Development of airflow limitation, dyspnoea, and both in the general population: the Nagahama study

Subjects with subclinical respiratory dysfunction who do not meet the chronic obstructive pulmonary disease (COPD) criteria have attracted attention with regard to early COPD intervention. Our aim was to longitudinally investigate the risks for the development of airflow limitation (AFL) and dyspnoea, the main characteristics of COPD, in a large-scale community-based general population study. The Nagahama study included 9789 inhabitants, and a follow-up evaluation was conducted after 5 years. AFL was diagnosed using a fixed ratio (forced expiratory volume in one second (FEV₁)/forced vital capacity (FVC) < 0.7). We enrolled normal subjects aged 40-75 years with no AFL, dyspnoea or prior diagnosis of asthma or COPD at baseline. In total, 5865 subjects were analysed, 310 subjects had subclinical respiratory dysfunction (FEV₁/FVC < the lower limit of normal; n = 57, and FEV₁ < 80% of the predicted value (preserved ratio impaired spirometry); n = 256). A total of 5086 subjects attended the follow-up assessment, and 449 and 1021 subjects developed AFL and dyspnoea, respectively. Of these, 100 subjects developed AFL with dyspnoea. Baseline subclinical respiratory dysfunction was independently and significantly associated with AFL with dyspnoea development within 5 years. Subjects with subclinical respiratory dysfunction are at risk of developing COPD-like features and require careful monitoring

Gastroesophageal reflux disease is a risk factor for sputum production in the general population: the Nagahama study

Background: Chronic sputum production in the general population is historically associated with clinical indices including male sex and smoking history. However, its relationship with gastroesophageal reflux disease (GERD), which may prove an underlying factor in sputum production, is unclear. We aimed to clarify factors associated with sputum production in the general population in cross-sectional and longitudinal manners. Methods: In the Nagahama study, a community-based cohort study, 9804 subjects were recruited between 2008 and 2010 (baseline assessment), 8293 of whom were followed from 2013 to 2015 (follow-up assessment). This study contained a self-completed questionnaire which included medical history, assessment of sputum production, and a frequency scale for symptoms of GERD. A Frequency Scale for Symptoms of Gastroesophageal Reflux Disease score of ≥ 8 was defined as GERD. In addition to the frequency of sputum production at each assessment, frequency of persistent sputum production defined as sputum production at both assessments was examined. Results: Frequency of sputum production was 32.0% at baseline and 34.5% at follow-up. Multivariable analysis demonstrated that sputum production at baseline was significantly associated with GERD [odds ratio (OR), 1.92; 95% confidence interval (CI) 1.73-2.13] and post-nasal drip (PND) (OR, 2.40; 95% CI 2.15-2.68), independent of other known factors such as older age, male sex and smoking history. These associations between sputum production and GERD or PND were also observed at follow-up. In longitudinal analysis, 19.4% had persistent sputum production and 12.3% had transient sputum production, i.e., at baseline only. Multivariable analysis for risk of persistence of sputum production revealed that persistent sputum production was associated with GERD and PND, in addition to the known risk factors listed above. The proportion of subjects with GERD at both assessments was highest among subjects with persistent sputum production. Conclusions: Cross-sectional and longitudinal analysis demonstrated an association in the general population between sputum production and GERD, as well as PND, independent of known risk factors. The presence of GERD should be assessed in patients complaining of sputum production

Metformin preferentially enhances the radio-sensitivity of cancer stem-like cells with highly mitochondrial respiration ability in HMPOS

Metformin has many anti-cancer effects, alone or in combination with radiation. However, the mechanism underlying its radio-sensitized effect is still unclear, especially for cancer stem-like cells (CSCs). Here, the radio-sensitized effect of metformin was investigated, and its mechanism was revealed in CSCs derived from canine osteosarcoma cell line (HMPOS), a canine osteosarcoma cell line. Spheroid cells (SCs) were used as CSCs-rich cells derived from sphere formation, and SCs were compared with normal adherent culture cells (ACs). The radio-sensitizing effect of metformin using clonogenic assay and tumor growth in mice xenograft model were evaluated, and the mechanism of its radio-sensitization focusing on mitochondrial function was revealed. Metformin significantly enhanced radio-sensitivity of SCs through its inhibition of the mitochondrial function, as shown by decreased oxygen consumption, decreased mitochondrial membrane potential, and decreased ATP production. Additionally, SCs had a higher ability of mitochondrial respiration than ACs, which may have caused difference of their sensitivity of metformin and irradiation. In conclusion, mitochondrial function might play an important role in the sensitivity of metformin and irradiation, and drugs that target mitochondrial respiration, such as metformin, are promising radio-sensitizers to target CSCs

Water soluble vitamin E (TMG) as a radioprotector

1365-1371<span style="font-size:14.0pt;mso-bidi-font-size:8.0pt; line-height:115%;font-family:" times="" new="" roman","serif";mso-fareast-font-family:="" "times="" roman";mso-ansi-language:en-us;mso-fareast-language:en-us;="" mso-bidi-language:ar-sa"="">Tocopherol monoglucoside (TMG), a water soluble derivative of vitamin E offers protection against deleterious effects of  ionizing radiation, both under <span style="font-size:14.5pt;mso-bidi-font-size:8.5pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">in vivo <span style="font-size:14.0pt;mso-bidi-font-size:8.0pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">and <span style="font-size:14.5pt;mso-bidi-font-size:8.5pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">in vitro <span style="font-size:14.0pt;mso-bidi-font-size:8.0pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">conditions, to biological systems. TMG was found to be a potent antioxidant and an effective free radical scavenger. It forms <span style="font-size:15.5pt; mso-bidi-font-size:9.5pt;line-height:115%;font-family:" times="" new="" roman","serif";="" mso-fareast-font-family:"times="" roman";mso-ansi-language:en-us;mso-fareast-language:="" en-us;mso-bidi-language:ar-sa"="">a <span style="font-size:14.0pt; mso-bidi-font-size:8.0pt;line-height:115%;font-family:" times="" new="" roman","serif";="" mso-fareast-font-family:"times="" roman";mso-ansi-language:en-us;mso-fareast-language:="" en-us;mso-bidi-language:ar-sa"="">phenoxy<span style="font-size:14.5pt; mso-bidi-font-size:8.5pt;line-height:115%;font-family:" arial","sans-serif";="" mso-fareast-font-family:"times="" new="" roman";mso-ansi-language:en-us;mso-fareast-language:="" en-us;mso-bidi-language:ar-sa"="">I <span style="font-size:14.0pt; mso-bidi-font-size:8.0pt;line-height:115%;font-family:" times="" new="" roman","serif";="" mso-fareast-font-family:"times="" roman";mso-ansi-language:en-us;mso-fareast-language:="" en-us;mso-bidi-language:ar-sa"="">radical similar to trolox upon reaction with various one-electron oxidants. TMG protected DNA from radiation-induced strand breaks. It also protected thymine glycol formation induced by gamma-radiation. Gamma-radiation-induced loss of viability of EL-tumor cells and peroxidation of lipids in microsomal and mitochondrial membranes were prevented by TMG. TMG was nontoxic to mice when administered orally up to <span style="font-size: 14.5pt;mso-bidi-font-size:8.5pt;line-height:115%;font-family:" times="" new="" roman","serif";="" mso-fareast-font-family:"times="" roman";mso-ansi-language:en-us;mso-fareast-language:="" en-us;mso-bidi-language:ar-sa"="">7.0 <span style="font-size:14.0pt; mso-bidi-font-size:8.0pt;line-height:115%;font-family:" times="" new="" roman","serif";="" mso-fareast-font-family:"times="" roman";mso-ansi-language:en-us;mso-fareast-language:="" en-us;mso-bidi-language:ar-sa"="">g/kg body weight. The LD50 dose of TMG for ip administration in mice was 1<span style="font-size:14.5pt; mso-bidi-font-size:8.5pt;line-height:115%;font-family:" arial","sans-serif";="" mso-fareast-font-family:"times="" new="" roman";mso-ansi-language:en-us;mso-fareast-language:="" en-us;mso-bidi-language:ar-sa"="">.15 <span style="font-size:14.0pt; mso-bidi-font-size:8.0pt;line-height:115%;font-family:" times="" new="" roman","serif";="" mso-fareast-font-family:"times="" roman";mso-ansi-language:en-us;mso-fareast-language:="" en-us;mso-bidi-language:ar-sa"="">g/kg body wt. In rats, following oral and ip administration of TMG, the absorption (distribution) half lives were <span style="font-size:14.5pt;mso-bidi-font-size:8.5pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">5.8 <span style="font-size:14.0pt;mso-bidi-font-size:8.0pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">and <span style="font-size:14.5pt;mso-bidi-font-size:8.5pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">3.0 <span style="font-size:14.0pt;mso-bidi-font-size:8.0pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">min respectively and elimination half  lives were <span style="font-size:14.5pt;mso-bidi-font-size:8.5pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">6.7 <span style="font-size:14.0pt;mso-bidi-font-size:8.0pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">and <span style="font-size:14.5pt;mso-bidi-font-size:8.5pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">3.1 <span style="font-size:14.0pt;mso-bidi-font-size:8.0pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">min respectively. Embryonic mortality resulting from exposure of pregnant mice to ionizing radiation <span style="font-size:14.5pt;mso-bidi-font-size:8.5pt;line-height:115%; font-family:" times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";="" mso-ansi-language:en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">(2 <span style="font-size:14.0pt;mso-bidi-font-size:8.0pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">Gy) was reduced by <span style="font-size:14.5pt;mso-bidi-font-size:8.5pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">75% <span style="font-size:14.0pt;mso-bidi-font-size:8.0pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">by ip administration of TMG <span style="font-size:14.5pt;mso-bidi-font-size:8.5pt; line-height:115%;font-family:" times="" new="" roman","serif";mso-fareast-font-family:="" "times="" roman";mso-ansi-language:en-us;mso-fareast-language:en-us;="" mso-bidi-language:ar-sa"="">(0.6 <span style="font-size:14.0pt;mso-bidi-font-size: 8.0pt;line-height:115%;font-family:" times="" new="" roman","serif";mso-fareast-font-family:="" "times="" roman";mso-ansi-language:en-us;mso-fareast-language:en-us;="" mso-bidi-language:ar-sa"="">g/kg, body wt) prior to irradiation. TMG offered protection to mice against whole body gamma-radiation-induced lethality and weight loss. The LD5<span style="font-size:11.0pt; mso-bidi-font-size:5.0pt;line-height:115%;font-family:" arial","sans-serif";="" mso-fareast-font-family:"times="" new="" roman";mso-ansi-language:en-us;mso-fareast-language:="" en-us;mso-bidi-language:ar-sa"="">0(30)<span style="font-size:11.0pt; mso-bidi-font-size:5.0pt;line-height:115%;font-family:" arial","sans-serif";="" mso-fareast-font-family:"times="" new="" roman";mso-ansi-language:en-us;mso-fareast-language:="" en-us;mso-bidi-language:ar-sa"=""> <span style="font-size:14.0pt; mso-bidi-font-size:8.0pt;line-height:115%;font-family:" times="" new="" roman","serif";="" mso-fareast-font-family:"times="" roman";mso-ansi-language:en-us;mso-fareast-language:="" en-us;mso-bidi-language:ar-sa"="">of mice increased from <span style="font-size:14.5pt;mso-bidi-font-size:8.5pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">6 <span style="font-size:14.0pt;mso-bidi-font-size:8.0pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">to <span style="font-size:14.5pt;mso-bidi-font-size:8.5pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">6.72 <span style="font-size:14.0pt;mso-bidi-font-size:8.0pt;line-height:115%;font-family: " times="" new="" roman","serif";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">Gy upon post irradiation administration of a single dose of TMG <span style="font-size:14.5pt; mso-bidi-font-size:8.5pt;line-height:115%;font-family:" times="" new="" roman","serif";="" mso-fareast-font-family:"times="" roman";mso-ansi-language:en-us;mso-fareast-language:="" en-us;mso-bidi-language:ar-sa"="">(0.6 <span style="font-size:14.0pt; mso-bidi-font-size:8.0pt;line-height:115%;font-family:" times="" new="" roman","serif";="" mso-fareast-font-family:"times="" roman";mso-ansi-language:en-us;mso-fareast-language:="" en-us;mso-bidi-language:ar-sa"="">g/kg, body wt) by ip.</span

Correlation between eosinophil count, its genetic background and body mass index: The Nagahama Study

Background: Obesity affects the pathogenesis of various chronic diseases, including asthma. Research on correlations between obesity/BMI and eosinophilic inflammation in asthma has yielded contradictory results, which could be partly ascribed to the absence of epidemiological data on the correlations. We aimed to elucidate the correlations between blood eosinophil count, its genetic backgrounds, and BMI in the general population. Methods: This community-based Nagahama study in Japan enrolled 9789 inhabitants. We conducted self-reporting questionnaires, lung function tests, and blood tests in the baseline and 5-year follow-up studies. A genome-wide association study (GWAS) was performed in 4650 subjects at the baseline and in 4206 of these at the follow-up to determine single-nucleotide polymorphisms for elevated blood eosinophil counts. We assessed the correlations between BMI and eosinophil counts using a multifaceted approach, including the cluster analysis. Results: Eosinophil counts positively correlated with BMI, observed upon the interchange of an explanatory variable, except for subjects with the highest quartile of eosinophils (≥200/μL), in whom BMI negatively correlated with eosinophil counts. GWAS and human leukocyte antigen (HLA) imputation identified rs4713354 variant (MDC1 on chromosome 6p21) for elevated eosinophil counts, independent of BMI and IgE. Rs4713354 was accumulated in a cluster characterized by elevated eosinophil counts (mean, 498 ± 178/μL) but normal BMI. Conclusions: Epidemiologically, there may be a positive association between blood eosinophil counts and BMI in general, but there was a negative correlation in the population with high eosinophil counts. Factors other than BMI, particularly genetic backgrounds, may contribute to elevated eosinophil counts in such populations