Elevated serum MMP-9/TIMP-1 ratio in patients with homozygous familial hypercholesterolemia: Effects of LDL-apheresis

ObjectiveMatrix degradation within an atherosclerotic plaque is an important pathogenic factor in atherosclerosis, and is largely modulated by the balance between matrix metalloproteinases (MMPs) and their endogenous inhibitors (i.e., tissue inhibitor of MMPs [TIMPs]). Familial hypercholesterolemia (FH) is a rare inherited disorder associated with premature coronary heart disease. The aim of the present study was to examine MMP-9 and TIMP-1 on plasma and cellular mRNA levels in homozygous FH patients (n = 7) compared with age- and sex-matched heterozygous FH patients (n = 6), and with healthy subjects (n = 7), and to test whether once-weekly LDL-apheresis (three consecutive sessions) of homozygous FH patients show short-term effects on these variables.ResultsThe main findings were that (i) Compared to healthy control subjects, homozygous FH patients have significantly higher serum levels of MMP-9 and lower levels of TIMP-1, and consequently significantly higher MMP-9/TIMP-1 ratio, potentially reflecting higher MMP-9 activity. (ii) Peripheral blood mononuclear cells (PBMC) isolated from FH homozygotes have significantly higher mRNA levels of MMP-9 compared to cells from heterozygotes. (iii) TNFα-stimulated PBMC from FH homozygotes released borderline-significantly more MMP-9 than cells from heterozygotes and healthy controls. (iv) LDL-apheresis (one day before treatment versus fifteen days later, on the day after the weekly treatment) had no significant short-term effect on any of the MMP-9 and TIMP-1 variables measured in serum and cells.ConclusionsThe data may suggest that homozygous FH patients have an enhanced matrix degrading potential as compared with heterozygous FH patients and healthy controls, potentially contributing to the increased cardiovascular risk observed in these patients.     

Screening for mutations in exon 4 of the LDL receptor gene in a German population with severe hypercholesterolemia

A group of 218 patients with severe hypercholesterolemia (LDL cholesterol >260 mg/dl) living in the Cologne area were screened for mutations in the 3 half of exon 4 of the low density lipoprotein (LDL) receptor gene by the single-strand conformation polymorphism (SSCP) method. The analysed fragment was 242 bp in length and comprised approximately 6% of the coding region. In 11 patients an abnormal SSCP pattern was observed. Two of the abnormal fragment patterns were identical. The results of the SSCP screening could be confirmed by direct DNA sequencing. Three of the ten different mutations were previously described (3 bp deletion: codon 197; Asp₂₀₀Gly; Glu₂₀₇stop). Of the newly identified mutations there were two deletions, two insertions, one combined insertion and deletion mutation and two single base pair substitutions [1 bp deletion: G in codon 197; 37 bp deletion: T in codon 196–208 or AT in 196–207 and GA in codon 208; 18 bp insertion: codon 201–206; 8 bp insertion: codon 155–156 and GA in codon 157; 6 bp insertion (codon 196–197) and 5 bp deletion (codon 199, C in codon 198 and G in codon 198 or 200); Asp₂₀₀Tyr; Asp₂₀₃Val]. The 8-bp insertion was detected in a second unrelated individual. The analysis of the functional consequences of the mutations indicates that all mutations were causative of the LDL cholesterol elevation.     

重症急性呼吸综合征病原学研究进展

SARS即重症急性呼吸综合征,是一种急性呼吸道传染病,对人类健康已构成巨大威胁。本就其病原寻找、病原基本特点、病原进化和变异、病原诊断、病原来源等方面对SARS病原学研究进展作一简要介绍。     

污染河道治理技术研究进展

河道综合整治已引起人们广泛关注。综述了国内外河道治理常用的物理、化学和生物等方法的原理和工艺。物理法介绍了调水、机械除藻、底泥疏浚等,该法治标不治本;化学法有混凝沉淀,它易造成产生二次污染;生态-生物法是国外近年来发展很快的,借助自然界自身的水体自净能力治理受污水体的一类新技术,包括河道曝气法、生物膜法、生物修复技术,土地处理法等。同时也介绍了目前发展起来的最新河道治理工艺,如悬浮填料移动床、曝气生态净化系统和底泥生物氧化等多种方法,这类工艺是将生物法与其他工艺相结合,具有多功能、高效率等特点。     

Advances in mesenchymal stem cell transplantation for the treatment of osteoporosis

Osteoporosis is a systemic metabolic bone disease with characteristics of bone loss and microstructural degeneration. The personal and societal costs of osteoporosis are increasing year by year as the ageing of population, posing challenges to public health care. Homing disorders, impaired capability of osteogenic differentiation, senescence of mesenchymal stem cells (MSCs), an imbalanced microenvironment, and disordered immunoregulation play important roles during the pathogenesis of osteoporosis. The MSC transplantation promises to increase osteoblast differentiation and block osteoclast activation, and to rebalance bone formation and resorption. Preclinical investigations on MSC transplantation in the osteoporosis treatment provide evidences of enhancing osteogenic differentiation, increasing bone mineral density, and halting the deterioration of osteoporosis. Meanwhile, the latest techniques, such as gene modification, targeted modification and co‐transplantation, are promising approaches to enhance the therapeutic effect and efficacy of MSCs. In addition, clinical trials of MSC therapy to treat osteoporosis are underway, which will fill the gap of clinical data. Although MSCs tend to be effective to treat osteoporosis, the urgent issues of safety, transplant efficiency and standardization of the manufacturing process have to be settled. Moreover, a comprehensive evaluation of clinical trials, including safety and efficacy, is still needed as an important basis for clinical translation.     

Effects of selective H.E.L.P. LDL-apheresis on plasma inflammatory markers concentration in severe dyslipidemia: Implication for anti-inflammatory response

Therapeutic plasmapheresis is a recognized medical procedure in which various techniques are used to separate and remove undesirable or excessively elevated plasma elements from blood. The main purpose of the procedure is to remove the substances responsible for the disease (autoantibodies, circulating immune complexes, lipoproteins and other molecules) from the patient's blood. Low-Density-Lipoproteins-apheresis (LDL_a) is the selective removal of all apolipoprotein-B100-containing lipoproteins: LDL, very low-density lipoprotein, and lipoprotein (a). They are lowered acutely by 65-75%. There is little effect on other plasma lipidic and non-lipidic components. LDL_a was reported to increase resistance of LDL to oxidation, counteract procoagulatory state and relief disturbances of hemorheology associated with atherosclerosis. These effects are likely to be regarded as to be pleiotropic effects. In the sense that they are not necessarily related to the apolipoprotein-B100-containing lipoproteins level in plasma. There is robust evidence that LDL_a can induce the stabilization of atherosclerotic plaques through its lipid-lowering action. However, other effects unrelated to the apolipoprotein-B100-containing lipoproteins extracorporeal removal, such as the decrease of cytokines and adhesion molecules induced by LDL_a were also reported. Altogether these actions are thought to favorably influence regression of florid, nonfibrous atherosclerotic lesions through a blockade of lipid deposition in the vessel wall, plaque stabilization, and ultimately, coronary and extracoronary artery disease progression. This brief review provides some indication on existing evidence of Heparin-induced Extracorporeal Low-density-lipoprotein Precipitation LDL_a effects on plasma mediators of inflammation.     

Propafenone for the treatment of severe ventricular arrhythmias.

Twenty-one patients whose severe ventricular arrhythmias were not controlled by other currently used antiarrhythmic agents or who were intolerant of those drugs were treated with a new antiarrhythmic agent, propafenone. This therapy was associated with complete or nearly complete suppression of premature ventricular beats in 15 (71%) of the patients, satisfactory control in 4 (19%) and no control in 2 (10%). The majority reported no adverse effects. The most frequent complaints were nausea or epigastric discomfort (in five patients) and lightheadedness or dizziness (in three patients). Thus, propafenone appeared to be an effective antiarrhythmic agent with an acceptable frequency of side effects when administered to patients whose ventricular arrhythmias were difficult to treat.     

A combined LDL receptor/LDL receptor adaptor protein 1 mutation as the cause for severe familial hypercholesterolemia

Familial hypercholesterolemia (FH) results from impaired catabolism of plasma low density lipoproteins (LDL), thus leading to high cholesterol, atherosclerosis, and a high risk of premature myocardial infarction. FH is commonly caused by defects of the LDL receptor or its main ligand apoB, together mediating cellular uptake and clearance of plasma LDL. In some cases FH is inherited by mutations in the genes of PCSK9 and LDLRAP1 (ARH) in a dominant or recessive trait. The encoded proteins are required for LDL receptor stability and internalization within the LDLR pathway. To detect the underlying genetic defect in a family of Turkish descent showing unregular inheritance of severe FH, we screened the four candidate genes by denaturing gradient gel electrophoresis (DGGE) mutation analysis. We identified different combinatory mixtures of LDLR- and LDLRAP1-gene defects as the cause for severe familial hypercholesterolemia in this family. We also show for the first time that a heterozygous LDLR mutation combined with a homozygous LDLRAP1 mutation produces a more severe hypercholesterolemia phenotype in the same family than a homozygous LDLR mutation alone.     

光免疫治疗的抗肿瘤研究进展

光免疫治疗是一种新兴的肿瘤靶向光疗手段,它将单克隆抗体的肿瘤特异性与光吸收剂的光毒性相结合,可以快速且极具免疫原选择性地诱导靶肿瘤细胞的死亡。由于靶向性强,光免疫治疗的副作用小。而且因为该疗法诱导的免疫原性死亡会引起垂死肿瘤细胞周围未成熟树突状细胞的快速成熟,继而将肿瘤抗原提呈给CD8+T细胞,导致治疗后CD8+T细胞的激活和增殖,增强宿主抗肿瘤免疫反应。不仅如此,光免疫治疗还能通过增强纳米药物的肿瘤组织穿透性而提高疗效。鉴于光免疫治疗的优良应用前景,文中从其免疫激活机制、超级高渗透长滞留效应、新进展与联合治疗等方面进行综述,旨在为其深入研究和临床转化提供参考。     

Advances in the treatment of problematic industrial biofilms

In nature, microorganisms tend to form biofilms that consist of extracellular polymeric substances with embedded sessile cells. Biofilms, especially mixed-culture synergistic biofilm consortia, are notoriously difficult to treat. They employ various defense mechanisms against attacks from antimicrobial agents. Problematic industrial biofilms cause biofouling as well as biocorrosion, also known as microbiologically influenced corrosion. Biocides are often used to treat biofilms together with scrubbing or pigging. Unfortunately, chemical treatments suppress vulnerable microbial species while allowing resistant species to take over. Repeated treatment cycles are typically needed in biofilm mitigation. This leads to biocide dosage escalation, causing environmental problems, higher costs and sometimes operational problems such as scale formation. New treatment methods are being developed such as enhanced biocide treatment and bacteriophage treatment. Special materials such as antibacterial stainless steels are also being created to combat biofilms. This review discussed some of the advances made in the fight against problematic industrial biofilms.