Exercise for patients with chronic kidney disease: from cells to systems to function.

Chronic kidney disease (CKD) is among the leading causes of death and disability, affecting an estimated 800 million adults globally. The underlying pathophysiology of CKD is complex creating challenges to its management. Primary risk factors for the development and progression of CKD include diabetes mellitus, hypertension, age, obesity, diet, inflammation, and physical inactivity. The high prevalence of diabetes and hypertension in patients with CKD increases the risk for secondary consequences such as cardiovascular disease and peripheral neuropathy. Moreover, the increased prevalence of obesity and chronic levels of systemic inflammation in CKD have downstream effects on critical cellular functions regulating homeostasis. The combination of these factors results in the deterioration of health and functional capacity in those living with CKD. Exercise offers protective benefits for the maintenance of health and function with age, even in the presence of CKD. Despite accumulating data supporting the implementation of exercise for the promotion of health and function in patients with CKD, a thorough description of the responses and adaptations to exercise at the cellular, system, and whole body levels is currently lacking. Therefore, the purpose of this review is to provide an up-to-date comprehensive review of the effects of exercise training on vascular endothelial progenitor cells at the cellular level; cardiovascular, musculoskeletal, and neural factors at the system level; and physical function, frailty, and fatigability at the whole body level in patients with CKD.

Fatigability and the Role of Neuromuscular Impairments in Chronic Kidney Disease.

BACKGROUND: The combination of neuromuscular impairments plus psychosocial aspects of chronic kidney disease (CKD) may predispose these patients to greater risk for experiencing increased levels of fatigability. There has been extensive clinical and scientific interest in the problem of fatigue in CKD and end-stage kidney disease (ESKD) patients, whereas less attention has been directed to understanding fatigability. Accordingly, the primary purposes of this review are to (1) discuss fatigue and fatigability and their potential interactions in patients with CKD and ESKD, (2) provide evidence for increased fatigability in CKD and ESKD patients, (3) examine how commonly experienced neuromuscular impairments in CKD and ESKD patients may contribute to the severity of performance fatigability, and (4) highlight preliminary evidence on the effects of exercise as a potential clinical treatment for targeting fatigability in this population. SUMMARY: Fatigue is broadly defined as a multidimensional construct encompassing a subjective lack of physical and/or mental energy that is perceived by the individual to interfere with usual or desired activities. In contrast, fatigability is conceptualized within the context of physical activity and is quantified as the interactions between reductions in objective measures of performance (i.e., performance fatigability) and perceptual adjustments regulating activity performance (i.e., perceived fatigability). We propose herein a conceptual model to extend current understandings of fatigability by considering the interactions among fatigue, perceived fatigability, and performance fatigability. Neuromuscular impairments reported in patients with CKD and ESKD, including reductions in force capacity, skeletal muscle atrophy, mitochondrial dysfunction, abnormal skeletal muscle excitability, and neurological complications, may each contribute to the greater performance fatigability observed in these patients. KEY MESSAGES: Considering the interactions among fatigue, perceived fatigability, and performance fatigability provides a novel conceptual framework to advance the understanding of fatigability in CKD and ESKD patients. Measures of fatigability may provide valuable clinical insights into the overall health status of CKD and ESKD patients. Existing data suggest that CKD and ESKD patients are at greater risk of experiencing increased fatigability, partly due to neuromuscular impairments associated with reduced kidney function. Further investigations are warranted to determine the potential clinical role fatigability measures can play in monitoring the health of CKD and ESKD patients, and in identifying potential treatments targeting fatigability in this patient population.

Association Between Muscle Strength and Modeling Estimates of Muscle Tissue Heterogeneity in Young and Old Adults.

OBJECTIVES: Assessing aging muscle through estimates of muscle heterogeneity may overcome some of the limitations of grayscale analyses. The objectives of this study included determining statistical model parameters that characterize muscle echogenicity and are associated with strength in younger and older participants. METHODS: Thirty-three community-dwelling participants were assigned to younger and older groups. Quantitative B-mode ultrasound scanning of the rectus femoris and isometric grip strength testing were completed. Shape or dispersion parameters from negative binomial distribution, Nakagami, gamma, and gamma mixture models were fitted to the grayscale histograms. RESULTS: The mean ages ± SDs of the younger and older groups were 24.0 ± 2.3 and 65.1 ± 6.5 years, respectively. Statistical model shape and dispersion parameters for the grayscale histograms significantly differed between the younger and older participants (P = .002-.006). Among all of the statistical models considered, the gamma mixture model showed the best fit with the grayscale histograms (χ2 goodness of fit = 62), whereas the Nakagami distribution displayed the poorest fit (χ2 goodness of fit = 2595). Grayscale values were significantly associated with peak grip strength force in younger adult participants (R2 = 0.36; P < .008). However, the negative binomial dispersion parameter k (adjusted R2 = 0.70; P < .001) and gamma shape parameter α (adjusted R2 = 0.68; P < .01) showed the highest associations with peak grip strength force in older adult participants. CONCLUSIONS: The negative binomial dispersion parameter k and the gamma shape parameter α have clinical relevance for the assessment of age-related muscle changes. Statistical models of muscle heterogeneity may characterize the association between muscle tissue composition estimates and strength better than grayscale measures in samples of community-dwelling older adults.

Differential expression of Annexin 2, SPINK1, and Hsp60 predict progression of prostate cancer through bifurcated WHO Gleason score categories in African American men.

BACKGROUND: Although studies have observed several markers correlate with progression of prostate cancer (PCa), no specific markers have been identified that accurately predict the progression of this disease, even in African American (AA) men who are generally at higher risk than other ethnic groups. The primary goal of this study was to explore whether three markers could predict the progression of PCa. METHOD: We investigated protein expression of Annexin 2 (ANX2), serine peptidase inhibitor, kazal type 1(SPINK1)/tumor-associated trypsin inhibitor (TATI), and heat shock protein 60 (Hsp60) in 79 archival human prostate trans-rectal ultrasound (TRUS) biopsy tissues according to a modified World Health Organization (WHO) classification: normal (WHO1a), Gleason Score (GS6 (WHO1b), GS7 subgroups (WHO2 = 3 + 4, WHO3 = 4 + 3), GS8 (WHO4), and GS9-10 (WHO5). AA men aged 41-90 diagnosed from 1990 to 2013 at Howard University were included. Automated staining assessed expression of each biomarker. Spearman correlation assessed the direction and relationship between biomarkers, WHO and modified WHO GS, age, and 5-year survival. A two-tailed t-test and ANOVA evaluated biomarkers expression in relationship to WHO normal and other GS levels, and between WHO GS levels. A logistic and linear regression analysis examined the relationship between biomarker score and WHO GS categories. Kaplan-Meier curves graphed survival. RESULTS: ANX2 expression decreased monotonically with the progression of PCa while expression of SPINK1/TATI and Hsp60 increased but had a more WHO GS-specific effect; SPINK1/TATI differed between normal and GS 2-6 and HSP60 differed between GS 7 and GS 2-6. WHO GS was found to be significantly and negatively associated with ANX2, and positively with SPINK1/TATI and Hsp60 expression. High SPINK1/TATI expression together with the low ANX2 expression at higher GS exhibited a bi-directional relationship that is associated with PCa progression and survival. CONCLUSION: Importantly, the data reveal that ANX2, and SPINK1/TAT1 highly associate with WHO GS and with the transition from one stage of PrCa to the next in AA men. Future research is needed in biracial and larger population studies to confirm this dynamic relationship between ANX2 and SPINK1 as independent predictors of PCa progression in all men.

Challenges to be overcome using population-based sampling methods to recruit veterans for a study of post-traumatic stress disorder and traumatic brain injury.

BACKGROUND: Many investigators are interested in recruiting veterans from recent conflicts in Afghanistan and Iraq with Traumatic Brain Injury (TBI) and/or Post Traumatic Stress Disorder (PTSD). Researchers pursuing such studies may experience problems in recruiting sufficient numbers unless effective strategies are used. Currently, there is very little information on recruitment strategies for individuals with TBI and/or PTSD. It is known that groups of patients with medical conditions may be less likely to volunteer for clinical research. This study investigated the feasibility of recruiting veterans returning from recent military conflicts--Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF)--using a population-based sampling method. METHODS: Individuals were sampled from a previous epidemiological study. Three study sites focused on recruiting survey respondents (n = 445) who lived within a 60 mile radius of one of the sites. RESULTS: Overall, the successful recruitment of veterans using a population-based sampling method was dependent on the ability to contact potential participants following mass mailing. Study enrollment of participants with probable TBI and/or PTSD had a recruitment yield (enrolled/total identified) of 5.4%. We were able to contact 146 individuals, representing a contact rate of 33%. Sixty-six of the individuals contacted were screened. The major reasons for not screening included a stated lack of interest in the study (n = 37), a failure to answer screening calls after initial contact (n = 30), and an unwillingness or inability to travel to a study site (n = 10). Based on the phone screening, 36 veterans were eligible for the study. Twenty-four veterans were enrolled, (recruitment yield = 5.4%) and twelve were not enrolled for a variety of reasons. CONCLUSIONS: Our experience with a population-based sampling method for recruitment of recent combat veterans illustrates the challenges encountered, particularly contacting and screening potential participants. The screening and enrollment data will help guide recruitment for future studies using population-based methods.

A diagnostic scoring system for myxedema coma.

OBJECTIVE: To develop diagnostic criteria for myxedema coma (MC), a decompensated state of extreme hypothyroidism with a high mortality rate if untreated, in order to facilitate its early recognition and treatment. METHODS: The frequencies of characteristics associated with MC were assessed retrospectively in patients from our institutions in order to derive a semiquantitative diagnostic point scale that was further applied on selected patients whose data were retrieved from the literature. Logistic regression analysis was used to test the predictive power of the score. Receiver operating characteristic (ROC) curve analysis was performed to test the discriminative power of the score. RESULTS: Of the 21 patients examined, 7 were reclassified as not having MC (non-MC), and they were used as controls. The scoring system included a composite of alterations of thermoregulatory, central nervous, cardiovascular, gastrointestinal, and metabolic systems, and presence or absence of a precipitating event. All 14 of our MC patients had a score of ≥60, whereas 6 of 7 non-MC patients had scores of 25 to 50. A total of 16 of 22 MC patients whose data were retrieved from the literature had a score ≥60, and 6 of 22 of these patients scored between 45 and 55. The odds ratio per each score unit increase as a continuum was 1.09 (95% confidence interval [CI], 1.01 to 1.16; P = .019); a score of 60 identified coma, with an odds ratio of 1.22. The area under the ROC curve was 0.88 (95% CI, 0.65 to 1.00), and the score of 60 had 100% sensitivity and 85.71% specificity. CONCLUSION: A score ≥60 in the proposed scoring system is potentially diagnostic for MC, whereas scores between 45 and 59 could classify patients at risk for MC.

Ultrasound measures of muscle morphology in people with multiple sclerosis are associated with muscle performance and functional mobility.

BACKGROUND: Neurologically-based muscle weakness is a common symptom in people with multiple sclerosis MS (MS), who may also exhibit muscle morphology changes and intrinsic muscle dysfunction. Diagnostic ultrasound (sonography) is a non-invasive, inexpensive, and clinically feasible method to measure muscle morphology. The purpose of this study was to investigate possible asymmetries in lower limb muscle morphology and performance in people with MS, and to assess the relationships of muscle morphology measures with individual patient characteristics, muscle performance, and functional mobility. METHODS: This cross-sectional study was conducted at the Washington, DC Veterans Affairs Medical Center. The study participants were 29 Veterans with MS (52% female, 79% African-American, 48.6 ± 11.2 years old, Mean Expanded Disability Status Scale: 3.6 ± 1.4) who completed seated knee extension isokinetic strength and power tests, functional assessments (Timed 25-Foot Walk - T25FW, 5-Times Sit-to-Stand - 5STS), and quantitative B-mode ultrasound image acquisition of the rectus femoris muscle to derive morphology measures (thickness and echogenicity). The limb with weaker knee extension strength was identified as the more-involved limb. Differences between the more and less-involved limb were quantified using a t-test for all muscle morphology and muscle performance measures. Relationships between muscle morphology and patient characteristics, muscle performance, and functional mobility were evaluated using bivariate and multivariate analyses. RESULTS: The rectus femoris thickness from the more-involved limb was lower (p<0.001) than that of the less-involved limb, whereas echogenicity was not different between the two limbs (p=0.147). Rectus femoris thickness of the more-involved limb was directly related to age (r=-0.63, p<0.001), muscle strength (r=0.53, p=0.003) and power (r=0.53, p=0.003), and gait speed (r=0.42, p=0.024); whereas its echogenicity was positively associated only with muscle strength (r=-0.46, p=0.013) and power (r=-0.50, p=0.006). Together rectus femoris thickness and echogenicity of the more involved limb explained 44% and 48% of the variance in muscle strength and power, respectively (p<0.001). CONCLUSION: This study supports the ability of sonography to measure muscle morphology in people with MS, identify asymmetries, and quantify associations with important clinical correlates. Compared with more invasive and costly alternatives, sonography is a clinically feasible, relatively low-cost tool that can be used to assess muscle morphology in people with MS. Further research is warranted to determine the potential clinical utility of sonographic measures of muscle morphology in evaluating changes due to disease progression or therapeutic interventions in this population.

Antibody-directed neutralization of annexin II (ANX II) inhibits neoangiogenesis and human breast tumor growth in a xenograft model.

Activation of the fibrinolytic pathway has long been associated with human breast cancer. Plasmin is the major end product of the fibrinolytic pathway and is critical for normal physiological functions. The mechanism by which plasmin is generated in breast cancer is not yet fully described. We previously identified annexin II (ANX II), a fibrinolytic receptor, in human breast tumor tissue samples and observed a strong positive correlation with advanced stage cancer (Sharma et al., 2006a). We further demonstrated that tissue plasminogen activator (tPA) binds to ANX II in invasive breast cancer MDA-MB231cells, which leads to plasmin generation (Sharma et al., 2010). We hypothesize that ANX II-dependent plasmin generation in breast tumor is necessary to trigger the switch to neoangiogenesis, thereby stimulating a more aggressive cancer phenotype. Our immunohistochemical studies of human breast tumor tissues provide compelling evidence of a strong positive correlation between ANX II expression and neoangiogenesis, and suggest that ANX II is a potential target to slow or inhibit breast tumor growth by inhibiting neoangiogenesis. We now report that administration of anti-ANX II antibody potently inhibits the growth of human breast tumor in a xenograft model. Inhibition of tumor growth is at least partly due to attenuation of neoangiogenic activity within the tumor. In vitro studies demonstrate that anti-ANX II antibody inhibits angiogenesis on three dimensional matrigel cultures by eliciting endothelial cell (EC) death likely due to apoptosis. Taken together, these data suggest that selective disruption of the fibrinolytic activity of ANX II may provide a novel strategy for specific inhibition of neoangiogenesis in human breast cancer.

Rate of Force Development Is Related to Maximal Force and Sit-to-Stand Performance in Men With Stages 3b and 4 Chronic Kidney Disease.

INTRODUCTION: The primary aims of the present study were to assess the relationships of early (0-50 ms) and late (100-200 ms) knee extensor rate of force development (RFD) with maximal voluntary force (MVF) and sit-to-stand (STS) performance in participants with chronic kidney disease (CKD) not requiring dialysis. METHODS: Thirteen men with CKD (eGFR = 35.17 ±.5 ml/min per 1.73 m2, age = 70.56 ±.4 years) and 12 non-CKD men (REF) (eGFR = 80.31 ± 4.8 ml/min per 1.73 m2, age = 70.22 ±.9 years) performed maximal voluntary isometric contractions to determine MVF and RFD of the knee extensors. RFD was measured at time intervals 0-50 ms (RFD0-50) and 100-200 ms (RFD100-200). STS was measured as the time to complete five repetitions. Measures of rectus femoris grayscale (RF GSL) and muscle thickness (RF MT) were obtained via ultrasonography in the CKD group only. Standardized mean differences (SMD) were used to examine differences between groups. Bivariate relationships were assessed by Pearson's product moment correlation. RESULTS: Knee extensor MVF adjusted for body weight (CKD=17.14 ±.1 N·kg0.67, REF=21.55 ±.3 N·kg0.67, SMD = 0.79) and STS time (CKD = 15.93 ±.4 s, REF = 12.23 ±.7 s, SMD = 1.03) were lower in the CKD group than the REF group. Absolute RFD100-200 was significantly directly related to adjusted MVF in CKD (r = 0.56, p = 0.049) and REF (r = 0.70, p = 0.012), respectively. STS time was significantly inversely related to absolute (r = -0.75, p = 0.008) and relative RFD0-50 (r = -0.65, p = 0.030) in CKD but not REF (r = 0.08, p = 0.797; r = 0.004, p = 0.991). Significant inverse relationships between RF GSL adjusted for adipose tissue thickness and absolute RFD100-200 (r =-0.59, p = 0.042) in CKD were observed. CONCLUSION: The results of the current study highlight the declines in strength and physical function that occur in older men with CKD stages 3b and 4 not requiring dialysis. Moreover, early RFD was associated with STS time in CKD while late RFD was associated MVF in both CKD and REF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT03160326 and NCT02277236.

Chronic Neurobehavioral Impairments and Decreased Hippocampal Expression of Genes Important for Brain Glucose Utilization in a Mouse Model of Mild TBI.

Glucose is an essential cellular fuel for maintaining normal brain functions. Traumatic brain injury (TBI) decreases brain glucose utilization in both human and experimental animals during the acute or subacute phase of TBI. It remains unclear as to how the damages affect brain glucose utilization and its association with persistent neurobehavioral impairments in the chronic phase of mild TBI (mTBI). Accordingly, we compared expression of selected genes important to brain glucose utilization in different brain regions of mice during the chronic phase in mTBI vs. sham operated mice. These genes included hexokinase-1 (HK1), phosphofructokinase (PFK), pyruvate kinase (PK), pyruvate dehydrogenase (PDH), capillary glucose transporter (Glut-1), neuron glucose transporter (Glut-3), astrocyte lactate transpor1 (MCT-1), neuron lactate transporter (MCT-2), lactate receptor (GPR81), and Hexokinase isoform-2 (HK2). Young adult male C57BL/6J mice were brain injured with repetitive closed-head concussions. Morris water maze (MWM), elevated plus maze (EPM), and neurological severity score test (NSS) were performed for evaluation of mice neurobehavioral impairments at 2, 4, and 6 months post mTBI. Two days after completion of the last behavioral test, the frontal cortex, hippocampus, brainstem, hypothalamus, and cerebellum were collected for gene expression measurements. The expression of the mRNAs encoding PK, and PDH, two critical enzymes in glucose metabolism, was decreased at all-time points only in the hippocampus, but was unchanged in the brainstem, hypothalamus, and cortex in mTBI mice. mTBI mice also exhibited the following behavioral alterations: (1) decreased spatial learning and memory 2, 4, and 6 months after the injury, (2) increased proportion of time spent on open vs. closed arms determined by EPM, and (3) accelerated reduction in motor activity observed at 4 months, two months earlier than observed in the sham group, during the EPM testing. There were no significant differences in NSS between injury and sham groups at any of the three time points. Thus, mTBI in male mice led to persistent decreased hippocampal expression of mRNAs that encode critical glucose utilization related enzymes in association with long-term impairments in selected neurobehavioral outcomes.

Complementary and alternative medicine (CAM).

The use of complementary and alternative medicine (CAM) appears to be on the rise in all adult age groups, including the elderly population. Many herbal and biologic preparations offer promise, but they are largely of unproven benefit. The content(s) are unregulated by government agencies, such as the Food and Drug Administration, making their use problematic to recommend and guide. Use of CAM modalities in assisted living communities (ALCs) is by and large a hidden practice, but it is estimated that 5%-9% of residents ingest some kind of herbal remedy. Belief systems among residents and their families-for example, that a certain kind of tea is a cure for dementia-can be persuasive. Responsible for resident well-being, assisted living nurses are caught in the middle. Nurse licensure considers herbals as medications, yet physicians refuse to prescribe them, and nurses (or certified med techs) cannot administer them. In some states, "alternative practitioners" are not viewed as legal prescribers. Undaunted, residents (or their families) purchase alternative "medicines" that are contraindicated by their traditional medical regimen. Secreted in their room, nurses are unaware of the stash and the self-administrating practice. This article describes the state of the science regarding the efficacy and safety of CAM modalities and actions that ALC nurses might undertake to collaborate with residents to address their CAM interest and use respectfully.

Effects of growth hormone on hepatic insulin sensitivity and glucose effectiveness in healthy older adults.

PURPOSE: Growth hormone (GH) replacement decreases insulin sensitivity in healthy individuals. However, the effects of GH on organ-specific insulin sensitivity and glucose effectiveness are not well characterized. The purpose of this study was to evaluate the effects of GH administration for 26 weeks on muscle and hepatic insulin sensitivity and glucose effectiveness in healthy older individuals. METHODS: This report is from a 26-week randomized, double-blind, placebo-controlled parallel-group trial in healthy, ambulatory, community-dwelling older women and men. We compared surrogate indices of insulin sensitivity [quantitative insulin-sensitivity check index (QUICKI), muscle insulin sensitivity index (MISI), hepatic insulin resistance index (HIRI)] and glucose effectiveness [oral glucose effectiveness index (oGE)] derived from oral glucose tolerance tests (OGTTs) in subjects before and after 26 weeks of administration of GH (n = 17) or placebo (n = 15) as an exploratory outcome. RESULTS: GH administration for 26 weeks significantly increased fasting insulin concentrations and HIRI but did not significantly change MISI or oGE compared to placebo. CONCLUSIONS: GH administration for 26 weeks in healthy older subjects impairs insulin sensitivity in the liver but not skeletal muscle and does not alter glucose effectiveness.

Lycopene inhibits IGF-I signal transduction and growth in normal prostate epithelial cells by decreasing DHT-modulated IGF-I production in co-cultured reactive stromal cells.

Prostate stromal and epithelial cell communication is important in prostate functioning and cancer development. Primary human stromal cells from normal prostate stromal cells (PRSC) maintain a smooth muscle phenotype, whereas those from prostate cancer (6S) display reactive and fibroblastic characteristics. Dihydrotestosterone (DHT) stimulates insulin-like growth factor-I (IGF-I) production by 6S but not PSRC cells. Effects of reactive versus normal stroma on normal human prostate epithelial (NPE or PREC) cells are poorly understood. We co-cultured NPE plus 6S or PRSC cells to compare influences of different stromal cells on normal epithelium. Because NPE and PREC cells lose androgen receptor (AR) expression in culture, DHT effects must be modulated by associated stromal cells. When treated with camptothecin (CM), NPE cells, alone and in stromal co-cultures, displayed a dose-dependent increase in DNA fragmentation. NPE/6S co-cultures exhibited reduced CM-induced cell death with exposure to DHT, whereas NPE/PRSC co-cultures exhibited CM-induced cell death regardless of DHT treatment. DHT blocked CM-induced, IGF-I-mediated, NPE death in co-cultured NPE/6S cells without, but not with, added anti-IGF-I and anti-IGF-R antibodies. Lycopene consumption is inversely related to human prostate cancer risk and inhibits IGF-I and androgen signaling in rat prostate cancer. In this study, lycopene, in dietary concentrations, reversed DHT effects of 6S cells on NPE cell death, decreased 6S cell IGF-I production by reducing AR and beta-catenin nuclear localization and inhibited IGF-I-stimulated NPE and PREC growth, perhaps by attenuating IGF-I's effects on serine phosphorylation of Akt and GSK3beta and tyrosine phosphorylation of GSK3. This study expands the understanding of the preventive mechanisms of lycopene in prostate cancer.

Human prostate stromal cells stimulate increased PSA production in DHEA-treated prostate cancer epithelial cells.

Dehydroepiandrosterone (DHEA) is commonly used as a dietary supplement and may affect prostate pathophysiology when metabolized to androgens and/or estrogens. Human prostate LAPC-4 cancer cells with a wild type androgen receptor (AR) were treated with DHEA, androgens dihydrotestosterone (DHT), T, or R1881), and E2 and assayed for prostate specific antigen (PSA) protein and gene expression. In LAPC-4 monocultures, DHEA and E2 induced little or no increase in PSA protein or mRNA expression compared to androgen-treated cells. When prostate cancer-associated (6S) stromal cells were added in coculture, DHEA stimulated LAPC-4 cell PSA protein secretion to levels approaching induction by DHT. Also, DHEA induced 15-fold more PSA mRNA in LAPC-4 cocultures than in monocultures. LAPC-4 proliferation was increased 2-3-fold when cocultured with 6S stromal cells regardless of hormone treatment. DHEA-treated 6S stromal cells exhibited a dose- and time-dependent increase in T secretion, demonstrating stromal cell metabolism of DHEA to T. Coculture with non-cancerous stroma did not induce LAPC-4 PSA production, suggesting a differential modulation of DHEA effect in a cancer-associated prostate stromal environment. This coculture model provides a research approach to reveal detailed endocrine, intracrine, and paracrine signaling between stromal and epithelial cells that regulate tissue homeostasis within the prostate, and the role of the tumor microenvironment in cancer progression.

Mitochondria as key components of the stress response.

The exquisitely orchestrated adaptive response to stressors that challenge the homeostasis of the cell and organism involves important changes in mitochondrial function. A complex signaling network enables mitochondria to sense internal milieu or environmental changes and to adjust their bioenergetic, thermogenic, oxidative and/or apoptotic responses accordingly, aiming at re-establishment of homeostasis. Mitochondrial dysfunction is increasingly recognized as a key component in both acute and chronic allostatic states, although the extent of its role in the pathogenesis of such conditions remains controversial. Genetic and environmental factors that determine mitochondrial function might contribute to the significant variation of the stress response. Understanding the often reciprocal interplay between stress mediators and mitochondrial function is likely to help identify potential therapeutic targets for many stress and mitochondria-related pathologies.

Low bone mass in premenopausal women with depression.

BACKGROUND: An increased prevalence of low bone mineral density (BMD) has been reported in patients with major depressive disorder (MDD), mostly women. METHODS: Study recruitment was conducted from July 1, 2001, to February 29, 2003. We report baseline BMD measurements in 89 premenopausal women with MDD and 44 healthy control women enrolled in a prospective study of bone turnover. The BMD was measured by dual-energy x-ray absorptiometry at the spine, hip, and forearm. Mean hourly levels of plasma 24-hour cytokines, 24-hour urinary free cortisol, and catecholamine excretion were measured in a subset of women. We defined MDD according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). RESULTS: The prevalence of low BMD, defined as a T score of less than -1, was greater in women with MDD vs controls at the femoral neck (17% vs 2%; P = .02) and total hip (15% vs 2%; P = .03) and tended to be greater at the lumbar spine (20% vs 9%; P = .14). The mean +/- SD BMD, expressed as grams per square centimeters, was lower in women with MDD at the femoral neck (0.849 +/- 0.121 vs 0.866 +/- 0.094; P = .05) and at the lumbar spine (1.024 +/- 0.117 vs 1.043 +/- 0.092; P = .05) and tended to be lower at the radius (0.696 +/- 0.049 vs 0.710 +/- 0.055; P = .07). Women with MDD had increased mean levels of 24-hour proinflammatory cytokines and decreased levels of anti-inflammatory cytokines. CONCLUSIONS: Low BMD is more prevalent in premenopausal women with MDD. The BMD deficits are of clinical significance and comparable in magnitude to those resulting from established risk factors for osteoporosis, such as smoking and reduced calcium intake. The possible contribution of immune or inflammatory imbalance to low BMD in premenopausal women with MDD remains to be clarified.

The Comparative Associations of Ultrasound and Computed Tomography Estimates of Muscle Quality with Physical Performance and Metabolic Parameters in Older Men.

Estimates of muscle tissue composition may have greater prognostic value than lean body mass levels regarding health-related outcomes. Ultrasound provides a relatively low cost, safe, and accessible mode of imaging to assess muscle morphology. The purpose of this study was to determine the construct validity of muscle echogenicity as a surrogate measure of muscle quality in a sample of older, predominantly African American (AA) participants. We examined the association of rectus femoris echogenicity with mid-thigh computed tomography (CT) scan estimates of intra- and intermuscular adipose tissue (IMAT), basic metabolic parameters via blood sample analysis, muscle strength, and mobility status. This observational study was conducted at a federal medical center and included 30 community-dwelling men (age, 62.5 ± 9.2; AA, n = 24; Caucasian, n = 6). IMAT estimates were significantly associated with echogenicity (r = 0.73, p < 0.001). Echogenicity and IMAT exhibited similar associations with the two-hour postprandial glucose values and high-density lipoproteins values (p < 0.04), as well as grip and isokinetic (180°/s) knee extension strength adjusted for body size (p < 0.03). The significant relationship between ultrasound and CT muscle composition estimates, and their comparative association with key health-related outcomes, suggests that echogenicity should be further considered as a surrogate measure of muscle quality.

Similar clinical benefits from below-target and target dose enalapril in patients with heart failure in the SOLVD Treatment trial.

AIMS: To examine associations of below-target and target dose of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, with outcomes in patients with heart failure and reduced ejection fraction (HFrEF) in the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial. METHODS AND RESULTS: Two thousand five hundred and sixty-nine patients with HFrEF (ejection fraction ≤35%) were randomized to below-target (5-10 mg/day) dose placebo (n = 1284) or enalapril (n = 1285). One month post-randomization, blind up-titration to target (20 mg/day) dose was attempted for both study drugs in 2458 patients. Among the 1444 patients who achieved dose up-titration (placebo, n = 748; enalapril, n = 696; mean dose for both groups, 20.0 mg/day), target dose enalapril (vs. target dose placebo) was associated with a 9% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality [adjusted hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.60-0.81; P < 0.001] during 4 years of follow-up. Among the 1014 patients who could not achieve target dose (placebo, n = 486; enalapril, n = 528; mean dose for both groups, 8.8 mg/day), below-target dose enalapril (vs. below-target dose placebo) was associated with a 12% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 0.68; 95% CI 0.57-0.81; P < 0.001). Among the 1224 patients receiving enalapril, target (vs. below-target) dose had no association with the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 1.04; 95% CI 0.87-1.23; P = 0.695). CONCLUSION: In patients with HFrEF, the clinical benefits of ACE inhibitors appear to be similar at both below-target and target doses.

Aging, androgens, and the metabolic syndrome in a longitudinal study of aging.

BACKGROUND: Based on Adult Treatment Panel III criteria, we previously reported that the prevalence of the metabolic syndrome (MS) increased with aging; was higher if elevated 2-h plasma postglucose challenge values were included as a criterion; and was greater in men, compared with women. The aim of this study was to evaluate the relationship between the MS and circulating androgen levels in a cohort of men in the Baltimore Longitudinal Study of Aging. METHODS AND RESULTS: Study participants were Caucasian community-dwelling adult men in the Baltimore Longitudinal Study of Aging, who underwent a fasting 2-h oral glucose tolerance test and had serum concentrations of total testosterone (T), dehydroepiandrosterone sulfate, and SHBG levels measured. The prevalence of the MS was 4, 21, 21, and 18% for men between the ages of 20 and 39, 40 and 59, 60 and 79, and 80 and 94 yr, respectively. Total T and SHBG were inversely related to the development of the MS over a mean follow-up period of 5.8 yr (range 1.5-14.0 yr), whereas the free T index and body mass index were positively related to the incidence of the MS. Age alone did not predict the development of the MS, nor did the inclusion of abnormal 2-h plasma postglucose challenge levels in the classification of the MS. Stepwise proportional hazards regression analyses showed that among the various measurements, SHBG levels exerted the greatest influence on development of the MS. CONCLUSION: The prevalence of the MS increased with aging, and this was associated with lower androgen levels. Lower total T and SHBG predicted a higher incidence of the MS.

Determinants of serum total and free testosterone levels in women over the age of 65 years.

CONTEXT: Little is known about testosterone (T) levels and their determinants in women of late postmenopausal age. OBJECTIVE: We describe levels of total and free T and selected factors that influence these levels in a random sample of older women. DESIGN: Levels of serum total T and free T by microdialysis were measured using ultrasensitive assays in 347 community-dwelling women aged 65-98 yr enrolled in the Cardiovascular Health Study. Cross-sectional analyses were performed to define factors associated with total and free T levels. RESULTS: In adjusted models: 1) total T levels declined with age until 80, whereas free T levels did not vary by age; 2) women with bilateral oophorectomy had 23% lower total T and 16% lower free T levels than those with at least one intact ovary; 3) oral estrogen users had total and free T levels that were 47% lower than never users; 4) obese women had 47% higher total T and 20% higher free T levels, and overweight women had 24% higher total T and 14% higher free T levels, than normal weight women; and 5) free T levels were 51% higher in black women. Corticosteroid users had 75% lower total T and 43% lower free T levels than nonusers. CONCLUSIONS: Bilateral oophorectomy, estrogen use, corticosteroid use, and low body mass index are independent risk factors for lower T levels in women aged 65 yr and over. Although highly prevalent in women of this age, the physiological significance of low T levels in late postmenopausal women requires further investigation.