Isolation of Human Lineage, Fluoroquinolone-Resistant and Extended-β-Lactamase-Producing Isolates from Companion Animals in Japan.

An increase in human and veterinary fluoroquinolone-resistant is a global concern. In this study, we isolated fluoroquinolone-resistant isolates from companion animals and characterized them using molecular epidemiological analysis, multiplex polymerase chain reaction to detect ST131 and CTX-M type extended-spectrum β-lactamases (ESBL), and multi-locus sequence typing analysis. Using plain-CHROMagar ECC, 101 isolates were isolated from 34 rectal swabs of dogs and cats.

Comprehensive analysis of cardiac function, blood biomarkers and histopathology for milrinone-induced cardiotoxicity in cynomolgus monkeys.

The objective of this study was to elucidate the underlying cardiotoxic mechanism of milrinone, a cAMP phosphodiesterase 3 inhibitor, by evaluating cardiac functions, blood biomarkers including cardiac troponin I (cTnI), microRNAs (miR-1, miR-133a and miR-499a) and various endogenous metabolites, and histopathology in conscious cynomolgus monkeys. Milrinone at doses of 0, 3 and 30 mg/kg were orally administered to monkeys (n = 3-4/group), and the endpoints were evaluated 1 to 24 h post-dosing. Milrinone caused myocardial injuries characterized by myocardial degeneration/necrosis, cell infiltration and hemorrhage 24 h after drug administration.

Psychometric profile of the Ages and Stages Questionnaires, Japanese translation.

Background: This study assessed the psychometric profile of 10 questionnaires (every 6 months, from 6 to 60 months) from the Japanese translation of the Ages and Stages Questionnaires, third edition (J-ASQ-3).

Methods: Data from 439 children in a birth cohort were used to identify the J-ASQ-3 score distribution, establish cut-off scores, and calculate the instrument's internal consistency. Data were also collected from 491 outpatients to examine J-ASQ-3 test-retest reliability and concurrent validity, which was examined using the Kyoto Scale of Psychological Development (KSPD) and the Japanese version of the Denver Developmental Screening Test II (J-Denver II).

Absolute Quantification of Plasma MicroRNA Levels in Cynomolgus Monkeys, Using Quantitative Real-time Reverse Transcription PCR.

RT-qPCR is one of the most common methods to assess individual target miRNAs. MiRNAs levels are generally measured relative to a reference sample. This approach is appropriate for examining physiological changes in target gene expression levels.

Circulating liver-specific microRNAs in cynomolgus monkeys.

Circulating microRNAs (miRNAs) can potentially be used as sensitive and specific biomarkers for tissue injury. However, the usefulness of circulating miRNAs as safety biomarkers in nonclinical toxicological studies using nonhuman primates is debatable owing to the limited information on organ-specific miRNAs. Therefore, a systematic investigation was performed to address this point.

Comprehensive Analysis of Circulating microRNA Specific to the Liver, Heart, and Skeletal Muscle of Cynomolgus Monkeys.

Circulating microRNAs (miRNAs) could represent sensitive and specific biomarkers for tissue injury. However, their utility as biomarkers in nonclinical toxicological studies using nonhuman primates is limited by a lack of information on their organ specificity and circulating levels under resting condition of the animals. Herein, liver, heart, and skeletal muscle-specific expression patterns of miRNAs were determined in 27 tissues/organs from male and female monkeys (n =2/sex) by next-generation sequencing (NGS) analysis.

A monkey model of acetaminophen-induced hepatotoxicity; phenotypic similarity to human.

Species-specific differences in the hepatotoxicity of acetaminophen (APAP) have been shown. To establish a monkey model of APAP-induced hepatotoxicity, which has not been previously reported, APAP at doses up to 2,000 mg/kg was administered orally to fasting male and female cynomolgus monkeys (n = 3-5/group) pretreated intravenously with or without 300 mg/kg of the glutathione biosynthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO). In all the animals, APAP at 2,000 mg/kg with BSO but not without BSO induced hepatotoxicity, which was characterized histopathologically by centrilobular necrosis and vacuolation of hepatocytes.

Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine when administered to healthy Japanese adults aged ≥50 years. An open-label trial.

This open-label study was designed to assess immunogenicity and safety of 13-valent pneumococcal conjugate vaccine (PCV13) when administered to Japanese adults aged ≥50 years not previously vaccinated with 23-valent pneumococcal polysaccharide vaccine and to compare this Japanese study population with similar study populations in the United States (US; 50-64 years age group) and European Union (EU; ≥65 years age group). Functional antibody immune responses were measured by opsonophagocytic activity assays. Immune responses in both Japanese age groups showed significant pre/postvaccination fold rises for each serotype.

[Gallbladder carcinoma, progressed along cholecystoduodenal fistula--a case report].

A 75-year-old woman had an operation for gallstone ileus without cholecystectomy in other hospital and she was admitted to our hospital because of duodenal adenoma with severe atypia and small carcinoid in proximal duodenal wall. Distal gastrectomy and cholecystectomy were performed. Histological studies revealed the existence of cholecystoduodenal fistula and suggested the existence of gallbladder carcinoma progressed to the duodenal wall through the fistula.

Efficient synthesis of isothiocyanates based on the tandem Staudinger/aza-Wittig reactions and mechanistic consideration of the tandem reactions.

The tandem and stepwise Staudinger/aza-Wittig reactions of several azides were examined in detail. The tandem reaction method (Method I) exhibited superior results in the yield of the corresponding isothiocyanates bearing an electron-withdrawing group than the conventional stepwise method (Method II) which involves the sequential treatment of the azides with triphenylphosphine and then carbondisulfide. The mechanistic consideration for both reaction methods was proposed on the basis of the 1H-NMR analyses.

A practical and facile synthesis of azetidine derivatives for oral carbapenem, L-084.

An orally active carbapenem L-084, which exhibits high bioavailability in humans, has a 1-(1,3-thiazolin-2-yl)azetidin-3-ylthio moiety at the C-2 position of the 1beta-methylcarbapenem skeleton. We established a practical and cost-effective synthesis of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (1) for further scale-up production of L-084. This synthesis method entails an industry-oriented reaction of azetidine ring-closure to yield N-benzyl-3-hydroxyazetidine (16), which is eventually converted to 1 via key intermediates, Bunte salts 19 and 20.

Syntheses and pharmacokinetic studies of prodrug esters for the development of oral carbapenem, L-084.

We discovered an orally active carbapenem, L-084, through pharmacokinetic studies on various prodrug esters of (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-l-methyl-2-[1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio-1-carbapen-2-em-3-carboxylic acid (LJC11,036). L-084 showed a strong antimicrobial activity against Gram-positive and Gram-negative bacteria and exhibited the highest intestinal absorption among synthesized prodrugs of LJC11,036.

A novel, mild, and facile method to prepare 6-methylidene penem derivatives.

A novel and mild method was established to synthesize 6-methylidene penem compounds. This method entails a MgBr(2)/Et(3)N-promoted aldol-type condensation on 6-bromopenem 12 with an appropriately substituted aldehyde to yield the intermediate acetylated bromohydrin, which was smoothly converted to the final product with simultaneous deprotection of C3 carboxylic acid ester using activated zinc dust and phosphate buffer at pH 6.5.