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Showing papers by "Icahn School of Medicine at Mount Sinai published in 1995"


Book ChapterDOI
TL;DR: This chapter discusses the integrated methods for the construction of three-dimensional models and computational probing of structure–function relations in G protein-coupled receptors (GPCR) and expects increased rate of success achieved by molecular modeling and computational simulation methods in providing structural insights relevant to the functions of biological molecules.
Abstract: Publisher Summary This chapter discusses the integrated methods for the construction of three-dimensional models and computational probing of structure–function relations in G protein-coupled receptors (GPCR). The rapid pace of cloning and expression of G protein-coupled receptors offers attractive opportunities to probe the structural basis of signal transduction mechanisms at the level of these cell-surface receptors. Major insights have emerged from comparisons and classifications of the amino acid sequences of GPCRs into families defined by evolutionary developments and adapted to perform selective functions. Structural data on GPCRs, based on biochemical, immunological, and biophysical approaches have validated consensus architecture of GPCRs with an extracellular N-terminus, a cytoplasmic C-terminus, and a transmembrane portion comprised of seven-transmembrane helical domains connected by loops. Developments in the molecular modeling and computational exploration of GPCR proteins indicate a tantalizing potential to alleviate some of these difficulties. These expectations are based on the increased rate of success achieved by molecular modeling and computational simulation methods in providing structural insights relevant to the functions of biological molecules.

2,567 citations


Book
01 Apr 1995
TL;DR: The author examines the immune system through the lens of Epstein-Barr Virus-Associated Diseases, as well as the biology of Stem Cells and Disorders of Hematopoiesis, and the approach to the Adult and Child with Anemia.
Abstract: Part I: Mollecular and Cellular Basis of Hematology. Anatomy and Physiology of the Gene. Protein Synthesis and Intracellular Sorting. Protein Architecture: Relationship of Form and Function. Membrane Biology. Cell Adhesion. Cellular Regulatory and Control Mechanism. Part II: Immunologic Basis of Hematology. Overview of the Immune System (including Compartmentalization of the Immune Response). Generation of B-cells. T-cell Immunity. Regulation of Activation of B and T-cells. Tolerance and Autoimmunity. Part III: Biology of Stem Cells and Disorders of Hematopoiesis. Stem Cell Model of Hematopoiesis. Anatomy and Physiology of Hematopoiesis. Growth Factors and the Control of Hematopoiesis. Biology of Erythropoiesis, Erythroid Differentiation and Maturation. Granulopoiesis and Monocytopoiesis. Thrombocytopoiesis. Inherited Forms of Bone Marrow Failure. Aplastic Anemia. Paroxysmal Nocturnal Hemoglobinuria. Pure Red Blood Cell Aplasia. Part IV: Red Blood Cells. Pathobiology of the Red Cell. Approach to the Adult and Child with Anemia. Anemia of Chronic Diseases. Erythrocytosis. Disorders of Iron Metabolism: Iron Deficiency and Overload. Heme Biosynthesis and Its Disorders: Porphyrias and Sideroblastic Anemias. Megaloblastic Anemias. Thalassemia Syndromes. Sickle Cell Disease. Hemoglobin Variants Associated with Hemolytic Anemia, Altered Oxygen Affinity, and Methemoglobinemias. Enzymopathies. Red Cell Membrane Disorders. Autoimmune Hemolytic Anemias. Extrinsic Nonimmune Hemolytic Anemias. Part V: Host Defense and Its Disorders. Immunoglobulins: Structure, Function, and Uses. Complement Biology. Neutrophil Structure and Function. Monocyte and Macrophage Development and Function. Eosinophils and the Hypereosinophilic Syndrome. Disorders of the Phagocyte Function. Disorders of the Lymphocyte Function. Histiocytic Syndromes. Lysosomal Storage Disease. Infectious Mononucleosis and Other Epstein-Barr Virus-Associated Diseases. Spleen and Its Disorders. Systemic Mastocytosis. Part VI: Hemat

1,646 citations


Journal ArticleDOI
23 Mar 1995-Nature
TL;DR: A linear zipper of molecules that mirrors the linear structure of the intracellular filaments with which cadherins associate may provide a mechanism to marshal individual molecular adhesive interactions into strong bonds between cells.
Abstract: Crystal structures of the amino-terminal domain of N-cadherin provide a picture at the atomic level of a specific adhesive contact between cells. A repeated set of dimer interfaces is common to the structure in three lattices. These interactions combine to form a linear zipper of molecules that mirrors the linear structure of the intracellular filaments with which cadherins associate. This cell-adhesion zipper may provide a mechanism to marshal individual molecular adhesive interactions into strong bonds between cells.

1,207 citations


Journal ArticleDOI
TL;DR: It is reported here that high expression of this altered gene in the central nervous systems of transgenic mice is associated with an age-related rapidly progressive decline of motor function accompanied by degenerative changes of motoneurons within the spinal cord, brain stem, and neocortex, indicating a causative relationship between altered SOD activity and motoneuron degeneration.
Abstract: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder primarily involving motoneurons. A subset of individuals with familial autosomal dominant forms of the disease have mutations of the copper/zinc superoxide dismutase (Cu/Zn SOD, SOD-1) gene, which encodes a ubiquitously expressed enzyme that plays a key role in oxygen free radical scavenging. This observation suggests that altered or reduced SOD-1 activity may play a role in the neurodegenerative process. To explore this possibility further, we have introduced a mutation into the mouse SOD-1 gene that corresponds to one of the changes found in the human gene in familial amyotrophic lateral sclerosis. Integration and expression of this mouse gene in transgenic mice was identified by the presence of a unique restriction enzyme site in the transgene coding sequence generated by introduction of the mutation. We report here that high expression of this altered gene in the central nervous systems of transgenic mice is associated with an age-related rapidly progressive decline of motor function accompanied by degenerative changes of motoneurons within the spinal cord, brain stem, and neocortex. These findings indicate a causative relationship between altered SOD activity and motoneuron degeneration. Moreover, biochemical studies indicate normal levels of total SOD activity in transgenic mouse tissues, results that indicate that the neurodegenerative disorder does not result from a diminution of activity and, as such, represents a dominant "gain of function" mutation.

703 citations


Journal ArticleDOI
TL;DR: The surface morphology and cytoarchitecture of human cingulate cortex was evaluated in the brains of 27 neurologically intact individuals to provide structural underpinnings for interpreting functional imaging studies of the human medial surface.
Abstract: The surface morphology land cytoarchitecture of human cingulate cortex was evaluated in the brains of 27 neurologically intact individuals. Variations in surface features included a single cingulate sulcus (CS) with or without segmentation or double parallel sulci with or without segmentation. The single CS was deeper (9.7 ± 0.81 mm) than in cases with double parallel sulci (7.5 ± 0.48 mm). There were dimples parallel to the CS in anterior cingulate cortex (ACC) and anastomoses between the CS and the superior CS. Flat maps of the medial cortical surface were made in a two-stage reconstruction process and used to plot areas. The ACC is agranular and has a prominent layer V. Areas 33 and 25 have poor laminar differentiation, and there are three parts of area 24: area 24a adjacent to area 33 and partially within the callosal sulcus has homogeneous layers II and III, area 24b on the gyral surface has the most prominent layer Va of any cingulate area and distinct layers IIIa-b and IIIc, and area 24c in the ventral bank of the CS has thin layers II–III and no differentiation of layer V. There are four caudal divisions of area 24. Areas 24a′ and 24b′ have a thinner layer Va and layer III is thicker and less dense than in areas 24a and 24b. Area 24c′ is caudal to area 24c and has densely packed, large pyramids throughout layer V. Area 24c'g is caudal to area 24c′ and has the largest layer Vb pyramidal neurons in cingulate cortex. Area 32 is a cingulofrontal transition cortex with large layer IIIc pyramidal neurons and a dysgranular layer IV. Area 32′ is caudal to area 32 and has an indistinct layer IV, larger layer IIIc pyramids, and fewer neurons in layer Va. Posterior cingulate cortex has medial and lateral parts of area 29, a dysgranular area 30, and three divisions of area 23: area 23a has a thin layer IIIc and moderate-sized pyramids in layer Va, area 23b has large and prominent pyramids in layers IIIc and Va, and area 23c has the thinnest layers V and VI in cingulate cortex. Area 31 is the cinguloparietal transition area in the parasplenial lobules and has very large layer IIIc pyramids. Finally, variations in architecture between cases were assessed in neuron perikarya counts in area 23a. There was an age-related decrease in neuron density in layer IV (r = −0.63; ages 45–102), but not in other layers. These observations provide structural underpinnings for interpreting functional imaging studies of the human medial surface. © 1995 Wiley-Liss, Inc.

697 citations


Journal ArticleDOI
TL;DR: It is suggested that rapamycin, but not FK520, inhibits vascular smooth muscle cell proliferation by reducing cell-cycle kinase activity.
Abstract: Multiple growth factors can stimulate quiescent vascular smooth muscle cells to exit from G0 and reenter the cell cycle. The macrolide antibiotic rapamycin, bound to its cytosolic receptor FKBP, is an immunosuppressant and a potent inhibitor of cellular proliferation. In the present study, the antiproliferative effects of rapamycin on human and rat vascular smooth muscle cells were examined and compared with the effects of a related immunosuppressant, FK520. In vascular smooth muscle cells, rapamycin, at concentrations as low as 1 ng/mL, inhibited DNA synthesis and cell growth. FK520, an analogue of the immunosuppressant FK506, is structurally related to rapamycin and binds to FKBP but did not inhibit vascular smooth muscle cell growth. Molar excesses of FK520 blocked the antiproliferative effects of rapamycin, indicating that the effects of rapamycin required binding to FKBP. Rapamycin-FKBP inhibited retinoblastoma protein phosphorylation at the G1/S transition. This inhibition of retinoblastoma protein phosphorylation was associated with a decrease in p33cdk2 kinase activity. These observations suggest that rapamycin, but not FK520, inhibits vascular smooth muscle cell proliferation by reducing cell-cycle kinase activity.

635 citations


Journal ArticleDOI
TL;DR: The author explores the historical, political, and social forces that have played a major role in the acceptance of the idea of trauma as a cause of the specific symptoms of posttraumatic stress disorder and to discuss the impact that current research findings have had on some of the initial conceptualizations of the disorder.
Abstract: Objective: The authors ‘ goal was to explore the historical, political, and social forces that have played a major role in the acceptance of the idea of trauma as a cause of the specific symptoms of posttraumatic stress disorder (PTSD) and to discuss the impact that current research findings have had on some ofthe initial conceptualizations ofthe disorder. Method: The conceptual origins of PTSD are described, and the literature on the prevalence, longitudinal course, phenomenology, and neurobiology of PTSD is reviewed. Results: Paradoxically, there are a series of findings that support the idea that PTSD is a distinct diagnostic entity, but these are different from those originally developed from psychosocial theory and stress research. �j clusions: PTSD has been a controversial diagnosis and is again at a vulnerable point. It is imperative that the field address how current findings challenge the original conceptualizations of this disorder so that the next generation of conceptual issues can be formulated. (Am J Psychiatry 1995; 152:1705-1713)

603 citations


Journal ArticleDOI
31 Mar 1995-Science
TL;DR: Serine phosphorylation appears to enhance or to be required for the formation of stable Stat3-Stat3, a member of the interleukin-6 family of cytokines, which binds to and activate receptors that contain a common subunit, gp130.
Abstract: Members of the interleukin-6 family of cytokines bind to and activate receptors that contain a common subunit, gp130. This leads to the activation of Stat3 and Stat1, two cytoplasmic signal transducers and activators of transcription (STATs), by tyrosine phosphorylation. Serine phosphorylation of Stat3 was constitutive and was enhanced by signaling through gp130. In cells of lymphoid and neuronal origins, inhibition of serine phosphorylation prevented the formation of complexes of DNA with Stat3-Stat3 but not with Stat3-Stat1 or Stat1-Stat1 dimers. In vitro serine dephosphorylation of Stat3 also inhibited DNA binding of Stat3-Stat3. The requirement of serine phosphorylation for Stat3-Stat3.DNA complex formation was inversely correlated with the affinity of Stat3-Stat3 for the binding site. Thus, serine phosphorylation appears to enhance or to be required for the formation of stable Stat3-Stat3.DNA complexes.

568 citations


Journal ArticleDOI
TL;DR: It is suggested that increased insulin receptor serine phosphorylation decreases its protein tyrosine kinase activity and is one mechanism for the post-binding defect in insulin action characteristic of PCOS.
Abstract: We investigated the cellular mechanisms of the unique disorder of insulin action found in the polycystic ovary syndrome (PCOS). Approximately 50% of PCOS women (PCOS-Ser) had a significant increase in insulin-independent beta-subunit [32P]phosphate incorporation (3.7-fold, P < 0.05 vs other groups) in skin fibroblast insulin receptors that was present in serine residues while insulin-induced tyrosine phosphorylation was decreased (both P < 0.05 vs other groups). PCOS skeletal muscle insulin receptors had the same abnormal phosphorylation pattern. The remaining PCOS women (PCOS-n1) had basal and insulin-stimulated receptor autophosphorylation similar to control. Phosphorylation of the artificial substrate poly GLU4:TYR1 by the PCOS-Ser insulin receptors was significantly decreased (P < 0.05) compared to control and PCOS-n1 receptors. The factor responsible for excessive serine phosphorylation appeared to be extrinsic to the receptor since no insulin receptor gene mutations were identified, immunoprecipitation before autophosphorylation corrected the phosphorylation defect and control insulin receptors mixed with lectin eluates from affected PCOS fibroblasts displayed increased serine phosphorylation. Our findings suggest that increased insulin receptor serine phosphorylation decreases its protein tyrosine kinase activity and is one mechanism for the post-binding defect in insulin action characteristic of PCOS.

543 citations


Journal ArticleDOI
TL;DR: Data support the notion that neocortical neuronal degeneration, as indicated by NFT formation, is a critical determinant of the clinical progression of Alzheimer's disease and suggest that medial temporal lobe structures may represent the initial site of NFT Formation.
Abstract: Objective: To determine the relationships between dementia severity and the extent of histopathologic lesions in a variety of brain regions. Neocortical and hippocampal ratings for neurofibrillary tangles (NFTs) and senile plaques (SPs) were compared in 70 cases of clinically and neuropathologically confirmed Alzheimer's disease. Design: Neuropathologic case series. Dementia severity was assessed by postmortem chart review with use of the extended Clinical Dementia Rating Scale (CDR). Linear association between CDR scores and NFT and SP scores were assessed by partial correlation, controlling for age at death. Setting: Studies were conducted at the Alzheimer's Disease Research Center of the Mount Sinai Medical Center, New York, NY. Main Outcome Measure: Association between CDR scores and neuropathologic changes assessed with the Consortium to Establish a Registry for Alzheimer's Disease semiquantitative scale. Results: Among these lesion scores, only NFTs showed a significant association with CDR score, and only for neocortical regions. In particular, NFT densities in the superior temporal cortex were most strongly correlated with dementia severity, followed by those in the inferior parietal and midfrontal cortex. No such correlations were apparent for the amygdala, hippocampus, or entorhinal cortex. Medial temporal lobe structures displayed high NFT scores, even in cases of mild dementia. Senile plaques did not correlate significantly with CDR score in any region. Conclusions: These data support the notion that neocortical neuronal degeneration, as indicated by NFT formation, is a critical determinant of the clinical progression of Alzheimer's disease and suggest that medial temporal lobe structures may represent the initial site of NFT formation. While SP density correlates with age at death, there is no correlation between SP counts and dementia severity. These results further suggest that the clinical presentation of dementia may be closely related to neurodegeneration in neocortical regions within the temporal lobe.

509 citations


Journal ArticleDOI
TL;DR: Analysis of the ASM deficient mice showed their tissues had no detectable ASM activity, the blood cholesterol levels and sphingomyelin in the liver and brain were elevated, and atrophy of the cerebellum and marked deficiency of Purkinje cells was evident.
Abstract: Types A and B Niemann–Pick disease (NPD) result from the deficient activity of acid sphingomyelinase (ASM) An animal model of NPD has been created by gene targeting In affected animals, the disease followed a severe, neurodegenerative course and death occurred by eight months of age Analysis of these animals showed their tissues had no detectable ASM activity, the blood cholesterol levels and sphingomyelin in the liver and brain were elevated, and atrophy of the cerebellum and marked deficiency of Purkinje cells was evident Microscopic analysis revealed NPD ‘cells’ in reticuloendothelial organs and characteristic NPD lesions in the brain Thus, the ASM deficient mice should be of great value for studying the pathogenesis and treatment of NPD, and for investigations into the role of ASM in signal transduction and apoptosis

Journal ArticleDOI
TL;DR: This paper used a linear structural relations modeling technique (LISREL) to examine longitudinal data for 1,192 persons from a community-based population to predict cognitive change over a 2.0-to 2.5-year period in older adults aged 70-79 at the initial evaluation.
Abstract: This study used a linear structural relations modeling technique (LISREL) to examine longitudinal data for 1,192 persons from a community-based population. The goal was to test the ability of an a priori model to predict cognitive change over a 2.0- to 2.5-year period in older adults aged 70-79 at the initial evaluation. The model included 22 demographic, physical, and psychosocial variables as predictors of cognitive function and cognitive change. The study used an exploratory-confirmatory design, enabling cross-validation of the model developed in the exploratory set in the confirmatory sample. Structural equation modeling analyses identified 4 endogenous model variable (education, strenuous activity, peak pulmonary expiratory flow rate, and self-efficacy) as direct predictors of cognitive change over the study period.

Journal ArticleDOI
TL;DR: The data support the hypothesis of an enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal axis in PTSD and combat veterans with PTSD suppressed cortisol to a greater extent than did combat veterans without PTSD and normal controls in response to both doses of dexamethasone.
Abstract: Background: Our previous studies have suggested that combat veterans with posttraumatic stress disorder (PTSD) have alterations in hypothalamic-pituitary-adrenal axis functioning that are different from the well-documented biological changes observed in major depressive disorder and following exposure to stress. Methods: In the present study, we examined cortisol and lymphocyte glucocorticoid receptor number before and after the administration of 0.50 and 0.25 mg of dexamethasone in 14 combat veterans with PTSD, 12 combat veterans without PTSD, and 14 nonpsychiatric healthy men. All subjects were medication free at the time of testing and none met diagnostic criteria for major depression or substance dependence. Results: Combat veterans with PTSD suppressed cortisol to a greater extent than did combat veterans without PTSD and normal controls in response to both doses of dexamethasone. Differences in cortisol suppression could not be attributed to substance dependence history or differences in dexamethasone bioavailability. Combat veterans with PTSD showed a larger number of baseline glucocorticoid receptors compared with normal men. Combat veterans without PTSD also had a larger number of baseline glucocorticoid receptors compared with normal men and in fact were comparable to combat veterans with PTSD on this measure. However, only veterans with PTSD showed a decrease in lymphocyte glucocorticoid receptor number following dexamethasone administration. Conclusion: The data support the hypothesis of an enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal axis in PTSD.

Journal ArticleDOI
TL;DR: The present findings replicate the authors’ previous observation of low urinary cortisol excretion in combat veterans with PTSD and extend these findings to a non-treatment-seeking civilian group, demonstrating that low cortisol levels are associated with PTSD symptoms of a clinically significant nature, rather than occurring as a result of exposure to trauma per se.
Abstract: Objective: The authors’ objective was to compare the urinary cortisol excretion of Holocaust survivors with posttraumatic stress disorder (PTSD) (N=22) to that ofHolocaust survivors without PTSD (N=25) and comparison subjects not exposed to the Holocaust (N=15). Method: Twenty-four-hour urine samples were collected, and the following day, subjects were evaluated for the presence and severity ofpast and current PTSD and other psychiatric conditions. Results: Holocaust survivors with PTSD showed significantly lower mean 24-hour urinary cortisol excretion than the two groups ofsubjects without PTSD. Multiple correlation analysis revealed a significant relationship between cortisol levels and severity of PTSD that was due to a substantial association with scores on the avoidance subscale. Conclusions: The present findings replicate the authors’ previous observation oflow urinary cortisol excretion in combat veterans with PTSD and extend these findings to a non-treatment-seeking civilian group. The results also demonstrate that low cortisol levels are associated with PTSD symptoms ofa clinically significant nature, rather than occurring as a result ofexposure to trauma per se, and that low cortisollevels may persist for decades following exposure to trauma among individuals with chronic PTSD. (AmJ Psychiatry 1995; 152:982-986)

Journal ArticleDOI
01 Jun 1995-Stroke
TL;DR: It is demonstrated that although reduced CPP causes the initial decrease in cortical blood flow after SAH, secondary reductions occurring after CPP has reached its nadir are caused by other factors such as acute vasoconstriction.
Abstract: Background and Purpose Acute cerebral ischemia after subarachnoid hemorrhage (SAH) is a major cause of morbidity whose precise etiology is unclear The purpose of this study was to examine the relationships between cerebral perfusion pressure (CPP) and cortical blood flow during SAH using a new experimental model in the rat Methods CPP (mean arterial pressure minus intracranial pressure), cortical laser-Doppler flowmetry (LDF), and electroencephalogram were continuously recorded during and after SAH in 16 ventilated rats SAH was produced by advancing an intraluminal suture from the external carotid artery through the internal carotid artery to perforate the vessel near its intracranial bifurcation Results Eight rats (50%) died within 24 hours of SAH In all rats, blood was widely distributed throughout the basal, convexity, and interhemispheric subarachnoid spaces and throughout the ventricular system CPP decreased after SAH at an initial rate of 11±02 mm Hg/s, reaching its nadir 59±9 seconds after the onset of SAH During the same period, LDF fell at a rate of 14±03%/s ( P =NS vs CPP) After reaching its nadir, CPP rose at a rate of 04±001 mm Hg/s, but LDF continued to fall at 02±003%/s ( P <05 vs CPP) reaching a nadir of 217±25% significantly later than CPP (1895±39 s after SAH, P <05) No correlation was found between peak changes in CPP and LDF Electroencephalogram activity followed the changes in LDF, reaching nadir values 289±55 seconds after SAH Conclusions These findings demonstrate that although reduced CPP causes the initial decrease in cortical blood flow after SAH, secondary reductions occurring after CPP has reached its nadir are caused by other factors such as acute vasoconstriction This noncraniotomy model of SAH in the rat has several advantages over existing models

Journal ArticleDOI
30 Mar 1995-Nature
TL;DR: It is shown that an inductive signal from dorsal ectodermal cells is required for activation of tinman in the underlying mesoderm and present evidence that Decapenta-plegic (Dpp), a member of the transforming growth factor-β superfamily, serves as a signalling molecule in this process.
Abstract: After gastrulation, progenitor cells of the cardiac, visceral and body wall musculature arise at defined positions within the mesodermal layer of the Drosophila embryo. The regulatory mechanisms underlying this process of pattern formation are largely unknown, although ablation experiments carried out in other insects indicate that inductive influences from ectodermal cells have major roles in embryonic mesoderm differentiation. An early and important event in the regional subdivision of the mesoderm is the restriction of tinman expression to dorsal mesodermal cells. Genetic analysis has shown that this homeobox gene controls the formation of the visceral musculature and the heart from dorsal portions of the mesoderm. We now show that an inductive signal from dorsal ectodermal cells is required for activation of tinman in the underlying mesoderm and present evidence that Decapentaplegic (Dpp), a member of the transforming growth factor-beta superfamily, serves as a signalling molecule in this process. This demonstrates that the spatial expression of dpp in the ectoderm determines which cells of the mesoderm become competent to develop into visceral mesoderm and the heart.

Journal ArticleDOI
David Lanier1, Neil Schram2, Ellen C. Cooper3, Kenneth A. Freedberg4, Kenneth H. Mayer5, Richard Blinkhorn6, Jerrold J. Ellner6, Fred Angulo2, Ruth L. Berkelman2, Robert F. Breiman2, Ralph T. Bryan2, James W. Buehler2, Blake Caldwell2, Kenneth G. Castro2, James E. Childs2, Susan Chu2, Carol A. Ciesielski2, D. Peter Drotman2, Brian R. Edlin2, Tedd V. Ellerbrock2, Patricia L. Fleming2, Larry Geiter2, Rana A. Hajjeh2, Debra L. Hanson2, Scott D. Holmberg2, James M. Hughes2, Harold W. Jaffe2, Jeffrey L. Jones2, Dennis D. Juranek2, Jonathan E. Kaplan2, David W. Keller2, William J. Martone2, Michael M. Mc Neil2, Bess Miller2, Thomas R. Navin2, Verla S. Neslund2, Stephen M. Ostroff2, Philip E. Pellett2, Robert W. Pinner2, Susan E. Reef2, William C. Reeves2, Russell L. Regnery2, Frank O. Richards2, Martha F. Rogers2, Lawrence B. Schonberger2, R. J. Simonds2, Patricia M. Simone2, Dawn K. Smith2, Steven L. Solomon2, Richard A. Spiegel2, John A. Stewart2, David L. Swerdlow2, Suzanne D. Vernon2, John W. Ward2, Joyce J. Neal7, Walter F. Schlech8, Catherine M. Wilfert9, Robert Horsburgh10, John Mc Gowan10, David Rimland10, Mark Goldberger11, Carol Braun Trapnell11, David Barr12, Gabriel Torres12, Harrison C. Stetler, Peter A. Gross13, Wafaa El-Sadr14, Deborah J. Cotton15, Wayne L. Greaves16, John Bartlett17, Richard E. Chaisson17, Judith Feinberg17, Thomas C. Quinn17, Joseph Horman18, Kristine Mac Donald, Mary E. Wilson19, Rhoda S. Sperling20, Alberto Avandano, A. Cornelius Baker, Anthony R. Kalica21, Joseph A. Kovacs21, Henry Masur21, Michael A. Polis21, Steven M. Schnittman21, Charles Nelson, John P. Phair22, Constance A. Benson23, Bob Wood, Walter T. Hughes24, Benjamin J. Luft25, Newton E. Hyslop26, Richard J. Whitley27, Neil M. Ampel28, W. Lawrence Drew29, Jane E. Koehler29, Constance B. Wofsy29, James D. Neaton30, Fred R. Sattler31, Sharon A. Baker32, Lawrence Corey32, King K. Holmes32, William G. Powderly33 

Journal ArticleDOI
TL;DR: The outcome of 60 patients with cranial base chordoma or chondrosarcoma treated with extensive surgical resection between 1984 and 1993 is analyzed to find postoperative leakage of cerebrospinal fluid was the most frequent complication and was found to increase the risk of permanent disability.
Abstract: THE MANAGEMENT OF chordomas and chondrosarcomas involving the cranial base remains controversial. The options for therapy include biopsy, partial resection, radical resection, and various forms of radiotherapy. In this article, we analyze the outcome of 60 patients with cranial base chordoma

Journal ArticleDOI
TL;DR: Functional assays in organ culture and in vivo and studies of KGF regulation by sex sterorid hormones reinforced the idea that KGF acts predominantly on epithelial cells to elicit a variety of responses including proliferation, migration and morphogenesis.

Journal ArticleDOI
TL;DR: Induction immunotherapy, by reducing the rate of early rejection, may delay the clinical recurrence of hepatitis C and is associated with a higher incidence and earlier presentation of recurrent hepatitis C.

Journal ArticleDOI
15 Feb 1995-Blood
TL;DR: APL associated with t(11;17) and fusion of the PLZF and RAR alpha genes is a discrete clinico-pathologic syndrome with a distinctly worse prognosis than t(15;17), and six patients failed to achieve complete remission after initial chemotherapy or differentiation therapy with all-trans retinoic acid (ATRA).

Journal ArticleDOI
01 Dec 1995-Neuron
TL;DR: Observations indicate that in early LTP the cAMP signaling pathway, instead of transmitting signals for the generation of LTP, gates LTP through postsynaptic protein phosphatases.


Journal ArticleDOI
TL;DR: Compared the expression pattern of the fibrillin genes during mammalian embryogenesis revealed that the two genes are differentially expressed, in terms of both developmental stages and tissue distribution, lending indirect support to the original hypothesis stating that fibrillins contribute to the compositional and functional heterogeneity of the microfibrils.
Abstract: Extracellular microfibrils, alone or in association with elastin, confer critical biomechanical properties on a variety of connective tissues. Little is known about the composition of the microfibrils or the factors responsible for their spatial organization into tissue-specific macroaggregates. Recent work has revealed the existence of two structurally related microfibrillar components, termed fibrillin-1 and fibrillin-2. The functional relationships between these glycoproteins and between them and other components of the microfibrils and elastic fibers are obscure. As a first step toward elucidating these important points, we compared the expression pattern of the fibrillin genes during mammalian embryogenesis. The results revealed that the two genes are differentially expressed, in terms of both developmental stages and tissue distribution. In the majority of cases, fibrillin-2 transcripts appear earlier and accumulate for a shorter period of time than fibrillin-1 transcripts. Synthesis of fibrillin-1 correlates with late morphogenesis and the appearance of well-defined organ structures; fibrillin-2 synthesis, on the other hand, coincides with early morphogenesis and, in particular, with the beginning of elastogenesis. The findings lend indirect support to our original hypothesis stating that fibrillins contribute to the compositional and functional heterogeneity of the microfibrils. The available evidence is also consistent with the notion that the fibrillins might have distinct, but related roles in microfibril physiology. Accordingly, we propose that fibrillin-1 provides mostly force-bearing structural support, whereas fibrillin-2 predominantly regulates the early process of elastic fiber assembly.

Journal ArticleDOI
TL;DR: The method of gene circuits is used, which is a new approach to the analysis of gene expression data to infer how concentrations of products of a given gene change with time and how these changes are influenced by the activating or repressing effects of the products of other genes.

Journal ArticleDOI
TL;DR: The older schizophrenic patients continued to experience psychotic and nonpsychotic symptoms in senescence and Somatic treatment appeared not to be responsible for the severe cognitive impairment and negative symptoms of the older patients.
Abstract: Objective: The goal ofthis study was to characterize the symptoms ofgeriatric, chronically ill, institutionalized schizophrenic patients and investigate age-related differences in schizophrenic symptoms and cognitive performance from early adulthood to late senescence. Method: The Positive and Negative Syndrome Scale and the Mini-Mental State examination were used to assess the schizophrenic symptoms and cognitive performance, respectively, of 3 93 institutionalized schizophrenic patients stratified into seven groups designated by 1 0-year age intervals from 25 years to over 85 years. Results: In the comparisons of the seven age groups, significant differences between groups in positive and negative subscale scores on the Positive and Negative Syndrome Scale and in Mini-Mental State scores were revealed. Significant correlations between Mini-Mental State scores and Positive and Negative Syndrome Scale negative symptom scores, but not positive symptom scores, were found for all age groups, except for the youngest patients studied. Current treatment with neuroleptics and prior treatment with ECT, insulin coma, or leukotomy could not account for the poor cognitive perf ormance of the older schizophrenic patients. Conclusions: The older schizophrenic patients continued to experience psychotic and nonpsychotic symptoms in senescence. Their positive symptoms were moderately less severe and their negative symptoms and cognitive impairment were significantly more severe than those ofthe younger patients. Somatic treatment appeared not to be responsible for the severe cognitive impairment and negative symptoms of the older patients. These data are relevant to chronically hospitalized geriatric schizophrenic patients but not necessarily to all geriatric schizophrenic patients. (AmJ Psychiatry 1995; 152:197-207)

Journal ArticleDOI
TL;DR: This article investigated a broad range of memory functions for stimuli unrelated to trauma to determine whether symptoms such as intrusive memories might reflect an underlying cognitive deficit unrelated to the psychological content of the traumatic memory in patients with posttraumatic stress disorder.
Abstract: Objective The authors investigated a broad range of memory functions for stimuli unrelated to trauma to determine whether symptoms such as intrusive memories might reflect an underlying cognitive deficit unrelated to the psychological content of the traumatic memory in patients with posttraumatic stress disorder (PTSD). Method The authors measured the intellectual functioning of 20 male combat veterans with PTSD and 12 normal comparison subjects using the WAIS and evaluated them for performance on memory using the California Verbal Learning Test. Results Veterans with PTSD showed normal abilities in the functions of initial attention, immediate memory, cumulative learning, and active interference from previous learning. However, these veterans showed a circumscribed cognitive deficit, manifested by the presence of substantial retroactive interference and revealed by a significant decrement in retention following exposure to an intervening word list. Conclusions The data suggest that patients with PTSD may have fairly specific deficits in the monitoring and regulation of memory information.

Journal ArticleDOI
26 May 1995-Science
TL;DR: The region defined by residues 956 to 982 of adenylyl cyclase 2 may contain determinants important for receiving signals from G beta gamma, which is conserved in regions of potassium channels and beta-adrenergic receptor kinases that participate in G beta Gamma interactions.
Abstract: Receptor-mediated activation of heterotrimeric guanine nucleotide-binding proteins (G proteins) results in the dissociation of alpha from beta gamma subunits, thereby allowing both to regulate effectors. Little is known about the regions of effectors required for recognition of G beta gamma. A peptide encoding residues 956 to 982 of adenylyl cyclase 2 specifically blocked G beta gamma stimulation of adenylyl cyclase 2, phospholipase C-beta 3, potassium channels, and beta-adrenergic receptor kinase as well as inhibition of calmodulin-stimulated adenylyl cyclases, but had no effect on interactions between G beta gamma and G alpha o. Substitutions in this peptide identified a functionally important motif, Gln-X-X-Glu-Arg, that is also conserved in regions of potassium channels and beta-adrenergic receptor kinases that participate in G beta gamma interactions. Thus, the region defined by residues 956 to 982 of adenylyl cyclase 2 may contain determinants important for receiving signals from G beta gamma.

Journal ArticleDOI
TL;DR: This study provides final proof of the association between FBN2 mutations and CCA pathology, thus establishing the role of the fibrillin-2 in extracellular matrix physiology and pathology.
Abstract: Congenital contractural arachnodactyly (CCA) is an autosomal dominant disorder that is phenotypically similar to Marfan syndrome (MFS) and characterized by arachnodactyly, dolichostenomelia, scoliosis, multiple congenital contractures and abnormalities of the external ears. In contrast to MFS, CCA does not affect the aorta or the eyes. Two closely related genes, FBN1 located on chromosome 15q15-21.3 and FBN2 located at 5q23-31, encode large fibrillin proteins found in extracellular matrix structures called microfibrils. The MFS is caused by mutations in FBN1, while CCA has been genetically linked to FBN2 (refs 2, 5, 6). We now describe a pair of FBN2 missense mutations in two CCA patients that cause substitution of distinct cysteine residues in separate epidermal growth-factor-like (EGF) repeats. Our study provides final proof of the association between FBN2 mutations and CCA pathology, thus establishing the role of the fibrillin-2 in extracellular matrix physiology and pathology.

Journal ArticleDOI
TL;DR: It is possible that neurofilament protein is crucial for the unique capacity of certain subsets of neurons to perform the highly precise mapping functions of the monkey visual system.
Abstract: Visual function in monkeys is subserved at the cortical level by a large number of areas defined by their specific physiological properties and connectivity patterns. For most of these cortical fields, a precise index of their degree of anatomical specialization has not yet been defined, although many regional patterns have been described using Nissl or myelin stains. In the present study, an attempt has been made to elucidate the regional characteristics, and to varying degrees boundaries, of several visual cortical areas in the macaque monkey using an antibody to neurofilament protein (SMI32). This antibody labels a subset of pyramidal neurons with highly specific regional and laminar distribution patterns in the cerebral cortex. Based on the staining patterns and regional quantitative analysis, as many as 28 cortical fields were reliably identified. Each field had a homogeneous distribution of labeled neurons, except area V1, where increases in layer IVB cell and in Meynert cell counts paralleled the increase in the degree of eccentricity in the visual field representation. Within the occipitotemporal pathway, areas V3 and V4 and fields in the inferior temporal cortex were characterized by a distinct population of neurofilament-rich neurons in layers II-IIIa, whereas areas located in the parietal cortex and part of the occipitoparietal pathway had a consistent population of large labeled neurons in layer Va. The mediotemporal areas MT and MST displayed a distinct population of densely labeled neurons in layer VI. Quantitative analysis of the laminar distribution of the labeled neurons demonstrated that the visual cortical areas could be grouped in four hierarchical levels based on the ratio of neuron counts between infragranular and supragranular layers, with the first (areas V1, V2, V3, and V3A) and third (temporal and parietal regions) levels characterized by low ratios and the second (areas MT, MST, and V4) and fourth (frontal regions) levels characterized by high to very high ratios. Such density trends may correspond to differential representation of corticocortically (and corticosubcortically) projecting neurons at several functional steps in the integration of the visual stimuli. In this context, it is possible that neurofilament protein is crucial for the unique capacity of certain subsets of neurons to perform the highly precise mapping functions of the monkey visual system.