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The Icahn School of Medicine at Mount Sinai , formerly the Mount Sinai School of Medicine , is an American medical school in the New York City borough of Manhattan in the state of New York. Chartered by Mount Sinai Hospital in 1963, the ISMMS is one of the foremost medical schools in the United States, ranking 19th in research according to U.S. News & World Report, 18th in NIH funding among U.S Medical Schools , and 3rd in NIH funding per primary investigator.ISMMS and the Mount Sinai Hospital occupy a four-block area adjacent to Central Park on the Upper East Side of Manhattan, with architecture designed by I. M. Pei. ISMMS and Mount Sinai Hospital comprise the Mount Sinai Medical Center, of which Kenneth L. Davis, MD, is the president and CEO.In 2012–13, The Mount Sinai Medical Center was recognized on the U.S. News & World Report "Best Hospitals Honor Roll," ranking 14th among the approximately 5000 hospitals in the US with 11 nationally ranked specialties including cancer, geriatrics, gastroenterology, cardiology & heart surgery, otolaryngology, rehabilitation, diabetes & endocrinology, neurology & neurosurgery, gynecology, urology, and kidney disorders. Wikipedia.

Pilla A.A.,Columbia University | Pilla A.A.,Mount Sinai School of Medicine
Biochemical and Biophysical Research Communications | Year: 2012

This study shows that a non-thermal pulse-modulated RF signal (PRF), configured to modulate calmodulin (CaM) activation via acceleration of Ca2+ binding kinetics, produced an immediate nearly 3-fold increase in nitric oxide (NO) from dopaminergic MN9D cultures (P<0.001). NO was measured electrochemically in real-time using a NO selective membrane electrode, which showed the PRF effect occurred within the first seconds after lipopolysaccharide (LPS) challenge. Further support that the site of action of PRF involves CaM is provided in human fibroblast cultures challenged with low serum and exposed for 15min to the identical PRF signal. In this case a CaM antagonist W-7 could be added to the culture 3h prior to PRF exposure. Those results showed the PRF signal produced nearly a two-fold increase in NO, which could be blocked by W-7 (P<0.001). To the authors' knowledge this is the first report of a real-time effect of non-thermal electromagnetic fields (EMF) on NO release from challenged cells. The results provide mechanistic support for the many reported bioeffects of EMF in which NO plays a role. Thus, in a typical clinical application for acute post operative pain, or chronic pain from, e.g., osteoarthritis, EMF therapy could be employed to modulate the dynamics of NO via Ca/CaM-dependent constitutive nitric oxide synthase (cNOS) in the target tissue. This, in turn, would modulate the dynamics of the signaling pathways the body uses in response to the various phases of healing after physical or chemical insult or injury. © 2012 Elsevier Inc.

Medalia A.,Columbia University | Thysen J.,Mount Sinai School of Medicine
Schizophrenia Research | Year: 2010

Background: Schizophrenia is associated with neuropsychological deficits that have been linked to poor functional outcome. To address this problem, pharmacologic and behavioral treatments are being developed for cognitive impairments, but they will not be well utilized if people with schizophrenia do not perceive a need for treatment. Aims: This study compared whether people with schizophrenia have a similar degree of insight into neuro-cognitive symptoms as clinical symptoms, and whether neuro-cognitive and clinical symptoms are similarly related to degree of insight into these two aspects of the illness. Method: Seventy-one patients with schizophrenia were administered measures of clinical and neuro-cognitive status as well as clinician rated measures of insight into clinical and neuro-cognitive symptoms. Results: Patients had significantly less insight into their neuro-cognitive symptoms than their clinical symptoms. On average, patients had good insight into clinical symptoms and partial insight into neuro-cognitive symptoms. Neuropsychological variables were related to insight into clinical symptoms, but not insight into neuro-cognition. Clinical variables were not significantly related to either type of insight. Conclusions: Insight is not a unitary concept and the differences between awareness of neuro-cognition and awareness of clinical symptoms suggest that they have to be addressed separately in treatment. Specific education about cognitive symptoms may be necessary to improve awareness of this aspect of the schizophrenia. © 2009 Elsevier B.V.

Provasi D.,Mount Sinai School of Medicine
Biophysical journal | Year: 2010

A major current focus of structural work on G-protein-coupled receptors (GPCRs) pertains to the investigation of their active states. However, for virtually all GPCRs, active agonist-bound intermediate states have been difficult to characterize experimentally owing to their higher conformational flexibility, and thus intrinsic instability, as compared to inactive inverse agonist-bound states. In this work, we explored possible activation pathways of the prototypic GPCR bovine rhodopsin by means of biased molecular dynamics simulations. Specifically, we used an explicit atomistic representation of the receptor and its environment, and sampled the conformational transition from the crystal structure of a photoactivated deprotonated state of rhodopsin to the low pH crystal structure of opsin in the presence of 11-trans-retinal, using adiabatic biased molecular dynamics simulations. We then reconstructed the system free-energy landscape along the predetermined transition trajectories using a path collective variable approach based on metadynamics. Our results suggest that the two experimental endpoints of rhodopsin/opsin are connected by at least two different pathways, and that the conformational transition is populated by at least four metastable states of the receptor, characterized by a different amplitude of the outward movement of transmembrane helix 6. Copyright 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Janeway K.A.,Dana-Farber Cancer Institute | Maki R.G.,Mount Sinai School of Medicine
Clinical Cancer Research | Year: 2012

The ability to better interrogate the genetic state of a given cancer is giving rise to a new paradigm in cancer therapeutics in which the specific genetic alterations that give rise to the cancer inform the therapeutic decision-making for that specific patient. Sarcomas of soft tissue and bone represent model diseases that underscore this paradigm. However,many barriers prevent linkage of one of the 75 or more different types of sarcoma to novel therapeutic agents. In the present perspective, the authors outline key therapeutic opportunities and hurdles in clinical sarcoma research, focusing on specific examples of sarcomas that are on the verge of new breakthroughs, as well as those in which promise has not lived up to expectations. Focused clinical trial design, ideally with several biomarker or histology-specific arms, is one means to be simultaneously parsimonious and inclusive. ©2012 AACR.

Greenhawt M.,University of Michigan | Wang J.,Mount Sinai School of Medicine
Journal of Allergy and Clinical Immunology: In Practice | Year: 2013

Background: Significant recent changes to the recommendations in providing trivalent seasonal influenza vaccine (TIV) to individuals with egg allergy were made, but their implementation has not been studied. Objectives: To investigate allergist-reported compliance with updated TIV administration guidelines for individuals with egg allergy. Methods: A 22-question electronic survey was distributed via e-mail to American Academy of Allergy, Asthma, and Immunology members (allergists), which queried practice styles and attitudes that pertain to TIV administration to individuals with egg allergy. Results: Only 1% of 895 respondents believed that TIV should be contraindicated for individuals with egg allergy, 3.8% reported not administering TIV to individuals with egg allergy, and 17% reported only administering TIV to individuals with mild egg allergy; 13.2% reported that risk-mitigating precautions (eg, vaccine skin testing, graded-dose challenges) were necessary. Postimplementation change compared with preimplementation change included less intradermal testing (30.6% vs 64.9%), less multistep desensitization (34.7% vs 65.3%), observing more patients for >30 minutes after vaccination (79.1% vs 20.9%), administering TIV despite positive TIV skin tests (65.4% vs 34.6%) (all P < .001), but no significant reduction in performing TIV prick skin testing (46.2% vs 53.8%). Factors associated with not performing TIV skin testing included reading the guidelines (P= .028), academic practice (P < .01), and fewer years in practice (P < .01). Only 48.6% agreed that TIV can safely be administered in the primary care setting to individuals with egg allergy, and only 41.9% advised their patients accordingly. Conclusion: There were significant shifts in practice style over time concurrent with newly established guidelines, except for vaccine skin testing. Physician opinions are also concurrent with guideline changes. Although TIV administration guideline recommendations are being successfully implemented, greater adherence should be promoted. © 2013 American Academy of Allergy, Asthma & Immunology.

Morland K.B.,Mount Sinai School of Medicine
American Journal of Preventive Medicine | Year: 2010

Background The impact of local availability of healthy foods on dietary intake and health has been established. Interventions to local environments are being evaluated for their efficacy and sustainability. Purpose The aim of this paper is to provide an evaluation of a community-driven approach to transform neighborhood healthy food availability. Methods The information provided comes from minutes of monthly meetings of the partners, newsletters, media, and other store and project documentation. In addition, qualitative interviews with key stakeholders and co-op members were conducted. All of the participating individuals were interviewed during 2008 and analysis took place in 2010. Each interview was audio-taped and transcribed to form verbatim transcripts, then content analyzed for themes. Results The implementation phase of the initiative had long-standing negative repercussions on the ability of the store to be successful because of renting too large a space; not branding the store early; early misperceptions by community members about the store; and the changing of organizational partners and personnel, which resulted in a lack of leadership for the store. Equally important, the lack of project personnel or consultants with business experience directly related to operating a food store reverberated into issues related to marketing, price structuring, decisions about stocking the store, as well as accounting. Conclusions Repercussions of these challenges included unmet goals in terms of attracting local residents to become members of the co-op, low sales levels, and reduced confidence in the long-term sustainability of the food cooperative. Approaches to modifications of local food environments are likely to require additional resources beyond funding in order to secure positive outcomes. © 2010 American Journal of Preventive Medicine.

Rosenson R.S.,Mount Sinai School of Medicine | Stafforini D.M.,University of Utah
Journal of Lipid Research | Year: 2012

Lipoprotein-associated phospholipase A2 (Lp-PLA2), also known as platelet-activating factor acetylhydrolase (PAF-AH), is a unique member of the phospholipase A2superfamily. This enzyme is characterized by its ability to specifically hydrolyze PAF as well as glycerophospholipids containing short, truncated, and/or oxidized fatty acyl groups at the sn-2 position of the glycerol backbone. In humans, Lp-PLA 2 circulates in active form as a complex with low- and high-density lipoproteins. Clinical studies have reported that plasma Lp-PLA2 activity and mass are strongly associated with atherogenic lipids and vascular risk. These observations led to the hypothesis that Lp-PLA2 activity and/or mass levels could be used as biomarkers of cardiovascular disease and that inhibition of the activity could offer an attractive therapeutic strategy. Darapladib, a compound that inhibits Lp-PLA2 activity, is anti-atherogenic in mice and other animals, and it decreases atherosclerotic plaque expansion in humans. However, disagreement continues to exist regarding the validity of Lp-PLA2 as an independent marker of atherosclerosis and a scientifically justified target for intervention. Circulating Lp-PLA 2 mass and activity are associated with vascular risk, but the strength of the association is reduced after adjustment for basal concentrations of the lipoprotein carriers with which the enzyme associates. Genetic studies in humans harboring an inactivating mutation at this locus indicate that loss of Lp-PLA2function is a risk factor for inflammatory and vascular conditions in Japanese cohorts. Consistently, overexpression of Lp-PLA 2 has anti-inflammatory and anti-atherogenic properties in animal models. This thematic review critically discusses results from laboratory and animal studies, analyzes genetic evidence, reviews clinical work demonstrating associations between Lp-PLA2 and vascular disease, and summarizes results from animal and human clinical trials in which administration of darapladib was tested as a strategy for the management of atherosclerosis. Copyright © 2012 by the American Society for Biochemistry and Molecular Biology, Inc.

Lee C.M.,Mount Sinai School of Medicine
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2014

c-MYC is an oncogenic transcription factor that is degraded by the proteasome pathway. However, the mechanism that regulates delivery of c-MYC to the proteasome for degradation is not well characterized. Here, the results show that the motor protein complex Kinesin-1 transports c-MYC to the cytoplasm for proteasomal degradation. Inhibition of Kinesin-1 function enhanced ubiquitination of c-MYC and induced aggregation of c-MYC in the cytoplasm. Transport studies showed that the c-MYC aggregates moved from the nucleus to the cytoplasm and KIF5B is responsible for the transport in the cytoplasm. Furthermore, inhibition of the proteasomal degradation process also resulted in an accumulation of c-MYC aggregates in the cytoplasm. Moreover, Kinesin-1 was shown to interact with c-MYC and the proteasome subunit S6a. Inhibition of Kinesin-1 function also reduced c-MYC-dependent transformation activities. Taken together, the results strongly suggest that Kinesin-1 transports c-MYC for proteasomal degradation in the cytoplasm and the proper degradation of c-MYC mediated by Kinesin-1 transport is important for transformation activities of c-MYC. In addition, the results indicate that Kinesin-1 transport mechanism is important for degradation of a number of other proteins as well. © 2014 Elsevier B.V.

Madias J.E.,Mount Sinai School of Medicine
Netherlands Heart Journal | Year: 2013

A variety of electrocardiogram (ECG) alterations in patients with apical hypertrophic cardiomyopathy (AHCM) have been described in the literature, but no relevant quantitative analysis has been provided; thus the objective of this communication was to review the relevant literature and using two cases of patients with AHCM, to provide such a quantitative analysis. Using PubMed to search the literature 13 studies on the ECG in patients with AHCM were identified and evaluated; also a quantitative analysis of the ECG attributes in two patients was carried out. Qualitative ECG features from the literature on patients with AHCM is discussed. Also a description of the ECG in two patients with AHCM has identified as typical features truly giant QRS complexes in the precordial leads, particularly in lead V4, with rightward superior, and posterior shift of the T-wave vector, the latter being a newly described ECG correlate of AHCM. A speculation as to the possible mechanism of the observed ECG features is included. © The Author(s) 2013.

Sugar I.P.,Mount Sinai School of Medicine | Chong P.L.-G.,Temple University
Journal of the American Chemical Society | Year: 2012

Despite extensive studies for nearly three decades, lateral distribution of molecules in cholesterol/phospholipid bilayers remains elusive. Here we present a statistical mechanical model of cholesterol/phospholipid mixtures that is able to rationalize almost every critical mole fraction (X cr) value previously reported for sterol superlattice formation as well as the observed biphasic changes in membrane properties at X cr. This model is able to explain how cholesterol superlattices and cholesterol/phospholipid condensed complexes are interrelated. It gives a more detailed characterization of the LG Iregion (a broader region than the liquid disordered-liquid ordered mixed-phase region), which is considered to be a sludgelike mixture of fluid phase and aggregates of rigid clusters. A rigid cluster is formed by a cholesterol molecule and phospholipid molecules that are condensed to the cholesterol. Rigid clusters of similar size tend to form aggregates, in which cholesterol molecules are regularly distributed into superlattices. According to this model, the extent and type of sterol superlattices, thus the lateral distribution of the entire membrane, should vary with cholesterol mole fraction in a delicate, predictable, and nonmonotonic manner, which should have profound functional implications. © 2011 American Chemical Society.

Brosius F.C.,University of Michigan | He J.C.,Mount Sinai School of Medicine
Current Opinion in Nephrology and Hypertension | Year: 2015

Purpose of review To review the role of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling in the progression of chronic kidney diseases. Recent findings The JAK-STAT pathway transmits signals from extracellular ligands, including many cytokines and chemokines. While these responses are best characterized in lymphoid cells, they also occur in kidney cells such as podocytes, mesangial cells, and tubular cells. JAK-STAT expression and signaling abnormalities occur in humans and animal models of different chronic kidney diseases. Enhanced expression and augmented activity of JAK1, JAK2, and STAT3 promote diabetic nephropathy and their inhibition appears to reduce the disease. Activation of JAK-STAT signaling in autosomal dominant polycystic kidney disease may play an important role in cyst growth. Activation of JAK-STAT signaling promotes HIV-associated nephropathy and may also participate in the tubular responses to chronic obstructive uropathy. On the basis of data from experimental models, inhibition of JAK-STAT signaling, via increased expression of the suppressors of cytokine signaling proteins or pharmacologic inhibition of JAK and STAT proteins, could play a therapeutic role in multiple chronic kidney diseases. Summary Activation of the JAK-STAT pathway appears to play a role in the progression of some chronic kidney diseases. More work is needed to determine the specific role the pathway plays in individual diseases. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Halperin J.J.,Mount Sinai School of Medicine
Neurologic Clinics | Year: 2010

Only two spirochetal infections are known to cause nervous system infection and damage: neurosyphilis and neuroborreliosis (nervous system Lyme disease). Diagnosis of both generally relies on indirect tools, primarily assessment of the host immune response to the organism. Reliance on these indirect measures poses some challenges, particularly as they are imperfect measures of treatment response. Despite this, both infections are known to be readily curable with straightforward antimicrobial regimens. The challenge is that, untreated, both infections can cause progressive nervous system damage. Although this can be microbiologically cured, the threat of permanent resultant neurologic damage, often severe in neurosyphilis and usually less so in neuroborreliosis, leads to considerable concern and emphasizes the need for prevention or early and accurate diagnosis and treatment. © 2010 Elsevier Inc. All rights reserved.

Miller A.E.,Mount Sinai School of Medicine
Mount Sinai Journal of Medicine | Year: 2011

The past decade has seen a surge of research interest in multiple sclerosis and an accelerated expansion of investigative efforts into multiple sclerosis therapeutics. Investigators have continued dissecting the complex immunological perturbations that may contribute to the disease and made major advances in understanding the genetics of multiple sclerosis. This article addresses current investigative issues and offers predictions about where the understanding and treatment of multiple sclerosis may stand at the end of the 21st century's second decade. Mt Sinai J Med 78:268-279, 2011. © 2011 Mount Sinai School of Medicine.

Klein R.S.,Mount Sinai School of Medicine
Substance Use and Misuse | Year: 2011

Drug users with HIV infection successfully treated with highly active antiretroviral therapy are now living to older ages. As persons with HIV infection age, they become at risk for comorbidities that occur in any group of aging individuals. However, some of these conditions occur at increased rates, with increasing severity, or pose special problems in older persons with HIV infection. This article discusses the epidemiology of HIV infection in aging drug users, and hormonal, cardiovascular, liver, renal, bone, and cognitive disorders and depression and cancer in these individuals, as well as problems related to taking multiple medications and HIV disease progression. © 2011 Informa Healthcare USA, Inc.

Li X.,Mount Sinai School of Medicine
Molecular Human Reproduction | Year: 2010

Maternal effect refers to the genetic phenomenon in which a phenotype in the progeny is caused by a genetic mutation in the maternal genome rather than a mutation of its own. Maternal effect genes are usually involved in the maternal-to-zygotic transition during embryonic development before zygotic genes are turned on. Although it is widely observed in invertebrate organisms, it is not common in vertebrate animals, especially in mammals. Genomic imprinting is an epigenetic phenomenon that is unique to eutherian mammals, marsupials and plants. One characteristic of genomic imprinting is parental origin-specific expression of imprinted genes. The molecular mechanisms underlying genomic imprinting are poorly understood. Mouse Zfp57 is the first example of a mammalian maternal-zygotic effect gene and it exhibits maternal-zygotic embryonic lethality around midgestation when both maternal and zygotic functions of Zfp57 are absent. Loss of Zfp57 also results in loss of differential DNA methylation at multiple imprinted regions. Interestingly, the midgestational embryonic lethality due to loss of both maternal and zygotic functions of Zfp57 occurs much later than the typically observed maternal-zygotic embryonic lethality during the maternal-to-zygotic transition period in early preimplantation embryos. I hypothesize that gradual loss of heritable genomic DNA methylation imprints over many cell divisions could account for this spatial and temporal discrepancy between the causative molecular defect and the observed phenotype in the Zfp57 mutant. © The Author 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

Buxbaum J.D.,Mount Sinai School of Medicine | Baron-Cohen S.,University of Cambridge
Molecular Autism | Year: 2013

We are fortunate to have invited commentaries from the laboratories of Dr Cathy Lord and Dr Fred Volkmar offering their perspectives on the new Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria for the autism spectrum. Both commentaries note how DSM-5 collapses the earlier diagnostic categories of the pervasive developmental disorders into a single category of autism spectrum disorder. In addition, DSM-5 collapses social and communication domains into a single combined domain. The commentaries go on to discuss the positive aspects of these changes and raise some areas of potential concern. We support the evidence-based changes to autism diagnosis found in DSM-5, and look forward to further studies on the autism phenotype as this has implications for diagnosis and treatment. As our mechanistic understanding of autism improves, diagnoses based on behavioral parameters will continue to provide opportunities for interventions targeting the behaviors, while etiological diagnoses will provide opportunities for interventions tailored to etiology. © 2013 Buxbaum and Baron-Cohen; licensee BioMed Central Ltd.

Garaude J.,Mount Sinai School of Medicine
Science translational medicine | Year: 2012

Toll-like receptor (TLR) ligands are increasingly being used as adjuvants in cancer vaccine trials to harness innate immunity and prime effective antitumor immune responses. Despite some success, enhancing tumor antigen presentation, promoting a protective antitumor response, and overcoming the immunosuppressive tumor microenvironment pose considerable challenges that necessitate further improvements in vaccine design. Here, we show that expression of the TLR ligand flagellin within tumor cells constitutes an effective antitumor vaccination strategy that relies on simultaneous engagement of TLR5 and the Nod-like receptors (NLRs) NLRC4/NAIP5 (neuronal apoptosis inhibitory protein 5) by flagellin along with associative recognition of tumor antigen for optimal antigen presentation to T cells. Although TLR5 signaling was critical for mediating rapid macrophage-dependent clearance of flagellin-expressing tumor cells in vivo, TLR5 and NLRC4/NAIP5 were equally important for priming antitumor CD4(+) and CD8(+) T cells and suppressing tumor growth. Vaccination with irradiated flagellin-expressing tumor cells prevented tumor development, and disrupting flagellin recognition by TLR5 or NLRC4/NAIP5 impaired protective immunization against an existing or subsequent tumor. Our findings delineate a new strategy to induce anticancer immune responses consisting of introducing microbial structures with dual TLR and NLR stimulatory activity into tumor cells. This ensures recognition of tumor-derived antigen within the inflammatory context of microbial recognition and additionally activates both the phagocytic and the cytosolic pathways of innate immune defense against the tumor.

Lucas A.L.,Mount Sinai School of Medicine
British Journal of Cancer | Year: 2016

Background:Pancreatic cancer is one of the leading causes of cancer mortality. Diet may be associated with pancreatic cancer, but it is unknown whether specific dietary components contribute to its risk. The potential differential role of dietary antioxidants warrants further investigation.Methods:We analysed data from a case–control study of 326 pancreatic cancer cases and 652 controls conducted between 1991 and 2008 in Northern Italy. Subjects’ usual diet was assessed through a validated and reproducible food frequency questionnaire. Using this information and an Italian food composition database, we calculated three indices of dietary total antioxidant capacity (TAC): Trolox equivalent antioxidant capacity (TEAC), total radical-trapping antioxidant parameter (TRAP) and ferric-reducing antioxidant power (FRAP). We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) for pancreatic cancer using multiple logistic regression models conditioned on study centre, sex and age, and adjusted for major known pancreatic cancer risk factors.Results:Significant inverse associations were found for the highest tertile of TAC compared with the lowest tertile for both TEAC and FRAP. The ORs were 0.61 (95% CI 0.39–0.94, P-value for trend 0.03) and 0.63 (95% CI 0.41–0.99, P-value for trend 0.05), respectively. Total radical-trapping antioxidant parameter was inversely, but not significantly, associated with pancreatic cancer risk, with an OR of 0.78 (95% CI 0.49–1.24, P-value for trend 0.27).Conclusions:Diet high in TAC, as measured by TEAC and FRAP, is inversely associated with pancreatic cancer risk.British Journal of Cancer advance online publication 12 May 2016; doi:10.1038/bjc.2016.114 www.bjcancer.com. © 2016 Cancer Research UK

Mueller T.M.,University of Alabama at Birmingham | Haroutunian V.,Mount Sinai School of Medicine | Meador-Woodruff J.H.,University of Alabama at Birmingham
Neuropsychopharmacology | Year: 2014

The molecular mechanisms of schizophrenia have been under investigation for decades; however, the exact causes of this debilitating neuropsychiatric disorder are still unknown. Previous studies have identified multiple affected neurotransmitter systems, brain regions, and cell types, each making a unique contribution to symptom presentation and pathophysiology. Numerous studies have identified gene and protein expression changes in schizophrenia, but the role of post-translational modifications, specifically N-glycosylation, has only recently become a target of investigation. N-glycosylation of molecules associated with glutamatergic neurotransmission is disrupted in schizophrenia, but it was unknown if these alterations are exclusive to the glutamatergic system or due to a more generalized deficit.In normal human cortex, we found evidence for N-glycosylation of the α1, β1, and β2 γ-aminobutyric type A receptor (GABAA R) subunits using deglycosylation protein shift assays. This was confirmed with lectin affinity assays that revealed glycan attachment on the α1, α4, and β1-3 GABAA R subunits. Examining GABAA R subunit N-glycosylation in matched pairs of schizophrenia (N=14) and comparison (N=14) of superior temporal gyrus revealed a smaller molecular mass of immature N-glycans on the α1 subunit, more immature N-glycosylation of the 49-kDa β1 subunit isoform, and altered total N-glycosylation of the β2 GABAA R subunit in schizophrenia. Measures of altered N-glycosylation of the β1 and β2 subunits were confounded by an increased apparent molecular mass of all β1 and β2 subunit isoforms in schizophrenia. Although N-glycosylation of α1, β1, and β2 were all changed in schizophrenia, the concentrations of GABAA R subunits themselves were unchanged. These findings suggest that disruptions of N-glycosylation in schizophrenia are not exclusive to glutamate and may indicate a potential disruption of a central cell signaling process in this disorder. © 2014 American College of Neuropsychopharmacology.

Ben-Zacharia A.B.,Mount Sinai School of Medicine
Mount Sinai Journal of Medicine | Year: 2011

Symptoms management in multiple sclerosis is an integral part of its care. Accurate assessment and addressing the different symptoms provides increased quality of life among patients with multiple sclerosis. Multiple sclerosis symptoms may be identified as primary, secondary, or tertiary symptoms. Primary symptoms, such as weakness, sensory loss, and ataxia, are directly related to demyelination and axonal loss. Secondary symptoms, such as urinary tract infections as a result of urinary retention, are a result of the primary symptoms. Tertiary symptoms, such as reactive depression or social isolation, are a result of the social and psychological consequences of the disease. Common multiple sclerosis symptoms include fatigue and weakness; decreased balance, spasticity and gait problems; depression and cognitive issues; bladder, bowel, and sexual deficits; visual and sensory loss; and neuropathic pain. Less-common symptoms include dysarthria and dysphagia, vertigo, and tremors. Rare symptoms in multiple sclerosis include seizures, hearing loss, and paralysis. Symptom management includes nonpharmacological methods, such as rehabilitation and psychosocial support, and pharmacological methods, ie, medications and surgical procedures. The keys to symptom management are awareness, knowledge, and coordination of care. Symptoms have to be recognized and management needs to be individualized. Multiple sclerosis therapeutics include nonpharmacological strategies that consist of lifestyle modifications, rehabilitation, social support, counseling, and pharmacological agents or surgical procedures. The goal is vigilant management to improve quality of life and promote realistic expectations and hope. Mt Sinai J Med 78:176-191, 2011. © 2011 Mount Sinai School of Medicine.

Purpose of review: Selective inhibitors of secretory phospholipase A 2 and lipoprotein-associated phospholipase A2 are potential candidates for reducing recurrent cardiovascular events in patients with established coronary heart disease (CHD). With the active enrollment of CHD patients into phase III clinical trials with both classes of inhibitors, this article reviews the available experimental animal and human trial evidence that provides the rationale for the development of the phospholipase A2 inhibitors varespladib methyl and darapladib as preventive therapy. Recent findings: Recently completed experimental animal studies, human biomarker data, and vascular imaging studies provide support for proceeding with clinical outcome trials secretory phospholipase A2 and lipoprotein-associated phospholipase A2 inhibition. Summary: Both secretory phospholipase A2 and lipoprotein-associated phospholipase A2 inhibitors hold promise for the reduction of recurrent cardiovascular events in patients treated with current standards of care. The completion of the ongoing clinical event trials has the potential to provide a new dimension to secondary preventive therapy. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Schuchman E.H.,Mount Sinai School of Medicine
FEBS Letters | Year: 2010

Acid sphingomyelinase (ASM) plays an important role in normal membrane turnover through the hydrolysis of sphingomyelin, and is one of the key enzymes responsible for the production of ceramide. ASM activity is deficient in the genetic disorder Types A and B Niemann-Pick disease (NPD). ASM knockout (ASMKO) mice were originally constructed to study this disorder, and numerous defects in ceramide-related signaling have been shown. Studies in these mice have further suggested that ASM may be involved in the pathogenesis of several common diseases through the reorganization of membrane microdomains. This review will focus on the role of ASM in membrane biology, with a specific emphasis on what a rare genetic disorder (NPD) has taught us about more common events. © 2009 Federation of European Biochemical Societies.

Sun H.B.,Mount Sinai School of Medicine
Annals of the New York Academy of Sciences | Year: 2010

Joint tissues are exquisitely sensitive to their mechanical environment, and mechanical loading may be the most important external factor regulating the development and long-term maintenance of joint tissues. Moderate mechanical loading maintains the integrity of articular cartilage; however, both disuse and overuse can result in cartilage degradation. The irreversible destruction of cartilage is the hallmark of osteoarthritis and rheumatoid arthritis. In these instances of cartilage breakdown, inflammatory cytokines such as interleukin-1 beta and tumor necrosis factor-alpha stimulate the production of matrix metalloproteinases (MMPs) and aggrecanases (ADAMTSs), enzymes that can degrade components of the cartilage extracellular matrix. In order to prevent cartilage destruction, tremendous effort has been expended to design inhibitors of MMP/ADAMTS activity and/or synthesis. To date, however, no effective clinical inhibitors exist. Accumulating evidence suggests that physiologic joint loading helps maintain cartilage integrity; however, the mechanisms by which these mechanical stimuli regulate joint homeostasis are still being elucidated. Identifying mechanosensitive chondroprotective pathways may reveal novel targets or therapeutic strategies in preventing cartilage destruction in joint disease. © 2010 New York Academy of Sciences.

Schachter E.N.,Mount Sinai School of Medicine
Drugs of Today | Year: 2013

Chronic obstructive pulmonary disease (COPD) is a worldwide problem causing prolonged and progressive morbidity as well as premature mortality. Pharmacologic treatment consists primarily in the relief of symptoms and preventing or minimizing the consequences of exacerbations. Central to the pharmacologic management of COPD is the use of bronchodilator therapy. Two major classes of agents are frequently used: b-adrenoceptor agonists and antimuscarinic agents. These drugs are used mainly in the inhalational form, primarily as rescue medication, but occasionally for maintenance in combination therapy. The availability of "ultra-long"-acting b-adrenoceptor agonists and long-acting antimuscarinic agents opens the way for combinations of these agents to be used in maintenance therapy. Such a combination offers the potential of enhanced efficacy due to additive effects and better compliance as the result of once-daily treatment. This article reviews the rationale for current bronchodilator therapy of COPD as well as the current status of a fixeddose combined inhaler using two novel long-acting agents: glycopyrronium bromide and indacaterol maleate. Copyright © 2013 Prous Science, S.A.U. or its licensors.

Ripoll L.H.,Mount Sinai School of Medicine
Dialogues in Clinical Neuroscience | Year: 2013

The best available evidence for psychopharmacologic treatment of borderline personality disorder (BPD) is outlined here. BPD is defined by disturbances in identity and interpersonal functioning, and patients report potential medication treatment targets such as impulsivity, aggression, transient psychotic and dissociative symptoms, and refractory affective instability. Few randomized controlled trials of psychopharmacological treatments for BPD have been published recently, although multiple reviews have converged on the effectiveness of specific anticonvulsants, atypical antipsychotic agents, and omega-3 fatty acid supplementation. Stronger evidence exists for medication providing significant improvements in impulsive aggression than in affective or other interpersonal symptoms. Future research strategies will focus on the potential role of neuropeptide agents and medications with greater specificity for 2A serotonin receptors, as well as optimizing concomitant implementation of evidence-based psychotherapy and psychopharmacology, in order to improve BPD patients' overall functioning. © 2013, AICH.

The sinoatrial node (SAN) is essential for rhythmic beating of the heart; however, our understanding of what controls proper functioning of the SAN remains primitive. To explore molecular control of SAN function, we specifically deleted Baf250a, a key regulatory component of the ATP-dependent chromatin remodeling complex SWI/SNF, in the SAN. Deletion of Baf250a in the SAN led to sinus bradycardia. Time series analysis of dysregulated genes after deletion of Baf250a reveals a transcriptional hierarchy maintaining pacemaker cell identity, i.e., Baf250a activates the expression of Tbx3, and Baf250a, Tbx3 and histone deacetylase 3 coordinately repress the expression of Nkx2.5. Disruption of this repressive pathway switches on expression of Nkx2.5, which stimulates expression of Gata4 and Tbx5. These three cardiac transcription factors further turn on a contractile cardiomyocyte program in the SAN, which eventually leads to sick sinus disease (SSD). Our study suggests that disruption of key genetic pathways regulating cardiac lineage segregation may cause SSD and cardiac arrhythmias in general.Cell Research advance online publication 22 August 2014; doi:10.1038/cr.2014.113.

Arbab-Zadeh A.,Johns Hopkins University | Fuster V.,Mount Sinai School of Medicine
Journal of the American College of Cardiology | Year: 2015

The cardiovascular science community has pursued the quest to identify vulnerable atherosclerotic plaque in patients for decades, hoping to prevent acute coronary events. However, despite major advancements in imaging technology that allow visualization of rupture-prone plaques, clinical studies have not demonstrated improved risk prediction compared with traditional approaches. Considering the complex relationship between plaque rupture and acute coronary event risk suggested by pathology studies and confirmed by clinical investigations, these results are not surprising. This review summarizes the evidence supporting a multifaceted hypothesis of the natural history of atherosclerotic plaque rupture. Managing patients at risk of acute coronary events mandates a greater focus on the atherosclerotic disease burden rather than on features of individual plaques. © 2015 American College of Cardiology Foundation.

De La Hoz R.E.,Mount Sinai School of Medicine
Current Opinion in Allergy and Clinical Immunology | Year: 2011

Purpose of Review: To summarize the knowledge about the occupational lower airway diseases that seem related to exposures at the World Trade Center disaster site. Recent Findings: Those diseases have been characterized as irritant-induced asthma, chronic nonspecific bronchitis, chronic bronchiolitis/small airway disease, and aggravated preexistent chronic obstructive lung disease (most frequently chronic obstructive pulmonary disease, but also asthma), with the expected overlapping features among them. One remarkable characteristic of the irritant-induced asthma observed among these workers was the slow onset of symptoms and long delay in clinical diagnoses. Summary: Longitudinal studies suggest that both the incidence and the associated functional decline of these predominantly obstructive lung diseases stabilized several years ago, but longer follow-up is clearly necessary. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Dijkers M.P.,Mount Sinai School of Medicine
Archives of Physical Medicine and Rehabilitation | Year: 2014

This article introduces the Archives supplement presenting a conceptual framework for the creation of a rehabilitation treatment taxonomy (RTT). It describes the key theoretical and empirical articles and their role, and the commentaries that were solicited. More importantly, based on feedback received to date, it sketches what the RTT is proposed to address, and what it explicitly excludes; therefore, the readers will have appropriate expectations and criteria for what is offered. © 2014 by the American Congress of Rehabilitation Medicine.

Sandin S.,Mount Sinai School of Medicine
Molecular Psychiatry | Year: 2015

Advancing paternal and maternal age have both been associated with risk for autism spectrum disorders (ASD). However, the shape of the association remains unclear, and results on the joint associations is lacking. This study tests if advancing paternal and maternal ages are independently associated with ASD risk and estimates the functional form of the associations. In a population-based cohort study from five countries (Denmark, Israel, Norway, Sweden and Western Australia) comprising 5 766 794 children born 1985–2004 and followed up to the end of 2004–2009, the relative risk (RR) of ASD was estimated by using logistic regression and splines. Our analyses included 30 902 cases of ASD. Advancing paternal and maternal age were each associated with increased RR of ASD after adjusting for confounding and the other parent's age (mothers 40–49 years vs 20–29 years, RR=1.15 (95% confidence interval (CI): 1.06–1.24), P-value<0.001; fathers⩾50 years vs 20–29 years, RR=1.66 (95% CI: 1.49–1.85), P-value<0.001). Younger maternal age was also associated with increased risk for ASD (mothers <20 years vs 20–29 years, RR=1.18 (95% CI: 1.08–1.29), P-value<0.001). There was a joint effect of maternal and paternal age with increasing risk of ASD for couples with increasing differences in parental ages. We did not find any support for a modifying effect by the sex of the offspring. In conclusion, as shown in multiple geographic regions, increases in ASD was not only limited to advancing paternal or maternal age alone but also to differences parental age including younger or older similarly aged parents as well as disparately aged parents.Molecular Psychiatry advance online publication, 9 June 2015; doi:10.1038/mp.2015.70. © 2015 Macmillan Publishers Limited

Waye J.D.,Mount Sinai School of Medicine
Gastroenterology Clinics of North America | Year: 2013

A retroview in the colon permits an 11-25% increase in the adenoma detection rate when compared with a standard straight forward view during colonoscopy. This can often be accomplished in the rectum or the proximal colon by using dial controls and shaft manipulation to turn the tip of a standard colonoscope 180°. A special slim caliber instrument, the "Third Eye Retroscope" (a backward viewing device) has been developed which is inserted through the working channel of a colonoscope. New colonoscopes are being developed that have the capability of side vision with accompanying light illumination which, with wide angle lenses, provide an almost complete retroview of the colon. © 2013 Elsevier Inc.

Identification and characterization of molecular mechanisms that connect genetic risk factors to initiation and evolution of disease pathophysiology represent major goals and opportunities for improving therapeutic and diagnostic outcomes in Alzheimer's disease (AD). Integrative genomic analysis of the human AD brain transcriptome holds potential for revealing novel mechanisms of dysfunction that underlie the onset and/or progression of the disease. We performed an integrative genomic analysis of brain tissue–derived transcriptomes measured from two lines of mice expressing distinct mutant AD-related proteins. The first line expresses oligomerogenic mutant APPE693Q inside neurons, leading to the accumulation of amyloid beta (Aβ) oligomers and behavioral impairment, but never develops parenchymal fibrillar amyloid deposits. The second line expresses APPKM670/671NL/PSEN1?exon9 in neurons and accumulates fibrillar Aβ amyloid and amyloid plaques accompanied by neuritic dystrophy and behavioral impairment. We performed RNA sequencing analyses of the dentate gyrus and entorhinal cortex from each line and from wild-type mice. We then performed an integrative genomic analysis to identify dysregulated molecules and pathways, comparing transgenic mice with wild-type controls as well as to each other. We also compared these results with datasets derived from human AD brain. Differential gene and exon expression analysis revealed pervasive alterations in APP/Aβ metabolism, epigenetic control of neurogenesis, cytoskeletal organization and extracellular matrix (ECM) regulation. Comparative molecular analysis converged on FMR1 (Fragile X Mental Retardation 1), an important negative regulator of APP translation and oligomerogenesis in the post-synaptic space. Integration of these transcriptomic results with human postmortem AD gene networks, differential expression and differential splicing signatures identified significant similarities in pathway dysregulation, including ECM regulation and neurogenesis, as well as strong overlap with AD-associated co-expression network structures. The strong overlap in molecular systems features supports the relevance of these findings from the AD mouse models to human AD.Molecular Psychiatry advance online publication, 10 November 2015; doi:10.1038/mp.2015.167. © 2015 Macmillan Publishers Limited

Cagan R.L.,Mount Sinai School of Medicine
Current Opinion in Nephrology and Hypertension | Year: 2011

Purpose of review The functioning kidney requires proper organization in multiple cell types that mediate filtration and removal of wastes. Interest has increasingly focused on the podocyte as an important mediator of kidney function; defects in podocyte function likely mediate a broad palate of kidney dysfunctions. Here I explore recent work that establishes the Drosophila nephrocyte as a useful model for podocyte function and dysfunction. Recent findings Although described many decades in the past, recent evidence has emphasized important similarities in the molecules that construct the 'nephrocyte diaphragm' and its vertebrate cousin the 'podocyte diaphragm'. For example, loss of Nephrin and its associated proteins lead to collapse of these structures and loss of proper filtration. Summary These data emphasize both differences between the podocyte and nephrocyte and also useful similarities. These similarities provide the promise of bringing Drosophila genetics - strongly successful in other disciplines - to the complex problem of how podocyte dysfunction leads to disease. To further explore this point I discuss work on Nephrin in a better understood tissue, the Drosophila eye, in which the role of Nephrin and its connection to actin dynamics is under intense study. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Llovet J.M.,University of Barcelona | Llovet J.M.,Catalan Institution for Research and Advanced Studies | Llovet J.M.,Mount Sinai School of Medicine | Hernandez-Gea V.,University of Barcelona
Clinical Cancer Research | Year: 2014

Hepatocellular carcinoma (HCC) is a major health problem. Most patients with HCC experience a recurrence after resection/ablation or are diagnosed at advanced stages. Sorafenib remains the only approved systemic drug for these patients. Molecular therapies targeting signaling cascades involved in hepatocarcinogenesis have been explored in phase III clinical trials. However, none of the drugs tested have shown positive results in the first-line (brivanib, sunitinib, erlotinib, and linifanib) or second-line (brivanib, everolimus) setting after sorafenib progression. Reasons for failure are heterogeneous and include lack of understanding of critical drivers of tumor progression/dissemination, liver toxicity, flaws in trial design, ormarginal antitumoral potency. These trials are also challenging time to progression as a surrogate endpoint of survival. Trials ongoing testing drugs head-to-head versus sorafenib in "all comers" might have difficulties in achieving superior results in the first line. Novel trials are also designed testing drugs in biomarker-based subpopulations of patients with HCC. Most common mutations, however, are undruggable, such as p53 and CTNNB1. Two types of studies are proposed: (i) phase II pivotal proof-of-concept studies testing drugs blocking potential oncogenic addiction loops, such as the one testing MEK inhibitors in RAS patients or amplification of FGF19 as a target; and (ii) phase II to III studies using biomarker-based trial enrichment for defining HCC subpopulations, such as the case of enriching for MET-positive tumors. These strategies have been deemed successful in breast, melanoma, and lung cancers, and are expected to change the landscape of trial design of HCC. © 2014 AACR.

Iyengar R.,Mount Sinai School of Medicine
Science translational medicine | Year: 2012

The emerging discipline of systems pharmacology aims to combine analysis and computational modeling of cellular regulatory networks with quantitative pharmacology approaches to drive the drug discovery processes, predict rare adverse events, and catalyze the practice of personalized precision medicine. Here, we introduce the concept of enhanced pharmacodynamic (ePD) models, which synergistically combine the desirable features of systems biology and current PD models within the framework of ordinary or partial differential equations. ePD models that analyze regulatory networks involved in drug action can account for a drug's multiple targets and for the effects of genomic, epigenomic, and posttranslational changes on the drug efficacy. This new knowledge can drive drug discovery and shape precision medicine.

Kocerha J.,Georgia Southern University | Dwivedi Y.,University of Alabama at Birmingham | Brennand K.J.,Mount Sinai School of Medicine
Molecular Psychiatry | Year: 2015

The human genome project has revolutionized our understanding of the underlying mechanisms in psychiatric disease. It is now abundantly clear that neurobehavioral phenotypes are epigenetically controlled by noncoding RNAs (ncRNAs). The microRNA (miRNA) class of ncRNAs are ubiquitously expressed throughout the brain and govern all major neuronal pathways. The attractive therapeutic potential of miRNAs is underscored by their pleiotropic capacities, putatively targeting multiple pathways within a single neuron. Many psychiatric diseases stem from a multifactorial origin, thus conventional drug targeting of single proteins may not prove most effective. In this exciting post-genome sequencing era, many new epigenetic targets are emerging for therapeutic investigation. Here we review the reported roles of miRNAs, as well as other ncRNA classes, in the pathology of psychiatric disorders; there are both common and unique ncRNA mechanisms that influence the various diagnoses. Collectively, these potent epigenetic regulators may clarify the disrupted signaling networks in psychiatric phenotypes.

Imperiale T.F.,Indiana University | Imperiale T.F.,Center for Innovation | Ransohoff D.F.,University of North Carolina at Chapel Hill | Itzkowitz S.H.,Mount Sinai School of Medicine | And 5 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: An accurate, noninvasive test could improve the effectiveness of colorectal-cancer screening. METHODS: We compared a noninvasive, multitarget stool DNA test with a fecal immunochemical test (FIT) in persons at average risk for colorectal cancer. The DNA test includes quantitative molecular assays for KRAS mutations, aberrant NDRG4 and BMP3 methylation, and β-actin, plus a hemoglobin immunoassay. Results were generated with the use of a logistic-regression algorithm, with values of 183 or more considered to be positive. FIT values of more than 100 ng of hemoglobin per milliliter of buffer were considered to be positive. Tests were processed independently of colonoscopic findings. RESULTS: Of the 9989 participants who could be evaluated, 65 (0.7%) had colorectal cancer and 757 (7.6%) had advanced precancerous lesions (advanced adenomas or sessile serrated polyps measuring ≥1 cm in the greatest dimension) on colonoscopy. The sensitivity for detecting colorectal cancer was 92.3% with DNA testing and 73.8% with FIT (P = 0.002). The sensitivity for detecting advanced precancerous lesions was 42.4% with DNA testing and 23.8% with FIT (P<0.001). The rate of detection of polyps with high-grade dysplasia was 69.2% with DNA testing and 46.2% with FIT (P = 0.004); the rates of detection of serrated sessile polyps measuring 1 cm or more were 42.4% and 5.1%, respectively (P<0.001). Specificities with DNA testing and FIT were 86.6% and 94.9%, respectively, among participants with nonadvanced or negative findings (P<0.001) and 89.8% and 96.4%, respectively, among those with negative results on colonoscopy (P<0.001). The numbers of persons who would need to be screened to detect one cancer were 154 with colonoscopy, 166 with DNA testing, and 208 with FIT. CONCLUSIONS: In asymptomatic persons at average risk for colorectal cancer, multitarget stool DNA testing detected significantly more cancers than did FIT but had more false positive results. Copyright © 2014 Massachusetts Medical Society.

Garrido M.M.,Geriatric Research | Garrido M.M.,Mount Sinai School of Medicine
Journal of Pain and Symptom Management | Year: 2014

When conducting research on pain and symptom management interventions for seriously ill individuals, randomized controlled trials are not always feasible or ethical to conduct. Secondary analyses of observational data sets that include information on treatments experienced and outcomes for individuals who did and did not receive a given treatment can be conducted, but confounding because of selection bias can obscure the treatment effect in which one is interested. Propensity scores provide a way to adjust for observable characteristics that differ between treatment and comparison groups. This article provides conceptual guidance in addition to an empirical example to illustrate two areas of propensity score analysis that often lead to confusion in practice: covariate selection and interpretation of resultant treatment effects. ©2014 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Magnon C.,Mount Sinai School of Medicine
Methods in molecular biology (Clifton, N.J.) | Year: 2011

Stem cells undergo regulated trafficking from the developmental stages to the adulthood. Stem cell migration is critical to organize developing organs and likely contributes postnatally to tissue regeneration. Here, we review the molecular mechanisms underlying migration of hematopoietic stem cells, neural stem cells, and primordial germ cells, revealing common operative pathways.

Popeo D.M.,Mount Sinai School of Medicine
Mount Sinai Journal of Medicine | Year: 2011

Delirium is a common neuropsychiatric syndrome in the elderly that can occur in several different settings caused by several different processes. It is common and causes increased morbidity and mortality to those affected. This clinical review discusses the prediction, prevention, diagnosis, and treatment of delirium in the elderly population. Several strategies to predict delirium are noted with the discussion of pharmacological and nonpharmacological trials of prevention and treatment. Diagnosis of delirium, specifically with the use of objective instruments, is discussed, as is the evidence for pharmacological and nonpharmacological treatment strategies. Discussion of the neurobiology and genetic markers for delirium may elucidate further areas for future research. © 2011 Mount Sinai School of Medicine.

Farraye F.A.,Boston University | Odze R.D.,Harvard University | Eaden J.,Coventry University | Itzkowitz S.H.,Mount Sinai School of Medicine
Gastroenterology | Year: 2010

The AGA Institute Medical Position Panel consisted of the authors of the technical review, a community-based gastroenterologist (Robert P. McCabe, MD, Minnesota Gastroenterology), academic-based gastroenterologists (Themistocles Dassopoulos, MD, James D. Lewis, MD, and Thomas A. Ullman, MD), an insurance provider representative (Tom James III, MD Physician Advisor, Strategic Advisory Group, Humana), a colon and rectal surgeon (Robin McLeod, MD, Mount Sinai Hospital-Canada), a pathologist (Lawrence J. Burgart, MD, Minnesota Gastroenterology), chair of the AGA Institute Clinical Practice and Quality Management Committee (John Allen, MD, Minnesota Gastroenterology), and chair of the Practice Management and Economics Committee (Joel V. Brill, MD, Predictive Health, LLC). © 2010 AGA Institute.

Cederbaum A.I.,Mount Sinai School of Medicine
Drug Metabolism and Drug Interactions | Year: 2012

CYP2E1 activates several hepatotoxins and contributes to alcoholic liver damage. In this report, we review our studies on whether induction of CYP2E1 can potentiate liver injury in obesity. Acetone- or pyrazole-induced severe liver injury in obese mice as compared to obese controls and lean mice. Severe liver injury was associated with elevated oxidative and nitrosative stress and could be blunted by inhibitors of CYP2E1 and inducible nitric oxide synthase (iNOS). S-Adenosyl-L-methionine (SAM) lowered the elevated oxidative and nitrosative stress, steatosis, liver injury and mitochondrial dysfunction in the pyrazole-treated obese mice. The protection by SAM may have therapeutic applications against metabolic complications caused by obesity. The role of CYP2E1 in chronic ethanol-induced liver injury was studied using wild-type (WT) mice, CYP2E1 knockout (KO) mice and humanized CYP2E1 knockin (KI) mice. Ethanol produced fatty liver and oxidant stress in WT mice; these effects were blunted in the CYP2E1 KO mice but restored in the CYP2E1 KI mice. Significant liver injury was produced in the ethanol-fed KI mice in association with elevated oxidant stress and levels of human CYP2E1. Collectively, these studies show that CYP2E1 contributes to ethanol-induced and obesityinduced oxidant stress and liver injury.

Pezic D.,California Institute of Technology | Manakov S.A.,California Institute of Technology | Sachidanandam R.,Mount Sinai School of Medicine | Aravin A.A.,California Institute of Technology
Genes and Development | Year: 2014

Transposable elements (TEs) occupy a large fraction of metazoan genomes and pose a constant threat to genomic integrity. This threat is particularly critical in germ cells, as changes in the genome that are induced by TEs will be transmitted to the next generation. Small noncoding piwi-interacting RNAs (piRNAs) recognize and silence a diverse set of TEs in germ cells. In mice, piRNA-guided transposon repression correlates with establishment of CpG DNA methylation on their sequences, yet the mechanism and the spectrum of genomic targets of piRNA silencing are unknown. Here we show that in addition to DNA methylation, the piRNA pathway is required to maintain a high level of the repressive H3K9me3 histone modification on long interspersed nuclear elements (LINEs) in germ cells. piRNA-dependent chromatin repression targets exclusively full-length elements of actively transposing LINE families, demonstrating the remarkable ability of the piRNA pathway to recognize active elements among the large number of genomic transposon fragments. © 2014 Pezic et al.

Landrigan P.J.,Mount Sinai School of Medicine
Academic Pediatrics | Year: 2016

Background Children's environmental health (CEH), the branch of pediatrics that studies the influence of the environment on children's health, has grown substantially in the past 3 decades and become an increasingly visible and important component of pediatric medicine. Goals To trace the historical origins of CEH; to identify factors responsible for its recent growth. Findings CEH has historical roots in toxicology, epidemiology, and occupational medicine. It arose in the second half of the 20th century through a melding of insights from pediatric toxicology, nutritional epidemiology, and social science research. Convergent research in these 3 fields has documented children's unique sensitivities to chemical, nutritional, and psychosocial hazards during windows of vulnerability in early development and has shown that early-life exposures can produce disease and disability in childhood and across the life span. Key events in the development of CEH were: 1) formation by the American Academy of Pediatrics in 1957 of a committee on environmental health that has nurtured the growth of the field for 5 decades and evolved into the Council on Environmental Health; 2) observations made in the 1980s that nutritional deficiency in utero increased risk for adult-onset obesity, diabetes, and cardiovascular disease - work that led to the hypothesis of the developmental origins of health and disease; 3) social science research showing that early exposure to psychosocial stress and trauma increases risk for chronic illness; and 4) publication in 1993 by the National Academy of Sciences of a report, Pesticides in the Diets of Infants and Children, which elevated awareness among national policy makers of children's vulnerability to toxic hazards, moved US environmental policy toward protection of children's health, and catalyzed research investment in CEH in the United States and globally. Conclusions CEH has made substantial progress but faces emerging challenges, including new chemicals and pesticides; increasing movement of polluting industries to poor countries where environmental and public health protections are few; and global climate change. In the future, CEH will require continued investment in research and education and will need to adopt an increasingly global perspective. © 2016 Academic Pediatric Association.

Rosell D.R.,Mount Sinai School of Medicine
Neuropsychopharmacology | Year: 2014

Pharmacological enhancement of prefrontal D1 dopamine receptor function remains a promising therapeutic approach to ameliorate schizophrenia-spectrum working memory deficits, but has yet to be rigorously evaluated clinically. This proof-of-principle study sought to determine whether the active enantiomer of the selective and full D1 receptor agonist dihydrexidine (DAR-0100A) could attenuate working memory impairments in unmedicated patients with schizotypal personality disorder (SPD). We performed a randomized, double-blind, placebo-controlled trial of DAR-0100A (15 mg/150 ml of normal saline administered intravenously over 30 min) in medication-free patients with SPD (n=16) who met the criteria for cognitive impairment (ie, scoring below the 25th percentile on tests of working memory). We employed two measures of verbal working memory that are salient to schizophrenia-spectrum cognitive deficits, and that clinical data implicate as being associated with prefrontal D1 availability: (1) the Paced Auditory Serial Addition Test (PASAT); and (2) the N-back test (ratio of 2-back:0-back scores). Study procedures occurred over four consecutive days, with working memory testing on Days 1 and 4, and DAR-0100A/placebo administration on Days 2-4. Treatment with DAR-0100A was associated with significantly improved PASAT performance relative to placebo, with a very large effect size (Cohen's d=1.14). Performance on the N-back ratio was also significantly improved; however, this effect rested on both a non-significant enhancement and diminution of 2-back and 0-back performance, respectively; therefore interpretation of this finding is more complicated. DAR-0100A was generally well tolerated, with no serious medical or psychiatric adverse events; common side effects were mild to moderate and transient, consisting mainly of sedation, lightheadedness, tachycardia, and hypotension; however, we were able to minimize these effects, without altering the dose, with supportive measures, eg, co-administered normal saline. Although preliminary, these findings lend further clinical support to the potential of D1 receptor agonists to treat schizophrenia-spectrum working memory impairments. These data suggest a need for further studies with larger group sizes, serum DAR-0100A levels, and a more comprehensive neuropsychological battery.Neuropsychopharmacology advance online publication, 27 August 2014; doi:10.1038/npp.2014.192.

Johnston M.V.,University of Wisconsin - Milwaukee | Dijkers M.P.,Mount Sinai School of Medicine
Archives of Physical Medicine and Rehabilitation | Year: 2012

Interventions and programs for people with disability should be based on the best - the most discriminating and rigorous - methods of systematic review and knowledge translation possible. Extant systems for systematic review and practice recommendations have excellent features but severe difficulties are encountered when attempting to apply them to disability and rehabilitation. This article identifies issues in evidence synthesis and linked practice recommendations and describes both new and long-tested methods to address them. Evidence synthesis in disability and rehabilitation can be improved by: explicating criteria for evaluating nonrandomized evidence, including the regression discontinuity, interrupted time series, and single-subject designs, as well as state-of-the-art methods of analysis of observational studies; greater use of meta-analysis; considering effect size, direction of biases, and dose-response relationships; employing more discriminating methods of evaluating flaws in masking, considering also measurement reliability and objectivity; considering overall biases and conflicts of interest; increased attention to composition of review panels; and greater transparency in reporting of the bases of reviewers' judgments. Review methods need to be developed for assistive technology and for measurement procedures. Application to practice can be improved by attention to treatment alternatives, explicit evaluation of generalizability, synthesizing clinical experience as a source of evidence, and a focus on the best - rather than the ideally most-rigorous - evidence. Study outcomes should be measured and reviewed in terms meaningful to persons served. In sum, methods are available to improve evidence synthesis and the application of resulting knowledge. We recommend that these methods be employed. © 2012 American Congress of Rehabilitation Medicine.

Based on recent bench and clinical research, the treatment of lung cancer has been refined, with treatments allocated according to histology and specific molecular features. For example, targeting mutations such as epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors has been particularly successful as a treatment modality, demonstrating response rates in selected patients with adenocarcinoma tumors harboring EGFR mutations that are significantly higher than those for conventional chemotherapy. However, the development of new targeted therapies is, in part, highly dependent on an improved understanding of the molecular underpinnings of tumor initiation and progression, knowledge of the role of molecular aberrations in disease progression, and the development of highly reproducible platforms for high-throughput biomarker discovery and testing. In this article, we review clinically relevant research directed toward understanding the biology of lung cancer. The clinical purposes of this research are (1) to identify susceptibility variants and field molecular alterations that will promote the early detection of tumors and (2) to identify tumor molecular alterations that serve as therapeutic targets, prognostic biomarkers, or predictors of tumor response. We focus on research developments in the understanding of lung cancer somatic DNA mutations, chromosomal aberrations, epigenetics, and the tumor microenvironment, and how they can advance diagnostics and therapeutics. Copyright © by the American College of Chest Physicians 2013.

Ma'ayan A.,Mount Sinai School of Medicine
Science Signaling | Year: 2011

This Teaching Resource provides lecture notes, slides, and a problem set for a set of three lectures from a course entitled "Systems Biology: Biomedical Modeling." The materials are from three separate lectures introducing applications of graph theory and network analysis in systems biology. The first lecture describes different types of intracellular networks, methods for constructing biological networks, and different types of graphs used to represent regulatory intracellular networks. The second lecture surveys milestones and key concepts in network analysis by introducing topological measures, random networks, growing network models, and topological observations from molecular biological systems abstracted to networks. The third lecture discusses methods for analyzing lists of genes and experimental data in the context of prior knowledge networks to make predictions.

Dubinsky M.,Mount Sinai School of Medicine | Braun J.,University of California at Los Angeles
Gastroenterology | Year: 2015

The microbiome plays multifaceted roles in the pathogenesis of inflammatory bowel diseases (IBD). Accordingly, the clinical challenge of patient heterogeneity in disease phenotype and response to treatment should in part be addressed by biomarkers that detect the host response to microbiota, and the levels of microbial taxa and products eliciting the host response in susceptible individuals. Molecular analysis has revealed much evidence for microbial taxonomic membership and microbial products in association with IBD, but their utility as clinical biomarkers is still in its infancy. A rich area of progress has been the development and validation of host serologic microbial biomarkers, which have achieved a distinctive position in the diagnosis and prognosis in IBD, and as a template for defining other categories of microbial biomarkers in disease state and phenotype. © 2015 AGA Institute.

McGovern D.P.B.,Cedars Sinai Medical Center | Kugathasan S.,Childrens Healthcare Of Atlanta | Cho J.H.,Mount Sinai School of Medicine
Gastroenterology | Year: 2015

In this review, we provide an update on genome-wide association studies (GWAS) in inflammatory bowel disease (IBD). In addition, we summarize progress in defining the functional consequences of associated alleles for coding and noncoding genetic variation. In the small minority of loci where major association signals correspond to nonsynonymous variation, we summarize studies defining their functional effects and implications for therapeutic targeting. Importantly, the large majority of GWAS-associated loci involve noncoding variation, many of which modulate levels of gene expression. Recent expression quantitative trait loci (eQTL) studies have established that the expression of most human genes is regulated by noncoding genetic variations. Significant advances in defining the epigenetic landscape have demonstrated that IBD GWAS signals are highly enriched within cell-specific active enhancer marks. Studies in European ancestry populations have dominated the landscape of IBD genetics studies, but increasingly, studies in Asian and African-American populations are being reported. Common variation accounts for only a modest fraction of the predicted heritability and the role of rare genetic variation of higher effects (ie, odds ratios markedly deviating from 1) is increasingly being identified through sequencing efforts. These sequencing studies have been particularly productive in more severe very early onset cases. A major challenge in IBD genetics will be harnessing the vast array of genetic discovery for clinical utility through emerging precision medical initiatives. In this article, we discuss the rapidly evolving area of direct-to-consumer genetic testing and the current utility of clinical exome sequencing, especially in very early onset, severe IBD cases. We summarize recent progress in the pharmacogenetics of IBD with respect to partitioning patient responses to anti-TNF and thiopurine therapies. Highly collaborative studies across research centers and across subspecialties and disciplines will be required to fully realize the promise of genetic discovery in IBD. © 2015 AGA Institute.

Miller A.E.,Mount Sinai School of Medicine
Expert Review of Clinical Immunology | Year: 2015

Teriflunomide, a once-daily, oral disease-modifying therapy, is a valuable new treatment option for the management of patients with relapsing-remitting multiple sclerosis. This article reviews key efficacy and safety data arising from pivotal teriflunomide studies that demonstrate the utility in treating both treatment-naïve patients and those previously treated with another disease-modifying therapy who, for a variety of reasons, may require an alternative treatment. © 2015 Informa UK, Ltd.

Braman S.S.,Mount Sinai School of Medicine
Allergy and Asthma Proceedings | Year: 2015

When asthma and chronic obstructive pulmonary disease (COPD) occur together the term COPD-asthma overlap syndrome has been applied. To date, there is no universally accepted definition of this overlap syndrome, just as there is no blood test or other technologic assessment that provides a simple way to distinguish asthma from COPD. One practical approach to the overlap diagnosis has been to include patients with a diagnosis of COPD by Global Initiative for Chronic Obstructive Lung Disease criteria and asthma defined by subject report of a physician diagnosis of asthma before the age of 40 years. Alternatively, it includes patients who meet criteria for COPD (fixed airflow obstruction) and who also have typical features of asthma (wheezing, atopy, eosinophilia, and positive bronchodilator response on spirometry). Compared with patients with COPD alone, the overlap patients are younger with less smoking intensity, have higher health-care utilization, have a worse disease-related quality of life, and have a higher mortality. Treatment with corticosteroids earlier in the course of the disease compared with the patient with only COPD has been recommended. Copyright © 2015, OceanSide Publications, Inc., U.S.A.

Lothane H.Z.,Mount Sinai School of Medicine
International Forum of Psychoanalysis | Year: 2015

This paper is a further contribution to dramatology, introduced in this journal in 2009. It focuses on the two basic modes of communication in any dramatic situation: (1) the nonverbal transfer of feelings and emotions, originating in the preverbal period of the love relationship between mother and child, and (2) the interchange of words and thoughts that develops with the acquisition of language. The early nonverbal mode of communication is the basis for proposing to rename Freud's concept of psychic reality "emotional reality." On this view, emotional reality is seen as the primary fact of psychological life versus thoughts expressed in words as the derivative fact. Developmentally, emotions and ideas become united in complexes combining the emotional coloration of ideas and the ideational content of emotions. From the perspective of methodology, Freud, his followers, and his critics all conflated theories of disorder and theories of treatment. At the beginning of his journey, Freud was dyadic and interpersonal in formulating a unified theory of disorder and a method of treatment. In later years, he formulated monadic and intrapersonal theories of disorder while remaining interpersonal in his method of treatment, contributing to conflicts among the various psychoanalytic schools. © 2014 The International Federation of Psychoanalytic Societies.

Varble A.,Mount Sinai School of Medicine
RNA biology | Year: 2011

MicroRNAs (miRNAs) are small noncoding RNAs that fine-tune protein expression through post-transcriptional regulation. Extensive deep sequencing efforts have identified hundreds of miRNAs from diverse eukaryotic lineages, in addition to a number of DNA virus-produced miRNAs. The absence of RNA virus-encoded miRNAs has led to the assumption that miRNA processing is deleterious to genomic integrity and therefore restricted to DNA-based organisms. However, we recently generated both cytoplasmic and nuclear RNA virus capable of producing a functional miRNA without loss of viral fitness. By exploiting the splicing activity of influenza A virus, we engineered the endogenous miR-124-2 locus into an intron of a viral gene product. Processing of viral-derived miR-124 followed canonical processing events and was comparable to its endogenous counterpart, while virus replication was unaffected. Furthermore, grafting the same locus into a duplicated non-essential subgenomic area of Sindbis virus, we can observe non-canonical cytoplasmic-based processing that is independent of any nuclear events. Although it remains unknown as to why there is little natural evidence of RNA virus-encoded miRNAs, successful generation of these vectors provide important insights into the relationship between miRNAs and RNA viruses and introduces a new delivery vehicle for the rapidly expanding therapeutic use of RNA interference (RNAi).

Nowak-Wegrzyn A.,Mount Sinai School of Medicine
Allergy and Asthma Proceedings | Year: 2015

Non-IgE-mediated food allergic disorders account for up to 40% of milk protein allergy in infants and young children. We aim to review the recent literature and to provide an update on diagnosis and management of food protein-induced enterocolitis syndrome (FPIES) and food protein-induced allergic proctocolitis (FPIAP). The peer-reviewed articles indexed in PubMed have been reviewed. FPIES manifests in infants as profuse, repetitive vomiting and lethargy, often with diarrhea, leading to acute dehydration, or weight loss and failure to thrive, in chronic form. FPIES is caused most commonly by cow's milk (CM) and soy proteins; rice, oat, and other solid foods may also trigger FPIES. FPIES rarely occurs in the exclusively breastfed infants. FPIES is underrecognized; children are often mismanaged as having acute viral gastrointestinal illness, sepsis, or surgical disease, delaying diagnosis of FPIES for many months. Approximately 25% of children with FPIES develop food-specific IgE antibodies and some transition to immediate food allergy; IgE positivity is associated with a more protracted course. FPIES is a self-limiting condition, with most cases resolving by age three to five years. Ondansetron may be helpful in managing acute FPIES. FPIAP is a benign condition of bloody stools in a well-appearing infant, with usual onset between one and four weeks of age. Up to 60% of cases occur in exclusively breastfed infants and resolve with maternal elimination of CM and soy proteins. The majority of cases resolve by age 12 months. FPIES may transition to IgE-mediated food allergy in some patients; IgE positivity to the FPIES food is a marker of a more persistent disease. FPIAP is benign and resolves by age 12 months in most patients. Copyright © 2015, OceanSide Publications, Inc., U.S.A.

Schiller D.,Mount Sinai School of Medicine
Current Biology | Year: 2015

Summary A mutation in the FAAH gene that enhances endocannabinoid signaling has been difficult to decipher, as it exists only in humans. A new study reports a knock-in mouse expressing an identical mutation, bridging an important translational gap. © 2015 Elsevier Ltd All rights reserved.

Zeichner J.A.,Mount Sinai School of Medicine
Journal of Drugs in Dermatology | Year: 2012

Given the multifactorial and complex contributors to acne development, combination therapy is standard of care. By addressing multiple pathogenic factors, combination therapy provides a quicker and more efficacious treatment outcome than monotherapy. Topical retinoids normalize follicular keratinocyte differentiation and are anti-inflammatory. Their use is limited by the potential for cutaneous irritation. Antimicrobials reduce Propionibacterium acnes colonization on the skin and reduce the bacteria's proinflammatory effects. Topical antibiotics and benzoyl peroxide (BPO) are commonly employed in fixed-dose combination products or two separate medications. BPO has the added benefit of being comedolytic and can minimize the risk for bacterial antibiotic resistance. Like topical retinoids, BPO may cause skin irritation, burning, erythema, and peeling. Managing cutaneous side effects when using multiple products that cause irritation can be a challenge. Careful product selection, dose titration, and patient-directed regimens can help to optimize outcomes. This review presents the latest data on two topical acne products that have demonstrated excellent efficacy and tolerability profiles. In addition, their in vitro profiles suggest the potential for combination use, affording greater dosing flexibility. © 2012-Journal of Drugs in Dermatology. All Rights Reserved.

Ripoll L.H.,James ters Va Medical Center | Ripoll L.H.,Mount Sinai School of Medicine
Current Opinion in Psychiatry | Year: 2012

Purpose of Review: Clinical considerations for evidence-based treatment of borderline personality disorder (BPD) are outlined in the context of the best available evidence, discussed with reference to BPD traits currently identified in the upcoming Diagnostic and Statistical Manual of Mental Disorders - 5 (DSM-5) revision. The DSM-5 will highlight refractory affective, interpersonal, and identity symptoms in BPD as potential treatment targets. In addition to providing a framework for clinical decision-making, future research strategies will also focus on neurotransmitter systems of greater relevance to understanding overall personality functioning. Recent Findings: Although only a few randomized controlled trials of psychopharmacological treatments for BPD have been published recently, several meta-analyses and systematic reviews converge on the consensus effectiveness of lamotrigine, topiramate, valproate, aripiprazole, olanzapine, and omega-3 fatty acid supplementation. Stronger evidence exists for treating disinhibition and antagonism than negative affectivity, particularly interpersonal facets of such traits. In addition, basic research suggests a future role for modifying glutamatergic, opioid, and oxytocinergic neurotransmitter systems to treat BPD. Summary: Clinicians should utilize omega-3, anticonvulsants, and atypical antipsychotic agents in treating specific DSM-5 BPD traits, notably disinhibition, antagonism, and some aspects of negative affectivity. Future research will focus on normalizing opioid and oxytocin dysregulation, as an adjunct to evidence-based psychotherapy, in an effort to improve interpersonal functioning. © Lippincott Williams & Wilkins.

Baron M.H.,Mount Sinai School of Medicine
Blood | Year: 2013

In this issue of Blood, Hosoya et al identify a requirement for the corepressor Tripartite Motif Protein 28 (TRIM28) in erythroblast maturation. © 2013 by The American Society of Hematology.

Cullen B.R.,Duke University | Cherry S.,University of Pennsylvania | Tenoever B.R.,Mount Sinai School of Medicine
Cell Host and Microbe | Year: 2013

While RNA interference (RNAi) functions as an antiviral response in plants, nematodes, and arthropods, a similar antiviral role in mammals has remained controversial. Three recent papers provide evidence that either favors or challenges this hypothesis. Here, we discuss these new findings in the context of previous research. © 2013 Elsevier Inc.

McGraw C.A.,Yeshiva University | Lublin F.D.,Mount Sinai School of Medicine
Neurotherapeutics | Year: 2013

Interferon beta and glatiramer acetate have been mainstays of treatment in relapsingremitting multiple sclerosis for two decades. Remarkable advances in our understanding of immune function and dysfunction as well as increasingly sophisticated clinical trial design have stemmed from efforts to better understand these drugs. In this chapter, we review the history of their development and elaborate on known and theorized mechanisms of action. We describe the pivotal clinical trials that have led to their widespread use. We evaluate the clinical use of the drugs including tolerability, side effects, and efficacy measures. Finally, we look to the future of interferon beta and glatiramer acetate in the context of an ever growing armamentarium of treatments for relapsing remitting multiple sclerosis. © 2012 The American Society for Experimental NeuroTherapeutics, Inc.

Galsky M.D.,Mount Sinai School of Medicine
Journal of Geriatric Oncology | Year: 2015

Bladder cancer is a disease of the elderly. There is a disconnect between the efficacy of treatments for patients with advanced disease, and their effectiveness, at least in part related to the advanced age at diagnosis. Standard treatments for patients with locally advanced or metastatic bladder cancer include radical cystectomy and/or cisplatin-based combination chemotherapy. However, there is significant potential for morbidity, and even mortality, with these treatments necessitating tools to risk stratify elderly patients to optimize the safety and benefit of treatments and alternative strategies in situations where the potential risks are likely to outweigh the potential benefits. This review considers the current standard treatments for advanced bladder cancer, approaches to risk stratify elderly patients, and highlights our relatively poor knowledge base regarding the optimal care of elderly patients with this disease. © 2014 Elsevier Inc.

Frangou S.,Mount Sinai School of Medicine
Schizophrenia Bulletin | Year: 2014

Neuroimaging studies have generated a large body of knowledge regarding the neural correlates of schizophrenia (SZ) and bipolar disorder (BD). However, the initial goal of identifying disease-specific topographical mappings to localized brain regions or to distinct neural networks has not materialized and may be untenable. This contribution will argue that a systems neuroscience approach may prove more fruitful. The supporting evidence presented covers (a) brain structural, functional, and connectivity alterations and their implication for the clinical and cognitive manifestations of SZ and BD, (b) the prevailing system neuroscience models of the 2 disorders, and (c) key hypotheses likely to produce new insights into the mechanisms of underlying psychotic disorders. © The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.

Karakikes I.,Mount Sinai School of Medicine
Journal of the American Heart Association | Year: 2013

MicroRNAs (miRNAs) play a key role in the development of heart failure, and recent studies have shown that the muscle-specific miR-1 is a key regulator of cardiac hypertrophy. We tested the hypothesis that chronic restoration of miR-1 gene expression in vivo will regress hypertrophy and protect against adverse cardiac remodeling induced by pressure overload. Cardiac hypertrophy was induced by left ventricular pressure overload in male Sprague-Dawley rats subjected to ascending aortic stenosis. When the hypertrophy was established at 2 weeks after surgery, the animals were randomized to receive either an adeno-associated virus expressing miR-1 (AAV9.miR-1) or green fluorescent protein (GFP) as control (AAV9.GFP) via a single-bolus tail-vein injection. Administration of miR-1 regressed cardiac hypertrophy (left ventricular posterior wall thickness,; 2.32±0.08 versus 2.75±0.07 mm, P<0.001) and (left ventricular septum wall thickness, 2.23±0.06 versus 2.54±0.10 mm, P<0.05) and halted the disease progression compared with control-treated animals, as assessed by echocardiography (fractional shortening, 37.60±5.01% versus 70.68±2.93%, P<0.05) and hemodynamic analyses (end-systolic pressure volume relationship/effective arterial elastance, 1.87±0.46 versus 0.96±0.38, P<0.05) after 7 weeks of treatment. Additionally, miR-1 replacement therapy lead to a marked reduction of myocardial fibrosis, an improvement in calcium handling, inhibition of apoptosis, and inactivation of the mitogen-activated protein kinase signaling pathways, suggesting a favorable effect on preventing the maladaptive ventricular remodeling. We also identified and validated a novel bona fide target of miR-1, Fibullin-2 (Fbln2), a secreted protein implicated in extracellular matrix remodeling. Taken together, our findings suggest that restoration of miR-1 gene expression is a potential novel therapeutic strategy to reverse pressure-induced cardiac hypertrophy and prevent maladaptive cardiac remodeling.

Kang J.-S.,Sungkyunkwan University | Krauss R.S.,Mount Sinai School of Medicine
Current Opinion in Clinical Nutrition and Metabolic Care | Year: 2010

Purpose of review: Skeletal muscle development serves as a paradigm for cell lineage specification and cell differentiation. Adult skeletal muscle has high regenerative capacity, with satellite cells the primary source of this capability. The present review describes Recent findings: on developmental and adult myogenesis with emphasis on emerging distinctions between various muscle groups and stages of myogenesis. Recent findings: Muscle progenitors of the body are derived from multipotent cells of the dermomyotome and express the transcription factors Pax3 and Pax7. These cells self-renew or induce expression of myogenic regulatory factors (MRFs) and differentiate. The roles of Pax3, Pax7 and specific myogenic regulatory factor+ progenitor populations in trunk and limb myogenesis have been identified through cell ablation in the mouse. Various head muscles and associated satellite cells have differing developmental origins, and rely on distinct combinations of transcriptional regulators, than trunk and limb muscles. Several genetic and sorting protocols demonstrate that satellite cells are heterogeneous with some possessing stem cell properties; the relative roles of lineage and niche in these properties are being explored. Although cellular mechanisms of developmental, postnatal and adult regenerative myogenesis are thought to be similar, recent studies reveal distinct genetic requirements for embryonic, fetal, postnatal and adult regenerative myogenesis. Summary: Genetic determinants of formation or repair of various muscles during different stages of myogenesis are unexpectedly diverse. Future studies should illuminate these differences, as well as mechanisms that underlie stem cell properties of satellite cells. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Winston J.A.,Mount Sinai School of Medicine
Advances in Chronic Kidney Disease | Year: 2010

Nephrologists can serve many important functions for HIV-infected patients, including identifying risks for developing kidney disease, detecting and diagnosing kidney disease, distinguishing antiretroviral-induced kidney injury from kidney disease in the setting of antiretroviral therapy, comanaging the clinical course and complications of CKD, and preparing patients for dialysis and/or transplantation. The epidemiology of kidney disease in HIV informs us for these functions by describing the natural history of disease, its frequent occurrence in high-risk communities, and its potential causes. Risk factors that drive CKD in HIV are black race, hypertension, diabetes, HIV viral replication with low CD4 cell counts, high viral load or acquired immune deficiency syndrome-defining conditions, and antiretroviral agents with nephrotoxic potential. The prevalence of these risk factors in any population determines the magnitude of the problem, which can range from as low as 2% to as high as 30%. Recent research focuses on kidney health in HIV. Important links between HIV viral replication and glomerular filtration rate, even in patients with normal kidney function, are now being reported. A review of these data provides the foundation for a better understanding of kidney disease and, hopefully, better treatment for patients with HIV. © 2010 National Kidney Foundation, Inc.

Magnon C.,Yeshiva University | Hall S.J.,Mount Sinai School of Medicine | Lin J.,Yeshiva University | Xue X.,Yeshiva University | And 5 more authors.
Science | Year: 2013

Nerves are a common feature of the microenvironment, but their role in tumor growth and progression remains unclear. We found that the formation of autonomic nerve fibers in the prostate gland regulates prostate cancer development and dissemination in mouse models. The early phases of tumor development were prevented by chemical or surgical sympathectomy and by genetic deletion of stromal b2- and b3-adrenergic receptors. Tumors were also infiltrated by parasympathetic cholinergic fibers that promoted cancer dissemination. Cholinergic-induced tumor invasion and metastasis were inhibited by pharmacological blockade or genetic disruption of the stromal type 1 muscarinic receptor, leading to improved survival of the mice. A retrospective blinded analysis of prostate adenocarcinoma specimens from 43 patients revealed that the densities of sympathetic and parasympathetic nerve fibers in tumor and surrounding normal tissue, respectively, were associated with poor clinical outcomes. These findings may lead to novel therapeutic approaches for prostate cancer.

Krakoff L.R.,Mount Sinai School of Medicine
American Journal of Hypertension | Year: 2016

The diagnosis of hypertension includes measurement of blood pressure out of the office by either 24-hour ambulatory monitoring or home blood pressure monitoring. These methods have led to recognition of "white coat hypertension" (WCH) and "masked hypertension" (MH). Research in the 1930s first demonstrated that blood pressures in the office were often far different from those out of the office, at a time when there was no effective treatment. International attention was focused on another imminent world war and a highly controversial election in the United States. Hypertension was not a priority for concern. From the 1950s onward: (i) epidemiology linked hypertension to risk of cardiovascular disease, (ii) effective and safe drugs for treatment of hypertension appeared, (iii) randomized clinical trials demonstrated that drug treatment of hypertension is highly effective for prevention of cardiovascular disease, and (iv) advances in technology led to development of small, portable devices for recording blood pressure noninvasively at home or during usual activities. Accurate measurement of blood pressure in "real life" is now necessary and feasible for appropriate diagnosis and assessment of treatment. Out-of-office blood pressure measurement is emerging as the standard of care for hypertension. © 2015 American Journal of Hypertension, Ltd. All rights reserved.

Fierer D.S.,Mount Sinai School of Medicine
Current Infectious Disease Reports | Year: 2010

Sexual contact is thought to be an inefficient mode of hepatitis C virus (HCV) transmission. However, reports of sexually transmitted HCV infection among HIVinfected men who have sex with men (MSM) began to appear in 2004. The patients were of early middle age with well-controlled HIV infection, participated in unprotected receptive sex, and frequently used noninjection recreational drugs. Molecular studies showed evidence of clusters of transmission between patients in different countries in Europe. Spontaneous clearance was relatively rare, but treatment with pegylated interferon and ribavirin resulted in cure in about two thirds of patients. Of concern was the finding of moderately advanced fibrosis during the early stages of HCV infection. HIV-infected MSM are a new risk group for HCV infection and so should be screened regularly for HCV infection. © The Author(s) 2010.

Schuchman E.H.,Mount Sinai School of Medicine
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2016

Ceramides are a diverse group of sphingolipids that play important roles in many biological processes. Acid ceramidase (AC) is one key enzyme that regulates ceramide metabolism. Early research on AC focused on the fact that it is the enzyme deficient in the rare genetic disorder, Farber Lipogranulomatosis. Recent research has revealed that deficiency of the same enzyme is responsible for a rare form of spinal muscular atrophy associated with myoclonic epilepsy (SMA-PME). Due to their diverse role in biology, accumulation of ceramides also has been implicated in the pathobiology of many other common diseases, including infectious lung diseases, diabetes, cancers and others. This has revealed the potential of AC as a therapy for many of these diseases. This review will focus on the biology of AC and the potential role of this enzyme in the treatment of human disease. © 2016 Elsevier B.V.

Der-Avakian A.,University of California at San Diego | Mazei-Robison M.S.,Michigan State University | Kesby J.P.,University of California at San Diego | Nestler E.J.,Mount Sinai School of Medicine | Markou A.,University of California at San Diego
Biological Psychiatry | Year: 2014

Background: Anhedonia, or diminished interest or pleasure in rewarding activities, characterizes depression and reflects deficits in brain reward circuitries. Social stress induces anhedonia and increases risk of depression, although the effect of social stress on brain reward function is incompletely understood. Methods: This study assessed the following: 1) brain reward function in rats (using the intracranial self-stimulation procedure) and protein levels of brain-derived neurotrophic factor and related signaling molecules in response to chronic social defeat, 2) brain reward function during social defeat and long-term treatment with the antidepressants fluoxetine (5 mg/kg/day) and desipramine (10 mg/kg/ day), and 3) forced swim test behavior after social defeat and fluoxetine treatment. Results: Social defeat profoundly and persistently decreased brain reward function, reflecting an enduring anhedonic response, in susceptible rats, whereas resilient rats showed no long-term brain reward deficits. In the ventral tegmental area, social defeat, regardless of susceptibility or resilience, decreased brain-derived neurotrophic factor and increased phosphorylated AKT, whereas only susceptibility was associated with increased phosphorylated mammalian target of rapamycin. Fluoxetine and desipramine reversed lower, but not higher, stress-induced brain reward deficits in susceptible rats. Fluoxetine decreased immobility in the forced swim test, as did social defeat. Conclusions: These results suggest that the differential persistent anhedonic response to psychosocial stress may be mediated by ventral tegmental area signaling molecules independent of brain-derived neurotrophic factor and indicate that greater stress-induced anhedonia is associated with resistance to antidepressant treatment. Consideration of these behavioral and neurobiological factors associated with resistance to stress and antidepressant action may promote the discovery of novel targets to treat stress-related mood disorders. © 2014 Society of Biological Psychiatry.

Shimoni Y.,Mount Sinai School of Medicine
PLoS computational biology | Year: 2010

Improving the ability to reverse engineer biochemical networks is a major goal of systems biology. Lesions in signaling networks lead to alterations in gene expression, which in principle should allow network reconstruction. However, the information about the activity levels of signaling proteins conveyed in overall gene expression is limited by the complexity of gene expression dynamics and of regulatory network topology. Two observations provide the basis for overcoming this limitation: a. genes induced without de-novo protein synthesis (early genes) show a linear accumulation of product in the first hour after the change in the cell's state; b. The signaling components in the network largely function in the linear range of their stimulus-response curves. Therefore, unlike most genes or most time points, expression profiles of early genes at an early time point provide direct biochemical assays that represent the activity levels of upstream signaling components. Such expression data provide the basis for an efficient algorithm (Plato's Cave algorithm; PLACA) to reverse engineer functional signaling networks. Unlike conventional reverse engineering algorithms that use steady state values, PLACA uses stimulated early gene expression measurements associated with systematic perturbations of signaling components, without measuring the signaling components themselves. Besides the reverse engineered network, PLACA also identifies the genes detecting the functional interaction, thereby facilitating validation of the predicted functional network. Using simulated datasets, the algorithm is shown to be robust to experimental noise. Using experimental data obtained from gonadotropes, PLACA reverse engineered the interaction network of six perturbed signaling components. The network recapitulated many known interactions and identified novel functional interactions that were validated by further experiment. PLACA uses the results of experiments that are feasible for any signaling network to predict the functional topology of the network and to identify novel relationships.

Swidler M.,Mount Sinai School of Medicine
Clinical Journal of the American Society of Nephrology | Year: 2013

Nephrologists have focused on the uremic syndrome as an indication for dialysis. The elderly frail renal patient approaching ESRD represents a complex biologic system that is already failing. This patient phenotype exhibits progressive geriatric disabilities and dependence interspersed with shrinking periods of stability regardless of whether dialysis is started. Consequently, the frail renal patient faces challenging treatment choices underpinned by ethical tensions. Identifying the advanced frail renal patient and optimizing the shared decision-making process will enable him or her to make well informed choices based on an understanding of his or her overall condition and personal values and preferences. This approach will also permit nephrologists to fulfill their ethical obligations to respect patient autonomy, promote patient benefit, and minimize patient harm. © 2013 by the American Society of Nephrology.

Tanenbaum L.N.,Mount Sinai School of Medicine
Magnetic Resonance Imaging Clinics of North America | Year: 2013

As in the brain, the sensitivity of diffusion-weighted imaging (DWI) to ischemic damage in the spinal cord may provide early identification of infarction. Diffusion anisotropy may enhance the detection and understanding of damage to the long fiber tracts with clinical implications for diseases such as multiple sclerosis and amyotrophic lateral sclerosis and may also yield insight into damage that occurs with spondylotic and traumatic myelopathy. This article reviews the basis for DWI for the evaluation of the spinal cord, osseous, and soft tissues of the spine and reviews the imaging appearance of a variety of disease states. © 2013 Elsevier Inc.

Morrison R.S.,Mount Sinai School of Medicine
Current Opinion in Supportive and Palliative Care | Year: 2013

Purpose of review To summarize the current United States healthcare system and describe current models of palliative care delivery. Recent findings Palliative care services in the USA have been heavily influenced by the public-private fee-for-service reimbursement system. Hospice provides care for 46% of adults at the end-of-life under the Medicare hospice benefit. Palliative care teams in hospitals have rapidly expanded to provide care for seriously ill patients irrespective of prognosis. To date, over two-thirds of all hospitals and over 85% of mid to large size hospitals report a palliative care team. With the passage of the Patient Protection and Affordable Care Act of 2010, healthcare reform provides an opportunity for new models of care. Summary Palliative care services are well established within hospitals and hospice. Future work is needed to develop quality metrics, create care models that provide services in the community, and increase the palliative care workforce. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Sicherer S.H.,Mount Sinai School of Medicine | Wood R.A.,Johns Hopkins University
Journal of Allergy and Clinical Immunology: In Practice | Year: 2013

Peanut allergy is often severe, potentially fatal, usually persistent, and appears to have increased in prevalence. An accurate diagnosis is essential because there is a significant burden on quality of life. The tools available for diagnosis include the medical history, skin prick test (SPT), determination of serum peanut-specific IgE antibodies (PN-IgE), and medically supervised oral food challenges. Numerous studies, almost exclusively in children, have correlated clinical outcomes against SPTs and PN-IgE with informative results. The diagnostic utility of SPT and PN-IgE is maximized by considering the degree of positive result and consideration of the medical history (a priori estimation of risk). Emerging tests that evaluate IgE binding to specific proteins in peanut (component testing) add important additional diagnostic information in specific settings. Studies are increasingly focused on how the results of tests considered in combination (or performed serially) may increase diagnostic accuracy. Here, we review the utility of currently available tests and provide suggestions on how to best use them to accurately predict peanut allergy. Still, the physician-supervised oral food challenge remains the most definitive test available. © 2013 American Academy of Allergy, Asthma & Immunology.

Mechanick J.I.,Mount Sinai School of Medicine
Internal and Emergency Medicine | Year: 2013

Nutritional medicine presents significant educational and clinical challenges worldwide. Major issues include physician shortages as a result of inadequate training, increasing prevalence of metabolic diseases, such as obesity, diabetes, and atherosclerosis, incorporation of molecular medicine into our understanding of nutrition, and lastly, an emergent transcultural variable that affecting implementation strategies. Examples of translating specific molecular targets to culturally sensitive food-based therapies are given. © 2013 SIMI.

Robakis N.K.,Mount Sinai School of Medicine
Neurodegenerative Diseases | Year: 2010

Alzheimer's disease (AD) is characterized by neurodegeneration in neocortical regions of the brain. Currently, Aβ-based theories, including amyloid depositions and soluble Aβ, form the basis of most therapeutic approaches to AD. It remains unclear, however, whether Aβ and its derivatives are the primary causative agents of neuronal loss in AD. Reported studies show no significant correlations between brain amyloid depositions and either degree of dementia or loss of neurons, and brain amyloid loads similar to AD are often found in normal individuals. Furthermore, behavioral abnormalities in animal models overexpressing amyloid precursor protein seem independent of amyloid depositions. Soluble Aβ theories propose toxic Aβ42 or its oligomers as the agents that promote cell death in AD. Aβ peptides, however, are normal components of human serum and CSF, and it is unclear under what conditions these peptides become toxic. Presently, there is little evidence of disease-associated abnormalities in soluble Aβ and no toxic oligomers specific to AD have been found. That familial AD mutations of amyloid precursor protein, PS1 and PS2 promote neurodegeneration suggests the biological functions of these proteins play critical roles in neuronal survival. Evidence shows that the PS/γ-secretase system promotes production of peptides involved in cell surface-to-nucleus signaling and gene expression, providing support for the hypothesis that familial AD mutations may contribute to neurodegeneration by inhibiting PS-dependent signaling pathways. Copyright © 2010 S. Karger AG, Basel.

Ramaswamy R.,Mount Sinai School of Medicine
Journal of the American Geriatrics Society | Year: 2013

Medication management is an important component of medical education, particularly in the field of geriatrics. The Association of American Medical Colleges has put forth 26 minimum geriatrics competencies under eight domains for graduating medical students; medication management is one of these domains. The Portal of Geriatric Online education (www.POGOe.org) is an online public repository of geriatrics educational materials and modules developed by geriatrics educators and academicians in the United States, freely available for use by educators and learners in the field. The three POGOe materials presented in this review showcase pearls of medication management for medical and other professional students in novel learning formats that can be administered without major prior preparation. The review compares and contrasts the three materials in descriptive and tabular formats to enable its appropriate use by educators in promoting self-learning or group learning among their learners. © 2013, The American Geriatrics Society.

Silbiger J.J.,Mount Sinai School of Medicine
Journal of the American Society of Echocardiography | Year: 2013

Ischemic mitral regurgitation (MR) is a common complication of myocardial infarction thought to result from leaflet tethering caused by displacement of the papillary muscles that occurs as the left ventricle remodels. The author explores the possibility that left atrial remodeling may also play a role in the pathogenesis of ischemic MR, through a novel mechanism: atriogenic leaflet tethering. When ischemic MR is hemodynamically significant, the left ventricle compensates by dilating to preserve forward output using the Starling mechanism. Left ventricular dilatation, however, worsens MR by increasing the mitral valve regurgitant orifice, leading to a vicious cycle in which MR begets more MR. The author proposes that several structural adaptations play a role in reducing ischemic MR. In contrast to the compensatory effects of left ventricular enlargement, these may reduce, rather than increase, its severity. The suggested adaptations involve the mitral valve leaflets, the papillary muscles, the mitral annulus, and the left ventricular false tendons. This review describes the potential role each may play in reducing ischemic MR. Therapies that exploit these adaptations are also discussed. © 2013 by the American Society of Echocardiography.

Jarvinen K.M.,Albany Medical College | Nowak-Wegrzyn A.,Mount Sinai School of Medicine
Journal of Allergy and Clinical Immunology: In Practice | Year: 2013

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal food hypersensitivity that manifests as profuse, repetitive vomiting, often with diarrhea, leading to acute dehydration and lethargy or weight loss and failure to thrive if chronic. FPIES is elicited most commonly by milk and soy proteins; however, rice, oat, and other solid foods may also elicit FPIES. Certain FPIES features overlap with food protein-induced enteropathy and proctocolitis, whereas others overlap with anaphylaxis. FPIES is not well recognized among pediatricians and emergency department physicians; the affected children are often mismanaged as having acute viral gastrointestinal illness, sepsis, or surgical disease, delaying diagnosis of FPIES for many months. The aim of this review is to provide case-driven presentation of the features of FPIES. Although randomized clinical trials on management options are missing, the relevant current literature and authors' experience are reviewed in detail. © 2013 American Academy of Allergy, Asthma & Immunology.

Woo P.,Mount Sinai School of Medicine
Journal of Voice | Year: 2014

Dr. Paul Moore pioneered the use of high-speed cinematography for observation of normal and abnormal vocal fold vibrations during phonation. His analysis of the glottal area waveform, opening and closing speed index, and open quotient from the high-speed films were labor intensive but relevant today. With advances in digital image capture and automated image extraction techniques, stroboscopy and high-speed images of vocal fold vibration may be analyzed with objective measures. Digital high-speed image capture in color is now clinically practical at high resolution. Digital kymography now allows analysis of the vibratory waveform from each vocal fold. Serial capture and comparison can document changes in vibratory function with treatment. Quantification of vocal fold vibration using such techniques is now practical. This is a review of vocal fold vibration capture and analysis techniques since Dr. Moore. © 2014 The Voice Foundation.

Cobin R.H.,Mount Sinai School of Medicine
Internal and Emergency Medicine | Year: 2013

Polycystic ovary syndrome, the most common endocrine disorder of reproductive age women, is often associated with insulin resistance and associated disorders. The frequency of type 2 diabetes, hyperlipidemia, cardiac risk markers, structural vascular disease, and clinical disease events are increased in this population of women. PCOS, however, represents a broad spectrum of clinical presentations, as defined by different criteria proposed in Europe and the United States. The role of insulin resistance and hence the risk of cardiometabolic disorders may in part be determined by the definition of PCOS used. Epidemiologic studies and clinical trials support the need to identify women with PCOS to determine their risk of cardiometabolic disorders to prevent and/or treat their serious consequences. © 2013 SIMI.

Patel G.,Mount Sinai School of Medicine | Bonomo R.A.,Research Service | Bonomo R.A.,University Hospitals Case Medical Center | Bonomo R.A.,Case Western Reserve University
Frontiers in Microbiology | Year: 2013

Carbapenems, once considered the last line of defense against of serious infections with Enterobacteriaceae, are threatened with extinction. The increasing isolation of carbapenem-resistant Gram-negative pathogens is forcing practitioners to rely on uncertain alternatives. As little as 5 years ago, reports of carbapenem resistance in Enterobacteriaceae, common causes of both community and healthcare-associated infections, were sporadic and primarily limited to case reports, tertiary care centers, intensive care units, and outbreak settings. Carbapenem resistance mediated by β-lactamases, or carbapenemases, has become widespread and with the paucity of reliable antimicrobials available or in development, international focus has shifted to early detection and infection control. However, as reports of Klebsiella pneumoniae carbapenemases, New Delhi metallo-β-lactamase-1, and more recently OXA-48 (oxacillinase-48) become more common and with the conveniences of travel, the assumption that infections with highly resistant Gram-negative pathogens are limited to the infirmed and the heavily antibiotic and healthcare exposed are quickly being dispelled. Herein, we provide a status report describing the increasing challenges clinicians are facing and forecast the "stormy waters" ahead. © 2013 Patel and Bonomo.

Posner M.R.,Mount Sinai School of Medicine
Annals of Oncology | Year: 2010

Although highly debated in the 1980s, randomized clinical trials have provided undeniable evidence that systemic chemotherapy, as part of a multimodality treatment collaboration, is effective in improving survival, organ preservation and local-regional control in locally advanced head and neck cancer (HNC). We are entering an exciting period in which new chemotherapy agents, new paradigms of treatment, new surgical and radiation technology, and new prognostic factors are rapidly becoming available. Information on how to integrate these new tools and on how they affect long-term outcomes are lacking, making decision making and treatment planning more difficult. With unprecedented survival and the changing demographics of HNC we must now consider long-term consequences in addition to survival and local and regional control as important factors in therapeutic decision making. The availability of different treatment plans that incorporate systemic chemotherapy, radiotherapy and surgery give us many tools with which to craft a treatment for each individual patient. Today, in this exciting and chaotic period, a multidisciplinary and collaborative approach for each HNC patient at the start of decision making and planning is a necessity and the absolute standard of medical treatment for excellent patient care. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Hajjar R.J.,Mount Sinai School of Medicine
Journal of Clinical Investigation | Year: 2013

Advances in understanding the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, make gene-based therapy a promising treatment option for heart conditions. Cardiovascular gene therapy has benefitted from recent advancements in vector technology, design, and delivery modalities. There is a critical need to explore new therapeutic approaches in heart failure, and gene therapy has emerged as a viable alternative. Advances in understanding of the molecular basis of myocardial dysfunction, together with the development of increasingly efficient gene transfer technology, has placed heart failure within reach of gene-based therapy. The recent successful and safe completion of a phase 2 trial targeting the cardiac sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump (SERCA2a) has the potential to open a new era for gene therapy for heart failure.

Sicherer S.H.,Mount Sinai School of Medicine | Leung D.Y.M.,National Jewish Health
Journal of Allergy and Clinical Immunology | Year: 2014

This review highlights some of the research advances in anaphylaxis; hypersensitivity reactions to foods, drugs, and insects; and allergic skin diseases that were reported in the Journal in 2013. Studies on food allergy suggest that (1) 7.6% of the US population is affected, (2) a "healthy" early diet might prevent food allergy, (3) the skin might be an important route of sensitization, (4) allergen component testing might aid diagnosis, (5) the prognosis of milk allergy might be predictable through early testing, (6) oral or sublingual immunotherapy show promise but also have caveats, and (7) preclinical studies show promising alternative modes of immunotherapy and desensitization. Studies on eosinophilic esophagitis show a relationship to connective tissue disorders and that dietary management is an effective treatment for adults. Markers of anaphylaxis severity have been determined and might inform potential diagnostics and therapeutic targets. Insights on serum tests for drug and insect sting allergy might result in improved diagnostics. Genetic and immune-mediated defects in skin epithelial differentiation contribute to the severity of atopic dermatitis. Novel management approaches to treatment of chronic urticaria, including use of omalizumab, are being identified. © 2013 American Academy of Allergy, Asthma & Immunology.

Fan J.,Queens College, City University of New York | Fan J.,Mount Sinai School of Medicine
Frontiers in Human Neuroscience | Year: 2014

Our ability to efficiently process information and generate appropriate responses depends on the processes collectively called cognitive control Despite a considerable focus in the literature on the cognitive control of information processing, neural mechanisms underlying control are still unclear, and have not been characterized by considering the quantity of information to be processed. A novel and comprehensive account of cognitive control is proposed using concepts from information theory, which is concerned with communication system analysis and the quantification of information. This account treats the brain as an information-processing entity where cognitive control and its underlying brain networks play a pivotal role in dealing with conditions of uncertainty. This hypothesis and theory article justifies the validity and properties of such an account and relates experimental findings to the frontoparietal network under the framework of information theory. © 2014 Fan.

Perl D.P.,Mount Sinai School of Medicine
Mount Sinai Journal of Medicine | Year: 2010

Alois Alzheimer first pointed out that the disease which would later bear his name has a distinct and recognizable neuropathological substrate. Since then, much has been added to our understanding of the pathological lesions associated with the condition. The 2 primary cardinal lesions associated with Alzheimer's disease are the neurofibrillary tangle and the senile plaque. The neurofibrillary tangle consists of abnormal accumulations of abnormally phosphorylated tau within the perikaryal cytoplasm of certain neurons. The senile plaque consists of a central core of beta-amyloid, a 4-kD peptide, surrounded by abnormally configured neuronal processes or neurites. Other neuropathological lesions are encountered in cases of Alzheimer's disease, but the disease is defined and recognized by these 2 cardinal lesions. Other lesions include poorly understood changes such as granulovacuolar degeneration and eosinophilic rod-like bodies (Hirano bodies). The loss of synaptic components is a change that clearly has a significant impact on cognitive function and represents another important morphological alteration. It is important to recognize that distinguishing between Alzheimer's disease, especially in its early stages, and normal aging may be very difficult, particularly if one is examining the brains of patients who died at an advanced old age. It is also noted that instances of pure forms of Alzheimer's disease, in the absence of other coexistent brain disease processes, such as infarctions or Parkinson's disease-related lesions, are relatively uncommon, and this must be taken into account by researchers who employ postmortem brain tissues for research. © 2010 Mount Sinai School of Medicine.

Nestler E.J.,Mount Sinai School of Medicine | Hyman S.E.,Harvard University
Nature Neuroscience | Year: 2010

Modeling of human neuropsychiatric disorders in animals is extremely challenging given the subjective nature of many symptoms, the lack of biomarkers and objective diagnostic tests, and the early state of the relevant neurobiology and genetics. Nonetheless, progress in understanding pathophysiology and in treatment development would benefit greatly from improved animal models. Here we review the current state of animal models of mental illness, with a focus on schizophrenia, depression and bipolar disorder. We argue for areas of focus that might increase the likelihood of creating more useful models, at least for some disorders, and for explicit guidelines when animal models are reported. © 2010 Nature America, Inc. All rights reserved.

Dijkers M.P.,Mount Sinai School of Medicine
Archives of Physical Medicine and Rehabilitation | Year: 2013

Change and growth are the bread and butter of rehabilitation research, but to date, most researchers have used less than optimal statistical methods to quantify change, its nature, speed, and form. Hierarchical linear modeling (HLM) (random/mixed effects or latent growth or multilevel modeling, individual/latent growth curve analysis) generally is superior to analysis of (co)variance and other methods, but has been underused in rehabilitation research. Apropos of the publication of 2 didactic articles setting forth the basics of HLM, this commentary sketches some of the advantages of this technique. © 2013 American Congress of Rehabilitation Medicine.

Miller A.E.,Mount Sinai School of Medicine
Current opinion in neurology | Year: 2012

The aim of this review is to summarize unmet needs for patients with multiple sclerosis (MS). It is important to understand the current status of these patients and both the benefits and limitations of the most commonly used MS treatments as new medications with the potential to simplify therapy and improve outcomes may soon be available. Current treatments for MS decrease the frequency of relapses and slow progressive disability. However, nearly all of these medications require frequent administration, and some patients also experience side effects. In some patients, adherence to MS treatment may be less than optimal. This may be associated with increased risk for relapses and hospitalizations and higher cost of care. Healthcare providers involved in the treatment of MS must be aware of the unmet needs of their patients and intervene as needed to improve adherence and/or modify treatment regimens to optimize outcomes.

Sicherer S.H.,Mount Sinai School of Medicine | Leung D.Y.M.,National Jewish Health
Journal of Allergy and Clinical Immunology | Year: 2015

This review highlights some of the research advances in anaphylaxis; hypersensitivity reactions to foods, drugs, and insects; and allergic skin diseases that were reported in the Journal in 2014. Studies on food allergy suggest worrisomely high rates of peanut allergy and food-induced anaphylaxis-related hospitalizations. Evidence is mounting to support the theory that environmental exposure to peanut, such as in house dust, especially with an impaired skin barrier attributed to atopic dermatitis (AD) and loss of function mutations in the filaggrin gene, is a risk factor for sensitization and allergy. Diagnostic tests are improving, with early studies suggesting the possibility of developing novel cellular tests with increased diagnostic utility. Treatment trials continue to show the promise and limitations of oral immunotherapy, and mechanistic studies are elucidating pathways that might define the degree of efficacy of this treatment. Studies have also provided insights into the prevalence and characteristics of anaphylaxis and insect venom allergy, such as suggesting that baseline platelet-activating factor acetylhydrolase activity levels are related to the severity of reactions. Advances in drug allergy include identification of HLA associations for penicillin allergy and a microRNA biomarker/mechanism for toxic epidermal necrolysis. Research identifying critical events leading to skin barrier dysfunction and the polarized immune pathways that drive AD have led to new therapeutic approaches in the prevention and management of AD. © 2014 American Academy of Allergy, Asthma & Immunology.

Nowak-Wegrzyn A.,Mount Sinai School of Medicine | Katz Y.,Tel Aviv University | Mehr S.S.,Childrens Hospital at Westmead | Koletzko S.,Ludwig Maximilians University of Munich
Journal of Allergy and Clinical Immunology | Year: 2015

Non-IgE-mediated gastrointestinal food-induced allergic disorders (non-IgE-GI-FAs) account for an unknown proportion of food allergies and include food protein-induced enterocolitis syndrome (FPIES), food protein-induced allergic proctocolitis (FPIAP), and food protein-induced enteropathy (FPE). Non-IgE-GI-FAs are separate clinical entities but have many overlapping clinical and histologic features among themselves and with eosinophilic gastroenteropathies. Over the past decade, FPIES has emerged as the most actively studied non-IgE-GI-FA, potentially because of acute and distinct clinical features. FPIAP remains among the common causes of rectal bleeding in infants, while classic infantile FPE is rarely diagnosed. The overall most common allergens are cow's milk and soy; in patients with FPIES, rice and oat are also common. The most prominent clinical features of FPIES are repetitive emesis, pallor, and lethargy; chronic FPIES can lead to failure to thrive. FPIAP manifests with bloody stools in well-appearing young breast-fed or formula-fed infants. Features of FPE are nonbloody diarrhea, malabsorption, protein-losing enteropathy, hypoalbuminemia, and failure to thrive. Non-IgE-GI-FAs have a favorable prognosis; the majority resolve by 1 year in patients with FPIAP, 1 to 3 years in patients with FPE, and 1 to 5 years in patients with FPIES, with significant differences regarding specific foods. There is an urgent need to better define the natural history of FPIES and the pathophysiology of non-IgE-GI-FAs to develop biomarkers and novel therapies. © 2015 American Academy of Allergy, Asthma & Immunology.

Simons F.E.R.,University of Manitoba | Sampson H.A.,Mount Sinai School of Medicine
Journal of Allergy and Clinical Immunology | Year: 2015

In this rostrum we aim to increase awareness of anaphylaxis in infancy in order to improve clinical diagnosis, management, and prevention of recurrences. Anaphylaxis is increasingly reported in this age group. Foods are the most common triggers. Presentation typically involves the skin (generalized urticaria), the respiratory tract (cough, wheeze, stridor, and dyspnea), and/or the gastrointestinal tract (persistent vomiting). Tryptase levels are seldom increased because of infant anaphylaxis, although baseline tryptase levels can be increased in the first few months of life, reflecting mast cell burden in the developing immune system. The differential diagnosis of infant anaphylaxis includes consideration of age-unique entities, such as food protein-induced enterocolitis syndrome with acute presentation. Epinephrine (adrenaline) treatment is underused in health care and community settings. No epinephrine autoinjectors contain an optimal dose for infants weighing 10 kg or less. After treatment of an anaphylactic episode, follow-up with a physician, preferably an allergy/immunology specialist, is important for confirmation of anaphylaxis triggers and prevention of recurrences through avoidance of confirmed specific triggers. Natural desensitization to milk and egg can occur. Future research should include validation of the clinical criteria for anaphylaxis diagnosis in infants, prospective longitudinal monitoring of baseline serum tryptase levels in healthy and atopic infants during the first year of life, studies of infant comorbidities and cofactors that increase the risk of severe anaphylaxis, development of autoinjectors containing a 0.1-mg epinephrine dose suitable for infants, and inclusion of infants in prospective studies of immune modulation to prevent anaphylaxis recurrences. © 2015 American Academy of Allergy, Asthma & Immunology.

Zenenberg R.D.,Mount Sinai School of Medicine
Hospital practice (1995) | Year: 2010

BACKGROUND: Hyponatremia is one of the most common electrolyte disorders encountered in clinical practice. The pathophysiology is complex, but its understanding is vital to the disorder's evaluation and treatment. The clinical manifestations of hyponatremia include headache, dizziness, nausea/vomiting, seizures, obtundation, and death. Undercorrection must be avoided, but overly aggressive treatment can also be detrimental. OBJECTIVES: We review normal water physiology, including central osmosensory mechanisms, that are now becoming better understood. We will then review the classification and causes of hyponatremia and the clinical evaluation and workup of the disorder. Treatment options will be briefly reviewed. DISCUSSION: Evaluation of hyponatremia begins with a detailed history and physical examination. Appropriate urine and serum studies can contribute to the evaluation and classification of the disorder. Treatment decisions are based on the underlying cause and severity of symptoms. CONCLUSION: We present an extensive review of the physiology, pathophysiology, clinical evaluation, and management ofhyponatremia.

Chakrabarti L.A.,Institute Pasteur Paris | Simon V.,Mount Sinai School of Medicine
Current Opinion in Immunology | Year: 2010

HIV-1 can be contained by the immune system, as demonstrated by the existence of rare individuals who spontaneously control HIV-1 replication in the absence of antiretroviral therapy. Emerging evidence points to the importance of a very active cellular immune response in mediating HIV-1 control. The rapid induction of interferon-dependent HIV restriction factors, the presence of protective MHC class I alleles, and the development of a high avidity T-cell response may all cooperate in limiting HIV replication at an early stage. This review will focus on recent advances in understanding the immune mechanisms of HIV control, and on the lessons that may be drawn for the development of candidate HIV vaccines. © 2010 Elsevier Ltd.

Fiel M.I.,Mount Sinai School of Medicine
Clinics in Liver Disease | Year: 2010

Histologic evaluation of the liver is a major component in the medical management and treatment algorithm of patients with chronic hepatitis B (HBV) and chronic hepatitis C (HCV). Liver biopsy in these patients remains the gold standard, and decisions on treatment are often predicated on the degree of damage and stage of fibrosis. This article outlines the clinical course and serologic diagnosis of HBV and HCV for the clinician and the pathologist, who together have a close working relationship in managing patients with acute and chronic liver disease. The salient histologic features are elucidated in an attempt to provide the clinician with an understanding of the basic histopathology underlying chronic HCV and HBV. © 2010 Elsevier Inc.

Rigel D.S.,New York University | Russak J.,Mount Sinai School of Medicine | Friedman R.,New York University
CA Cancer Journal for Clinicians | Year: 2010

Early detection of malignant melanoma remains the key factor in lowering mortality from this cancer. Recognizing the importance of this issue 25 years ago, our group at New York University published in CA: A Cancer Journal for Clinicians the mnemonic "ABCD" to facilitate the early diagnosis of melanoma. Studies have demonstrated the usefulness of this paradigm in enhancing early melanoma diagnosis as a part of clinical examinations, mass screenings, and public education programs. Approaches to melanoma diagnosis have dynamically evolved during the ensuing quarter century. In the 1990s, dermoscopy enabled the recognition of new subsurface features to differentiate between malignant and benign pigmented lesions. During the last decade, new computer-based technologies have improved diagnostic sensitivity and specificity and may result in optimizing lesion selection for biopsy and pathology review. Despite all of the advances in melanoma diagnosis, timely recognition, detection, and rapid treatment of melanoma remain critical. Although pathologic examination remains the gold standard for diagnosis, this cancer has the potential to be diagnosed through noninvasive approaches because of its cutaneous location. From the development of the ABCDs through current attempts that use complex computer algorithms and genetic markers, a clinician's ability to detect melanoma in its earliest form has been augmented. However, a "good clinical eye" is still fundamental to selecting the lesions for evaluation among the sea of those that are prevalent. As current approaches are refined and new techniques are developed, the improved ability to diagnose this cancer will hopefully enhance reaching the goal of reducing melanoma mortality. © 2010 American Cancer Society, Inc.

Moucha C.S.,Mount Sinai School of Medicine
Instructional course lectures | Year: 2011

Multiple risk factors for orthopaedic surgical site infection have been identified. Some of these factors directly affect the wound-healing process, whereas others can lead to blood-borne sepsis or relative immunosuppression. Modifying a patient's medications; screening for comorbidities, such as HIV or diabetes mellitus; and advising the patient on options to diminish or eliminate adverse behaviors, such as smoking, should lower the risk for surgical site infections.

Jarvinen K.M.,Mount Sinai School of Medicine
Current Opinion in Allergy and Clinical Immunology | Year: 2011

Purpose of review: Food-induced anaphylaxis is the leading single cause of anaphylaxis treated in emergency departments and increasing in prevalence. Recent findings: Food allergy is an increasing problem in westernized countries around the world, with a cumulative prevalence of 3-6%. Peanut, tree nuts, and shellfish are the most commonly implicated foods in anaphylaxis, although milk is a common trigger in children. Asthmatics, adolescents, and those with a prior reaction are at increased risk for more severe reactions. Most first reactions and reactions in children most commonly occur at home, whereas most subsequent reactions and reactions in adults occur outside home. Studies on schools have identified inadequate management plans and symptom recognition whereas those on restaurants report lack of prior notification by allergic individuals and lack in staff education. Epinephrine, although underutilized is the drug of choice with multiple doses needed in up to one-fifth of reactions. Diagnosis is currently based on convincing history and allergy testing supported by elevated serum tryptase, if available. Long-term management includes strict avoidance and emergency action plan. Summary: With a growing population of food-allergic children and adults, markers to predict which individuals are at increased risk for anaphylaxis as well as new therapies are vigorously sought. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Sicherer S.H.,Mount Sinai School of Medicine | Leung D.Y.M.,National Jewish Health
Journal of Allergy and Clinical Immunology | Year: 2012

This review highlights some of the research advances in anaphylaxis; hypersensitivity reactions to foods, drugs, and insects; and allergic skin diseases that were reported in the Journal in 2011. Food allergy appears to be increasing in prevalence and carries a strong economic burden. Risk factors can include dietary ones, such as deficiency of vitamin D and timing of complementary foods, and genetic factors, such as filaggrin loss-of-function mutations. Novel mechanisms underlying food allergy include the role of invariant natural killer T cells and influences of dietary components, such as isoflavones. Among numerous preclinical and clinical treatment studies, promising observations include the efficacy of sublingual and oral immunotherapy, a Chinese herbal remedy showing promising in vitro results, the potential immunotherapeutic effects of having children ingest foods with baked-in milk if they tolerate it, and the use of anti-IgE with or without concomitant immunotherapy. Studies of allergic skin diseases, anaphylaxis, and hypersensitivity to drugs and insect venom are elucidating cellular mechanisms, improved diagnostics, and potential targets for future treatment. The role of skin barrier abnormalities, as well as the modulatory effects of the innate and adaptive immune responses, are major areas of investigation. © 2011 American Academy of Allergy, Asthma & Immunology.

Berin M.C.,Mount Sinai School of Medicine
Immunology and Allergy Clinics of North America | Year: 2012

The default response of the mucosal immune system to antigens derived from food is one of active immune tolerance carried out by regulatory T cells and induced by dendritic cells residing in the intestinal mucosa. This tolerance response must be inhibited or bypassed to generate allergic sensitization in experimental food allergy and this has been achieved by 3 main approaches: genetic modifications, experimental adjuvants, and bypassing oral tolerance by administering the antigen through alternative routes. This article discusses the implications of these approaches for understanding the mechanisms of sensitization to food allergens in human disease. © 2012 Elsevier Inc.

Frost E.A.M.,Mount Sinai School of Medicine
Mount Sinai Journal of Medicine | Year: 2012

The enormous diversity of physician practices, including specialists, and patient requirements and comorbidities make integration of appropriate perioperative information difficult. Lack of communicating computer systems adds to the difficulty of assembling data. Meta analysis and evidence-based studies indicate that far too many tests are performed perioperatively. Guidelines for appropriate perioperative management have been formulated by several specialties. Education as to current findings and requirements should be better communicated to surgeons, consultants, and patients to improve healthcare needs and at the same time decrease costs. Means to better communication by interpersonal collaboration are outlined. © 2012 Mount Sinai School of Medicine.

Sicherer S.H.,Mount Sinai School of Medicine | Leung D.Y.M.,National Jewish Health
Journal of Allergy and Clinical Immunology | Year: 2011

This review highlights some of the research advances in anaphylaxis; hypersensitivity reactions to foods, drugs, and insects; and allergic skin disease that were reported in the Journal in 2010. Key epidemiologic observations include an apparent increase in peanut allergy, with more than 1% of children affected, and increasing evidence that early food allergen exposure, rather than avoidance, might improve allergy outcomes. Advances in food allergy diagnosis include improved insights into prognosis and estimation of severity through component-resolved diagnostics and characterization of IgE binding to specific epitopes. Regarding treatment, oral and epicutaneous immunotherapy show promise. Studies of drug allergies show insights into pathophysiology, and studies on insect hypersensitivity reveal improved diagnostic methods. Genetic and functional studies have revealed the important role of epidermal differentiation products in the pathogenesis of atopic dermatitis. Cross-talk between the atopic immune response with the innate immune response have also been found to predispose to infection in patients with atopic dermatitis. New therapeutic approaches to control chronic urticaria have also been identified during the past year. © 2010 American Academy of Allergy, Asthma & Immunology.

Akar F.G.,Mount Sinai School of Medicine
Journal of Interventional Cardiac Electrophysiology | Year: 2013

Mitochondrial dysfunction is a hallmark of common cardiovascular disorders, including ischemia-reperfusion injury, hypertrophy, heart failure, and diabetes mellitus. While the role of the mitochondrial network in regulating energy production and cell death pathways is well established, its active control of other critical cellular functions, including excitation-contraction coupling and excitability, is less understood. The purpose of this focused review article is to highlight the growing mechanistic link between mitochondrial dysfunction and arrhythmogenesis. The goal is not to provide a comprehensive listing of all factors by which mitochondrial bioenergetics and altered cellular redox status affect ion channel function but rather to focus on one central mechanism of arrhythmogenesis which arises from a mitochondrial origin. In doing so, we discuss the role of mitochondrial targets for suppressing arrhythmias through this mechanism. © 2013 Springer Science+Business Media New York.

Sicherer S.H.,Mount Sinai School of Medicine | Leung D.Y.M.,National Jewish Health
Journal of Allergy and Clinical Immunology | Year: 2013

This review highlights some of the research advances in anaphylaxis; hypersensitivity reactions to foods, drugs, and insects; and allergic skin diseases that were reported in the Journal in 2012. Studies support an increase in peanut allergy prevalence in children and exposure to the antibacterial agent triclosan and having filaggrin (FLG) loss-of-function mutations as risk factors for food sensitization. The role of specific foods in causing eosinophilic esophagitis is elucidated by several studies, and microRNA analysis is identified as a possible noninvasive disease biomarker. Studies on food allergy diagnosis emphasize the utility of component testing and the possibility of improved diagnosis through stepped approaches, epitope-binding analysis, and bioinformatics. Treatment studies of food allergy show promise for oral immunotherapy, but tolerance induction remains elusive, and additional therapies are under study. Studies on anaphylaxis suggest an important role for platelet-activating factor and its relationship to the need for prompt treatment with epinephrine. Insights on the pathophysiology and diagnosis of non-IgE-mediated drug allergy are offered, with novel data regarding the interaction of drugs with HLA molecules. Numerous studies support influenza vaccination of persons with egg allergy using modest precautions. Evidence continues to mount that there is cross-talk between skin barrier defects and immune responses in patients with atopic dermatitis. Augmentation of the skin barrier with reduction in skin inflammatory responses will likely lead to the most effective intervention in patients with this common skin disease. © 2012 American Academy of Allergy, Asthma & Immunology.

La Merrill M.,Mount Sinai School of Medicine | Birnbaum L.S.,U.S. National Cancer Institute
Mount Sinai Journal of Medicine | Year: 2011

Childhood and adolescent rates of obesity and overweight are continuing to increase in much of the world. Risk factors such as diet composition, excess caloric intake, decreased exercise, genetics, and the built environment are active areas of etiologic research. The obesogen hypothesis, which postulates that prenatal and perinatal chemical exposure can contribute to risk of childhood and adolescent obesity, remains relatively underexamined. This review surveys numerous classes of chemicals for which this hypothesis has been explored. We focus on human data where they exist and also discuss the findings of rodent and cell culture studies. Organochlorine chemicals as well as several classes of chemicals that are peroxisome proliferator-activated receptor agonists are identified as possible risk factors for obesity. Recommendations for future epidemiologic and experimental research on the chemical origins of obesity are also given. © 2011 Mount Sinai School of Medicine.

Rozenfeld R.,Mount Sinai School of Medicine
Traffic | Year: 2011

The majority of G-protein-coupled receptors (GPCRs) function at the cell surface, where they are activated by their ligands present in the extracellular milieu. Interestingly, type I cannabinoid receptor (CB1R), one of the most abundant GPCRs in the central nervous system, is predominantly intracellular. The important physiological roles of CB1R have sparked interest in the elucidation of the molecular mechanisms underlying the trafficking of this receptor and the role of intracellular CB1Rs. Thus far, results from different groups have been, at least in part, contradictory and the basis of CB1R intracellular localization remains controversial. In this commentary, by comparing the studies examining CB1R trafficking and localization, we identify technical or experimental ground responsible for the conflicting results. Finally, we propose a possible mechanism of CB1R trafficking that may reconcile the different models. © 2010 John Wiley & Sons A/S.

Wright R.,Mount Sinai School of Medicine | Saul R.A.,Childrens Hospital
Pediatrics | Year: 2013

Epigenetics, the study of functionally relevant chemical modifications to DNA that do not involve a change in the DNA nucleotide sequence, is at the interface between research and clinical medicine. Research on epigenetic marks, which regulate gene expression independently of the underlying genetic code, has dramatically changed our understanding of the interplay between genes and the environment. This interplay alters human biology and developmental trajectories, and can lead to programmed human disease years after the environmental exposure. In addition, epigenetic marks are potentially heritable. In this article, we discuss the underlying concepts of epigenetics and address its current and potential applicability for primary care providers. © 2013 by the American Academy of Pediatrics.

Funk A.J.,University of Alabama at Birmingham | McCullumsmith R.E.,University of Alabama at Birmingham | Haroutunian V.,Mount Sinai School of Medicine | Meador-Woodruff J.H.,University of Alabama at Birmingham
Neuropsychopharmacology | Year: 2012

Recent evidence suggests that schizophrenia may result from alterations of integration of signaling mediated by multiple neurotransmitter systems. Abnormalities of associated intracellular signaling pathways may contribute to the pathophysiology of schizophrenia. Proteins and phospho-proteins comprising mitogen activated protein kinase (MAPK) and 3′-5′-cyclic adenosine monophosphate (cAMP)-associated signaling pathways may be abnormally expressed in the anterior cingulate (ACC) and dorsolateral prefrontal cortex (DLPFC) in schizophrenia. Using western blot analysis we examined proteins of the MAPK- and cAMP-associated pathways in these two brain regions. Postmortem samples were used from a well-characterized collection of elderly patients with schizophrenia (ACC=36, DLPFC=35) and a comparison (ACC=33, DLPFC=31) group. Near-infrared intensity of IR-dye labeled secondary antisera bound to targeted proteins of the MAPK- and cAMP-associated signaling pathways was measured using LiCor Odyssey imaging system. We found decreased expression of Rap2, JNK1, JNK2, PSD-95, and decreased phosphorylation of JNK1/2 at T183/Y185 and PSD-95 at S295 in the ACC in schizophrenia. In the DLPFC, we found increased expression of Rack1, Fyn, Cdk5, and increased phosphorylation of PSD-95 at S295 and NR2B at Y1336. MAPK- and cAMP-associated molecules constitute ubiquitous intracellular signaling pathways that integrate extracellular stimuli, modify receptor expression and function, and regulate cell survival and neuroplasticity. These data suggest abnormal activity of the MAPK- and cAMP-associated pathways in frontal cortical areas in schizophrenia. These alterations may underlie the hypothesized hypoglutamatergic function in this illness. Together with previous findings, these data suggest that abnormalities of intracellular signaling pathways may contribute to the pathophysiology of schizophrenia. © 2012 American College of Neuropsychopharmacology. All rights reserved.

Sengupta P.P.,Mount Sinai School of Medicine
JACC: Cardiovascular Imaging | Year: 2013

Accelerating trends in the dynamic digital era (from 2004 onward) has resulted in the emergence of novel parametric imaging tools that allow easy and accurate extraction of quantitative information from cardiac images. This review principally attempts to heighten the awareness of newer emerging paradigms that may advance acquisition, visualization and interpretation of the large functional data sets obtained during cardiac ultrasound imaging. Incorporation of innovative cognitive software that allow advanced pattern recognition and disease forecasting will likely transform the human-machine interface and interpretation process to achieve a more efficient and effective work environment. Novel technologies for automation and big data analytics that are already active in other fields need to be rapidly adapted to the health care environment with new academic-industry collaborations to enrich and accelerate the delivery of newer decision making tools for enhancing patient care. © 2013 By The American College of Cardiology Foundation.

Siu A.L.,Mount Sinai School of Medicine | Siu A.L.,James ters Veterans Affairs Medical Center
JAMA - Journal of the American Medical Association | Year: 2016

DESCRIPTION New US Preventive Services Task Force (USPSTF) recommendation on screening for autism spectrum disorder (ASD) in young children. METHODS The USPSTF reviewed the evidence on the accuracy, benefits, and potential harms of brief, formal screening instruments for ASD administered during routine primary care visits and the benefits and potential harms of early behavioral treatment for young children identified with ASD through screening. POPULATION This recommendation applies to children aged 18 to 30 months who have not been diagnosed with ASD or developmental delay and for whom no concerns of ASD have been raised by parents, other caregivers, or health care professionals. RECOMMENDATION The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for ASD in young children for whom no concerns of ASD have been raised by their parents or a clinician. (I statement). © 2016 American Medical Association.

Thompson J.W.,Harvard University | Carlson M.D.,Mount Sinai School of Medicine | Bradley E.H.,Yale University
Health Affairs | Year: 2012

The US hospice industry, which provides palliative and supportive care to patients with terminal illness, has undergone substantial changes during the last decade. The magnitude of these changes has not been fully captured in previous studies or reports. In this longitudinal study of hospices active in Medicare during 1999-2009, we analyzed Provider of Services files to understand key shifts in the industry. We found evidence of substantial turbulence. One-fifth of Medicare-certified hospices active in 1999 had closed or withdrawn from the program by 2009, and more than 40 percent had experienced one or more changes in ownership. The most prominent trend was the shift in ownership type from nonprofit to for-profit ownership. Four out of five Medicare-certified hospices that entered the marketplace between 2000 and 2009 were for-profit. Hospices also became larger, as the proportion with 100 or more full-time employees doubled to 5 percent from 1999 to 2009. Although each of the Census regions had more hospices in 2009 than in 1999, the geographic distribution of hospices in the country changed, with proportionally more in the South and West. The impact of all of these changes on cost and quality of hospice care, as well as patient access, remains a critical area for future research. © 2012 Project HOPE-The People-to-People Health Foundation, Inc.

Sicherer S.H.,Mount Sinai School of Medicine
Journal of Allergy and Clinical Immunology | Year: 2011

Adverse reactions to foods can occur for a variety of reasons, but a food allergy is caused by a specific immune response. Challenges to determine the prevalence of food allergy include misclassification, biased participation, lack of simple diagnostic tests, rapid evolution of disease, large numbers of potential triggers, and varied clinical phenotypes. Nonetheless, it is clear that this is a common disorder, with studies suggesting a cumulative prevalence of 3% to 6%, representing a significant impact on quality of life and costs. The inclusion of mild reactions to fruits and vegetables could result in calculation of prevalence exceeding 10% in some regions. There are data from numerous studies to suggest an increase in prevalence, but methodologic concerns warrant caution. Prevalence varies by age, geographic location, and possibly race/ethnicity. Many childhood food allergies resolve. Population-based epidemiologic studies have generated numerous novel theories regarding risks, including modifiable factors such as components of the maternal and infant diet, obesity, and the timing of food introduction. Recent and ongoing studies provide insights on risk factors, prevalence, and natural course that may inform clinical trials to improve diagnosis, prevention, and treatment. © 2010 American Academy of Allergy, Asthma and Immunology.

Lublin F.D.,Mount Sinai School of Medicine
European Neurology | Year: 2014

Background: In 1996, the clinical course of multiple sclerosis (MS) was characterized as relapsing-remitting, primary progressive, secondary progressive or progressive relapsing. Since then, an increased understanding of MS and its pathology prompted a re-examination of these clinical phenotypes. Main recommendations of the 2013 revisions are provided herein. Summary: Clinically isolated syndrome has been added, and progressive relapsing MS has been eliminated, from the clinical course descriptions. All forms of MS should be further subcategorized as either active or non-active. Active MS is defined as the occurrence of clinical relapse or the presence of new T2 or gadolinium-enhancing lesions over a specified period of time, preferably at least one year. An additional subcategory for patients with progressive MS differentiates between those who have shown signs of disability progression over a given time period and those who have remained stable. The term 'worsening' is recommended to describe patients whose disease is advancing for any reason, whereas 'disease progression' should be reserved for those with progressive disease who are truly progressing (as opposed to worsening from a relapse). The term 'benign' should be used with caution as the course of MS can worsen at any time, even after many years of apparent stability. Key Messages: Newer characterizations of MS phenotypes include a consideration of disease activity (based on the clinical relapse rate and imaging findings) and disease progression. Accurate clinical course descriptions are useful for communication, prognostication, clinical trial design and to guide everyday clinical decision-making. © 2014 S. Karger AG, Basel.

Yasny J.S.,Mount Sinai School of Medicine
Anesthesia progress | Year: 2012

For several decades, anesthetic gases have greatly enhanced the comfort and outcome for patients during surgery. The benefits of these agents have heavily outweighed the risks. In recent years, the attention towards their overall contribution to global climate change and the environment has increased. Anesthesia providers have a responsibility to minimize unnecessary atmospheric pollution by utilizing techniques that can lessen any adverse effects of these gases on the environment. Moreover, health care facilities that use anesthetic gases are accountable for ensuring that all anesthesia equipment, including the scavenging system, is effective and routinely maintained. Implementing preventive practices and simple strategies can promote the safest and most healthy environment.

Sokol S.Y.,Mount Sinai School of Medicine
Seminars in Cell and Developmental Biology | Year: 2015

Wnt signaling pathways act at multiple locations and developmental stages to specify cell fate and polarity in vertebrate embryos. A long-standing question is how the same molecular machinery can be reused to produce different outcomes. The canonical Wnt/β-catenin branch modulates target gene transcription to specify cell fates along the dorsoventral and anteroposterior embryonic axes. By contrast, the Wnt/planar cell polarity (PCP) branch is responsible for cell polarization along main body axes, which coordinates morphogenetic cell behaviors during gastrulation and neurulation. Whereas both cell fate and cell polarity are modulated by spatially- and temporally-restricted Wnt activity, the downstream signaling mechanisms are very diverse. This review highlights recent progress in the understanding of Wnt-dependent molecular events leading to the establishment of PCP and linking it to early morphogenetic processes. © 2015 Elsevier Ltd.

Cederbaum A.I.,Mount Sinai School of Medicine
World Journal of Gastroenterology | Year: 2010

S-adenosyl-L-methionine (SAM) acts as a methyl donor for methylation reactions and participates in the synthesis of glutathione. SAM is also a key metabolite that regulates hepatocyte growth, differentiation and death. Hepatic SAM levels are decreased in animal models of alcohol liver injury and in patients with alcohol liver disease or viral cirrhosis. This review describes the protection by SAM against alcohol and cytochrome P450 2E1-dependent cytotoxicity both in vitro and in vivo and evaluates mechanisms for this protection. © 2010 Baishideng.

Scott S.A.,Mount Sinai School of Medicine
Clinical Pharmacology and Therapeutics | Year: 2013

One of the major barriers to implementing clinical pharmacogenomics has been the efficient integration of rapid turnaround-time genetic testing into routine clinical practice. To address this specific challenge, both point-of-care and preemptive pharmacogenomic testing programs, initially centered on cardiovascular pharmacogenomics, have recently been deployed. Early results indicate that these strategies are feasible and probably beneficial clinically; however, despite these exciting advances toward implementing clinical pharmacogenomics, challenges to widespread adoption remain.

Kim M.K.,Mount Sinai School of Medicine
Gut and Liver | Year: 2012

Endoscopic ultrasound (EUS) is an advanced endoscopic technique currently used in the staging and diagnosis of many gastrointestinal neoplasms. The proximity of the echoendoscope to the gastrointestinal tract lends itself to a detailed view of the luminal pathology and the pancreas. This unique ability enables endoscopists to use EUS in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Diagnostic EUS allows previously unidentified NETs to be localized. EUS also determines tumor management by staging the GEP-NETS, enabling the clinicians to choose the appropriate endoscopic or surgical management. The ability to obtain a tissue diagnosis with EUS guidance enables disease confirmation. Finally, recent developments suggest that EUS may be used to deliver therapeutic agents for the treatment of NETs. This review will highlight the advances in our knowledge of EUS in the clinical management of these tumors.

Sher L.,Mount Sinai School of Medicine
International Journal of Adolescent Medicine and Health | Year: 2012

Predicting and preventing suicide represent very difficult challenges for clinicians. The awareness of adolescent suicide as a major social and medical problem has increased over the past years. However, many health care professionals who have frequent contact with adolescents are not sufficiently trained in suicide evaluation techniques and approaches to adolescents with suicidal behavior. Suicide prevention efforts among adolescents are restricted by the fact that there are five key problems related to the evaluation and management of suicidality in adolescents: 1. Many clinicians underestimate the importance of the problem of adolescent suicidal behavior and underestimate its prevalence. 2. There is a misconception that direct questioning of adolescents about suicidality is sufficient to evaluate suicide risk. 3. Another misconception is that adolescents with non-psychiatric illnesses do not need to be evaluated for suicidality. 4. Many clinicians do not know about or underestimate the role of contagion in adolescent suicidal behavior. 5. There is a mistaken belief that adolescent males are at lower suicide risk than adolescent females. Educating medical professionals and trainees about the warning signs and symptoms of adolescent suicide and providing them with tools to recognize, evaluate, and manage suicidal patients represent a promising approach to adolescent suicide prevention. © 2012 by Walter de Gruyter.

Pinney S.P.,Mount Sinai School of Medicine
Journal of Cardiac Failure | Year: 2015

Clinical outcomes for patients with advanced heart failure receiving left ventricular assist devices are driven by appropriate patient selection, refined surgical technique, and coordinated medical care. Perhaps even more important is innovative pump design. The introduction and widespread adoption of continuous-flow ventricular assist devices has led to a paradigm shift within the field of mechanical circulatory support, making the promise of lifetime device therapy closer to reality. The disruption caused by this new technology, on the one hand, produced meaningful improvements in patient survival and quality of life, but also introduced new clinical challenges, such as bleeding, pump thrombosis, and acquired valvular heart disease. Further evolution within this field will require financial investment to sustain innovation leading to a fully implantable, durable, and cost-effective pump for a larger segment of patients with advanced heart failure. © 2015 Elsevier Inc.

Papatsenko D.,Mount Sinai School of Medicine | Levine M.,University of California at Berkeley
PLoS ONE | Year: 2011

Drosophila "gap" genes provide the first response to maternal gradients in the early fly embryo. Gap genes are expressed in a series of broad bands across the embryo during first hours of development. The gene network controlling the gap gene expression patterns includes inputs from maternal gradients and mutual repression between the gap genes themselves. In this study we propose a modular design for the gap gene network, involving two relatively independent network domains. The core of each network domain includes a toggle switch corresponding to a pair of mutually repressive gap genes, operated in space by maternal inputs. The toggle switches present in the gap network are evocative of the phage lambda switch, but they are operated positionally (in space) by the maternal gradients, so the synthesis rates for the competing components change along the embryo anterior-posterior axis. Dynamic model, constructed based on the proposed principle, with elements of fractional site occupancy, required 5-7 parameters to fit quantitative spatial expression data for gap gradients. The identified model solutions (parameter combinations) reproduced major dynamic features of the gap gradient system and explained gap expression in a variety of segmentation mutants. © 2011 Papatsenko, Levine.

Roberts A.E.,Childrens | Allanson J.E.,Childrens Hospital of Eastern | Gelb B.D.,Mount Sinai School of Medicine
The Lancet | Year: 2013

Noonan syndrome is a genetic multisystem disorder characterised by distinctive facial features, developmental delay, learning diffi culties, short stature, congenital heart disease, renal anomalies, lymphatic malformations, and bleeding diffi culties. Mutations that cause Noonan syndrome alter genes encoding proteins with roles in the RAS-MAPK pathway, leading to pathway dysregulation. Management guidelines have been developed. Several clinically relevant genotype-phenotype correlations aid risk assessment and patient management. Increased understanding of the pathophysiology of the disease could help development of pharmacogenetic treatments.

Yue Z.,Mount Sinai School of Medicine
Autophagy | Year: 2010

A recent study published in the Journal of Neuroscience by Nishiyama et al., has revisited an autophagy-neurodegeneration model of lurcher (Lc) mice and promoted further discussion regarding the "autophagic cell death" hypothesis.1 While the study confirmed the previous report by Yue et al., that GluRD2Lc induces autophagy both in vitro and in vivo, 2 it also suggests that GluRD2Lc-mediated autophagy and cell death occur via pathways outside the nPIST-Beclin 1 pathway.1 For example, the study makes an interesting observation that GluRD2 Lc-induced degeneration is associated with energy crisis and an aberrant AMPK activity. The result provides insight into the downstream events induced by GluRD2Lc; however, it is not surprising considering that constitutive ion influx caused by the Lc mutation is expected to cause activation of multiple cellular pathways or responses. In conclusion, the authors state that "constitutive ion flux causes cell death with, but not by, autophagy." The conclusion appears consistent with the primary function of autophagy, from an evolutionary point of view, as a survival mechanism. However, careful examination of some results may call into question the conclusion. © 2010 Landes Bioscience.

Fisher R.P.,Mount Sinai School of Medicine
Genes and Cancer | Year: 2012

Cyclin-dependent kinases (CDKs) play essential roles in cell proliferation and gene expression. Although distinct sets of CDKs work in cell division and transcription by RNA polymerase II (Pol II), they share a CDK-activating kinase (CAK), which is itself a CDK-Cdk7-in metazoans. Thus a unitary CDK network controls and may coordinate cycles of cell division and gene expression. Recent work reveals decisive roles for Cdk7 in both pathways. The CAK function of Cdk7 helps determine timing of activation and cyclin-binding preferences of different CDKs during the cell cycle. In the transcription cycle, Cdk7 is both an effector kinase, which phosphorylates Pol II and other proteins and helps establish promoter-proximal pausing; and a CAK for Cdk9 (P-TEFb), which releases Pol II from the pause. By governing the transition from initiation to elongation, Cdk7, Cdk9 and their substrates influence expression of genes important for developmental and cell-cycle decisions, and ensure co-transcriptional maturation of Pol II transcripts. Cdk7 engaged in transcription also appears to be regulated by phosphorylation within its own activation (T) loop. Here I review recent studies of CDK regulation in cell division and gene expression, and propose a model whereby mitogenic signals trigger a cascade of CDK T-loop phosphorylation that drives cells past the restriction (R) point, when continued cell-cycle progression becomes growth factor-independent. Because R-point control is frequently deregulated in cancer, the CAK-CDK pathway is an attractive target for chemical inhibition aimed at impeding the inappropriate commitment to cell division. © The Author(s) 2013.

Wyatt C.M.,Mount Sinai School of Medicine
Topics in Antiviral Medicine | Year: 2012

Acute kidney injury (AKI) and chronic kidney disease (CKD) are more common in HIV-infected persons than in the general population. AKI is associated with poor health outcomes, including increased risk of heart failure, cardiovascular events, end-stage renal disease (ESRD), and mortality. The most common causes of AKI in HIV-infected persons are systemic infections and adverse drug effects. The prevalence of CKD is rising in the HIV-infected population and CKD is increasingly likely to be caused by comorbid conditions, such as diabetes and hypertension, that frequently cause CKD in the general population. Guidelines for CKD screening in HIV-infected patients are being revised. It is currently recommended that all patients be screened for creatinine-based estimates of glomerular filtration rate and for urine protein at the time of HIV diagnosis. Annual screening is recommended for highrisk patients. Hemodialysis, peritoneal dialysis, and kidney transplantation are all options for treating ESRD in HIV-infected patients. Hemodialysis and peritoneal dialysis offer similar survival in HIV-infected patients with ESRD. In selected patients with well-controlled HIV infection, kidney transplantation is associated with survival intermediate between that in the overall transplant population and that among transplant recipients older than 65 years. © 2011, IAS-USA.

Weingart S.D.,Mount Sinai School of Medicine
Journal of Emergency Medicine | Year: 2011

Background: The goal of preoxygenation is to provide us with a safe buffer of time before desaturation during Emergency Department intubation. For many intubations, the application of an oxygen mask is sufficient to provide us with ample time to safely intubate our patients. However, some patients are unable to achieve adequate saturations by conventional means and are at high risk for immediate desaturation during apnea and laryngoscopy. For these patients, more advanced methods to achieve preoxygenation and prevent desaturation are vital. Discussion: We will review the physiology of hypoxemia and the means to correct it before intubation. Next, we will discuss apneic oxygenation as a means to blunt desaturation and the optimal way to reoxygenate a patient if desaturation does occur. Last, we will discuss the new concept of delayed sequence intubation, a technique to be used when the discomfort and delirium of hypoxia and hypercapnia prevents patient tolerance of conventional preoxygenation. Conclusions: These new concepts in preoxygenation and reoxygenation may allow safer airway management of the high-risk patient. © 2011 Elsevier Inc.

Ginhoux F.,A+ Network | Schultze J.L.,University of Bonn | Schultze J.L.,German Center for Neurodegenerative Diseases | Murray P.J.,St Jude Childrens Research Hospital | And 3 more authors.
Nature Immunology | Year: 2016

Macrophages have protective roles in immunity to pathogens, tissue development, homeostasis and repair following damage. Maladaptive immunity and inflammation provoke changes in macrophage function that are causative of disease. Despite a historical wealth of knowledge about macrophages, recent advances have revealed unknown aspects of their development and function. Following development, macrophages are activated by diverse signals. Such tissue microenvironmental signals together with epigenetic changes influence macrophage development, activation and functional diversity, with consequences in disease and homeostasis. We discuss here how recent discoveries in these areas have led to a multidimensional concept of macrophage ontogeny, activation and function. In connection with this, we also discuss how technical advances facilitate a new roadmap for the isolation and analysis of macrophages at high resolution. © 2016 Nature America, Inc.

Basler C.F.,Mount Sinai School of Medicine
Virology | Year: 2015

Ebola viruses and Marburg viruses, members of the filovirus family, cause severe hemorrhagic fever. The ability of these viruses to potently counteract host innate immune responses is thought to be an important component of viral pathogenesis. Several mechanisms of filoviral innate immune evasion have been defined and are reviewed here. These mechanisms include suppression of type I interferon (IFN) production; inhibition of IFN-signaling and mechanisms that either prevent cell stress responses or allow the virus to replicate in the face of such responses. A greater understanding of these innate immune evasion mechanisms may suggest novel therapeutic approaches for these deadly pathogens. © 2015 Elsevier Inc.

Glioblastoma multiforme is the most common and most aggressive type of primary brain tumor, accounting for 52% of all primary brain tumor cases and 20% of all intracranial tumors. Recently, evidence for a viral cause has been postulated, possibly cytomegalovirus (CMV). In one report, 80% of patients with newly diagnosed glioblastoma multiforme had detectable cytomegalovirus DNA in their peripheral blood, while sero-positive normal donors and other surgical patients did not exhibit detectable virus. However, another study reported that five glioblastoma patients showed no circulating CMV detected either with RT-PCR or blood culture. But CMV could still be a factor in the genesis of glioblastoma multiforme, if age at infection is taken into account, since the incidence of both glioblastoma multiforme and CMV infection are inversely related to socioeconomic status. CMV infection in early childhood, more common in lower socioeconomic groups, may be protective against glioblastoma multiforme, whereas CMV infection in later childhood or adulthood may be a risk factor for glioblastoma. If so, glioblastoma multiforme occurrence would resemble paralytic polio, where low socioeconomic status, poor hygiene and early infection are protective. © 2012 Elsevier Ltd.

Sand I.K.,Mount Sinai School of Medicine
Current Opinion in Neurology | Year: 2015

The increasing availability of effective therapies for multiple sclerosis as well as research demonstrating the benefits of early treatment highlights the importance of expedient and accurate multiple sclerosis diagnosis. This review will discuss the classification, diagnosis, and differential diagnosis of multiple sclerosis. Recent findings An international panel of multiple sclerosis experts, the MS Phenotype Group, recently revised the multiple sclerosis phenotypic classifications and published their recommendations in 2014. Recent research developments have helped improve the accuracy of multiple sclerosis diagnosis, especially with regard to differentiating multiple sclerosis from neuromyelitis optica spectrum disorders. Summary Current multiple sclerosis phenotypic classifications include relapsing-remitting multiple sclerosis, clinically isolated syndrome, radiologically isolated syndrome, primary-progressive multiple sclerosis, and secondary-progressive multiple sclerosis. The McDonald 2010 diagnostic criteria provide formal guidelines for the diagnosis of relapsing-remitting multiple sclerosis and primary-progressive multiple sclerosis. These require demonstration of dissemination in space and time, with consideration given to both clinical findings and imaging data. The criteria also require that there exist no better explanation for the patient's presentation. The clinical history, examination, and MRI should be most consistent with multiple sclerosis, including the presence of features typical for the disease as well as the absence of features that suggest an alternative cause, for a diagnosis of multiple sclerosis to be proposed. © 2015 Wolters Kluwer Health, Inc.

Sanyal A.J.,Virginia Commonwealth University | Friedman S.L.,Mount Sinai School of Medicine | Mccullough A.J.,Cleveland Clinic | Dimick-Santos L.,U.S. Food and Drug Administration
Hepatology | Year: 2015

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease (CLD) in North America. It is a growing contributor to the burden of CDL requiring liver transplantation. Cirrhosis is also associated with an increased risk of hepatocellular cancer, which may occur even in the absence of cirrhosis in subjects with nonalcoholic steatohepatitis (NASH), the histological form of NAFLD associated with increased liver-related mortality. The diagnosis of NASH currently requires a liver biopsy. There are also no U.S. Food and Drug Administration (FDA)-approved therapies for NASH. Therefore, there is a need to develop better diagnostic and therapeutic strategies for patients with NASH, targeting both those with early-stage disease as well as those with advanced liver fibrosis. There are unique challenges in the design of studies for these target populations. The long relatively asymptomatic time interval in the progression of NAFLD and NASH to cirrhosis and ultimately liver failure, along with gaps in knowledge regarding disease modifiers, combine to present significant challenges in trial design. Therefore, there is an urgent need to develop methods to identify the populations at particular risk of disease progression and validate endpoints that reflect meaningful changes in health status in this population. This article summarizes the discussion at a joint workshop held September 5 and 6, 2013 in Silver Spring, Maryland, sponsored by the FDA and the American Association for the Study of Liver Diseases to develop guidance on diagnostic and therapeutic modalities for NASH. (Hepatology 2015;61:1392-1405) © 2015 by the American Association for the Study of Liver Diseases.

Steenland K.,Emory University | Fletcher T.,London School of Hygiene and Tropical Medicine | Savitz D.A.,Mount Sinai School of Medicine
Environmental Health Perspectives | Year: 2010

Objective and sources: We reviewed the epidemiologic literature for PFOA. Data synthesis: Perfluorooctanoic acid (PFOA) does not occur naturally but is present in the serum of most residents of industrialized countries (U.S. median, 4 ng/mL). Drinking water is the primary route of exposure in some populations, but exposure sources are not well understood. PFOA has been used to manufacture such products as Gore-Tex and Teflon. PFOA does not break down in the environment; the human half-life is estimated at about 3 years. PFOA is not metabolized in the body; it is not lipophilic. PFOA is not directly genotoxic; animal data indicate that it can cause several types of tumors and neonatal death and may have toxic effects on the immune, liver, and endocrine systems. Data on the human health effects of PFOA are sparse. There is relatively consistent evidence of modest positive associations with cholesterol and uric acid, although the magnitude of the cholesterol effect is inconsistent across different exposure levels. There is some but much less consistent evidence of a modest positive correlation with liver enzymes. Most findings come from cross-sectional studies, limiting conclusions. Two occupational cohort studies do not provide consistent evidence for chronic disease; both are limited by sample size and reliance on mortality data. Reproductive data have increased recently but are inconsistent, and any observed adverse effects are modest. Conclusions: Epidemiologic evidence remains limited, and to date data are insufficient to draw firm conclusions regarding the role of PFOA for any of the diseases of concern.

Ayuso R.,Mount Sinai School of Medicine
Current Allergy and Asthma Reports | Year: 2011

Shellfish allergy is a frequent, long-lasting, lifethreatening disorder. As shellfish consumption increases, the number of allergic reactions to shellfish is expected to continue to rise as well. During the past decade, much has been learned about the allergens involved in shellfish allergy. Potential cross-reacting allergens between shellfish and other arthropods have been identified. As our knowledge of shellfish allergen improves, we will be able to develop more accurate methods of diagnosing shellfish allergy. In addition, extensive research is currently under way for the development of safer, more effective methods of managing shellfish hypersensitivity. © Springer Science+Business Media, LLC 2011.

Li X.-M.,Mount Sinai School of Medicine
Mount Sinai Journal of Medicine | Year: 2011

Prevalence of asthma and allergy has increased over the past 2-3 decades in Westernized countries. Despite increased understanding of the pathogenesis of asthma and allergic diseases, control of severe asthma is still difficult. Asthma is also associated with a high prevalence of anxiety, particularly in adolescents. There is no effective treatment for food allergy. Food allergy is often associated with severe and recalcitrant eczema. Novel approaches for treatment of asthma and food allergy and comorbid conditions are urgently needed. Traditional Chinese medicine, used in Asia for centuries, is beginning to play a role in Western healthcare. There is increasing scientific evidence supporting the use of traditional Chinese medicine for asthma treatment. Since 2005, several controlled clinical studies of "antiasthma" herbal remedies have been published. Among the herbal medicines, antiasthma herbal medicine intervention is the only antiasthma traditional Chinese medicine product that is a Food and Drug Administration investigational new drug that has entered clinical trials in the United States. Research into the effects and mechanisms of action of antiasthma herbal medicine intervention in animal models is actively being pursued. Research on traditional Chinese medicine herbal medicines for treating food allergy is rare. The herbal intervention Food Allergy Herbal Formula-2 is the only Food and Drug Administration botanical investigational new drug under investigation as a multiple food allergy therapy. This review article discusses promising traditional Chinese medicine interventions for asthma, food allergy, and comorbid conditions, and explores their possible mechanisms of action. © 2011 Mount Sinai School of Medicine.

Silbiger J.J.,Mount Sinai School of Medicine
Journal of the American Society of Echocardiography | Year: 2016

Hypertrophic cardiomyopathy is a genetic disorder characterized by increased cardiac muscle mass. This disorder has broad phenotypic expression, including, among others, asymmetric septal hypertrophy, midcavity hypertrophy, and apical hypertrophy. In recent years, it has been recognized that hypertrophic cardiomyopathy is not characterized solely by ventricular hypertrophy but that a number of abnormalities of the mitral apparatus (papillary muscles, leaflets, chords, and annulus) may also occur. These figure prominently in the echocardiographic evaluation and surgical planning of patients with hypertrophic cardiomyopathy and serve as the focus of this review. © 2016 American Society of Echocardiography.

Robakis N.K.,Mount Sinai School of Medicine
Neurochemical Research | Year: 2014

Presenilins (PSs) are catalytic components of the γ-secretase complex that produces Aβ peptides. Substrates of γ-secretase are membrane-bound protein fragments deriving from the cleavage of extracellular sequence of cell surface proteins. APP-derived γ-secretase substrates are cleaved at gamma (γ) sites to produce Aβ while cleavage at the epsilon (ε) site produces AICD proposed to function in transcription. In addition to APP, γ-secretase promotes the ε-cleavage of a large number of cell surface proteins producing cytosolic peptides shown to function in cell signaling. A common hypothesis suggests that Alzheimer's disease (AD) is caused by Aβ peptides or their products. Treatment of patients with inhibitors of Aβ production however, showed no therapeutic benefits while inducing cytotoxicity. Similarly, treatments with anti-Aβ antibodies yielded disappointing results. Importantly, recent evidence shows that PS familial AD (FAD) mutations cause a loss of γ-secretase cleavage activity at ε site of substrates thus inhibiting production of biologically important cell signaling peptides while promoting accumulation of membrane-bound cytotoxic substrates. These data support a hypothesis that FAD mutations may increase neurotoxicity by inhibiting the γ-secretase-catalyzed ε cleavage of substrates thus interfering with cell signaling while also promoting accumulation of cytotoxic peptides. Similar mechanisms may explain γ-secretase inhibitor-associated toxicities observed in clinical trials. Here we discuss evidence that FAD neurodegeneration may be caused by loss of γ-secretase cleavage function at ε sites of substrates. © 2013 Springer Science+Business Media.

Gorog D.A.,Imperial College London | Fuster V.,Mount Sinai School of Medicine
Journal of the American College of Cardiology | Year: 2013

This review is a critical evaluation of publications in the past decade on the usefulness of platelet function tests (PFTs) in clinical cardiology, in aiding diagnosis, predicting risk, and monitoring therapy. The ideal PFT should: 1) detect baseline platelet hyperreactivity; 2) allow individualization of antiplatelet medication; 3) predict thrombotic risk; and 4) predict bleeding risk. The practicalities of clinical cardiology demand rapid, accurate, and reliable tests that are simple to operate at the bedside and available 24 h a day, 7 days a week. Point-of-care PFTs most widely evaluated clinically include PFA-100 and VerifyNow. None of these tests can reliably detect platelet hyperreactivity and thus identify a prothrombotic state. Identification of antiplatelet nonresponsiveness or hyporesponsiveness is highly test specific, and does not allow individualization of therapy. The power of PFTs in predicting thrombotic events for a given individual is variable and often modest, and alteration of antithrombotic treatment on the basis of the results of PFTs has not been shown to alter clinical outcome. PFTs in current mainstream use cannot reliably assess bleeding risk. These tests have been in use for over a decade, but the hopes raised by PFTs in clinical practice remain unfulfilled. Although physiologically relevant measurement of platelet function now is more important than ever, a critical reappraisal of available techniques in light of clinical requirements is needed. The use of native blood, global stimulus instead of individual agonists, contribution of thrombin generation by activated platelets to the test results, and establishment of a PFT therapeutic range for each antiplatelet drug should be considered and is discussed. © 2013 American College of Cardiology Foundation.

Xiao Y.,Mount Sinai School of Medicine
Visual Neuroscience | Year: 2014

The short-wavelength-sensitive (S) cones play an important role in color vision of primates, and may also contribute to the coding of other visual features, such as luminance and motion. The color signals carried by the S cones and other cone types are largely separated in the subcortical visual pathway. Studies on nonhuman primates or humans have suggested that these signals are combined in the striate cortex (V1) following a substantial amplification of the S-cone signals in the same area. In addition to reviewing these studies, this review describes the circuitry in V1 that may underlie the processing of the S-cone signals and the dynamics of this processing. It also relates the interaction between various cone signals in V1 to the results of some psychophysical and physiological studies on color perception, which leads to a discussion of a previous model, in which color perception is produced by a multistage processing of the cone signals. Finally, I discuss the processing of the S-cone signals in the extrastriate area V2. Copyright © Cambridge University Press 2013.

Amrock L.G.,Mount Sinai School of Medicine
Anesthesiology | Year: 2014

BACKGROUND:: Neonatal exposure to general anesthetics may pose significant neurocognitive risk. Human epidemiological studies demonstrate higher rates of learning disability among children with multiple, but not single, exposures to anesthesia. The authors employ a rat model to provide a histological correlate for these population-based observations. The authors examined long-term differences in hippocampal synaptic density, mitochondrial density, and dendritic spine morphology.METHODS:: Twenty male rat pups (n = 5/condition) were exposed to 2.5% sevoflurane under one of four conditions: single 2-h exposure on postnatal day 7 (P7); single 6-h exposure on P7; repeated 2-h exposures on P7, P10, and P13 for a cumulative 6 h of general anesthetics; or control exposure to 30% oxygen on P7, P10, and P13.RESULTS:: Repeated exposure to general anesthetics resulted in greater synaptic loss relative to a single 2-h exposure (P < 0.001). The magnitude of synaptic loss induced by three 2-h exposures (1.977 ± 0.040 μm [mean ± SEM]) was more profound than that of a single 6-h exposure (2.280 ± 0.045 μm, P = 0.022). Repeated exposures did not alter the distribution of postsynaptic density length, indicating a uniform pattern of loss across spine types. In contrast, mitochondrial toxicity was best predicted by the cumulative duration of exposure. Relative to control (0.595 ± 0.017), both repeated 2-h exposures (0.479 ± 0.015) and a single 6-h exposure (0.488 ± 0.013) were associated with equivalent reductions in the fraction of presynaptic terminals containing mitochondria (P < 0.001).CONCLUSION:: This suggests a “threshold effect” for general anesthetic–induced neurotoxicity, whereby even brief exposures induce long-lasting alterations in neuronal circuitry and sensitize surviving synapses to subsequent loss. © 2014 American Society of Anesthesiologists, Inc.

Yakushin S.B.,Mount Sinai School of Medicine
Journal of Neurophysiology | Year: 2012

The gain of the vertical angular vestibulo-ocular reflex (aVOR) was adaptively increased and decreased in a side-down head orientation for 4 h in two cynomolgus monkeys. Adaptation was performed at 0.25, 1, 2, or 4 Hz. The gravity-dependent and -independent gain changes were determined over a range of head orientations from left-side-down to right-sidedown at frequencies from 0.25 to 10 Hz, before and after adaptation. Gain changes vs. frequency data were fit with a Gaussian to determine the frequency at which the peak gain change occurred, as well as the tuning width. The frequency at which the peak gravity-dependent gain change occurred was approximately equal to the frequency of adaptation, and the width increased monotonically with increases in the frequency of adaptation. The gravity-independent component was tuned to the adaptive frequency of 0.25 Hz but was uniformly distributed over all frequencies when the adaptation frequency was 1-4 Hz. The amplitude of the gravity-independent gain changes was larger after the aVOR gain decrease than after the gain increase across all tested frequencies. For the aVOR gain decrease, the phase lagged about 4° for frequencies below the adaptation frequency and led for frequencies above the adaptation frequency. For gain increases, the phase relationship as a function of frequency was inverted. This study demonstrates that the previously described dependence of aVOR gain adaptation on frequency is a property of the gravity-dependent component of the aVOR only. The gravity-independent component of the aVOR had a substantial tuning curve only at an adaptation frequency of 0.25 Hz. © 2012 the American Physiological Society.

Krieger S.,Mount Sinai School of Medicine
Mount Sinai Journal of Medicine | Year: 2011

The year 2010 marked the beginning of the era of oral medications for the treatment of multiple sclerosis, with the approval of dalfampridine to improve walking and fingolimod as the first oral disease-modifying agent. This review provides an overview of these and other emerging therapies, with an emphasis on the opportunities for new treatment paradigms they have the potential to offer, followed by a discussion of the challenges they will pose in the new era of multiple sclerosis management. Therapeutics in late-stage development for MS include non-selective immunosupressants, targeted immune-modulators, and monoclonal antibodies. Oral agents including cladribine, teriflunomide, laquinimod, and dimethyl fumarate, as well as monoclonal antibodies alemtuzumab, daclizumab, and rituximab are considered. Potential side effects and adverse event monitoring, including opportunistic infections, emergent malignancies, and other systemic consequences of immunosuppression are discussed in a unified section. Challenges of optimally staging, sequencing, and combining treatments in the expanding multiple sclerosis armamentarium are discussed. This review emphasizes the multifactorial decision making that these new therapeutics will warrant in terms of patient selection and personalization/individualization of therapy, and the increasingly interdisciplinary approach that will be necessitated by the new generation of agents. Mt Sinai J Med 78:192-206, 2011 © 2011 Mount Sinai School of Medicine.

Golden S.A.,Mount Sinai School of Medicine
Cold Spring Harbor perspectives in medicine | Year: 2012

Psychostimulants robustly induce alterations in neuronal structural plasticity throughout brain reward circuits. However, despite our extensive understanding of how these circuits modulate motivated behavior, it is still unclear whether structural plasticity within these regions drives pathological behavioral responses in addiction. Although these structural changes have been subjected to an exhaustive phenomenological characterization, we still have a limited understanding of the molecular mechanisms regulating their induction and the functional relevance of such changes in mediating addiction-like behavior. Here we have highlighted the known molecular pathways and intracellular signaling cascades that regulate psychostimulant-induced changes in neuronal morphology and synaptic restructuring, and we discuss them in the larger context of addiction behavior.

Sarikas A.,TU Munich | Hartmann T.,TU Munich | Pan Z.,Mount Sinai School of Medicine
Genome Biology | Year: 2011

Cullin proteins are molecular scaffolds that have crucial roles in the post-translational modification of cellular proteins involving ubiquitin. The mammalian cullin protein family comprises eight members (CUL1 to CUL7 and PARC), which are characterized by a cullin homology domain. CUL1 to CUL7 assemble multi-subunit Cullin-RING E3 ubiquitin ligase (CRL) complexes, the largest family of E3 ligases with more than 200 members. Although CUL7 and PARC are present only in chordates, other members of the cullin protein family are found in Drosophila melanogaster, Caenorhabditis elegans, Arabidopsis thaliana and yeast. A cullin protein tethers both a substrate-targeting unit, often through an adaptor protein, and the RING finger component in a CRL. The cullin-organized CRL thus positions a substrate close to the RING-bound E2 ubiquitin-conjugating enzyme, which catalyzes the transfer of ubiquitin to the substrate. In addition, conjugation of cullins with the ubiquitin-like molecule Nedd8 modulates activation of the corresponding CRL complex, probably through conformational regulation of the interactions between cullin's carboxy-terminal tail and CRL's RING subunit. Genetic studies in several model organisms have helped to unravel a multitude of physiological functions associated with cullin proteins and their respective CRLs. CRLs target numerous substrates and thus have an impact on a range of biological processes, including cell growth, development, signal transduction, transcriptional control, genomic integrity and tumor suppression. Moreover, mutations in CUL7 and CUL4B genes have been linked to hereditary human diseases. © 2011 BioMed Central Ltd.

Llovet J.M.,Mount Sinai School of Medicine
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

Factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma (HCC). An unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who cannot tolerate it. This multicenter, double-blind, randomized, placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib. In all, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib 800 mg orally once per day plus best supportive care (BSC) or placebo plus BSC. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), and disease control rate based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and safety. Median OS was 9.4 months for brivanib and 8.2 months for placebo (hazard ratio [HR], 0.89; 95.8% CI, 0.69 to 1.15; P = .3307). Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 (95% CI, 0.63 to 1.04; P = .1044). Exploratory analyses showed a median time to progression of 4.2 months for brivanib and 2.7 months for placebo (HR, 0.56; 95% CI, 0.42 to 0.76; P < .001), and an mRECIST ORR of 10% for brivanib and 2% for placebo (odds ratio, 5.72). Study discontinuation due to treatment-related adverse events (AEs) occurred in 61 brivanib patients (23%) and nine placebo patients (7%). The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension (17%), fatigue (13%), hyponatremia (11%), and decreased appetite (10%). In patients with HCC who had been treated with sorafenib, brivanib did not significantly improve OS. The observed benefit in the secondary outcomes of TTP and ORR warrants further investigation.

Wei Y.,Mount Sinai School of Medicine
Investigative ophthalmology & visual science | Year: 2013

To provide standard operating procedures (SOPs) for measuring tear inflammatory cytokine concentrations and to validate the resulting profile as a minimally invasive objective metric and biomarker of ocular surface inflammation for use in multicenter clinical trials on dry eye disease (DED). Standard operating procedures were established and then validated with cytokine standards, quality controls, and masked tear samples collected from local and distant clinical sites. The concentrations of the inflammatory cytokines in tears were quantified using a high-sensitivity human cytokine multiplex kit. A panel of inflammatory cytokines was initially investigated, from which four key inflammatory cytokines (IL-1β, IL-6, INF-γ, and TNF-α) were chosen. Results with cytokine standards statistically satisfied the manufacturer's quality control criteria. Results with pooled tear samples were highly reproducible and reliable with tear volumes ranging from 4 to 10 μL. Incorporation of the SOPs into clinical trials was subsequently validated. Tear samples were collected at a distant clinical site, stored, and shipped to our Biomarker Laboratory, where a masked analysis of the four tear cytokines was successfully performed. Tear samples were also collected from a feasibility study on DED. Inflammatory cytokine concentrations were decreased in tears of subjects who received anti-inflammatory treatment. Standard operating procedures for human tear cytokine assessment suitable for multicenter clinical trials were established. Tear cytokine profiling using these SOPs may provide objective metrics useful for diagnosing, classifying, and analyzing treatment efficacy in inflammatory conditions of the ocular surface, which may further elucidate the mechanisms involved in the pathogenesis of ocular surface disease.

Ciociola A.A.,Alcon | Cohen L.B.,Mount Sinai School of Medicine | Kulkarni P.,University of South Florida
American Journal of Gastroenterology | Year: 2014

Objectives: This article provides an overview of FDA's regulatory processes for drug development and approval, and the estimated costs associated with the development of a drug, and also examines the issues and challenges facing the FDA in the near future. Methods: A literature search was performed using MEDLINE to summarize the current FDA drug approval processes and future directions. MEDLINE was further utilized to search for all cost analysis studies performed to evaluate the pharmaceutical industry R&D productivity and drug development cost estimates. Results: While the drug approval process remains at high risk and spans over multiple years, the FDA drug review and approval process has improved, with the median approval time for new molecular drugs been reduced from 19 months to 10 months. The overall cost to development of a drug remains quite high and has been estimated to range from $868M to $1,241M USD. Several new laws have been enacted, including the FDA Safety and Innovation Act (FDASIA) of 2013, which is designed to improve the drug approval process and enhance access to new medicines. Conclusions: The FDA's improved processes for drug approval and post-market surveillance have achieved the goal of providing patients with timely access to effective drugs while minimizing the risk of drug-related harm. The FDA drug approval process is not without controversy, as a number of well-known gastroenterology drugs have been withdrawn from the US market over the past few years. With the approval of the new FDASIA law, the FDA will continue to improve their processes and, working together with the ACG through the FDA-Related Matters Committee, continue to develop safe and effective drugs for our patients. © 2014 by the American College of Gastroenterology.

Hodes G.E.,Mount Sinai School of Medicine
Biology of Sex Differences | Year: 2013

Women have a higher incidence of stress related disorders including depression and generalized anxiety disorder, and epigenetic mechanisms likely contribute to this sex difference. Evidence from preclinical research suggests that epigenetic mechanisms are responsible for both sexual dimorphism of brain regions and sensitivity of the stress response. Epigenetic modifications such as DNA methylation and histone modifications can occur transgenerationally, developmentally, or in response to environmental stimuli such as stress exposure. This review will provide an overview of the various forms of epigenetic modifications observed in the central nervous system and will explain how these mechanisms contribute to a sexually dimorphic brain. It will also discuss the ways in which epigenetic alterations coincide with, and functionally contribute to, the behavioral response to stress across the lifespan. Ultimately, this review will focus on novel research utilizing animal models to investigate sex differences in epigenetic mechanisms that influence susceptibility to stress. Exploration of this relationship reveals epigenetic mechanisms with the potential to explain sexual dimorphism in the occurrence of stress related disorders. © 2013 Hodes; licensee BioMed Central Ltd.

Olanow C.W.,Mount Sinai School of Medicine | Kieburtz K.,University of Rochester
Movement Disorders | Year: 2010

A disease-modifying therapy that slows or stops disease progression is one of the major unmet needs in the management of Parkinson's disease. To date, no therapy has been approved for disease modification despite promising laboratory data and positive results in clinical trials. This is because confounding symptomatic or pharmacologic effects cannot be excluded. The delayed start study provides an opportunity to define therapies that provide benefit that cannot be explained by an early symptomatic effect alone. However, this trial design does not necessarily provide a meaningful measure of the effect of the intervention on cumulative disability. In contrast, the long-term simple study provides a measure of the effect of the drug on cumulative disability but does not address mechanism of action. Together these two trials provide a road map for defining a disease modifying drug and determining the long term cumulative effect of the drug on the disease. © 2010 Movement Disorder Society.

Kutty S.,Creighton University | Sengupta P.P.,Mount Sinai School of Medicine | Khandheria B.K.,University of Wisconsin - Milwaukee
Journal of the American College of Cardiology | Year: 2012

The patent foramen ovale (PFO) is a normal interatrial communication during fetal life that persists after birth in approximately 1 of every 4 adults. PFO is a potential route for embolic transit from the systemic venous circulation to the brain. Though there is compelling circumstantial evidence implicating PFO, the precise role of PFO in the pathogenesis of cryptogenic stroke is not yet established. Several randomized trials of transcatheter PFO closure versus medical management are ongoing. Results of these trials may improve our ability to select the best treatment for individual patients. Further well-designed studies are necessary to address several unresolved issues related to PFO stroke and PFO migraine pathophysiology, and to identify the patients who would most likely benefit from PFO closure. The purpose of this review is to summarize contemporary understanding, discuss current treatments, and explore some of the knowledge gaps pertaining to the clinical significance of PFO. © 2012 American College of Cardiology Foundation.

Brown M.,Mount Sinai School of Medicine
Archives of Physical Medicine and Rehabilitation | Year: 2010

The insider-outsider distinction is discussed in the context of people with disabilities. Insiders to disability are likely to have different subjective responses to life situations than do those who experience disability as onlookers. The importance of including the insider's perspective is discussed with respect to assessing participation in terms of setting goals, evaluating programs, setting research agendas, and conducting needs assessments. In terms of incorporating the insider's subjective response to participation into assessment, it is argued that both importance and salience are required to reflect the person's values and goals fully. A review of a sample of currently used assessment approaches is provided with a focus on how each instrument either incorporates or fails to incorporate the insider's perspective on participation. A distinction is made between instruments that tap into the perspective of a specific person at the point of assessment versus those that substitute a perspective based on discussions by groups of insiders, such as emerges from focus groups. © 2010 American Congress of Rehabilitation Medicine.

Nestler E.J.,Mount Sinai School of Medicine
PLoS Biology | Year: 2016

There has been increasing interest in the possibility that behavioral experience—in particular, exposure to stress—can be passed on to subsequent generations through heritable epigenetic modifications. The possibility remains highly controversial, however, reflecting the lack of standardized definitions of epigenetics and the limited empirical support for potential mechanisms of transgenerational epigenetic inheritance. Nonetheless, growing evidence supports a role for epigenetic regulation as a key mechanism underlying lifelong regulation of gene expression that mediates stress vulnerability. This Perspective provides an overview of the multiple meanings of the term epigenetic, discusses the challenges of studying epigenetic contributions to stress susceptibility—and the experimental evidence for and against the existence of such mechanisms—and outlines steps required for future investigations. © 2016 Eric J. Nestler.

Jepsen K.J.,Mount Sinai School of Medicine
Clinical Orthopaedics and Related Research | Year: 2011

Background: Advances in diagnostic and treatment regimens that aim to reduce fracture incidence will benefit from a better understanding of how bone morphology and tissue quality define whole-bone mechanical properties. Questions/purposes: The goal of this article was to review what is known about the interactions among morphologic and tissue quality traits and how these interactions contribute to bone quality (ie, whole-bone mechanical function). Several questions were addressed. First, how do interactions among morphology and tissue quality traits relate to functional adaptation? Second, what are the emergent patterns of functionally adapted trait sets in long bones? Third, how effective is phenotypic integration at establishing function across a population? Fourth, what are the emergent patterns of functionally adapted trait sets in corticocancellous structures? Fifth, how do functional interactions change with aging? Methods: A literature review was conducted with papers identified primarily through citations listed in reference sections as well as general searches using Google Scholar and PubMed. Results: The interactions among adult traits or phenotypic integration are an emergent property of the compensatory mechanisms complex systems used to establish function or homeostasis. Traits are not regulated independently but vary simultaneously (ie, covary) in specific ways to establish function. This covariation results in individuals acquiring unique sets of traits to establish bone quality. Conclusions and Clinical Relevance: Biologic constraints imposed on the skeletal system result in a population showing a pattern of trait sets that is predictable based on external bone size and that can be used to identify individuals with reduced bone quality relative to their bone size and body size. © 2010 The Association of Bone and Joint Surgeons®.

Jeng C.L.,Mount Sinai School of Medicine
British journal of anaesthesia | Year: 2010

Complications of peripheral nerve blocks are fortunately rare, but can be devastating for both the patient and the anaesthesiologist. This review will concentrate on current knowledge about peripheral nerve injury secondary to nerve blocks, complications from continuous peripheral nerve catheter techniques, and local anaesthetic systemic toxicity.

Dijkers M.P.,Mount Sinai School of Medicine
Archives of Physical Medicine and Rehabilitation | Year: 2010

While participation is increasingly defined as the key outcome of rehabilitation, disagreements on and shortcomings in the definition, operationalization, and measurement of this concept abound and interfere with the progress of clinical services and research. This article explores a number of the major issues related to the quantification of participation and makes suggestions for new directions, using the following orienting questions: What is the definition of participation? Where is the border between Participation and Activity? Is there more to participation than performance? What domains should be included in a participation measure? What are the appropriate metrics in quantifying participation? How do we define adequate participation? How should participation be operationalized? What is the proper measurement model for participation instruments? How should we collect data on participation? How do we evaluate the quality of a participation instrument? © 2010 American Congress of Rehabilitation Medicine.

Kelley K.A.,Mount Sinai School of Medicine
Methods in Enzymology | Year: 2010

Cryopreservation of mouse sperm has become an essential method for the long-term storage of novel, genetically modified mouse lines. Cryopreserved sperm from most hybrid lines can be effectively used for in vitro fertilization (IVF) of mouse oocytes. Unfortunately, IVF recovery with cryopreserved sperm from inbred lines is very inefficient. This is especially troublesome since many transgenic lines are created on the popular C57Bl/6 inbred strain. Cryopreserved sperm from C57Bl/6 inbred and genetically modified lines is generally very inefficient when used in standard IVF recovery experiments, with fertilization rates that can be lower than 10%. Assisted reproductive techniques have been developed to improve the IVF efficiencies of cryopreserved inbred sperm. These techniques include zona-drilling, which introduces a hole into the zona pellucida (ZP) surrounding mouse oocytes, using a chemical solution (acid Tyrode's), mechanical disruption (partial zona dissection or piezo-driven micropipette drilling), or laser photoablation. By allowing direct access of the sperm to the cytoplasmic membrane, zona-drilling can improve the efficiency of IVF fertilization rates with inbred sperm to greater than 90%, thus improving the chances of recovering mouse lines on inbred backgrounds that are maintained with cryopreserved sperm. The technique described in this chapter makes use of a piezo controller to mechanically disrupt the ZP, resulting in dramatic increases in the fertilization efficiency of cryopreserved sperm. © 2010 Elsevier Inc.

Halperin J.J.,Overlook Medical Center | Halperin J.J.,Mount Sinai School of Medicine
Infectious Disease Clinics of North America | Year: 2015

Lymphocytic meningitis, cranial neuritis or radiculoneuritis occur in up to 15% of patients with untreated Borrelia burgdorferi infection. Presentations of multifocal PNS involvement can range from painful monoradiculitis to confluent mononeuropathy multiplex. Serologic testing is highly accurate after 4 to 6 weeks of infection. In CNS infection, production of anti-. B burgdorferi antibody is often demonstrable in CSF. Oral antimicrobials are microbiologically curative in virtually all patients, including acute European neuroborreliosis. Severe cases may require parenteral treatment. The fatigue and cognitive symptoms seen in some patients with extra-neurological disease are neither evidence of CNS infection nor specific to Lyme disease. © 2015 Elsevier Inc.

Bunyavanich S.,Icahn Institute for Genomics and Multiscale Biology | Bunyavanich S.,Mount Sinai School of Medicine | Schadt E.E.,Icahn Institute for Genomics and Multiscale Biology
Journal of Allergy and Clinical Immunology | Year: 2015

Systems biology is an approach to understanding living systems that focuses on modeling diverse types of high-dimensional interactions to develop a more comprehensive understanding of complex phenotypes manifested by the system. High-throughput molecular, cellular, and physiologic profiling of populations is coupled with bioinformatic and computational techniques to identify new functional roles for genes, regulatory elements, and metabolites in the context of the molecular networks that define biological processes associated with system physiology. Given the complexity and heterogeneity of asthma and allergic diseases, a systems biology approach is attractive, as it has the potential to model the myriad connections and interdependencies between genetic predisposition, environmental perturbations, regulatory intermediaries, and molecular sequelae that ultimately lead to diverse disease phenotypes and treatment responses across individuals. The increasing availability of high-throughput technologies has enabled system-wide profiling of the genome, transcriptome, epigenome, microbiome, and metabolome, providing fodder for systems biology approaches to examine asthma and allergy at a more holistic level. In this article we review the technologies and approaches for system-wide profiling, as well as their more recent applications to asthma and allergy. We discuss approaches for integrating multiscale data through network analyses and provide perspective on how individually captured health profiles will contribute to more accurate systems biology views of asthma and allergy. © 2014 American Academy of Allergy, Asthma & Immunology.

Cohen E.,Mount Sinai School of Medicine
Current Opinion in Anaesthesiology | Year: 2014

PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is a progressive, debilitating disease that in its final stages cripples the patient. The disappointing results of the National Emphysema Treatment Trial study led to a decrease in the acceptance of lung volume reduction surgery as a therapy. Thus, it became clear that debilitated COPD patients would need innovative alternative nonsurgical procedures to potentially alleviate their symptoms. This review will address the various techniques of bronchoscopic lung volume reduction (BLVR). RECENT FINDINGS: In recent years, a variety of noninvasive BLVR procedures were developed in the hope of improving the respiratory status of these patients. BLVR aims to decrease the extent of hyperinflation due to emphysema and result in a beneficial effect similar to that from surgical resection. The most widely used BLVR devices are: endobronchial valves, foam sealant, metallic coils, airway bypass stents and vapor thermal ablation.In the USA, BLVR remains in the experimental phase. The treatment modalities should be individually tailored for each patient. Endobronchial valves are designed to exclude the most affected emphysematous regions from ventilation in order to induce lobar absorption atelectasis. Airway bypass stents target homogenous emphysema, whereas valves and thermal vapor ablation target heterogeneous emphysema. Biological sealants and endoscopic coil implants have been used in both homogenous and heterogeneous emphysema. SUMMARY: BLVR appears to be safer than surgery and presents an attractive alternative for the treatment of COPD patients. Unfortunately, the outcome data to date are inconclusive; the procedures remain experimental and any benefits unproven. However, the data that are emerging continue to appear promising. © 2014 Lippincott Williams and Wilkins.

Bechhofer D.H.,Mount Sinai School of Medicine
Wiley Interdisciplinary Reviews: RNA | Year: 2011

Representatives of two new ribonuclease families have recently been discovered in the gram-positive model organism, Bacillus subtilis. The RNase J family founding members, RNase J1 and RNase J2, are highly homologous but show differential activities. Although both are broad-specificity endonucleases, only the essential RNase J1 is a 5′ → 3′ exonuclease-a type of ribonuclease activity that was previously thought not to exist in bacteria. Current data suggest that RNase J1 is highly involved in the turnover of mRNA decay intermediates and may also be involved in the initiation of mRNA decay. A second family of ribonucleases is represented by RNase Y, an endonuclease that exerts a large effect on global mRNA half-life. The presence of these ribonucleases in B. subtilis predicts significant differences from the well-established model of mRNA decay in Escherichia coli. © 2010 John Wiley & Sons, Ltd.

Herbin O.,Mount Sinai School of Medicine
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2016

OBJECTIVE—: The chronic inflammation associated with atherosclerosis is caused by lipid deposition followed by leukocyte recruitment to the arterial wall. We previously showed that the hematopoietic cell–specific adaptor protein Cas- and Hef1-associated signal transducer hematopoietic isoform (Chat-H)/SHEP1 regulated lymphocyte adhesion and migration. In this study, we analyzed the role of Chat-H in atherosclerosis development. APPROACH AND RESULTS—: Using Chat-H–deficient bone marrow transplantation in low-density lipoprotein receptor–deficient mice, we found that Chat-H regulated atherosclerotic plaque formation. Chat-H deficiency in hematopoietic cells associated with lower plaque complexity and fewer leukocytes in the lesions, whereas myeloid-specific deletion of Chat-H was sufficient for conferring atheroprotection. Chat-H deficiency resulted in reduced recruitment of classical Ly6c and nonclassical Ly6c monocytes to the plaques, which was accompanied by increased numbers of both monocyte subsets in the blood. This was associated with defective adhesion of Chat-H–deficient Ly6c and Ly6c monocytes to vascular cell adhesion molecule-1 in vitro and impaired infiltration of fluorescent bead–loaded monocytes to atherosclerotic plaques. In contrast, Chat-H was dispensable for CX3CL1 and CCR1/CCR5-dependent migration of monocytes. CONCLUSIONS—: Our findings highlight Chat-H as a key protein that regulates atherosclerosis development by controlling monocyte adhesion and recruitment to the plaques and identify a novel target that may be exploited for treating atherosclerosis. © 2016 American Heart Association, Inc.

Calenda B.W.,Mount Sinai School of Medicine
Nature Reviews Cardiology | Year: 2016

Atrial fibrillation (AF) is a complex phenomenon associated with electrical, mechanical, and structural abnormalities of the atria. Ischaemic stroke in AF is only partially understood, but the mechanisms are known to be related to the atrial substrate as well as the atrial rhythm. The temporal dissociation between timing of AF and occurrence of stroke has led to the hypothesis that fibrotic, prothrombotic atrial tissue is an important cause of thrombus formation in patients with AF, independent of the atrial rhythm. Current stroke risk scores are practical, but limited in their capacity to predict stroke risk accurately in individual patients. Stroke prediction might be improved by the addition of emerging risk factors, many of which are expressions of atrial fibrosis. The use of novel parameters, including clinical criteria, biomarkers, and imaging data, might improve stroke risk prediction and inform on optimal treatment for patients with AF and perhaps individuals only at risk of AF. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Thurberg B.L.,Mount Sinai School of Medicine
American Journal of Surgical Pathology | Year: 2016

Acid sphingomyelinase deficiency (ASMD; Niemann-Pick disease type A and B) is a lysosomal storage disorder characterized by abnormal intracellular sphingomyelin (SM) accumulation. Prominent liver involvement results in hepatomegaly, fibrosis/cirrhosis, abnormal liver chemistries, and a proatherogenic lipid profile. Olipudase alfa (recombinant human ASM) is in clinical development as an investigational enzyme replacement therapy for the non-neurological manifestations of ASMD. In a phase 1b study conducted to evaluate the safety and tolerability of within-patient dose escalation with olipudase alfa, measurement of SM levels in liver biopsies was used as a pharmacodynamic biomarker of substrate burden. Five adult patients with non neuronopathic ASMD received escalating doses of olipudase alfa every 2 weeks for 26 weeks. Liver biopsies obtained at baseline and 26 weeks after treatment were evaluated for SM storage by histomorphometric analysis, biochemistry, and electron microscopy. Biopsies were also assessed for inflammation and fibrosis, and for the association of SM levels with liver volume, liver function tests, and lipid profiles. At baseline, SM storage present in Kupffer cells and hepatocytes ranged from 9.8% to 53.8% of the microscopic field. After 26 weeks of treatment, statistically significant reductions in SM (P<0.0001) measured by morphometry were seen in 4 patients with evaluable liver biopsies. The 26-week biopsy of the fifth patient was insufficient for morphometric quantitation. Posttreatment SM levels ranged from 1.2% to 9.5% of the microscopic field, corresponding to an 84% to 92% relative reduction from baseline. Improvements in liver volume, liver function tests, and lipid profiles were also observed. This study illustrates the utility of SM assessment by liver biopsy as a pharmacodynamic biomarker of disease burden in these patients. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Schanzer H.,Mount Sinai School of Medicine
Vascular and Endovascular Surgery | Year: 2010

Objective: The purpose of this study was to establish how often after the performance of endovenous ablation (EA), a second stage is required. Methods: Eighty-six consecutive lower extremities in 76 patients treated with laser EA were the cohort of this study. The clinical result after EA at 1 month was classified as excellent (no varicosities), good (major reduction in size), and poor (no change). Need for further intervention (sclerotherapy or microphlebectomy) was determined at the 1-month follow-up. Results: Complete resolution of varicosities after EA was found in 36 extremities (41.8%), reduction in size in 48 extremities (55.8%), and no change in 2 extremities (2.3%). Of the 86 extremities studied, 36 (41.8%) were considered in need of a second stage procedure. Conclusion: After EA, 58.2% of extremities did not require further treatment. These results add further justification to the performance of EA alone as a first stage. © The Author(s) 2010.

Madias J.E.,Mount Sinai School of Medicine | Madias J.E.,Elmhurst Hospital Center
International Journal of Cardiology | Year: 2014

Diagnosis of Takotsubo syndrome (TTS), the reversible, acute heart failure pathological entity, precipitated by stress, is based on the fulfillment of sets of criteria, developed by careful characterization of the precipitants, symptoms, results of imaging testing, clinical course, and follow-up of many patients presented with this affliction. As understanding of TTS, increase in its awareness, and the diversion in its presentation have evolved, the various proposed diagnostic criteria, naturally have started to appear outmoded. The author argues that the initially proposed Mayo Clinic criteria, the subsequently revised Mayo Clinic criteria, the Japanese Circulation Society guidelines, the Johns Hopkins criteria, and the Gothenburg criteria for the diagnosis of TTS have been outpaced by the rapidly accumulating clinical experience, and thus need to be replaced by more realistic sets of diagnostic rules. To this effect the author proposes a set of diagnostic criteria for TTS, which include 2 plausible, albeit speculative, notions, that of the milder forms or formes frustes of TTS, and the existence of "TTS comorbidity" in patients with various other illnesses, which either precipitate TTS, or are being brought about by TTS. © 2014 Elsevier Ireland Ltd.

Haraldsson B.S.,Sahlgrenska University Hospital | Haraldsson B.S.,Mount Sinai School of Medicine
Kidney International | Year: 2014

A new study by Xu et al. presents compelling evidence for an important role of the glomerular endothelium in acute kidney injury. They show that lipopolysaccharide reduces the endothelial surface layer, resulting in mild albuminuria, reduced glomerular filtration rate, and fewer endothelial fenestrae. Tumor necrosis factor- (TNF-) is identified as instrumental in these lipopolysaccharide effects through the TNF- type 1 receptor. The study highlights that the glomerular endothelium has a key role in the maintenance of the glomerular filtration barrier © 2013 International Society of Nephrology.

Badr H.,Mount Sinai School of Medicine | Krebs P.,New York University
Psycho-Oncology | Year: 2013

Objective Quality of life (QOL) is a multidimensional construct that includes physical, psychological, and relationship well-being. Methods We conducted a systematic review and meta-analysis of randomized controlled studies published between 1980 and 2012 of interventions conducted with both cancer patients and their partners that were aimed at improving QOL. Using bibliographic software and manual review, two independent raters reviewed 752 articles with a systematic process for reconciling disagreement, yielding 23 articles for systematic review and 20 for meta-analysis. Results Most studies were conducted in breast and prostate cancer populations. Study participants (N = 2645) were primarily middle aged (mean = 55 years old) and white (84%). For patients, the weighted average effect size (g) across studies was 0.25 (95% CI = 0.12-0.32) for psychological outcomes (17 studies), 0.31 (95% CI = 0.11-0.50) for physical outcomes (12 studies), and 0.28 (95% CI = 0.14-0.43) for relationship outcomes (10 studies). For partners, the weighted average effect size was 0.21 (95% CI = 0.08-0.34) for psychological outcomes (12 studies) and 0.24 (95% CI = 0.6-0.43) for relationship outcomes (7 studies). Conclusion Therefore, couple-based interventions had small but beneficial effects in terms of improving multiple aspects of QOL for both patients and their partners. Questions remain regarding when such interventions should be delivered and for how long. Identifying theoretically based mediators and key features that distinguish couple-based from patient-only interventions may help strengthen their effects on patient and partner QOL. Copyright © 2012 John Wiley & Sons, Ltd.

Friedman G.,Mount Sinai School of Medicine
Gastroenterology Clinics of North America | Year: 2012

Clostridium difficile colitis is the most common gastrointestinal infection, exceeding all other gastrointestinal infections combined. There has been a dramatic increase in Clostridium difficile infection (CDI) worldwide during the past decade. Antibiotic therapy is a trigger precipitating antibiotic-associated diarrhea (AAD), which may lead to CDI. The antibiotic alters the protective, diverse bacteria allowing pathogenic bacteria to cause disease. Probiotics have been effective in reducing AAD and preventing CDI. © 2012 Elsevier Inc.

Aledort L.M.,Mount Sinai School of Medicine | Navickis R.J.,Hygeia Associates | Wilkes M.M.,Hygeia Associates
Journal of Thrombosis and Haemostasis | Year: 2011

Background: As a result of the infrequency of inhibitors in previously treated patients (PTPs) with hemophilia A and the small size of available clinical studies, the immunogenicity of factor (F)VIII products has been difficult to assess. Objectives: A meta-analysis of prospective clinical studies was conducted to test the hypothesis that de novo inhibitor incidence differs between PTPs receiving full-length recombinant FVIII (FL-rFVIII) and B-domain deleted recombinant FVIII (BDD-rFVIII). Methods: Prospective studies with data on inhibitors in PTPs receiving FL-rFVIII or BDD-rFVIII were sought using systematic methods including bibliographic database searches. Data were secured from published study reports and inquiries to investigators. Between-group differences in inhibitor incidence rates were evaluated using mixed effects Cox regression. Results: Twenty-nine studies with 3012 total PTPs were included. Patients were at risk of de novo inhibitor development for a median of 79 exposure days. A total of 35 de novo inhibitors were observed. The cumulative hazard for all de novo inhibitors was 1.25% with a 95% confidence interval (CI) of 0.63-1.88%. The corresponding rate for high-titer de novo inhibitors [>5 Bethesda units (BU)] was 0.29% (CI, 0.01-0.57%). Exposure to BDD-rFVIII was associated with an increased risk of all de novo inhibitors (hazard ratio, 7.26; CI, 2.12-24.9; P=0.0016) and of high-titer de novo inhibitors (hazard ratio, 10.8; CI, 2.17-53.7; P=0.0037), compared with FL-rFVIII. Conclusions: This meta-analysis of prospective clinical studies suggests that recombinant FVIII products may differ in immunogenicity. © 2011 International Society on Thrombosis and Haemostasis.

Goldberg J.F.,Mount Sinai School of Medicine | Goldberg J.F.,New Hill | Harrow M.,University of Illinois at Chicago
Bipolar Disorders | Year: 2011

Objectives: Outcome studies have previously documented substantial functional disability among individuals with bipolar disorder, although few follow-up studies have examined the prospective course of illness beyond 10years' duration. Methods: A total of 95 patients with mood disorders (46 with bipolar I disorder and 49 with unipolar nonpsychotic depression) were assessed 15years after index hospitalization. Logistic and linear regression models were used to identify predictors of global functioning, work disability, and social adjustment. Results: At 15-year follow-up, good overall functioning was significantly less common among subjects with bipolar disorder (35%) than unipolar depression (73%) (p<0.001). Work disability was significantly more extensive in bipolar than unipolar disorder subjects (p<0.001). Logistic regression indicated that good outcome 15years after index hospitalization was significantly predicted by a unipolar rather than bipolar disorder diagnosis and the absence of a depressive episode in the preceding year. Past-year depressive, but not past-year manic, syndromes were associated with poorer global outcome and greater work disability. In addition, subsyndromal depression was significantly associated with poorer global, work, and social outcome among bipolar, but not unipolar disorder subjects. Conclusions: A majority of individuals with bipolar I disorder manifest problems with work and global functioning 15years after an index hospitalized manic episode Recurrent syndromal and subsyndromal depression disrupts multiple domains of functional outcome more profoundly in bipolar than unipolar mood disorders. The prevalence, and correlates, of impaired long-term outcome parallel those reported in shorter-term functional outcome studies of bipolar disorder. © 2011 John Wiley and Sons A/S.

Background-Luminal esophageal temperature (LET) monitoring is one strategy to minimize esophageal injury during atrial fibrillation ablation procedures. However, esophageal ulceration and fistulas have been reported despite adequate LET monitoring. The objective of this study was to assess a novel approach to LET monitoring with a deflectable LET probe on the rate of esophageal injury in patients undergoing atrial fibrillation ablation. Methods and Results-Forty-five consecutive patients undergoing an atrial fibrillation ablation procedure followed by esophageal endoscopy were included in this prospective observational pilot study. LET monitoring was performed with a 7F deflectable ablation catheter that was positioned as close as possible to the site of left atrial ablation using the deflectable component of the catheter guided by visualization of its position on intracardiac echocardiography. Ablation in the posterior left atrial was limited to 25 W and terminated when the LET increased 2°C from baseline. Endoscopy was performed 1 to 2 days after the procedure. All patients had at least 1 LET elevation >2°C necessitating cessation of ablation. Deflection of the LET probe was needed to accurately measure LET in 5% of patients when ablating near the left pulmonary veins, whereas deflection of the LET probe was necessary in 88% of patients when ablating near the right pulmonary veins. The average maximum increase in LET was 2.5±1.5°C. No patients had esophageal thermal injury on follow-up endoscopy. Conclusions-A strategy of optimal LET probe placement using a deflectable LET probe and intracardiac echocardiography guidance, combined with cessation of radiofrequency ablation with a 2°C rise in LET, may reduce esophageal thermal injury during left atrial ablation procedures. © 2011 American Heart Association, Inc.

Eichenbaum J.W.,Mount Sinai School of Medicine
Mount Sinai Journal of Medicine | Year: 2012

The major causes of impaired vision in the elderly population of the United States are cataracts, macular degeneration, and open-angle glaucoma. Cataracts and macular degeneration usually reduce central vision, especially reading and near activities, whereas chronic glaucoma characteristically attacks peripheral vision in a silent way, impacting balance, walking, and driving. Untreated, these visual problems lead to issues with regard to taking medications, keeping track of finances and personal information, walking, watching television, and attending the theater, and often create social isolation. Thus, visually impaired individuals enter nursing homes 3 years earlier, have twice the risk of falling, and have 4x the risk of hip fracture. Consequently, many elderly with low vision exercise greater demands on community services. With the prospect of little improvement and sustained visual loss, in the face of poor tolerance of low-vision services and not accepting magnification as the only way to read, clinical depression is common. In many instances, however, early and accurate diagnosis can result in timely treatment and can preserve quality of life. This review will look at current diagnostic and therapeutic considerations. Currently, about 20.5 million people in the United States have cataracts. The number will reach 30 million by 2020. About 1.75 million Americans currently have some form of macular degeneration, and the number is estimated to increase to 2.95 million in 2020. Approximately 2.2 million Americans have glaucoma, and by 2020 that number is estimated to be close to 3.4 million people. It is projectedthat by 2030 there will be 72.1 million seniors. With some overlap of the above 3 groups conservatively estimated (if you add the 2030 cataract group to the macular degeneration and glaucoma groups), then about 1 in 2 senior individuals by 2030 may have some significant ocular disease, which could account for about 50% of the healthcare budget for the elderly. © 2012 Mount Sinai School of Medicine.

Nead K.T.,Stanford University | Cooke J.P.,Stanford University | Olin J.W.,Mount Sinai School of Medicine | Leeper N.J.,Stanford University
Journal of the American College of Cardiology | Year: 2013

Objectives The aim of this study was to determine whether use of an alternative ankle-brachial index (ABI) calculation method improves mortality risk prediction compared with traditional methods. Background The ABI is used to diagnose peripheral arterial disease (PAD) and to identify those at risk for cardiovascular events. Traditionally, the ABI is calculated with the higher of the dorsalis pedis and posterior tibial ankle arteries. Studies directly comparing calculation methods are limited. Methods The ABI was calculated at baseline in 1,413 study participants undergoing nonemergent coronary angiography subsequently followed for all-cause and cardiovascular mortality. There were 224 individuals assigned to the traditional-PAD group (ABI <0.90) with the traditional ABI method. Of those remaining, an alternative ABI method using the lower of the 2 ankle pressures assigned 282 patients to the alternative-PAD group. The 862 individuals not assigned to PAD by either method were the no-PAD group. Results There were 163 mortalities during a median follow-up of 5.0 years. Adjusted Cox regression models showed that the alternative-PAD group had an increased risk for all-cause (hazard ratio [HR]: 1.49; 95% confidence interval: 1.01 to 2.19) and cardiovascular mortality (HR: 3.21; 95% confidence interval: 1.53 to 6.37) versus the no-PAD group. Additionally, in the no-PAD group, there was an 11% (HR: 1.11; 95% confidence interval: 1.05 to 1.17) increased risk of all-cause mortality/1-mm Hg increased difference between the left and right brachial systolic pressures. Conclusions The implementation of an alternative ABI method and use of the brachial difference identifies individuals at an increased risk for mortality who are currently missed with traditional ABI methods. Current ABI protocols might need to be evaluated. © 2013 by the American College of Cardiology Foundation.

Olanow C.W.,Mount Sinai School of Medicine | Obeso J.A.,University of Navarra
Movement Disorders | Year: 2012

A body of clinical and pathologic evidence supports the concept that there a pre-Parkinson state exists prior to the time when Parkinson's disease (PD) can be formally diagnosed. The ability to define a the preclinical or prodromal PD state has many important implications. First, understanding the timing and sequence of pathologic change that occurs in PD could provide important clues as to the etiology and pathogenesis of PD, and provide insight into cell vulnerability factors. Second, defining a population of patients with preclinical PD would provide a potentially important group of subjects for clinical trials attempting to define disease-modifying therapies. And, finally, being able to determine that a person has PD at an earlier time point than is currently possible would permit the introduction of a putative disease-modifying therapy at a time when it could have more profound and long-lasting effects. This paper reviews the clinical significance of defining preclinical PD. © 2012 Movement Disorder Society.

Rackovsky S.,Mount Sinai School of Medicine | Rackovsky S.,Cornell University
Physical Review Letters | Year: 2011

The existence of conformational switching in proteins, induced by single amino acid mutations, presents an important challenge to our understanding of the physics of protein folding. Sequence-local methods, commonly used to detect structural homology, are incapable of accounting for this phenomenon. We examine a set of proteins, derived from the GA and GB domains of Streptococcus protein G, which are known to show a dramatic conformational change as a result of single-residue replacement. It is shown that these sequences, which are almost identical locally, can have very different global patterns of physical properties. These differences are consistent with the observed complete change in conformation. These results suggest that sequence-local methods for identifying structural homology can be misleading. They point to the importance of global sequence analysis in understanding sequence-structure relationships. © 2011 American Physical Society.

Iosifescu D.V.,Mount Sinai School of Medicine | Iosifescu D.V.,Harvard University
European Neuropsychopharmacology | Year: 2012

Impairments in cognitive performance and inability to function in everyday life situations are present, in various degrees, in many severe mental illnesses, including major depressive disorder, bipolar disorder, and schizophrenia. Persistent mood symptoms (e.g., depression and mania) are associated with functional deficits in major depression and bipolar disorder, but also in conditions where mood symptoms are not the primary markers of the illness, such as in schizophrenia. While mood symptoms impact cognitive performance, both mood symptoms and cognitive deficits have a significant - and to some extent independent - impact on psychosocial functioning in psychiatric patients. Improved control of mood symptoms may represent an important strategy leading to improved functional outcomes. However, cognitive impairment may be an important independent dimension of many psychiatric disorders and such symptoms should also be considered a potential target of treatments aiming to reduce functional deficits. © 2012.

Macarthur B.D.,University of Southampton | Lemischka I.R.,Mount Sinai School of Medicine
Cell | Year: 2013

Recent reports using single-cell profiling have indicated a remarkably dynamic view of pluripotent stem cell identity. Here, we argue that the pluripotent state is not well defined at the single-cell level but rather is a statistical property of stem cell populations, amenable to analysis using the tools of statistical mechanics and information theory. © 2013 Elsevier Inc.

Basler C.F.,Mount Sinai School of Medicine
Expert Review of Anti-Infective Therapy | Year: 2013

Evaluation of: Mohan GS, Li W, Ye L, Compans RW, Yang C. Antigenic subversion: a novel mechanism of host immune evasion by Ebola virus. PLoS Pathog. 8(12), e1003065 (2012). Ebola viruses encode two glycoproteins (GPs): a membrane-associated GP that is present in the viral membrane and mediates viral attachment and entry into host cells; and a secreted, nonstructural glycoprotein (sGP) that is identical to GP over approximately 90% of its length. A recent study by Mohan and colleagues attributes a novel immune evasion mechanism dubbed 'antigenic subversion' to sGP. Using DNA immunization in mice, the authors demonstrate that sGP elicits antibodies that crossreact with GP, but these antibodies are non-neutralizing. Coimmunization with sGP plus GP or sequential immunizations with GP and sGP direct the host antibody response toward non-neutralizing epitopes. Therefore, the production of sGP may prevent effective neutralization of the virus during Ebola virus infection, and may reduce the effectiveness of vaccines that rely upon neutralizing antibody responses. © 2013 Expert Reviews Ltd.

Nieto N.,Mount Sinai School of Medicine
Liver International | Year: 2012

Among the pathogenesis and risk factors of alcoholic liver disease (ALD) are the source of dietary fat, obesity, insulin resistance, adipokines and acetaldehyde. Translocation of Gram-negative bacteria from the gut, the subsequent effects mediated by endotoxin, and the increased production of matricellular proteins, cytokines, chemokines and growth factors, actively participate in the progression of liver injury. In addition, generation of reactive oxygen and nitrogen species and the activation of non-parenchymal cells also contribute to the pathophysiology of ALD. A key event leading to liver damage is the transition of quiescent hepatic stellate cells into activated myofibroblasts, with the consequent deposition of fibrillar collagen I resulting in significant scarring. Thus, it is becoming clearer that matricellular proteins are critical players in the pathophysiology of liver disease; however, additional mechanistic insight is needed to understand the signalling pathways involved in the up-regulation of collagen I protein. At present, systems biology approaches are helping to answer the many unresolved questions in this field and are allowing to more comprehensively identify protein networks regulating pathological collagen I deposition in hopes of determining how to prevent the onset of liver fibrosis and/or to slow disease progression. Thus, this review article provides a snapshot on current efforts for identifying pathological protein regulatory networks in the liver using systems biology tools. These approaches hold great promise for future research in liver disease. © 2011 John Wiley & Sons A/S.

Leichsenring F.,Justus Liebig University | Leibing E.,University of Gottingen | Kruse J.,Justus Liebig University | New A.S.,Mount Sinai School of Medicine | Leweke F.,Justus Liebig University
The Lancet | Year: 2011

Recent research findings have contributed to an improved understanding and treatment of borderline personality disorder. This disorder is characterised by severe functional impairments, a high risk of suicide, a negative effect on the course of depressive disorders, extensive use of treatment, and high costs to society. The course of this disorder is less stable than expected for personality disorders. The causes are not yet clear, but genetic factors and adverse life events seem to interact to lead to the disorder. Neurobiological research suggests that abnormalities in the frontolimbic networks are associated with many of the symptoms. Data for the effectiveness of pharmacotherapy vary and evidence is not yet robust. Specific forms of psychotherapy seem to be beneficial for at least some of the problems frequently reported in patients with borderline personality disorder. At present, there is no evidence to suggest that one specific form of psychotherapy is more effective than another. Further research is needed on the diagnosis, neurobiology, and treatment of borderline personality disorder. © 2011 Elsevier Ltd.

Colvin A.C.,Mount Sinai School of Medicine | Harrast J.,930 North York Road | Harner C.,University of Pittsburgh
Journal of Bone and Joint Surgery - Series A | Year: 2012

Background: Recent advances in diagnosis and instrumentation have facilitated the arthroscopic treatment of hip pathology. However, little has been reported on trends in the utilization of hip arthroscopy. The purpose of this study was to examine changes in the use of hip arthroscopy as reflected in the American Board of Orthopaedic Surgery (ABOS) database. We also surveyed directors of both sports and joint reconstruction fellowships to determine attitudes toward hip arthroscopy training. Methods: The number of hip arthroscopy cases in the ABOS database during 1999 through 2009 was determined. A survey was devised to determine the type of hip arthroscopy training that was currently being offered at the fellowship level. Results: The number of hip arthroscopy procedures performed by ABOS candidates increased significantly from 0.02 cases per candidate in 1999 to 0.36 cases per candidate in 2009 (p < 0.0001). From 2003 through 2009, a significantly greater percentage of ABOS candidates with sports fellowship training (10.4%) than candidates without such training (2.9%) performed hip arthroscopy (p < 0.0001). During this same time period, candidates in the Northeast and Northwest performed the most hip arthroscopy procedures as a percentage of total procedures (p < 0.0001). Nearly half of the sports and joint reconstruction fellowships that included hip arthroscopy as a component of the training in 2010 had added it within the past three years. Fellows performed fewer than twenty hip arthroscopy cases per year in the majority of training programs. Conclusions: The number of hip arthroscopy procedures performed by candidates taking Part II of the ABOS examination increased eighteenfold between 1999 and 2009. This increase is likely the result of several factors, including an increase in the number of programs offering training in hip arthroscopy. Copyright © 2012 by The Journal of Bone and Joint Surgery, Incorporated.

Sachar D.B.,Mount Sinai School of Medicine
Journal of Digestive Diseases | Year: 2012

When a patient is hospitalized with acute, severe ulcerative colitis, the primary decision is whether or not to proceed directly to surgery. Absolute indications for an immediate colectomy include exsanguinating hemorrhage, perforation and cancer. If medical therapy is undertaken, however, the decision for urgent surgery or non-operative salvage therapy will still be required in 15-50% of the patients in which there is a failure to respond within 3-5 days to a standard regimen of i.v. steroids, antibiotics, decompressive maneuvers, fluid and electrolyte replacement and other supportive measures. The options for medical salvage therapy are usually cyclosporine or infliximab. There are theoretical and practical arguments on each side; the current GETAID and CONSTRUCT trials will probably provide support for either. The choice between colectomy or medical salvage therapy, however, must not be delayed under any circumstances. Before choosing salvage therapy, one must first be certain that there is the luxury of time, that there is a post-hospital strategy for the maintenance of remission and that the colon is worth saving. The priority is not so much saving colons as it is saving lives. © 2012 The Author. Journal of Digestive Diseases © 2012 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.

McBride C.M.,National Human Genome Research Institute | Koehly L.M.,National Human Genome Research Institute | Sanderson S.C.,Mount Sinai School of Medicine | Kaphingst K.A.,National Human Genome Research Institute
Annual Review of Public Health | Year: 2010

This report describes the use of information emerging from genetic discovery to motivate risk-reducing health behaviors. Most research to date has evaluated the effects of information related to rare genetic variants on screening behaviors, in which genetic risk feedback has been associated consistently with improved screening adherence. The limited research with common genetic variants suggests that genetic information, when based on single-gene variants with low-risk probabilities, has little impact on behavior. The effect on behavioral outcomes of more realistic testing scenarios in which genetic risk is based on numerous genetic variants is largely unexplored. Little attention has been directed to matching genetic information to the literacy levels of target audiences. Another promising area for research is consideration of using genetic information to identify risk shared within kinship networks and to expand the influence of behavior change beyond the individual. Copyright © 2010 by Annual Reviews. All rights reserved.

Purpose To evaluate the risks and quality-of-life (QoL) outcomes of fluocinolone acetonide implant versus systemic therapy with corticosteroid and immunosuppression when indicated for intermediate uveitis, posterior uveitis, and panuveitis. Design Additional follow-up of a randomized trial cohort. Participants Two hundred fifty-five patients with intermediate uveitis, posterior uveitis, or panuveitis, randomized to implant or systemic therapy. Methods Randomized subjects with intermediate uveitis, posterior uveitis, or panuveitis (479 eyes) were followed up over 54 months, with 79.2% completing the 54-month visit. Main Outcome Measures Local and systemic potential complications of the therapies and self-reported health utility and vision-related and generic health-related QoL were studied prospectively. Results Among initially phakic eyes, cataract and cataract surgery occurred significantly more often in the implant group (hazard ratio [HR], 3.0; P = 0.0001; and HR, 3.8; P < 0.0001, respectively). In the implant group, most cataract surgery occurred within the first 2 years. Intraocular pressure elevation measures occurred more frequently in the implant group (HR range, 3.7-5.6; all P < 0.0001), and glaucoma (assessed annually) also occurred more frequently (26.3% vs. 10.2% by 48 months; HR, 3.0; P = 0.0002). In contrast, potential complications of systemic therapy, including measures of hypertension, hyperlipidemia, diabetes, bone disease, and hematologic and serum chemistry indicators of immunosuppression toxicity, did not differ between groups through 54 months. Indices of QoL initially favored implant therapy by a modest margin. However, all summary measures of health utility and vision-related or generic health-related QoL were minimally and nonsignificantly different by 54 months, with the exception of the 36-item Short-Form Health Survey physical component summary score, which favored implant by a small margin at 54 months (3.17 on a scale of 100; P = 0.01, not adjusted for multiple comparisons). Mean QoL results were favorable in both groups. Conclusions These results suggest that fluocinolone acetonide implant therapy is associated with a clinically important increased risk of glaucoma and cataract with respect to systemic therapy, suggesting that careful monitoring and early intervention to prevent glaucoma is warranted with implant therapy. Systemic therapy subjects avoided a significant excess of toxicities of systemic corticosteroid and immunosuppressive therapies in the trial. Self-reported QoL measures initially favored implant therapy, but over time the measures converged, with generally favorable QoL in both groups. © 2015 American Academy of Ophthalmology.

Dekosky S.T.,University of Virginia | Blennow K.,Gothenburg University | Ikonomovic M.D.,University of Pittsburgh | Gandy S.,Mount Sinai School of Medicine
Nature Reviews Neurology | Year: 2013

Over the past decade, public awareness of the long-term pathological consequences of traumatic brain injury (TBI) has increased. Such awareness has been stimulated mainly by reports of progressive neurological dysfunction in athletes exposed to repetitive concussions in high-impact sports such as boxing and American football, and by the rising number of TBIs in war veterans who are now more likely to survive explosive blasts owing to improved treatment. Moreover, the entity of chronic traumatic encephalopathy (CTE) - which is marked by prominent neuropsychiatric features including dementia, parkinsonism, depression, agitation, psychosis, and aggression - has become increasingly recognized as a potential late outcome of repetitive TBI. Annually, about 1% of the population in developed countries experiences a clinically relevant TBI. The goal of this Review is to provide an overview of the latest understanding of CTE pathophysiology, and to delineate the key issues that are challenging clinical and research communities, such as accurate quantification of the risk of CTE, and development of reliable biomarkers for single-incident TBI and CTE. © 2013 Macmillan Publishers Limited. All rights reserved.

Noda S.,Rockefeller University | Krueger J.G.,Rockefeller University | Guttman-Yassky E.,Rockefeller University | Guttman-Yassky E.,Mount Sinai School of Medicine
Journal of Allergy and Clinical Immunology | Year: 2015

Psoriasis and atopic dermatitis (AD) are common inflammatory skin diseases characterized by immune-mediated inflammation and abnormal keratinocyte differentiation. Although T-cell infiltration characterizes both diseases, T-cell polarization differs. Psoriasis is currently the best model for translational medicine because many targeted therapeutics have been developed and testing of targeted therapeutics has cemented psoriasis as IL-23/TH17 polarized. In patients with AD, although therapeutic development is approximately a decade behind that in patients with psoriasis, there is now active development and testing of targeted therapeutics against various immune axes (TH2, TH22, and IL-23/TH17). These clinical trials and subsequent molecular analyses using human samples will be able to clarify the relative roles of polar cytokines in patients with AD. © 2014 American Academy of Allergy, Asthma & Immunology.

Betancur C.,French Institute of Health and Medical Research | Betancur C.,French National Center for Scientific Research | Betancur C.,University Pierre and Marie Curie | Buxbaum J.D.,Mount Sinai School of Medicine
Molecular Autism | Year: 2013

Autism spectrum disorders (ASD) are etiologically heterogeneous, with hundreds of rare, highly penetrant mutations and genomic imbalances involved, each contributing to a very small fraction of cases. In this issue of Molecular Autism, Soorya and colleagues evaluated 32 patients with Phelan-McDermid syndrome, caused by either deletion of 22q13.33 or SHANK3 mutations, using gold-standard diagnostic assessments and showed that 84% met criteria for ASD, including 75% meeting criteria for autism. This study and prior studies demonstrate that this syndrome appears to be one of the more penetrant causes of ASD. In this companion review, we show that in samples ascertained for ASD, SHANK3 haploinsufficiency is one of the more prevalent monogenic causes of ASD, explaining at least 0.5% of cases. We note that SHANK3 haploinsufficiency remains underdiagnosed in ASD and developmental delay, although with the increasingly widespread use of chromosomal microarray analysis and targeted sequencing of SHANK3, the number of cases is bound to rise. © 2013Betancur and Buxbaum; licensee BioMed Central Ltd.©2013 Betancur and Buxbaum; licensee BioMed Central Ltd.

Olanow C.W.,Mount Sinai School of Medicine
Movement Disorders | Year: 2015

This review article considers the question of whether or not levodopa is toxic in Parkinson's disease (PD). l-dopa is the most effective symptomatic treatment for PD and has provided benefit for millions of patients. However, there has been a longstanding concern that l-dopa might be toxic and accelerate neuronal degeneration and clinical progression as a consequence of reactive oxygen species generated by the drug's oxidative metabolism. In vitro, l-dopa can induce degeneration of dopaminergic neurons, but it is not clear that the effects of the drug on cultured dopamine neurons reflect what happens in the PD brain. In vivo, l-dopa has not been demonstrated to have toxic effects on dopamine neurons in normal, dopamine-lesioned, or oxidatively stressed animal models, but none of these models precisely replicates the PD condition. Clinical trials have tested the effect of l-dopa on clinical progression and have not demonstrated any findings indicative of toxicity. However, the symptomatic and long-duration effects of the drug could mask ongoing neuronal degeneration. Furthermore, l-dopa induces a greater decline in imaging measures of dopaminergic function than placebo or dopamine agonists, consistent with toxicity. Pathological studies have not demonstrated evidence of accelerated loss of dopamine neurons, but prospective and properly controlled studies with stereological unbiased counting have not been performed. Thus, although there is no hard evidence to suggest that l-dopa is toxic in PD patients, the issue has not been fully resolved. It is generally recommended that physicians continue to use l-dopa, but in the lowest dose that provides satisfactory clinical control. © 2014 International Parkinson and Movement Disorder Society.

There is growing evidence of shared risk alleles for complex traits (pleiotropy), including autoimmune and neuropsychiatric diseases. This might be due to sharing among all individuals (whole-group pleiotropy) or a subset of individuals in a genetically heterogeneous cohort (subgroup heterogeneity). Here we describe the use of a well-powered statistic, BUHMBOX, to distinguish between those two situations using genotype data. We observed a shared genetic basis for 11 autoimmune diseases and type 1 diabetes (T1D; P < 1 × 10-4) and for 11 autoimmune diseases and rheumatoid arthritis (RA; P < 1 × 10-3). This sharing was not explained by subgroup heterogeneity (corrected PBUHMBOX > 0.2; 6,670 T1D cases and 7,279 RA cases). Genetic sharing between seronegative and seropostive RA (P < 1 × 10-9) had significant evidence of subgroup heterogeneity, suggesting a subgroup of seropositive-like cases within seronegative cases (PBUHMBOX = 0.008; 2,406 seronegative RA cases). We also observed a shared genetic basis for major depressive disorder (MDD) and schizophrenia (P < 1 × 10-4) that was not explained by subgroup heterogeneity (PBUHMBOX = 0.28; 9,238 MDD cases). © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Hadi A.,New York University | Lebwohl M.,Mount Sinai School of Medicine
Journal of the American Academy of Dermatology | Year: 2011

Background: The diagnosis of pyoderma gangrenosum (PG) can be exceedingly difficult, and misdiagnosis can potentially yield serious consequences. Clinical criteria for establishing a reliable diagnosis have been previously proposed, but a consensus in their application has yet to be reached. Objective: We sought to review recent trends in diagnosing PG and compare them with previously suggested diagnostic criteria. Methods: Data for this article were obtained by searching the PubMed database using the key words "pyoderma gangrenosum." Our search was limited to adult case reports that appeared in the English-language literature and received a final diagnosis of PG. The full text of the latest published 30 case reports that fulfilled these search criteria was reviewed. The articles spanned the years 2008 and 2009. Clinical features that appeared in the case descriptions were summarized and compared with the diagnostic criteria for the disease that were previously proposed. Results: Of the 30 case reports, 16 described ulcers involving one or both legs, whereas only one case had peristomal involvement. Although 8 cases were associated with inflammatory bowel disease, 11 of the 30 patients did not have a systemic comorbidity. Fifteen lesions were noted to manifest at sites of trauma, which ranged from surgical incision sites to prolonged seatbelt compression. Nine case reports mentioned an undermined border in their clinical description, whereas only 5 authors commented on pustules and 6 described a purulent discharge. Only two authors commented on cribriform scarring. Limitations: We only reviewed the latest published 30 case reports. Case series, which may have shown more typical cases, were excluded. Conclusion: Currently, there is an underemphasis of clinical features in the diagnosis of PG, which can potentially lead to overdiagnosis. Establishing firm clinical criteria for diagnosing PG will ensure that case reports describe the same disease. This has implications in optimizing treatment strategies and improving patient outcomes. © 2010 by the American Academy of Dermatology, Inc.

Jeff J.M.,Mount Sinai School of Medicine
Current Opinion in Lipidology | Year: 2016

PURPOSE OF REVIEW: Rare variant association studies (RVAS) target the class of genetic variation with frequencies less than 1%. Recently, investigators have used exome sequencing in RVAS to identify rare alleles responsible for Mendelian diseases but have experienced greater difficulty discovering such alleles for complex diseases. In this review, we describe what we have learned about lipoprotein metabolism and coronary heart disease through the conduct of RVAS. RECENT FINDINGS: Rare protein-altering genetic variation can provide important insights that are not as easily attainable from common variant association studies. First, RVAS can facilitate gene discovery by identifying novel rare protein-altering variants in specific genes that are associated with disease. Second, rare variant associations can provide supportive evidence for putative drug targets for novel therapies. Finally, rare variants can uncover new pathways and reveal new biologic mechanisms. SUMMARY: The field of human genetics has already made tremendous progress in understanding lipoprotein metabolism and the causes of coronary heart disease in the context of rare variants. As next generation sequencing becomes more cost-effective, RVAS with larger sample sizes will be conducted. This will lead to more novel rare variant discoveries and the translation of genomic data into biological knowledge and clinical insights for cardiovascular disease. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Polydorides A.D.,Mount Sinai School of Medicine
Seminars in Diagnostic Pathology | Year: 2014

The histologic finding of chronic inflammation in an endoscopic mucosal biopsy of the stomach (chronic gastritis) is very common and usually reflects the presence of Helicobacter pylori infection. However, infectious organisms are not always present in biopsy material, and some cases of chronic gastritis do not result from H. pylori infection. Thus, the differential diagnosis of this finding is an important one for pathologists to keep in mind. This review presents the three most common and clinically significant causes of chronic, noninfectious gastritis, namely, autoimmune atrophic gastritis, lymphocytic gastritis, and gastric involvement in the setting of inflammatory bowel disease, especially Crohn disease. For each entity, a brief discussion of its etiology and pathogenesis, a review of the clinical and endoscopic features, and a description of the microscopic findings are presented in the context of the differential diagnosis of chronic gastritis with emphasis on helpful histopathologic hints and long-term sequelae. © 2014 Elsevier Inc.

Ross M.J.,Mount Sinai School of Medicine
Kidney International | Year: 2014

Despite improved outcomes among persons living with HIV who are treated with antiretroviral therapy, they remain at increased risk for acute and chronic kidney diseases. Moreover, since HIV can infect renal epithelial cells, the kidney might serve as a viral reservoir that would need to be eradicated when attempting to achieve full virologic cure. In recent years, much progress has been made in elucidating the mechanism by which HIV infects renal epithelial cells and the viral and host factors that promote development of kidney disease. Polymorphisms in APOL1 confer markedly increased risk of HIV-associated nephropathy; however, the mechanism by which ApoL1 variants may promote kidney disease remains unclear. HIV-positive persons are at increased risk of acute kidney injury, which may be a result of a high burden of subclinical kidney disease and/or viral factors and frequent exposure to nephrotoxins. Despite the beneficial effect of antiretroviral therapy in preventing and treating HIVAN, and possibly other forms of kidney disease in persons living with HIV, some of these medications, including tenofovir, indinavir, and atazanavir can induce acute and/or chronic kidney injury via mitochondrial toxicity or intratubular crystallization. Further research is needed to better understand factors that contribute to acute and chronic kidney injury in HIV-positive patients and to develop more effective strategies to prevent and treat kidney disease in this vulnerable population. © 2014 International Society of Nephrology.

Purpose To compare the benefits of fluocinolone acetonide implant therapy versus systemic corticosteroid therapy supplemented (when indicated) with immunosuppression for intermediate uveitis, posterior uveitis, and panuveitis. Design Additional follow-up of a randomized comparative effectiveness trial cohort. Participants Two hundred fifty-five patients with intermediate uveitis, posterior uveitis, or panuveitis randomized to implant or systemic therapy. Main Outcome Measures Best-corrected visual acuity (BCVA), visual field mean deviation (MD), activity of uveitis, and presence of macular edema (per reading center grading) ascertained prospectively. Methods Trial participants were followed-up for 54 months from original randomization. Results The visual function trajectory in uveitic eyes demonstrated a similar (P = 0.73) degree of modest (not statistically significant) improvement from baseline to 54 months in both groups (mean improvement in BCVA at 54 months, 2.4 and 3.1 letters in the implant and systemic groups, respectively). Many had excellent initial visual acuity, limiting the potential for improvement. The mean automated perimetry MD score remained similar to baseline throughout 48 months of follow-up in both groups. Overall control of inflammation was superior in the implant group at every time point assessed (P < 0.016), although most eyes in the systemic therapy arm also showed substantial improvement, achieving complete control or low levels of inflammation. Although macular edema improved significantly more often with implant treatment within the first 6 months, the systemic group gradually improved over time such that the proportions with macular edema converged in the 2 groups by 36 months and overlapped thereafter (P = 0.41 at 48 months). Conclusions Visual outcomes of fluocinolone acetonide implant and systemic treatment for intermediate uveitis, posterior uveitis, and panuveitis were similarly favorable through 54 months. The implant maintained a clear advantage in controlling inflammation through 54 months. Nevertheless, with systemic therapy, most patients also experienced greatly improved inflammatory status. Macular edema improved equally with longer follow-up. Based on cost effectiveness and side-effect considerations, systemic therapy may be indicated as the initial treatment for many bilateral uveitis cases. However, implant therapy is a reasonable alternative, especially for unilateral cases and when systemic therapy is not feasible or is not successful. © 2015 American Academy of Ophthalmology.

Cunningham-Rundles C.,Mount Sinai School of Medicine
Clinical and Experimental Immunology | Year: 2011

The elucidation of the genes leading to selected immune defects has accelerated our understanding of the molecular basis of tolerance in autoimmunity disorders. Mutations in genes of the immune system are known to lead to a catalogue of functional deficits, including loss of activation-induced Fas-mediated apoptosis, an inability to remove self-reactive T and/or B cells and insufficient numbers or functions of regulatory T cells. In most cases, microbial antigen stimulation occurs simultaneously, leading to further inflammatory responses. In each case, probing the molecular pathways involved in these primary immune defects has led to a better understanding of autoimmune diseases in general. While subjects with X-linked agammaglobulinaemia are almost devoid of autoimmune diseases, B cells which are present, but dysfunctional in other defects, lead to a significant incidence of autoimmune disease. Autoimmunity is also particularly common in the antibody deficiency states. Although organ-based autoimmunity also occurs, for unclear reasons the main conditions are immune thrombocytopenia purpura and autoimmune haemolytic anaemia. The common variable immune deficiency subjects most afflicted by these cytopenias are those with specific peripheral blood memory B cell phenotypes. B cells of these subjects have a retained autoimmune potential, lack of somatic hypermutation, profound loss of proliferative potential, accelerated apoptosis and loss of normal Toll-like receptor signalling. Treatment with high-dose immunoglobulin and/or steroids can be helpful, while rituximab provides benefits in the treatment of refractory cytopenias with apparently little risk, even with repeated use, due to ongoing immune globulin therapy. © 2011 The Author. Clinical and Experimental Immunology © 2011 British Society for Immunology.

Stocchi F.,IRCCS San Raffaele Pisana | Olanow C.W.,IRCCS San Raffaele Pisana | Olanow C.W.,Mount Sinai School of Medicine
Movement Disorders | Year: 2013

A neuroprotective or disease-modifying therapy that can slow or stop disease progression and prevent the development of intolerable disability is the major unmet medical need in the treatment of Parkinson's disease (PD). Many putative neuroprotective agents have been identified in the laboratory, but none has been unequivocally demonstrated to provide disease-modifying effects in PD patients, even when clinical trials are positive. Obstacles to defining a neuroprotective therapy in PD include: (1) uncertainty about the cause of PD and precisely what to target, (2) a reliable animal model in which to test putative neuroprotective agents that accurately predicts results in PD patients, (3) insight about which dose to employ in clinical trials and which patient group to study, (4) a clinical trial design that reliably differentiates disease-modifying and symptomatic effects and that is acceptable to regulatory authorities, and (5) the cost and time of the development program. Advances have been made in each of these areas, thereby increasing the prospects of developing a neuroprotective or disease-modifying therapy in the not-too-distant future. These issues are reviewed in the present article. © 2013 Movement Disorder Society.

Bernstein D.L.,North Shore Long Island Jewish Health System | Hulkova H.,Charles University | Bialer M.G.,North Shore Long Island Jewish Health System | Desnick R.J.,Mount Sinai School of Medicine
Journal of Hepatology | Year: 2013

Cholesteryl ester storage disease (CESD) is caused by deficient lysosomal acid lipase (LAL) activity, predominantly resulting in cholesteryl ester (CE) accumulation, particularly in the liver, spleen, and macrophages throughout the body. The disease is characterized by microvesicular steatosis leading to liver failure, accelerated atherosclerosis and premature demise. Although CESD is rare, it is likely that many patients are unrecognized or misdiagnosed. Here, the findings in 135 CESD patients described in the literature are reviewed. Diagnoses were based on liver biopsies, LAL deficiency and/or LAL gene (LIPA) mutations. Hepatomegaly was present in 99.3% of patients; 74% also had splenomegaly. When reported, most patients had elevated serum total cholesterol, LDL-cholesterol, triglycerides, and transaminases (AST, ALT, or both), while HDL-cholesterol was decreased. All 112 liver biopsied patients had the characteristic pathology, which is progressive, and includes microvesicular steatosis, which leads to fibrosis, micronodular cirrhosis, and ultimately to liver failure. Pathognomonic birefringent CE crystals or their remnant clefts were observed in hepatic cells. Extrahepatic manifestations included portal hypertension, esophageal varices, and accelerated atherosclerosis. Liver failure in 17 reported patients resulted in liver transplantation and/or death. Genotyping identified 31 LIPA mutations in 55 patients; 61% of mutations were the common exon 8 splice-junction mutation (E8SJM-1G>A), for which 18 patients were homozygous. Genotype/phenotype correlations were limited; however, E8SJM-1G>A homozygotes typically had early-onset, slowly progressive disease. Supportive treatment included cholestyramine, statins, and, ultimately, liver transplantation. Recombinant LAL replacement was shown to be effective in animal models, and recently, a phase I/II clinical trial demonstrated its safety and indicated its potential metabolic efficacy. © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Golden S.A.,Mount Sinai School of Medicine
Nature protocols | Year: 2011

A major impediment to novel drug development has been the paucity of animal models that accurately reflect symptoms of affective disorders. In animal models, prolonged social stress has proven to be useful in understanding the molecular mechanisms underlying affective-like disorders. When considering experimental approaches for studying depression, social defeat stress, in particular, has been shown to have excellent etiological, predictive, discriminative and face validity. Described here is a protocol whereby C57BL/6J mice that are repeatedly subjected to bouts of social defeat by a larger and aggressive CD-1 mouse results in the development of a clear depressive-like syndrome, characterized by enduring deficits in social interactions. Specifically, the protocol consists of three important stages, beginning with the selection of aggressive CD-1 mice, followed by agonistic social confrontations between the CD-1 and C57BL/6J mice, and concluding with the confirmation of social avoidance in subordinate C57BL/6J mice. The automated detection of social avoidance allows a marked increase in throughput, reproducibility and quantitative analysis. This protocol is highly adaptable, but in its most common form it requires 3-4 weeks for completion.

Glassberg J.,Mount Sinai School of Medicine
Emergency medicine practice | Year: 2011

Sickle cell disease (SCD) is the most common genetic disease in the US, affecting approximately 100,000 individuals. In SCD, genetically mutated hemoglobin (HbS) forms rigid polymers when deoxygenated, giving red blood cells a characteristic sickled shape. Increased blood viscosity and cell adhesion produce intermittent vaso-occlusion. The vaso-occlusive phenotype of SCD, which is marked by higher hemoglobin, manifests with frequent painful crises and is associated with a higher risk for developing acute chest syndrome. The hemolytic phenotype is characterized by lower baseline levels of hemoglobin and elevated markers of hemolysis. There are no reliable markers of vaso-occlusive crisis (VOC), ie, vital signs and laboratory tests are normal. After intravenous (IV) opiate titration, patient-controlled anesthesia (PCA) pumps are encouraged. Excess IV fluids have been associated with development of atelectasis, a risk factor for acute chest syndrome. Acute chest syndrome has clinical symptoms similar to pneumonia; these patients will develop progressive hypoxemia, acute respiratory distress syndrome, and death if exchange transfusion is not initiated.

Lebwohl M.,Mount Sinai School of Medicine | Swanson N.,Oregon Health And Science University | Anderson L.L.,Dermatology Associates of Tyler | Melgaard A.,Data Management | And 2 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Actinic keratosis is a common precursor to sun-related squamous-cell carcinoma. Treating actinic keratoses and the surrounding skin area (i.e., field therapy) can eradicate clinical and subclinical actinic keratoses. Topical field therapy currently requires weeks or months of treatment. We investigated the efficacy and safety of a new topical field therapy for actinic keratosis, ingenol mebutate gel (0.015% for face and scalp and 0.05% for trunk and extremities). METHODS: In four multicenter, randomized, double-blind studies, we randomly assigned patients with actinic keratoses on the face or scalp or on the trunk or extremities to receive ingenol mebutate or placebo (vehicle), self-applied to a 25-cm 2 contiguous field once daily for 3 consecutive days for lesions on the face or scalp or for 2 consecutive days for the trunk or extremities. Complete clearance (primary outcome) was assessed at 57 days, and local reactions were quantitatively measured. RESULTS: In a pooled analysis of the two trials involving the face and scalp, the rate of complete clearance was higher with ingenol mebutate than with placebo (42.2% vs. 3.7%, P<0.001). Local reactions peaked at day 4, with a mean maximum composite score of 9.1 on the local-skin-response scale (which ranges from 0 to 4 for six types of reaction, yielding a composite score of 0 to 24, with higher numbers indicating more severe reactions), rapidly decreased by day 8, and continued to decrease, approaching baseline scores by day 29. In a pooled analysis of the two trials involving the trunk and extremities, the rate of complete clearance was also higher with ingenol mebutate than with placebo (34.1% vs. 4.7%, P<0.001). Local skin reactions peaked between days 3 and 8 and declined rapidly, approaching baseline by day 29, with a mean maximum score of 6.8. Adverse events were generally mild to moderate in intensity and resolved without sequelae. CONCLUSIONS: Ingenol mebutate gel applied topically for 2 to 3 days is effective for field treatment of actinic keratoses. (Funded by LEO Pharma; ClinicalTrials.gov numbers, NCT00742391, NCT00916006, NCT00915551, and NCT00942604.) Copyright © 2012 Massachusetts Medical Society.

Weinfeld S.B.,Mount Sinai School of Medicine
Medical Clinics of North America | Year: 2014

Achilles tendon disorders include tendinosis, paratenonitis, insertional tendinitis, retrocalcaneal bursitis, and frank rupture. Patients present with pain and swelling in the posterior aspect of the ankle. Magnetic resonance imaging and ultrasound are helpful in confirming the diagnosis and guiding treatment. Nonsurgical management of Achilles tendon disorders includes nonsteroidal anti-inflammatory drugs, physical therapy, bracing, and footwear modification. Surgical treatment includes debridement of the diseased area of the tendon with direct repair. Tendon transfer may be necessary to augment the strength of the Achilles tendon. © 2014 Elsevier Inc.

Dijkers M.P.,Mount Sinai School of Medicine
Archives of Physical Medicine and Rehabilitation | Year: 2015

Observers commonly note the poor reporting of research, including rehabilitation research. The Consolidated Standards of Reporting Trials (CONSORT) checklist (supplemented by the CONSORT extension for nonpharmacologic interventions) has been published for improving the reporting of intervention research. However, the items on these checklists are considered to be inadequate to guide authors as to which information to include when reporting on the intervention(s) studied, and the Template for Intervention Description and Replication, Journal Article Reporting Standards, and the checklist of the Western Journal of Nursing Research are recommended to rehabilitation researchers. The Rehabilitation Treatment Taxonomy framework is recommended as a conceptual scheme to assist authors in thinking through the linkages between intervention ingredients, targets of treatment, and the mechanisms of action linking these 2 areas. Recommendations are made for prospective authors and journal editors who desire to see improved reporting of rehabilitation interventions. © 2015 American Congress of Rehabilitation Medicine.

Neale B.M.,Harvard University | Neale B.M.,The Broad Institute of MIT and Harvard | Sklar P.,Mount Sinai School of Medicine
Current Opinion in Neurobiology | Year: 2015

Over the last few years, genetics research has made significant strides in identifying many risk factors for schizophrenia and bipolar disorder. These risk factors include inherited common single nucleotide polymorphisms, copy number variants, and rare single nucleotide variants, as well as rare de novo variants. For all variants, the common theme has been that of polygenicity, meaning that many small genetic risk factors influence risk in the population and that no gene or variant on its own has been shown to be fully deterministic of schizophrenia or bipolar. When taken together, biological themes that have emerged including the importance of synaptic function and calcium signaling. This has implications for our understanding of the biological underpinnings of these diseases. © 2014 Published by Elsevier Ltd.

Faith J.J.,Immunology Institute and Institute for Genomics and Multiscale Biology | Colombel J.-F.,Mount Sinai School of Medicine | Gordon J.I.,University of Washington
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

It has been 35 y since Carl Woese reported in PNAS how sequencing ribosomal RNA genes could be used to distinguish the three domains of life on Earth. During the past decade, 16S rDNA sequencing has enabled the now frequent enumeration of bacterial communities that populate the bodies of humans representing different ages, cultural traditions, and health states. A challenge going forward is to quantify the contributions of community members to wellness, disease risk, and disease pathogenesis. Here, we explore a theoretical framework for studies of the inheritance of bacterial strains and discuss the advantages and disadvantages of various study designs for assessing the contribution of strains to complex diseases.

Swidler M.A.,Mount Sinai School of Medicine
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2012

Elderly patients with advanced chronic kidney disease or who are on dialysis should be able to live as fully and comfortably as possible. Geriatric patients are most interested in outcomes that will optimize mental and physical function and limit suffering and pain. Nephrologists must help them answer the question: "How will my kidney problem affect the way I live now and in the future?" This means management must move beyond glomerular filtration rate-related targets and incorporate geriatric principles that focus on assessment of function, comorbidities, geriatric syndromes, and quality of life issues. Therapeutic decisions should be individualized and directed by patient goals of care, which must be explored and documented. Accomplishing this requires inclusion of the patient's family-support system in the shared decision-making process. There is no substitute for spending time listening to and understanding the patient and family agenda, providing timely medical and prognostic updates; discussing realistic scenarios to balance expectations; and planting the seeds of change as the quantity and quality of medical events, geriatric syndromes, and comorbidities accumulate. Synergy of the interdisciplinary renal team with geriatric and palliative medicine specialists provides the expertise to achieve these goals. This falls into the domain of geriatric renal palliative or supportive care (1) and is the subject of this practical review. © The Author 2012. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.

Goldenberg G.,Mount Sinai School of Medicine
Journal of Clinical and Aesthetic Dermatology | Year: 2013

Seborrheic dermatitis is a chronic, recurring, cutaneous condition that causes erythema and flaking, sometimes appearing as macules or plaques with dry white or moist oily scales. In adults, it commonly occurs in areas with high concentrations of sebaceous glands. The face and scalp are the most frequently affected areas, and involvement of multiple sites is common. Dandruff is regarded as a mild noninflammatory form of seborrheic dermatitis. There is a high incidence of seborrheic dermatitis among persons with human immunodeficiency virus infection or Parkinson's disease. The cause of seborrheic dermatitis is not well understood, but appears to be related to the composition of the sebaceous gland secretions, the proliferation of Malessezia yeasts, and the host immune response. Treatment options for nonscalp and scalp seborrheic dermatitis include topical agents and shampoos containing antifungal agents, anti-inflammatory agents, keratolytic agents, and calcineurin inhibitors. Because multiple body sites are usually involved, the physician should examine all commonly affected areas. Patients should be made aware that seborrheic dermatitis is a chronic condition that will probably recur even after successful treatment.

Ahern P.P.,University of Washington | Faith J.J.,University of Washington | Faith J.J.,Mount Sinai School of Medicine | Gordon J.I.,University of Washington
Immunity | Year: 2014

The gut microbiota codevelops with the immune system beginning at birth. Mining the microbiota for bacterial strains responsible for shaping the structure and dynamic operations of the innate and adaptive arms of the immune system represents a formidable combinatorial problem but one that needs to be overcome to advance mechanistic understanding of microbial community and immune system coregulation and to develop new diagnostic and therapeutic approaches that promote health. Here, we discuss a scalable, less biased approach for identifying effector strains in complex microbial communities that impact immune function. The approach begins by identifying uncultured human fecal microbiota samples that transmit immune phenotypes to germ-free mice. Clonally arrayed sequenced collections of bacterial strains are constructed from representative donor microbiota. If the collection transmits phenotypes, effector strains are identified by testing randomly generated subsets with overlapping membership in individually housed germ-free animals. Detailed mechanistic studies of effector strain-host interactions can then be performed. Determining which combinations of human gut bacterial strains shape immune function presents a huge challenge. Ahern etal. propose an approach that should facilitate discovery of microbe-based therapeutics, which involves culturing a person's gut community and efficiently mining it for strains that transmit immunomodulatory activities to germ-free mice. © 2014 Elsevier Inc.

Brennand K.J.,Mount Sinai School of Medicine | Landek-Salgado M.A.,University of Baltimore | Sawa A.,University of Baltimore
Biological Psychiatry | Year: 2014

Schizophrenia (SZ) is a devastating complex genetic mental condition that is heterogeneous in terms of clinical etiologies, symptoms, and outcomes. Despite decades of postmortem, neuroimaging, pharmacological, and genetic studies of patients, in addition to animal models, much of the biological mechanisms that underlie the pathology of SZ remain unknown. The ability to reprogram adult somatic cells into human induced pluripotent stem cells (hiPSCs) provides a new tool that supplies live human neurons for modeling complex genetic conditions such as SZ. The purpose of this review is to discuss the technical and clinical constraints currently limiting hiPSC-based studies. We posit that reducing the clinical heterogeneity of hiPSC-based studies, by selecting subjects with common clinical manifestations or rare genetic variants, will help our ability to draw meaningful insights from the necessarily small patient cohorts that can be studied at this time. © 2014 Society of Biological Psychiatry.

Pfleger C.M.,Mount Sinai School of Medicine
Science Signaling | Year: 2011

Signal transduction through Ras translates extracellular signals into biological responses, including cell proliferation, cell survival, growth, and differentiation. For these reasons, dysregulating Ras can have dramatic effects at the cellular and organismal levels. Germline mutations that increase Ras signaling disrupt development, whereas mutational activation of Ras in somatic cells can cause cancer. Thus, identifying additional mechanisms that positively or negatively regulate Ras could have profound implications for treating human diseases. New evidence identifies K-Ras monoubiquitination as a previously unknown means to potentiate Ras signaling.

Sudol M.,Weis Center for Research | Sudol M.,Mount Sinai School of Medicine
Oncogene | Year: 2011

Plasminogen activator (PLAU) is a serine protease that converts plasminogen to plasmin, a general protease, which promotes fibrinolysis and degradation of extracellular matrix. PLAU was reported in 1970s as one of the robustly induced enzymatic activities in Rous sarcoma virus (RSV)-transformed chicken cells. More than three decades later, with the completion of the sequencing of the chicken genome and the subsequent availability of Affymetrix GeneChip genome arrays, several laboratories have surveyed the transcriptional program affected by the RSV transformation. Interestingly, the PLAU gene was shown to be the most highly upregulated transcript. The induction of PLAU was a transformation-dependent process because viruses with deleted Src gene did not induce the transcription of the PLAU gene. Both Src and PLAU genes are associated with and contribute to the complex phenotype of human cancer. Although the activity and structures of these two enzymes are well characterized, the precise molecular function of these gene products in signaling networks is still not fully understood. Yet, the knowledge of their association with cancer is already translated into the clinical setting. Src kinase inhibitors are being tested in clinical trials of cancer therapy, and PLAU gene and its inhibitor have been included as biomarkers with strong prognostic and therapeutic predictive values. This vignette reviews the history of PLAU and Src discovery, and illuminates the complexity of their relationship, but also points to their emerging impact on public health. © 2011 Macmillan Publishers Limited All rights reserved.

Chess A.,Mount Sinai School of Medicine
Neuropsychopharmacology | Year: 2013

Monoallelic expression poses an intriguing problem in epigenetics because it requires the unequal treatment of two segments of DNA that are present in the same nucleus and which can have absolutely identical sequences. This review will consider different known types of monoallelic expression. For all monoallelically expressed genes, their respective allele-specific patterns of expression have the potential to affect brain function and dysfunction. © 2013 American College of Neuropsychopharmacology. All rights reserved.

O'Carroll D.,Mouse Biology Unit | Schaefer A.,Mount Sinai School of Medicine
Neuropsychopharmacology | Year: 2013

MicroRNAs (miRNAs) are small, noncoding RNAs that mediate posttranscriptional gene suppression in a sequence-specific manner. The ability of a single miRNA species to target multiple messenger RNAs (mRNAs) makes miRNAs exceptionally important regulators of various cellular functions. The regulatory capacity of miRNAs is increased further by the miRNA ability to suppress gene expression using multiple mechanisms that range from translational inhibition to mRNA degradation. The high miRNA diversity multiplied by the large number of individual miRNA targets generates a vast regulatory RNA network than enables flexible control of mRNA expression. The gene-regulatory capacity and diversity of miRNAs is particularly valuable in the brain, where functional specialization of neurons and persistent flow of information requires constant neuronal adaptation to environmental cues. In this review we will summarize the current knowledge about miRNA biogenesis and miRNA expression regulation with a focus on the role of miRNAs in the mammalian nervous system. © 2013 American College of Neuropsychopharmacology. All rights reserved.

Berin M.C.,Mount Sinai School of Medicine
Journal of Allergy and Clinical Immunology | Year: 2015

There is increasing recognition of the non-IgE-mediated gastrointestinal food allergy known as food protein-induced enterocolitis syndrome (FPIES), with several recent publications summarizing the clinical experience with FPIES in the United States, the United Kingdom, Europe, and Australia. Our understanding of the mechanisms linking food exposure to typical symptoms of vomiting, hypotension, and diarrhea has lagged far behind our understanding of the immune mechanisms of IgE-mediated food allergy. The goal of this overview is to summarize and critique the current state of knowledge of the immunology of FPIES and to identify major gaps in our knowledge that need to be addressed to make significant gains in developing therapies and prevention strategies for FPIES. © 2015 American Academy of Allergy, Asthma & Immunology.

Rosenson R.S.,Mount Sinai School of Medicine | Hurt-Camejo E.,Astrazeneca
European Heart Journal | Year: 2012

Certain members of the phospholipase A2 superfamily of enzymes have established causal involvement in atherosclerosis, thus at least two groups of this family of enzymes have been considered potential candidates for the prevention of cardiovascular events. Recently completed experimental animal studies, human biomarker data, vascular imaging studies, and genome-wide atherosclerosis studies provide the rationale for proceeding with clinical outcome trials directed at inhibition of secretory phospholipase A2 and lipoprotein-associated phospholipase A2. A clinical trial with the sPLA2 inhibitor varespladib methyl was recently terminated, while clinical trials with the Lp-PLA2 inhibitor darapladib are being conducted in coronary heart disease patients. This article reviews the available experimental animal and human trial evidence that serve as the basis for the development of these two classes of phospholipase A2 inhibitors. © 2012 The Author.

Kenny P.J.,Mount Sinai School of Medicine
Dialogues in Clinical Neuroscience | Year: 2014

Drug addiction is characterized by uncontrolled drug consumption and high rates of relapse to drug taking during periods of attempted abstinence. Addiction is now largely considered a disorder of experience-dependent neuroplasticity, driven by remodeling of synapses in reward and motivation relevant brain circuits in response to a history of prolonged drug intake. Alterations in gene expression play a central role in addiction-relevant neuroplasticity, but the mechanisms by which additive drugs remodel brain motivation circuits remains unclear. MicroRNAs (miRNAs) are a class of noncoding RNA that can regulate the expression of large numbers of protein-coding mRNA transcripts by binding to the 3' untranslated region (3' UTR) of target transcripts and blocking their translation into the encoded protein or triggering their destabilization and degradation. Emerging evidence has implicated miRNAs in regulating addiction-relevant neuroplasticity in the brain, and in controlling the motivational properties of cocaine and other drugs of abuse. Here, the role for miRNAs in regulating basic aspects of neuronal function is reviewed. The involvement of miRNAs in controlling the motivational properties of addictive drugs is also summarized. Finally, mechanisms by which miRNAs exert their actions on drug intake, when known, are considered. © 2014, AICH - Servier Research Group.

Nestler E.J.,Mount Sinai School of Medicine
Clinical Psychopharmacology and Neuroscience | Year: 2012

Regulation of gene expression is considered a plausible mechanism of drug addiction given the stability of behavioral abnormalities that define an addicted state. Numerous transcription factors, proteins that bind to regulatory regions of specific genes and thereby control levels of their expression, have been implicated in the addiction process over the past decade or two. Here we review the growing evidence for the role played by several prominent transcription factors, including a Fos family protein (ΔFosB), cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB), among several others, in drug addiction. As will be seen, each factor displays very different regulation by drugs of abuse within the brain's reward circuitry, and in turn mediates distinct aspects of the addiction phenotype. Current efforts are geared toward understanding the range of target genes through which these transcription factors produce their functional effects and the underlying molecular mechanisms involved. This work promises to reveal fundamentally new insight into the molecular basis of addiction, which will contribute to improved diagnostic tests and therapeutics for addictive disorders. Copyright © 2012, Korean College of Neuropsychopharmacology.

Akbarian S.,Mount Sinai School of Medicine
Dialogues in Clinical Neuroscience | Year: 2014

Schizophrenia is a major psychiatric disorder that lacks a unifying neuropathology, while currently available pharmacological treatments provide only limited benefits to many patients. This review will discuss how the field of neuroepigenetics could contribute to advancements of the existing knowledge on the neurobiology and treatment of psychosis. Genome-scale mapping of DNA methylation, histone modifications and variants, and chromosomal loopings for promoter-enhancer interactions and other epigenetic determinants of genome organization and function are likely to provide important clues about mechanisms contributing to dysregulated expression of synaptic and metabolic genes in schizophrenia brain, including the potential links to the underlying genetic risk architecture and environmental exposures. In addition, studies in animal models are providing a rapidly increasing list of chromatin- regulatory mechanisms with significant effects on cognition and complex behaviors, thereby pointing to the therapeutic potential of epigenetic drug targets in the nervous system. © 2014, AICH - Servier Research Group.

Leung D.W.,University of Washington | Basler C.F.,Mount Sinai School of Medicine | Amarasinghe G.K.,University of Washington
Trends in Microbiology | Year: 2012

Activation of innate immune signaling pathways through cytosolic RIG-I-like receptors (RLR) is a crucial response that is antagonized by many viruses. A variety of RNA-related pathogen-associated molecular patterns (PAMPS) have been identified and their role in RLR activation has been examined. Recent studies suggest that several virus-encoded components that antagonize RLR signaling interact with and inhibit the interferon (IFN)-α/β activation pathway using both RNA-dependent and RNA-independent mechanisms. The structural basis for these RLR inhibitory mechanisms, as well as the multifunctional nature of viral RLR antagonists, is reviewed in the context of recent biochemical and structural studies. © 2011 Elsevier Ltd.

Samatar A.A.,TheraMet Biosciences | Poulikakos P.I.,Mount Sinai School of Medicine
Nature Reviews Drug Discovery | Year: 2014

The RAS-RAF-MEK-ERK signalling pathway is hyperactivated in a high percentage of tumours, most frequently owing to activating mutations of the KRAS, NRAS and BRAF genes. Recently, the use of compounds targeting components of ERK signalling, such as RAF or MEK inhibitors, has led to substantial improvement in clinical outcome in metastatic melanoma and has shown promising clinical activity in additional tumour types. However, response rates are highly variable and the efficacy of these drugs is primarily limited by the development of resistance. Both intrinsic and acquired resistance to RAF and MEK inhibitors are frequently associated with the persistence of ERK signalling in the presence of the drug, implying the need for more innovative approaches to target the pathway. © 2014 Macmillan Publishers Limited. All rights reserved.

Schapira A.H.V.,University College London | Olanow C.W.,Mount Sinai School of Medicine | Greenamyre J.T.,University of Pittsburgh | Bezard E.,Institut Universitaire de France | Bezard E.,French National Center for Scientific Research
The Lancet | Year: 2014

Summary Several important advances have been made in our understanding of the pathways that lead to cell dysfunction and death in Parkinson's disease and Huntington's disease. These advances have been informed by both direct analysis of the post-mortem brain and by study of the biological consequences of the genetic causes of these diseases. Some of the pathways that have been implicated so far include mitochondrial dysfunction, oxidative stress, kinase pathways, calcium dysregulation, inflammation, protein handling, and prion-like processes. Intriguingly, these pathways seem to be important in the pathogenesis of both diseases and have led to the identification of molecular targets for candidate interventions designed to slow or reverse their course. We review some recent advances that underlie putative therapies for neuroprotection in Parkinson's disease and Huntington's disease, and potential targets that might be exploited in the future. Although we will need to overcome important hurdles, especially in terms of clinical trial design, we propose several target pathways that merit further study. In Parkinson's disease, these targets include agents that might improve mitochondrial function or increase degradation of defective mitochondria, kinase inhibitors, calcium channel blockers, and approaches that interfere with the misfolding, templating, and transmission of α-synuclein. In Huntington's disease, strategies might also be directed at mitochondrial bioenergetics and turnover, the prevention of protein dysregulation, disruption of the interaction between huntingtin and p53 or huntingtin-interacting protein 1 to reduce apoptosis, and interference with expression of mutant huntingtin at both the nucleic acid and protein levels. © 2014 Elsevier Ltd.

Silbiger J.J.,Mount Sinai School of Medicine
Journal of the American Society of Echocardiography | Year: 2013

Left ventricular (LV) false tendons are chordlike structures that traverse the LV cavity. They attach to the septum, to the papillary muscles, or to the free wall of the ventricle but not to the mitral valve. They are found in approximately half of human hearts examined at autopsy. Although it has been more than 100 years since their initial description, the functional significance of these structures remains largely unexplored. It has been suggested that they retard LV remodeling by tethering the walls to which they are attached, but there are few data to substantiate this. Some studies have suggested that false tendons reduce the severity of functional mitral regurgitation by stabilizing the position of the papillary muscles as the left ventricle enlarges. LV false tendons may also have deleterious effects and have been implicated in promoting membrane formation in discrete subaortic stenosis. This article reviews current understanding of the anatomy, echocardiographic characteristics, and pathophysiology of these structures. © 2013 by the American Society of Echocardiography.

Rose A.E.,New York University | Goldberg D.J.,Mount Sinai School of Medicine
Dermatologic Surgery | Year: 2013

Objective To evaluate the safety and efficacy of intradermal injection of abobotulinumtoxinA for the treatment of oily skin. Methods and Materials Twenty-five patients with oily skin were treated in the forehead region with intradermal injections of botulinum toxin. Baseline and post-treatment sebum production was measured using a sebometer. Photographs were taken. Patients were also asked to rate their satisfaction with the treatment in terms of improvement in their oily skin. Results Treatment with botulinum toxin resulted in significantly lower sebum production at 1 week and 1, 2, and 3 months after injection (p <.001, t-test). Twenty-one patients (91%) reported that they were satisfied (50-75% improvement) with intradermal botulinum toxin as a treatment for oily skin. [Correction added after online publication 7-Jan-2013: the number of satisfied patients has been updated] Conclusion Intradermal injection of botulinum toxin significantly reduced sebum production in the forehead region, with a high degree of patient satisfaction. Intradermal botulinum toxin may be an effective treatment to reduce sebum production in patients with oily skin. Larger, randomized, blinded, placebo-controlled studies are warranted. © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc.

Gorevic P.D.,Mount Sinai School of Medicine
Clinical and Developmental Immunology | Year: 2012

Low serum level of complement component 4 (C4) that occurs in mixed cryoglobulinemia (MC) may be due to in vivo or ex vivo activation of complement by the classical pathway. Potential activators include monoclonal IgM rheumatoid factor (RF), IgG antibodies, and the complexing of the two in the cold, perhaps modulated by the rheology and stoichiometry of cryocomplexes in specific microcirculations. There is also the potential for activation of complement by the alternative and lectin pathways, particularly in the setting of chronic infection and immune stimulation caused by hepatitis C virus (HCV). Engagement of C1q and interaction with specific cell surface receptors serve to localize immune complexes (ICs) to the sites of pathology, notably the cutaneous and glomerular microcirculations. Defective or saturated clearance of ICs by CR1and/or Fc receptors may explain persistence in the circulation. The phlogistic potential of cryoprecipitable ICs depends upon the cleavage of complement components to generate fragments with anaphylatoxin or leukocyte mobilizing activity, and the assembly of the membrane attack complex (C5b-9) on cell surfaces. A research agenda would include further characterization of the effector arm of complement activation in MC, and elucidation of activation mechanisms due to virus and viral antigens in HCV infection. © 2012 Peter D. Gorevic.

Smouha E.,Mount Sinai School of Medicine
NeuroRehabilitation | Year: 2013

OBJECTIVES: To present a framework for the diagnosis and treatment of inner ear disorders, with an emphasis on problems common to neuro-rehabilitation. INTRODUCTION: Disorders of the inner ear can cause hearing loss, tinnitus, vertigo and imbalance. Hearing loss can be conductive, sensorineural, or mixed; conductive hearing loss arises from the ear canal or middle ear, while sensorineural hearing loss arises from the inner ear or auditory nerve. Vertigo is a hallucination of motion, and is the cardinal symptom of vestibular system disease. It should be differentiated from other causes of dizziness: gait imbalance, disequilibrium, lightheadedness (pre-syncope). Vertigo can be caused by problems in the inner ear or central nervous system. METHODS: The diagnosis of inner ear disorders begins with a targeted physical examination. The initial work-up of hearing loss is made by audiometry, and vertigo by electronystagmography (ENG). Supplemental tests and MRI are obtained when clinically indicated. RESULTS: The clinical pattern and duration of vertigo are the most important clinical features in the diagnosis. Common inner ear causes of vertigo include: vestibular neuritis (sudden, unilateral vestibular loss), Meniere's disease (episodic vertigo), benign paroxysmal positional vertigo (BPPV), and bilateral vestibular loss. Common central nervous system causes of vertigo include: post concussion syndrome, cervical vertigo, vestibular migraine, cerebrovascular disease, and acoustic neuroma. CONCLUSION: A basic knowledge of vestibular physiology, coupled with a understanding of common vestibular syndromes, will lead to correct diagnosis and treatment in most cases. © 2013 - IOS Press and the authors. All rights reserved.

Das T.,Mount Sinai School of Medicine
Thyroid : official journal of the American Thyroid Association | Year: 2010

BACKGROUND: Multiple endocrine neoplasia type II (MEN2) is a rare but aggressive cancer for which no effective treatment currently exists. A Drosophila model was developed to identify novel genetic modifier loci of oncogenic RET, as well as to provide a whole animal system to rapidly identify compounds that suppressed RET-dependent MEN2. ZD6474 (Vandetanib), currently in phase III trials, suppressed tumorigenesis in MEN2 model flies, demonstrating for the first time the effectiveness of a Drosophila-based whole animal model for identifying therapeutically useful compounds. SUMMARY: Clinical data suggest that drug mono-therapy for MEN2 and other cancers typically yield only moderate benefits as patients develop drug resistance and suffer from drug-induced pathway feedback. Combinations of drugs that target different nodes of the oncogenic pathway are an effective way to prevent resistance as well as feedback. Identifying the optimal drug-dose combinations for therapy poses a significant challenge in existing mouse models. Fly models offer a means to quickly and effectively identify drug combinations that are well tolerated and potently suppress the MEN2 phenotype. This approach may also identify differences in therapeutic responses between the two subtypes of MEN2--MEN2A and MEN2B--providing additional therapeutic insights. CONCLUSIONS: Fly models have proven useful for identifying known drugs as well as novel compounds that, as single agents or in combinations, effectively suppress the MEN2 syndrome. These findings validate the use of fly models for both drug discovery as well as identification of useful drug combinations. In the future, rapid pairing of new genomic information with increasingly complex fly models will aid us in efforts to further tailor drug treatments toward personalized medicine.

Palucka K.,Baylor Research Institute | Palucka K.,Mount Sinai School of Medicine | Banchereau J.,Hoffmann-La Roche
Nature Reviews Cancer | Year: 2012

Cancer immunotherapy attempts to harness the power and specificity of the immune system to treat tumours. The molecular identification of human cancer-specific antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re-infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. Owing to their properties, dendritic cells (DCs) are often called 'nature's adjuvants' and thus have become the natural agents for antigen delivery. After four decades of research, it is now clear that DCs are at the centre of the immune system owing to their ability to control both immune tolerance and immunity. Thus, DCs are an essential target in efforts to generate therapeutic immunity against cancer. © 2012 Macmillan Publishers Limited. All rights reserved.

Ishikawa K.,Mount Sinai School of Medicine
Molecular Therapy | Year: 2014

Cardiac gene therapy has emerged as a promising option to treat advanced heart failure (HF). Advances in molecular biology and gene targeting approaches are offering further novel options for genetic manipulation of the cardiovascular system. The aim of this study was to improve cardiac function in chronic HF by overexpressing constitutively active inhibitor-1 (I-1c) using a novel cardiotropic vector generated by capsid reengineering of adeno-associated virus (BNP116). One month after a large anterior myocardial infarction, 20 Yorkshire pigs randomly received intracoronary injection of either high-dose BNP116.I-1c (1.0 × 1013 vector genomes (vg), n = 7), low-dose BNP116.I-1c (3.0 × 1012 vg, n = 7), or saline (n = 6). Compared to baseline, mean left ventricular ejection fraction increased by 5.7% in the high-dose group, and by 5.2% in the low-dose group, whereas it decreased by 7% in the saline group. Additionally, preload-recruitable stroke work obtained from pressure-volume analysis demonstrated significantly higher cardiac performance in the high-dose group. Likewise, other hemodynamic parameters, including stroke volume and contractility index indicated improved cardiac function after the I-1c gene transfer. Furthermore, BNP116 showed a favorable gene expression pattern for targeting the heart. In summary, I-1c overexpression using BNP116 improves cardiac function in a clinically relevant model of ischemic HF.Molecular Therapy (2014); doi:10.1038/mt.2014.127.

Boran A.D.W.,Mount Sinai School of Medicine
Biochemical Society Transactions | Year: 2012

Although the EGFR (epidermal growth factor receptor) was discovered over 30 years ago, its mechanism of activation is still the subject of intense study. There are many published studies on the mechanism of EGFR activation and regulation, including biochemical and biophysical analyses and crystallographic structures of EGFR in different activation states and conformations, mutated at various amino acids or bound to different pharmacological inhibitors. The cumulative biochemical, biophysical and structural data have led to a nearly complete account of the mechanism of activation of EGFR. The role of the JXM (juxtamembrane) domain in EGFR structure and activity has only recently begun to be elucidated through biochemical, biophysical and structural studies. In the present article, I review the studies that have highlighted the role of the JXM domain in EGFR activation. ©The Authors Journal compilation ©2012 Biochemical Society.

Mosoian A.,Mount Sinai School of Medicine
Future Medicinal Chemistry | Year: 2011

Prothymosin α (ProTα) is a 12.5-kDa, highly acidic protein widely distributed in different cell types expressed intracellularly and extracellularly. ProTα does not contain a secretion-signal sequence and is released by a nonclassical secretory pathway with a cargo protein. New findings on the extracellular function of ProTα have yielded exciting insights into the cytokine-like functions of this host protein that stimulates type I interferon via Toll-like receptor 4. Here, we discuss the intracellular function of ProTα, how new findings of cytokine-like activities of ProTα aid our understanding of mechanisms that direct ProTα functions, and the potential application of these new insights to the development of immunotherapies. © 2011 Future Science Ltd.

Ellis-Davies G.C.R.,Mount Sinai School of Medicine
ACS Chemical Neuroscience | Year: 2011

Microscopes using nonlinear excitation of chromophores with pulsed near-IR light can generate highly localized foci of molecules in the electronic singlet state that are concentrated in volumes of less than 1 fL. The three-dimensional confinement of excitation arises from the simultaneous absorption of two IR photons of approximately half the energy required for linear excitation. Two-photon microscopy is especially useful for two types of interrogation of neural processes. The first is uncaging of signaling molecules such as glutamate, because stimulation is so refined it can be used to mimic normal unitary synaptic levels. In addition, uncaging allows complete control of the timing and position of stimulation, so the two-photon light beam provides the chemical neuroscientist with an "optical conductor's baton", which can command synaptic activity at will. A second powerful feature of two-photon microscopy is that when used for fluorescence imaging it enables the visualization of cellular structure and function in living animals at depths far beyond that possible with normal confocal microscopes. In this review, I provide a survey of the many important applications of two-photon microscopy in these two fields of neuroscience and suggest some areas for future technical development. © 2011 American Chemical Society.