Clinical and genetic features of cystic fibrosis in Japan.

Cystic fibrosis (CF) is an autosomal recessive disease caused by pathogenic variants in CF transmembrane conductance regulator (CFTR). While CF is the most common hereditary disease in Caucasians, it is rare in East Asia. In the present study, we have examined clinical features and the spectrum of CFTR variants of CF patients in Japan. Clinical data of 132 CF patients were obtained from the national epidemiological survey since 1994 and CF registry. From 2007 to 2022, 46 patients with definite CF were analyzed for CFTR variants. All exons, their boundaries, and part of promoter region of CFTR were sequenced and the presence of large deletion and duplications were examined by multiplex ligation-dependent probe amplification. CF patients in Japan were found to have chronic sinopulmonary disease (85.6%), exocrine pancreatic insufficiency (66.7%), meconium ileus (35.6%), electrolyte imbalance (21.2%), CF-associated liver disease (14.4%), and CF-related diabetes (6.1%). The median survival age was 25.0 years. The mean BMI percentile was 30.3%ile in definite CF patients aged < 18 years whose CFTR genotypes were known. In 70 CF alleles of East Asia/Japan origin, CFTR-dele16-17a-17b was detected in 24 alleles, the other variants were novel or very rare, and no pathogenic variants were detected in 8 alleles. In 22 CF alleles of Europe origin, F508del was detected in 11 alleles. In summary, clinical phenotype of Japanese CF patients is similar to European patients, but the prognosis is worse. The spectrum of CFTR variants in Japanese CF alleles is entirely different from that in European CF alleles.

Soy protein intake increased bone mineral density under nonenergy-deficiency conditions but decreased it under energy-deficiency conditions in young female rats.

Many young individuals attempt to lose too much weight because of a false body image, which induces low bone mineral density (BMD) resulting from energy restriction. In addition, a decrease in estrogen has been observed along with the decrease in BMD. Estrogen is responsible for maintaining bone mass, and soybeans contain high levels of isoflavones, which have estrogen-like effects. Thus, we hypothesized that soy protein prevents low BMD caused by energy deficiency in young female rats. The purpose of this study was to examine the effect of soy protein intake on bone loss by energy deficiency in young female rats. Female Sprague-Dawley rats (6 weeks old) were randomly divided into the following 4 experimental groups: ad libitum feeding and casein diet (AL-Cas); ad libitum feeding and soy diet (AL-Soy); 40% energy restriction and casein diet (ER-Cas); and 40% energy restriction and soy diet (ER-Soy). The experimental period was 10.5 weeks. The AL-soy group had significantly higher BMD of the femur than the AL-Cas group (AL-Cas = 156 ± 5 mg/cm2, AL-Soy = 165 ± 7 mg/cm2; P < .05). Meanwhile, the ER-Soy group had significantly lower BMD of the tibia, femur, and lumbar spine than the ER-Cas group (ER-Cas = 147 ± 7 mg/cm2, ER-Soy = 133 ± 10 mg/cm2; P < .01). These results show that compared with ad libitum control groups, soy protein resulted in higher BMD under nonenergy deficiency, but under energy-deficiency conditions, it resulted in lower BMD.

Bicarbonate transport of airway surface epithelia in luminally perfused mice bronchioles.

HCO3- secretion in distal airways is critical for airway mucosal defense. HCO3-/H+ transport across the apical membrane of airway surface epithelial cells was studied by measuring intracellular pH in luminally microperfused freshly dissected mice bronchioles. Functional studies demonstrated that CFTR, ENaC, Cl--HCO3- exchange, Na+-H+ exchange, and Na+-HCO3- cotransport are involved in apical HCO3-/H+ transport. RT-PCR of isolated bronchioles detected fragments from Cftr, α, ß, γ subunits of ENaC, Ae2, Ae3, NBCe1, NBCe2, NBCn1, NDCBE, NBCn2, Nhe1, Nhe2, Nhe4, Nhe5, Slc26a4, Slc26a6, and Slc26a9. We assume that continuous decline of intracellular pH following alkaline load demonstrates time course of HCO3- secretion into the lumen which is perfused with a HCO3--free solution. Forskolin-stimulated HCO3- secretion was substantially inhibited by luminal application of CFTRinh-172 (5 µM), H2DIDS (200 µM), and amiloride (1 µM). In bronchioles from a cystic fibrosis mouse model, basal and acetylcholine-stimulated HCO3- secretion was substantially impaired, but forskolin transiently accelerated HCO3- secretion of which the magnitude was comparable to wild-type bronchioles. In conclusion, we have characterized apical HCO3-/H+ transport in native bronchioles. We have demonstrated that cAMP-mediated and Ca2+-mediated pathways are involved in HCO3- secretion and that apical HCO3- secretion is largely mediated by CFTR and H2DIDS-sensitive Cl--HCO3- exchanger, most likely Slc26a9. The impairment of HCO3- secretion in bronchioles from a cystic fibrosis mouse model may be related to the pathogenesis of early lung disease in cystic fibrosis.