Stressed to death: targeting endoplasmic reticulum stress response induced apoptosis in gliomas

Glial tumors are the main primary adult brain tumor. Even with the most advanced treatments, which include stereotactic microscope aided surgical resection, internal and external radiation therapy and local and systemic chemotherapy, median survival time for patients diagnosed with these malignancies is about 12 months. We explore here the possibility that the endoplasmic reticulum stress response (ERSR) could be a possible target to develop chemotherapeutic agents to induce toxicity in glioma cells. ERSR has the dual capacity of activating repair and/or cytotoxic mechanisms. ERSR is triggered by the accumulation of unfolded proteins in the ER. The presence of unfolded proteins in the ER regulates, via a complex biochemical cascade, the upregulation of molecular chaperones, inhibition of protein synthesis, and an increase of proteasome mediated unfolded protein degradation. ERSR in particular conditions can also contribute to cell death via activation of programmed cell death. Apoptosis activation during ERSR is usually caused by the activation of one or a combination of three biochemical cascades. Induction of these pathways ultimately leads to caspase 3 activation culminating in apoptosis. Glioma cells are in a condition of constant low grade ERSR, which possibly contributes to their resistance to treatment protocols. It is conceivable that small molecules that interact with this phenomenon ultimately could be used to modulate the system to activate apoptosis and cause gliotoxicity. We will discuss here ERSR biochemically relevant features to death mechanisms and already identified small molecules that by modulating ERSR are able to activate glioma cell death.     

Circadian Activity Rhythms and Mortality: The Study of Osteoporotic Fractures

OBJECTIVES: To determine whether circadian activity rhythms are associated with mortality in community‐dwelling older women. DESIGN: Prospective study of mortality. SETTING: A cohort study of health and aging. PARTICIPANTS: Three thousand twenty‐seven community‐dwelling women from the Study of Osteoporotic Fractures cohort (mean age 84). MEASUREMENTS: Activity data were collected using wrist actigraphy for a minimum of three 24‐hour periods, and circadian activity rhythms were computed. Parameters of interest included height of activity peak (amplitude), midline estimating statistic of rhythm (mesor), strength of activity rhythm (robustness), and time of peak activity (acrophase). Vital status, with cause of death adjudicated through death certificates, was prospectively ascertained. RESULTS: Over an average of 4.1 years of follow‐up, there were 444 (14.7%) deaths. There was an inverse association between peak activity height and all‐cause mortality rates, with higher mortality rates observed in the lowest activity quartile (hazard ratio (HR)=2.18, 95% confidence interval (CI)=1.63–2.92) than in the highest quartile after adjusting for age, clinic site, race, body mass index, cognitive function, exercise, instrumental activity of daily living impairments, depression, medications, alcohol, smoking, self‐reported health status, married status, and comorbidities. A greater risk of mortality from all causes was observed for those in the lowest quartiles of mesor (HR=1.71, 95% CI=1.29–2.27) and rhythm robustness (HR=1.97, 95% CI=1.50–2.60) than for those in the highest quartiles. Greater mortality from cancer (HR=2.09, 95% CI=1.04–4.22) and stroke (HR=2.64, 95% CI=1.11–6.30) was observed for later peak activity (after 4:33 p.m.; >1.5 SD from mean) than for the mean peak range (2:50–4:33 p.m.). CONCLUSION: Older women with weak circadian activity rhythms have higher mortality risk. If confirmed in other cohorts, studies will be needed to test whether interventions (e.g., physical activity, bright light exposure) that regulate circadian activity rhythms will improve health outcomes in older adults.     

Multiple point-of-testing nutrition counseling sessions reduce risk factors for chronic disease among older adults

The objectives of this study were to explore the relationships of baseline dietary intakes and frequency of attendance at point-of-testing nutrition counseling sessions to selected risk factors for chronic diseases during a 3-year intervention. This study was part of a large multidisciplinary, community-based health outreach project conducted in a rural community of northern Louisiana. Screenings, point-of-testing counseling, weekly group exercise sessions, and group nutrition education sessions were provided over a period of 3 years. Outcome variables assessed at 6-month intervals over 3 years were body mass index (BMI), systolic and diastolic blood pressure, fasting blood glucose, and total and LDL cholesterol and dietary intake. Repeated measure analysis of variance was used to investigate the impact of the frequency of counseling sessions on outcome variables. Paired t-tests were used to identify points at which significant changes occurred. A total of 159 subjects ages 65 years and older participated in this study. The majority of the participants were female (62%) and White (82%). Attending the point of testing counseling for more than two sessions was important for a significant improvement in BMI (p ≤ 0.001), LDL cholesterol (p ≤ 0.03), blood glucose (p ≤ 0.03), and diastolic blood pressure (p ≤ 0.045). Participants who attended at least three sessions had significant reductions in risk factors for obesity and related chronic diseases, underscoring the importance of follow-up sessions after health screening.     

Metabolic syndrome and physical performance in elderly men: the osteoporotic fractures in men study

OBJECTIVES: To examine the association between metabolic syndrome (MetS) and objective measures of physical performance. DESIGN: Cross‐sectional analysis of the cohort study, the Osteoporotic Fractures in Men Study. SETTING: Six clinical sites in the United States. PARTICIPANTS: Five thousand four hundred fifty‐seven ambulatory men (mean age 73.6 ± 5.9). MEASUREMENTS: Physical performance assessed according to grip strength, narrow walk speed, walking speed, and time to complete five repeated chair stands. Individual scores were converted to quintiles (worst=1 to best=5; unable to complete=0) and summed for an overall score (mean 11.6 ± 4.3, range, 1–20). MetS was defined according to World Health Organization criteria that include evidence of glucose dysregulation (insulin resistance, diabetes mellitus, or hyperinsulinemia) and at least two additional characteristics: high blood pressure, low high‐density lipoprotein cholesterol, high triglycerides, obesity. RESULTS: More than one‐quarter (26.3%) of participants met criteria for MetS. In separate linear regression models, four of five MetS components were related to performance (P<.001); only high blood pressure was unrelated. Men with MetS had a 1.1‐point lower performance score (mean 10.8, 95% confidence interval (CI)=10.6–11.0) than men without MetS (mean 11.9, 95% CI=11.8–12.0) (P<.001), adjusting for age, race, education, and site. With further covariate adjustment, this difference was reduced but remained significant (β=?0.78, P<.001). A graded association was observed between number of MetS components (0, 1, 2, or ≥3) and performance (P for trend <.001). Findings were similar excluding men with diabetes mellitus or obese men. CONCLUSION: Metabolic dysregulation is related to objectively assessed poorer physical performance in relatively healthy older men.     

Association between depressive symptoms and sleep disturbances in community-dwelling older men

OBJECTIVES: To examine the association between depressive symptoms and subjective and objective measures of sleep in community-dwelling older men.
DESIGN: Cross-sectional.
SETTING: Six U.S. clinical centers.
PARTICIPANTS: Three thousand fifty-one men aged 67 and older.
MEASUREMENTS: Depressive symptoms assessed using the 15-item Geriatric Depression Scale and categorized as 0 to 2 (normal, referent group), 3 to 5 (some depressive symptoms), and 6 to 15 (depressed); objective sleep measures ascertained using wrist actigraphy (mean duration 5.2 nights); and subjective sleep measures assessed using the Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale.
RESULTS: There was a strong multivariable-adjusted association between level of depressive symptoms and subjective sleep disturbances ( P -trend <.001). For example, the odds of reporting poor sleep quality were 3.7 times (95% confidence interval (CI)=2.5–5.3) higher for depressed men as for normal men, and 2.1 times (95% CI=1.7–2.6) higher for men with some depressive symptoms. For objectively measured sleep disturbances, men with more depressive symptoms had greater odds of sleep latency of 1 hour or more ( P -trend=.006). There was no association between level of depressive symptoms and sleep efficiency, awakening after sleep onset, multiple long-wake episodes, or total sleep time. Excluding 384 men taking antidepressants, benzodiazepines, or other anxiolytic or hypnotics did not alter the results.
CONCLUSION: Depressive symptoms have a strong, graded association with subjective sleep disturbances and are moderately associated with objectively measured prolonged sleep latency. Future studies should address temporality of depression and sleep disturbances.     

Sleep-disordered breathing and urinary albumin excretion in older men

Purpose  

Sleep-disordered breathing(SDB) may be deleterious to the cardiovascular system and other organs, including the kidney. Although older men are at increased risk for both kidney disease and SDB, it is unknown whether SDB is associated with higher urinary albumin excretion in this population.     

‘I won’t be able to go home being pregnant’: sex work and pregnancy in Dhaka,Bangladesh

Sex workers report high rates of unintended pregnancy that are inconsistent with widespread reports of condom use. Greater understanding of the implications of an unintended pregnancy and barriers to contraceptive use is needed to better meet the broader sexual and reproductive health needs of this population. We conducted in-depth interviews with 20 women sex workers in Dhaka, Bangladesh. Findings reveal that most women are trying to conform to societal norms and protect their reputations. They fear pregnancy would reveal that they are having unsanctioned sex and that they are sex workers. This could lead to ostracism from families and society, resulting in homelessness and abandonment by partners. Pregnancy may affect a sex worker’s ability to work and leave her unable to meet financial obligations. All study participants were using condoms but most acknowledged they could not use them consistently. They had all tried other contraceptive methods, notably injectables and the pill, but some noted experience of side-effects, difficulties in adherence and the desire to use other methods. Understanding the context of sex workers’ lives is an important step in informing stakeholders about the range of services needed to improve their sexual and reproductive health.