Common genetic variants do not associate with CAD in familial hypercholesterolemia

In recent years, multiple loci dispersed on the genome have been shown to be associated with coronary artery disease (CAD). We investigated whether these common genetic variants also hold value for CAD prediction in a large cohort of patients with familial hypercholesterolemia (FH). We genotyped a total of 41 single-nucleotide polymorphisms (SNPs) in 1701 FH patients, of whom 482 patients (28.3%) had at least one coronary event during an average follow up of 66 years. The association of each SNP with event-free survival time was calculated with a Cox proportional hazard model. In the cardiovascular disease risk factor adjusted analysis, the most significant SNP was rs1122608:G>T in the SMARCA4 gene near the LDL-receptor (LDLR) gene, with a hazard ratio for CAD risk of 0.74 (95% CI 0.49–0.99; P-value 0.021). However, none of the SNPs reached the Bonferroni threshold. Of all the known CAD loci analyzed, the SMARCA4 locus near the LDLR had the strongest negative association with CAD in this high-risk FH cohort. The effect is contrary to what was expected. None of the other loci showed association with CAD.     

Comparative Dose Titration Responses to the Introduction of Bisoprolol or Carvedilol in Stable Chronic Systolic Heart Failure

Introduction Several beta blocking drugs (BB) reduce mortality in systolic heart failure (LVSD). We have compared the initial response to introduction of carvedilol and bisoprolol during the standard dose titration protocols for each drug. Methods Approximately 31 unselected patients with stable LVSD were randomised to either carvedilol or bisoprolol measuring blood pressure, heart rate responses and both time and frequency domain heart rate variability (HRV). Results One subject died; five withdrew due to intolerable BB related side effects. Carvedilol (n = 13) and bisoprolol (n = 12) attained similar maximal heart rate reduction and induced comparable falls in systolic and diastolic blood pressure. Higher carvedilol doses were associated with lower blood pressure compared to baseline. Individual time domain HRV indices remained unchanged over the initial titration period. Significant increases in triangular Index (TI) were seen with both BB. Carvedilol demonstrated greater (but non-significant) rises in TI compared to Bisoprolol. Conclusions In this study we found similar degrees and rate of onset of HR, HRV and BP response to both carvedilol and bisoprolol in treated LVSD patients. Carvedilol appears to show superior HRV rises compared to bisoprolol during initial titration. Any significant increases in HRV attributable to carvedilol compared to bisoprolol may emerge over a longer treatment interval in LVSD.     

Exploring coronary atherosclerosis with intravascular imaging

Coronary angiography has been widely used for five decades to evaluate a range of vascular pathologies and triage patients to therapeutic interventions. The inability to directly visualize the artery wall with conventional angiographic techniques has stimulated development of a number of intravascular imaging modalities. These approaches have the potential to provide a more comprehensive characterization of the burden, composition and functionality of atherosclerotic plaque, neointimal hyperplasia and allograft vasculopathy that develop within coronary arteries. The ability to use these modalities in vivo and in a serial fashion has provided a greater insight into the factors that underlie the disease process and guide therapeutic interventions.     

Genetic screening protocol for familial hypercholesterolemia which includes splicing defects gives an improved mutation detection rate

Familial hypercholesterolemia (FH) is a common single gene disorder, which predisposes to coronary artery disease. In a previous study, we have shown that in patients with definite FH around 20% had no identifiable gene defect after screening the entire exon coding area of the low density lipoprotein receptor (LDLR) and testing for the common Apolipoprotein B (ApoB) R3500Q mutation. In this study, we have extended the screen to additional families and have included the non-coding intron splice regions of the gene. In families with definite FH (tendon xanthoma present, n=68) the improved genetic screening protocol increased the detection rate of mutations to 87%. This high detection rate greatly enhances the potential value of this test as part of a clinical screening program for FH. In contrast, the use of a limited screen in patients with possible FH (n=130) resulted in a detection rate of 26%, but this is still of significant benefit in diagnosis of this genetic condition. We have also shown that 14% of LDLR defects are due to splice site mutations and that the most frequent splice mutation in our series (c.1845+11 c>g) is expressed at the RNA level. In addition, DNA samples from the patients in whom no LDLR or ApoB gene mutations were found, were sequenced for the NARC-1 gene. No mutations were identified which suggests that the role of NARC-1 in causing FH is minor. In a small proportion of families (<10%) the genetic cause of the high cholesterol remains unknown, and other genes are still to be identified that could cause the clinical phenotype FH.     

Comparison of B-type natriuretic peptides for assessment of cardiac function and prognosis in stable ischemic heart disease.

In 1,049 patients with stable ischemic heart disease (IHD), brain natriuretic peptide (BNP) and amino terminal pro-brain natriuretic peptide (NTproBNP) correlated closely (r = 0.09, p < 0.001) and were similarly related to left ventricular ejection fraction (LVEF) (r = -0.50 and -0.46, respectively), age (0.44 and 0.47), and creatinine clearance (-0.51 and -0.51). Receiver-operating characteristic curves for detection of LVEF <30% were similar (area under the curves = 0.83 and 0.80, both p < 0.001), and both peptides had strong negative predictive value (95% and 94%). Both independently predicted all-cause mortality and/or heart failure with closely overlapping event-free survival curves; BNP and NTproBNP display strong, near-identical test performance in ruling about severely reduced LVEF and in prediction of all-cause mortality or heart failure in stable IHD. OBJECTIVES: The aim of this work was to test B-type natriuretic peptides for assessment of function and prognosis in stable ischemic heart disease (IHD) and to compare brain natriuretic peptide (BNP) with amino terminal pro-brain natriuretic peptide (NTproBNP), including the relative effects of age and renal function on test performance. BACKGROUND: Brain natriuretic peptide and NTproBNP are emerging diagnostic and prognostic markers in heart failure and acute coronary syndromes. Their performance in assessing function and prognosis in stable IHD is unknown. Whether one marker is superior and the relative effects of age and renal function on test performance are uncertain. METHODS: In 1,049 patients with stable IHD, left ventricular ejection fraction (LVEF) was measured by radionuclide scanning and creatinine clearance estimated by the Cockroft-Gault equation. Age, gender, and body mass index were recorded. Twelve-month all-cause mortality or admission with heart failure was prospectively recorded; BNP and NTproBNP were measured by radioimmunoassay. RESULTS: Brain natriuretic peptide and NTproBNP correlated closely (r = 0.90, p < 0.001) and had similar relationships to LVEF (r = -0.50 and -0.46, respectively, both p < 0.001), age (0.44 and 0.47, both p < 0.001), and creatinine clearance (-0.51 and -0.51, both p < 0.001). Areas under receiver-operating characteristic curves for detection of LVEF <30% were similar (0.83 and 0.80, both p < 0.001) with strong negative predictive values for both (95% and 94%). Both markers independently predicted the clinical end point with closely overlapping event-free survival curves. CONCLUSIONS: In stable IHD, BNP and NTproBNP display strong and near-identical test performance in ruling out severely reduced LVEF and in prediction of all-cause mortality or heart failure despite significant effects of age, gender, and renal function on levels of both markers.     

Mutation screening and genotype:phenotype correlation in familial hypercholesterolaemia

The aim of this study was to develop a mutation screening protocol for familial hypercholesterolaemia (FH) patients and to assess genotype/phenotype effects in terms of pre-treatment lipid profiles and presentation of tendon xanthomata (TX). A total of 158 families with clinical definitions of possible (120) or definite (38) FH were studied using a tiered screening protocol. Mutations were identified in 52 families, 44 families showing 23 different LDLR gene defects and eight families showing the common Apo B100 gene defect R3500Q. LDLR defects were detected in various regions of the gene with 56% in the LDL binding domain (exons 2-6) and 37% in the EGF precursor homology domain (exons 7-14). The most common mutations were D461N(7), C210X(5), 932delA(5), and C163Y(4). Frameshift mutations accounted for 20% with nonsense 13%, mis-sense 35%, splice 3%, Apo B 13% and 2% large deletion, 13% of clinically definite FH remained undefined. In conclusion, DNA based diagnosis is possible in 79% (30/38) of clinically definite FH families and of the 120 possible FH families at the start of the screening program, 18% (22/120) now have defined mutations. Overall 60 families from the original 158 meet the clinical and/or genetic criteria for definite FH. Tendon xanthomata were present in only 58% (30/52) of genetically defined FH families, thus limiting its use as a strict diagnostic criteria. Families with low density lipoprotein receptor (LDLR) defects present with higher total and LDL cholesterol levels and a higher incidence of TX than do those with the common Apo B variant, and frameshift mutations appear to have the most severe presentation.     

Blood supply of the olfactory nerve

Summary The authors report the results of a series of dissections and anatomic sections of the fronto-basal region of the brain and of the anterior cranial fossa in human cadavers. The constant presence of an arachnoidal cistern above the olfactory nerve was verified. The arachnoid separates from the pial membrane and forms a bridge with the ventral part of the olfactory bulb and tract, from the lateral edge of the olfactory sulcus to the medial edge of the gyrus rectus. The cistern is wide in its anterior portion, between the gyrus rectus and the olfactory bulb, and is reduced to a virtual slit in its posterior portion where the tract is lodged in the olfactory sulcus. The olfactory nerve can be separated without damaging fronto-basal arachnoidial adhesions over several centimeters. Dissection of this region after intravascular injection of colored media shows the constant presence of an artery destined to the olfactory bulb and tract. It originates either from the lateral surface of the anterior cerebral a. (segment A2), or from the medial fronto-basal a., and consistently provides terminal branches in front of the olfactory trigone in the medial olfactory sulcus. At their ventral extremity, the olfactory structures are therefore vascularised independently for several centimeters, from the lower face of the frontal lobe. The independent vascularisation of the olfactory nerve, the tenuous and easily detachable adhesions, and the actual presence of a true arachnoidal cistern all contribute to enabling surgical techniques which conserve olfactory function during anterior approaches.

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Vascularisation du nerf olfactif. Rapports méningés et applications chirurgicales

Résumé Les auteurs rapportent les résultats d'une série de dissections et de coupes de la région fronto-basale de l'encéphale et de la fosse crânienne antérieure sur sujets cadavériques. La présence constante d'une citerne arachnoïdienne au dessus du n. olfactif a été vérifiée. L'arachnoïde se sépare du feuillet pial et passe en pont à la partie ventrale du bulbe et du tractus olfactifs, du bord latéral du sillon olfactif au bord médial du gyrus rectus. La citerne est large dans sa portion antérieure, entre le gyrus rectus et le bulbe olfactif, se réduit à une fente virtuelle postérieure lorsque le tractus se loge dans le sillon olfactif. Le n. olfactif peut être séparé sans dommage des adhérences arachnoïdiennes fronto-basales sur quelques centimètres. La dissection de cette région, après injection intravasculaire de masses colorées montre, de façon originale, la présence constante d'une artère destinée au tractus et au bulbe olfactifs. Elle naît soit de la face latérale de l'a. cérébrale antérieure (segment A2), soit de l'a. fronto-basale médiale, pour donner ses branches terminales toujours en avant du trigone olfactif dans le sillon orbitaire médial. Sur quelques centimètres à leur extrémité ventrale, les structures olfactives ont donc une vascularisation indépendante de la face inférieure du lobe frontal. L'indépendance vasculaire du n. olfactif, des adhérences ténues, facilement détachables, et la réalité vérifiée d'une véritable citerne arachnoïdienne permettent d'imaginer des techniques conservatrices de la fonction olfactive utilisées dans plusieurs indications de la chirurgie de la fosse crânienne antérieure.

     

胶体磷酸铬^32P关节腔内注射改善佐剂型关节炎大鼠的相关指标

目的:观察胶体磷酸铬32P关节腔内注射治疗大鼠佐剂型关节炎的效果。方法:实验于2006-07/09在南京市第一医院动物实验室完成。选择6～8周龄清洁级SD雌性大鼠30只,按随机数字表法分为3组,正常对照组、模型组、胶体磷酸铬32P治疗组,每组10只。大鼠左足跖皮内注射完全弗氏佐剂0.1mL免疫法制备佐剂型关节炎模型。胶体磷酸铬32P治疗组于造模后10d左踝关节腔内注射37GBq/L胶体磷酸铬32P0.02mL,即0.74MBq,正常对照组和模型组分别给予等量生理盐水左踝关节腔内注射。①每2周观察1次大鼠左踝关节左右径宽度。②关节炎指数评定采用关节炎评分法(0～4分),分数越高,症状越重。③于用药后2,4,6周采用99Tcm-MDP显像感兴趣区分析法计算大鼠左踝关节区和右胫腓骨的放射性计数比。④于用药后4,6周测定血清肿瘤坏死因子和白细胞介素1β水平。⑤于用药后4,6周观察大鼠滑膜组织和软骨组织病理学改变。结果:纳入大鼠30只,均进入结果分析。①用药后2周模型组大鼠左踝关节左右径宽度大于正常对照组[分别为(7.82±0.36),(5.89±0.35)mm],差异有显著性意义(t=12.16,P<0.001),胶体磷酸铬32P治疗组大鼠左踝关节左右径宽度大于模型组,差异无显著性意义(P>0.05)。用药后6周胶体磷酸铬32P治疗组大鼠左踝关节左右径宽度小于模型组[分别为(6.87±0.27),(7.25±0.26)mm],差异有显著性意义(t=2.87,P<0.05)。②用药后2周和4周胶体磷酸铬32P治疗组大鼠关节炎指数高于模型组,用药后6周胶体磷酸铬32P治疗组大鼠关节炎指数低于模型组,两组间差异均无显著性意义(P>0.05)。③用药后2周模型组大鼠感兴趣区放射性计数比高于正常对照组(分别为2.05±0.20,1.46±0.15),差异有显著性意义(t=7.46,P<0.001)。用药后6周胶体磷酸铬32P治疗组大鼠感兴趣区放射性计数比低于模型组(分别为1.52±0.18,1.78±0.24),差异有显著性意义(t=2.45,P<0.05)。④用药后4,6周模型组大鼠血清肿瘤坏死因子和白细胞介素1β水平高于正常对照组,差异有显著性意义[用药后4周分别为(2.039±0.344),(1.115±0.192)μg/L;(0.305±0.034),(0.192±0.041)μg/L,t=7.42,6.71,P<0.001。用药后6周分别为(1.694±0.305),(1.126±0.256)μg/L;(0.259±0.027),(0.191±0.019)μg/L,t=4.03,5.83,P<0.01,0.001]。用药后4,6周胶体磷酸铬32P治疗组在血清肿瘤坏死因子和白细胞介素1β水平与模型组比较,差异无显著性意义(P>0.05)。⑤用药后4周胶体磷酸铬32P治疗组和模型组滑膜组织增生和炎症细胞浸润均较明显;用药后6周胶体磷酸铬32P治疗组与正常对照组比较仍有滑膜组织增生和炎症细胞浸润,与模型组比较滑膜组织增生程度明显减轻,而炎症细胞浸润程度稍轻。用药后6周胶体磷酸铬32P治疗组大鼠左踝关节的软骨组织未见有异常改变。结论:胶体磷酸铬32P关节腔注射可减轻完全弗氏佐剂免疫大鼠受注射关节的滑膜增生程度,改善关节肿胀症状,疗效肯定。     

多孔髓芯减压联合干细胞移植治疗股骨头坏死的早期随访结果

目的:探讨多孔髓芯减压联合自体骨髓干细胞移植治疗股骨头坏死的疗效及临床分析。方法:选择2003-02/2006-12在南京医科大学附属南京第一医院骨关节中心采用多孔髓芯减压联合干细胞移植治疗的股骨头坏死患者22例,共28髋,年龄17～48岁,根据世界骨循环研究学会(ARCO)的国际骨坏死分期标准:Ⅰ期13髋,Ⅱ期11髋,Ⅲ期4髋。长期使用激素史9例,长期酗酒史6例,外伤史5例,原因不明者2例。纳入标准:有髋关节疼痛,功能受限;经髋关节X射线片及MRI检查确诊;ARCO分期Ⅰ～Ⅲ期;患者知情同意并签署知情同意书。排除标准:其他髋关节疾病。自患者髂前上棘处行骨髓穿刺分离与培养骨髓间充质干细胞。取患肢大粗隆下大腿外侧纵向直切口约3.0cm,钝性分离至股骨,在C形臂机引导下自股骨头中心钻入3枚直径4.0mm斯氏针,选位置较好的斯氏针,将直径约8.0mm特制套管在斯氏针的引导下钻至股骨头关节软骨面下1.0～2.0mm,不穿破关节面。将一长注射器针头置入股骨头坏死中心,立即行X射线正侧位摄片,确保针头位于股骨头内,从针头向股骨头内加压注入自体骨髓间充质干细胞悬液1.5～2.0mL。术后12个月随访,每3个月1次,随访时门诊复查,拍正、侧位和蛙式位X射线片,行MRI检查,观察病情变化。使用髋关节Harris评分进行疗效评价,>90分为优,75～90分为良,60～74分为可,<60分评定为差。若Harris评分提高,X射线骨形态变化改善及MRI股骨头坏死区体积变小可认为联合治疗有效。结果:①22例患者均完成随访,进入结果分析。②随访3个月时X射线及MRI检查:2例(2髋)激素引起的Ⅲ期患者股骨头发生进一步变形及塌陷,其余患者在随访期间未出现严重并发症,不良反应及病情恶化。股骨头坏死体积由术前31.07%减小到17.46%。激素组治疗前后股骨头坏死体积差值小于外伤、酗酒组,就本随访资料而言激素组疗效不如外伤及酗酒组。③随访12个月Harris评分:由术前54.3上升到84.6,有较明显提高,其中优7髋(25.0%),良15髋(53.6%),可4髋(14.3%),差2髋(0.07%)。结论:多孔髓芯减压联合干细胞移植是治疗股骨头坏死的一种新手段,尤其适合于年青、ARCO-Ⅰ或Ⅱ期、非激素导致的股骨头坏死治疗。