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Punnen S.,University of California at San Francisco | Freedland S.J.,Duke University | Freedland S.J.,Durham Veterans Administration Medical Center | Presti Jr. J.C.,Stanford University | And 10 more authors.
European Urology | Year: 2014

Background The University of California, San Francisco, Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) score uses pathologic data from radical prostatectomy (RP) to predict prostate cancer recurrence and mortality. However, this clinical tool has never been validated externally. Objective To validate CAPRA-S in a large, multi-institutional, external database. Design, setting, and participants The Shared Equal Access Regional Cancer Hospital (SEARCH) database consists of 2892 men who underwent RP from 2001 to 2011. With a median follow-up of 58 mo, 2670 men (92%) had complete data to calculate a CAPRA-S score. Intervention RP. Outcome measurements and statistical analysis The main outcome was biochemical recurrence. Performance of CAPRA-S in detecting recurrence was assessed and compared with a validated postoperative nomogram by concordance index (c-index), calibration plots, and decision curve analysis. Prediction of cancer-specific mortality was assessed by Kaplan-Meier analysis and the c-index. Results and limitations The mean age was 62 yr (standard deviation: 6.3), and 34.3% of men had recurrence. The 5-yr progression-free probability for those patients with a CAPRA-S score of 0-2, 3-5, and 6-10 (defining low, intermediate, and high risk) was 72%, 39%, and 17%, respectively. The CAPRA-S c-index was 0.73 in this validation set, compared with a c-index of 0.72 for the Stephenson nomogram. Although CAPRA-S was optimistic in predicting the likelihood of being free of recurrence at 5 yr, it outperformed the Stephenson nomogram on both calibration plots and decision curve analysis. The c-index for predicting cancer-specific mortality was 0.85, with the caveat that this number is based on only 61 events. Conclusions In this external validation, the CAPRA-S score predicted recurrence and mortality after RP with a c-index >0.70. The score is an effective prognostic tool that may aid in determining the need for adjuvant therapy. © 2013 European Association of Urology.


Vickrey B.G.,University of California at Los Angeles | Vickrey B.G.,Veterans Administration Greater Los Angeles Healthcare System | Hirtz D.,U.S. National Institutes of Health | Waddy S.,U.S. National Institutes of Health | And 3 more authors.
Annals of Neurology | Year: 2012

There is an enormous unmet need for knowledge about how new insights from discovery and translational research can yield measurable, population-level improvements in health and reduction in mortality among those having or at risk for neurological disease. Once several, well-conducted randomized controlled trials establish the efficacy of a given therapy, implementation research can generate new knowledge about barriers to uptake of the therapy into widespread clinical care, and what strategies are effective in overcoming those barriers and in addressing health disparities. Comparative effectiveness research aims to elucidate the relative value (including clinical benefit, clinical harms, and/or costs) of alternative efficacious management approaches to a neurological disorder, generally through direct comparisons, and may include comparisons of methodologies for implementation. Congress has recently appropriated resources and established an institute to prioritize funding for such research. Neurologists and neuroscientists should understand the scope and objectives of comparative effectiveness and implementation research, their range of methodological approaches (formal literature syntheses, randomized trials, observational studies, modeling), and existing research resources (centers for literature synthesis, registries, practice networks) relevant to research for neurological conditions, to close the well-documented evidence-to-practice gap. Future directions include building this research resource capacity, producing scientists trained to conduct rigorous comparative effectiveness and implementation research, and embracing innovative strategies to set research priorities in these areas. © 2012 American Neurological Association.


Mayer E.A.,University of California at Los Angeles | Knight R.,Howard Hughes Medical Institute | Mazmanian S.K.,California Institute of Technology | Cryan J.F.,Alimentary Pharmabiotic Center | And 2 more authors.
Journal of Neuroscience | Year: 2014

The discovery of the size and complexity of the human microbiome has resulted in an ongoing reevaluation of many concepts of health and disease, including diseases affecting the CNS. A growing body of preclinical literature has demonstrated bidirectional signaling between the brain and the gut microbiome, involving multiple neurocrine and endocrine signaling mechanisms. While psychological and physical stressors can affect the composition and metabolic activity of the gut microbiota, experimental changes to the gut microbiome can affect emotional behavior and related brain systems. These findings have resulted in speculation that alterations in the gut microbiomemayplay a pathophysiological role inhumanbrain diseases, including autism spectrum disorder, anxiety, depression, and chronic pain. Ongoing large-scale population-based studies of the gut microbiome and brain imaging studies looking at the effect of gut microbiome modulation on brain responses to emotion-related stimuli are seeking to validate these speculations. This article is a summary of emerging topics covered in a symposium and is not meant to be a comprehensive review of the subject. © 2014 the authors.


Kraut J.A.,University of California at Los Angeles | Kraut J.A.,Veterans Administration Greater Los Angeles Healthcare System
American Journal of Kidney Diseases | Year: 2016

Methanol intoxication is an uncommon but serious poisoning. Its adverse effects are due primarily to the impact of its major metabolite formic acid and lactic acid resulting from cellular hypoxia. Symptoms including abdominal pain and loss of vision can appear a few hours to a few days after exposure, reflecting the time necessary for accumulation of the toxic byproducts. In addition to a history of exposure, increases in serum osmolal and anion gaps can be clues to its presence. However, increments in both parameters can be absent depending on the nature of the toxic alcohol, time of exposure, and coingestion of ethanol. Definitive diagnosis requires measurement with gas or liquid chromatography, which are laborious and expensive procedures. Tests under study to detect methanol or its metabolite formate might facilitate the diagnosis of this poisoning. Treatment can include administration of ethanol or fomepizole, both inhibitors of the enzyme alcohol dehydrogenase to prevent formation of its metabolites, and hemodialysis to remove methanol and formate. In this Acid-Base and Electrolyte Teaching Case, a patient with methanol intoxication due to ingestion of model airplane fuel is described, and the value and limitations of current and new diagnostic and treatment measures are discussed. © 2016 National Kidney Foundation, Inc.


Kraut J.A.,University of California at Los Angeles | Kraut J.A.,Veterans Administration Greater Los Angeles Healthcare System
Clinical Toxicology | Year: 2015

Context. Methanol, ethylene glycol, diethylene glycol, and propylene glycol intoxications are associated with cellular dysfunction and an increased risk of death. Adverse effects can develop quickly; thus, there is a need for methods for rapidly detecting their presence. Objective. To examine the value and limitations of present methods to diagnose patients with possible toxic alcohol exposure. Methods. I searched MEDLINE for articles published between 1969 and 2014 using the terms: toxic alcohols, serum osmolality, serum osmol gap, serum anion gap, metabolic acidosis, methanol, ethylene glycol, diethylene glycol, propylene glycol, and fomepizole. Each article was reviewed for additional references. Results. The diagnosis of toxic alcohol exposure is often made on the basis of this history and physical findings along with an increase in the serum osmol and anion gaps. However, an increase in the osmol and/or anion gaps is not always present. Definitive detection in blood requires gas or liquid chromatography, laborious and expensive procedures which are not always available. Newer methods including a qualitative colorimetric test for detection of all alcohols or enzymatic tests for a specific alcohol might allow for more rapid diagnosis. Conclusions. Exposure to toxic alcohols is associated with cellular dysfunction and increased risk of death. Treatment, if initiated early, can markedly improve outcome, but present methods of diagnosis including changes in serum osmol and anion gap, and use of gas or liquid chromatography have important limitations. Development of more rapid and effective tests for detection of these intoxications is essential for optimal care of patients. © 2015 Informa Healthcare USA, Inc.


Bergman J.,University of California at Los Angeles | Bergman J.,Veterans Administration Greater Los Angeles Healthcare System | Litwin M.S.,University of California at Los Angeles
Journal of the National Cancer Institute - Monographs | Year: 2012

Active surveillance is an important arrow in the quiver of physicians advising men with prostate cancer. Quality-of-life considerations are paramount for patient-centered decision making. Although the overall deleterious impact on health is less dramatic than for those who pursue curative treatment, men on active surveillance also suffer sexual dysfunction and distress. Five-year outcomes revealed more erectile dysfunction (80% vs 45%) and urinary leakage (49% vs 21%) but less urinary obstruction (28% vs 44%) in men undergoing prostatectomy. Bowel function, anxiety, depression, well-being, and overall health-related quality of life (HRQOL) were similar after 5 years, but at 6-8 years, other domains of HRQOL, such as anxiety and depression, deteriorated significantly for those who chose watchful waiting. Further research is needed to compare prospectively HRQOL outcomes in men choosing active surveillance and those never diagnosed with prostate cancer, in part to help weigh the potential benefits and harms of prostate cancer screening. © The Author 2012. Published by Oxford University Press. All rights reserved.


Lee H.,University of California at Los Angeles | Brecha N.C.,University of California at Los Angeles | Brecha N.C.,Veterans Administration Greater Los Angeles Healthcare System
European Journal of Neuroscience | Year: 2010

Horizontal cells are lateral interneurons that participate in visual processing in the outer retina but the cellular mechanisms underlying transmitter release from these cells are not fully understood. In non-mammalian horizontal cells, GABA release has been shown to occur by a non-vesicular mechanism. However, recent evidence in mammalian horizontal cells favors a vesicular mechanism as they lack plasmalemmal GABA transporters and some soluble NSF attachment protein receptor (SNARE) core proteins have been identified in rodent horizontal cells. Moreover, immunoreactivity for GABA and the molecular machinery to synthesize GABA have been found in guinea pig horizontal cells, suggesting that if components of the SNARE complex are expressed they could contribute to the vesicular release of GABA. In this study we investigated whether these vesicular and synaptic proteins are expressed by guinea pig horizontal cells using immunohistochemistry with well-characterized antibodies to evaluate their cellular distribution. Components of synaptic vesicles including vesicular GABA transporter, synapsin I and synaptic vesicle protein 2A were localized to horizontal cell processes and endings, along with the SNARE core complex proteins, syntaxin-1a, syntaxin-4 and synaptosomal-associated protein 25 (SNAP-25). Complexin I/II, a cytosolic protein that stabilizes the activated SNARE fusion core, strongly immunostained horizontal cell soma and processes. In addition, the vesicular Ca2+-sensor, synaptotagmin-2, which is essential for Ca2+-mediated vesicular release, was also localized to horizontal cell processes and somata. These morphological findings from guinea pig horizontal cells suggest that mammalian horizontal cells have the capacity to utilize a regulated Ca2+-dependent vesicular pathway to release neurotransmitter, and that this mechanism may be shared among many mammalian species. © Federation of European Neuroscience Societies and Blackwell Publishing Ltd.


Aneshensel C.S.,University of California at Los Angeles | Ko M.J.,University of California at Los Angeles | Chodosh J.,University of California at Los Angeles | Chodosh J.,Veterans Administration Greater Los Angeles Healthcare System | Wight R.G.,University of California at Los Angeles
Journal of Health and Social Behavior | Year: 2011

This study examines the association of cognitive functioning with urban neighborhood socioeconomic disadvantage and racial/ethnic segregation for a U.S. national sample of persons in late middle age, a time in the life course when cognitive deficits begin to emerge. The key hypothesis is that effects of neighborhood on cognitive functioning are not uniform but are most pronounced among subgroups of the population defined by socioeconomic status and race/ethnicity. Data are from the third wave of the Health and Retirement Survey for the birth cohort of 1931 to 1941, which was 55 to 65 years of age in 1996 (analytic N = 4,525), and the 1990 U.S. Census. Neighborhood socioeconomic disadvantage has an especially large negative impact on cognitive functioning among persons who are themselves poor, an instance of compound disadvantage. These findings have policy implications supporting "upstream" interventions to enhance cognitive functioning, especially among those most adversely affected by neighborhood socioeconomic disadvantage. © American Sociological Association 2011.


Potter R.M.,Molecular Therapeutics | Harikumar K.G.,Molecular Therapeutics | Wu S.V.,Veterans Administration Greater Los Angeles Healthcare System | Miller L.J.,Molecular Therapeutics
Journal of Lipid Research | Year: 2012

Recent studies indicate that membrane cholesterol can associate with G protein-coupled receptors (GPCRs) and affect their function. Previously, we reported that manipulation of membrane cholesterol affects ligand binding and signal transduction of the type 1 cholecystokinin receptor (CCK1R), a Class A GPCR. We now demonstrate that the closely related type 2 cholecystokinin receptor (CCK2R) does not share this cholesterol sensitivity. The sequences of both receptors reveal almost identical cholesterol interaction motifs in analogous locations in transmembrane segments two, three, four, and five. The disparity in cholesterol sensitivity between these receptors, despite their close structural relationship, provides a unique opportunity to define the possible structural basis of cholesterol sensitivity of CCK1R. To evaluate the relative contributions of different regions of CCK1R to cholesterol sensitivity, we performed ligand binding studies and biological activity assays of wildtype and CCK2R/CCK1R chimeric receptor-bearing Chinese hamster ovary cells after manipulation of membrane cholesterol. We also extended these studies to site-directed mutations within the cholesterol interaction motifs. The results contribute to a better understanding of the structural requirements for cholesterol sensitivity in CCK1R and provides insight into the function of other cholesterol-sensitive Class A GPCRs.


Singh B.N.,Veterans Administration Greater Los Angeles Healthcare System
Journal of Cardiovascular Pharmacology and Therapeutics | Year: 2010

In recent years, a major development in the treatment of atrial fibrillation (AF) is the use of catheter ablation, and a significant number of patients may benefit from this mode of therapy. On a global scale, it may not be feasible to deal with most patients solely on the basis of ablation. Therefore, it is likely that much of the therapy for AF will continue to rely on antiarrhythmic agents for maintaining sinus rhythm. For many years, amiodarone and sotalol have been the dominant antiarrhythmic agents, with amiodarone being the most effective antiarrhythmic in suppressing AF; however, amiodarone use is limited due to concerns of end-organ toxicity. Upstream therapies, such as statins, fish oil, angiotensin converting enzyme (ACE) inhibitors, and angiotensin receptor blockers may also provide additive efficacy to these and other membrane-active antiarrhythmics. In recent years, a number of new agents are being developed and the first successful congener of amiodarone, dronedarone, has been shown to be effective in controlling AF and reducing cardiovascular hospitalization. This paper explores the possibility of augmenting the extent of controlling AF by combining multiple potent antiarrhythmic agents old and new. © The Author(s) 2010.

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