New York Veterans Affairs Medical Center

New York City, NY, United States

New York Veterans Affairs Medical Center

New York City, NY, United States
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Agarwal A.,New York University | Oronsaye E.,New York University | Zolla-Pazner S.,New York Veterans Affairs Medical Center | Cardozo T.,New York University
2011 ACM Conference on Bioinformatics, Computational Biology and Biomedicine, BCB 2011 | Year: 2011

HIV-1 requires engagement of host co-receptor CCR5 or CXCR4 in order to infect human cells. Amino acid identity at positions 11 and/or 25 in the V3 loop of HIV-1 gp120 (positions 306 and 322 in terms of standard HXB2 gp120 numbering) has been shown to strongly influence which co-receptor is utilized by a viral strain. To identify additional sites in other gp120 regions that may influence co-receptor usage, we compared, position-by-position, the electrostatic charge distributions at each location in the 3D structure of X4-tropic gp120 core domains to each structurally equivalent location in R5-tropic gp120 core domains. Seven sites in the gp120 core showed a significant difference in charge distribution between the viral sets. The two strongest differences were positions 440 and 373, both located adjacent to the origin of the V3 loop, suggesting that the co-receptor binding surface of gp120 is a single hotspot formed by the V3 loop and adjacent gp120 core regions. Copyright © 2011 ACM.


Kalantar-Zadeh K.,University of California at Irvine | Kalantar-Zadeh K.,Veterans Affairs Long Beach Healthcare System | Unruh M.,University of New Mexico | Zager P.G.,University of New Mexico | And 8 more authors.
American Journal of Kidney Diseases | Year: 2014

Mortality is highest in the first months of maintenance hemodialysis (HD) therapy. In many Western countries, patients who transition to kidney replacement therapy usually begin thrice-weekly HD regardless of their level of residual kidney function (RKF). RKF is a major predictor of survival. RKF may decline more rapidly with thrice-weekly HD treatments, is associated with a reduced need for dialytic solute clearance, and is an important factor in the prescription of peritoneal dialysis. In this article, we review the concept of incremental HD, in which weekly dialysis dose, in particular HD treatment frequency, is based on a variety of clinical factors, such as RKF (including urine output > 0.5 L/d), volume status, cardiovascular symptoms, body size, potassium and phosphorus levels, nutritional status, hemoglobin level, comorbid conditions, hospitalizations, and health-related quality of life. These 10 clinical criteria may identify which patients might benefit from beginning maintenance HD therapy twice weekly. Periodic monitoring of these criteria will determine the timing for increasing dialysis dose and frequency. We recognize that twice-weekly HD represents a major paradigm shift for many clinicians and jurisdictions. Therefore, we propose conducting randomized controlled trials of twice-weekly versus thrice-weekly HD to assess the potential of twice-weekly HD to improve survival and health-related quality of life while simultaneously reducing costs, protecting fragile vascular accesses, and optimizing resource use during the first year of hemodialysis therapy. Such incremental and individualized HD therapy may prove to be the most appropriate approach for transitioning to dialytic therapy. © 2014 by the National Kidney Foundation, Inc.


PubMed | University of California at Irvine, Veterans Affairs Long Beach Healthcare System, Nephrolife Dialysis, New York Veterans Affairs Medical Center and 6 more.
Type: Journal Article | Journal: American journal of kidney diseases : the official journal of the National Kidney Foundation | Year: 2014

Mortality is highest in the first months of maintenance hemodialysis (HD) therapy. In many Western countries, patients who transition to kidney replacement therapy usually begin thrice-weekly HD regardless of their level of residual kidney function (RKF). RKF is a major predictor of survival. RKF may decline more rapidly with thrice-weekly HD treatments, is associated with a reduced need for dialytic solute clearance, and is an important factor in the prescription of peritoneal dialysis. In this article, we review the concept of incremental HD, in which weekly dialysis dose, in particular HD treatment frequency, is based on a variety of clinical factors, such as RKF (including urine output > 0.5 L/d), volume status, cardiovascular symptoms, body size, potassium and phosphorus levels, nutritional status, hemoglobin level, comorbid conditions, hospitalizations, and health-related quality of life. These 10 clinical criteria may identify which patients might benefit from beginning maintenance HD therapy twice weekly. Periodic monitoring of these criteria will determine the timing for increasing dialysis dose and frequency. We recognize that twice-weekly HD represents a major paradigm shift for many clinicians and jurisdictions. Therefore, we propose conducting randomized controlled trials of twice-weekly versus thrice-weekly HD to assess the potential of twice-weekly HD to improve survival and health-related quality of life while simultaneously reducing costs, protecting fragile vascular accesses, and optimizing resource use during the first year of hemodialysis therapy. Such incremental and individualized HD therapy may prove to be the most appropriate approach for transitioning to dialytic therapy.


Dominianni C.,New York University | Sinha R.,U.S. National Institutes of Health | Goedert J.J.,U.S. National Institutes of Health | Pei Z.,New York University | And 4 more authors.
PLoS ONE | Year: 2015

Increasing evidence suggests that the composition of the human gut microbiome is important in the etiology of human diseases; however, the personal factors that influence the gut microbiome composition are poorly characterized. Animal models point to sex hormone-related differentials in microbiome composition. In this study, we investigated the relationship of sex, body mass index (BMI) and dietary fiber intake with the gut microbiome in 82 humans. We sequenced fecal 16S rRNA genes by 454 FLX technology, then clustered and classified the reads to microbial genomes using the QIIME pipeline. Relationships of sex, BMI, and fiber intake with overall gut microbiome composition and specific taxon abundances were assessed by permutational MANOVA and multivariate logistic regression, respectively. We found that sex was associated with the gut microbiome composition overall (p=0.001). The gut microbiome in women was characterized by a lower abundance of Bacteroidetes (p=0.03). BMI (>25 kg/m2 vs. <25 kg/m2) was associated with the gut microbiome composition overall (p=0.05), and this relationship was strong in women (p=0.03) but not in men (p=0.29). Fiber from beans and from fruits and vegetables were associated, respectively, with greater abundance of Actinobacteria (p=0.006 and false discovery rate adjusted q=0.05) and Clostridia (p=0.009 and false discovery rate adjusted q=0.09). Our findings suggest that sex, BMI, and dietary fiber contribute to shaping the gut microbiome in humans. Better understanding of these relationships may have significant implications for gastrointestinal health and disease prevention. © 2015, Public Library of Science. All rights reserved.


Ahn J.,New York University | Sinha R.,U.S. National Institutes of Health | Pei Z.,New York University | Pei Z.,New York Veterans Affairs Medical Center | And 6 more authors.
Journal of the National Cancer Institute | Year: 2013

We tested the hypothesis that an altered community of gut microbes is associated with risk of colorectal cancer (CRC) in a study of 47 CRC case subjects and 94 control subjects. 16S rRNA genes in fecal bacterial DNA were amplified by universal primers, sequenced by 454 FLX technology, and aligned for taxonomic classification to microbial genomes using the QIIME pipeline. Taxonomic differences were confirmed with quantitative polymerase chain reaction and adjusted for false discovery rate. All statistical tests were two-sided. From 794217 16S rRNA gene sequences, we found that CRC case subjects had decreased overall microbial community diversity (P =. 02). In taxonomy-based analyses, lower relative abundance of Clostridia (68.6% vs 77.8%) and increased carriage of Fusobacterium (multivariable odds ratio [OR] = 4.11; 95% confidence interval [CI] = 1.62 to 10.47) and Porphyromonas (OR = 5.17; 95% CI = 1.75 to 15.25) were found in case subjects compared with control subjects. Because of the potentially modifiable nature of the gut bacteria, our findings may have implications for CRC prevention. © 2013 The Author .


Swetnam J.,New York University | Shmelkov E.,New York University | Zolla-Pazner S.,New York University | Zolla-Pazner S.,New York Veterans Affairs Medical Center | Cardozo T.,New York University
PLoS ONE | Year: 2010

Although the sequence variable loops of the human immunodeficiency virus' (HIV-1) surface envelope glycoprotein (gp120) can exhibit good immunogenicity, characterizing conserved (invariant) cross-strain neutralization epitopes within these loops has proven difficult. We recently developed a method to derive sensitive and specific signature motifs for the threedimensional (3D) shapes of the HIV-1 neutralization epitopes in the third variable (V3) loop of gp120 that are recognized by human monoclonal antibodies (mAbs). We used the signature motif method to estimate the conservation of these epitopes across circulating worldwide HIV-1 strains. The epitope targeted by the anti-V3 loop neutralizing mAb 3074 is present in 87% of circulating strains, distributed nearly evenly among all subtypes. The results for other anti-V3 Abs are: 3791, present in 63% of primarily non-B subtypes; 2219, present in 56% of strains across all subtypes; 2557, present in 52% across all subtypes; 447-52D, present in 11% of primarily subtype B strains; 537-10D, present in 9% of primarily subtype B strains; and 268-D, present in 5% of primarily subtype B strains. The estimates correlate with in vitro tests of these mAbs against diverse viral panels. The mAb 3074 thus targets an epitope that is nearly completely conserved among circulating HIV-1 strains, demonstrating the presence of an invariant structure hidden in the dynamic and sequence-variable V3 loop in gp120. Since some variable loop regions are naturally immunogenic, designing immunogens to mimic their conserved epitopes may be a promising vaccine discovery approach. Our results suggest one way to quantify and compare the magnitude of the conservation. © 2010 Swetnam et al.


Frey G.,Harvard University | Chen J.,Harvard University | Rits-Volloch S.,Harvard University | Freeman M.M.,Harvard University | And 3 more authors.
Nature Structural and Molecular Biology | Year: 2010

HIV-1 envelope glycoprotein gp41 undergoes large conformational changes to drive fusion of viral and target cell membranes, adopting at least three distinct conformations during the viral entry process. Neutralizing antibodies against gp41 block HIV-1 infection by targeting gp41′s membrane-proximal external region in a fusion-intermediate state. Here we report biochemical and structural evidence that non-neutralizing antibodies, capable of binding with high affinity to an immunodominant segment adjacent to the neutralizing epitopes in the membrane-proximal region, recognize a gp41 conformation that exists only when membrane fusion is complete. We propose that these non-neutralizing antibodies are induced in HIV-1ginfected individuals by gp41 in a triggered, postfusion form and contribute to production of ineffective humoral responses. These results have important implications for gp41-based vaccine design. © 2010 Nature America, Inc. All rights reserved.


Agarwal A.,New York University | Hioe C.E.,New York University | Hioe C.E.,New York Veterans Affairs Medical Center | Swetnam J.,New York University | And 3 more authors.
Vaccine | Year: 2011

Despite the frequent observation of masking of HIV-1 neutralization epitopes, its extent has not been previously systematically assessed either for multiple epitopes presented by individual viruses or for individual epitopes across multiple viral strains. Using a recently developed method to identify amino acid sequence motifs required for recognition by HIV-1-neutralizing monoclonal antibodies (mAbs), we visualized the patterns of masking of specific epitopes targeted by mAbs in a diverse panel of HIV-1 isolates. We also calculated a specific masking intensity score for each virus based on the observed neutralization activity of mAbs against the epitopes in the virus. Finally, we combined these data with estimates of the conservation of each mAb-targeted epitope in circulating HIV-1 strains to estimate the effective neutralization potential (E N) for each mAb. Focusing on the V3 loop of gp120 as a prototype neutralization domain, we found that the V3 loop epitope targeted by mAb 2219 is one of the least masked mAbs and it has the highest E N. Interestingly, although the V3 loop epitope targeted by mAb 3074 is present in over 87% of all viruses, it is 82.2% masked, so its E N is lower than that for mAb 2219. Notably, 50% of the viruses that mAb 3074 is able to neutralize are classified as subtype C viruses, while 70% or more of the viruses neutralized by mAbs 2219, 2557 or 447-52D are classified as subtype B. Thus, neutralization epitopes (in this case, in the V3 loop) have differential patterns of masking and also display distinct patterns of distribution among circulating HIV-1 viruses. Both factors combine to contribute to the practical vaccine value of any single epitope/mAb. Here we have developed a quantitative score for this value. These results have important implications for rational design of vaccines designed to induce neutralizing Abs by revealing epitopes that are minimally masked and maximally reactive with neutralizing Abs. © 2010 Elsevier Ltd.


PubMed | New York Veterans Affairs Medical Center
Type: Clinical Trial, Phase II | Journal: The Journal of rheumatology | Year: 2011

Hyperuricemia of gout can arise due to either overproduction or underexcretion of uric acid. Not all available urate-lowering therapies are equally effective and safe for use in patients with renal disease. The objective of this post-hoc analysis was to determine the effectiveness of the xanthine oxidase inhibitor febuxostat in reducing serum urate (sUA) levels in gouty patients who were either overproducers or underexcretors.Gouty subjects 18 to 85 years of age with sUA 8.0 mg/dl at baseline were enrolled in a Phase 2, 28-day, multicenter, randomized, double-blind, placebo-controlled trial and randomized to receive febuxostat 40 mg, 80 mg, or 120 mg daily, or placebo. The primary efficacy endpoint was the proportion of subjects with sUA < 6.0 mg/dl at Day 28. Secondary efficacy endpoints included percentage reductions in sUA and urinary uric acid (uUA) from baseline to Day 28.Of the 153 subjects, 118 (77%) were underexcretors (uUA 800 mg/24 h) and 32 (21%) were overproducers (uUA > 800 mg/24 h); baseline uUA data were missing for 3 subjects. Treatment with febuxostat led to the majority of subjects achieving sUA < 6.0 mg/dl at Day 28. Treatment with any dose of febuxostat led to significantly greater percentage reductions in uUA than that observed in the placebo group, for both underexcretors and overproducers.Febuxostat is a highly efficacious urate-lowering therapy in patients with gout regardless of overproduction or underexcretion status.

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