Structure–activity relationship study on senktide for development of novel potent neurokinin-3 receptor selective agonists

Neurokinin B (NKB) regulates the secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus via activation of the cognate neurokinin-3 receptor (NK3R). The stimulatory effect of NKB and the derivatives on gonadotropin secretion can potentially be used for development of novel regulatory and therapeutic agents for reproductive dysfunctions. Here, we report a comprehensive structure–activity relationship study on the NK3R-selective agonist peptide, senktide. Substitution of the N-terminal succinyl-Asp substructure in senktide with oxalyl-Glu, oxalyl-D-Glu or oxalyl-L-2-aminoadipic acid (Aad) increased receptor binding and NK3R activation. Among these modifications, the oxalyl-D-Glu substructure prevented neutral endopeptidase (NEP) 24.11-mediated degradation, thus providing a novel NK3R agonist peptide with favourable biological and stability properties

Bronchial thermoplasty for severe asthma

Despite the relatively short follow-up period in our previous study, we had reported that increased cough reflex sensitivity (CRS) may predict the efficacy of bronchial thermoplasty (BT) for treating asthma. Herein, we examined whether CRS predicts the efficacy of BT 2 years after the final BT treatment. We also investigated the influence of BT on CRS. We reviewed 10 patients 2 years after their final BT treatment. CRS, asthma-related symptoms, asthma exacerbations, and cough-related quality of life were assessed at baseline and 2 years after BT. Five patients responded positively to BT (BT responders) and their asthma control improved. No significant difference in CRS at baseline was detected between the BT responders and nonresponders. In contrast, BT responders exhibited significant improvements in CRS 2 years after BT. CRS at baseline could not predict the BT efficacy after 2 years. This is the first report demonstrating BT desensitized CRS in consecutive case series

The measurement of cough response to bronchoconstriction induced by methacholine inhalation in healthy subjects: An examination using the Astograph method

Background: We demonstrated that heightened cough response to bronchoconstriction is a fundamental feature of cough variant asthma (CVA). To evaluate this physiological feature of CVA in daily clinical practice, it is necessary to clarify the cough response to bronchoconstriction in healthy subjects. We evaluated cough response to methacholine (MCh)-induced bronchoconstriction in healthy subjects. A forced oscillometry technique was used to measure airway resistance changes with Mch. Methods: Healthy never-smokers (21 men, 20 women; mean 22.3 ± 3.7 years) participated. None had a >3-week cough history, clinically significant respiratory or cardiovascular disorders, or disorders that might put subjects at risk or influence the study results or the subjects’ ability to participate. Twofold increasing concentrations of Mch chloride diluted in phosphate-buffered saline (0.039 to 160 mg/mL) were inhaled from nebulizers at 1-minute intervals during subjects’ tidal breathing after the baseline respiratory resistance (Rrs) was recorded. Mch inhalation continued until Rrs reached twice the baseline value and forced expiratory volume in 1 second (FEV1) decreased to <90% of baseline value. Spirometry was measured before Mch inhalation and immediately after Rrs had increased twofold. Coughs were counted during and for 30 minutes after Mch inhalation. The cough reflex sensitivity to capsaicin was also examined. Results: The number of coughs was 11.1 ± 14.3 (median, 7.0; range, 0 to 71; reference range, 0 to 39.7). There was no significant difference in the cough response between the sexes. The reproducibility of the cough response to bronchoconstriction was sufficient. No correlation existed between the bronchoconstriction-induced cough response and capsaicin cough-reflex sensitivity. Conclusions: Using the Astograph method, cough response to bronchoconstriction could be measured easily, safely and highly reproducibly in healthy subjects. © 2017 Taylor & FrancisEmbargo Period 12 month

Effects of Asian dust on daily cough occurrence in patients with chronic cough: A panel study

Asian dust, known as kosa in Japanese, is a major public health concern. In this panel study, we evaluated the effects of exposure to kosa on daily cough occurrence. The study subjects were 86 patients being treated for asthma, cough variant asthma, or atopic cough in Kanazawa University Hospital from January 2011 to June 2011. Daily mean concentrations of kosa and spherical particles were obtained from light detection and ranging (LIDAR) measurements, and were categorized from Grade 1 (0μg/m3) to 5 (over 100μg/m3). The association between kosa and cough was analyzed by logistic regression with a generalized estimating equation. Kosa effects on cough were seen for all Grades with potential time lag effect. Particularly at Lag 0 (the day of exposure), a dose-response relationship was observed: the odds ratios for Grades 2, 3, 4, and 5 above the referent (Grade 1) were 1.111 (95% confidence interval (CI): 0.995-1.239), 1.171 (95% CI: 1.006-1.363), 1.357 (95% CI: 1.029-1.788), and 1.414 (95% CI: 0.983-2.036), respectively. Among the patients without asthma, the association was higher: the odds ratios for Grades 2, 3, 4 and 5 were 1.223 (95% CI: 0.999-1.497), 1.309 (95% CI: 0.987-1.737), 1.738 (95% CI: 1.029-2.935) and 2.403 (95% CI: 1.158-4.985), respectively. These associations remained after adjusting for the concentration of spherical particles or particulate matter with an aerodynamic diameter of less than 2.5μm (PM2.5). Our findings demonstrate that kosa is an environmental factor which induces cough in a dose-response relationship. © 2014 Elsevier Ltd

Reprint of: Effects of Asian dust on daily cough occurrence in patients with chronic cough: A panel study

金沢大学医薬保健研究域医学系Asian dust, known as kosa in Japanese, is a major public health concern. In this panel study, we evaluated the effects of exposure to kosa on daily cough occurrence. The study subjects were 86 patients being treated for asthma, cough variant asthma, or atopic cough in Kanazawa University Hospital from January 2011 to June 2011. Daily mean concentrations of kosa and spherical particles were obtained from light detection and ranging (LIDAR) measurements, and were categorized from Grade 1 (0 μg/m3) to 5 (over 100 μg/m3). The association between kosa and cough was analyzed by logistic regression with a generalized estimating equation. Kosa effects on cough were seen for all Grades with potential time lag effect. Particularly at Lag 0 (the day of exposure), a dose-response relationship was observed: the odds ratios for Grades 2, 3, 4, and 5 above the referent (Grade 1) were 1.111 (95% confidence interval (CI): 0.995-1.239), 1.171 (95% CI: 1.006-1.363), 1.357 (95% CI: 1.029-1.788), and 1.414 (95% CI: 0.983-2.036), respectively. Among the patients without asthma, the association was higher: the odds ratios for Grades 2, 3, 4 and 5 were 1.223 (95% CI: 0.999-1.497), 1.309 (95% CI: 0.987-1.737), 1.738 (95% CI: 1.029-2.935) and 2.403 (95% CI: 1.158-4.985), respectively. These associations remained after adjusting for the concentration of spherical particles or particulate matter with an aerodynamic diameter of less than 2.5 μm (PM2.5). Our findings demonstrate that kosa is an environmental factor which induces cough in a dose-response relationship. © 2014 Elsevier B.V.Embargo Period 12 month

Inelastic strain rate in the seismogenic layer of Kyushu Island, Japan

Seismic activity is associated with crustal stress relaxation, creating inelastic strain in a medium due to faulting. Inelastic strain affects the stress field around a weak body and causes stress concentration around the body, because the body itself has already released stress. Therefore, the understanding of inelastic deformation is important as it generates earthquakes. We investigated average inelastic strain in a spatial bin of Kyushu Island, Japan, and obtained the inelastic strain rate distribution associated with crustal earthquakes, based on the analysis of fault plane solutions and seismic moments. Large inelastic strains (>10-7 year-1) were found in the Beppu-Shimabara area, located in the center of Kyushu Island. The strain rate tensor was similar to that of the stress tensor except the absolute value in the area, implying that the inelastic strain was controlled by the stress field. The 2016 Kumamoto earthquake sequence (maximum magnitude 7.3) occurred in the Beppu-Shimabara area, with the major earthquakes located around the high inelastic strain rate area. Inelastic strain in the volume released the stress. In addition, the inelastic strain created an increment of stress around the volume. This indicates that the spatial heterogeneity of inelastic strain might concentrate stress

Male faces and odours evoke differential patterns of neurochemical release in the mediobasal hypothalamus of the ewe during oestrus : an insight into sexual motivation ?

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