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Salem, VA, United States

Kovesdy C.P.,Salem Veterans Affairs Medical Center | Kovesdy C.P.,University of Virginia | Kalantar-Zadeh K.,University of California at Los Angeles
Seminars in Dialysis | Year: 2012

Uremic malnutrition, also known as protein-energy wasting (PEW), is a common phenomenon in maintenance dialysis patients and a risk factor for poor clinical outcomes including worse quality of life and increased hospitalization and mortality. The paradoxical association between traditional cardiovascular risk factors and better outcomes in dialysis patients also referred to as "reverse epidemiology," is a good example of the powerful effect-modifying impact of the nutritional status in this population. Measures of food intake, body composition tools, nutritional scoring systems, and laboratory values such as serum albumin are used to diagnose PEW and to assess the degree of severity of PEW without clearly validated diagnostic criteria. Some observational studies suggest that inflammation is a missing link between the PEW and poor clinical outcomes in dialysis patients, although PEW per se may also predispose to illness and inflammation. Ongoing debate as to whether such surrogates as serum albumin or prealbumin concentrations are markers of nutritional status, inflammation, comorbidity, or other conditions has led to confusion and diagnostic and therapeutic nihilism. Irrespective of the cause of hypoalbuminemia in dialysis patients, evidence suggests that nutritional interventions can increase serum albumin in dialysis patients. Hence, we should continue assessing serum albumin and other surrogates of nutritional status to risk-stratify patients and to allocate nutritional therapy, while well-designed, large-scale, randomized, controlled trials of the effects of nutritional intake on clinical outcomes are awaited. Published 2012. This article is a U.S. Government work and it is in the public domain in the USA. Source


Richard M.D.,Salem Veterans Affairs Medical Center | Brahm N.C.,University of Oklahoma
American Journal of Health-System Pharmacy | Year: 2012

Purpose. Published evidence on established and theoretical connections between immune system dysfunction and schizophrenia is reviewed, with a discussion of developments in the search for immunologically-targeted treatments. Summary. A growing body of evidence indicates that immunologic influences may play an important role in the etiology and course of schizophrenia. A literature search identified more than 100 articles pertaining to suspected immunologic influences on schizophrenia published over the past 15 years. Schizophrenia researchers have explored a wide range of potential immune system-related causal or contributory factors, including neurobiological and neuroanatomical disorders, genetic abnormalities, and environmental influences such as maternal perinatal infection. Efforts to establish an immunologic basis for schizophrenia and identify reliable immune markers continue to be hindered by sampling challenges and methodological problems. In aggregate, the available evidence indicates that at least some cases of schizophrenia have an immunologic component, suggesting that immune-focused prevention strategies (e.g., counseling of pregnant women to avoid immune stressors) and close monitoring of at-risk children are appropriate. While antipsychotics remain the standard treatments for schizophrenia, a variety of drugs with immunologic effects have been investigated as adjunctive therapies, with variable and sometimes conflicting results; these include the cyclooxygenase-2 inhibitor celecoxib, immune-modulating agents (e.g., azathioprine and various anticytokine agents such as atlizumab, anakinra, and tumor necrosis factor-α blockers), and an investigational anti-interferon-γ agent. Conclusion. The published evidence indicates that immune system dysfunction related to genetic, environmental, and neurobiological influences may play a role in the etiology of schizophrenia in a subset of patients. Copyright © 2012, American Society of Health-System Pharmacists, Inc. All rights reserved. Source


Keenan D.M.,University of Virginia | Iranmanesh A.,Salem Veterans Affairs Medical Center | Veldhuis J.D.,Mayo Medical School
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2011

Luteinizing hormone (LH) administered in pharmacological amounts downregulates Leydig cell steroidogenesis. Whether reversible downregulation of physiological gonadotropin drive operates in vivo is unknown. Most of the analytical models of dose-response functions that have been constructed are biased by the assumption that no downregulation exists. The present study employs a new analytical platform to quantify potential (but not required) pulsatile cycles of LH-testosterone (T) dose-response stimulation, desensitization, and recovery (pulse-by-pulse hysteresis) in 26 healthy men sampled every 10 min for 24 h. A sensitivity-downregulation hysteresis construct predicted marked hysteresis with a median time delay to LH dose-response inflection within individual T pulses of 23 min and with median T pulse onset and recovery LH sensitivities of 1.1 and 0.10 slope unit, respectively (P < 0.001). A potency-downregulation model yielded median estimates of one-half maximally stimulatory LH concentrations (EC50 values) of 0.66 and 7.5 IU/l for onset and recovery, respectively (P < 0.001). An efficacydownregulation formulation of hysteresis forecasts median LH efficacies of 20 and 8.3 ng·dl-1·min-1 for onset and offset of T secretory burst, respectively (P = 0.002). Segmentation of the LH-T data by age suggested greater sensitivity, higher EC50 (increased LH potency), and markedly (2.7-fold) attenuated LH efficacy in older individuals. Each of the three hysteresis models yielded a marked (P < 0.005) reduction in estimated model residual error compared with no hysteresis. In summary, model-based analyses allowing for (but not requiring) reversible pituitary-gonadal effector-response downregulation are consistent with a hypothesis of recurrent, brief cycles of LH-dependent stimulation, desensitization, and recovery of pulsatile T secretion in vivo and an age-associated reduction of LH efficacy. Prospective studies would be required to prove this aging effect. Source


Kovesdy C.P.,Salem Veterans Affairs Medical Center | Kovesdy C.P.,University of Virginia | Kovesdy C.P.,Semmelweis University
Nephrology Dialysis Transplantation | Year: 2012

Metabolic acidosis is a common complication associated with progressive loss of kidney function. The diminishing ability of the kidneys to maintain acidbase homeostasis results in acid accumulation, leading to various complications such as impairment in nutritional status, worsened uremic bone disease and an association with increased mortality. In addition to these adverse effects which are related to acid retention, metabolic acidosis may also cause kidney damage, possibly through the stimulation of adaptive mechanisms aimed at maintaining acidbase homeostasis in the face of decreasing kidney function. Recent clinical trials have suggested that correction or prevention of metabolic acidosis by alkali administration is able to attenuate kidney damage and to slow progression of chronic kidney disease (CKD), and may hence offer an effective, safe and affordable renoprotective strategy. We review the physiology and pathophysiology of acidbase homeostasis in CKD, the mechanisms whereby metabolic acidosis may be deleterious to kidney function, and the results of clinical trials suggesting a benefit of alkali therapy, with special attention to details related to the practical implementation of the results of these trials. © The Author 2012. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. Source


Iranmanesh A.,Salem Veterans Affairs Medical Center | Lawson D.,Salem Veterans Affairs Medical Center | Veldhuis J.D.,Mayo Medical School
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: GH secretion declines rapidly after glucose ingestion and then recovers to higher-than-baseline levels (rebound GH release). Hypothesis: Selective metabolic markers predict the magnitude of glucose-suppressed GH release and postglucose rebound-like GH secretion. Design: Prospectively randomized crossover study of GH secretion after glucose vs. water ingestion. Setting: The study was conducted at a clinical translational research center. Participants: Sixty-nine healthy men aged 19-78 yr with a body mass index of 18-39 kg/m2 participated in the study. Outcomes: Outcomes included nadir vs. peak GH concentrations and basal vs. pulsatile GH secretion. Results: Mean nadir GH concentrations were determined positively by sex hormone binding globulin (SHBG) after glucose administration (R2 = 0.088, P = 0.0077). Peak rebound GH concentrations were related positively to adiponectin and negatively to computed tomography-estimated abdominal visceral fat (AVF) (R2=0.182, P = 0.00049) after glucose ingestion. Deconvolution analysis showed that SHBG specifically predicted basal (nonpulsatile) GH secretion after glucose exposure (R2 = 0.153, P = 0.00052). In contrast, together exercise history and adiponectin (both positively) and AVF (negatively) predicted pulsatile GH escape after glucose suppression (R 2 = 0.206, P = 0.00043). Moreover, adiponectin uniquely determined the size (mass), and AVF the mode (duration), of GH secretory bursts after glucose exposure (both P < 0.006). Conclusion: Glucose ingestion provides a clinical model for investigating complementary metabolic surrogates that determine suppression and recovery of basal and pulsatile GH secretion in healthy men. Copyright © 2012 by The Endocrine Society. Source

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