Sub-chronic agmatine treatment modulates hippocampal neuroplasticity and cell survival signaling pathways in mice

Agmatine is an endogenous neuromodulator which, based on animal and human studies, is a putative novel antidepressant drug. In this study, we investigated the ability of sub-chronic (21 days) p.o. agmatine administration to produce an antidepressant-like effect in the tail suspension test and examined the hippocampal cell signaling pathways implicated in such an effect. Agmatine at doses of 0.01 and 0.1 mg/kg (p.o.) produced a significant antidepressant-like effect in the tail suspension test and no effect in the open-field test. Additionally, agmatine (0.001–0.1 mg/kg, p.o.) increased the phosphorylation of protein kinase A substrates (237–258% of control), protein kinase B/Akt (Ser⁴⁷³) (116–127% of control), glycogen synthase kinase-3β (Ser⁹) (110–113% of control), extracellular signal-regulated kinases 1/2 (119–137% and 121–138% of control, respectively) and cAMP response elements (Ser¹³³) (127–152% of control), and brain-derived-neurotrophic factor (137–175% of control) immunocontent in a dose-dependent manner in the hippocampus. Agmatine (0.001–0.1 mg/kg, p.o.) also reduced the c-jun N-terminal kinase 1/2 phosphorylation (77-71% and 65-51% of control, respectively). Neither protein kinase C nor p38^MAPK phosphorylation was altered under any experimental conditions. Taken together, the present study extends the available data on the mechanisms that underlie the antidepressant action of agmatine by showing an antidepressant-like effect following sub-chronic administration. In addition, our results are the first to demonstrate the ability of agmatine to elicit the activation of cellular signaling pathways associated with neuroplasticity/cell survival and the inhibition of signaling pathways associated with cell death in the hippocampus.     

Do sleep,stress, and illness explain daily variations in fatigue? A prospective study

Objective

Fatigue is related to a number of serious diseases, as well as to general well-being. It is also a major cause of sickness absence and use of health facilities. Still, the determinants of variations in fatigue are little investigated. The purpose of present study was to investigate the relationships between the daily variations of fatigue with sleep during the previous night, stress or disease symptoms during the same day — across 42 consecutive days of normal life.

Methods

50 individuals participated and gave diary reports and used an actigraph across the 42 days. The data was analyzed using a multilevel approach with mixed model regression.

Results

The analyses showed that the day-to-day variation in fatigue was related to (poor) sleep quality (p < .001) and (reduced) sleep duration (p < .01) the previous night, as well as to higher stress (p < .05), and to the occurrence of a cold or fever (p < .001) during the same day as the fatigue rating. Fatigue was also strongly related to poorer subjective health (p < .001) and sleepiness (p < .001) during the same day.

Conclusion

The results indicate that prior sleep (and sleepiness) as well as stress and illness are consistently connected to how fatigue is experienced during normal living conditions.     

选择性痔上直肠全层切闭术治疗痔病180例临床疗效观察

目的：探讨选择性痔上直肠全层切闭术治疗痔病的临床疗效。方法将360例痔病患者随机分成两组,试验组180例采用选择性痔上直肠全层切闭术,对照组180例采用选择性痔上直肠黏膜切除术,均用TST器械,术后均采用抗炎、止血、坐浴、换药及对症治疗,观察两组资料及术后情况。结果两组间的近期临床治愈率比较,差异无统计学意义（P＞0．05）。两组间的远期临床治愈率比较,差异有统计学意义（P＜0．05）。两组手术切除标本面积、手术标本重量比较,差异有统计学意义（P＜0．05）。两组手术时间、术中出血量、术后疼痛差异无统计学意义（P＞0．05）。结论两组治疗痔病的治疗效果相似。选择性痔上直肠全层切闭术,切除直肠全层,悬吊效果更优,远期疗效更好,是一种选择微创、精确治疗痔病新方法。     

TST结合聚桂醇注射治疗混合痔疗效观察

为观察TsT结合聚桂醇注射治疗混合痔的疗效,将混合痔患者60例随机分为治疗组与对照组各30例。治疗组采用TST结合聚桂醇注射治疗,对照组采用单纯TsT治疗。结果显示,治疗组在疗效、术后不良反应及复发情况等方面优于对照组（P〈0．05）。结果表明,TST结合聚桂醇注射治疗混合痔的疗效优于单纯TsT。     

Latent TB infection in newly diagnosed lung cancer patients – A multicenter prospective observational study

Objectives

Lung cancer and tuberculosis (TB) share common risk factors and are associated with high morbidity and mortality. Coexistence of lung cancer and TB were reported in previous studies, with uncertain pathogenesis. The association between lung cancer and latent TB infection (LTBI) remains to be explored.

Methods

Newly diagnosed, treatment-naïve lung cancer patients were prospectively enrolled from four referral medical centers in Taiwan. The presence of LTBI was determined by QuantiFERON-TB Gold In-Tube (QFT-GIT). Demographic characteristics and cancer-related factors associated with LTBI were investigated. The survival status was also analyzed according to the status of LTBI.

Results

A total of 340 lung cancer patients were enrolled, including 96 (28.2%) LTBI, 214 (62.9%) non-LTBI, and 30 (8.8%) QFT-GIT results-indeterminate cases. Non-adenocarcinoma cases had higher proportion of LTBI than those of adenocarcinoma, especially in patients with younger age. In multivariate analysis, COPD (OR 2.41, 95% CI 1.25–4.64), fibrocalcified lesions on chest radiogram (OR 2.73, 95% CI 1.45–5.11), and main tumor located in typical TB areas (OR 2.02, 95% CI 1.15–3.55) were independent clinical predictors for LTBI. Kaplan–Meier survival analysis demonstrated patients with indeterminate QFT-GIT results had significantly higher 1-year all-cause mortality than those with LTBI (p < 0.001) and non-LTBI (p = 0.003). In multivariate analysis, independent predictors for 1-year all-cause mortality included BMI < 18.5 (HR 2.09, 95% CI 1.06–4.14, p = 0.033), advanced stage of lung cancer (RR 7.76, 95% CI 1.90–31.78, p = 0.004), and indeterminate QFT-GIT results (RR 2.40, 95% CI 1.27–4.54, p = 0.007).

Conclusions

More than one-quarter of newly diagnosed lung cancer patients in Taiwan have LTBI. The independent predictors for LTBI include COPD, fibrocalcified lesions on chest radiogram, and main tumor located in typical TB areas. The survival rate is comparable between LTBI and non-LTBI cases. However, indeterminate QFT-GIT result was an independent predictor for all-cause mortality in lung cancer patients.     

Efficacy and safety of almorexant in adult chronic insomnia: a randomized placebo-controlled trial with an active reference

Background and objectivesThe orally active dual OX₁R and OX₂R antagonist, almorexant, targets the orexin system for the treatment of primary insomnia. This clinical trial assessed the effect of almorexant on sleep maintenance and other sleep endpoints, and its safety and tolerability in adults.Patients and methodsProspective, randomized, double-blind, placebo-controlled, active referenced trial in male and female adults aged 18–64 years with chronic, primary insomnia. Patients were randomized 1:1:1:1 to receive placebo, almorexant 100 mg, almorexant 200 mg, or zolpidem 10 mg (active reference) for 16 days. Primary efficacy assessments were objective (polysomnography-measured) and subjective (patient-recorded) wake time after sleep onset (WASO). Further sleep variables were also evaluated.ResultsFrom 709 randomized patients, 707 (mean age 45.4 years; 61.7% female) received treatment and 663 (93.8%) completed the study. A significant decrease versus placebo in median objective WASO was observed with almorexant 200 mg at the start and end of randomized treatment (−26.8 min and −19.5 min, respectively; both p < 0.0001); subjective WASO also decreased over the two-week treatment period (p = 0.0006). Objective and subjective total sleep time (TST) were increased with almorexant 200 mg (p < 0.0001). Almorexant 200 mg significantly reduced objective and subjective latency to persistent sleep and latency to sleep onset at initiation of therapy, and provided longer duration of sleep stages with no suppression of slow-wave sleep. No impaired next-day performance, rebound insomnia, or withdrawal effects were observed. Adverse events were similar with almorexant and placebo.ConclusionAlmorexant reduced time to sleep onset and maintained sleep without residual effects on next-day performance or safety concerns. This study provides further support for the role of the endogenous orexin system in insomnia disorder.ClinicalTrials.gov registrationNCT00608985.     

Evidence for the involvement of the serotonergic 5-HT2A/C and 5-HT3 receptors in the antidepressant-like effect caused by oral administration of bis selenide in mice

The present study investigated a possible antidepressant-like activity of bis selenide using two predictive tests for antidepressant effect on rodents: the forced swimming test (FST) and the tail suspension test (TST). Bis selenide (0.5–5 mg/kg, p.o.) decreased the immobility time in the mouse FST and TST. The anti-immobility effect of bis selenide (1 mg/kg, p.o.) in the TST was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis), ketanserin (1 mg/kg, i.p., a 5-HT_2A/2C receptor antagonist), and ondasentron (1 mg/kg, i.p., a 5-HT₃ receptor antagonist). Pretreatment of mice with prazosin (1 mg/kg, i.p., an α₁-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a β-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D₁ receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D₂ receptor antagonist), or WAY 100635 (0.1 mg/kg, s.c., a selective 5-HT_1A receptor antagonist) did not block the antidepressant-like effect of bis selenide (1 mg/kg, p.o.) in the TST. Administration of bis selenide (0.1 mg/kg, p.o.) and fluoxetine (1 mg/kg), at subeffective doses, produced an antidepressant-like effect in the TST. Bis selenide did not alter Na⁺ K⁺ ATPase, MAO-A and MAO-B activities in whole brains of mice. Bis selenide produced an antidepressant-like effect in the mouse TST and FST, which may be related to the serotonergic system (5-HT_2A/2C and 5-HT₃ receptors).     

Inhibitory effects of polyphenols on human cytochrome P450 3A4 and 2C9 activity

Polyphenols present in foods and supplements may contribute to human health by preventing cardiovascular diseases and cancer. Drug–food or drug–herb interactions have recently come into focus but, except for some phytochemicals, few components of food or herbs participate in such interactions. In this study, we systematically evaluated the inhibitory effects of 60 polyphenols and related compounds on human cytochrome P450 (CYP) 3A4 and CYP2C9 activity by in vitro assay to investigate whether some polyphenols induce drug interactions. In addition, the kinetics of potent CYP inhibitors was investigated by Lineweaver–Burk plot analysis. Three coumarins and 12 flavonoids significantly suppressed CYP3A4 or CYP2C9 activities. Lineweaver–Burk plot analysis indicated that apigenin and its dimer amentoflavone and imperatorin displayed a mixed type of inhibition on CYP3A4 or CYP2C9. Among the inhibitors, amentoflavone was the most potent inhibitor of CYP3A4 and CYP2C9 activities with IC₅₀ values of 0.07 and 0.03 μM, respectively. The K_i value of amentoflavone was significantly lower than that of the CYP2C9 inhibition positive control sulfaphenazole. These findings suggest that some dietary polyphenols may have the potential to inhibit the metabolism of clinical drugs.     

Intraindividual sleep variability and its association with insomnia identity and poor sleep

ObjectiveInsomnia identity refers to the conviction that one has insomnia, which can occur independently of poor sleep. Night-to-night variability in sleep (termed intraindividual variability [IIV]) may contribute to insomnia identity yet remain undetected via conventional mean analyses. This study compared sleep IIV across four subgroups: noncomplaining good sleepers (NG), complaining poor sleepers (CP), complaining good sleepers (CG), and noncomplaining poor sleepers (NP).MethodsThis study analyzed 14 days of sleep diary data from 723 adults. Participants were classified according to presence/absence of a sleep complaint and presence/absence of poor sleep. A 2 × 2 multivariate analysis of covariance (MANCOVA) was performed to explore differences on five measures of sleep IIV: intraindividual standard deviation in total sleep time (iSD TST), sleep onset latency (iSD SOL), wake after sleep onset (iSD WASO), number of nightly awakenings (iSD NWAK), and sleep efficiency (iSD SE).ResultsMANCOVA revealed significant main effects of poor sleep, sleep complaint, and their interaction on sleep IIV. Poor sleepers exhibited greater IIV across all sleep parameters compared to good sleepers. Similarly, individuals with a sleep complaint exhibited greater IIV compared to individuals with no complaint. The interaction revealed that iSD SOL was significantly greater among CP than NP, and iSD NWAK was significantly greater among CG than NG.ConclusionsGreater night-to-night variability in specific sleep parameters was present among complaining versus noncomplaining sleepers in good and poor sleep subgroups. These findings suggest certain aspects of sleep consistency may be salient for treatment-seeking individuals based on their quantitative sleep status.