A common polymorphism in the mineralocorticoid receptor modulates stress responsiveness

CONTEXT: Mineralocorticoid receptors (MR) mediate the action of aldosterone on sodium resorption in kidney tubular cells, but in brain they respond to the glucocorticoid cortisol in stress regulation and cognitive processes. OBJECTIVE: The objective of the study was to investigate the role of the MR gene variant I180V in the neuroendocrine response to a psychosocial stressor and in electrolyte regulation. DESIGN: Associations between the MRI180V and outcome variables in a healthy cohort subjected to psychosocial challenge (Trier Social Stress Test) and in a mild hypertensive cohort exposed to acute salt loading (Weinberger's test) were investigated. In vitro transactivational assays were applied to compare the effects of cortisol and aldosterone on the MRI180V. RESULTS: Carriers of the MR180V allele showed higher saliva (P < 0.01), plasma cortisol (P < 0.01), and heart rate responses (P < 0.05) to the Trier Social Stress Test than noncarriers (MR180I). After 3 d of a normal salt diet and the Weinberger's test, no association was found with urinary sodium excretion, plasma aldosterone, and plasma renin activity or with changes in blood pressure, aldosterone, and renin responses. In vitro testing of the MR180V allele revealed a mild loss of function using cortisol as a ligand, compared with the MR180I allele. Significantly higher doses of cortisol were needed for half-maximal induction on the TAT-1 (P < 0.002), TAT-3 (P < 0.03), or mouse mammary tumor virus (P < 0.02) promoters, whereas maximal induction was not different. These differences were not observed using aldosterone as a ligand. CONCLUSION: The findings reveal that cortisol and heart rate responses to a psychosocial stressor are enhanced in carriers of the MR180V variant.     

Chronic frequent headache in the general population: prevalence and associated factors

We studied the prevalence and short-term natural course of chronic frequent headache (CFH) in the general population and identified risk factors. In the Netherlands everyone is registered at a single general practice. We sent questionnaires to all persons (n = 21 440) aged 25-55 years, registered at 16 general practices. We compared the characteristics of 177 participants with CFH (>14 headache days/month for >3 months) with 141 participants with infrequent headache (1-4 days/month) and 526 without headache (<1 day/month). The prevalence of CFH was 3.7% [95% confidence interval (CI) 3.4, 4.0]. In 5 months, 12% showed a clinically relevant decrease to <7 days/month. In both headache groups 70% were women vs. 41% in the group without headache. Compared with the group with infrequent headache, the CFH group had more subjects with low educational level [35% vs. 11%; odds ratio (OR) 4.3, 95% CI 2.3, 7.8], medication overuse (62% vs. 3%; OR 38.4, 95% CI 13.8, 106.9), sleeping problems (44% vs. 8%; OR 8.1, 95% CI 3.6, 18.1), a history of head/neck trauma (36% vs. 14%; OR 4.0, 95% CI 2.2, 7.1), high scores on the General Health Questionnaire (62% vs. 34%; OR 2.7, 95% CI 1.3, 3.6) and more smokers (45% vs. 19%; OR 3.1, 95% CI 1.9, 5.3). We conclude that headache frequency fluctuates. CFH is common and associated with overuse of analgesics, psychopathology, smoking, sleeping problems, a history of head/neck trauma and low educational level. Female sex is a risk factor for headache, not for chronification of headache.     

Dispositional optimism and the risk of depressive symptoms during 15 years of follow-up: the Zutphen Elderly Study

OBJECTIVE: It is unclear whether the personality trait of dispositional optimism, defined in terms of generalized positive outcome expectancies, life engagement, and a future orientation, has a protective effect on the development of depression in community-dwelling elderly men. METHODS: We included 464 men aged 64 to 84 years (mean 70.8; SD 4.6) with complete data at baseline and at 5 years of follow-up in a prospective cohort study with a follow-up period of 15 years. In 1985, 1990, 1995 and 2000 dispositional optimism was assessed using a 4-item questionnaire, and in 1990, 1995 and 2000 depressive symptoms were assessed by the Zung self-rating depression scale (SDS). Logistic regression was used to estimate odds ratios for the development of depressive symptoms (i.e., Zung SDS > or = 50). RESULTS: The cumulative incidence for depressive symptoms was 44% (n = 202) after 15 years follow-up. Dispositional optimism predicted for a lower cumulative incidence of depressive symptoms with an odds ratio of 0.23 (95% confidence interval 0.15-0.36; high vs. low optimism). The protective effect remained unaffected after multivariate adjustment for age, self-rated health, cardiovascular disease, education, and physical activity. In men free of depressive symptoms in 1990, the protective effect of dispositional optimism persisted. LIMITATION: The dispositional optimism scale has not been validated against the 'Life Orientation Test'. CONCLUSIONS: Dispositional optimism protects against the development of depressive symptoms during 15 years of follow-up in elderly community-dwelling men.     

Enhanced tolerability of the 5-hydroxytryptophane challenge test combined with granisetron

A recently developed oral serotonergic challenge test consisting of 5-Hydroxytryptophane (5-HTP, 200 mg) combined with carbidopa (CBD, 100 mg + 50 mg) exhibited dose-related neuroendocrine responsiveness and predictable pharmacokinetics. However, its applicability is limited by nausea and vomiting. A randomized, double-blind, placebo-controlled, four-way crossover trial was performed in 12 healthy male volunteers. The 5-HTP/CBD-challenge was combined with two oral anti-emetics (granisetron, 2 mg or domperidone, 10 mg) to investigate its reliability when side-effects are suppressed. The neuroendocrine response (serum cortisol and prolactin), the side-effect profile [Visual Analogue Scale Nausea (VAS)] and vomiting subjects per treatment were the main outcome measures. Compared to 5-HTP/CBD/placebo, 5-HTP/CBD/ granisetron had no impact on cortisol [% change with 95% confidence interval: -7.1% (18.9; 6.5)] or prolactin levels [-9.6% (-25.1; 9.1)]; 5-HTP/CBD/domperidone increased cortisol [+13.0% (-4.2; 33.4)], and increased prolactin extensively [+336.8% (245.7; 451.9)]. Compared to placebo, VAS Nausea increased non-significantly with granisetron [+7.6 mm (-1.3; 16.5)], as opposed to domperidone [+16.2 mm (7.2; 25.2)] and 5-HTP/CBD/placebo [+14.7 mm (5.5; 23.8)]. No subjects vomited with granisetron, compared to two subjects treated with 5-HTP/CBD/placebo and five subjects with domperidone. Compared with 5-HTP/CBD/placebo, granisetron addition decreased C(max) of 5-HTP statistically significantly different (from 1483 to 1272 ng/ml) without influencing AUC(0- infinity). Addition of granisetron to the combined 5-HTP/CBD challenge suppresses nausea and vomiting without influencing the neuroendocrine response or pharmacokinetics, enhancing its clinical applicability in future psychiatric research and drug development.     

Availability, content and quality of local guidelines for the assessment of suicide attempters in university and general hospitals in the Netherlands

OBJECTIVE: This study was performed to investigate the availability, content and quality of local guidelines for the assessment of suicide attempters in the Netherlands. METHOD: All university and general hospitals in the Netherlands were asked to provide their local guidelines. Published national guidelines and the Appraisal of Guidelines for Research and Education (AGREE) instrument were used to evaluate the content and quality of the local guidelines. RESULTS: Eighty-eight hospitals (90.7%) responded; 34 (38.6%) reported that they used local guidelines. Twenty-seven guidelines were submitted for evaluation. Most of the guidelines were more than 5 years old and had not been updated recently. The contents of the guidelines differed. Criteria addressing patient safety, staff attitude toward patients, reassessment of nonalert patients, relevant stressors, involvement of significant others and aftercare were found in less than 50% of the guidelines. Although psychiatric consultation was incorporated in almost 80%, the psychiatrist's tasks were specified infrequently. The guidelines seldom required monitoring of staff compliance. Only in the AGREE domain "clarity and presentation" was the mean score above 60% of the maximum. According to the instructions for the AGREE instrument, 10 (37.0%) of the 27 guidelines were recommended (with provisos or alterations) and 1 was strongly recommended for use in practice. CONCLUSIONS: In the Netherlands, a minority of hospitals reported use of local guidelines for the assessment of suicide attempters. When available, the guidelines were mostly not based on international standards, their contents varied greatly and their quality was unsatisfactory.     

Neuromuscular synaptic function in mice lacking major subsets of gangliosides

Gangliosides are a family of sialylated glycosphingolipids enriched in the outer leaflet of neuronal membranes, in particular at synapses. Therefore, they have been hypothesized to play a functional role in synaptic transmission. We have measured in detail the electrophysiological parameters of synaptic transmission at the neuromuscular junction (NMJ) ex vivo of a GD3-synthase knockout mouse, expressing only the O- and a-series gangliosides, as well as of a GM2/GD2-synthase*GD3-synthase double-knockout (dKO) mouse, lacking all gangliosides except GM3. No major synaptic deficits were found in either null-mutant. However, some extra degree of rundown of acetylcholine release at high intensity use was present at the dKO NMJ and a temperature-specific increase in acetylcholine release at 35 degrees C was observed in GD3-synthase knockout NMJs, compared with wild-type. These results indicate that synaptic transmission at the NMJ is not crucially dependent on the particular presence of most ganglioside family members and remains largely intact in the sole presence of GM3 ganglioside. Rather, presynaptic gangliosides appear to play a modulating role in temperature- and use-dependent fine-tuning of transmitter output.     

Effectiveness of Influenza Vaccine in Hemodialyzed Patients: A Retrospective Study

Infection is one of the leading causes of mortality in dialysis patients, second only to cardiovascular disease. This retrospective study assessed the efficacy and clinical outcomes of influenza vaccination among hemodialysis (HD) patients. In the 2014–2015 season, 104 of 164 (63.6%) HD patients were vaccinated for influenza by the outpatient community health system facilities. Significantly more patients, 159 of 170 (93.8%), were vaccinated in 2015–2016 by the hospital dialysis unit staff during an inpatient HD session (P <0.001). A trend toward fewer complications from influenza infection was observed in vaccinated patients. Among HD patients with diabetes (who comprised 56% of the study population), the incidence of influenza was 17% among nonvaccinated patients vs. 6.3% among those who were vaccinated (P =0.026). The inpatient vaccination policy resulted in a greater rate of vaccination. HD patients with diabetes benefit from influenza vaccination, with a significantly lower incidence of influenza infection.