Va St Louis Health Care System

North Kansas City, MO, United States

Va St Louis Health Care System

North Kansas City, MO, United States
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Gerstein H.C.,Hamilton Health Sciences | Bigger J.T.,Columbia University | Buse J.B.,University of North Carolina at Chapel Hill | Cushman W.C.,Veterans Affairs Medical Center | And 13 more authors.
Diabetes Care | Year: 2016

OBJECTIVE: In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, ∼4 years of intensive versus standard glycemic control in participants with type 2 diabetes and other cardiovascular risk factors had a neutral effect on the composite cardiovascular outcome, increased cardiovascular and total mortality, and reduced nonfatal myocardial infarction. Effects of the intervention during prolonged follow-up were analyzed. RESEARCH DESIGN AND METHODS: All surviving ACCORD participants were invited to participate in the ACCORD Follow-on (ACCORDION) study, during which participants were treated according to their health care provider's judgment. Cardiovascular and other health-related outcomes were prospectively collected and analyzed using an intention-to-treat approach according to the group to which participants were originally allocated. RESULTS: A total of 8,601 people, representing 98% of those who did not suffer a primary outcome or death during the ACCORD trial, were monitored for a median of 8.8 years and a mean of 7.7 years from randomization. Intensive glucose lowering for a mean of 3.7 years had a neutral long-term effect on the primary composite outcome (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death), death from any cause, and an expanded composite outcome that included all-cause death. Moreover, the risk of cardiovascular mortality noted during the active phase (hazard ratio 1.49; 95% CI 1.19, 1.87; P < 0.0001) decreased (HR 1.20; 95% CI 1.03, 1.39; P = 0.02). CONCLUSIONS: In high-risk people with type 2 diabetes monitored for 9 years, a mean of 3.7 years of intensive glycemic control had a neutral effect on death and nonfatal cardiovascular events but increased cardiovascular-related death. © 2016 by the American Diabetes Association.

Panagopoulos V.N.,Va St Louis Health Care System | Panagopoulos V.N.,University of Washington | Ralevski E.,Yale University
Psychopharmacology | Year: 2014

Rationale: Ghrelin is a fast-acting hormone that is produced primarily by the stomach and by the brain although in smaller quantities. The regulation and the secretion of ghrelin are complex and not limited to aspects of feeding. Ghrelin exerts powerful effects on multiple processes, and it has been demonstrated that it mediates the rewarding properties of food as well as of drugs of abuse. Objectives: The purpose of this review is to summarize the findings of preclinical and clinical studies related to ghrelin's possible role in addiction for each specific class of substances. Questions related to ghrelin's involvement in addiction are highlighted. Recurrent methodological issues that render the interpretation of the findings challenging are discussed. Also, the potential of targeting ghrelin as a pharmacologic treatment strategy for addiction is explored. Results: Ghrelin signaling is implicated in the mediation of behavioral and biochemical effects of drugs of abuse that are cardinal for the development of addiction, especially for alcohol, nicotine, and stimulants. The available literature implicating ghrelin in opioid or cannabis use disorders is currently limited and inconclusive. Conclusions: There is intriguing, although not always consistent, evidence for the involvement of ghrelin signaling in aspects of addiction, especially in the cases of alcohol, nicotine, and stimulants. Further research, particularly in humans, is recommended to replicate and expand on the findings of the current literature. Improved and novel methodologies that take into account the volatile and complex nature of ghrelin are required to clarify the inconsistencies of the findings. © 2014 Springer-Verlag Berlin Heidelberg.

Esakky P.,Va St Louis Health Care System | Esakky P.,University of Washington | Hansen D.A.,Va St Louis Health Care System | Drury A.M.,Va St Louis Health Care System | And 2 more authors.
Reproductive Sciences | Year: 2013

Laser microdissection (LMD) is a selective cell isolation technique that enables the separation of desired homogenous cell subpopulations from complex tissues such as the testes under direct microscopic visualization. The LMD accompanied by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) represents an indispensable tool in quantifying messenger RNA (mRNA) expression among defined cell populations. Gene expression is temporally and spatially regulated at 3 sequential phases of mitotic, meiotic, and postmeiotic stages of spermatogenesis. The present study demonstrates a short modified LMD protocol based upon hematoxylin and eosin (H&E) staining. Stage-specific LMD success was validated by the use of mRNA profiling of "marker genes" which are conserved across species and are known to be differentially expressed during spermatogenesis. Magea4, Hspa2, Cox6b2, Tnp1, Prm1, and Prm2 are used to differentiate among the microdissected cell populations, namely spermatogonia (group I), spermatocytes (group II), round and condensing spermatids (group III), and elongated and condensed spermatids (group IV), respectively. The LMD combined with qRT-PCR is further extended to assess the cell stage-specific distribution of selected stress response genes such as Hsp90aa1, Gpx4, Ucp2, Sod1, and Sod2. The germ cell-specific mRNA profiles are suitably complemented by Western blot of the LMD samples, immunohistochemistry, and confocal localization of the corresponding proteins. The current study suggests that LMD can successfully isolate cell subpopulations from the complex tissues of the testes; and establish cell stage-specific basal expression patterns of selected stress response genes and proteins. It is our hypothesis that the baseline expression of stress response genes will differ by cell stage to create discrete stage-specific vulnerabilities to reproductive toxicants. © 2013 The Author(s).

van den Berk-Clark C.,University of Washington | van den Berk-Clark C.,Va St Louis Health Care System | Patterson Silver Wolf D.A.,University of Washington | Ramsey A.,University of Washington
Administration and Policy in Mental Health and Mental Health Services Research | Year: 2015

This study evaluated motivational interviewing (MI) in a permanent supportive housing agency. The agency’s contradictory social service and business missions resulted in an incompatible organizational culture theorized to diminish MI’s effectiveness. A combination of observational, interview, and archival data collected over 3 years were used to examine MI implementation within an incompatible supportive housing agency. Two major themes arose: how MI is used to categorize and change clients in permanent supportive housing and how worker–worker relationships affect MI implementation. The results suggest that within incompatible organizational environments, key elements of effective MI implementation are greatly weakened. © 2014, Springer Science+Business Media New York.

Basta J.,Saint Louis University | Basta J.,Va St Louis Health Care System | Rauchman M.,Saint Louis University | Rauchman M.,Va St Louis Health Care System
Translational Research | Year: 2015

The nucleosome remodeling and deacetylase (NuRD) complex is one of the major chromatin remodeling complexes found in cells. It plays an important role in regulating gene transcription, genome integrity, and cell cycle progression. Through its impact on these basic cellular processes, increasing evidence indicates that alterations in the activity of this macromolecular complex can lead to developmental defects, oncogenesis, and accelerated aging. Recent genetic and biochemical studies have elucidated the mechanisms of NuRD action in modifying the chromatin landscape. These advances have the potential to lead to new therapeutic approaches to birth defects and cancer.

Basta J.M.,Saint Louis University | Robbins L.,Saint Louis University | Robbins L.,Va St Louis Health Care System | Kiefer S.M.,Saint Louis University | And 3 more authors.
Development (Cambridge) | Year: 2014

The formation of the proper number of functional nephrons requires a delicate balance between renal progenitor cell self-renewal and differentiation. The molecular factors that regulate the dramatic expansion of the progenitor cell pool and differentiation of these cells into nephron precursor structures (renal vesicles) are not well understood. Here we show that Sall1, a nuclear transcription factor, is required to maintain the stemness of nephron progenitor cells. Transcriptional profiling of Sall1 mutant cells revealed a striking pattern, marked by the reduction of progenitor genes and amplified expression of renal vesicle differentiation genes. These global changes in gene expression were accompanied by ectopic differentiation at E12.5 and depletion of Six2+Cited1+ cap mesenchyme progenitor cells. These findings highlight a novel role for Sall1 in maintaining the stemness of the progenitor cell pool by restraining their differentiation into renal vesicles. © 2014. Published by The Company of Biologists Ltd.

Hansen D.A.,Va St Louis Health Care System | Esakky P.,Va St Louis Health Care System | Esakky P.,University of Washington | Drury A.,Va St Louis Health Care System | And 3 more authors.
Biology of Reproduction | Year: 2014

The aryl hydrocarbon receptor (AHR) is known for its roles in xenobiotic metabolism and essential physiologic processes such as cell growth, death, and differentiation. AHR is also an important regulator of male reproductive processes. However, no studies have characterized the consequences of loss of AHR in spermatogenesis. We used Ahr knockout (Ahr-/-) mice to assess the effects of loss of AHR on the architecture and gene expression of the seminiferous epithelium and functional sperm outcomes. The histopathological defects of the Ahr-/- seminiferous epithelium included vacuoles, multinucleated giant cells, hypocellularity with widened intercellular spaces, apical sloughing, and an excess number of retained elongated spermatids. Quantitative real-time PCR revealed significant down-regulation of Testin and Magea4, indicating Sertoli cell and spermatogenic dysregulation. Moreover, the reduced expression of Hspa2, Prm1, and Prm2 as well as decreased expression of Nrf2, Sod2, and Ucp2 suggested poorly remodeled germ cells with increased vulnerability to oxidative stress. In wild-type sperm, AHR protein was localized to the acrosome and the principal piece of the mature sperm flagellum. The in vitro fertilization rate was significantly lower with Ahr-/- sperm as compared to wild-type sperm, and there were morphologic abnormalities of the Ahr-/- sperm head and tail. Taken together, our data indicate that AHR plays an important role in normal sperm development.

van den Berk-Clark C.,University of Washington | van den Berk-Clark C.,Va St Louis Health Care System | McGuire J.,West Los Angeles Health Care Center
Journal of Health Care for the Poor and Underserved | Year: 2014

We examined whether a combination of predisposing, enabling, need, and primary care experience variables would predict trust in medical health care providers for homeless veterans over 18 months. Linear mixed model analysis indicated that, among these variables, race, social support, service-connected disability status, and satisfaction and continuity with providers predicted trust in provider over time. Trust in providers improved during the initial stages of the relationship between patient and provider and then declined to slightly below baseline levels over time. Further research is needed to determine generalizability and effects of provider trust on patient health care status over longer periods of time. © Meharry Medical College.

Purnell J.Q.,Washington University in St. Louis | Gernes R.,Washington University in St. Louis | Stein R.,University of Washington | Sherraden M.S.,University of Missouri-St. Louis | Knoblock-Hahn A.,VA St Louis Health Care System
Journal of the Academy of Nutrition and Dietetics | Year: 2014

In light of the obesity epidemic, there is growing interest in the use of financial incentives for dietary behavior change. Previous reviews of the literature have focused on randomized controlled trials and found mixed results. The purpose of this systematic review is to update and expand on previous reviews by considering a broader range of study designs, including randomized controlled trials, quasi-experimental, observational, and simulation studies testing the use of financial incentives to change dietary behavior and to inform both dietetic practice and research. The review was guided by theoretical consideration of the type of incentive used based on the principles of operant conditioning. There was further examination of whether studies were carried out with an institutional focus. Studies published between 2006 and 2012 were selected for review, and data were extracted regarding study population, intervention design, outcome measures, study duration and follow-up, and key findings. Twelve studies meeting selection criteria were reviewed, with 11 finding a positive association between incentives and dietary behavior change in the short term. All studies pointed to more specific information on the type, timing, and magnitude of incentives needed to motivate individuals to change behavior, the types of incentives and disincentives most likely to affect the behavior of various socioeconomic groups, and promising approaches for potential policy and practice innovations. Limitations of the studies are noted, including the lack of theoretical guidance in the selection of incentive structures and the absence of basic experimental data. Future research should consider these factors, even as policy makers and practitioners continue to experiment with this potentially useful approach to addressing obesity. © 2014 Academy of Nutrition and Dietetics.

Lawrence D.W.,Saint Louis University | Kornbluth J.,Saint Louis University | Kornbluth J.,Va St Louis Health Care System
Cellular Signalling | Year: 2016

Signal transducer and activator of transcription 1 (STAT1) is critically important for the transcription of a large number of immunologically relevant genes. In macrophages, interferon gamma (IFNγ) signal transduction occurs via the JAK/STAT pathway and ends with the transcription of a number of genes necessary for a successful host immune response. The predominant mechanism of regulation of STAT1 is phosphorylation; however, there is a growing body of evidence that demonstrates STAT1 is also regulated by ubiquitination. In this report we show that JAK1 and STAT1 in macrophages deficient in an E3 ubiquitin ligase termed Natural Killer Lytic-Associated Molecule (NKLAM) are hyperphosphorylated following IFNγ stimulation. We found NKLAM was transiently localized to the IFNγ receptor complex during stimulation with IFNγ, where it bound to and mediated K63-linked ubiquitination of STAT1. In vitro nucleofection studies demonstrated that STAT1-mediated transcription was significantly reduced in NKLAM-KO macrophages. There was no obvious defect in STAT1 nuclear translocation; however, STAT1 from NKLAM-KO macrophages had a reduced ability to bind a functional gamma activation DNA sequence. There was also less mRNA expression of STAT1-mediated genes in NKLAM-KO macrophages treated with IFNγ. Our results demonstrate for the first time that NKLAM is a positive regulator of STAT1-mediated transcriptional activity and is an important component of the innate immune response. © 2016

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