Study Profile of the Tsuruoka Metabolomics Cohort Study (TMCS).

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35-74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study used an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability, functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women's health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

Reliability of Time-Series Plasma Metabolome Data over 6 Years in a Large-Scale Cohort Study.

Studies examining long-term longitudinal metabolomic data and their reliability in large-scale populations are limited. Therefore, we aimed to evaluate the reliability of repeated measurements of plasma metabolites in a prospective cohort setting and to explore intra-individual concentration changes at three time points over a 6-year period. The study participants included 2999 individuals (1317 men and 1682 women) from the Tsuruoka Metabolomics Cohort Study, who participated in all three surveys-at baseline, 3 years, and 6 years. In each survey, 94 plasma metabolites were quantified for each individual and quality control (QC) sample. The coefficients of variation of QC, intraclass correlation coefficients, and change rates of QC were calculated for each metabolite, and their reliability was classified into three categories: excellent, fair to good, and poor. Seventy-six percent (71/94) of metabolites were classified as fair to good or better. Of the 39 metabolites grouped as excellent, 29 (74%) in men and 26 (67%) in women showed significant intra-individual changes over 6 years. Overall, our study demonstrated a high degree of reliability for repeated metabolome measurements. Many highly reliable metabolites showed significant changes over the 6-year period, suggesting that repeated longitudinal metabolome measurements are useful for epidemiological studies.

Effectiveness of real-time PCR for diagnosis and prognosis of varicella-zoster virus keratitis.

PURPOSE: To determine the efficacy of real-time PCR for the diagnosis and prognosis of varicella-zoster virus (VZV) keratitis. STUDY DESIGN: Retrospective case series. METHODS: Patients: 545 consecutive patients with keratitis were examined to quantify copy numbers of VZV DNA by real-time PCR. Association of copy numbers of VZV DNA to clinical signs and disease course was assessed by logistic regression analysis and Cox proportional hazard model. RESULTS: Of the 545 eyes, 38 (6.9%) were diagnosed as VZV keratitis. The median copy number of the VZV DNA was 104.19 copies; this number was significantly associated with diagnosis of VZV keratitis with the highest odds ratio of 3390 (for median copy) compared to the clinical signs. The diagnostic accuracy of the VZV DNA copy indicated good diagnostic value of area under the curve (0.92) by receiver operating characteristic analysis, and detection of unrelated VZV DNA from the cornea was very rare (0.2%). When the VZV DNA copy and clinical signs were assessed for association with the disease course of herpes zoster ophthalmicus, the disease duration was significantly prolonged in VZV keratitis cases with higher numbers of VZV DNA copies, iritis, and history of recurrences. The amount of VZV DNA led to a continuous risk of prolonged disease duration until the ocular inflammation subsided (hazard ratio 0.17, 95% CI 0.07-0.42, for median copies). CONCLUSIONS: Higher VZV DNA copy numbers are associated with the refractoriness of VZV keratitis, and its evaluation may be a useful way to clinically diagnose and manage VZV keratitis.

Assessment of Autistic Traits in Children Aged 2 to 4½ Years With the Preschool Version of the Social Responsiveness Scale (SRS-P): Findings from Japan.

The recent development and use of autism measures for the general population has led to a growing body of evidence which suggests that autistic traits are distributed along a continuum. However, as most existing autism measures were designed for use in children older than age 4, to date, little is known about the autistic continuum in children younger than age 4. As autistic symptoms are evident in the first few years, to address this research gap, the current study tested the preschool version of the Social Responsiveness Scale (SRS-P) in children aged 2 to 4½ years in clinical (N = 74, average age 40 months, 26-51 months) and community settings (N = 357, average age 39 months, 25-50 months) in Japan. Using information obtained from different raters (mothers, other caregivers, and teachers) it was found that the scale demonstrated a good degree of internal consistency, inter-rater reliability and test-retest reliability, and a satisfactory degree of convergent validity for the clinical sample when compared with scores from diagnostic "gold standard" autism measures. Receiver operating characteristic analyses and the group comparisons also showed that the SRS-P total score discriminated well between children with autism spectrum disorder (ASD) and those without ASD. Importantly, this scale could identify autistic symptoms or traits distributed continually across the child population at this age irrespective of the presence of an ASD diagnosis. These findings suggest that the SRS-P might be a sensitive instrument for case identification including subthreshold ASD, as well as a potentially useful research tool for exploring ASD endophenotypes. Autism Res 2017, 10: 852-865. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Efficacy and safety of sitagliptin for the treatment of diabetes mellitus complicated by chronic liver injury.

AIM: To investigate the efficacy and safety of a dipeptidyl peptidase-4 inhibitor, sitagliptin, for treating diabetes mellitus complicated by chronic liver injury. METHODS: Sitagliptin was administered for 13.7 ± 10.1 months to 122 patients with DM complicated by chronic liver injury (including 19 patients with liver cirrhosis), and changes in hemoglobin A1c (HbA1c) and liver enzymes (transaminases, etc.) were evaluated. RESULTS: HbA1c was reduced from 8.48 ± 1.43% to 7.87 ± 1.35% (P < 0.001). Among liver enzymes, alanine aminotransferase (ALT) levels improved from 75.1 ± 45.2 to 65.8 ± 35.8 IU/L (P = 0.012) and gamma-glut amyl-trans peptidase from 155.2 ± 161.1 to 133.2 ± 127.4 IU/L (P = 0.044). Among the causes of liver injury, non-alcoholic fatty liver disease and alcoholic liver disease both showed the reductions in HbA1c with no deterioration of liver enzymes. An analysis of 19 patients with liver cirrhosis also showed reductions in HbA1c with no deterioration of liver enzymes. CONCLUSION: It is suggested that sitagliptin can be administered effectively and safely to patients with diabetes mellitus complicated by chronic liver injury, including liver cirrhosis.

Brief report: large individual variation in outcomes of autistic children receiving low-intensity behavioral interventions in community settings.

BACKGROUND: Despite widespread awareness of the necessity of early intervention for children with autism spectrum disorders (ASDs), evidence is still limited, in part, due to the complex nature of ASDs. This exploratory study aimed to examine the change across time in young children with autism and their mothers, who received less intensive early interventions with and without applied behavior analysis (ABA) methods in community settings in Japan. METHODS: Eighteen children with autism (mean age: 45.7 months; range: 28-64 months) received ABA-based treatment (a median of 3.5 hours per week; an interquartile range of 2-5.6 hours per week) and/or eclectic treatment-as-usual (TAU) (a median of 3.1 hours per week; an interquartile range of 2-5.6 hours per week). Children's outcomes were the severity of autistic symptoms, cognitive functioning, internalizing and externalizing behavior after 6 months (a median of 192 days; an interquartile range of 178-206 days). In addition, maternal parenting stress at 6-month follow-up, and maternal depression at 1.5-year follow-up (a median of 512 days; an interquartile range of 358-545 days) were also examined. RESULTS: Large individual variations were observed for a broad range of children's and mothers' outcomes. Neither ABA nor TAU hours per week were significantly associated with an improvement in core autistic symptoms. A significant improvement was observed only for internalizing problems, irrespective of the type, intensity or monthly cost of treatment received. Higher ABA cost per month (a median of 1,188 USD; an interquartile range of 538-1,888 USD) was associated with less improvement in language-social DQ (a median of 9; an interquartile range of -6.75-23.75). CONCLUSIONS: To determine an optimal program for each child with ASD in areas with poor ASD resources, further controlled studies are needed that assess a broad range of predictive and outcome variables focusing on both individual characteristics and treatment components.

A Case of Rathke's Cleft Cyst Associated with Transient Central Adrenal Insufficiency and Masked Diabetes Insipidus.

A 73-year-old woman admitted to our hospital because of headache, poor appetite, malaise, weight loss, and vomiting was found to have central adrenal insufficiency and thyrotoxicosis due to silent thyroiditis. Polyuria developed after replacement with glucocorticoid (masked diabetes insipidus), which was controlled with nasal administration of desmopressin. Magnetic resonance imaging of the brain showed a large cystic pituitary mass (18 × 18 × 12 mm) extending suprasellarly to the optic chiasm. Transsphenoidal surgery revealed that the pituitary tumor was Rathke's cleft cyst. Following surgery, replacement with neither glucocorticoid nor desmopressin was needed any more. Therefore, it is suggested that Rathke's cleft cyst is responsible for the masked diabetes insipidus and the central insufficiency. Furthermore, it is speculated that thyrotoxicosis with painless thyroiditis might induce changes from subclinical adrenal insufficiency to transiently overt insufficiency.

[Efficacy of Gram-Fungiflora Y double staining in diagnosing infectious keratitis].

PURPOSE: To evaluate the efficacy of Gram-Fungiflora Y double staining for corneal scraping samples collected by impression in diagnosing infectious keratitis. SUBJECTS AND METHODS: Two hundred and thirteen eyes of 192 patients suspected of having infectious keratitis were retrospectively studied for the sensitivity and specificity of Gram-Fungiflora Y based on final diagnosis. RESULTS: Of 165 infectious keratitis eyes, 107 had bacterial keratitis, 54 had fungal keratitis, and 15 had Acanthamoeba keratitis. Of these, 147 eyes were positive for one or other of the pathogens by the double staining method (overall sensitivity/specificity was 89.1% (95% confidence interval 83.1%-93.2%)/ 79.1% (64.6%-89.0%)). Sensitivity/specificity of the double staining for each of the pathogens was 88.8% 82.1% for bacterial keratitis, 81.4%/98.1% for fungal keratitis and 80.0%/97.0% for Acanthamoeba keratitis. CONCLUSION: The double staining method for impression specimens was effective in diagnosing infectious keratitis with high sensitivity, and was especially useful for the diagnosis of fungal or Acanthamoeba keratitis.

Negative regulation by SHPS-1 of Toll-like receptor-dependent proinflammatory cytokine production in macrophages.

SHPS-1 is a transmembrane protein predominantly expressed in macrophages. The possible role of SHPS-1 in regulation of Toll-like receptor (TLR)-dependent production of proinflammatory cytokines by macrophages has remained unknown, however. We now show that expression either of a mutant version of mouse SHPS-1 (SHPS-1-4F) in which the four tyrosine phosphorylation sites in the cytoplasmic region are replaced by phenylalanine or of a chimeric protein comprising the extracellular and transmembrane regions of human CD8 fused to the cytoplasmic region of SHPS-1-4F (CD8-4F) markedly promoted the production of tumor necrosis factor-alpha (TNF-alpha) or interleukin-6 (IL-6) induced by lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid [poly(I : C)] in RAW264.7 macrophages. In contrast, expression of a mutant form of SHPS-1 that lacks most of the cytoplasmic region did not promote such responses. Expression of SHPS-1-4F promoted the LPS- or poly(I : C)-induced activation of NF-kappaB. LPS and poly(I : C) each induced the tyrosine phosphorylation of SHPS-1 through a Src family kinase and the association of SHPS-1 with SHP-1 and SHP-2. These results suggest that LPS or poly(I : C) induces tyrosine phosphorylation of SHPS-1 and the association of SHPS-1 with SHP-1 and SHP-2 in a manner dependent on a Src family kinase. SHPS-1 then negatively regulates TLR4- or TLR3-dependent cytokine production through inhibition of NF-kappaB-dependent signaling.