Different inhibitory effect of adrenaline on platelet adenylate cyclase in the presence of GTP plus cholera toxin and of stable GTP analogues

Summary GTP is generally required for hormonal stimulation of adenylate cyclase. On the other hand, the presence of GTP is essential for hormone-induced inhibition of adenylate cyclase in cell-free preparations of human platelets and other cells. In order to differentiate the dual roles of GTP in hormonal stimulation and inhibition of adenylate cyclase, we have studied the effect of adrenaline on the platelet enzyme under conditions where guanine mucleotides caused marked stimulation. In the presence of GTP (1 M), which by itself had no or only a small stimulatory effect on adenylate cyclase, adrenaline inhibited the basal and prostaglandin E₁-stimulated forms of the enzyme. In contrast, the stable GTP analogues, GMP-P(NH)P and GTP--S, which caused a time-dependent, persistent activation of the enzyme, reversed or prevented the inhibitory effect of adrenaline. Cholera toxin, which activates adenylate cyclase presumably by inhibition of a specific GTPase, increased cyclase activity in platelet membranes up to 4-fold, and GTP addition (0.1–30 M) augmented this activation about 2-fold. The -adrenergic component of adrenaline (0.1–100 M), in a concentration-dependent manner, prevented the GTP-induced increase in cholera toxin-stimulated activity. The inhibition was also observed in enzyme preparations that had been fully activated by pretreatment with cholera toxin. These data suggest that -adrenergic agonists may inhibit platelet adenylate cyclase through increased inactivation of the enzyme, possibly involving a stimulation of the GTPase connected to the adenylate cyclase system.Abbreviations GMP-P(NH)P guanylyl 5-imidodiphosphate - GTP--S guanosine 5-(-thio)triphosphate - GTPase guanosine 5-triphosphatase - P_i inorganic phosphate. Parts of the data were presented in preliminary form (Jakobs and Schultz, 1978)     

羧甲基-β-环糊精为手性选择剂拆分托吡卡胺等4种手性药物对映体

目的以羧甲基-β-环糊精(CM-β-CD)为手性选择剂,建立毛细管区带电泳法分离托吡卡胺、文拉法辛、美托洛尔和瑞格列奈4种药物对映体。方法采用未涂壁熔融石英毛细管柱,磷酸盐缓冲液作为背景电解质溶液,分离电压为20 kV。考察了缓冲溶液的pH值、环糊精质量浓度、缓冲盐浓度对对映体分离的影响。结果在优化的分离条件下,4种手性药物均能达到完全分离。结论CM-β-CD适用于上述4种药物的对映体分离。     

Evaluation of olfactory dysfunction to estimate the presence of eosinophilic chronic rhinosinusitis in patients with asthma

BackgroundEosinophilic chronic rhinosinusitis (ECRS) is often complicated by asthma and can be difficult to diagnose. This study aimed to clarify the usefulness of the self-administered odor questionnaire (SAOQ) and visual analog scale (VAS) to identify olfactory disorders in patients with asthma.MethodsThis retrospective study was conducted on patients with asthma who were referred to the Otolaryngology clinic between May and September 2018. The treatment step of asthma, asthma control test (ACT), pulmonary function test, peripheral blood eosinophils, and fractional exhaled nitric oxide (FeNO) were analyzed. ECRS was diagnosed based on the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis Study score. Olfactory dysfunction was evaluated using the SAOQ and VAS for olfactory disorders.ResultsThe study included 56 patients (18 males and 38 females), who were divided into two groups; those with ECRS (n = 18) and those without ECRS (n = 38). Age, sex, treatment step, ACT score, and pulmonary function were not significantly different between the groups. The ECRS group had a significantly higher FeNO value (89.1 ppb vs. 39.1 ppb) and a significantly lower SAOQ score (40.1% vs. 96.1%). The area under the receiver operating characteristic curve for the efficacy of ECRS diagnosis was 0.88, 0.889, 0.799, and 0.757 for SAOQ, VAS, blood eosinophil count, and FeNO, respectively.ConclusionThe SAOQ and VAS scores were useful tools that presented similar results to the blood eosinophil count and FeNO, and may help to improve the diagnosis of ECRS in patients with asthma.     

Randomized Trial of Ivabradine in Patients With Hyperadrenergic Postural Orthostatic Tachycardia Syndrome

BackgroundPostural orthostatic tachycardia syndrome (POTS) is a complex, multifaceted disorder that impairs functional status and quality of life. Current pharmacological treatments are limited.ObjectivesThis study investigated the effect of ivabradine (selective blocker of the I_funny channel in the sinoatrial node) on heart rate, quality of life (QOL), and plasma norepinephrine (NE) levels in patients with hyperadrenergic POTS defined by plasma NE >600 pg/ml and abnormal tilt table test.MethodsIn total, 22 patients with hyperadrenergic POTS as the predominant subtype completed a randomized, double-blinded, placebo-controlled, crossover trial with ivabradine. Patients were randomized to start either ivabradine or placebo for 1 month, and then were crossed over to the other treatment for 1 month. Heart rate, QOL, and plasma NE levels were measured at baseline and at the end of each treatment month.ResultsThe average age was 33.9 ± 11.7 years, 95.5% were women (n = 21), and 86.4% were White (n = 23). There was a significant reduction in heart rate between placebo and ivabradine (p < 0.001). Patients reported significant improvements in QOL with RAND 36-Item Health Survey 1.0 for physical functioning (p = 0.008) and social functioning (p = 0.021). There was a strong trend in reduction of NE levels upon standing with ivabradine (p = 0.056). Patients did not experience any significant side-effects, such as bradycardia or hypotension, with ivabradine.ConclusionIvabradine is safe and effective in significantly improving heart rate and QOL in patients with hyperadrenergic POTS as the predominant subtype.     

Phenotype classification using the combination of lung sound analysis and fractional exhaled nitric oxide for evaluating asthma treatment

Background

We report the utility of combining lung sound analysis and fractional exhaled nitric oxide (FeNO) for phenotype classification of airway inflammation in patients with bronchial asthma.We investigated the usefulness of the combination of the expiration-to-inspiration sound power ratio in the mid-frequency range (E/I MF) of 200–400 Hz and FeNO for comprehensively classifying disease type and evaluating asthma treatment.

Effectiveness of Physical Therapy Combined With Epidural Steroid Injection for Individuals With Lumbar Spinal Stenosis: A Randomized Parallel-Group Trial

Objective

To examine the effectiveness of epidural steroid injection (ESI) and back education with and without physical therapy (PT) in individuals with lumbar spinal stenosis (LSS).

Comparison of four early posttherapy imaging changes (EPTIC; RECIST 1.0, tumor shrinkage, computed tomography tumor density, Choi criteria) in assessing outcome to vascular endothelial growth factor-targeted therapy in patients with advanced renal cell carcinoma

Background

Vascular endothelial growth factor (VEGF)-targeted therapy has become standard treatment for patients with metastatic renal cell cancer (mRCC). Since these therapies can induce tumor necrosis and minimal tumor shrinkage, Response Evaluation Criteria in Solid Tumors (RECIST) may not be optimal for predicting clinical outcome.

Objective

To systematically determine the optimal early posttherapy imaging changes (EPTIC) to separate responders and nonresponders at the first posttreatment follow-up computed tomography (CT).

Design, setting, and participants

Seventy mRCC patients with 155 target lesions treated with first-line sunitinib, sorafenib, or bevacizumab at academic medical centers underwent contrast-enhanced thoracic and abdominal CT at baseline and first follow-up after therapy initiation (median: 78 d after therapy initiation; range: 31–223 d).

Measurements

Evaluations were performed according to (1) RECIST 1.0; (2) Choi criteria; (3) tumor shrinkage (TS) of ≥10% decrease in sum of the longest unidimensional diameter (SLD); and (4) 15% or 20% decrease in mean CT tumor density. Correlation with time to treatment failure (TTF) and overall survival (OS) were compared and stratified by response to each of the radiologic criteria.

Results and limitations

Eleven patients were considered responders by RECIST 1.0; 49 based on Choi criteria; 31 patients had ≥10% decrease in the SLD; and 36 and 32 patients had ≥15% and ≥20% decrease, respectively, in mean tumor density on CT. Only the threshold of 10% decrease in the SLD was statistically significant in predicting TTF (10.4 vs 5.1 mo; p = 0.02) and OS (32.5 vs 15.8 mo; p = 0.002). Receiver operating characteristic analysis yielded a 10% decrease in SLD as the optimal size change threshold for responders. The retrospective nature of the study and measurements by a single oncoradiologist are inherent limitations.

Conclusions

In the retrospectively analyzed study population of mRCC patients receiving VEGF-targeted agents, a 10% reduction in the SLD on the first follow-up CT was an optimal early predictor of outcome.     

Interprofessional learning involving medical students or doctors

AIMS: There is a belief that interprofessional learning among health care professionals promotes teamwork and collaboration, leading to improved patient care, but supporting data have not been available. Our aim was to identify recent studies on interprofessional learning involving medical students or doctors. METHODS: The medical education literature was searched for relevant publications since 1998 and the studies were subsequently classified according to various criteria. RESULTS: A total of 24 'research papers' and 36 'literature review/editorial-type papers' were identified. Research papers generally described interprofessional learning initiatives and evaluated their success in terms of knowledge or attitudes by data collection. Seven collected qualitative data, 4 collected quantitative data and 11 collected both. None of the studies identified conformed to the Cochrane Collaboration guidelines for a rigorous source of quantitative information on an intervention's effectiveness. DISCUSSION: The authors suspect that significantly more studies have been performed than those published. This may indicate research of variable quality, leading to a large proportion of papers being rejected for publication. More and better quality research is required as more resources become available to academic and health care organisations for interprofessional learning.     

Extent of pulmonary fibrosis on high-resolution computed tomography is a prognostic factor in patients with pleuroparenchymal fibroelastosis

BackgroundSeveral prognostic factors for pleuroparenchymal fibroelastosis (PPFE) have recently been reported. However, detailed high-resolution computed tomography (HRCT) findings have not yet been evaluated as prognostic factors. This study retrospectively investigated whether HRCT findings are prognostic factors in patients with PPFE compared to those with idiopathic pulmonary fibrosis (IPF).MethodsPatients with PPFE and IPF diagnosed at our hospital between January 2008 and December 2016 were enrolled. Clinical and HRCT characteristics were obtained. In addition to our patients, we also analyzed data of PPFE patients whose cause of death had been identified in previous studies.ResultsWe enrolled 15 patients with PPFE and 75 patients with IPF. Consolidation and maximum pleural thickening were significantly higher in patients with PPFE than in those with IPF (both P < .001). Fibrosis score, honeycomb area, and traction bronchiectasis were not significantly different between these patient groups but were significant prognostic factors in patients with PPFE in univariate analysis (P = .021, P = .017, and P = .014, respectively). The proportions of deaths by acute exacerbation or lung cancer were significantly lower in patients with PPFE than in those with IPF (P < .001 and P = .001, respectively), whereas death by respiratory failure was significantly more frequent in PPFE patients (P < .001).ConclusionsHRCT findings, such as fibrosis score, honeycomb area, and traction bronchiectasis, were independent prognostic factors in patients with PPFE. Respiratory failure, but not acute exacerbation and lung cancer, was the main cause of death in patients with PPFE.