San Diego Veterans Affairs Healthcare System

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San Diego Veterans Affairs Healthcare System

San Diego, CA, United States
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Lau D.,University of California at San Diego | Kwan W.,University of California at San Diego | Guatelli J.,University of California at San Diego | Guatelli J.,San Diego Veterans Affairs Healthcare System
Journal of Virology | Year: 2011

The interferon-inducible transmembrane protein BST-2 (CD317, tetherin) restricts the release of several enveloped viruses from infected cells. BST-2 is broadly active against retroviruses, including HIV-1 and HIV-2. To counteract this host defense, HIV-1 uses the accessory protein Vpu, whereas HIV-2 uses its envelope glycoprotein (Env). In both cases, viral antagonism is associated with decreased expression of BST-2 at the cell surface. Here, we provide evidence supporting a role for the clathrin-mediated endocytic pathway in the downregulation of BST-2 from the cell surface and the counteraction of restricted virion release. A catalytically inactive, dominant negative version of the vesicle "pinch-ase" dynamin 2 (dyn2K44A) inhibited the downregulation of BST-2 by Vpu, and it inhibited the release of wild-type (Vpu-expressing) HIV-1 virions. Similarly, dyn2K44A inhibited the downregulation of BST-2 by HIV-2 Env, and it inhibited the release of vpu-negative HIV-1 virions when HIV-2 Env was provided in trans. dyn2K44A inhibited Env more robustly than Vpu, suggesting that dynamin 2, while a cofactor for both Env and Vpu, might support just one of several pathways though which Vpu counteracts BST-2. In support of a role for clathrin in these effects, the C-terminal domain of the clathrin assembly protein AP180 also inhibited the downregulation of BST-2 by either Vpu or HIV-2 Env. Consistent with modulation of the postendocytic itinerary of BST-2, Vpu enhanced the accumulation of cell surface-derived BST-2 in transferrin-containing endosomes. Vpu also inhibited the transport of BST-2 from a brefeldin A-insensitive compartment to the cell surface, consistent with a block to endosomal recycling. We propose that HIV-1 Vpu, and probably HIV-2 Env, traps BST-2 in an endosomal compartment following endocytosis, reducing its level at the cell surface to counteract restricted viral release. © 2011, American Society for Microbiology.

Fung M.M.,San Diego Veterans Affairs Healthcare System | Peters K.,California Pacific Medical Center Research Institute | Redline S.,Harvard University | Barrett-Connor E.,University of California at San Diego | Stone K.L.,California Pacific Medical Center Research Institute
Hypertension | Year: 2011

The importance of sleep to health and cardiovascular disease has become increasingly apparent. Sleep-disordered breathing, sleep duration, and sleep architecture may all influence metabolism and neurohormonal systems, yet no previous study has evaluated these sleep characteristics concurrently in relation to incident hypertension. Our objective was to determine whether incident hypertension is associated with polysomnography measures of sleep-disordered breathing, sleep duration, and sleep architecture in older men. Participants were 784 community-dwelling, ambulatory men 65 years of age (mean age: 75.1±4.9 years) from the Outcomes of Sleep Disorders in Older Men Study who did not have hypertension at the time of their in-home polysomnography sleep studies (2003-2005) and who returned for follow-up (2007-2009). Of 784 older men included in this report, 243 met criteria for incident hypertension after a mean follow-up of 3.4 years. In unadjusted analyses, incident hypertension was associated with increased hypoxemia, increased sleep stages N1 and N2, and decreased stage N3 (slow wave sleep [SWS]). After adjustment for age, nonwhite race, study site, and body mass index, the only sleep index to remain significantly associated with incident hypertension was SWS percentage (odds ratio for lowest to highest quartile of SWS: 1.83 [95% CI: 1.18 to 2.85]). No attenuation of this association was seen after accounting for sleep duration, sleep fragmentation, and indices of sleep-disordered breathing. Percentage time in SWS was inversely associated with incident hypertension, independent of sleep duration and fragmentation, and sleep-disordered breathing. Selective deprivation of SWS may contribute to adverse blood pressure in older men. © 2011 American Heart Association, Inc.

Lin S.C.,University of California at San Diego | Heba E.,University of California at San Diego | Wolfson T.,University of California at San Diego | Ang B.,University of California at San Diego | And 8 more authors.
Clinical Gastroenterology and Hepatology | Year: 2015

Background & Aims: Liver biopsy analysis is the standard method used to diagnose nonalcoholic fatty liver disease (NAFLD). Advanced magnetic resonance imaging is a noninvasive procedure that can accurately diagnose and quantify steatosis, but is expensive. Conventional ultrasound is more accessible but identifies steatosis with low levels of sensitivity, specificity, and quantitative accuracy, and results vary among technicians. A new quantitative ultrasound (QUS) technique can identify steatosis in animal models. We assessed the accuracy of QUS in the diagnosis and quantification of hepatic steatosis, comparing findings with those from magnetic resonance imaging proton density fat fraction (MRI-PDFF) analysis as a reference. Methods: We performed a prospective, cross-sectional analysis of a cohort of adults (N= 204) with NAFLD (MRI-PDFF, ≥5%) and without NAFLD (controls). Subjects underwent MRI-PDFF and QUS analyses of the liver on the same day at the University of California, San Diego, from February 2012 through March 2014. QUS parameters and backscatter coefficient (BSC) values were calculated. Patients were assigned randomly to training (n= 102; mean age, 51 ± 17 y; mean body mass index, 31 ± 7 kg/m2) and validation (n= 102; mean age, 49 ± 17 y; body mass index, 30 ± 6 kg/m2) groups; 69% of patients in each group had NAFLD. Results: BSC (range, 0.00005-0.25 1/cm-sr) correlated with MRI-PDFF (Spearman ρ= 0.80; P < .0001). In the training group, the BSC analysis identified patients with NAFLD with an area under the curve value of 0.98 (95% confidence interval, 0.95-1.00; P < .0001). The optimal BSC cut-off value identified patients with NAFLD in the training and validation groups with 93% and 87% sensitivity, 97% and 91% specificity, 86% and 76% negative predictive values, and 99% and 95% positive predictive values, respectively. Conclusions: QUS measurements of BSC can accurately diagnose and quantify hepatic steatosis, based on a cross-sectional analysis that used MRI-PDFF as the reference. With further validation, QUS could be an inexpensive, widely available method to screen the general or at-risk population for NAFLD. © 2015 AGA Institute.

Criqui M.H.,University of California at San Diego | Denenberg J.O.,University of California at San Diego | McClelland R.L.,University of Washington | Allison M.A.,University of California at San Diego | And 7 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2014

OBJECTIVE - To evaluate the predictive value of abdominal aortic calcium (AAC) for incident cardiovascular disease (CVD) independent of coronary artery calcium (CAC). APPROACH AND RESULTS - We evaluated the association of AAC with CVD in 1974 men and women aged 45 to 84 years randomly selected from the Multi-Ethnic Study of Atherosclerosis participants who had complete AAC and CAC data from computed tomographic scans. AAC and CAC were each divided into following 3 percentile categories: 0 to 50th, 51st to 75th, and 76th to 100th. During a mean of 5.5 years of follow-up, there were 50 hard coronary heart disease events, 83 hard CVD events, 30 fatal CVD events, and 105 total deaths. In multivariable-adjusted Cox models including both AAC and CAC, comparing the fourth quartile with the ≤50th percentile, AAC and CAC were each significantly and independently predictive of hard coronary heart disease and hard CVD, with hazard ratios ranging from 2.4 to 4.4. For CVD mortality, the hazard ratio was highly significant for the fourth quartile of AAC, 5.9 (P=0.01), whereas the association for the fourth quartile of CAC (hazard ratio, 2.1) was not significant. For total mortality, the fourth quartile hazard ratio for AAC was 2.7 (P=0.001), and for CAC, it was 1.9, P=0.04. Area under the receiver operating characteristic curve analyses showed improvement for both AAC and CAC separately, although improvement was greater with CAC for hard coronary heart disease and hard CVD, and greater with AAC for CVD mortality and total mortality. Sensitivity analyses defining AAC and CAC as continuous variables mirrored these results. CONCLUSIONS - AAC and CAC predicted hard coronary heart disease and hard CVD events independent of one another. Only AAC was independently related to CVD mortality, and AAC showed a stronger association than CAC with total mortality. © 2014 American Heart Association, Inc.

Worley M.J.,San Diego State University | Tate S.R.,San Diego Veterans Affairs Healthcare System | Brown S.A.,University of California at San Diego
Addiction | Year: 2012

Aims: Among patients with substance dependence and comorbid major depressive disorder (MDD) receiving treatment in a controlled trial, we examined if group differences in depression were mediated by 12-Step involvement, and if the effects of 12-Step involvement on future alcohol and drug use were mediated by reductions in depression. Design: Controlled trial of Twelve-Step facilitation (TSF) and integrated cognitive-behavioral therapy (ICBT), delivered in out-patient groups for 6 months with adjunct pharmacotherapy. Setting: Out-patient dual diagnosis clinic in Veteran's Affairs Healthcare Center. Participants: Veterans (n=209) diagnosed with alcohol, stimulant or marijuana dependence and substance-independent MDD. Measurements: Twelve-Step attendance and affiliation, depression severity, percentage of days drinking and percentage of days using drugs assessed at baseline and months 3, 6 and 9. Findings: In multi-level analyses greater 12-Step meeting attendance predicted lower depression and mediated the superior depression outcomes of the TSF group, explaining 24.3% of the group difference in depression. Independent of treatment group, lower depression severity predicted lower future alcohol use and mediated the effects of 12-Step meetings, explaining 15.7% of their effects on future drinking. Controlled, lagged models indicated these effects were not confounded by current substance use, suggesting that depression had unique associations with 12-Step meeting attendance and future drinking. Conclusions: For patients with substance dependence and major depressive disorder, attendance at 12-Step meetings is associated with mental health benefits that extend beyond substance use, and reduced depression could be a key mechanism whereby 12-Step meetings reduce future drinking in this population. © 2012 Society for the Study of Addiction.

Edwards A.,University of Paris Descartes | Castrop H.,University of Regensburg | Laghmani K.,University of Paris Descartes | Vallon V.,University of California at San Diego | And 2 more authors.
American Journal of Physiology - Renal Physiology | Year: 2014

This study aims to understand the extent to which modulation of the Na+-K+-2Cl- cotransporter NKCC2 differential splicing affects NaCl delivery to the macula densa. NaCl absorption by the thick ascending limb and macula densa cells is mediated by apical NKCC2. A recent study has indicated that differential splicing of NKCC2 is modulated by dietary salt (Schieβl IM, Rosenauer A, Kattler V, Minuth WW, Oppermann M, Castrop H. Am J Physiol Renal Physiol 305: F1139-F1148, 2013). Given the markedly different ion affinities of its splice variants, modulation of NKCC2 differential splicing is believed to impact NaCl reabsorption. To assess the validity of that hypothesis, we have developed a mathematical model of macula densa cell transport and incorporated that cell model into a previously applied model of the thick ascending limb (Weinstein AM, Krahn TA. Am J Physiol Renal Physiol 298: F525-F542, 2010). The macula densa model predicts a 27.4- and 13.1-mV depolarization of the basolateral membrane [as a surrogate for activation of tubuloglomerular feedback (TGF)] when luminal NaCl concentration is increased from 25 to 145 mM or luminal K+ concentration is increased from 1.5 to 3.5 mM, respectively, consistent with experimental measurements. Simulations indicate that with luminal solute concentrations consistent with in vivo conditions near the macula densa, NKCC2 operates near its equilibrium state. Results also suggest that modulation of NKCC2 differential splicing by low salt, which induces a shift from NKCC2-A to NKCC2-B primarily in the cortical thick ascending limb and macula densa cells, significantly enhances salt reabsorption in the thick limb and reduces Na+ and Cl- delivery to the macula densa by 3.7 and 12.5%, respectively. Simulation results also predict that the NKCC2 isoform shift hyperpolarizes the macula densa basolateral cell membrane, which, taken in isolation, may inhibit the release of the TGF signal. However, excessive early distal salt delivery and renal salt loss during a low-salt diet may be prevented by an asymmetric TGF response, which may be more sensitive to flow increases. © 2014 the American Physiological Society.

Hauser H.,University of Southern California | Lopez L.A.,University of Southern California | Yang S.J.,University of Southern California | Oldenburg J.E.,University of Southern California | And 4 more authors.
Retrovirology | Year: 2010

Background: In the absence of the Vpu protein, newly formed HIV-1 particles can remain attached to the surface of human cells due to the action of an interferon-inducible cellular restriction factor, BST-2/tetherin. Tetherin also restricts the release of other enveloped viral particles and is counteracted by a several viral anti-tetherin factors including the HIV-2 Env, SIV Nef and KSHV K5 proteins.Results: We observed that a fraction of tetherin is located at the surface of restricting cells, and that co-expression of both HIV-1 Vpu and HIV-2 Env reduced this population. In addition, Vpu, but not the HIV-2 Env, reduced total cellular levels of tetherin. An additional effect observed for both Vpu and the HIV-2 Env was to redirect tetherin to an intracellular perinuclear compartment that overlapped with markers for the TGN (trans-Golgi network). Sequestration of tetherin in this compartment was independent of tetherin's normal endocytosis trafficking pathway.Conclusions: Both HIV-1 Vpu and HIV-2 Env redirect tetherin away from the cell surface and sequester the protein in a perinuclear compartment, which likely blocks the action of this cellular restriction factor. Vpu also promotes the degradation of tetherin, suggesting that it uses more than one mechanism to counteract tetherin restriction. © 2010 Hauser et al; licensee BioMed Central Ltd.

Wang V.,University of California at San Diego | Depp C.A.,University of California at San Diego | Depp C.A.,San Diego Veterans Affairs Healthcare System | Ceglowski J.,University of California at San Diego | And 4 more authors.
American Journal of Geriatric Psychiatry | Year: 2015

Background Sexual health and function is an important yet understudied aspect of overall health and well-being in older adults. There are limited data on the relative strength of associations between various aspects of sexual health with the physical, emotional, and cognitive function in older adults. Additionally, there is little information on how these associations differ by age and sex. Methods In this Successful Aging Evaluation (SAGE) study, 606 community-dwelling adults in San Diego County, aged 50-99 years and who had a partner, were included in the analysis. Evaluations included a phone-based cognitive screening followed by a comprehensive mail-in survey including rating scales of sexual health, depression, anxiety, and physical function. Results The mean age of the sample was 75.2 years. Over 80% of respondents had engaged in sexual activity in the past year, over 70% engaged in sexual activity weekly or more than once a week, and over 60% were somewhat or very satisfied with their sex lives. No sex differences were evident on dimensions of sexual health except for a higher rate of rejection of sexual overtures by women. Depressive symptoms were negatively associated with all assessed aspects of sexual health, even after adjusting for age, physical functioning, anxiety, cognitive ability, or perceived stress in both men and women. Conclusions In this population-based study older men and women who had a partner reported frequent engagement in and satisfaction with sexual activity. Depressive symptoms were broadly associated with worse sexual health, more so than physical function, anxiety or stress, or age itself. © 2015 American Association for Geriatric Psychiatry.

Fitzpatrick K.,University of California at San Diego | Skasko M.,University of California at San Diego | Deerinck T.J.,University of California at San Diego | Crum J.,University of California at San Diego | And 3 more authors.
PLoS Pathogens | Year: 2010

Investigation of the Vpu protein of HIV-1 recently uncovered a novel aspect of the mammalian innate response to enveloped viruses: retention of progeny virions on the surface of infected cells by the interferon-induced, transmembrane and GPI-anchored protein BST-2 (CD317; tetherin). BST-2 inhibits diverse families of enveloped viruses, but how it restricts viral release is unclear. Here, immuno-electron microscopic data indicate that BST-2 is positioned to directly retain nascent HIV virions on the plasma membrane of infected cells and is incorporated into virions. Virion-incorporation was confirmed by capture of infectivity using antibody to the ectodomain of BST-2. Consistent with a direct tethering mechanism, we confirmed that proteolysis releases restricted virions and further show that this removed the ectodomain of BST-2 from the cell surface. Unexpectedly, enzymatic cleavage of GPI anchors did not release restricted virions, weighing against models in which individual BST-2 molecules span the virion and host cell membranes. Although the exact molecular topology of restriction remains unsolved, we suggest that the incorporation of BST-2 into viral envelopes underlies its broad restrictive activity, whereas its relative exclusion from virions and sites of viral assembly by proteins such as HIV-1 Vpu may provide viral antagonism of restriction.

Simpson D.R.,University of California at San Diego | Martinez M.E.,University of California at San Diego | Gupta S.,University of California at San Diego | Gupta S.,San Diego Veterans Affairs Healthcare System | And 7 more authors.
Journal of the National Cancer Institute | Year: 2013

Background Black patients with metastatic colorectal cancer have inferior survival compared to white patients. The purpose of this study was to examine disparity in specialist consultation and multimodality treatment and the impact that treatment inequality has on survival. Methods We identified 9935 non-Hispanic white and 1281 black patients with stage IV colorectal cancer aged 66 years and older from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Logistic regression models identified race-based differences in consultation rates and subsequent treatment with surgery, chemotherapy, or radiation. Multivariable Cox regression models identified potential factors that explain race-based survival differences. All statistical tests were two-sided. Results Black patients had lower rates of consultation with surgery, medical oncology, and radiation oncology. Among patients seen in consultation, black patients received less surgery directed at the primary tumor, liver- or lungdirected surgery, chemotherapy, and radiotherapy. Unadjusted survival analysis found a 15% higher chance of dying for black patients compared with white patients (hazard ratio [HR] = 1.15; 95% confidence interval (CI) = 1.08 to 1.22; P < .001). Adjustment for patient, tumor, and demographic variables marginally reduced the risk of death (HR = 1.08; 95% CI = 1.01 to 1.15; P = .03). After adjustment for differences in treatment, the increased risk of death for black patients disappeared. Conclusions Our study shows racial disparity in specialist consultation as well as subsequent treatment with multimodality therapy for metastatic colorectal cancer, and it suggests that inferior survival for black patients may stem from this treatment disparity. Further research into the underlying causes of this inequality will improve access to treatment and survival in metastatic colorectal cancer. © The Author 2013.

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