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The past, present and future of African dust. - Nature
African dust emission and transport exhibits variability on diurnal to decadal timescales and is known to influence processes such as Amazon productivity, Atlantic climate modes, regional atmospheric composition and radiative balance and precipitation in the Sahel. To elucidate the role of African dust in the climate system, it is necessary to understand the factors governing its emission and transport. However, African dust is correlated with seemingly disparate atmospheric phenomena, including the El NiÃ±o/Southern Oscillation, the North Atlantic Oscillation, the meridional position of the intertropical convergence zone, Sahelian rainfall and surface temperatures over the Sahara Desert, all of which obfuscate the connection between dust and climate. Here we show that the surface wind field responsible for most of the variability in North African dust emission reflects the topography of the Sahara, owing to orographic acceleration of the surface flow. As such, the correlations between dust and various climate phenomena probably arise from the projection of the winds associated with these phenomena onto an orographically controlled pattern of wind variability. A 161-year time series of dust from 1851 to 2011, created by projecting this wind field pattern onto surface winds from a historical reanalysis, suggests that the highest concentrations of dust occurred from the 1910s to the 1940s and the 1970s to the 1980s, and that there have been three periods of persistent anomalously low dust concentrations--in the 1860s, 1950s and 2000s. Projections of the wind pattern onto climate models give a statistically significant downward trend in African dust emission and transport as greenhouse gas concentrations increase over the twenty-first century, potentially associated with a slow-down of the tropical circulation. Such a dust feedback, which is not represented in climate models, may be of benefit to human and ecosystem health in West Africa via improved air quality and increased rainfall. This feedback may also enhance warming of the tropical North Atlantic, which would make the basin more suitable for hurricane formation and growth.
Label-free proteomic methodology for the analysis of human kidney stone matrix composition. - Proteome science
Kidney stone matrix protein composition is an important yet poorly understood aspect of nephrolithiasis. We hypothesized that this proteome is considerably more complex than previous reports have indicated and that comprehensive proteomic profiling of the kidney stone matrix may demonstrate relevant constitutive differences between stones. We have analyzed the matrices of two unique human calcium oxalate stones (CaOx-Ia and CaOx-Id) using a simple but effective chaotropic reducing solution for extraction/solubilization combined with label-free quantitative mass spectrometry to generate a comprehensive profile of their proteomes, including physicochemical and bioinformatic analysis.`.We identified and quantified 1,059 unique protein database entries in the two human kidney stone samples, revealing a more complex proteome than previously reported. Protein composition reflects a common range of proteins related to immune response, inflammation, injury, and tissue repair, along with a more diverse set of proteins unique to each stone.The use of a simple chaotropic reducing solution and moderate sonication for extraction and solubilization of kidney stone powders combined with label-free quantitative mass spectrometry has yielded the most comprehensive list to date of the proteins that constitute the human kidney stone proteome.
Duration of Androgen Deprivation Therapy for High-Risk Prostate Cancer: Application of Randomized Trial Data in a Tertiary Referral Cancer Center. - Clinical genitourinary cancer
We evaluated the incidence and predictors of the use of long-term (2-3 years) versus shorter term androgen deprivation therapy (ADT) in radiation-managed men with high-risk prostate cancer.We identified 302 patients from the Dana-Farber Cancer Institute patient registry who had been diagnosed with high-risk prostate cancer (T3a or prostate-specific antigen [PSA] > 20 ng/mL or Gleason score 8-10) from 1993 to 2015. We assessed the intended duration of ADT and used multivariable Cox regression to evaluate the predictors of receiving a shorter course of ADT than recommended by the guidelines (< 2 years).The course of ADT intended by physicians increased after the 2008/2009 publication of trials showing the superiority of long-term versus short-term ADT, with 43.5% intendingÂ â‰¥ 2 years before versus 61.4% after (PÂ = .014). Starting in 2010, 49.4% of patients actually receivedÂ < 2 years of ADT. The most common reasons for receipt of shorter course ADT were intolerance of ADT side effects, patient comorbidity/age, the presence of T3a on magnetic resonance imaging only as the sole high-risk feature, or participation in a clinical trial. Moderate to severe comorbidity assessed using the Adult Comorbidity Evaluation-27 (adjusted hazard ratio [AHR]Â = 2.94), Gleason scoreÂ < 8 (AHRÂ = 5.66), and PSAÂ < 20 ng/mL (AHRÂ = 4.19) all predicted for receipt of shorter course ADT (PÂ < .05 for all).In a tertiary-care setting, the rates of long-course ADT for high-risk disease have increased since the 2008/2009 trials supporting its use. However, approximately one half of patients continued to receive shorter course ADT, often because of intolerance of side effects, underlying comorbidity, or physician judgment about the aggressiveness of the disease.Copyright Â© 2015 Elsevier Inc. All rights reserved.
A MYC-Driven Change in Mitochondrial Dynamics Limits YAP/TAZ Function in Mammary Epithelial Cells and Breast Cancer. - Cancer cell
In several developmental lineages, an increase in MYC expression drives the transition from quiescent stem cells to transit-amplifying cells. We show that MYC activates a stereotypic transcriptional program of genes involved in cell growth in mammary epithelial cells. This change in gene expression indirectly inhibits the YAP/TAZ co-activators, which maintain the clonogenic potential of these cells. We identify a phospholipase of the mitochondrial outer membrane, PLD6, as the mediator of MYC activity. MYC-dependent growth strains cellular energy resources and stimulates AMP-activated kinase (AMPK). PLD6 alters mitochondrial fusion and fission dynamics downstream of MYC. This change activates AMPK, which in turn inhibits YAP/TAZ. Mouse models and human pathological data show that MYC enhances AMPK and suppresses YAP/TAZ activity in mammary tumors.Copyright Â© 2015 Elsevier Inc. All rights reserved.
On the decadal scale correlation between African dust and Sahel rainfall: The role of Saharan heat low-forced winds. - Science advances
A large body of work has shown that year-to-year variations in North African dust emission are inversely proportional to previous-year monsoon rainfall in the Sahel, implying that African dust emission is highly sensitive to vegetation changes in this narrow transitional zone. However, such a theory is not supported by field observations or modeling studies, as both suggest that interannual variability in dust is due to changes in wind speeds over the major emitting regions, which lie to the north of the Sahelian vegetated zone. We reconcile this contradiction showing that interannual variability in Sahelian rainfall and surface wind speeds over the Sahara are the result of changes in lower tropospheric air temperatures over the Saharan heat low (SHL). As the SHL warms, an anomalous tropospheric circulation develops that reduces wind speeds over the Sahara and displaces the monsoonal rainfall northward, thus simultaneously increasing Sahelian rainfall and reducing dust emission from the major dust "hotspots" in the Sahara. Our results shed light on why climate models are, to date, unable to reproduce observed historical variability in dust emission and transport from this region.
p53 Restoration in Induction and Maintenance of Senescence: Differential Effects in Premalignant and Malignant Tumor Cells. - Molecular and cellular biology
The restoration of p53 has been suggested as a therapeutic approach in tumors. However, the timing of p53 restoration in relation to its efficacy during tumor progression still is unclear. We now show that the restoration of p53 in murine premalignant proliferating pineal lesions resulted in cellular senescence, while p53 restoration in invasive pineal tumors did not. The effectiveness of p53 restoration was not dependent on p19(Arf) expression but showed an inverse correlation with Mdm2 expression. In tumor cells, p53 restoration became effective when paired with either DNA-damaging therapy or with nutlin, an inhibitor of p53-Mdm2 interaction. Interestingly, the inactivation of p53 after senescence resulted in reentry into the cell cycle and rapid tumor progression. The evaluation of a panel of human supratentorial primitive neuroectodermal tumors (sPNET) showed low activity of the p53 pathway. Together, these data suggest that the restoration of the p53 pathway has different effects in premalignant versus invasive pineal tumors, and that p53 activation needs to be continually sustained, as reversion from senescence occurs rapidly with aggressive tumor growth when p53 is lost again. Finally, p53 restoration approaches may be worth exploring in sPNET, where the p53 gene is intact but the pathway is inactive in the majority of examined tumors.Copyright Â© 2016 Harajly et al.
Intraluminal measurement of papillary duct urine pH, in vivo: a pilot study in the swine kidney. - Urolithiasis
We describe the in vivo use of an optic-chemo microsensor to measure intraluminal papillary duct urine pH in a large mammal. Fiber-optic pH microsensors have a tip diameter of 140-Âµm that allows insertion into papillary Bellini ducts to measure tubule urine proton concentration. Anesthetized adult pigs underwent percutaneous nephrolithotomy to access the lower pole of the urinary collecting system. A flexible nephroscope was advanced towards an upper pole papilla with the fiber-optic microsensor contained within the working channel. The microsensor was then carefully inserted into Bellini ducts to measure tubule urine pH in real time. We successfully recorded tubule urine pH values in five papillary ducts from three pigs (1 farm pig and 2 metabolic syndrome Ossabaw pigs). Our results demonstrate that optical microsensor technology can be used to measure intraluminal urine pH in real time in a living large mammal. This opens the possibility for application of this optical pH sensing technology in nephrolithiasis.
Percutaneous Renal Access: Surgical Factors Involved in the Acute Reduction of Renal Function. - Journal of endourology / Endourological Society
Studies in patients and experimental animals have shown that percutaneous nephrolithotomy (PCNL) can acutely impair glomerular filtration and renal perfusion, but the factors contributing to this decline in renal function are unknown. The present study assessed the contribution of needle puncture of the kidney vs dilation of the needle tract to the acute decline in renal hemodynamic and tubular transport function associated with PCNL surgery.Acute experiments were performed in three groups of anesthetized adult farm pigs: sham-percutaneous access (PERC), that is, no surgical procedure (nâ€‰=â€‰7); a single-needle stick to access the renal collecting system (nâ€‰=â€‰8); expansion of the single-needle access tract with a 30F NephroMax balloon dilator and insertion of a nephrostomy sheath (nâ€‰=â€‰10). The glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and renal extraction of para-amino hippurate (EPAH, estimates tubular organic anion transporter [OAT] activity) were assessed before and 1 to 4.5 hours after sham-PERC or PERC surgical procedures.Overall, GFR responses were similar in all three groups. Sham-treated PERC pigs showed no significant change in ERPF over the experimental observation period, whereas a single-needle stick to access the renal collecting system resulted in renal vasoconstriction (âˆ¼30% reduction in ERPF, pâ€‰<â€‰0.05). Dilation of the single-needle access tract to create the nephrostomy did not lead to a further decline in ERPF. PERC surgical procedure-mediated renal vasoconstriction was most evident at the 1-hour posttreatment time point. A reduction in EPAH was only observed in pig kidneys with a nephrostomy.Needle puncture of the kidney for percutaneous access to the renal collecting system is the major driving force for the renal vasoconstriction observed after PCNL surgery, whereas creation of the nephrostomy appears to be largely responsible for decreasing tubular OAT activity.
A Proposed Grading System to Standardize the Description of Renal Papillary Appearance at the Time of Endoscopy in Patients with Nephrolithiasis. - Journal of endourology / Endourological Society
The appearance of the renal papillae in patients with nephrolithiasis can be quite variable and can range from entirely healthy to markedly diseased. The implications of such findings remain unknown. One potential reason is the lack of a standardized system to describe such features. We propose a novel grading scale to describe papillary appearance at the time of renal endoscopy.Comprehensive endoscopic renal assessment and mapping were performed on more than 300 patients with nephrolithiasis. Recurring abnormal papillary characteristics were identified and quantified based on degree of severity.Four unique papillary features were chosen for inclusion in the PPLA scoring system- ductal Plugging, Pitting, Loss of contour, and Amount of Randall's plaque. Unique scores are calculated for individual papillae based on reference examples.The description and study of renal papillary appearance in stone formers have considerable potential as both a clinical and research tool; however, a standardized grading system is necessary before using it for these purposes.
Do kidney stone formers have a kidney disease? - Kidney international
Nephrolithiasis is a highly prevalent disorder affecting approximately one in eleven people and is associated with multiple complications including hypertension, cardiovascular disease, and chronic kidney disease. Significant epidemiologic associations with chronic kidney disease and ESRD have been noted and are reviewed herein, but debate persists in the literature as to whether kidney stone formation is a pathogenic process contributing to kidney disease. Corroborating evidence supporting the presence of kidney disease in stone formers includes the variability of renal function by stone type, the positive association of stone size with renal dysfunction, the presence of markers of renal injury in the urine of even asymptomatic stone formers, and direct evidence of renal tissue injury on histopathology. Proposed pathogenic mechanisms include recurrent obstruction and comorbid conditions such as recurrent urinary tract infections and structural abnormalities. Recent work evaluating the renal histopathology of different groups of stone formers adds further granularity, suggesting variability in mechanisms of renal injury by stone type and confirming the pathogenic effects of crystal formation. Genetic abnormalities leading to stone formation including cystinuria and primary hyperoxaluria, among others, contribute to the burden of disease in the stone-forming population.
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