Computed tomography of aortoiliac atherosclerosis

Twenty-three patients with atherosclerotic peripheral vascular disease underwent angiography and CT of the aortoiliac segment within a 72-hour interval. Examinations were evaluated for depiction of disease in the aortic and iliac segments in five categories: stenosis, plaque morphology, vascular ectasia, calcification, and other pathologic conditions. Angiography and CT were equally accurate in their depiction of the degree of aortic stenosis or occlusion and in identification of aortic ectasia. Angiography proved superior to CT in the display of plaque morphology in 57% of aortic lesions and 74% of iliac abnormalities. Angiography also showed clear superiority over CT in quantification of iliac stenosis in 75% of patients with abnormalities, as well as in identification of iliac ectasia. CT detected both intimal calcification and incidental disease or congenital abnormalities better than angiography, including an unsuspected chronic contained aortic rupture. Overall, CT compared favorably with angiography in the identification of all types of aortic disease but major disadvantages of CT were evident in the iliac segment because of vessel tortuosity or heavy calcification. CT cannot replace arteriography in detecting atherosclerotic disease of the aortoiliac segment but can help to clarify angiographic findings in selected groups of patients.     

Association between the expression of mast cell chymase and intraperitoneal adhesion formation in mice

BACKGROUND: Adhesion formation is a major source of postoperative morbidity and mortality. Mast cells and their major protease, chymase, have been shown to participate in the healing process as well as in tissue remodeling. We aimed to identify the role of mast cells in intraperitoneal adhesion formation and to assess whether there is an association between the expression of mast cell chymase and adhesion formation. MATERIALS AND METHODS: Both mast cell-deficient W/W(V) mice and congenic +/+ mice received a standardized lesion produced by cecal scraping and the application of 95% ethanol. Adhesions were assessed blindly 1 week later using a standardized scale. In addition, histamine content, mast cell numbers, and chymase activity in cecum as well as at the healing sites were evaluated before and 7 days after surgical injury. RESULTS: A significant reduction in adhesion formation was seen in mast cell-deficient W/W(V) mice (P < 0.05). In the normal cecum, histamine content did not significantly differ between W/W(V) and +/+ mice. Chymase activity in cecum was detected in control +/+ mice, but not in W/W(V) mice. Mast cell numbers and chymase activity levels at the healing sites of +/+ mice were significantly increased 7 days after surgery. CONCLUSIONS: Our results indicate that mast cells contribute to intraperitoneal adhesion formation in mice, and suggest that chymase originating from mast cells is important in the development of adhesions.     

手术治疗特殊部位子宫肌瘤82例临床分析

目的探讨特殊部位子宫肌瘤的临床特点及腹腔镜手术治疗的可行性和优越性。方法回顾性分析2010年1月至2014年1月,山西医科大学第二医院妇产科收治的82例特殊部位子宫肌瘤患者的临床资料,其中52例行腹腔镜下子宫肌瘤切除术(观察组),30例行开腹子宫肌瘤切除术(对照组),比较两组患者术前、术中及术后各项指标的情况。结果 82例特殊部位子宫肌瘤中,53例(64.63%)经体检发现,仅7例(8.54%)表现为阴道不规则流血及月经改变。所有患者术前均联合超声检查进一步诊断并成功行子宫肌瘤切除术。两组患者肌瘤大小及术前术后诊断符合率差异无统计学意义;两组患者术前输尿管导管放置、手术时间、术中出血量、术中输血率、平均住院时间、手术费用及术后膀胱直肠功能恢复时间比较,差异有统计学意义(P0.05);两组患者超声及生育功能随访比较,差异无统计学意义。结论特殊部位子宫肌瘤临床症状不典型,多由体检或妇科检查时发现,影像学检查是特殊部位子宫肌瘤诊断的重要依据。腹腔镜手术治疗是一种经济安全有效的术式。     

Arrestin Facilitates Rhodopsin Dephosphorylation in Vivo

Deactivation of G-protein-coupled receptors (GPCRs) involves multiple phosphorylations followed by arrestin binding, which uncouples the GPCR from G-protein activation. Some GPCRs, such as rhodopsin, are reused many times. Arrestin dissociation and GPCR dephosphorylation are key steps in the recycling process. In vitro evidence suggests that visual arrestin (ARR1) binding to light-activated, phosphorylated rhodopsin hinders dephosphorylation. Whether ARR1 binding also affects rhodopsin dephosphorylation in vivo is not known. We investigated this using both male and female mice lacking ARR1. Mice were exposed to bright light and placed in darkness for different periods of time, and differently phosphorylated species of rhodopsin were assayed by isoelectric focusing. For WT mice, rhodopsin dephosphorylation was nearly complete by 1 h in darkness. Surprisingly, we observed that, in the Arr1 KO rods, rhodopsin remained phosphorylated even after 3 h. Delayed dephosphorylation in Arr1 KO rods cannot be explained by cell stress induced by persistent signaling, since it is not prevented by the removal of transducin, the visual G-protein, nor can it be explained by downregulation of protein phosphatase 2A, the putative rhodopsin phosphatase. We further show that cone arrestin (ARR4), which binds light-activated, phosphorylated rhodopsin poorly, had little effect in enhancing rhodopsin dephosphorylation, whereas mice expressing binding-competent mutant ARR1-3A showed a similar time course of rhodopsin dephosphorylation as WT. Together, these results reveal a novel role of ARR1 in facilitating rhodopsin dephosphorylation in vivo.SIGNIFICANCE STATEMENT G-protein-coupled receptors (GPCRs) are transmembrane proteins used by cells to receive and respond to a broad range of extracellular signals that include neurotransmitters, hormones, odorants, and light (photons). GPCR signaling is terminated by two sequential steps: phosphorylation and arrestin binding. Both steps must be reversed when GPCRs are recycled and reused. Dephosphorylation, which is required for recycling, is an understudied process. Using rhodopsin as a prototypical GPCR, we discovered that arrestin facilitated rhodopsin dephosphorylation in living mice.     

肿瘤坏死因子—α单抗对烫伤大鼠组织脂多糖结合蛋白mRNA表达 …

探讨肿瘤坏死因子－α单抗治疗对烫伤后组织ＴＮＦ－α及脂多糖结合蛋白ｍＲＮＡ表达、不同器官功能改变的影响。方法采用大鼠３５％体表面积Ⅲ度烫伤模型,检测伤后肺,肝,肠肾等组织ＴＮＦ－α及ＬＢＰｍＲＮＡ水平。结果烫伤后肺,肝,肠,肾等组织ＴＮＦ－α及ＬＢＰＭｒｎａ表达前水平均有显著升高,约为正常对照地１．７－２．５倍。     

糖尿病足分级系统及其评价

The classification system of diabetic foot not only helps to assess the wound,but it also can be used to predict the outcome of diabetic foot ulcer in the early stage,dynamically monitor the changes in...     

Revascularization in treatment of mesenteric infarction.

This study compares results of primary revascularization with primary intestinal resection in treatment of acute mesenteric artery occlusion in 48 surgical patients. All cases were verified by surgical exploration, angiography or autopsy. Fifteen occlusions were caused by mesenteric thrombosis and 33 by superior mesenteric artery embolization. Primary revascularization was done in 6 of 15 patients with arteriosclerotic mesenteric thrombosis. Total bowel salvage was achieved in 4 patients but no patient with mesenteric thrombosis treated by any method survived long term. Primary embolectomy was done in 11 patients with superior mesenteric artery embolization. Ttoal bowel salvage was achieved in 8 patients. Three of 11 patients died. Primary exploration and/or resection was done in 11 patients; 9 died. All 11 umoperated patients died. A continuation of attempts at mesenteric revascularization is advocated.     

A mild and concise synthesis of aryloxy phosphoramidate prodrug of alcohols via transesterification reaction

A synthesis of aryloxy phosphoramidate prodrug of alcohols enabled by a transesterification strategy is described here. This reaction operates under mild conditions and thus has excellent functional group tolerance. This method provides an efficient and practical solution to the rapid construction of the aryloxy phosphoramidate prodrugs library for potential SAR studies.

A synthesis of aryloxy phosphoramidate prodrug of alcohols enabled by a transesterification strategy is described here.

The phosphate and phosphonate prodrug strategy is widely recognized as an effective approach to improve the physicochemical and pharmacological properties of therapeutic nucleosides and sugars.¹ Over the last few decades, the ProTide prodrug strategy pioneered by Prof. Chris McGuigan has emerged as a powerful platform for developing nucleotide therapeutics.² This prodrug approach has been extensively studied in the antiviral and anticancer fields, enabling the discovery and development of three FDA-approved antiviral drugs and several clinical candidates (Fig. 1a).³ Whereas early efforts focused mainly on nucleoside-based medicines, many recent discoveries suggested that this technology can be applied to non-nucleoside substrates as well.⁴ The nature of different components of the phosphoramidate core is essential for the prodrug''s potency, especially for the case of non-nucleoside drug candidates in which other amino acid motifs are more effective than the commonly used l-alanine.⁵ As a result, SAR studies of amino acid ester and aryl moieties would be necessary to identify the optimal combination of these masking groups when applying ProTide technology to a new therapeutic chemical entity. Consequently, an efficient method capable of rapidly assembling aryloxy phosphoramidate prodrug library from parent drug would be very attractive to the discovery of new ProTide prodrugs.Open in a separate windowFig. 1Pharmaceutical importance and the synthetic methods of aryloxy phosphoramidate prodrugs.Current methods for the preparation of aryloxy phosphoramidate structures include: (a) phosphorylating the nucleoside with phosphorochloridate reagent,⁶ (b) ester exchange between nucleoside and a diarylphosphite followed by oxidative amination,⁷ (c) coupling of the amino acid ester with a nucleoside aryl phosphate or its derivatives.⁸ Among these methods, coupling nucleosides with phosphorochloridate reagents in the presence of either N-methylimidazole (NMI) or tert-butyl magnesium chloride (tBuMgCl) is the most popular strategy for ProTide prodrug construction (Fig. 1b). Although this method has enabled the synthesis of numerous nucleoside prodrugs, regioselectivity and diastereoselectivity issues associated with this approach remained challenging.⁹ As a result, numerous efforts have been devoted to develop methods with high regioselectivity¹⁰ and diastereoselectivity.¹¹ While these advances offer a variety of choices on batch synthesis of designated compounds, other issues remain to be addressed. First, the current method mainly focused on accessing phosphoramidate prodrugs containing l-alanine and nucleoside. The compatibility of these methods towards other amino acid motif and non-nucleosides substrates are less investigated. Second, compatible substrate nucleoside bases are limited due to the high reactivity of phosphorylating reagents such as phosphorchloridate or diarylphosphite, which have to involve protection of the nucleobase moiety sometimes.Given the growing interest in expanding ProTide technology to other therapeutic areas and the unmet need for rapid access to the prodrug library for hit screenings or SAR studies, we wonder if we can develop a practical method capable of preparing aryloxy phosphoramidates prodrugs from both nucleoside and non-nucleoside substrates. We reasoned that N-diphenyl phosphoryl amino acid ester could serve as a mild phosphorylating reagent and afford aryloxy phosphoramidate prodrugs via a simple transesterification process. Herein, we report our discovery on a DBU promoted synthesis of aryloxy phosphoramidates prodrugs from stable and readily available N-diphenylphosphoryl amino acid esters and alcoholic substrates (Fig. 1c).We began our study by examining the reaction of phosphoramidate 1 and stavudine (d4T, anti-HIV drug) in the presence of diisopropylethylamine (DIPEA) as the base in acetonitrile (CH₃CN) at 25 °C (12 Increasing the equivalents of phosphorylating reagent 1 to 2.0 equivalent or 3.0 equivalent afforded the target product in 91% and 92% yield, respectively (entries 5–6). Stoichiometry optimization on base revealed that 2.0 equivalent of DBU was optimal, with 1.0 or 3.0 equivalent of DBU gave impaired yield (entries 7–8). In addition, solvent is proved to be vital for a productive reaction, as replacing CH₃CN with DCM, DMF, and THF only afford product 3 in 27% to 71% yield (entries 9–11). To test the scalability of this strategy, we conducted a 1.5 mmol scale synthesis of product 3 under the standard conditions. This reaction afforded the desired product in 85% isolated yield, demonstrating the scalability and potential synthetic application of this protocol.¹³Optimization of the reaction conditions^a