Assessment of the efficacy of different statins in murine collagen‐induced arthritis

Objective

Hydroxymethylglutaryl‐coenzyme A reductase inhibitors (statins) are widely used lipid‐lowering agents. In addition to their well‐known effect on cholesterol levels, statins have been reported to display antiinflammatory activities both in vitro and in vivo. In this context, in vivo prophylactic and therapeutic effects of simvastatin were recently demonstrated in mouse collagen‐induced arthritis, a well‐described experimental model for human rheumatoid arthritis (RA). The aim of this study was to further investigate in vivo effects of 3 different statins, atorvastatin, rosuvastatin, and simvastatin, using the same experimental model.

Methods

Different doses and routes of administration were used for the various statins in an attempt to elicit antiarthritic activity in preventive and curative treatment protocols.

Results

Atorvastatin and rosuvastatin had no in vivo efficacy, as indicated by clinical, histologic (synovial hyperplasia, exudate, and cartilage damage), immunologic (anti–type II collagen IgG production), and biochemical (interleukin‐6, serum amyloid A, and glucocorticoid production) parameters of inflammation and autoimmunity. The previously described beneficial effects of administration of intraperitoneal simvastatin were reproduced in our experiments, but could be accounted for by very severe side effects of the treatment, leading to increased glucocorticoid levels.

Conclusion

This work shows that different statins have no effect in a murine model of arthritis, an unexpected observation given the previously described therapeutic effect of statins in immune‐mediated inflammatory diseases. It is still unclear whether statins will have benefit in the treatment of RA.

     

Evaluation of noninvasive markers for the diagnosis of cystic fibrosis liver disease

Abstract

Objectives: In cystic fibrosis (CF), liver disease (LD) is the third leading cause of mortality. As liver biopsy was considered inconsistent in CFLD diagnosis, a combination of modalities were utilized in the conventional Debray criteria (DC). More recently, noninvasive liver fibrosis biomarkers were applied by Koh et al (New criteria-NC). In the current study, we aimed to evaluate noninvasive biomarkers for the CFLD diagnosis.

Methods: Longitudinal data were collected from a cohort of genetically confirmed CF patients. CFLD was diagnosed by both DC and NC. Apart from transient elastography (TE)?>?6.8?kPa, biomarkers incorporated in the NC included AST/ALT-ratio (AAR)?≥?1, FIB-4 index ≥3.25 and APRI >0.50.

Results: 62 patients with CF, [56.5% male, age at enrollment 25 (22–31) years], were prospectively followed-up for 33 (28–36) months. Sixteen (25.8%) and 27 (43.5%) patients met DC and NC, respectively. Twenty-four fulfilling NC had at least one positive biomarker (6 TE, 7 AAR, 6 both TE and AAR, 2 both APRI and AAR and 3 both APRI and TE). Thirteen (48.1%) had diffuse LD/cirrhosis by the NC and all had at least one additional parameter classifying them as CFLD. From the 14 (51.8%) with no-diffuse-LD, 64.3%, 14.3% and 21.4% had 2, 3 and 4 of the necessary modalities incorporated in NC, respectively, confirming their classification as CFLD. TE was 100% specific to rule in CFLD but had a moderate sensitivity.

Conclusions: NC were able to identify 17.7% more CFLD patients compared to DC. The multiple biomarkers incorporated in NC may enhance the ability to detect CFLD.     

我国心力衰竭患者疾病认知程度的现况调查

目的:了解我国心力衰竭患者的疾病认知程度,并评估与其相关的人口学及临床因素,为实施相应的临床干预提供依据。方法:对我国2012~2014年不同地区、不同级别医院(24家)的970例心力衰竭患者进行问卷调查,内容包括心力衰竭知晓、生活方式、药物依从性、就医便利性、经济负担、健康宣教。生活方式改善包括低盐饮食、适量运动和监测体重。采用Pearson卡方分析探究可能影响心力衰竭认知程度的人口学及临床因素。结果:我国心力衰竭患者中心力衰竭知晓率、药物依从率及健康教育接受率分别为74.8%、83.0%和40.8%。全面改善生活方式的患者仅占5.6%。不同的医院级别、患者受教育程度、NYHA心功能分级、婚姻状况影响患者的心力衰竭知晓率(P均<0.01)。农村患者的疾病知晓率、药物依从率及健康教育接受率明显低于城镇患者(P均<0.01)。二、三级医院患者的药物依从率和健康教育接受率显著高于一级医院(P均<0.01)。结论:我国心力衰竭患者总体疾病认知程度较差,表现为知晓率、药物依从率、健康教育接受率低下,自我保健意识匮乏。各级医护人员应履行疾病告知义务,加强健康宣教力度,以期改善药物依从性,督促生活方式改良。     

一种华支睾吸虫亲肌素样基因的克隆、表达与免疫学功能初步研究

目的对新发现的华支睾吸虫亲肌素样蛋白(CsMLP)进行克隆、原核表达,初步了解其重组产物的免疫学功能。方法应用生物信息学分析软件,分析CsMLP的序列特点和基本理化特征;将CsMLP基因克隆到原核表达质粒pET-28a(+)中,诱导表达并用镍离子金属螯合剂亲和层析柱进行纯化,用纯化的CsMLP蛋白免疫SD大鼠获得抗血清;用Westernblot进行免疫反应性及免疫原性分析;应用免疫荧光方法观察CsMLP在华支睾吸虫成虫的定位。结果该cDNA序列全长为900bp,编码190个氨基酸,具有Calponin功能域;PCR、双酶切及DNA测序结果均表明pET-28a(+)-CsMLP重组质粒构建成功;SDS-PAGE结果表明目的基因在大肠杆菌BL21/DE3中获得高效表达,分子量为21300Mr;经亲和层析获得了高纯度蛋白;重组蛋白可被其免疫的SD大鼠血清、感染了华支睾吸虫的SD大鼠血清识别;CsMLP主要定位于虫体富含肌肉组织的口、腹吸盘、咽部,在表膜、肠壁也有分布。结论 CsMLP可在原核表达系统中呈现高效的可溶性表达,具有免疫原性,其主要分布在华支睾吸虫肌肉丰富的组织。     

白内障超声乳化术后盘周视网膜神经纤维层厚度及黄斑视网膜厚度与视力相关性研究

目的：应用光学相干断层扫描仪（optical coherence tomography,OCT）定量测量眼底盘周视网膜神经纤维层（retinal nerve fiber layer,RNFL）厚度以及黄斑视网膜厚度的变化,了解白内障患者施行超声乳化（phacoemulsification,Phaco）吸除手术后盘周 RNFL厚度以及黄斑视网膜厚度变化特点与视力的相关性。方法选取在首都医科大学宣武医院眼科确诊为年龄相关性白内障患者49例（70眼）,分不伴有糖尿病患者为正常组29例（38眼）,伴有糖尿病患者为糖尿病组20例（32眼）,成功施行白内障 Phaco联合人工晶体植入手术,利用 OCT定量测量Phaco手术后不同时间（包括术后3 d、2周、1个月、3个月、6个月）眼底盘周RNFL厚度和黄斑视网膜厚度,对比不同时间点 RNFL厚度和黄斑视网膜厚度变化,探讨上述指标与术眼最佳矫正视力（corrected visual acuity, CVA）的相关性。结果正常组术后2周、1个月、3个月盘周 RNFL厚度与视力呈负相关（r＝-0．466、-0．490、-0．511,P＜0．01）;正常组术后2周、1个月黄斑视网膜厚度与视力呈负相关（r＝-0．309、-0．315,P＜0．05）。糖尿病组术后2周至术后6个月盘周RNFL厚度与视力呈负相关（r＝-0．365、-0．447、-0．512、-0．499,P＜0．01）;糖尿病组术后3d至术后6个月黄斑视网膜厚度与视力呈负相关（r＝-0．427、-0．490、-0．653、-0．451、-0．353, P＜0.01）。结论白内障Phaco术后黄斑视网膜厚度的改变是影响视力变化的主要原因,同时白内障 Phaco术后盘周 RNFL厚度也在不同时期、不同程度地对视力造成着影响。     

Slowly progressive hemiparesis in childhood as a consequence of Rasmussen encephalitis without or with delayed-onset seizures

Five young children developed slowly progressive hemiparesis as the initial manifestation of Rasmussen encephalitis (RE). Three have remained seizure free over an observational period of 1.3–1.9 years. In the remaining two patients, seizures occurred after 0.5 and 0.6 years respectively. We suggest that RE might be presently underdiagnosed and should be suspected in cases of new onset hemiparesis. In this series, three out of five patients showed oligoclonal bands on examination of cerebrospinal fluid (CSF) which represented additional diagnostic hints towards an immune-mediated condition. According to recently published formal diagnostic criteria, evidence of progressive cerebral hemiatrophy or bioptic identification of RE-typical inflammation confirms the diagnosis in such cases. Long-term immunotherapy is recommended in order to prevent further tissue loss and functional decline.     

The Influence of Cryogenic Treatment on the Microstructure and Mechanical Characteristics of Aluminum Silicon Carbide Matrix Composites

Aluminum matrix composites have been widely used in aerospace and automotive fields due to their excellent physical properties. Cryogenic treatment was successfully adopted to improve the performance of aluminum alloy components, while its effect and mechanism on the aluminum matrix composite remained unclear. In this work, the effects of cryogenic treatment on the microstructure evolution and mechanical properties of 15%SiCp/2009 aluminum matrix composites were systematically investigated by means of Thermoelectric Power (TEP), Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM). The results showed that TEP measurement can be an effective method for evaluating the precipitation characteristics of 15%SiCp/2009 aluminum matrix composites during aging. The addition of cryogenic treatment after solution and before aging treatment promoted the precipitation from the beginning stage of aging. Furthermore, the aging time for the maximum precipitation of the θ″ phase was about 4 h advanced, as the conduction of cryogenic treatment accelerates the aging kinetics. This was attributed to the great difference in the linear expansion coefficient between the aluminum alloy matrix and SiC-reinforced particles, which could induce high internal stress in their boundaries for precipitation. Moreover, the lattice contraction of the aluminum alloy matrix during cryogenic treatment led to the increase in dislocation density and micro defects near the boundaries, thus providing more nucleation sites for precipitation during the aging treatment. After undergoing artificial aging treatment for 20 h, the increase in dispersive, distributed precipitates after cryogenic treatment improved the hardness and yield strength by 4% and 16 MPa, respectively.     

Parental occupational pesticide exposure and the risk of childhood leukemia in the offspring: Findings from the childhood leukemia international consortium

Maternal occupational pesticide exposure during pregnancy and/or paternal occupational pesticide exposure around conception have been suggested to increase risk of leukemia in the offspring. With a view to providing insight in this area we pooled individual level data from 13 case‐control studies participating in the Childhood Leukemia International Consortium (CLIC). Occupational data were harmonized to a compatible format. Pooled individual analyses were undertaken using unconditional logistic regression. Using exposure data from mothers of 8,236 cases, and 14,850 controls, and from fathers of 8,169 cases and 14,201 controls the odds ratio (OR) for maternal exposure during pregnancy and the risk of acute lymphoblastic leukemia (ALL) was 1.01 [95% confidence interval (CI) 0.78, 1.30] and for paternal exposure around conception 1.20 (95% 1.06, 1.38). For acute myeloid leukemia (AML), the OR for maternal exposure during pregnancy was 1.94 (CI 1.19, 3.18) and for paternal exposure around conception 0.91 (CI 0.66, 1.24.) based on data from 1,329 case and 12,141 control mothers, and 1,231 case and 11,383 control fathers. Our finding of a significantly increased risk of AML in the offspring with maternal exposure to pesticides during pregnancy is consistent with previous reports. We also found a slight increase in risk of ALL with paternal exposure around conception which appeared to be more evident in children diagnosed at the age of 5 years or more and those with T cell ALL which raises interesting questions on possible mechanisms.     

Antitumor effects of a monoclonal antibody that binds anionic phospholipids on the surface of tumor blood vessels in mice.

PURPOSE: We recently reported that anionic phospholipids, principally phosphatidylserine, become exposed on the external surface of viable vascular endothelial cells in tumors, possibly in response to oxidative stresses present in the tumor microenvironment. In the present study, we tested the hypothesis that a monoclonal antibody directed against anionic phospholipids might exert antitumor effects by causing vascular damage in tumors. EXPERIMENTAL DESIGN: A new mouse immunoglobulin G3 monoclonal antibody, 3G4, was raised that binds anionic phospholipids in the presence of serum or beta2-glycoprotein I. The antibody was tested for its ability to localize to tumor vessels and exert antitumor effects in mice. RESULTS: 3G4 recognized anionic phospholipids on the external membrane of H(2)O(2)-treated endothelial cells and in vitro. It localized specifically to tumor vascular endothelium and to necrotic tumor cells after injection into severe combined immunodeficient mice bearing orthotopic MDA-MB-435 tumors. Treatment with 3G4 retarded the growth of four different tumors in mice. It reduced the growth of established orthotopic MDA-MB-231 and MDA-MB-435 human breast tumors in mice by 75% and 65% respectively, large L540 human Hodgkin's tumors by 50%, and small syngeneic Meth A fibrosarcomas by 90%. Histologic examination revealed vascular damage, a reduction in vascular density, and a reduction in tumor plasma volume. Treatment with 3G4 induced the binding of monocytes to tumor endothelium and infiltration of macrophages into MDA-MB-435 and MDA-MB-231 tumors. No toxicity to the mice was observed. CONCLUSIONS: 3G4 localizes specifically to complexes of anionic phospholipids and serum proteins on the surface of vascular endothelial cells in tumors in mice. This results in damage to tumor vasculature and suppression of tumor growth.