Differential Free Intracellular Calcium Release by Class II Antiarrhythmics in Cancer Cell Lines

Class II antiarrhythmics or β-blockers are antisympathetic nervous system agents that act by blocking β-adrenoceptors. Despite their common clinical use, little is known about the effects of β-blockers on free intracellular calcium (Ca2+i), an important cytosolic second messenger and a key regulator of cell function. We investigated the role of four chemical analogs, commonly prescribed β-blockers (atenolol, metoprolol, propranolol, and sotalol), on Ca2+i release and whole-cell currents in mammalian cancer cells (PC3 prostate cancer and MCF7 breast cancer cell lines). We discovered that only propranolol activated free Ca2+i release with distinct kinetics, whereas atenolol, metoprolol, and sotalol did not. The propranolol-induced Ca2+i release was significantly inhibited by the chelation of extracellular calcium with ethylene glycol tetraacetic acid (EGTA) and by dantrolene, an inhibitor of the endoplasmic reticulum (ER) ryanodine receptor channels, and it was completely abolished by 2-aminoethoxydiphenyl borate, an inhibitor of the ER inositol-1,4,5-trisphosphate (IP3) receptor channels. Exhaustion of ER stores with 4-chloro-m-cresol, a ryanodine receptor activator, or thapsigargin, a sarco/ER Ca2+ ATPase inhibitor, precluded the propranolol-induced Ca2+i release. Finally, preincubation of cells with sotalol or timolol, nonselective blockers of β-adrenoceptors, also reduced the Ca2+i release activated by propranolol. Our results show that different β-blockers have differential effects on whole-cell currents and free Ca2+i release and that propranolol activates store-operated Ca2+i release via a mechanism that involves calcium-induced calcium release and putative downstream transducers such as IP3. The differential action of class II antiarrhythmics on Ca2+i release may have implications on the pharmacology of these drugs

Hyposalivation and Poor Dental Health Status Are Potential Correlates of Age-Related Cognitive Decline in Late Midlife in Danish Men

Introduction: Peripheral correlates of age-associated cognitive decline are important tools in the screening for potentially abnormal courses of cognitive aging. Since salivary gland function is controlled by the autonomic and central nervous system, associations between cognitive changes and salivary gland hypofunction were tested in two groups of middle-aged men in late midlife, who differed substantially with respect to their midlife performance in verbal intelligence when compared with their performance in young adulthood.Materials and Methods: Participants (n = 193) were recruited from the Danish Metropolit Cohort of men born in 1953. Based on their individual change in performance in two previously administered intelligence tests, they were allocated to one group of positive and one group of negative outliers in midlife cognition scores, indicating no decline versus decline in test performance. All participants underwent a clinical oral examination including assessments of their dental, periodontal, and mucosal conditions. Whole and parotid saliva flow rates were measured, and the number of systemic diseases and medication intake as well as daytime and nocturnal xerostomia were registered.Results: Participants with decline in cognitive test performance in midlife had significantly lower unstimulated whole saliva flow rates, higher prevalence of hyposalivation and daytime xerostomia and a higher caries experience than participants with no decline in midlife performance. Daytime and nocturnal xerostomia were associated with daily intake of medication and alcohol.Discussion: Overall, hyposalivation, xerostomia and poor dental status distinguished a group of men displaying relative decline in cognitive performance from a group of men without evidence of cognitive decline. Thus, hyposalivation and poor dental health status may represent potential correlates of age-related cognitive decline in late midlife, provided that other causes can be excluded

Onset of Workplace Bullying and Risk of Weight Gain:A Multicohort Longitudinal Study

Objective This study aimed to examine the onset of workplace bullying as a risk factor for BMI increase. Methods Repeated biennial survey data from three Nordic cohort studies were used, totaling 46,148 participants (67,337 participant observations) aged between 18 and 65 who did not have obesity and who were not bullied at the baseline. Multinomial logistic regression was applied for the analysis under the framework of generalized estimating equations. Results Five percent reported onset of workplace bullying within 2 years from the baseline. In confounder-adjusted models, onset of workplace bullying was associated with a higher risk of weight gain of >= 1 BMI unit (odds ratio = 1.09; 95% CI: 1.01-1.19) and of >= 2.5 BMI units (odds ratio = 1.24; 95% CI: 1.06-1.45). A dose-response pattern was observed, and those exposed to workplace bullying more frequently showed a higher risk (P-trend = 0.04). The association was robust to adjustments, restrictions, stratifications, and use of relative/absolute scales for BMI change. Conclusions Participants with exposure to the onset of workplace bullying were more likely to gain weight, a possible pathway linking workplace bullying to increased long-term risk of type 2 diabetes.Peer reviewe

Safety of hospital discharge before return of bowel function after elective colorectal surgery

Background Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function. Methods A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien-Dindo classification system. Results A total of 3288 patients were included in the analysis, of whom 301 (9 center dot 2 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4-7) and 7 (6-8) days respectively (P < 0 center dot 001). There were no significant differences in rates of readmission between these groups (6 center dot 6 versus 8 center dot 0 per cent; P = 0 center dot 499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0 center dot 90, 95 per cent c.i. 0 center dot 55 to 1 center dot 46; P = 0 center dot 659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34 center dot 7 versus 39 center dot 5 per cent; major 3 center dot 3 versus 3 center dot 4 per cent; P = 0 center dot 110). Conclusion Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients

Safety and efficacy of non-steroidal anti-inflammatory drugs to reduce ileus after colorectal surgery

Background Ileus is common after elective colorectal surgery, and is associated with increased adverse events and prolonged hospital stay. The aim was to assess the role of non-steroidal anti-inflammatory drugs (NSAIDs) for reducing ileus after surgery. Methods A prospective multicentre cohort study was delivered by an international, student- and trainee-led collaborative group. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The primary outcome was time to gastrointestinal recovery, measured using a composite measure of bowel function and tolerance to oral intake. The impact of NSAIDs was explored using Cox regression analyses, including the results of a centre-specific survey of compliance to enhanced recovery principles. Secondary safety outcomes included anastomotic leak rate and acute kidney injury. Results A total of 4164 patients were included, with a median age of 68 (i.q.r. 57-75) years (54 center dot 9 per cent men). Some 1153 (27 center dot 7 per cent) received NSAIDs on postoperative days 1-3, of whom 1061 (92 center dot 0 per cent) received non-selective cyclo-oxygenase inhibitors. After adjustment for baseline differences, the mean time to gastrointestinal recovery did not differ significantly between patients who received NSAIDs and those who did not (4 center dot 6 versus 4 center dot 8 days; hazard ratio 1 center dot 04, 95 per cent c.i. 0 center dot 96 to 1 center dot 12; P = 0 center dot 360). There were no significant differences in anastomotic leak rate (5 center dot 4 versus 4 center dot 6 per cent; P = 0 center dot 349) or acute kidney injury (14 center dot 3 versus 13 center dot 8 per cent; P = 0 center dot 666) between the groups. Significantly fewer patients receiving NSAIDs required strong opioid analgesia (35 center dot 3 versus 56 center dot 7 per cent; P < 0 center dot 001). Conclusion NSAIDs did not reduce the time for gastrointestinal recovery after colorectal surgery, but they were safe and associated with reduced postoperative opioid requirement