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

Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals

Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10–8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci—TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A—are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout

Identification of novel biomarker as citrullinated inter-alpha-trypsin inhibitor heavy chain 4, specifically increased in sera with experimental and rheumatoid arthritis

BackgroundAnticitrullinated protein antibodies (ACPA) and citrullinated proteins play key roles in the pathogenesis of rheumatoid arthritis (RA). Many candidate citrullinated antigens have been identified in joints, but citrullinated proteins in sera are mostly uncertain in patients with RA. We explored the expression of citrullinated proteins in joints and sera of experimental arthritis, and we further investigated their specific expression correlated with the disease activity in patients with RA.MethodsCitrullinated protein expression in tissues was examined by IHC in peptide glucose-6-phosphate isomerase-induced arthritis (pGIA). Serum citrullinated proteins from pGIA were examined by Western blotting, and the sequence was identified by MS. With the same methods, serum citrullinated proteins were analyzed in patients with RA, primary Sjögren’s syndrome, systemic lupus erythematosus, and osteoarthritis as well as in healthy subjects, by Western blotting and MS. In patients with RA, the relationship between the expression of the identified protein (inter-alpha-trypsin inhibitor heavy chain 4 [ITIH4]) and clinical features was evaluated, and the levels of citrullinated ITIH4 were compared before and after biological treatment. The antibody response against citrullinated ITIH4 peptide was measured by enzyme-linked immunosorbent assay.ResultsCitrullinated proteins were detected specifically in arthritic joints and sera from pGIA relative to controls. In sera, a common band of citrullinated protein at 120 kDa was revealed, and it fluctuated in parallel with arthritis score of pGIA by Western blotting. Interestingly, in 82% of RA patient sera, similar bands of citrullinated protein were specifically detected. These proteins were identified as citrullinated ITIH4, and especially the R438 site was commonly citrullinated between mice and humans. Citrullinated ITIH4 levels were associated with clinical parameters such as C-reactive protein (CRP), rheumatoid factor, and Disease Activity Score in 28 joints as measured by CRP in patients with RA. Its levels were decreased in correlation with the reduction of disease activity score after effective treatment in patients with RA. Moreover, antibody response to citrullinated epitope in ITIH4 was specifically observed in patients with RA.ConclusionsOur results suggest that serum citrullinated ITIH4 was specifically increased in patients with RA and could be a novel biomarker for assessing disease activity in patients with RA

Mutation rate that mazimizes evolvability

In this study, we calculated optimum mutation rate that maximizes the transition rate of the quasispeceis from one fitness peak to the next. We consider that quasispecies is localized at a fitness peak, and each of quasispecies is defined by binary sequence. Suppose a new fitness peak is emerged n step away from current peak, and then ask which mutation rate maximizes the transition rate from one to another.\nFrom the analysis of the model, we showed that the optimum mutation rate depends on height of current peak and Hamming distance between new peak and current peak. In this presentaion, we will discuss validity of the model by simulation results of individual based model and infinite population model.第14回日本数理生物学シンポジウ

The optimum mutation rate to adapt a new fitness peak

We examined the optimum mutation rate the fitness peak randomly disappears and reappears at a distance in the sequence space. We assumed that fitness landscape has a single peak and the peak position in the sequence space changes randomly with the rate of environment fluctuation P. The optimum mutation rate per genome depends on the rate P of environmental fluctuation , the relative fitness a0 of the peak sequence, and the Hamming distance n between the current peak and the new peak.Our analytical approximation shows that the mutation rate equals zero if there is no environmental fluctuation, and that the rate monotonically increases with the rate of environmental fluctuation.Comparing with analytical approximation and the simulation, the approximation agrees well with the simulation results as long as the rate of environmental fluctuation is small.European Conference on Mathematical and Theoretical Biolog

Synergy and additivity on the combined exposure of X-ray and ENU on lymphomagenesis

Cancer is one of the major causes of death in the developed countries. Under the circumstances of modern lifestyle, cancer cause could be ascribed to exposure to not single carcinogen but combinations of multiple ones. They interact with each other, and dose-effect relationship of combined exposures is not necessarily additive, but sometimes more than additive (synergistic) or less than additive (antagonistic). We have found a synergistic effect of repeated X-ray irradiation to mice, and followed by chronic exposure to ethylnitrosourea (ENU) in drinking water. Each treatment alone induced thymic lymphomas in 10% mice exposed, whereas combined treatment induced lymphomas in more than 90% mice. However, when the order was reversed, ENU followed by X-rays, the combination of these two treatments induced thymic lymphomas in an additive or slightly supra-additive manner To explain the combined exposures, we developed the simple mathematical two-stage model, which takes account of the exposure order (sequence) of two carcinogens (e.g. X-ray and ENU). We consider three states (normal, intermediate, and malignant) in the population. The transition rates from normal to intermediate, , and from intermediate to malignant, , are enhanced by the carcinogens. We assumed each transition rate as monotonically increasing function of each carcinogen. We examined the model for the several cases of which change the effect of the carcinogens to transition rates. From the analysis, we found that the X-ray mainly acts at the first step and ENU acts at the second step.Japanese-Korean Joint Meeting for Mathematical Biolog