Exertional evaluation for BT

Bronchial thermoplasty (BT) had been reported to improve the symptoms of severe asthma. However, the exertional responses of BT based on the mechanisms have not been elucidated. A 57-year-old man and a 60-year-old woman underwent BT due to intractable severe asthma. We evaluated the therapeutic effects of BT using cardiopulmonary exercise testing (CPET). After BT, the exercise time during CPET substantially prolonged reducing exertional dyspnea in the former (good), but not in the latter (poor). In the good responder, the high air remaining in the lung after expiration (i.e., inspiratory tidal volume minus expiratory tidal volume) during CPET decreased after BT. In contrast, in the poor responder, the high air remaining after expiration during exercise was not obtained before BT. Further investigations are necessary to confirm that the presence or absence of the exertional wasted ventilation on CPET may be informative to evaluate the therapeutic effects of BT

Sensory processing sensitivity and culturally modified resilience education: Differential susceptibility in Japanese adolescents

This study investigated the efficacy of a culturally modified resilience education program on Japanese adolescents’ well-being from a differential susceptibility perspective. First, a culturally modified resilience education intervention was developed by employing the SPARK resilience program and implemented with 407 Japanese high school students in Tokyo (age = 15–16, M = 192, F = 215). To test intervention efficacy, students’ level of resilience, self-esteem, self-efficacy, and depression were measured pre-, post-, and three months after intervention. Additionally, sensory processing sensitivity, using the Japanese version of the Highly Sensitive Child Scale for Adolescence, was measured as an index of individual sensitivity. Analysis of variance was used to examine the baseline differences and interaction effects of students’ gender and level of sensory processing sensitivity. Latent growth curve models were used to assess the overall effects of the intervention and change over time. Results indicated that the intervention was effective in enhancing students’ overall self-efficacy; and that highly sensitive students, who scored significantly lower in well-being than their counterparts at baseline, responded more positively to the intervention, and had a greater reduction in depression and promotion of self-esteem. These findings provided unique evidence in line with the differential susceptibility perspective and useful implications to develop personalized treatment interventions for adolescents in different cultural contexts

Efficacy of Dietary Behavior Modification for Preserving Cardiovascular Health and Longevity

Cardiovascular disease (CVD) and its predisposing risk factors are major lifestyle and behavioral determinants of longevity. Dietary lifestyle choices such as a heart healthy diet, regular exercise, a lean weight, moderate alcohol consumption, and smoking cessation have been shown to substantially reduce CVD and increase longevity. Recent research has shown that men and women who adhere to this lifestyle can substantially reduce their risk of coronary heart disease (CHD). The preventive benefits of maintaining a healthy lifestyle exceed those reported for using medication and procedures. Among the modifiable preventive measures, diet is of paramount importance, and recent data suggest some misconceptions and uncertainties that require reconsideration. These include commonly accepted recommendations about polyunsaturated fat intake, processed meat consumption, fish choices and preparation, transfatty acids, low carbohydrate diets, egg consumption, coffee, added sugar, soft drink beverages, glycemic load, chocolate, orange juice, nut consumption, vitamin D supplements, food portion size, and alcohol

Human airway trypsin-like protease in saliva

We first discovered human airway trypsin-like protease (HAT) in human mucoid sputum. Precursor HAT (47 kDa), a cell surface type II transmembrane serine protease, is proteolyzed to mature HAT (27 kDa). Hitherto, HAT has not been detected in other biological fluids except for human sputum. We aimed to clarify whether human saliva contains mature HAT. Trypsin-like protease was isolated from saliva of healthy volunteers by a method adopted for isolation of HAT from sputum using Boc-Phe-Ser-Arg-MCA as the substrate. Biochemical properties of purified protease were similar to those of recombinant HAT (rHAT). HAT concentration in saliva was measured by ELISA, and immunoreactive HAT : total protein ratio (ng/mg) in saliva samples from healthy subjects was similar to that in mucoid sputum. RT-PCR showed that HAT mRNA was expressed in human gingival epithelial cells but not in gingival fibroblasts. Both indirect immunofluorescence and western blotting using monoclonal antibody for α-smooth muscle actin (α-SMA ; a myofibroblast marker) showed that HAT enhanced α-SMA fiber expression in gingival fibroblasts. These results indicate that both mucoid sputum and saliva from healthy subjects have similar concentrations of mature HAT, and HAT is related to certain physiological functions and pathological states of myofibroblasts in the oral cavity

Insulin receptor cleavage induced by estrogen impairs insulin signaling

Introduction: Soluble insulin receptor (sIR), which is the ectodomain of insulin receptor (IR), is present in human plasma. Plasma sIR levels are positively correlated with blood glucose levels and negatively correlated with insulin sensitivity. An in vitro model of IR cleavage shows that extracellular calpain 2 directly cleaves IR, which generates sIR, and sequential cleavage of the IRβ subunit by γ-secretase impairs insulin signaling in a glucose concentration-dependent manner. Nevertheless, sIR levels vary among subjects with normal glucose levels. Research design and methods: We examined sIR levels of pregnant women throughout gestation. Using an in vitro model, we also investigated the molecular mechanisms of IR cleavage induced by estradiol. Results: In pregnant women, sIR levels were positively correlated with estrogen levels and significantly increased at late pregnancy independent of glucose levels. Using an in vitro model, estrogen elicited IR cleavage and impaired cellular insulin signaling. Estradiol-induced IR cleavage was inhibited by targeting of calpain 2 and γ-secretase. Estrogen exerted these biological effects via G protein-coupled estrogen receptor, and its selective ligand upregulated calpain 2 expression and promoted exosome secretion, which significantly increased extracellular calpain 2. Simultaneous stimulation of estrogen and high glucose levels had a synergic effect on IR cleavage. Metformin prevented calpain 2 release in exosomes and restored insulin signaling impaired by estrogen. Conclusions: Estradiol-induced IR cleavage causes cellular insulin resistance, and its molecular mechanisms are shared with those by high glucose levels. sIR levels at late pregnancy are significantly elevated along with estrogen levels. Therefore, estradiol-induced IR cleavage is preserved in pregnant women and could be part of the etiology of insulin resistance in gestational diabetes mellitus and overt diabetes during pregnancy

The somatic mutations in Interferon-γ signal molecules in human uterine leiomyosarcoma

Human uterine leiomyosarcoma (U-LMS) is neoplastic malignancy that typically arises in tissues of mesenchymal origin. The identification of novel molecular mechanism leading to human U-LMS formation and the establishment of new therapies has been hampered by several critical points. We earlier reported that mice with a homozygous deficiency for proteasome beta subunit 9 (Psmb9)/β1i, an interferon (IFN)-γ inducible factor, spontaneously develop U-LMS. The use of research findings of the experiment with mouse model has been successful in increasing our knowledge and understanding of how alterations, in relevant oncogenic, tumour suppressive, and signaling pathways directly impact sarcomagenesis. The IFN-γ pathway is important for control of tumour growth and invasion and has been implicated in several malignant tumours. In this study, experiments with human tissues revealed a defective expression of PSMB9/β1i in human U-LMS that was traced to the IFN-γ pathway and the specific effect of somatic mutations of JANUS KINASE (JAK) 1 molecule or promoter region on the locus cording PSMB9/β1i gene. Understanding the molecular mechanisms of human U-LMS may lead to identification of new diagnostic candidates or therapeutic targets against human U-LMS

Dyspnea and the Varying Pathophysiologic Manifestations of Chronic Obstructive Pulmonary Disease Evaluated by Cardiopulmonary Exercise Testing With Arterial Blood Analysis

Background: Patients with chronic obstructive pulmonary disease (COPD) show varying mechanisms of exertional dyspnea with different exercise capacities.Methods: To investigate the pathophysiologic conditions related to exertional dyspnea, 294 COPD patients were evaluated using cardiopulmonary exercise testing (CPET) with arterial blood analyses, with the patients classified into two groups according to their exercise limitation: the leg fatigue group (n = 58) and the dyspnea group (n = 215). The dyspnea group was further subdivided into four groups based on peak oxygen uptake (V°O2 in mL/min/kg): group A (< 11), group B (11 to < 15), group C (15 to < 21), and group D (≥21).Results: In the dyspnea group, group A (n = 28) showed the following findings: (i) the forced expiratory volume in 1 s was not correlated with the peak V°O2 (p = 0.288), (ii) the arterial oxygen tension (PaO2) slope (peak minus resting PaO2/ΔV°O2) was the steepest (p < 0.0001) among all subgroups, (iii) reduced tidal volume (VT) was negatively correlated with respiratory frequency at peak exercise (p < 0.0001), and (iv) a break point in exertional VT curve was determined in 17 (61%) patients in group A. In these patients, there was a significant negative correlation between bicarbonate ion (HCO3-) levels at peak exercise and VT level when the VT-break point occurred (p = 0.032). In group D (n = 46), HCO3- levels were negatively correlated with plasma lactate levels (p < 0.0001). In all subgroups, the HCO3- level was negatively correlated with minute ventilation. The dyspnea subgroups showed no significant differences in the overall mean pH [7.363 (SD 0.039)] and Borg scale scores [7.4 (SD, 2.3)] at peak exercise.Conclusions: During exercise, ventilation is stimulated to avoid arterial blood acidosis and hypoxemia, but ventilatory stimulation is restricted in the setting of reduced respiratory system ability. These conditions provoke the exertional dyspnea in COPD. Although symptom levels were similar, the exertional pathophysiologic conditions differed according to residual exercise performance; moreover, COPD patients showed great inter-individual variability. An adequate understanding of individual pathophysiologic conditions using CPET is essential for proper management of COPD patients