Association of coffee, green tea, and caffeine with the risk of dementia in older Japanese people.

OBJECTIVES: Coffee, green tea, and caffeine are potential preventive factors for dementia, but the underlying evidence is insufficient. This study aimed to examine associations between the consumption of coffee, green tea, and caffeine and dementia risk in middle-aged and older people. METHODS: This was a cohort study with an 8.0-year follow-up. Participants were community-dwelling individuals (n = 13,757) aged 40-74 years. A self-administered questionnaire survey was conducted in 2011-2013. Predictors were the consumption of coffee/green tea, from which caffeine consumption was estimated. The outcome was incident dementia obtained from the long-term care insurance database. Covariates were demographic factors, body mass index, physical activity, energy, smoking, drinking, and disease history. Adjusted hazard ratios (HRs) were calculated using Cox proportional hazards models. HRs were also calculated using a Cox model with delayed entry. RESULTS: The number of dementia cases during the study period was 309. Participants with higher coffee consumption had lower HRs (adjusted p for trend = 0.0014), with the fifth quintile (≥326 ml/day) having a significantly lower HR (0.49, 95% confidence interval [CI]: 0.30-0.79) than the first quintile (<26 ml/day, reference). Similarly, participants with higher caffeine consumption had a significantly lower HR (adjusted p for trend = 0.0004) than the reference. The Cox model with delayed entry yielded similar results. These associations were significant in men, but not in women. Moreover, participants who consumed 2-2.9 cups/day and ≥3 cups/day of coffee had lower HRs (0.69, 95% CI: 0.48-0.98 and 0.53, 95% CI: 0.31-0.89, respectively) than those who consumed 0 cup/day. The association between green tea consumption and reduced dementia risk was significant (adjusted p for trend = 0.0146) only in the 60-69 years age subgroup. CONCLUSIONS: High levels of coffee and caffeine consumption were significantly associated with a reduced dementia risk in a dose-dependent manner, especially in men. Moreover, coffee consumption of ≥3 cups/day was associated with a 50% reduction in dementia risk.

A monoclonal antibody raised against a synthetic oxytocin peptide stains mouse hypothalamic neurones.

A monoclonal antibody against oxytocin was generated in 7a5 hybridoma cells derived from myeloma cells and lymphocytes from the spleen of mice immunised with a synthetic oxytocin peptide. The 7a5 monoclonal antibody bound with oxytocin in enzyme-linked immunosorbent assays. 7a5 cell growth medium was diluted up to 5000-fold and used for immunohistochemistry. First, to test the specificity of the 7a5 antibody against oxytocin, we stained brain tissues of oxytocin knockout mice, comprising mice in which the first exon of the oxytocin-neurophysin gene is deleted. No 7a5 immunoreactivity was detected in the paraventricular nucleus (PVN) of the hypothalamus of oxytocin knockout mice; however, this area was strongly stained with the anti-vasopressin polyclonal antibody, HM07. Tissue preparations of the wild-type mouse PVN and supraoptic nucleus (SON) displayed 7a5 immunoreactivity that was indistinguishable from the staining produced with an anti-oxytocin polyclonal antibody, HM06. The immunoreactivity of HM06 in the PVN was similar to that of an anti-oxytocin monoclonal antibody, PS38. We then examined the cross-reactivity of 7a5 with arginine vasopressin. The majority of cell soma and processes stained by 7a5 were not co-stained with the vasopressin antibody in SON and PVN regions. Furthermore, the suprachiasmatic nucleus was stained by the vasopressin antibody but not by 7a5. These results demonstrate that 7a5 is a new anti-oxytocin monoclonal antibody recognising oxytocin and not vasopressin; therefore, 7a5 can be used to investigate the role of oxytocin in the brain.

Effects of active dried Saccharomyces cerevisiae on ruminal fermentation and bacterial community during the short-term ruminal acidosis challenge model in Holstein calves.

We investigated the effects of active dried Saccharomyces cerevisiae (ADSC) on ruminal pH, fermentation, and the fluid bacterial community during the short-term ruminal acidosis challenge. Five rumen-fistulated male Holstein calves (147.0 ± 5.8 kg of body weight; 3.6 ± 0.2 mo of age) were used in a crossover design, and 0 g (control group, n = 5) or 2 g (SC group, n = 5) of ADSC (1 × 1010 cfu/g) was administered twice daily for 21 consecutive days. Calves were fed a high-forage diet during the first 15 d (d -14 to d 0; prechallenge), a high-grain diet for 2 d (d 1 and 2; ruminal acidosis challenge), and a high-forage diet for 4 d (d 3 to 6; postchallenge). Ruminal pH was measured continuously. Rumen fluid samples were collected once daily (0800 h) on d 0, 3, 4, and 6 and twice daily (0800 and 1100 h) on d 1 and 2. Bacterial DNA was extracted from fluid samples collected on d 0 and 3. The 24-h and 1-h mean ruminal pH was significantly depressed during the ruminal acidosis challenge in each group, although the changes were more severe in the SC group, consistent with a significant increase in lactic acid on d 2 (1100 h) compared with d 0 and a significantly higher proportion of butyric acid on d 2 (1100 h) compared with the control group. Feeding a high-grain diet caused a decrease in bacterial diversity due to high acidity in both groups. The relative abundances of the genus Bifidobacterium and operational taxonomic unit (OTU) 3 (Bifidobacterium species) increased significantly in both groups but were higher in the SC group. Correlation analyses indicated that OTU3 (Bifidobacterium species) were positively correlated with lactic acid concentration and that OTU1 (Prevotella species) and OTU5 (Succinivibrio species) were correlated with the proportion of butyric acid. These results suggest that ADSC supplementation induced the intense decreases in ruminal pH by increased butyric and lactic acid production through a high-grain diet fermentation by rumen fluid bacterial species during the short-term ruminal acidosis challenge in Holstein calves after weaning.

Physical activity modifies the effect of calcium supplements on bone loss in perimenopausal and postmenopausal women: subgroup analysis of a randomized controlled trial.

We aimed to determine whether the effect of calcium supplements on bone metabolism is modified by physical activity (PA) through a subgroup analysis of an RCT. PA may be a favorable effect modifier of the association between calcium intake and bone loss in perimenopausal and postmenopausal women. PURPOSE: Physical exercise can potentially modify bone metabolism. Here we aimed to determine whether the effect of calcium supplements on bone metabolism is modified by physical activity (PA) through a subgroup analysis of a randomized, double-blind, placebo-controlled trial. METHODS: The trial was conducted over the course of 2 years, and participants were 450 healthy women between 50 and 75 years of age who were randomly assigned to three equally-sized (N = 150 each) groups (500 mg calcium, 250 mg calcium, and placebo). Levels of PA at baseline were evaluated by quantifying moderate (4 METs) and vigorous (6 METs) activities based on a 7-day activity recall, and the total MET-hours per week was calculated. Follow-up BMD examinations were conducted 2 years later. Two-year changes in BMD were compared between the intention-to-treat higher PA subgroup (≥ 10 MET-hours/week) and the lower PA subgroup (< 10 MET-hours/week). RESULTS: Of the 450 participants, 418 underwent follow-up BMD measurements. Regarding the lower PA subgroup, spinal BMD in the 500 mg/day calcium supplement group decreased significantly less (- 0.029 g/cm2, P = 0.042) than in the placebo group (- 0.045 g/cm2), and femoral neck BMD in the 500 mg/day calcium supplement group decreased significantly less (- 0.027 g/cm2, P = 0.049) than in the placebo group (- 0.038 g/cm2). In contrast, changes in neither spinal nor femoral neck BMD significantly differed between the three treatment groups in the higher PA subgroup. CONCLUSIONS: PA is a favorable effect modifier of the association between calcium intake and bone loss in perimenopausal and postmenopausal women with low calcium intake. CLINICAL TRIALS REGISTRY NUMBER: UMIN000001176.

Discovery of 2-[(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor.

Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics.