The common 'thermolabile' variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia

Mild hyperhomocysteinaemia is a major risk factor for vascular disease and neural tube defects (NTDs), conferring an approximately three-fold relative risk for each condition. It has several possible causes: heterozygosity for rare loss of function mutations in the genes for 5,10-methylene tetrahydrofolate reductase (MTHFR) or cystathionine-&bgr;-synthase (CBS); dietary insufficiency of vitamin co-factors B6, B12 or folates; or homozygosity for a common 'thermolabile' mutation in the MTHFR gene which has also been associated with vascular disease and NTDs. We quantified the contribution of the thermolabile mutation to the hyperhomocysteinaemic phenotype in a working male population (625 individuals). Serum folate and vitamin B12 concentrations were also measured and their relationship with homocysteine status and MTHFR genotype assessed. The homozygous thermolabile genotype occurred in 48.4, 35.5, and 23.4% for the top 5, 10 and 20% of individuals repectively) ranked by plasma homocysteine levels, compared with a frequency of 11.5% in the study population as a whole establishing that the mutation is a major determinant of homocystein levels at the upper end of the range. Serum folate concentrations also varied with genotype, being lowest in thermolabile homozygotes. The MTHFR thermolabile genotype should be considered when population studies are designed to determine the effective homocysteine-lowering dose of dietary folate supplements, and when prophylactic doses of folate are recommended for individuals.      

Partitioning of hepatitis C virus during Cohn-Oncley fractionation of plasma

Because of concern about the safety of immune globulins with respect to transmission of hepatitis C, the partitioning of hepatitis C virus (HCV) during alcohol fractionation of a plasma pool prepared exclusively from anti-HCV-reactive donations was examined. Quantitation of HCV RNA was accomplished by nested polymerase chain reaction (PCR) at limiting dilutions. One PCR unit was arbitrarily defined as the minimum amount of HCV RNA from which an amplified product could be detected. The starting plasma pool contained 1.4 x 10(5) PCR units per mL. Most of the HCV RNA was found in cryoprecipitate and in Cohn fractions I and III, but it was also detected in fraction II, which is used for immunoglobulin G preparations. A 3.4-percent solution of IgG prepared from this fraction II contained 30 PCR units per mL. The fractionation process leading to immune globulin resulted in overall reduction in HCV RNA by a factor of 4.7 x 10(4). Although the presence of HCV RNA in the final product does not necessarily imply the presence of infectious virus, this work suggests that the safety of immune globulins with respect to HCV transmission is not due solely to the partitioning of HCV away from the immunoglobulin fraction.     

Lipoprotein-induced modulation of cyclosporine-A-mediated immunosuppression

Human serum lipoproteins form complexes with cyclosporine-A and act as a carrier of cyclosporine-A in vivo. We compared the immunosuppressive effects of free cyclosporine-A, a complex composed of cyclosporine-A and lipoproteins, free cyclosporine-A in the presence of each unbound lipoprotein, and each lipoprotein without cyclosporine-A with one another at concentrations comparable with in vivo conditions on PHA-stimulated peripheral blood mononuclear cells. Free cyclosporine-A reduced the proliferation of the PHA-stimulated mononuclear cells to 50% at a concentration of 300 ng ml-1 (SD +/- 30, n = 12) lipoprotein-deficient medium. Cyclosporine-A loaded into VLDL showed a 50% proliferation rate reduction at 60 micrograms VLDL ml-1 (SD +/- 10, n = 12) and 180 ng cyclosporine-A ml-1. In the presence of 100 ng ml-1 cyclosporine-A 180 micrograms ml-1 VLDL (SD +/- 25, n = 12) showed a proliferation rate reduction of 50%. In the same way VLDL without cyclosporine-A induced a reduction to 50% at 740 micrograms ml-1 (SD +/- 30, n = 12). Cyclosporine-A loaded into LDL showed a 50% proliferation rate reduction at 27 micrograms ml-1 LDL (SD +/- 5, n = 12) with 80 ng ml-1 cyclosporine-A. In the presence of 100 ng ml-1, cyclosporine-A 150 micrograms ml-1 LDL (SD +/- 25, n = 12) showed a proliferation rate reduction of 50%. In the same way, LDL without cyclosporine-A induced a reduction to 50% at 950 micrograms ml-1 (SD +/- 50, n = 12).(ABSTRACT TRUNCATED AT 250 WORDS)     

多种反映心血管病的相关因子与急性冠状动脉综合征患者颈动脉斑块负荷

目的:探讨急性冠状动脉综合征患者心血管病因子之间的相关性。方法:选择2004-08/2006-12青岛大学附属青岛市立医院的急性冠状动脉综合征患者76例,男44例,女32例,年龄(60±11)岁,纳入标准:必须至少具备下列3条标准中的2条:①缺血性胸痛的临床病史。②心电图的动态演变。③心脏血清学标志物肌钙蛋白阳性,其中不稳定性心绞痛46例、心肌梗死30例,患者知情同意。入院后经2周内行择期冠脉造影检查。术前行颈动脉超声检查,分为颈动脉斑块阳性组(n=28)和颈动脉斑块阴性组(n=48)。发病时取血,应用液相蛋白芯片结合流式细胞分析方法测定血清白细胞介素6、白细胞介素8、可溶性CD40配体、单核细胞趋化蛋白1、可溶性P-选择素、组织型纤溶酶原激活剂、可溶性血管细胞粘附分子1;常规冠状动脉造影,颈动脉超声检查。结果:纳入急性冠状动脉综合征患者76例,均进入结果分析。组织型纤溶酶原激活剂与其余的炎症因子之间未见显著相关性;而这些炎症因子之间大部分存在相关性。颈动脉斑块阳性组血清组织型纤溶酶原激活剂水平明显低于颈动脉斑块阴性组[(1359.2±714.6),(2052.8±1700.4)ng/L,P<0.05],其他因子浓度结果比较,差异无显著性意义。不稳定心绞痛组组织型纤溶酶原激活剂水平为(3722.2±647.9)ng/L,急性心肌梗死组组织型纤溶酶原激活剂水平为(2712.9±622.4)ng/L,两组比较无显著差异(P>0.05)。结论:组织型纤溶酶原激活剂是独立于急性冠状动脉综合征炎症反应以外,而反映斑块负荷的标志,急性冠状动脉综合征患者颈动脉斑块阳性结果可能提示纤溶系统受损较重。     

大鼠脑局灶性缺血再灌注后梗死体积变化与低分子肝素的保护效应

目的:观察低分子肝素对大鼠脑缺血再灌注后不同时间点脑梗死体积的影响。方法:实验于2005-03/2005-06在华北煤炭医学院动物实验中心完成。①选用雄性SD大鼠90只,体质量280～330g。应用随机数字表法将大鼠分为3组:假手术组、缺血再灌注组、低分子肝素组,每组30只。假手术组:只游离右侧颈总动脉、颈内动脉、颈外动脉。缺血再灌注组和低分子肝素组:均采用改良Longa法制作大鼠右侧大脑中动脉闭塞局灶性脑缺血再灌注模型。缺血2h后分别腹腔注射生理盐水1mL和皮下注射低分子肝素(200IU/kg)生理盐水稀释液1mL。2组均于缺血2.5h后开始再灌注3,6,12,24,48h,每个时间点取6只进行观察。②分别称重应用四氮唑红染色法染成白色的梗死组织与染成红色的正常组织,以梗死组织占全脑湿重的百分比表示脑梗死体积。③采用两样本均数的t检验对两组间数据进行分析。结果:大鼠90只均进入结果分析。缺血再灌注组大鼠脑缺血再灌注3,6,12,24,48h时脑梗死体积分别为(17.28±2.69)%,(22.66±2.16)%,(30.17±4.17)%,(38.83±4.54)%,(43.75±2.66)%,低分子肝素组分别为(12.54±1.35)%,(19.83±2.32)%,(23.83±3.19)%,(30.33±2.50)%,(36.25±2.54)%,假手术组均为0。随着缺血再灌注时间的延长,缺血再灌注组脑梗死体积逐渐增大,低分子肝素组梗死体积较缺血再灌注同一时间组明显缩小(t=-2.376,-2.191,-2.96,-4.019,-4.446,P<0.05)。结论:脑缺血再灌注损伤随再灌注时间延长而加重,低分子肝素能减少脑梗死体积,缩小梗死范围,对大鼠脑缺血再灌注损伤后具有保护作用。     

Influence of Different Atrioventricular and Interventricular Delays on Cardiac Output During Cardiac Resynchronization Therapy

Restoration of the atrioventricular (AVD) and interventricular (VVD) delays increases the hemodynamic benefit conferred by biventricular (BiV) stimulation. This study compared the effects of different AVD and VVD on cardiac output (CO) during three stimulation modes: BiV-LV = left ventricle (LV) preceding right ventricle (RV) by 4 ms; BiV-RV = RV preceding LV by 4 ms; LVP = single-site LV pacing. We studied 19 patients with chronic heart failure due to ischemic or idiopathic dilated cardiomyopathy, QRS ≥ 150 ms, mean LV end-diastolic diameter = 78 ± 7 mm, and mean LV ejection fraction = 21 ± 3%. CO was estimated by Doppler echocardiographic velocity time integral formula with sample volume placed in the LV outflow tract. Sets of sensed-AVDs (S-AVD) 90–160 ms, paced-AVDs (P-AVD) 120–160 ms, and VVDs 4–20 ms were used. BiV-RV resulted in lower CO than BiV-LV. S-AVD 120 ms and P-AVD 140 ms caused the most significant increase in CO for all three pacing modes. LVP produced a similar increase in CO as BiV stimulation; however, AV sequential pacing was associated with a nonsignificantly higher CO during LVP than with BiV stimulation. CO during BiV stimulation was the highest when LV preceded RV, and VVD ranged between 4 and 12 ms. The most negative effect on CO was observed when RV preceded LV by 4 ms. Hemodynamic improvement during BiV stimulation was dependent both on optimized AVD and VVD. LV preceding RV by 4–12 ms was the most optimal. Advancement of the RV was not beneficial in the majority of patients.     

Strategic planning by the palliative care steering committee of the Middle East Cancer Consortium

High quality comprehensive palliative care is a critical need for millions of patients and families, but remains only a dream in many parts of the world. The failure to do a strategic planning process is one obstacle to advancing education and pain prevention and relief. The Middle Eastern Cancer Consortium Steering Committee attendees completed an initial strategic planning process and identified "developmental steps" to advance palliative care. Underscoring the multi-disciplinary nature of comprehensive palliative care, discipline-specific planning was done (adult and pediatric cancer and medicine, pharmacy, nursing) in a separate process from country-specific planning. Delineating the layers of intersection and differences between disciplines and countries was very powerful. Finding the common strengths and weaknesses in the status quo creates the potential for a more powerful regional response to the palliative care needs. Implementing and refining these preliminary strategic plans will augment and align the efforts to advance palliative care education and pain management in the Middle East. The dream to prevent and relieve suffering for millions of patients with advanced disease will become reality with a powerful strategic planning process well implemented.     

Aging compromises oligodendrocyte precursor cell maturation and efficient remyelination in the monkey brain

GeroScience - Age-associated cognitive decline is common among otherwise healthy elderly people, even in the absence of Alzheimer’s disease and neuron loss. Instead, white matter loss and...