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Childhood Adversities and Adult Headache in Poland and Germany. - PloS one
Various childhood adversities have been found to be associated with chronic pain in adulthood. However, associations were moderate in most studies, i.e. odds ratios (OR) were between one and two.An internet survey was performed in 508 Polish and 500 German subjects. A total of 19 childhood adversities were selected and their associations with headaches explored. Age, gender and country were included as potential confounders, as well as their two-way interaction with the risk factors.Two strong risk factors were identified. (1) A combined score for physical and emotional neglect showed an odds ratio (OR) of 2.78 (p < .002) to the frequency of headache in adulthood as a main effect. (2) Father having had chronic pain showed an OR of 4.36 (p < .001) with headache in adulthood for women, but not for men (OR = 0.86, p < .556). The majority of the examined childhood adversities were not associated with adult headache, neither when tested individually nor as a sum score.This study confirms results from previous ones that childhood adversities may play a role in the development of adult headache, but it is a rather minor one. Contrary to other studies, neglect turned out to be one of the strongest predictors.
Ubiquitin-specific protease 20 Regulates the Reciprocal Functions of Beta-arrestin2 in Toll-like Receptor 4-promoted NFkappaB Activation. - The Journal of biological chemistry
Toll-like receptor 4 (TLR4) promotes vascular inflammatory disorders such as neointimal hyperplasia and atherosclerosis. TLR4 triggers NFÎºB signaling through the ubiquitin ligase TRAF6 (Tumor Necrosis Factor Receptor-associated factor 6). TRAF6 activity can be impeded by deubiquitinating enzymes like ubiquitin-specific protease 20 (USP20), which can reverse TRAF6 auto-ubiquitination, and by association with the multi-functional adaptor protein Î²-arrestin2. Whereas Î²-arrestin2 effects on TRAF6 suggest an anti-inflammatory role, physiologic Î²-arrestin2 promotes inflammation in atherosclerosis and neointimal hyperplasia. We hypothesized that anti- and pro-inflammatory dimensions of Î²-arrestin2 activity could be dictated by Î²-arrestin2's ubiquitination status, which has been linked with its ability to scaffold and localize activated ERK1/2 to signalosomes. With purified proteins and in intact cells, our protein interaction studies showed that TRAF6/USP20 association and subsequent USP20-mediated TRAF6 deubiquitination were Î²-arrestin2-dependent. Generation of transgenic mice with smooth muscle cell (SMC)-specific expression of either USP20 or its catalytically inactive mutant revealed anti-inflammatory effects of USP20 in vivo and in vitro. Carotid endothelial denudation showed that antagonizing SMC USP20 activity increased NFÎºB activation and neointimal hyperplasia. We found that Î²-arrestin2 ubiquitination was promoted by TLR4 and reversed by USP20. The association of USP20 with Î²-arrestin2 was augmented when Î²-arrestin2 ubiquitination was prevented, and reduced when Î²-arrestin2 ubiquitination was rendered constitutive. Constitutive Î²-arrestin2 ubiquitination also augmented NFÎºB activation. We infer that pro- and anti-inflammatory activities of Î²-arrestin2 are determined by Î²-arrestin2 ubiquitination, and that changes in USP20 expression and/or activity can therefore regulate inflammatory responses, at least in part, by defining the ubiquitination status of Î²-arrestin2.Copyright Â© 2016, The American Society for Biochemistry and Molecular Biology.
Plug-and-Display: decoration of Virus-Like Particles via isopeptide bonds for modular immunization. - Scientific reports
Virus-like particles (VLPs) are non-infectious self-assembling nanoparticles, useful in medicine and nanotechnology. Their repetitive molecularly-defined architecture is attractive for engineering multivalency, notably for vaccination. However, decorating VLPs with target-antigens by genetic fusion or chemical modification is time-consuming and often leads to capsid misassembly or antigen misfolding, hindering generation of protective immunity. Here we establish a platform for irreversibly decorating VLPs simply by mixing with protein antigen. SpyCatcher is a genetically-encoded protein designed to spontaneously form a covalent bond to its peptide-partner SpyTag. We expressed in E. coli VLPs from the bacteriophage AP205 genetically fused to SpyCatcher. We demonstrated quantitative covalent coupling to SpyCatcher-VLPs after mixing with SpyTag-linked to malaria antigens, including CIDR and Pfs25. In addition, we showed coupling to the VLPs for peptides relevant to cancer from epidermal growth factor receptor and telomerase. Injecting SpyCatcher-VLPs decorated with a malarial antigen efficiently induced antibody responses after only a single immunization. This simple, efficient and modular decoration of nanoparticles should accelerate vaccine development, as well as other applications of nanoparticle devices.
Enhancing immunogenicity and transmission-blocking activity of malaria vaccines by fusing Pfs25 to IMX313 multimerization technology. - Scientific reports
Transmission-blocking vaccines (TBV) target the sexual-stages of the malaria parasite in the mosquito midgut and are widely considered to be an essential tool for malaria elimination. High-titer functional antibodies are required against target antigens to achieve effective transmission-blocking activity. We have fused Pfs25, the leading malaria TBV candidate antigen to IMX313, a molecular adjuvant and expressed it both in ChAd63 and MVA viral vectors and as a secreted protein-nanoparticle. Pfs25-IMX313 expressed from viral vectors or as a protein-nanoparticle is significantly more immunogenic and gives significantly better transmission-reducing activity than monomeric Pfs25. In addition, we demonstrate that the Pfs25-IMX313 protein-nanoparticle leads to a qualitatively improved antibody response in comparison to soluble Pfs25, as well as to significantly higher germinal centre (GC) responses. These results demonstrate that antigen multimerization using IMX313 is a very promising strategy to enhance antibody responses against Pfs25, and that Pfs25-IMX313 is a highly promising TBV candidate vaccine.
Mobile Behavioral Sensing for Outpatients and Inpatients With Schizophrenia. - Psychiatric services (Washington, D.C.)
This study examined the feasibility, acceptability, and utility of behavioral sensing among individuals with schizophrenia.Nine outpatients and 11 inpatients carried smartphones for two- or one-week periods, respectively. Device-embedded sensors (accelerometers, microphone, global positioning system, WiFi, and Bluetooth) collected behavioral data and ascertained the patients' location, activity, and exposure to human speech as they went about their day. Participants rated this approach by completing usability and acceptability measures.Sensing successfully captured individuals' activity, time spent proximal to human speech, and time spent in various locations. Participants felt comfortable using the sensing system (95%), and most were interested in receiving feedback (65%) and suggestions (65%). Approximately 20% reported that sensing made them upset. One-third of inpatients were concerned about their privacy, but no outpatients expressed this concern.Mobile behavioral sensing was a feasible, acceptable, and informative approach for data collection among outpatients and inpatients with schizophrenia.
Atypical sympathetic arousal in children with autism spectrum disorder and its association with anxiety symptomatology. - Molecular autism
Autism spectrum disorder (ASD) has been associated with autonomic atypicalities, although the nature of these differences remains largely unknown. Moreover, existing literature suggests large variability in autonomic function in ASD, motivating the need to examine the existence of subgroups that exhibit more homogeneous autonomic features.Electrodermal activity (EDA), a non-invasive physiological indicator of autonomic activity, was measured in typically developing children (nâ€‰=â€‰33) and those with ASD (nâ€‰=â€‰38) as participants performed tasks that elicit anxiety, attention, response inhibition, and social cognition processes. The ASD group was divided into low- (nâ€‰=â€‰18) and high-anxiety (nâ€‰=â€‰20) participants, and the groups were compared to mean EDA level and electrodermal reactions frequency (EDR).The ASD group had a significantly blunted mean EDA response to the anxiety tasks (pâ€‰<â€‰0.004). The EDR response to all tasks, except response inhibition, was also blunted in the ASD group (pâ€‰<â€‰0.04). For this group, EDR frequency during the anxiety and social cognition tasks was negatively correlated with behavioral scores in the domains that were probed by each task (pâ€‰<â€‰0.002). The high-anxiety ASD group showed significantly decreased mean EDA compared to both the low-anxiety ASD group (pâ€‰=â€‰0.02) and the typically developing control group (pâ€‰=â€‰0.04). The high-anxiety ASD group also had significantly more severe symptoms than the low-anxiety ASD group on domains related to anxiety, attention, rule breaking, aggression, obsessions and compulsions, and depression.Our results suggest atypical autonomic function in children with ASD, specifically with respect to sympathetic activity. Moreover, anxiety symptomatology defined subgroups with distinct physiological and behavioral profiles. Overall, the results add to the body of literature supporting autonomic dysfunction in ASD and highlight the role of anxiety and autonomic features in explaining the variability in the autism spectrum.
Evading anti-angiogenic therapy: resistance to anti-angiogenic therapy in solid tumors. - American journal of translational research
Vascular endothelial growth factor (VEGF) dependent tumor angiogenesis is an essential step for the initiation and promotion of tumor progression. The hypothesis that VEGF-driven tumor angiogenesis is necessary and sufficient for metastatic progression of the tumor, has been the major premise of the use of anti-VEGF therapy for decades. While the success of anti-VEGF therapy in solid tumors has led to the success of knowledge-based-therapies over the past several years, failures of this therapeutic approach due to the development of inherent/acquired resistance has led to the increased understanding of VEGF-independent angiogenesis. Today, tumor-angiogenesis is not a synonymous term to VEGF-dependent function. The extensive study of VEGF-independent angiogenesis has revealed several key factors responsible for this phenomenon including the role of myeloid cells, and the contribution of entirely new phenomenon like vascular mimicry. In this review, we will present the cellular and molecular factors related to the development of anti-angiogenic resistance following anti-VEGF therapy in different solid tumors.
The Social ABCs caregiver-mediated intervention for toddlers with autism spectrum disorder: Feasibility, acceptability, and evidence of promise from a multisite study. - Autism research : official journal of the International Society for Autism Research
The Social ABCs is a parent-mediated intervention for toddlers with suspected or confirmed autism spectrum disorder (ASD). We undertook a multi-site pilot study to evaluate feasibility and acceptability, and to identify trends in child and parent behavior to inform future research using a larger sample and a rigorous research design. The program involved 12 weeks of parent coaching, followed by 12 weeks' implementation, and 3-month follow-up assessment for 20 parent-toddler dyads (age range: 12-32 months). Parents successfully learned the techniques and rated the intervention as highly acceptable. Paired samples t-tests revealed significant gains in children's functional communication (responsivity, initiations), and language gains (age-equivalents on standardized measures) commensurate with typical developmental rates. Significant increases in shared smiling and social orienting also emerged, but were attenuated at follow-up. Parents' fidelity was positively associated with child responsivity. Training parents as mediators is a feasible and highly acceptable approach that provides a potentially cost-effective opportunity for intensive intervention at a very young age at the first signs of ASD risk. Child and parent gains in several key variables demonstrate the promise of this intervention. Autism Res 2015. Â© 2015 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.Â© 2015 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.
Stability and change in autism spectrum disorder diagnosis from age 3 to middle childhood in a high-risk sibling cohort. - Autism : the international journal of research and practice
Considerable evidence on autism spectrum disorder emergence comes from longitudinal high-risk samples (i.e. younger siblings of children with autism spectrum disorder). Diagnostic stability to age 3 is very good when diagnosed as early as 18-24â€‰months, but sensitivity is weaker, and relatively little is known beyond toddlerhood. We examined stability and change in blinded, clinical best-estimate diagnosis from age 3 to middle childhood (mean ageâ€‰=â€‰9.5â€‰years) in 67 high-risk siblings enrolled in infancy. Good agreement emerged for clinical best-estimate diagnoses (89.6% overall; kappaâ€‰=â€‰0.76, pâ€‰<â€‰0.001, 95% confidence intervalâ€‰=â€‰0.59-0.93). At age 3, 18 cases (26.9%) were classified with "autism spectrum disorder": 17 retained their autism spectrum disorder diagnosis (94.4%; 13 boys, 4 girls) and 1 no longer met autism spectrum disorder criteria at follow-up. Among "non-autism spectrum disorder" cases at age 3, 43/49 remained non-autism spectrum disorder at follow-up (87.8%; 22 boys, 21 girls) and 6/49 met lower autism symptomatology criteria ("Later-Diagnosed"; 3 boys, 3 girls). Later-diagnosed cases had significantly lower autism spectrum disorder symptomatology and higher receptive language at age 3 and trends toward lower autism symptoms and higher cognitive abilities at follow-up. Emerging developmental concerns were noted in all later-diagnosed cases, by age 3 or 5. High-risk children need to be followed up into middle childhood, particularly when showing differences in autism-related domains.Â© The Author(s) 2015.
The role of ADME pharmacogenomics in early clinical trials: perspective of the Industry Pharmacogenomics Working Group (I-PWG). - Pharmacogenomics
Genetic polymorphisms in metabolizing enzymes and drug transporters have been shown to significantly impact the exposure of drugs having a high dependence on a single mechanism for their absorption, distribution or clearance, such that genotyping can lead to actionable steps in disease treatment. Recently, global regulatory agencies have provided guidance for assessment of pharmacogenomics during early stages of drug development, both in the form of formal guidance and perspectives published in scientific journals. The Industry Pharmacogenomics Working Group (I-PWG), conducted a survey among member companies to assess the practices relating to absorption, distribution, metabolism, excretion pharmacogenomics) during early stages of clinical development, to assess the impact of the recent Regulatory Guidance issued by the US FDA and EMA on Industry practices.
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