Novel azapeptide inhibitors of cathepsins B and K. Structural background to increased specificity for cathepsin B

Abstract: We have designed and synthesized a new series of azapeptides which act as potential inhibitors of cathepsin B and/or cathepsin K. Their structures are based upon the inhibitory sites of natural cysteine protease inhibitors, cystatins. For the synthesized azapeptides, the equilibrium constants for dissociation of inhibitor–enzyme complex, K_i, were determined. Comparison of these values indicated that all of the azainhibitors act much stronger toward cathepsin B. Z‐Arg‐Leu‐His‐Agly‐Ile‐Val‐OMe ( 7 ) proved to be approximately 500 times more potent for cathepsin B than for cathepsin K. To be able to explain the obtained experimental values we used the molecular dynamics procedures to analyze the interactions between cathepsin B and compound 7 . We also determined the structure of the most potent and selective cathepsin B azainhibitor by means of NMR studies and theoretical calculations. In this report, we describe SAR studies of azapeptide inhibitors indicating the influence of the conformational flexibility of the examined compounds on inhibition of cathepsins B and K.     

成人阴茎的三维数字化图像分析

目的对成人阴茎进行三维数字化图像分析,为阴茎整形修复获得手术前后形变参数及手术方案的选择,提供精确的形态学数据。方法采用Angel数字快速测量诊断系统,分别测量200例正常成人阴茎安静状态和勃起时的长度、周长、以及勃起时角度与阴茎长度、周径的关系。结果随着年龄和身高增长,阴茎也随之增长;身高与阴茎长度不成正比;阴茎勃起时随着角度的增加硬度增强,但勃起硬度变化时阴茎体积无明显变化。结论从不同径线不同角度对阴茎进行计算机三维测量分析,为阴茎整形修复术前设计、术后效果评价提供重要的量化指标。     

罕见Brugada样心电图图形一例

1临床资料男,28岁,因间断性发冷、寒战、高热4 d入院.患者4 d前无明显诱因出现发冷、寒战,继之高热,体温达40℃,伴恶心、呕吐,无咳嗽、咳痰,无腹痛、腹泻,无尿痛、尿急、尿频等症状.经服退热和抗疟疾药体温有所下降,因疑疟疾"而来我院.既往体健,无输血史.患者曾经在非洲工作2个月6d前归国,同事中有患疟疾"者.家族无类似病史及猝死者.查体:T 39·3℃,P 88次/min,R 22次/min,BP 110/70 mmHg.神清,全身皮肤未见皮疹及出血点,浅表淋巴结不大.心肺未闻异常.腹平软,肝脾肋下未及.实验室检查:血常规WBC 5·59×109/L,N 86·3%,Eo 2%;RBC 4·8…     

腰椎后路非融合固定系统的临床应用

复习腰椎后路非融合固定系统的设计原理、临床应用及治疗效果等相关文献,与传统的脊柱融合术相比,应用非融合系统可获得很好的疗效,并可以减少邻近节段退变的发生率。     

Pharmacology of the internal anal sphincter and its relevance to faecal incontinence

1 The internal anal sphincter (IAS) has a spontaneous tone and is the main contributor to the maintenance of faecal continence. The spontaneous resting tone exhibited by the sphincter can be modified by neurotransmitters from the autonomic and enteric nervous systems. 2 In this review, the influence of the sympathetic and parasympathetic nervous systems on IAS tone are discussed and the putative roles of nitric oxide, carbon monoxide, vasoactive intestinal peptide and adenosine triphosphate in non‐adrenergic non‐cholinergic transmission are considered. 3 Faecal incontinence is a common condition that places a heavy financial burden on the health service and severely affects patients’ quality of life. Resting anal pressure is reduced in patients with faecal incontinence and agents that increase sphincter tone tend to relieve symptoms. The results of clinical studies of the use of phenylephrine to treat faecal incontinence are reviewed. 4 It is concluded that the IAS is a potential target for drug development for the treatment of faecal incontinence.     

Endoscopic pH monitoring for patients with suspected or refractory gastroesophageal reflux disease.

BACKGROUND: Wireless pH studies can offer prolonged pH monitoring, which may potentially facilitate the diagnosis and management of patients with gastroesophageal reflux disease (GERD). The aim of the present study was to evaluate the detection rate of abnormal esophageal acid exposure using prolonged pH monitoring in patients with suspected or refractory GERD symptoms. METHODS: Patients undergoing prolonged ambulatory pH studies for the evaluation of GERD-related symptoms were assessed. Patients with a known diagnosis of GERD were tested on medical therapy, while patients with suspected GERD were tested off therapy. The wireless pH capsules were placed during upper endoscopy 6 cm above the squamocolumnar junction. RESULTS: One hundred ninety-one patients underwent a total of 198 pH studies. Fifty ambulatory pH studies (25%) were excluded from the analysis: 27 patients (14%) had insufficient data capture (less than 18 h on at least one day of monitoring), 15 patients had premature capsule release (7%), seven were repeat studies (3.5%) and one had intolerable pain requiring capsule removal (0.5%). There were 115 patients undergoing pH studies who were off medication, and 33 patients were on therapy. For the two groups of patients, results were as follows: 32 (28%) and 22 (67%) patients with normal studies on both days; 58 (50%) and five (15%) patients with abnormal studies on both days; 18 (16%) and three (9%) patients with abnormal studies on day 1 only; and seven (6%) and three (9%) patients with abnormal studies on day 2 only, respectively. CONCLUSIONS: Prolonged 48 h pH monitoring can detect more abnormal esophageal acid exposure but is associated with a significant rate of incomplete studies.     

ES05ROUTINE PARAFIBROMIN IMMUNOHISTOCHEMISTRY OF LARGE PARATHYROID ADENOMAS IS NOT AN EFFECTIVE SCREENING STRATEGY FOR CARCINOMA

Purpose Parathyroid carcinoma (PC) is rare and accounts for less than 1% of all cases of primary hyperparathyroidism (PHPT). The definitive histopathologic diagnosis of PC requires unequivocal invasion or metastasis which may be absent at first presentation. As a result, many cases of PC can only be diagnosed retrospectively. Parafibromin is the protein encoded by HRPT2 which is mutated and not expressed in many parathyroid carcinomas. Given that PCs generally weigh more than parathyroid adenomas (PA)s, we hypothesized that amongst large PAs there may be a high incidence of occult PC which could be identified by negative staining for parafibromin. Methodology 57 parathyroid glands weighing greater than 2 grams excised from 1998–2006 were identified from the University of Sydney Endocrine Surgical Database. Two specimens with a histopathologic diagnosis of PC were excluded. Immunohistochemical staining for parafibromin was performed on the remaining 55 PAs. Results Of the 55 specimens stained for parafibromin only one definite negative stain was detected. This case was originally classified as an “atypical adenoma” because it showed nuclear and architectural atypia without unequivocal evidence of invasive growth. In view of the negative staining for parafibromin it therefore probably represents occult carcinoma. There has been no evidence of recurrence or metastasis after 6.5 years. Conclusions Complete loss of staining for parafibromin is very rare in giant parathyroid adenomas suggesting that occult carcinoma is equally rare. As a result routine immunohistochemical staining for parafibromin does not appear to be an effective screening test for carcinoma in large PA without histopathologic features of PC.