Wm. Jennings Bryan Dorn VA Medical Center

Healthy biological systems exhibit complex patterns of variability that can be described by mathematical chaos. Heart rate variability (HRV) consists of changes in the time intervals between consecutive heartbeats called interbeat intervals (IBIs). A healthy heart is not a metronome. The oscillations of a healthy heart are complex and constantly changing, which allow the cardiovascular system to rapidly adjust to sudden physical and psychological challenges to homeostasis. This article briefly reviews current perspectives on the mechanisms that generate 24 h, short-term (~5 min), and ultra-short-term (<5 min) HRV, the importance of HRV, and its implications for health and performance. The authors provide an overview of widely-used HRV time-domain, frequency-domain, and non-linear metrics. Time-domain indices quantify the amount of HRV observed during monitoring periods that may range from ~2 min to 24 h. Frequency-domain values calculate the absolute or relative amount of signal energy within component bands. Non-linear measurements quantify the unpredictability and complexity of a series of IBIs. The authors survey published normative values for clinical, healthy, and optimal performance populations. They stress the importance of measurement context, including recording period length, subject age, and sex, on baseline HRV values. They caution that 24 h, short-term, and ultra-short-term normative values are not interchangeable. They encourage professionals to supplement published norms with findings from their own specialized populations. Finally, the authors provide an overview of HRV assessment strategies for clinical and optimal performance interventions.

Further investigation of the biological properties of streptococcal cells and their components has produced a model of erosive synovitis in rats. A single intraperitoneal injection of an aqueous suspension of whole cell sonicate of group A streptococci into Sprague-Dawley rats induced an acute arthritis which evolved into a prolonged inflammatory process characterized by several complete or partial remissions, joint deformity, and ankylosis. The toxic moiety is a peptidoglycan-polysaccharide fragment of the cell wall which persists in tissue. Histologic features of the arthritis include an acute exudative phase followed by an erosive synovitis that leads to destruction of cartilage and subchondral bone and fibrous ankylosis of the joints. The arthropathic properties of whole cell sonicates of several species of streptococci are compared along with studies of the ability of heat-killed, whole cells of groups A, B, and C streptococci to induce arthritis in rats. Whole cells induce arthritis after a latent period of 57-120 days when group A cells are injected and 7-10 days when group B cells are tested.

BACKGROUND: Despite limited and conflicting data on the use of hydroxychloroquine in patients with Covid-19, the U.S. Food and Drug Administration has authorized the emergency use of this drug when clinical trials are unavailable or infeasible. Hydroxychloroquine, alone or in combination with azithromycin, is being widely used in Covid-19 therapy based on anecdotal and limited observational evidence. METHODS: We performed a retrospective analysis of data from patients hospitalized with confirmed SARS-CoV-2 infection in all United States Veterans Health Administration medical centers until April 11, 2020. Patients were categorized based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) as treatments in addition to standard supportive management for Covid-19. The two primary outcomes were death and the need for mechanical ventilation. We determined the association between treatment and the primary outcomes using competing risk hazard regression adjusting for clinical characteristics via propensity scores. Discharge and death were taken into account as competing risks and subdistribution hazard ratios are presented. RESULTS: A total of 368 patients were evaluated (HC, n=97; HC+AZ, n=113; no HC, n=158). Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively. Compared to the no HC group, the risk of death from any cause was higher in the HC group (adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P=0.03) but not in the HC+AZ group (adjusted hazard ratio, 1.14; 95% CI, 0.56 to 2.32; P=0.72). The risk of ventilation was similar in the HC group (adjusted hazard ratio, 1.43; 95% CI, 0.53 to 3.79; P=0.48) and in the HC+AZ group (adjusted hazard ratio, 0.43; 95% CI, 0.16 to 1.12; P=0.09), compared to the no HC group. CONCLUSIONS: In this study, we found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19. An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone. These findings highlight the importance of awaiting the results of ongoing prospective, randomized, controlled studies before widespread adoption of these drugs.

STUDY OBJECTIVES: To evaluate the efficacy of a 12-week exercise training program for reducing obstructive sleep apnea (OSA) severity and improving sleep quality, and to explore possible mechanisms by which exercise may reduce OSA severity. DESIGN: Randomized controlled trial. SETTING: Clinical exercise physiology center, sleep laboratory. PARTICIPANTS: Forty-three sedentary and overweight/obese adults aged 18-55 years with at least moderate-severity untreated OSA (screening apnea-hypopnea index [AHI] ≥ 15). INTERVENTIONS: Participants randomized to exercise training (n = 27) met 4 times/week for 12 weeks and performed 150 min/week of moderate-intensity aerobic activity, followed by resistance training twice/week. Participants randomized to a stretching control (n = 16) met twice weekly for 12 weeks to perform low-intensity exercises designed to increase whole-body flexibility. MEASUREMENTS AND RESULTS: OSA severity was assessed with one night of laboratory polysomnography (PSG) before and following the 12-week intervention. Measures of sleep quality included PSG, actigraphy (7-10 days), and the Pittsburgh Sleep Quality Index. Compared with stretching, exercise resulted in a significant AHI reduction (exercise: 32.2 ± 5.6 to 24.6 ± 4.4, stretching: 24.4 ± 5.6 to 28.9 ± 6.4; P < 0.01) as well as significant changes in oxygen desaturation index (ODI; P = 0.03) and stage N3 sleep (P = 0.03). Reductions in AHI and ODI were achieved without a significant decrease in body weight. Improvements in actigraphic sleep and subjective sleep quality were also noted following exercise compared with stretching. CONCLUSIONS: Exercise training had moderate treatment efficacy for the reduction of AHI in sedentary overweight/obese adults, which suggests that exercise may be beneficial for the management of OSA beyond simply facilitating weight loss. TRIAL REGISTRATION: Clinicaltrials.gov identification number NCT00956423.

OBJECTIVES: To determine whether the dietary inflammatory index (DII) is associated with inflammatory or metabolic biomarkers and metabolic syndrome (MetSyn) among police officers. METHODS: Cross-sectional data from the Buffalo Cardio-Metabolic Occupational Police Stress study were derived from saliva and fasting blood samples, anthropometric measurements, long-term shiftwork histories, and demographic, stress/depression, and food frequency questionnaires (FFQs). Metabolic syndrome was defined using standard criteria. RESULTS: Officers in DII quartiles 2 to 4 were more likely to exceed a threshold of 3.0 mg/L for C-reactive protein (odds ratio [OR] = 1.88; 95% confidence interval [95% CI] = 1.02 to 3.45; OR = 2.17; 95% CI = 1.19 to 3.95; OR = 1.57; 95% CI = 0.85 to 2.88, respectively) compared with quartile 1. The glucose intolerance component of MetSyn was more prevalent among officers in DII quartile 4 than among those in quartile 1 (OR = 2.03; 95% CI = 1.08 to 3.82). CONCLUSIONS: A pro-inflammatory diet was associated with elevated CRP and with the glucose intolerance component of MetSyn.

Probiotics contain microorganisms, most of which are bacteria similar to the beneficial bacteria that occur naturally in the human gut. Probiotics have been widely studied in a variety of gastrointestinal diseases. The most-studied species include Lactobacillus, Bifidobacterium, and Saccharomyces. However, a lack of clear guidelines on when to use probiotics and the most effective probiotic for different gastrointestinal conditions may be confusing for family physicians and their patients. Probiotics have an important role in the maintenance of immunologic equilibrium in the gastrointestinal tract through the direct interaction with immune cells. Probiotic effectiveness can be species-, dose-, and disease-specific, and the duration of therapy depends on the clinical indication. There is high-quality evidence that probiotics are effective for acute infectious diarrhea, antibiotic-associated diarrhea, Clostridium difficile- associated diarrhea, hepatic encephalopathy, ulcerative colitis, irritable bowel syndrome, functional gastrointestinal disorders, and necrotizing enterocolitis. Conversely, there is evidence that probiotics are not effective for acute pancreatitis and Crohn disease. Probiotics are safe for infants, children, adults, and older patients, but caution is advised in immunologically vulnerable populations.

OBJECTIVES: We evaluated the relationship between smoking and adenocarcinoma of the prostate. METHODS: We pooled data from 24 cohort studies enrolling 21 579 prostate cancer case participants for a general variance-based meta-analysis. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated separately for mortality and incidence studies. We tested the robustness of effect measures and evaluated statistical heterogeneity with sensitivity analyses. RESULTS: In the pooled data, current smokers had no increased risk of incident prostate cancer (RR = 1.04; 95% CI = 0.87, 1.24), but in data stratified by amount smoked they had statistically significant elevated risk (cigarettes per day or years: RR = 1.22; 95% CI = 1.01, 1.46; pack years of smoking: RR = 1.11; 95% CI = 1.01, 1.22). Former smokers had an increased risk (RR = 1.09; 95% CI = 1.02, 1.16). Current smokers had an increased risk of fatal prostate cancer (RR = 1.14; 95% CI = 1.06, 1.19). The heaviest smokers had a 24% to 30% greater risk of death from prostate cancer than did nonsmokers. CONCLUSIONS: Observational cohort studies show an association of smoking with prostate cancer incidence and mortality. Ill-defined exposure categories in many cohort studies suggest that pooled data underestimate risk.

Insulin receptors (IRs) are expressed in discrete neuronal populations in the central nervous system, including the hippocampus. To elucidate the functional role of hippocampal IRs independent of metabolic function, we generated a model of hippocampal-specific insulin resistance using a lentiviral vector expressing an IR antisense sequence (LV-IRAS). LV-IRAS effectively downregulates IR expression in the rat hippocampus without affecting body weight, adiposity, or peripheral glucose homeostasis. Nevertheless, hippocampal neuroplasticity was impaired in LV-IRAS-treated rats. High-frequency stimulation, which evoked robust long-term potentiation (LTP) in brain slices from LV control rats, failed to evoke LTP in LV-IRAS-treated rats. GluN2B subunit levels, as well as the basal level of phosphorylation of GluA1, were reduced in the hippocampus of LV-IRAS rats. Moreover, these deficits in synaptic transmission were associated with impairments in spatial learning. We suggest that alterations in the expression and phosphorylation of glutamate receptor subunits underlie the alterations in LTP and that these changes are responsible for the impairment in hippocampal-dependent learning. Importantly, these learning deficits are strikingly similar to the impairments in complex task performance observed in patients with diabetes, which strengthens the hypothesis that hippocampal insulin resistance is a key mediator of cognitive deficits independent of glycemic control.

Current treatment of secondary hyperparathyroidism in chronic kidney failure with calcium and active vitamin D is potentially limited by hypercalcemia and hyperphosphatemia. AMG 073 represents a new class of compounds for the treatment of hyperparathyroidism known as calcimimetics, which reduce parathyroid hormone (PTH) synthesis and secretion by increasing the sensitivity of the parathyroid calcium-sensing receptor (CaR) to extracellular calcium. The current study evaluates the efficacy and safety of AMG 073 when added to conventional treatment of secondary hyperparathyroidism in end-stage renal disease (ESRD). Seventy-one hemodialysis patients with uncontrolled secondary hyperparathyroidism, despite standard therapy with calcium, phosphate binders, and active vitamin D sterols, were treated in this 18-wk, dose-titration study with single daily oral doses of AMG 073/placebo up to 100 mg. Changes in plasma PTH, serum calcium, serum phosphorus, and calcium x phosphorus levels were compared between AMG 073 and placebo groups. Mean PTH decreased by 33% in the AMG 073 patients compared with an increase of 3% in placebo patients (P = 0.001). A significantly greater proportion of AMG 073 patients (44%) had a mean PTH < or = 250 pg/ml compared with placebo patients (20%; P = 0.029). Also, a significantly greater proportion of AMG 073 patients (53%) had a decrease in PTH > or =30% compared with placebo patients (23%; P = 0.009). Calcium x phosphorus levels decreased by 7.9% in AMG 073 patients compared with an increase of 11.3% in placebo patients (P = 0.013). Adverse event rates were low and mostly mild to moderate in severity; however, the incidence of vomiting was higher in AMG 073 patients. In this study, the calcimimetic AMG 073 at doses up to 100 mg for 18 wk provided a safe and effective means to attain significant reductions in PTH and calcium x phosphorus levels in ESRD patients. AMG 073 represents a novel and promising therapy to improve the management of secondary hyperparathyroidism.

Tissue available (bioavailable) testosterone (T) includes circulating free T (FT) and albumin-bound T. A reasonable assessment of bioavailable T can be made by using 50% ammonium sulfate to precipitate sex hormone-binding globulin (SHBG)-bound T. The supernatant non-SHBG-bound T (non-SHBG-T) correlates well with physiological androgen activity. To assess bioavailable T in normal aging men, we analyzed serum samples from seven healthy aged men (65-83 yr old) and compared the results to samples from 13 young men (22-39 yr old). Mean serum T, FT, and LH concentrations were not significantly different in the 2 groups. However, the mean absolute non-SHBG-T level was significantly lower (P less than 0.005) in the older group. In a separate population of 20 impotent but otherwise healthy men (5 27-37 yr old, 10 48-64 yr old, and 5 66-69 yr old), the mean absolute non-SHBG-T concentration was lower in middle-aged (P less than .01) and elderly men (P less than 0.001) than in young men. The absolute FT was lower only in the elderly group (P less than 0.05), while mean LH and T levels were similar in all 3 age groups. These data suggest that serum concentrations of tissue available T are decreased in aged men and that non-SHBG-T measurement is a more sensitive indicator of this decrease than are serum T or serum FT measurements. These changes appear to begin by middle age.

BACKGROUND: Most cases of hyponatremia--serum sodium concentration ([Na+]) < 135 mEq/l (< 135 mM)--are associated with an elevated plasma arginine vasopressin level. This study investigated the efficacy and tolerability of intravenous conivaptan (YM087), a vasopressin V1A/V2-receptor antagonist, in treating euvolemic and hypervolemic hyponatremia. METHODS: Eighty-four hospitalized patients with euvolemic or hypervolemic hyponatremia (serum [Na+] 115 to < 130 mEq/l) were randomly assigned to receive intravenous placebo or conivaptan administered as a 30-min, 20-mg loading dose followed by a 96-hour infusion of either 40 or 80 mg/day. The primary efficacy measure was change in serum [Na+], measured by the baseline-adjusted area under the [Na+]-time curve. The secondary measures included time from first dose to a confirmed > or = 4 mEq/l serum [Na+] increase, total time patients had serum [Na+] > or = 4 mEq/l higher than baseline, change in serum [Na+] from baseline to the end of treatment, and number of patients with a confirmed > or = 6 mEq/l increase in serum [Na+] or normal [Na+] (> or = 135 mEq/l). RESULTS: Both conivaptan doses increased area under the [Na+]-time curve during the 4-day treatment (p < 0.0001 vs. placebo). From baseline to the end of treatment, the least-squares mean +/- standard error serum [Na+] increase associated with placebo was 0.8 +/- 0.8 mEq/l; with conivaptan 40 mg/day, 6.3 +/- 0.7 mEq/l; and with conivaptan 80 mg/day, 9.4 +/- 0.8 mEq/l. Conivaptan significantly improved all secondary efficacy measures (p < 0.001 vs. placebo, both doses). Conivaptan was generally well tolerated, although infusion-site reactions led to the withdrawal of 1 (3%) and 4 (15%) of patients given conivaptan 40 and 80 mg/day, respectively. CONCLUSION: Among patients with euvolemic or hypervolemic hyponatremia, 4-day intravenous infusion of conivaptan 40 mg/day significantly increased serum [Na+] and was well tolerated.

Characterization of insulin and type I insulin-like growth factor (IGF-I) receptors and the effects of insulin and IGF-I on steroidogenesis were evaluated by using purified adult Leydig cells from Sprague-Dawley rats. Purified Leydig cells were found to contain both high and low affinity binding sites for insulin, with Ka values of 1.08 X 10(9) and 1.1 X 10(7) M-1, respectively. Using affinity cross-linking of [125I]iodoinsulin to plasma membrane insulin receptor, several bands were identified by autoradiography under nonreduced conditions with mol wt of 230,000, 280,000, and 300,000. After reduction with 50 mM dithiothreitol, only one band was identified with a mol wt of 130,000, consistent with the alpha-subunit of insulin receptor. Purified Leydig cells also contain specific type I IGF receptors with estimated binding affinity of 0.6 X 10(9) M-1. Multiple high mol wt bands (greater than 250,000) were identified under nonreduced conditions by affinity cross-linking. Under reduced conditions, one band with an approximate mol wt of 135,000 was identified. Purified Leydig cells (10(5) cells/ml) were cultured in Dulbecco's Modified Eagle's Medium-Ham's F-12 Nutrient Mixture (1:1) containing 0.1% fetal calf serum at 37 C in a humidified atmosphere of 5% CO2-95% air. Insulin and IGF-I stimulated testosterone formation as early as 3 h after administration, and their effects were completely blocked by the addition of a protein synthesis inhibitor, cycloheximide (1 microgram/ml). Insulin and IGF-I also significantly potentiated hCG-and 8-bromo-cAMP-induced testosterone formation. Furthermore, insulin and IGF-I potentiated hCG-stimulated cAMP formation. This suggests that insulin and IGF-I have effects at both the LH receptor sites and the steps beyond adenylate cyclase. The ED50 values of insulin and IGF-I-stimulated testosterone formation were comparable (25 ng/ml). In conclusion, we found that Leydig cells contain specific insulin and type I IGF receptors, and both insulin and IGF-I are capable of modulating Leydig cell steroidogenesis.

Inflammation and infection induce an acute phase response. The response is characterized by fever and production of interleukin-1 (IL-1). In the present study we evaluated the effects of interleukin-1 on Leydig cell function in primary culture. hCG-stimulated testosterone formation was markedly reduced by IL-1, with an ED50 of 1 U/ml. Basal testosterone production was slightly enhanced in the presence of low concentrations of IL-1, while high concentrations of IL-1 inhibited testosterone formation. Significant inhibition of hCG-stimulated testosterone formation was noted as early as 8 h after the addition of IL-1. IL-1 also inhibited hCG-stimulated cAMP formation, as well as 8-bromo-cAMP- and forskolin-stimulated testosterone synthesis. Furthermore, LH binding to Leydig cells was reduced by human IL-1. The inhibitory effects of IL-1 were reversed only partially by the addition of a cyclooxygenase inhibitor, indomethacin (0.1 mM), even though prostaglandin E2 formation was completely blocked. This indicates that the observed effects of IL-1 are not completely mediated by increased PGE2 formation. The present study suggests that IL-1 is a potent modulator of Leydig cell steroidogenesis. Decreased testosterone formation may modulate the immune response and contribute to the catabolic changes occurring during infection.

The present work demonstrates the use of a dielectrophoretic lab-on-a-chip device in effectively separating different cancer cells of epithelial origin for application in circulating tumor cell (CTC) identification. This study uses dielectrophoresis (DEP) to distinguish and separate MCF-7 human breast cancer cells from HCT-116 colorectal cancer cells. The DEP responses for each cell type were measured against AC electrical frequency changes in solutions of varying conductivities. Increasing the conductivity of the suspension directly correlated with an increasing frequency value for the first cross-over (no DEP force) point in the DEP spectra. Differences in the cross-over frequency for each cell type were leveraged to determine a frequency at which the two types of cell could be separated through DEP forces. Under a particular medium conductivity, different types of cells could have different DEP behaviors in a very narrow AC frequency band, demonstrating a high specificity of DEP. Using a microfluidic DEP sorter with optically transparent electrodes, MCF-7 and HCT-116 cells were successfully separated from each other under a 3.2 MHz frequency in a 0.1X PBS solution. Further experiments were conducted to characterize the separation efficiency (enrichment factor) by changing experimental parameters (AC frequency, voltage, and flow rate). This work has shown the high specificity of the described DEP cell sorter for distinguishing cells with similar characteristics for potential diagnostic applications through CTC enrichment.

A large proportion of individuals affected by sleep disorders are untreated and susceptible to accidents, injuries, long-term sequelae (e.g., risk of cardiovascular disease, cancer, psychiatric disorders), and increased mortality risk. Few studies have examined the scope and magnitude of sleep disorder diagnoses in the United States (US) or factors influencing them. Veterans are particularly vulnerable to factors that elicit or exacerbate sleep disorders. This serial cross-sectional study characterized secular trends in diagnosed sleep disorders among veterans seeking care in US Veterans Health Administration facilities over an eleven-year span (FY2000–2010, n = 9,786,778). Electronic medical records from the national Veterans Administration Informatics and Computing Infrastructure database were accessed. Cases were defined using diagnostic codes specified by the American Academy of Sleep Medicine. Age-adjusted annual prevalence was summarized by sex, race, combat exposure, body mass index, and comorbid diagnoses (cardiovascular disease, cancer, mental disorders). Sleep apnea (47%) and insomnia (26%) were the most common diagnoses among patients with any sleep disorder. There was a six-fold relative increase in total sleep disorder prevalence over the study period. Posttraumatic stress disorder, which tripled over the same time period, was associated with the highest prevalence of sleep disorders (16%) among the comorbid conditions evaluated. The results indicate a growing need for integration of sleep disorder management with patient care and health care planning among US veterans. A commentary on this article appears in this issue on page 1331. Trends in diagnosed sleep disorders were characterized among United States veterans seeking care in Veterans Health Administration facilities between FY2000 and FY2010 (n = 9,786,778). A six-fold relative increase in the age-adjusted prevalence of any sleep disorder diagnosis was observed during the study period. The largest increases were observed among those with posttraumatic stress disorder, other mental health disorders, or combat experience. Veterans with cardiovascular disease, cancer, or other chronic diseases also experienced higher rates of sleep disorder diagnoses relative to those without such conditions. This study identified a growing need for integration of sleep disorder management with veteran care and health care planning.

Colorectal cancer risk is increased in shift workers with presumed circadian disruption. Intestinal epithelial cell proliferation is gated throughout each day by the circadian clock. Period 2 (Per2) is a key circadian clock gene. Per2 mutant (Per2(m/m)) mice show an increase in lymphomas and deregulated expression of cyclin D and c-Myc genes that are key to proliferation control. We asked whether Per2 clock gene inactivation would accelerate intestinal and colonic tumorigenesis. The effects of PER2 on cell proliferation and beta-catenin were studied in colon cancer cell lines by its down-regulation following RNA interference. The effects of Per2 inactivation in vivo on beta-catenin and on intestinal and colonic polyp formation were studied in mice with Per2 mutation alone and in combination with an Apc mutation using polyp-prone Apc(Min/+) mice. Down-regulation of PER2 in colon cell lines (HCT116 and SW480) increases beta-catenin, cyclin D, and cell proliferation. Down-regulation of beta-catenin along with Per2 blocks the increase in cyclin D and cell proliferation. Per2(m/m) mice develop colonic polyps and show an increase in small intestinal mucosa beta-catenin and cyclin D protein levels compared with wild-type mice. Apc(Min/+)Per2(m/m) mice develop twice the number of small intestinal and colonic polyps, with more severe anemia and splenomegaly, compared with Apc(Min/+) mice. These data suggest that Per2 gene product suppresses tumorigenesis in the small intestine and colon by down-regulation of beta-catenin and beta-catenin target genes, and this circadian core clock gene may represent a novel target for colorectal cancer prevention and control.

While the immunological dysfunction in combat Veterans with post-traumatic stress disorder (PTSD) has been well documented, the precise mechanisms remain unclear. The current study evaluated the role of microRNA (miR) in immunological dysfunction associated with PTSD. The presence of peripheral blood mononuclear cells (PBMC) and various lymphocyte subsets in blood collected from PTSD patients were analyzed. Our studies demonstrated that the numbers of both PBMC and various lymphocyte subsets increased significantly in PTSD patients. When T cells were further analyzed, the percentage of Th1 cells and Th17 cells increased, regulatory T cells(Tregs) decreased, while Th2 cells remained unaltered in PTSD patients. These data correlated with increased plasma levels of IFN-γ and IL-17 while IL-4 showed no significant change. The increase in PBMC counts, Th1 and Th17 cells seen in PTSD patients correlated with the clinical scores. High-throughput analysis of PBMCs for 1163 miRs showed that the expression of a significant number of miRs was altered in PTSD patients. Pathway analysis of dysregulated miRs seen in PTSD patients revealed relationship between selected miRNAs and genes that showed direct/indirect role in immunological signaling pathways consistent with the immunological changes seen in these patients. Of interest was the down-regulation of miR-125a in PTSD, which specifically targeted IFN-γ production. Together, the current study demonstrates for the first time that PTSD was associated with significant alterations in miRNAs, which may promote pro-inflammatory cytokine profile. Such epigenetic events may provide useful tools to identify potential biomarkers for diagnosis, and facilitate therapy of PTSD.

For decades the brain was erroneously considered an insulin insensitive organ. Although gaps in our knowledge base remain, conceptual frameworks are starting to emerge to provide insight into the mechanisms through which insulin facilitates critical brain functions like metabolism, cognition, and motivated behaviors. These diverse physiological and behavioral activities highlight the region-specific activities of insulin in the CNS; that is, there is an anatomical context to the activities of insulin in the CNS. Similarly, there is also a temporal context to the activities of insulin in the CNS. Indeed, brain insulin receptor activity can be conceptualized as a continuum in which insulin promotes neuroplasticity from development into adulthood where it is an integral part of healthy brain function. Unfortunately, brain insulin resistance likely contributes to neuroplasticity deficits in obesity and type 2 diabetes mellitus (T2DM). This neuroplasticity continuum can be conceptualized by the mechanisms through which insulin promotes cognitive function through its actions in brain regions like the hippocampus, as well as the ability of insulin to modulate motivated behaviors through actions in brain regions like the nucleus accumbens and the ventral tegmental area. Thus, the goals of this review are to highlight these anatomical, temporal, and functional contexts of insulin activity in these brain regions, and to identify potentially critical time points along this continuum where the transition from enhancement of neuroplasticity to impairment may take place. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'

A woman receives a diagnosis of diffuse large B-cell lymphoma; a standard chemotherapy regimen is recommended. Use of prophylactic granulocyte CSF is considered. G-CSF stimulates proliferation of neutrophil progenitors and release of mature neutrophils from bone marrow.

The extracellular matrix (ECM) is a complex entity containing a large portfolio of structural proteins, signaling molecules, and proteases. Changes in the overall integrity and activational state of these ECM constituents can contribute to tissue structure and function, which is certainly true of the myocardium. Changes in the expression patterns and activational states of a family of ECM proteolytic enzymes, the matrix metalloproteinases (MMPs), have been identified in all forms of left ventricle remodeling and can be a contributory factor in the progression to heart failure. However, new clinical and basic research has identified some surprising and unpredicted changes in MMP profiles in left ventricle remodeling processes, such as with pressure or volume overload, as well as with myocardial infarction. From these studies, it has become recognized that proteolytic processing of signaling molecules by certain MMP types, particularly the transmembrane MMPs, actually may facilitate ECM accumulation and modulate fibroblast transdifferentiation; both are critical events in adverse left ventricle remodeling. Based on the ever-increasing substrates and diversity of biological actions of MMPs, it is likely that continued research about the relationship of left ventricle remodeling in this family of proteases will yield new insights into the ECM remodeling process and new therapeutic targets.