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A wide variety of drugs bind to human serum albumin (HSA) at its two principal sites, namely site I and site II. A number of reports indicate that drug binding to these two binding sites are not completely independent, and that interactions between ligands of these two discrete sites can play a role. In this study, the effect of the binding of long-chain fatty acids on the interactive binding between dansyl-L-asparagine (DNSA; site I ligand) and ibuprofen (site II ligand) at pH6.5 was examined. Binding experiments showed that the binding of sodium oleate (Ole) to HSA induces conformational changes in the molecule, which, in turn, changes the individual binding of DNSA and ibuprofen, as well as the mode of interaction between these two ligands from a 'competitive-like' allosteric interaction in the case of the defatted HSA conformer to a 'nearly independent' binding in the case of non-defatted HSA conformer. Circular dichroism measurements indicated that ibuprofen and Ole are likely to modify the spatial orientation of DNSA at its binding site. Docking simulations suggest that the long-distance electric repulsion between DNSA and ibuprofen on defatted HSA contributes to a 'competitive-like' allosteric interaction, whereas extending the distance between ligands and/or increasing the flexibility or size of the DNSA binding site in fatted HSA evokes a change in the interaction mode to 'nearly independent' binding. The present findings provide further insights into the structural dynamics of HSA upon the binding of fatty acids, and its effects on drug binding and drug-drug interactions that occur on HSA.

Allergic rhino-conjunctivitis with pollen allergy has been prevalent worldwide and Pollen-food allergy syndrome (PFAS) refers to individuals with pollen allergy who develop oral allergy syndrome (OAS) on consuming fruits and vegetables. The prevalence of PFAS varies by region and that in Japanese adolescents remains to be elucidated. In this cross-sectional study, we examined the epidemiological characteristics of PFAS in a general population of Japanese adolescents according to pollen allergy, OAS, and IgE component sensitization. Participants comprised adolescents, at age 13 years, from a prospective birth cohort study in Japan. We administered questionnaires to collect information from parents regarding pollen allergy, PFAS and OAS at each child's age 13 years. ImmunoCAP ISAC was used to assess IgE component sensitization. Among 506 participants with a complete questionnaire and ISAC measurement results, 56.5% had a history of hay fever, 16.0% had a history of OAS, 51.0% had pollen allergy, and 11.7% had a history of PFAS; additionally, 72.7% were sensitized to one or more tree, grass, and/or weed allergens. The most common sensitization (95.7%) among adolescents with pollen allergy was to Japanese cedar (Cry j 1). The most common causal foods were kiwi and pineapple (both 39.0%). Knowledge levels about PFAS were poor among affected adolescents. We found a high prevalence of PFAS among adolescents in Japan. Although it affects approximately 1/10 adolescents in the general population, public awareness regarding PFAS is poor. Interventional strategies are needed to increase knowledge and to prevent PFAS in the general population.

BACKGROUND:Spontaneous pneumothorax is a complication that occurs in patients with connective tissue disease-associated interstitial lung disease (CTD-ILD); however, few studies on the clinical implications of pneumothorax for patients with CTD-ILD have been performed. OBJECTIVES:This study aimed to investigate the incidence and prognostic significance of pneumothorax and the risk factors for its onset in patients with CTD-ILD. METHODS:This study included 140 consecutive patients with CTD-ILD. Clinical characteristics, laboratory findings, pulmonary function test results, and chest high-resolution computed tomography (HRCT) images were retrospectively evaluated. RESULTS:A total of 18 patients (12.9%) developed pneumothorax during their clinical course. The cumulative incidence of pneumothorax from the time of CTD-ILD diagnosis was 6.5%, 8.7%, and 11.3% at 1, 3, and 5 years, respectively. The 10-year survival rate was significantly lower in patients with pneumothorax (29.6%) than that in those without pneumothorax (81.3%). The development of pneumothorax was significantly associated with poor prognosis (HR 22.0; p < 0.010). Furthermore, a lower body mass index, greater extent of reticular abnormalities on HRCT, and administration of methylprednisolone pulse therapy were significantly associated with the development of pneumothorax. CONCLUSION:Pneumothorax is a serious complication in the clinical course of patients with CTD-ILD and the onset of pneumothorax predicts a poor outcome.

BackgroundIn Japan, swimming school attendance is promoted as a form of therapy or as a prophylactic measure against asthma in young children. However, the putative beneficial effects have not been sufficiently verified.ObjectiveThe aim of the present study was to clarify whether or not swimming school attendance at age 3 years affects the onset and/or improvement of wheeze and rhinitis at age 5 years.MethodsThis study was a single-center, prospective, general, longitudinal cohort study (T-CHILD Study). Between November 2003 and December 2005, 1776 pregnant women were enrolled, and their offspring were followed up until age 5 years. Swimming school attendance at age 3 years and the presence of wheeze and/or rhinitis in the previous one year were examined using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. The relationship between swimming school attendance and wheeze and/or rhinitis was analyzed using multivariable logistic regression analysis.ResultsData on the 1097 children were analyzed. At age 3 years, 126 (11.5%) children attended a swimming school, and at age 5 years, the prevalence of wheeze was 180 (16.4%) while that of rhinitis was 387 (35.3%). Swimming school attendance at age 3 showed no significant relationship with the development of either wheeze (aOR 0.83, 95% CI (0.43-1.60) or rhinitis (aOR 0.80, 95% CI (0.43-1.60) at age 5.ConclusionsSwimming school attendance at age 3 years showed neither a preventive nor therapeutic effect on wheeze or rhinitis at age 5 years. There is thus no scientific evidence yet that swimming school attendance has a positive impact on the development of childhood wheeze or rhinitis.

Spinal fusion and bone defect after injuries, removal of bone tumors, and infections need to be repaired by implantation. In an aging society, recovery from these procedures is often difficult. In this study, we found that injection of SPG-178 leads to expression of several bone marker genes and mineralization in vitro, and revealed a significantly higher degree of newly formed bone matrix with use of SPG-178 in vivo. MC3T3-E1 cells were used to evaluate osteoblast differentiation promoted by SPG-178. To analyze gene expression, total RNA was isolated from MC3T3-E1 cells cultured for 7 and 14 days with control medium or SPG-178 medium. Among the several bone marker genes examined, SPG-178 significantly increased the mRNA levels for ALP, BMP-2 and Osteocalcin, OPN, BSP and for the Osterix. Ten-week-old female Wistar rats were used for all transplantation procedures. A PEEK cage was implanted into a bony defect (5 mm) within the left femoral mid-shaft, and stability was maintained by an external fixator. The PEEK cages were filled with either a SPG-178 hydrogel plus allogeneic bone chips (n = 4) or only allogeneic bone chips (n = 4). The rats were then kept for 56 days. Newly formed bone matrix was revealed inside the PEEK cage and there was an increased bone volume per total volume with the cage filled with SPG-178, compared to the control group. SPG-178 has potential in clinical applications because it has several benefits. These include its favorable bone conduction properties its ability to act as a support for various different cells and growth factors, its lack of infection risk compared with materials of animal origin such as ECM, and the ease with which it can be used to fill defects with complex shapes and combined with a wide range of other materials.

BACKGROUND:Recent studies have shown that the microbiome, namely Aspergillus species, play a previously unrecognized role in both stable and exacerbated chronic obstructive pulmonary disease (COPD). Galactomannan is a major component of the Aspergillus cell wall that has been widely used as a diagnostic marker. OBJECTIVES:To explore whether serum levels of Aspergillus-galactomannan antigen could be used to evaluate the risk of severe acute exacerbation of COPD (AE-COPD). METHODS:We measured the Aspergillus-galactomannan antigen levels of 191 patients with stable COPD, and examined its clinical relevance including AE-COPD. RESULTS:There were 77 (40.3%) patients who were positive for serum Aspergillus-galactomannan antigen (≥0.5). High Aspergillus-galactomannan antigen level (≥0.7) was associated with older age and presence of bronchiectasis and cysts on computed tomography images. Compared to patients with low Aspergillus-galactomannan antigen level (

It is well known that humans run with a fore-foot strike (FFS), a mid-foot strike (MFS) or a rear-foot strike (RFS). A modular neural control mechanism of human walking and running has been discussed in terms of muscle synergies. However, the neural control mechanisms for different foot strike patterns during running have been overlooked even though kinetic and kinematic differences between different foot strike patterns have been reported. Thus, we examined the differences in the neural control mechanisms of human running between FFS and RFS by comparing the muscle synergies extracted from each foot strike pattern during running. Muscle synergies were extracted using non-negative matrix factorization with electromyogram activity recorded bilaterally from 12 limb and trunk muscles in ten male subjects during FFS and RFS running at different speeds (5-15 km/h). Six muscle synergies were extracted from all conditions, and each synergy had a specific function and a single main peak of activity in a cycle. The six muscle synergies were similar between FFS and RFS as well as across subjects and speeds. However, some muscle weightings showed significant differences between FFS and RFS, especially the weightings of the tibialis anterior of the landing leg in synergies activated just before touchdown. The activation patterns of the synergies were also different for each foot strike pattern in terms of the timing, duration, and magnitude of the main peak of activity. These results suggest that the central nervous system controls running by sending a sequence of signals to six muscle synergies. Furthermore, a change in the foot strike pattern is accomplished by modulating the timing, duration and magnitude of the muscle synergy activity and by selectively activating other muscle synergies or subsets of the muscle synergies.

Radiologic pleuroparenchymal fibroelastosis (PPFE)-like lesion including pulmonary apical cap can be occasionally observed in clinical settings. However, the significance of radiologic PPFE-like lesion is unclear in connective tissue disease (CTD)-related interstitial lung disease (ILD).A total of 113 patients with CTD-related ILD were enrolled and assessed for radiologic PPFE-like lesion, which was defined as bilateral, upper lobe, and subpleural dense consolidations with or without pleural thickening on chest high-resolution computed tomography. The clinical, radiologic, and pathologic characteristics were evaluated.Radiologic PPFE-like lesion was found in 21 patients (19%) and were relatively frequent in those with systemic sclerosis (6/14: 43%) and primary Sjögren's syndrome (4/14: 29%). Patients with PPFE-like lesion were significantly older, had lower body mass index, higher ratio of residual volume to total lung capacity, and higher complication rate of pneumothorax and/or pneumomediastinum than those without. Twelve of the 21 patients were diagnosed radiologically as usual interstitial pneumonia (UIP) or possible UIP pattern. Two of three patients who underwent surgical lung biopsy of the upper lobes showed UIP on histopathology. Another patient was confirmed to have upper lobe PPFE on autopsy. During the clinical course, progression of the radiologic PPFE-like lesions was observed in 13 of 21 patients. Six patients died (mortality rate: 29%) and their PPFE-like lesions were commonly progressive. In the total cohort, our multivariate analysis identified the presence of PPFE-like lesion as a significant risk factor for respiratory death (hazard ratio: 4.10, 95% confidence interval: 1.33-12.65, p = 0.01).In patients with CTD-related ILD, radiologic PPFE-like lesion, which may present as not only PPFE but also apical cap and upper lobe subpleural fibrosis commonly due to UIP, was not uncommon and was associated with poor prognosis. Clinicians should be cautious with this radiologic finding, particularly when it is progressive.

Primary auditory neurons (PANs) connect cochlear sensory hair cells in the mammalian inner ear to cochlear nucleus neurons in the brainstem. PANs develop from neuroblasts delaminated from the proneurosensory domain of the otocyst and keep maturing until the onset of hearing after birth. There are two types of PANs: type I, which innervate the inner hair cells (IHCs), and type II, which innervate the outer hair cells (OHCs). Glial cells surrounding these neurons originate from neural crest cells and migrate to the spiral ganglion. Several transcription factors are known to regulate the development and differentiation of PANs. Here we systematically examined the spatiotemporal expression of five transcription factors: Sox2, Sox10, Gata3, Mafb, and Prox1 from early delamination at embryonic day (E) 10.5 to adult. We found that Sox2 and Sox10 were initially expressed in the proneurosensory cells in the otocyst (E10.5). By E12.75 both Sox2 and Sox10 were downregulated in the developing PANs; however, Sox2 expression transiently increased in the neurons around birth. Furthermore, both Sox2 and Sox10 continued to be expressed in spiral ganglion glial cells. We also show that Gata3 and Prox1 were first expressed in all developing neurons, followed by a decrease in expression of Gata3 and Mafb in type I PANs and Prox1 in type II PANs as they matured. Moreover, we describe two subtypes of type II neurons based on Peripherin expression. These results suggest that Sox2, Gata3 and Prox1 play a role during neurogenesis as well as maturation of the PANs.