James ters Medical Center
James ters Medical Center
Sillivan S.E.,Mount Sinai School of Medicine |
Whittard J.D.,Mount Sinai School of Medicine |
Jacobs M.M.,Mount Sinai School of Medicine |
Ren Y.,Mount Sinai School of Medicine |
And 10 more authors.
Biological Psychiatry | Year: 2013
Background Abuse of heroin and prescription opiate medications has grown to disturbing levels. Opioids mediate their effects through mu opioid receptors (MOR), but minimal information exists regarding MOR-related striatal signaling relevant to the human condition. The striatum is a structure central to reward and habitual behavior and neurobiological changes in this region are thought to underlie the pathophysiology of addiction disorders. Methods We examined molecular mechanisms related to MOR in postmortem human brain striatal specimens from a homogenous European Caucasian population of heroin abusers and control subjects and in an animal model of heroin self-administration. Expression of ets-like kinase 1 (ELK1) was examined in relation to polymorphism of the MOR gene OPRM1 and drug history. Results A characteristic feature of heroin abusers was decreased expression of MOR and extracellular regulated kinase signaling networks, concomitant with dysregulation of the downstream transcription factor ELK1. Striatal ELK1 in heroin abusers associated with the polymorphism rs2075572 in OPRM1 in a genotype dose-dependent manner and correlated with documented history of heroin use, an effect reproduced in an animal model that emphasizes a direct relationship between repeated heroin exposure and ELK1 dysregulation. A central role of ELK1 was evidenced by an unbiased whole transcriptome microarray that revealed ~20% of downregulated genes in human heroin abusers are ELK1 targets. Using chromatin immune precipitation, we confirmed decreased ELK1 promoter occupancy of the target gene Use1. Conclusions ELK1 is a potential key transcriptional regulatory factor in striatal disturbances associated with heroin abuse and relevant to genetic mutation of OPRM1. © 2013 Society of Biological Psychiatry.
Pol S.,Hopital Cochin |
Ghalib R.H.,The Texas Institute |
Rustgi V.K.,Metropolitan Research |
Martorell C.,The Research Institute |
And 18 more authors.
The Lancet Infectious Diseases | Year: 2012
Background: Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV. Methods: In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 μg per week) and ribavirin (1000-1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with. ClinicalTrials.gov, number. NCT00874770. Findings: 48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22-64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61-96%) who received 10 mg daclatasvir, nine of 12 (75%, 53-90%) who received 60 mg daclatasvir, and one of 12 (8%, 1-29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups. Interpretation: Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection. Funding: Bristol-Myers Squibb. © 2012 Elsevier Ltd.
Garrido M.M.,James ters Medical Center |
Garrido M.M.,Mount Sinai School of Medicine |
Idler E.L.,Emory University |
Leventhal H.,Rutgers University |
Carr D.,Rutgers University
Gerontologist | Year: 2013
Purpose of the Study: To evaluate the extent to which religious affiliation and self-identified religious importance affect advance care planning (ACP) via beliefs about control over life length and end-of-life values. Design and Methods: Three hundred and five adults aged 55 and older from diverse racial and socioeconomic groups seeking outpatient care in New Jersey were surveyed. Measures included discussion of end-of-life preferences; living will (LW) completion; durable power of attorney for healthcare (DPAHC) appointment; religious affiliation; importance of religion; and beliefs about who/what controls life length, end-of-life values, health status, and sociodemographics. Results: Of the sample, 68.9% had an informal discussion and 46.2% both discussed their preferences and did formal ACP (LW and/or DPAHC). Conservative Protestants and those placing great importance on religion/spirituality had a lower likelihood of ACP. These associations were largely accounted for by beliefs about God's controlling life length and values for using all available treatments. Implications: Beliefs and values about control account for relationships between religiosity and ACP. Beliefs and some values differ by religious affiliation. As such, congregations may be one nonclinical setting in which ACP discussions could be held, as individuals with similar attitudes toward the end of life could discuss their treatment preferences with those who share their views. © The Author 2013. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.
Katsel P.,Mount Sinai School of Medicine |
Tan W.,Mount Sinai School of Medicine |
Abazyan B.,Johns Hopkins University |
Davis K.L.,Mount Sinai School of Medicine |
And 4 more authors.
Schizophrenia Research | Year: 2011
Abnormalities in oligodendrocyte (OLG) differentiation and OLG gene expression deficit have been described in schizophrenia (SZ). Recent studies revealed a critical requirement for Disrupted-in-Schizophrenia 1 (DISC1) in neural development. Transgenic mice with forebrain restricted expression of mutant human DISC1 (δhDISC1) are characterized by neuroanatomical and behavioral abnormalities reminiscent of some features of SZ. We sought to determine whether the expression of δhDISC1 may influence the development of OLGs in this mouse model.OLG- and cell cycle-associated gene and protein expression were characterized in the forebrain of δhDISC1 mice during different stages of neurodevelopment (E15 and P1 days) and in adulthood.The results suggest that the expression of δhDISC1 exerts a significant influence on oligodendrocyte differentiation and function, evidenced by premature OLG differentiation and increased proliferation of their progenitors. Additional findings showed that neuregulin 1 and its receptors may be contributing factors to the observed upregulation of OLG genes.Thus, OLG function may be perturbed by mutant hDISC1 in a model system that provides new avenues for studying aspects of the pathogenesis of SZ. © 2011 Elsevier B.V.
Horesh Y.,Weizmann Institute of Science |
Katsel P.,Mount Sinai School of Medicine |
Haroutunian V.,Mount Sinai School of Medicine |
Haroutunian V.,James ters Medical Center |
Domany E.,Weizmann Institute of Science
European Journal of Neurology | Year: 2011
Background: Alzheimer's disease and Schizophrenia are two common diseases of the brain with significant differences in neuropathology, etiology and symptoms. This dissimilarity in the two diseases makes a comparison of the two ideal for detecting molecular substrates that are common to brain disorders in general. Methods: In this study, we compared gene expression profiles across multiple brain areas, taken postmortem from patients with well-characterized Alzheimer's disease and Schizophrenia, and from cognitively normal control group with no neuro- or psychopathology. Results: Although the totality of gene expression changes in the two diseases is dissimilar, a subset of genes appears to play a role in both diseases in specific brain regions. We find at Brodmann area 22, the superior temporal gyrus, a statistically significant number of genes with apparently disregulated expression in both diseases. Furthermore, we found genes that differentiate the two diseases from the control across multiple brain regions, and note that these genes were usually down-regulated. Brodmann area 8, part of the superior frontal cortex, is relatively abundant with them. Conclusion: We show overwhelming statistical evidence for Alzheimer's and Schizophrenia sharing a specific molecular background at the superior temporal gyrus. We suggest that impairment of the regulation of autophagy pathway is shared, in BA 22, by the two diseases. © 2010 The Author(s). European Journal of Neurology © 2010 EFNS.
Caesar I.,Mount Sinai School of Medicine |
Caesar I.,James ters Medical Center |
Gandy S.,Mount Sinai School of Medicine |
Gandy S.,James ters Medical Center
BMC Medicine | Year: 2012
emporal lobe epilepsy (TLE) is associated with some of the same neuropathological features as those reported for early stages of typical Alzheimer's disease (AD). The APOE ε4 allele is associated with a gene-dose-dependent increase in AD risk and in the severity of amyloid-β (Aβ) pathology. In a study published in the current BMC Medicine, Sue Griffin and colleagues studied markers of brain resilience in the amputated temporal lobes of TLE patients. They discovered compelling evidence that the APOE ε3 isoform in TLE patients is apparently more neuroprotective from Aβ toxicity than is the APOE ε4 isoform, as shown by the reduced levels of neuronal damage, glial activation, and expression of IL-1α in the APOE ε3/ε3 brains. This result points to a new property of APOE isoforms: not only are APOE ε4 alleles associated with increased brain amyloid plaque burden, but these alleles are also apparently inferior to APOE ε3 alleles in conveying resistance to Aβ neurotoxicity. This 'double whammy' result opens up a new direction for studies aimed at elucidating the relevant neurobiological activities of APOE isoforms in the pathogenesis of AD. Please see related article: http://www.biomedcentral.com/1741-7015/10/35 © 2012 Caesar and Gandy.
Hertzberg L.,Weizmann Institute of Science |
Hertzberg L.,Tel Aviv University |
Katsel P.,Mount Sinai School of Medicine |
Roussos P.,Mount Sinai School of Medicine |
And 3 more authors.
Schizophrenia Research | Year: 2015
The number of Genome Wide Association Studies (GWAS) of schizophrenia is rapidly growing. However, the small effect of individual genes limits the number of reliably implicated genes, which are too few and too diverse to perform reliable pathway analysis; hence the biological roles of the genes implicated in schizophrenia are unclear. To overcome these limitations we combine GWAS with genome-wide expression data from human post-mortem brain samples of schizophrenia patients and controls, taking these steps: 1) Identify 36 GWAS-based genes which are expressed in our dataset. 2) Find a cluster of 19 genes with highly correlated expression. We show that this correlation pattern is robust and statistically significant. 3) GO-enrichment analysis of these 19 genes reveals significant enrichment of ion channels and calcium-related processes. This finding (based on analyzing a small number of coherently expressed genes) is validated and enhanced in two ways: First, the emergence of calcium channels and calcium signaling is corroborated by identifying proteins that interact with those encoded by the cluster of 19. Second, extend the 19 cluster genes into 1028 genes, whose expression is highly correlated with the cluster's average profile. When GO-enrichment analysis is performed on this extended set, many schizophrenia related pathways appear, with calcium-related processes enriched with high statistical significance. Our results give further, expression-based validation to GWAS results, support a central role of calcium-signaling in the pathogenesis of schizophrenia, and point to additional pathways potentially related to the disease. © 2015 Elsevier B.V.
Goodman M.,James ters Medical Center
Journal of personality disorders | Year: 2010
Borderline personality disorders (BPD) and major depressive disorder (MDD) are distinct disorders with overlapping biological processes pertaining to emotional regulatory functions. However, while both disorders share affective symptomatology, the disturbance central to BPD is affective lability and its character is entirely different from the affective disturbance of MDD. This review highlights data from the last ten years and compares the two disorders' phenotypes, putative endophenotypes and genotypes, focusing heavily on neuroimaging findings. The familiality and phenotypic differences suggest that BPD differs in important ways with respect to symptomatology, prognosis, and heritability. The neurobiological findings in both MDD and BPD are still preliminary at present, and no coherent model for either disorder can be said to have emerged. Overlapping biological processes including amygdala hyperreactivity, volume changes in subgenual anterior cingulate cortex, and deficient serotonergic function appear to underlie emotional dysregulation in both disorders. However, the disorders seem to differ in their patterns of brain region involvement, neurohormonal indices, and sleep architecture. At present, the minimal data available for putative genotypes of BPD is still emerging, nonspecific to the disorder and demonstrates significant overlap with MDD. The ability to discern commonalities and differences in the neurobiology of these two disorders is limited by the differing methodologies applied in different studies. Definitive clarification of what MDD and BPD have in common and in what ways they are distinct will only be derived from studies that examine both illnesses using the same study design and methodology.
Koenigsberg H.W.,James ters Medical Center
Journal of personality disorders | Year: 2010
Affective instability is a prominent feature of a wide variety of psychiatric and neurological disorders, yet it has not been systematically studied. It encompasses a number of distinct phenomena, including: (1) frequent affective category shifts, (2) disturbances in affect intensity, (3) excessively rapid emotion rise-times, (4) delayed return to emotional baseline, (5) excessive reactivity to psychosocial cues, (6) endogenously driven, random, chaotic or rapid-cycling changes, and (7) overdramatic expression. To further clarify the construct of affective instability, this article examines the manifestations of affective instability in a range of psychiatric and neurologic disorders, reviews relevant neurobiological and psychological emotion regulatory processes, and considers the psychology of affective instability.
Podolak E.,James ters Medical Center
International Journal of Adolescent Medicine and Health | Year: 2015
Suicide is a major public health problem and the 10th leading cause of death in the United States. Due to low base rates and the numerous comorbid risk factors associated with suicide, accurate prediction is difficult. This is particularly true for adolescents and young adults. In this article, some associated risk factors are discussed in the context of two high-risk populations (young adult prison inmates and young adult veterans) and several recommendations are made for conducting suicide risk assesments. General prescriptions for intervention are also outlined with the goal of reducing overly defensive practice and increasing the likelihood that high-risk individuals will receive effective intervention. Finally, several suggestions for future research are made. © 2015 by De Gruyter.