Acute Dose-Response Effectiveness of Combined Catechins and Chlorogenic Acids on Postprandial Glycemic Responses in Healthy Men: Results from Two Randomized Studies.

Epidemiologic studies show that the risk of diabetes can be reduced by ingesting green tea or coffee. Previous studies have shown that simultaneously taking green tea catechins (GTC) and coffee chlorogenic acid (CCA) alters postprandial gastrointestinal hormones secretion and improves insulin sensitivity. However, there is no evidence on the acute effects of GTC and CCA on incretin and blood glucose, and on the respective dose of polyphenols. In this randomized, double-blind, placebo-controlled crossover study, we examined the effective dose of GTC and CCA on postprandial glucose, insulin, and incretin responses to a high-fat and high-carbohydrate cookie meal containing 75 g of glucose in healthy men. Study 1 (n = 18) evaluated two doses of GTC (270 or 540 mg) containing a fixed dose of CCA (270 mg) with 113 mg of caffeine and a placebo (0 mg GTC and 0 mg CCA) with 112 mg of caffeine. Study 2 (n = 18) evaluated two doses of CCA (150 or 300 mg) containing a fixed dose of GTC (540 mg) and a placebo with 99 mg of caffeine. The single combined ingestion of GTC and CCA significantly altered the incretin response and suppressed glucose and insulin levels. These findings suggest that the effective minimum dose is 540 mg of GTC and 150 mg of CCA.

Cerebrospinal Fluid Protein Concentration in Healthy Older Japanese Volunteers.

The concentration of cerebrospinal fluid total protein (CSF-TP) is important for the diagnosis of neurological emergencies. Recently, some Western studies have shown that the current upper reference limit of CSF-TP is quite low for older patients. However, little is reported about the concentration of CSF-TP in the older Asian population. In this study, we retrospectively analyzed the CSF-TP concentrations in healthy older Japanese volunteers. CSF samples in 69 healthy Japanese volunteers (age range: 55-73 years) were collected by lumbar puncture, and the data of CSF were retrospectively analyzed. The mean (standard deviation) CSF-TP was 41.7 (12.3) mg/dL. The older group (≥65 years old) had higher CSF-TP concentration than the younger group (55-64 years old). The 2.5th percentile and 97.5th percentile of CSF-TP were estimated as 22.5 and 73.2 mg/dL, respectively, which were higher than the current reference range in Japan (10-40 mg/dL). Conclusions: The reference interval of CSF-TP in the older population should be reconsidered for the precise diagnosis of neurological emergencies.

Safety and Pharmacokinetics of High-Dose TAS-303 in Healthy Japanese Volunteers: A Single-Center, Single-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multiple-Ascending-Dose Study.

Preclinical data of TAS-303 (4-piperidinyl 2,2-diphenyl-2-[propoxy-1,1,2,2,3,3,3-d7 ] acetate hydrochloride), a noradrenaline reuptake inhibitor, show that it increases urethral contraction in rats and may therefore benefit stress urinary incontinence patients. In this single-blind, randomized, placebo-controlled, parallel-group, multiple-ascending-dose phase 1 study, we evaluated the safety and tolerability of once-daily TAS-303 8, 10, 12, 15, or 18 mg administered for 16 days in healthy subjects. In addition, we investigated the pharmacokinetics and inhibitory effect of TAS-303 on hepatic cytochrome P450 (CYP) 3A activity. Rates of adverse events, adverse drug reactions, and pharmacokinetic parameters of TAS-303 were evaluated. Fifty subjects were randomized: 7 subjects each were assigned to receive TAS-303 8-18 mg, and 3 subjects each were assigned to receive placebo at each dose. The overall incidences of adverse events and adverse drug reactions in all subjects administered TAS-303 (n = 35) was 25.7% and 2.9%, respectively, and those for the placebo groups (n = 15) were 46.7% and 0%, respectively. No deaths or serious adverse events occurred. TAS-303 displayed a dose-proportional pharmacokinetic profile across doses of 8-18 mg over the 16-day multiple administration period, and TAS-303 might inhibit hepatic CYP3A activity within this dose range. TAS-303 at a dose of 8-18 mg was confirmed to be safe and tolerable.

Bactericidal/Permeability-Increasing Fold-Containing Family B Member 4 May Be Associated with NSAID-Induced Enteropathy.

BACKGROUND: There is considerable individual variability in nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy. AIM: To identify the SNP that is most significantly involved with NSAID-induced enteropathy. METHODS: One hundred fifty human subjects who were known to have a certain degree of loxoprofen- or celecoxib-induced small-intestinal damage from a previous study were enrolled. The subjects were divided into groups based on treatments and also on the increased number of small intestinal mucosal breaks. The candidate SNP was selected by an initial analysis of GWAS among the groups in various combinations. After the initial analysis, the gene including the specified SNP was analyzed in detail using GWAS and genotype imputation. RESULTS: After analysis, 70 subjects receiving the loxoprofen treatment and 69 subjects receiving celecoxib treatment were determined to be eligible for the analysis. The minimum p value in GWAS was detected in the analysis of 16 cases with an increase of five or more mucosal breaks and 123 controls with zero to four mucosal breaks. In the GWAS, five SNPs in the bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) gene showed the lowest p value (p = 2.69 × 10-7 with an odds ratio of 40.9). Of the five SNPs, four were nonsynonymous SNPs (rs2070325: V268I, rs2889732: T320N, rs11699009: F527L, rs11696307: T533I, and rs11696310: intronic). Furthermore, 23 SNPs in BPIFB4 detected by genotype imputation based on the GWAS data also showed suggestive associations (p < 1 × 10-6). CONCLUSION: The results indicate that SNPs in BPIFB4 were associated with NSAID-induced small intestinal mucosal injury (UMIN: 000007936).

Repeatability of small bowel transit time in capsule endoscopy in healthy subjects.

BACKGROUND: There are no reports to prove the repeatability of gastric transit time (GTT) and small bowel transit time (SBTT) in capsule endoscopy (CE). OBJECTIVE: To clarify the repeatability and factors that affect GTT/SBTT in CE. METHODS: We analyzed the data of 150 healthy subjects from our previous randomized controlled trial that compared small intestinal injuries between two 14-day treatment groups: 1) celecoxib and 2) loxoprofen + lansoprazole. Correlation of GTT/SBTT with pre- and post-treatment CE was analyzed. In addition, the associations of pre-treatment CE SBTT with physical factors, post-treatment CE SBTT and the presence of small intestinal mucosal injuries were analyzed. RESULTS: Analyses of 148 subjects pre-treatment CE and 146 subjects post-treatment CE were performed. There were no significant differences between mean GTT and SBTT before and after treatment. Both GTT (𝜌 = 0.22, p < 0.01) and SBTT (𝜌 = 0.47, p < 0.0001) showed positive correlations between pre- and post-treatment CE. In pre-treatment CE, physical factors and the presence of small intestinal mucosal injury had no associations with SBTT. CONCLUSIONS: Moderate correlation in SBTT and slight correlation in GTT were shown on repeated CE. The factors affecting SBTT were not clarified in this analysis.

Celecoxib Monotherapy Maintained Small Intestinal Mucosa Better Compared With Loxoprofen Plus Lansoprazole Treatment: A Double-blind, Randomized, Controlled Trial.

GOALS: The aim of this study was to compare celecoxib with loxoprofen for protection of small intestine. BACKGROUND: RCT studies report that COX-2 selective inhibitor celecoxib induces fewer small intestinal injuries than nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). Loxoprofen is a prodrug nonselective NSAID developed to protect upper gastrointestinal tract. STUDY: A total of 150 healthy volunteers (40 to 70 y) were enrolled. After medical checkup including laboratory data, subjects were randomly assigned to celecoxib (200 mg daily) or loxoprofen (180 mg daily) plus lansoprazole (15 mg daily). All drugs were prepared using inactive capsules. After randomization, all subjects were first examined by baseline capsule endoscopy (CE). After 14 days, subjects underwent posttreatment CE. We compared baseline and posttreatment CE findings of the 2 groups. All CE data were evaluated blindly by 3 reviewers. Pretreatment and posttreatment laboratory variables were also compared. RESULTS: A total of 74 subjects (49±6 y, F/M: 36/38) were enrolled in celecoxib group and 76 subjects (49±7 y, F/M: 39/37)in loxoprofen group. Five in celecoxib group and 4 in loxoprofen group were excluded from CE analysis mainly due to incomplete CE. The percentage of subjects with at least 1 posttreatment mucosal break was lower in celecoxib group (10%) than in loxoprofen group (49%) (P<0.0001). A total of 0.3±1.0 posttreatment small intestinal mucosal breaks were detected in the celecoxib group, and 6.8±21.5 in the loxoprofen group (P<0.0001). Posttreatment hemoglobin concentration in loxoprofen group (5.1% reduction) was lower compared with celecoxib group (2.1% reduction) (P=0.006). CONCLUSIONS: In terms of protection of small intestine from NSAIDs toxicity, celecoxib monotherapy was superior to loxoprofen+lansoprazole combination therapy (UMIN: 000007936).

Immunogenicity and safety of the 13-valent pneumococcal conjugate vaccine compared to the 23-valent pneumococcal polysaccharide vaccine in elderly Japanese adults.

Streptococcus pneumoniae is a major cause of severe disease worldwide, particularly in the elderly population. Due to increasing life expectancy in Japan and elsewhere, an effective vaccine which offers the possibility of prolonged protection is required. Protein conjugated pneumococcal vaccines, which have the ability to boost immunity (immunologic memory) on natural exposure or revaccination, may meet these requirements. An unconjugated 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been available for decades; however data on protection against pneumonia are inconsistent. For the first time, a randomized, modified double-blind trial comparing the 13-valent pneumococcal conjugate vaccine (PCV13) with PPSV23 was conducted in PPSV23-naive adults ≥65 years of age in Japan. This study showed that statistically significantly greater functional antibody responses as measured by opsonophagocytic assays 1 month after vaccination were elicited in the PCV13 group (n = 366) compared with the PPSV23 group (n = 367) for 9 of the 12 serotypes in common with both vaccines and for serotype 6A, unique to PCV13. Local reactions collected within 14 days of vaccination were more frequent in the PCV13 (57.5%, 211/367) than PPSV23 (44.9%, 166/370) group, although severity was generally mild to moderate; systemic and adverse events were similar across groups. There were no treatment-related serious adverse events. Consistent with global studies comparing PCV13 with PPSV23, PCV13 use in Japanese subjects was safe and well-tolerated and elicited greater functional immune responses than PPSV23 for the majority of PCV13-serotypes. PCV13 has the potential to protect against pneumococcal disease in Japanese elderly adults.

Arrhythmias observed during high-G training: proposed training safety criterion.

INTRODUCTION: Most arrhythmias during centrifuge training are physiological responses to high +Gz stress. However, potentially dangerous arrhythmias occasionally occur during centrifuge training. We reviewed all arrhythmias recorded during the Japan Air Self-Defense Force (JASDF) centrifuge training from April 2001 to March 2003, and developed a criterion for suspending G-training based on observed arrhythmias. METHOD: There were 195 male fighter pilots who received high-G centrifuge training monitored with electrocardiographs (ECGs). We evaluated types and occurrences of all arrhythmias during high-G training over a 24-mo period. RESULTS: Sinus arrhythmia (48.7%), single premature atrial contraction (32.3%), and single (58.5%) or paired (9.7%) premature ventricular contraction were commonly occurring arrhythmias during high-G training. We considered these arrhythmias as variant physiological responses to high-G training (category 1). In addition, we observed ventricular tachycardia (2.6%), paroxysmal supraventricular tachycardia (1.5%), and paroxysmal atrial fibrillation (0.5%). Further investigation of these trainees revealed a significant proportion with cardiac anomalies. As a result, the JASDF currently categorizes these arrhythmias as indicators to suspend G-training and initiate cardiac workup (category 3). Other arrhythmias, such as non-sustained ventricular tachycardia (VT) or Morbitz type I atrioventricular (AV) block, were considered borderline anomalies; whether training was allowed to continue depended on the decision of the physicians monitoring the training (category 2). CONCLUSION: Routine ECG monitoring during centrifuge training is recommended to catch the pathology underlying dangerous arrhythmias for flight safety. Our proposed criterion for stopping the centrifuge is intended to differentiate between serious arrhythmias and arrhythmias of physiologic response.

Antagonizing potencies of saturated and unsaturated long-chain free fatty acids to isoflurane in goldfish.

PURPOSE: We have previously reported that myristate, a saturated free fatty acid (FFA) with 14 carbons (C14), antagonizes volatile anesthetics in goldfish. The hydrophobicity and molecular configuration of FFAs may play an important role in the antagonizing effect. To examine their contribution, we investigated the antagonizing potencies of saturated and unsaturated long-chain FFAs in goldfish. METHODS: Saturated and monounsaturated FFAs of C14-18 were tested. We determined the anesthetic concentration producing a 50% effect (EC50) of isoflurane in the absence or presence of FFA by observing the escape reaction of goldfish against an electrical stimulus. RESULTS: All FFAs increased the EC50 of isoflurane dose-dependently compared with reactions in the absence of FFA ( P < 0.05). For saturated FFAs, the relationship between chain lengths and antagonizing potencies was not linear. C18 was the most effective and C16 was the least effective antagonist ( P < 0.05). Among unsaturated FFAs, C14 was the most effective antagonist ( P < 0.05). In a comparison of saturated and unsaturated FFAs, saturated C14 and C18 were more effective antagonists than unsaturated FFAs of the same carbon numbers ( P <<0.05). CONCLUSION: The hydrophobicity of FFAs increases as the chain length increases. Therefore, our findings suggest that the antagonizing effect of long-chain FFAs in goldfish, in terms of their capacity to perturb the lipid membrane structure, may be determined not solely by their hydrophobicity but also by their molecular configuration.

Long-term disability among aviators in Japan Air Self-Defense Force: analysis of 260 cases.

BACKGROUND: As part of a study of the risks associated with aviator incapacitation, we identified the diseases that caused long-term disability (LTD) among aviators in the Japan Air Self-Defense Force (JASDF), and then assessed the magnitude of the problem that each group of diseases represented with regard to the safety of flight. METHODS: Case-notes for JASDF aviators who stopped work for more than 3 mo during 1980-2002 were identified from all files kept at the Medical Evaluation Section of the Aeromedical Laboratory. The case-notes were divided into four age groups and analyzed by diagnostic category or injury. RESULTS: We identified 260 aviators with LTD, including 217 active-duty pilots and 43 navigators with flying status. Of those, 59 cases (22.7%) had permanent disability for flight. About 75% of LTD cases could be attributed to five diagnostic categories: neoplasms, nervous system and sense organs, circulatory system, digestive system, and musculoskeletal system. Peaks in LTD were found in the 20-29 and 40-49 age-groups. In the younger group, 78.2% of the patients were students, of whom 23 were found to have a disability associated with a preexisting medical condition which was not detected in the initial screening process for pilots. In the 20-29 yr age-group, the most common reason for LTD was the nervous system and sense organs, while in the 40-49 yr age-group it was the circulatory system. CONCLUSION: Reduction in the frequency of LTD might be accomplished by improving the medical screening process for applicants and emphasizing the prevention of circulatory diseases during a pilot's career.