Increased Expression of Intranuclear Matrix Metalloproteinase 9 in Atrophic Renal Tubules Is Associated with Renal Fibrosis

Background

Reduced turnover of extracellular matrix has a role in renal fibrosis. Matrix metalloproteinases (MMPs) is associated with many glomerular diseases, but the histological association of MMPs and human renal fibrosis is unclear.

Methods

This is a retrospective study. Institutional Review Board approval was obtained for the review of patients’ medical records, data analysis and pathological specimens staining with waiver of informed consents. Specimens of forty-six patients were examined by immunohistochemical stain of MMP-9 in nephrectomized kidneys, and the association of renal expression of MMP-9 and renal fibrosis was determined. MMP-9 expression in individual renal components and fibrosis was graded as high or low based on MMP-9 staining and fibrotic scores.

Results

Patients with high interstitial fibrosis scores (IFS) and glomerular fibrosis scores (GFS) had significantly higher serum creatinine, lower estimated glomerular filtration rate (eGFR), and were more likely to have chronic kidney disease (CKD) and urothelial cell carcinoma. Univariate analysis showed that IFS and GFS were negatively associated with normal and atrophic tubular cytoplasmic MMP-9 expression and IFS was positively correlated with atrophic tubular nuclear MMP-9 expression. Multivariate stepwise regression indicated that MMP-9 expression in atrophic tubular nuclei (r = 0.4, p = 0.002) was an independent predictor of IFS, and that MMP-9 expression in normal tubular cytoplasm (r = −0.465, p<0.001) was an independent predictor of GFS.

Conclusions

Interstitial fibrosis correlated with MMP-9 expression in the atrophic tubular nuclei. Our results indicate that renal fibrosis is associated with a decline of MMP-9 expression in the cytoplasm of normal tubular cells and increased expression of MMP-9 in the nuclei of tubular atrophic renal tubules.     

ESA Hyporesponsiveness Is Associated with Adverse Events in Maintenance Hemodialysis (MHD) Patients,But Not with Iron Storage

Objective

It has been reported that hyporesponsiveness to erythropoiesis-stimulating agent (ESA) is associated with adverse events in patients on maintenance hemodialysis (MHD). However, it has not been determined whether higher iron storage is associated with an improved response, including better survival, to ESA.

Design and Method

We measured serum ferritin, hemoglobin (Hb), and transferrin saturation (TSAT) levels every three months for two years in 1,095 MHD patients. The weekly dose of ESA to Hb ratio was also calculated as an index of ESA responsiveness (ERI).

Results

A significant correlation (p<0.001, R = 0.89) between ferritin and Hb was only observed in the patients with ferritin levels <50 ng/mL. High-dose (≥50 mg/week) intravenous iron administration, female sex, low serum albumin, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were significant predictors of a high ERI value (>280); however, serum ferritin and TSAT levels did not predict a higher ERI. In the time-dependent Cox hazard model, the risk for a composite event in the patients with a high ERI (≥280) and a high ferritin level (≥100 ng/mL) was significantly greater (hazard ratio [HR], 2.09, P = 0.033) than that for patients with a high ERI and a low ferritin (<100 ng/mL) level.

Conclusion

Hb was dependent upon ferritin levels in patients with ferritin levels <50 ng/mL but not in patients with ferritin levels ≥50 ng/mL. Patients with hyporesponsiveness to ESA had a greater risk of composite events, but ERI was unrelated to iron storage.     

Elevated Ratio of Urinary Metabolites of Thromboxane and Prostacyclin Is Associated with Adverse Cardiovascular Events in ADAPT

Results from prevention trials, including the Alzheimer''s Disease Anti-inflammatory Prevention Trial (ADAPT), have fueled discussion about the cardiovascular (CV) risks associated with non-steroidal anti-inflammatory drugs (NSAIDs). We tested the hypotheses that (i) adverse CV events reported among ADAPT participants (aged 70 years and older) are associated with increased ratio of urine 11-dehydrothromboxane B₂ (Tx-M) to 2′3-donor–6-keto-PGF1 (PGI-M) attributable to NSAID treatments; (ii) coincident use of aspirin (ASA) would attenuate NSAID-induced changes in Tx-M/PGI-M ratio; and (iii) use of NSAIDs and/or ASA would not alter urine or plasma concentrations of F₂-isoprostanes (IsoPs), in vivo biomarkers of free radical damage. We quantified urine Tx-M and PGI-M, and urine and plasma F₂-IsoPs from 315 ADAPT participants using stable isotope dilution assays with gas chromatography/mass spectrometry, and analyzed these data by randomized drug assignment and self-report compliance as well as ASA use. Adverse CV events were significantly associated with higher urine Tx-M/PGI-M ratio, which seemed to derive mainly from lowered PGI-M. Participants taking ASA alone had reduced urine Tx-M/PGI-M compared to no ASA or NSAID; however, participants taking NSAIDs plus ASA did not have reduced urine Tx-M/PGI-M ratio compared to NSAIDs alone. Neither NSAID nor ASA use altered plasma or urine F₂-IsoPs. These data suggest a possible mechanism for the increased risk of CV events reported in ADAPT participants assigned to NSAIDs, and suggest that the changes in the Tx-M/PGI-M ratio was not substantively mitigated by coincident use of ASA in individuals 70 years or older.     

Obstructive Sleep Apnea Is Associated with Liver Damage and Atherosclerosis in Patients with Non-Alcoholic Fatty Liver Disease

Background/Aims

We assessed whether obstructive sleep apnea (OSA) and nocturnal hypoxemia are associated with severity of liver fibrosis and carotid atherosclerosis in patients with biopsy-proven NAFLD and low prevalence of morbid obesity. Secondary aim was to explore the association of OSA and hypoxemia with NASH and severity of liver pathological changes.

Methods

Consecutive patients (n = 126) with chronically elevated ALT and NAFLD underwent STOP-BANG questionnaire to estimate OSA risk and ultrasonographic carotid assessment. In patients accepting to perform cardiorespiratory polygraphy (PG, n = 50), OSA was defined as an apnea/hypopnea index ≥5. A carotid atherosclerotic plaque was defined as a focal thickening >1.3 mm.

Results

Prevalence of high OSA risk was similar in patients refusing or accepting PG (76% vs 68%, p = 0.17). Among those accepting PG, overall OSA prevalence was significantly higher in patients with F2-F4 fibrosis compared to those without (72% vs 44%; p = 0.04). Significant fibrosis was independently associated with mean nocturnal oxygen saturation (SaO₂)<95% (OR 3.21, 95%C.I. 1.02–7.34; p = 0.04). Prevalence of OSA tended to be higher in patients with, than in those without, carotid plaques (64% vs 40%; p = 0.08). Carotid plaques were independently associated with %time at SaO2<90% >1 (OR 6.30, 95%C.I. 1.02–12.3; p = 0.01).

Conclusions

In NAFLD patients with chronically elevated ALT at low prevalence of morbid obesity, OSA was highly prevalent and indexes of SaO₂ resulted independently associated with severity of liver fibrosis and carotid atherosclerosis. These data suggest to consider sleep disordered breathing as a potential additional therapeutic target in severe NAFLD patients.     

原发性高血压患者颈动脉粥样硬化、新发心脑血管事件与幽门螺旋杆菌感染的关系

目的:研究原发性高血压(PH)患者颈动脉粥样硬化、新发心脑血管事件与幽门螺旋杆菌(HP)感染的关系。方法:选择从2015年6月到2017年6月在我院接受诊治的PH患者150例纳入本次研究。按照13C尿素呼气试验所测定的HP结果将患者分成HP阳性59例(即超基准值4.0,记为观察组)和HP阴性91例(即超基准值≥4.0,记为对照组),检测并对比两组血脂指标、超敏C反应蛋白(hs-CRP)、同型半胱氨酸(Hcy)水平以及颈动脉超声检查结果,随访3个月,比较两组新发心脑血管事件。结果:与对照组比较,观察组的低密度脂蛋白型胆固醇(LDL-C)、Hcy及hs-CRP、甘油三酯(TG)、总胆固醇(TC)水平明显升高,高密度脂蛋白型胆固醇(HDL-C)水平明显降低(P0.05)。观察组CIMT增厚率为28.82%,形成斑块率为49.15%,均分别高于对照组的15.38%、30.77%,而CIMT正常率为22.03%,明显低于对照组的53.85%,差异均有统计学意义(P0.05)。观察组新发心脑血管事件的总发生率为13.56%,高于对照组的4.40%,差异有统计学意义(P0.05)。结论:PH患者的颈动脉粥样硬化、新发心脑血管事件均与HP感染密切相关,临床可考虑清除或预防HP感染,从而科学有效地预防患者的不良预后。     

痛风患者血管内皮功能及颈动脉粥样硬化的临床研究

目的:观察痛风患者氧化应激指标与颈动脉内膜中层厚度(IMT)的变化,探讨高尿酸引起内皮功能损伤和颈动脉粥样硬化的机制。方法:选择痛风患者123例,正常健康者116例,检测两组患者血尿酸、细胞间粘附分子1(ICAM-1)、内皮素-1(ET-1)、一氧化氮(NO)、纤溶酶原激活抑制剂-1(PAI-1)、收缩压、舒张压、空腹血糖、HDL-C、LDL-C、TC、TG等糖、脂代谢指标及颈动脉内膜中层厚度(IMT)。分析痛风患者内皮损伤相关因子水平和颈动脉IMT的关系。结果:痛风组血清细胞间粘附分子1(ICAM-1)、内皮素-1(ET-1)、纤溶酶原激活抑制剂-1(PAI-1)水平较对照组增高,颈动脉IMT明显增厚,NO水平较对照组降低,差异均有统计学意义(P0.05)。血尿酸水平、ICAM-1、ET-1、PAI-1与IMT密切相关(P0.01)。结论:痛风患者较对照组存在更明显的代谢紊乱,血管内皮功能损伤,更易发生动脉粥样硬化。     

急性脑梗死患者颈动脉斑块与基质金属蛋白酶、血清白介素及多肽生长因子的关系研究

目的:探讨基质金属蛋白酶、血清白介素及多肽生长因子与急性脑梗死患者颈动脉斑块的关系。方法:选取于2017年1月至2017年12月期间北京中医药大学第三附属医院老年病科收治的60例急性脑梗死患者作为观察组,根据彩色多普勒超声检测仪进行颈动脉超声检查,将结果分为无斑块组(20例),稳定斑块组(20例)和不稳定斑块组(20例),选取同期的60例门诊体检健康者作为对照组。采用双抗体夹心酶标免疫吸附法(ELISA)测定血清基质金属蛋白酶MMP-7、MMP-9、MMP-12水平,血清白介素IL-6、IL-8、IL-18以及血清多肽生长因子VEGF和TGF-β1水平,对观察组及对照组的检测结果以及无斑块组、稳定斑块组、不稳定斑块组及对照组的检测结果进行分析研究。结果:观察组的血清基质金属蛋白酶MMP-7、MMP-9、MMP-12水平,血清白介素IL-6、IL-8、IL-18水平以及血清多肽生长因子VEGF水平显著高于对照组,差异有统计学意义(P0.05),观察组的血清多肽生长因子TGF-β1水平则显著低于对照组,差异有统计学意义(P0.05)。稳定性斑块组体质指数显著高于对照组(P0.05);不稳定性斑块组与对照组相比,BMI、TC及TG水平均显著升高(P0.05),且与无斑块组相比,甘油三酯水平也偏高(P0.05)。无斑块组,稳定斑块组及不稳定斑块组的血清基质金属蛋白酶MMP-7、MMP-9、MMP-12水平,血清白介素IL-6、IL-8、IL-18水平以及血清多肽生长因子VEGF和TGF-β1水平比较,差异有统计学意义(P0.05),其中除血清多肽生长因子TGF-β1水平显著低于其它2组外,不稳定斑块组的血清基质金属蛋白酶MMP-7、MMP-9、MMP-12水平,血清白介素IL-6、IL-8、IL-18水平以及血清VEGF水平显著高于其它2组,差异有统计学意义(均P0.05)。结论:急性脑梗死患者的血清基质金属蛋白酶、血清白介素以及血清多肽生长因水平与颈动脉斑块密切相关。     

Psychiatrists' Attitudes toward Metabolic Adverse Events in Patients with Schizophrenia

Background

There is growing concern about the metabolic abnormalities in patients with schizophrenia.

Aims

The aim of this study was to assess the attitudes of psychiatrists toward metabolic adverse events in patients with schizophrenia.

Method

A brief questionnaire was constructed to cover the following broad areas: the psychiatrists'' recognition of the metabolic risk of antipsychotic therapy, pattern of monitoring patients for physical risks, practice pattern for physical risks, and knowledge of metabolic disturbance. In March 2012, the questionnaire was mailed to 8,482 psychiatrists who were working at hospitals belonging to the Japan Psychiatric Hospitals Association.

Results

The overall response rate was 2,583/8,482 (30.5%). Of the respondents, 85.2% (2,200/2,581) reported that they were concerned about prescribing antipsychotics that have a risk of elevating blood sugar; 47.6% (1,201/2,524) stated that their frequency of monitoring patients under antipsychotic treatment was based on their own experiences; and only 20.6% (5,22/2,534) of respondents answered that the frequency with which they monitored their patients was sufficient to reduce the metabolic risks.

Conclusions

Psychiatrists practicing in Japan were generally aware and concerned about the metabolic risks for patients being treated with antipsychotics. Although psychiatrists should monitor their patients for metabolic abnormalities to balance these risks, a limited number of psychiatrists answered that the frequency with which they monitored patients to reduce the metabolic risks was sufficient. Promotion of the best practices of pharmacotherapy and monitoring is needed for psychiatrists treating patients with schizophrenia.     

Mitral Tissue Inhibitor of Metalloproteinase 2 Is Associated with Mitral Valve Surgery Outcome

Background

Matrix metalloproteinases play a role in regulating cardiac remodeling. We previously reported an association between tissue inhibitor of metalloproteinase 2 (TIMP-2) expression and mitral valve (MV) disease. However, the determinants and prognostic value of mitral TIMP2 after MV surgery are unknown.

Methods

This retrospective study of 164 patients after MV surgery in a tertiary medical center in Taiwan assessed mitral TIMP2 on a semiquantitative scale (0–2) by immunohistochemical staining. The primary endpoints were the composite of cardiovascular death and heart failure admission.

Results

Mean age was 50.4±13.7 years. After a mean follow-up period of 101±59 months, primary endpoints had occurred in 25 (15.2%) subjects. Patients with and without primary endpoint events significantly differed in terms of age (56.6±14.4 vs. 49.2±13.4 years, respectively; p = 0.013) and left ventricular end-systolic diameter (LVESD) (39.7±8.2 vs. 35.5±7.5 mm, p = 0.010) at surgery. The TIMP2 had a significant dose-dependent association with development of a primary endpoint (p = 0.002). Kaplan–Meier analysis showed that TIMP2 expression has a significant positive association with primary endpoint-free survival (log-rank test; p = 0.004). Cox regression analysis showed that independent predictors of primary endpoints were TIMP2 (hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.12–0.65; p = 0.003), age (HR 1.05; 95% CI 1.02–1.09; p = 0.003) and LVESD (HR 1.05; 95% CI 1.01–1.10; p = 0.020).

Conclusions

The lack of mitral TIMP2 expression is associated with increases in cardiovascular death and heart failure following MV surgery.     

Overexpression of the Promigratory and Prometastatic PTK7 Receptor Is Associated with an Adverse Clinical Outcome in Colorectal Cancer

Biomarkers and novel therapeutic targets are urgently needed in colorectal cancer (CRC). The pseudo tyrosine kinase receptor 7 (PTK7) is involved in planar cell polarity and it is deregulated in various malignancies, including CRC. Yet, little is known about its protein expression in human CRC, or about a possible correlation of its expression with clinical endpoints. Using a clinically annotated Tissue MicroArray (TMA) produced from from 192 consecutive CRC patients treated by initial surgery, we examined PTK7 expression by immunohistochemistry in tumoral tissue and matched normal mucosae, and correlated its expression with clinico-pathological features and patient outcome. PTK7 depletion by specific shRNA in HCT116 and HCT15 CRC cell lines was found to affect cell proliferation, resistance to drugs and cell migration. Tumor growth and metastatic phenotype were investigated in vivo using a xenograft mouse model of CRC cells with modulated expression of PTK7 levels. PTK7 was significantly up-regulated in CRC tissue as compared to matched healthy mucosae, and significant overexpression was found in 34% of patients. PTK7 overexpression was significantly associated with a reduced metastasis-free survival in non-metastatic patients. In HCT116 and HCT15 cells, shRNA PTK7 reduced migration but did not affect cell proliferation and resistance to drugs. In a xenograft mouse of HCT15 cells, downregulation of PTK7 led to reduced tumor growth, whereas its overexpression in PTK7-negative cancer cells led to increased metastatic events. PTK7 expression thus represents a potential prognostic biomarker and a novel therapeutic target in CRC.     

Increased Systemic and Local Interleukin 9 Levels in Patients with Carotid and Coronary Atherosclerosis

Objective

Atherosclerosis is a chronic inflammatory disorder that involves a range of inflammatory mediators. Although interleukin (IL)-9 has been related to inflammation, there are at present no data on its role in atherosclerosis. Here we have examined IL-9 and IL-9 receptor (IL-9R) systemically and locally in patients with coronary and carotid atherosclerosis.

Methods

Plasma IL-9 was quantified by enzyme immunoassay and multiplex technology. IL-9 and IL-9R mRNA were quantified by real-time RT-PCR, and their localization within the lesion was assessed by immunohistochemistry.

Results

The main findings were: (i) Patients with carotid atherosclerosis had significantly raised IL-9 plasma levels compared with healthy controls (n = 28), with no differences between asymptomatic (n = 56) and symptomatic (n = 88) patients. (ii) On admission, patients with acute ST-elevation myocardial infarction (STEMI) (n = 42) had markedly raised IL-9 plasma levels which gradually declined during the first week post-MI. (iii) T cells and monocytes from patients with unstable angina (n = 17) had increased mRNA levels of IL-9 as compared with controls (n = 11). (iv) Carotid plaques (n = 68) showed increased mRNA levels of IL-9 and IL-9R compared to non-atherosclerotic vessels (n = 10). Co-localization to T cells (IL-9 and IL-9R) and macrophages (IL-9) were shown by immunohistochemistry. (v) IL-9 increased IL-17 release in peripheral blood mononuclear cells from patients with unstable angina (n = 5) and healthy controls (n = 5) with a particularly enhancing effect in cells from the patient group.

Conclusion

Our findings show increased IL-9 levels in different atherosclerotic disorders both systemically and within the lesion, suggesting a role for the IL-9/IL-9R axis in the atherosclerotic process, potentially involving IL-17 mediated mechanisms. However, the functional consequences of these findings should be further investigated.     

脑卒中患者血管危险因素与颈动脉粥样硬化的关系

目的研究脑卒中患者血管危险因素与颈动脉粥样硬化的关系。方法受试者151人主要为脑梗死及椎-基底动脉供血不足病例。将所有受试对象行颈动脉超声检查,采用二分类变量的Logistic回归分析方法对其危险因素进行筛选,找出与颈动脉粥样硬化改变相关的因素。结果年龄及吸烟与颈动脉内中膜增厚之间存在相关性,P=0.006（OR=1.08,95%CI 1.02-1.14）和0.01（OR=5.09,95%CI 1.47-17.61）;年龄、吸烟同样与颈动脉斑块之间存在相关性,P=0.006（ORn=n1.06,95%CI 1.06-1.11）和0.04（ORn=2.97,95%CI 1.04-8.50）,收缩压与颈动脉斑块呈正相关,P=0.04（OR=1.03,95%CI 1.00-1.05）,舒张压与颈动脉斑块呈负相关P=0.04（OR=0.96,95%CI 0.92-1.00）。结论随年龄的增大动脉内中膜增厚及颈动脉斑块的患病率增加,吸烟者内中膜增厚及颈动脉斑块比率高于不吸烟者;收缩压增加颈动脉斑块患病率增加,舒张压增加斑块患病率下降。     

脑梗死患者血浆纤维蛋白原水平与颈动脉粥样硬化的关系

目的：探讨脑梗死患者血浆纤维蛋白原（Human Fibrinogen,Fro）水平的改变与颈动脉粥样硬化（CAS）的关系。方法：选取2009年5月-2012年6月入住解放军八一医院神经内科脑梗死患者508例。采用彩色多普勒超声检测脑梗死患者颈内动脉颅外段（／ntemalcarotidartery,ICA）、总动脉（common carotid artery,CCA）、颈总动脉分叉处内一中膜厚度（Intima—medial Thickness,IMT）。评定标准：颈动脉IMT〉0．9toni或（和）颈动脉斑决定义为CAS。24h内将患者空腹静脉血送检,记录测定后的生化指标及№水平,记录吸烟史、糖尿痛、高血压病等病史,采用Logistic回归分析测定的相关危险因素对颈动脉粥样硬化的作用强度。结果：按FIB水平分组（FIB≤3g／L组、FIB〉3g／L组）,Logistic回归分析显示FIB〉3g／L组的危险度为2．04,年龄、FIB水平、高血压病史及吸烟史对CAS有影响,差异有统计学意义（P〈0．05）,其中FIB与CAS的相关性最强。结论：FIB水平与脑梗死患者CAS的发展密切相关,其作用可能强于其他的传统危险因素。     

脑梗死患者颈动脉粥样硬化的相关因素分析

目的:探讨脑梗死患者颈动脉粥样硬化的危险因素。方法:选取148例脑梗死患者作为实验组和同期住院的80例非脑梗死疾病患者为对照组,检测并比较各组年龄、吸烟、血压、饮酒、糖尿病、血脂、同型半胱氨酸和磷脂酶A2等指标,然后进行卡方检验、相关性和Logistic回归分析。结果:实验组颈动脉粥样硬化检出率为82.43%,对照组为12.5%,其差异具有统计学意义(P0.05)。高龄、吸烟、高血压、高血脂、高同型半胱氨酸血症、高磷脂酶A2(LP-PLA2)血症是经动脉粥样硬化的危险因素,且血浆同型半胱氨酸水平、LP-PLA2水平、血压与颈动脉斑块稳定性有关(P0.05)。结论:颈动脉粥样硬化是脑梗死的病理基础,与高龄、吸烟、高血压、高血脂、高同型半胱氨酸血症、高磷脂酶A2(LP-PLA2)血症有关,对高同型半胱氨酸血症、LP-PLA2和高血压患者要关注其斑块的稳定性。     

Mildly Elevated Serum Bilirubin Levels Are Negatively Associated with Carotid Atherosclerosis among Elderly Persons

Serum bilirubin may have a beneficial role in preventing oxidative changes in atherosclerosis. Limited information is available on whether serum total bilirubin is an independent confounding factor for carotid atherosclerosis {for example, intima-media thickness (IMT), plaque} measured noninvasively by B-mode ultrasonography only among elderly persons. The study subjects were 325 men aged 79±8 (mean ± standard deviation) years and 509 women aged 81±8 years that were enrolled consecutively from patients aged ≥60 years in the medical department. Carotid IMT and plaque were derived via B-mode ultrasonography. Multiple linear regression analysis showed that in men age (β = 0.199, p = 0.002), smoking status (β = 0.154, p = 0.006), GGT (β = -0.139, p = 0.039), and GGT (β = -0.133, p = 0.022) were significantly and independently associated with carotid IMT, and in women age (β = 0.186, p<0.001), systolic blood pressure (β = 0.104, p = 0.046), diastolic blood pressure (β = -0.148, p = 0.004), prevalence of antihypertensive medication (β = 0.126, p = 0.004), fasting plasma glucose (β = 0.135, p = 0.003), GGT (β = -0.104, p = 0.032), estimated glomerular filtration rate, serum bilirubin (β = -0.119, p = 0.006), and prevalence of cardiovascular disease (CVD) (β = 0.103, p = 0.017) were also independently associated with carotid IMT. The odds ratios (ORs) {95% confidence interval (CI)} of increasing serum bilirubin category were negatively associated with carotid IMT ≥1.0 mm and plaque in both genders. Compared to subjects with a serum bilirubin of Quartile-1, the multivariate-OR (95% CI) of carotid plaque was 0.25 (0.11–0.57) in the Quartile-4 male group, and 0.41 (0.21–0.78) in the Quartile-2 female group, 0.51 (0.26–0.98) in the Quartile-3 female group, and 0.46 (0.24–0.89) in the Quartile-4 female group. Our data demonstrated an independently negative association between serum bilirubin and carotid atherosclerosis in both genders.     

基质金属蛋白酶与血管壁细胞外基质重建

细胞外基质（ECM）不仅维持血管壁的完整性,而且还为血管细胞传递增殖,迁移,分化和凋亡的调控信号,基质金属蛋白酶（MMP）及其内源性抑制剂（TIMP）通过调节ECM合成与降解之间的动态平衡,使ECM维持正常的结构与功能。在高血压,动脉粥样硬化与血管再狭窄的发生与发展过程中,MMP和TIMP的合成与分泌出现异常,由此所引起的ECM合成与降解失调使ECM迅速发生重建。     

Evaluation of Endarterectomy Recanalization under Ultrasound Guidance in Symptomatic Patients with Carotid Artery Occlusion

Rigorous screening and good imaging would help perform surgery on carotid artery occlusion CAO safely and effectively. The purpose of this study was to retrospectively evaluate carotid endarterectomy (CEA) recanalization in patients with common carotid artery occlusion (CCAO) or internal carotid artery occlusion (ICAO) with color Doppler flow imaging (CDFI). A total of 59 patients undergoing CEA were enrolled. According to the results of CEA, the patients were divided into successful recanalization (group A) and unsuccessful recanalization (group B) groups. The original diameter, lesion length, proximal-to-distal diameter ratio and echo characteristics of the lesion within the lumen of the carotid artery were recorded before CEA and compared between the two groups. In regards to the achievement of repatency by CEA, the overall success rate was 74.6% (44/59), the success rate in CCAO patients was 75.9% (22/29) and the success rate in ICAO patients was 73.3% (22/30). There was no significant difference in the success rates between the CCAO and ICAO patients (χ² = 0.050, P = 0.824). The overall rate of stroke and death within 30 postoperative days was 5.1% (3/59). For the CCAO patients, the lesion length in group A was shorter than that in group B (t = 3.221, P = 0.004). For the ICAO patients, the original diameter of the distal ICA was broader (t = 6.254, P = 0.000) and the proximal-to-distal ICA diameter ratio was smaller (t = 8.036, P = 0.000) in group A than in group B. The rate of recanalization for lumens with a homogeneous echo pattern (hypoecho or isoecho) was significantly higher than that for lumens with echo heterogeneity for both the CCAO and ICAO patients (χ² = 14.477, P = 0.001; χ² = 10.519, P = 0.003). However, for both the CCAO and ICAO patients, there was no difference in the rate of recanalization between patients with hypoecho and isoecho lesions (χ² = 0.109, P = 0.742; χ² = 0.836, P = 0.429). The original diameter, proximal-to-distal ICA diameter ratio, lesion length and echo characteristics may affect the success of CEA recanalization in patients with CCAO and ICAO. CDFI is helpful in screening patients with carotid artery occlusion and may improve the success rate of CEA.     

冠脉PCI治疗后血浆脂蛋白相关磷脂酶A2与基质金属蛋白酶-9水平的变化及临床意义

目的:探讨冠脉经皮冠状动脉介入(PCI)治疗后血浆脂蛋白相关磷脂酶A2(LP-PLA2)与基质金属蛋白酶-9(MMP-9)水平的变化及其临床意义。方法:选择150例急性冠脉综合征(ACS)患者、128例稳定型心绞痛(SAP)患者及100例健康者分为作为ACS组、SAP组及对照组。比较三组入院时血浆MMP-9、LP-PLA2水平及ACS组经PCI治疗前后血浆MMP-9、LP-PLA2水平的变化。结果:与对照组比较,SAP组与ACS组的血浆MMP-9、LP-PLA2水平均明显增高(P0.05);与SAP组比较,ACS组明显增高(P0.05)。与术前比较,ACS组术后血浆MMP-9、LP-PLA2水平明显降低(P0.05)。MMP-9与LP-PLA2在ACS组血浆中呈显著正相关(r=0.617,P0.05),在SAP组与对照组中无相关性(P0.05)。结论:冠脉病变程度越严重,血浆MMP-9和LP-PLA2水平更高;PCI治疗后冠脉斑块趋于稳定,血浆MMP-9和LP-PLA2水平降低,且二者有相关性,提示MMP-9和LP-PLA2参与冠状动脉粥样硬化的发病与发展,且对预测ACS高危人群及评价疗效有一定的临床价值。     

Ontology-Based Combinatorial Comparative Analysis of Adverse Events Associated with Killed and Live Influenza Vaccines

Vaccine adverse events (VAEs) are adverse bodily changes occurring after vaccination. Understanding the adverse event (AE) profiles is a crucial step to identify serious AEs. Two different types of seasonal influenza vaccines have been used on the market: trivalent (killed) inactivated influenza vaccine (TIV) and trivalent live attenuated influenza vaccine (LAIV). Different adverse event profiles induced by these two groups of seasonal influenza vaccines were studied based on the data drawn from the CDC Vaccine Adverse Event Report System (VAERS). Extracted from VAERS were 37,621 AE reports for four TIVs (Afluria, Fluarix, Fluvirin, and Fluzone) and 3,707 AE reports for the only LAIV (FluMist). The AE report data were analyzed by a novel combinatorial, ontology-based detection of AE method (CODAE). CODAE detects AEs using Proportional Reporting Ratio (PRR), Chi-square significance test, and base level filtration, and groups identified AEs by ontology-based hierarchical classification. In total, 48 TIV-enriched and 68 LAIV-enriched AEs were identified (PRR>2, Chi-square score >4, and the number of cases >0.2% of total reports). These AE terms were classified using the Ontology of Adverse Events (OAE), MedDRA, and SNOMED-CT. The OAE method provided better classification results than the two other methods. Thirteen out of 48 TIV-enriched AEs were related to neurological and muscular processing such as paralysis, movement disorders, and muscular weakness. In contrast, 15 out of 68 LAIV-enriched AEs were associated with inflammatory response and respiratory system disorders. There were evidences of two severe adverse events (Guillain-Barre Syndrome and paralysis) present in TIV. Although these severe adverse events were at low incidence rate, they were found to be more significantly enriched in TIV-vaccinated patients than LAIV-vaccinated patients. Therefore, our novel combinatorial bioinformatics analysis discovered that LAIV had lower chance of inducing these two severe adverse events than TIV. In addition, our meta-analysis found that all previously reported positive correlation between GBS and influenza vaccine immunization were based on trivalent influenza vaccines instead of monovalent influenza vaccines.     

Autophagic Marker MAP1LC3B Expression Levels Are Associated with Carotid Atherosclerosis Symptomatology

Objectives

The mechanism by which atheroma plaque becomes unstable is not completely understood to date but analysis of differentially expressed genes in stable versus unstable plaques may provide clues. This will be crucial toward disclosing the mechanistic basis of plaque instability, and may help to identify prognostic biomarkers for ischaemic events. The objective of our study was to identify differences in expression levels of 59 selected genes between symptomatic patients (unstable plaques) and asymptomatic patients (stable plaques).

Methods

80 carotid plaques obtained by carotid endarterectomy and classified as symptomatic (>70% stenosis) or asymptomatic (>80% stenosis) were used in this study. The expression levels of 59 genes were quantified by qPCR on RNA extracted from the carotid plaques obtained by endarterectomy and analyzed by means of various bioinformatic tools.

Results

Several genes associated with autophagy pathways displayed differential expression levels between asymptomatic and symptomatic (i.e. MAP1LC3B, RAB24, EVA1A). In particular, mRNA levels of MAP1LC3B, an autophagic marker, showed a 5−fold decrease in symptomatic samples, which was confirmed in protein blots. Immune system−related factors and endoplasmic reticulum-associated markers (i.e. ERP27, ITPR1, ERO1LB, TIMP1, IL12B) emerged as differently expressed genes between asymptomatic and symptomatic patients.

Conclusions

Carotid atherosclerotic plaques in which MAP1LC3B is underexpressed would not be able to benefit from MAP1LC3B−associated autophagy. This may lead to accumulation of dead cells at lesion site with subsequent plaque destabilization leading to cerebrovascular events. Identified biomarkers and network interactions may represent novel targets for development of treatments against plaque destabilization and thus for the prevention of cerebrovascular events.