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Background: Outdoor play (OP), which is considered important for children's development, is declining every year. Perceived physical competence (PPC) is a vital factor that promotes physical activity such as OP, sports clubs, etc., but the relationship between PPC and OP was unknown. The purpose of this research was to investigate the relationship between PPC and OP in children and consider whether there were any sex-specific changes., Methods: A cross-sectional study was conducted in Japan with 288 children (134 girls, age: 10.6 ± 1.01 years). OP was assessed using an original self-report questionnaire. Each weekday, the children reported the time of OP and were classified as "high" if they played outside for at least an hour three times. PPC was evaluated with a self-report questionnaire developed by Okazawa et al. (1996). It has 12 questions and was assessed on a 5-point Likert scale. After adjusting for age, sex, BMI, screen time, sports club participation, and the number of friends, logistic regression analyses were carried out., Results: Children with better PPC were significantly more likely to be classified as "high" [crude odds ratio (OR): 1.04; 95% confidence interval (CI): 1.00-1.08; adjusted OR: 1.04; 95% CI: 1.00-1.08]. Only girls with better PPC were significantly more likely to be classified as "high" in a sex-based stratified analysis [crude OR: 1.08; 95% CI: 1.01-1.15, adjusted OR 1.09; 95% CI: 1.02-1.17]., Conclusions: Particularly among girls, OP could be promoted as a voluntary physical activity with improved PPC.

Objective: This study aimed to investigate whether longitudinal changes in exercise capacity in patients with acute myocardial infarction (AMI) differ by sex and clarified what contributed to these differences., Methods: We retrospectively examined the differences in each variable between men and women in 156 patients with AMI (mean age: 65 ± 12 years; 82.0% male) who participated in a 3-month cardiac rehabilitation (CR) program and could be followed-up for exercise capacity 12-months after AMI onset. Sex-related differences in the change in peak oxygen uptake (peak VO 2 ) at baseline, 3-months, and 12-months after AMI were analyzed., Results: Male patients with AMI were younger and had higher body mass index and employment rate than women. The attendance of the CR program was higher in women (men vs. women; 10 [3-15] vs. 14 [11-24] sessions, p = 0.0002). Women showed a significant lower %change in peak VO 2 after 12 months (men vs. women; 7.8% [-0.49% to 14.6%] vs. 1.3% [-5.7% to 7.5%], p = 0.013). In multiple linear regression analysis, age (β = -0.76, 95% confidence interval [CI] = -1.0 to -0.50, p <0.0001) and female sex (β = -6.3, 95% CI = -9.1 to -3.5, p <0.0001) were negative independent predictors of change in peak VO 2 over 12 months, while CR attendance (β = 0.21, 95% CI = 0.0032-0.42, p = 0.047) and recommended exercise habit after the CR program (β = 2.1, 95% CI = 0.095-4.1, p = 0.040) were positive independent predictors of change in peak VO 2 over 12 months., Conclusion: In female patients, exercise capacity improved during the CR program but decreased to AMI onset levels after 12 months., (©2022 Japanese Society of Physical Therapy.)

Background: Alcohol problems in parents have been revealed to affect adolescent alcohol misuse. However, few studies examine the effects of parental drinking on adolescent risky drinking (including binge drinking) in the general population. In particular, previous study findings are inconsistent regarding the influence of parental drinking according to parental composition. In this study, we aimed to examine the relationship between parental drinking, according to parental composition, and binge drinking among high school students in Japan., Methods: We performed a secondary analysis of the Nationwide High School Survey on Drug Use and Lifestyle 2018, Japan. A total of 46,848 valid surveys from high school students of 78 schools were included for analysis. Logistic regression analysis with a generalized linear mixed model was conducted with binge drinking as the dependent variable and "parental drinking according to parental composition" (e.g., father's drinking, mother's drinking, father's absence, mother's absence, both parents drinking, and neither parent at home) as the independent variable, after adjusting with covariates. Binge drinking was defined as five or more alcoholic drinks for male adolescents or four or more alcoholic drinks for females on the same occasion within two hours., Results: In the fully adjusted models, adolescents whose mothers drink (adjusted odds ratio (AOR): 1.50, 95% confidence interval (CI): 1.06-2.12) were significantly associated with adolescent binge drinking. This risk was significantly higher among students with neither parent living at home (AOR: 4.35, 95% CI: 2.10-9.02)., Conclusion: Parental drinking and absence do affect adolescent binge drinking; our findings show that adolescents are more likely to engage in binge drinking if their mothers drink or if they are not living with either parent. Therefore, it is important to engage parents and non-parental family members in future programs and interventions to prevent adolescent binge drinking.

Background: Cardiac resynchronization therapy (CRT) is an effective treatment of heart failure (HF) with ventricular dyssynchrony, but not all patients respond to a similar extent. We investigated the efficacy and safety of exercise training (ET) in patients without response to CRT. Methods and Results: Thirty-four patients who participated in a 3-month ET program and underwent cardiopulmonary exercise testing at baseline and after the program were divided into 17 responders and 17 non-responders based on echocardiographic response criteria: either an increase in ejection fraction (EF) ≥10% or a reduction in left ventricular (LV) end-systolic volume ≥10%. Baseline characteristics including peak oxygen uptake (V̇O 2 ) and isometric knee extensor muscle strength (IKEMS) were similar in both groups, but non-responders had lower EF and larger LV. During the ET program, neither group had exercise-related adverse event including life-threatening ventricular arrhythmia. Peak V̇O 2 and IKEMS were significantly improved in both groups and there was no significant difference in change in peak V̇O 2 or IKEMS between responders and non-responders. On multiple regression analysis, change in IKEMS was an independent predictor of change in peak V̇O 2 , whereas the response to CRT was not. Conclusions: In HF patients undergoing CRT implantation, ET safely improved exercise capacity regardless of response to CRT, suggesting that even advanced HF patients without response to CRT can possibly benefit from ET., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2019, THE JAPANESE CIRCULATION SOCIETY.)

Infection with Helicobacter pylori is known to decrease the level of glutathione in gastric epithelial cells and increase the production of reactive oxygen species (ROS), which can lead to DNA damage and the development of gastric cancer. Cation transport regulator 1 (CHAC1) has γ-glutamylcyclotransferase activity that degrades glutathione. We found that cagA -positive H. pylori infection triggered CHAC1 overexpression in human gastric epithelial (AGS) cells leading to glutathione degradation and the accumulation of ROS. Nucleotide alterations in the TP53 tumour suppressor gene were induced in AGS cells overexpressing CHAC1, whereas no mutations were detected in cells overexpressing a catalytically inactive mutant of CHAC1. A high frequency of TP53 mutations occurred in H. pylori -infected AGS cells, but this was prevented in cells transfected with CHAC1 siRNA. These findings indicate that H. pylori -mediated CHAC1 overexpression degrades intracellular glutathione, allowing the accumulation of ROS which subsequently causes mutations that could contribute to the development of gastric cancer.

Patients with inflammatory bowel disease (IBD) have an increased risk of developing colitis-associated colorectal cancer (CAC). CAC cells often develop chemoresistance, resulting in a poorer prognosis than that of sporadic colorectal cancer (CRC). The mechanism by which CAC enhances malignant potential remains unknown. We have previously reported that the proteasomal degradation of the transcription factor Atonal homolog 1 (Atoh1) protein results in the non-mucinous form of CRC. It also remains unknown whether Atoh1 protein is expressed in CAC. Therefore, in the present study, we investigated whether Atoh1 protein stabilizes in CAC. Consequently, the treatment with TNF-α stabilized Atoh1 protein through the inactivation of GSK-3β via Akt, resulting in the mucinous form of CRC cell lines. Atoh1 protein also enriched cancer stem cells with upregulated Lgr5 expression and cells in G0/G1 cell cycle phase, resulting in both the chemoresistance to 5-fluorouracil and oxaliplatin and the promotion of cell migration. Immunofluorescence of the human mucinous CAC specimens showed the accumulation of NF-κB p65 at nuclei with the expression of Atoh1 in mucinous cancer. In conclusion, the inflammation associated with carcinogenesis may preserve the differentiation system of intestinal epithelial cell (IEC), resulting in the acquisition of both the mucinous phenotype and high malignant potential associated with the enrichment of cancer stem cell., (© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Background: Gastric "crawling-type" adenocarcinoma (CTAC) is a neoplasm histologically comprising irregularly fused glands with low-grade cellular atypia that tends to spread laterally in the mucosa. It is necessary to elucidate the clinicopathological characteristics of CTAC., Methods: We evaluated 25 CTACs-16 intramucosal (M-) and 9 submucosal invasive (SM-) cancers-clinicopathologically and immunohistochemically., Results: CTAC was most frequently located in the lesser curvature of the middle-third of the stomach. Macroscopically, 21 lesions were superficial-depressed and 4 were superficial-flat type. Histologically, all CTACs had cystic dilated glands and 16 lesions had focal signet-ring cells. All invasive areas of the SM-CTACs were occupied by poorly differentiated adenocarcinoma with an infiltrative growth pattern and abundant stroma. Fifteen CTACs were surrounded by mucosa with partial or no intestinal metaplasia. In the intramucosal area, 24 lesions were mixed phenotype with mucin and brush border immunoexpression. SM-CTAC was frequent in lesions with an intramucosal poorly differentiated component (PDC) greater than 10 mm in size (P = 0.041), and lymph node metastasis (LNM) was frequent in lesions with a PDC greater than 20 mm (P = 0.039). The frequency of an expanded pattern (Ki-67-positive cells occupying > 50 % of the mucosa) was higher in SM-CTAC than in M-CTAC (P = 0.027). p53 overexpression was not detected in the intramucosal areas of any of the lesions., Conclusion: CTAC is a distinct subgroup of gastric adenocarcinoma in the early phase. A larger PDC and a Ki-67 expanded pattern were predictive of submucosal invasion or LNM.

For patients chronically infected with hepatitis C virus (HCV), mutations in the non-structural 5A (NS5A) gene are important predictive factors for the response to interferon (IFN) therapy. In the present study, factor analysis of the therapeutic response of patients following pegylated IFN and ribavirin combination therapy was assessed in a multicenter study. Chronic HCV-infected patients with genotype 1b and high viral load (n=96, mean age 56.5 years; 59 males, 68 females) treated with pegylated IFN-α-2b and ribavirin combination therapy were enrolled. This study was conducted at Kobe University Hospital and 25 affiliated hospitals in Hyogo prefecture. Sixty-five patients (68%) completed treatment with both pegylated IFN and ribavirin at >80% of the weight-based scheduled dosages. Patients who reduced or terminated therapy were frequently aged women (mean age 60.8 years; 11 males, 17 females). Overall, a sustained viral response (SVR) was achieved in 42 (44%) patients out of 96. Based on per-protocol-based (PPB) analysis, the SVR rate in patients with ≥6 amino acid (aa) mutations in the IFN resistance-determining region (IRRDR) (75%) or ≥1 aa mutation in the IFN sensitivity-determining region (ISDR) (61%) was significantly higher than that in patients with <5 aa mutations in IRRDR (30%) or no mutation in ISDR (29%). Multivariate analysis revealed that rapid viral response (RVR) (odds ratio, 18.1) and mutations of ≥6 in IRRDR (odds ratio, 15.5) were significantly associated with SVR. In conclusion, mutations in the NS5A region, particularly in patients with ≥6 aa mutations in IRRDR were strongly associated with a therapeutic response to pegylated IFN and ribavirin combination therapy.

Histologic evaluation of low-grade or high-grade intraepithelial neoplasia (LG-IN or HG-IN) of the esophagus is important for estimating the risk of progression to invasive carcinoma. Discrimination between LG-IN and HG-IN, or neoplasia and non-neoplastic lesion (NNL), however, is occasionally difficult. This study was designed to evaluate whether cytokeratin expression can be used for discrimination of these lesions. Esophageal Iodine-unstained lesions (n=154), less than 10 mm, were classified into HG-IN, LG-IN, and NNL. These lesions together with 154 foci of normal esophageal epithelium (NEE) were examined by immunohistochemistry for cytokeratins (CK4 and CK13), p53 overexpression, and the MIB-1 labeling index. The ratios of CK4- and CK13-positive staining were scored from 1 to 3. The CK4- and CK13-positive staining ratios were decreased in NNL (73% and 78%), LG-IN (55% and 69%), and HG-IN (33% and 48%), compared to NEE (91% and 95%). The differences between LG-IN and HG-IN, neoplasia and NNL, and among these three lesions and NEE were statistically significant (p < 0.005). The cytokeratin scores correlated with the MIB-1 labeling index (both: p < 0.0001), but not with p53 overexpression. CK4 and CK13 immunohistochemistry could be an objective method for evaluating the risk for progression to invasive carcinoma.

Murine models of acute atopic asthma may be inadequate to study the effects of recurrent exposure to inhaled allergens, such as the epithelial changes seen in asthmatic patients. We developed a murine model in which chronic airway inflammation is maintained by repeated allergen [ovalbumin (OVA)] inhalation; using this model, we examined the response to mucosal administration of CpG DNA (oligonucleotides) and specific antigen immunotherapy. Mice repeatedly exposed to OVA developed significantly greater airway hyperresponsiveness and goblet cell hyperplasia, but not airway eosinophilia, compared with those exposed only twice. CpG-based immunotherapy significantly reversed both acute and chronic markers of inflammation as well as airway hyperresponsiveness. We further examined the effect of mucosal immunotherapy on the response to a second, unrelated antigen. Mice sensitized to both OVA and schistosome eggs, challenged with inhaled OVA, and then treated with OVA-directed immunotherapy demonstrated significant reduction of airway hyperresponsiveness and a moderate reduction in eosinophilia, after inhalation challenge with schistosome egg antigens. In this model, immunotherapy treatment reduced bronchoalveolar lavage (BAL) levels of Th2 cytokines (IL-4, IL-5, IL-13, and IL-10) without changing BAL IFN-gamma. Antigen recall responses of splenocytes from these mice demonstrated an antigen-specific (OVA) enhanced release of IL-10 from splenocytes of treated mice. These results suggest that CpG DNA may provide the basis for a novel form of immunotherapy of allergic asthma. Both antigen-specific and, to a lesser extent, antigen-nonspecific responses to mucosal administration of CpG DNA are seen.

CpG oligodeoxynucleotides (CpG ODNs) are known to induce type 1 T-helper-cell (Th1) responses. We have previously demonstrated that CpG ODNs administered during sensitization prevent Th2-mediated eosinophilic airway inflammation in vivo. We also reported that key Th1 cytokines, gamma interferon (IFN-gamma) and interleukin 12 (IL-12), are not necessary for this protection. Recent in vivo data suggest that CpG ODNs might also reverse established pulmonary eosinophilia. In order to clarify how CpG ODNs can inhibit established Th2 responses, we evaluated the cytokine production from splenocytes from antigen- and alum-immunized mice. Restimulation with antigen induced IL-5, which was clearly inhibited by coculture with CpG ODNs in a concentration-dependent manner. CpG ODNs also induced IFN-gamma, but in a concentration-independent manner. The inhibition of IL-5 production was not mediated through natural killer cells or via CD8(+) T lymphocytes. Although IFN-gamma plays an important role in inhibition of antigen-induced IL-5 production by CpG ODNs, IFN-gamma was not the sole factor in IL-5 inhibition. CpG ODNs also induced IL-10, and this induction correlated well with IL-5 inhibition. Elimination of IL-10 reduced the anti-IL-5 effect of CpG ODNs, although incompletely. This may be because IFN-gamma, induced by CpG ODNs, is also inhibited by IL-10, serving as a homeostatic mechanism for the Th1-Th2 balance. Overproduction of IFN-gamma was downregulated by CpG ODN-induced IL-10 via modulation of IL-12 production. These data suggest that CpG ODNs may inhibit established Th2 immune responses through IFN-gamma and IL-10 production, the latter serving to regulate excessive Th1 bias. These properties of CpG ODNs might be a useful feature in the development of immunotherapy adjuvants against allergic diseases such as asthma.

Allergen immunotherapy is an effective but underutilized treatment for atopic asthma. We have previously demonstrated that CpG oligodeoxynucleotides (CpG ODN) can prevent the development of a murine model of asthma. In the current study, we evaluated the role of CpG ODN in the treatment of established eosinophilic airway inflammation and bronchial hyperreactivity in a murine model of asthma. In this model, mice with established ovalbumin (OVA)-induced airway disease were given a course of immunotherapy (using low doses of OVA) in the presence or absence of CpG ODN. All mice then were rechallenged with experimental allergen. Untreated mice developed marked airway eosinophilia and bronchial hyperresponsiveness, which were significantly reduced by treatment with OVA and CpG. CpG ODN leads to induction of antigen-induced Th1 cytokine responses; successful therapy was associated with induction of the chemokines interferon-gamma-inducible protein-10 and RANTES and suppression of eotaxin. Unlike previous studies, these data demonstrate that the combination of CpG ODN and allergen can effectively reverse established atopic eosinophilic airway disease, at least partially through redirecting a Th2 to a Th1 response.

Effects of R[+]-8-([1-[3,4-dimethoxyphenyl]-2-hydroxyethyl]amino) -3,7-dihydro-7-[2-methoxyethyl]-1,3-dimethyl-1H-purine-2,6-dione (MKS-492), a reported type III isozyme inhibitor of cyclic nucleotide phosphodiesterase, on antigen- or platelet activating factor (PAF)-induced bronchoconstriction and allergic reactions in guinea pigs and rats were investigated. 1) MKS-492 inhibited antigen-induced bronchoconstriction in guinea pigs. Aminophylline also inhibited the reaction. 2) MKS-492 inhibited PAF-induced bronchoconstriction and inhibited the increase in airway responsiveness to histamine in guinea pigs, although aminophylline failed to affect these reactions. 3) MKS-492 relaxed guinea pig tracheal muscle in vitro more potently than aminophylline. 4) MKS-492 inhibited leukotriene B4 (LTB4)-induced airway eosinophilia in guinea pigs. 5) MKS-492 inhibited passive cutaneous anaphylaxis and mediator-induced skin reactions in rats more potently than aminophylline. Both drugs inhibited antigen- and phospholipase A2-induced histamine release from guinea pig lung tissue. 6) MKS-492 inhibited PAF-induced O2- generation from guinea pig alveolar macrophages. These results indicate that MKS-492 is a more potent inhibitor of allergic bronchoconstriction and PAF- or LTB4-induced inflammatory reactions in guinea pigs and the allergic cutaneous reactions in rats when compared to aminophylline.

Tranilast, an anti-asthmatic drug with anti-allergic properties, inhibited endothelin (ET)-induced asthmatic like respiratory obstruction in guinea pigs when administered orally at 200 mg/kg 1 h prior to the intravenous injection of ET. ET also caused a bronchoconstriction detected as an increase in inflation pressure in Konzett-Rössler apparatus. Tranilast (200 mg/kg, p.o. 1 h before ET) inhibited ET-induced increased inflation pressure. ET-induced bronchoconstriction detected as an increase in inflation pressure was clearly inhibited by the administration of indomethacin (used as a reference drug) at doses of 1 and 5 mg/kg 30 min prior to onset of the reaction. In addition to the above in vivo experiments, tranilast at concentrations between 10(-5) and 10(-4) g/ml inhibited ET-induced contraction of isolated guinea pig tracheal muscle, whereas indomethacin did not affect this in vitro response. In order to elucidate the inhibitory mechanism of tranilast on ET-induced bronchoconstriction, the effects in Ca(2+)-free medium and on ET-induced histamine and prostaglandin F2 alpha release from tracheal muscle were investigated. Consequently, tranilast did not affect ET-induced contraction of guinea pig tracheal muscle in Ca(2+)-free Tyrode's solution and ET induced neither histamine nor PGF2 alpha release. These results suggest that tranilast inhibits ET-induced bronchoconstriction by inhibiting the ET-induced calcium influx into tracheal muscle.

The anti-allergic and anti-asthmatic activities of three potassium (K+) channel openers, cromakalim, pinacidil, and nicorandil, were investigated. 1) Forty-eight-hour homologous passive cutaneous anaphylaxis (PCA) in mice was not affected by cromakalim, pinacidil, or nicorandil. Ketotifen significantly inhibited the reaction. 2) Antigen-induced histamine release from sensitized guinea pig lung tissue was not affected by cromakalim, pinacidil or nicorandil (except for 10(-4) M nicorandil). Salbutamol inhibited the release of histamine. 3) Histamine, serotonin and LTC4-induced vasculitis in rat back skin was not affected by any of these three K+ channel openers. 4) Antigen-induced constriction of isolated sensitized guinea pig tracheal muscle was relaxed by each of the K+ channel openers. 5) Constrictions of isolated guinea pig tracheal muscle caused by high potassium, histamine, LTC4, or U-46619 were clearly relaxed by each of the three K+ channel openers. 6) Increases of airway resistance caused by histamine, LTD4, or U-46619 in guinea pigs in vivo were inhibited by administration of each of the three K+ channel openers. 7) Experimental asthma caused by the IgE antibody and antigen system in guinea pigs was inhibited by each of the three K+ channel openers.

The immunotoxicity of triphenyltin chloride (TPTC) in mice was investigated. 1) When TPTC was injected intraperitoneally (i.p.) into mice at doses between 1 and 10 mg/kg for 14 d, a reduction in the weights of thymus and spleen was noticed, however, the body weight was not changed significantly. 2) The production of hemolytic plaque forming cells in the spleen of mice immunized with sheep red blood cells (SRBC) was inhibited by the administration of 10 mg/kg of TPTC. 3) The i.p. injection of TPTC at a dose of 10 mg/kg for 5 d after the primary immunization of mice with dinitrophenylated ascaris antigen resulted in suppression of immunoglobulin E antibody formation in primary immune response, but did not affect the secondary immune response. 4) The production of antibody against polyvinylpyrrolidone (T cell independent antigen) was not affected by the administration of TPTC. 5) The production of effector T cells which are able to cause SRBC- or tuberculin-induced footpad reaction in mice and the induction of cytotoxic T cell in local graft versus host reaction in mice were also inhibited by TPTC. These results indicate that TPTC inhibits both the T cell dependent humoral and cellular immune responses in mice.