism (0.95% donor cells) detected by how cytometry measurement of monoclonal antibodies to the donor MHC. In addition, this animal demonstrated hyporesponsiveness to donor lymphocytes in an MLR assay while reacting strongly to third-party stimulator cells. A split-thickness skin graft from the donor was accepted, and a third-party graft was rapidly rejected. (C) 2000 Academic Press. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. RP Lee, WPA (reprint author), Massachusetts Gen Hosp, Div Plast Surg, WACC 453, Boston, MA 02114 USA. OI Butler, Peter/0000-0001-7419-1493 NR 22 TC 16 Z9 16 U1 0 U2 1 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 FEB PY 2001 VL 95 IS 2 BP 188 EP 194 DI 10.1006/jsre.2000.6044 PG 7 WC Surgery SC Surgery GA 399GM UT WOS:000166803300016 PM 11162044 ER PT J AU Kalluri, R Shera, CA AF Kalluri, R Shera, CA TI Distortion-product source unmixing: A test of the two-mechanism model for DPOAE generation SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID EVOKED OTOACOUSTIC EMISSIONS; COCHLEAR HEARING-LOSS; FINE-STRUCTURE; ACOUSTIC DISTORTION; AUDITORY-SENSITIVITY; FREQUENCY PLACE; GUINEA-PIG; TONE; SUPPRESSION; LATENCY AB This paper tests key predictions of the "two-mechanism model" for the generation of distortion-product otoacoustic emissions (DPOAEs). The two-mechanism model asserts that lower-sideband DPOAEs constitute a mixture of emissions arising not simply from two distinct cochlear locations las is now well established) but, more importantly, by two fundamentally different mechanisms: nonlinear distortion induced by the traveling wave and linear coherent reflection off pre-existing micromechanical impedance perturbations. The model predicts that (1) DPOAEs evoked by frequency-scaled stimuli (e.g., at fixed f(2)/f(1)) can be unmixed into putative distortion- and reflection-source components with the frequency dependence of their phases consistent with the presumed mechanisms of generation; (2) The putative reflection-source component of the total DPOAE closely matches the reflection-source emission (e.g., low level stimulus-frequency emission) measured at the same frequency under similar conditions. These predictions were tested by unmixing DPOAEs into components using two completely different methods: (a) selective suppression of the putative reflection source using a third tone near the distortion-product frequency and (b) spectral smoothing (or, equivalently, time-domain windowing). Although the two methods unmix in very different ways, they yield similar DPOAE components. The properties of the two DPOAE components are consistent with the predictions of the two-mechanism model. (C) 2001 Acoustical Society of America. C1 Massachusetts Eye & Ear Infirm, Eaton Peabody Lab Auditory Physiol, Boston, MA 02114 USA. Harvard Univ, MIT, Div Hlth Sci & Technol, Speech & Hearing Sci Program, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Massachusetts Eye & Ear Infirm, Eaton Peabody Lab Auditory Physiol, 243 Charles St, Boston, MA 02114 USA. FU NIDCD NIH HHS [R01 DC003687, R01 DC03687, T32 DC00038] NR 55 TC 120 Z9 125 U1 1 U2 5 PU ACOUSTICAL SOC AMER AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0001-4966 EI 1520-8524 J9 J ACOUST SOC AM JI J. Acoust. Soc. Am. PD FEB PY 2001 VL 109 IS 2 BP 622 EP 637 DI 10.1121/1.1334597 PG 16 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA 400EX UT WOS:000166860200019 PM 11248969 ER PT J AU Elbaum, M Kopf, AW Rabinovitz, HS Langley, RGB Kamino, H Mihm, MC Sober, AJ Peck, GL Bogdan, A Gutkowitcz-Krusin, D Greenebaum, M Keem, S Oliviero, M Wang, S AF Elbaum, M Kopf, AW Rabinovitz, HS Langley, RGB Kamino, H Mihm, MC Sober, AJ Peck, GL Bogdan, A Gutkowitcz-Krusin, D Greenebaum, M Keem, S Oliviero, M Wang, S TI Automatic differentiation of melanoma from melanocytic nevi with multispectral digital dermoscopy: A feasibility study SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID PIGMENTED SKIN-LESIONS; INVIVO EPILUMINESCENCE MICROSCOPY; MALIGNANT-MELANOMA; DIAGNOSIS; ACQUISITION; CAMERA AB Background: Differentiation of melanoma from melanocytic nevi is difficult even for skin cancer specialists. This motivates interest in computer-assisted analysis of lesion images. Objective: Our purpose was to offer fully automatic differentiation of melanoma from dysplastic and other melanocytic nevi through multispectral digital dermoscopy. Method: At 4 clinical centers, images were taken of pigmented lesions suspected of being melanoma before biopsy Ten gray-level (MelaFind) images of each lesion were acquired, each in a different portion of the visible and near-infrared spectrum. The images of 63 melanomas (33 invasive, 30 in situ) and 183 melanocytic nevi (of which 111 were dysplastic) were processed automatically through a computer expert system to separate melanomas from nevi. The expert system used either a linear or a nonlinear classifier. The "gold standard" for training and testing these classifiers was concordant diagnosis by two dermatopathologists. Results: On resubstitution, 100% sensitivity was achieved at 85% specificity with a W-parameter linear classifier and 100%-/73% with a 12-parameter nonlinear classifier. Under leave-one-out cross-validation, the linear classifier gave 100%/84% (sensitivity/specificity), whereas the nonlinear classifier gave 95%/68%. Infrared image features were significant, as were features based on wavelet analysis. Conclusion: Automatic differentiation of invasive and in situ melanomas from melanocytic nevi is feasible, through multispectral digital dermoscopy. C1 Electroopt Sci Inc, Irvington, NY 10533 USA. NYU, Sch Med, New York, NY USA. Skin & Canc Associates, Plantation, FL USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Washington Canc Inst, Washington, DC USA. RP Elbaum, M (reprint author), Electroopt Sci Inc, 1 Bridge St,Suite 15, Irvington, NY 10533 USA. OI Kamino, Hideko/0000-0001-9256-5284 FU NCI NIH HHS [1R43 CA74628-01, 2R44 CA/AR60299-02, 2R44 CA74628-02] NR 29 TC 123 Z9 123 U1 1 U2 4 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD FEB PY 2001 VL 44 IS 2 BP 207 EP 218 DI 10.1067/mjd.2001.110395 PG 12 WC Dermatology SC Dermatology GA 398EX UT WOS:000166744900006 PM 11174377 ER PT J AU Wong, P Choo, JK Inglessis, I Choi, CJ Oesterle, SN Gimelli, G Jang, IK AF Wong, P Choo, JK Inglessis, I Choi, CJ Oesterle, SN Gimelli, G Jang, IK TI The effect of glycoprotein (GP) IIb/IIIa receptor inhibitor, Tirofiban, on the microcirculation in patients undergoing high-risk coronary stenting SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 31A EP 31A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914400140 ER PT J AU Reifart, N Hauptmann, E Yeung, A Hayase, M Oesterle, SN AF Reifart, N Hauptmann, E Yeung, A Hayase, M Oesterle, SN TI The first successful clinical case of a novel catheter-based coronary artery bypass procedure: Percutaneous in-situ coronary venous arterialization SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Krankenhaus Barmherzigen Bruder, Trier, Germany. Massachusetts Gen Hosp, 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 59A EP 59A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914400271 ER PT J AU Kusumoto, W Raitt, MH AF Kusumoto, W Raitt, MH TI Atrial electrical remodeling following cardioversion of atrial fibrillation in humans SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Portland VA Med Ctr, Portland, OR USA. Oregon Hlth Sci Univ, Portland, OR 97201 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 102A EP 102A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914400468 ER PT J AU Choo, JK Abernethy, WB Hutter, AM AF Choo, JK Abernethy, WB Hutter, AM TI The electrocardiographic (ECG) pattern is frequently abnormal in professional football players: An analysis in 1282 athletes SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 115A EP 115A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914400529 ER PT J AU Ammer, R Keane, D Ruskin, JN Aretz, T AF Ammer, R Keane, D Ruskin, JN Aretz, T TI Goats in chronic atrial fibrillation show apoptotic atrial myocytes and Bcl-2 upregulation in ventricular myocytes SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. German Heart Ctr, D-8000 Munich, Germany. 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 120A EP 121A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914400554 ER PT J AU Lloyd-Jones, DM Larson, MG Beiser, A D'Agostino, RB Vasan, RS Benjamin, EJ Levy, D AF Lloyd-Jones, DM Larson, MG Beiser, A D'Agostino, RB Vasan, RS Benjamin, EJ Levy, D TI Increasing pulse pressure contributes to lifetime risk of congestive heart failure SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Lloyd-Jones, Donald/C-5899-2009 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 157A EP 157A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914400717 ER PT J AU Ansari, MN Tutar, A Bullard, J Teerlink, JR Massie, BM AF Ansari, MN Tutar, A Bullard, J Teerlink, JR Massie, BM TI Heart failure in a veteran cohort: Predictors of outcome SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 San Francisco VAMC, San Francisco, CA USA. UCSF, San Francisco, CA USA. RI Teerlink, John/D-2986-2012 NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 158A EP 158A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914400721 ER PT J AU Nemoto, S DeFreitas, G Mann, DL Carabello, BA AF Nemoto, S DeFreitas, G Mann, DL Carabello, BA TI Which contractile index is most sensitive in examining murine cardiac contractility? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 VA Med Ctr, Houston, TX USA. Baylor Coll Med, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 216A EP 216A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914400986 ER PT J AU Nikolaidis, LA Egan, JM Elahi, D Shannon, RP AF Nikolaidis, LA Egan, JM Elahi, D Shannon, RP TI GLP-1 improves myocardial performance in conscious dogs with pacing induced heart failure SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 218A EP 218A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914400996 ER PT J AU Beran, GP Post, M Simons, M Glogar, D Laham, RJ AF Beran, GP Post, M Simons, M Glogar, D Laham, RJ TI Biosense NOGA mapping for detection of myocardial ischemia: Comprehensive assessment in 74 pigs SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, BIDMC, Boston, MA 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 329S EP 329S PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401518 ER PT J AU Kapadia, SR Martin, GV Flores, JR Anderson, RV Caldwell, JH Lehmann, KG AF Kapadia, SR Martin, GV Flores, JR Anderson, RV Caldwell, JH Lehmann, KG TI Isolated left main trunk stenosis: How common is it? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 VA Puget Sound Hlth Care Syst, Seattle, WA USA. Univ Washington, Seattle, WA 98195 USA. NR 0 TC 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 375A EP 375A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401722 ER PT J AU Fox, ER Picard, MH Chow, CM Levine, RA Kerr, AJ AF Fox, ER Picard, MH Chow, CM Levine, RA Kerr, AJ TI Interatrial septal aneurysms predict larger shunts across patent foramen ovales: An analysis by transmitral Doppler SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 379A EP 379A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401737 ER PT J AU Kerr, AJ Picard, MH Chow, CM Levine, RA Schwamm, LH AF Kerr, AJ Picard, MH Chow, CM Levine, RA Schwamm, LH TI Degree of patent foramen ovale shunting quantified by transthoracic transmitral Doppler is associated with likelihood of cryptogenic cerebral ischemic events SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 379A EP 379A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401736 ER PT J AU Danias, PG Tritos, NA Stuber, M Salton, CJ Kissinger, KV Manning, WJ AF Danias, PG Tritos, NA Stuber, M Salton, CJ Kissinger, KV Manning, WJ TI Obesity is associated with altered apical left ventricular rotation: A cardiac magnetic resonance tagging study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Joslin Diabet Ctr, Boston, MA 02215 USA. RI Stuber, Matthias/B-2949-2010 OI Stuber, Matthias/0000-0001-9843-2028 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 392A EP 392A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401795 ER PT J AU Beeri, R Leavitt, M Palacios, IF Levine, RA AF Beeri, R Leavitt, M Palacios, IF Levine, RA TI Prevalence and coronary correlations of the T-sign in patients with inferior left ventricular wall motion abnormalities: Clue to avoid right ventricular neglect SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Beeri, Ronen/A-4035-2009 OI Beeri, Ronen/0000-0002-8014-0702 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 394A EP 394A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401802 ER PT J AU Zabalgoitia, M Erikson, J Oraby, MA Delgado, A AF Zabalgoitia, M Erikson, J Oraby, MA Delgado, A TI Myocardial contrast echocardiography in conjunction with dipyridamole thallium SPECT in assessing myocardial perfusion in patients with suspected coronary artery disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Audie L Murphy Mem Vet Hosp, San Antonio, TX 78284 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 411A EP 411A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401873 ER PT J AU Abernethy, WB Choo, JK Hutter, AM AF Abernethy, WB Choo, JK Hutter, AM TI Echocardiographic characteristics of professional football players SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 430A EP 431A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401962 ER PT J AU Sekar, NS King, ME MacQuillan, BM Hung, JW Januzzi, JL Palacios, IF Picard, MH AF Sekar, NS King, ME MacQuillan, BM Hung, JW Januzzi, JL Palacios, IF Picard, MH TI Atrial septal mobility does not prevent successful transcatheter closure of patent foremen ovale SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 430A EP 430A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914401961 ER PT J AU Hung, J Guerrero, JL Handschumacher, MD Sullivan, S Supple, GE Levine, RA AF Hung, J Guerrero, JL Handschumacher, MD Sullivan, S Supple, GE Levine, RA TI Repositioning of the papillary muscles using external myocardial devices: A novel approach to repair of ischemic mitral regurgitation. SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 481A EP 481A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914402183 ER PT J AU Chow, CM Levine, RA Handschumacher, MD Messas, E Feinberg, MS Schwammenthal, E AF Chow, CM Levine, RA Handschumacher, MD Messas, E Feinberg, MS Schwammenthal, E TI Aortic stenosis with poor ventricular function: Aortic valve pliability at rest predicts results of dobutamine testing SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 482A EP 482A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914402190 ER PT J AU Freed, LA Benjamin, EJ Levy, D Larson, MG Evans, JC Fuller, DL Lehman, B Levine, RA AF Freed, LA Benjamin, EJ Levy, D Larson, MG Evans, JC Fuller, DL Lehman, B Levine, RA TI The progression of mitral valve prolapse: A follow-up investigation in the Framingham Heart Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 SU A BP 490A EP 490A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401EM UT WOS:000166914402226 ER PT J AU Otsuji, Y Handschumacher, MD Liel-Cohen, N Tanabe, H Jiang, L Schwammenthal, E Guerrero, JL Nicholls, LA Vlahakes, GJ Levine, RA AF Otsuji, Y Handschumacher, MD Liel-Cohen, N Tanabe, H Jiang, L Schwammenthal, E Guerrero, JL Nicholls, LA Vlahakes, GJ Levine, RA TI Mechanism of ischemic mitral regurgitation with segmental left ventricular dysfunction: Three-dimensional echocardiographic studies in models of acute and chronic progressive regurgitation SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID DOPPLER COLOR-FLOW; PAPILLARY-MUSCLE DYSFUNCTION; 3-DIMENSIONAL ECHOCARDIOGRAPHY; MYOCARDIAL-INFARCTION; VALVE-REPLACEMENT; HEART-FAILURE; 3 DIMENSIONS; ORIFICE AREA; SURVIVAL; RECONSTRUCTION AB OBJECTIVES This study aimed to separate proposed mechanisms for segmental ischemic mitral regurgitation (MR), including left ventricular (LV) dysfunction versus geometric distortion by LV dilation, using models of acute and chronic segmental ischemic LV dysfunction evaluated by three-dimensional (3D) echocardiography. BACKGROUND Dysfunction and dilation-both mechanisms with practical therapeutic implications-are difficult to separate in patients. METHODS In seven dogs with acute left circumflex (LCX) coronary ligation, LV expansion was initially restricted and then permitted to occur. In seven sheep with LCX branch ligation, LV expansion was also initially limited but became prominent with remodeling over eight weeks. Three-dimensional echo reconstruction quantified mitral apparatus geometry and MR volume. RESULTS In the acute model, despite LV dysfunction with ejection fraction = 23 +/- 8%, MR was initially trace with limited LV dilation, but it became moderate with subsequent prominent dilation. In the chronic model, MR was also initially trace, but it became moderate over eight weeks as the LV dilated and changed shape. In both models, the only independent predictor of MR volume was increased tethering distance from the papillary muscles (PMs) to the anterior annulus, especially medial and posterior shift of the ischemic medial PM, measured by 3D reconstruction (r(2) = 0.75 and 0.86, respectively). Mitral regurgitation volume did not correlate with LV ejection fraction or dP/dt. CONCLUSIONS Segmental ischemic LV contractile dysfunction without dilation, even in the PM territory, fails to produce important MR. The development of MR relates strongly to changes in the 3D geometry of the mitral apparatus, with implications for approaches to restore a more favorable configuration. (C) 2001 by the American College of Cardiology. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac Ultrasound Lab,Dept Med & Surg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Surg Unit,Dept Med & Surg, Boston, MA 02115 USA. RP Levine, RA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac Ultrasound Lab,Dept Med & Surg, Boston, MA 02115 USA. FU NHLBI NIH HHS [HL 38176, HL 53702] NR 48 TC 184 Z9 196 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2001 VL 37 IS 2 BP 641 EP 648 DI 10.1016/S0735-1097(00)01134-7 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 400AV UT WOS:000166847200043 PM 11216991 ER PT J AU Weyman, AE Butler, A Subhiyah, R Appleton, C Geiser, E Goldstein, SA King, ME Kaul, S Labovitz, A Picard, M Ryan, T Shanewise, J AF Weyman, AE Butler, A Subhiyah, R Appleton, C Geiser, E Goldstein, SA King, ME Kaul, S Labovitz, A Picard, M Ryan, T Shanewise, J TI Concept, development, administration, and analysis of a certifying examination in echocardiography for physicians SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article AB In 1993, the American Society of Echocardiography appointed a committee to develop an objective examination in echocardiography. In 1995, a pilot of this examination was administered, with operational examinations offered each year from 1996 to 1999. This report describes the development of the examination, including its underlying philosophy, the test itself, and the scoring process, and includes results from the first 4 examinations. To date, 1266 physicians have taken the examination, and roughly 60% of those have passed. The number of echocardiograms performed or interpreted each week had the largest effect on examination scores; the effects of both the amount of training and the practice discipline were small but significant. The evolution of the original committee and new directions for the testing organization are also discussed. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Mayo Clin, Natl Board Med Examiners, Scottsdale, AZ USA. Washington Hosp Ctr, Washington, DC 20010 USA. Univ Florida, Gainesville, FL USA. Univ Virginia, Charlottesville, VA USA. St Louis Univ, Hlth Sci Ctr, St Louis, MO 63103 USA. Duke Univ, Med Ctr, Durham, NC USA. Emory Univ Hosp, Atlanta, GA 30322 USA. RP Weyman, AE (reprint author), Massachusetts Gen Hosp, VBK 508,55 Fruit St, Boston, MA 02114 USA. OI Picard, Michael/0000-0002-9264-3243 NR 5 TC 10 Z9 10 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 FEB PY 2001 VL 14 IS 2 BP 158 EP 168 DI 10.1067/mje.2001.108119 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 402YT UT WOS:000167016300013 PM 11174452 ER PT J AU Shrager, JB Kim, DK Hashmi, YJ Lankford, EB Wahl, P Stedman, HH Levine, S Kaiser, LR AF Shrager, JB Kim, DK Hashmi, YJ Lankford, EB Wahl, P Stedman, HH Levine, S Kaiser, LR TI Lung volume reduction surgery restores the normal diaphragmatic length-tension relationship in emphysematous rats SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article; Proceedings Paper CT 80th Annual Meeting of the American-Association-for-Thoracic-Surgery CY APR 30-MAY 03, 2000 CL TORONTO, CANADA SP Amer Assoc Thorac Surg ID RESPIRATORY MUSCLE FUNCTION; ELASTASE-INDUCED EMPHYSEMA; HAMSTERS; DYSPNEA; ADAPTABILITY; IMPROVEMENT; MECHANICS; EXERCISE; DISEASE; RECOIL AB Objective: Improved respiratory muscle function is a major effect of a lung volume reduction surgery. We studied length adaptation in rat diaphragmatic muscle in an attempt to elucidate the mechanism by which diaphragmatic function improves after this controversial operation. Methods: We developed a model of elastase-induced emphysema and bilateral volume reduction through median sternotomy in rats. Five months after emphysema induction, maximum exchangeable lung volume was determined in intubated and anesthetized control animals and animals with emphysema. Costal diaphragmatic length was measured in vivo, and the length at which maximal twitch force is generated was determined on muscle strips in vitro, Also 5 months after elastase administration, another cohort underwent volume reduction or sham sternotomy. Five months after the operation, these animals were similarly studied. Results: Lung volume was increased in emphysematous rats versus control rats (50.9 +/- 1.7 vs 45.4 +/- 1.3 mL, P = 001). Lung volume was decreased in emphysematous animals that had undergone volume reduction versus sham sternotomy (44.7 +/- 0.60 vs 49.4 +/- 1.0 mL, P = .001). In situ diaphragm length (1.99 +/- 0.04 vs 2.24 +/- 0.07 cm, P = .001) and the length at which maximal twitch force is generated (2.25 +/- 0.06 vs 2.48 +/- 0.09 cm, P = .038) were shorter in emphysematous than control animals. After volume reduction, in situ diaphragm length (2.13 +/- 0.06 vs 1.83 +/- 0.02 cm, P < .001) and the length at which maximal twitch force is generated (2.50 0.08 vs 2.27 +/- 0.06 cm, P = .013) were longer than in animals undergoing sham sternotomy. Conclusions: In this experimental model of emphysema and lung volume reduction surgery, emphysema shortens the length at which maximal twitch force is generated and shifts the diaphragmatic length-tension curve to lower lengths; volume reduction returns the length at which maximal twitch force is generated toward normal and shifts the diaphragmatic length-tension curve back to longer lengths. This restoration toward normal physiology may enable the improvement in diaphragmatic function seen after lung volume reduction surgery. The mechanism by which these length adaptations occur merits further investigation. C1 Univ Penn, Sch Med, Dept Surg, Sect Gen Thorac Surg, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Penn Muscle Inst, Philadelphia, PA 19104 USA. Philadelphia Vet Affairs Med Ctr, Dept Surg, Philadelphia, PA USA. Philadelphia Vet Affairs Med Ctr, Dept Med, Philadelphia, PA USA. Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. RP Shrager, JB (reprint author), Hosp Univ Penn, 6 Silverstein Pavil,3400 Spruce St, Philadelphia, PA 19104 USA. NR 22 TC 10 Z9 11 U1 1 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD FEB PY 2001 VL 121 IS 2 BP 217 EP 224 DI 10.1067/mtc.2001.111208 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 402XW UT WOS:000167014300006 PM 11174726 ER PT J AU Shipp, TD Bromley, B Mascola, M Benacerraf, B AF Shipp, TD Bromley, B Mascola, M Benacerraf, B TI Variation in fetal femur length with respect to maternal race SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article ID BIPARIETAL DIAMETER; GESTATIONAL-AGE; DOWNS-SYNDROME; FETUSES AB We sought to evaluate whether the expected fetal femur length, based on biparietal diameter, varies in second-trimester fetuses with respect to maternal race. The study population was composed of all fetuses scanned from 15 to 20 completed weeks' gestation during a 2-month period (June to August 1998). Maternal race was documented at the time of the ultrasonographic: examination. Biparietal diameter and femur length were prospectively documented. The variance from the expected femur length, given the biparietal diameter, was calculated, and the mean variations were compared according to maternal race. The study subgroups were composed of the fetuses of 39 Asian mothers, 31 black mothers, and the first 100 white mothers. The mean values of the variance from the expected fetal femur length by biparietal diameter +/- 1 SD for the various racial groups were as follows: fetuses of Asian mothers, -0.66 +/- 1.64 mm; fetuses of black mothers, 0.88 +/- 1.57 mm; and fetuses of white mothers, 0.13 +/- 1.66 mm (P = .0007). To isolate the differences among the 3 racial groups, the mean values of the variance from the expected femur length by biparietal diameter for the fetuses of Asian and black mothers were compared with the mean value for the fetuses of white mothers (Asian versus white mothers, P = .014; black versus white mothers, P = .026). A significant difference in the mean variance from the expected femur length by biparietal diameter was identified among the fetuses of women in the second trimester with respect to racial group. Less-than-expected femur lengths were noted among the fetuses of Asian mothers, and greater-than-expected femur lengths were noted among the fetuses of black mothers, compared with the femurs of fetuses of white mothers. The implications for the use of fetal femur length as a component of the genetic sonogram in patients of various races require further study. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA USA. RP Shipp, TD (reprint author), Diagnost Ultrasound Associates PC, 333 Longwood Ave,Suite 400, Boston, MA 02115 USA. NR 15 TC 32 Z9 32 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 FEB PY 2001 VL 20 IS 2 BP 141 EP 144 PG 4 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 416AF UT WOS:000167755200008 PM 11211134 ER PT J AU Beebe, HG Cronenwett, JL Katzen, BT Brewster, DC Green, RM AF Beebe, HG Cronenwett, JL Katzen, BT Brewster, DC Green, RM CA Vanguard Endograft Trial Investiga TI Results of an aortic endograft trial: Impact of device failure beyond 12 months SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT 48th Annual Meeting of the North American Chapter of the International-Society-for-Cardiovascular-Surgery/54th Annual Meeting of the Society-for-Vascular-Surgery CY JUN 10-14, 2000 CL TORONTO, CANADA SP Int Soc Cardiovascular, N Amer Chapter, Soc Vascular Surg ID ANEURX STENT GRAFT; ENDOVASCULAR REPAIR; PERIPROSTHETIC LEAK; ENDOLUMINAL REPAIR; RUPTURE AB Purpose: Analysis endpoints of patient survival and aortic rupture at a reporting interval of 12 months are regularly used to compare endograft aortic aneurysm (EAG) repair to conventional open surgical (COS) repair. This study reports a multicenter EAG repair versus COS repair parallel cohort trial at 12 months and additional observations of specific device failure types and their impact on an aortic endograft design beyond that follow-up period. Methods: From August 1997 to September 1998, 240 patients who were treated with bifurcation EAG repairs and 28 patients who were treated with straight EAG repairs were compared with 98 patients who were treated with COS repair for elective infrarenal aortic aneurysm repair. Allocation to treatment was based on aneurysm anatomy. All cohorts underwent infrarenal procedures. Data from concurrent, nonrandomized patient accrual from 17 United States institutions were prospectively gathered and independently adjudicated for safety and efficacy. An independent core laboratory evaluated all imaging data. Results: There were 308 men and 58 women (mean age, 72 years; range, 42-94 years) treated for infrarenal aortic aneurysm (mean diameter, 55 mm; range, 40-115 mm). Mean preoperative aneurysm diameters were clinically similar (EAG repair, 54 mm vs COS repair, 57 mm). The two cohorts were not significantly different in terms of gender (P = .30) or age (P = .32). EAG repair technical success (aneurysm exclusion, graft patency, patient survival) at 30 days was 89.2%. Five patients required immediate conversion to COS repair, four caused by access complications and one caused by operator-induced EAG repair malposition. The 30-day mortality rate was 1.5% for EAG repair and 3.1% for COS repair (P = .59). The 12-month survival rate was 94.3% for EAG repair and 95.9% for COS repair. The intermediate-term cumulative survival rate at 24 months was 84.9% for EAG repair and 80.3% for COS repair (P = .48). EAG repair device failure occurred from fabric erosion in six patients, with two deaths from ruptured aneurysm at 18 and 28 months after endografting and four device failures resolved by secondary procedures. Five endograft limb dislocations were all resolved by secondary endovascular procedures. Major or minor endograft migration required secondary procedures in five patients, including conversion in two patients. Conclusion: The clinical outcome at 12 months demonstrated effective aneurysm treatment and comparable safety between EAG repair and COS repair by conventional endpoints. Ongoing follow-up beyond 12 months revealed device-related adverse events that required endograft design changes. Diligent surveillance of outcomes beyond 12 months is necessary to adequately evaluate EAG repair devices. C1 Jobst Vasc Ctr, Toledo, OH 43606 USA. Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. Miami Cardiac & Vasc Inst, Miami, FL USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Rochester, Med Ctr, Rochester, NY 14642 USA. RP Beebe, HG (reprint author), Jobst Vasc Ctr, 2109 Hughes Dr,Suite 400, Toledo, OH 43606 USA. NR 22 TC 105 Z9 108 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD FEB PY 2001 VL 33 IS 2 SU S BP S55 EP S63 PG 9 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 408NP UT WOS:000167332500008 PM 11174813 ER PT J AU Moore, WS Brewster, DC Bernhard, VM AF Moore, WS Brewster, DC Bernhard, VM CA EVT Guidant Invest TI Aorto-uni-iliac endograft for complex aortoiliac aneurysms compared with tube/bifurcation endografts: Results of the EVT/Guidant trials SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT 48th Annual Meeting of the North American Chapter of the International-Society-for-Cardiovascular-Surgery/54th Annual Meeting of the Society-for-Vascular-Surgery CY JUN 10-14, 2000 CL TORONTO, CANADA SP Int Soc Cardiovasc Surg, N Amer Chapter, Soc Vasc Surg ID ENDOVASCULAR GRAFT PLACEMENT; STENT-GRAFT; FEMOROFEMORAL BYPASS; INITIAL EXPERIENCE; ENDOLUMINAL REPAIR; FOLLOW-UP; POPULATION; SURGERY; CLASSIFICATION; COMPLICATIONS AB Objective: Our objective was to present the results of the multicenter EVT/Guidant aorto-uni-iliac trial and to compare them with the tube, bifurcated graft, and open control series in regard to patient demographics, medical comorbidity, 30-day morbidity/mortality, and outcome at 1 year. Methods: One hundred twenty-one patients not eligible for tube or bifurcated endografts were entered into the aorto-uni-iliac trial (A-I). These were compared with 153 patients in a tube (T) group, 268 patients in a bifurcated endograft (BI) group, and 111 patients in an open control (C) group. Al data were audited and independently analyzed for presentation to the Food and Drug Administration. Results: Group demographics were similar with the following exceptions. Aneurysm diameter was significantly less in the T group (51.2 mm) but similar for the A-I (57 mm), BI (54.6 mm), and C (55.6 mm) groups (P < .001). There were more male patients in all endograft groups (A-I 92.6%, BI 89.5%, T 85.6% vs 76.6% for C, P = .002). Peripheral arterial occlusion was present more frequently in the A-I group (25.6% vs 13.8% BI, 10.5% T, and 10.8% C, P = .003). However, no differences were found in mean age, incidence of coronary artery disease, and American Society of Anesthesiologists III/IV classification. Implantation was achieved in 94.2% of the A-I group, 90.3% of the BI group, and 92% of the T group. No significant difference was seen in the operative mortality rate (4.2% A-I, 2.6% BI, 0% T, 2.7% C). Postoperative cardiac complications were similar for the A-I (22%) and C (20.7%) groups but significantly less for the BI and T groups (13.4% and 10.5%, P = .019), whereas pulmonary problems were significantly reduced in all endogaft groups (A-I 11.9%, BI 10.1%, and T 7.2% vs 22.5% for C, P = .002). Transient renal dysfunction occurred in 6.8% of the A-I group and 8.2% of the BI group but in only 3.3% of the T group and 1.8% of the C group (P = .028), Operating time was significantly longer for the A-I group than for the BI, T, or C groups (258 minutes vs 156, 179, and 174 minutes). Median blood loss, intensive care unit use, and hospital stays were markedly and significantly reduced in all endograft groups compared with the control group. The incidences of type I endoleak at 1 year were 2.4% A-I, 2.3% BI, and 3.8% T, and no ruptures occurred in any of the patients treated with endografts. No femoral-femoral graft thromboses occurred in the A-I group. Conclusion: Despite the fact that patients with combined aortic and iliac aneurysms have a more complex repair requirement and have an increased rate of comorbidity, the results are competitive with endovascular repair of aortic aneurysm by tube and bifurcated graft systems and are associated with a lower morbidity than open operation. C1 Univ Calif Los Angeles, Sch Med, Div Vasc Surg, Los Angeles, CA 90095 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Chicago, Vasc Sect, Dept Surg, Chicago, IL 60637 USA. RP Univ Calif Los Angeles, Sch Med, Div Vasc Surg, Box 956904, Los Angeles, CA 90095 USA. NR 50 TC 63 Z9 64 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD FEB PY 2001 VL 33 IS 2 SU S BP S11 EP S20 DI 10.1067/mva.2001.111681 PG 10 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 408NP UT WOS:000167332500002 PM 11174807 ER PT J AU Yang, XZ Wyatt, R Sodroski, J AF Yang, XZ Wyatt, R Sodroski, J TI Improved elicitation of neutralizing antibodies against primary human immunodeficiency viruses by soluble stabilized envelope glycoprotein trimers SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN MONOCLONAL-ANTIBODY; TYPE-1 ENVELOPE; HIV-1 ENTRY; V3 REGION; IMMUNE-RESPONSES; CD4-BINDING SITE; ATOMIC-STRUCTURE; T4 MOLECULE; HTLV-III; GP120 AB Human immunodeficiency virus (HIV-1) envelope glycoprotein subunits, such as the gp120 exterior glycoprotein, typically elicit antibodies that neutralize T-cell-line-adapted (TCLA), but not primary, clinical isolates of HIV-1. Here we compare the immunogenicity of gp120 and soluble stabilized trimers, which were designed to resemble the functional envelope glycoprotein oligomers of primary and TCLA HIV-1 strains. For both primary and TCLA virus proteins, soluble stabilized trimers generated neutralizing antibody responses more efficiently than gp120 did. Trimers derived from a primary isolate elicited antibodies that neutralized primary and TCLA HIV-1 strains. By contrast, trimers derived from a TCLA isolate generated antibodies that neutralized only the homologous TCLA virus. Thus, soluble stabilized envelope glycoprotein trimers derived from primary HIV-1 isolates represent defined immunogens capable of eliciting neutralizing antibodies that are active against clinically relevant HIV-1 strains. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Sodroski, J (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St,JFB 824, Boston, MA 02115 USA. FU NIAID NIH HHS [AI24755, AI31783, AI39420, P30 AI028691, R01 AI031783, R01 AI039420, R37 AI024755] NR 85 TC 163 Z9 168 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 FEB PY 2001 VL 75 IS 3 BP 1165 EP 1171 DI 10.1128/JVI.75.3.1165-1171.2001 PG 7 WC Virology SC Virology GA 391WF UT WOS:000166378700008 PM 11152489 ER PT J AU Wong, DKH Dudley, DD Dohrenwend, PB Lauer, GM Chung, RT Thomas, DL Walker, BD AF Wong, DKH Dudley, DD Dohrenwend, PB Lauer, GM Chung, RT Thomas, DL Walker, BD TI Detection of diverse hepatitis C virus (HCV)-specific cytotoxic T lymphocytes in peripheral blood of infected persons by screening for responses to all translated proteins of HCV SO JOURNAL OF VIROLOGY LA English DT Article ID INJECTION-DRUG USERS; IMMUNODEFICIENCY-VIRUS; QUANTITATIVE-ANALYSIS; CELL RESPONSES; B VIRUS; EPITOPES; IDENTIFICATION; PEPTIDES; NUCLEOPROTEIN; PREVALENCE AB Broadly directed hepatitis C virus (HCV)-specific cytotoxic T lymphocytes (CTL) have been identified from liver-infiltrating lymphocytes but have been more difficult to assess in peripheral blood of infected persons. To enhance the detection of CTL from peripheral blood mononuclear cells (PBMC), we cocultured PBMC with autologous Epstein-Barr virus-transformed B-lymphoblastoid cell lines that had been infected with recombinant vaccinia virus constructs so that they expressed the entire translated polyprotein of HCV-H, a type 1a strain. These stimulated cells from HCV-infected as well as exposed seronegative persons were then cloned at limiting dilution and tested for HCV-specific CTL activity using a standard Cr-51 release assay. HCV-specific CTL were detected in PBMC from seven of nine persons with chronic hepatitis, including five of seven in whom CTL had previously been detected from liver biopsy specimens but not PBMC. In a single person with chronic HCV infection, CTL directed against as many as five different epitopes were detected in peripheral blood and were similar in specificity to those detected in liver tissue. This technique was used to evaluate eight subjects identified to be at high risk for HCV exposure due to continued injection drug abuse; no evidence of CTL in PBMC was found. We conclude that CTL can be detected in PBMC from the majority of persons with chronic HCV infection but are present at lower levels or absent in exposed but persistently seronegative persons. The high degree of concordance of HCV epitopes identified from liver and PBMC suggests that this strategy is a reasonable alternative to liver biopsy for characterizing the CTL response to HCV in chronically infected persons. C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Div Infect Dis, Boston, MA 02114 USA. Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Johns Hopkins Sch Med, Baltimore, MD USA. RP Walker, BD (reprint author), Partners AIDS Res Ctr, Room 5212D,MGH E,149 13th St, Charlestown, MA 02129 USA. NR 41 TC 64 Z9 64 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2001 VL 75 IS 3 BP 1229 EP 1235 DI 10.1128/JVI.75.3.1229-1235.2001 PG 7 WC Virology SC Virology GA 391WF UT WOS:000166378700015 PM 11152496 ER PT J AU Altfeld, MA Livingston, B Reshamwala, N Nguyen, PT Addo, MM Shea, A Newman, M Fikes, J Sidney, J Wentworth, P Chesnut, R Eldridge, RL Rosenberg, ES Robbins, GK Brander, C Sax, PE Boswell, S Flynn, T Buchbinder, S Goulder, PJR Walker, BD Sette, A Kalams, SA AF Altfeld, MA Livingston, B Reshamwala, N Nguyen, PT Addo, MM Shea, A Newman, M Fikes, J Sidney, J Wentworth, P Chesnut, R Eldridge, RL Rosenberg, ES Robbins, GK Brander, C Sax, PE Boswell, S Flynn, T Buchbinder, S Goulder, PJR Walker, BD Sette, A Kalams, SA TI Identification of novel HLA-A2-restricted human immunodeficiency virus type 1-specific cytotoxic T-lymphocyte epitopes predicted by the HLA-A2 supertype peptide-binding motif SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; HIV-INFECTED PATIENTS; PROTEASE INHIBITOR THERAPY; LOW VIRAL LOAD; CELL RECONSTITUTION; CONSERVED REGIONS; FINE SPECIFICITY; SALVAGE THERAPY; RESPONSES; DISEASE AB Virus-specific cytotoxic T-lymphocyte (CTL) responses are critical in the control of human immunodeficiency virus type 1 (HIV-1) infection and will play an important part in therapeutic and prophylactic HIV-1 vaccines. The identification of virus specific epitopes that are efficiently recognized by CTL is the first step in the development of future vaccines. Here we describe the immunological characterization of a number of novel HIV-1-specific, HLA-A2-restricted CTL epitopes that share a high degree of conservation within HIV-1 and a strong binding to different alleles of the HLA-A2 superfamily. These novel epitopes include the first reported CTL epitope in the Vpr protein. Two of the novel epitopes were immunodominant among the HLA-A2-restricted CTL responses of individuals with acute and chronic HIV-1 infection. The novel CTL epitopes identified here should be included in future vaccines designed to induce HIV-1-specific CTL responses restricted by the HLA-A2 superfamily and will be important to assess in immunogenicity studies in infected persons and in uninfected recipients of candidate HIV-1 vaccines. C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA USA. Fenway Community Hlth Ctr, Boston, MA USA. Epimmune Inc, San Diego, CA USA. Dept Publ Hlth, AIDS Off, San Francisco, CA USA. RP Kalams, SA (reprint author), MGH E, CNY, 5th Floor,149 13th St, Charlestown, MA 02129 USA. RI Robbins, Gregory/F-7988-2011 FU NIAID NIH HHS [U01 AI048023, R37 AI028568, U19 AI38584, U01 AI041531, N01AI95362, U01 AI038858, R01 AI044656, R01 AI039966, AI39966, R01 AI040873, AI38858] NR 85 TC 79 Z9 81 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2001 VL 75 IS 3 BP 1301 EP 1311 DI 10.1128/JVI.75.3.1301-1311.2001 PG 11 WC Virology SC Virology GA 391WF UT WOS:000166378700022 PM 11152503 ER PT J AU Goulder, PJR Addo, MM Altfeld, MA Rosenberg, ES Tang, YH Govender, U Mngqundaniso, N Annamalai, K Vogel, TU Hammond, M Bunce, M Coovadia, HM Walker, BD AF Goulder, PJR Addo, MM Altfeld, MA Rosenberg, ES Tang, YH Govender, U Mngqundaniso, N Annamalai, K Vogel, TU Hammond, M Bunce, M Coovadia, HM Walker, BD TI Rapid definition of five novel HLA-A*3002-restricted human immunodeficiency virus-specific cytotoxic T-lymphocyte epitopes by Elispot and intracellular cytokine staining assays SO JOURNAL OF VIROLOGY LA English DT Article ID INFECTION; VIREMIA; CELLS; RISE AB Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) play a major role in control of viral replication. To understand the contribution of this antiviral response, an initial step is to fully define the specific epitopes targeted by CTL. These studies focused on CTL responses restricted by HLA-A*3002, one of the HLA-A molecules most prominent in African populations. To avoid the time-consuming effort and expense involved in culturing CTL prior to defining epitopes and restricting alleles, we developed a method combining Elispot assays with intracellular gamma interferon staining of peripheral blood mononuclear cells to first map the optimal epitopes targeted and then define the HLA restriction of novel epitopes. In two A*3002-positive subjects whose CTL responses were characterized in detail, the strongest response in both cases was to an epitope in p17 Gag, RSLYNTVATLY (residues 76 to 86). Using this method, CTL epitopes for which there were no motif predictions were optimized and the HLA restriction was established within 48 to 72 h of receipt of blood. This simple and convenient approach should prove useful especially in the characterization of CTL responses specific to HIV and other viruses, particularly in localities where performing cytotoxicity assays would be problematic. C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA. Univ Natal, Dept Paediat, ZA-4001 Durban, South Africa. Natal Blood Transfus Serv, Pinetown, South Africa. Univ Wisconsin, Wisconsin Reg Primate Res Ctr, Madison, WI 53715 USA. Churchill Hosp, Oxford Transplant Ctr, Oxford OX3 7LJ, England. RP Goulder, PJR (reprint author), John Radcliffe Hosp, Nuffield Dept Med, Dept Paediat, Level 7, Oxford OX3 9DU, England. FU NIAID NIH HHS [R37 AI028568, AI 01541, R01 AI030914, AI46995, R01 AI046995, R01 AI028568, AI28568] NR 27 TC 81 Z9 82 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2001 VL 75 IS 3 BP 1339 EP 1347 DI 10.1128/JVI.75.3.1339-1347.2001 PG 9 WC Virology SC Virology GA 391WF UT WOS:000166378700026 PM 11152507 ER PT J AU Hsu, CY Bates, DW Kuperman, GJ Curhan, GC AF Hsu, CY Bates, DW Kuperman, GJ Curhan, GC TI Relationship between hematocrit and renal function in men and women SO KIDNEY INTERNATIONAL LA English DT Article DE anemia; hemoglobin; chronic renal insufficiency; glomerular filtration rate; creatinine clearance ID RECOMBINANT-HUMAN-ERYTHROPOIETIN; LEFT-VENTRICULAR HYPERTROPHY; SERUM CREATININE; PREDIALYSIS PATIENTS; FAILURE; DISEASE; PREDICTION; PREVALENCE; CLEARANCE; IMPACT AB Background. Anemia is a known complication of renal insufficiency, but the relationship between level of renal function and magnitude of reduction in hematocrit is not well defined. Men have higher hematocrit and absolute glomerular filtration rate (GFR) than women: however, it is unknown whether the level of clearance associated with decreased hematocrit is the same in men and women. Methods. We conducted a cross-sectional study of 12,055 adult ambulatory patients. General linear models were used to analyze the relationship between hematocrit and Cockcroft-Gault equation estimated creatinine clearance (C-Cr: mL/min) and Modification of Diet in Renal Disease (MDRD) formula estimated the GFR indexed to body surface area (mL/min/ 1.73 m(2)). Results. The hematocrit decreased progressively below estimated C-Cr 60 mL/min in men and 40 mL/min in women. Com pared with subjects with C-Cr >80 mL/min, men with C-Cr 60 to 50 mL/min, 50 to 40 mL/min, 40 to 30 mL/min, 30 to 20 mL/min, and less than or equal to 20 mL/min had mean hematocrits that were lower by 1.0, 2.4, 3.7, 3.5, and 10.0%, respectively; the corresponding reductions in women with C-Cr, 40 to 30 mL/min, 30 to 20 mL/min, and (20 mL/min were 1.7, 2.9, and 6.3% tall P < 0.05). This between-sex difference diminished when renal function measurement was indexed to body size. Compared with subjects with GFR >80 mL/min/1.73 m(2), men with GFR 50 to 40 mL/min/ 1.73 m(2), 40 to 30 mL/min/1.73 m(2). 30 to 20 mL/min/1.73 m(2), and less than or equal to 20 mL/min/1.73 m(2) had mean hematocrits that were lower by 2.0, 4.4. 5.3, and 9.4%: the corresponding reductions in women with GFR 50 to 30 mL/min/1.73 m(2), 40 to 30 mL/min/ 1.73 m(2), 30 to 20 mL/min/1.73 m(2) and less than or equal to 20 mL/min/1.73 m(2) were 0.6, 1.6, 3.8, and 5.3% (all P < 0.05). Conclusions. A decrease in hematocrit is apparent even among patients with mild to moderate renal insufficiency. At any given level of renal function below estimated C-Cr 60 mL/min, men have a larger decrease in hematocrit than women. C1 Univ Calif San Francisco, Div Nephrol, San Francisco, CA 94143 USA. Brigham & Womens Hosp, Partners Informat Syst, Div Gen Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Partners Informat Syst, Channing Lab, Boston, MA 02115 USA. Massachusetts Gen Hosp, Renal & Gen Med Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Hsu, CY (reprint author), Univ Calif San Francisco, Div Nephrol, Room 672 HSE,Box 0532,513 Parnassus Ave, San Francisco, CA 94143 USA. FU NIDDK NIH HHS [R01 DK 52866] NR 29 TC 70 Z9 72 U1 0 U2 5 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD FEB PY 2001 VL 59 IS 2 BP 725 EP 731 DI 10.1046/j.1523-1755.2001.059002725.x PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 402GX UT WOS:000166979200034 PM 11168955 ER PT J AU Morse, HC Kearney, JF Isaacson, PG Carroll, M Fredrickson, TN Jaffe, ES AF Morse, HC Kearney, JF Isaacson, PG Carroll, M Fredrickson, TN Jaffe, ES TI Cells of the marginal zone - origins, function and neoplasia SO LEUKEMIA RESEARCH LA English DT Article DE marginal zone lymphomas; marginal zone B cells; hepatitis C virus; API/ML; BCL10; FAS ID NON-HODGKIN-LYMPHOMA; B-CELL; HELICOBACTER-PYLORI; GASTRIC LYMPHOMA; REGION GENES; MUCOSA; TISSUE; INFECTION; MICE; ERADICATION AB Splenic marginal zone B cells of humans and mice are anatomically positioned with specialized macrophages, dendritic and endothelial cells. Together, they function as the first line of defense against blood borne pathogens with a low triggering threshold for B cells providing a rapid proliferative and antibody response to infections. In humans, B cells with similar cytology and physical relations to follicles are found in lymph nodes and Peyer's patches. However, they also develop in mucosa-associated lymphoid tissue (MALT) and other sites, such as the thyroid and salivary gland, that normally lack organized lymphoid tissue. Chronic antigenic stimulation at these sites or in response to infection with Hepatitis C provides the milieu for mutations at FAS, API2/ML TP53 and INK4a/p19ARF and the development of marginal zone lymphomas (MZL) in node, spleen and MALT. Only splenic MZL are seen in mice. A reduced threshold for triggering to proliferation may predispose the marginal zone B cell to neoplasia with mutations in genes regulating apoptosis playing a leading role. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 NIAAA, Immunopathol Lab, Bethesda, MD 20892 USA. Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. Univ Coll & Middlesex Sch Med, Dept Pathol, London, England. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Morse, HC (reprint author), NIAAA, Immunopathol Lab, Bldg 7,Room 304,7 Ctr Dr,MSC 0760, Bethesda, MD 20892 USA. OI Morse, Herbert/0000-0002-9331-3705 FU NIAID NIH HHS [R01 AI014782] NR 38 TC 46 Z9 47 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD FEB PY 2001 VL 25 IS 2 BP 169 EP 178 DI 10.1016/S0145-2126(00)00107-7 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 403DC UT WOS:000167026400010 PM 11166833 ER PT J AU Denis, CV Frenette, PS AF Denis, CV Frenette, PS TI Platelets and endothelium: born for each other SO M S-MEDECINE SCIENCES LA French DT Article ID P-SELECTIN; IN-VIVO; ADHESION; CELLS; DEPOSITION; VENULES; ALPHA C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. RP Frenette, PS (reprint author), CUNY Mt Sinai Sch Med, Dept Med, 1 Gustave L Levy Pl,Box 1079, New York, NY 10029 USA. RI Frenette, Paul/J-8272-2012; Denis , Cecile/A-7649-2011 OI Denis , Cecile/0000-0001-5152-9156 NR 25 TC 0 Z9 0 U1 0 U2 0 PU MASSON EDITEUR PI PARIS 06 PA 120 BLVD SAINT-GERMAIN, 75280 PARIS 06, FRANCE SN 0767-0974 J9 M S-MED SCI JI M S-Med. Sci. PD FEB PY 2001 VL 17 IS 2 BP 252 EP 255 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 403GP UT WOS:000167034400020 ER PT J AU Atalay, MK Poncelet, BP Kantor, HL Brady, TJ Weisskoff, RM AF Atalay, MK Poncelet, BP Kantor, HL Brady, TJ Weisskoff, RM TI Cardiac susceptibility artifacts arising from the heart-lung interface SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE susceptibility artifact; cardiac; MRI; swine; lung ID IN-VIVO; 1.5 T; T-ASTERISK(2); OXYGENATION; MAPS AB Cardiac MRI studies often show susceptibility artifacts along the inferoapical myocardial margin in both human and in vivo animal experiments at field strengths of 1.5T and greater. This study was designed to determine the cause of these artifacts in porcine myocardium at 3T. Gradient echo images were obtained under various anatomic and physiologic conditions to systematically study potential sources of local susceptibility gradients. Lung resection in the open-chested, euthanized swine was the only intervention that eliminated the artifact. The data suggest that in the porcine model, the heart-lung interface is the primary cause of these artifacts. Magn Reson Med 45: 341-345, 2001, (C) 2001 Wiley-Liss, Inc. C1 Johns Hopkins Med Inst, Dept Radiol, Baltimore, MD 21287 USA. Massachusetts Gen Hosp, NMR Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Cardiol, Cardiac Unit, Boston, MA 02114 USA. RP Atalay, MK (reprint author), Johns Hopkins Med Inst, Dept Radiol, 601 N Caroline St, Baltimore, MD 21287 USA. FU NCI NIH HHS [P01 CA48729]; NHLBI NIH HHS [R01-HL5460, R01-HL57409] NR 8 TC 58 Z9 59 U1 0 U2 0 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD FEB PY 2001 VL 45 IS 2 BP 341 EP 345 DI 10.1002/1522-2594(200102)45:2<341::AID-MRM1043>3.0.CO;2-Q PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 397WF UT WOS:000166720300021 PM 11180442 ER PT J AU Rigotti, NA Thorndike, AN AF Rigotti, NA Thorndike, AN TI Reducing the health burden of tobacco use: What's the doctor's role? SO MAYO CLINIC PROCEEDINGS LA English DT Editorial Material ID COST-EFFECTIVENESS; SMOKING-CESSATION; MANAGEMENT C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gen Internal Med Unit, Boston, MA 02114 USA. RP Rigotti, NA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gen Internal Med Unit, S50-9, Boston, MA 02114 USA. NR 28 TC 12 Z9 12 U1 3 U2 3 PU MAYO CLINIC PROCEEDINGS PI ROCHESTER PA 660 SIEBENS BLDG MAYO CLINIC, ROCHESTER, MN 55905 USA SN 0025-6196 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD FEB PY 2001 VL 76 IS 2 BP 121 EP 123 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 398CK UT WOS:000166738200002 PM 11213298 ER PT J AU Castle, SC Uyemura, K Makinodan, T AF Castle, SC Uyemura, K Makinodan, T TI The SENIEUR Protocol after 16 years: a need for a paradigm shift? SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE SENIEUR Protocol; aging; immunosenescence; chronic illness C1 US Dept Vet Affairs, Ctr Geriatr Res Educ & Clin, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Div Geriatr, Los Angeles, CA 90073 USA. RP Castle, SC (reprint author), US Dept Vet Affairs, Ctr Geriatr Res Educ & Clin, VA Greater Los Angeles Healthcare Syst, Mail Code 11G,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 7 TC 12 Z9 12 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD FEB PY 2001 VL 122 IS 2 BP 127 EP 130 DI 10.1016/S0047-6374(00)00238-4 PG 4 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 403FG UT WOS:000167031500003 PM 11166349 ER PT J AU Payne, TL Postlethwait, JH Yelick, PC AF Payne, TL Postlethwait, JH Yelick, PC TI Functional characterization and genetic mapping of alk8 SO MECHANISMS OF DEVELOPMENT LA English DT Article DE zebrafish; transforming growth factor beta family member signaling; activin-like-kinase receptors; bone morphogenetic protein signaling; dorsoventral patterning ID GROWTH-FACTOR-BETA; BONE MORPHOGENETIC PROTEINS; EARLY XENOPUS DEVELOPMENT; SERINE/THREONINE KINASE RECEPTOR; DORSOVENTRAL PATTERN-FORMATION; ZEBRAFISH DANIO-RERIO; NO TAIL; WILD-TYPE; SPEMANN ORGANIZER; FAMILY MEMBERS AB The novel type I TGF beta family member receptor alk8 is expressed both maternally and zygotically. Functional characterization of alk8 was performed using microinjection studies of constitutively active (CPI), kinase modified/dominant negative (DN), and truncated alk8 mRNAs. CA Alk8 expression produces ventralized embryos while DN Alk8 expression results in dorsalized phenotypes. Truncated alk8 expressing embryos display a subtle dorsalized phenotype closely resembling that of the identified zebrafish dorsalized mutant, lost-a-fin (laf). Single-strand conformation polymorphism (SSCP) analysis was used to map alk8 to zebrafish LG02 in a region demonstrating significant conserved synteny to Hsa2, and which contains the human alk2 gene, ACVRI. Altogether, these functional, gene mapping and phylogenetic analyses suggest that alk8 may be the zebrafish orthologue to human ACVRI (alk2), and therefore extend previous studies of Alk2 conducted in Xenopus. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Forsyth Inst, Dept Cytokine Biol, Boston, MA 02115 USA. Forsyth Inst, Harvard Forsyth Dept Oral Biol, Boston, MA 02115 USA. Univ Oregon, Inst Neurosci, Eugene, OR 97403 USA. RP Yelick, PC (reprint author), Forsyth Inst, Dept Cytokine Biol, 140 Fenway, Boston, MA 02115 USA. FU NICHD NIH HHS [9 P01HD22486]; NIDCR NIH HHS [DE12024, DE05736, DE12076] NR 72 TC 27 Z9 28 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD FEB PY 2001 VL 100 IS 2 BP 275 EP 289 DI 10.1016/S0925-4773(00)00541-4 PG 15 WC Developmental Biology SC Developmental Biology GA 399WQ UT WOS:000166837600011 PM 11165484 ER PT J AU Malone, DC Carter, BL Billups, SJ Valuck, RJ Barnette, DJ Sintek, CD Okano, GJ Ellis, S Covey, D Mason, B Jue, S Carmichael, J Guthrie, K Sloboda, L Dombrowski, R Geraets, DR Amato, AG AF Malone, DC Carter, BL Billups, SJ Valuck, RJ Barnette, DJ Sintek, CD Okano, GJ Ellis, S Covey, D Mason, B Jue, S Carmichael, J Guthrie, K Sloboda, L Dombrowski, R Geraets, DR Amato, AG TI Can clinical pharmacists affect SF-36 scores in veterans at high risk for medication-related problems? SO MEDICAL CARE LA English DT Article DE pharmaceutical care; quality of life; SF-36 ID HEALTH SURVEY SF-36; QUALITY-OF-LIFE; PHARMACEUTICAL CARE; CONTROLLED TRIAL; HEART-FAILURE; MANAGEMENT; OUTCOMES; INTERVENTIONS; SELECTION; VALIDITY AB BACKGROUND. An objective of pharmaceutical care is for pharmacists to improve patients' health-related quality of life (HRQOL) by optimizing medication therapy. OBJECTIVES. The objective of this study was to determine whether ambulatory care clinical pharmacists could affect HRQOL in veterans who were likely to experience a drug-related problem. RESEARCH DESIGN. This was a 9-site, randomized, controlled trial involving Veterans Affairs Medical Centers (VAMCs), Patients were eligible if they met greater than or equal to3 criteria for being at high risk for drug-related problems. Enrolled patients were randomized to either usual medical care or usual medical care plus clinical pharmacist interventions. HRQOL was measured with the SF-36 questionnaire administered at baseline and at 6 and 12 months. RESULTS. In total, 1,054 patients were enrolled; 523 were randomized to intervention, and 531 to control. After patient age, site, and chronic disease score were controlled for, the only domain that was significantly different between groups over time was the bodily pain scale, which converged to similar values at the end of the study. Patients' rating; of the change in health status in the past 12 months was statistically different between groups, intervention patients declining less (-2.4 units) than control subjects (-6.3 units) (P < 0.004). This difference was not considered clinically meaningful. However, a dose-response relationship was observed for general health perceptions (P = 0.004), vitality (P = 0.006), and change in health over the past year (P = 0.007), CONCLUSIONS. These results suggest that clinical pharmacists had no significant impact on HRQOL as measured by the SF-36 for veterans at high risk for medication-related problems. C1 Univ Colorado, Hlth Sci Ctr, Boulder, CO 80309 USA. STVHCS, Audie Murphy Div, San Antonio, TX USA. Univ Arizona, Coll Pharm, Tucson, AZ 85721 USA. Univ Colorado, Hlth Sci Ctr, Sch Pharm, Denver, CO USA. Kaiser Permanente, Denver, CO USA. Costal Area Hlth Educ Ctr, Wilmington, NC USA. Denver VAMC, Denver, CO USA. Strateg Outcomes Serv, Res Triangle Pk, NC USA. James A Haley Veterans Hosp, Tampa, FL USA. Boise VAMC, Boise, ID USA. Reno VAMC, Reno, NV USA. John L McClellan Mem Veterans Hosp, Little Rock, AR USA. VA Chicago Hlth Care Syst, Lakeside Div, Chicago, IL USA. Baltimore VAMC, Baltimore, MD USA. Iowa City VAMC, Iowa City, IA USA. Massachusetts Coll Pharm & Hlth Sci, Boston, MA USA. RP Malone, DC (reprint author), Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci, POB 210207, Tucson, AZ 85721 USA. NR 42 TC 33 Z9 33 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD FEB PY 2001 VL 39 IS 2 BP 113 EP 122 DI 10.1097/00005650-200102000-00002 PG 10 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 396TD UT WOS:000166651900002 PM 11176549 ER PT J AU Harlow, SP Krag, DN Ashikaga, T Weaver, DL Meijer, SJ Loggie, BW Tanabe, KK Whitworth, P Kuhn, J Kusminsky, R Carp, NZ Gadd, M Rawlings, M Slingluff, CL AF Harlow, SP Krag, DN Ashikaga, T Weaver, DL Meijer, SJ Loggie, BW Tanabe, KK Whitworth, P Kuhn, J Kusminsky, R Carp, NZ Gadd, M Rawlings, M Slingluff, CL TI Gamma probe guided biopsy of the sentinel node in malignant melanoma: a multicentre study SO MELANOMA RESEARCH LA English DT Article DE melanoma; sentinel lymph node ID REGIONAL LYMPH-NODES; EARLY-STAGE MELANOMA; II MELANOMA; DISSECTION; EXPERIENCE; RECURRENCE; MANAGEMENT AB Sentinel lymph node biopsy was attempted in 336 patients with clinically node-negative cutaneous melanoma. All patients were injected with technetium-99m labelled radio-colloid, with 108 patients simultaneously receiving vital blue dye for sentinel node identification. Sentinel lymph nodes were identified in 329 patients, giving a technical success rate of 97.9%. Metastatic disease was identified in 39 (11.9%) of the patients in whom sentinel nodes were found. Patients with negative sentinel nodes were observed and patients with positive sentinel nodes underwent comprehensive lymph node dissection. The presence of metastatic disease in the sentinel nodes and primary tumour depth by Breslow or Clark levels were joint predictors of survival based on Cox proportional hazards modelling. Disease recurrences occurred in 26 (8.8%) patients with negative sentinel lymph nodes, with isolated regional recurrences as the first site in 10 (3.4%). No patients with Clark level II primary tumours were found to have positive sentinel nodes or disease recurrences. One patient with a thin (<0.75 mm) Clark level III primary had metastatic disease in a sentinel node. Patients with metastases confined to the sentinel nodes had similar survival rates regardless of the number of nodes involved (C) 2001 Lippincott Williams & Wilkins. C1 Univ Vermont, Coll Med, Ctr Canc, Burlington, VT 05405 USA. Univ Vermont, Coll Med, Dept Surg, Burlington, VT 05405 USA. Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. Univ Vermont, Coll Med, Dept Biometry, Burlington, VT 05405 USA. Free Univ Amsterdam, Dept Surg, Amsterdam, Netherlands. Wake Forest Univ, Bowman Gray Sch Med, Dept Surg, Winston Salem, NC 27103 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. Baylor Univ, Med Ctr, Dept Surg, Dallas, TX 75246 USA. Baptist Hosp, Dept Surg, Nashville, TN USA. Charleston Area Med Ctr, Charleston, WV USA. Lackenau Hosp, Ctr Canc, Wynnewood, PA USA. Mem Hosp, Chattanooga, TN USA. Univ Virginia, Sch Med, Dept Surg, Charlottesville, VA 22908 USA. RP Harlow, SP (reprint author), Univ Vermont, Coll Med, Ctr Canc, Given Bldg Room E309, Burlington, VT 05405 USA. FU NCI NIH HHS [P30CA22435] NR 18 TC 50 Z9 51 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-8931 J9 MELANOMA RES JI Melanoma Res. PD FEB PY 2001 VL 11 IS 1 BP 45 EP 55 DI 10.1097/00008390-200102000-00006 PG 11 WC Oncology; Dermatology; Medicine, Research & Experimental SC Oncology; Dermatology; Research & Experimental Medicine GA 409XX UT WOS:000167411900006 PM 11254115 ER PT J AU Huncharek, M Caubet, JF McGarry, R AF Huncharek, M Caubet, JF McGarry, R TI Single-agent DTIC versus combination chemotherapy with or without immunotherapy in metastatic melanoma: a meta-analysis of 3273 patients from 20 randomized trials SO MELANOMA RESEARCH LA English DT Article DE dacarbazine; interferon; meta-analysis; response rate ID DISSEMINATED MALIGNANT-MELANOMA; PHASE-III TRIAL; DACARBAZINE; INTERFERON-ALPHA-2B; VINCRISTINE; SCHEDULES; TAMOXIFEN; THERAPY; BCNU; CCNU AB It is currently unclear whether any combination therapy for the treatment of metastatic melanoma is superior to standard single-agent dacarbazine (DTIC) in terms of tumour response and overall survival. The available randomized clinical trial data were combined in a meta-analysis to address this question. Initially a thorough MEDLARS search was conducted covering the time period from January 1970 to January 1999. This literature search was supplemented by manual searches of study bibliographies (including review articles) and review of relevant textbooks. The meta-analysis was performed according to a prospective protocol using strict study eligibility criteria. Data derived from randomized controlled trials comparing single-agent DTIC with combination chemo/immunotherapy were combined using a fixed effects model. Data were stratified into three combination therapy groups: DTIC-containing regimens, non-DTIC-containing therapy, and chemotherapy plus immunotherapy. The primary outcome of interest was the proportion of patients demonstrating a complete or partial response to treatment. A total of 20 randomized trials comprising 3273 patients were initially combined in a meta-analysis. This yielded an odds ratio (OR) of 1.23 (95% confidence interval [CI] 1.02-1.48), demonstrating that combination drug therapies are associated with a 23% increase in response rate compared with single-agent DTIC. The combination of DTIC plus interferon-a produced a tumour response rate 53% greater (95% CI 1.10-2.13) than that seen with DTIC alone. This increase was greater than that seen with DTIC-containing multi-drug regimens, which had an OR of 1.33 (95% CI 0.99-1.78). No difference in overall survival was demonstrated. Non-DTIC-containing treatment programmes showed no advantage over DTIC in terms of tumour response rate (OR = 0.77, 95% CI 0.45-1.32). The combination of DTIC and interferon-a appears more active than standard single-agent DTIC in metastatic melanoma. Further randomized clinical trials employing a DTIC plus interferon arm are necessary to confirm these results. (C) 2001 Lippincott Williams & Wilkins. C1 St Michaels Hosp, Marshfield Clin, Ctr Canc, Div Radiat Oncol, Stevens Point, WI 54481 USA. Meta Anal Res Grp, Stevens Point, WI USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Univ Nebraska, Med Ctr, Dept Radiat Oncol, Omaha, NE USA. Univ Nebraska, Sch Med, Omaha, NE 68198 USA. RP Huncharek, M (reprint author), St Michaels Hosp, Marshfield Clin, Ctr Canc, Div Radiat Oncol, 900 Illinois Ave, Stevens Point, WI 54481 USA. NR 27 TC 112 Z9 114 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-8931 J9 MELANOMA RES JI Melanoma Res. PD FEB PY 2001 VL 11 IS 1 BP 75 EP 81 DI 10.1097/00008390-200102000-00009 PG 7 WC Oncology; Dermatology; Medicine, Research & Experimental SC Oncology; Dermatology; Research & Experimental Medicine GA 409XX UT WOS:000167411900009 PM 11254118 ER PT J AU Hirose, M Kaneki, M Sugita, H Yasuhara, S Martyn, JAJ Iebunjo, C AF Hirose, M Kaneki, M Sugita, H Yasuhara, S Martyn, JAJ Iebunjo, C TI Long-term denervation impairs insulin receptor substrate-1-mediated insulin signaling in skeletal muscle SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID NECROSIS-FACTOR-ALPHA; PHOSPHATIDYLINOSITOL 3-KINASE; MICE LACKING; TYROSINE PHOSPHORYLATION; PHOSPHOTYROSINE PROTEIN; 3T3-L1 ADIPOCYTES; SUBSTRATE FAMILY; RESISTANCE; CERAMIDE; APOPTOSIS AB Long-term denervation is associated with insulin resistance. To investigate the molecular bases of insulin resistance, the downstream signaling molecules of insulin receptor including insulin receptor substrate-1 (IRS-1) and phosphatidylinositol 3-kinase (PI 3-K) were examined in skeletal muscle of rats after 7 days of denervation. Long-term denervation attenuated insulin-stimulated activation of the initial steps of the intracellular signaling pathway. Insulin-stimulated tyrosine phosphorylation of insulin receptor was reduced to 36% (P < .005), as was the phosphorylation of IRS-l to 34% (P < .0001) of control. While insulin receptor protein level was unchanged, the protein expression of IRS-1 was significantly decreased in denervated muscles. Insulin-stimulated percent tyrosine phosphorylation of IRS-1, normalized to the IRS-1 protein expression, was also reduced to 55% (P < .01) of control in denervated muscle. Denervation caused a decline in the insulin-induced binding of p85 regulatory subunit of PI 3-K to IRS-1 to 61% (P < .001) and IRS-l-associated PI 3-K activity to 57% (P < .01). These results provide evidence that long-term denervation results in insulin resistance because of derangements at multiple points, including tyrosine phosphorylation of insulin receptor and its downstream signaling molecule, IRS-1, protein expression of IRS-1, and activation of PI 3-K. Copyright (C) 2001 by W.B. Saunders Company. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Anesthesia Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Anesthesia & Crit Care, Boston, MA 02115 USA. Shriners Hosp Children, Boston, MA USA. RP Martyn, JAJ (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Anesthesia Serv, 32 Fruit St, Boston, MA 02114 USA. FU NIGMS NIH HHS [GM61411, GM31569, GM55082] NR 42 TC 19 Z9 20 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 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD FEB PY 2001 VL 50 IS 2 BP 216 EP 222 DI 10.1053/meta.2001.20169 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 399WV UT WOS:000166838000015 PM 11229432 ER PT J AU Shinjyo, T Kuribara, R Inukai, T Hosoi, H Kinoshita, T Miyajima, A Houghton, PJ Look, AT Ozawa, K Inaba, T AF Shinjyo, T Kuribara, R Inukai, T Hosoi, H Kinoshita, T Miyajima, A Houghton, PJ Look, AT Ozawa, K Inaba, T TI Downregulation of Bim, a proapoptotic relative of Bcl-2, is a pivotal step in cytokine-initiated survival signaling in murine hematopoietic progenitors SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PRO-B LYMPHOCYTES; PROTEIN-KINASE; TRANSACTIVATION DOMAINS; TRANSCRIPTION FACTOR; BAD PHOSPHORYLATION; DEFICIENT MICE; CELL-SURVIVAL; X-L; APOPTOSIS; DEATH AB Tw distinct signaling pathways regulate the survival of interleukin-3 (IL3)-dependent hematopoietic progenitors. One originates from the membrane-proximal portion of the cytoplasmic domain of the IL-3 receptor (betac chain), which is shared by IL-3 and granulocyte-macrophage colony-stimulating factor and is involved in the regulation of Bcl-x(L) through activation of STAT5. The other pathway emanates from the distal region of the betac chain and overlaps with downstream signals from constitutively active Res proteins. Although the latter pathway is indispensable for cell survival, its downstream targets remain largely undefined. Here we show that the expression of Bim, a member of the BH3-only subfamily of cell death activators, is downregulated by IL-3 signaling through either of two major Ras pathways: Raf/mitogen-activated protein kinase and the phosphatidylinositol 3-kinase/mammalian target of rapamycin. Akt/phosphokinase B does not appear to play a significant role in this regulatory cascade. Bim downregulation has important implications for fell survival, since enforced expression of this death activator at levels equivalent to those induced by cytokine withdrawal led to apoptosis even in the presence of IL-3, We conclude that Bim is a pivotal molecule in cytokine regulation of hematopoietic cell survival. C1 Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Mol Oncol, Minami Ku, Hiroshima 7348553, Japan. Jichi Med Sch, Dept Mol Biol, Minami Kawachi, Tochigi 3290498, Japan. Jichi Med Sch, Dept Hematol, Minami Kawachi, Tochigi 3290498, Japan. Yamanashi Med Univ, Dept Pediat, Yamanashi 4093898, Japan. Univ Tokyo, Inst Mol & Cellular Biosci, Tokyo 174, Japan. Kyoto Prefectural Med Sch, Dept Pediat, Kyoto 606, Japan. St Jude Childrens Res Hosp, Dept Mol Pharmacol, Memphis, TN 38105 USA. Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Inaba, T (reprint author), Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Mol Oncol, Minami Ku, 1-2-3 Kasumi, Hiroshima 7348553, Japan. NR 50 TC 169 Z9 172 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2001 VL 21 IS 3 BP 854 EP 864 DI 10.1128/MCB.21.3.854-864.2001 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 391JW UT WOS:000166353700016 PM 11154272 ER PT J AU Guyon, JR Narlikar, GJ Sullivan, EK Kingston, RE AF Guyon, JR Narlikar, GJ Sullivan, EK Kingston, RE TI Stability of a human SWI-SNF remodeled nucleosomal array SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID YEAST SWI/SNF COMPLEX; TRANSCRIPTION FACTOR-BINDING; MULTISUBUNIT COMPLEX; FACILITATED BINDING; HISTONE TAILS; GENE-PRODUCTS; AMINO TERMINI; DNA; CHROMATIN; ACETYLATION AB SWI-SNF alters DNA-histone interactions within a nucleosome in an ATP-dependent manner. These alterations cause changes in the topology of a closed circular nucleosomal array that persist after removal of ATP from the reaction. We demonstrate here that a remodeled closed circular array will revert toward its original topology when ATP is removed, indicating that the remodeled array has a higher energy than that of the starting state. However, reversion occurs with a half-life measured in hours, Implying a high energy barrier between the remodeled and standard states. The addition of competitor DNA accelerates reversion of the remodeled array by more than 10-fold, and we interpret this result to mean that binding of human SWI-SNF (hSWI-SNF), even in the absence of ATP hydrolysis, stabilizes the remodeled state. In addition, we also show that SWI-SNF is able to remodel a closed circular array in the absence of topoisomerase I, demonstrating that hSWI-SNF can induce topological changes even when conditions are highly energetically unfavorable. We conclude that the remodeled state is less stable than the standard state but that the remodeled state is kinetically trapped by the high activation energy barrier separating it from the unremodeled conformation. C1 Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Univ Notre Dame, Dept Chem & Biochem, Grad Program, Notre Dame, IN 46556 USA. RP Kingston, RE (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Wellman 10, Boston, MA 02114 USA. NR 51 TC 33 Z9 34 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2001 VL 21 IS 4 BP 1132 EP 1144 DI 10.1128/MCB.21.4.1132-1144.2001 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 396TC UT WOS:000166651800015 PM 11158300 ER PT J AU Gaubatz, S Lees, JA Lindeman, GJ Livingston, DM AF Gaubatz, S Lees, JA Lindeman, GJ Livingston, DM TI E2F4 is exported from the nucleus in a CRM1-dependent manner SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID FUNCTIONAL RETINOBLASTOMA PROTEIN; UBIQUITIN-PROTEASOME PATHWAY; CELL-CYCLE INHIBITION; FAMILY PROTEINS; LEPTOMYCIN-B; SUBCELLULAR-LOCALIZATION; GROWTH SUPPRESSION; MESSENGER-RNA; CRM1; SIGNAL AB E2F is a family of transcription factors required for normal cell cycle control and for cell cycle arrest in G(1). E2F4 is the most abundant E2F protein in many cell types, In quiescent cells, it is localized to the nucleus, where it is bound to the retinoblastoma-related protein p130. During entry into the cell cycle, the protein disappears from the nucleus and appears in the cytoplasm, The mechanism by which this change occurs has, in the past, been unclear. We have found that E2F4 is actively exported from the nucleus and that leptomycin B, a specific inhibitor of nuclear export, inhibits this process. E2F4 export is mediated by two hydrophobic export sequences, mutations in either of which result in export failure. Individual export mutants of E2F4, but not a mutant with inactivation of both export signals, can be efficiently excluded from the nucleus by forced coexpression of the nuclear export receptor CRM1. Similarly, CRM1 overexpression can prevent cell cycle arrest induced by the cyclin kinase inhibitor p16(INK4a), an E2F4-dependent process. Taken together, these data suggest that nuclear export contributes to the regulation of E2F4 function, including its ability to regulate exit from G(1) in association with a suitable pocket protein. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. MIT, Ctr Canc Res, Cambridge, MA 02139 USA. RP Livingston, DM (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 41 TC 58 Z9 59 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2001 VL 21 IS 4 BP 1384 EP 1392 DI 10.1128/MCB.21.4.1384-1392.2001 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 396TC UT WOS:000166651800038 PM 11158323 ER PT J AU Lim, S Sala, C Yoon, JY Park, S Kuroda, S Sheng, M Kim, E AF Lim, S Sala, C Yoon, JY Park, S Kuroda, S Sheng, M Kim, E TI Sharpin, a novel postsynaptic density protein that directly interacts with the Shank family of proteins SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Article ID METABOTROPIC GLUTAMATE RECEPTORS; 90/POSTSYNAPTIC DENSITY-95-ASSOCIATED PROTEIN; KINASE-LIKE DOMAIN; SYNAPTIC PROTEINS; RAT-BRAIN; INTRAMOLECULAR INTERACTION; GUANYLATE KINASES; MOLECULAR-CLONING; BINDING-PROTEIN; PDZ PROTEINS AB The Shank family of proteins (also termed CortBP, ProSAP, or Synamon) is highly enriched in the postsynaptic density (PSD) of excitatory synapses in brain. Shank contains multiple domains for protein-protein interactions, including ankyrin repeats, SH3 domain, PDZ domain, SAM domain, and an extensive proline-rich region. We have identified a novel protein, termed Sharpin, that directly interacts with the ankyrin repeats of Shank, Sharpin is enriched in the PSD and forms a complex with Shank in heterologous cells and brain. Immunostaining reveals the presence of Sharpin at excitatory synapses and its colocalization with Shank. While the C-terminal half of Sharpin interacts with Shank, the N-terminal half of Sharpin mediates homomultimerization. Considering the fact that the ankyrin repeats and the SH3 domain of Shank can be truncated by alternative splicing, these results define Sharpin as a novel PSD protein that may regulate the complexity of the Shank-based protein network in an alternative splicing-dependent manner. C1 Korea Adv Inst Sci & Technol, Dept Biol Sci, Yusong Ku, Taejon 305701, South Korea. Howard Hughes Med Inst, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurobiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Hallym Univ, Inst Environm & Life Sci, Chunchon 200702, South Korea. Osaka Univ, Inst Sci & Ind Res, Dept Struct Mol Biol, Ibaraki, Osaka 5670047, Japan. RP Kim, E (reprint author), Korea Adv Inst Sci & Technol, Dept Biol Sci, Yusong Ku, Taejon 305701, South Korea. RI Kim, Eunjoon/C-1566-2011; Sala, Carlo/A-2493-2009 OI Sala, Carlo/0000-0003-0662-9523 NR 58 TC 72 Z9 80 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1044-7431 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD FEB PY 2001 VL 17 IS 2 BP 385 EP 397 DI 10.1006/mcne.2000.0940 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 403XJ UT WOS:000167068200011 PM 11178875 ER PT J AU Zhang, XA Bontrager, AL Stipp, CS Kraeft, SK Bazzoni, G Chen, LB Hemler, ME AF Zhang, XA Bontrager, AL Stipp, CS Kraeft, SK Bazzoni, G Chen, LB Hemler, ME TI Phosphorylation of a conserved integrin alpha 3 QPSXXE motif regulates signaling, motility, and cytoskeletal engagement SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID PROTEIN-KINASE-C; ACTIVATION-DEPENDENT ADHESION; CYTOPLASMIC DOMAIN; CELL-MIGRATION; EXTRACELLULAR-MATRIX; TYROSINE PHOSPHORYLATION; LAMININ RECEPTOR; FIBRONECTIN RECEPTOR; TISSUE DISTRIBUTION; LEUKOCYTE ADHESION AB Integrin alpha 3A cytoplasmic tail phosphorylation was mapped to amino acid S1042, as determined by mass spectrometry, and confirmed by mutagenesis. This residue occurs within a "QPSXXE" motif conserved in multiple alpha chains (alpha 3A, alpha 6A, alpha 7A), from multiple species. Phosphorylation of a3A and a6A did not appear to be directly mediated by protein kinase C (PKC) alpha, beta, gamma, delta, epsilon, zeta or mu, or by any of several other known serine kinases, although PKC has an indirect role in promoting phosphorylation. A S1042A mutation did not affect alpha3-Chinese hamster ovary (CHO) cell adhesion to laminin-5, but did alter 1) alpha3-dependent tyrosine phosphorylation of focal adhesion kinase and paxillin (in the presence or absence of phorbol 12-myristate 13 acetate stimulation), and p130(CAS) (in the absence of phorbol 12-myristate 13 acetate stimulation), 2) the shape of cells spread on laminin-5, and 3) alpha3-dependent random CHO cell migration on laminin-5. In addition, S1042A mutation altered the PKC-dependent, ligand-dependent subcellular distribution of alpha3 and F-actin in CHO cells. Together, the results demonstrate clearly that alpha 3A phosphorylation is functionally relevant. In addition, the results strongly suggest that alpha3 phosphorylation may regulate alpha3 integrin interaction with the cytoskeleton. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Hemler, ME (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. FU NCI NIH HHS [CA-86712, R01 CA086712, CA-42368, R01 CA042368] NR 81 TC 47 Z9 48 U1 0 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB PY 2001 VL 12 IS 2 BP 351 EP 365 PG 15 WC Cell Biology SC Cell Biology GA 461CU UT WOS:000170348000009 PM 11179420 ER PT J AU Timmers, C Taniguchi, T Hejna, J Reifsteck, C Lucas, L Bruun, D Thayer, M Cox, B Olson, S D'Andrea, AD Moses, R Grompe, M AF Timmers, C Taniguchi, T Hejna, J Reifsteck, C Lucas, L Bruun, D Thayer, M Cox, B Olson, S D'Andrea, AD Moses, R Grompe, M TI Positional cloning of a novel fanconi anemia gene, FANCD2 SO MOLECULAR CELL LA English DT Article ID FIBROBLAST CELL-LINES; NUCLEAR-COMPLEX; COMPLEMENTATION; LOCALIZATION; PROTEINS; FAA; FANCG/XRCC9; MOSAICISM; HOMOLOGY; INTERACT AB Fanconi anemia (FA) is a genetic disease with birth defects, bone marrow failure, and cancer susceptibility. To date, genes for five of the seven known complementation groups have been cloned. Complementation group D is heterogeneous, consisting of two distinct genes, FANCD1 and FANCD2. Here we report the positional cloning of FANCD2. The gene consists of 44 exons, encodes a novel 1451 amino acid nuclear protein, and has two protein isoforms. Similar to other FA proteins, the FANCD2 protein has no known functional domains, but unlike other known FA genes, FANCD2 is highly conserved in A. thaliana, C. elegans, and Drosophila. Retroviral transduction of the cloned FANCD2 cDNA into FA-D2 cells resulted in functional complementation of MMC sensitivity. C1 Oregon Hlth Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Vollum Inst, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Pediat, Portland, OR 97201 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Grompe, M (reprint author), Oregon Hlth Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA. NR 34 TC 274 Z9 282 U1 1 U2 5 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 FEB PY 2001 VL 7 IS 2 BP 241 EP 248 DI 10.1016/S1097-2765(01)00172-1 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 406BA UT WOS:000167194000001 PM 11239453 ER PT J AU Garcia-Higuera, I Taniguchi, T Ganesan, S Meyn, MS Timmers, C Hejna, J Grompe, M D'Andrea, AD AF Garcia-Higuera, I Taniguchi, T Ganesan, S Meyn, MS Timmers, C Hejna, J Grompe, M D'Andrea, AD TI Interaction of the fanconi anemia proteins and BRCA1 in a common pathway SO MOLECULAR CELL LA English DT Article ID DNA-DAMAGE RESPONSE; NUCLEAR-COMPLEX; FUNCTIONAL-ACTIVITY; GENE-PRODUCT; CELL-LINE; IN-VIVO; PHOSPHORYLATION; FAC; UBIQUITINATION; FANCG/XRCC9 AB Fanconi anemia (FA) is a human autosomal recessive cancer susceptibility disorder characterized by cellular sensitivity to mitomycin C and ionizing radiation. Although six FA genes (for subtypes A, C, D2, E, F, and G) have been cloned, their relationship to DNA repair remains unknown. In the current study, we show that a nuclear complex containing the FANCA, FANCC, FANCF, and FANCG proteins is required for the activation of the FANCD2 protein to a monoubiquitinated isoform. In normal (non-FA) cells, FANCD2 is monoubiquitinated in response to DNA damage and is targeted to nuclear foci (dots). Activated FANCD2 protein colocalizes with the breast cancer susceptibility protein, BRCA1, in ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes. The FANCD2 protein, therefore, provides the missing link between the FA protein complex and the cellular BRCA1 repair machinery. Disruption of this pathway results in the cellular and clinical phenotype common to all FA subtypes. C1 Harvard Univ, Sch Med, Childrens Hosp, Dana Farber Canc Inst,Dept Pediat Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Childrens Hosp, Dept Pediat, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Oncol, Boston, MA 02115 USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. Oregon Hlth Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Pediat, Portland, OR 97201 USA. RP D'Andrea, AD (reprint author), Harvard Univ, Sch Med, Childrens Hosp, Dana Farber Canc Inst,Dept Pediat Oncol, Boston, MA 02115 USA. RI Garcia-Higuera, Irene/L-5004-2014 FU NHLBI NIH HHS [P01HL54785-04, R01HL52725-04]; NIDDK NIH HHS [R01DK43889-09] NR 67 TC 782 Z9 798 U1 2 U2 27 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 FEB PY 2001 VL 7 IS 2 BP 249 EP 262 DI 10.1016/S1097-2765(01)00173-3 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 406BA UT WOS:000167194000002 PM 11239454 ER PT J AU Tsujikawa, K Kawakami, N Uchino, Y Ichijo, T Furukawa, T Saito, H Yamamoto, H AF Tsujikawa, K Kawakami, N Uchino, Y Ichijo, T Furukawa, T Saito, H Yamamoto, H TI Distinct functions of the two protein tyrosine phosphatase domains of LAR (leukocyte common antigen-related) on tyrosine dephosphorylation of insulin receptor SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID SIGNAL-TRANSDUCTION; HOMOPHILIC BINDING; CRYSTAL-STRUCTURE; IN-VIVO; LIGAND; ALPHA; BETA; EXPRESSION; KINASE; MU AB Most receptor-like, transmembrane protein tyrosine phosphatases (PTPases), such as CD45 and the leukocyte common antigen-related (LAR) molecule, have two tandemly repeated PTPase domains in the cytoplasmic segment. The role of each PTPase domain in mediating PTPase activity remains unclear; however, it has been proposed that PTPase activity is associated with only the first of the two domains, PTPase domain 1, and the membrane-distal PTPase domain 2, which has no catalytic activity, would regulate substrate specificity. In this paper, we examine the function of each PTPase domain of LAR in vivo using a potential physiological substrate, namely insulin receptor, and LAR mutant proteins in which the conserved cysteine residue was changed to a serine residue in the active site of either or both PTPase domains. LAR associated with and preferentially dephosphorylated the insulin receptor that was tyrosine phosphorylated by insulin stimulation. Its association was mediated by PTPase domain 2, because the mutation of Cys-1813 to Ser in domain 2 resulted in weakening of the association. The Cys-1522 to Ser mutant protein, which is defective in the LAR PTPase domain 1 catalytic site, was tightly associated with tyrosine-phosphorylated insulin receptor, but failed to dephosphorylate it, indicating that LAR PTPase domain 1 is critical for dephosphorylation of tyrosine-phosphorylated insulin receptor. This hypothesis was further confirmed by using LAR mutants in which either PTPase domain 1 or domain 2 was deleted. Moreover, the association of the extracellular domains of both LAR and insulin receptor was supported by using the LAR mutant protein without the two PTPase domains. LAR was phosphorylated by insulin receptor tyrosine kinase and autodephosphorylated by the catalytic activity of the PTPase domain 1. These results indicate that each domain of LAR plays distinct functional roles through phosphorylation and dephosphorylation in vivo. C1 Osaka Univ, Grad Sch Pharmaceut Sci, Dept Immunol, Suita, Osaka 5650871, Japan. Kagoshima Univ, Fac Med, Inst Canc Res, Dept Canc Chemotherapy, Kagoshima 8908520, Japan. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Tsujikawa, K (reprint author), Osaka Univ, Grad Sch Pharmaceut Sci, Dept Immunol, 1-6 Yamadaoka, Suita, Osaka 5650871, Japan. NR 42 TC 31 Z9 34 U1 0 U2 2 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD FEB PY 2001 VL 15 IS 2 BP 271 EP 280 DI 10.1210/me.15.2.271 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 398NH UT WOS:000166762200006 PM 11158333 ER PT J AU Gerard, C Rollins, BJ AF Gerard, C Rollins, BJ TI Chemokines and disease SO NATURE IMMUNOLOGY LA English DT Review ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA; COLLAGEN-INDUCED ARTHRITIS; CENTRAL-NERVOUS-SYSTEM; CELL LUNG-CANCER; MULTIPLE-SCLEROSIS; RHEUMATOID-ARTHRITIS; SMOOTH-MUSCLE; C CHEMOKINE AB We examine here several diseases that are associated with inappropriate activation of the chemokine network. Detailed comment has been restricted to pathological states for which there are compelling data either from clinical observations or animal models. These include cardiovascular disease, allergic inflammatory disease, transplantation, neuroinflammation, cancer and HIV-associated disease. Discussion focuses on therapeutic directions in which the rapidly evolving chemokine field appears to be headed. C1 Harvard Univ, Childrens Hosp, Sch Med, Dept Pediat, Boston, MA 02115 USA. Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. RP Gerard, C (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Dept Pediat, Boston, MA 02115 USA. NR 118 TC 955 Z9 1005 U1 10 U2 65 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD FEB PY 2001 VL 2 IS 2 BP 108 EP 115 DI 10.1038/84209 PG 8 WC Immunology SC Immunology GA 398WD UT WOS:000166778700005 PM 11175802 ER PT J AU Skobe, M Hawighorst, T Jackson, DG Prevo, R Janes, L Velasco, P Riccardi, L Alitalo, K Claffey, K Detmar, M AF Skobe, M Hawighorst, T Jackson, DG Prevo, R Janes, L Velasco, P Riccardi, L Alitalo, K Claffey, K Detmar, M TI Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis SO NATURE MEDICINE LA English DT Article ID LYMPH-NODE METASTASIS; GROWTH-FACTOR VEGF; EXPRESSION; ANGIOGENESIS; CARCINOMA; ENDOTHELIUM; RECEPTOR-3; TRANSPORT; CELLS; GENE AB Metastasis of breast cancer occurs primarily through the lymphatic system, and the extent of lymph node involvement is a key prognostic factor for the disease. Whereas the significance of angiogenesis for tumor progression has been well documented, the ability of tumor cells to induce the growth of lymphatic vessels (lymphangiogenesis) and the presence of intratumoral lymphatic vessels have been controversial. Using a novel marker for lymphatic endothelium, LYVE-1, we demonstrate here the occurrence of intratumoral lymphangiogenesis within human breast cancers after orthotopic transplantation onto nude mice. Vascular endothelial growth factor (VEGF)-C overexpression in breast cancer cells potently increased intratumoral lymphangiogenesis, resulting in significantly enhanced metastasis to regional lymph nodes and to lungs. The degree of tumor lymphangiogenesis was highly correlated with the extent of lymph node and lung metastases. These results establish the occurrence and biological significance of intratumoral lymphangiogenesis in breast cancer and identify VEGF-C as a molecular link between tumor lymphangiogenesis and metastasis. C1 Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA USA. John Radcliffe Hosp, Inst Mol Med, Oxford OX3 9DU, England. Univ Helsinki, Haartman Inst, Helsinki, Finland. Univ Connecticut, Ctr Hlth, Farmington, CT 06030 USA. RP Detmar, M (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. RI Alitalo, Kari/J-5013-2014 OI Alitalo, Kari/0000-0002-7331-0902 FU NCI NIH HHS [CA86410, CA69184] NR 44 TC 1085 Z9 1208 U1 5 U2 47 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD FEB PY 2001 VL 7 IS 2 BP 192 EP 198 DI 10.1038/84643 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 398KU UT WOS:000166756300036 PM 11175850 ER PT J AU Ji, RR Woolf, CJ AF Ji, RR Woolf, CJ TI Neuronal plasticity and signal transduction in nociceptive neurons: Implications for the initiation and maintenance of pathological pain SO NEUROBIOLOGY OF DISEASE LA English DT Review DE pathological pain; MAP kinase; nociceptive neurons; spinal cord; primary sensory neurons; central sensitization; neuronal plasticity; signal transduction; transcription ID ACTIVATED PROTEIN-KINASE; DORSAL-ROOT GANGLIA; RAT SPINAL-CORD; NITRIC-OXIDE SYNTHASE; TRANSCRIPTION FACTOR CREB; RECEPTOR MESSENGER-RNA; C-FOS TRANSCRIPTION; NEUROPATHIC PAIN; SENSORY NEURONS; INFLAMMATORY PAIN AB Pathological pain, consisting of tissue injury-induced inflammatory and nerve injury-induced neuropathic pain, is an expression of neuronal plasticity. One component of this is that the afferent input generated by injury and intense noxious stimuli triggers an increased excitability of nociceptive neurons in the spinal cord. This central sensitization is an activity-dependent functional plasticity that results from activation of different intracellular kinase cascades leading to the phosphorylation of key membrane receptors and channels, increasing synaptic efficacy. Central sensitization is both induced and maintained in a transcription-independent manner. Several different intracellular signal transduction cascades converge on MAPK (mitogen-activated protein kinase), activation of which appears to be a master switch or gate for the regulation of central sensitization. In addition to posttranslational regulation, the MAPK pathway may also regulate long-term pain hypersensitivity, via transcriptional regulation of key gene products. Pharmacological intervention targeted specifically at the signal transduction pathways in nociceptive neurons may provide, therefore, new therapeutic opportunities for pathological pain. (C) 2001 Academic Press. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Ji, RR (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, Boston, MA 02114 USA. OI Ji, Ru-Rong/0000-0002-9355-3688 FU NINDS NIH HHS [NS38253-01] NR 91 TC 387 Z9 412 U1 1 U2 30 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD FEB PY 2001 VL 8 IS 1 BP 1 EP 10 DI 10.1006/nbdi.2000.0360 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 403XY UT WOS:000167069500001 PM 11162235 ER PT J AU Ditaranto, K Tekirian, TL Yang, AJ AF Ditaranto, K Tekirian, TL Yang, AJ TI Lysosomal membrane damage in soluble A beta-mediated cell death in Alzheimer's disease SO NEUROBIOLOGY OF DISEASE LA English DT Article ID CARBOXYL-TERMINAL DERIVATIVES; AMYLOID PROTEIN-PRECURSOR; NEUROFIBRILLARY TANGLES; ACRIDINE-ORANGE; CULTURED-CELLS; PC12 CELLS; PEPTIDE; BRAIN; AGGREGATION; NEURONS AB Our previous studies suggest that a failure to degrade aggregated A beta1-42 in late endosomes or secondary lysosomes is a mechanism that contributes to intracellular accumulation in Alzheimer's disease. In this study, we demonstrate that cultured primary neurons are able to internalize soluble A beta1-42 from the culture medium and accumulate inside the endosomal/lysosomal system. The intracellular A beta1-42 is resistant to protease degradation and stable for at least 48 h within the cultured neurons. Incubation of cultured neurons with a cytotoxic concentration of soluble A beta1-42 invokes the rapid free radical generation within lysosomes and disruption of lysosomal membrane proton gradient which precedes cell death. The loss of lysosomal membrane impermeability is only specific to the A beta1-42 isoform since incubation of cells with high concentrations of A beta1-40 has no effect on lysosomal hydrolase release. To further support the role of lysosomal membrane damage in A beta -mediated cell death, we demonstrate that photodisruption of acridine orange (AO)-loaded lysosomes with intense blue light induces a relatively rapid synchronous lysosomal membrane damage and neuronal death similar to that observed as a result of A beta exposure. AO leaks quickly from late endosomes and lysosomes and partially shifts the fluorescence from an orange fluorescence to a diffuse, green cytoplasmic fluorescence. Such AO relocalization is due to an initial disruption of the lysosomal proton gradient, followed by the release of lysosomal hydrolases into the cytoplasmic compartment. Treatment of cells with either the antioxidant n-propyl gallate or lysosomotropic amine (methylamine) partially blocks the release of lysosomal contents suggesting that this AO relocalization is due to lysosomal membrane oxidation. Based on these findings, we propose that the cell death mediated by the soluble A beta may be fundamentally different from the cell loss observed following extracellular A beta deposition. (C) 2001 Academic Press. C1 Nathan S Kline Inst Psychiat Res, Dementia Res Program, Orangeburg, NY 10962 USA. Massachusetts Gen Hosp, Genet & Aging Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Ditaranto, K (reprint author), Nathan S Kline Inst Psychiat Res, Dementia Res Program, Orangeburg, NY 10962 USA. FU NIA NIH HHS [R01 AG025323, F32 AG05817-02]; NIMH NIH HHS [R01 MH59786, R01 MH059786] NR 42 TC 115 Z9 120 U1 1 U2 8 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD FEB PY 2001 VL 8 IS 1 BP 19 EP 31 DI 10.1006/nbdi.2000.0364 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 403XY UT WOS:000167069500003 PM 11162237 ER PT J AU Cha, JHJ Farrell, LA Ahmed, SF Frey, A Hsiao-Ashe, KK Young, AB Penney, JB Locascio, JJ Hyman, BT Irizarry, MC AF Cha, JHJ Farrell, LA Ahmed, SF Frey, A Hsiao-Ashe, KK Young, AB Penney, JB Locascio, JJ Hyman, BT Irizarry, MC TI Glutamate receptor dysregulation in the hippocampus of transgenic mice carrying mutated human amyloid precursor protein SO NEUROBIOLOGY OF DISEASE LA English DT Article ID METHYL-D-ASPARTATE; ALZHEIMERS-DISEASE; BINDING-SITES; QUANTITATIVE AUTORADIOGRAPHY; NEUROTRANSMITTER RECEPTORS; HUNTINGTON-DISEASE; NEURONAL LOSS; RAT; EXPRESSION; BRAIN AB Alzheimer's disease transgenic mice overexpressing human amyloid precursor protein (hAPP) with the Swedish double mutation (hAPP(Sw)) develop age-related amyloid deposition and behavioral and electrophysiologic changes by an unknown mechanism. Analysis of glutamatergic receptor subtypes in 4- and 15-month-old heterozygous hAPP(Sw) transgenic mice revealed a selective increase in AMPA receptor binding in the hippocampus of 15-month-old transgenic mice, which have established cortical and hippocampal amyloid deposits. There were no significant alterations of GluR1, GluR2, and GluR4 protein expression by semiquantitative confocal analysis or GluR1 mRNA by in situ hybridization. There was no significant alteration in NMDA, in group I and II metabotropic glutamate and in muscarinic receptor binding, or in striatal dopamine and adenosine receptor binding in 15-month-old mice. These data suggest that mutant APP overexpression or age-related amyloid deposition produce a subtle specific alteration in hippocampal glutamate receptors with aging. (C) 2001 Academic Press. C1 Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Univ Minnesota, Dept Neurol, Minneapolis, MN 55455 USA. MIT, Dept Brain & Cognit Sci, Cambridge, MA USA. RP Irizarry, MC (reprint author), Massachusetts Gen Hosp E, Alzheimer DIs Rwes Unit, CNY 6028,149 13th St, Charlestown, MA 02129 USA. FU NIA NIH HHS [K08-AG00793, AG13617, AG11337]; NINDS NIH HHS [NS01916] NR 37 TC 27 Z9 27 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD FEB PY 2001 VL 8 IS 1 BP 90 EP 102 DI 10.1006/nbdi.2000.0330 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 403XY UT WOS:000167069500009 PM 11162243 ER PT J AU Badgaiyan, RD Schacter, DL Alpert, NM AF Badgaiyan, RD Schacter, DL Alpert, NM TI Priming within and across modalities: Exploring the nature of rCBF increases and decreases SO NEUROIMAGE LA English DT Article ID WORD-STEM COMPLETION; EXPLICIT MEMORY; IMPLICIT MEMORY; RECOGNITION MEMORY; FUNCTIONAL MRI; VISUAL-CORTEX; AREA V3A; ACTIVATION; EXTRASTRIATE; RETRIEVAL AB Neuroimaging studies suggest that within-modality priming is associated with reduced regional cerebral blood how (rCBF) in the extrastriate area, whereas cross-modality priming is associated with increased rCBF in prefrontal cortex. To characterize the nature of rCBF changes in within- and cross-modality priming, we conducted two neuroimaging experiments using positron emission tomography (PET), In experiment 1, rCBF changes in within-modality auditory priming on a word stem completion task were observed under same- and different-voice conditions. Both conditions were associated with decreased rCBF in extrastriate cortex. In the different-voice condition there were additional rCBF changes in the middle temporal gyrus and prefrontal cortex. Results suggest that the extrastriate involvement in within-modality priming is sensitive to a change in sensory modality of target stimuli between study and test, but not to a change in the feature of a stimulus within the same modality. In experiment 2, we studied cross-modality priming on a visual stem completion test after encoding under full- and divided-attention conditions, Increased rCBF in the anterior prefrontal cortex was observed in the full- but not in the divided-attention condition. Because explicit retrieval is compromised after encoding under the divided-attention condition, prefrontal involvement in cross-modality priming indicates recruitment of an aspect of explicit retrieval mechanism. The aspect of explicit retrieval that is most likely to be involved in cross-modality priming is the familiarity effect. (C) 2001 Academic Press. C1 Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, VA Med Ctr, Dept Psychiat, Brockton, MA USA. Massachusetts Gen Hosp, PET Imaging Lab, 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. EM rajendra@wjh.harvard.edu OI Schacter, Daniel/0000-0002-2460-6061 FU NIMH NIH HHS [MH60941, MH57915] NR 63 TC 55 Z9 58 U1 3 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB PY 2001 VL 13 IS 2 BP 272 EP 282 DI 10.1006/nimg.2000.0693 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 397ZM UT WOS:000166729100004 PM 11162268 ER PT J AU Hevner, RF Shi, LM Justice, N Hsueh, TP Sheng, M Smiga, S Bulfone, A Goffinet, AM Campagnoni, AT Rubenstein, JLR AF Hevner, RF Shi, LM Justice, N Hsueh, TP Sheng, M Smiga, S Bulfone, A Goffinet, AM Campagnoni, AT Rubenstein, JLR TI Tbr1 regulates differentiation of the preplate and layer 6 SO NEURON LA English DT Article ID DEVELOPING CEREBRAL-CORTEX; NEURONAL MIGRATION; SUBPLATE NEURONS; THALAMOCORTICAL AXONS; EXTRACELLULAR-MATRIX; BRAIN-DEVELOPMENT; MARGINAL ZONE; MUTANT MICE; MOUSE; CONNECTIONS AB During corticogenesis, early-born neurons of the pre-plate and layer 6 are important for guiding subsequent neuronal migrations and axonal projections. Tbr1 is a putative transcription factor that is highly expressed in glutamatergic early-born cortical neurons. In Tbr1-deficient mice, these early-born neurons had molecular and functional defects. Cajal-Retzius cells expressed decreased levels of Reelin, resulting in a reeler-like cortical migration disorder. Impaired subplate differentiation was associated with ectopic projection of thalamocortical fibers into the basal telencephalon. Layer 6 defects contributed to errors in the thalamocortical, corticothalamic, and callosal projections. These results show that Tbr1 is a common genetic determinant for the differentiation of early-born glutamatergic neocortical neurons and provide insights into the functions of these neurons as regulators of cortical development. C1 Univ Calif San Francisco, Dept Psychiat, Nina Ireland Lab Dev Neurobiol, San Francisco, CA 94143 USA. Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurobiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Univ Calif Los Angeles, Sch Med, Inst Neuropsychiat, Los Angeles, CA 90024 USA. Fac Univ Notre Dame Paix, Sch Med, Neurobiol Unit, B-5000 Namur, Belgium. RP Rubenstein, JLR (reprint author), Univ Calif San Francisco, Dept Psychiat, Nina Ireland Lab Dev Neurobiol, San Francisco, CA 94143 USA. OI Hsueh, Yi-Ping/0000-0002-0866-6275 FU NIMH NIH HHS [K02 MH01046]; NINDS NIH HHS [NS01973, R01 NS34661]; Telethon [F.2] NR 51 TC 481 Z9 486 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD FEB PY 2001 VL 29 IS 2 BP 353 EP 366 DI 10.1016/S0896-6273(01)00211-2 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 405DD UT WOS:000167141700011 PM 11239428 ER PT J AU Bar, M Tootell, RBH Schacter, DL Greve, DN Fischl, B Mendola, JD Rosen, BR Dale, AM AF Bar, M Tootell, RBH Schacter, DL Greve, DN Fischl, B Mendola, JD Rosen, BR Dale, AM TI Cortical mechanisms specific to explicit visual object recognition SO NEURON LA English DT Article ID HUMAN EXTRASTRIATE CORTEX; COORDINATE SYSTEM; SURFACE; FMRI; AREA AB The cortical mechanisms associated with conscious object recognition were studied using functional magnetic resonance imaging (fMRI). Participants were required to recognize pictures of masked objects that were presented very briefly, randomly and repeatedly. This design yielded a gradual accomplishment of successful recognition. Cortical activity in a ventrotemporal visual region was linearly correlated with perception of object identity. Therefore, although object recognition is rapid, awareness of an object's identity is not a discrete phenomenon but rather associated with gradually increasing cortical activity. Furthermore, the focus of the activity in the temporal cortex shifted anteriorly as subjects reported an increased knowledge regarding identity. The results presented here provide new insights into the processes underlying explicit object recognition, as well as the analysis that takes place immediately before and after recognition is possible. C1 Massachusetts Gen Hosp, NMR Ctr, Charlestown, MA 02129 USA. Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. RP Bar, M (reprint author), Massachusetts Gen Hosp, NMR Ctr, Charlestown, MA 02129 USA. RI Dale, Anders/A-5180-2010; OI Schacter, Daniel/0000-0002-2460-6061 FU NCRR NIH HHS [R01 RR13609]; NEI NIH HHS [EY07980]; NIMH NIH HHS [R01 MH60941] NR 24 TC 287 Z9 294 U1 4 U2 15 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD FEB PY 2001 VL 29 IS 2 BP 529 EP 535 DI 10.1016/S0896-6273(01)00224-0 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 405DD UT WOS:000167141700024 PM 11239441 ER PT J AU Albert, MR Ostheimer, KG Breman, JG AF Albert, MR Ostheimer, KG Breman, JG TI The last smallpox epidemic in Boston and the vaccination controversy, 1901-1903 SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article C1 NCI, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Breman, JG (reprint author), Fogarty Int Ctr, NIH, 31 Center Dr, MSC 2220, Bethesda, MD 20892 USA. NR 36 TC 37 Z9 37 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 1 PY 2001 VL 344 IS 5 BP 375 EP 379 DI 10.1056/NEJM200102013440511 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 397CM UT WOS:000166675800011 PM 11172172 ER PT J AU Shipp, TD Zelop, CM Repke, JT Cohen, A Lieberman, E AF Shipp, TD Zelop, CM Repke, JT Cohen, A Lieberman, E TI Interdelivery interval and risk of symptomatic uterine rupture SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID CESAREAN DELIVERY; LABOR; TRIAL; WOMEN AB Objective: To relate interdelivery interval to risk of uterine rupture during a trial of labor after prior cesarean delivery. Methods: We reviewed the medical records of all women who had a trial of labor after cesarean delivery over 12 years (July 1984 to June 1996). Analysis was limited to women with only one prior cesarean delivery and no prior vaginal deliveries who delivered term singletons and whose medical records included the month and year of the prior delivery. The time in months between the prior cesarean delivery and the index trial of labor was calculated, and the women were divided accordingly to permit comparison with respect to symptomatic uterine rupture. Results: Two thousand four hundred nine women had trials of labor after one prior cesarean delivery and had complete data from the medical records. There were 29 uterine ruptures (1.2%) in the population. For interdelivery intervals up to 18 months, the uterine rupture rate was 2.25% (seven of 311) compared with 1.05% (22 of 2098) with intervals of 19 months or longer (P = .07). Multiple logistic regression was used to assess the risk of uterine rupture according to interdelivery interval while controlling for maternal age, public assistance, length of labor, gestational age at least 41 weeks, and oxytocin use. Women with interdelivery intervals of up to 18 months were three times as likely (95% confidence interval, 1.2, 7.2) to have symptomatic uterine rupture. Conclusion: Interdelivery intervals of up to 18 months were associated with increased risk of symptomatic uterine rupture during a trial of labor after cesarean delivery compared with that for longer interdelivery intervals. (Obstet Gynecol 2001;97:175-7. (C) 2001 by The American College of Obstetricians and Gynecologists.). C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. Lenox Hill Hosp, Dept Obstet & Gynecol, New York, NY 10021 USA. Univ Nebraska, Med Ctr, Dept Obstet & Gynecol, Omaha, NE USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA USA. RP Shipp, TD (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Obstet & Gynecol, Founders 430,Fruit St, Boston, MA 02114 USA. NR 10 TC 71 Z9 75 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2001 VL 97 IS 2 BP 175 EP 177 DI 10.1016/S0029-7844(00)01129-7 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 401CX UT WOS:000166910500003 PM 11165577 ER PT J AU Kales, SN Polyhronopoulos, GN Aldrich, JM Mendoza, PJ Suh, JH Christiani, DC AF Kales, SN Polyhronopoulos, GN Aldrich, JM Mendoza, PJ Suh, JH Christiani, DC TI Prospective study of hepatic, renal, and haematological surveillance in hazardous materials firefighters SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article DE hazardous materials; firefighters; medical surveillance ID MEDICAL SURVEILLANCE; WASTE WORKERS AB Objectives - To evaluate possible health effects related to work with hazardous materials as measured by end organ effect markers in a large cohort over about 2 years, and in a subcohort over 5 years. Methods - Hepatic, renal, and haematological variables were analysed from 1996-98 in hazardous materials firefighters including 288 hazardous materials technicians (81%) and 68 support workers (19%). The same end organ effect markers in a subcohort of the technicians were also analysed (n=35) from 1993-98. Support workers were considered as controls because they are also firefighters, but had a low potential exposure to hazardous materials. Results - During the study period, no serious injuries or exposures were reported. For the end organ effect markers studied, no significant differences were found between technicians and support workers at either year 1 or year 3. After adjustment for a change in laboratory, no significant longitudinal changes were found within groups for any of the markers except for creatinine which decreased for both technicians (p<0.001) and controls (p<0.01). Conclusions - Health effects related to work are infrequent among hazardous materials technicians. Haematological, hepatic, and renal testing is not required on an annual basis and has limited use in detecting health effects in hazardous materials technicians. C1 Cambridge Hosp, Dept Med, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Occupat Hlth Program, Boston, MA USA. Massachusetts Gen Hosp, Pulm Crit Care Unit, Braintree, MA USA. Massachusetts Resp Hosp, Ctr Occupat & Environm Med, Braintree, MA USA. RP Kales, SN (reprint author), Cambridge Hosp, Dept Med, 1493 Cambridge St, Cambridge, MA 02139 USA. FU NIEHS NIH HHS [ES00002]; NIOSH CDC HHS [OH00156]; PHS HHS [0H03729] NR 18 TC 3 Z9 3 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD FEB PY 2001 VL 58 IS 2 BP 87 EP 94 DI 10.1136/oem.58.2.87 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 397ZJ UT WOS:000166728800003 PM 11160986 ER PT J AU August, M Dodson, TB Nastri, A Chuang, SK AF August, M Dodson, TB Nastri, A Chuang, SK TI Nasopharyngeal carcinoma: Clinical assessment and review of 176 cases SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTICS LA English DT Article ID EPSTEIN-BARR-VIRUS; SQUAMOUS-CELL CARCINOMAS; DISTANT METASTASIS; RADIOTHERAPY; CHEMOTHERAPY; DETERMINANTS AB Objective. The objective of this study was to delineate salient disease characteristics and to determine factors associated with survival in a series of patients with nasopharyngeal carcinoma (NPC). Study design. To address our research objective, we used a retrospective cohort study design and a sample of patients who presented for evaluation and management of NPC. Demographic data, medical history, radiographic findings, staging, and histology were recorded. Treatment and follow-up information were ascertained. Survival data and descriptive statistics were calculated. Multivariate analyses identified risk factors associated with survival rates for ail World Health Organization (WHO) types. Results, The sample comprised 123 men and 53 women (n = 176) of which 70% were white and 23% were Asian. A neck mass was the initial symptom in 49% of patients. In 99% of cases, radiation therapy was the primary treatment mode. WHO types 1 and 3 were most common. Overall 5-year disease-free survival rate was 45.5%. Age, use of tobacco or ethanol, and number of presenting symptoms were statistically associated with decreased survival rate in WHO 1 (squamous cell) tumors. Male gender and total number of presenting symptoms were associated with decreased survival rate for WHO 2 and 3 (nonkeratinizing or undifferentiated) tumors. Conclusions. Being attuned to the presenting signs of NPC may lead to a more expedient diagnosis. The differing risk factors associated with WHO 1 tumors become clear in this predominantly white population. C1 Harvard Sch Publ Hlth, Harvard Sch Dent Med, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP August, M (reprint author), Harvard Sch Publ Hlth, Harvard Sch Dent Med, Dept Oral & Maxillofacial Surg, 70 Blossom St, Boston, MA 02114 USA. FU NIDCR NIH HHS [K16 DE00275, K24 DE00448] NR 28 TC 11 Z9 12 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1079-2104 J9 ORAL SURG ORAL MED O JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. PD FEB PY 2001 VL 91 IS 2 BP 205 EP 214 DI 10.1067/moe.2001.110698 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 403PH UT WOS:000167051300017 PM 11174599 ER PT J AU Montgomery, WW AF Montgomery, WW TI State-of-the-art for osteoplastic frontal sinus operation SO OTOLARYNGOLOGIC CLINICS OF NORTH AMERICA LA English DT Article AB Endoscopic ethmoid and frontal sinus surgery have reduced but not eliminated the indication for the osteoplastic adipose obliteration operation. An updated technique for this operation is presented for treating chronic frontal sinus disease, cerebrospinal fluid leakage by way of frontal sinus, and sinucutaneous fistulae. C1 Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Boston, MA USA. RP Montgomery, WW (reprint author), 243 Charles St, Boston, MA 02114 USA. NR 12 TC 14 Z9 15 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 FEB PY 2001 VL 34 IS 1 BP 167 EP + DI 10.1016/S0030-6665(05)70304-2 PG 12 WC Otorhinolaryngology SC Otorhinolaryngology GA 431BC UT WOS:000168611200015 PM 11344071 ER PT J AU Winters, SL Packer, DL Marchlinski, FE Lazzara, R Cannom, DS Breithardt, GE Wilber, DA Camm, AJ Ruskin, JN AF Winters, SL Packer, DL Marchlinski, FE Lazzara, R Cannom, DS Breithardt, GE Wilber, DA Camm, AJ Ruskin, JN TI Consensus statement on indications, guidelines for use, and recommendations for follow-up of implantable cardioverter defibrillators SO PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY LA English DT Article ID LONG QT SYNDROME; VENTRICULAR ARRHYTHMIAS; SUDDEN-DEATH; COST-EFFECTIVENESS; CARDIAC-ARREST; HIGH-RISK; ELECTROPHYSIOLOGY; CARDIOMYOPATHY; THERAPY; DISEASE C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. St Georges Med Sch, London, England. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Univ Munster, D-4400 Munster, Germany. Hosp Good Samaritan, Los Angeles, CA 90017 USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. Univ Penn, Med Ctr, Philadelphia, PA 19104 USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. Morristown Mem Hosp, Morristown, NJ USA. RP Winters, SL (reprint author), Care of Bishop Marilyn, NASPE, 6 Strathmore Rd, Natick, MA 01760 USA. OI Marchlinski, Francis/0000-0001-7962-9423 NR 35 TC 40 Z9 40 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 FEB PY 2001 VL 24 IS 2 BP 262 EP 269 DI 10.1046/j.1460-9592.2001.00262.x PG 8 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA 411CL UT WOS:000167480500024 PM 11270713 ER PT J AU Tan, G Jensen, MP Robinson-Whelen, S Thomby, JI Monga, TN AF Tan, G Jensen, MP Robinson-Whelen, S Thomby, JI Monga, TN TI Coping with chronic pain: a comparison of two measures SO PAIN LA English DT Article DE chronic pain; coping; depression; disability ID LOW-BACK-PAIN; RHEUMATOID-ARTHRITIS; STRATEGIES; ADJUSTMENT; DISABILITY; DEPRESSION; INVENTORY; VALIDITY AB Cognitive-behavioral models of chronic pain hypothesize that how a person copes with pain influences how well he or she adjusts to the pain. Several measures have been developed to assess pain coping, but no studies have yet examined whether these measures are complementary or redundant. In the current study, two pain coping measures (the Chronic Pain Coping Inventory, CPCI, and the Coping Strategies Questionnaire, CSQ) were completed by a large number (N = 564) of primarily male veterans referred to a chronic pain program. Regression analyses indicated that the CPCI scales did not contribute unique Variance to the prediction of depression over and above the CSQ scales. The CSQ Catastrophizing scale was the single most powerful predictor of depression, although several other CSQ scales (Coping Self-Statements, Diverting Attention, and Increasing Behavioral Activities) also contributed. Both the CPCI and the CSQ contributed unique Variance to the prediction of disability, although the CPCI scales appear to be more strongly related to disability than the CSQ scales. The CPCI Guarding scale was the single most powerful predictor of disability of all the coping responses assessed in this study. Other scales predicting disability were the CPCI Seeking Social Support, the CSQ Catastrophizing, and the CSQ Increasing Behavioral Activities. While both CSQ and CPCI contribute unique but modest variance to the prediction of pain severity, the CSQ Catastrophizing scale was the single most powerful predictor of pain severity. The findings of this study are consistent with cognitive-behavioral models of pain. Future research will need to determine whether changes in coping responses (catastrophizing and guarding, in particular) merely reflect, or actually influence, adjustment to chronic pain. In the meantime, clinicians would be wise to give these coping responses particular attention in chronic pain programs. (C) 2001 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. C1 Dept Vet Affairs Med Ctr, Houston, TX 77030 USA. RP Tan, G (reprint author), Dept Vet Affairs Med Ctr, 2002 Holcombe Blvd, Houston, TX 77030 USA. NR 25 TC 84 Z9 84 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD FEB 1 PY 2001 VL 90 IS 1-2 BP 127 EP 133 DI 10.1016/S0304-3959(00)00395-X PG 7 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 406CY UT WOS:000167198400015 PM 11166978 ER PT J AU Weinger, K Jacobson, AM AF Weinger, K Jacobson, AM TI Psychosocial and quality of life correlates of glycemic control during intensive treatment of type 1 diabetes SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE type 1 diabetes; quality of life; emotional distress; barriers ID BLOOD-GLUCOSE CONTROL; METABOLIC CONTROL; SELF-CARE; MELLITUS; THERAPY; HYPOGLYCEMIA; MANAGEMENT; DEPRESSION; BEHAVIORS; EDUCATION AB To identify emotional and attitudinal barriers to improved glycemic control (HbA(1c)) during intensive diabetes treatment, 55 patients attending a 4-5 month intensive diabetes medical/education clinic were followed. Subjects completed a battery of psychological surveys, had HbA(1c) and body mass index measured, and rated their attitude toward weight gain and the extent of problems with specific self-management behaviors before and after the medical intervention. Although HbA(1c) improved on average, 29% had only modest improvement and 16% showed no improvement. The number of diabetes-related annoyances, worry about hypoglycemia, and diabetes-related emotional distress diminished. Only the satisfaction subscale of the Diabetes Quality of Life survey, diabetes-related emotional distress, and problems with self-management behaviors correlated with HbA(1c). Treatment-related frustration and emotional distress may initially act as motivators to improve glycemia but can later become barriers to that goal. Interventions designed to help patients overcome attitudinal barriers should be incorporated into medical programs geared toward improving glycemia. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Behav & Mental Hlth Res, Boston, MA 02215 USA. RP Weinger, K (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Behav & Mental Hlth Res, Boston, MA 02215 USA. FU NIDDK NIH HHS [NIDDK42315, R01 DK042315-08]; NINR NIH HHS [F32 NR007157-03, F32 NR007157-02, F32 NR007157-01A1, NR07157] NR 30 TC 40 Z9 42 U1 1 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD FEB PY 2001 VL 42 IS 2 BP 123 EP 131 DI 10.1016/S0738-3991(00)00098-7 PG 9 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 392XW UT WOS:000166438700004 PM 11118778 ER PT J AU Brancaleon, L Durkin, AJ Tu, JH Menaker, G Fallon, JD Kollias, N AF Brancaleon, L Durkin, AJ Tu, JH Menaker, G Fallon, JD Kollias, N TI In vivo fluorescence spectroscopy of nonmelanoma skin cancer SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID BASAL-CELL CARCINOMA; SPECTROPHOTOMETRIC EVALUATION; PIGMENTED LESIONS; COLLAGENASE; AUTOFLUORESCENCE; DIAGNOSIS; LOCALIZATION; ULTRAVIOLET; DYSPLASIA; TUMORS AB In vivo and ex vivo tissue autofluorescence (endogenous fluorescence) have been employed to investigate the presence of markers that could be used to detect tissue abnormalities and/or malignancies, We present a study of the autofluorescence of normal skin and tumor in vivo, conducted on 18 patients diagnosed with nonmelanoma skin cancers (NMSC), We observed that both in basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) the endogenous fluorescence due to tryptophan residues was more intense in tumor than in normal tissue, probably due to epidermal thickening and/or hyperproliferation, Conversely, the fluorescence intensity associated with dermal collagen crosslinks was generally lower in tumors than in the surrounding normal tissue, probably because of degradation or erosion of the connective tissue due to enzymes released by the tumor. The decrease of collagen fluorescence in the connective tissue adjacent to the tumor loci was validated by fluorescence imaging on fresh-frozen tissue sections obtained from 33 NMSC excised specimens, Our results suggest that endogenous fluorescence of NMSC, excited in the UV region of the spectrum, has characteristic features that are different from normal tissue and may be exploited for noninvasive diagnostics and for the detection of tumor margins. C1 Massachusetts Gen Hosp, Wellman Labs Photomed, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dermatol Surg Unit, Boston, MA 02114 USA. Candela Corp, Wayland, MA USA. Johnson & Johnson, Consumer Prod World Wide, Skillhan, NJ USA. RP Brancaleon, L (reprint author), Univ Dundee, Ninewells Hosp & Med Sch, Dept Dermatol, Dundee DD1 9SY, Scotland. RI Brancaleon, Lorenzo/B-5625-2009 NR 37 TC 136 Z9 139 U1 1 U2 16 PU AMER SOC PHOTOBIOLOGY PI AUGUSTA PA BIOTECH PARK, 1021 15TH ST, SUITE 9, AUGUSTA, GA 30901-3158 USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD FEB PY 2001 VL 73 IS 2 BP 178 EP 183 DI 10.1562/0031-8655(2001)073<0178:IVFSON>2.0.CO;2 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 403YG UT WOS:000167070300012 PM 11272732 ER PT J AU Meyer, JH Elashoff, JD AF Meyer, JH Elashoff, JD TI Dilutions of low- vs. high-fat diets on intakes and gastric volumes in rats SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE fat; sensation; satiety; gastric distension; compensation; adaptation ID FOOD-INTAKE; ENERGY-INTAKE; INTRAGASTRIC BALLOON; OBESE SUBJECTS; SOLID FOOD; SATIETY; WEIGHT; DENSITY; CARBOHYDRATE; ABSORPTION AB Rats adapt to changes in dietary energy to maintain nearly constant energy intakes. This regulation indicates that animals sense and respond to nutrient content. We sought to determine whether this response was affected by the fat content of the diet. Our second goal was to determine how energy dilution affected intragastric volumes. Rats were randomized to high (18% w/w) and low fat (4.5% w/w) as the energy density of the diet was altered from 2.0 to 3.5 kcal/g. Average energy intake during 7-h feeds rose steeply (P<.01) when density was increased from 2.0 to 3.0 kcal/g, but modestly as density increased from 3.0 to 3.5 kcal/g. In other rats on 18% vs. 32% fat diets, energy intakes increased significantly (P<.01) as density of the diet was raised from 3.5 to 4.5 kcal/g. During diets at 2.0 and 2.5 kcal/g, animals on 18% fat ate fewer kilocalories than those on 4.5% fat; but over 3.0-4.5 kcal/g, energy intake was;similar regardless of fat concentration (4.5-32%). Gastric contents after 7-h feeds increased with grams of food ingested similarly for high- and low-fat diets; We concluded that in rats: (a) compensation to energy dilution or concentration was inexact but (b) was about equal for high- vs, low-fat diets; thus, high fat was as well sensed as high carbohydrate; (c) compensations for energy densities were made despite varied gastric volumes;thus, rats learned to override the stimulus of gastric sh-etch and to sense energy via extra gastric mechanisms. (C) 2001 Elsevier Science Inc. All rights reserved. C1 VA Greater Los Angeles Healthcare Syst, W Los Angeles Healthcare Ctr, Dept Med, Los Angeles, CA USA. Cedars Sinai Med Ctr, Biostat Core Res Inst, Los Angeles, CA 90048 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. RP Meyer, JH (reprint author), VA Greater Los Angeles Healthcare Syst, W Los Angeles Healthcare Ctr, Dept Med, Bldg 115,11301 Wilshire Blvd, Los Angeles, CA USA. NR 51 TC 1 Z9 1 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD FEB PY 2001 VL 72 IS 3 BP 325 EP 337 DI 10.1016/S0031-9384(00)00419-4 PG 13 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 413RT UT WOS:000167626300006 PM 11274674 ER PT J AU Emmons, K AF Emmons, K TI Commentary SO PREVENTIVE MEDICINE LA English DT Editorial Material C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Div Community Based Res, Boston, MA 02115 USA. RP Emmons, K (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 FEB PY 2001 VL 32 IS 2 BP 93 EP 94 PG 2 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 399QZ UT WOS:000166825000001 PM 11162332 ER PT J AU Kwabi-Addo, B Ropiquet, F Giri, D Ittmann, M AF Kwabi-Addo, B Ropiquet, F Giri, D Ittmann, M TI Alternative splicing of fibroblast growth factor receptors in human prostate cancer SO PROSTATE LA English DT Article DE prostate cancer; fibroblast growth factor; fibroblast growth factor receptor; alternative splicing ID FGF RECEPTORS; CELL-LINES; EXPRESSION; FAMILY; SPECIFICITY; INHIBITION; INVASION; DOMAIN; GENES; IIIB AB BACKGROUND. Fibroblast growth factors (FGFs) are known to play an important role in the growth of normal prostatic epithelial cells and may promote proliferation of neoplastic prostatic epithelial cells via autocrine or paracrine mechanisms. The affinity of FCFs for FGF receptors 1-3 is critically dependent on an alternative splicing event involving the coding region for the carboxy terminal portion of the third extracellular immunoglobulin-like domain that leads to two different isoforms of each receptor (IIIb and IIIc). We therefore sought to determine whether changes in alternative splicing of FGF receptors occur in human prostate cancer. METHODS. RNAs from normal prostate and clinically localized or metastatic prostate cancers were analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) followed by digestion of products with restriction enzymes specific for each FGF receptor isoform and quantitation of the relative amounts of each isoform after electrophoresis. For FGFR-2, this was correlated with immunohistochemistry to determine the localization of the protein product. RESULTS. FGFR-1 is expressed exclusively as the IIIc isoform in prostate cancer while FCFR-3 is expressed predominantly as the IIIb isoform, similar to the expression pattern in normal prostatic epithelial cells. In contrast, there was variable expression of the FGFR-2 IIIb and IIIc isoforms. In the majority of cases the FGFR-2 IIIb isoform was the predominant or exclusive isoform expressed, similar to normal epithelial cells, but in a subset of cases the IIIc isoform was increased, indicating a change in alternative splicing of FGFR-2 in some cases. CONCLUSIONS. In most cases of prostate cancer there are no changes in alternative splicing of FGF receptors, but in a subgroup there is increased expression of the FGFR-2 IIIc isoform. Given that the affinity of FGFs is highly dependent on the isoform of FGF receptor expressed, this information is critical in understanding the effects of FGFs on prostate cancer cells in vivo. Prostate 46:163-172, 2001. (C) 2001 Wiley-Liss, Inc. C1 Baylor Coll Med, Dept Pathol, Houston Dept Vet Affairs Med Ctr, Res Serv, Houston, TX 77030 USA. RP Ittmann, M (reprint author), Baylor Coll Med, Dept Pathol, Houston Dept 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 67 Z9 68 U1 0 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0270-4137 J9 PROSTATE JI Prostate PD FEB 1 PY 2001 VL 46 IS 2 BP 163 EP 172 DI 10.1002/1097-0045(20010201)46:2<163::AID-PROS1020>3.0.CO;2-T PG 10 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 398JC UT WOS:000166752500009 PM 11170144 ER PT J AU Kramer, TL Glazer, WN AF Kramer, TL Glazer, WN TI Best Practices: Our quest for excellence in behavioral health care SO PSYCHIATRIC SERVICES LA English DT Article ID BENCHMARKING C1 Univ Arkansas Med Sci, Ctr Outcomes Res & Effectiveness, Little Rock, AR 72204 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. RP Kramer, TL (reprint author), Univ Arkansas Med Sci, Ctr Outcomes Res & Effectiveness, 5800 W 10th St,Suite 605, Little Rock, AR 72204 USA. NR 14 TC 3 Z9 3 U1 0 U2 0 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1075-2730 J9 PSYCHIATR SERV JI Psychiatr. Serv. PD FEB PY 2001 VL 52 IS 2 BP 157 EP 159 DI 10.1176/appi.ps.52.2.157 PG 3 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 398HC UT WOS:000166750000004 PM 11157109 ER PT J AU Sattar, P AF Sattar, P TI A new vision for mental health treatment laws: A report by the LPS Reform Task Force SO PSYCHIATRIC SERVICES LA English DT Book Review C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA. RP Sattar, P (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1075-2730 J9 PSYCHIATR SERV JI Psychiatr. Serv. PD FEB PY 2001 VL 52 IS 2 BP 249 EP 250 DI 10.1176/appi.ps.52.2.249 PG 2 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 398HC UT WOS:000166750000039 ER PT J AU Petrie, EC Peskind, ER Dobie, DJ Veith, RC Raskind, MA AF Petrie, EC Peskind, ER Dobie, DJ Veith, RC Raskind, MA TI Plasma catecholamine and cardiovascular responses to physostigmine in Alzheimer's disease and aging SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE Alzheimer's; aging; norepinephrine; epinephrine; physostigmine; blood pressure ID CENTRAL CHOLINERGIC STIMULATION; ADRENOCORTICAL AXIS RESPONSES; BLOOD-PRESSURE; NERVOUS-SYSTEM; AGE-DIFFERENCES; DOUBLE-BLIND; NOREPINEPHRINE; EPINEPHRINE; STRESS; RELEASE AB Stimulation of brain cholinergic systems increases activity of both the sympathoneural (SN) and sympathoadrenomedullary (SAM) components of the peripheral sympathetic nervous system. Because presynaptic cholinergic neuron numbers are substantially reduced in Alzheimer's disease (AD), we predicted decreased responsiveness in AD of plasma norepinephrine (NE), an estimate of SN activity, and of epinephrine (EPI), an estimate of SAM activity, to central cholinergic stimulation by the cholinesterase inhibitor physostigmine (0.0125 mg/kg i.v.). Because previous studies have demonstrated that normal human aging increases SN activity but not SAM activity, we specifically hypothesized: (1) a smaller NE response to physostigmine in subjects with mild to moderate AD (n=11; age 72+/-2 yrs; mini-mental state exam [MMSE] scores of 19+/-2) than in healthy older subjects (n=20; age 71+/-1 yrs); and (2) a smaller EPI response in AD subjects than in either healthy older or healthy young subjects (n=9; age 27+/-2 yrs), Unexpectedly, the plasma NE increase following physostigmine only achieved significance in AD subjects and plasma EPI responses were greater in both AD and older subjects than in young subjects. Blood pressure responses to physostigmine were consistent with the catecholamine responses. These data suggest that the presence of mild to moderate AD increases the SN response to cholinergic stimulation and that both AD and normal aging increase the SAM response to cholinergic stimulation. As a result, plasma catecholamine responses to physostigmine do not appear to be useful peripheral neuroendocrine estimates of the severity of brain cholinergic deficits in mild to moderate AD. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Vet Affairs Puget Sound Hlth Care Syst, Mental Hlth Serv S116, Seattle, WA 98108 USA. Vet Affairs Puget Sound Hlth Care Syst, Vet Affairs NW Network Mental Illness Res Educ, Seattle, WA 98108 USA. Vet Affairs Puget Sound Hlth Care Syst, Ctr Clin, MIRECC, Seattle, WA 98108 USA. Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Petrie, EC (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Mental Hlth Serv S116, 1660 S Columbian Way, Seattle, WA 98108 USA. FU NIA NIH HHS [AG05136, AG08419] NR 74 TC 4 Z9 5 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD FEB PY 2001 VL 26 IS 2 BP 147 EP 164 DI 10.1016/S0306-4530(00)00041-X PG 18 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA 391QZ UT WOS:000166367800003 PM 11087961 ER PT J AU Weissleder, R AF Weissleder, R TI Experimental radiology in the USA SO RADIOLOGE LA German DT Editorial Material C1 Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Dept Radiol, Ctr Mol Imaging Res, Boston, MA 02114 USA. RP Weissleder, R (reprint author), Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-832X J9 RADIOLOGE JI Radiologe PD FEB PY 2001 VL 41 IS 2 BP 115 EP 115 DI 10.1007/s001170050952 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 407QD UT WOS:000167281500001 PM 11253095 ER PT J AU Hogemann, D Basilion, JP Weissleder, R AF Hogemann, D Basilion, JP Weissleder, R TI Molecular imaging techniques in magnetic resonance imaging and nuclear imaging SO RADIOLOGE LA German DT Article DE molecular imaging; gene therapy; magnetic resonance imaging; nuclear imaging ID GENE-EXPRESSION; RECEPTOR; SPECTROSCOPY; CANCER; LOCALIZATION; MICROSCOPY; DISEASE; TUMOR; PET AB The identification of genetic and biochemical changes allows a more conclusive characterization and classification of disease. Up to now this information is mostly obtained through in vitro analysis after resection or biopsy by immunohistopathology and molecular biology. There is a definite need for non-invasive detection and repeated monitoring of such changes in experimental research as well as in clinical trials. Therefore, it is necessary to develop radiological imaging techniques that not only visualize morphologic and physiologic alterations, but track genetic and biochemical processes. This short review reports some of the various ongoing research projects that address this problem and provide some very promising approaches. C1 Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. RP Hogemann, D (reprint author), Massachusetts Gen Hosp, CMIR Radiol, Bldg 149,13th St,5403, Charlestown, MA 02129 USA. NR 27 TC 3 Z9 3 U1 0 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-832X J9 RADIOLOGE JI Radiologe PD FEB PY 2001 VL 41 IS 2 BP 116 EP + DI 10.1007/s001170050953 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 407QD UT WOS:000167281500002 PM 11253096 ER PT J AU Wunderbaldinger, P Weissleder, R AF Wunderbaldinger, P Weissleder, R TI Experimental and clinical application for lymph-node imaging SO RADIOLOGE LA German DT Article DE lymph nodes; lymphatic system; metastases; experimental radiology ID SUPERPARAMAGNETIC IRON-OXIDE; MAGNETIC-RESONANCE LYMPHOGRAPHY; POSITRON-EMISSION-TOMOGRAPHY; INTRAVENOUS CONTRAST AGENT; ENHANCED MR LYMPHOGRAPHY; GRAY-SCALE US; BREAST-CANCER; LUNG-CANCER; IN-VIVO; COMPUTED-TOMOGRAPHY AB Exact assessment of lymph nodes is crucial to tumor staging, choice of therapy and in predicting the outcome. Although imaging plays a central role in the evaluation of lymph nodes, current imaging methods have low sensitivity and specificity primarily because they rely on insensitive morphological criteria or because they have low spacial resolution. Because of this diagnostic dilemma invasive, expansive and uncomfortable diagnostic techniques and/or unnecessary aggressive therapies are still in use. This brief overview is intended to summarize current imaging strategies and to give an outlook on experimental and clinical strategies in lymph node imaging in cancer. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Mol Imaging Res, Boston, MA USA. RP Wunderbaldinger, P (reprint author), MGH CMIR, Bldg 149,13th st,Room 5403, Charlestown, MA 02129 USA. EM wunderba@helix.mgh.harvard.edu NR 83 TC 5 Z9 5 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-832X J9 RADIOLOGE JI Radiologe PD FEB PY 2001 VL 41 IS 2 BP 121 EP + DI 10.1007/s001170050954 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 407QD UT WOS:000167281500003 PM 11253097 ER PT J AU Bremer, C Ntziachristos, V Mahmood, U Tung, CH Weissleder, R AF Bremer, C Ntziachristos, V Mahmood, U Tung, CH Weissleder, R TI Advances in optical imaging SO RADIOLOGE LA German DT Article DE optical imaging; optical contrast media; diffuse optical tomography; DOT; near infrared fluorescence; NIRF ID MATRIX-METALLOPROTEINASE INHIBITORS; BREAST-CANCER DETECTION; TRANS-ILLUMINATION; CONTRAST AGENTS; MAMMOGRAPHY; DIAPHANOGRAPHY; SPECTROSCOPY; PROTEASES; LESIONS AB Different optical imaging technologies have significantly progressed over the last years. Besides advances in imaging techniques and image reconstruction, new "smart" optical contrast agents have been developed which can be used to detect molecular targets (such as endogenous enzymes) in vivo. The combination of novel imaging technologies coupled with smart agents bears great diagnostic potential both clinically and experimentally. This overview outlines the basic principles of optical imaging and summarizes the current state of the art. C1 Massachusetts Gen Hosp, Ctr Mol Imaging Res, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Bremer, C (reprint author), Massachusetts Gen Hosp, Ctr Mol Imaging Res, Bldg 149,13th St,5403, Charlestown, MA 02129 USA. NR 35 TC 16 Z9 17 U1 0 U2 4 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-832X J9 RADIOLOGE JI Radiologe PD FEB PY 2001 VL 41 IS 2 BP 131 EP + DI 10.1007/s001170050955 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 407QD UT WOS:000167281500004 PM 11253098 ER PT J AU Bremer, C Bogdanov, AA Weissleder, R AF Bremer, C Bogdanov, AA Weissleder, R TI Imaging angiogenesis SO RADIOLOGE LA German DT Article DE angiogenesis; anti-angiogenic treatment; imaging ID FIBROBLAST GROWTH-FACTOR; DTPA ENHANCED MRI; TUMOR ANGIOGENESIS; IN-VIVO; CONTRAST-MEDIA; ANTIANGIOGENIC THERAPY; MICROVESSEL DENSITY; BREAST-CARCINOMA; VASCULAR VOLUME; BLOOD-VOLUME AB Angiogenesis of tumors has gained tremendous attention in the research community over the last years. Novel anti-angiogenic treatment protocols are currently in various phases of clinical testing. Thus, the major challenge for Radiological diagnostics is to develop imaging methods which reliably measure the angiogenic tumor burden as well as tumor response to anti-angiogenic treatment in vivo. This article intends to provide a brief overview of imaging strategies for angiogenesis and anti-angiogenic treatment. C1 Massachusetts Gen Hosp, Ctr Mol Imaging Res, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Bremer, C (reprint author), Massachusetts Gen Hosp, Ctr Mol Imaging Res, Bldg 149,13th,5403, Charlestown, MA 02129 USA. NR 52 TC 5 Z9 5 U1 1 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-832X J9 RADIOLOGE JI Radiologe PD FEB PY 2001 VL 41 IS 2 BP 138 EP + DI 10.1007/s001170050956 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 407QD UT WOS:000167281500005 PM 11253099 ER PT J AU Filler, TJ Bremer, C Peuker, ET Bankert, J Kreft, G Reimer, P AF Filler, TJ Bremer, C Peuker, ET Bankert, J Kreft, G Reimer, P TI Pathomorphology of laser-induced interstitial tumor thermotherapy for the liver SO RADIOLOGE LA German DT Article DE LITT; histology; electronmicroscopy; ultrastructure; liver ID PRELIMINARY CLINICAL-EXPERIENCE; OPTICAL-PROPERTIES; MRI; TISSUES; COAGULATION AB The aim of this study was to analyse pathomorphological findings after treatment with laser induced tumor thermotherapy (LITT) on liver tissue and to correlate the results with magnetic resonance imaging. LITT was performed ex vivo and in vivo using a Neodym-YAG-Laser. Lesions were monitored by MR-thermometry ex vivo and by contrast-enhanced MRI in vivo. After LITT the lesions were examined macroscopically, histologically,and electronmicrosopically. LITT-induced tissue damage was qualitatively evaluated, classified, and quantified by means of digital image analysis. Four different zones of tissue damage were identified within the lesions. Adjacent to the applicator the tissue was completely ablated while more peripheral lesions exhibited only sublethal cell damages seen by EM. In vivo the pattern of tissue injury followed the lobular architecture of the liver tissue. Ultrastructural examination revealed only in areas of minor tissue injury intact sinusoidal patterns. MRI overestimated the diameter of the core zone of complete tissue ablation both ex vivo and to a lesser extent in vivo. C1 Univ Munster, Inst Anat, D-48149 Munster, Germany. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Mol Imaging Res, Boston, MA USA. Univ Munster, Inst Klin Radiol, D-48149 Munster, Germany. Stadt Klinikum Karlsruhe, Zent Inst Bildgebende Diagnost, Karlsruhe, Germany. RP Filler, TJ (reprint author), Univ Munster, Inst Anat, Vesaliusweg 2-4, D-48149 Munster, Germany. RI Filler, Timm/I-5779-2014 OI Filler, Timm/0000-0002-2922-5110 NR 24 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-832X J9 RADIOLOGE JI Radiologe PD FEB PY 2001 VL 41 IS 2 BP 181 EP + DI 10.1007/s001170050961 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 407QD UT WOS:000167281500010 PM 11253104 ER PT J AU Athanasoulis, CA AF Athanasoulis, CA TI Vascular radiology: Looking into the past to learn about the future SO RADIOLOGY LA English DT Editorial Material DE angiography; interventional procedures; perspectives; radiology and radiologists, history C1 Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Athanasoulis, CA (reprint author), Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. NR 11 TC 9 Z9 9 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD FEB PY 2001 VL 218 IS 2 BP 317 EP 322 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 397ZE UT WOS:000166728200002 PM 11161140 ER PT J AU Smith, JJ AF Smith, JJ TI Regulation of medical devices in radiology: Current standards and future opportunities SO RADIOLOGY LA English DT Review DE diagnostic radiology; quality assurance; review; US Food and Drug Administration AB Today's radiology community depends heavily on cutting-edge diagnostic and therapeutic medical devices to serve patients. These products are regulated by the U.S. Food and Drug Administration (FDA) under a system that grants marketing approval for only those indications for which the safety and effectiveness have been established. Although this complex system is the result of a societal decision to ensure device safety and effectiveness, it has the potential to delay product marketing and impede innovation. Medical device regulation recently has undergone major changes with the enactment of the Food and Drug Administration Modernization Act of 1997 (FDAMA), legislation that is intended to increase system efficiency while retaining the requirement of safety and effectiveness. However, many of the envisioned improvements cannot occur without cooperative interaction between stakeholders in the device development process, including the FDA and the clinical medicine community. The radiology field must continue to build on its strong history of productive dialogue with the FDA to transform the legislative vision of FDAMA into regulatory reality. Such action will ensure timely access to the new device technologies that are necessary for the growth of our specialty and the effective care of our patients. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Ctr Integrat Med & Innovat Technol, Boston, MA USA. RP Smith, JJ (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. NR 16 TC 4 Z9 4 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD FEB PY 2001 VL 218 IS 2 BP 329 EP 335 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 397ZE UT WOS:000166728200005 PM 11161144 ER PT J AU Patronas, NJ Courcoutsakis, N Bromley, CM Katzman, GL MacCollin, M Parry, DM AF Patronas, NJ Courcoutsakis, N Bromley, CM Katzman, GL MacCollin, M Parry, DM TI Intramedullary and spinal canal tumors in patients with neurofibromatosis 2: MR imaging findings and correlation with genotype SO RADIOLOGY LA English DT Article DE genes and genetics; neurofibromatosis; spinal cord, MR; spinal cord, neoplasms ID GERM-LINE MUTATIONS; TYPE-2 NEUROFIBROMATOSIS; GENE; NF2; DISEASE; SUPPRESSOR; SEVERITY; CORD AB PURPOSE: To determine the appearance of spinal tumors on magnetic resonance (MR) images of patients with neurofibromatosis 2 (NF2), to assess the biologic behavior of these tumors, and to determine the correlation between NF2 germline mutations and these tumors. MATERIALS AND METHODS: Spinal MR images in 49 patients with NF2 were reviewed retrospectively. Intramedullary and intradural extramedullary tumors were counted, and imaging features and growth patterns of intramedullary tumors were determined. Medical records were reviewed for spinal tumor surgery. Data on spinal tumors and NF2 germline mutations in 37 patients from 19 families were analyzed for genotype-phenotype correlation. RESULTS: Thirty-one patients (63%) had spinal tumors: Twenty-six (53%) had intramedullary tumors, 27 (55%) had intradural extramedullary tumors, and 22 (45%) had at least one tumor of each type. Three (12%) patients with intramedullary tumors versus 16 (59%) with extramedullary tumors had undergone surgery for the respective types of tumors. Compared with patients with all other types of mutations, a higher percentage of patients with nonsense and frameshift mutations had intramedullary tumors (P < .025); these patients also had higher mean numbers of all tumors (P < .001), intramedullary tumors (P < .001), and nerve sheath tumors (NSTs) (P < .001). CONCLUSION: in patients with NF2 and spinal tumors, extramedullary tumors (predominantly NSTs) were present in higher numbers and were associated with more surgery than were intramedullary tumors. Our data suggest that the association between nonsense and frameshift mutations and severe NF2 may extend to specific categories of spinal tumors. C1 NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. Northwestern Mem Hosp, Dept Radiol, Chicago, IL USA. NCI, Genet Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Patronas, NJ (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, 10 Ctr Dr,MSC 1182,Rm 1C660, Bethesda, MD 20892 USA. NR 21 TC 47 Z9 50 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD FEB PY 2001 VL 218 IS 2 BP 434 EP 442 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 397ZE UT WOS:000166728200020 PM 11161159 ER PT J AU Ko, JP Shepard, JAO Drucker, EA Aquino, SL Sharma, A Sabloff, B Halpern, E McLoud, TC AF Ko, JP Shepard, JAO Drucker, EA Aquino, SL Sharma, A Sabloff, B Halpern, E McLoud, TC TI Factors influencing pneumothorax rate at lung biopsy: Are dwell time and angle of pleural puncture contributing factors? SO RADIOLOGY LA English DT Article DE biopsies, complications; computed tomography (CT), guidance; lung, biopsy; pneumothorax ID NEEDLE ASPIRATION BIOPSY; DELAYED PNEUMOTHORAX; GUIDED BIOPSY; RISK; COMPLICATIONS; LESIONS AB PURPOSE: To study factors that may influence pneumothorax and chest tube placement rate, especially needle dwell time and pleural puncture angle. MATERIALS AND METHODS: In 159 patients, 160 coaxial computed tomography (CT)-guided lung biopsies were performed. Dwell time, the time between pleural puncture and needle removal, was calculated. The smallest angle of the needle with the pleura ("needle-pleural angle") was measured. These and other variables were correlated with pneumothorax and chest tube rates. RESULTS: One hundred fifty biopsies were included. There were 58 (39%) pneumothoraces (14 noted only at CT), with eight (5%) biopsies resulting in chest tube placement. Longer dwell times (mean, 29 minutes; range, 12-66 minutes) did not correlate with pneumothoraces (P = .81). Smaller needle-pleural angles (80 degrees), decreased forced expiratory volume in 1 second to vital capacity ratio (< 50%), lateral pleural puncture, and lesions along fissures were associated with lower pneumothorax rates (P < .05). Emphysema along the needle path, pulmonary function tests showing ventilatory obstruction, and lesions along fissures predisposed patients to chest tube placement (P < .05). Pleural thickening and prior surgery were associated with lower pneumothorax rates (P < .05). CONCLUSION: Longer dwell times do not correlate with pneumothorax and should not influence the decision to obtain more biopsy samples. A shallow pleural puncture angle may increase the pneumothorax rate. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Barts & London NHS Trust, London, England. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Ko, JP (reprint author), NYU, Med Ctr, Dept Radiol, New York, NY 10016 USA. NR 18 TC 67 Z9 80 U1 0 U2 2 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD FEB PY 2001 VL 218 IS 2 BP 491 EP 496 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 397ZE UT WOS:000166728200028 PM 11161167 ER PT J AU Ali, SH DeCaprio, JA AF Ali, SH DeCaprio, JA TI Cellular transformation by SV40 large T antigen: interaction with host proteins SO SEMINARS IN CANCER BIOLOGY LA English DT Article DE SV40; T antigen; p53; pRB ID LARGE TUMOR-ANTIGEN; RETINOBLASTOMA GENE-PRODUCT; PRB-RELATED PROTEINS; S-PHASE ENTRY; J-DOMAIN; TRANSCRIPTIONAL ACTIVITY; SV40-TRANSFORMED CELLS; SUSCEPTIBILITY GENE; DNA-REPLICATION; P53 AB SV40 large T antigen (TAg) is a powerful oncoprotein capable of transforming a variety of cell types. The transforming activity of TAg is due in large part to its perturbation of the retinoblastoma (pRB) and p53 tumor suppressor proteins. In addition, TAg binds to several other cellular factors, including the transcriptional coactivators p300 and CBP, which may contribute to its transformation function. Several other features of TAg that appear to contribute to its full transformation potential are yet to be completely understood. Study of TAg therefore continues to provide new insights into the mechanism of cellular transformation. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP DeCaprio, JA (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [R01-CA63113, R01-CA50661] NR 80 TC 245 Z9 249 U1 3 U2 19 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD FEB PY 2001 VL 11 IS 1 BP 15 EP 22 DI 10.1006/scbi.2000.0342 PG 8 WC Oncology SC Oncology GA 409ZR UT WOS:000167416000003 PM 11243895 ER PT J AU Shepherd, FA Fossella, FV Lynch, T Armand, JP Rigas, JR Kris, MG AF Shepherd, FA Fossella, FV Lynch, T Armand, JP Rigas, JR Kris, MG TI Docetaxel (Taxotere) shows survival and quality-of-life benefits in the second-line treatment of non-small cell lung cancer: A review of two phase III trials SO SEMINARS IN ONCOLOGY LA English DT Review ID CHEMOTHERAPY C1 Univ Toronto, Princess Margaret Hosp, Toronto, ON M5G 2M9, Canada. Univ Texas, MD Anderson Canc Ctr, Dept Med Oncol, Houston, TX 77030 USA. Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. Inst Gustave Roussy, Serv Oncol, Villejuif, France. Dartmouth Hitchcock Med Ctr, Dept Med, Hematol Oncol Sect, Hanover, NH USA. Mem Sloan Kettering Canc Ctr, Dept Med Oncol, New York, NY 10021 USA. RP Shepherd, FA (reprint author), Univ Toronto, Princess Margaret Hosp, 5-104,610 Univ Ave, Toronto, ON M5G 2M9, Canada. NR 19 TC 40 Z9 41 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 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD FEB PY 2001 VL 28 IS 1 SU 2 BP 4 EP 9 DI 10.1053/sonc.2001.18389 PG 6 WC Oncology SC Oncology GA 413GM UT WOS:000167604000002 PM 11284623 ER PT J AU Belani, C Lynch, T AF Belani, C Lynch, T TI Docetaxel (Taxotere) in combination with platinums in patients with non-small cell lung cancer: Trial data and implications for clinical management SO SEMINARS IN ONCOLOGY LA English DT Review ID PHASE-II; CISPLATIN C1 Univ Pittsburgh, Sch Med, Inst Canc, Dept Med,Div Med Oncol, Pittsburgh, PA 15213 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Belani, C (reprint author), Univ Pittsburgh, Sch Med, Inst Canc, Dept Med,Div Med Oncol, MUH N-755,200 Lothrop St, Pittsburgh, PA 15213 USA. OI Belani, Chandra/0000-0001-5049-5329 NR 35 TC 30 Z9 32 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 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD FEB PY 2001 VL 28 IS 1 SU 2 BP 10 EP 14 DI 10.1053/sonc.20901.18403 PG 5 WC Oncology SC Oncology GA 413GM UT WOS:000167604000003 PM 11441409 ER PT J AU Grant, EG AF Grant, EG TI Sonographic contrast agents in vascular imaging SO SEMINARS IN ULTRASOUND CT AND MRI LA English DT Article ID RENAL-ARTERY STENOSIS; CODED DUPLEX SONOGRAPHY; INTRAHEPATIC PORTOSYSTEMIC SHUNTS; COLOR DOPPLER SONOGRAPHY; WAVE-FORM PARAMETERS; ULTRASOUND CONTRAST; POWER DOPPLER; PORTAL-VEIN; IN-VITRO; US C1 Greater Los Angeles VA Healthcare Syst, Dept Radiol, Los Angeles, CA USA. Univ Calif Los Angeles, Ctr Hlth Sci, Dept Radiol, Los Angeles, CA 90024 USA. RP Grant, EG (reprint author), W Los Angeles Vet Affairs Med Ctr, Imaging Dept W114, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 60 TC 11 Z9 11 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 0887-2171 J9 SEMIN ULTRASOUND CT JI Semin. Ultrasound CT MRI PD FEB PY 2001 VL 22 IS 1 BP 25 EP 41 DI 10.1016/S0887-2171(01)90016-2 PG 17 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 411AH UT WOS:000167475600004 PM 11300585 ER PT J AU Basile, J AF Basile, J TI New strategies for improving heart failure management: A primary care perspective SO SOUTHERN MEDICAL JOURNAL LA English DT Article ID CONVERTING ENZYME-INHIBITORS; CARVEDILOL; MORTALITY; MORBIDITY; READMISSION; PROGRESSION AB Most patients with heart failure today are treated by primary care practitioners, not cardiologists. The Consensus Recommendations for the Management of Chronic Heart Failure, developed by the Advisory Council to Improve Outcomes Nationwide in Heart Failure, provide practice guidelines for the prevention, diagnosis, and treatment of heart failure. Although hemodynamic abnormalities contribute to the symptoms of heart failure, disease progression is attributable to neurohormonal abnormalities, primarily activation of the renin-angiotensin system and the sympathetic nervous system. Pharmacologic treatment that antagonizes these neurohormonal abnormalities reduces the morbidity and mortality associated with heart failure. Guidelines recommend that patients with systolic dysfunction and symptoms of fluid retention receive a diuretic followed by an angiotensin-converting enzyme inhibitor, and, once the patient is euvolemic, a beta -blocker. Digoxin may be added to therapy for patients with persistent symptoms or rapid atrial fibrillation. Clinical trials have shown that such combination regimens reduce the risk of hospitalization and death in patients with heart failure. C1 Ralph H Johnson VA Med Ctr, Primary Care Div, Charleston, SC 29403 USA. Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. RP Basile, J (reprint author), Ralph H Johnson VA Med Ctr, Primary Care Div, 109 Bee St, Charleston, SC 29403 USA. NR 30 TC 3 Z9 3 U1 0 U2 0 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 FEB PY 2001 VL 94 IS 2 BP 166 EP 174 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 406CH UT WOS:000167197000001 PM 11235030 ER PT J AU Kelly, PJ Stein, J Shafqat, S Eskey, C Doherty, D Chang, Y Kurina, A Furie, KL AF Kelly, PJ Stein, J Shafqat, S Eskey, C Doherty, D Chang, Y Kurina, A Furie, KL TI Functional recovery after rehabilitation for cerebellar stroke SO STROKE LA English DT Article DE cerebral infarction; cerebral hemorrhage; cerebellum; rehabilitation ID INDEPENDENCE MEASURE; INFARCTION; PROGNOSIS AB Background ann Purpose-Relatively few data exist concerning functional recovery after ischemic and hemorrhagic cerebellar stroke. We studied patients admitted to a rehabilitation hospital after cerebellar stroke to quantify recovery after rehabilitation therapy and to identify variables that predicted functional outcome. Methods-This study was a retrospective review of consecutive cases admitted in a ii-year period with new cerebellar infarct or hemorrhage. Clinical features of stroke were recorded and comorbidities scored with the Charlson Index. Follow-up information was obtained by telephone interview. The Functional Independence Measure (FIM) was scored at admission (AFIM), discharge (DFIM), and follow-up (FFIM). Outcome measures were DFIM and FFIM. Univariate and multivariate analyses were performed. Results-Fifty-eight cases were identified (mean age 69.2 years; 49 infarcts, 9 hemorrhages). Mean AFIM was 65,5, and mean DFIM was 89.8, Mean AFIM was significantly higher in the infarct than in the hemorrhage subgroup (70 versus 43, P = 0,006). Mean DFIM was also higher in the infarct subgroup but did not reach statistical significance (93 versus 74, P = 0.1). Follow-up information was obtained for 45 cases (78%) (mean interval 19.5 months). Median FFIM was 123,5, Outcome was significantly positively correlated with AFIM and initial presenting syndrome of vertigo/vomiting/ ataxia/headache. Outcome correlated negatively with preexisting comorbidity score, altered level of consciousness at initial presentation, and superior cerebellar artery infarction. On multivariate analysis, AFIM and comorbidity score were independent predictors of outcome. Conclusions-Substantial improvement of mean FIM score frequently occurs after rehabilitation after cerebellar infarction. Functional outcome is best predicted by preexisting comorbidities and functional status at the time of discharge from acute hospitalization. C1 Massachusetts Gen Hosp, Dept Neurol, Stroke Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Med Practices Evaluat Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Div Neuroradiol, Boston, MA 02114 USA. Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA USA. Harvard Mit Hlth Sci & Technol, Beth Israel Deaconess Med Ctr, Pfizer Inc, Clin Investigator Training Program, Boston, MA USA. RP Kelly, PJ (reprint author), Massachusetts Gen Hosp, Dept Neurol, Stroke Serv, Fruit St,VBK 802, Boston, MA 02114 USA. NR 19 TC 56 Z9 60 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2001 VL 32 IS 2 BP 530 EP 534 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 400CM UT WOS:000166851100026 PM 11157193 ER PT J AU Soybel, DI AF Soybel, DI TI Adaptation to ileal diversion SO SURGERY LA English DT Article ID SHORT-BOWEL SYNDROME; ULCERATIVE-COLITIS; CONVENTIONAL ILEOSTOMY; RESTORATIVE PROCTOCOLECTOMY; DIETARY FIBER; J-POUCH; SURGERY; OUTPUT; WATER; MANAGEMENT C1 Harvard Univ, Sch Med, Boston VA Healthcare Syst, W Roxbury Div, Boston, MA 02114 USA. Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. RP Soybel, DI (reprint author), 1400 VFW Pkwy, W Roxbury, MA 02132 USA. NR 40 TC 2 Z9 2 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 FEB PY 2001 VL 129 IS 2 BP 123 EP 127 DI 10.1067/msy.2001.107980 PG 5 WC Surgery SC Surgery GA 401BP UT WOS:000166907300001 PM 11174703 ER PT J AU Nigri, GR Dio, LJAD Baptista, CAC AF Nigri, GR Dio, LJAD Baptista, CAC TI Papillary muscles and tendinous cords of the right ventricle of the human heart: morphological characteristics SO SURGICAL AND RADIOLOGIC ANATOMY LA English DT Article DE right atrioventricular valve; tricuspid valve; papillary muscles; chordae tendineae; cardiac surgery ID CHORDAE TENDINEAE; MITRAL-VALVE AB A series of 79 normal human hearts was studied focusing on the morphological characteristics of the papillary muscles of the right ventricle and their tendinous cords (chordae tendineae). The number, incidence, length and shape of the anterior, septal and posterior papillary muscles were observed. The tendinous cords attached to each papillary muscle were counted at their origin. The papillary muscles and the tendinous cords were measured in situ and after the removal of the right atrioventricular valve (tricuspid valve). The anterior and posterior papillary muscles (apm, ppm) were present in 100% of the cases. The septal papillary muscle (spm) was absent in 21.5% of the hearts. The apm presented 1 head in 81% and 2 heads in 19%; it was 19.16 mm in length. The spm was one-headed in 41.7% and presented two heads in 16.5%; the presence of a 3 and 4 heads appeared in 12.7% and 7.6% respectively; the spm was 5.59 mm in length. The ppm had 1 head in 25.4%, 2 heads in 46.8%, 3 heads in 21.5% and 4 heads in 6.3% of the cases: it was 11.53 mm in length. Tendinous cords (TC) varied as follows: from 1 to 11 TC originated in the apm (mean 4.74), from 1 to 8 TC originated in the ppm (mean 2.67) and from 1 to 5 TC originated in the spm (mean 1.77). C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02114 USA. Univ Santo Amaro, Sch Med, Dept Surg, Inst Heart InCor,HC,FM,USP,Natl Council Res,CNPq, Sao Paulo, Brazil. Med Coll Ohio, Dept Pathol, Toledo, OH 43699 USA. RP Nigri, GR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, 55 Fruit St,BHX 630, Boston, MA 02114 USA. NR 18 TC 20 Z9 24 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0930-1038 J9 SURG RADIOL ANAT JI Surg. Radiol. Anat. PD FEB PY 2001 VL 23 IS 1 BP 45 EP 49 DI 10.1007/s00276-001-0045-7 PG 5 WC Anatomy & Morphology; Radiology, Nuclear Medicine & Medical Imaging; Surgery SC Anatomy & Morphology; Radiology, Nuclear Medicine & Medical Imaging; Surgery GA 420UL UT WOS:000168023600010 PM 11370142 ER PT J AU Holmes, LB AF Holmes, LB TI Editor's introduction SO TERATOLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Genet & Teratol Unit, Boston, MA 02114 USA. RP Holmes, LB (reprint author), Massachusetts Gen Hosp, Genet & Teratol Unit, Warren 801,55 Fruit St, Boston, MA 02114 USA. NR 5 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 0040-3709 J9 TERATOLOGY JI Teratology PD FEB PY 2001 VL 63 IS 2 BP 61 EP 61 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 408EP UT WOS:000167313800001 ER PT J AU Marino, M Lisi, S Pinchera, A Mazzi, B Latrofa, F Sellari-Franceschini, S McCluskey, RT Chiovato, L AF Marino, M Lisi, S Pinchera, A Mazzi, B Latrofa, F Sellari-Franceschini, S McCluskey, RT Chiovato, L TI Identification of thyroglobulin in orbital tissues of patients with thyroid-associated ophthalmopathy SO THYROID LA English DT Article ID GRAVES-OPHTHALMOPATHY; THYROTROPIN-RECEPTOR; MEGALIN GP330; ENDOCYTIC RECEPTOR; EYE DISEASE; HYPERTHYROIDISM; ANTIBODIES; MUSCLE; CELLS; PATHOGENESIS AB Thyroid-associated ophthalmopathy (TAO) is thought to have an autoimmune pathogenesis because of its association with autoimmune thyroid disease, in particular with Graves' disease. Nevertheless, the nature of the autoimmune reaction is unclear, and a target orbital autoantigen has not been conclusively identified. A widely discussed hypothesis is that antigens constitutively shared by the thyroid and orbital tissues are targets of an autoimmune reaction. It has been also postulated that a thyroid-soluble antigen, namely thyroglobulin (Tg), is transported to orbital tissues through the lymphatics, where it accumulates and elicits autoimmune damages in susceptible individuals. Here we have investigated whether Tg is present in orbital tissues from patients with TAO. Retrobulbar tissue specimens were obtained from three patients with Graves' disease and TAO who underwent decompressive orbitotomy, and at autopsy from two patients with no thyroid or eye disease. All patients with TAO had been previously treated with radioiodine to control Graves' hyperthyroidism. Western blot analysis with a monoclonal anti-Tg antibody showed the presence of intact Tg, both in soluble and membrane-associated fractions of orbital tissue extracts from the patients with TAO, in amounts estimated to range from similar to 320 to similar to 900 pg/mug Of tissue protein. In contrast, Tg was not detected in orbital tissue extracts from patients with no thyroid or eye disease. Tg was also demonstrated in orbital tissue extracts from two of three patients with TAO by enzyme-linked immunosorbent assay (ELISA), in amounts estimated to range from similar to 450 to similar to 1000 pg/mug of protein. In addition, Tg in orbital tissue extracts from patients with TAO was immunoprecipitated by a rabbit anti-Tg antibody, suggesting that it retained its native conformation. An anti-thyroxine (T4) antibody captured in solid-phase Tg from orbital tissue extracts, showing that it contained thyroid hormone residues and had therefore originated in the thyroid. Tg-anti-Tg immune complexes were not found in orbital tissues, suggesting that if an autoimmune reaction to Tg occurs in TAO, it is likely to be cell mediated. C1 Univ Pisa, Dept Endocrinol, I-56124 Pisa, Italy. Univ Pisa, Dept Neurosci, ORL Sect, I-56124 Pisa, Italy. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Pathol Res Lab, Charlestown, MA USA. RP Marino, M (reprint author), Univ Pisa, Dept Endocrinol, Via Paradisa 2, I-56124 Pisa, Italy. OI Latrofa, Francesco/0000-0003-0297-5904 FU PHS HHS [46301] NR 37 TC 28 Z9 30 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1050-7256 J9 THYROID JI Thyroid PD FEB PY 2001 VL 11 IS 2 BP 177 EP 185 DI 10.1089/105072501300042929 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 413GH UT WOS:000167601600013 PM 11288989 ER PT J AU Stock, UA Vacanti, JP AF Stock, UA Vacanti, JP TI Cardiovascular physiology during fetal development and implications for tissue engineering SO TISSUE ENGINEERING LA English DT Review ID LEFT-VENTRICULAR OUTPUT; SMOOTH-MUSCLE CELLS; HEART-RATE; IN-VITRO; BLOOD-PRESSURE; SHEAR-STRESS; HUMAN-FETUS; GROWTH; PROLIFERATION; HYPOXIA AB Shear stress in fluid dynamics has a well-known impact on vascular cell morphology, proliferation, orientation, and the organization and composition of extracellular matrix. There is an increasing interest in the field of tissue engineering to use defined shear stress in bioreactors for tissue conditioning and guided tissue formation. Especially for cardiovascular structures like heart valves or blood vessels, the type and appropriate amount of shear stress needed to improve tissue formation remains speculative. The authors believe that fetal-like conditions may be more optimal for new tissue formation in a bioreactor. The purpose of this review is to delineate parameters of cardiovascular physiology during embryonic and fetal development that may have a potential impact on the design and setting of bioreactors for cardiovascular tissue engineering. C1 Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Surg,Ctr Innovat Minimally Invas Therapies, Tissue Engn & Organ Fabricat Lab, Boston, MA 02115 USA. RP Vacanti, JP (reprint author), Massachusetts Gen Hosp, Dept Surg, Fruit St 55, Boston, MA 02114 USA. NR 35 TC 32 Z9 37 U1 0 U2 4 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1076-3279 J9 TISSUE ENG JI Tissue Eng. PD FEB PY 2001 VL 7 IS 1 BP 1 EP 7 DI 10.1089/107632701300003241 PG 7 WC Cell & Tissue Engineering SC Cell Biology GA 406UW UT WOS:000167235200001 PM 11224919 ER PT J AU Arevalo-Silva, CA Cao, YL Weng, YL Vacanti, M Rodriguez, A Vacanti, CA Eavey, RD AF Arevalo-Silva, CA Cao, YL Weng, YL Vacanti, M Rodriguez, A Vacanti, CA Eavey, RD TI The effect of fibroblast growth factor and transforming growth factor-beta on porcine chondrocytes and tissue-engineered autologous elastic cartilage SO TISSUE ENGINEERING LA English DT Article ID ARTICULAR CHONDROCYTES; CELLS AB Elastic cartilage responds mitogenically in vitro to transforming growth factor-beta (TGF-beta) and basic fibroblast growth factor (basic FGF). We studied the effects of these growth factors separately or in a combination on porcine auricular chondrocytes in vitro and on the autologous elastic cartilage produced. Cells were harvested from the elastic auricular cartilage of 16- to 18-kg Yorkshire swine. Viability and quantification of the cells was determined. Cells were plated at equal concentration and studied in vitro in one of four identical media environments except for the growth factors: Group I contained Ham's F-12 with supplements but no growth factors, Group II also contained basic-FGF, Group III also contained TGF-beta, and Group IV also contained a combination of both growth factors. After 3 weeks in vitro, the cells were chemically dissociated with 0.25% trypsin. Cell suspensions composed of 3 x 10(7) cells/cc in 30% Pluronic F-127/Ham's F-12 were injected subcutaneously. Implants were harvested at 6, 8, 10, and 12 weeks of in vivo culture and then were examined with histologic stains. After 3 weeks of in vitro culture the total number of cells was as follows: Group I, 1.8 x 10(8); Group II, 3.5 x 10(8); Group III, 1.3 x 10(8); Group IV, 2.5 x 10(8). After 8 weeks of in vivo autologous implantation, the average weight (g) and volume (cm(3)) of each group was as follows: Group I, 0.7 g/0.15 cm(3); Group II, 1.5 g/0.8 cm(3); Group III, 0.6 g/0.1 cm(3); Group IV, 1.2 g/0.3 cm(3). Histologically, Groups I, II, and IV generated cartilage similar to native elastic cartilage, but Group III specimens demonstrated fibrous tissue ingrowth. Basic FGF produced the most positive enhancement on the quantity and quality of autologous tissue engineered elastic cartilage produced in this porcine model both in vitro and in vivo. C1 Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Univ Massachusetts, Med Ctr, Dept Anesthesiol, Ctr Tissue Engn, Worcester, MA USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. Univ Massachusetts, Med Ctr, Dept Pathol, Worcester, MA USA. RP Eavey, RD (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. NR 13 TC 36 Z9 51 U1 0 U2 4 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1076-3279 J9 TISSUE ENG JI Tissue Eng. PD FEB PY 2001 VL 7 IS 1 BP 81 EP 88 DI 10.1089/107632700300003314 PG 8 WC Cell & Tissue Engineering SC Cell Biology GA 406UW UT WOS:000167235200008 PM 11224926 ER PT J AU Stowell, CP Levin, J Spiess, BD Winslow, RM AF Stowell, CP Levin, J Spiess, BD Winslow, RM TI Progress in the development of RBC substitutes SO TRANSFUSION LA English DT Review ID CROSS-LINKED HEMOGLOBIN; LIPOSOME-ENCAPSULATED HEMOGLOBIN; RED-CELL SUBSTITUTE; HUMAN POLYMERIZED HEMOGLOBIN; BLOOD SUBSTITUTE; OXYGEN CARRIER; NITRIC-OXIDE; PYRIDOXYLATED HEMOGLOBIN; EXCHANGE-TRANSFUSION; PERFLUBRON EMULSION C1 Massachusetts Gen Hosp, Blood Transfus Serv, Boston, MA 02114 USA. Univ Calif San Francisco, Sch Med, Dept Lab Med, San Francisco, CA 94143 USA. Virginia Commonwealth Univ, Med Coll Virginia, Div Cardiothorac Anesthesia, Richmond, VA 23298 USA. Sangart Inc, San Diego, CA USA. RP Stowell, CP (reprint author), Massachusetts Gen Hosp, Blood Transfus Serv, GRJ148,55 Fruit St, Boston, MA 02114 USA. NR 94 TC 74 Z9 75 U1 1 U2 6 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD FEB PY 2001 VL 41 IS 2 BP 287 EP 299 DI 10.1046/j.1537-2995.2001.41020287.x PG 13 WC Hematology SC Hematology GA 410BQ UT WOS:000167420500024 PM 11239237 ER PT J AU Fuchimoto, Y Huang, CA Yamada, K Gleit, ZL Kitamura, H Griesemer, A Scheier-Dolberg, R Melendy, E White-Scharf, ME Sachs, DH AF Fuchimoto, Y Huang, CA Yamada, K Gleit, ZL Kitamura, H Griesemer, A Scheier-Dolberg, R Melendy, E White-Scharf, ME Sachs, DH TI Induction of kidney allograft tolerance through mixed chimerism in miniature swine SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc C1 Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Harvard Med Sch, Boston, MA 02129 USA. BioTransplant, Boston, MA USA. RP Sachs, DH (reprint author), Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Harvard Med Sch, MGH E,Bldg 149-9019,13th St, Boston, MA 02129 USA. NR 3 TC 6 Z9 6 U1 0 U2 1 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 77 EP 77 DI 10.1016/S0041-1345(00)01910-2 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900017 PM 11266710 ER PT J AU Wu, A Ierino, FL Yamada, K Sachs, DH AF Wu, A Ierino, FL Yamada, K Sachs, DH TI Specific suppression of proliferative responses by primed lymphocytes of tolerant miniature swine SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID RENAL-ALLOGRAFTS; CLASS-I C1 Massachusetts Gen Hosp East, Transplantat Biol Res Ctr, Harvard Med Sch, Boston, MA 02129 USA. RP Sachs, DH (reprint author), Massachusetts Gen Hosp East, Transplantat Biol Res Ctr, Harvard Med Sch, Bldg 149, Boston, MA 02129 USA. 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 87 EP 87 DI 10.1016/S0041-1345(00)01916-3 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900024 PM 11266717 ER PT J AU Lee, RS Rusche, JR Maloney, ME Sachs, DH Sayegh, MH Madsen, JC AF Lee, RS Rusche, JR Maloney, ME Sachs, DH Sayegh, MH Madsen, JC TI CTLA4lg-induced linked regulation of allogeneic T cell responses SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID COSTIMULATION; CD28-B7 C1 Massachusetts Gen Hosp, Dept Surg, Transplantat Biol Res Ctr, Boston, MA 02114 USA. Repligen Corp, Needham, MA USA. Harvard Univ, Brigham & Womens Hosp, Sch Med,Lab Immunogenet & Transplantat, Dept Med,Renal Div, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Surg, Harvard Med Sch, Div Cardiac Surg, Boston, MA 02114 USA. RP Madsen, JC (reprint author), Massachusetts Gen Hosp, Dept Surg, Transplantat Biol Res Ctr, EDR 105, Boston, MA 02114 USA. NR 4 TC 1 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 88 EP 89 DI 10.1016/S0041-1345(00)01917-5 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900025 PM 11266718 ER PT J AU Mathes, DW Yamada, K Randolph, MA Utsugi, R Solari, MG Gazelle, GS Wu, A Sachs, DH Lee, WPA AF Mathes, DW Yamada, K Randolph, MA Utsugi, R Solari, MG Gazelle, GS Wu, A Sachs, DH Lee, WPA TI In utero induction of transplantation tolerance SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID HEMATOPOIETIC STEM-CELLS; DISPARATE RENAL-ALLOGRAFTS; MINIATURE SWINE; IN-UTERO; INUTERO TRANSPLANTATION; SURVIVAL; MONKEYS; SHEEP C1 Massachusetts Gen Hosp, Plast Surg Res Lab, Boston, MA 02114 USA. Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. RP Lee, WPA (reprint author), Massachusetts Gen Hosp, Plast Surg Res Lab, WAC 453,15 Parkman St, Boston, MA 02114 USA. NR 13 TC 13 Z9 13 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 98 EP 100 DI 10.1016/S0041-1345(00)01924-2 PG 3 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900033 PM 11266726 ER PT J AU Utsugi, R Barth, RN Kitamura, H Ambroz, J Sachs, DH Yamada, K AF Utsugi, R Barth, RN Kitamura, H Ambroz, J Sachs, DH Yamada, K TI Tolerance across a two-haplotype, fully MHC-mismatched barrier induced in miniature swine renal allografts treated with a 12-day course of tacrolimus SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID MAJOR HISTOCOMPATIBILITY COMPLEX; CYCLOSPORINE; FK506; TRANSPLANTATION C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. RP Yamada, K (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, MGH-E,Bldg 149-9019,13th St, Boston, MA 02129 USA. RI Barth, Rolf/B-2542-2014 NR 8 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 101 EP 101 DI 10.1016/S0041-1345(00)01925-4 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900034 PM 11266727 ER PT J AU Sogawa, H Kawai, T Wee, SL Boskovic, S Nadazdin, O Phelan, J Abrahamian, G Ko, DSC Hong, H Mauiyyedi, S Colvin, RB Sachs, DH Cosimi, AB AF Sogawa, H Kawai, T Wee, SL Boskovic, S Nadazdin, O Phelan, J Abrahamian, G Ko, DSC Hong, H Mauiyyedi, S Colvin, RB Sachs, DH Cosimi, AB TI Comparison of horse antithymocyte globulin with other T cell-depleting antibodies for induction of chimerism and renal allograft tolerance in nonhuman primates SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID CYNOMOLGUS MONKEYS; MIXED CHIMERISM; REGIMEN C1 Massachusetts Gen Hosp, Transplantat Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Cosimi, AB (reprint author), Massachusetts Gen Hosp, Transplantat Unit, WHT515,55 Fruit St, Boston, MA 02114 USA. FU NHLBI NIH HHS [P01-HL18646]; NIAID NIH HHS [R01 AI037692, R01 AI037692-09, R01 AI37692-05, R21 AI037692, R21 AI037692-06] NR 4 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 116 EP 117 DI 10.1016/S0041-1345(00)01933-3 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900042 PM 11266735 ER PT J AU Fuchimoto, Y Huang, CA Gleit, ZL Kitamura, H Griesemer, A Melendy, E Scheier-Dolberg, R White-Scharf, ME Sachs, DH AF Fuchimoto, Y Huang, CA Gleit, ZL Kitamura, H Griesemer, A Melendy, E Scheier-Dolberg, R White-Scharf, ME Sachs, DH TI Mixed chimerism using a nonmyelosuppressive regimen in miniature swine SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID TOLERANCE C1 Harvard Univ, Transplantat Biol Res Ctr, Massachusetts Gen Hosp, Sch Med, Boston, MA 02129 USA. BioTransplant, Boston, MA USA. RP Sachs, DH (reprint author), Harvard Univ, Transplantat Biol Res Ctr, Massachusetts Gen Hosp, Sch Med, MGH-E,Bldg 149-9019,13th St, Boston, MA 02129 USA. NR 5 TC 4 Z9 4 U1 0 U2 1 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 118 EP 119 DI 10.1016/S0041-1345(00)01934-5 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900043 PM 11266736 ER PT J AU Leykin, I Nikolic, B Sykes, M AF Leykin, I Nikolic, B Sykes, M TI Mixed bone marrow chimerism as a treatment for autoimmune diabetes SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc C1 Harvard Univ, BMT Sect, TBRC, Massachusetts Gen Hosp,Med Sch, Boston, MA 02129 USA. RP Sykes, M (reprint author), Harvard Univ, BMT Sect, TBRC, Massachusetts Gen Hosp,Med Sch, MGH E,Bldg 149-5102,13th St, Boston, MA 02129 USA. NR 2 TC 12 Z9 12 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 120 EP 120 DI 10.1016/S0041-1345(00)01935-7 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900044 PM 11266737 ER PT J AU Nikolic, B Zhao, G Sykes, M AF Nikolic, B Zhao, G Sykes, M TI A role for donor-derived B cells but not T cells in the maintenance of mixed hematopoietic chimerism SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID TRANSPLANTATION TOLERANCE; DELETION; REGIMEN C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med,TBRC, BMT Sect, Boston, MA 02129 USA. RP Sykes, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,TBRC, BMT Sect, MGH East,Bldg 149-5102,13th St, Boston, MA 02129 USA. FU NHLBI NIH HHS [R01 HL49915] NR 3 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 182 EP 182 DI 10.1016/S0041-1345(00)01966-7 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900077 PM 11266770 ER PT J AU Tkaczuk, J Milford, E Yu, C Baksh, S Carpenter, C Burakoff, S McKay, D AF Tkaczuk, J Milford, E Yu, C Baksh, S Carpenter, C Burakoff, S McKay, D TI Intracellular signaling consequences of anti-IL-2R alpha blockade by daclizumab SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID RENAL-TRANSPLANTATION C1 Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP McKay, D (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. RI Yu, Chao-Lan/D-1834-2011 OI Yu, Chao-Lan/0000-0002-9381-6011 FU NIDDK NIH HHS [K08-NIDDK] NR 3 TC 9 Z9 11 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 212 EP 213 DI 10.1016/S0041-1345(00)01978-3 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900090 PM 11266783 ER PT J AU Kawai, T Abrahamian, G Sogawa, H Wee, S Boskovic, S Andrew, D Nadazdin, O Mauiyyedi, S Weymouth, D Ko, D Colvin, R Sachs, D Cosimi, A AF Kawai, T Abrahamian, G Sogawa, H Wee, S Boskovic, S Andrew, D Nadazdin, O Mauiyyedi, S Weymouth, D Ko, D Colvin, R Sachs, D Cosimi, A TI Costimulatory blockade for induction of mixed chimerism and renal allograft tolerance in nonhuman primates SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID CYNOMOLGUS MONKEYS; REGIMEN C1 Massachusetts Gen Hosp, Transplantat Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Surg, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Kawai, T (reprint author), Massachusetts Gen Hosp, Transplantat Unit, White 510,55 Fruit St, Boston, MA 02114 USA. FU NHLBI NIH HHS [P01-HL18646]; NIAID NIH HHS [R01 AI037692-09, R01 AI037692, R01 AI037692-10, R01-AI37692-05] NR 4 TC 29 Z9 31 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 221 EP 222 DI 10.1016/S0041-1345(00)01982-5 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900094 PM 11266787 ER PT J AU Lee, RS Yamada, K Houser, SL Womer, KL Maloney, ME Rose, HS Sayegh, MH Madsen, JC AF Lee, RS Yamada, K Houser, SL Womer, KL Maloney, ME Rose, HS Sayegh, MH Madsen, JC TI Indirect allorecognition promotes the development of cardiac allograft vasculopathy SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID MAJOR HISTOCOMPATIBILITY COMPLEX; MINIATURE SWINE; TRANSPLANT RECIPIENTS; INDIRECT RECOGNITION; CHRONIC REJECTION; ALLOPEPTIDES; TOLERANCE C1 Massachusetts Gen Hosp, Dept Surg, Div Cardiac Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. Brigham & Womens Hosp, Lab Immunogenet & Transplantat, Boston, MA 02115 USA. RP Madsen, JC (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Cardiac Surg, EDR 105, Boston, MA 02114 USA. FU NHLBI NIH HHS [2RO1-HL54211-04] NR 15 TC 9 Z9 9 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 308 EP 310 DI 10.1016/S0041-1345(00)02021-2 PG 3 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900139 PM 11266832 ER PT J AU Allan, JS Wain, JC Schwarze, ML Houser, SL Madsen, JC Sachs, DH AF Allan, JS Wain, JC Schwarze, ML Houser, SL Madsen, JC Sachs, DH TI Obliterative bronchiolitis develops in miniature swine transplanted across a minor histocompatibility barrier SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc C1 Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Allan, JS (reprint author), Massachusetts Gen Hosp, Div Thorac Surg, Blake 1570,55 Fruit St, Boston, MA 02114 USA. NR 2 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 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD FEB-MAR PY 2001 VL 33 IS 1-2 BP 358 EP 359 DI 10.1016/S0041-1345(00)02047-9 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900167 PM 11266860 ER PT J AU Grey, ST Lock, J Bach, FH Ferran, C AF Grey, ST Lock, J Bach, FH Ferran, C TI Adenovirus-mediated gene transfer of A20 in murine islets inhibits Fas-induced apoptosis SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc C1 Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Ctr Immunobiol, Boston, MA 02115 USA. RP Ferran, C (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. RI Grey, Shane/B-3020-2008 OI Grey, Shane/0000-0003-2160-1625 FU NIDDK NIH HHS [1PO1DK53087/01] NR 6 TC 12 Z9 14 U1 0 U2 1 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 577 EP 578 DI 10.1016/S0041-1345(00)02149-7 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900272 PM 11266965 ER PT J AU Vacanti, MP Leonard, JL Dore, B Bonassar, LJ Cao, Y Stachelek, SJ Vacanti, JP O'Connell, F Yu, CS Farwell, AP Vacanti, CA AF Vacanti, MP Leonard, JL Dore, B Bonassar, LJ Cao, Y Stachelek, SJ Vacanti, JP O'Connell, F Yu, CS Farwell, AP Vacanti, CA TI Tissue-engineered spinal cord SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID CENTRAL-NERVOUS-SYSTEM; NEURAL STEM-CELL; MOUSE-BRAIN; RAT; CNS; TRANSECTION; EXPRESSION; RECOVERY; NEURONS; GROWTH C1 Univ Massachusetts, Sch Med, Ctr Tissue Engn, Dept Anesthesiol, Worcester, MA 01655 USA. Univ Massachusetts, Sch Med, Ctr Tissue Engn, Dept Pathol, Worcester, MA 01655 USA. Univ Massachusetts, Sch Med, Ctr Tissue Engn, Dept Physiol, Worcester, MA 01655 USA. Univ Massachusetts, Sch Med, Ctr Tissue Engn, Mol Endocrinol Lab, Worcester, MA 01655 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Vacanti, CA (reprint author), Univ Massachusetts, Sch Med, Ctr Tissue Engn, Dept Anesthesiol, Rm S2-751,55 Lake Ave N, Worcester, MA 01655 USA. RI Bonassar, Lawrence/C-2103-2016 OI Bonassar, Lawrence/0000-0003-1094-6433 NR 21 TC 42 Z9 52 U1 0 U2 7 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 592 EP 598 DI 10.1016/S0041-1345(00)02158-8 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900281 PM 11266974 ER PT J AU Mathes, DW Bourget, JL Randolph, MA Solari, MG Wu, A Sachs, DH Lee, WPA AF Mathes, DW Bourget, JL Randolph, MA Solari, MG Wu, A Sachs, DH Lee, WPA TI Tolerance to vascularized musculoskeletal allografts SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc C1 Massachusetts Gen Hosp, Plast Surg Res Lab, Boston, MA 02114 USA. Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. RP Lee, WPA (reprint author), Massachusetts Gen Hosp, Plast Surg Res Lab, WAC 453,15 Parkman St, Boston, MA 02114 USA. NR 5 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 616 EP 617 DI 10.1016/S0041-1345(00)02168-0 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900291 PM 11266984 ER PT J AU Buhler, L Yamada, K Alwayn, I Kitamura, H Basker, M Barth, RN Appel, J Awwad, M Thall, A White-Scharf, ME Sachs, DH Cooper, DKC AF Buhler, L Yamada, K Alwayn, I Kitamura, H Basker, M Barth, RN Appel, J Awwad, M Thall, A White-Scharf, ME Sachs, DH Cooper, DKC TI Miniature swine and hDAF pig kidney transplantation in baboons treated with a nonmyeloablative regimen and CD154 blockade SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc C1 Harvard Univ, Transplantat Biol Res Ctr, Massachusetts Gen Hosp, Sch Med, Boston, MA 02129 USA. Harvard Univ, Dept Pathol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02129 USA. BioTransplant Inc, Charlestown, MA USA. RP Cooper, DKC (reprint author), Harvard Univ, Transplantat Biol Res Ctr, Massachusetts Gen Hosp, Sch Med, MGH E,Bldg 149-9019,13th St, Boston, MA 02129 USA. RI Barth, Rolf/B-2542-2014 NR 2 TC 7 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 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD FEB-MAR PY 2001 VL 33 IS 1-2 BP 716 EP 716 DI 10.1016/S0041-1345(00)02220-X PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900342 PM 11267035 ER PT J AU Wang, N Lee, JM Soares, MP Csizmadia, E Robson, SC Smith, N Bach, FH Lin, Y AF Wang, N Lee, JM Soares, MP Csizmadia, E Robson, SC Smith, N Bach, FH Lin, Y TI Long-term survival of hamster hearts in presensitized rats SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Immunobiol Res Ctr,Dept Surg, Boston, MA 02215 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02215 USA. RP Lin, Y (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Immunobiol Res Ctr,Dept Surg, 99 Brookline Ave, Boston, MA 02215 USA. OI LEE, JANG-MING/0000-0001-9727-227X; Soares, Miguel/0000-0002-9314-4833 FU NHLBI NIH HHS [R01HL 58688] NR 3 TC 2 Z9 2 U1 0 U2 1 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 747 EP 748 DI 10.1016/S0041-1345(00)02235-1 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900358 PM 11267051 ER PT J AU Wu, A Yamada, K Awwad, M Kitamura, H Wain, J Neville, DM Cooper, DKC Sykes, M Sachs, DH AF Wu, A Yamada, K Awwad, M Kitamura, H Wain, J Neville, DM Cooper, DKC Sykes, M Sachs, DH TI Effects of xenogeneic thymic transplantation in baboons SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. RP Wu, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, 13th St,Bldg 149, Boston, MA 02129 USA. NR 0 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 766 EP 766 DI 10.1016/S0041-1345(00)02244-2 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900367 PM 11267060 ER PT J AU Wang, N Lee, JM Soares, MP Csizmadia, E Xu, D Liew, FY Smith, N Bach, FH Lin, Y AF Wang, N Lee, JM Soares, MP Csizmadia, E Xu, D Liew, FY Smith, N Bach, FH Lin, Y TI TH2 cytokines regulate gene expression and proinflammatory responses in xenografts SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID CELLS C1 Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Surg,Immunobiol Res Ctr, Boston, MA 02215 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02215 USA. Univ Glasgow, Dept Immunol, Glasgow, Lanark, Scotland. RP Lin, Y (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Surg,Immunobiol Res Ctr, 99 Brookline Ave, Boston, MA 02215 USA. RI Xu, Damo/A-8212-2011; OI LEE, JANG-MING/0000-0001-9727-227X; Soares, Miguel/0000-0002-9314-4833 FU NHLBI NIH HHS [R01HL58688] NR 5 TC 2 Z9 2 U1 0 U2 1 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 776 EP 777 DI 10.1016/S0041-1345(00)02249-1 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900372 PM 11267065 ER PT J AU Kauffman, HM Cherikh, WS Delmonico, FL AF Kauffman, HM Cherikh, WS Delmonico, FL TI Drug regimens affect cadaveric kidney graft survival SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID MYCOPHENOLATE-MOFETIL; TRANSPLANTATION; COMBINATION; TACROLIMUS C1 United Network Organ Sharing, Richmond, VA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kauffman, HM (reprint author), 1100 Boulders Pkwy,Suite 500, Richmond, VA 23225 USA. NR 4 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 1029 EP 1030 DI 10.1016/S0041-1345(00)02316-2 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900483 PM 11267176 ER PT J AU Fishman, JA Rubin, RH AF Fishman, JA Rubin, RH TI Solid organ transplantation in HIV-infected individuals: Obstacles and opportunities SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEPATITIS-C VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; INOSINE MONOPHOSPHATE DEHYDROGENASE; CD4 CELL COUNTS; CYCLOSPORINE-A; MYCOPHENOLIC-ACID; PROTEASE INHIBITORS; KAPOSIS-SARCOMA; MIXED CHIMERISM C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Infect Dis,Transplant Infect Dis Program, Boston, MA 02114 USA. RP Fishman, JA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Infect Dis,Transplant Infect Dis Program, Boston, MA 02114 USA. FU NIAID NIH HHS [P01-AI39755] NR 72 TC 19 Z9 19 U1 0 U2 1 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 1310 EP 1314 DI 10.1016/S0041-1345(00)02488-X PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900610 PM 11267303 ER PT J AU Rabkin, JM Corless, CL Rosen, HR Olyaei, AJ AF Rabkin, JM Corless, CL Rosen, HR Olyaei, AJ TI Pharmacoeconomic study of tacrolimus-based versus cyclosporine-based immunosuppressive therapy following liver transplantation SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID ALLOGRAFT RECIPIENTS; COST; STRATEGIES; REJECTION; FK506 C1 Oregon Hlth Sci Univ, Dept Surg, Sect Liver Transplantat, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Med, Div Gastroenterol, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Pathol, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Pharm, Portland, OR 97201 USA. Portland Vet Affairs Med Ctr, Portland, OR USA. RP Rabkin, JM (reprint author), 3181 SW Sam Jackson Pk Rd,L590, Portland, OR 97201 USA. NR 13 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 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD FEB-MAR PY 2001 VL 33 IS 1-2 BP 1532 EP 1534 DI 10.1016/S0041-1345(00)02585-9 PG 3 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900718 PM 11267411 ER PT J AU Tolkoff-Rubin, NE Fishman, JA Rubin, RH AF Tolkoff-Rubin, NE Fishman, JA Rubin, RH TI The bidirectional relationship between cytomegalovirus and allograft injury SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID TUMOR-NECROSIS-FACTOR; TRANSPLANT RECIPIENTS; ENDOTHELIAL-CELLS; CHRONIC REJECTION; OBLITERATIVE BRONCHIOLITIS; RENAL-TRANSPLANTATION; GANCICLOVIR THERAPY; RAT CYTOMEGALOVIRUS; VIRAL-LOAD; INFECTION C1 Massachusetts Gen Hosp, Program Transplant Infect Dis, Boston, MA 02114 USA. RP Rubin, RH (reprint author), Massachusetts Gen Hosp, Program Transplant Infect Dis, 55 Fruit St, Boston, MA 02114 USA. NR 40 TC 9 Z9 10 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 1773 EP 1775 DI 10.1016/S0041-1345(00)02674-9 PG 3 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900813 PM 11267506 ER PT J AU Colvin, RB Mauiyyedi, S AF Colvin, RB Mauiyyedi, S TI Differential diagnosis between infection and rejection in renal allografts SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID HEPATITIS-C; INTERSTITIAL NEPHRITIS; RECIPIENTS; DISEASE C1 Massachusetts Gen Hosp, Dept Pathol, Cambridge, MA 02140 USA. RP Colvin, RB (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren 225, Cambridge, MA 02140 USA. NR 12 TC 15 Z9 15 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 1778 EP 1779 DI 10.1016/S0041-1345(00)02676-2 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900815 PM 11267508 ER PT J AU Kauffman, HM McBride, MA Delmonico, FL AF Kauffman, HM McBride, MA Delmonico, FL TI UNOS transplant tumor registry: Donors with a history of cancer SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 18th World Congress of the Transplantation-Society CY AUG 27-SEP 01, 2000 CL ROME, ITALY SP Transplant Soc ID TRANSMISSION; RECIPIENT C1 United Network Organ Sharing, Richmond, VA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kauffman, HM (reprint author), 1100 Boulders Pkwy,Ste 500, Richmond, VA 23225 USA. NR 10 TC 4 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 FEB-MAR PY 2001 VL 33 IS 1-2 BP 1844 EP 1845 DI 10.1016/S0041-1345(00)02703-2 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 413UK UT WOS:000167629900844 PM 11267537 ER PT J AU Carroll, P Coley, C McLeod, D Schellhammer, P Sweat, G Wasson, J Zietman, A Thompson, I AF Carroll, P Coley, C McLeod, D Schellhammer, P Sweat, G Wasson, J Zietman, A Thompson, I TI Prostate-specific antigen best practice policy - part I: Early detection and diagnosis of prostate cancer SO UROLOGY LA English DT Editorial Material ID DIGITAL RECTAL EXAMINATION; TERM FOLLOW-UP; RADICAL PROSTATECTOMY; MULTIVARIATE-ANALYSIS; CLINICAL-TRIAL; PATIENT AGE; MEN; PROGRESSION; MANAGEMENT; PREDICTION C1 Univ Texas, Hlth Sci Ctr, Div Urol, San Antonio, TX 78284 USA. Univ Calif San Francisco, Med Ctr, Dept Urol, San Francisco, CA 94143 USA. Harvard Univ, Hlth Serv, Dept Med, Cambridge, MA 02138 USA. Walter Reed Army Med Ctr, Dept Urol, Washington, DC 20307 USA. Eastern Virginia Grad Sch Med, Norfolk, VA USA. Mayo Clin, Dept Family Med, Rochester, MN USA. Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Community & Family Med, Hanover, NH 03756 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. RP Thompson, I (reprint author), Univ Texas, Hlth Sci Ctr, Div Urol, Mail Code 7845,7703 Floyd Curl Dr, San Antonio, TX 78284 USA. NR 59 TC 44 Z9 44 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD FEB PY 2001 VL 57 IS 2 BP 217 EP 224 DI 10.1016/S0090-4295(00)00993-6 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 403BU UT WOS:000167023300002 PM 11182324 ER PT J AU Carroll, P Coley, C McLeod, D Schellhammer, P Sweat, G Wasson, J Zietman, A Thompson, I AF Carroll, P Coley, C McLeod, D Schellhammer, P Sweat, G Wasson, J Zietman, A Thompson, I TI Prostate-specific antigen best practice policy - part II: Prostate cancer staging and post-treatment follow-up SO UROLOGY LA English DT Editorial Material ID BEAM RADIATION-THERAPY; LYMPH-NODE METASTASES; RADICAL PROSTATECTOMY; PELVIC LYMPHADENECTOMY; CRYOSURGICAL ABLATION; BONE-SCINTIGRAPHY; HORMONAL-THERAPY; GLEASON SCORE; PSA NADIR; RECURRENCE C1 Univ Texas, Hlth Sci Ctr, Div Urol, San Antonio, TX 78284 USA. Univ Calif San Francisco, Med Ctr, Dept Urol, San Francisco, CA 94143 USA. Harvard Univ, Hlth Serv, Dept Med, Cambridge, MA 02138 USA. Walter Reed Army Med Ctr, Dept Urol, Washington, DC 20307 USA. Eastern Virginia Grad Sch Med, Norfolk, VA USA. Mayo Clin, Dept Family Med, Rochester, MN USA. Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Community & Family Med, Hanover, NH 03756 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. RP Thompson, I (reprint author), Univ Texas, Hlth Sci Ctr, Div Urol, Mail Code 7845,7703 Floyd Curl Dr, San Antonio, TX 78284 USA. NR 38 TC 30 Z9 31 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD FEB PY 2001 VL 57 IS 2 BP 225 EP 229 DI 10.1016/S0090-4295(00)00994-8 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 403BU UT WOS:000167023300003 PM 11182325 ER PT J AU Schultze, JL Maecker, B von Bergwelt-Baildon, MS Anderson, KS Vongerheide, RH AF Schultze, JL Maecker, B von Bergwelt-Baildon, MS Anderson, KS Vongerheide, RH TI Tumour immunotherapy: new tools, new treatment modalities and new T-cell antigens SO VOX SANGUINIS LA English DT Review ID PULSED DENDRITIC CELLS; MELANOMA PATIENTS; IN-VIVO; METASTATIC MELANOMA; IMMUNE SURVEILLANCE; PROTECTIVE IMMUNITY; ANTITUMOR IMMUNITY; PERIPHERAL-BLOOD; PRESENTING CELLS; CARCINOMA-CELLS AB Tumour immunology has seen many exciting developments in the last few years. In addition to tumour antigens that are defined by antitumour T- and B-cell responses in patients, the human telomerase reverse transcriptase has been identified by 'reverse immunology' as the first truly universal tumour antigen. Molecular remission has been associated with a cancer vaccine that targets the clonal idiotype of B-cell malignancies, and sophisticated cellular vaccines (including fusions of tumour cells and antigen-presenting cells) have demonstrated promising results. Moreover, our capabilities of measuring immunity have been significantly enhanced by novel technology, such as major histocompatibility complex (MHC)-peptide tetramers and ELISPOT analysis. We are now capable of tracking antigen-specific T cells at a single cell level. This review will analyse recent developments and highlight some important issues that need to be addressed in the future. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Schultze, JL (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St,D540C, Boston, MA 02115 USA. RI Schultze, Joachim/D-7794-2011 OI Schultze, Joachim/0000-0003-2812-9853 NR 68 TC 16 Z9 17 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0042-9007 J9 VOX SANG JI Vox Sang. PD FEB PY 2001 VL 80 IS 2 BP 81 EP 89 DI 10.1046/j.1423-0410.2001.00014.x PG 9 WC Hematology SC Hematology GA 426NR UT WOS:000168355700001 PM 11378969 ER PT J AU Wright, CD Mathisen, DJ AF Wright, CD Mathisen, DJ TI Mediastinal tumors: Diagnosis and treatment SO WORLD JOURNAL OF SURGERY LA English DT Article ID NEUROGENIC TUMORS; EPITHELIAL-CELLS; PRIMARY CYSTS; THYMOMA; LYMPHOMA; SUBCLASSIFICATION; PARAGANGLIOMA; MANAGEMENT; ANTERIOR; THERAPY AB Mediastinal tumors are uncommon and often asymptomatic if benign. Tumors have a predilection for arising in one of three mediastinal compartments; anterior, middle, or posterior. If symptoms are present, they are usually compressive in origin. Computed tomography is almost always the imaging modality of choice. Benign-appearing lesions are usually resected for cure. Malignant-appearing lesions usually require biopsy by the least invasive route appropriate for the suspected tumor type. C1 Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. RP Mathisen, DJ (reprint author), Massachusetts Gen Hosp, Dept Surg, Blake 1570,32 Fruit St, Boston, MA 02114 USA. NR 35 TC 20 Z9 22 U1 1 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0364-2313 J9 WORLD J SURG JI World J.Surg. PD FEB PY 2001 VL 25 IS 2 BP 204 EP 209 PG 6 WC Surgery SC Surgery GA 422QV UT WOS:000168131500017 PM 11338023 ER PT J AU Jaklitsch, MT Grondin, SC Sugarbaker, DJ AF Jaklitsch, MT Grondin, SC Sugarbaker, DJ TI Treatment of malignant mesothelioma SO WORLD JOURNAL OF SURGERY LA English DT Article ID PLEURAL MESOTHELIOMA; EXTRAPLEURAL PNEUMONECTOMY; MULTIMODALITY THERAPY; UNITED-STATES; CISPLATIN; CANCER; SIMIAN-VIRUS-40; DIFFUSE; MR; MANAGEMENT AB Malignant pleural mesothelioma (MPM) is a rare tumor that predominantly afflicts men over 50 years of age. Nearly 3000 MPMs are reported annually in the United States with the incidence expected to rise into the new millenium. Over the past 40 years, MPM has been unequivocally linked to asbestos exposure worldwide. Recently, however, a new theory on the carcinogenesis of this tumor has been proposed with the isolation of a simian virus (SV 40) like gene sequence in mesothelioma tumor cells. The clinical presentation of MPM is variable, although most patients typically present with dyspnea, chest pain, or pleural effusion. Obtaining a diagnosis of MPM has been greatly assisted by video-assisted surgery and the use of immunohistochemistry and electron microscopic techniques, which help distinguish MPM from other tumor pathologies such as adenocarcinoma. Computed tomography and magnetic resonance imaging have been also useful for determining tumor burden and resectability. Traditionally, strategies for the treatment of MPM have included supportive care, surgery, radiotherapy, and chemotherapy. Survival with supportive care alone ranges between 4 and 12 months. Single-modality therapy using traditional approaches (surgery, radiotherapy, chemotherapy) alone has failed to improve patient survival significantly. Recently, results using a multimodality approach have been favorable. In particular, cytoreductive surgery (pleuropneumonectomy) followed by sequential chemotherapy and radiotherapy have demonstrated improved survival, especially for patients,vith epithelial histology, negative resection margins, and no metastases to extrapleural lymph nodes. Innovative therapies such as the use of photodynamic, targeted cytokines and gene therapy are currently being investigated for management of MPM. C1 Brigham & Womens Hosp, Dept Surg, Div Thorac Surg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Jaklitsch, MT (reprint author), Brigham & Womens Hosp, Dept Surg, Div Thorac Surg, 75 Francis St, Boston, MA 02115 USA. NR 60 TC 43 Z9 46 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0364-2313 J9 WORLD J SURG JI World J.Surg. PD FEB PY 2001 VL 25 IS 2 BP 210 EP 217 DI 10.1007/s002680020021 PG 8 WC Surgery SC Surgery GA 422QV UT WOS:000168131500018 PM 11338024 ER PT J AU Krane, RJ AF Krane, RJ TI Changes in ED therapy in the Viagra era SO WORLD JOURNAL OF UROLOGY LA English DT Article C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Krane, RJ (reprint author), Massachusetts Gen Hosp, 55 Fruit St,GRB 1102, Boston, MA 02114 USA. NR 6 TC 7 Z9 8 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0724-4983 J9 WORLD J UROL JI World J. Urol. PD FEB PY 2001 VL 19 IS 1 BP 23 EP 24 DI 10.1007/s003450000172 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 405VV UT WOS:000167182000004 PM 11289566 ER PT J AU Seebach, JD Schneider, MKJ Comrack, CA LeGuern, A Kolb, SA Knolle, PA Germana, S DerSimonian, H LeGuern, C Sachs, DH AF Seebach, JD Schneider, MKJ Comrack, CA LeGuern, A Kolb, SA Knolle, PA Germana, S DerSimonian, H LeGuern, C Sachs, DH TI Immortalized bone-marrow derived pig endothelial cells SO XENOTRANSPLANTATION LA English DT Article DE bone marrow; endothelium; phenotype; porcine; transformation; xenotransplantation ID MAJOR HISTOCOMPATIBILITY COMPLEX; NATURAL-KILLER-CELLS; LARGE T-ANTIGEN; HUMAN NK CELLS; VONWILLEBRAND-FACTOR; MINIATURE SWINE; PORCINE; EXPRESSION; LINE; TRANSPLANTATION AB Primary cultures of porcine endothelial cells (EC) can only be maintained for a limited number of passages. To facilitate studies of xenogeneic human anti-pig immune responses in vitro, pig microvascular bone-marrow (BM) and macrovascular aortic EC were obtained from our herd of partially inbred miniature: swine, homozygous for the major histocompatibility locus, and immortalized with a modified SV40 large T vector. The resulting BM-derived (2A2) and aortic (PEDSV. 15) immortalized EC lines showed unlimited growth and EC phenotype as indicated by expression of von Willebrand Faster (VWF) and low density lipoprotein (LDL) receptors as well as by formation:of typical cobblestone monolayers. Ultrastructural studies revealed morphological similarities in primary and immortalized EC. Flow cytometry analysis demonstrated constitutive SLA class I expression by all lines whereas SLA class II was only expressed after stimulation with porcine IFN gamma. Furthermore, pig CD34 mRNA was detected by Northern blot analysis in primary and immortalized aortic EC but not in 2A2. Both EC lines expressed a number of myeloid markers, adhesion molecules and xenoantigens, the latter being determined by binding of human natural antibodies. Gene transfer into the porcine EC lines was successfully performed by electroporation or calcium-phosphate transfection, as well as by adenoviral infection. Finally, the functional similarity between primary and immortalized EC was demonstrated in adhesion and cytotoxicity assays. Together, these results suggest that 2A2 and PEDSV.15 represent valuable tools to study both human cellular and humoral immune responses in vitro against pig EC derived from microvascular and large vessels. C1 Univ Zurich Hosp, Dept Internal Med, Lab Transplantat Immunol, CH-8091 Zurich, Switzerland. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. Biotransplant Inc, Charlestown, MA 02129 USA. Univ Zurich Hosp, Dept Pathol, Electron Microscopy Lab, CH-8091 Zurich, Switzerland. Univ Heidelberg, Zentrum Mol Biol, D-69120 Heidelberg, Germany. RP Seebach, JD (reprint author), Univ Zurich Hosp, Dept Internal Med, Lab Transplantat Immunol, Ramistr 100,C HOER 31, CH-8091 Zurich, Switzerland. OI Knolle, Percy A./0000-0003-2983-0414 FU NIAID NIH HHS [2RO1 AI3305306, 2RO1 AI31046] NR 41 TC 45 Z9 46 U1 0 U2 0 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 FEB PY 2001 VL 8 IS 1 BP 48 EP 61 DI 10.1034/j.1399-3089.2001.00075.x PG 14 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 403DD UT WOS:000167026500006 PM 11208191 ER PT J AU Roth, CM Kohen, RL Walton, SP Yarmush, ML AF Roth, CM Kohen, RL Walton, SP Yarmush, ML TI Coupling of inflammatory cytokine signaling pathways probed by measurements of extracellular acidification rate SO BIOPHYSICAL CHEMISTRY LA English DT Article DE microphysiometer; desensitization; acute phase response; signaling dynamics; dose response mechanisms ID ACUTE-PHASE RESPONSE; LEUKEMIA INHIBITORY FACTOR; HUMAN HEPATOMA-CELLS; ONCOSTATIN-M; DESIGNER CYTOKINE; TRANSDUCER GP130; GROWTH-FACTORS; INTERLEUKIN-6; PROTEIN; RECEPTOR AB There is a growing interest in the mechanisms of how cells integrate the multitude of signals that emanate during inflammatory stimuli, such as the hepatic acute phase response to burn or trauma. We have used measurements of extracellular acidification rate (ECAR) of HepG2 cells cultured on microporous membranes to probe the coupling between signaling pathways for gp130 family cytokines (interleukin-6, oncostatin M) and IL-1, each of which is considered to play a significant role in the hepatic acute phase response. We found that brief (30 min or less) exposure to any of these cytokines desensitized the HepG2 cells to subsequent exposure with the same cytokine, Furthermore, we found that this property serves as a probe of the coupling of signaling pathways: exposure to IL-1 did not desensitize the cells to exposure to OSM and vice versa. However, cells exposed to IL-6 with soluble gp80, which together share with OSM the use of gp130 as a signal transducing receptor, were subsequently unable to respond to OSM, and vice versa. Simultaneous exposure of cells to moderate concentrations (near their respective EC50 values) of both IL-1 and OSM resulted in synergistic effects on the ECAR, but simultaneous exposure to saturating concentrations of IL-1 and OSM resulted in a response that tracked that of OSM alone. These results suggest that the signaling pathways of IL-1 and OSM may be simultaneously activated in HepG2 cells under moderate inflammatory cytokine challenge bur that the cells must prioritize their response under extreme cytokine challenges, (C) 2001 Elsevier Science B.V. All rights reserved. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn,Med Serv, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn,Surg Serv, Boston, MA 02114 USA. Shriners Burns Hosp, Boston, MA 02114 USA. RP Roth, CM (reprint author), Rutgers State Univ, Dept Chem & Biochem Engn, 98 Brett Rd,Room C-257, Piscataway, NJ 08854 USA. RI Walton, S. Patrick/A-7007-2008; OI Walton, S. Patrick/0000-0003-1708-8603; Roth, Charles/0000-0002-4924-0721 NR 51 TC 11 Z9 12 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-4622 J9 BIOPHYS CHEM JI Biophys. Chem. PD JAN 31 PY 2001 VL 89 IS 1 BP 1 EP 12 DI 10.1016/S0301-4622(00)00212-X PG 12 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA 397WQ UT WOS:000166721200001 PM 11246741 ER PT J AU Chen, SQ Springer, TA AF Chen, SQ Springer, TA TI Selectin receptor-ligand bonds: Formation limited by shear rate and dissociation governed by the Bell model SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID P-SELECTIN; GLYCOPROTEIN LIGAND-1; KINETIC-ANALYSIS; ADHESION; BINDING; LEUKOCYTES; THRESHOLD; TRANSIENT; FLOW; STRENGTH AB We have studied the principles that govern the formation and dissociation of an adhesive bond between a cell moving in shear flow and a substrate and tested different theories of how force affects bond dissociation. Viscosity relates the kinematics of fluid movement (shear rate, units of time(-1)) to shear stress (units of force/area, the product of shear rate and viscosity). At different medium viscosities, the formation of receptor-ligand bonds between a cell in the flowstream and P-selectin on the vessel wall showed a similar efficiency as a function of shear rate but not of shear stress. Therefore, bond formation was a function of shear rate and hence of the kinematics of receptor and ligand movement. By contrast, the kinetics of bond dissociation was a function of shear stress and hence of force on the bond. The different requirements for bond formation and dissociation allowed dissociation kinetics to be measured at higher forces on the bond by increasing medium viscosity. Data over an extended range of forces on the bond therefore could be collected that enabled five different proposed equations, relating force to bond dissociation, to be compared for fit to experimental data. The relationship proposed by Bell [Bell, G. I. (1978) Science 200, 618-627] fit the data significantly the best and also predicted an off-rate in the absence of force that best matched an independent measurement [Mehta, P., Cummings, R. D. & McEver, R. P. (1998) J. Biol. Chem. 273, 32506-32513]. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. RP Springer, TA (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, 200 Longwood Ave, Boston, MA 02115 USA. FU NHLBI NIH HHS [HL-48675, P01 HL048675] NR 26 TC 139 Z9 143 U1 2 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 30 PY 2001 VL 98 IS 3 BP 950 EP 955 DI 10.1073/pnas.98.3.950 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399JF UT WOS:000166807300037 PM 11158576 ER PT J AU Dutta, S Gannon, M Peers, B Wright, C Bonner-Weir, S Montminy, M AF Dutta, S Gannon, M Peers, B Wright, C Bonner-Weir, S Montminy, M TI PDX : PBX complexes are required for normal proliferation of pancreatic cells during development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GENE-TRANSCRIPTION FACTOR; HOMEOBOX FACTOR STF-1; HOMEODOMAIN PROTEIN; INSULIN GENE; EXPRESSION; IPF1; EPITHELIUM; EXOCRINE; DUODENUM; RELIES AB The homeobox factor PDX-1 is a key regulator of pancreatic morphogenesis and glucose homeostasis; targeted disruption of the PDX-1 gene leads to pancreatic agenesis in pdx-1(-/-) homozygotes. Pdx-1 heterozygotes develop normally, but they display glucose intolerance in adulthood. Like certain other homeobox proteins, PDX-1 contains a consensus FPWMK motif that promotes heterodimer formation with the ubiquitous homeodomain protein PBX. To evaluate the importance of PDX-1:PBX complexes in pancreatic morphogenesis and glucose homeostasis, we expressed either wild-type or PBX interaction defective PDX-1 transgenes under control of the PDX-1 promoter. Both wild-type and mutant PDX-1 transgenes corrected glucose intolerance in pdx-1 heterozygotes. The wild-type PDX-1 transgene rescued the development of all pancreatic lineages in pdx-1(-/-) animals, and these mice survived to adulthood. In contrast, pancreata from pdx-1(-/-) mice expressing the mutant PDX-1 transgene were hypoplastic, and these mice died within 3 weeks of birth from pancreatic insufficiency. All pancreatic cell types were observed in pdx-1(-/-) mice expressing the mutant PDX-1 transgene; but the islets were smaller, and increased numbers of islet hormone-positive cells were noted within the ductal epithelium. These results indicate that PDX-1:PBX complexes are dispensable for glucose homeostasis and for differentiation of stem cells into ductal, endocrine, and acinar lineages; but they are essential for expansion of these populations during development. C1 Salk Inst Biol Studies, Clayton Fdn Labs Peptide Biol, La Jolla, CA 92037 USA. Vanderbilt Univ, Sch Med, Dept Cell Biol, Nashville, TN 37232 USA. Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Univ Liege, Inst Chim, Lab Biol Mol & Genie Genet, B-4000 Sart Tilman, Belgium. RP Montminy, M (reprint author), Salk Inst Biol Studies, Clayton Fdn Labs Peptide Biol, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. RI Gannon, Maureen/F-9060-2012 FU NIDDK NIH HHS [R01 DK49777, DK 44523, R01 DK044523, R01 DK049777] NR 24 TC 96 Z9 110 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 30 PY 2001 VL 98 IS 3 BP 1065 EP 1070 DI 10.1073/pnas.031561298 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399JF UT WOS:000166807300056 PM 11158595 ER PT J AU Gonzalez-Perrett, S Kim, K Ibarra, C Damiano, AE Zotta, E Batelli, M Harris, PC Reisin, IL Arnaout, MA Cantiello, HF AF Gonzalez-Perrett, S Kim, K Ibarra, C Damiano, AE Zotta, E Batelli, M Harris, PC Reisin, IL Arnaout, MA Cantiello, HF TI Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PKD2; GENE; MEMBRANE; IDENTIFICATION; IONS AB Defects in polycystin-2, a ubiquitous transmembrane glycoprotein of unknown function, is a major cause of autosomal dominant polycystic kidney disease (ADPKD), whose manifestation entails the development of fluid-filled cysts in target organs. Here, we demonstrate that polycystin-2 is present in term human syncytiotrophoblast, where it behaves as a nonselective cation channel. Lipid bilayer reconstitution of polycystin-2-positive human syncytiotrophoblast apical membranes displayed a nonselective cation channel with multiple subconductance states, and a high permselectivity to Ca2+. This channel was inhibited by anti-polycystin-2 antibody, Ca2+, La3+, Gd3+, and the diuretic amiloride. Channel function by polycystin-2 was confirmed by patch-clamping experiments of polycystin-2 heterologously infected Sf9 insect cells. Further, purified insect cell-derived recombinant polycystin-2 and in vitro translated human polycystin-2 had similar ion channel activity. The polycystin-2 channel may be associated with fluid accumulation and/or ion transport regulation in target epithelia, including placenta. Dysregulation of this channel provides a mechanism for the onset and progression of ADPKD. C1 Massachusetts Gen Hosp E, Renal Unit, Charlestown, MA USA. Univ Buenos Aires, Fac Farm & Bioquim, Dept Fisicoquim & Quim Analit, Lab Canales Ion, RA-1113 Buenos Aires, DF, Argentina. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Univ Buenos Aires, Fac Med, Dept Fisiol, RA-1121 Buenos Aires, DF, Argentina. Mayo Clin & Mayo Fdn, Dept Nephrol, Rochester, MN 55905 USA. RP Arnaout, MA (reprint author), Massachusetts Gen Hosp, Renal Unit, 149 13th St, Charlestown, MA 02129 USA. FU NIDDK NIH HHS [P01 DK054711] NR 26 TC 307 Z9 313 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 30 PY 2001 VL 98 IS 3 BP 1182 EP 1187 DI 10.1073/pnas.021456598 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399JF UT WOS:000166807300076 PM 11252306 ER PT J AU Trivedi, N Keegan, M Steil, GM Hollister-Lock, J Hasenkamp, WM Colton, CK Bonner-Weir, S Weir, GC AF Trivedi, N Keegan, M Steil, GM Hollister-Lock, J Hasenkamp, WM Colton, CK Bonner-Weir, S Weir, GC TI Islets in alginate macrobeads reverse diabetes despite minimal acute insulin secretory responses SO TRANSPLANTATION LA English DT Article ID PANCREATIC-ISLETS; RAT ISLETS; BIOARTIFICIAL PANCREAS; INVITRO KINETICS; PORCINE ISLETS; RELEASE; MICE; SURVIVAL; TRANSPLANTATION; XENOGRAFTS AB Background. Encapsulation of islets has been widely investigated as a treatment for diabetes, The characteristics and dynamics of insulin secretion by encapsulated islets in response to glucose and other secretagogues are not well understood. Methods. In our study, macroencapsulated syngeneic islets at 3-4 wk after transplantation were studied for insulin release in response to i.v. glucose (hyperglycemic clamps at 250 or 350 mg/dl plasma glucose), arginine (i.v. bolus, 100 mg/kg), glucagon-like peptide-1 (i.v. infusion for 20 min, 2.2 pmol/kg/min), and meal challenge, Syngeneic islets (6000 islets) were encapsulated in alginate macrobeads (2-3 mm diameter) with or without poly-L-Iysine coating and transplanted into the peritoneal cavity of STZ-diabetic Lewis rats. Normal (nontransplanted) and diabetic Lewis rats transplanted with "naked" islets under the kidney capsule served as controls. Results. Animals transplanted with macrobeads displayed subnormal insulin responses to glucose, arginine, and glucagon-like peptide-1 despite achieving normoglycemia faster than animals with renal subcapsular islet transplants, Plasma insulin responses to meal challenges were blunted in animals with macrobeads resulting in increased plasma glucose excursions. Conclusions, We conclude that, after transplantation into diabetic Lewis rats, macroencapsulated islets have significantly impaired insulin secretion despite achieving normal fed glycemic levels. C1 Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. RP Weir, GC (reprint author), Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [DK 50657] NR 36 TC 46 Z9 47 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JAN 27 PY 2001 VL 71 IS 2 BP 203 EP 211 DI 10.1097/00007890-200101270-00006 PG 9 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 399KP UT WOS:000166810500006 PM 11213060 ER PT J AU Sattler, M Verma, S Pride, YB Salgia, R Rohrschneider, LR Griffin, JD AF Sattler, M Verma, S Pride, YB Salgia, R Rohrschneider, LR Griffin, JD TI SHIP1, an SH2 domain containing polyinositol-5-phosphatase, regulates migration through two critical tyrosine residues and forms a novel signaling complex with DOK1 and CRKL SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; INOSITOL PHOSPHATASE SHIP; POLYPHOSPHATE 5-PHOSPHATASE SHIP; PHOSPHOTYROSINE BINDING DOMAIN; MULTIPLE CYTOKINES; INSULIN-RECEPTOR; ADAPTER PROTEINS; KINASE-ACTIVITY; CELL-MIGRATION; GROWTH-FACTORS AB SHIP1 is an SH2 domain containing inositol-5-phosphatase that appears to be a negative regulator of hematopoiesis, The tyrosine kinase oncogene BCR/ABL drastically reduces expression of SHIP1. The major effect of re-expressing SHIP1 in BCR/ABL-transformed cells is reduction of hypermotility, To investigate the potential signaling pathways involving SHIP1 in hematopoietic cells, we overexpressed SHIP1 in a murine BCR/ABL-transformed Ba/F3 cell line and identified SHIP1-associated proteins. SHIP1 was found to form a novel signaling complex with BCR/ABL that includes DOK1 (p62(DOK)), phosphatidylinositol 3-kinase (PI3K), and CRKL, each of which has been previously shown to regulate migration in diverse cell types. We found that DOK1 binds directly through its PTB domain to SHIP1. Direct interaction of SHIP1 with CRKL was mediated through the CRKL-SH2 domain. Go-precipitation experiments suggest that Tyr(917) and Tyr(1020) in SHIP1 are likely to mediate interactions with DOK1, In contrast to wild type SHIP1, expression of tyrosine mutant SHIP1 by transient transfection did not alter migration. PI3K was likely linked to this complex by CRKL, Thus, this complex may serve to generate a very specific set of phosphoinositol products, possibly involved in regulating migration. Overall, these data suggest that proteins that interact with SHIP1 through Tyr(917) and Tr-1020, such as DOK1 and SHC, are likely to be involved in the regulation of SHIP1 dependent migration. C1 Harvard Univ, Sch Med, Dept Adult Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. RP Sattler, M (reprint author), Harvard Univ, Sch Med, Dept Adult Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. FU NCI NIH HHS [CA78348, CA82499]; NIDDK NIH HHS [DK50654] NR 60 TC 42 Z9 48 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 JAN 26 PY 2001 VL 276 IS 4 BP 2451 EP 2458 DI 10.1074/jbc.M006250200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 398YV UT WOS:000166784800022 PM 11031258 ER PT J AU Sachs, CS AF Sachs, CS TI A 25-year-old woman with bipolar disorder SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID LOW SERUM LEVELS; LITHIUM; RECURRENCE; PLACEBO; MANIA; RISK; DEPRESSION; POPULATION; PREGNANCY; STANDARD C1 Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Harvard Bipolar Res Program, Boston, MA 02114 USA. RP Sachs, CS (reprint author), Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, 330 Brookline Ave,LY318, Boston, MA 02215 USA. NR 61 TC 1 Z9 1 U1 2 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 JAN 24 PY 2001 VL 285 IS 4 BP 454 EP 462 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 394CG UT WOS:000166506000034 ER PT J AU Lotufo, PA Gaziano, JM Chae, CU Ajani, UA Moreno-John, G Buring, JE Manson, JE AF Lotufo, PA Gaziano, JM Chae, CU Ajani, UA Moreno-John, G Buring, JE Manson, JE TI Diabetes and all-cause and coronary heart disease mortality among US male physicians SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID FIRST MYOCARDIAL-INFARCTION; IMPAIRED GLUCOSE-TOLERANCE; CARDIOVASCULAR-DISEASE; RISK-FACTORS; UNITED-STATES; SURVIVAL; IMPACT; DEATH; POPULATION; PREVENTION AB Background: While diabetes has long been associated with increased risk of coronary heart disease (CHD), the magnitude of risk of diabetes-related CHD is uncertain. Objective: To evaluate the impact of diabetes and prior CHD on all-cause and CHD mortality. Methods: In a prospective cohort study of 91 285 US male physicians aged 40 to 84 years, participants were divided into 4 groups. (1) a reference group of 82 247 men free of both diabetes and CHD (previous myocardial infarction and/or angina) at baseline, (2) 2317 men with a history of diabetes but not CHD, (3) 5906 men with a history of CHD but not diabetes, and (4) 815 men with a history of both diabetes and CHD. Rates of all-cause and CHD mortality were compared in these groups. Results: Over 5 years (49 7952 person-years of followup), 3627 deaths from all causes were documented, including 1242 deaths from CHD. Compared with men with no diabetes or CHD, the age-adjusted relative risk of death from any cause was 2.3 (95% confidence interval [CI], 2.0-2.6) among men with diabetes and without CHD, 2.2 (95% CI, 2.0-2.4) among men with CHD and without diabetes, and 4.7 (95% CI, 4.0-5.4) among men with both diabetes and CHD. The relative risk of CHD death was 3.3 (95% CI, 2.6-4.1) among men with diabetes and without CHD, 5.6 (95% CI, 4.9-6.3) among men with CHD and without diabetes, and 12.0 (95% CI, 9.9-14.6) among men with both diabetes and CHD. Multivariate adjustment for body mass index, smoking status, alcohol intake, and physical activity as well as stratification by these variables did not materially alter these associations. Conclusions: These prospective data indicate that diabetes is associated with a substantial increase in all-cause and CHD mortality. For all-cause mortality, the magnitude of excess risk conferred by diabetes is similar to that conferred by a history of CHD; for mortality from CHD, a history of CHD is a more potent predictor of death. The presence of both diabetes and CHD, however, identifies a particularly high-risk group. C1 Brigham & Womens Hosp, Div Prevent Med, Dept Med, Boston, MA 02215 USA. Brigham & Womens Hosp, Div Cardiovasc Dis, Boston, MA 02215 USA. Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. Vet Affairs Med Ctr, Massachusetts Vet Epidemiol Res & Informat Ctr, Brockton W Roxbury, MA USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94143 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Manson, JE (reprint author), Brigham & Womens Hosp, Div Prevent Med, Dept Med, 900 Commonwealth Ave E, Boston, MA 02215 USA. RI Lotufo, Paulo/A-9843-2008 OI Lotufo, Paulo/0000-0002-4856-8450 FU NHLBI NIH HHS [HL-42441] NR 35 TC 130 Z9 131 U1 0 U2 3 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 JAN 22 PY 2001 VL 161 IS 2 BP 242 EP 247 DI 10.1001/archinte.161.2.242 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 393QE UT WOS:000166480500013 PM 11176738 ER PT J AU Steininger, TL Gong, H McGinty, D Szymusiak, R AF Steininger, TL Gong, H McGinty, D Szymusiak, R TI Subregional organization of preoptic area/anterior hypothalamic projections to arousal-related monoaminergic cell groups SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE hypothalamus; anterograde tracing; biotinylated dextran; tuberomammillary nucleus; locus coeruleus; dorsal raphe nucleus ID SLEEP-WAKING DISCHARGE; RAT LOCUS-COERULEUS; EYE-MOVEMENT SLEEP; BARRINGTONS NUCLEUS; TUBEROMAMMILLARY NUCLEUS; HISTIDINE-DECARBOXYLASE; POSTERIOR HYPOTHALAMUS; HISTAMINERGIC NEURONS; BASAL FOREBRAIN; DIAGONAL BAND AB Pathways mediating the generation and/or maintenance of sleep reside within the preoptic/ anterior hypothalamus (POAH). Reproduction, water balance, thermoregulation, and neuroendocrine functions are also associated with POAH, but it is not fully understood whether sleep is consolidated with these behavioral and physiological functions, or whether sleep-related circuitry is segregated from other POAH regions. Recent studies indicate that sleep mechanisms may be localized to the ventrolateral preoptic area (VLPO) and that this region sends inhibitory projections to walking/arousal-related neurons in the histaminergic tuberomammillary nucleus (TM), the noradrenergic locus coeruleus (LC), and the serotonergic dorsal raphe (DR). The present study is a quantitative investigation of preoptic area efferents to these monoaminergic groups. The results demonstrate that biotinylated dextran injections in the VLPO region reveal a robust innervation of TM that was as much as five times greater than innervation derived from other POAH subregions. The innervation of TM originated almost exclusively from injection sites in the region of galanin neurons. VLPO projections to the LC were moderately dense and were greater than in other POAH regions except for equivalent input from the medial preoptic area. Projections to the dorsal raphe were equivalent to LC innervation and were generally two to three times greater from VLPO than from other POAH regions, except for projections from the lateral preoptic region, which were similar in magnitude. The rostral and caudal levels projected more to the TM, whereas the midrostral region of VLPO strongly innervated the LC core. These findings, with recent studies demonstrating medial and lateral extensions of the sleep-related VLPO neuronal group, indicate that descending arousal state control may be mediated by this specific galaninergic/gamma -aminobutyric acid (GABA)ergic cell group. J. Comp. Neural. 429:638-653, 2001. (C) 2001 Wiley-Liss, Inc. C1 Vet Adm Greater Los Angeles Heath Care Syst, Sepulveda, CA 91343 USA. Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. RP Szymusiak, R (reprint author), Vet Adm Greater Los Angeles Heath Care Syst, Sepulveda, CA 91343 USA. FU NHLBI NIH HHS [HL60296]; NIMH NIH HHS [MH18825, MH4780] NR 70 TC 119 Z9 126 U1 1 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD JAN 22 PY 2001 VL 429 IS 4 BP 638 EP 653 PG 16 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 385HY UT WOS:000165999100010 PM 11135241 ER PT J AU Jaeckle, KA Phuphanich, S van den Bent, MJ Aiken, R Batchelor, T Campbell, T Fulton, D Gilbert, M Heros, D Rogers, L O'Day, SJ Akerley, W Allen, J Baldas, S Gertler, SZ Greenberg, HS LaFollette, S Lesser, G Mason, W Recht, L Wong, E Chamberlain, MC Cohn, A Glantz, MJ Guthell, JC Maria, B Moots, P New, P Russell, C Shapiro, W Swinnen, L Howell, SB AF Jaeckle, KA Phuphanich, S van den Bent, MJ Aiken, R Batchelor, T Campbell, T Fulton, D Gilbert, M Heros, D Rogers, L O'Day, SJ Akerley, W Allen, J Baldas, S Gertler, SZ Greenberg, HS LaFollette, S Lesser, G Mason, W Recht, L Wong, E Chamberlain, MC Cohn, A Glantz, MJ Guthell, JC Maria, B Moots, P New, P Russell, C Shapiro, W Swinnen, L Howell, SB TI Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine SO BRITISH JOURNAL OF CANCER LA English DT Article DE breast cancer; neoplastic meningitis; cytarabine; drug delivery ID MENINGEAL CARCINOMATOSIS; PROGNOSTIC-FACTORS; INTRAVENTRICULAR METHOTREXATE; CEREBROSPINAL-FLUID; CHEMOTHERAPY; FEATURES; THERAPY; DISEASE; TRIAL AB DepoCyte is a slow-release formulation of cytarabine designed for intrathecal administration. The goal of this multi-centre cohort study was to determine the safety and efficacy of DepoCyte for the intrathecal treatment of neoplastic meningitis due to breast cancer. DepoCyte 50 mg was injected once every 2 weeks for one month of induction therapy; responding patients were treated with an additional 3 months of consolidation therapy. All patients had metastatic breast cancer and a positive CSF cytology or neurologic findings characteristic of neoplastic meningitis. The median number of DepoCyte doses was 3, and 85% of patients completed the planned 1 month induction. Median follow up is currently 19 months. The primary endpoint was response, defined as conversion of the CSF cytology from positive to negative at all sites known to be positive, and the absence of neurologic progression at the time the cytologic conversion was documented. The response rate among the 43 evaluable patients was 28% (CI 95%: 14-41%). the intent-to-treat response rate was 21% (CI 95%: 12-34%). Median time to neurologic progression was 49 days (range 1-515(+)); median survival was 88 days (range 1-515(+)), and 1 year survival is projected to be 19%. The major adverse events were headache and arachnoiditis. When drug-related, these were largely of low grade, transient and reversible. Headache occurred on 11% of cycles; 90% were grade 1 or 2. Arachnoiditis occurred on 19% of cycles; 88% were grade 1 or 2. DepoCyte demonstrated activity in neoplastic meningitis due to breast cancer that is comparable to results reported with conventional intrathecal agents. However, this activity was achieved with one fourth as many intrathecal injections as typically required in conventional therapy. The every 2 week dose schedule is a major advantage for both patients and physicians. (C) 2001 Cancer Research Campaign. C1 Univ Texas San Antonio, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. Dr Daniel den Hoed Canc Clin, Rotterdam, Netherlands. Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Emory Clin, Atlanta, GA 30322 USA. Mt Sinai Comprehens Canc Ctr, New York, NY 10029 USA. Wayne State Univ, Ctr Hlth, Detroit, MI 48202 USA. NYU Med Ctr, New York, NY 10016 USA. Georgetown Univ, Med Ctr, Washington, DC 20057 USA. Ottawa Reg Canc Ctr, Ottawa, ON, Canada. Univ Michigan Hosp, Ann Arbor, MI 48109 USA. Rush Canc Inst, Chicago, IL 60612 USA. Wake Forest Univ, Ctr Comprehens Canc, Winston Salem, NC 27109 USA. Ontario Canc Ctr, Ottawa, ON, Canada. Univ Massachusetts, Sch Med, Amherst, MA 01003 USA. Univ Calif San Diego, La Jolla, CA 92093 USA. Univ Colorado, Boulder, CO 80309 USA. Univ Florida, Gainesville, FL 32611 USA. Vanderbilt Univ, Med Ctr, Nashville, TN 37212 USA. Univ Texas San Antonio, San Antonio, TX 78285 USA. Loyola Univ, New Orleans, LA 70118 USA. RP Howell, SB (reprint author), Univ Calif San Diego, Dept Med 0058, La Jolla, CA 92093 USA. NR 22 TC 50 Z9 53 U1 0 U2 2 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 JAN 19 PY 2001 VL 84 IS 2 BP 157 EP 163 DI 10.1054/bjoc.2000.1574 PG 7 WC Oncology SC Oncology GA 397WV UT WOS:000166721600002 PM 11161370 ER PT J AU Scheller, M Forman, SA AF Scheller, M Forman, SA TI Butanol effects on gamma-aminobutyric acid concentration-responses in human alpha(1)beta(2)gamma(2L) gamma-aminobutyric acid type A receptors with a mutation at alpha(1)S270 SO NEUROSCIENCE LETTERS LA English DT Article DE alcohols; anesthetics; ethanol; ion channel; oocyte; nicotinic receptor ID GLYCINE RECEPTORS; GABA(A) RECEPTORS; ANESTHETIC ACTION; POTENTIATION; VOLATILE; ETHANOL; MODULATION; SUBTYPES; CURRENTS; NEURONS AB Alcohol enhancement of gamma -aminobutyric acid type A receptor (GABA(A)R) gating at low GABA is reduced by a serine-to-isoleucine mutation at residue alpha S270, suggesting that alpha S270 forms an enhancement site. However, whether the alpha (S2701) mutation strengthens alcohol inhibition of GABA(A)Rs remains unexplored. Furthermore, alpha S270 mutations have not been studied in the most prevalent form of mammalian GABA(A)Rs consisting of alpha (1), beta (2), and gamma (2) subunits. In voltage-clamped Xenopus oocytes expressing recombinant alpha (1)beta (2)gamma (2L) GABA(A)RS, electrophysiological analysis of GABA concentration-responses demonstrates that the alpha (1)(S2701) mutation increases apparent GABA affinity and significantly reduces the Hill coefficient of GABA(A)R activation. Butanol-induced leftward-shifts in GABA concentration-responses for both wildtype alpha (1)beta (2)gamma (2L) and alpha (1)(S2701)beta (2)gamma (2L) GABA(A)Rs are equal. At high GABA, butanol neither enhances nor inhibits alpha (1)(S2701)beta (2)gamma (2L) responses. Thus, in the dominant mammalian GABA(A)R isoform, the a(S2701) mutation affects neither enhancement nor inhibition by butanol, but alters the gating mechanism by reducing cooperativity, producing an apparent reduction in alcohol enhancement at low GABA. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Tech Univ Munich, Inst Anasthesiol, Klinikum Rechts Isar, Munich, Germany. Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02113 USA. RP Forman, SA (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. FU NIAAA NIH HHS [K21-AA00206]; NIGMS NIH HHS [P01-GM58448] NR 20 TC 4 Z9 5 U1 0 U2 0 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 JAN 19 PY 2001 VL 297 IS 3 BP 179 EP 182 DI 10.1016/S0304-3940(00)01695-5 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 400LG UT WOS:000166872600009 PM 11137757 ER PT J AU Delany, NS Hurle, M Facer, P Alnadaf, T Plumpton, C Kinghorn, I See, CG Costigan, M Anand, P Woolf, CJ Crowther, D Sanseau, P Tate, SN AF Delany, NS Hurle, M Facer, P Alnadaf, T Plumpton, C Kinghorn, I See, CG Costigan, M Anand, P Woolf, CJ Crowther, D Sanseau, P Tate, SN TI Identification and characterization of a novel human vanilloid receptor-like protein, VRL-2 SO PHYSIOLOGICAL GENOMICS LA English DT Article DE dorsal root ganglia; capsaicin; autonomic nervous system; expressed sequence tag ID NERVE GROWTH-FACTOR; CAPSAICIN-RECEPTOR; CATION CHANNEL; CALCIUM; SUBUNIT; CLONING; HEAT AB Remarkable progress has been made recently in identifying a new gene family related to the capsaicin (vanilloid) receptor, VR1. Using a combination of in silico analysis of expressed sequence tag (EST) databases and conventional molecular cloning, we have isolated a novel vanilloid-like receptor, which we call VRL-2, from human kidney. The translated gene shares 46% and 43% identity with VR1 and VRL-1, respectively, and maps to chromosome 12q23-24.1, a locus associated with bipolar affective disorder. VRL-2 mRNA was most strongly expressed in the trachea, kidney, and salivary gland. An affinity-purified antibody against a peptide incorporating the COOH terminal of the receptor localized VRL-2 immunolabel in the distal tubules of the kidney, the epithelial linings of both trachea and lung airways, serous cells of submucosal glands, and mononuclear cells. Unlike VR1 and VRL-1, VRL-2 was not detected in cell bodies of dorsal root ganglia (DRG) or sensory nerve fibers. However, VRL-2 was found on sympathetic and parasympathetic nerve fibers, such as those innervating the arrector pili smooth muscle in skin, sweat glands, intestine, and blood vessels. At least four vanilloid receptor-like genes exist, the newest member, VRL-2 is found in airway and kidney epithelia and in the autonomic nervous system. C1 Glaxo Wellcome Res & Dev Ltd, Ion Channel Sect, Med Res Ctr, Stevenage SG1 2NY, Herts, England. Glaxo Wellcome Res & Dev Ltd, Genone Informat & Anal, Med Res Ctr, Stevenage SG1 2NY, Herts, England. Glaxo Wellcome Res & Dev Ltd, Virol & Vaccine Syst, Med Res Ctr, Stevenage SG1 2NY, Herts, England. Glaxo Wellcome Res & Dev Ltd, Mol Recognit, Med Res Ctr, Stevenage SG1 2NY, Herts, England. Glaxo Wellcome Res & Dev Ltd, Mol Genet, Med Res Ctr, Stevenage SG1 2NY, Herts, England. Hammersmith Hosp, Imperial Coll Sch Med, Peripheral Neuropathy Unit, London W12 OHN, England. Massachusetts Gen Hosp, Neural Plast Res Grp, Dept Anesthesia & Crit Care, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Tate, SN (reprint author), Glaxo Wellcome Res & Dev Ltd, Ion Channel Sect, Med Res Ctr, Gunnels Wood Rd, Stevenage SG1 2NY, Herts, England. NR 29 TC 138 Z9 147 U1 1 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD JAN 19 PY 2001 VL 4 IS 3 BP 165 EP 174 PG 10 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 393TF UT WOS:000166485200001 PM 11160995 ER PT J AU Szostak, JW Bartel, DP Luisi, PL AF Szostak, JW Bartel, DP Luisi, PL TI Synthesizing life SO NATURE LA English DT Article ID COMPLEMENTARY-STRAND RNA; FATTY-ACID VESICLES; MEMBRANE-PERMEABILITY; FUSION; RIBOZYME; WORLD; REPLICATION; SEQUENCES; LIPOSOMES; MICELLES AB Advances in directed evolution and membrane biophysics make the synthesis of simple living cells, if not yet foreseeable reality, an imaginable goal. Overcoming the many scientific challenges along the way will deepen our understanding of the essence of cellular life and its origin on Earth. C1 Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. MIT, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. MIT, Dept Biol, Cambridge, MA 02142 USA. ETH Zentrum, Inst Polymere, CH-8092 Zurich, Switzerland. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. NR 33 TC 689 Z9 718 U1 30 U2 231 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 18 PY 2001 VL 409 IS 6818 BP 387 EP 390 DI 10.1038/35053176 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 392VY UT WOS:000166434300060 PM 11201752 ER PT J AU Lindsay, R Silverman, SL Cooper, C Hanley, DA Barton, I Broy, SB Licata, A Benhamou, L Geusens, P Flowers, K Stracke, H Seeman, E AF Lindsay, R Silverman, SL Cooper, C Hanley, DA Barton, I Broy, SB Licata, A Benhamou, L Geusens, P Flowers, K Stracke, H Seeman, E TI Risk of new vertebral fracture in the year following a fracture SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID WOMEN; OSTEOPOROSIS AB Context Vertebral fractures significantly increase lifetime risk of future fractures, but risk of further vertebral fractures in the period immediately following a vertebral fracture has not been evaluated. Objective To determine the incidence of further vertebral fracture in the year following a vertebral fracture. Design and setting Analysis of data from 4 large 3-year osteoporosis treatment trials conducted at 373 study centers in North America, Europe, Australia, and New Zealand from November 1993 to April 1998. Subjects Postmenopausal women who had been randomized to a placebo group and for whom vertebral fracture status was known at entry (n=2725). Main Outcome Measure Occurrence of radiographically identified vertebral fracture during the year following an incident vertebral fracture. Results Subjects were a mean age of 74 years and had a mean of 28 years since menopause. The cumulative incidence of new vertebral fractures in the first year was 6.6%. Presence of 1 or more vertebral fractures at baseline increased risk of sustaining a vertebral fracture by 5-fold during the initial year of the study compared with the incidence in subjects without prevalent vertebral fractures at baseline (relative risk [RR], 5.1;95% confidence interval [CI], 3.1-8.4; P<.001). Among the 381 participants who developed an incident vertebral fracture, the incidence of a new vertebral fracture in the subsequent year was 19.2% (95% CI, 13.6%-24.8%). This risk was also increased in the presence of prevalent vertebral fractures (RR, 9.3; 95% CI, 1.2-71.6; P=.03). Conclusion Our data indicate that women who develop a vertebral fracture are at substantial risk for additional fracture within the next year. C1 Helen Hayes Hosp, Reg Bone Ctr, W Haverstraw, NY 10993 USA. Cedars Sinai Med Ctr, Osteoporosis Med Ctr, Los Angeles, CA 90048 USA. Greater Los Angeles VA Hlth Syst, Los Angeles, CA USA. Univ Southampton, MRC, Environm Epidemiol Unit, Southampton, Hants, England. Univ Calgary, Hlth Sci Ctr, Calgary, AB, Canada. Procter & Gamble Pharmaceut, Staines, Middx, England. Illinois Bone & Joint Inst, Ctr Arthrit & Osteoporosis, Des Plaines, IL USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Ctr Hosp Orleans, Orleans, France. Limburgs Univ Ctr, Diepenbeek, Belgium. Univ Maastricht, Maastricht, Netherlands. Procter & Gamble Co, Cincinnati, OH USA. Univ Giessen, Giessen, Germany. Univ Melbourne, Melbourne, Vic, Australia. RP Lindsay, R (reprint author), Helen Hayes Hosp, Reg Bone Ctr, Route 9W, W Haverstraw, NY 10993 USA. OI Seeman, Ego/0000-0002-9692-048X NR 14 TC 848 Z9 915 U1 2 U2 17 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 17 PY 2001 VL 285 IS 3 BP 320 EP 323 DI 10.1001/jama.285.3.320 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 390XD UT WOS:000166324300023 PM 11176842 ER PT J AU Joffe, S Cook, EF Cleary, PD Clark, JW Weeks, JC AF Joffe, S Cook, EF Cleary, PD Clark, JW Weeks, JC TI Quality of informed consent: A new measure of understanding among research subjects SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID RANDOMIZED CLINICAL-TRIAL; PHASE-I; ANTICANCER AGENTS; CANCER-PATIENTS; ETHICAL ISSUES; INVESTIGATORS; PERCEPTIONS; PERSPECTIVE; CONDUCT; IMPACT AB Background: The informed consent of participants is ethically and legally required for most research involving human subjects. However, standardized methods for assessing the adequacy of informed consent to research are lacking. Methods and Results: We designed a brief questionnaire, the Quality of Informed Consent (QuIC), to measure subjects' actual (objective) and perceived (subjective) understanding of cancer clinical trials, The QuIC incorporates the basic elements of informed consent specified in federal regulations, assesses the therapeutic misconception (the belief that all aspects of a clinical trial are designed to directly benefit the subject), and employs the language and structure of the new National Cancer Institute template for informed consent documents, We modified the QuIC after receiving feedback from pilot tests with cancer research subjects, as well as validation from two independent expert panels. We then sent the QuIC to 287 adult cancer patients enrolled on phase I, II, or III clinical trials, Two hundred seven subjects (72%) completed the QuIC, To assess test-retest reliability, a random sample of 32 respondents was selected, of whom 17 (53%) completed the questionnaire a second time. The test-retest reliability was good with intraclass correlation coefficients of .66 for tests of objective understanding and .77 for tests of subjective understanding. The current version of the QuIC, which consists of 20 questions for objective understanding and 14 questions for subjective understanding, was tested for time and ease of administration in a sample of nine adult cancer patients. The QuIC required an average of 7.2 minutes to complete. Conclusions: The QuIC is a brief, reliable, and valid questionnaire that holds promise as a standardized way to assess the outcome of the informed consent process in cancer clinical trials. C1 Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Dept Pediat, Boston, MA 02115 USA. Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Gen Internal Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA USA. Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Weeks, JC (reprint author), Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Dept Pediat, 454 BRK,Suite 21,44 Binney St, Boston, MA 02115 USA. OI Joffe, Steven/0000-0002-0667-7384 FU AHRQ HHS [T32 HS00063] NR 42 TC 178 Z9 181 U1 0 U2 12 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 17 PY 2001 VL 93 IS 2 BP 139 EP 147 DI 10.1093/jnci/93.2.139 PG 9 WC Oncology SC Oncology GA 391NM UT WOS:000166362100014 PM 11208884 ER PT J AU Raitt, MH Renfroe, EG Epstein, AE McAnulty, JH Mounsey, P Steinberg, JS Lancaster, SE Jadonath, RL Hallstrom, AP AF Raitt, MH Renfroe, EG Epstein, AE McAnulty, JH Mounsey, P Steinberg, JS Lancaster, SE Jadonath, RL Hallstrom, AP TI "Stable" ventricular tachycardia is not a benign rhythm - Insights from the antiarrhythmics versus implantable defibrillators (AVID) registry SO CIRCULATION LA English DT Article DE death, sudden; tachycardia; cardioversion; defibrillation ID SUDDEN CARDIAC DEATH; MYOCARDIAL-INFARCTION; ARREST; RISK AB Background-Sustained ventricular tachycardia (VT) can be unstable, can be associated with serious symptoms, or can be stable and relatively free of symptoms. Patients with unstable VT are at high risk for sudden death and are best treated with an implantable defibrillator. The prognosis of patients with stable VT is controversial, and it is unknown whether implantable cardioverter-defibrillator therapy is beneficial. Methods and Results-Screening for the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial identified patients with both stable and unstable VT. Both groups were included in a registry, and their clinical characteristics and discharge treatments were recorded. Mortality data were obtained through the National Death Index. The mortality in 440 patients with stable VT tended to be greater than that observed in 1029 patients presenting with unstable VT (33.6% versus 27.6% at 3 years; relative risk [RR]=1.22; P=0.07). After adjustment for baseline and treatment differences, the RR was little changed (RR=1.25, P=0.06). Conclusions-Sustained VT without serious symptoms or hemodynamic compromise is associated with a high mortality rate and may be a marker for a substrate capable of producing a more malignant arrhythmia. Implantable cardioverter-defibrillator therapy may be indicated in patients presenting with stable VT. C1 Portland VA Med Ctr, Portland, OR USA. Univ Washington, Seattle, WA 98195 USA. Univ Alabama, Birmingham, AL USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Univ Virginia, Med Ctr, Charlottesville, VA USA. St Lukes Roosevelt Hosp Ctr, New York, NY USA. N Shore Univ Hosp, Cornell Univ Med Coll, Div Biostat, Manhasset, NY 11030 USA. RP Raitt, MH (reprint author), AVID Clin Trial Ctr, 1107 NE 45th St,Room 505, Seattle, WA 98105 USA. FU NHLBI NIH HHS [N01-HC-25117] NR 10 TC 38 Z9 39 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 16 PY 2001 VL 103 IS 2 BP 244 EP 252 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 394NA UT WOS:000166529100021 PM 11208684 ER PT J AU Denis, CV Kwack, K Saffaripour, S Maganti, S Andre, P Schaub, RG Wagner, DD AF Denis, CV Kwack, K Saffaripour, S Maganti, S Andre, P Schaub, RG Wagner, DD TI Interleukin 11 significantly increases plasma von Willebrand factor and factor VIII in wild type and von Willebrand disease mouse models SO BLOOD LA English DT Article ID RECOMBINANT HUMAN INTERLEUKIN-11; RECEPTOR ALPHA-CHAIN; VONWILLEBRAND DISEASE; DESMOPRESSIN DDAVP; PLATELET-ADHESION; P-SELECTIN; MPL-LIGAND; IN-VIVO; EXPRESSION; CHEMOTHERAPY AB Interleukin (IL)-11 is a cytokine with thrombopoietic activity that has been shown to increase plasma von Willebrand factor (vWf) in preliminary clinical studies. This led to further evaluation of the effect of recombinant human (rh)lL-11 on vWf and factor VIII (FVIII) secretion. In vitro, rhlL-11 did not increase vWf production by cultured endothelial cells, which suggests an indirect mechanism. Also, in vivo, plasma vWf was not elevated in mice shortly after a single intravenous (IV) bolus injection of 250 or 1000 mug/kg rhlL-11, The effect of continuous exposure to rhlL-11 was accessed by treating wild type mice for 7 consecutive days with subcutaneous 250 mug/kg/d rhlL-11. Platelet counts increased by 25% and 40% after 4 and 7 days, respectively. Plasma vWf and FVIII levels increased 5-fold after 4 and 7 days. Surprisingly, no effect of rhlL-11 on vWf or FVIII messenger RNA was observed, which suggests that the regulation by rhlL-11 occurs after transcription, No increase in soluble P-selectin was observed after rhll-11 treatment, indicating that platelet activation is not the source of elevated vWf, Similarly to wild type mice, vWf heterozygous mice responded to rhlL-11 treatment by a significant increase in platelet counts and vWf and FVIII levels. Importantly, in vWf-deficient mice, rhlL-11 also induced a significant increase in FVIII independent of vWf and was able to reduce skin bleeding time. These results suggest that a clinical evaluation of the effects of rhll-11-induced vWf/FVIII elevation in maintaining hemostasis in mild hemophilia A or von Willebrand disease would be worthwhile, (C) 2001 by The American Society of Hematology. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Wyeth Genet Inst, Cambridge, MA USA. RP Wagner, DD (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. RI Denis , Cecile/A-7649-2011 OI Denis , Cecile/0000-0001-5152-9156 FU NHLBI NIH HHS [P01 HL56949, R37 HL41002] NR 50 TC 30 Z9 30 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 JAN 15 PY 2001 VL 97 IS 2 BP 465 EP 472 DI 10.1182/blood.V97.2.465 PG 8 WC Hematology SC Hematology GA 392AG UT WOS:000166388000019 PM 11154224 ER PT J AU Boussiotis, VA Chen, ZM Zeller, JC Murphy, WJ Berezovskaya, A Narula, S Roncarolo, MG Blazar, BR AF Boussiotis, VA Chen, ZM Zeller, JC Murphy, WJ Berezovskaya, A Narula, S Roncarolo, MG Blazar, BR TI Altered T-cell receptor+CD28-mediated signaling and blocked cell cycle progression in interleukin 10 and transforming growth factor-beta-treated alloreactive T cells that do not induce graft-versus-host disease SO BLOOD LA English DT Article ID ALLOANTIGEN-SPECIFIC HYPORESPONSIVENESS; HUMAN LYMPHOCYTES-T; KINASE-ACTIVITY; DEPENDENT KINASES; DNA-REPLICATION; MAMMALIAN-CELLS; PLASMA-MEMBRANE; DOWN-REGULATION; CYCLOSPORINE-A; IN-VIVO AB The induction of anergy in T cells, although widely accepted as critical for the maintenance of tolerance, is still poorly understood at the molecular level, Recent evidence demonstrates that in addition to blockade of costimulation using monoclonal antibodies (mAbs) directed against cell surface determinants, treatment of mixed lymphocyte reaction (MLR) cultures with interleukin 10 (IL-10) and transforming growth factor-beta (TGF-beta) results in induction of tolerance, rendering alloreactive murine CD4(+) T cells incapable of inducing graft-versus-host disease (GVHD) after in vivo transfer to histoincompatible recipients. The present study, using these cells prior to adoptive transfer, determined that IL-10 + TGF-beta -tolerant CD4(+) T cells exhibit an altered pattern of T-cell receptor (TCR) + CD28-mediated signaling and are incapable of progressing out of the G1 phase of the cell cycle during stimulation with HLA class II disparate antigen-presenting cells. TGF beta + IL-10-tolerant cells were incapable of phosphorylating TCR-xi, or activating ZAP-70, Ras, and MAPK, similarly to T-cell tolerized by blockade of B7/CD28 and CD40/CD40L pathways. Moreover, these cells were incapable of clonal expansion due to defective synthesis of cyclin D3 and cyclin A, and defective activation of cyclin-dependent kinase (cdk)4, cdk6, and cdk2. These cells also exhibited defective down-regulation of p27(kip1) cdk inhibitor and lack of cyclin D2-cdk4 activation, Rb hyperphosphorylation, and progression to the S phase of the cell cycle, These data link anergy-specific proximal biochemical alterations and the downstream nuclear pathways that control T-cell expansion and provide a biochemical profile of IL-10 + TGF-beta -tolerant alloreactive T cells that do not induce GVHD when transferred into MHC class II disparate recipients in vivo. (C) 2001 by The American Society of Hematology. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp,Div Med Oncol, Dept Med,Dana Farber Canc Inst,Dept Adult Oncol, Boston, MA 02115 USA. Univ Minnesota, Ctr Canc, Div Bone Marrow Transplantat, Dept Pediat, Minneapolis, MN USA. MCI FCRDC, Lab Leukocyte Biol, Frederick, MD USA. SAIC Frederick, Frederick, MD USA. Shering Plough Res Inst, Kenilworth, NJ USA. TIGET HS RAFFAELE, Milan, Italy. RP Boussiotis, VA (reprint author), Dana Farber Canc Inst, Meyer 547,44 Binney St, Boston, MA 02115 USA. OI RONCAROLO, Maria Grazia/0000-0002-2193-9186 FU NHLBI NIH HHS [HL 54785]; NIAID NIH HHS [AI 41584, AI 43552]; Telethon [TGT00Z04, TGT06S01] NR 69 TC 35 Z9 37 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 JAN 15 PY 2001 VL 97 IS 2 BP 565 EP 571 DI 10.1182/blood.V97.2.565 PG 7 WC Hematology SC Hematology GA 392AG UT WOS:000166388000033 PM 11154238 ER PT J AU Mitsiades, N Yu, WH Poulaki, V Tsokos, M Stamenkovic, I AF Mitsiades, N Yu, WH Poulaki, V Tsokos, M Stamenkovic, I TI Matrix metalloproteinase-7-mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity SO CANCER RESEARCH LA English DT Article ID INDUCED APOPTOSIS; ANTICANCER DRUGS; DOWN-REGULATION; SOLUBLE FORM; EXPRESSION; ACTIVATION; CANCER; INHIBITORS; METASTASIS; CARCINOMA AB Recent evidence suggests that one mechanism whereby cytotoxic drugs, such as doxorubicin, kill tumors is the induction or up-regulation of Fas ligand (FasL) expression on the tumor cell surface. The ensuing engagement of Fas by FasL on adjacent cells leads to apoptosis. However, despite cytotoxic drug-induced Fast expression, Fas-sensitive tumors frequently resist chemotherapy, suggesting that they may possess a mechanism that prevents or inactivates Fas-FasL interactions. In the present work, we addressed the involvement of the FasL/Fas signaling pathway in doxorubicin-indureed apoptosis and the ability of matrix metalloproteinases (MMPs) to proteolytically cleave Fast in tumor cells. Doxorubicin-induced apoptosis was inhibited by expression of soluble Fas or incubation of the tumor cells with MMP-7 but not with MMP-2 or MMP-9. Resistance to doxorubicin was also induced by expression in the tumor cells of constitutively active MMP-7 but not of a catalytically inactive mutant. Conversely, inhibition of MMP-7 expression in tumor cells by transfection of MMP-7 cDNA in antisense orientation resulted in sensitization to doxorubicin. MMP-7 efficiently cleaved recombinant Fast in vitro and reduced cell surface FasL expression. Our observations provide evidence that one mechanism whereby MMP-7 may promote tumor survival and resistance to doxorubicin is by cleaving Fast and reducing its effectiveness in triggering Fas-mediated apoptosis. C1 Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA 02129 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02129 USA. NCI, Bethesda, MD 20892 USA. RP Mitsiades, N (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Mayer Bldg,Room M57,44 Binney St, Boston, MA 02115 USA. OI Yu, Wei-Hsuan/0000-0002-1782-3738 NR 32 TC 224 Z9 245 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 JAN 15 PY 2001 VL 61 IS 2 BP 577 EP 581 PG 5 WC Oncology SC Oncology GA 399NT UT WOS:000166819800031 PM 11212252 ER PT J AU Hirao, T Nelson, HH Ashok, TDS Wain, JC Mark, EJ Christiani, DC Wiencke, JK Kelsey, KT AF Hirao, T Nelson, HH Ashok, TDS Wain, JC Mark, EJ Christiani, DC Wiencke, JK Kelsey, KT TI Tobacco smoke-induced DNA damage and an early age of smoking initiation induce chromosome loss at 3p21 in lung cancer SO CANCER RESEARCH LA English DT Article ID PRENEOPLASTIC LESIONS; P53; GENE; DELETION; HETEROZYGOSITY; ABNORMALITIES; MUTATIONS; CARCINOMA; SURVIVAL; TISSUE AB The short arm of chromosome 3 is thought to harbor a novel oncogenic locus that is important in the genesis of lung cancer, The region at 3p21 is believed to contain a distinct locus that is sensitive to loss from the action of tobacco smoke carcinogens and has been reported to be specifically targeted for deletion in lung cancer. To investigate whether 3p21 alteration in lung cancer is associated with carcinogen exposure, PCR-based analysis was performed to detect loss of heterozygosity (LOH) on chromosome 3 at 3p21 in non-small cell lung carcinoma (NSCLC), We also measured instability at the BAT-26 locus, because the mismatch DNA repair gene, hMLH1, is found at 3p21, LOH at 3p21 was analyzed for association with the clinical features of NSCLC, p53 mutation status, polynuclear aromatic hydrocarbon-DNA adduct levels (measured using P-32-postlabeling) and carcinogen exposure information including cigarette smoking and asbestos exposure, Of 219 lung cancers, 150 cases (68.5%) were informative at the D3S1478 locus, and 44.2% of squamous cell carcinoma cases and 30.2% of adenocarcinoma cases showed 3p21 LOH, None of the cancers showed BAT-26 instability, The prevalence of 3p21 LOH was higher in both current and former smokers compared with never smokers and was higher in p53 mutated cases. Among squamous cell carcinoma cases, there was a strong association of increased 3p21 LOH with increasing polynuclear aromatic hydrocarbon-DNA adducts levels (P = 0.03), as well as an increased prevalence LOH with earlier age of smoking initiation (P = 0.02), Our results confirm that 3p21 LOH is strongly associated with measures of biologically effective dose of exposure to tobacco carcinogens, Our results also suggest that alterations of hMLH1 are not related to any of the reported associations, because there was no evidence of microsatellite instability. Finally, LOH in 3p21 may be an early molecular event in NSCLC, because it is significantly associated with a tendency to start smoking at a young age. C1 Harvard Univ, Sch Publ Hlth, Dept Canc Cell Biol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Occupat Hlth Program, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Thorac Surg Unit, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pulm & Crit Care Unit,Dept Med, Boston, MA 02114 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, Lab Mol Epidemiol, San Francisco, CA 94143 USA. RP Kelsey, KT (reprint author), Harvard Univ, Sch Publ Hlth, Dept Canc Cell Biol, 665 Huntington Ave, Boston, MA 02115 USA. RI Kelsey, Karl/I-1252-2014 FU NIEHS NIH HHS [ES00002, ES04705, ES08357] NR 26 TC 58 Z9 60 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2001 VL 61 IS 2 BP 612 EP 615 PG 4 WC Oncology SC Oncology GA 399NT UT WOS:000166819800037 PM 11212258 ER PT J AU Knudson, CM Johnson, GM Lin, Y Korsmeyer, SJ AF Knudson, CM Johnson, GM Lin, Y Korsmeyer, SJ TI Bax accelerates tumorigenesis in p53-deficient mice SO CANCER RESEARCH LA English DT Article ID CELL-CYCLE ENTRY; TUMOR-SUPPRESSOR P53; TRANSGENIC MICE; IN-VIVO; CHROMOSOMAL BREAKPOINT; FRAMESHIFT MUTATIONS; T-CELLS; BCL-2; APOPTOSIS; DEATH AB Bax is a Bcl-2 family member that promotes apoptosis and counters the protective effect of Bcl-2, Bax Is a downstream effector of p53-induced apoptosis and is transcriptionally regulated by p53. Moreover, the introduction of Bax deficiency accelerates the onset of tumors in transgenic mice expressing truncated large T antigen, These results implicate Bax as a tumor suppressor. Consequently, we asked whether the levels of Ban expression would influence tumor development by comparing Bax-deficient and Ban transgenic mice in the presence or absence of p53. We found that Bax-deficient mice did not display an increased incidence of spontaneous cancers when followed for >1.5 years. In addition, Bax-deficiency did not further accelerate oncogenesis in mice also deficient in p53, We generated Lck(pr)-Bax transgenic mice to examine the effects of overexpressed BAX on T-cell development and tumorigenesis, Lck(pr)-Bax mice show increased apoptosis consistent with the pro-apoptotic function of Bax. The introduction of p53-deficiency did not interfere with BAX-induced apoptosis; this is consistent with BAX operating downstream or independent of p53, However, we found that Lck(pr)-Bax/p53-deficient mice have an increased incidence of T-cell lymphomas when compared with p53-deficient mice. The Lck(pr)-Bax transgenic mice have an increased percentage of cells in cycle. These findings extend previous work suggesting that Bcl-2 family proteins regulate proliferation as well as cell death, We conclude that BAX-induced proliferation is synergistic with a defect in apoptosis contributed by p53-deficiency. Thus, the dual roles of BAX can either accelerate or inhibit tumorigenesis depending on the genetic context. C1 Univ Iowa, Coll Med, Dept Pathol, Iowa City, IA 52242 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pathol & Med, Boston, MA 02115 USA. RP Knudson, CM (reprint author), Univ Iowa, Coll Med, Dept Pathol, Room 145 MRC, Iowa City, IA 52242 USA. FU NCI NIH HHS [CA49712] NR 45 TC 61 Z9 64 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2001 VL 61 IS 2 BP 659 EP 665 PG 7 WC Oncology SC Oncology GA 399NT UT WOS:000166819800044 PM 11212265 ER PT J AU Pogue, BW Ortel, B Chen, N Redmond, RW Hasan, T AF Pogue, BW Ortel, B Chen, N Redmond, RW Hasan, T TI A photobiological and photophysical-based study of phototoxicity of two chlorins SO CANCER RESEARCH LA English DT Article ID TIN ETHYL ETIOPURPURIN; MOUSE LYMPHOMA-CELLS; PHOTODYNAMIC THERAPY; SINGLET OXYGEN; IN-VITRO; APOPTOSIS; PHOTOSENSITIZERS; DOSIMETRY; PHTHALOCYANINE; ENVIRONMENTS AB To understand the fundamental determinants of phototoxic efficacy and absorbed photodynamic dose, the triplet state and photobleaching quantum yields in living cells, cellular uptake, intracellular localization, and correlation with cell viability were studied for the two purpurins tin ethyl etiopurpurin I (SnET2) and tin octaethylbenzochlorin (SnOEBC) in ovarian cancer cells (OVCARS), Although the triplet yields of these two photosensitizers were not significantly affected by cellular incorporation, the photobleaching yields were shown to be 3 orders of magnitude higher for cellular-bound sensitizer than for free or albumin-bound photosensitizer and higher for SnET, than for SnOEBC for all of the cases. The intracellular concentration of SnOEBC was half that of SnET, after 3 hand 24 h-incuhation times for both 0.1 muM and 1.0 phl incubation concentrations. Despite the lower concentrations of SnOEBC, the phototoxicity of the two photosensitizers was comparable at 1-muM incubation concentration and was up to 10-fold higher for SnOEBC at the lower concentration, The subcellular localization established using: confocal microscopy and molecular probes showed that both photosensitizers were primarily lysosomally localized. SnOEBC, however, had an extra-lysosomal, mitochondrial localization component. The photophysical measurements allowed calculation of the intracellular singlet oxygen production, which indicated that the photosensitizer-light dose reciprocity was limited by photobleaching for SnET, but only minimally for SnOEBC, and this was confirmed through cell-survival studies. Taken together, these data indicate that the critical determinant of differences in phototoxicity between the two molecules was their relative rates of photobleaching and their subcellular localization. The study points to the importance of combining photosensitizer uptake and localization with photophysical measurements in the relevant biological milieu to reasonably interpret and/or predict photosensitization efficacies. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Labs Photomed,Dept Dermatol, Boston, MA 02114 USA. Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. RP Hasan, T (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Labs Photomed,Dept Dermatol, 50 Blossom St WEL224, Boston, MA 02114 USA. FU NCI NIH HHS [1R01CA78734]; PHS HHS [R01 C68524A] NR 42 TC 33 Z9 36 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2001 VL 61 IS 2 BP 717 EP 724 PG 8 WC Oncology SC Oncology GA 399NT UT WOS:000166819800053 PM 11212274 ER PT J AU Hohmann, EL AF Hohmann, EL TI Nontyphoidal salmonellosis SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID SEROTYPE TYPHIMURIUM DT104; MULTIDRUG-RESISTANT; UNITED-STATES; BACTEREMIA; GASTROENTERITIS; CIPROFLOXACIN; INFECTION; EMERGENCE; CHILDREN; PLACEBO AB Nontyphoidal Salmonella are important foodborne pathogens that cause gastroenteritis, bacteremia, and subsequent focal infection. These hardy bacteria are especially problematic in a wide variety of immunocompromised individuals, including (but not limited to) patients with malignancy, human immunodeficiency virus, or diabetes, and those receiving corticosteroid therapy or treatment with other immunotherapy agents. Endovascular infection and deep bone or visceral abscesses are important complications that may be difficult to treat. The site of infection and the individual's immune status influence treatment choices. The harbingers of resistance of nontyphoidal Salmonella to both fluoroquinolones and third-generation cephalosporins have been reported recently, and such resistance is likely to be a therapeutic problem in the future. The current report presents a brief overview of the problems and trends associated with salmonellosis that are of interest to the infectious diseases clinician. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Hohmann, EL (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Infect Dis, Gray Jackson 504,55 Fruit St, Boston, MA 02114 USA. NR 28 TC 389 Z9 403 U1 2 U2 14 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JAN 15 PY 2001 VL 32 IS 2 BP 263 EP 269 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 393JK UT WOS:000166465300013 PM 11170916 ER PT J AU Pierrat, B Simonen, M Cueto, M Mestan, J Ferrigno, P Heim, J AF Pierrat, B Simonen, M Cueto, M Mestan, J Ferrigno, P Heim, J TI SH3GLB, a new endophilin-related protein family featuring an SH3 domain SO GENOMICS LA English DT Article ID PROGRAMMED CELL-DEATH; ENDOPLASMIC-RETICULUM; 2-HYBRID SYSTEM; YEAST RVS161; APOPTOSIS; BAX; BCL-2; PATHWAY; MITOCHONDRIA; INHIBITION AB A new cDNA encoding a protein of 362 amino acids designated SH3GLB1, for SHY domain GRB2-like endophilin B1, was identified in a yeast two-hybrid screen devoted to the identification of new partners interacting with the apoptosis inducer Bax. SR3GLB1 shows strong similarities to the SH3 domain-containing proteins of the endophilin family and presumably represents the human homologue of the potential Caenorhabditis elegans SH3 containing-protein identified by systematic translation of the C. elegans genome (GenBank Accession No. U46675). Reversing prey to bait in the yeast screen, a second protein, SH3GLB2, of 395 amino acids showing 65% identity to SH3GLB1 was identified as an interacting partner of SH3GLB1. The discovery of SH3GLB1 itself in the screening with SH3GLB1 as a bait and further mapping experiments demonstrated that a core coiled-coil-type region is required for the formation of SH3GLB homo- and/or heterodimers, whereas the SH3 domain is not involved in these interactions. Interestingly, the similarities with the endophilin proteins cover the entire sequence of the SH3GLB family, suggesting a common fold and presumably a common mode of action. Furthermore, SH3GLB members colocalize to the cytoplasmic compartment of the cell together with Bax and are excluded from the nucleus. SH3GLB1 and SH3GLB2 do not significantly influence the onset and time course of Bax-mediated apoptosis in HeLa or 293T cells. (C) 2001 Academic Press. C1 Novartis Pharma Res, Mol & Cell Biol Expert Lab, CH-4002 Basel, Switzerland. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Pierrat, B (reprint author), Novartis Pharma Res, Mol & Cell Biol Expert Lab, K-125,12-13, CH-4002 Basel, Switzerland. NR 52 TC 61 Z9 65 U1 0 U2 2 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 JAN 15 PY 2001 VL 71 IS 2 BP 222 EP 234 DI 10.1006/geno.2000.6378 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 401YR UT WOS:000166957200011 PM 11161816 ER PT J AU Nemunaitis, J Khuri, F Ganly, I Arseneau, J Posner, M Vokes, E Kuhn, J McCarty, T Landers, S Blackburn, A Romel, L Randlev, B Kaye, S Kirn, D AF Nemunaitis, J Khuri, F Ganly, I Arseneau, J Posner, M Vokes, E Kuhn, J McCarty, T Landers, S Blackburn, A Romel, L Randlev, B Kaye, S Kirn, D TI Phase II trial of intratumoral administration of ONYX-015, a replication-selective adenovirus, in patients with refractory head and neck cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SQUAMOUS-CELL CARCINOMA; SOUTHWEST-ONCOLOGY-GROUP; HIGH-DOSE CISPLATIN; HUMAN BREAST-CANCER; HUMAN TUMOR-CELLS; 5-FU INFUSION; MALIGNANT-MELANOMA; MEDIATED TRANSFER; METASTATIC HEAD; RECURRENT HEAD AB Purpose: To determine the safety, humoral immune response replication, and activity of multiple intratumoral injections of ONYX-015 (replication selective adenovirus) in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods: This phase II trial enrolled patients with SCCHN who had recurrence/relapse after prior conventional treatment. Patients received ONYX-015 at a dose of 2 x 10(11) particles via intratumoral injection for either 5 consecutive days (standard) or twice daily for 2 consecutive weeks (hyperfractionated) during a 21-day cycle. Patients were monitored for tumor response, toxicity, and antibody formation. Results: forty patients (30 standard and 10 hyperfractionated) received 533 injections of ONYX-015. Standard treatment resulted in 14% partial to complete regression, 41% stable disease, and 45% progressive disease rates, Hyperfractionated treatment resulted in 10% complete response, 62% stable disease, and 29% progressive disease rates, Treatment-related toxicity included mild to moderate fever (67% overall) and injection site pain (47% on the standard regimen, 80% on the hyperfractionated regimen). Detectable circulating ONYX-015 genome suggestive of intratumoral replication was identified in 41% of tested patients on days 5 and 6 of cycle 1;9% of patients had evidence of viral replication 10 days alter injection during cycle 1, and no patients had evidence of replication greater than or equal to 22 days after injection, Conclusion: ONYX-015 can be safely administered via intratumoral injection to patients with recurrent/ refractory SCCHN. ONYX-015 viremia is transient. Evidence of modest antitumoral activity is suggested. J Clin Oncol 19:289-298. (C) 2001 by American Society of Clinical Oncology. C1 US Oncol, Dallas, TX 75246 USA. Baylor Univ, Med Ctr, Dallas, TX USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Western Infirm & Associated Hosp, Beatson Oncol Ctr, Glasgow G11 6NT, Lanark, Scotland. Albany Reg Canc Ctr, Albany, NY USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Chicago, Chicago, IL 60637 USA. Onyx Pharmaceut Inc, Richmond, CA USA. RP Nemunaitis, J (reprint author), US Oncol, 3535 Worth St,Collins Bldg,5th Floor, Dallas, TX 75246 USA. NR 90 TC 335 Z9 359 U1 3 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 15 PY 2001 VL 19 IS 2 BP 289 EP 298 PG 10 WC Oncology SC Oncology GA 394QD UT WOS:000166534000003 PM 11208818 ER PT J AU Vose, JM Link, BK Grossbard, ML Czuczman, M Grillo-Lopez, A Gilman, P Lowe, A Kunkel, LA Fisher, RI AF Vose, JM Link, BK Grossbard, ML Czuczman, M Grillo-Lopez, A Gilman, P Lowe, A Kunkel, LA Fisher, RI TI Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ANTI-CD20 MONOCLONAL-ANTIBODY; B-CELL LYMPHOMA; BCL-2 PROTEIN EXPRESSION; PROGNOSTIC-SIGNIFICANCE; M-BACOD; IDEC-C2B8; TRIAL; REARRANGEMENT; THERAPY AB Purpose: To determine the safety and efficacy of the combination of the chimeric anti-CD20 antibody Rituxan (rituximab, IDEC-C2B8; Genentech Inc, South San Francisco, CA) and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in patients with aggressive non-Hodgkin's lymphoma (NHL), Patients and Methods: Thirty-three patients with previously untreated advanced aggressive B-cell NHL received six infusions of Rituxan (375 mg/m(2) per dose) on day 1 of each cycle in combination with six doses of CHOP chemotherapy given on day 3 of each cycle, Results: The ORR by investigator assessment confirmed by the sponsor was 94% (31 of 33 patients). Twenty patients experienced a complete response (CR) (61%), 11 patients had a partial response (PR) (33%), and two patients were classified as having progressive disease, In the 18 patients with an International Prognostic Index (IPI) score greater than or equal to 2, the combination of Rituxan plus CHOP achieved an ORR of 89% and CR of 56%, The median duration of response and time to progression had not been reached after a median observation rime of 26 months. Twenty-nine of 31 responding patients remained in remission during this follow-up period, including 15 of 16 patients with an IPI score greater than or equal to 2, The most frequent adverse events attributed to Rituxan were fever and chills, primarily during the first infusion, Rituxan did not seem to compromise the ability of patients to tolerate CHOP; all patients completed the entire six courses of the combination. The bcl-2 translocation of blood or bone marrow wets positive at baseline in 13 patients; 11 patients had follow-up specimens obtained (eight CR, three PR), and all had a negative bcl-2 status after therapy. Only one patient has reconverted to bcl-2 positivity, and all patients remain in clinical remission. Conclusion: This is the first report to demonstrate the safety and efficacy of the Rituxan chimeric anti-CD20 antibody in combination with standard-dose CHOP in the treatment of aggressive B-cell lymphoma. The clinical responses are at least comparable to those achieved with CHOP alone with no significant added toxicity. The presence or absence of the bcl-2 translocation did not affect the ability of patients to achieve a CR with this regimen. The ability to achieve sustained remissions in patients with an IPI score greater than or equal to 2 warrants further investigation with a randomized study. J Clin Oncol 19:389-397. (C) 2001 by American Society of Clinical Oncology. C1 Univ Nebraska, Med Ctr, Omaha, NE USA. Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. Gen Clin Res Ctr, Iowa City, IA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. IDEC Pharmaceut, San Diego, CA USA. Genentech Inc, S San Francisco, CA 94080 USA. Loyola Univ, Sch Med, Maywood, IL 60153 USA. RP Vose, JM (reprint author), 987680 Nebraska Med Ctr, Omaha, NE 68198 USA. NR 26 TC 259 Z9 286 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 15 PY 2001 VL 19 IS 2 BP 389 EP 397 PG 9 WC Oncology SC Oncology GA 394QD UT WOS:000166534000015 PM 11208830 ER PT J AU Schiller, JH Adak, S Feins, RH Keller, SM Fry, WA Livingston, RB Hammond, MEM Wolf, B Sabatini, L Jett, J Kohman, L Johnson, DH AF Schiller, JH Adak, S Feins, RH Keller, SM Fry, WA Livingston, RB Hammond, MEM Wolf, B Sabatini, L Jett, J Kohman, L Johnson, DH TI Lack of prognostic significance of p53 and K-ras mutations in primary resected non-small-cell lung cancer on E4592: A laboratory ancillary study on an Eastern Cooperative Oncology Group prospective randomized trial of postoperative adjuvant therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID GENE-MUTATIONS; ONCOGENE ACTIVATION; CLINICAL-SIGNIFICANCE; STAGE-I; EXPRESSION; ADENOCARCINOMA; SURVIVAL; PROTEIN; LINES; ONCOPROTEIN AB Purpose: To determine the prognostic and predictive significance of p53 and K-ras mutations in patients with completely resected non-small-cell lung cancer (NSCLC). Patients and Methods: Patients were randomized preoperatively to receive adjuvant postoperative radiotherapy (Arm A) or radiotherapy plus concurrent chemotherapy (Arm 8). p53 protein expression was studied by immunohistochemistry (IHC) and p53 mutations in exons 5 to 8 were evaluated by single-strand conformational analysis. K-ras mutations in codons 12, 13, and 61 were determined using engineered restriction fragment length polymorphisms. Results: Four hundred eighty-eight patients were entered onto E3590; 197 tumors were assessable for analysis. Neither presence nor absence of p53 mutations, p53 protein expression, or K-ras mutations correlated with survived ar progression-free survival. There was a trend toward improved survival for patients with wildtype K-ras (median, 42 months) compared with survival of patients with mutant K-ros who were randomized to chemotherapy plus radiotherapy (median, 25 months; P =.09), Multivariate analysis revealed only age and tumor stage to be significant prognostic factors, although there was a trend bordering on statistical significance for K-ras (P =.066). Analysis of survival difference by p53 by single-stranded conformational polymorphism and IHC, interaction of p53 and K-ras, interaction of p53 and treatment arm, nodal station, extent of surgery, weight loss, and histology did not reach statistical significance. Conclusion: p53 mutations and protein overexpression are not significant prognostic or predictive factors in resected stage II or IIIA NSCLC. K-ros mutations may be a weak prognostic marker. p53 or K-ras should nat be routinely used in the clinical management of these patients. J Clin Oncol 19:448-457. (C) 2001 by American Society of Clinical Oncology. C1 Univ Wisconsin, Dept Med, Med Oncol Sect, Clin Sci Ctr K4 666, Madison, WI 53792 USA. Univ Wisconsin Hosp & Clin, William S Middleton Mem Vet Adm Hosp, Madison, WI 53792 USA. Univ Wisconsin, Milwaukee, WI 53201 USA. Dana Farber Canc Inst, Eastern Cooperat Oncol Grp, Boston, MA 02115 USA. Univ Rochester, Ctr Canc, Rochester, NY 14627 USA. Beth Israel Med Ctr, New York, NY 10003 USA. Albany Med Ctr, Albany, NY 12208 USA. SUNY Syracuse, Syracuse, NY 13210 USA. Northwestern Univ, Evanston Hosp, Evanston, IL 60201 USA. Univ Washington, Seattle, WA 98195 USA. Latter Day St Hosp, Salt Lake City, UT 84143 USA. Univ Utah, Sch Med, Salt Lake City, UT 84112 USA. Mayo Clin, Rochester, MN 55905 USA. Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. RP Schiller, JH (reprint author), Univ Wisconsin, Dept Med, Med Oncol Sect, Clin Sci Ctr K4 666, 600 Highland Ave, Madison, WI 53792 USA. RI Johnson, David/A-7437-2009 FU NCI NIH HHS [CA21115, CA21076, CA23318, CA49957, CA66636] NR 46 TC 121 Z9 123 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 15 PY 2001 VL 19 IS 2 BP 448 EP 457 PG 10 WC Oncology SC Oncology GA 394QD UT WOS:000166534000023 PM 11208838 ER PT J AU Packer, RJ Boyett, JM Janss, AJ Stavrou, T Kun, L Wisoff, J Russo, C Geyer, R Phillips, P Kieran, M Greenberg, M Goldman, S Hyder, D Heideman, R Jones-Wallace, D August, GP Smith, SH Moshang, T AF Packer, RJ Boyett, JM Janss, AJ Stavrou, T Kun, L Wisoff, J Russo, C Geyer, R Phillips, P Kieran, M Greenberg, M Goldman, S Hyder, D Heideman, R Jones-Wallace, D August, GP Smith, SH Moshang, T TI Growth hormone replacement therapy in children with medulloblastoma: Use and effect on tumor control SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; LEUKEMIA; IRRADIATION; ANTAGONIST; RADIATION; CHILDHOOD; SEQUELAE; RISK AB Purpose: Progress has been made in the treatment of medulloblastoma, the most common childhood malignant brain tumor: However, many long-term survivors will have posttherapy growth hormone insufficiency with resultant linear growth retardation. Growth hormone replacement therapy (GHRT) may significantly improve growth, but there is often reluctance to initiate GHRT because of concerns of an increased likelihood of tumor relapse. Patients and Methods: This study retrospectively reviewed the use of GHRT for survivors of medulloblastoma in 11 neuro-oncology centers in North America who received initial treatment for disease between 1980 and 1993 to determine its impact on disease control. A Landmark analysis was used to evaluate the relative risk of relapse in surviving patients. Results: Five hundred forty-five consecutive patients less than 15 years of age at diagnosis were identified. Six-year progression-free survival (mean +/- SD) was 40% +/- 5% in children less than 3 years of age at diagnosis compared with 59% +/- 3% for older patients. Older patients with total or near-total resections (P =.003) and localized disease at diagnosis (P <.0001) had the highest likelihood of survival. One hundred seventy patients (33% +/- 3% of the cohort) received GHRT. GHRT use varied widely among institutions, ranging from 5% to 73%. GHRT was begun a mean of 3.9 years after diagnosis, later in children younger than 3 years at diagnosis (5.4 years). By Landmark analyses, for those surviving 2, 3, and 5 years after diagnosis, there was no evidence that GHRT increased the rate of disease relapse. Conclusion: This large retrospective review demonstrates that GHRT is underutilized in survivors of medulloblastoma and is used relatively late in the course of the illness. GHRT is not associated with an increased likelihood of disease relapse. J Clin Oncol 19:480-487. (C) 2001 by American Society of Clinical Oncology. C1 George Washington Univ, Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. George Washington Univ, Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. St Jude Childrens Res Hosp, Dept Biostat, Memphis, TN 38105 USA. St Jude Childrens Res Hosp, Dept Neurooncol, Memphis, TN 38105 USA. Childrens Hosp Philadelphia, Dept Oncol, Philadelphia, PA 19104 USA. Childrens Hosp Philadelphia, Dept Neurol, Philadelphia, PA 19104 USA. Childrens Hosp Philadelphia, Dept Endocrinol, Philadelphia, PA 19104 USA. NYU, Dept Neurosurg, New York, NY 10016 USA. SUNY Coll Buffalo, Childrens Hosp Buffalo, Buffalo, NY 14222 USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94143 USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. Childrens Mem Hosp, Chicago, IL 60614 USA. Childrens Hosp & Reg Med Ctr, Dept Pediat, Seattle, WA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. RP Packer, RJ (reprint author), George Washington Univ, Childrens Natl Med Ctr, Dept Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA. OI Kieran, Mark/0000-0003-2184-7692; Wisoff, Jeffrey/0000-0003-3303-2220 FU NCI NIH HHS [CA21765] NR 22 TC 63 Z9 67 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 15 PY 2001 VL 19 IS 2 BP 480 EP 487 PG 8 WC Oncology SC Oncology GA 394QD UT WOS:000166534000027 PM 11208842 ER PT J AU Sorensen, AG Patel, S Harmath, C Bridges, S Synnott, J Sievers, A Yoon, YH Lee, EJ Yang, MC Lewis, RF Harris, GJ Lev, M Schaefer, PW Buchbinder, BR Barest, G Yamada, K Ponzo, J Kwon, HY Gemmete, J Farkas, J Tievsky, AL Ziegler, RB Salhus, MRC Weisskoff, R AF Sorensen, AG Patel, S Harmath, C Bridges, S Synnott, J Sievers, A Yoon, YH Lee, EJ Yang, MC Lewis, RF Harris, GJ Lev, M Schaefer, PW Buchbinder, BR Barest, G Yamada, K Ponzo, J Kwon, HY Gemmete, J Farkas, J Tievsky, AL Ziegler, RB Salhus, MRC Weisskoff, R TI Comparison of diameter and perimeter methods for tumor volume calculation SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID GRAY-MATTER; BRAIN; SEGMENTATION; IMAGES; WHITE AB Purpose: Lesion volume is often used as an end point in clinical trials of oncology therapy. We sought to compare the common method of using orthogonal diameters to estimate lesion volume (the diameter method) with a computer-assisted planimetric technique (the perimeter method). Methods: Radiologists reviewed 825 magnetic resonance imaging studies from 219 patients with glioblastoma multiforme. Each study had lesion volume independently estimated via the diameter and perimeter methods. Cystic areas were subtracted out or excluded from the outlined lesion. Inter- and intrareader variability was measured by using multiple readings on 48 cases. Where serial studies were available in noncystic cases, a mock response analysis was used. Results: The perimeter method had a reduced interreader and intrareader variability compared with the diameter method (using SD of differences): intrareader, 1.76 mt v 7.38 mt (P <.001); interreader, 2.51 mt v 9.07 mt (P <.001) for perimeter and diameter results, respectively. Of the 121 noncystic cases, 23 had serial data. In six (26.1%) of those 23, a classification difference occurred when the perimeter method was used versus the diameter method. Conclusion: Variability of measurements was reduced with the computer-assisted perimeter method compared with the diameter method, which suggests that changes in volume can be detected more accurately with the perimeter method. The differences between these techniques seem large enough to have an impact on grading the response to therapy. J Clin Oncol 19:551-557. (C) 2001 by American Society of Clinical Oncology. C1 Massachusetts Gen Hosp, NMR Ctr, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Dept Radiol, Neuroradiol Div, Charlestown, MA 02129 USA. RP Sorensen, AG (reprint author), Massachusetts Gen Hosp, NMR Ctr, 149 13th St, Charlestown, MA 02129 USA. NR 13 TC 136 Z9 137 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 15 PY 2001 VL 19 IS 2 BP 551 EP 557 PG 7 WC Oncology SC Oncology GA 394QD UT WOS:000166534000035 PM 11208850 ER PT J AU Duncan, LM Deeds, J Cronin, FE Donovan, M Sober, AJ Kauffman, M McCarty, JJ AF Duncan, LM Deeds, J Cronin, FE Donovan, M Sober, AJ Kauffman, M McCarty, JJ TI Melastatin expression and prognosis in cutaneous malignant melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SENTINEL LYMPH-NODES; TUMOR PROGRESSION; STAGE-I; METASTASIS; SURVIVAL; LOCALIZATION; DIAGNOSIS; INVASION; MODEL; CELLS AB Purpose: Melastatin(MLSN-1), a novel melanocyte-specific gene recently identified using a genomic approach, is expressed in murine and human melanoma cells at levels inversely proportional to metastatic rates in vivo. We studied the relationship between expression of melastatin mRNA in the primary cutaneous tumor and prognosis in patients with localized malignant melanoma. Patients and Methods: Melastatin mRNA was evaluated by in situ hybridization in primary cutaneous melanoma from 150 patients with localized disease (American Joint Committee on Cancer [AJCC] stage I and II). Multivariate Cox proportional hazards regression analysis wets performed to assess the prognostic utility of melastatin mRNA expression while adjusting for other prognostic indicators, Results: Uniform melastatin mRNA expression in the primary tumor was correlated with prolonged disease-free survival (P<.0001). Multivariate analysis revealed that melastatin status, mitotic rate, and tumor thickness influence disease-free survival independently. The 8-year disease-free survival rate in AJCC stage I patients whose tumors diffusely expressed melastatin mRNA was 100%, whereas in stage I patients with melastatin loss, the disease-free survival rate was 77% +/- 15% (median +/- SE). In patients with stage II disease whose tumors diffusely expressed melastatin mRNA, the 8-year disease-free survival rate wets 90% +/- 7%, whereas in patients with melastatin loss, the disease-free survival rate was 51% +/- 8%. Conclusion: Downregulation of melastatin mRNA in the primary cutaneous tumor is a prognostic marker for metastasis in patients with localized malignant melanoma and is independent of tumor thickness and other variables. Used in combination, melastatin states and tumor thickness allow for the identification of subgroups of patients at high and low risk of developing metastatic disease, J Clin Oncol 19:568-576, (C) 2001 by American Society of Clinical Oncology. C1 Massachusetts Gen Hosp, Dermatopathol Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Millennium Predict Med Inc, Cambridge, MA USA. RP Duncan, LM (reprint author), Massachusetts Gen Hosp, Dermatopathol Unit, WRN827,55 Fruit St, Boston, MA 02114 USA. NR 39 TC 138 Z9 143 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 15 PY 2001 VL 19 IS 2 BP 568 EP 576 PG 9 WC Oncology SC Oncology GA 394QD UT WOS:000166534000037 PM 11208852 ER PT J AU Altfeld, M Rosenberg, ES Shankarappa, R Mukherjee, JS Hecht, FM Eldridge, RL Addo, MM Poon, SH Phillips, MN Robbins, GK Sax, PE Boswell, S Kahn, JO Brander, C Goulder, PJR Levy, JA Mullins, JI Walker, BD AF Altfeld, M Rosenberg, ES Shankarappa, R Mukherjee, JS Hecht, FM Eldridge, RL Addo, MM Poon, SH Phillips, MN Robbins, GK Sax, PE Boswell, S Kahn, JO Brander, C Goulder, PJR Levy, JA Mullins, JI Walker, BD TI Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE cytotoxic T lymphocytes; T helper cell responses; viral evolution; cytotoxic T lymphocyte epitopes; human leukocyte antigen ID IMMUNODEFICIENCY-VIRUS TYPE-1; CYTOTOXIC T-LYMPHOCYTE; ACTIVE ANTIRETROVIRAL THERAPY; FINE SPECIFICITY; VIREMIA; CELLS; PROGRESSION; EVOLUTION; EFFECTOR; LOAD AB Immune responses induced during the early stages of chronic viral infections are thought to influence disease outcome. Using HIV as a model, we examined virus-specific cytotoxic T lymphocytes (CTLs), T helper cells, and viral genetic diversity in relation to duration of infection and subsequent response to antiviral therapy. Individuals with acute HIV-1 infection treated before seroconversion had weaker CTL responses directed at fewer epitopes than persons who were treated after seroconversion. However, treatment-induced control of viremia was associated with the development of strong T helper cell responses in both groups. After 1 yr of antiviral treatment initiated in acute or early infection, all epitope-specific CTL responses persisted despite undetectable viral loads. The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy. We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population. Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses. These data also provide rationale for therapeutic immunization aimed at broadening CTL responses in treated primary HIV infection. C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02129 USA. Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Posit Hlth Program, San Francisco, CA 94143 USA. Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Fenway Community Hlth Ctr, Boston, MA 02116 USA. RP Walker, BD (reprint author), MGH E,CNY 5212,149 13th St, Charlestown, MA 02129 USA. RI Robbins, Gregory/F-7988-2011 FU NIAID NIH HHS [R01 AI040873, R01 AI044656, R01 AI30914, R01 AI44656, R37 AI028568, R37 AI28568, U01 AI041531, R01 AI030914] NR 60 TC 301 Z9 314 U1 1 U2 10 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JAN 15 PY 2001 VL 193 IS 2 BP 169 EP 180 DI 10.1084/jem.193.2.169 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 392UR UT WOS:000166431400005 PM 11148221 ER PT J AU Goulder, PJR Altfeld, MA Rosenberg, ES Nguyen, T Tang, YH Eldridge, RL Addo, MM He, SQ Mukherjee, JS Phillips, MN Bunce, M Kalams, SA Sekaly, RP Walker, BD Brander, C AF Goulder, PJR Altfeld, MA Rosenberg, ES Nguyen, T Tang, YH Eldridge, RL Addo, MM He, SQ Mukherjee, JS Phillips, MN Bunce, M Kalams, SA Sekaly, RP Walker, BD Brander, C TI Substantial differences in specificity of HIV-specific cytotoxic T cells in acute and chronic HIV infection SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE acute; chronic; HIV infection; immunodominance; epitope targeting ID IMMUNODEFICIENCY-VIRUS TYPE-1; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; PRIMARY IMMUNE-RESPONSE; CLASS-I; DISEASE PROGRESSION; EFFECTOR FUNCTION; FINE SPECIFICITY; PLASMA VIREMIA; HLA-C; EPITOPES AB Cytotoxic T lymphocytes (CTLs) play a vital part in controlling viral replication during human viral infections. Most studies in human infections have focused on CTL specificities in chronic infection and few data exist regarding the specificity of the initial CTL response induced in acute infection. In this study, HIV-I infection in persons expressing human histocompatibility leukocyte antigen (HLA)-A*0201 was used as a means of addressing this issue. In chronic infection, the dominant HLA-A*0201-restricted CTL response is directed towards the epitope SLYNTVATL ("SL9") in p17 Gag (residues 77-85). This epitope is targeted by 75% of HLA-A*0201-positive adults, and the magnitude of this A*0201-SL9 response shows a strong negative association with viral load in progressive infection. Despite using the highly sensitive peptide-major histocompatibility complex tetramer and intracellular cytokine assays, responses to the SL9 epitope were not detectable in any of 11 HLA-A*0201-positive subjects with acute HIV-1 infection (P = 2 X 10(-6)), even when assays were repeated using the SL9 peptide valiant that was encoded by their autologous virus. In contrast, multiple responses (median 3) to other epitopes were evident in 7 of the 11 A*0201-positive subjects. Longitudinal study of two subjects confirmed that the A*0201-SL9 response emerged later than other CTL responses, and after viral set point had been reached. Together, these data show that the CTL responses that are present and that even may dominate in chronic infection may differ substantially from those that constitute the initial antiviral CTL response. This finding is an important consideration in vaccine design and in the evaluation of vaccine candidates. C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA. Churchill Hosp, Oxford Transplant Ctr, Oxford OX3 7LJ, England. Clin Res Inst Montreal, Immunol Lab, Montreal, PQ H2W 1R7, Canada. RP Altfeld, MA (reprint author), Massachusetts Gen Hosp, Partners AIDS Res Ctr, 13th St,Bldg 149,Rm 5218, Charlestown, MA 02129 USA. FU NIAID NIH HHS [AI01541, AI28568, AI46995, R01 AI028568, R01 AI030914, R01 AI039966, R01 AI046995, R37 AI028568] NR 82 TC 215 Z9 218 U1 1 U2 9 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 JAN 15 PY 2001 VL 193 IS 2 BP 181 EP 193 DI 10.1084/jem.193.2.181 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 392UR UT WOS:000166431400006 PM 11148222 ER PT J AU Nikolic, B Cooke, DT Zhao, GL Sykes, M AF Nikolic, B Cooke, DT Zhao, GL Sykes, M TI Both gamma delta T cells and NK cells inhibit the engraftment of xenogeneic rat bone marrow cells and the induction of xenograft tolerance in mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PORCINE ENDOTHELIAL-CELLS; NATURAL-KILLER-CELLS; VERSUS-HOST DISEASE; NONLETHAL PREPARATIVE REGIMEN; INTRATHYMIC CLONAL DELETION; HEMATOPOIETIC STEM-CELLS; PIG THYMUS GRAFTS; HLA-G EXPRESSION; MONOCLONAL-ANTIBODIES; NEGATIVE SELECTION AB In murine allogeneic bone marrow transplantation recipients, treatment of the hosts with a nonmyeloablative regimen, including depleting anti-CD4 and anti-CD8 mAbs, allows establishment of long-term mixed chimerism and donor-specific tolerance. However, in the xenogeneic rat-to-mouse combination, additional anti-Thy1.2 and anti-NK1.1 mAbs are required. We have now attempted to identify the xenoresistant mouse cell populations that are targeted by anti-NK1.1 and anti-Thy1.2 mAbs. C57BL/6 (B6) wild-type, B6 TCR beta (-/-), and B6 TCR delta (-/-) mice received anti-CD4 and anti-CDS mAbs, followed by 3 Gy of whole body irradiation, 7 Gy of thymic irradiation, and transplantation of T cell-depleted rat bone marrow cells. Anti-NK1.1 and anti-Thy1.2 mAbs were additionally administered to some groups. Increased rat chimerism was observed in TCR delta (-/-) mice treated with anti-CD4, anti-CD8, and anti-NK1.1 mAbs compared with similarly treated TCR beta (-/-) mice. In TCR beta (-/-) mice, but not in TCR delta (-/-) mice, donor chimerism was increased by treatment with anti-Thy1.2 mAb, indicating that CD4(-)CD8(-)TCR gamma delta (+)Thy1.2(+)NK1.1(-) cells (gamma delta T cells) are involved in the rejection of rat marrow. In addition, chimerism was enhanced in both TCR beta (-/-) and TCR delta (-/-) mice treated with anti-CD4, anti-CD8, and anti-Thy1.2 mAbs by the addition of anti-NK1.1 mAb to the conditioning regimen. Donor-specific skin graft prolongation was enhanced by anti-Thy1.2 and anti-NK1.1 mAbs in TCR delta (-/-) mice. Therefore, in addition to CD4 and CD8 T cells, gamma delta T cells and NK cells play a role in resisting engraftment of rat marrow and the induction of xenograft tolerance in mice. 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 [P01 HL 18646] NR 57 TC 41 Z9 42 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 JAN 15 PY 2001 VL 166 IS 2 BP 1398 EP 1404 PG 7 WC Immunology SC Immunology GA 389VP UT WOS:000166259600085 PM 11145725 ER PT J AU Burette, A Khatri, L Wyszynski, M Sheng, M Ziff, EB Weinberg, RJ AF Burette, A Khatri, L Wyszynski, M Sheng, M Ziff, EB Weinberg, RJ TI Differential cellular and subcellular localization of AMPA receptor-binding protein and glutamate receptor-interacting protein SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cerebral cortex; pyramidal neurons; PDZ; scaffolding proteins; GluR2/3; AMPA receptors; ABP; GRIP ID LONG-TERM POTENTIATION; POSTSYNAPTIC DENSITY; HIPPOCAMPAL INTERNEURONS; CEREBRAL-CORTEX; NMDA RECEPTORS; EXCITATORY SYNAPSES; SIGNALING PATHWAYS; RAT HIPPOCAMPUS; SUBUNITS; NEURONS AB Excitatory synaptic currents in the mammalian brain are typically mediated by the neurotransmitter glutamate, acting at AMPA receptors. We used immunocytochemistry to investigate the distribution of AMPA receptor-binding protein (ABP) in the cerebral neocortex. ABP was most prominent in pyramidal neurons, although it was also present (at lower levels) in interneurons. ABP and its putative binding partners, the GluR2/3 subunits of the AMPA receptor, exhibited prominent cellular colocalization. Under appropriate processing conditions, colocalization could also be documented in puncta, many of which could be recognized as dendritic spines. However, a sizable minority of GluR2/3-positive puncta were immunonegative for ABP. Because glutamate receptor-interacting protein (GRIP) may also anchor GluR2, we studied the relative distribution of ABP and GRIP. There was extensive colocalization of these two antigens at the cellular level, although GRIP, unlike ABP, was strongest in nonpyramidal neurons. Different parts of a single dendrite could stain selectively for ABP or GRIP. To further characterize this heterogeneity, we investigated punctate staining of neuropil using synaptophysin and the membrane tracer DiA to identify probable synapses. Some puncta were comparably positive for both ABP and GRIP, but the majority were strongly positive for one antigen and only weakly positive or immunonegative for the other. This heterogeneity could be seen even within adjacent spines of a single dendrite. These data suggest that ABP may act as a scaffold for AMPA receptors either in concert with or independently from GRIP. C1 Univ N Carolina, Dept Cell Biol & Anat, Chapel Hill, NC 27599 USA. NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA. NYU, Sch Med, Dept Biochem, New York, NY 10016 USA. Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurobiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Weinberg, RJ (reprint author), Univ N Carolina, Dept Cell Biol & Anat, CB 7090, Chapel Hill, NC 27599 USA. FU NIA NIH HHS [AG13620]; NINDS NIH HHS [NS35050, NS35527] NR 42 TC 38 Z9 41 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 15 PY 2001 VL 21 IS 2 BP 495 EP 503 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 394WB UT WOS:000166545300016 PM 11160429 ER PT J AU Baskin, F Rosenberg, RN Iyer, L Schellenberg, GD Hynan, L Nee, LE AF Baskin, F Rosenberg, RN Iyer, L Schellenberg, GD Hynan, L Nee, LE TI Platelet APP isoform ratios in asymptomatic young adults expressing an AD-related presenilin-1 mutation SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE Alzheimer amyloid precursor protein (APP); platelets; presenilin 1 (PS1) ID AMYLOID PROTEIN-PRECURSOR; ALZHEIMERS-DISEASE AB The Alzheimer's disease (AD) related amyloid precursor protein (APP) is stored, cleaved and released similarly from neurons and from platelets. We have reported that the proportion of 120-130 to 110 kDa carboxyl-cleaved APP present in the platelets of AD patients is significantly lower than that of platelets of age-matched controls. This reduced APP isoform ratio, not seen in several other disease groups, is further reduced as the severity of AD increases. Since the neuropathology of AD is believed to begin many years before the onset of cognitive loss, we have also compared platelet APP ratios of four pre-symptomatic young adults carrying a presenilin-1 mutation to seven siblings homozygous for the normal PS-1 gene in an effort to determine whether reduced APP ratios are present before apparent cognitive loss in familial AD. Decreased platelet APP ratios were not seen in any of these subjects at this time. We will continue to monitor these subjects as they near the mean age of AD onset in these families. As the magnitude of the APP ratio reduction is proportional to the severity of cognitive loss in sporadic AD, these cognitively normal incipient AD subjects would not be expected to present significant reductions in this AD severity index at this time. Alternatively, the absence of platelet APP ratio reductions may result from a failure of platelets from familial PS-I AD subjects to manifest altered APPs, as has been reported for PS-2 AD subjects, unlike those of sporadic AD patients. Continued monitoring of cognitive status in our sub-set of controls with AD-like low APP ratios may yet validate the ability of this assay to detect incipient sporadic AD. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Univ Texas, SW Med Ctr, Dept Neurol, Dallas, TX 75390 USA. Univ Washington, Dept Neurol, Seattle, WA 98108 USA. Vet Affairs Puget Sound Hlth Care Syst, Seattle Div, Ctr Geriatr Res Educ & Clin, Seattle, WA 98108 USA. Univ Texas, SW Med Ctr, Dept Acad Comp Serv, Dallas, TX 75390 USA. NINDS, Family Studies Unit, Bethesda, MD 20892 USA. RP Baskin, F (reprint author), Univ Texas, SW Med Ctr, Dept Neurol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. OI Hynan, Linda/0000-0002-4642-7769 FU NIA NIH HHS [AG-05136, P30AG-12300] NR 22 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD JAN 15 PY 2001 VL 183 IS 1 BP 85 EP 88 DI 10.1016/S0022-510X(00)00483-4 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 401VZ UT WOS:000166950500015 PM 11166800 ER PT J AU Masellis, M Basile, VS Meltzer, HY Lieberman, JA Sevy, S Goldman, DA Hamblin, MW Macciardi, FM Kennedy, JL AF Masellis, M Basile, VS Meltzer, HY Lieberman, JA Sevy, S Goldman, DA Hamblin, MW Macciardi, FM Kennedy, JL TI Lack of association between the T -> C 267 serotonin 5-MT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE clozapine response; pharmacogenetic; polymorphism; serotonin receptor ID HALOPERIDOL-INDUCED CATALEPSY; 5-HT2A RECEPTOR; CLINICAL-RESPONSE; TOURETTES-SYNDROME; ALLELIC VARIATION; NO EVIDENCE; RFLP; DISORDERS; EXCLUSION; 8-OH-DPAT AB The affinity of clozapine for 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, and 5-HT1A receptors has been suggested to contribute to various aspects of its complex clinical actions. This study examined the hypothesis that genetic variation in 5-HT1A, 5-HT6, and 5-HT7 receptor genes is involved in the variability observed in response to clozapine. We employed a pharmacogenetic approach in a group (n=185) of schizophrenia patients that have been clinically well characterized for clozapine response. Polymorphisms in the 5-HT6 (HTR6), 5-MT1A (HTR6) and 5-HT7 (HTR7) receptor genes were genotyped. No evidence for either an allelic or genotypic association of the T-->C 267 HTR6 polymorphism with response to clozapine was found in our sample (allele: chi (2)=0.06, 1 df, P=0.80; genotype: chi (2)=1.21. 2 df, P=0.55), The pro161eu HTR1A polymorphism was not observed in our sample: all individuals genotyped were pro/pro 16 homozygotes, With respect to the pro279leu HTR7 polymorphism, one Caucasian male responder to clozapine was observed to be heterozygous (pro/leu 279 genotype), This individual was clinically similar to the other clozapine responders. Overall, our findings do not support a role for the T-->C 267 polymorphism of the 5-HT6 receptor gene in response to clozapine, although replication is required to confirm this finding. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Univ Toronto, Ctr Addict & Mental Hlth, Clarke Div, Neurogenet Sect, Toronto, ON M5T 1R8, Canada. Vanderbilt Univ, Dept Psychiat, Nashville, TN USA. Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. Bronx Vet Adm Med Ctr, Dept Vet Affairs, New York, NY USA. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. Univ Washington, VA Puget Sound Hlth Care Syst, GRECC, Seattle, WA 98195 USA. Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Kennedy, JL (reprint author), Univ Toronto, Ctr Addict & Mental Hlth, Clarke Div, Neurogenet Sect, 100 Coll St, Toronto, ON M5T 1R8, Canada. RI Meltzer, Herbert/E-8131-2013; Macciardi, Fabio/N-3768-2014; Goldman, David/F-9772-2010 OI Macciardi, Fabio/0000-0003-0537-4266; Goldman, David/0000-0002-1724-5405 NR 63 TC 62 Z9 63 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JAN 15 PY 2001 VL 47 IS 1 BP 49 EP 58 DI 10.1016/S0920-9964(00)00016-5 PG 10 WC Psychiatry SC Psychiatry GA 400CY UT WOS:000166852100005 PM 11163544 ER PT J AU Cserhalmi-Friedman, PB Olson, PF Koch, M Champliaud, MF Brunken, WJ Burgeson, RE Christiano, AM AF Cserhalmi-Friedman, PB Olson, PF Koch, M Champliaud, MF Brunken, WJ Burgeson, RE Christiano, AM TI Structural analysis and mutation detection strategy for the human LamC3 gene SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID CONGENITAL MUSCULAR-DYSTROPHY; LAMININ LAMININ BETA-2; CHAIN AB Laminins are heterotrimeric extracellular matrix molecules, present in a wide range of basement membranes within human tissues. They consist of a combination of different alpha, beta, and gamma subunits. Three different gamma subunits have been described to date. Two of them, the gamma1 and gamma2 chains are constituents of basement membrane related laminins, while the gamma3 chain was detected in skin, heart, lung, reproductive tract, brain, and in the retina. Unlike other laminins, the expression of the gamma3 chain was localized to peripheral nerves and to the apical surface of ciliated epithelial cells and in the retina. To further investigate the function and the possible pathogenic role of laminin gamma3 in human disease, we elucidated the structure of the corresponding LAMC3 gene which encodes this polypeptide. Here we report the genomic organization of the LAMC3 gene and a mutation detection strategy for use in genetic studies. (C) 2001 Academic Press. C1 Columbia Univ, Dept Dermatol, New York, NY 10032 USA. Columbia Univ, Dept Genet & Dev, New York, NY 10032 USA. Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Dermatol, Charlestown, MA 02129 USA. RP Cserhalmi-Friedman, PB (reprint author), Columbia Univ, Dept Dermatol, 630 W 168th St VC-1526, New York, NY 10032 USA. OI Brunken, William J/0000-0001-7330-1814 FU NINDS NIH HHS [R01 NS039502-03, R01 NS039502] NR 14 TC 2 Z9 2 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 JAN 12 PY 2001 VL 280 IS 1 BP 39 EP 44 DI 10.1006/bbrc.2000.4086 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 392HB UT WOS:000166404700008 PM 11162474 ER PT J AU Tang, D Xie, Y Zhao, MJ Stevenson, MA Calderwood, SK AF Tang, D Xie, Y Zhao, MJ Stevenson, MA Calderwood, SK TI Repression of the HSP70B promoter by NFIL6, Ku70, and MAPK involves three complementary mechanisms SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE heat shock factor 1 (HSF1); heat shock protein 70 (HSP70); nuclear factor of interleukin-6 (NF-IL6); Ku70 protein; mitogen-activated protein kinase (MAPK); gene repression ID HEAT-SHOCK FACTOR; EXPRESSION; GENE; AUTOANTIGEN; CLONING AB We have studied mechanisms of HSP70 gene regulation at 37 degreesC by the cellular factors NF-IL6 and Ku70. As both factors repress HSF1, we first examined whether phosphorylation on serine 303 and 307 of HSF1 by MAPK and GSK3, which has known to inhibit HSF1, was involved in the repression. However, repression by NF-IL6 was found using HSF1 mutants S303G and S307G refractory to the effects of MAPK and GSK3. We then examined whether NF-IL6 repressed HSP 70B by a mechanism resembling Ku proteins. However, in Ku-deficient cells, NF-IL6 was still able to displace HSF1 from heat shock element (HSE) and repressed HSF1 activation. In addition, activation of the HSP70B promoter by wild type, S303G, or S307G HSF1 was observed to be much more pronounced in Ku-deficient cells. In vitro translated Ku70 interacted with HSF1 by binding to and displacing it from HSE. These data indicate that the repression of the HSP70B promoter by NF-IL6, Ku70, and MAPK occurs independently of each other and involves three complementary mechanisms. (C) 2000 Academic Press. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02115 USA. RP Calderwood, SK (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, 44 Binney St,Dana Room 810, Boston, MA 02115 USA. FU NCI NIH HHS [CA 47407, CA 31303, CA 80642] NR 14 TC 12 Z9 15 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 JAN 12 PY 2001 VL 280 IS 1 BP 280 EP 285 DI 10.1006/bbrc.2000.4118 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 392HB UT WOS:000166404700045 PM 11162511 ER PT J AU Guzman-Marin, R Alam, MN Mihailescu, S Szymusiak, R McGinty, D Drucker-Colin, R AF Guzman-Marin, R Alam, MN Mihailescu, S Szymusiak, R McGinty, D Drucker-Colin, R TI Subcutaneous administration of nicotine changes dorsal raphe serotonergic neurons discharge rate during REM sleep SO BRAIN RESEARCH LA English DT Article DE nicotine; serotonergic neuron; dorsal raphe nucleus; REM-off neuron; single-unit recording ID DEPRESSION; RECEPTOR; NUCLEI; CATS AB In the present study nicotine (0.1 mg/kg, s.c.) increased discharge rate of putative dorsal raphe (DRN) serotonergic neurons of behaving rats during REM sleep (362.61%), without any significant change during waking and non-REM sleep. Since serotonergic DRN neurons gate PGO onset, these results suggest that nicotine-induced suppression of PGO spikes during REM sleep previously reported is achieved through stimulation of dorsal raphe serotonergic cells. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Fac Med, Dept Fisiol, Mexico City 04510, DF, Mexico. Vet Affairs Greater Los Angeles HealthCare Syst, N Hills, CA 91343 USA. Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA USA. Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Dept Neurociencias, Mexico City 04510, DF, Mexico. RP Drucker-Colin, R (reprint author), Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Fac Med, Dept Fisiol, AP 70-250, Mexico City 04510, DF, Mexico. NR 21 TC 17 Z9 19 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 JAN 12 PY 2001 VL 888 IS 2 BP 321 EP 325 DI 10.1016/S0006-8993(00)03104-8 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 392TD UT WOS:000166427900018 PM 11150492 ER PT J AU Sheng, SH Li, JQ McNulty, KA Kieber-Emmons, T Kleyman, TR AF Sheng, SH Li, JQ McNulty, KA Kieber-Emmons, T Kleyman, TR TI Epithelial sodium channel pore region - Structure and role in gating SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SENSITIVE NA+ CHANNEL; CAENORHABDITIS-ELEGANS; CYSTEINE MUTAGENESIS; POTASSIUM CHANNEL; K+-CHANNEL; MEMBRANE TOPOLOGY; MOLECULAR-BASIS; ION PERMEATION; ALPHA-SUBUNIT; SELECTIVITY AB Epithelial sodium channels (ENaC) have a crucial role in the regulation of extracellular fluid volume and blood pressure. To study the structure of the pore region of ENaC, the susceptibility of introduced cysteine residues to sulfhydryl-reactive methanethiosulfonate derivatives ((a-aminoethyl)methanethiosulfonate hydrobromide (MTSEA) and [(2-(trimethylammonium)ethyl]methanethiosulfonate bromide (MTSET)) and to Cd2+ was determined. Selected mutants within the amino-terminal portion (alpha Val(569)-alpha Trp(582)) of the pore region responded to MTSEA, MTSET, or Cd2+ with stimulation or inhibition of whole cell Na+ current. The reactive residues were not contiguous but were separated by 23 residues where substituted cysteine residues did not respond to the reagents and line one face of an cu-helix. The activation of (alpha S580C beta gamma mENaC by MTSET was associated with a large increase in channel open probability. Within the carboxyl-terminal portion (alpha Ser(583)-alpha Ser(592)) of the pore region, only one mutation (alpha S583C) conferred a rapid, nearly complete block by MTSEA, MTSET, and Cd2+, whereas several other mutant channels were partially blocked by MTSEA or Cd2+ but not by MTSET. Our data suggest that the outer pore of ENaC is formed by an cr-helix, followed by an extended region that forms a selectivity filter. Furthermore, our data suggest that the pore region participates in ENaC gating. C1 Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Physiol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Pathol, Philadelphia, PA 19104 USA. Dept Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. RP Kleyman, TR (reprint author), Div Renal, A919 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15213 USA. OI Sheng, Shaohu/0000-0002-7198-1702 FU NIDDK NIH HHS [DK50268, DK54354] NR 45 TC 43 Z9 44 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 JAN 12 PY 2001 VL 276 IS 2 BP 1326 EP 1334 DI 10.1074/jbc.M008117200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 392UL UT WOS:000166430900064 PM 11022046 ER PT J AU Fernandez, M Pissiota, A Frans, O von Knorring, L Fischer, H Fredrikson, M AF Fernandez, M Pissiota, A Frans, O von Knorring, L Fischer, H Fredrikson, M TI Brain function in a patient with torture related post-traumatic stress disorder before and after fluoxetine treatment: a positron emission tomography provocation study SO NEUROSCIENCE LETTERS LA English DT Article DE torture; anxiety; fear; positron emission tomography; neuroimaging; regional cerebral blood-flow ID CEREBRAL BLOOD-FLOW; CHILDHOOD SEXUAL ABUSE; SCRIPT-DRIVEN IMAGERY; PET; NEUROANATOMY; MEMORIES; PTSD; FEAR AB We report positron emission tomographic measurements of regional cerebral blood flow (rCBF) in a male patient with war and torture related post-traumatic stress disorder (PTSD) du ring symptom provocation. The subject was exposed to war related sounds before and after treatment with a selective serotonin reuptake inhibitor (SSRI; Fluoxetine; Fontex(R)). Therapy reduced PTSD symptoms, provoked anxiety and heart rate. Before treatment trauma reminders resulted in decreased rCBF in the insula, prefrontal, and inferior frontal cortices. Increased activity was evident in the cerebellum, precuneus and supplementary motor cortex. This was normalized after SSRI administration. Prefrontal and cingulate rCBF correlated with heart rate. Hence, the anxiolytic effect of SSRI for PTSD could be mediated by prefrontal and paralimbic cortices. Data suggest that SSRI treatment normalize provocation induced rCBF alterations in areas involved in memory, emotion, attention and motor-control. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Dept Psychol, SE-75142 Uppsala, Sweden. Univ Uppsala Hosp, Dept Neurosci Psychiat, Uppsala, Sweden. Massachusetts Gen Hosp, Psychiat Neuroimaging Grp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Uppsala Univ, PET Ctr, Uppsala, Sweden. RP Fredrikson, M (reprint author), Dept Psychol, Box 1225, SE-75142 Uppsala, Sweden. RI von Knorring, Lars/D-2125-2010 NR 25 TC 63 Z9 66 U1 0 U2 6 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JAN 12 PY 2001 VL 297 IS 2 BP 101 EP 104 DI 10.1016/S0304-3940(00)01674-8 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 389CK UT WOS:000166220900010 PM 11121880 ER PT J AU Inskip, PD Tarone, RE Hatch, EE Wilcosky, TC Shapiro, WR Selker, RG Fine, HA Black, PM Loeffler, JS Linet, MS AF Inskip, PD Tarone, RE Hatch, EE Wilcosky, TC Shapiro, WR Selker, RG Fine, HA Black, PM Loeffler, JS Linet, MS TI Cellular-telephone use and brain tumors SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MOBILE COMMUNICATION; EXPOSURE; HEAD; RADIATION; PHONE; RISK; SAR AB Background: Concern has arisen that the use of hand-held cellular telephones might cause brain tumors. If such a risk does exist, the matter would be of considerable public health importance, given the rapid increase worldwide in the use of these devices. Methods: We examined the use of cellular telephones in a case-control study of intracranial tumors of the nervous system conducted between 1994 and 1998. We enrolled 782 patients through hospitals in Phoenix, Arizona; Boston; and Pittsburgh; 489 had histologically confirmed glioma, 197 had meningioma, and 96 had acoustic neuroma. The 799 controls were patients admitted to the same hospitals as the patients with brain tumors for a variety of nonmalignant conditions. Results: As compared with never, or very rarely, having used a cellular telephone, the relative risks associated with a cumulative use of a cellular telephone for more than 100 hours were 0.9 for glioma (95 percent confidence interval, 0.5 to 1.6), 0.7 for meningioma (95 percent confidence interval, 0.3 to 1.7), 1.4 for acoustic neuroma (95 percent confidence interval, 0.6 to 3.5), and 1.0 for all types of tumors combined (95 percent confidence interval, 0.6 to 1.5). There was no evidence that the risks were higher among persons who used cellular telephones for 60 or more minutes per day or regularly for five or more years. Tumors did not occur disproportionately often on the side of head on which the telephone was typically used. Conclusions: These data do not support the hypothesis that the recent use of hand-held cellular telephones causes brain tumors, but they are not sufficient to evaluate the risks among long-term, heavy users and for potentially long induction periods. (N Engl J Med 2001;344:79-86.) Copyright (C) 2001 Massachusetts Medical Society. C1 NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Neurooncol Branch, Bethesda, MD 20892 USA. Res Triangle Inst, Epidemiol & Med Studies Program, Res Triangle Pk, NC 27709 USA. St Josephs Hosp & Med Ctr, Barrow Neurol Inst, Dept Neurol, Phoenix, AZ USA. Western Penn Hosp, Div Neurosurg, Pittsburgh, PA 15224 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Inskip, PD (reprint author), Execut Plaza S,Rm 7052,6120 Execut Blvd, Rockville, MD 20852 USA. NR 40 TC 273 Z9 290 U1 11 U2 44 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 JAN 11 PY 2001 VL 344 IS 2 BP 79 EP 86 DI 10.1056/NEJM200101113440201 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 390DU UT WOS:000166281100001 PM 11150357 ER PT J AU Wong, IHN Yeo, WN Chan, AT Johnson, PJ AF Wong, IHN Yeo, WN Chan, AT Johnson, PJ TI Quantitative relationship of the circulating tumor burden assessed by reverse transcription-polymerase chain reaction for cytokeratin 19 mRNA in peripheral blood of colorectal cancer patients with Dukes' stage, serum carcinoembryonic antigen level and tumor progression SO CANCER LETTERS LA English DT Article DE semi-quantitative reverse transcription-polymerase chain reaction; cytokeratin 19 mRNA; serum carcinoembryonic antigen; tumor stage; metastasis/recurrence ID MESSENGER-RNA; BREAST-CANCER; BONE-MARROW; HEPATOCELLULAR-CARCINOMA; GASTROINTESTINAL CANCER; GENE FAMILY; CELL-LINES; PLASMA DNA; IDENTIFICATION; DISSEMINATION AB We prospectively analyzed the circulating tumor burden in colorectal cancer patients using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) for carcinoembryonic antigen (CEA) and cytokeratin 19 (CK19). We distinguished the mRNA levels in peripheral blood between 33 patients and 26 healthy controls with reference to SK-BR-3 cell line. We found CEA-mRNA in 88% of patients and 92% of controls, and CK19 mRNA in 64% of patients and 19% of controls. Our CK19 mRNA assay was sufficiently sensitive to detect one SK-BR-3 cell among 106 normal blood cells. The upper limit of CK19 mRNA among controls was exceeded by 14 patients, and 12 patients (86%) developed systemic metastases/recurrence. Significantly elevated CK19 mRNA levels appeared to originate from circulating malignant cells (P < 0.0001). Of relevance, the CK19 mRNA level increased with advancing Dukes' stage and correlated directly with the serum CEA level (P = 0.016). CK19 mRNA quantification may prove valuable for cancer staging and disease monitoring. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Chinese Univ Hong Kong, Prince Wales Hosp, Dept Anat & Cellular Pathol, Shatin, Hong Kong, Peoples R China. Chinese Univ Hong Kong, Prince Wales Hosp, Dept Clin Oncol, Shatin, Hong Kong, Peoples R China. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Wong, IHN (reprint author), Chinese Univ Hong Kong, Prince Wales Hosp, Dept Anat & Cellular Pathol, Shatin, Hong Kong, Peoples R China. NR 35 TC 36 Z9 38 U1 0 U2 6 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD JAN 10 PY 2001 VL 162 IS 1 BP 65 EP 73 DI 10.1016/S0304-3835(00)00630-3 PG 9 WC Oncology SC Oncology GA 428BA UT WOS:000168440200009 PM 11121864 ER PT J AU Chiara, DC Kloczewiak, MA Addona, GH Yu, JA Cohen, JB Miller, KW AF Chiara, DC Kloczewiak, MA Addona, GH Yu, JA Cohen, JB Miller, KW TI Site of resting state inhibition of the nicotinic acetylcholine receptor by a hydrophobic inhibitor SO BIOCHEMISTRY LA English DT Article ID NONCOMPETITIVE ANTAGONIST; BINDING-SITE; AMINO-ACIDS; PROTEINS; TETRACAINE; IDENTIFICATION; REGIONS AB The lipophilic photoactivatable probe 3-(trifluoromethyl)-3-(m-iodophenyl) diazirine (TID) is a noncompetitive, resting-state inhibitor of the nicotinic acetylcholine receptor (nAChR) that requites tens of milliseconds of preincubation to inhibit agonist-induced cation efflux. At equilibrium, [I-125]TID photoincorporates into both the ion channel and the lipid-protein interface of the Torpedo nAChR. To determine which of these regions is responsible for resting-state inhibition, we characterized the interactions between [I-125]TID and nAChR-rich membranes milliseconds after mixing, by use of time-resolved photolabeling. Photolabeling was performed after preincubation times of 2 ms or 600 s (equilibrium), and the efficiencies of incorporation at specific residues were determined by amino-terminal sequence analysis of nAChR-subunit proteolytic fragments isolated by SDS-PAGE and/or reversed-phase HPLC. Equilibration of TID with lipid was complete within a millisecond as determined by both stopped-flow fluorescence quenching of diphenylhexatriene in lipid bilayers and photoincorporation into nAChR-rich membrane phospholipids. Equilibration with the lipid-protein interface (alpha M4) was slightly slower, reaching similar to 50% that at equilibrium after 2 ms preincubation, In contrast, equilibration with the channel region (alpha M2 and delta M2) was much slower, reaching only 10% that at equilibrium after 2 ms preincubation, Within the ion channel, the ratio of [I-125]TID incorporation between M2 residues 9', 13', and 16' was independent of preincubation time. We conclude that TID's access to the ion channel is more restricted than to the lipid-protein inter face and that TID bound within the ion channel is responsible for flux inhibition upon activation of the nAChR. C1 Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Miller, KW (reprint author), Harvard Univ, Sch Med, Dept Neurobiol, 220 Longwood Ave, Boston, MA 02115 USA. FU NIGMS NIH HHS [GM 15904, GM 58448] NR 24 TC 14 Z9 14 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 9 PY 2001 VL 40 IS 1 BP 296 EP 304 DI 10.1021/bi0021481 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 391ZD UT WOS:000166385400035 PM 11141083 ER PT J AU Freedman, R Leonard, S Gault, JM Hopkins, J Cloninger, CR Kaufmann, CA Tsuang, MT Farone, SV Malaspina, D Svrakic, DM Sanders, A Gejman, P AF Freedman, R Leonard, S Gault, JM Hopkins, J Cloninger, CR Kaufmann, CA Tsuang, MT Farone, SV Malaspina, D Svrakic, DM Sanders, A Gejman, P TI Linkage disequilibrium for schizophrenia at the chromosome 15q13-14 locus of the alpha 7-nicotinic acetylcholine receptor subunit gene (CHRNA7) SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE human chromosome pair 15; genetic linkage; nicotinic receptor; polymorphism; schizophrenia ID NO EVIDENCE; TDT AB The transmission/disequilibrium test was used for fine mapping of the linkage of schizophrenia to the chromosome 15q13-14 region, the site of a candidate gene, the alpha7 nicotinic acetylcholine receptor subunit gene (CHRNA7), in parent-child triads from the NIMH Schizophrenia Genetics Initiative families. This candidate gene was identified from neurobiological studies of deficits in schizophrenics of the inhibitory gating of the P50 auditory evoked potential. The neurobiological deficit was also used as a phenotype for subsequent linkage analysis. In the present study, significant genotype-wise disequilibrium (P < 0.007) was found at D15S165, a polymorphic simple sequence marker physically located within 1 megabase of both CHRNA7 and a partially duplicated, expressed sequence that includes exons 5-10 of CHRNA7, Replication of this result was found in an additional set of families. The results support this region as a chromosomal location involved in the genetic transmission of schizophrenia. Am. J, Med, Genet, (Neuropsychiatr,Genet,) 105: 20-22, 2001, (C) 2001 Wiley-Liss, Inc. C1 Univ Colorado, Hlth Sci Ctr, Dept Pharmacol, Denver, CO 80262 USA. Denver VA Med Ctr, Denver, CO USA. NIMH, Schizophrenia Genet Initiat, Bethesda, MD 20892 USA. Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. Univ Colorado, Hlth Sci Ctr, Dept Psychiat, Denver, CO 80262 USA. RP Freedman, R (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Psychiat C268 71, 4200 E 9th Ave, Denver, CO 80262 USA. RI Cloninger, Claude/F-5357-2012 OI Cloninger, Claude/0000-0003-3096-4807 FU NIDA NIH HHS [DA09457]; NIMH NIH HHS [MH38321] NR 17 TC 137 Z9 142 U1 0 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD JAN 8 PY 2001 VL 105 IS 1 BP 20 EP 22 DI 10.1002/1096-8628(20010108)105:1<20::AID-AJMG1047>3.3.CO;2-3 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 390GA UT WOS:000166286300006 PM 11424985 ER PT J AU D'Elia, JA Weinrauch, LA Gleason, RE Lipinska, I Keough, J Pendse, S Roshan, B Lee, AT Tofler, GH AF D'Elia, JA Weinrauch, LA Gleason, RE Lipinska, I Keough, J Pendse, S Roshan, B Lee, AT Tofler, GH TI Fibrinogen and factor VII levels improve with glycemic control in patients with type 1 diabetes mellitus who have microvascular complications SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID FIBRINOLYTIC-ACTIVITY; HEART-DISEASE; INSULIN; PROTEINURIA; NEPHROPATHY; MORTALITY; HUMANS AB To determine whether the hypercoagulable state of patients with complications of diabetes can be reversed toward normal, a group of insulin-dependent individuals with proteinuria was treated with intensive insulin protocols. A statistically significant (P<.001) improvement in control of diabetes was achieved (mean+/-SEM glycosylated hemoglobin, 9.51%+/-0.35% at baseline to 8.36%+/-0.39% at 12 months; and mean+/-SEM advanced glycosylated end products, 14.8+/-2.8 U/mL at baseline to 8.4+/-1.5 U/mL at 12 months). There were statistically significant decreases in 2 procoagulant factors: mean+/-SEM baseline elevated plasma factor VII, 128.69%+/-5.63% at baseline to 106.24%+/-3.43% at 12 months (P = .002); and mean+/-SEM plasma fibrinogen, 12.3+/-0.7 mol/L (417.3+/-24.7 mg/dL) at baseline to 10.2+/-0.7 mu mol/L (348.8+/-22.6 mg/dL) at 12 months (P = .04). Throughout the study, lipid fractions did not change significantly. Because plasma factor VII and fibrinogen concentrations were elevated while cholesterol and triglyceride concentrations were not, more attention should be paid to procoagulants as markers for thromboembolic complications in diabetic patients undergoing intensive insulin therapy. C1 Joslin Diabet Ctr, John Cook Renal Unit, Boston, MA 02215 USA. Mt Auburn Hosp, Clin Res Sect, Cambridge, MA 02238 USA. Beth Israel Deaconess Med Ctr, Inst Prevent Cardiovasc Dis, Boston, MA 02215 USA. Brigham & Womens Hosp, Endocrine Hypertens Unit, Biostat Sect, Boston, MA 02115 USA. Picower Inst Med Res, Manhasset, NY USA. Harvard Univ, Sch Med, Boston, MA USA. RP D'Elia, JA (reprint author), 1 Joslin Pl, Boston, MA 02215 USA. OI Weinrauch, Larry/0000-0003-1357-9528 NR 27 TC 7 Z9 8 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 JAN 8 PY 2001 VL 161 IS 1 BP 98 EP 101 DI 10.1001/archinte.161.1.98 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 387LN UT WOS:000166124200011 PM 11146704 ER PT J AU Fechner, FP Nadol, JB Burgess, BJ Brown, MC AF Fechner, FP Nadol, JB Burgess, BJ Brown, MC TI Innervation of supporting cells in the apical turns of the guinea pig cochlea is from type II afferent fibers SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE outer hair cell; spiral ganglion cell; organ of Corti; Hensen's cells; Deiters' cells ID SPIRAL GANGLION; HORSERADISH-PEROXIDASE; GOLGI METHOD; ADULT CATS; NEURONS; MORPHOLOGY; MECHANISMS; DEITERS; NERVE; LIGHT AB The outer supporting cells in the apical turns of the guinea pig cochlea receive a dense innervation. Our previous study (Fechner et al. [1998] J. Comp. Neurol. 400:299-300) suggested that this innervation of the Deiters' and Hensen's supporting cells was not derived from efferent fibers of the olivocochlear bundle, but its origin has not been further specified. To test the hypothesis that the innervation was afferent in origin, we traced apical afferent fibers that were retrogradely labeled by extracellular injections of horseradish peroxidase. Labeled afferent fibers were of two types: type I fibers contacted inner hair cells, whereas type II fibers crossed the tunnel and contacted outer hair cells. Significantly, most of the type II fibers also formed branches to the outer supporting cells. Although a few olivocochlear efferent fibers formed such branches, counts indicated that the overwhelming majority of the branches were produced by type II afferent fibers. These branches were not produced by basal type LI fibers. Apical type II fibers also differed from basal fibers by having shorter lengths, spiraling both apically and basally, and contacting all three rows of outer hair cells. These innervation differences suggest differences in the ways that information from outer hair cells is processed in the apex versus the base of the cochlea. J. Comp. Neurol. 429:289-298, 2001. (C) 2001 Wiley-Liss, Inc. C1 Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. Harvard MIT Div Hlth Sci & Technol, Boston, MA 02114 USA. RP Brown, MC (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. FU NIDCD NIH HHS [5T32 DC00020, 5RO1 DC000152, 5RO1 DC01089] NR 35 TC 26 Z9 28 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD JAN 8 PY 2001 VL 429 IS 2 BP 289 EP 298 DI 10.1002/1096-9861(20000108)429:2<289::AID-CNE9>3.0.CO;2-Z PG 10 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 379LA UT WOS:000165642500009 PM 11116221 ER PT J AU Sinnaeve, P Chiche, JD Nong, ZX Varenne, O Van Pelt, N Gillijns, H Collen, D Bloch, KD Janssens, S AF Sinnaeve, P Chiche, JD Nong, ZX Varenne, O Van Pelt, N Gillijns, H Collen, D Bloch, KD Janssens, S TI Soluble guanylate cyclase alpha(1) and beta(1) gene transfer increases NO responsiveness and reduces neointima formation after balloon injury in rats via antiproliferative and antimigratory effects SO CIRCULATION RESEARCH LA English DT Article DE cyclic GMP; soluble guanylate cyclase; nitric oxide; adenovirus; gene therapy ID SMOOTH-MUSCLE CELLS; NITRIC-OXIDE SYNTHASE; DEPENDENT PROTEIN-KINASE; CAROTID-ARTERY; IN-VIVO; INTIMAL HYPERPLASIA; ANGIOTENSIN-II; EXPRESSION; PROLIFERATION; CGMP AB In vascular smooth muscle cells, NO stimulates the synthesis of cGMP by soluble guanylate cyclase (sGC), a heterodimer composed of alpha (1) and beta (1) subunits, NO/cGMP signal transduction affects multiple cell functions that contribute to neointima formation after Vascular injury. Balloon-induced vascular injury was found to decrease sGC subunit expression and enzyme activity in rat carotid arteries. The effect of restoring sGC enzyme activity on neointima formation was investigated using recombinant adenoviruses specifying sGC alpha (1) and beta (1) subunits (Ad alpha1 and Ad beta1). Coinfection of cultured rat aortic smooth muscle cells with Ad alpha1 and Ad beta1 increased NO-stimulated intracellular cGMP levels 60-fold and decreased DNA synthesis and migration by 16% and 48%, respectively. Immunoreactivity for alpha (1) and beta (1) subunits colocalized in carotid arteries infected with Ad alpha1 and Ad beta1. Molsidomine-stimulated carotid tissue cGMP levels were greater after coinfection with Ad alpha1 and Ad beta1 than after infection with a control virus, AdRR5 (0.53 +/- 0.09 pmol/mg protein, mean+/-SEM, versus 0.23+/-0.09, P<0.05). Mean intima/media ratio, 2 weeks after balloon injury and twice-daily administration of 5 mg/kg molsidomine, was less in rats coinfected with Ad1 and Ad beta1 than in rats infected with AdRR5 or in uninfected rats (0.36+/-0.11 versus 0.81+/-0.13 and 0.75+/-0.25, respectively, P<0.05). Thus, Ad1 and Ad beta1 gene transfer to balloon-injured rat carotid arteries increases NO responsiveness and attenuates neointima formation via a direct antiproliferative and antimigratory effect on vascular smooth muscle cells. C1 Katholieke Univ Leuven VIB, Ctr Transgene Technol & Gene Therapy, Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. Katholieke Univ Leuven, Univ Hosp Gasthuisberg, Cardiac Unit, B-3000 Louvain, Belgium. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med Div Cardiol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. RP Janssens, S (reprint author), Katholieke Univ Leuven, Cardiac Unit, Campus Gasthuisberg,Herestr 49, B-3000 Louvain, Belgium. EM stefan.janssens@med.kuleuven.ac.be FU NHLBI NIH HHS [HL57172] NR 35 TC 35 Z9 36 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JAN 5 PY 2001 VL 88 IS 1 BP 103 EP 109 PG 7 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 412NZ UT WOS:000167562400019 PM 11139481 ER PT J AU Harrington, RH Sharma, A AF Harrington, RH Sharma, A TI Transcription factors recognizing overlapping C1-A2 binding sites positively regulate insulin gene expression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BETA-CELL LINE; NF-KAPPA-B; HOMEODOMAIN PROTEIN; TRANSGENIC MICE; II GENE; PANCREATIC MESENCHYME; GLUCOSE-CONCENTRATION; CHRONIC EXPOSURE; CONTROL ELEMENT; ISLET CELLS AB Transcription factors binding the insulin enhancer region, RIPE3b, mediate beta -cell type-specific and glucose-responsive expression of the insulin gene. Earlier studies demonstrate that activator present in the beta -cell-specific RIPE3b1-binding complex is critical for these actions. The DNA binding activity of the RIPE3b1 activator is induced in response to glucose stimulation and is inhibited under glucotoxic conditions. The C1 element within the RIPE3b region has been implicated as the binding site for RIPE3b1 activator. The RTPE3b region also contains an additional element, A2, which shares homology with the A elements in the insulin enhancer. Transcription factors (PDX-1 and HNF-1 alpha) binding to A elements are critical regulators of insulin gene expression and/or pancreatic development. Hence, to understand the roles of C1 and A2 elements in regulating insulin gene expression, we have systematically mutated the RIPE3b region and analyzed the effect of these mutations on gene expression. Our results demonstrate that both C1 and A2 elements together constitute the binding site for the RIPE3b1 activator, In addition to C1-A2 (RIPE3b) binding complexes, three binding complexes that specifically recognize A2 elements are found in nuclear extracts from insulinoma cell lines; the A2.2 complex is detected only in insulin-producing cell lines. Furthermore, two base pairs in the A2 element were critical for binding of both RIPE3b1 and A2.2 activators. Transient transfection results indicate that both C1-A2 and A2-specific binding activators cooperatively activate insulin gene expression. In addition, RIPE3b1- and A2-specific activators respond differently to glucose, suggesting that their overlapping binding specificity and functional cooperation may play an important role in regulating insulin gene expression. C1 Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Sharma, A (reprint author), Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [DK-36836] NR 67 TC 19 Z9 19 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 JAN 5 PY 2001 VL 276 IS 1 BP 104 EP 113 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 390DP UT WOS:000166280700016 PM 11024035 ER PT J AU Trotti, D Aoki, M Pasinelli, P Berger, UV Danbolt, NC Brown, RH Hediger, MA AF Trotti, D Aoki, M Pasinelli, P Berger, UV Danbolt, NC Brown, RH Hediger, MA TI Amyotrophic lateral sclerosis-linked glutamate transporter mutant has impaired glutamate clearance capacity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GATED CHLORIDE CHANNEL; AMINO-ACID TRANSPORTER; RAT-BRAIN; ASPARTATE TRANSPORTER; SPINAL-CORD; GLT-1; EXPRESSION; EAAT2; GENE; ASTROCYTES AB We have investigated the functional impact of a naturally occurring mutation of the human glutamate transporter GLT1 (EAAT2), which had been detected in a patient with sporadic amyotrophic lateral sclerosis, The mutation involves a substitution of the putative N-linked glycosylation site asparagine 206 by a serine residue (N206S) and results in reduced glycosylation of the transporter and decreased uptake activity. Electrophysiological analysis of N206S revealed a pronounced reduction in transport rate compared with wild-type, but there was no alteration in the apparent affinities for glutamate and sodium. In addition, no change in the sensitivity for the specific transport inhibitor dihydrokainate was observed, However, the decreased rate of transport was associated with a reduction of the N206S transporter in the plasma membrane. Under ionic conditions, which favor the reverse operation mode of the transporter, N206S exhibited an increased reverse transport capacity. Furthermore, if coexpressed in the same cell, N206S manifested a dominant negative effect on the wild-type GLT1 activity, whereas it did not affect wild-type EAAC1, These findings provide evidence for a role of the N-linked glycosylation in both cellular trafficking and transport function. The resulting alteration in glutamate clearance capacity likely contributes to excitotoxicity that participates in motor neuron degeneration in amyotrophic lateral sclerosis. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Membrane Biol Program, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cecil B Day Lab Neuromuscular Res, Charlestown, MA 02129 USA. Univ Oslo, Inst Basic Med Sci, Dept Physiol, N-0337 Oslo, Norway. RP Hediger, MA (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Membrane Biol Program, Harvard Inst Med Bldg,Rm 570,77 Ave Louis Pasteur, Boston, MA 02115 USA. RI Danbolt, Niels Christian/A-1907-2014 OI Danbolt, Niels Christian/0000-0003-4227-4520 FU AHRQ HHS [5F32HS10064]; NIA NIH HHS [1PO1AG12992-04]; ONDIEH CDC HHS [1PO1ND31248-05]; Fondazione Telethon NR 53 TC 115 Z9 121 U1 0 U2 5 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 JAN 5 PY 2001 VL 276 IS 1 BP 576 EP 582 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 390DP UT WOS:000166280700078 PM 11031254 ER PT J AU Pedraza-Alva, G Sawasdikosol, S Liu, YC Merida, LB Cruz-Munoz, ME Oceguera-Yanez, F Burakoff, SJ Rosenstein, Y AF Pedraza-Alva, G Sawasdikosol, S Liu, YC Merida, LB Cruz-Munoz, ME Oceguera-Yanez, F Burakoff, SJ Rosenstein, Y TI Regulation of Cbl molecular interactions by the co-receptor molecule CD43 in human T cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHOTYROSINE-BINDING DOMAIN; GROWTH-FACTOR RECEPTOR; PROTEIN-KINASE-C; PROTOONCOGENE PRODUCT; TYROSINE PHOSPHORYLATION; SIGNAL-TRANSDUCTION; IN-VIVO; PHOSPHATIDYLINOSITOL 3-KINASE; MONOCLONAL-ANTIBODY; NEGATIVE REGULATOR AB CD43, one of the most abundant glycoproteins on the T cell surface, has been implicated in selection and maturation of thymocytes and migration, adhesion, and activation of mature T cells. The adapter molecule Cbl has been shown to be a negative regulator of Pas, Furthermore, it may also regulate intracellular signaling through the formation of several multi-molecular complexes. Here we investigated the role of Cbl in the CD43-mediated signaling pathway in human T cells. Unlike T cell receptor signaling, the interaction of the adapter protein Cbl with Vav and phosphatidylinositol 3-kinase, resulting from CD QS-specific signals, is independent of Cbl tyrosine phosphorylation, suggesting an alternative mechanism of interaction. CD43 signals induced a Cbl serine phosphorylation-dependent interaction with the tau -isoform of 14-3-3. protein. Protein kinase C-mediated Cbl serine phosphorylation was required for this interaction, because the PKC inhibitor RO-31-8220 prevented it, as well as 14-3-3 dimerization. Moreover, mutation of Cbl serine residues 619, 623, 639, and 642 abolished the interaction between Cbl and 14-3-3, Overexpression of Cbl in Jurkat cells inhibited the CD43-dependent activation of the mitogen-activated protein kinase (MAPK) pathway and AP-1 transcriptional activity, confirming nevertheless a negative role for Cbl in T cell signaling. However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway. These data suggest that by inducing its phosphorylation on serine residues, CD43-mediated signals may regulate the molecular associations and functions of the Cbl adapter protein. C1 Univ Nacl Autonoma Mexico, Inst Biotecnol, Cuernavaca 62250, Morelos, Mexico. Dana Farber Canc Inst, Boston, MA 02115 USA. La Jolla Inst Allergy & Immunol, San Diego, CA 92121 USA. RP Rosenstein, Y (reprint author), Univ Nacl Autonoma Mexico, Inst Biotecnol, APDO Postal 510-3, Cuernavaca 62250, Morelos, Mexico. EM yvonne@ibt.unam.mx NR 96 TC 27 Z9 28 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 5 PY 2001 VL 276 IS 1 BP 729 EP 737 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 390DP UT WOS:000166280700098 PM 11024037 ER PT J AU Tramo, MJ AF Tramo, MJ TI Biology and music - Music of the hemispheres SO SCIENCE LA English DT Editorial Material ID DISCRIMINATION; PITCH; REPRESENTATION; PERCEPTION; INFANTS; CORTEX C1 Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Tramo, MJ (reprint author), Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02114 USA. NR 32 TC 47 Z9 50 U1 3 U2 15 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JAN 5 PY 2001 VL 291 IS 5501 BP 54 EP 56 DI 10.1126/science.10.1126/SCIENCE.1056899 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 389VJ UT WOS:000166259100028 PM 11192009 ER PT J AU McAdam, AJ Greenwald, RJ Levin, MA Chernova, T Malenkovich, N Ling, V Freeman, GJ Sharpe, AH AF McAdam, AJ Greenwald, RJ Levin, MA Chernova, T Malenkovich, N Ling, V Freeman, GJ Sharpe, AH TI ICOS is critical for CD40-mediated antibody class switching SO NATURE LA English DT Article ID GERMINAL CENTER FORMATION; IMMUNE-RESPONSES; CO-STIMULATION; DIFFERENTIATION; ACTIVATION; EXPRESSION; CELLS; MICE; B7-1 AB The inducible co-stimulatory molecule (ICOS) is a CD28 homologue implicated in regulating T-cell differentiation(1-5). Because co-stimulatory signals are critical for regulating T-cell activation, an understanding of co-stimulatory signals may enable the design of rational therapies for immune-mediated diseases(6). According to the two-signal model for T-cell activation, T cells require an antigen-specific signal and a second, co-stimulatory, signal for optimal T-cell activation(6). The co-stimulatory signal promotes T-cell proliferation, lymphokine secretion and effector function. The B7-CD28 pathway provides essential signals for T-cell activation, but does not account for all co-stimulation. We have generated mice lacking ICOS (ICOS-/-) to determine the essential functions of ICOS. Here we report that ICOS-/- mice exhibit profound deficits in immunoglobulin isotype class switching, accompanied by impaired germinal centre formation. Class switching was restored in ICOS-/- mice by CD40 stimulation, showing that ICOS promotes T-cell/B-cell collaboration through the CD40/CD40L pathway. C1 Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Genet Inst, Dept Immunol, Cambridge, MA 02081 USA. RP Sharpe, AH (reprint author), Brigham & Womens Hosp, Dept Pathol, 221 Longwood Ave, Boston, MA 02115 USA. NR 22 TC 438 Z9 478 U1 1 U2 9 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 4 PY 2001 VL 409 IS 6816 BP 102 EP 105 DI 10.1038/35051107 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 388HT UT WOS:000166175600048 PM 11343122 ER PT J AU Tsuji, T Usui, S Aida, T Tachikawa, T Hu, GF Sasaki, A Matsumura, T Todd, R Wong, DTW AF Tsuji, T Usui, S Aida, T Tachikawa, T Hu, GF Sasaki, A Matsumura, T Todd, R Wong, DTW TI Induction of epithelial differentiation and DNA demethylation in hamster malignant oral keratinocyte by ornithine decarboxylase antizyme SO ONCOGENE LA English DT Article DE oral cancer; hamster; ornithine decarboxylase antizyme; differentiation; DNA demethylation ID MOUSE-TISSUE INHIBITOR; POUCH CARCINOGENESIS MODEL; ALPHA-DIFLUOROMETHYLORNITHINE; METHYLTRANSFERASE ACTIVITY; POLYAMINE LEVELS; GENE-EXPRESSION; RETINOIC ACID; COLON-CANCER; ANTITUMOR-ACTIVITY; METHYLATION STATUS AB The hamster ornithine decarboxylase antizyme (ODC-Az) cDNA was transfected into the hamster malignant oral keratinocyte cell line, HCPC-1, Ectopic expression of ODC-Az resulted in the reversion of malignant phenotypes and alteration of DNA methylation status of CCGG sites. The phenotypes examined include ODC enzymatic activity, doubling time, morphological change, anchorage dependent growth, tumorigenicity in nude mice, induction of epithelial differentiation marker protein (involucrin), and change of cell cycle position. Comparison of CCGG DNA methylation status of the ODC-Az and control vector transfectants revealed a significant increase in demethylation of 5-methyl cytosines (m(5)C) of CCGG sites in the ODC-Az transfectants. Ectopic expression of ODC-Az gene in hamster malignant oral keratinocytes led to reduce ODC activity and the subsequent demethylation of 5-methyl cytosines, presumably via the ODC/ polyamines/ decarboxylated S-adenosylmethionine (dc-AdoMet) pathways. Our data suggest that ODC-Az shared the same pathway of polyamines/ dc-AdoMet/DNA methyltransferase (DNA MTase), We propose that ODC-Az mediates a novel mechanism in tumor suppression by DNA demethylation and presumably re-activation of key cellular genes silenced by DNA hypermethylation during cancer development. C1 Showa Univ, Sch Dent, Dept Oral Pathol, Tokyo 1428555, Japan. Harvard Univ, Sch Med, Dept Radiol, Ctr Biochem & Biophys Sci & Med, Boston, MA 02115 USA. Okayama Univ, Sch Dent, Dept Oral & Maxillofacial Surg 2, Okayama 7008525, Japan. Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. RP Wong, DTW (reprint author), Harvard Univ, Sch Dent Med, Dept Oral Med & Diagnost Sci, Div Oral Pathol, Boston, MA 02115 USA. FU NIDCR NIH HHS [DE-11983, DE-12467, DE-12529] NR 83 TC 36 Z9 40 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 JAN 4 PY 2001 VL 20 IS 1 BP 24 EP 33 DI 10.1038/sj.onc.1204051 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 391NE UT WOS:000166361400004 PM 11244502 ER PT J AU Goroll, AH Morrison, G Bass, EB Jablonover, R Blackman, D Platt, R Whelan, A Hekelman, FP AF Goroll, AH Morrison, G Bass, EB Jablonover, R Blackman, D Platt, R Whelan, A Hekelman, FP TI Reforming the core clerkship in internal medicine: The SGIM/CDIM project SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID PRIMARY-CARE; EDUCATION; STUDENTS; SETTINGS; CULTURE; SCHOOLS AB Dramatic changes in health care have stimulated reform of undergraduate medical education. In an effort to improve the teaching of generalist competencies and encourage learning in the outpatient setting, the Society of General Internal Medicine joined with the Clerkship Directors in Internal Medicine in a federally sponsored initiative to develop a new curriculum for the internal medicine core clerkship. Using a broad-based advisory committee and working closely with key stakeholders (especially clerkship directors), the project collaborators helped forge a new national consensus on the leaming agenda for the clerkship (a prioritized set of basic generalist competencies) and on the proportion of time that should be devoted to outpatient care (at least one third of the clerkship). From this consensus emerged a new curricular model that served as the basis for production of a curriculum guide and faculty resource package. The guide features the prioritized set of basic generalist competencies and specifies the requisite knowledge, skills, and attitudes/values needed to master them, as well as a list of suggested training problems. it also includes recommended training experiences, schedules, and approaches to faculty development, precepting, and student evaluation. Demand for the guide has been strong and led to production of a second edition, which includes additional materials, an electronic version, and a pocket guide for students and faculty. A follow-up survey of clerkship directors administered soon after completion of the first edition revealed widespread use of the curricular guide but also important barriers to full implementation of the new curriculum, Although this collaborative effort appears to have initiated clerkship reform, long-term success will require an enhanced educational infrastructure to support teaching in the outpatient setting. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Mt Sinai Sch Med, New York, NY USA. Washington Univ, Sch Med, St Louis, MO USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Goroll, AH (reprint author), Massachusetts Gen Hosp, ACC Suite 645, Boston, MA 02114 USA. NR 26 TC 24 Z9 28 U1 2 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 2 PY 2001 VL 134 IS 1 BP 30 EP 37 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 386CV UT WOS:000166043300005 PM 11187418 ER PT J AU Huang, WD Chung, U Kronenberg, HM de Crombrugghe, B AF Huang, WD Chung, U Kronenberg, HM de Crombrugghe, B TI The chondrogenic transcription factor Sox9 is a target of signaling by the parathyroid hormone-related peptide in the growth plate of endochondral bones SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID AUTOSOMAL SEX REVERSAL; CHONDROCYTE-SPECIFIC ENHANCER; SRY-RELATED GENE; PRO-ALPHA-1(II) COLLAGEN GENE; CAMPOMELIC DYSPLASIA; II COLLAGEN; METAPHYSEAL CHONDRODYSPLASIA; INDIAN HEDGEHOG; CELL-LINE; RECEPTOR AB In the growth plate of endochondral bones, parathyroid hormone (PTH)-related peptide (PTHrP) regulates the rate of chondrocyte maturation from prehypertrophic chondrocytes to hypertrophic chondrocytes. Using an antibody specific for Sox9 phosphorylated at serine 181 (S-181), one of the two consensus protein kinase A phosphorylation sites of Sox9, we showed that the addition of PTHrP strongly increased the phosphorylation of SOX9 in COS7 cells transfected with both SOX9- and PTH/PTHrP receptor-expressing vectors. PTHrP also increased the SOX9-dependent activity of chondrocyte-specific enhancers in the gene for type II collagen (Col2a1) in transient transfection experiments. This increased enhancer activity did not occur with a Sox9 mutant harboring serine-to-alanine substitutions in its two consensus protein kinase A phosphorylation sites. Consistent with these results, PTHrP also increased Col2a1 mRNA levels in rat chondrosarcoma cells as well as 10T1/2 mesenchymal cells transfected with a PTH/PTHrP receptor expressing plasmid. No phosphorylation of Sox9 at S-181 was detected in prehypertrophic chondrocytes of the growth plate or any chondrocytes of PTH/PTHrP receptor null mutants. In contrast in wild-type mouse embryos, previous immunohistochemistry experiments indicated that Sox9 phosphorylated at S-181 was detected almost exclusively in chondrocytes of the prehypertrophic zone. Sox9, regardless of the phosphorylation state, was present in all chondrocytes of both genotypes except hypertrophic chondrocytes. Our results indicated that Sox9 is a target of PTHrP signaling in prehypertrophic chondrocytes in the growth plate. We hypothesize that Sox9 mediates at least some effects of PTHrP in the growth plate and that the PTHrP-dependent increased transcriptional activity of Sox9 helps maintain the chondrocyte phenotype of cells in the prehypertrophic zone and inhibits their maturation to hypertrophic chondrocytes. C1 Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. RP de Crombrugghe, B (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA. FU NCI NIH HHS [CA 16672, P30 CA016672]; NIAMS NIH HHS [P01 AR 42919-02, P01 AR042919, R01 AR42909]; NIDDK NIH HHS [DK47038] NR 40 TC 148 Z9 157 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 2 PY 2001 VL 98 IS 1 BP 160 EP 165 DI 10.1073/pnas.011393998 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 389DD UT WOS:000166222600033 PM 11120880 ER PT J AU Geng, Y Yu, QY Sicinska, E Das, M Bronson, RT Sicinski, P AF Geng, Y Yu, QY Sicinska, E Das, M Bronson, RT Sicinski, P TI Deletion of the p27(Kip1) gene restores normal development in cyclin D1-deficient mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MAMMARY-GLAND DEVELOPMENT; CDK INHIBITORS; RETINOBLASTOMA PROTEIN; CELL-PROLIFERATION; DEPENDENT KINASES; S-PHASE; D1; LACKING; BREAST; GROWTH AB D-type cyclins (cyclins D1, D2, and D3) are key components of cell cycle machinery in mammalian cells. These proteins are believed to drive cell cycle progression by associating with their kinase partners, cyclin-dependent kinases, and by directing phosphorylation of critical cellular substrates. In addition, D-cyclins play a kinase-independent role by sequestering cell cycle inhibitors p27(Kip1) and p21(Cip1). In the past, we and others generated cyclin D1-deficient mice and have shown that these mice display developmental abnormalities, hypoplastic retinas, and pregnancy-insensitive mammary glands. To test the significance of cyclin D1-p27(Kip1) interaction within a living mouse, we crossed cyclin D1-deficient mice with mice lacking p27(Kip1), and we generated double-mutant cyclin D1(-/-)p27(-/-) animals. Here we report that ablation of p27(Kip1) restores essentially normal development in cyclin D1-deficient mice. Our results provide genetic evidence that p27(Kip1) functions downstream of cyclin D1. C1 Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Tufts Univ, Sch Vet Med, Dept Pathol, Boston, MA 02111 USA. RP Sicinski, P (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA83688-01, R01 CA083688] NR 25 TC 123 Z9 125 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 2 PY 2001 VL 98 IS 1 BP 194 EP 199 DI 10.1073/pnas.011522998 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 389DD UT WOS:000166222600039 PM 11134518 ER PT S AU Eddington, DK Rabinowitz, WM Delhorne, LA AF Eddington, DK Rabinowitz, WM Delhorne, LA GP IEEE IEEE TI Sound processing for cochlear implants SO 2001 IEEE INTERNATIONAL CONFERENCE ON ACOUSTICS, SPEECH, AND SIGNAL PROCESSING, VOLS I-VI, PROCEEDINGS: VOL I: SPEECH PROCESSING 1; VOL II: SPEECH PROCESSING 2 IND TECHNOL TRACK DESIGN & IMPLEMENTATION OF SIGNAL PROCESSING SYSTEMS NEURALNETWORKS FOR SIGNAL PROCESSING; VOL III: IMAGE & MULTIDIMENSIONAL SIGNAL PROCESSING MULTIMEDIA SIGNAL PROCESSING - VOL IV: SIGNAL PROCESSING FOR COMMUNICATIONS; VOL V: SIGNAL PROCESSING EDUCATION SENSOR ARRAY & MULTICHANNEL SIGNAL PROCESSING AUDIO & ELECTROACOUSTICS; VOL VI: SIGNAL PROCESSING THEORY & METHODS STUDENT FORUM SE International Conference on Acoustics Speech and Signal Processing (ICASSP) LA English DT Proceedings Paper CT IEEE International Conference on Acoustics, Speech, and Signal Processing CY MAY 07-11, 2001 CL SALT LAKE CITY, UT SP IEEE Signal Processing Soc ID SPEECH RECOGNITION AB Cochlear implants are devices designed to provide a measure of hearing to the deaf. Most deaf individuals have lost the ability to translate sound into the patterns of electric activity normally present on the 30,000 fibers of the auditory nerve. Because these patterns of activity are the inputs to the brain that result in sound sensation, cochlear implants deliver electric stimuli to these fibers in an attempt to artificially elicit patterns of spike activity that mimic the patterns present in a normal-hearing ear. We introduce cochlear implants by describing the signal processing used by current devices. Measurements of patient performance in quiet and in noise are used to demonstrate the limitations of today's devices and to introduce the avenues of current research that show promise for improving the performance of these devices. C1 Massachusetts Eye & Ear Infirm, Cochlear Implant Res Lab, Boston, MA 02114 USA. RP Eddington, DK (reprint author), Massachusetts Eye & Ear Infirm, Cochlear Implant Res Lab, Boston, MA 02114 USA. NR 6 TC 0 Z9 1 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1520-6149 BN 0-7803-7041-4 J9 INT CONF ACOUST SPEE PY 2001 BP 3449 EP 3452 PG 4 WC Acoustics; Computer Science, Artificial Intelligence; Computer Science, Theory & Methods; Engineering, Electrical & Electronic SC Acoustics; Computer Science; Engineering GA BT70T UT WOS:000173806500864 ER PT J AU Gordon, JA AF Gordon, JA TI Cost-benefit analysis of social work services in the emergency department: A conceptual model SO ACADEMIC EMERGENCY MEDICINE LA English DT Article DE economic model; cost-benefit; emergency department; costs; social services AB Objective: To describe an economic model for formal cost-benefit analysis of emergency department (ED)-based social services. Methods: The varied monetary costs and benefits associated with ED-based social work services were projected for three hypothetical levels of ED volume (30,000, 60,000, and 90,000 patients/year). Primary benefits included the prevention of return ED visits, the prevention of "social" hospital admissions, and the protection of doctor and nurse time. The primary cost was salary support for full-time social work staffing. Sensitivity analysis was performed to account for varying estimates. Results: For a small-volume ED, total benefits to offset costs ranged fi om $43,869 to $81,504, yielding a net cost of $99,936 up to $137,571 for full-time social work coverage. For a moderate-size ED, total benefits ranged from $87,660 to $162,930, yielding a net cost of only $18,510 on the high end of the sensitivity analysis, and $87,668 on the low end. For a large-volume ED, total benefits ranged from $131,529 to $247,434, yielding a net cost of $49,911 on the low end of the sensitivity analysis, but a net benefit of $65,994 on the high end. Conclusions: Dedicated social work staffing of EDs may yield net economic benefits, especially in large urban centers. Moderate-size EDs may almost "break even" in economic terms, and small EDs may realize a net cost, but in either case, the cost of social services can be significantly offset by decreased utilization of hospital and ED services, and by more efficient use of medical staff time. C1 Harvard Univ, Sch Med,Inst Hlth Policy, Massachusetts Gen Hosp,Partners HealthCare Syst, Dept Emergency Med,Div Emergency Med,Clin 115, Boston, MA 02114 USA. RP Gordon, JA (reprint author), Harvard Univ, Sch Med,Inst Hlth Policy, Massachusetts Gen Hosp,Partners HealthCare Syst, Dept Emergency Med,Div Emergency Med,Clin 115, 55 Fruit St, Boston, MA 02114 USA. NR 13 TC 17 Z9 17 U1 2 U2 5 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 JAN PY 2001 VL 8 IS 1 BP 54 EP 60 DI 10.1111/j.1553-2712.2001.tb00552.x PG 7 WC Emergency Medicine SC Emergency Medicine GA 408GT UT WOS:000167319000010 PM 11136149 ER PT J AU Campbell, EG Weissman, JS Ausiello, J Wyatt, S Blumenthal, D AF Campbell, EG Weissman, JS Ausiello, J Wyatt, S Blumenthal, D TI Understanding the relationship between market competition and students' ratings of the managed care content of their undergraduate medical education SO ACADEMIC MEDICINE LA English DT Article ID VALIDITY; SCHOOLS; FACULTY; VIEWS; PHYSICIANS; CURRICULUM; DEANS AB Purpose. The increase in managed care has led to questions about the inadequacy of instruction undergraduate medical students receive in curricular areas related to managed care. This study examined (1) the percentages of graduating medical students who felt they had received inadequate instruction in six curricular content areas (CCAs): primary care, care of ambulatory patients, health promotion and disease prevention, medical care cost control, teamwork with other health professionals, and cost-effective medical practice; and (2) whether the market competitiveness of these students' medical schools affected their reports of inadequacy of instruction in these CCAs. Method. Data from the Association of American Medical Colleges' Graduation Questionnaires (GQs) from 1994 to 1997 were analyzed. The GR asked graduating students to rate the adequacy of instruction they had received in the six CCAs. Students' ratings were collapsed into the dichotomous variables "inadequate" and "not inadequate." The market competitiveness of medical schools was determined using the four-stage Market Evolution Model developed by the University HealthSystem Consortium. Only responses from students graduating from medical schools that could be staged for all four years of the study were analyzed. Statistical analyses were performed to determine trends for each CCA by year, across the entire study period, by market stage, and by market stage across the entire study period. Results. A total of 39,136 respondents from 86 medical schools were used in the study. The percentages of graduating medical students who reported inadequate instruction decreased over the study period for five of the six CCAs: primary care (27.6% in 1994 to 13.7% in 1997), ambulatory care (37.4% to 23.9%), medical care cost control (62.9% to 52.9%) cost-effectiveness of medical practice (62.7% to 53.9%), and health promotion and disease prevention (44.4% to 23.7%); all at P < .001. The responses for inadequacy of instruction for teamwork with other health professionals remained steady from 1994 to 1996 (10.2% to 10.6%), then increased 21.8% in 1997. Over the course of the study, students graduating from schools in more competitive markets (Stage 3 or Stage 4) were more likely to report inadequate instruction in three CCAs, primary care, ambulatory care, and health promotion and disease prevention, than were those graduating from schools in less competitive markets (Stage 1 and Stage 2). Conversely, students graduating from schools in the more competitive health care markets were less likely to report inadequate instruction in cost-effectiveness and cost control than were students from schools in less competitive markets. Conclusion. Graduating students' reports of inadequacy of instruction decreased over the study period for five of the six CCAs, increasing only for teamwork with other professionals. Findings were mixed with regard to the relationship of medical schools' market competitiveness and graduating students' reports of inadequacy of instruction, More research is needed to confirm graduating students' perceptions of the inadequacy of their instruction in CCAs related to managed care, particularly once they have gained experience treating patients in managed care environments. C1 Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. Partners HealthCare Syst, Boston, MA USA. Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. George Washington Univ, Washington, DC USA. RP Campbell, EG (reprint author), Inst Hlth Policy, 50 Staniford St,9th Floor, Boston, MA 02114 USA. NR 34 TC 4 Z9 4 U1 0 U2 0 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD JAN PY 2001 VL 76 IS 1 BP 51 EP 59 DI 10.1097/00001888-200101000-00016 PG 9 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 391UB UT WOS:000166373200012 PM 11154197 ER PT J AU Bremer, C Weissleder, R AF Bremer, C Weissleder, R TI Molecular imaging - In vivo imaging of gene expression: MR and optical technologies SO ACADEMIC RADIOLOGY LA English DT Article DE genes and genetics; magnetic resonance (MR); experimental; optical imaging ID GREEN-FLUORESCENT PROTEIN; MAGNETIC-RESONANCE MICROSCOPY; IRON-RESPONSIVE ELEMENTS; MESSENGER-RNA LEVELS; IN-VIVO; LIVING MAMMALS; REAL-TIME; BIOLUMINESCENT REPORTER; TRANSGENE EXPRESSION; EUKARYOTIC CELLS AB With the ability to readily engineer genes, create knock-in and knock-out models of human disease, and replace and insert genes in clinical trials of gene therapy, it has become clear that imaging will play a critical role in these fields. Imaging is particularly helpful in recording temporal and spatial resolution of gene expression in vivo, determining vector distribution, and, ultimately, understanding endogenous gene expression during disease development. While endeavors are under way to image targets ranging from DNA to entire phenotypes in vivo, this short review focuses on in vivo imaging of gene expression with magnetic resonance and optical techniques. C1 Massachusetts Gen Hosp, Ctr Mol Imaging Res, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Weissleder, R (reprint author), Massachusetts Gen Hosp, Ctr Mol Imaging Res, Bldg 149,13th St,5403, Boston, MA 02129 USA. NR 77 TC 51 Z9 56 U1 0 U2 6 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD JAN PY 2001 VL 8 IS 1 BP 15 EP 23 DI 10.1016/S1076-6332(03)80739-0 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 433PZ UT WOS:000168770100003 PM 11201452 ER PT J AU Mullins, ME Mehta, A Patel, H McLoud, TC Novelline, RA AF Mullins, ME Mehta, A Patel, H McLoud, TC Novelline, RA TI Impact of PACS on the education of radiology residents: The residents' perspective SO ACADEMIC RADIOLOGY LA English DT Article DE education; picture archiving and communication system (PACS); radiography, digital ID COMMUNICATION-SYSTEM PACS; IN-TRAINING EXAMINATION; FILMLESS RADIOLOGY; CARE AB Rationale and Objectives. Because digital imaging and the picture archiving and communication system (PACS) are replacing radiographic film, the effect of PACS on residents' perceptions and their educational experience was investigated. Materials and Methods. Residents taking part in large diagnostic radiology training programs at two hospitals were surveyed. Approximately 75% of radiographic studies were reviewed with the use of PACS at both hospitals. Survey topics included technical and didactic issues based on direct and indirect comparison with analog (conventional film) images. Results. Fifty residents were polled (20 respondents). The majority has been using PACS for more than 1 year (14 of 20, 70%) to interpret 75%-100% of cases (11 of 20, 55%). The majority believed that PACS improved patient care (15 of 20, 75%) and their educational experience (15 of 20, 75%). A minority believed that increased patient throughput was harmful to the educational experience (five of 20. 25%) because it permitted attending radiologists to review cases too quickly (four of 20, 20%). Residents favored PACS over hard-copy images for ease of manipulation, resolution. and ability to see pathologic conditions and normal anatomic characteristics. Conclusion. Residents believe that PACS has positively affected their learning experience and does not negatively affect the quality of resident education. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Mullins, ME (reprint author), Massachusetts Gen Hosp, Dept Radiol, Founders House, Boston, MA 02115 USA. NR 17 TC 14 Z9 15 U1 0 U2 0 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD JAN PY 2001 VL 8 IS 1 BP 67 EP 73 DI 10.1016/S1076-6332(03)80745-6 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 433PZ UT WOS:000168770100009 PM 11201459 ER PT J AU Morag, E Lieberman, G Volkan, K Shaffer, K Novelline, R Lang, EV AF Morag, E Lieberman, G Volkan, K Shaffer, K Novelline, R Lang, EV TI Clinical competence assessment in radiology: Introduction of an objective structured clinical examination in the medical school curriculum SO ACADEMIC RADIOLOGY LA English DT Article DE education; medical students; radiology clerkship; testing; clinical performance ID PERFORMANCE; RESIDENTS AB Rationale and Objectives. Traditional oral and written examinations can be limited in predicting future clinical performance. Therefore Objective Structured Clinical Examinations (OSCEs) have been introduced in other specialties. The au thors assessed their value in radiology. Materials and Methods. The study includes 122 Harvard medical students who undertook I-month compulsory clerkships at one of three hospitals (A, B, or C) in their 3rd and 4th year and a compulsory OSCE in their 4th year. The OSCE was constructed from five cases. Each had eight or nine standardized questions designed to test, within a set time, the perception of essential findings, their interpretation, and clinical judgment (maximum possible score, 100). Clerkship grades were high honors (score of 3), honors (score of 2), satisfactory (score of 1), and fail (score of 0). Predictors of OSCE scores-clerkship grade and affiliated hospital-were modeled as linear functions. Time elapsed between clerkship and OSCE was modeled as a nonlinear function. Results. Although there was a positive relation between clerkship grade and OSCE grade, it accounted for an increase of only 5.7% in OSCE score per clerkship grade and did not predict performance of individual students. Students who trained in hospital B showed significantly higher OSCE grades. OSCE scores were highest when the examination was taken 8 months after the clerkship. Conclusion. The OSCE may be useful to uncover deficits in individuals and groups beyond the ones detected with traditional clerkship evaluations and provide guidance for remediation. The improved performance after additional clinical exposure suggests that the OSCE may be well suited to test the integration of radiologic and clinical knowledge. C1 Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Off Educ Dev, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Lang, EV (reprint author), Beth Israel Deaconess Med Ctr, Dept Radiol, 330 Brookline Ave,W Campus CC 308, Boston, MA 02215 USA. FU NCCIH NIH HHS [8 RO1 AT00002-04] NR 12 TC 12 Z9 12 U1 1 U2 4 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD JAN PY 2001 VL 8 IS 1 BP 74 EP 81 DI 10.1016/S1076-6332(03)80746-8 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 433PZ UT WOS:000168770100010 PM 11201460 ER PT J AU Richardson, P Guinan, E AF Richardson, P Guinan, E TI Hepatic veno-occlusive disease following hematopoietic stem cell transplantation SO ACTA HAEMATOLOGICA LA English DT Review DE chemotherapy, high-dose; endothelial injury; stem cell transplantation, hematopoietic; veno-occlusive disease, hepatic; veno-occlusive disease, prevention and; treatment ID BONE-MARROW TRANSPLANTATION; TISSUE-PLASMINOGEN-ACTIVATOR; SEVERE VENOOCCLUSIVE DISEASE; HIGH-DOSE CHEMOTHERAPY; ACUTE-RENAL-FAILURE; LIVER-TRANSPLANTATION; ANTITHROMBOTIC AGENT; GLUTATHIONE DEFENSE; RANDOMIZED TRIAL; III PROCOLLAGEN AB The clinical syndrome of hepatic veno-occlusive disease (VOID) is one of the most common and serious complications following hematopoietic stem cell transplantation (SCT). High-dose chemotherapy or chemoradiation therapy in the context of autologous and allogeneic SCT can profoundly injure sinusoidal endothelium and hepatocytes within zone 3 of the liver acinus, producing the clinical syndrome of hepatomegaly and/or right upper quadrant pain with jaundice and fluid retention, typically manifest as weight gain. The incidence is variable and ranges from 10 to 60%. Mild to moderate disease is characterized by eventual complete resolution. In contrast, severe disease frequently results in multiorgan failure and death. The purpose of this review is to discuss the pathophysiology and clinical features of VOID, and the current status and future directions of research for both prevention and treatment. Copyright (C) 2001 S. Karger AG, Basel. C1 Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA. RP Richardson, P (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. NR 119 TC 49 Z9 56 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0001-5792 J9 ACTA HAEMATOL-BASEL JI Acta Haematol. PY 2001 VL 106 IS 1-2 BP 57 EP 68 DI 10.1159/000046590 PG 12 WC Hematology SC Hematology GA 475LN UT WOS:000171165700009 PM 11549778 ER PT J AU Black, PM Villavicencio, AT Rhouddou, C Loeffler, JS AF Black, PM Villavicencio, AT Rhouddou, C Loeffler, JS TI Aggressive surgery and focal radiation in the management of meningiomas of the skull base: Preservation of function with maintenance of local control SO ACTA NEUROCHIRURGICA LA English DT Article DE meningioma; skull base; brain tumor; management; surgery; radiosurgery ID INTRACRANIAL MENINGIOMAS; PETROCLIVAL MENINGIOMAS; RESECTED MENINGIOMAS; STEREOTAXIC RADIOSURGERY; LINEAR-ACCELERATOR; THERAPY; RECURRENCE; EXPERIENCE; CLIVUS; TOMOGRAPHY AB Background. Recent study series have reported that post-operative external beam radiation therapy and stereotactic radiosurgery with the linear accelerator or gamma knife improves long-term local control of subtotally resected or recurrent meningiomas. Methods. Analysis of treatment results in 100 consecutive patients with skull base meningiomas managed by one surgeon with a median follow-up of five years. Treatment principles included observation for asymptomatic tumors; surgery for progressive or symptomatic tumors unless surgery was medically contraindicated or refused by the patient; to make surgery as aggressive as possible but with the goal of preserving full function of the patient; and to use radiosurgery or conformal fractionated radiation therapy if residual tumor was demonstrated. Preoperative. postoperative, and observational data were prospectively accumulated and stored in a large database system. Median follow up was 5 years with a range From 2 to 10 years. Findings. The most frequent presenting symptoms were headache (45%) and changes in vision (29%). Cranial nerve deficits (49%) and cerebellar signs (24%) were the most common physical findings. Seventy-two patients had surgical resection. Of these, 93% had greater than 50% resection and 47% had radiographically complete resection. There were no perioperative deaths and there were five surgical complications for a rate of 7%. Complications included hemiparesis (2.8%), new cranial nerve palsy (2.8%), and indolent osteomyelitis (1.4%). Fifteen patients had observation only: none of who progressed. Thirteen patients had radiation only. primarily because of patient preference or medical contraindications to surgery in the setting of substantial symptoms. There were no complications of this therapy. With a median five-year follow-up, only one patient (1%) demonstrated tumor progression using the treatment paradigm outlined here. Interpretation. These results demonstrate that skull base meningiomas which require treatment can be managed with a combination of aggressive surgery and conformal radiation with an acceptable functional status in 99% of cases. C1 Brigham & Womens Hosp, Brain Tumor Ctr, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Neurosurg Serv, Boston, MA 02115 USA. Brigham & Womens Hosp, Stereotact Radiosurg Program, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Surg & Radiat Oncol, Boston, MA 02115 USA. RP Black, PM (reprint author), Brigham & Womens Hosp, Brain Tumor Ctr, 75 Francis St, Boston, MA 02115 USA. NR 63 TC 33 Z9 33 U1 0 U2 0 PU SPRINGER-VERLAG WIEN PI VIENNA PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 VIENNA, AUSTRIA SN 0001-6268 J9 ACTA NEUROCHIR JI Acta Neurochir. PY 2001 VL 143 IS 6 BP 555 EP 562 DI 10.1007/s007010170060 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 448ZG UT WOS:000169659400009 PM 11534672 ER PT J AU Villavicencio, AT Black, PM Shrieve, DC Fallon, MP Alexander, E Loeffler, JS AF Villavicencio, AT Black, PM Shrieve, DC Fallon, MP Alexander, E Loeffler, JS TI Linac radiosurgery for skull base meningiomas SO ACTA NEUROCHIRURGICA LA English DT Article DE meningiomas; skull base tumors; radiosurgery; brain tumors ID INTRACRANIAL MENINGIOMAS; RADIATION-THERAPY; STEREOTAXIC RADIOSURGERY; PETROCLIVAL MENINGIOMAS; RESECTED MENINGIOMAS; COMPUTED-TOMOGRAPHY; SURGICAL-TREATMENT; TRIGEMINAL NERVE; MECKELS CAVE; SURGERY AB Introduction. Skull base meningiomas present a difficult surgical challenge because of the high potential morbidity of radical surgical extirpation and their low potential for incapacitating symptomatology. The focal character of meningiomas makes stereotactic radiosurgery an attractive adjuvant treatment modality to resection. The purpose of this study was to evaluate the local control rates and complications in 56 patients with base of skull meningiomas undergoing radiosurgery. Methods. Patients underwent radiosurgery using the dedicated stereotactic linear accelerator at the Brigham and Women's Hospital. Minimal peripheral doses of radiosurgery ranged from 12 to 18.5 Gy (mean 15 Gy). Doses were designed to conform to the frequently irregular tumor volumes using the X-Knife treatment planning system. Multiple isocenters were used when required to increase conformality of dose. For 36 patients (64%), radiosurgery was used as an adjunct to surgery, for 20 patients (36%) it was the primary treatment. Results, Median followup was five years. Nineteen patients (34%) were improved clinically at follow-ups 32 (57%) were unchanged; and 5 patients (9%) developed new or worsened neurologic deficits. Serial imaging studies after radiosurgery showed a reduction in tumor volume in 23 patients (41%) 30 (54%) showed stable disease; 3 patients (5%) had tumors which increased in size (2 being outside the radiosurgery treatment site). The actuarial freedom from progression rate (defined as further tumor growth) was thus 95% with a median imaging follow-up of 26 months (range, 6-66 months). Although further follow-up is necessary. the results of this series clearly demonstrate that these lesions are feasible for treatment by modern radiosurgical techniques. Linac radiosurgery can stabilize skull base meningiomas, with decreased or unchanged tumor volumes on radiologic follow-up in approximately 95% of patients. Radiosurgery is a low-morbidity, effective technique as adjunct and sometimes primary treatment of small to moderate-sized meningiomas of the skull base. C1 Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Univ Utah, Salt Lake City, UT USA. RP Black, PM (reprint author), Brigham & Womens Hosp, Dept Neurosurg, 75 Francis St, Boston, MA 02115 USA. NR 57 TC 40 Z9 40 U1 0 U2 0 PU SPRINGER-VERLAG WIEN PI VIENNA PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 VIENNA, AUSTRIA SN 0001-6268 J9 ACTA NEUROCHIR JI Acta Neurochir. PY 2001 VL 143 IS 11 BP 1141 EP 1152 DI 10.1007/s007010100005 PG 12 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 497TR UT WOS:000172472000014 PM 11731865 ER PT J AU Gomez-Tortosa, E Sanders, JL Newell, K Hyman, BT AF Gomez-Tortosa, E Sanders, JL Newell, K Hyman, BT TI Cortical neurons expressing calcium binding proteins are spared in dementia with Lewy bodies SO ACTA NEUROPATHOLOGICA LA English DT Article DE Lewy bodies; alpha-synuclein; dementia; calcium binding proteins ID HUMAN CEREBRAL-CORTEX; ALZHEIMERS-DISEASE; DOPAMINERGIC-NEURONS; PARKINSONS-DISEASE; BODY DISEASE; NEUROFIBRILLARY TANGLES; IMMUNOREACTIVE NEURONS; SUBSTANTIA-NIGRA; TEMPORAL CORTEX; CELLS AB The consistent regional and laminar distribution of cortical Lewy bodies (LB) in brains of patients with dementia with Lewy bodies (DLB) suggests that only a certain subpopulation of neurons develops these alpha -synuclein-immunoreactive cytoplasmic inclusions. This study examined whether four non-overlapping neuronal subpopulations, defined by the expression of non-phosphorylated neurofilaments (SMI-32) and several calcium binding proteins (parvalbumin, calretinin and calbindin D-28k), are vulnerable to LB formation. We performed peroxidase immunostaining to examine the distribution and to quantitate each neuronal subpopulation within the superior temporal sulcus (STS) area, and double-label immunohistochemistry to test for colocalization of alpha -synuclein and each neuronal marker in the STS and the entorhinal cortex. There were no significant differences between DLB brains and controls in the proportional quantity or laminar distribution of each neuronal subpopulation. Parvalbumin-immunoreactive neurons represented around 7%, calbindin D-28k 8%, calretinin 10%, and SMI-32 about 20% of the total neuronal population in the STS cortex. Neurons expressing parvalbumin and SMI-32 showed a widespread distribution across layers II to VI. Neurons expressing calretinin were present in superficial layers (II to IV), and calbindin D-28k-immunoreactive neurons were mostly distributed within granular layers II:and IV. None of the LB observed in the STS or the entorhinal cortex were located in neurons expressing calcium binding proteins; 25% of the LB were contained in SMI-32 immunoreactive neurons. In conclusion, cortical neurons expressing calcium binding proteins are spared in DLB, while SMI-32-positive neurons are affected in proportion to their density in the cortex. However, the majority of cortical LB develop in neurons not identified by any of these markers. C1 Massachusetts Gen Hosp, Dept Nephrol, Alzheimers Res Unit, Charlestown, MA 02129 USA. Univ Complutense Madrid, Fdn Jimenez Diaz & Banco Tejidos Invest Neurol, Neurol Serv, Madrid, Spain. RP Hyman, BT (reprint author), Massachusetts Gen Hosp, Dept Nephrol, Alzheimers Res Unit, East 149 13th St,Room 6405, Charlestown, MA 02129 USA. FU NIA NIH HHS [P50-AGO5134] NR 35 TC 18 Z9 19 U1 3 U2 4 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0001-6322 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD JAN PY 2001 VL 101 IS 1 BP 36 EP 42 PG 7 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 381BP UT WOS:000165742700007 PM 11194939 ER PT J AU Weichselbaum, RR Kufe, DW Advani, SJ Roizman, B AF Weichselbaum, RR Kufe, DW Advani, SJ Roizman, B TI Molecular targeting of gene therapy and radiotherapy SO ACTA ONCOLOGICA LA English DT Article; Proceedings Paper CT Nobel Conference 2000 CY AUG 19-22, 2000 CL KAROLINSKA INST, STOCKHOLM, SWEDEN HO KAROLINSKA INST ID TUMOR-NECROSIS-FACTOR; IONIZING-RADIATION; GLIOMA; VIRUS; TNF; TRANSCRIPTION; VASCULATURE; GROWTH; EGR1 AB The full promise of gene therapy has been limited by the lack of specificity of vectors for tumor tissue as well as the lack of antitumor efficacy of transgenes encoded by gene delivery systems. In this paper we review our studies investigating two modifications of gene therapy combined with radiotherapy. The first investigations described include studies of radiation inducible gene therapy. In this paradigm, radio-inducible DNA sequences from the CarG elements of the Egr-1 promoter are cloned upstream of a cDNA encoding TNF alpha. The therapeutic gene (TNF alpha) is induced by radiation within the tumor microenvironment. In the second paradigm, genetically engineered herpes simplex virus (HSV-1) is induced by ionizing radiation to proliferate within the tumor volume. These modifications of radiotherapy and gene therapy may enhance the efficacy of both treatments. C1 Univ Chicago, Dept Radiat & Cellular Oncol, Pritzker Sch Med, Chicago, IL 60637 USA. Univ Chicago, Marjorie B Kovler Viral Oncol Labs, Chicago, IL 60637 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Weichselbaum, RR (reprint author), Univ Chicago, Dept Radiat & Cellular Oncol, Pritzker Sch Med, 5758 S Maryland Ave, Chicago, IL 60637 USA. NR 23 TC 34 Z9 55 U1 0 U2 1 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0284-186X J9 ACTA ONCOL JI Acta Oncol. PY 2001 VL 40 IS 6 BP 735 EP 738 PG 4 WC Oncology SC Oncology GA 495GM UT WOS:000172331900010 PM 11765068 ER EF