FH/Wjd大鼠的生物学特性及其在药理学研究中的应用

Fawn-Hooded(FH/Wjd)大鼠是一种近交系大鼠,属于FH大鼠中的一个亚系,具备饮酒量大(>5 g.kg-1.d-1)和酒精偏爱度高(>65%)的特点,存在明显的酒精剥夺效应,并可在短期内建立操作性自身饮酒行为,是一种理想的先天性嗜酒动物模型。此外,FH/Wjd大鼠中枢神经系统5-羟色胺(5-hydroxytryptamine,5-HT)功能低下,在强迫游泳实验中,FH/Wjd大鼠的行为绝望表现明显。因此,可以作为研究抑郁症的动物模型。     

Complement factor I in health and disease

Factor I (FI) is a crucial inhibitor controlling all complement pathways due to its ability to degrade activated complement proteins C3b and C4b in the presence of cofactors such as factor H, C4b-binding protein, complement receptor 1 or CD46. Complete deficiency of FI, which is synthesized mainly in the liver is rare and leads to complement consumption resulting in recurrent severe infections, glomerulonephritis or autoimmune diseases. Incomplete FI deficiency is in turn associated with atypical haemolytic uremic syndrome, a severe disease characterized by thrombocytopenia, microangiopathic haemolytic anaemia and acute renal failure. Structurally, FI is a 88 kDa heterodimer of a heavy chain consisting of one FI-membrane attack complex (FIMAC) domain, one CD5 domain and two low-density lipoprotein receptor domains (LDLr), and a light chain which is a serine protease domain (SP), linked to the heavy chain by a disulfide bond. FI cleaves its in vivo substrates C3b and C4b only in the presence of cofactors, it shows poor enzymatic activity towards synthetic substrates tested so far and it has no natural inhibitor.     

Adolescents at risk for alcohol abuse demonstrate altered frontal lobe activation during Stroop performance

Background: Children and adolescents, family history positive (FH+) for alcoholism, exhibit differences in brain structure and functional activation when compared to family history negative (FH?) counterparts. Given that frontal brain regions, and associated reciprocal connections with limbic structures, undergo the most dramatic maturational changes during adolescence, the objective of this study was to compare functional brain activation during a frontally mediated test of response inhibition in 32 adolescents separated into low‐risk (FH?) and high‐risk (FH+) groups. Methods: Functional magnetic resonance (fMRI) blood oxygen level–dependent data were acquired at 1.5 Tesla during performance of Stroop Color Naming, Word Reading, and Interference. Preprocessing and statistical analyses, covaried for age, were conducted in SPM99 using a search territory that included superior, middle, and inferior frontal gyri (trigone region), anterior cingulate gyrus (CG), and left and right amygdala. Results: Significantly greater activation in the fronto‐limbic search territory was observed in FH+ relative to FH? subjects during Stroop Interference. In addition, a significant regression between brain activation and family history density was observed, with a greater density being associated with increased activation in regions including middle frontal gyrus (BA9) and CG (BA24). Conclusions: These data demonstrate a significant influence of FH status on brain activation during the performance of a response inhibition task, perhaps reflecting a neurobiological vulnerability associated with FH status that may include reduced neuronal efficiency and/or recruitment of additional neuronal resources. These findings are important given that the adolescent developmental period is already associated with reduced inhibitory capacity, even prior to the onset of alcohol use.     

Altered hemostatic balance and endothelial activation in pregnant women with familial hypercholesterolemia

INTRODUCTION: Patients with familial hypercholesterolemia (FH) are prone to premature cardiovascular disease. During pregnancy plasma lipids reach higher absolute values in FH than in healthy women. Pregnancy is associated with activation of coagulation and possibly also of vascular endothelium, which might further increase the risk of cardiovascular disease in FH. However, whether hemostatic and endothelial activation markers are increased in pregnant FH women compared with non-FH pregnancies, is unknown. MATERIALS AND METHODS: Activation markers of hemostasis and endothelium were analyzed in blood samples collected prospectively from 22 heterozygous FH women during pregnancy and compared with those of a reference group of 149 healthy, pregnant women. RESULTS: A procoagulant pattern was detected in both groups, but was more evident among FH women at least partly due to their enhanced thrombin generation, and because tissue factor pathway inhibitor type 1 increased in the reference group only. Furthermore, plasminogen activator inhibitor type 2 antigen increased more in FH than in the reference group. Whereas C-reactive protein, intercellular adhesion marker-1 and E-selectin did not change appreciably, vascular endothelial cell adhesion molecule 1 rose markedly in FH. CONCLUSION: Increased lipid levels as well as a net procoagulant activity and an enhanced endothelial activation possibly confer additional risks of cardiovascular disease among pregnant FH women.     

Plasma therapy in atypical haemolytic uremic syndrome: lessons from a family with a factor H mutation

Whilst randomised control trials are undoubtedly the best way to demonstrate whether plasma exchange or infusion alone is the best first-line treatment for patients with atypical haemolytic uremic syndrome (aHUS), individual case reports can provide valuable information. To that effect, we have had the unique opportunity to follow over a 10-year period three sisters with aHUS associated with a factor H mutation (CFH). Two of the sisters are monozygotic twins. A similar natural evolution and response to treatment would be expected for the three patients, as they all presented with the same at-risk polymorphisms for CFH and CD46 and no identifiable mutation in either CD46 or CFI. Our report of different modalities of treatment of the initial episode and of three transplantations and relapses in the transplant in two of them, strongly suggest that intensive plasma exchange, both acutely and prophylactically, can maintain the long-term function of both native kidneys and allografts. In our experience, the success of plasma therapy is dependent on the use of plasma exchange as opposed to plasma infusion alone, the prolongation of daily plasma exchange after normalisation of haematological parameters followed by prophylactic plasma exchange, the use of prophylactic plasma exchange prior to transplantation and the use of prophylactic plasma exchange at least once a week posttransplant with immediate intensification of treatment if there are any signs of recurrence.     

Screening for familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is an autosomal dominant disorder characterised by increased plasma concentrations of low density lipoprotein (LDL) cholesterol leading to atherosclerosis and premature coronary heart disease (CHD) and death. The clinical diagnosis of FH is based on a personal and family history, physical examination findings and LDL-cholesterol concentrations. FH is primarily caused by mutations in the LDL-receptor gene (LDLR), and less frequently by mutations in genes for APOB and the more recently identified PCSK9. Lifestyle modification and pharmacotherapy can delay or prevent the onset of CHD in FH. It is estimated that only 20% of cases have been diagnosed in Australia and that the majority are inadequately treated. Screening options for FH include population screening (of children or adults), targeted screening of patients with premature CHD and their relatives, or opportunistic screening such as flagging laboratory lipid reports. Cascade screening, a form of targeted screening, is an ethically acceptable, cost-effective strategy for the identification of FH. However, for screening to be successful, medical practitioners need to be aware of the signs and diagnosis of FH and the benefits of early treatment.     

应用定量组织多普勒成像技术评价家族性高胆固醇血症患者的左室功能

目的探讨定量组织多普勒成像技术(quantitative tissue velocity imaging,QTVI)在评价家族性高胆固醇血症(familial hypercholesterolemia,FH)患者左心室功能方面的临床应用价值。方法运用QTVI对24例FH患者和25例健康人心肌各节段速度曲线进行分析,测量后室间隔、侧壁、前壁、下壁、前室间隔、后壁六个壁的瓣环、基底段和中间段三个位置的心肌收缩峰值速度(Vs),左室舒张早期的运动速度(Ve)和舒张晚期的运动速度(Va),计算Ve/Va值;常规超声心动图脉冲多普勒检测二尖瓣口E、A峰流速,计算E/A值;利用M型超声测量左室射血分数(EF);计算左室Tei指数。结果FH组与对照组常规超声心动图测值均在正常范围内,差别无统计学意义;QTVI方法测得的侧壁瓣环、侧壁基底段的Ve,侧壁瓣环、侧壁基底段、后间隔基底段、后壁基底段的Ve/Va,FH组均小于对照组,差别有统计学意义(P0.05)。结论QTVI为临床检测FH患者左室功能变化提供一种无创性方法。     

Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer

Germline heterozygous loss-of-function mutations of fumarate hydratase (FH) predispose to the autosomal dominant syndrome of multiple cutaneous and uterine leiomyomatosis (MCUL). Forty-five distinct FH mutations have been identified in 76 of 89 (85%) reported probands with skin leiomyomas. This suggests that MCUL is a genetically homogeneous condition and that most patients presenting with skin leiomyomas will have underlying FH mutations. FH mutations identified include 26/45 (58%) missense; 12/45 (27%) frameshift, 4/45 (9%) nonsense changes and 3/45 (7%) different whole gene deletions. In MCUL kindreds, the majority of females with FH mutations have both skin and uterine leiomyomas. A proportion of individuals with FH mutations have associated renal cancer, a variant known as hereditary leiomyomatosis and renal cell cancer (HLRCC). If selection bias is removed, the prevalence of renal cancer in MCUL lies between one of 46 (2%) families who were not radiologically screened, and two of 32 (6%) families who were radiologically screened. Truncating, particularly frameshift, mutations appear to be significantly associated with renal cancer (P = 0.003), suggesting a possible basis for selective screening. There may also be a significantly increased rate of renal cancer in females (P = 0.004), suggesting a possible role for hormonal factors. Review of the literature suggests that, unlike most individuals presenting with skin leiomyomas, the majority of patients presenting with uterine leiomyomas or renal cancer will not have underlying FH mutations.     

Value of Measuring Lipoprotein(a) During Cascade Testing for Familial Hypercholesterolemia

Background

Familial hypercholesterolemia (FH) and elevated lipoprotein(a) [Lp(a)] are inherited disorders associated with premature atherosclerotic cardiovascular disease (ASCVD). Cascade testing is recommended for FH, but there are no similar recommendations for elevated Lp(a).