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Oct1 and OCA-B are selectively required for CD4 memory T cell function. - The Journal of experimental medicine
Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4(+) memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4(+) T cells. OCA-B is also required for the robust reexpression of multiple other genes including Ifng. ChIPseq identifies âˆ¼50 differentially expressed direct Oct1 and OCA-B targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2, Ifng, and Zbtb32. The findings pinpoint Oct1 and OCA-B as central mediators of CD4(+) T cell memory.Â© 2015 Shakya et al.
Identifying finite-time coherent sets from limited quantities of Lagrangian data. - Chaos (Woodbury, N.Y.)
A data-driven procedure for identifying the dominant transport barriers in a time-varying flow from limited quantities of Lagrangian data is presented. Our approach partitions state space into coherent pairs, which are sets of initial conditions chosen to minimize the number of trajectories that "leak" from one set to the other under the influence of a stochastic flow field during a pre-specified interval in time. In practice, this partition is computed by solving an optimization problem to obtain a pair of functions whose signs determine set membership. From prior experience with synthetic, "data rich" test problems, and conceptually related methods based on approximations of the Perron-Frobenius operator, we observe that the functions of interest typically appear to be smooth. We exploit this property by using the basis sets associated with spectral or "mesh-free" methods, and as a result, our approach has the potential to more accurately approximate these functions given a fixed amount of data. In practice, this could enable better approximations of the coherent pairs in problems with relatively limited quantities of Lagrangian data, which is usually the case with experimental geophysical data. We apply this method to three examples of increasing complexity: The first is the double gyre, the second is the Bickley Jet, and the third is data from numerically simulated drifters in the Sulu Sea.
Stabilization of Helical Macromolecular Phases by Confined Bending. - Physical review letters
By means of extensive replica-exchange simulations of generic coarse-grained models for helical polymers, we systematically investigate the structural transitions into all possible helical phases for flexible and semiflexible elastic polymers with self-interaction under the influence of torsion barriers. The competing interactions lead to a variety of conformational phases including disordered helical arrangements, single helices, and ordered, tertiary helix bundles. Most remarkably, we find that a bending restraint entails a clear separation and stabilization of the helical phases. This aids in understanding why semiflexible polymers such as double-stranded DNA tend to form pronounced helical structures and proteins often exhibit an abundance of helical structures, such as helix bundles, within their tertiary structure.
Social Marketing Risk-Framing Approaches for Dental Sealants in Rural American Indian Children. - Public health nursing (Boston, Mass.)
To compare three variants of a culturally relevant and theoretically based message to determine the most influential risk-framing approach for improving intention to place dental sealants for preschool children.A convenience sample of adult, American Indian participants (nÂ =Â 89) attending a community health fair were assigned to view a gain-framed, loss-framed, or mix-framed dental sealant message.We compared participants' scores on a 46-item survey to determine the relative effect of the frame assignment on seven indices of behavior change.The mean difference in participants' stage-of-change scores (xÂ =Â 1.17, nÂ =Â 89, SDÂ =Â 1.90) demonstrated a significant improvement for all groups after watching the dental sealant message t88 Â =Â 5.81, pÂ <Â .0001, 95% CI [0.77-1.57]. Self-efficacy was the only construct for which we detected a statistically significant difference as a function of frame assignment. Overall, the mix-framed message resulted in the highest scores. The gain-framed message was the least influential on four constructs. This finding is in contrast to findings that gain-framed oral health messages are most influential (Gallagher & Updegraff, 2012; O'Keefe & Jensen, 2007).Community advisory board members determined to use the mix-framed approach in an oral health social marketing campaign with a rural, American Indian audience.Â© 2015 Wiley Periodicals, Inc.
Effectiveness and cost-effectiveness of mindfulness-based cognitive therapy compared with maintenance antidepressant treatment in the prevention of depressive relapse or recurrence (PREVENT): a randomised controlled trial. - Lancet (London, England)
Individuals with a history of recurrent depression have a high risk of repeated depressive relapse or recurrence. Maintenance antidepressants for at least 2 years is the current recommended treatment, but many individuals are interested in alternatives to medication. Mindfulness-based cognitive therapy (MBCT) has been shown to reduce risk of relapse or recurrence compared with usual care, but has not yet been compared with maintenance antidepressant treatment in a definitive trial. We aimed to see whether MBCT with support to taper or discontinue antidepressant treatment (MBCT-TS) was superior to maintenance antidepressants for prevention of depressive relapse or recurrence over 24 months.In this single-blind, parallel, group randomised controlled trial (PREVENT), we recruited adult patients with three or more previous major depressive episodes and on a therapeutic dose of maintenance antidepressants, from primary care general practices in urban and rural settings in the UK. Participants were randomly assigned to either MBCT-TS or maintenance antidepressants (in a 1:1 ratio) with a computer-generated random number sequence with stratification by centre and symptomatic status. Participants were aware of treatment allocation and research assessors were masked to treatment allocation. The primary outcome was time to relapse or recurrence of depression, with patients followed up at five separate intervals during the 24-month study period. The primary analysis was based on the principle of intention to treat. The trial is registered with Current Controlled Trials, ISRCTN26666654.Between March 23, 2010, and Oct 21, 2011, we assessed 2188 participants for eligibility and recruited 424 patients from 95 general practices. 212 patients were randomly assigned to MBCT-TS and 212 to maintenance antidepressants. The time to relapse or recurrence of depression did not differ between MBCT-TS and maintenance antidepressants over 24 months (hazard ratio 0Â·89, 95% CI 0Â·67-1Â·18; p=0Â·43), nor did the number of serious adverse events. Five adverse events were reported, including two deaths, in each of the MBCT-TS and maintenance antidepressants groups. No adverse events were attributable to the interventions or the trial.We found no evidence that MBCT-TS is superior to maintenance antidepressant treatment for the prevention of depressive relapse in individuals at risk for depressive relapse or recurrence. Both treatments were associated with enduring positive outcomes in terms of relapse or recurrence, residual depressive symptoms, and quality of life.National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme, and NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula.Copyright Â© 2015 Kuyken et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.
Sodium nitrite potentiates renal oxidative stress and injury in hemoglobin exposed guinea pigs. - Toxicology
Methemoglobin-forming drugs, such as sodium nitrite (NaNO2), may exacerbate oxidative toxicity under certain chronic or acute hemolytic settings. In this study, we evaluated markers of renal oxidative stress and injury in guinea pigs exposed to extracellular hemoglobin (Hb) followed by NaNO2 at doses sufficient to simulate clinically relevant acute methemoglobinemia. NaNO2 induced rapid and extensive oxidation of plasma Hb in this model. This was accompanied by increased renal expression of the oxidative response effectors nuclear factor erythroid 2-derived-factor 2 (Nrf-2) and heme oxygenase-1 (HO-1), elevated non-heme iron deposition, lipid peroxidation, interstitial inflammatory cell activation, increased expression of tubular injury markers kidney injury-1 marker (KIM-1) and liver-fatty acid binding protein (L-FABP), podocyte injury, and cell death. Importantly, these indicators of renal oxidative stress and injury were minimal or absent following infusion of Hb or NaNO2 alone. Together, these results suggest that the exposure to NaNO2 in settings associated with increased extracellular Hb may potentiate acute renal toxicity via processes that are independent of NaNO2 induced erythrocyte methemoglobinemia.Published by Elsevier Ireland Ltd.
Equivalence in colonoscopy results between gastroenterologists and general surgery residents following an endoscopy simulation curriculum. - Journal of surgical education
In 2011, multiple gastroenterology societies published a position statement expressing concern over the American Board of Surgery guidelines regarding endoscopy education. Their position asserted that the American Board of Surgery's guidelines were inadequate to produce competency and the requirements should be similar to those adopted by the American Society for Gastrointestinal Endoscopy. This assertion failed to take into account the increasing use of simulation in surgical and endoscopic education.Surgery residents were required to complete a self-paced endoscopy simulation curriculum. A retrospective review of all patients undergoing colonoscopy at a single institution over a 6-month period was then undertaken. Specifically, the quality measures associated with colonoscopy including the cecal intubation rate and the adenoma detection rate (ADR) were compared between those colonoscopies that were performed by faculty gastroenterologists and general surgery residents.In total, 818 colonoscopies were performed during the study period-598 were performed by the gastroenterology service (GI) and 220 were performed by general surgery residents on the surgery service (GS). Baseline characteristics of the groups were similar. Cecal intubation rates for GI and GS were 98.4% and 93.5% respectively. ADRs were similar between the groups (GI-29.8% in men and 15.3% in women; GS-26.8% in men and 18.7% in women). GI was found to perform biopsies at a higher rate than GS: 0.92 vs 0.62 (not significant, NS). GS had a higher rate of adenomas biopsied: 0.42 vs 0.32 (NS).Following endoscopy simulation training, general surgery residents, under the supervision of surgical staff, are capable of achieving quality measures equivalent to those of staff gastroenterologists at a single institution. The ADRs and cecal intubation rates seen in this study are consistent with those previously identified in the literature.Published by Elsevier Inc.
Evaluation of head orientation and neck muscle EMG signals as three-dimensional command sources. - Journal of neuroengineering and rehabilitation
High cervical spinal cord injuries result in significant functional impairments and affect both the injured individual as well as their family and care givers. To help restore function to these individuals, multiple user interfaces are available to enable command and control of external devices. However, little work has been performed to assess the 3D performance of these interfaces.We investigated the performance of eight human subjects in using three user interfaces (head orientation, EMG from muscles of the head and neck, and a three-axis joystick) to command the endpoint position of a multi-axis robotic arm within a 3D workspace to perform a novel out-to-center 3D Fitts' Law style task. Two of these interfaces (head orientation, EMG from muscles of the head and neck) could realistically be used by individuals with high tetraplegia, while the joystick was evaluated as a standard of high performance. Performance metrics were developed to assess the aspects of command source performance. Data were analyzed using a mixed model design ANOVA. Fixed effects were investigated between sources as well as for interactions between index of difficulty, command source, and the five performance measures used. A 5% threshold for statistical significance was used in the analysis.The performances of the three command interfaces were rather similar, though significant differences between command sources were observed. The apparent similarity is due in large part to the sequential command strategy (i.e., one dimension of movement at a time) typically adopted by the subjects. EMG-based commands were particularly pulsatile in nature. The use of sequential commands had a significant impact on each command source's performance for movements in two or three dimensions.While the sequential nature of the commands produced by the user did not fit with Fitts' Law, the other performance measures used were able to illustrate the properties of each command source. Though pulsatile, given the overall similarity between head orientation and the EMG interface, (which also could be readily included in a future implanted neuroprosthesis) the use of EMG as a command source for controlling an arm in 3D space is an attractive choice.
Development of a prototype over-actuated biomimetic prosthetic hand. - PloS one
The loss of a hand can greatly affect quality of life. A prosthetic device that can mimic normal hand function is very important to physical and mental recuperation after hand amputation, but the currently available prosthetics do not fully meet the needs of the amputee community. Most prosthetic hands are not dexterous enough to grasp a variety of shaped objects, and those that are tend to be heavy, leading to discomfort while wearing the device. In order to attempt to better simulate human hand function, a dexterous hand was developed that uses an over-actuated mechanism to form grasp shape using intrinsic joint mounted motors in addition to a finger tendon to produce large flexion force for a tight grip. This novel actuation method allows the hand to use small actuators for grip shape formation, and the tendon to produce high grip strength. The hand was capable of producing fingertip flexion force suitable for most activities of daily living. In addition, it was able to produce a range of grasp shapes with natural, independent finger motion, and appearance similar to that of a human hand. The hand also had a mass distribution more similar to a natural forearm and hand compared to contemporary prosthetics due to the more proximal location of the heavier components of the system. This paper describes the design of the hand and controller, as well as the test results.
Drosophila muller f elements maintain a distinct set of genomic properties over 40 million years of evolution. - G3 (Bethesda, Md.)
The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25-50%) than euchromatic reference regions (3-11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11-27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4-3.6 vs. 8.4-8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.Copyright Â© 2015 Leung et al.
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